Amino Acids and Proteins

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28 Amino Acids and Proteins

28.1 Amino acids 28.2 Synthesis of amino acids 28.3 Separation of amino acids 28.4 Enantioselective synthesis of amino acids 28.5 Peptides 28.6 Peptide sequencing 28.7 Peptide synthesis 28.8 Automated peptide synthesis 28.9 Protein structure 28.10 Important proteins

Myoglobin is a globular protein that contains 153 amino acids joined together, as well as a non- protein portion called a heme unit. The heme group consists of a large nitrogen heterocycle complexed with the Fe2+ cation. The Fe2+ cation binds oxygen in the blood and stores it in tissues. Whales have a particularly high myoglobin concentration in their muscles. It serves as an oxygen reservoir for the whale while it is submerged for long periods of time. In Chapter 28, we discuss the properties of proteins and the amino acids from which they are synthesized.

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Of the four major groups of biomolecules—lipids, carbohydrates, nucleic acids, and proteins—proteins have the widest array of functions. Keratin and collagen, for example, are part of a large group of structural proteins that form long insoluble fi bers, giving strength and support to tissues. Hair, horns, hooves, and fi ngernails are all made up of keratin. Collagen is found in bone, connective tissue, tendons, and cartilage. Enzymes are proteins that catalyze and regulate all aspects of cellular function. Membrane proteins transport small organic molecules and ions across cell membranes. Insulin, the hormone that regulates blood glucose levels, fi brinogen and thrombin, which form blood clots, and hemoglobin, which transports oxygen from the lungs to tissues, are all proteins. In Chapter 28 we discuss proteins and their primary components, the amino acids.

28.1 Amino Acids

Naturally occurring amino acids have an amino group (NH2) bonded to the α carbon of a car- Amino acids were fi rst boxy group (COOH), and so they are called `-amino acids. discussed in Section 19.14.

• All proteins are polyamides formed by joining amino acids together.

COOH OOR H RH N N H2N CH N N α carbon R R HOO RH `-amino acid portion of a protein molecule

28.1A General Features of α-Amino Acids The 20 amino acids that occur naturally in proteins differ in the identity of the R group bonded to the α carbon. The R group is called the side chain of the amino acid. The simplest amino acid, called glycine, has R = H. All other amino acids (R ñ H) have a stereogenic center on the ` carbon. As is true for monosaccharides, the prefi xes d and l are used to designate the confi guration at the stereogenic center of amino acids. Common, naturally occurring amino acids are called l-amino acids. Their enantiomers, d-amino acids, are rarely found in nature. These general structures are shown in Figure 28.1. According to R,S designations, all l-amino acids except cysteine have the S confi guration. All amino acids have common names. These names can be represented by either a one-letter or a three-letter abbreviation. Figure 28.2 is a listing of the 20 naturally occurring amino acids, together with their abbreviations. Note the variability in the R groups. A side chain can be a simple alkyl group, or it can have additional functional groups such as OH, SH, COOH, or NH2.

• Amino acids with an additional COOH group in the side chain are called acidic amino acids. • Those with an additional basic N atom in the side chain are called basic amino acids. • All others are neutral amino acids.

Figure 28.1 Simplest amino acid, R = H Two possible enantiomers when R H The general features of α NH NH an -amino acid COOH 2 2 H N CH C C 2 R R COOH HOOC H H H glycine L-amino acid D-amino acid no stereogenic centers Only this isomer occurs in proteins.

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Figure 28.2 The 20 naturally occurring amino acids Neutral amino acids Name Structure Abbreviations Name Structure Abbreviations

O O CH3 C C Alanine OH Ala A Phenylalanine* OH Phe F

H2NH H2NH

O O

H2N C C Asparagine OH Asn N Proline OH Pro P O H NH N H 2 H O O C C Cysteine HS OH Cys C Serine HO OH Ser S H NH 2 H2NH O O HHO O C C Glutamine H2N OH Gln Q Threonine* OH Thr T

H2NH H2NH O O H C C Glycine OH Gly G Tryptophan* OH Trp W H NH H2NH N 2 H O H CH O 3 C C OH Isoleucine* OH Ile I Tyrosine Tyr Y H2NH H2NH HO O O C C Leucine* OH Leu L Valine* OH Val V

H2NH H2NH O

CH3S C Methionine* OH Met M

H2N H

Acidic amino acids Basic amino acids Name Structure Abbreviations Name Structure Abbreviations

O NH O HO C C C Aspartic acid OH Asp D Arginine* H2N N OH Arg R H O H2NH H2N H O O O C C Glutamic acid HO OH Glu E Histidine* N OH His H

H2NH NH H2NH O

H2N C Lysine* OH Lys K

H2N H

Essential amino acids are labeled with an asterisk (*).

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Look closely at the structures of proline, isoleucine, and threonine. • All amino acids are 1° amines except for proline, which has its N atom in a fi ve- membered ring, making it a 2° amine. • Isoleucine and threonine contain an additional stereogenic center at the β carbon, so there are four possible stereoisomers, only one of which is naturally occurring.

H CH O HHO O H α carbon 3 C C COOH * * OH * * OH N H 2° amine H2NH H2NH L-proline L-isoleucine L-threonine [* denotes a stereogenic center.]

Humans can synthesize only 10 of these 20 amino acids. The remaining 10 are called essential amino acids because they must be obtained from the diet. These are labeled with an asterisk in Figure 28.2.

Problem 28.1 Draw the other three stereoisomers of L-isoleucine, and label the stereogenic centers as R or S.

28.1B Acid–Base Behavior Recall from Section 19.14B that an amino acid has both an acidic and a basic functional group, so proton transfer forms a salt called a zwitterion.

an acid ammonium cation a base COOH COO– carboxylate anion proton transfer + 2NHCH 3NHCH R R The zwitterion is neutral.

This neutral form of an amino This salt is the neutral acid does not really exist. form of an amino acid.

This form exists at pH ≈ 6.

• Amino acids do not exist to any appreciable extent as uncharged neutral compounds. They exist as salts, giving them high melting points and making them water soluble.

Amino acids exist in different charged forms, as shown in Figure 28.3, depending on the pH of the aqueous solution in which they are dissolved. For neutral amino acids, the overall charge is +1, 0, or –1. Only at pH ~6 does the zwitterionic form exist. + The – COOH and – NH3 groups of an amino acid are ionizable, because they can lose a proton in aqueous solution. As a result, they have different pKa values. The pKa of the – COOH group is + typically ~2, whereas that of the – NH3 group is ~9, as shown in Table 28.1. Some amino acids, such as aspartic acid and lysine, have acidic or basic side chains. These additional ionizable groups complicate somewhat the acid–base behavior of these amino acids. Table 28.1 lists the pKa values for these acidic and basic side chains as well.

Figure 28.3 Increasing pH How the charge of a neutral COOH COO– COO– amino acid depends on the pH – – + HO + HO H3NHC 3NHCH 2NHCH H+ H+ R R R overall (+1) charge neutral overall (–1) charge pH ≈ 2 pH ≈ 6 pH ≈ 10

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Table 28.1 pKa Values for the Ionizable Functional Groups of an `-Amino Acid + Amino acid `-COOH `-NH3 Side chain pI Alanine 2.35 9.87 — 6.11 Arginine 2.01 9.04 12.48 10.76 Asparagine 2.02 8.80 — 5.41 Aspartic acid 2.10 9.82 3.86 2.98 Cysteine 2.05 10.25 8.00 5.02 Glutamic acid 2.10 9.47 4.07 3.08 Glutamine 2.17 9.13 — 5.65 Glycine 2.35 9.78 — 6.06 Histidine 1.77 9.18 6.10 7.64 Isoleucine 2.32 9.76 — 6.04 Leucine 2.33 9.74 — 6.04 Lysine 2.18 8.95 10.53 9.74 Methionine 2.28 9.21 — 5.74 Phenylalanine 2.58 9.24 — 5.91 Proline 2.00 10.00 — 6.30 Serine 2.21 9.15 — 5.68 Threonine 2.09 9.10 — 5.60 Tryptophan 2.38 9.39 — 5.88 Tyrosine 2.20 9.11 10.07 5.63 Valine 2.29 9.72 — 6.00

Table 28.1 also lists the isoelectric points (pI) for all of the amino acids. Recall from Section 19.14C that the isoelectric point is the pH at which an amino acid exists primarily in its neutral form, and that it can be calculated from the average of the pKa values of the α-COOH and + α-NH3 groups (for neutral amino acids only).

Problem 28.2 What form exists at the isoelectric point of each of the following amino acids: (a) valine; (b) leucine; (c) proline; (d) glutamic acid?

+ Problem 28.3 Explain why the pKa of the – NH3 group of an α-amino acid is lower than the pKa of the ammonium + + ion derived from a 1° amine (RNH3 ). For example the pKa of the – NH3 group of alanine is 9.7 but + the pKa of CH3NH3 is 10.63.

28.2 Synthesis of Amino Acids Amino acids can be prepared in a variety of ways in the laboratory. Three methods are described, each of which is based on reactions learned in previous chapters. α 28.2A SN2 Reaction of -Halo Acids with NH3

The most direct way to synthesize an α-amino acid is by SN2 reaction of an `-halo carboxylic acid with a large excess of NH3.

General NH3 R CHCOOH R CHCOO–NH + + NH +Br– reaction (large excess) 4 4 Br NH2

NH3 Example (CH ) CH CHCOOH (CH ) CH CHCOO–NH + + NH +Br– 3 2 (large excess) 3 2 4 4 Br NH2 SN2 valine

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Although the alkylation of ammonia with simple alkyl halides does not generally afford high yields of 1° amines (Section 25.7A), this reaction using α-halo carboxylic acids does form the desired amino acids in good yields. In this case, the amino group in the product is both less basic and more sterically crowded than other 1° amines, so that a single alkylation occurs and the desired amino acid is obtained.

Problem 28.4 What α-halo carbonyl compound is needed to synthesize each amino acid: (a) glycine; (b) isoleucine; (c) phenylalanine?

28.2B Alkylation of a Diethyl Malonate Derivative The second method for preparing amino acids is based on the malonic ester synthesis. Recall from Section 23.9 that this synthesis converts diethyl malonate to a carboxylic acid with a new alkyl group on its α carbon atom.

H H three steps Overall reaction H C COOEt R C COOH COOEt H diethyl malonate from RX

This reaction can be adapted to the synthesis of α-amino acids by using a commercially available derivative of diethyl malonate as starting material. This compound, diethyl acetamidomalonate, has a nitrogen atom on the α carbon, which ultimately becomes the NH2 group on the α carbon of the amino acid.

from RX O H R three steps Overall reaction C N C COOEt H2N C COOH H CH3 COOEt H diethyl acetamidomalonate The malonic ester synthesis consists of three steps, and so does this variation to prepare an amino acid.

– deprotonation OEt O H O R–X [1] – Steps in the synthesis C N C COOEt C N C COOEt + EtOH of an amino acid H NaOEt H CH3 COOEt CH3 COOEt diethyl acetamidomalonate SN2 [2] alkylation

– R new C C bond [3] O R H2N C COOH + ∆ C N C COOEt + X– H3O , H H CH3 COOEt hydrolysis + CO2 + EtOH and (2 equiv) decarboxylation

+ CH3COOH

[1] Deprotonation of diethyl acetamidomalonate with NaOEt forms an enolate by removal of the acidic proton between the two carbonyl groups.

[2] Alkylation of the enolate with an unhindered alkyl halide (usually CH3X or RCH2X) forms a substitution product with a new R group on the α carbon. [3] Heating the alkylation product with aqueous acid results in hydrolysis of both esters and the amide, followed by decarboxylation to form the amino acid.

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Phenylalanine, for example, can be synthesized as follows:

O H O CH2C6H5 CH2C6H5 [1] NaOEt [3] Example CCN COOEt CCN COOEt + ∆ H2N C COOH H [2] C6H5CH2Br H H3O , CH3 COOEt CH3 COOEt H phenylalanine

Problem 28.5 The enolate derived from diethyl acetamidomalonate is treated with each of the following alkyl halides. After hydrolysis and decarboxylation, what amino acid is formed: (a) CH3I; (b) (CH3)2CHCH2Cl; (c) CH3CH2CH(CH3)Br?

Problem 28.6 What amino acid is formed when CH3CONHCH(CO2Et)2 is treated with the following series of + reagents: [1] NaOEt; [2] CH2 – O; [3] H3O , ∆?

28.2C Strecker Synthesis The third method, the Strecker amino acid synthesis, converts an aldehyde into an amino acid by a two-step sequence that adds one carbon atom to the aldehyde carbonyl. Treating an aldehyde with NH4Cl and NaCN fi rst forms an` -amino nitrile, which can then be hydrolyzed in aqueous acid to an amino acid. O NH2 + NH2 Strecker synthesis NH4Cl H O C R C CN 3 RC COOH R H NaCN H H new C–C bond amino acid

α-amino nitrile The Strecker synthesis of alanine, for example, is as follows:

O NH2 + NH2 NH4Cl H3O Example C CH3 C CN CH3 C COOH CH H NaCN 3 H H new C–C bond alanine

α-amino nitrile Mechanism 28.1 for the formation of the α-amino nitrile from an aldehyde (the fi rst step in the Strecker synthesis) consists of two parts: nucleophilic addition of NH3 to form an imine, followed by addition of cyanide to the C – N bond. Both parts are related to earlier mechanisms involving imines (Section 21.11) and cyanohydrins (Section 21.9).

Mechanism 28.1 Formation of an `-Amino Nitrile

Part [1] Nucleophilic attack of NH3 to form an imine – O O OH NH • Part [1] Nucleophilic attack of [1] + [2] [3] NH3 followed by proton transfer C RNHC 3 RNHC 2 C R H proton –H2O R H and loss of H O forms an H H 2 transfer (three steps) imine. Loss of H O occurs by imine 2 the same three-step process NH Cl NH + HCl 4 3 + H2O outlined in Mechanism 21.5.

Part [2] Nucleophilic attack of –CN to form an α-amino nitrile

– + H Cl • Part [2] Protonation of the NH NH2 NH2 [4] [5] imine followed by nucleophilic C C + Cl– R C CN RH R H attack of –CN gives the – H C N α-amino nitrile. α-amino nitrile

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Figure 28.4 Br NH3 [1] CH SCH CH C COOH The synthesis of methionine 3 2 2 large excess by three different methods H

O H CH CH SCH NH2 [1] NaOEt 2 2 3 H O+ [2] 3 CCN COOEt CH3CONH C COOEt ∆ CH3SCH2CH2 C COOH H [2] ClCH2CH2SCH3 CH3 COOEt COOEt H

O methionine NH2 + C NH4Cl H3O [3] CH SCH CH H CH SCH CH C CN 3 2 2 NaCN 3 2 2 H Three methods of amino acid synthesis:

[1] SN2 reaction using an α-halo carboxylic acid [2] Alkylation of diethyl acetamidomalonate [3] Strecker synthesis

The details of the second step of the Strecker synthesis, the hydrolysis of a nitrile (RCN) to a carboxylic acid (RCOOH), have already been presented in Section 22.18A. Figure 28.4 shows how the amino acid methionine can be prepared by all three methods in Sec- tion 28.2.

Problem 28.7 What aldehyde is needed to synthesize each amino acid by the Strecker synthesis: (a) valine; (b) leucine; (c) phenylalanine?

Problem 28.8 Draw the products of each reaction.

NH3 [1] NH4Cl, NaCN a. BrCH2COOH c. CH3CH2CH(CH3)CHO + large excess [2] H3O H H [1] NaOEt [1] NaOEt b. CH3CONH C COOEt d. CH3CONH C COOEt [2] (CH ) CHCl [2] BrCH CO Et COOEt 3 2 COOEt 2 2 + ∆ + ∆ [3] H3O , [3] H3O ,

28.3 Separation of Amino Acids No matter which of the preceding methods is used to synthesize an amino acid, all three yield a racemic mixture. Naturally occurring amino acids exist as a single enantiomer, however, so the two enantiomers obtained must be separated if they are to be used in biological applications. This is not an easy task. Two enantiomers have the same physical properties, so they cannot be separated by common physical methods, such as distillation or chromatography. Moreover, they react in the same way with achiral reagents, so they cannot be separated by chemical reactions either. Nonetheless, strategies have been devised to separate two enantiomers using physical separation techniques and chemical reactions. We examine two different strategies in Section 28.3. Then, in Section 28.4, we will discuss a method that affords optically active amino acids without the need for separation.

• The separation of a racemic mixture into its component enantiomers is called resolution. Thus, a racemic mixture is resolved into its component enantiomers.

28.3A Resolution of Amino Acids The oldest, and perhaps still the most widely used method to separate enantiomers exploits the following fact: enantiomers have the same physical properties, but diastereomers have

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Figure 28.5 One enantiomer of Separate Remove Y a chiral reagent Y Resolution of a racemic mixture by converting it to a AY A + Y mixture of diastereomers [3] Y

[1] [2]

BY BY+ [3] A + B AY + BY

enantiomers diastereomers Enantiomers A and B can be separated by reaction with a single enantiomer of a chiral reagent, Y. The process of resolution requires three steps:

[1] Reaction of enantiomers A and B with Y forms two diastereomers, AY and BY. [2] Diastereomers AY and BY have different physical properties, so they can be separated by physical methods such as fractional distillation or crystallization. [3] AY and BY are then re-converted to A and B by a chemical reaction. The two enantiomers A and B are now separated from each other, and resolution is complete.

different physical properties. Thus, a racemic mixture can be resolved using the following general strategy. [1] Convert a pair of enantiomers into a pair of diastereomers, which are now separable because they have different melting points and boiling points. [2] Separate the diastereomers. [3] Re-convert each diastereomer into the original enantiomer, now separated from the other. This general three-step process is illustrated in Figure 28.5. To resolve a racemic mixture of amino acids such as (R)- and (S)-alanine, the racemate is fi rst treated with acetic anhydride to form N-acetyl amino acids. Each of these amides contains one stereogenic center and they are still enantiomers, so they are still inseparable.

H H2N COOH CH3 N COOH AcNH COOH C (CH CO) O CC C (S)-alanine 3 2 = (S)-isomer O H CH3 H CH3 H CH3 O C = Ac enantiomers N-acetyl amino acids enantiomers CH3 H H2N COOH CH3 N COOH AcNH COOH C (CH CO) O C C C (R)-alanine 3 2 = (R)-isomer O CH3 H CH3 H CH3 H H2N C6H5 C Both enantiomers of N-acetyl alanine have a free carboxy group that can react with an amine

CH3 H in an acid–base reaction. If a chiral amine is used, such as (R)-`-methylbenzylamine, the (R)-α-methylbenzylamine two salts formed are diastereomers, not enantiomers. Diastereomers can be physically separated from each other, so the compound that converts enantiomers into diastereomers is called a a resolving agent resolving agent. Either enantiomer of the resolving agent can be used.

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HOW TO Use (R)-α-Methylbenzylamine to Resolve a Racemic Mixture of Amino Acids

Step [1] React both enantiomers with the R isomer of the chiral amine.

AcNH COOH AcNH COOH C + C enantiomers H CH3 CH3 H

H2N C6H5 C proton transfer (R isomer only) CH3 H

+ + – – AcNH COO H3N C6H5 AcNH COO H3N C6H5 C C C C diastereomers H CH3 CH3 H CH3 H CH3 H

SR R R

These salts have the same confi guration around one stereogenic center, but the opposite confi guration about the other stereogenic center.

Step [2] Separate the diastereomers.

separate

++ – – AcNH COO H3N C6H5 AcNH COO H3N C6H5 C C C C CH H 3 CH3 H CH3 H CH3 H

SR R R

Step [3] Regenerate the amino acid by hydrolysis of the amide.

– – H2O, OH H2O, OH

NH2 COOH NH2 COOH H2N C6H5 C C + C H H CH3 CH3 H CH3

The chiral amine is (S)-alanine (R)-alanine also regenerated.

The amino acids are now separated.

Step [1] is just an acid–base reaction in which the racemic mixture of N-acetyl alanines reacts with the same enantiomer of the resolving agent, in this case (R)-α-methylbenzylamine. The salts that form are diastereomers, not enantiomers, because they have the same confi guration about one stereogenic center, but the opposite confi guration about the other stereogenic center. In Step [2], the diastereomers are separated by some physical technique, such as crystallization or distillation. In Step [3], the amides can be hydrolyzed with aqueous base to regenerate the amino acids. The amino acids are now separated from each other. The optical activity of the amino acids can be measured and compared to their known rotations to determine the purity of each enantiomer.

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Problem 28.9 Which of the following amines can be used to resolve a racemic mixture of amino acids? N

CH3 H

a. C6H5CH2CH2NH2 b. c. C d. H N CH3CH2 NH2 N H H O H O strychnine (a powerful poison)

Problem 28.10 Write out a stepwise sequence that shows how a racemic mixture of leucine enantiomers can be resolved into optically active amino acids using (R)-α-methylbenzylamine.

28.3B Kinetic Resolution of Amino Acids Using Enzymes A second strategy used to separate amino acids is based on the fact that two enantiomers react differently with chiral reagents. An enzyme is typically used as the chiral reagent. To illustrate this strategy, we begin again with the two enantiomers of N-acetyl alanine, which were prepared by treating a racemic mixture of (R)- and (S)-alanine with acetic anhydride (Sec- tion 28.3A). Enzymes called acylases hydrolyze amide bonds, such as those found in N-acetyl alanine, but only for amides of l-amino acids. Thus, when a racemic mixture of N-acetyl alanines is treated with an acylase, only the amide of l-alanine (the S stereoisomer) is hydrolyzed to generate l-alanine, whereas the amide of d-alanine (the R stereoisomer) is untouched. The reaction mixture now consists of one amino acid and one N-acetyl amino acid. Because they have different functional groups with different physical properties, they can be physically separated.

This amide bond is cleaved. This amide bond does not react.

H H CH3 N COOH CH3 N COOH enantiomers CC C C O CH O H H 3 CH3

(S)-isomer from L-alanine (R)-isomer from D-alanine

acylase acylase No reaction

H H2N COOH CH3 N COOH C C C CH O H H 3 CH3 (S)-alanine This amide is recovered unchanged.

These two compounds are separable because they have different functional groups.

• Separation of two enantiomers by a chemical reaction that selectively occurs for only one of the enantiomers is called kinetic resolution.

Problem 28.11 Draw the organic products formed in the following reaction. COOH [1] (CH3CO)2O H N C H 2 [2] acylase CH2CH(CH3)2 (mixture of enantiomers)

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28.4 Enantioselective Synthesis of Amino Acids Although the two methods introduced in Section 28.3 for resolving racemic mixtures of amino acids make enantiomerically pure amino acids available for further research, half of the reaction product is useless because it has the undesired confi guration. Moreover, each of these procedures is costly and time-consuming. If we use a chiral reagent to synthesize an amino acid, however, it is possible to favor the formation of the desired enantiomer over the other, without having to resort to a resolution. For example, single enantiomers of amino acids have been prepared by using enantioselective (or asymmetric) hydrogenation reactions. The success of this approach depends on fi nding a chiral catalyst, in much the same way that a chiral catalyst is used for the Sharpless asymmetric epoxidation (Section 12.15).

The necessary starting material is an alkene. Addition of H2 to the double bond forms an N-acetyl amino acid with a new stereogenic center on the α carbon to the carboxy group. With proper choice of a chiral catalyst, the naturally occurring S confi guration can be obtained as product.

R NHAc NHAc H2 AcNH COOH CC RCH C COOH C chiral catalyst S H COOH H H H CH2R achiral alkene new stereogenic center With proper choice of catalyst, the naturally occurring S isomer is formed.

Several chiral catalysts with complex structures have now been developed for this purpose. Many contain rhodium as the metal, complexed to a chiral molecule containing one or more phosphorus atoms. One example, abbreviated simply as Rh*, is drawn below.

Ph Ph P + Rh = Rh* P

Ph Ph – ClO4 Ph = C6H5 Ryoji Noyori shared the 2001 Nobel Prize in Chemistry chiral hydrogenation catalyst for developing methods for asymmetric hydrogenation reactions using the chiral This catalyst is synthesized from a rhodium salt and a phosphorus compound, 2,2'- BINAP catalyst. bis(diphenylphosphino)-1,1'-binaphthyl (BINAP). It is the BINAP moiety (Figure 28.6) that makes the catalyst chiral.

Figure 28.6 The two naphthalene rings are oriented The structure of BINAP at right angles to each other.

PPh2

2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

BINAP 3-D model of BINAP

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BINAP is one of a small number of molecules that is chiral even though it has no tetrahe- Twistofl ex and helicene dral stereogenic centers. Its shape makes it a chiral molecule. The two naphthalene rings of the (Section 17.5) are two more BINAP molecule are oriented at almost 90° to each other to minimize steric interactions between aromatic compounds whose shape makes them chiral. the hydrogen atoms on adjacent rings. This rigid three-dimensional shape makes BINAP non- superimposable on its mirror image, and thus it is a chiral compound. The following graphic shows how enantioselective hydrogenation can be used to synthesize a single stereoisomer of phenylalanine. Treating achiral alkene A with H2 and the chiral rhodium catalyst Rh* forms the S isomer of N-acetyl phenylalanine in 100% ee. Hydrolysis of the acetyl group on nitrogen then yields a single enantiomer of phenylalanine.

Example

AcNH H H O, –OH 2 AcNH COOH 2 H2N COOH C C C C Rh* HOOC H H CH2 hydrolysis H CH2 A enantioselective S enantiomer (S)-phenylalanine hydrogenation 100% ee

Problem 28.12 What alkene is needed to synthesize each amino acid by an enantioselective hydrogenation reaction using H2 and Rh*: (a) alanine; (b) leucine; (c) glutamine?

28.5 Peptides When amino acids are joined together by amide bonds, they form larger molecules called peptides and proteins.

• A dipeptide has two amino acids joined together by one amide bond. • A tripeptide has three amino acids joined together by two amide bonds.

Dipeptide Tripeptide

R1 H O R1 H O R3 H H H C N C C N C C OH H2N C C OH H2N C C N C H O O O H R2 H R2

Two amino acids joined together. Three amino acids joined together. [Amide bonds are drawn in red.]

Polypeptides and proteins both have many amino acids joined together in long linear chains, but the term protein is usually reserved for polymers of more than 40 amino acids.

• The amide bonds in peptides and proteins are called peptide bonds. • The individual amino acids are called amino acid residues.

28.5A Simple Peptides To form a dipeptide, the amino group of one amino acid forms an amide bond with the carboxy group of another amino acid. Because each amino acid has both an amino group and a carboxy group, two different dipeptides can be formed. This is illustrated with alanine and cysteine.

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[1] The COOH group of alanine can combine with the NH2 group of cysteine.

CH3 H O CH3 H O C OH H N C H 2 – H2N C + C OH C N C Ala Cys H2N CCOH O CH SH H 2 O H CH2SH alanine cysteine Ala Cys peptide bond

[2] The COOH group of cysteine can combine with the NH2 group of alanine.

O HSCH2 H HSCH2 H O H H2N C C OH + C OH C N C H2N C H2N C C OH Cys–Ala

O H CH3 O H CH3 cysteine alanine Cys Ala

peptide bond

These compounds are constitutional isomers of each other. Both have a free amino group at one end of their chains and a free carboxy group at the other.

• The amino acid with the free amino group is called the N-terminal amino acid. • The amino acid with the free carboxy group is called the C-terminal amino acid.

By convention, the N-terminal amino acid is always written at the left end of the chain and the C-terminal amino acid at the right. The peptide can be abbreviated by writing the one- or three-letter symbols for the amino acids in the chain from the N-terminal to the C-terminal end. Thus, Ala–Cys has alanine at the N-terminal end and cysteine at the C-terminal end, whereas Cys–Ala has cysteine at the N-terminal end and alanine at the C-terminal end. Sample Problem 28.1 shows how this convention applies to a tripeptide.

Sample Problem 28.1 Draw the structure of the following tripeptide, and label its N-terminal and C-terminal amino acids: Ala–Gly–Ser. Solution Draw the structures of the amino acids in order from left to right, placing the COOH of one amino acid

next to the NH2 group of the adjacent amino acid. Always draw the NH2 group on the left and the COOH group on the right. Then, join adjacent COOH and NH2 groups together in amide bonds to form the tripeptide.

Make amide bonds here.

H H HOCH CH3 O HOCH2 H CH3 O 2 H H C OH H N C C OH C N C C OH H N C ++2 C OH H N C H N C C N C 2 2 2 H O O O O H H H H

Ala Gly Ser N-terminal C-terminal amino acid amino acid

tripeptide Ala–Gly–Ser [The new peptide bonds are drawn in red.]

The N-terminal amino acid is alanine, and the C-terminal amino acid is serine.

The tripeptide in Sample Problem 28.1 has one N-terminal amino acid, one C-terminal amino acid, and two peptide bonds.

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• No matter how many amino acid residues are present, there is only one N-terminal amino acid and one C-terminal amino acid. • For n amino acids in the chain, the number of amide bonds is n – 1.

Problem 28.13 Draw the structure of each peptide. Label the N-terminal and C-terminal amino acids and all amide bonds. a. Val–Glu b. Gly–His–Leu c. M–A–T–T

Problem 28.14 Name each peptide using both the one-letter and the three-letter abbreviations for the names of the component amino acids. N HN CONH2 H H O CH2 O O CH2 O H H a. H2N C C N C b. H2N C C N C C N C C OH C N C C OH H H O O H CH2 H CH(CH3)2 H CH2 H CH2 CH CH2 CH2 2

CH2 CH2 CONH2

NH CH2

C NH2 HN NH2

Problem 28.15 How many different tripeptides can be formed from three different amino acids?

28.5B The Peptide Bond The carbonyl carbon of an amide is sp2 hybridized and has trigonal planar geometry. A second resonance structure can be drawn that delocalizes the nonbonded electron pair on the N atom. Amides are more resonance stabilized than other acyl compounds, so the resonance structure having the C – N makes a signifi cant contribution to the hybrid.

– O O C C + N N H H two resonance structures for the peptide bond

Resonance stabilization has important consequences. Rotation about the C – N bond is restricted because it has partial double bond character. As a result, there are two possible conformations.

Two conformations of O O the peptide bond C R C H R N R N H R s-trans s-cis Recall from Section 16.6 that 1,3-butadiene can also exist as s-cis and • The s-trans conformation has the two R groups oriented on opposite sides of the s-trans conformations. In C – N bond. 1,3-butadiene, the s-cis • The s-cis conformation has the two R groups oriented on the same side of the C – N conformation has the two bond. double bonds on the same side • The s-trans conformation of a peptide bond is typically more stable than the s-cis, of the single bond (dihedral because the s-trans has the two bulky R groups located farther from each other. angle = 0°), whereas the s- trans conformation has them A second consequence of resonance stabilization is that all six atoms involved in the peptide on opposite sides (dihedral bond lie in the same plane. All bond angles are ~120° and the C – O and N – H bonds are ori- angle = 180°). ented 180° from each other.

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The planar geometry of the peptide bond is analogous to 120° the planar geometry of ethylene (or any other alkene), where 120° the double bond between 2 sp hybridized carbon atoms These six atoms lie in a plane. makes all of the bond angles ~120° and puts all six atoms in The structure of a tetrapeptide illustrates the results of these effects in a long peptide chain. the same plane. • The s-trans arrangement makes a long chain with a zigzag arrangement. • In each peptide bond, the N – H and C – O bonds lie parallel and at 180° with respect to each other.

A tetrapeptide

O HR O HR R R H H NC NC C C OH = 2 CNC CNC H H R H R O H R O R

Problem 28.16 Draw the s-cis and s-trans conformations for the dipeptide formed from two glycine molecules.

28.5C Interesting Peptides Even relatively simple peptides can have important biological functions. Bradykinin, for example, is a peptide hormone composed of nine amino acids. It stimulates smooth muscle contraction, dilates blood vessels, and causes pain. Bradykinin is a component of bee venom.

Arg–Pro–Pro–Gly–Phe–Ser–Pro–Phe–Arg bradykinin Oxytocin and vasopressin are nonapeptide hormones, too. Their sequences are identical except for two amino acids, yet this is enough to give them very different biological activities. Oxytocin induces labor by stimulating the contraction of uterine muscles, and it stimulates the fl ow of milk in nursing mothers. Vasopressin, on the other hand, controls blood pressure by regulating smooth muscle contraction. The N-terminal amino acid in both hormones is a cysteine residue, and the C-terminal residue is glycine. Instead of a free carboxy group, both peptides have an NH2 group in place of OH, so this is indicated with the additional NH2 group drawn at the end of the chain.

N-terminal amino acid N-terminal amino acid

Cys Tyr Ile Cys Tyr Phe S Gln S Gln disulfide bond disulfide bond S Asn S Asn Cys Cys

Pro Leu GlyNH2 Pro Arg GlyNH2 oxytocin vasopressin The structure of both peptides includes a disulfi de bond, a form of covalent bonding in which the – SH groups from two cysteine residues are oxidized to form a sulfur–sulfur bond. In oxytocin and vasopressin, the disulfi de bonds make the peptides cyclic. Three-dimensional structures of oxytocin and vasopressin are shown in Figure 28.7.

[O] R2 S H R S S R

thiol disulfide bond

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Figure 28.7 Three-dimensional structures of vasopressin and oxytocin

vasopressin oxytocin

The artifi cial sweetener aspartame (Figure 27.11) is the methyl ester of the dipeptide Asp–Phe. This synthetic peptide is 180 times sweeter (on a gram-for-gram basis) than sucrose (common table sugar). Both of the amino acids in aspartame have the naturally occurring l-confi guration. If the d-amino acid is substituted for either Asp or Phe, the resulting compound tastes bitter.

O H H N OCH 2 N 3 H H COOH O

aspartame the methyl ester of Asp–Phe a synthetic artificial sweetener

Problem 28.17 Draw the structure of leu-enkephalin, a pentapeptide that acts as an analgesic and opiate, and has the following sequence: Tyr–Gly–Gly–Phe–Leu. (The structure of a related peptide, met-enkephalin, appeared in Section 22.6B.)

Problem 28.18 Glutathione, a powerful antioxidant that destroys harmful oxidizing agents in cells, is composed of glutamic acid, cysteine, and glycine, and has the following structure:

HS O H O

H2N N N OH COOH H O

glutathione

a. What product is formed when glutathione reacts with an oxidizing agent? b. What is unusual about the peptide bond between glutamic acid and cysteine?

28.6 Peptide Sequencing To determine the structure of a peptide, we must know not only what amino acids comprise it, but also the sequence of the amino acids in the peptide chain. Although mass spectrometry has become an increasingly powerful method for the analysis of high molecular weight proteins (Section 13.4), chemical methods to determine peptide structure are still widely used and presented in this section.

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28.6A Amino Acid Analysis The structure determination of a peptide begins by analyzing the total amino acid composition. The amide bonds are fi rst hydrolyzed by heating with hydrochloric acid for 24 h to form the individual amino acids. The resulting mixture is then separated using high-performance liquid chromatography (HPLC), a technique in which a solution of amino acids is placed on a column and individual amino acids move through the column at characteristic rates, often dependent on polarity. This process determines both the identity of the individual amino acids and the amount of each present, but it tells nothing about the order of the amino acids in the peptide. For example, complete hydrolysis and HPLC analysis of the tetrapeptide Gly–Gly–Phe–Tyr would indicate the presence of three amino acids—glycine, phenylalanine, and tyrosine—and show that there are twice as many glycine residues as phenylalanine or tyrosine residues. The exact order of the amino acids in the peptide chain must then be determined by additional methods

28.6B Identifying the N-Terminal Amino Acid—The Edman Degradation To determine the sequence of amino acids in a peptide chain, a variety of procedures are often combined. One especially useful technique is to identify the N-terminal amino acid using the Edman degradation. In the Edman degradation, amino acids are cleaved one at a time from the N-terminal end, the identity of the amino acid determined, and the process repeated until the entire sequence is known. Automated sequencers using this methodology are now available to sequence peptides containing up to about 50 amino acids.

The Edman degradation is based on the reaction of the nucleophilic NH2 group of the N-terminal – – amino acid with the electrophilic carbon of phenyl isothiocyanate, C6H5N – C – S. When the N-terminal amino acid is removed from the peptide chain, two products are formed: an N-phenylthiohydantoin (PTH) and a new peptide with one fewer amino acid.

Edman degradation

O H C H O N 6 5 C6H5 N PEPTIDE R NCS + N + H N PEPTIDE S 2 H2N R H phenyl isothiocyanate N-terminal amino acid N-phenylthiohydantoin (PTH) This peptide contains a new N-terminal amino acid. This product characterizes the N-terminal amino acid.

The N-phenylthiohydantoin derivative contains the atoms of the N-terminal amino acid. This product identifi es the N-terminal amino acid in the peptide because the PTH derivatives of all 20 naturally occurring amino acids are known and characterized. The new peptide formed in the Edman degradation has one amino acid fewer than the original peptide. Moreover, it contains a new N-terminal amino acid, so the process can be repeated. Mechanism 28.2 illustrates some of the key steps of the Edman degradation. The nucleophilic N-terminal NH2 group adds to the electrophilic carbon of phenyl isothiocyanate to form an N-phenylthiourea, the product of nucleophilic addition (Part [1]). Intramolecular cyclization followed by elimination results in cleavage of the terminal amide bond in Part [2] to form a new peptide with one fewer amino acid. A sulfur heterocycle, called a thiazolinone, is also formed, which rearranges by a multistep pathway (Part [3]) to form an N-phenylthiohydantoin. The R group in this product identifi es the amino acid located at the N-terminal end.

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Mechanism 28.2 Edman Degradation

Part [1] Formation of an N-phenylthiourea H C H O N H H 6 5 PEPTIDE O N O N NCS + S PEPTIDE S PEPTIDE – H N R C6H5 + C6H5 2 [1] N N R [2] N N R phenyl isothiocyanate HH H H

nucleophilic addition proton transfer N-phenylthiourea

• Addition of the free amino group from the N-terminal amino acid to the electrophilic carbon of phenyl isothiocyanate followed by proton transfer forms an N-phenylthiourea.

Part [2] Cleavage of the amide bond from the N-terminal amino acid

HA H HO H O O N N PEPTIDE S PEPTIDE S – H+ S C6H5 R H A R + H2N PEPTIDE N N R [3] + [4] H H C6H5 N C6H5 N N H N H – A H thiazolinone

• Nucleophilic addition in Step [3] followed by loss of the amino group in Step [4] forms two products: a fi ve-membered thiazolinone ring and a peptide chain that contains one fewer amino acid than the original peptide.

Part [3] Rearrangement to form an N-phenylthiohydantoin (PTH)

O O C6H5 S several steps N R R C6H5 N N N H S H thiazolinone N-phenylthiohydantoin (PTH)

• Under the conditions of the reaction, the thiazolinone rearranges by a multistep pathway to form an N-phenylthiohydantoin (PTH). This product contains the original N-terminal amino acid.

In theory a protein of any length can be sequenced using the Edman degradation, but in practice, the accumulation of small quantities of unwanted by-products limits sequencing to proteins having fewer than approximately 50 amino acids.

Problem 28.19 Draw the structure of the N-phenylthiohydantoin formed by initial Edman degradation of each peptide: (a) Ala–Gly–Phe–Phe; (b) Val–Ile–Tyr.

28.6C Partial Hydrolysis of a Peptide Additional structural information can be obtained by cleaving some, but not all, of the amide bonds in a peptide. Partial hydrolysis of a peptide with acid forms smaller fragments in a random fashion. Sequencing these peptides and identifying sites of overlap can be used to determine the sequence of the complete peptide, as shown in Sample Problem 28.2.

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Sample Problem 28.2 Give the amino acid sequence of a hexapeptide that contains the amino acids Ala, Val, Ser, Ile, Gly, Tyr, and forms the following fragments when partially hydrolyzed with HCl: Gly–Ile–Val, Ala–Ser–Gly, and Tyr–Ala. Solution Looking for points of overlap in the sequences of the smaller fragments shows how the fragments should be pieced together. In this example, the fragment Ala–Ser–Gly contains amino acids common to the two other fragments, thus showing how the three fragments can be joined together.

common amino acids

Answer: Tyr Ala Gly Ile Val Tyr AlaSer Gly Ile Val Ala Ser Gly hexapeptide

Problem 28.20 Give the amino acid sequence of an octapeptide that contains the amino acids Tyr, Ala, Leu (2 equiv), Cys, Gly, Glu, and Val, and forms the following fragments when partially hydrolyzed with HCl: Val–Cys–Gly–Glu, Ala–Leu–Tyr, and Tyr–Leu–Val–Cys.

Peptides can also be hydrolyzed at specifi c sites using enzymes. The enzyme carboxypeptidase catalyzes the hydrolysis of the amide bond nearest the C-terminal end, forming the C-terminal amino acid and a peptide with one fewer amino acid. In this way, carboxypeptidase is used to identify the C-terminal amino acid. Other enzymes catalyze the hydrolysis of amide bonds formed with specifi c amino acids. For example, trypsin catalyzes the hydrolysis of amides with a carbonyl group that is part of the basic amino acids arginine and lysine. Chymotrypsin hydrolyzes amides with carbonyl groups that are part of the aromatic amino acids phenylalanine, tyrosine, and tryptophan. Table 28.2 summarizes these enzyme specifi cities used in peptide sequencing.

Chymotrypsin cleaves here. Carboxypeptidase cleaves here.

Ala Phe Gly Leu Trp Val Arg His Pro Pro Gly

Trypsin cleaves here.

Table 28.2 Cleavage Sites of Speciﬁ c Enzymes in Peptide Sequencing Enzyme Site of cleavage

Carboxypeptidase Amide bond nearest to the C-terminal amino acid Chymotrypsin Amide bond with a carbonyl group from Phe, Tyr, or Trp Trypsin Amide bond with a carbonyl group from Arg or Lys

Problem 28.21 (a) What products are formed when each peptide is treated with trypsin? (b) What products are formed when each peptide is treated with chymotrypsin? [1] Gly–Ala–Phe–Leu–Lys–Ala [2] Phe–Tyr–Gly–Cys–Arg–Ser [3] Thr–Pro–Lys–Glu–His–Gly–Phe–Cys–Trp–Val–Val–Phe

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Sample Problem 28.3 Deduce the sequence of a pentapeptide that contains the amino acids Ala, Glu, Gly, Ser, and Tyr, from the following experimental data. Edman degradation cleaves Gly from the pentapeptide, and carboxypeptidase forms Ala and a tetrapeptide. Treatment of the pentapeptide with chymotrypsin forms a dipeptide and a tripeptide. Partial hydrolysis forms Gly, Ser, and the tripeptide Tyr–Glu–Ala. Solution Use each result to determine the location of an amino acid in the pentapeptide. Experiment Result • Edman degradation identifi es the N-terminal amino acid—in this → Gly– – – – case, Gly. • Carboxypeptidase identifi es the C-terminal amino acid (Ala) → Gly– – – –Ala when it is cleaved from the end of the chain. • Chymotrypsin cleaves amide bonds that contain a carbonyl group → Gly–Tyr– – –Ala from an aromatic amino acid—Tyr in this case. Because a dipeptide or and tripeptide are obtained after treatment with chymotrypsin, Tyr Gly– –Tyr– –Ala must be the C-terminal amino acid of either the di- or tripeptide. As a result, Tyr must be either the second or third amino acid in the pentapeptide chain. • Partial hydrolysis forms the tripeptide Tyr–Glu–Ala. Because Ala is → Gly– –Tyr–Glu–Ala the C-terminal amino acid, this result identifi es the last three amino acids in the chain. • The last amino acid, Ser, must be located at the only remaining → Gly–Ser–Tyr–Glu–Ala position, the second amino acid in the pentapeptide, and the complete sequence is determined.

Problem 28.22 Deduce the sequence of a heptapeptide that contains the amino acids Ala, Arg, Glu, Gly, Leu, Phe, and Ser, from the following experimental data. Edman degradation cleaves Leu from the heptapeptide, and carboxypeptidase forms Glu and a hexapeptide. Treatment of the heptapeptide with chymotrypsin forms a hexapeptide and a single amino acid. Treatment of the heptapeptide with trypsin forms a pentapeptide and a dipeptide. Partial hydrolysis forms Glu, Leu, Phe, and the tripeptides Gly–Ala–Ser and Ala–Ser–Arg.

28.7 Peptide Synthesis The synthesis of a specifi c dipeptide, such as Ala–Gly from alanine and glycine, is complicated because both amino acids have two functional groups. As a result, four products—namely, Ala– Ala, Ala–Gly, Gly–Gly, and Gly–Ala—are possible.

From two amino acids...... there are four possible dipeptides.

CH3 H O CH3 H O CH3 H O H H C OH H2N C C N C C N C H2N C + C OH H2N C C OH + H2N C C OH O O O H H H CH3 H H Ala Gly Ala–Ala Ala–Gly + H H O H H O H H C N C C N C H2N C C OH + H2N C C OH O O H H H CH3 Gly–Gly Gly–Ala

How do we selectively join the COOH group of alanine with the NH2 group of glycine?

• Protect the functional groups that we don’t want to react, and then form the amide bond.

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HOW TO Synthesize a Dipeptide from Two Amino Acids

Example CH3 H O CH3 H O H C N C C OH H2N C H2N C C OH H2N C + C OH O O H H H H Ala–Gly Ala Gly Join these two functional groups.

Step [1] Protect the NH2 group of alanine.

CH3 H CH3 H C OH C OH H N C PG N C [PG = protecting group] 2 H O O

Ala

Step [2] Protect the COOH group of glycine.

O O

H2N C H2N C C OH C O PG

H H H H Gly

Step [3] Form the amide bond with DCC.

CH3 H O CH3 H O H C OH + H2N C DCC C N C PG N C C O PG PG N C C O PG H H O O H H H H

The amide forms here. new amide bond

Dicyclohexylcarbodiimide (DCC) is a reagent commonly used to form amide bonds (see Section 22.10D). DCC makes the OH group of the carboxylic acid a better leaving group, thus activating the carboxy group toward nucleophilic attack.

DCC = NCN

dicyclohexylcarbodiimide

Step [4] Remove one or both protecting groups.

CH3 H O CH3 H O H H C N C C N C PG N C C O PG H2N CCOH H O O H H H H Ala–Gly

Two widely used amino protecting groups convert an amine into a carbamate, a functional group having a carbonyl bonded to both an oxygen and a nitrogen atom. Since the N atom of the carbamate is bonded to a carbonyl group, the protected amino group is no longer nucleophilic.

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Amino acid N-Protected amino acid

HR O HR COH H N C CCOH 2 protection R' O N C O H O carbamate For example, the tert-butoxycarbonyl protecting group, abbreviated as Boc, is formed by reacting the amino acid with di-tert-butyl dicarbonate in a nucleophilic acyl substitution reaction.

Adding a Boc protecting group

O O HR O HR HR

CC COH(CH3CH2)3N C COH COH (CH3)3CO O OC(CH3)3 +=H2N C (CH3)3CO N C Boc N C H H di-tert-butyl dicarbonate O O O

This N is now protected as a Boc derivative. O To be a useful protecting group, the Boc group must be removed under reaction conditions that C (CH3)3CO do not affect other functional groups in the molecule. It can be removed with an acid such as trifl uoroacetic acid, HCl, or HBr. tert-butoxycarbonyl Boc O HR HR CF3CO2H or Removing a Boc C COH COH+ CO2 protecting group (CH3)3CO N C HCl H2N C O H or + O O C HBr (CH3)2C CH2 CH2O This bond is cleaved. A second amino protecting group, the 9-fl uorenylmethoxycarbonyl protecting group, abbrevi- 9-fluorenylmethoxycarbonyl ated as Fmoc, is formed by reacting the amino acid with 9-fl uorenylmethyl chloroformate in a Fmoc nucleophilic acyl substitution reaction.

Adding an Fmoc protecting group Fmoc

HR HR O HR O C C COH COH CH O Cl + COH 2 Na CO CH2O N C = Fmoc N C H2N C 2 3 H H H O O O O 2

9-fluorenylmethyl Fmoc-protected amino acid chloroformate Fmoc Cl While the Fmoc protecting group is stable to most acids, it can be removed by treatment with base (NH3 or an amine), to regenerate the free amino group.

Removing an Fmoc protecting group

O HR HR C COH COH CH2O N C H2N C + + CO2 H O O

N This bond is cleaved H

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The carboxy group is usually protected as a methyl or benzyl ester by reaction with an alcohol and an acid. O + CH3OH, H H2N C Protection of the O C OCH3 carboxy group H2N C H R C OH The OH group is now protected as an ester. + O H R C6H5CH2OH, H H2N C C OCH2C6H5 H R These esters are usually removed by hydrolysis with aqueous base. O

Removal of the ester H2N C C protecting group OCH3 O R – H H2O, OH H2N C C OH O H R H2N C C OCH2C6H5 H R

One advantage of using a benzyl ester for protection is that it can also be removed with H2 in the presence of a Pd catalyst. This process is called hydrogenolysis. These conditions are especially mild, because they avoid the use of either acid or base. Benzyl esters can also be removed with HBr in acetic acid. O O Hydrogenolysis of H2N C H2 H2N C benzyl esters C O CH C H C OH + CH C H 2 6 5 Pd-C 3 6 5 H R H R

This bond is cleaved.

The specifi c reactions needed to synthesize the dipeptide Ala–Gly are illustrated in Sample Prob- lem 28.4.

Sample Problem 28.4 Draw out the steps in the synthesis of the dipeptide Ala–Gly.

CH3 H O CH3 H O H C OH H2N C ? C N C H2N C + C OH H2N C C OH O HH O HH Ala Gly Ala–Gly

Solution

Step [1] Protect the NH2 group of alanine using a Boc group.

CH3 H CH3 H C OH [(CH3)3COCO]2O H2N C C OH (CH3CH2)3N Boc N C O H O Ala

Step [2] Protect the COOH group of glycine as a benzyl ester. O O + H2N C C6H5CH2OH, H H2N C C OH C OCH2C6H5 HH HH Gly

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Step [3] Form the amide bond with DCC.

CH3 H O CH3 H O C OH H N C H 2 DCC N Boc N C + C OCH2C6H5 C C H Boc N C C OCH2C6H5 O HH H O HH

The amide forms here. new amide bond

Step [4] Remove one or both protecting groups.

The protecting groups can be removed in a stepwise fashion, or in a single reaction.

Remove the benzyl group.

H CH3 H O CH3 O H H2 H C N C C N C - Boc N C C OCH2C6H5 Pd C Boc N C C OH H H O O H H H H

CF3COOH Remove the Boc group.

CH3 H O H HBr C N C H2N C C OH CH3COOH O H H Remove both protecting groups. Ala–Gly

This method can be applied to the synthesis of tripeptides and even larger polypeptides. After the protected dipeptide is prepared in Step [3], only one of the protecting groups is removed, and this dipeptide is coupled to a third amino acid with one of its functional groups protected, as illustrated in the following equations.

Carboxy protected N-Protected dipeptide amino acid

CH3 H O O H C N C + H2N C Boc N C C OH C OCH C H H 2 6 5 O H H H H

DCC Form the amide bond.

H H H CH3 H O H H CH3 O H HBr H N C C OCH C H C N C C OH C 2 6 5 CH COOH N C Boc N C C N C 3 H2N C C H H H O O O O H H H H

Remove both Ala–Gly–Gly new amide bond protecting groups. tripeptide

Problem 28.23 Devise a synthesis of each peptide from amino acid starting materials: (a) Leu–Val; (b) Ala–Ile–Gly; (c) Ala–Gly–Ala–Gly.

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28.8 Automated Peptide Synthesis The method described in Section 28.7 works well for the synthesis of small peptides. It is extremely time-consuming to synthesize larger proteins by this strategy, however, because each step requires isolation and purifi cation of the product. The synthesis of larger polypeptides is usually accomplished by using the solid phase technique originally developed by R. Bruce Merrifi eld of Rockefeller University. In the Merrifi eld method an amino acid is attached to an insoluble polymer. Amino acids Development of the solid phase are sequentially added, one at a time, thereby forming successive peptide bonds. Because technique earned Merrifi eld the impurities and by-products are not attached to the polymer chain, they are removed simply 1984 Nobel Prize in Chemistry by washing them away with a solvent at each stage of the synthesis. and has made possible the synthesis of many polypeptides A commonly used polymer is a polystyrene derivative that contains – CH2Cl groups bonded to and proteins. some of the benzene rings in the polymer chain. The Cl atoms serve as handles that allow attachment of amino acids to the chain.

abbreviated as Polystyrene polymer derivative ClCH2 POLYMER

CH2Cl CH2Cl

These side chains allow amino acids to be attached to the polymer.

An Fmoc-protected amino acid is attached to the polymer at its carboxy group by an SN2 reaction.

Cl CH2 POLYMER R1 H R1 H R1 H – C OH base C O C O CH2 POLYMER Fmoc N C Fmoc N C Fmoc N C H H SN2 H O O O The amino acid is now bound to the insoluble polymer.

Once the fi rst amino acid is bound to the polymer, additional amino acids can be added sequentially. The steps of the solid phase peptide synthesis technique are illustrated in the accompanying scheme. In the last step, HF cleaves the polypeptide chain from the polymer.

HOW TO Synthesize a Peptide Using the Merriﬁ eld Solid Phase Technique

R1 H Step [1] C OH Fmoc N C Attach an Fmoc-protected amino acid H to the polymer. O

[1] base

[2] Cl CH2 POLYMER

R1 H

C O CH2 POLYMER Fmoc N C H O

new bond to the polymer

—Continued

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HOW TO, continued . . .

Step [2] Remove the protecting group. N H

R1 H

C O CH2 POLYMER free amino group H2N C O

O Step [3] H Form the amide bond with DCC. DCC Fmoc N C C OH

H R2

O R1 H H Fmoc N C C O CH POLYMER C N C 2 H O H R2

new amide bond

[1] [2] DCC Step [4] R3 H Repeat Steps [2] and [3]. N C OH Fmoc N C H H O R 3 H O R1 H H C N C C O CH POLYMER Fmoc N C C N C 2 H H O O H R2

new amide bond

[1] Step [5] Remove the protecting group and detach N the peptide from the polymer. H [2] HF R 3 H O R1 H H C N C C OH + F CH2 POLYMER H N C C N C 2 H O O H R2

tripeptide

The Merrifi eld method has now been completely automated, so it is possible to purchase peptide synthesizers that automatically carry out all of the above operations and form polypeptides in high yield in a matter of hours, days, or weeks, depending on the length of the chain of the desired product. The instrument is pictured in Figure 28.8. For example, the protein ribonucle- ase, which contains 128 amino acids, has been prepared by this technique in an overall yield of 17%. This remarkable synthesis involved 369 separate reactions, and thus the yield of each individual reaction was > 99%.

Problem 28.24 Outline the steps needed to synthesize the tetrapeptide Ala–Leu–Ile–Gly using the Merrifi eld technique.

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Figure 28.8 Automated peptide synthesizer

28.9 Protein Structure Now that you have learned some of the chemistry of amino acids, it’s time to study proteins, the large polymers of amino acids that are responsible for so much of the structure and function of all living cells. We begin with a discussion of the primary, secondary, tertiary, and quaternary structure of proteins.

28.9A Primary Structure The primary structure of proteins is the particular sequence of amino acids that is joined together by peptide bonds. The most important element of this primary structure is the amide bond.

• Rotation around the amide C – N bond is restricted because of electron delocalization, and the s-trans conformation is the more stable arrangement. • In each peptide bond, the N – H and C – O bonds are directed 180° from each other.

restricted rotation O HR H α C NC α CNα C C = R H O α α α

two amide bonds in a peptide chain

Although rotation about the amide bonds is restricted, rotation about the other r bonds in the protein backbone is not. As a result, the peptide chain can twist and bend into a variety of different arrangements that constitute the secondary structure of the protein.

28.9B Secondary Structure The three-dimensional conformations of localized regions of a protein are called its secondary structure. These regions arise due to hydrogen bonding between the N – H proton of one amide and C – O oxygen of another. Two arrangements that are particularly stable are called the `-helix and the a-pleated sheet.

O C N H hydrogen bond O C N H

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`-Helix The `-helix forms when a peptide chain twists into a right-handed or clockwise spiral, as shown in Figure 28.9. Four important features of the α-helix are as follows: [1] Each turn of the helix has 3.6 amino acids. [2] The N – H and C – O bonds point along the axis of the helix. All C – O bonds point in one direction, and all N – H bonds point in the opposite direction. [3] The C – O group of one amino acid is hydrogen bonded to an N – H group four amino acid residues farther along the chain. Thus, hydrogen bonding occurs between two amino acids in the same chain. Note, too, that the hydrogen bonds are parallel to the axis of the helix. [4] The R groups of the amino acids extend outward from the core of the helix. An α-helix can form only if there is rotation about the bonds at the α carbon of the amide carbonyl group, and not all amino acids can do this. For example, proline, the amino acid whose nitrogen atom forms part of a fi ve-membered ring, is more rigid than other amino acids, and its Cα – N bond cannot rotate the necessary amount. Additionally, it has no N – H proton with which to form an intramolecular hydrogen bond to stabilize the helix. Thus, proline cannot be part of an α-helix. Both the myosin in muscle and α-keratin in hair are proteins composed almost entirely of α-helices.

a-Pleated Sheet The a-pleated sheet secondary structure forms when two or more peptide chains, called strands, line up side-by-side, as shown in Figure 28.10. All β-pleated sheets have the following characteristics: [1] The C – O and N – H bonds lie in the plane of the sheet. [2] Hydrogen bonding often occurs between the N – H and C – O groups of nearby amino acid residues.

Figure 28.9 a. The right-handed α-helix b. The backbone of the α-helix Two different illustrations of the α-helix

R hydrogen R bond

R 3.6 residues

All atoms of the α-helix are drawn in this Only the peptide backbone is drawn in this representation. All C – O bonds are pointing up representation. The hydrogen bonds between and all N – H bonds are pointing down. the C – O and N – H of amino acids four residues away from each other are shown.

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Figure 28.10 Three-dimensional structure of the β-pleated sheet

• The β-pleated sheet consists of extended strands of the peptide chains held together by hydrogen bonding. The C – O and N – H bonds lie in the plane of the sheet, and the R groups (shown as orange balls) alternate above and below the plane.

[3] The R groups are oriented above and below the plane of the sheet, and alternate from one side to the other along a given strand. The β-pleated sheet arrangement most commonly occurs with amino acids with small R groups, like alanine and glycine. With larger R groups steric interactions prevent the chains from getting close together and so the sheet cannot be stabilized by hydrogen bonding. The peptide strands of β-pleated sheets can actually be oriented in two different ways, as shown in Figure 28.11.

• In a parallel a-pleated sheet, the strands run in the same direction from the N- to C-terminal amino acid. • In an antiparallel a-pleated sheet, the strands run in the opposite direction.

Most proteins have regions of α-helix and β-pleated sheet, in addition to other regions that cannot be characterized by either of these arrangements. Shorthand symbols are often used to indicate regions of a protein that have α-helix or β-pleated sheet. A fl at helical ribbon is used for

Figure 28.11 The parallel and antiparallel forms of the β-pleated sheet

Parallel a-pleated sheet Antiparallel a-pleated sheet

H O H O H O H O H O H O NCC N C C N C C N C C N CCN C C N C C N C C N C C N C C N C C N O H O H O H O H O H O H

H O H O H O H O H O H O NCC N C C N C C NCC N C C N C C C N C C N C C N C N C C N C C N O H O H O H O H O H O H

The two peptide chains are arranged in the same direction. The two peptide chains are arranged in opposite directions. Hydrogen bonds occur between N – H and C – O bonds in Hydrogen bonding between the N – H and C – O groups still adjacent chains. holds the two chains together. [Note: R groups on the carbon chain are omitted for clarity.]

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the α-helix, and a fl at wide arrow is used for the β-pleated sheet. These representations are often used in ribbon diagrams to illustrate protein structure.

`-helix shorthand a-pleated sheet shorthand Proteins are drawn in a variety of ways to illustrate different aspects of their structure. Figure 28.12 illustrates three different representations of the protein lysozyme, an enzyme found in both plants and animals. Lysozyme catalyzes the hydrolysis of bonds in bacterial cell walls, weaken- ing them, often causing the bacteria to burst. Spider dragline silk is a strong yet elastic protein because it has regions of β-pleated sheet and regions of α-helix (Figure 28.13). α-Helical regions impart elasticity to the silk because the peptide chain is twisted (not fully extended), so it can stretch. β-Pleated sheet regions are almost fully extended, so they can’t be stretched further, but their highly ordered three-dimensional structure imparts strength to the silk. Thus, spider silk suits the spider by comprising both types of secondary structure with benefi cial properties.

Problem 28.25 Suggest a reason why antiparallel β-pleated sheets are generally more stable than parallel β- pleated sheets.

Problem 28.26 Consider two molecules of a tetrapeptide composed of only alanine residues. Draw the hydrogen bonding interactions that result when these two peptides adopt a parallel β-pleated sheet arrangement. Answer this same question for the antiparallel β-pleated sheet arrangement.

28.9C Tertiary and Quaternary Structure The three-dimensional shape adopted by the entire peptide chain is called its tertiary structure. A peptide generally folds into a conformation that maximizes its stability. In the aqueous environment of the cell, proteins often fold in such a way as to place a large number of polar and charged groups on their outer surface, to maximize the dipole–dipole and hydrogen bonding interactions with water. This generally places most of the nonpolar side chains in the interior of the protein, where van der Waals interactions between these hydrophobic groups help stabilize the molecule, too.

Figure 28.12 Lysozyme

a. Ball-and-stick model b. Space-filling model c. Ribbon diagram

(a) The ball-and-stick model of lysozyme shows the protein backbone with color-coded C, N, O, and S atoms. Individual amino acids are most clearly located using this representation. (b) The space-fi lling model uses color-coded balls for each atom in the backbone of the enzyme and illustrates how the atoms fi ll the space they occupy. (c) The ribbon diagram shows regions of α-helix and β-sheet that are not clearly in evidence in the other two representations.

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Figure 28.13 Different regions of secondary structure in spider silk single strand of silk

spider web

regions of β-pleated sheets and α-helices

Spider silk has regions of α-helix and β-pleated sheet that make it both strong and elastic. The green coils represent the α-helical regions, and the purple arrows represent the β-pleated sheet regions. The yellow lines represent other areas of the protein that are neither α-helix nor β-pleated sheet.

In addition, polar functional groups hydrogen bond with each other (not just water), and amino – + acids with charged side chains like – COO and – NH3 can stabilize tertiary structure by electrostatic interactions. Finally, disulfi de bonds are the only covalent bonds that stabilize tertiary structure. As previously mentioned, these strong bonds form by oxidation of two cysteine residues either on the same polypeptide chain or another polypeptide chain of the same protein.

Disulfide bonds can form in two different ways.

Between two SH groups on the same chain. Between two SH groups on different chains.

CH2SH CH2 S CH2SH CH2S [O] [O]

HSCH SCH CH2SH CH2 S 2 2

The nonapeptides oxytocin and vasopressin (Section 28.5C) contain intramolecular disulfi de bonds. Insulin, on the other hand, consists of two separate polypeptide chains (A and B) that are covalently linked by two intermolecular disulfi de bonds, as shown in Figure 28.14. The A chain, which also has an intramolecular disulfi de bond, has 21 amino acid residues, whereas the B chain has 30. Figure 28.15 schematically illustrates the many different kinds of intramolecular forces that stabilize the secondary and tertiary structures of polypeptide chains. The shape adopted when two or more folded polypeptide chains aggregate into one protein complex is called the quaternary structure of the protein. Each individual polypeptide chain is called a subunit of the overall protein. Hemoglobin, for example, consists of two α and two β subunits held together by intermolecular forces in a compact three-dimensional shape. The unique function of hemoglobin is possible only when all four subunits are together. The four levels of protein structure are summarized in Figure 28.16.

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Figure 28.14 The amino acid sequence of human insulin Insulin residue 1 S S 21 A chain Gly-Ile-Val-Glu-Gln-Cys-Cys-Thr-Ser-Ile-Cys-Ser-Leu-Tyr-Gln-Leu-Glu-Asn-Tyr-Cys-Asn 8910 S S S S

B chain Phe-Val-Asn-Gln-His-Leu-Cys-Gly-Ser-His-Leu-Val-Glu-Ala-Leu-Tyr-Leu-Val-Cys-Gly Thr-Lys-Pro-Thr-Tyr-Phe-Phe-Gly-Arg-Glu residue 1 30

Insulin is a small protein consisting of two polypeptide chains (designated as the A and B chains) held together by two disulfi de bonds. An additional disulfi de bond joins two cysteine residues within the A chain.

3-D model of insulin islets of Langerhans pancreas

Synthesized by groups of cells in the pancreas called the islets of Langerhans, insulin is the protein that regulates the levels of glucose in the blood. Insuffi ciency of insulin results in diabetes. Many of the abnormalities associated with this disease can be controlled by the injection of insulin. Until the availability of human insulin through genetic engineering techniques, all insulin used by diabetics was obtained from pigs and cattle. The amino acid sequences of these insulin proteins is slightly different from that of human insulin. Pig insulin differs in one amino acid only, whereas bovine insulin has three different amino acids. This is shown in the accompanying table. Chain A Chain B Position of residue ã 8 9 10 30 Human insulin Thr Ser Ile Thr Pig insulin Thr Ser Ile Ala Bovine insulin Ala Ser Val Ala

Problem 28.27 What types of stabilizing interactions exist between each of the following pairs of amino acids? a. Ser and Tyr b. Val and Leu c. Two Phe residues

Problem 28.28 The fi broin proteins found in silk fi bers consist of large regions of β-pleated sheets stacked one on top of another. (a) Explain why having a glycine at every other residue allows the β-pleated sheets to stack on top of each other. (b) Why are silk fi bers insoluble in water?

28.10 Important Proteins Proteins are generally classifi ed according to their three-dimensional shapes. • Fibrous proteins are composed of long linear polypeptide chains that are bundled together to form rods or sheets. These proteins are insoluble in water and serve structural roles, giving strength and protection to tissues and cells. • Globular proteins are coiled into compact shapes with hydrophilic outer surfaces that make them water soluble. Enzymes and transport proteins are globular to make them soluble in the blood and other aqueous environments in cells.

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Figure 28.15 hydrogen bond hydrogen bond The stabilizing interactions in hydrogen bond + secondary and tertiary NH3

protein structure CH3

CHO HOCH2 H O

CH2C NH O CO H N 2 C

hydrogen O + bond (CH2)4NH3 CCH2 –O

CH3 CH2 S S CH2 CH2CH(CH3)2 CH hydrogen bond CH CH3 3 COO– CH2 CHCH2 helical

CH3 structure electrostatic attraction disulfide bond

van der Waals van der Waals interaction interaction

28.10A `-Keratins `-Keratins are the proteins found in hair, hooves, nails, skin, and wool. They are composed almost exclusively of long sections of α-helix units, having large numbers of alanine and leucine residues. Because these nonpolar amino acids extend outward from the α-helix, these proteins are very water insoluble. Two α-keratin helices coil around each other, forming a structure called

Figure 28.16 The primary, secondary, tertiary, and quaternary structure of proteins

OC H C R NH CO R C β-pleated sheet H HN CO H C R NH CO R 3-D shape of a protein complex of C polypeptide chain polypeptide chains H HN α-helix

amino acid sequence

Primary structure Secondary structure Tertiary structure Quaternary structure

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Figure 28.17 Hair is composed of α-keratin, Anatomy of a hair— made up largely of an α-helix. It begins with α-keratin.

Two α-helices wind around each other to form a supercoil.

Strand of hair

Supercoil Larger bundles of strands come together to form a hair.

a supercoil or superhelix. These, in turn, form larger and larger bundles of fi bers, ultimately forming a strand of hair, as shown schematically in Figure 28.17. α-Keratins also have a number of cysteine residues, and because of this, disulfi de bonds are formed between adjacent helices. The number of disulfi de bridges determines the strength of the material. Claws, horns, and fi ngernails have extensive networks of disulfi de bonds, making them extremely hard. Straight hair can be made curly by cleaving the disulfi de bonds in α-keratin, and then rearranging and re-forming them, as shown schematically in Figure 28.18. First, the disulfi de bonds in the straight hair are reduced to thiol groups, so the bundles of α-keratin chains are no longer held in their specifi c “straight” orientation. Then, the hair is wrapped around curlers and treated with an oxidizing agent that converts the thiol groups back to disulfi de bonds, now with twists and turns in the keratin backbone. This makes the hair look curly and is the chemical basis for a “permanent.”

28.10B Collagen Collagen, the most abundant protein in vertebrates, is found in connective tissues such as bone, cartilage, tendons, teeth, and blood vessels. Glycine and proline account for a large fraction of its amino acid residues, whereas cysteine accounts for very little. Because of the high proline content, it cannot form a right-handed α-helix. Instead, it forms an elongated left-handed helix, and then three of these helices wind around each other to form a right-handed superhelix or triple helix. The side chain of glycine is only a hydrogen atom, so the high glycine content allows the

Figure 28.18 Straight hair Curly hair The chemistry of a “permanent”—Making straight hair curly S S [H] SH SH [O] S S S SS SH SH S

Re-form the disulfide bonds Reduce the disulfide bonds. to form curled strands of hair.

To make straight hair curly, the disulfi de bonds holding the α-helical chains together are cleaved by reduction. This forms free thiol groups (–SH). The hair is turned around curlers and then an oxidizing agent is applied. This re-forms the disulfi de bonds in the hair, but between different thiol groups, now giving it a curly appearance.

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Figure 28.19 Two different representations for the triple helix of collagen

• In collagen, three polypeptide chains having an unusual left-handed helix wind around each other in a right-handed triple helix. The high content of small glycine residues allows the chains to lie close to each other, permitting hydrogen bonding between the chains.

collagen superhelices to lie compactly next to each other, thus stabilizing the superhelices via hydrogen bonding. Two views of the collagen superhelix are shown in Figure 28.19.

28.10C Hemoglobin and Myoglobin Hemoglobin and myoglobin, two globular proteins, are called conjugated proteins because they are composed of a protein unit and a nonprotein molecule called a prosthetic group. The prosthetic group in hemoglobin and myoglobin is heme, a complex organic compound containing the Fe2+ ion complexed with a nitrogen heterocycle called a porphyrin. The Fe2+ ion of hemoglobin and myoglobin binds oxygen in the blood. Hemoglobin, which is present in red blood cells, transports oxygen to wherever it is needed in the body, whereas myoglobin stores oxygen in tissues. Ribbon diagrams for myoglobin and hemoglobin are shown in Figure 28.20.

Figure 28.20 a. Myoglobin b. Hemoglobin Protein ribbon diagrams for myoglobin and hemoglobin

heme

Myoglobin consists of a single Hemoglobin consists of two α and two β chains polypeptide chain with a heme unit shown in red and blue, respectively, and four shown in a ball-and-stick model. heme units shown in ball-and-stick models.

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NFe2+ N HO N O

O heme OH Myoglobin, the chapter-opening molecule, has 153 amino acid residues in a single polypeptide chain. It has eight separate α-helical sections that fold back on one another, with the prosthetic heme group held in a cavity inside the polypeptide. Most of the polar residues are found on the outside of the protein so that they can interact with the water solvent. Spaces in the interior of the protein are fi lled with nonpolar amino acids. Myoglobin gives cardiac muscle its characteristic red color. Hemoglobin consists of four polypeptide chains (two α subunits and two β subunits), each of which carries a heme unit. Hemoglobin has more nonpolar amino acids than myoglobin. When each subunit is folded, some of these remain on the surface. The van der Waals attraction between these hydrophobic groups is what stabilizes the quaternary structure of the four subunits. Carbon monoxide is poisonous because it binds to the Fe2+ of hemoglobin more strongly than does oxygen. Hemoglobin complexed with CO cannot carry O2 from the lungs to the tissues. Without O2 in the tissues for metabolism, cells cannot function, so they die. The properties of all proteins depend on their three-dimensional shape, and their shape depends on their primary structure—that is, their amino acid sequence. This is particularly well exempli- fi ed by comparing normal hemoglobin with sickle cell hemoglobin, a mutant variation in which a single amino acid of both β subunits is changed from glutamic acid to valine. The replacement of one acidic amino acid (Glu) with one nonpolar amino acid (Val) changes the shape of hemoglobin, which has profound effects on its function. Deoxygenated red blood cells with sickle cell When red blood cells take on hemoglobin become elongated and crescent shaped, and they are unusually fragile. As a result, a “sickled” shape in persons they do not fl ow easily through capillaries, causing pain and infl ammation, and they break open with sickle cell disease, they easily, leading to severe anemia and organ damage. The end result is often a painful and prema- occlude capillaries (causing ture death. organ injury) and they break easily (leading to profound This disease, called sickle cell anemia, is found almost exclusively among people originat- anemia). This devastating ing from central and western Africa, where malaria is an enormous health problem. Sickle cell illness results from the change hemoglobin results from a genetic mutation in the DNA sequence that is responsible for the syn- of a single amino acid in thesis of hemoglobin. Individuals who inherit this mutation from both parents develop sickle cell hemoglobin. Note the single anemia, whereas those who inherit it from only one parent are said to have the sickle cell trait. sickled cell surrounded by They do not develop sickle cell anemia and they are more resistant to malaria than individuals three red cells with normal without the mutation. This apparently accounts for this detrimental gene being passed on from morphology. generation to generation.

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KEY CONCEPTS

Amino Acids and Proteins Synthesis of Amino Acids (28.2)

[1] From α-halo carboxylic acids by SN2 reaction

NH3 R CHCOOH R CHCOO–NH + + NH + Br– (large excess) 4 4 Br NH S 2 2 N

[2] By alkylation of diethyl acetamidomalonate H R O [1] NaOEt C N C COOEt H2N C COOH • Alkylation works best with unhindered alkyl halides—that H [2] RX CH COOEt + ∆ H is, CH3X and RCH2X. 3 [3] H3O ,

[3] Strecker synthesis

O NH2 + NH2 NH4Cl H3O C R C CN R C COOH R H NaCN H H α-amino nitrile

Preparation of Optically Active Amino Acids [1] Resolution of enantiomers by forming diastereomers (28.3A)

• Convert a racemic mixture of amino acids into a racemic mixture of N-acetyl amino acids [(S)- and (R)-CH3CONHCH(R)COOH]. • Treat the enantiomers with a chiral amine to form a mixture of diastereomers. • Separate the diastereomers. • Regenerate the amino acids by protonation of the carboxylate salt and hydrolysis of the N-acetyl group.

[2] Kinetic resolution using enzymes (28.3B)

H2N COOH AcNH COOH H2N COOH C (CH3CO)2O C acylase C

HR H R HR (S)-isomer (S)-isomer separate

H2N COOH AcNH COOH C (CH3CO)2O C acylase AcNH COOH C RH R H (R)-isomer R H enantiomers enantiomers NO REACTION

[3] By enantioselective hydrogenation (28.4)

R NHAc – H2 AcNH COOH H2O, OH H2N COOH CC C C Rh* H COOH HCH2R H CH2R S enantiomer S amino acid Rh* = chiral Rh hydrogenation catalyst

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Summary of Methods Used for Peptide Sequencing (28.6) • Complete hydrolysis of all amide bonds in a peptide gives the identity and amount of the individual amino acids. • Edman degradation identifi es the N-terminal amino acid. Repeated Edman degradations can be used to sequence a peptide from the N-terminal end. • Cleavage with carboxypeptidase identifi es the C-terminal amino acid. • Partial hydrolysis of a peptide forms smaller fragments that can be sequenced. Amino acid sequences common to smaller fragments can be used to determine the sequence of the complete peptide. • Selective cleavage of a peptide occurs with trypsin and chymotrypsin to identify the location of specifi c amino acids (Table 28.2).

Adding and Removing Protecting Groups for Amino Acids (28.7) [1] Protection of an amino group as a Boc derivative RH RH [(CH3)3COCO]2O C C (CH CH ) N H2NCO2H 3 2 3 Boc N CO2H H

[2] Deprotection of a Boc-protected amino acid RH RH CF3CO2H or C C HCl or HBr Boc N CO2H H2NCO2H H

[3] Protection of an amino group as an Fmoc derivative

HR HR O C Na CO C OH C OH 2 3 + CH2O CI Fmoc N C H2N C H2O H O O Fmoc CI

[4] Deprotection of an Fmoc-protected amino acid HR HR

C OH C OH Fmoc N C H2N C H O O

N H

[5] Protection of a carboxy group as an ester O O O O + + H2N C CH3OH, H H2N C H2N C C6H5CH2OH, H H2N C C OH C OCH3 C OH C OCH2C6H5 HR HR HR HR methyl ester benzyl ester

[6] Deprotection of an ester group O O O O – – H2N C OH H2N C H2N C H2O, OH H2N C C OCH3 C OH C OCH2C6H5 or C OH H2O H , Pd-C HR HR HR 2 HR methyl ester benzyl ester

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Synthesis of Dipeptides (28.7) [1] Amide formation with DCC RH O RH O H C OH H2N C DCC C N C Boc N C + C OCH C H Boc N C C OCH C H H 2 6 5 H 2 6 5 O HR O HR

[2] Four steps are needed to synthesize a dipeptide: a. Protect the amino group of one amino acid with a Boc or Fmoc group. b. Protect the carboxy group of the second amino acid as an ester. c. Form the amide bond with DCC. d. Remove both protecting groups in one or two reactions.

Summary of the Merriﬁ eld Method of Peptide Synthesis (28.8) [1] Attach an Fmoc-protected amino acid to a polymer derived from polystyrene. [2] Remove the Fmoc protecting group. [3] Form the amide bond with a second Fmoc-protected amino acid by using DCC. [4] Repeat steps [2] and [3]. [5] Remove the protecting group and detach the peptide from the polymer.

PROBLEMS Amino Acids 28.29 Explain why L-alanine has the S confi guration but L-cysteine has the R confi guration.

28.30 CH3 a. ( S)-Penicillamine, an amino acid that does not occur in proteins, is used as a copper chelating

CH3 C CH COOH agent to treat Wilson’s disease, an inherited defect in copper metabolism. (R)-Penicillamine is toxic, sometimes causing blindness. Draw the structures of (R)- and SH NH2 S penicillamine ( )-penicillamine. b. What disulfi de is formed from oxidation of L-penicillamine? 28.31 Explain why amino acids are insoluble in diethyl ether but N-acetyl amino acids are soluble. 28.32 Histidine is classifi ed as a basic amino acid because one of the N atoms in its fi ve-membered ring is readily protonated by acid. Which N atom in histidine is protonated and why? 28.33 Tryptophan is not classifi ed as a basic amino acid even though it has a heterocycle containing a nitrogen atom. Why is the N atom in the fi ve-membered ring of tryptophan not readily protonated by acid? 28.34 What is the structure of each amino acid at its isoelectric point: (a) alanine; (b) methionine; (c) aspartic acid; (d) lysine? 28.35 To calculate the isoelectric point of amino acids having other ionizable functional groups, we must also take into account the

pKa of the additional functional group in the side chain. For an acidic amino acid (one with an additional acidic For a basic amino acid (one with an additional basic NH OH group): group): pK (α-COOH) + pK (second COOH) pK (α-NH +) + pK (side chain NH) pI = a a pI = a 3 a 2 2

a. Indicate which pKa values must be used to calculate the pI of each of the following amino acids: [1] glutamic acid; [2] lysine; [3] arginine. b. In general, how does the pI of an acidic amino acid compare to that of a neutral amino acid? c. In general, how does the pI of a basic amino acid compare to the pI of a neutral amino acid? 28.36 What is the predominant form of each of the following amino acids at pH = 1? What is the overall charge on the amino acid at this pH? (a) threonine; (b) methionine; (c) aspartic acid; (d) arginine 28.37 What is the predominant form of each of the following amino acids at pH = 11? What is the overall charge on the amino acid? (a) valine; (b) proline; (c) glutamic acid; (d) lysine

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28.38 a. Draw the structure of the tripeptide A–A–A, and label the two ionizable functional groups. b. What is the predominant form of A–A–A at pH = 1?

c. The pKa values for the two ionizable functional groups (3.39 and 8.03) differ considerably from the pKa values of alanine (2.35 and 9.87; see Table 28.1). Account for the observed pKa differences.

Synthesis and Reactions of Amino Acids 28.39 Draw the organic product formed when the amino acid leucine is treated with each reagent. + a. CH3OH, H g. C6H5COCl, pyridine b. CH3COCl, pyridine h. [(CH3)3COCO]2O, (CH3CH2)3N + c. C6H5CH2OH, H i. The product in (d), then NH2CH2COOCH3 + DCC d. Ac2O, pyridine j. The product in (h), then NH2CH2COOCH3 + DCC e. HCl (1 equiv) k. Fmoc–Cl, Na2CO3, H2O

f. NaOH (1 equiv) l. C6H5N – C – S 28.40 Answer Problem 28.39 using phenylalanine as a starting material. 28.41 Draw the organic products formed in each reaction. O NH3 [1] NH4Cl, NaCN a. (CH ) CHCH CHCOOH d. 3 2 2 CH O CHO + excess 3 [2] H3O Br

[1] NaOEt [1] NaOEt b. CH3CONHCH(COOEt)2 e. CH3CONHCH(COOEt)2 [2] O [2] ClCH2CH2CH2CH2NHAc [3] H O+, ∆ C O CH2Br 3 CH3 + ∆ [3] H3O , O O [1] NH Cl, NaCN c. 4 H N [2] H O+ H 3 28.42 What alkyl halide is needed to synthesize each amino acid from diethyl acetamidomalonate: (a) Asn; (b) His; (c) Trp? 28.43 Devise a synthesis of threonine from diethyl acetamidomalonate.

28.44 Devise a synthesis of each amino acid from acetaldehyde (CH3CHO): (a) glycine; (b) alanine. 28.45 Identify the lettered intermediates in the following reaction scheme. This is an alternative method to synthesize amino acids, based on the Gabriel synthesis of 1° amines (Section 25.7A). O

N–K+

Br2 O [1] NaOEt [1] NaOH, H2O CH2(COOEt)2 A B CD+ ∆ CH3COOH [2] ClCH2CH2SCH3 [2] H3O ,

28.46 Glutamic acid is synthesized by the following reaction sequence. Draw a stepwise mechanism for Steps [1]–[3].

COOEt + [1] NaOEt H3O H2N CHCOOH CH3CONHCH(COOEt)2 CH3CONH C COOEt ∆ [2] CH2 CHCOOEt CH2 + [3] H3O CH2CH2COOEt CH2COOH glutamic acid

Resolution; The Synthesis of Chiral Amino Acids

28.47 Write out a scheme for the resolution of the two enantiomers of racemic lactic acid [CH3CH(OH)COOH] using (R)-α-methylbenzylamine as resolving agent.

smi75625_ch28_1074-1118.indd 1114 11/13/09 12:15:38 PM Problems 1115

28.48 Another strategy used to resolve amino acids involves converting the carboxy group to an ester and then using a chiral carboxylic acid to carry out an acid–base reaction at the free amino group. The general plan is drawn below using (R)-mandelic acid as resolving agent. Using a racemic mixture of alanine enantiomers and (R)-mandelic acid as resolving agent, write out the steps showing how a resolution process would occur. HOH C CH OH C H COOH [1] separate 3 6 5 diastereomeric individual NH2CHCOOH NH2CHCOOCH3 H+ salts [2] base amino acids R R (two enantiomers) (two enantiomers) (R)-mandelic acid

28.49 Brucine is a poisonous alkaloid obtained from Strychnos nux vomica, a tree that grows in India, Sri Lanka, and northern Australia. Write out a resolution scheme similar to the one given in Section 28.3A, which shows how a racemic mixture of phenylalanine can be resolved using brucine.

CH3O

CH3O N H H O O brucine

28.50 Draw the organic products formed in each reaction. COOH NH 2 – Ac2O acylase H2 OH a. (CH3)2CH CH COOH c. NHAc chiral H2O racemic mixture Rh catalyst N H CH3CONH – H2 OH b. NHCOCH3 chiral H2O Rh catalyst COOH

28.51 What two steps are needed to convert A to L-dopa, an uncommon amino acid that is effective in treating Parkinson's disease? These two steps are the key reactions in the fi rst commercial asymmetric synthesis using a chiral transition metal catalyst. This process was developed at Monsanto in 1974.

CH3O COOH HO COOH

N CH3 HNH2 O H HO O CH3 O A L-dopa

Peptide Structure and Sequencing 28.52 Draw the structure for each peptide: (a) Phe–Ala; (b) Gly–Gln; (c) Lys–Gly; (d) R – H. 28.53 For each tetrapeptide [1] Ala–Gln–Cys–Ser; [2] Asp–Arg–Val–Tyr: a. Name the peptide using one-letter abbreviations. c. Label all amide bonds. b. Draw the structure. d. Label the N-terminal and C-terminal amino acids.

smi75625_ch28_1074-1118.indd 1115 11/13/09 12:15:39 PM 1116 Chapter 28 Amino Acids and Proteins

28.54 Name each peptide using both the three-letter and one-letter abbreviations of the component amino acids.

CH2COOH HH HH O CH2 H O H H a. C N C C OH b. HOOC N C C NH2 2N CH C N C C C N C H H O O O HCH2 HCH2 HCH3

COOH CH2

CH2 NH C HN NH2 28.55 Explain why a peptide C – N bond is stronger than an ester C – O bond. 28.56 Draw the s-trans and s-cis conformations of the peptide bond in the dipeptide Ala–Ala. 28.57 Draw the amino acids and peptide fragments formed when the decapeptide A–P–F–L–K–W–S–G–R–G is treated with each

reagent or enzyme: (a) chymotrypsin; (b) trypsin; (c) carboxypeptidase; (d) C6H5N – C – S. 28.58 Give the amino acid sequence of each peptide using the fragments obtained by partial hydrolysis of the peptide with acid. a. A tetrapeptide that contains Ala, Gly, His, and Tyr, which is hydrolyzed to the dipeptides His–Tyr, Gly–Ala, and Ala–His. b. A pentapeptide that contains Glu, Gly, His, Lys, and Phe, which is hydrolyzed to His–Gly–Glu, Gly–Glu–Phe, and Lys–His. 28.59 Angiotensin is an octapeptide that narrows blood vessels, thereby increasing blood pressure. ACE inhibitors are a group of drugs used to treat high blood pressure by blocking the synthesis of angiotensin in the body. Angiotensin contains the amino acids Arg (2 equiv), His, Ile, Phe, Pro, Tyr, and Val. Determine the sequence of angiotensin using the following fragments obtained by partial hydrolysis with acid: Ile–His–Pro–Phe, Arg–Arg–Val, Tyr–Ile–His, and Val–Tyr. 28.60 Use the given experimental data to deduce the sequence of an octapeptide that contains the following amino acids: Ala, Gly (2 equiv), His (2 equiv), Ile, Leu, and Phe. Edman degradation cleaves Gly from the octapeptide, and carboxypeptidase forms Leu and a heptapeptide. Partial hydrolysis forms the following fragments: Ile–His–Leu, Gly, Gly–Ala–Phe–His, and Phe–His–Ile. 28.61 An octapeptide contains the following amino acids: Arg, Glu, His, Ile, Leu, Phe, Tyr, and Val. Carboxypeptidase treatment of the octapeptide forms Phe and a heptapeptide. Treatment of the octapeptide with chymotrypsin forms two tetrapeptides, A and B. Treatment of A with trypsin yields two dipeptides, C and D. Edman degradation cleaves the following amino acids from each peptide: Glu (octapeptide), Glu (A), Ile (B), Glu (C), and Val (D). Partial hydrolysis of tetrapeptide B forms Ile–Leu in addition to other products. Deduce the structure of the octapeptide and fragments A–D.

Peptide Synthesis 28.62 Draw all the products formed in the following reaction.

HH O DCC C OH + H2N C Boc N C C OH H O H CH(CH3)2

28.63 Draw the organic products formed in each reaction. O O + H CH3OH, H H2 H2N C (CH3)3CO N C a. COH e. CC OCH2C6H5 Pd-C O H CH(CH3)2 H CH(CH3)2 O + H N C C6H5CH2OH, H HBr b. 2 COH f. starting material in (e) CH3COOH HCH2CH(CH3)2

[(CH3)3COCO]2O CF3COOH c. NH2CH2COOH g. product in (e) (CH3CH2)3N O C DCC OH Na2CO3 d. product in (b) + product in (c) h. + Fmoc CI H2NH H2O

smi75625_ch28_1074-1118.indd 1116 11/13/09 12:15:39 PM Problems 1117

28.64 Draw all the steps in the synthesis of each peptide from individual amino acids: (a) Gly–Ala; (b) Phe–Leu; (c) Ile–Ala–Phe. 28.65 Write out the steps for the synthesis of each peptide using the Merrifi eld method: (a) Ala–Leu–Phe–Phe; (b) Phe–Gly–Ala–Ile.

28.66 An amino acid [RCH(NH2)COOH] can readily be converted to an N-acetyl amino acid [RCH(NHCOCH3)COOH] using acetic anhydride. Why can’t this acetyl group be used as an amino protecting group, in place of the Boc group, for peptide synthesis? 28.67 Another method to form a peptide bond involves a two-step process: [1] Conversion of a Boc-protected amino acid to a p-nitrophenyl ester. [2] Reaction of the p-nitrophenyl ester with an amino acid ester.

R H R1 H R1 H 1 O H COH[1] CO NO [2] C N C 2 C OR' Boc N C Boc N C O Boc N C H H H O O O 2N CH H R2 p-nitrophenyl ester C OR' new amide bond H R2

– + O NO2

a. Why does a p-nitrophenyl ester “activate” the carboxy group of the fi rst amino acid to amide formation? b. Would a p-methoxyphenyl ester perform the same function? Why or why not?

R1 H

CO OCH3 Boc N C H O p-methoxyphenyl ester

28.68 In addition to forming an Fmoc-protected amino acid using Fmoc–Cl, an Fmoc protecting group can also be added to an amino group using reagent A. a. Draw the mechanism for the following reaction that adds an Fmoc group to an amino acid.

O RH O O RH O C C COH CH2O O N ++COH CH2O N C HO N H2NC Na2CO3 H H O O O 2 A O Fmoc-protected O amino acid N-hydroxysuccinimide b. Draw the mechanism for the reaction that removes an Fmoc group from an amino acid under the following conditions:

RH O RH N C COH H CH2OCN C ++CO2 OH H DMF H NC O 2 O

smi75625_ch28_1074-1118.indd 1117 11/13/09 12:15:40 PM 1118 Chapter 28 Amino Acids and Proteins

28.69 Many different insoluble polymers, called resins, are currently available for automated peptide synthesis. For example, the Wang

resin contains benzene rings substituted with – CH2OH groups that serve as sites of attachment for amino acids. Propose reaction conditions that would bind an Fmoc-protected amino acid to a Wang resin. What reaction conditions could be used to remove the polypeptide from the resin after the synthesis is complete?

O O Wang resin

OH OH

Proteins 28.70 Which of the following amino acids are typically found in the interior of a globular protein, and which are typically found on the surface: (a) phenylalanine; (b) aspartic acid; (c) lysine; (d) isoleucine; (e) arginine; (f) glutamic acid? 28.71 After the peptide chain of collagen has been formed, many of the proline residues are hydroxylated on one of the ring carbon atoms. Why is this process important for the triple helix of collagen? O O

N [O] N

Challenge Problems

28.72 Devise a stepwise synthesis of the tripeptide Val–Leu–Val from 3-methylbutanal [(CH3)2CHCH2CHO] as the only organic starting material. You may also use any required inorganic or organic reagents. 28.73 Besides asymmetric hydrogenation (Section 28.4), several other methods are now available for the synthesis of optically active amino acids. How might a reaction like the Strecker synthesis be adapted to the preparation of chiral amino acids? 28.74 As shown in Mechanism 28.2, the fi nal steps in the Edman degradation result in rearrangement of a thiazolinone to an N-phenylthiohydantoin. Draw a stepwise mechanism for this acid-catalyzed reaction.

O O

+ C6H5 S H3O N R R C6H5 N N N H S H thiazolinone N-phenylthiohydantoin

smi75625_ch28_1074-1118.indd 1118 11/13/09 12:15:40 PM Lipids 29

29.1 Introduction 29.2 Waxes 29.3 Triacylglycerols 29.4 Phospholipids 29.5 Fat-soluble vitamins 29.6 Eicosanoids 29.7 Terpenes 29.8 Steroids

Cholesterol is the most prominent member of the steroid family, a group of organic lipids that contains a tetracyclic structure. Cholesterol is synthesized in the liver and is found in almost all body tissues. It is a vital component for healthy cell membranes and serves as the starting material for the synthesis of all other steroids. But, as the general public now knows well, elevated cholesterol levels can lead to coronary artery disease. For this reason, consumer products are now labeled with their cholesterol content. In Chapter 29, we learn about the properties of cholesterol and other lipids. 1119

smi75625_ch29_1119-1147.indd 1119 11/13/09 9:11:09 AM 1120 Chapter 29 Lipids

We conclude the discussion of the organic molecules in biological systems by turning our attention to lipids, biomolecules that are soluble in organic solvents. Unlike the carbohydrates in Chapter 27 and the amino acids and proteins in Chapter 28, lipids contain many carbon–carbon and carbon–hydrogen bonds and few functional groups. Since lipids are the biomolecules that most closely resemble the hydrocarbons we studied in Chapters 4 and 10, we have already learned many facts that directly explain their properties. Since there is no one functional group that is present in all lipids, however, the chemistry of lipids draws upon knowledge learned in many prior chapters.

29.1 Introduction

The word lipid comes from the • Lipids are biomolecules that are soluble in organic solvents. Greek word lipos for “fat.” Lipids are unique among organic molecules because their identity is defi ned on the basis of a physical property and not by the presence of a particular functional group. Because of this, lipids come in a wide variety of structures and they have many different functions in the cell. Three examples are given in Figure 29.1. The large number of carbon–carbon and carbon–hydrogen r bonds in lipids makes them very soluble in organic solvents and insoluble in water. Monosaccharides (from which carbohydrates are formed) and amino acids (from which proteins are formed), on the other hand, are very polar, so they tend to be water soluble. Because lipids share many properties with hydrocarbons, several features of lipid structure and properties have already been discussed. Table 29.1 summarizes sections of the text where aspects of lipid chemistry were covered previously.

Table 29.1 Summary of Lipid Chemistry Discussed Prior to Chapter 29 Topic Section Topic Section

• Vitamin A 3.5 • Lipid oxidation 15.11 • Soap 3.6 • Vitamin E 15.12 • Phospholipids, the cell membrane 3.7 • Steroid synthesis 16.14 • Lipids Part 1 4.15 • Prostaglandins 19.6 • Leukotrienes 9.16 • Lipid hydrolysis 22.12A • Fats and oils 10.6 • Soap 22.12B • Oral contraceptives 11.4 • Cholesteryl esters 22.17 • Hydrogenation of oils 12.4 • Steroid synthesis 24.8

Figure 29.1 Three examples of lipids O O HO O COOH O O H

HO H H OH O O PGF2α O a triacylglycerol progesterone a prostaglandin a steroid All lipids have many C – C and C – H bonds, but there is no one functional group common to all lipids.

smi75625_ch29_1119-1147.indd 1120 11/13/09 9:11:11 AM 29.2 Waxes 1121

Lipids can be categorized as hydrolyzable or nonhydrolyzable. [1] Hydrolyzable lipids can be cleaved into smaller molecules by hydrolysis with water. Most hydrolyzable lipids contain an ester unit. We will examine three subgroups: waxes, triacylglycerols, and phospholipids.

Hydrolyzable lipids

waxes triacylglycerols phospholipids

[2] Nonhydrolyzable lipids cannot be cleaved into smaller units by aqueous hydrolysis. Nonhydrolyzable lipids tend to be more varied in structure. We will examine four different types: fat-soluble vitamins, eicosanoids, terpenes, and steroids.

Nonhydrolyzable lipids

fat-soluble vitamins eicosanoids terpenes steroids

29.2 Waxes Waxes are the simplest hydrolyzable lipids. Waxes are esters (RCOOR') formed from a high molecular weight alcohol (R'OH) and a fatty acid (RCOOH). Because of their long hydrocarbon chains, waxes are very hydrophobic. They form a protective coating on the feathers of birds to make them water repellent, and on leaves to prevent water evaporation. Lanolin, a wax composed of a complex mixture of high molecular weight esters, coats the wool fi bers of sheep. Spermaceti wax, isolated from the heads of sperm whales, is largely CH3(CH2)14COO(CH2)15CH3. The three-dimensional structure of this compound shows how small the ester group is compared to the long hydrocarbon chains. Water beads up on the surface of a leaf because of the leaf’s waxy coating. Wax Example

O O C C R OR' CH3(CH2)14 O(CH2)15CH3 long chains of C’s spermaceti wax (from sperm whales)

spermaceti wax 3-D structure

Problem 29.1 Carnauba wax, a wax that coats the leaves of the Brazilian palm tree, is used for hard, high- gloss fi nishes for fl oors, boats, and automobiles. (a) Draw the structure of one component of carnauba wax, formed from an unbranched 32-carbon carboxylic acid and a straight chain 34-carbon alcohol. (b) Draw the structure of a second component of carnauba wax, formed by

the polymerization of HO(CH2)17COOH.

smi75625_ch29_1119-1147.indd 1121 11/13/09 9:11:11 AM 1122 Chapter 29 Lipids

29.3 Triacylglycerols Triacylglycerols, or triglycerides, are the most abundant lipids, and for this reason we have already discussed many of their properties in earlier sections of this text.

• Triacylglycerols are triesters that produce glycerol and three molecules of fatty acid upon hydrolysis.

O R OH H O O 2 O O O Line structures of stearic, oleic, (H+ or –OH) linoleic, and linolenic acids can O OH + C + C + C or HO R HO R' HO R'' be found in Table 10.2. Ball- R' enzymes and-stick models of these fatty O R'' OH Three fatty acids containing acids are shown in Figure 10.6. glycerol 12–20 C’s are formed as products. O triacylglycerol the most common type of lipid Simple triacylglycerols are composed of three identical fatty acid side chains, whereas mixed triacylglycerols have two or three different fatty acids. Table 29.2 lists the most common fatty acids used to form triacylglycerols. What are the characteristics of these fatty acids?

The most common saturated • All fatty acid chains are unbranched, but they may be saturated or unsaturated. fatty acids are palmitic and • Naturally occurring fatty acids have an even number of carbon atoms. stearic acids. The most • Double bonds in naturally occurring fatty acids generally have the Z conﬁ guration. common unsaturated fatty acid • The melting point of a fatty acid depends on the degree of unsaturation. is oleic acid.

Linoleic and linolenic acids are Fats and oils are triacylglycerols; that is, they are triesters of glycerol and these fatty acids. called essential fatty acids • Fats have higher melting points, making them solids at room temperature. because we cannot synthesize them and must acquire them in • Oils have lower melting points, making them liquids at room temperature. our diets. This melting point difference correlates with the number of degrees of unsaturation present in the fatty acid side chains. As the number of double bonds increases, the melting point decreases, as it does for the constituent fatty acids as well. Table 29.2 The Most Common Fatty Acids in Triacylglycerols Number of Number of C atoms C – C bonds Structure Name Mp (°C)

Saturated fatty acids

12 0 CH3(CH2)10COOH lauric acid 44

14 0 CH3(CH2)12COOH myristic acid 58

16 0 CH3(CH2)14COOH palmitic acid 63

18 0 CH3(CH2)16COOH stearic acid 69

20 0 CH3(CH2)18COOH arachidic acid 77

Unsaturated fatty acids

16 1 CH3(CH2)5CH – CH(CH2)7COOH palmitoleic acid 1

18 1 CH3(CH2)7CH – CH(CH2)7COOH oleic acid 4

18 2 CH3(CH2)4(CH – CHCH2)2(CH2)6COOH linoleic acid –5

18 3 CH3CH2(CH – CHCH2)3(CH2)6COOH linolenic acid –11

20 4 CH3(CH2)4(CH – CHCH2)4(CH2)2COOH arachidonic acid –49

smi75625_ch29_1119-1147.indd 1122 11/13/09 9:11:12 AM 29.3 Triacylglycerols 1123

Figure 29.2 A saturated triacylglycerol An unsaturated triacylglycerol Three-dimensional structures of a saturated and unsaturated triacylglycerol

• Three saturated side chains lie parallel to each • One Z double bond in a fatty acid side chain other, making a compact lipid. produces a twist so the lipid is no longer so compact.

Three-dimensional structures of a saturated and unsaturated triacylglycerol are shown in Figure 29.2. With no double bonds, the three side chains of the saturated lipid lie parallel to each other, making it possible for this compound to pack relatively effi ciently in a crystalline lattice, thus leading to a high melting point. In the unsaturated lipid, however, a single Z double bond places a kink in the side chain, making it more diffi cult to pack effi ciently in the solid state, thus leading to a lower melting point. Solid fats have a relatively high percentage of saturated fatty acids and are generally of animal origin. Liquid oils have a higher percentage of unsaturated fatty acids and are generally of vegetable origin. Table 29.3 lists the fatty acid composition of some common fats and oils.

Table 29.3 Fatty Acid Composition of Some Fats and Oils Unlike other vegetable oils, Source % Saturated fatty acids % Oleic acid % Linoleic acid oils from palm and coconut trees are very high in saturated beef 49–62 37–43 2–3 fats. Considerable evidence milk 37 33 3 currently suggests that diets high in saturated fats lead to coconut 86 7 — a greater risk of heart disease. corn 11–16 19–49 34–62 For this reason, the demand olive 11 84 4 for coconut and palm oils has decreased considerably in palm 43 40 8 recent years, and many coconut saffl ower 9 13 78 plantations previously farmed in the South Pacifi c are no longer soybean 15 20 52 in commercial operation. Data from Merck Index, 10th ed. Rahway, NJ: Merck and Co.; and Wilson, et al., 1967, Principles of Nutrition, 2nd ed. New York: Wiley.

Fish oils, such as cod liver and herring oils, are very rich in polyunsaturated triacylglycerols. These triacylglycerols pack so poorly that they have very low melting points; thus, they remain liquids even in the cold water inhabited by these fi sh.

smi75625_ch29_1119-1147.indd 1123 11/13/09 9:11:12 AM 1124 Chapter 29 Lipids

The hydrolysis, hydrogenation, and oxidation of triacylglycerols—reactions originally discussed in Chapters 12, 15, and 22—are summarized here for your reference.

[1] Hydrolysis of triacylglycerols (Section 22.12A)

O R OH H O O 2 O O O H+ or –OH O OH ++C C +C or HO R HO R' HO R'' R' enzymes O R'' OHO three fatty acids glycerol O

Three ester units are cleaved.

Hydrolysis of a triacylglycerol with water in the presence of either acid, base, or an enzyme yields glycerol and three fatty acids. This cleavage reaction follows the same mechanism as any other ester hydrolysis (Section 22.11). This reaction is the fi rst step in triacylglycerol metabolism.

[2] Hydrogenation of unsaturated fatty acids (Section 12.4)

O O

O O O O H2 O O Pd-C

O O

O O Addition of H2 occurs here. saturated side chain

The double bonds of an unsaturated fatty acid can be hydrogenated by using H2 in the presence of a transition metal catalyst. Hydrogenation converts a liquid oil to a solid fat. This process, sometimes called hardening, is used to prepare margarine from vegetable oils.

[3] Oxidation of unsaturated fatty acids (Section 15.11)

O O

O O O O O2 O O OOH O O a hydroperoxide O Oxidation occurs at an allylic carbon. O

further oxidation products

Allylic C – H bonds are weaker than other C – H bonds and are thus susceptible to oxidation with molecular oxygen by a radical process. The hydroperoxide formed by this process is unstable, and it undergoes further oxidation to products that often have a disagreeable odor. This oxidation process turns an oil rancid.

smi75625_ch29_1119-1147.indd 1124 11/13/09 9:11:14 AM 29.3 Triacylglycerols 1125

In the cell, the principal function of triacylglycerols is energy storage. Complete metabolism of a triacylglycerol yields CO2 and H2O, and a great deal of energy. This overall reaction is remi- niscent of the combustion of alkanes in fossil fuels, a process that also yields CO2 and H2O and provides energy to heat homes and power automobiles (Section 4.14B). Fundamentally both pro- cesses convert C – C and C – H bonds to C – O bonds, a highly exothermic reaction.

O Metabolism of a lipid O O O The average body fat content of CO2 + H2O + energy men and women is ~20% and O ~25%, respectively. (For elite tristearin athletes, however, the averages O identical products are more like <10% for men and a saturated triacylglycerol <15% for women.) This stored Combustion of CO + H O + energy fat can fi ll the body’s energy an alkane 2 2 needs for two or three months. 2,2,4-trimethylpentane (isooctane) a component of gasoline

Carbohydrates provide an energy boost, but only for the short term, such as during strenuous exercise. Our long-term energy needs are met by triacylglycerols, because they store ~38 kJ/g, whereas carbohydrates and proteins store only ~16 kJ/g. Because triacylglycerols release heat on combustion, they can in principle be used as fuels for vehicles. In fact, coconut oil was used as a fuel during both World War I and World War II, when gasoline and diesel supplies ran short. Since coconut oil is more viscous than petroleum products and freezes at 24 °C, engines must be modifi ed to use it and it can’t be used in cold climates. Nonetheless, a limited number of trucks and boats can now use vegetable oils, sometimes blended with diesel, as a fuel source. When the price of crude oil is high, the use of these bio fuels becomes economically attractive.

Problem 29.2 How would you expect the melting point of eicosapentaenoic acid [CH3CH2(CH – CHCH2)5(CH2)2COOH] to compare with the melting points of the fatty acids listed in Table 29.2?

Problem 29.3 Draw the products formed when triacylglycerol A is treated with each reagent. Rank compounds A, B, and C in order of increasing melting point.

O a. H O, H+ O 2 → B O b. H2 (excess), Pd-C c. H (1 equiv), Pd-C → C O 2

O A

Problem 29.4 The main fatty acid component of the triacylglycerols in coconut oil is lauric acid, CH3(CH2)10COOH. Explain why coconut oil is a liquid at room temperature even though it contains a large fraction of this saturated fatty acid.

Problem 29.5 Unlike many fats and oils, the cocoa butter used to make chocolate is remarkably uniform in composition. All triacylglycerols contain oleic acid esterifi ed to the 2° OH group of glycerol, and either palmitic acid or stearic acid esterifi ed to the 1° OH groups. Draw the structures of two possible triacylglycerols that compose cocoa butter.

smi75625_ch29_1119-1147.indd 1125 11/13/09 9:11:14 AM 1126 Chapter 29 Lipids

29.4 Phospholipids Phospholipids are hydrolyzable lipids that contain a phosphorus atom. There are two common types of phospholipids: phosphoacylglycerols and sphingomyelins. Both classes are found almost exclusively in the cell membranes of plants and animals, as discussed in Section 3.7. Phospholipids are organic derivatives of phosphoric acid, formed by replacing two of the H atoms The phosphorus atom in a by R groups. This type of functional group is called a phosphodiester, or a phosphoric acid phosphodiester shares 10 diester. These compounds are phosphorus analogues of carboxylic esters. In cells, the remaining electrons. Recall that third-row elements (such as P and S) can OH group on phosphorus loses its proton, giving the phosphodiester a net negative charge. be surrounded by more than O O O eight electrons. OH P HO OR P R'O OR PR'O OH OH O– phosphoric acid phosphodiester This form exists in cells. H3PO4

29.4A Phosphoacylglycerols Phosphoacylglycerols (or phosphoglycerides) are the second most abundant type of lipid. They form the principal lipid component of most cell membranes. Their structure resembles the triacylglycerols of Section 29.3 with one important difference. In phosphoacylglycerols, only two of the hydroxy groups of glycerol are esterifi ed with fatty acids. The third OH group is part of a phosphodiester, which is also bonded to another low molecular weight alcohol. O

OR fatty acids O glycerol O backbone O R' OOP R'' R'' is typically one of two different groups. phosphodiester O–

phosphoacylglycerol There are two prominent types of phosphoacylglycerols. They differ in the identity of the R'' group in the phosphodiester. + • When R'' = CH2CH2NH3 , the compound is called a phosphatidylethanolamine or cephalin. + • When R'' = CH2CH2N(CH3)3 , the compound is called a phosphatidylcholine, or lecithin.

O O

OR OR O O stereogenic stereogenic O O center center O R' O R' + + OOP CH2CH2NH3 OOP CH2CH2N(CH3)3 O– O– phosphatidylethanolamine phosphatidylcholine or or cephalin lecithin The middle carbon of the glycerol backbone of all of these compounds is a stereogenic center, usually with the R confi guration. The phosphorus side chain of a phosphoacylglycerol makes it different from a triacylglycerol. The two fatty acid side chains form two nonpolar “tails” that lie parallel to each other, while the phosphodiester end of the molecule is a charged or polar “head.” A three-dimensional structure of a phosphoacylglycerol is shown in Figure 29.3. As discussed in Section 3.7, when these phospholipids are mixed with water, they assemble in an arrangement called a lipid bilayer. The ionic heads of the phospholipid are oriented on the outside

smi75625_ch29_1119-1147.indd 1126 11/13/09 9:11:16 AM 29.4 Phospholipids 1127

Figure 29.3 O C18 fatty acid chains Three-dimensional structure of a phosphoacylglycerol O O O O + (CH3)3NCH2CH2 O P O a lecithin molecule O– charged atoms

two nonpolar tails

3-D structure

polar head Often drawn as:

polar head nonpolar tails

• A phosphoacylglycerol has two distinct regions: two nonpolar tails due to the long-chain fatty acids, and a very polar head from the charged phosphodiester.

and the nonpolar tails on the inside. The identity of the fatty acids in the phospholipid determines the rigidity of this bilayer. When the fatty acids are saturated, they pack well in the interior of the lipid bilayer, and the membrane is quite rigid. When there are many unsaturated fatty acids, the nonpolar tails cannot pack as well and the bilayer is more fl uid. Thus, important characteristics of this lipid bilayer are determined by the three-dimensional structure of the molecules that comprise it. Cell membranes are composed of these lipid bilayers (see Figure 3.7). Proteins and cholesterol are embedded in the membranes as well, but the phospholipid bilayer forms the main fabric of the insoluble barrier that protects the cell.

Problem 29.6 Draw the structure of a lecithin containing oleic acid and palmitic acid as the fatty acid side chains.

Problem 29.7 Phosphoacylglycerols should remind you of soaps (Section 3.6). In what ways are these compounds similar?

29.4B Sphingomyelins Sphingomyelins, the second major class of phospholipids, are derivatives of the amino alcohol sphingosine, in much the same way that triacylglycerols and phosphoacylglycerols are derivatives of glycerol. Other notable features of a sphingomyelin include: • A phosphodiester at C1. • An amide formed with a fatty acid at C2.

Examples of sphingomyelins E configuration (CH ) CH (CH ) CH (CH ) CH 2 12 3 2 12 3 2 12 3 HO O HO O HO NH and NH C2 NH 2 R R O O C1 ++ OH OCHPO 2CH2NH3 OCHPO 2CH2N(CH3)3 sphingosine O– O– The phosphodiester group is located at the terminal carbon.

smi75625_ch29_1119-1147.indd 1127 11/13/09 9:11:16 AM 1128 Chapter 29 Lipids

Figure 29.4 O O (CH ) CH A comparison of 2 12 3 OR a triacylglycerol, a O R HO O O phosphoacylglycerol, and a O NH O sphingomyelin O R O R' O R' + + OOP CH CH NR'' OCHPO CH NR'' O R'' 2 2 3 2 2 3 O– O–

O R'' = H, CH3 R'' = H, CH3 • A triacylglycerol has three • A phosphoacylglycerol has two • A sphingomyelin has two nonpolar side chains. nonpolar side chain tails and nonpolar side chain tails and • The three OH groups of one ionic head. one ionic head. glycerol are esterifi ed with • Two OH groups of glycerol are • A sphingomyelin is formed three fatty acids. esterifi ed with fatty acids. from sphingosine, not glycerol. • A phosphodiester is located on One of the nonpolar tails is an a terminal carbon. amide. • A phosphodiester is located on a terminal carbon.

Like phosphoacylglycerols, sphingomyelins are also a component of the lipid bilayer of cell membranes. The coating that surrounds and insulates nerve cells, the myelin sheath, is particularly rich in sphingomyelins, and is vital for proper nerve function. Deterioration of the myelin sheath as seen in multiple sclerosis leads to disabling neurological problems. Figure 29.4 compares the structural features of the most common hydrolyzable lipids: a triacylglycerol, a phosphoacylglycerol, and a sphingomyelin.

Problem 29.8 Why are phospholipids, but not triacylglycerols, found in cell membranes?

29.5 Fat-Soluble Vitamins Vitamins are organic compounds required in small quantities for normal metabolism (Sec- tion 3.5). Because our cells cannot synthesize these compounds, they must be obtained in the diet. Vitamins can be categorized as fat soluble or water soluble. The fat-soluble vitamins are lipids. The four fat-soluble vitamins—A, D, E, and K—are found in fruits and vegetables, fi sh, liver, and dairy products. Although fat-soluble vitamins must be obtained from the diet, they do not have to be ingested every day. Excess vitamins are stored in fat cells, and then used when needed. Figure 29.5 shows the structure of these vitamins and summarizes their functions. Electrostatic potential plots of vitamins A and E (Figure 29.6) show that the electron density is virtually uniform in these compounds. The large regions of nonpolar C – C and C – H bonds tend to obscure small dipoles that occur in the one or two polar bonds, making these vitamins nonpolar and hydrophobic.

Problem 29.9 Explain why regularly ingesting a large excess of a fat-soluble vitamin can lead to severe health problems, whereas ingesting a large excess of a water-soluble vitamin often causes no major health problems.

smi75625_ch29_1119-1147.indd 1128 11/13/09 9:11:16 AM 29.6 Eicosanoids 1129

Figure 29.5 The fat-soluble vitamins • Vitamin A (retinol, Section 3.5) is obtained from fi sh liver oils and dairy products, and is synthesized from β-carotene, the orange pigment in carrots. • In the body, vitamin A is converted to 11-cis-retinal, the light- OH sensitive compound responsible for vision in all vertebrates (Section 21.11B). It is also needed for healthy mucous membranes. vitamin A • A defi ciency of vitamin A causes night blindness, as well as dry eyes and skin.

• Vitamin D3 is the most abundant of the D vitamins. Strictly speaking, it is not a vitamin because it can be synthesized in the body from cholesterol. Nevertheless, it is classifi ed as such, and many foods

(particularly milk) are fortifi ed with vitamin 3D so that we get enough H of this vital nutrient. vitamin D 3 • Vitamin D helps regulate both calcium and phosphorus metabolism. • A defi ciency of vitamin D causes rickets, a bone disease CH 2 characterized by knock-knees, spinal curvature, and other deformities. HO

HO • The term vitamin E refers to a group of structurally similar compounds, the most potent being α-tocopherol (Section 15.12). O • Vitamin E is an antioxidant, so it protects unsaturated side chains in H H fatty acids from oxidation. vitamin E • A defi ciency of vitamin E causes numerous neurologic problems. (α-tocopherol)

O • Vitamin K (phylloquinone) regulates the synthesis of prothrombin and other proteins needed for blood to clot. • A defi ciency of vitamin K leads to excessive and sometimes fatal vitamin K bleeding because of inadequate blood clotting. O

29.6 Eicosanoids The eicosanoids are a group of biologically active compounds containing 20 carbon eicosanoid The word is atoms derived from arachidonic acid. The prostaglandins (Section 19.6) and the leuko- derived from the Greek word trienes (Section 9.16) are two types of eicosanoids. Two others are the thromboxanes and eikosi, meaning 20. prostacyclins.

Figure 29.6 Electrostatic potential plots of vitamins A and E

vitamin A vitamin E • The electron density is distributed fairly evenly among the carbon atoms of these vitamins due to their many nonpolar C – C and C – H bonds.

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HO OH COOH COOH

C5H11 S CH2 HO OH CHCONHCH2COOH

NHCOCH2CH2CHCOOH

PGF2α LTC4 NH2 a prostaglandin a leukotriene

HOOC COOH O O O OH

HO OH

TXA2 PGI2 a thromboxane a prostacyclin All eicosanoids are very potent compounds present in low concentration in cells. They are local mediators, meaning that they perform their function in the environment in which they are synthesized. This distinguishes them from hormones, which are fi rst synthesized and then transported in the bloodstream to their site of action. Eicosanoids are not stored in cells; rather, they are synthesized from arachidonic acid in response to an external stimulus. The synthesis of prostaglandins, thromboxanes, and prostacyclins begins with the oxidation of arachidonic acid with O2 by a cyclooxygenase enzyme, which forms an unstable cyclic intermediate, PGG2. PGG2 is then converted via different pathways to these three classes of compounds. Leukotrienes are formed by a different pathway, using an enzyme called a lipoxygenase. These four paths for arachidonic acid are summarized in Figure 29.7. Each eicosanoid is associated with specifi c types of biological activity (Table 29.4). In some cases, Other details of the the effects oppose one another. For example, thromboxanes are vasoconstrictors that trigger blood biosynthesis of leukotrienes platelet aggregation, whereas prostacyclins are vasodilators that inhibit platelet aggregation. The and prostaglandins were given in Sections 9.16 and 19.6, levels of these two eicosanoids must be in the right balance for cells to function properly. respectively. Because of their wide range of biological functions, prostaglandins and their analogues have found several clinical uses. For example, dinoprostone, the generic name for PGE2, is administered to relax the smooth muscles of the uterus when labor is induced, and to terminate pregnan- cies in the early stages. O

COOH

HO OH

PGE2 (dinoprostone)

Table 29.4 Biological Activity of the Eicosanoids Eicosanoid Effect Eicosanoid Effect

Prostaglandins • Lower blood pressure Thromboxanes • Constrict blood vessels • Inhibit blood platelet aggregation • Trigger blood platelet aggregation • Control infl ammation Prostacyclins • Dilate blood vessels • Lower gastric secretions • Inhibit blood platelet aggregation • Stimulate uterine contractions • Relax smooth muscles of the uterus Leukotrienes • Constrict smooth muscle, especially in the lungs

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Figure 29.7 OH The conversion of arachidonic COOH acid to prostaglandins, thromboxanes, prostacyclins, C5H11 S CH2 and leukotrienes CHCONHCH2COOH

NHCOCH2CH2CHCOOH

LTC4 NH2 a leukotriene 5-lipoxygenase

COOH Two different pathways begin with arachidonic acid. C5H11 arachidonic acid

cyclooxygenase [COX-1 and COX-2 enzymes]

O COOH

OOH

PGG2

HO HOOC COOH COOH O O O HO OH OH PGF TXA 2α 2 HO OH and other a thromboxane prostaglandins PGI2 a prostacyclin

Because prostaglandins themselves are unstable in the body, often having half-lives of only minutes, more stable analogues have been developed that retain their important biological activity longer. For example, misoprostol, an analogue of PGE1, is sold as a mixture of stereoisomers. Misoprostol is administered to prevent gastric ulcers in patients who are at high risk of developing them.

O O O COOH COOCH3 COOCH3 OH + HO

HO HO HO OH

PGE1 misoprostol (sold as a mixture of stereoisomers)

Studying the biosynthesis of eicosanoids has led to other discoveries as well. For example, aspirin and other nonsteroidal anti-infl ammatory drugs (NSAIDs) inactivate the cyclooxygenase enzyme needed for prostaglandin synthesis. In this way, NSAIDs block the synthesis of the prostaglandins that cause infl ammation (Section 19.6). More recently, it has been discovered that two different cyclooxygenase enzymes, called COX-1 and COX-2, are responsible for prostaglandin synthesis. COX-1 is involved with the usual production of prostaglandins, but COX-2 is responsible for the synthesis of additional prostaglandins in infl ammatory diseases like arthritis. NSAIDs like aspirin and ibuprofen inactivate both the

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COX-1 and COX-2 enzymes. This activity also results in an increase in gastric secretions, making an individual more susceptible to ulcer formation. A group of anti-infl ammatory drugs that block only the COX-2 enzyme was developed in the 1990s. These drugs—rofecoxib, valdecoxib, and celecoxib—do not cause an increase in gastric secretions, and thus were touted as especially effective NSAIDs for patients with arthritis, who need daily doses of these medications. Unfortunately, both rofecoxib and valdecoxib have now been removed from the market, since their use has been associated with an increased risk of heart attack and stroke.

H2NSO2 H2NSO2 O N N O O CF3 N

CH3SO2

Generic name: rofecoxib Generic name: valdecoxib Generic name: celecoxib A COX-3 enzyme was also Trade name: Vioxx Trade name: Bextra Trade name: Celebrex reported in 2002. Its activity is The discovery of drugs that block prostaglandin synthesis illustrates how basic research in organic inhibited by acetaminophen, chemistry can lead to important practical applications. Elucidating the structure and biosynthesis of the active ingredient in the pain reliever Tylenol. prostaglandins began as a project in basic research. It has now resulted in a number of applications that benefi t many individuals with various illnesses.

Problem 29.10 How are the two isomers of misoprostol related?

29.7 Terpenes Terpenes are lipids composed of repeating fi ve-carbon units called isoprene units. An isoprene unit has fi ve carbons: four in a row, with a one-carbon branch on a middle carbon.

An isoprene unit

1 C branch C C C = CC 4 C’s in a row

Terpenes have a wide variety of structures. They can be acyclic or have one or more rings. They may have only carbon and hydrogen atoms, or they may have heteroatoms as well. The most common heteroatom in terpenes is oxygen. Many essential oils, a group of compounds isolated from plant sources by distillation, are terpenes. Examples include myrcene and menthol.

Both compounds have 10 C’s. OH

myrcene menthol (isolated from bayberry oil) (isolated from peppermint oil)

29.7A Locating Isoprene Units in Terpenes How do we identify the isoprene units in these molecules? Start at one end of the molecule near a branch point. Then look for a four-carbon chain with a one-carbon branch. This forms one isoprene unit. Continue along the chain or around the ring until all the carbons are part of an isoprene unit. Keep in mind the following:

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• An isoprene unit may be composed of C – C r bonds only, or there may be o bonds at any position. • Isoprene units are always connected by one or more carbon–carbon bonds. • Each carbon atom is part of one isoprene unit only. • Every isoprene unit has ﬁ ve carbon atoms. Heteroatoms may be present but their presence is ignored in locating isoprene units.

Myrcene and menthol, for example, each have 10 carbon atoms, so they are composed of two isoprene units.

bayberry plant 2 C–C bonds joining the 2 isoprene units (source of myrcene) C–C bond joining 2 units OH Ignore the OH group.

myrcene menthol

Terpenes are classifi ed by the number of isoprene units they contain. A monoterpene contains 10 carbons and has two isoprene units, a sesquiterpene contains 15 carbons and has three isoprene units, and so forth. The different terpene classes are summarized in Table 29.5. Several examples, with the isoprene units labeled in red, are given in Figure 29.8.

peppermint plant Table 29.5 Classes of Terpenes (source of menthol) Name Number of C atoms Number of isoprene units

Monoterpene 10 2 Sesquiterpene 15 3 Diterpene 20 4 Sesterterpene 25 5 Triterpene 30 6 Tetraterpene 40 8

Figure 29.8 O Examples of some H common terpenes citral (lemon grass) OH

OH farnesol zingiberene cedrol (lily of the valley) (ginger) (cedar)

squalene α-phellandrene (shark oil) (eucalyptus) • Isoprene units are labeled in red, with C – C bonds (in black) joining two units. • The source of each terpene is given in parentheses.

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Problem 29.11 Locate the isoprene units in each compound. OH a. c. OH grandisol geraniol (sex pheromone of the (roses and geraniums) male boll weevil)

OH b. d. camphor vitamin A O

Problem 29.12 Manoalide, a sesterterpene isolated from the Pacifi c marine sponge Luffariella veriabilis by Scheuer and co-workers at the University of Hawai‘i at Ma-noa, has anti-infl ammatory, analgesic, and antifungal properties. Find the isoprene units in manoalide.

HO O O manoalide O HO

29.7B The Biosynthesis of Terpenes Terpene biosynthesis is an excellent example of how syntheses in nature occur with high effi - ciency. There are two ways this is accomplished. [1] The same reaction is used over and over again to prepare progressively more complex compounds. [2] Key intermediates along the way serve as the starting materials for a wide variety of other compounds. All terpenes are synthesized from dimethylallyl diphosphate and isopentenyl diphosphate. Both of these fi ve-carbon compounds are synthesized, in turn, in a multistep process from three molecules of acetyl CoA (Section 22.17).

The starting materials for terpene biosynthesis O O O O O C 3 CH3 SCoA OPO POH and OPO POH O– O– O– O– acetyl CoA dimethylallyl diphosphate isopentenyl diphosphate Diphosphate, abbreviated as OPP, is often used as a leaving group in biological systems. It is a good leaving group because it is a weak, resonance-stabilized base.

O O O O R OPO POH R OPP RNu +=–OPP –OPO POH O– O– O– O– Nu– good leaving group diphosphate a good leaving group

R OPP

The overall strategy of terpene biosynthesis from dimethylallyl diphosphate and isopentenyl diphosphate is summarized in Figure 29.9. There are three basic parts:

[1] The two C5 diphosphates are converted to geranyl diphosphate, a C10 monoterpene. Gera- nyl diphosphate is the starting material for all other monoterpenes.

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Figure 29.9 C5 An outline of terpene OPP + OPP biosynthesis [1]

C10 OPP Monoterpenes 10 C’s geranyl diphosphate

[2]

Sesquiterpenes 15 C’s

C15 OPP farnesyl diphosphate Diterpenes 20 C’s

[3]

Triterpenes 30 C’s

C30 squalene All steroids

[2] Geranyl diphosphate is converted to farnesyl diphosphate, a C15 sesquiterpene, by addition of a fi ve-carbon unit. Farnesyl diphosphate is the starting material for all sesquiterpenes and diterpenes.

[3] Two molecules of farnesyl diphosphate are converted to squalene, a C30 triterpene. Squa- lene is the starting material for all triterpenes and steroids. The biological formation of geranyl diphosphate from the two fi ve-carbon diphosphates involves three steps: loss of the leaving group, nucleophilic attack, and loss of a proton, as shown in Mechanism 29.1.

Mechanism 29.1 Biological Formation of Geranyl Diphosphate

Steps [1]–[2] Loss of the leaving group and nucleophilic attack to form a new C – C bond

new C–C bond

+ + OPP [1] + OPP [2] OPP 1° allylic 1° diphosphate 3° carbocation diphosphate

+ + –OPP • Loss of the diphosphate leaving group forms a resonance-stabilized carbocation in Step [1], which reacts with the nucleophilic double bond of the 1° diphosphate to form a new C – C bond and a 3° carbocation in Step [2]. – • Steps [1] and [2] are analogous to an SN1 mechanism because the leaving group ( OPP) is lost before the nucleophile (a C – C) attacks.

Step [3] Loss of a proton

new π bond

+ OPP OPP +–HB+ H geranyl diphosphate B • Loss of a proton forms geranyl diphosphate in Step [3].

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The biological conversion of geranyl diphosphate to farnesyl diphosphate involves the same three steps, as shown in Mechanism 29.2.

Mechanism 29.2 Biological Formation of Farnesyl Diphosphate

Steps [1]–[2] Loss of the leaving group and nucleophilic attack to form a new C – C bond

new C–C bond

+ + OPP [1] + OPP [2] OPP 1° allylic diphosphate isopentenyl 3° carbocation diphosphate

+ + –OPP • Loss of the diphosphate leaving group forms a resonance-stabilized carbocation in Step [1], which reacts with isopentenyl diphosphate to form a new C – C bond and a 3° carbocation in Step [2].

Step [3] Loss of a proton

new π bond

+ OPP OPP farnesyl diphosphate H + B + HB • Loss of a proton forms a new π bond and farnesyl diphosphate in Step [3].

Two molecules of farnesyl diphosphate react to form squalene, from which all other triterpenes and steroids are synthesized.

These C’s are joined.

OPP + OPP farnesyl diphosphate farnesyl diphosphate

new C–C bond

squalene

Aqueous hydrolysis of geranyl and farnesyl diphosphates forms the monoterpene geraniol and the sesquiterpene farnesol, respectively.

H2O OPP OH geraniol

H2O OPP OH farnesol

All other terpenes are biologically derived from geranyl and farnesyl diphosphates by a series of reactions. Cyclic compounds are formed by intramolecular reactions involving nucleophilic attack of π bonds on intermediate carbocations. To form some cyclic compounds, the E

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double bond in geranyl diphosphate must fi rst isomerize to an isomeric diphosphate with a Z double bond, neryl diphosphate, by the process illustrated in Mechanism 29.3. Isomerization forms a substrate with a leaving group and nucleophilic double bond in close proximity, so that an intramolecular reaction can occur.

Mechanism 29.3 Isomerization of Geranyl Diphosphate to Neryl Diphosphate

Steps [1]–[2] Isomerization of geranyl diphosphate to linalyl diphosphate

–OPP E configuration OPP + OPP + a single bond with [1] [2] free rotation

geranyl diphosphate resonance-stabilized carbocation linalyl diphosphate

• Loss of the diphosphate leaving group forms a resonance-stabilized carbocation in Step [1], which reacts with the diphosphate anion to form linalyl diphosphate, a constitutional isomer. • The original E double bond is now a single bond that can rotate freely.

Steps [3]–[4] Isomerization of linalyl diphosphate to neryl diphosphate OPP Z configuration

+ The leaving group and [3] [4] OPP nucleophile are now –OPP close to each other.

linalyl diphosphate resonance-stabilized carbocation neryl diphosphate

• Loss of the diphosphate leaving group forms a resonance-stabilized carbocation in Step [3]. The only difference in the products of Steps [1] and [3] is the geometry around the internal carbon–carbon double bond. • Nucleophilic attack with diphosphate forms neryl diphosphate, a stereoisomer of geranyl diphosphate. The diphosphate leaving group of neryl diphosphate is now in closer proximity to the double bond at the other end of the chain, so that intramolecular cyclization can occur.

In the synthesis of α-terpineol or limonene, for example, geranyl diphosphate isomerizes to form neryl diphosphate (Step [1] in the following reaction sequence). Neryl diphosphate then cyclizes to a 3° carbocation by intramolecular attack (Steps [2]–[3]). Nucleophilic attack of water on this carbocation yields α-terpineol (Step [4]) or loss of a proton yields limonene (Step [5]). Both products are cyclic monoterpenes.

nucleophilic attack [4]

H2O isomerization cyclization OPP OH [1] [2] [3] + α-terpineol OPP

+ geranyl diphosphate neryl diphosphate + 3° carbocation [5] –OPP loss of H+

limonene

smi75625_ch29_1119-1147.indd 1137 11/13/09 9:11:20 AM 1138 Chapter 29 Lipids

Problem 29.13 Write a stepwise mechanism for the following reaction.

OPP OPP farnesyl diphosphate +

OPP isopentenyl diphosphate

Problem 29.14 Draw a stepwise mechanism for the conversion of geranyl diphosphate to α-terpinene.

OPP α-terpinene

29.8 Steroids The steroids are a group of tetracyclic lipids, many of which are biologically active.

29.8A Steroid Structure Steroids are composed of three six-membered rings and one fi ve-membered ring, joined together as drawn. Many steroids also contain two methyl groups, called angular methyl groups, at the two ring junctions indicated. The steroid rings are lettered A, B, C, and D, and the 17 ring carbons are numbered as shown. The two angular methyl groups are numbered C18 and C19.

General steroid skeleton Numbering the steroid skeleton

CH3 12 CH3 19 17 11 13 16 CH3 C D 1 CH3 2 9 14 10 8 15 AB 3 5 7 4 6

Whenever two rings are fused together, the substituents at the ring fusion can be arranged cis or trans. To see more easily why this is true, consider decalin, which consists of two six-membered rings fused together. trans-Decalin has the two hydrogen atoms at the ring fusion on opposite sides, whereas cis-decalin has them on the same side.

H H

H H decalin trans-decalin cis-decalin Two six-membered rings 2 H’s on opposite sides 2 H’s on the same side share a C–C bond.

Three-dimensional structures of these molecules show how different these two possible arrangements actually are. The two rings of trans-decalin lie roughly in the same plane, whereas the two rings of cis-decalin are almost perpendicular to each other. The trans arrangement is lower in energy and therefore more stable.

smi75625_ch29_1119-1147.indd 1138 11/13/09 9:11:20 AM 29.8 Steroids 1139

Figure 29.10

The three-dimensional CH3 structure of the steroid nucleus CH3 H

H H Atoms at the ring fusions are shown in red. H All rings are trans fused.

• The four steroid rings occupy approximately the same plane. • The 2 CH3 groups project above the plane of the molecule. • All C’s are drawn in. • H’s and CH3’s at the ring fusions are drawn in. • All other H’s are omitted.

2 H’s on opposite sides H trans-decalin =

H The 2 H’s at the ring fusion 2 H’s on the same side are shown in red. H

cis-decalin H =

In steroids, each ring fusion could theoretically have the cis or trans confi guration, but, by far the most common arrangement is all trans. Because of this, all four rings of the steroid skeleton lie in the same plane, and the ring system is fairly rigid. The two angular methyl groups are oriented perpendicular to the plane of the molecule. These methyl groups make one side of the steroid skeleton signifi cantly more hindered than the other, as shown in Figure 29.10. Although steroids have the same fused-ring arrangement of carbon atoms, they differ in the identity and location of the substituents attached to that skeleton.

Problem 29.15 (a) Draw a skeletal structure of the anabolic steroid 4-androstene-3,17-dione, also called “andro,” from the following description. Andro contains the tetracyclic steroid skeleton with carbonyl groups at C3 and C17, a double bond between C4 and C5, and methyl groups bonded to C10 and C13. (b) Add wedges and dashes for all stereogenic centers with the following information: the confi guration at C10 is R, the confi guration at C13 is S, and all substituents at ring fusions are trans to each other.

29.8B Cholesterol Cholesterol, the chapter-opening molecule, has the tetracyclic carbon skeleton characteristic of steroids. It also has eight stereogenic carbons (seven on rings and one on a side chain), so there are 28 = 256 possible stereoisomers. In nature, however, only the following stereoisomer exists:

Cholesterol has also been H discussed in Sections 3.4C and * 4.15. The role of cholesterol H * in plaque formation and H * atherosclerosis was discussed * * [* denotes a stereogenic center.] in Section 22.17. * HH* * HO cholesterol

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Cholesterol is essential to life because it forms an important component of cell membranes and Konrad Bloch and Feodor is the starting material for the synthesis of all other steroids. Humans do not have to ingest cho- Lynen shared the 1964 Nobel lesterol, because it is synthesized in the liver and then transported to other tissues through the Prize in Physiology or Medicine – for unraveling the complex bloodstream. Because cholesterol has only one polar OH group and many nonpolar C C and transformation of squalene to C – H bonds, it is insoluble in water (and, thus, in the aqueous medium of the blood). cholesterol. Cholesterol is synthesized in the body from squalene, a C30 triterpene that is itself prepared from smaller terpenes, as discussed in Section 29.7B. Because the biosynthesis of all terpenes begins with acetyl CoA, every one of the 27 carbon atoms of cholesterol comes from the same two-carbon precursor. The major steps in the conversion of squalene to cholesterol are given in Figure 29.11. The conversion of squalene to cholesterol consists of fi ve different parts: [1] Epoxidation of squalene with an enzyme, squalene epoxidase, gives squalene oxide, which contains a single epoxide on one of the six double bonds. [2] Cyclization of squalene oxide yields a carbocation, called the protosterol cation. This reaction results in the formation of four new C – C bonds and the tetracyclic ring system. [3] The protosterol carbocation rearranges by a series of 1,2-shifts of either a hydrogen or methyl group to form another 3° carbocation. [4] Loss of a proton gives an alkene called lanosterol. Although lanosterol has seven stereogenic centers, a single stereoisomer is formed. [5] Lanosterol is then converted to cholesterol by a multistep process that results in removal of three methyl groups. Several drugs are now available to reduce the level of cholesterol in the bloodstream. These compounds act by blocking the biosynthesis of cholesterol at its very early stages. Two examples include atorvastatin (Lipitor) and simvastatin (Zocor), whose structures appear in Figure 29.12.

Problem 29.16 Draw the enantiomer and any two diastereomers of cholesterol. Does the OH group of cholesterol occupy an axial or equatorial position?

Figure 29.11 The biosynthesis of cholesterol

[1] O2 squalene epoxidase squalene squalene oxide O + H [2] cyclization + H CH3 H CH3 CH3 [3] CH3 + 1,2-shifts CH3 H CH3 HO protosterol cation HO

[4] loss of H+ H H CH3 H CH 3 H [5] CH3 several steps CH3 H

CH3 H H HO H H lanosterol HO H cholesterol

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HO Figure 29.12 HO O Two cholesterol-lowering O drugs HO F O HO O N H (CH3)2CH O H N C H O

Generic name: atorvastatin Generic name: simvastatin Trade name: Lipitor Trade name: Zocor

Problem 29.17 Treatment of cholesterol with mCPBA results in formation of a single epoxide A, with the stereochemistry drawn. Why isn’t the isomeric epoxide B formed to any extent? H H

H H H H

H H H H HO HO H OOA H B

29.8C Other Steroids Many other important steroids are hormones secreted by the endocrine glands. Two classes are the sex hormones and the adrenal cortical steroids. There are two types of female sex hormones, estrogens and progestins. The male sex hormones are called androgens. The most important members of each hormone type are given in Table 29.6.

Table 29.6 The Female and Male Sex Hormones Structure Properties OH O H • Estradiol and estrone are estrogens synthesized in the H H ovaries. They control the development of secondary sex characteristics in females and regulate the menstrual cycle. H H H H HO HO estradiol estrone O H H • Progesterone is often called the “pregnancy hormone.” It is responsible for the preparation of the uterus for implantation H H of a fertilized egg. O progesterone OH O H H H • Testosterone and androsterone are androgens H H H H synthesized in the testes. They control the development of O HO secondary sex characteristics in males. H testosterone androsterone

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Synthetic analogues of these steroids have found important uses, such as in oral contraceptives, fi rst mentioned in Section 11.4.

OH OH CCH CCH H H H Synthetic oral contraceptives H H H H HO O ethynylestradiol norethindrone

Synthetic androgen analogues, called anabolic steroids, promote muscle growth. They were fi rst developed to help individuals whose muscles had atrophied from lack of use following surgery. They have since come to be used by athletes and body builders, although their use is not permitted in competitive sports. Many physical and psychological problems result from their prolonged use. Anabolic steroids, such as stanozolol, nandrolone, and tetrahydrogestrinone have the same effect on the body as testosterone, but they are more stable, so they are not metabolized as quickly. Tetrahydrogestrinone (also called THG or The Clear), the performance-enhancing drug used by track star Marion Jones during the 2000 Sydney Olympics, was considered a “designer steroid” because it was initially undetected in urine tests for doping. After its chemical structure and properties were determined, it was added to the list of banned anabolic steroids in 2004.

OH OH OH Anabolic steroids Some body builders use anabolic steroids to increase H H H H muscle mass. Long-term or excessive use can cause many N H H H H H health problems, including high N H O O blood pressure, liver damage, H and cardiovascular disease. stanozolol nandrolone tetrahydrogestrinone A second group of steroid hormones includes the adrenal cortical steroids. Three examples of these hormones are cortisone, cortisol, and aldosterone. All of these compounds are synthesized in the outer layer of the adrenal gland. Cortisone and cortisol serve as anti-infl ammatory agents and they also regulate carbohydrate metabolism. Aldosterone regulates blood pressure and volume by controlling the concentration of Na+ and K+ in body fl uids.

O O OHO Three adrenal CH OH CH OH CH OH cortical steroids 2 2 O 2 O OH HO OH H H H

H H H H H H O O O cortisone cortisol aldosterone

smi75625_ch29_1119-1147.indd 1142 11/13/09 9:11:21 AM Key Concepts 1143

KEY CONCEPTS

Lipids Hydrolyzable Lipids [1] Waxes (29.2)—Esters formed from a long-chain alcohol and a long-chain carboxylic acid.

O C R, R' = long chains of C’s R OR'

[2] Triacylglycerols (29.3)—Triesters of glycerol with three fatty acids. O

O R O O R, R', R'' = alkyl groups with 11–19 C’s R' O R''

[3] Phospholipids (29.4)

a. Phosphatidylethanolamine (cephalin) b. Phosphatidylcholine (lecithin) c. Sphingomyelin O O (CH2)12CH3 O R O R H HO O O O NH O O R R' R' O O O + + + O P O CH2CH2NR'3 O P OCH2CH2NH3 O P OCH2CH2N(CH3)3 – O– O– O R, R' = long carbon chain R, R' = long carbon chain R = long carbon chain R' = H or CH3

Nonhydrolyzable Lipids [1] Fat-soluble vitamins (29.5)—Vitamins A, D, E, and K.

[2] Eicosanoids (29.6)—Compounds containing 20 C’s derived from arachidonic acid. There are four types: prostaglandins, thromboxanes, prostacyclins, and leukotrienes.

[3] Terpenes (29.7)—Lipids composed of repeating 5 C units called isoprene units.

Isoprene unit Types of terpenes

C [1] monoterpene 10 C’s [4] sesterterpene 25 C’s C C [2] sesquiterpene 15 C’s [5] triterpene 30 C’s CC [3] diterpene 20 C’s [6] tetraterpene 40 C’s

[4] Steroids (29.8)—Tetracyclic lipids composed of three six-membered and one fi ve-membered ring.

12 CH3 19 17 11 13 16 1 CH3 CD 2 9 14 10 8 15 AB 3 5 7 46

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PROBLEMS Waxes, Triacylglycerols, and Phospholipids 29.18 One component of lanolin, the wax that coats sheep’s wool, is derived from cholesterol and stearic acid. Draw its structure, including the correct stereochemistry at all stereogenic centers. 29.19 Draw all possible constitutional isomers of a triacylglycerol formed from one mole each of palmitic, oleic, and linoleic acids. Locate the tetrahedral stereogenic centers in each constitutional isomer. 29.20 What is the structure of an optically inactive triacylglycerol that yields two moles of oleic acid and one mole of palmitic acid when hydrolyzed in aqueous acid?

29.21 Triacylglycerol L yields compound M when treated with excess H2, Pd-C. Ozonolysis of L ([1] O3; [2] (CH3)2S) affords compounds N – P. What is the structure of L? O O

O O O O

O O CHO CH3(CH2)4CHO = O

O O CH2(CHO)2 = P

O MNO

29.22 Draw the structure of the following phospholipids: a. A cephalin formed from two molecules of stearic acid. b. A sphingomyelin formed from palmitic acid.

Prostaglandins

29.23 A diffi cult problem in the synthesis of PGF2α is the introduction of the OH group at C15 in the desired confi guration. a. Label this stereogenic center as R or S.

b. A well known synthesis of PGF2α involves reaction of A with Zn(BH4)2, a metal hydride reagent similar in reactivity to NaBH4, to form two isomeric products, B and C. Draw their structures and indicate their stereochemical relationship. c. Suggest a reagent to convert A to the single stereoisomer X.

O O HO O O COOH O O

HO C15 O O OH A O X OH PGF2α [1] Zn(BH4)2 [2] H2O B and C

smi75625_ch29_1119-1147.indd 1144 11/13/09 9:11:21 AM Problems 1145

Terpenes 29.24 Locate the isoprene units in each compound.

a. f. i.

neral CHO COOH humulene dextropimaric acid

O OH

b. g. j.

carvone patchouli alcohol HO β-amyrin O O

c. h. O

α-pinene periplanone B

d. lycopene

e. β-carotene

29.25 Classify each terpene in Problem 29.24 (e.g., as a monoterpene, sesquiterpene, etc.). 29.26 An isoprene unit can be thought of as having a head and a tail. The “head” of the isoprene unit is located at the end of the chain nearest the branch point, and the “tail” is located at the end of the carbon chain farthest from the branch point. Most isoprene units are connected together in a “head-to-tail” fashion, as illustrated. For both lycopene (Problem 29.24), and squalene (Figure 29.9), decide which isoprene units are connected in a head-to-tail fashion and which are not.

head tail headtail These two isoprene units are connected in a head-to-tail fashion.

29.27 Draw a stepwise mechanism for the conversion of neryl diphosphate to α-pinene. α-Pinene is a component of pine oil and rosemary oil.

OPP =

α-pinene neryl diphosphate

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29.28 Flexibilene is a terpene isolated from Sinularia ﬂ exibilis, a soft coral found in the Indian Ocean. Draw a stepwise mechanism for the formation of fl exibilene from farnesyl diphosphate and isopentenyl diphosphate. What is unusual about the cyclization that forms the 15-membered ring of fl exibilene?

flexibilene

29.29 The biosynthesis of lanosterol from squalene has intrigued chemists since its discovery. It is now possible, for example, to synthesize polycyclic compounds from acyclic or monocyclic precursors by reactions that form several C – C bonds in a single reaction mixture. a. Draw a stepwise mechanism for the following reaction. b. Show how X can be converted to 16,17-dehydroprogesterone. (Hint: See Figure 24.5 for a related conversion.)

+ H3O

OH O X 16,17-dehydroprogesterone

Steroids 29.30 Draw three-dimensional structures for each decalin derivative.

a. b.

H H 29.31 Draw three-dimensional structures for each alcohol. Label the OH groups as occupying axial or equatorial positions. H H H H HO HO a. b. c. d. HO HO H H H H 29.32 Axial alcohols are oxidized faster than equatorial alcohols by PCC and other Cr6+ oxidants. Which OH group in each compound is oxidized faster? H H OH a. b. HO HO OH H H 29.33 (a) Draw a skeletal structure of the anabolic steroid methenolone from the following description. Methenolone contains the tetracyclic steroid skeleton with a carbonyl group at C3, a hydroxyl at C17, a double bond between C1 and C2, and methyl groups bonded to C1, C10, and C13. (b) Add wedges and dashes for all stereogenic centers with the following information: the confi guration at C10 is R, the confi guration at C13 is S, the confi guration at C17 is S, and all substituents at ring fusions are

trans to each other. (c) Draw the structure of Primobolan, the product formed when methenolone is treated with CH3(CH2)5COCl and pyridine. Primobolan is an anabolic steroid that can be taken orally or by injection and has been used illegally by well- known Major League Baseball players.

smi75625_ch29_1119-1147.indd 1146 11/13/09 9:11:22 AM Problems 1147

29.34 Draw a three-dimensional representation for androsterone.

H H HO H androsterone

29.35 a. Draw a three-dimensional structure for the following steroid.

b. What is the structure of the single stereoisomer formed by reduction of this ketone with H2, Pd-C? Explain why only one stereoisomer is formed.

H H O H

29.36 Draw the products formed when cholesterol is treated with each reagent. Indicate the stereochemistry around any stereogenic centers in the product. – a. CH3COCl c. PCC e. [1] BH3•THF; [2] H2O2, OH + b. H2, Pd-C d. oleic acid, H

Challenge Problems 29.37 Draw a stepwise mechanism for the following conversion, which forms camphene. Camphene is a component of camphor and citronella oils.

= OPP

camphene 29.38 Draw a stepwise mechanism for the following reaction. O

+ H3O OH

29.39 Farnesyl diphosphate is cyclized to sesquiterpene A, which is then converted to the bicyclic product epi-aristolochene. Write a stepwise mechanism for both reactions.

OPP

farnesyl diphosphate A epi-aristolochene

smi75625_ch29_1119-1147.indd 1147 11/13/09 9:11:22 AM 30 Synthetic Polymers

30.1 Introduction 30.2 Chain-growth polymers— Addition polymers 30.3 Anionic polymerization of epoxides 30.4 Ziegler–Natta catalysts and polymer stereochemistry 30.5 Natural and synthetic rubbers 30.6 Step-growth polymers— Condensation polymers 30.7 Polymer structure and properties 30.8 Green polymer synthesis 30.9 Polymer recycling and disposal

Polyethylene terephthalate (PET) is a synthetic polymer formed by the reaction of ethylene glycol (HOCH2CH2OH) and terephthalic acid. Because PET is lightweight and impervious to air and moisture, it is commonly used for transparent soft drink containers. PET is also used to produce synthetic ﬁ bers, sold under the trade name of Dacron. Of the six most common synthetic polymers, PET is the most easily recycled, in part because beverage bottles that bear the recycling code “1” are composed almost entirely of PET. Recycled polyethylene terephthalate is used for ﬂ eece clothing and carpeting. In Chapter 30, we learn about the preparation and properties of synthetic polymers like polyethylene terephthalate. 1148

smi75625_ch30_1148-1179.indd 1148 11/13/09 12:22:46 PM 30.1 Introduction 1149

Chapter 30 discusses polymers, large organic molecules composed of repeating units— called monomers—that are covalently bonded together. Polymers occur naturally, as in the polysaccharides and proteins of Chapters 27 and 28, respectively, or they are synthesized in the laboratory. This chapter concentrates on synthetic polymers, and expands on the material already presented in Chapters 15 and 22. Thousands of synthetic polymers have now been prepared. While some exhibit properties that mimic naturally occurring compounds, many others have unique properties. Although all polymers are large molecules, the size and branching of the polymer chain and the identity of the functional groups all contribute to determining an individual polymer’s properties, thus making it suited for a particular product.

30.1 Introduction Synthetic polymers are perhaps more vital to the fabric of modern society than any other group polymer A is a large organic of compounds prepared in the laboratory. Nylon backpacks and polyester clothing, car bumpers molecule composed of and CD cases, milk jugs and grocery bags, artifi cial heart valves and condoms—all these prod- repeating units—called monomers—that are ucts and innumerable others are made of synthetic polymers. Since 1976, the U.S. production covalently bonded together. of synthetic polymers has exceeded its steel production. Figure 30.1 illustrates several consumer The word polymer is derived products and the polymers from which they are made. poly from the Greek words + Synthetic polymers can be classifi ed as chain-growth or step-growth polymers. meros meaning “many parts.” • Chain-growth polymers, also called addition polymers, are prepared by chain reac- Polymerization is the joining tions. These compounds are formed by adding monomers to the growing end of a polymer together of monomers to make chain. The conversion of vinyl chloride to poly(vinyl chloride) is an example of chain- polymers. growth polymerization. These reactions were introduced in Section 15.14.

initiator Cl Cl Cl Cl Cl vinyl chloride poly(vinyl chloride)

monomer polymer

Figure 30.1 Polymers in some common consumer products

H O O O N N C O O O O H O Lexan nylon 6,6 (polycarbonate helmet and goggles) (backpack)

rubber polyethylene (tires) (water bottle)

• We are surrounded by synthetic polymers in our daily lives. This cyclist rides on synthetic rubber tires, drinks from a polyethylene water bottle, wears a protective Lexan helmet and goggles, and uses a lightweight nylon backpack.

smi75625_ch30_1148-1179.indd 1149 11/13/09 12:22:48 PM 1150 Chapter 30 Synthetic Polymers

• Step-growth polymers, also called condensation polymers, are formed when monomers containing two functional groups come together and lose a small molecule such as H2O or HCl. In this method, any two reactive molecules can combine, so the monomer is not necessarily added to the end of a growing chain. Step-growth polymerization is used to prepare polyamides and polyesters, as discussed in Section 22.16.

H N 2 H O H O NH2 + N N O N N Cl H O H O Cl O nylon 6,6 + HCl

monomers polymer

In contrast to many of the organic molecules encountered in Chapters 1–26, which have molecular weights much less than 1000 grams per mole (g/mol), polymers generally have high molecular weights, ranging from 10,000 to 1,000,000 grams per mole (g/mol). Synthetic polymers are really mixtures of individual polymer chains of varying lengths, so the reported molecular weight is an average value based on the average size of the polymer chain. By convention, we often simplify the structure of a polymer by placing brackets around the repeating unit that forms the chain, as shown in Figure 30.2.

Problem 30.1 Give the shorthand structures of poly(vinyl chloride) and nylon 6,6 in Section 30.1.

30.2 Chain-Growth Polymers—Addition Polymers Chain-growth polymerization is a chain reaction that converts an organic starting material, usually an alkene, to a polymer via a reactive intermediate—a radical, cation, or anion.

initiator Chain-growth polymerization Z Z ZZZ

• The alkene can be ethylene (CH2 – CH2) or a derivative of ethylene (CH2 – CHZ or CH2 – CZ2). • The substituent Z (in part) determines whether radicals, cations, or anions are formed as intermediates. • An initiator—a radical, cation, or anion—is needed to begin polymerization. • Since chain-growth polymerization is a chain reaction, the mechanism involves initiation, propagation, and termination (Section 15.4).

Figure 30.2 repeating unit HO O repeating unit Drawing a polymer in a shorthand representation O OH terephthalic acid O O + O O OH n HO n styrene polystyrene ethylene glycol polyethylene terephthalate (PET)

smi75625_ch30_1148-1179.indd 1150 11/13/09 12:22:48 PM 30.2 Chain-Growth Polymers—Addition Polymers 1151

In most chain-growth polymerizations, an initiator adds to the carbon–carbon double bond of one monomer to form a reactive intermediate, which then reacts with another molecule of mono- – mer to build the chain. Polymerization of CH2 – CHZ results in a carbon chain having the Z substituents on every other carbon atom.

Problem 30.2 What polymer is formed by chain-growth polymerization of each monomer? Cl

a. b. OCH3 c. d. OCH Cl 3 CO2CH3

30.2A Radical Polymerization Radical polymerization of alkenes was fi rst discussed in Section 15.14, and is included here to emphasize its relationship to other methods of chain-growth polymerization. The initiator is often a peroxy radical (RO·), formed by cleavage of the weak O – O bond in an organic peroxide, – ROOR. Mechanism 30.1 is written with styrene (CH2 – CHPh) as the starting material.

– Mechanism 30.1 Radical Polymerization of CH2 – CHPh

Part [1] Initiation: Formation of a carbon radical in two steps [1] [2] • Homolysis of the weak O – O bond of the peroxide RO OR 2 RO + RO forms RO·, which then adds to a molecule of monomer to form a carbon radical.

Part [2] Propagation: Growth of the polymer chain by C – C bond formation • In Step [3], the carbon radical formed during RO RO initiation adds to another alkene molecule to form new C C bond a new C – C bond and another carbon radical. [3] + Addition gives the more substituted carbon radical—that is, the unpaired electron is always located on the carbon atom having the phenyl Repeat Step [3] over and over. substituent. • Step [3] occurs repeatedly, thus growing the polymer chain.

Part [3] Termination: Removal of radicals by formation of a σ bond • To terminate the chain, two radicals can combine to form a stable bond, thus ending the [4] polymerization process. +

– Radical polymerization of CH2 – CHZ is favored by Z substituents that stabilize a radical by electron delocalization. Each addition step occurs to put the intermediate radical on the carbon bearing the Z substituent. With styrene as the starting material, the intermediate radical is benzylic and highly resonance stabilized. Figure 30.3 shows several monomers used in radical polymerization reactions.

Figure 30.3 O Monomers used in radical CH2 CH2 Cl O polymerization reactions

ethylene vinyl chloride styrene vinyl acetate

smi75625_ch30_1148-1179.indd 1151 11/13/09 12:22:49 PM 1152 Chapter 30 Synthetic Polymers

H H H H H

five resonance structures for the benzylic radical

Problem 30.3 What polymer is formed by the radical polymerization of each monomer? – – a. CH2 – C(CH3)CO2CH3 b. CH2 – C(CH3)CN – Problem 30.4 Draw the mechanism for the radical polymerization of vinyl acetate (CH2 – CHOCOCH3) using (CH3)3CO – OC(CH3)3 as the initiator.

Chain termination can occur by radical coupling, as shown in Mechanism 30.1. Chain termination can also occur by disproportionation, a process in which a hydrogen atom is transferred from one polymer radical to another, forming a new C – H bond on one polymer chain, and a double bond on the other.

new C H bond H H Disproportionation— One method of chain termination ++new π bond

30.2B Chain Branching The choice of reaction parameters greatly affects the properties of a synthetic polymer. In Sec- tion 15.14, we learned that there are two common types of polyethylene—high-density polyethylene (HDPE) and low-density polyethylene (LDPE). High-density polyethylene, which consists of long chains of CH groups joined together in a linear fashion, is strong and hard HDPE is used in milk 2 because the linear chains pack well, resulting in strong van der Waals interactions. Low-density containers and water jugs, whereas LDPE is used in polyethylene, on the other hand, consists of long carbon chains with many branches along the plastic bags and insulation. chain. Branching prohibits the chains from packing well, so LDPE has weaker intermolecular interactions, making it a much softer, pliable material.

Linear polyethylene Branched polyethylene

Linear polyethylene molecules pack well. Branched polyethylene molecules do not pack well.

smi75625_ch30_1148-1179.indd 1152 11/13/09 12:22:50 PM 30.2 Chain-Growth Polymers—Addition Polymers 1153

Branching occurs when a radical on one growing polyethylene chain abstracts a hydrogen atom from a CH2 group in another polymer chain, as shown in Mechanism 30.2. The new 2° radical then continues chain propagation by adding to another molecule of ethylene, thus forming a branch point.

Mechanism 30.2 Forming Branched Polyethylene During Radical Polymerization

Step [1] Abstraction of a hydrogen atom

H [1] + CH2 CH3 + growing polyethylene polyethylene 2° radical polymer chain polymer polymer

• Abstraction of a hydrogen atom from an existing polymer chain forms a 2° radical in the middle of the polymer chain.

Step [2] Growth of the polymer chain forming a branch point

[2] Repeat Step [2] + CH CH 2 2 over and over. 2° radical branch point

• Addition of the radical to another molecule of ethylene forms a new radical and a branch point along the polymer chain. Step [2] occurs repeatedly, and a long branch grows off the original polymer chain.

Problem 30.5 Explain why radical polymerization of styrene forms branched chains with 4° carbons as in A, but none with 3° carbons as in B. Ph ° 3° C 4 C Ph

Ph Ph Ph Ph Ph Ph AB

30.2C Ionic Polymerization Chain-growth polymerization can also occur by way of cationic or anionic intermediates. Cat- ionic polymerization is an example of electrophilic addition to an alkene involving carbocations. Cationic polymerization occurs with alkene monomers that have substituents capable of stabilizing intermediate carbocations, such as alkyl groups or other electron-donor groups. The initiator is an electrophile such as a proton source or Lewis acid. – Mechanism 30.3 illustrates cationic polymerization of the general monomer CH2 – CHZ using BF3·H2O, the Lewis acid–base complex formed from BF3 and H2O, as the initiator. Since cationic polymerization involves carbocations, addition follows Markovnikov’s rule to form the more stable, more substituted carbocation. Chain termination can occur by a variety of pathways, such as loss of a proton to form an alkene. Examples of alkene monomers that undergo cationic polymerization are shown in Figure 30.4.

– Problem 30.6 Explain why cationic polymerization is an effective method of polymerizing CH2 – C(CH3)2 but not – CH2 – CH2.

smi75625_ch30_1148-1179.indd 1153 11/13/09 12:22:50 PM 1154 Chapter 30 Synthetic Polymers

– Mechanism 30.3 Cationic Polymerization of CH2 – CHZ

Part [1] Initiation: Formation of a carbocation + H F H • Electrophilic addition of H from BF3·H2O [1] [2] + – – + CH + F BOH forms a carbocation. F3BO F B O + 3 3 Z H F H Z Lewis acid–base carbocation complex Z = electron-donor group

Part [2] Propagation: Growth of the polymer chain by C – C bond formation

[3] CH3 • In Step [3], the carbocation adds to + + CH3 + Repeat Step [3] another alkene molecule to form a new Z Z ZZ over and over. C – C bond. Addition always forms a carbocation stabilized by an electron- new C C bond donating Z substituent. • Step [3] occurs repeatedly, thus growing the polymer chain.

Part [3] Termination: Loss of a proton

H • Loss of a proton forms a new π bond to

– [4] – + terminate the chain. + F3B OH + F3BOH2 ZZ ZZ (E or Z double bond)

Although alkenes readily react with electron-defi cient radicals and electrophiles, alkenes do not generally react with anions and other nucleophiles. Consequently, anionic polymerization takes place only with alkene monomers that contain electron-withdrawing groups such as COR, COOR, or CN, which can stabilize an intermediate negative charge. The initiator is a strong nucleophile, such as an organolithium reagent, RLi. Mechanism 30.4 illustrates anionic poly- – merization of the general monomer CH2 – CHZ. – Mechanism 30.4 Anionic Polymerization of CH2 – CHZ

Part [1] Initiation: Formation of a carbanion • Nucleophilic addition of RLi forms a carbanion stabilized [1] – RLi + R Li+ by an electron-withdrawing group Z. Z Z carbanion Z = electron-withdrawing group

Part [2] Propagation: Growth of the polymer chain by C – C bond formation Repeat Step [2] • In Step [2], the carbanion adds to another alkene – [2] – R R molecule to form a new C – C bond. Addition always over and over. Z Z Z Z forms a carbanion adjacent to the Z substituent. new C C bond • Step [2] occurs repeatedly, thus growing the polymer chain.

Part [3] Termination: Addition of a proton source to stop the chain

– [3] H – • Addition of H2O (or another electrophile) terminates the HHO + OH chain by a Brønsted–Lowry acid–base reaction. ZZ ZZ

In contrast to other types of chain-growth polymerization, there are no effi cient methods of ter- minating the chain mechanism in anionic polymerization. The reaction continues until all the initiator and monomer have been consumed, so that the end of each polymer chain contains

smi75625_ch30_1148-1179.indd 1154 11/13/09 12:22:51 PM 30.2 Chain-Growth Polymers—Addition Polymers 1155

Figure 30.4 Monomer Polymer Consumer product Common polymers formed • Polymers formed by cationic polymerization by ionic chain-growth polymerization

n 2-methylpropene (common name: isobutylene) polyisobutylene balls made with polyisobutylene

O O O vinyl acetate O n poly(vinyl acetate) paints containing poly(vinyl acetate)

• Polymers formed by anionic polymerization

CN CN acrylonitrile n polyacrylonitrile

Orlon fibers

CN NC O CO Et EtO 2 n ethyl α-cyanoacrylate poly(ethyl α-cyanoacrylate) Super glue

• A chain-growth polymer is named by adding the prefi x poly to the name of the monomer from which it is made. When the name of the monomer contains two words, this name is enclosed in parentheses and preceded by the prefi x poly.

a carbanion (Step [2] in Mechanism 30.4). Anionic polymerization is often called living polymerization because polymerization will begin again if more monomer is added at this stage. To terminate anionic polymerization an electrophile such as H2O or CO2 must be added. Examples of alkene monomers that undergo anionic polymerization are shown in Figure 30.4.

Problem 30.7 Which method of ionic polymerization—cationic or anionic—is preferred for each monomer? Explain your choices. – – – – a. CH2 – C(CH3)COOCH3 b. CH2 – CHCH3 c. CH2 – CHOC(CH3)3 d. CH2 – CHCOCH3 – – Problem 30.8 Draw a stepwise mechanism for the conversion of acrylonitrile (CH2 – CHC – N) to polyacrylonitrile, – – [CH2CHC – N]n – , using butyllithium (BuLi) as the initiator and CO2 as the electrophile to terminate the chain.

smi75625_ch30_1148-1179.indd 1155 11/13/09 12:22:51 PM 1156 Chapter 30 Synthetic Polymers

– Problem 30.9 Explain why styrene (CH2 – CHPh) can be polymerized to polystyrene by all three methods of chain- growth polymerization.

30.2D Copolymers All polymers discussed thus far are homopolymers, because they have been prepared by the polymerization of a single monomer. Copolymers, on the other hand, are polymers prepared by joining two or more monomers (X and Y) together.

Two different copolymers, formed from monomers and

alternating copolymer random copolymer

X = Y =

• An alternating copolymer is formed when X and Y alternate regularly along the chain. • A random copolymer is formed when X and Y are randomly distributed along the chain.

The structure of the copolymer depends on the relative amount and reactivity of X and Y, as well as the conditions used for polymerization. Several copolymers are commercially important and used in a wide range of consumer products. For example, the copolymer of vinyl chloride and vinylidene chloride forms Saran, the fi lm used in the well-known plastic food wrap. Copolymerization of 1,3-butadiene and styrene forms styrene–butadiene rubber (SBR), the polymer used almost exclusively in automobile tires.

Two widely used copolymers Cl

Cl + Cl vinyl chloride vinylidene chloride Cl Cl Cl n Saran

+ 1,3-butadiene

styrene

n styrene–butadiene rubber (SBR)

Problem 30.10 Draw the alternating copolymer formed from each set of monomers. – – – – a. CH2 – CHPh and CH2 – CHCN b. F2C – CFCF3 and CH2 – CF2

– – – Problem 30.11 Draw the mechanism for the radical copolymerization of CH2 – CHCH – CH2 and CH2 – CHPh to – form styrene–butadiene rubber, – [CH2CH – CHCH2CH2CHPh]n – .

30.3 Anionic Polymerization of Epoxides Alkene monomers are the most common starting materials in chain-growth polymerizations, but epoxides can also serve as starting materials, forming polyethers. The strained three-membered ring of an epoxide is readily opened with a nucleophile (such as –OH or –OR) to form an alkoxide, which can then ring open another epoxide monomer to build the polymer chain. Unlike the other methods of chain-growth polymerization that join monomers together with C – C bonds, this process forms new C – O bonds in the polymer backbone. For example, the ring opening of ethylene oxide with a –OH initiator affords an alkoxide nucleophile, which propagates the chain by reacting with more ethylene oxide. This process yields

smi75625_ch30_1148-1179.indd 1156 11/13/09 12:22:53 PM 30.4 Ziegler–Natta Catalysts and Polymer Stereochemistry 1157

poly(ethylene glycol), PEG, a polymer used in lotions and creams. The many C – O bonds in these polymers make them highly water soluble.

new C O bond

– [1] – HO + O O HO + O ethylene alkoxide oxide [2]

Repeat Step [2] O – O OH HO O HO O over and over. n new C O bond poly(ethylene glycol) PEG

The ring opening of epoxides Under anionic conditions, the ring opening follows an SN2 mechanism. Thus, the ring opening of with nucleophiles was fi rst an unsymmetrical epoxide occurs at the more accessible, less substituted carbon. discussed in Section 9.15. less substituted C CH3 – – O [1] O HO ++HO O

CH3 CH3 [2] less substituted C CH3 CH3

O – Repeat Step [2] O OH HO O HO O over and over. CH3 CH3 n CH3

Problem 30.12 What polymer is formed by anionic polymerization of each monomer? O O O a. b. c.

30.4 Ziegler–Natta Catalysts and Polymer Stereochemistry – Polymers prepared from monosubstituted alkene monomers (CH2 – CHZ) can exist in three different confi gurations, called isotactic, syndiotactic, and atactic:

= Z H Z H Z H Z H Z H Z H isotactic polymer

Z H H Z Z H H Z Z H H Z syndiotactic polymer

= Z H H Z H Z H Z Z H Z H atactic polymer

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• An isotactic polymer has all Z groups on the same side of the carbon backbone. • A syndiotactic polymer has the Z groups alternating from one side of the carbon chain to the other. • An atactic polymer has the Z groups oriented randomly along the polymer chain.

The more regular arrangement of the Z substituents in isotactic and syndiotactic polymers allows them to pack together better, making the polymer stronger and more rigid. In contrast, the chains of an atactic polymer tend to pack less closely together, resulting in a lower melting, softer polymer. Radical polymerization often affords an atactic polymer, but the particular reaction conditions can greatly affect the stereochemistry of the polymer formed. In 1953, Karl Ziegler and Giulio Natta developed a new method of polymerizing alkene monomers using a metal catalyst to promote chain-growth polymerization. These catalysts, now called Ziegler– Natta catalysts, offer two advantages over other methods of chain-growth polymerization.

• The stereochemistry of the polymer is easily controlled. Polymerization affords isotactic, syndiotactic, or atactic polymers depending on the catalyst. • Long, linear chains of polymer are prepared without signiﬁ cant branching. Radicals are not formed as reactive intermediates, so intermolecular hydrogen abstraction, which leads to chain branching, does not occur.

Many different Ziegler–Natta catalysts are used for polymerization, but most consist of an Ziegler and Natta received the organoaluminum compound such as (CH3CH2)2AlCl and TiCl4, a Lewis acid. The active catalyst 1963 Nobel Prize in Chemistry is thought to be an alkyl titanium compound, formed by transfer of an ethyl group from for their pioneering work on (CH CH ) AlCl to TiCl , although many mechanistic details are not known with certainty. It is polymerization catalysts. 3 2 2 4 generally agreed that the alkene monomer coordinates to an alkyl titanium complex, and then inserts into the Ti – C bond to form a new carbon–carbon bond, as shown in Mechanism 30.5.

– Mechanism 30.5 Ziegler–Natta Polymerization of CH2 – CH2

Step [1] Formation of the catalyst • Reaction of the organoaluminum [1] CH CH compound with TiCl forms a (CH CH ) AlCl+ TiCl Ti 2 3 4 3 2 2 4 Ziegler–Natta catalyst with a Ti – C bond. Ziegler–Natta catalyst

Steps [2] and [3] Growth of the polymer chain by C – C bond formation

new C C bond • An alkene monomer coordinates with the titanium catalyst in CH CH [2] CH CH [3] CH CH CH CH Step [2]. Ti 2 3 Ti 2 3 Ti 2 2 2 3 • Insertion of CH2 – CH2 into the CH2 – – + H2C Repeat Ti C bond forms a new C C Steps [2] and [3]. bond in Step [3]. CH2 CH2 • Repeating Steps [2] and [3] again and again yields the long polymer long, linear polyethylene chain.

The Ziegler–Natta polymerization of ethylene forms high-density polyethylene, HDPE, composed of long linear carbon chains that pack closely together, forming a rigid polymer. By using specialized manufacturing techniques that force the polymer chains to pack closely in the solid phase as a set of linear extended chains, this material is converted to ultra high-density polyethylene, a synthetic organic material stronger than steel.

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Recently developed Ziegler–Natta polymerizations utilize zirconium complexes that are soluble in the reaction solvents typically used, and so they are homogeneous catalysts. Reactions that use these soluble catalysts are called coordination polymerizations.

30.5 Natural and Synthetic Rubbers Natural rubber is a terpene composed of repeating isoprene units, in which all the double bonds have the Z confi guration. Because natural rubber is a hydrocarbon, it is water insoluble, and thus useful for waterproofi ng. The Z double bonds cause bends and kinks in the polymer chain, making it a soft material. Dyneema, the strongest Z configuration fabric known, is made of ultra high-density polyethylene (Section 30.4), and is used for ropes, nets, bulletproof vests, and crash helmets. isoprene natural rubber (2-methyl-1,3-butadiene) Locating isoprene units in The polymerization of isoprene under radical conditions forms a stereoisomer of natural rubber terpenes was discussed in called gutta-percha, in which all the double bonds have the E confi guration. Gutta-percha is Section 29.7. also a naturally occurring polymer, although considerably less common than its Z stereoisomer. Polymerization of isoprene with a Ziegler–Natta catalyst forms natural rubber with all the double bonds having the desired Z confi guration.

radical initiator gutta-percha E configuration

isoprene

Natural rubber is obtained Ziegler–Natta catalyst from latex that oozes from cuts natural rubber made to the bark of the rubber Z configuration tree. Waterproof latex is the Natural rubber is too soft to be a useful material for most applications. Moreover, when natural rubber tree’s natural protection, rubber is stretched, the chains become elongated and slide past each other until the material exuded in response to an pulls apart. In 1839, Charles Goodyear discovered that mixing hot rubber with sulfur produced injury. Although rubber was a stronger and more elastic material. This process, called vulcanization, results in cross-linking produced exclusively in Brazil until the late 1800s, today most of the hydrocarbon chains by disulfi de bonds, as shown in Figure 30.5. When the polymer is of the world’s rubber comes stretched, the chains no longer can slide past each other and tearing does not occur. Vulcanized from plantations in Southeast rubber is an elastomer, a polymer that stretches when stressed but then returns to its original Asia, Sri Lanka, and Indonesia. shape when the stress is alleviated.

Figure 30.5 Vulcanized rubber

S disulfide bond S

S S disulfide bond disulfide bond S S

• Vulcanized rubber contains many disulfi de bonds that cross-link the hydrocarbon chains together.

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Other synthetic rubbers can be prepared by the polymerization of different 1,3-dienes using Gutta-percha, a much harder Ziegler–Natta catalysts. For example, the polymerization of 1,3-butadiene affords (Z)-poly(1,3- material than natural rubber butadiene), and the polymerization of 2-chloro-1,3-butadiene yields neoprene, a polymer used in obtained from latex, is used in golf ball casings. wet suits and tires. Z configuration The degree of cross-linking affects the rubber’s properties. Harder rubber used for Ziegler–Natta automobile tires has more 1,3-butadiene catalyst (Z )-poly(1,3-butadiene) cross-linking than the softer rubber used for rubber bands. Cl Cl Cl Cl

Ziegler–Natta 2-chloro-1,3-butadiene neoprene catalyst

Problem 30.13 Assign the E or Z confi guration to the double bonds in neoprene. Draw a stereoisomer of neoprene in which all the double bonds have the opposite confi guration.

– – Problem 30.14 The polymerization of CH2 – CHCH – CH2 under radical conditions affords products A and B. Draw a mechanism that accounts for their formation.

30.6 Step-Growth Polymers—Condensation Polymers Step-growth polymers, the second major class of polymers, are formed when monomers containing two functional groups come together and lose a small molecule such as H2O or HCl. Commercially important step-growth polymers include: • Polyamides • Polyesters • Polyurethanes • Polycarbonates • Epoxy resins

30.6A Polyamides Nylons are polyamides formed by step-growth polymerization. In Section 22.16A, we learned Nylon 6,6 is used in many that nylon 6,6 can be prepared by the reaction of a diacid chloride and a diamine. Nylon 6,6 can products including parachutes also be prepared by heating adipic acid and 1,6-diaminohexane. A Brønsted–Lowry acid–base and clothing. reaction forms a diammonium salt, which loses H2O at high temperature. In both methods, each starting material has two identical functional groups.

O O proton + OH ++H N O– H N + 2 – 3 HO NH2 transfer O NH3 O O adipic acid 1,6-diaminohexane ∆ (–H2O) H O H O N N N N H O H O nylon 6,6

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Nylon 6 is another polyamide, which is made by heating an aqueous solution of ε-caprolactam. Nylon 6, trade name Perlon, The seven-membered ring of the lactam (a cyclic amide) is opened to form 6-aminohexanoic is used to make rope and tire cord. acid, the monomer that reacts with more lactam to form the polyamide chain. This step-growth polymerization thus begins with a single difunctional monomer that has two different functional groups, NH2 and COOH. O O O O H NH H2O NH NH N HO 2 N ε O H -caprolactam 6-aminohexanoic acid ∆ or base nylon 6 (–H2O) Kevlar is a polyamide formed from terephthalic acid and 1,4-diaminobenzene. The aromatic rings of the polymer backbone make the chains less fl exible, resulting in a very strong material. Kevlar is light in weight compared to other materials that are similar in strength, so it is used in many products, such as bulletproof vests, army helmets, and the protective clothing used by fi refi ghters. H O N N Armadillo bicycle tires O OH ∆ reinforced with Kevlar are hard + H2NNH2 H (–H2O) to pierce with sharp objects, so HO O O a cyclist rarely gets a fl at tire. terephthalic acid 1,4-diaminobenzene Kevlar

Problem 30.15 What polyamide is formed from each monomer or pair of monomers? O HOOC COOH H2NNH2 OH a. + H2N(CH2)6NH2 c. + HO O O b. NH

30.6B Polyesters Polyesters are formed by step-growth polymerization using nucleophilic acyl substitution reactions, as we learned in Section 22.16B. For example, the reaction of terephthalic acid and ethylene glycol forms polyethylene terephthalate (PET), the chapter-opening molecule.

HO O O O + OH O HO acid catalyst O OH O terephthalic acid ethylene glycol polyethylene terephthalate (PET) Although PET is a very stable material, some polyesters are more readily hydrolyzed to carboxylic acids and alcohols in aqueous medium, making them suited for applications in which slow degradation is useful. For example, copolymerization of glycolic acid and lactic acid forms a copolymer used by surgeons in dissolving sutures. Within weeks, the copolymer is hydrolyzed to the monomers from which it was prepared, which are metabolized readily by the body. These sutures are used internally to hold tissues together while healing and scar formation occur. O O O + HO HO OH copolymerization O OH O O glycolic acid lactic acid copolymer enzymatic hydrolysis

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Problem 30.16 Polyethylene terephthalate is also prepared by the transesterifi cation of dimethyl terephthalate with ethylene glycol. Draw the mechanism for this nucleophilic acyl substitution.

H3CO O O O + OH O HO acid catalyst O OCH3 O dimethyl terephthalate ethylene glycol polyethylene terephthalate (PET)

Problem 30.17 The fi rst synthetic fi bers were prepared by the step-growth polymerization of HOOC(CH2)4COOH and HOCH2CH2OH. Draw the structure of this polymer and suggest reasons why it is less suitable than either nylon 6,6 or PET for use in consumer products.

30.6C Polyurethanes A urethane (also called a carbamate) is a compound that contains a carbonyl group bonded to both an OR group and an NHR (or NR2) group (Section 28.6). Urethanes are prepared by the nucleophilic addition of an alcohol to the carbonyl group of an isocyanate, RN – C – O.

O R C N OR' RNCO + R'OH nucleophilic addition isocyanate H urethane or carbamate

Polyurethanes are polymers formed by the reaction of a diisocyanate and a diol.

CH CH3 3 H H OCN NNCO N N O O + OH HO O O toluene 2,6-diisocyanate ethylene glycol a polyurethane

A well-known polyurethane is spandex, a strong and fl exible polymer that illustrates how the macroscopic properties of a polymer depend on its structure at the molecular level. Spandex was fi rst used in women’s corsets, girdles, and support hose, but is now routinely used in both men’s and women’s active wear. Spandex is strong and lends “support” to the wearer, but it also stretches. Spandex is lighter in weight than many other elastic polymers, and it does not break down when exposed to perspiration and detergents. On the molecular level, it has rigid regions that are joined together by soft, fl exible segments. The fl exible regions allow the polymer to expand and then recover its original shape. The rigid regions strengthen the polymer.

flexible portion O O H H O N N O N NN O n H HH O N O rigid segment H

spandex Trade name: Lycra [The urethane units are indicated in red.]

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30.6D Polycarbonates A carbonate is a compound that contains a carbonyl group bonded to two OR groups. Carbonates Although it is not acutely toxic, can be prepared by the reaction of phosgene (Cl C – O) with two equivalents of an alcohol (ROH). bisphenol A (BPA) mimics the 2 – body’s own hormones and O O disrupts normal endocrine + ROH C (2 equiv) nucleophilic substitution C functions. Concern over low- Cl Cl RO OR dose exposure by infants has carbonate led to a voluntary phase-out of BPA-based polymers in infant Polycarbonates are formed from phosgene and a diol. The most widely used polycarbonate is formula packaging. Lexan, a lightweight, transparent material that is formed from phosgene and bisphenol A, and used in bike helmets, goggles, catcher’s masks, and bulletproof glass.

O O O + Cl Cl C HO OH O O O O phosgene bisphenol A Lexan

Problem 30.18 Lexan can also be prepared by the acid-catalyzed reaction of diphenyl carbonate with bisphenol A. Draw a stepwise mechanism for this process.

O acid O O + C6H5OOC6H5 C HO OH O O O O diphenyl carbonate bisphenol A Lexan + 2 C6H5OH

30.6E Epoxy Resins Epoxy resins represent a class of step-growth polymer familiar to anyone who has used “epoxy” to glue together a broken object. An epoxy resin consists of two components: a fl uid prepolymer composed of short polymer chains with reactive epoxides on each end, and a hardener, usually a diamine or triamine that ring opens the epoxides and cross-links the chains together. The prepolymer is formed by reacting two difunctional monomers, bisphenol A and epichloro hydrin.

HO OH O + Cl

epichlorohydrin

bisphenol A

Bisphenol A has two nucleophilic OH groups, while epichlorohydrin has polar C – O and C – Cl bonds that can react with two different nucleophiles. The general reaction of epichlorohydrin with nucleophiles is given in the accompanying equation. Nucleophilic attack on the strained epoxide ring affords an alkoxide that displaces chloride by an intramolecular SN2 reaction, forming a new epoxide. Ring opening with a second nucleophile gives a 2° alcohol.

– O OH O O [1] Nu– Cl Nu Cl Nu Nu Nu S 2 [2] protonation Nu– N epichlorohydrin alkoxide + 2 C Nu bonds Cl–

When bisphenol A is treated with excess epichlorohydrin, this stepwise process continues until all the phenolic OH groups have been used in ring-opening reactions, leaving epoxy groups on both ends of the polymer chains. This constitutes the fl uid prepolymer, as shown in Figure 30.6.

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Figure 30.6 HO OH Formation of an epoxy OH resin from a O O O OO O prepolymer and bisphenol A a hardening + agent O Cl n prepolymer epichlorohydrin (excess) H2NNH2 N H hardening agent

OH OH OH O O O O

NH HN

n HN NH

NH HN

O O O O

OH OH n OH epoxy resin The polymer chains are cross-linked together.

When the prepolymer is mixed with a diamine or triamine (the hardener), the reactive epoxide rings can be opened by the nucleophilic amino groups to cross-link polymer chains together, causing the polymer to harden. A wide range of epoxy resins is commercially prepared by this process, making them useful for adhesives and coatings. The longer and more extensively cross- linked the polymer chains, the harder the resin.

Problem 30.19 (a) Draw the structure of the prepolymer A formed from 1,4-dihydroxybenzene and excess epichlorohydrin. (b) Draw the structure of the cross-linked polymer B formed when A is treated

with H2NCH2CH2CH2NH2 as the hardening agent.

H N NH O 2 2 HO OH + Cl A B epichlorohydrin 1,4-dihydroxybenzene (excess)

30.7 Polymer Structure and Properties While the chemistry of polymer synthesis can be explained by the usual themes of organic reactions, the large size of polymer molecules gives them some unique physical properties compared to small organic molecules. Linear and branched polymers do not form crystalline solids because their long chains prevent effi cient packing in a crystal lattice. Most polymer chains have crystalline regions and amorphous regions:

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amorphous regions crystalline region

crystalline region

• Ordered crystalline regions, called crystallites, are places where sections of the polymer chain lie in close proximity and are held together by intermolecular interactions. Ordered regions of polyethylene, – [CH2CH2]n – , are held together by van der Waals interactions, whereas ordered regions of nylon chains are held together by intermolecular hydrogen bonding. • Amorphous regions are places where the polymer chains are randomly arranged, resulting in weak intermolecular interactions. Crystalline regions impart toughness to a polymer, while amorphous regions impart fl exibility. The greater the crystallinity of a polymer—that is, the larger the percentage of ordered regions—the harder the polymer. Branched polymers are generally more amorphous and, since branching prevents chains from packing closely, they are softer, too.

Two temperatures, Tg and Tm, often characterize a polymer’s behavior on heating:

• Tg, the glass transition temperature, is the temperature at which a hard amorphous polymer becomes soft.

• Tm, the melt transition temperature, is the temperature at which the crystalline regions of the polymer melt to become amorphous. More ordered polymers have higher Tm values.

Thermoplastics are polymers that can be melted and then molded into shapes that are retained when the polymer is cooled. Although they have high Tg values and are hard at room temperature, heating causes individual polymer chains to slip past each other, causing the material to soften. Polyethylene terephthalate and polystyrene are thermoplastic polymers. Thermosetting polymers are complex networks of cross-linked polymers. Thermosetting polymers are formed by chemical reactions that occur when monomers are heated together to form a network of covalent bonds. Thermosetting polymers cannot be re-melted to form a liquid phase, because covalent bonds hold the network together. Bakelite, a thermosetting polymer prepared – from phenol (PhOH) and formaldehyde (H2C – O) in the presence of a Lewis acid, is formed by electrophilic aromatic substitution reactions. Since formaldehyde is a reactive electrophile and phenol contains a strongly electron-donating OH group, substitution occurs at all ortho and para positions to the OH group, resulting in a highly cross-linked polymer, shown in Figure 30.7.

Problem 30.20 Draw a stepwise mechanism for Step [2] in Figure 30.7 using AlCl3 as the Lewis acid catalyst.

Sometimes a polymer is too stiff and brittle to be useful in many applications. In this case, a low molecular weight compound called a plasticizer is added to soften the polymer and give it fl exibility. The plasticizer interacts with the polymer chains, replacing some of the intermolecular interactions between the polymer chains. This lowers the crystallinity of the polymer, making it more amorphous and softer. Dibutyl phthalate is a plasticizer added to the poly(vinyl chloride) used in vinyl upholstery and garden hoses. Since plasticizers are more volatile than the high molecular weight polymers, they

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Figure 30.7 OH The synthesis of Bakelite from OH OH OH OH phenol and formaldehyde O [1] OH + HHLewis Lewis acid acid phenol formaldehyde [2] Repeat Steps [1] and [2]. OH OH

OH OH

• Bakelite, the fi rst totally synthetic polymeric material, was patented by Leo Baekeland in 1910. Bowling balls are made of Bakelite. Bakelite

slowly evaporate with time, making the polymer brittle and easily cracked. Plasticizers like dibutyl phthalate that contain hydrolyzable functional groups are also slowly degraded by chemical reactions.

COOCH2CH2CH2CH3

COOCH2CH2CH2CH3 dibutyl phthalate

30.8 Green Polymer Synthesis One hundred fi fty years ago there were no chemical manufacturing plants and no synthetic polymers, and petroleum had little value. Synthetic polymers have transformed the daily lives of many in the modern world, but not without a hefty price. Polymer synthesis and disposal have a tremendous impact on the environment, creating two central issues: • Where do polymers come from? What raw materials are used for polymer synthesis and what environmental consequences result from their manufacture? • What happens to polymers once they are used? How does polymer disposal affect the environment, and what can be done to minimize its negative impact?

30.8A Environmentally Friendly Polymer Synthesis—The Feedstock In Chapter 12, you were introduced to green chemistry, the use of environmentally benign methods to synthesize compounds. Given the billions of pounds of polymers manufactured worldwide each year, there is an obvious need for methods that minimize the environmental impact. To date, green polymer synthesis has been approached in a variety of ways: Recall from Section 4.7 that 3% of a barrel of crude oil • Using starting materials that are derived from renewable sources, rather than petro- is used as the feedstock for leum. The starting materials for an industrial process are often called the chemical chemical synthesis. feedstock. • Using safer, less toxic reagents that form fewer by-products.

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• Carrying out reactions in the absence of solvent or in aqueous solution (instead of an organic solvent). Until recently, the feedstock for all polymer synthesis has been petroleum; that is, the monomers for virtually all polymer syntheses are made from crude oil, a nonrenewable raw material. As an example, nylon 6,6 is prepared industrially from adipic acid [HOOC(CH2)4COOH] and 1,6-diaminohexane [H2N(CH2)6NH2], both of which originate from benzene, a product of petroleum refi ning (Figure 30.8). Besides beginning with a nonrenewable chemical feedstock, adipic acid synthesis has other problems. The use of benzene, a carcinogen and liver toxin, is undesirable, especially in a large- scale reaction. Moreover, oxidation with HNO3 in Step [3] produces N2O as a by-product. N2O depletes ozone in the stratosphere in much the same way as the CFCs discussed in Chapter 15. In addition, N2O also absorbs thermal energy from the earth’s surface like CO2, and may therefore contribute to global warming, as discussed in Section 4.14. As a result, several research groups are working to develop new methods of monomer synthesis that begin with renewable, more environmentally friendly raw materials and produce fewer hazardous by-products. As an example, chemists at Michigan State University have devised a two- step synthesis of adipic acid from d-glucose, a monosaccharide available from plant sources. The synthesis uses a genetically altered E. coli strain (called a biocatalyst) to convert d-glucose to (2Z,4Z)-2,4-hexadienoic acid, which is then hydrogenated to adipic acid. Methods such as this, which avoid starting materials derived from petroleum, are receiving a great deal of attention in the chemical community.

HO O O genetically engineered COOH H2 OH HO bacteria HOOC catalyst HO OH O OH (2Z,4Z )-2,4-hexadienoic acid adipic acid D-glucose

Sorona(R), DuPont’s trade name for poly(trimethylene terephthalate), is a large-volume polymer that can now be made at least in part from glucose derived from a renewable plant source such as corn. A biocatalyst converts d-glucose to 1,3-propanediol, which forms poly(trimethylene terephthalate) (PTT) on reaction with terephthalic acid, as shown in Figure 30.9. In related chemistry, poly(lactic acid) (PLA) is a polymer used in bottles and packaging, and it can also be made into a synthetic fi ber (trade name Ingeo) used in clothing and carpets.

Figure 30.8 Monomers needed for nylon 6,6 synthesis Synthesis of adipic acid and 1,6-diaminohexane for nylon 6,6 synthesis O OH O H2 O2 HNO3 OH ++HO N O catalyst catalyst [3] 2 [1] [2] O by-product benzene adipic acid (from petroleum)

O O NH3 H2 OH NH2 NH2 HO ∆ H2NHcatalyst 2N O O 1,6-diaminohexane adipic acid

• The synthesis of both monomers needed for nylon 6,6 synthesis begins with benzene, a petroleum product.

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Figure 30.9 A swimsuit made (in part) from corn—The synthesis of poly(trimethylene terephthalate) from 1,3-propanediol derived from corn

biocatalyst HO OH 1,3-propanediol O + HO O O OO poly(trimethylene terephthalate) O OH (PTT) terephthalic acid

swimsuit made from Sorona(R) fibers Carbohydrates in corn can be converted to 1,3-propanediol.

• Poly(trimethylene terephthalate), sold as Sorona(R) by the DuPont Corporation, is made into fi bers used in clothing and other materials. Although 1,3-propanediol, one of the monomers needed for its synthesis, has been prepared from petroleum feedstocks in the past, it is now available from a renewable plant source such as corn.

Poly(lactic acid) is prepared on a large scale by the fermentation of carbohydrates obtained from corn. Fermentation initially yields a cyclic lactone called lactide, derived from two molecules of lactic acid [CH3CH(OH)CO2H]. Heating lactide with acid forms poly(lactic acid). PLA is an especially attractive polymer choice, because it readily degrades in a landfi ll.

O O O O fermentation H+ O O carbohydrates O O O O lactide poly(lactic acid)

30.8B Polymer Synthesis with Less Hazardous Reagents Other approaches to green polymer synthesis have concentrated on using less hazardous reagents and avoiding solvents. For example, Lexan can now be prepared by the reaction of bisphenol A with – diphenyl carbonate [(PhO)2C – O] in the absence of solvent. This process avoids the use of phosgene – (Cl2C – O, Section 30.6D), an acutely toxic reagent that must be handled with extreme care, as well as the large volume of CH2Cl2 typically used as the solvent for the polymerization process.

A “greener” reagent

O O + C C6H5OOC6H5 HO OH O O diphenyl carbonate bisphenol A Lexan used in place of Cl2C O

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Problem 30.21 Thermosetting resins similar to Bakelite (Section 30.7) have also been prepared from renewable feedstocks. One method uses cardinol, the major constituent of the liquid obtained from roasted – cashew nutshells. What polymer is obtained when cardinol is treated with formaldehyde (H2C – O) in the presence of a proton source? OH

H2C O H+ cardinol

30.9 Polymer Recycling and Disposal The same desirable characteristics that make polymers popular materials for consumer products— durability, strength, and lack of reactivity—also contribute to environmental problems. Polymers do not degrade readily, and as a result, billions of pounds of polymers end up in landfi lls every year. Estimates suggest that synthetic polymers comprise 11% of solid municipal waste, 30% of which comes from packaging materials. Two solutions to address the waste problem created by polymers are recycling existing polymer types to make new materials, and using biodegradable polymers that will decompose in a fi nite and limited time span.

30.9A Polymer Recycling Although thousands of different synthetic polymers have now been prepared, six compounds, called the “Big Six,” account for 76% of the synthetic polymers produced in the United States each year. Each polymer is assigned a recycling code (1–6) that indicates its ease of recycling; the lower the number, the easier to recycle. Table 30.1 lists these six most common polymers, as well as the type of products made from each recycled polymer. Recycling begins with sorting plastics by type, shredding the plastics into small chips, and washing the chips to remove adhesives and labels. After the chips are dried and any metal caps or rings are removed, the polymer chips are melted and molded for reuse.

Table 30.1 Recyclable Polymers Recycling code Polymer name Structure Recycled product

O O 1 PET fl eece jackets Polyethylene terephthalate O carpeting O n plastic bottles

2 HDPE Tyvek insulation High-density polyethylene n sports clothing

3 PVC fl oor mats Poly(vinyl chloride) n Cl

4 LDPE trash bags Low-density polyethylene n

5 PP furniture Polypropylene n

6 PS n molded trays Polystyrene Ph trash cans

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Of the Big Six, only the polyethylene terephthalate (PET) in soft drink bottles and the high- density polyethylene (HDPE) in milk jugs and juice bottles are recycled to any great extent. Since recycled polymers are often still contaminated with small amounts of adhesives and other materials, these recycled polymers are generally not used for storing food or drink products. Recycled HDPE is converted to Tyvek, an insulating wrap used in new housing construction, and recycled PET is used to make fi bers for fl eece clothing and carpeting. Currently about 23% of all plastics are recycled in the United States. An alternative recycling process is to re-convert polymers back to the monomers from which they were made, a process that has been successful with acyl compounds that contain C – O or C – N bonds in the polymer backbone. For example, heating polyethylene terephthalate with CH3OH cleaves the esters of the polymer chain to give ethylene glycol (HOCH2CH2OH) and dimethyl terephthalate. These monomers then serve as starting materials for more PET. This chemical recycling process is a transesterifi cation reaction that occurs by nucleophilic acyl substitution, as discussed in Chapter 22.

Polymer Two monomers

OO CH O O CH OH 3 3 OH + H+ HO O O O OCH ethylene glycol 3 n dimethyl terephthalate polyethylene terephthalate (PET)

chemical recycling

Similarly, treatment of discarded nylon 6 polymer with NH3 cleaves the polyamide backbone, forming ε-caprolactam, which can be purifi ed and re-converted to nylon 6.

O OHNH 3 NH N n nylon 6 ε-caprolactam

chemical recycling

Problem 30.22 Why can’t chemical recycling—that is, the conversion of polymer to monomers and re-conversion of monomers to polymer—be done easily with HDPE and LDPE?

Problem 30.23 Organic polymers can also be incinerated as a means of disposal. (a) What products are formed on combustion of polyethylene? (b) What products are formed on combustion of polyethylene terephthalate? (c) Are these reactions exothermic or endothermic? (See Sections 6.4 and 29.3 for related reactions.) (d) Propose a reason why HDPE and PET must be separated from poly(vinyl chloride) prior to incineration.

30.9B Biodegradable Polymers Another solution to the accumulation of waste polymers in landfi lls is to design and use polymers that are biodegradable.

• Biodegradable polymers are polymers that can be degraded by microorganisms— bacteria, fungi, or algae—naturally present in the environment.

Several biodegradable polyesters have now been developed. For example, the polyhydroxyalkanoates (PHAs) are polymers of 3-hydroxy carboxylic acids, such as 3-hydroxybutyric acid or 3-hydroxyvaleric acid.

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General structure— Polyhydroxyalkanoate Monomer RORO RO

O O HO OH PHA 3-hydroxy carboxylic acid

R = CH3, 3-hydroxybutyric acid R = CH2CH3, 3-hydroxyvaleric acid

The two most common PHAs are polyhydroxybutyrate (PHB) and a copolymer of polyhydroxybutyrate and polyhydroxyvalerate (PHBV). PHAs can be used as fi lms, fi bers, and coatings for hot beverage cups made of paper.

OO OO

OO OO PHB PHBV

Bacteria in the soil readily degrade PHAs, and in the presence of oxygen, the fi nal degradation products are CO2 and H2O. The rate of degradation depends on moisture, temperature, and pH. Degradation is slower in enclosed landfi lls that are lined and covered. An additional advantage of the polyhydroxyalkanoates is that the polymers can be produced by fermentation. Certain types of bacteria produce PHAs for energy storage when they are grown in glucose solution in the absence of specifi c nutrients. The polymer forms as discrete granules within the bacterial cell, and it is then removed by extraction to give a white powder that can be melted and modifi ed into a variety of different products. Biodegradable polyamides have also been prepared from amino acids. For example, aspartic PHAs are bioplastics. PHAs are acid can be converted to polyaspartate, abbreviated as TPA (thermal polyaspartate). TPA is com- not synthesized from petroleum products, and they are degraded monly used as an alternative to poly(acrylic acid), which is used to line the pumps and boilers of wastewater treatment facilities. by soil microorganisms to CO2 and H2O. COO– O O H H2N [1] ∆ N OH N [2] –OH, H O H 2 O COOH COOH COOH – COO poly(acrylic acid) aspartic acid polyaspartate (TPA)

Problem 30.24 What polymers are formed from each monomer?

OH O OH a. b. H2N OH O

smi75625_ch30_1148-1179.indd 1171 11/13/09 12:23:03 PM 1172 Chapter 30 Synthetic Polymers

KEY CONCEPTS

Synthetic Polymers Chain-Growth Polymers—Addition Polymers [1] Chain-growth polymers with alkene starting materials (30.2)

• General reaction: initiator Z ZZZZ • Mechanism—three possibilities, depending in part on the identity of Z:

Type Identity of Z Initiator Comments

[1] radical polymerization Z stabilizes a radical. A source of radicals Termination occurs by radical Z = R, Ph, Cl, etc. (ROOR) coupling or disproportionation. Chain branching occurs. [2] cationic polymerization Z stabilizes a carbocation. H – A or a Lewis acid Termination occurs by loss of

Z = R, Ph, OR, etc. (BF3 + H2O) a proton. [3] anionic polymerization Z stabilizes a carbanion. An organolithium reagent Termination occurs only when an Z = Ph, COOR, COR, CN, etc. (R – Li) acid or other electrophile is added.

[2] Chain-growth polymers with epoxide starting materials (30.3)

R O –OH O • The mechanism is SN2. O R • Ring opening occurs at the less substituted carbon of the epoxide. R

Examples of Step-Growth Polymers—Condensation Polymers (30.6) Polyamides Polyesters H OO N O O O nylon 6 polyethylene terephthalate

H O O N N O H O O O Kevlar copolymer of glycolic and lactic acids

Polyurethanes Polycarbonates H H NON O O O O C O O a polyurethane Lexan [Key functional groups are indicated in red.]

smi75625_ch30_1148-1179.indd 1172 11/13/09 12:23:05 PM Problems 1173

Structure and Properties – • Polymers prepared from monomers having the general structure CH2 – CHZ can be isotactic, syndiotactic, or atactic depending on the identity of Z and the method of preparation (30.4). • Ziegler–Natta catalysts form polymers without signifi cant branching. Polymers can be isotactic, syndiotactic, or atactic depending on the catalyst. Polymers prepared from 1,3-dienes have the E or Z confi guration depending on the catalyst (30.4, 30.5). • Most polymers contain ordered crystalline regions and less ordered amorphous regions (30.7). The greater the crystallinity, the harder the polymer. • Elastomers are polymers that stretch and can return to their original shape (30.5). • Thermoplastics are polymers that can be molded, shaped, and cooled such that the new form is preserved (30.7). • Thermosetting polymers are composed of complex networks of covalent bonds so they cannot be re-melted to form a liquid phase (30.7).

PROBLEMS Polymer Structure and Properties 30.25 Draw the structure of the polymer formed by chain-growth polymerization of each monomer. O F CH3O O a. b. c. N d. F H CH3CH2O2C 30.26 Draw the structure of the alternating copolymer formed from each pair of monomers.

a. CN and c. CN and e. and

Cl b. and d. and Cl 30.27 What monomer(s) are used to prepare each polymer or copolymer?

C(CH3)3 a. d. O O

EtO2CCO2Et CO2Et C(CH3)3

O O b. e. O CN CN O

O H OO N c. N f. H OO OO O

30.28 Draw each polymer in Problem 30.27 using the shorthand representation shown in Figure 30.2. 30.29 Draw a short segment of each polymer: (a) isotactic poly(vinyl chloride); (b) syndiotactic polyacrylonitrile; (c) atactic polystyrene. – 30.30 Draw the structure of the polymer that results from anionic polymerization of p-trichloromethylstyrene (CCl3C6H4CH – CH2) using ethylene oxide as the electrophile to terminate the chain.

smi75625_ch30_1148-1179.indd 1173 11/13/09 12:23:06 PM 1174 Chapter 30 Synthetic Polymers

30.31 Draw the structure of the polymer formed by step-growth polymerization of each monomer or pair of monomers.

H2NNH2

a. and HO2C CO2H d. O N H

O b. OOCCNNand HO OH e. HO OH and Cl Cl

COCl c. and HO OH f. HO COOH COCl

30.32 ABS, a widely produced copolymer used for high-impact applications like car bumpers and crash helmets, is formed from three – – – – monomers—acrylonitrile (CH2 – CHCN), 1,3-butadiene (CH2 – CH – CH – CH2), and styrene (CH2 – CHPh). Draw a possible structure for ABS. 30.33 Draw the structures of Quiana and Nomex, two commercially available step-growth polymers formed from the given monomers. Nomex is a strong polymer used in aircraft tires and microwave transformers. Quiana has been used to make wrinkle-resistant fabrics. O H2NNH2 HO a. + OH Quiana O

ClOC COCl H2NNH2 b. + Nomex

30.34 Kevlar (Section 30.6A) is a very stiff polymer because its backbone contains many aromatic rings and its polymer chains are extensively hydrogen bonded to each other. Draw a short segment of two Kevlar chains, and indicate how the chains are hydrogen bonded to each other.

30.35 Explain the differences observed in the Tg and Tm values for each pair of polymers: (a) polyester A and PET; (b) polyester A and nylon 6,6. (c) How would you expect the Tm value for Kevlar (Section 30.6A) to compare with the Tm value for nylon 6,6? Explain your prediction.

O O O O H O O N O N O H O n n O n polyester A PET nylon 6,6 ° ° ° Tg < 0 C Tg = 70 C Tg = 53 C ° ° ° Tm = 50 C Tm = 265 C Tm = 265 C

30.36 Explain why diester A is now often used as a plasticizer in place of dibutyl phthalate.

O O

O O O O

O O A dibutyl phthalate

smi75625_ch30_1148-1179.indd 1174 11/13/09 12:23:06 PM Problems 1175

Mechanism

30.37 Draw a stepwise mechanism for the polymerization of isoprene to gutta-percha using (CH3)3CO – OC(CH3)3 as the initiator.

(CH3)3CO OC(CH3)3 isoprene gutta-percha

– 30.38 Cationic polymerization of 3-phenylpropene (CH2 – CHCH2Ph) affords A as the major product rather than B. Draw a stepwise mechanism to account for this observation. Ph Ph Ph Ph BF3 H2O Ph A B major product – – 30.39 Explain why acrylonitrile (CH2 – CHCN) undergoes cationic polymerization more slowly than 3-butenenitrile (CH2 – CHCH2CN). – 30.40 Draw a stepwise mechanism for the anionic polymerization of styrene (CH2 – CHPh) to form polystyrene – [CH2CHPh]n – using BuLi as the initiator. Use CO2 as the electrophile that terminates the chain mechanism. 30.41 Although styrene undergoes both cationic and anionic polymerization equally well, one method is often preferred with substituted styrenes. Which method is preferred with each compound? Explain.

a. OCH3 b. NO2 c. CF3 d. CH2CH3

30.42 Rank the following compounds in order of increasing ability to undergo anionic chain-growth polymerization.

O CN

OCH3 OCH3 O O O

+ 30.43 In the presence of H3O , 2-methylpropene oxide undergoes chain-growth polymerization such that nucleophilic attack occurs at the more substituted end of the epoxide. Draw a stepwise mechanism for this process, and explain this regioselectivity. Nucleophilic attack occurs here.

+ O H3O O OH HO O

2-methylpropene oxide n

30.44 Draw a stepwise mechanism for the conversion of dihalide A and 1,4-cyclohexanediol to polyether B in the presence of AlCl3.

AlCl3 ClCH2 CH2Cl + HO OH CH2 CH2 OO

A 1,4-cyclohexanediol B n

30.45 Draw a stepwise mechanism for the reaction of an alcohol with an isocyanate to form a urethane.

H N OCH3

NCO + CH3OH O

a urethane

smi75625_ch30_1148-1179.indd 1175 11/13/09 12:23:07 PM 1176 Chapter 30 Synthetic Polymers

Reactions and Synthesis 30.46 Draw the products of each reaction. OH

(CH3)3CO OC(CH3)3 O a. f. + Cl

OCH3 OH (excess)

O O Ziegler–Natta O – b. g. OH catalyst H O O 2

O H BuLi (initiator) –OH c. h. N H2O O

BF3 + H2O d. i. OCN NCO+ HO OH

O –OH Cl CO e. j. HO 2 OH

30.47 Explain why aqueous NaOH solution can be stored indefi nitely in polyethylene bottles, but spilling aqueous base on a polyester shirt or nylon stockings quickly makes a hole. 30.48 What epoxy resin is formed by the following reaction sequence?

NH2 O H2N HO CH2 OH + Cl prepolymer

– 30.49 (a) Explain why poly(vinyl alcohol) cannot be prepared by the radical polymerization of vinyl alcohol (CH2 – CHOH). (b) Devise a – stepwise synthesis of poly(vinyl alcohol) from vinyl acetate (CH2 – CHOCOCH3). (c) How can poly(vinyl alcohol) be converted to poly(vinyl butyral), a polymer used in windshield safety glass?

OH OH OO poly(vinyl alcohol)

poly(vinyl butyral)

30.50 Although 1,3-propanediol (HOCH2CH2CH2OH) can now be prepared from carbohydrate feedstocks (Section 30.8), it can also be – prepared from petroleum feedstocks. Devise a synthesis of HOCH2CH2CH2OH from CH3CH – CH2, a product of petroleum refi ning. 30.51 Devise a synthesis of terephthalic acid and ethylene glycol, the two monomers needed for polyethylene terephthalate synthesis, from the given starting materials.

OH HOOC COOH CH2 CH2 HO ethylene glycol terephthalic acid

– – 30.52 The reaction of p-cresol with CH2 – O resembles the reaction of phenol (PhOH) with CH2 – O, except that the resulting polymer is thermoplastic but not thermosetting. Draw the structure of the polymer formed, and explain why the properties of these two polymers are so different.

CH3 OH + CH2 O

p-cresol

smi75625_ch30_1148-1179.indd 1176 11/13/09 12:23:08 PM Problems 1177

Biological Applications 30.53 In addition to glycolic and lactic acids (Section 30.6B), dissolving sutures can also be prepared from each of the following lactone monomers. Draw the structure of the polymer formed from each monomer. O O

O O a. polycaprolactone b. polydioxanone O ε-caprolactone p-dioxanone

30.54 Compound A is a novel poly(ester amide) copolymer that can be used as a bioabsorbable coating for the controlled release of drugs. A is a copolymer of four monomers, two of which are amino acids or amino acid derivatives. The body’s enzymes recognize the naturally occurring amino acids in the polymer backbone, allowing for controlled enzymatic breakdown of the polymer and steady release of an encapsulated drug. Identify the four monomers used to synthesize A; then use Figure 28.2 to name the two amino acids.

O O O H H H N O N N O N H O O O OO

poly(ester amide) A

30.55 Researchers at Rutgers University have developed biocompatible polymers that degrade into nonsteroidal anti-infl ammatory drugs. For example, the reaction of two equivalents of benzyl salicylate and one equivalent of sebacoyl chloride forms a poly(anhydride ester) called PolyAspirin, which hydrolyzes to salicylic acid (an anti-infl ammatory agent) and sebacic acid, which is excreted. This technology can perhaps be used for localized drug delivery at specifi c sites of injury. What is the structure of PolyAspirin?

CO2CH2Ph OH CO2H OH O OH benzyl salicylate PolyAspirin + HO O + sebacic acid O Cl salicylic acid Cl sebacoyl chloride O

Challenge Questions – 30.56 Melmac, a thermosetting polymer formed from melamine and formaldehyde (CH2 – O), is used to make dishes and countertops. Draw a stepwise mechanism for the condensation of one mole of formaldehyde with two moles of melamine, which begins the synthesis of Melmac. H H H H H H H2N N NH2 H2N NNN N NH2 N NNN N N

CH2 O NN NN NN N NNN [1]

NH2 NH2 NH2 HN HN melamine H H N NNNNN

NNNN

HN HN

Melmac

smi75625_ch30_1148-1179.indd 1177 11/13/09 12:23:09 PM 1178 Chapter 30 Synthetic Polymers

30.57 Although chain branching in radical polymerizations can occur by intermolecular H abstraction as shown in Mechanism 30.2, chain branching can also occur by intramolecular H abstraction to form branched polyethylene that contains butyl groups as branches. [1] intramolecular H abstraction

[2] CH2 CH2 n [3] Repeat Step [2]. butyl substituent

a. Draw a stepwise mechanism that illustrates which H must be intramolecularly abstracted to form butyl substituents. b. Suggest a reason why the abstraction of this H is more facile than the abstraction of other H’s. – – 30.58 The reaction of urea [(NH2)2C – O] and formaldehyde (CH2 – O) forms a highly cross-linked polymer used in foams. Suggest a structure for this polymer. [Hint: Examine the structures of Bakelite (Figure 30.7) and Melmac (Problem 30.56).]

smi75625_ch30_1148-1179.indd 1178 11/13/09 12:23:09 PM This page intentionally left blank Appendix pKa Values for Selected A Compounds

Compound pKa Compound pKa HI –10 HBr –9 Br COOH 4.0 H2SO4 –9 +OH COOH 4.2 C –7.3 CH3 CH3

CH COOH 4.3 CH3 SO3H –7 3

HCl –7 CH3O COOH 4.5 + [(CH3)2OH] –3.8 [CH OH ]+ –2.5 3 2 + + NH3 4.6 H3O –1.7

CH3SO3H –1.2 CH3COOH 4.8 +OH (CH3)3CCOOH 5.0 C 0.0 CH NH 3 2 + CH3 NH3 5.1 CF3COOH 0.2

CCl3COOH 0.6

+ 5.2 + O2N NH3 1.0 N H Cl CHCOOH 1.3 2 + CH3O NH3 5.3 H3PO4 2.1

FCH2COOH 2.7 H2CO3 6.4 ClCH2COOH 2.8 H2S 7.0 BrCH2COOH 2.9

ICH2COOH 3.2 O2N OH 7.1 HF 3.2

SH 7.8 O2N COOH 3.4

HCOOH 3.8 O O

+ 8.9 Br NH3 3.9 H

A-1

smi75625_apps_1180-1197.indd 1180 11/13/09 10:57:41 AM Appendix A pKa Values for Selected Compounds A-2

Compound pKa Compound pKa – HC – N 9.1 CH3OH 15.5

H2O 15.7 Cl OH 9.4 CH3CH2OH 16

+ CH3CONH2 16 NH4 9.4 + – CH3CHO 17 H3NCH2COO 9.8 (CH3)3COH 18 10.0 OH (CH3)2C – O 19.2

CH3CO2CH2CH3 24.5 HC – CH 25 CH3 OH 10.2 – CH3C – N 25 HCO – 10.2 3 CHCl3 25 CH NO 10.2 3 2 CH3CON(CH3)2 30

H2 35 NH2 OH 10.3 NH3 38

CH3CH2SH 10.5 CH3NH2 40 + [(CH3)3NH] 10.6 CH3 41 O O

OEt 10.7 H 43 H + [CH3NH3] 10.7 CH2 – CHCH3 43 – + CH2 – CH2 44 NH3 10.7 H 46 + [(CH3)2NH2] 10.7 CH4 50 CF3CH2OH 12.4 CH3CH3 50 O O

EtO OEt 13.3 H

H 15

smi75625_apps_1180-1197.indd 1181 11/13/09 10:57:42 AM Appendix B Nomenclature

Although the basic principles of nomenclature are presented in the body of this text, additional information is often needed to name many complex organic compounds. Appendix B concentrates on three topics: · Naming alkyl substituents that contain branching · Naming polyfunctional compounds · Naming bicyclic compounds

Naming Alkyl Substituents That Contain Branching Alkyl groups that contain any number of carbons and no branches are named as described in Sec- tion 4.4A: change the -ane ending of the parent alkane to the suffi x -yl. Thus the seven-carbon alkyl group CH3CH2CH2CH2CH2CH2CH2 – is called heptyl. When an alkyl substituent also contains branching, follow a stepwise procedure:

[1] Identify the longest carbon chain of the alkyl group that begins at the point of attachment to the parent. Begin numbering at the point of attachment and use the suffi x -yl to indicate an alkyl group.

1 3 1 3 5 24 24

Start numbering here. Start numbering here.

4 C’s in the chain butyl group 5 C’s in the chain pentyl group

[2] Name all branches off the main alkyl chain and use the numbers from Step [1] to designate their location.

methyl groups at C1 and C3

methyl group at C3

1 3 1 3 5 24 24 3-methylbutyl 1,3-dimethylpentyl

A-3

smi75625_apps_1180-1197.indd 1182 11/13/09 10:57:43 AM Appendix B Nomenclature A-4

[3] Set the entire name of the substituent in parentheses, and alphabetize this substituent name by the fi rst letter of the complete name.

C1 of the six-membered ring

(3-methylbutyl)cyclohexane 1-(1,3-dimethylpentyl)-2-methylcyclohexane

• Alphabetize the d of dimethylpentyl before the m of methyl. • Number the ring to give the lower number to the first substituent alphabetically: place the dimethylpentyl group at C1.

Naming Polyfunctional Compounds Many organic compounds contain more than one functional group. When one of those functional groups is halo (X – ) or alkoxy (RO – ), these groups are named as substituents as described in Sections 7.2 and 9.3B. To name other polyfunctional compounds, we must learn which functional group is assigned a higher priority in the rules of nomenclature. Two steps are usually needed: [1] Name a compound using the suffi x of the highest priority group, and name other functional groups as substituents. Table B.1 lists the common functional groups in order of decreasing priority, as well as the prefi xes needed when a functional group must be named as a substituent. [2] Number the carbon chain to give the lower number to the highest priority functional group, and then follow all other rules of nomenclature. Examples are shown in Figure B.1. Polyfunctional compounds that contain C – C double and triple bonds have characteristic suffi xes to identify them, as shown in Table B.2. The higher priority functional group is assigned the lower number.

Table B.1 Summary of Functional Group Nomenclature Functional group Sufﬁ x Substituent name (preﬁ x)

Carboxylic acid -oic acid carboxy Ester -oate alkoxycarbonyl Amide -amide amido Nitrile -nitrile cyano Aldehyde -al oxo ( – O) or formyl ( – CHO) Ketone -one oxo Alcohol -ol hydroxy Amine -amine amino

Increasing priority Alkene -ene alkenyl Alkyne -yne alkynyl Alkane -ane alkyl Ether — alkoxy Halide — halo

smi75625_apps_1180-1197.indd 1183 11/13/09 10:57:43 AM A-5 Appendix B Nomenclature

NH O Figure B.1 2 CN highest priority Examples of nomenclature of 2 13 polyfunctional compounds H OH COOH higher priority 3-amino-2-hydroxybutanal o-cyanobenzoic acid Name as a derivative of an aldehyde since Name as a derivative of benzoic acid since CHO is the highest priority functional group. COOH is the higher priority functional group.

O highest priority O NH higher priority 2 4 1 H OCH3 O O OCH3 methyl 4-oxohexanoate 4-formyl-3-methoxycyclohexanecarboxamide Name as a derivative of an ester since Name as a derivative of an amide since COOR is the higher priority functional group. CONH2 is the highest priority functional group.

Table B.2 Naming Polyfunctional Compounds with C–C Double and Triple Bonds Functional groups Sufﬁ x Example

C – C and OH enol Start numbering here.

5-methyl-4-hexen-1-ol

– – C – C + C – O (ketone) enone Start numbering here. O

(4E)-4-hepten-3-one

C – C + C – C enyne – – Start numbering here.

HC CCH2CH2CH CH2 1-hexen-5-yne

Naming Bicyclic Compounds Bicyclic ring systems—compounds that contain two rings that share one or two carbon atoms— can be bridged, fused, or spiro.

bridged ring fused ring spiro ring

• A bridged ring system contains two rings that share two non-adjacent carbons. • A fused ring system contains two rings that share a common carbon–carbon bond. • A spiro ring system contains two rings that share one carbon atom.

smi75625_apps_1180-1197.indd 1184 11/13/09 10:57:43 AM Appendix B Nomenclature A-6

Fused and bridged ring systems are named as bicyclo[x.y.z]alkanes, where the parent alkane corresponds to the total number of carbons in both rings. The numbers x, y, and z refer to the number of carbons that join the shared carbons together, written in order of decreasing size. For a fused ring system, z always equals zero, because the two shared carbons are directly joined together. The shared carbons in a bridged ring system are called the bridgehead carbons.

C 1 C joining the bridgehead C’s

C C C C 3 C’s joining the bridgehead C’s C 8 C’s in the ring system 2 C’s joining the bridgehead C’s

Name: bicyclo[3.2.1]octane bicyclooctane

C C C C 4 C’s joining the common C’s C C C C No C’s join the shared C’s at the ring fusion. 10 C’s in the ring system 4 C’s joining the common C’s

Name: bicyclo[4.4.0]decane bicyclodecane

Rings are numbered beginning at a shared carbon, and continuing around the longest bridge fi rst, then the next longest, and so forth.

8 Start numbering here. 7 Start numbering here.

1 1 7 2 6 2 5 4 6 4 5 3 3

3,3-dimethylbicyclo[3.2.1]octane 7,7-dimethylbicyclo[2.2.1]heptane

Spiro ring systems are named as spiro[x.y]alkanes where the parent alkane corresponds to the total number of carbons in both rings, and x and y refer to the number of carbons that join the shared carbon (the spiro carbon), written in order of increasing size. When substituents are present, the rings are numbered beginning with a carbon adjacent to the spiro carbon in the smaller ring.

5 6 3 4 2 7 Start numbering here. 8 1 10 C’s in the ring system 8 C’s in the ring system

Name: spiro[4.5]decane Name: 2-methylspiro[3.4]octane

smi75625_apps_1180-1197.indd 1185 11/13/09 10:57:44 AM Appendix Bond Dissociation Energies for Some Common Bonds C [A–B → A• + •B]

Bond ∆Ho kJ/mol (kcal/mol) H – Z bonds H– F 569 (136) H– Cl 431 (103) H– Br 368 (88) H– I 297 (71) H– OH 498 (119)

Z – Z bonds H– H 435 (104) F– F 159 (38) Cl – Cl 242 (58) Br – Br 192 (46) I – I 151 (36) HO – OH 213 (51)

R – H bonds

CH3 – H 435 (104)

CH3CH2 – H 410 (98)

CH3CH2CH2 – H 410 (98)

(CH3)2CH – H 397 (95)

(CH3)3C – H 381 (91)

CH2 – CH – H 435 (104) HC – C – H 523 (125)

CH2 – CHCH2 – H 364 (87)

C6H5 – H 460 (110)

C6H5CH2 – H 356 (85)

R – R bonds

CH3 – CH3 368 (88)

CH3 – CH2CH3 356 (85)

CH3 – CH – CH2 385 (92) – CH3 – C – CH 489 (117)

A-7

smi75625_apps_1180-1197.indd 1186 11/13/09 10:57:44 AM Appendix C Bond Dissociation Energies for Some Common Bonds [A–B → A• + •B] A-8

Bond ∆Ho kJ/mol (kcal/mol) R – X bonds

CH3 – F 456 (109)

CH3 – Cl 351 (84)

CH3 – Br 293 (70)

CH3 – I 234 (56)

CH3CH2 – F 448 (107)

CH3CH2 – Cl 339 (81)

CH3CH2 – Br 285 (68)

CH3CH2 – I 222 (53)

(CH3)2CH – F 444 (106)

(CH3)2CH – Cl 335 (80)

(CH3)2CH – Br 285 (68)

(CH3)2CH – I 222 (53)

(CH3)3C – F 444 (106)

(CH3)3C – Cl 331 (79)

(CH3)3C – Br 272 (65)

(CH3)3C – I 209 (50)

R – OH bonds

CH3 – OH 389 (93)

CH3CH2 – OH 393 (94)

CH3CH2CH2 – OH 385 (92)

(CH3)2CH – OH 401 (96)

(CH3)3C – OH 401 (96)

Other bonds

CH2 – CH2 635 (152) HC – CH 837 (200) O– C – O 535 (128)

O2 497 (119)

smi75625_apps_1180-1197.indd 1187 11/13/09 10:57:45 AM Appendix Reactions That Form D Carbon–Carbon Bonds

Section Reaction – – 11.11A SN2 reaction of an alkyl halide with an acetylide anion, C – CR 11.11B Opening of an epoxide ring with an acetylide anion, –C – CR 15.14 Radical polymerization of an alkene 16.12 Diels–Alder reaction 18.5 Friedel–Crafts alkylation 18.5 Friedel–Crafts acylation 20.10 Reaction of an aldehyde or ketone with a Grignard or organolithium reagent 20.13A Reaction of an acid chloride with a Grignard or organolithium reagent 20.13A Reaction of an ester with a Grignard or organolithium reagent 20.13B Reaction of an acid chloride with an organocuprate reagent

20.14A Reaction of a Grignard reagent with CO2 20.14B Reaction of an epoxide with an organometallic reagent 20.15 Reaction of an α,β-unsaturated carbonyl compound with an organocuprate reagent 21.9 Cyanohydrin formation 21.10 Wittig reaction to form an alkene

22.18 SN2 reaction of an alkyl halide with NaCN 22.18C Reaction of a nitrile with a Grignard or organolithium reagent 23.8 Direct enolate alkylation using LDA and an alkyl halide 23.9 Malonic ester synthesis to form a carboxylic acid 23.10 Acetoacetic ester synthesis to form a ketone 24.1 Aldol reaction to form a β-hydroxy carbonyl compound or an α,β-unsaturated carbonyl compound 24.2 Crossed aldol reaction 24.3 Directed aldol reaction 24.5 Claisen reaction to form a β-keto ester 24.6 Crossed Claisen reaction to form a β-dicarbonyl compound 24.7 Dieckmann reaction to form a fi ve- or six-membered ring 24.8 Michael reaction to form a 1,5-dicarbonyl compound 24.9 Robinson annulation to form a 2-cyclohexenone 25.14 Reaction of a diazonium salt with CuCN

26.1 Coupling of an organocuprate reagent (R2CuLi) with an organic halide (R'X) 26.2 The palladium-catalyzed Suzuki reaction of an organic halide with an organoborane 26.3 The palladium-catalyzed Heck reaction of a vinyl or aryl halide with an alkene 26.4 Addition of a dihalocarbene to an alkene to form a cyclopropane

26.5 Simmons–Smith reaction of an alkene with CH2I2 and Zn(Cu) to form a cyclopropane 26.6 Olefi n metathesis 27.10B Kiliani–Fischer synthesis of an aldose 28.2B Alkylation of diethyl acetamidomalonate to form an amino acid 28.2C Strecker synthesis of an amino acid 30.2 Chain-growth polymerization 30.4 Polymerization using Ziegler–Natta catalysts A-9

smi75625_apps_1180-1197.indd 1188 11/13/09 10:57:46 AM Appendix Characteristic IR Absorption Frequencies E

Bond Functional group Wavenumber (cm–1) Comment O – H • ROH 3600–3200 broad, strong • RCOOH 3500–2500 very broad, strong

N – H

• RNH2 3500–3300 two peaks

• R2NH 3500–3300 one peak

• RCONH2, RCONHR 3400–3200 one or two peaks; N – H bending also observed at 1640 cm–1

C – H

• Csp – H 3300 sharp, often strong

• Csp2 – H 3150–3000 medium

• Csp3 – H 3000–2850 strong

• Csp2 – H of RCHO 2830–2700 one or two peaks

C – C 2250 medium

C – N 2250 medium

C – O strong • RCOCl 1800

• (RCO)2O 1800, 1760 two peaks • RCOOR 1745–1735 increasing ν~ with decreasing ring size • RCHO 1730 ~ • R2CO 1715 increasing ν with decreasing ring size

• R2CO, conjugated 1680 • RCOOH 1710 ~ • RCONH2, RCONHR, 1680–1630 increasing ν with decreasing RCONR2 ring size

C – C • Alkene 1650 medium • Arene 1600, 1500 medium C – N 1650 medium

A-10

smi75625_apps_1180-1197.indd 1189 11/13/09 10:57:46 AM Appendix F Characteristic NMR Absorptions

1H NMR Absorptions

Compound type Chemical shift (ppm) Alcohol R HO 1–5 H R OC 3.4–4.0

Aldehyde O C 9–10 R H

Alkane 0.9–2.0

RCH3 ~0.9

R2CH2 ~1.3

R3CH ~1.7

Alkene H C C sp2 C–H 4.5–6.0

C H C C allylic sp3 C–H 1.5–2.5

Alkyl halide

H RFC 4.0–4.5

H RClC 3.0–4.0

H RBrC 2.7–4.0

H CR I 2.2–4.0

Alkyne C CH ~2.5 A-11

smi75625_apps_1180-1197.indd 1190 11/13/09 10:57:47 AM Compound type Chemical shift (ppm) Amide O C 7.5–8.5 R NH

Amine R HN 0.5–5.0

R NC 2.3–3.0

Aromatic compound

H sp2 C–H 6.5–8

CH benzylic sp3 C–H 1.5–2.5

Carbonyl compound O CH C sp3 C–H on the α carbon 2.0–2.5

Carboxylic acid O C 10–12 R OH

Ether H R COR 3.4–4.0

13C NMR Absorptions

Carbon type Structure Chemical shift (ppm)

Alkyl, sp3 hybridized C C H 5–45

Alkyl, sp3 hybridized C bonded C Z 30–80 to N, O, or X Z = N, O, X

Alkynyl, sp hybridized C CC 65–100

Alkenyl, sp2 hybridized C CC 100–140

Aryl, sp2 hybridized C C 120–150

Carbonyl C C O 160–210

A-12

smi75625_apps_1180-1197.indd 1191 11/13/09 10:57:47 AM Appendix General Types G of Organic Reactions

Substitution Reactions [1] Nucleophilic substitution at an sp3 hybridized carbon atom

– a. Alkyl halides (Chapter 7) R X + Nu– NuR + X nucleophile

b. Alcohols (Section 9.11) OHR + HX XR + H2O

c. Ethers (Section 9.14) OR'R + HX XR + XR' + H2O X = Br or I

O – OH [1] Nu [2] H2O d. Epoxides (Section 9.15) CC C C or HZ Nu Nu or Z = nucleophile (Z)

[2] Nucleophilic acyl substitution at an sp2 hybridized carbon atom

Carboxylic acids and their O O derivatives (Chapter 22) C + Nu– C + Z– R Z R Nu nucleophile Z = OH, Cl, OCOR, OR', NR'2

[3] Radical substitution at an sp3 hybridized C – H bond

Alkanes (Section 15.3) R H + X XR + HX 2 hν or ∆

[4] Electrophilic aromatic substitution

Aromatic compounds H E (Chapter 18) + E+ + H+ electrophile

A-13

smi75625_apps_1180-1197.indd 1192 11/16/09 12:38:36 PM Appendix G General Types of Organic Reactions A-14

Elimination Reactions a Elimination at an sp3 hybridized carbon atom

a. Alkyl halides – (Chapter 8) CC + B CHBC +++ X H X base new π bond

b. Alcohols HA (Section 9.8) CC CHC + 2O H OH new π bond

Addition Reactions [1] Electrophilic addition to carbon–carbon multiple bonds

a. Alkenes (Chapter 10) CXC + Y CC XY

b. Alkynes XY (Section 11.6) CC + XY CC XY

[2] Nucleophilic addition to carbon–oxygen multiple bonds

Aldehydes and ketones O OH H2O (Chapter 21) C + Nu– R H(R')C R H(R') nucleophile Nu

smi75625_apps_1180-1197.indd 1193 11/13/09 10:57:48 AM Appendix How to Synthesize Particular H Functional Groups

Acetals · Reaction of an aldehyde or ketone with two equivalents of an alcohol (21.14) Acid chlorides · Reaction of a carboxylic acid with thionyl chloride (22.10) Alcohols – · Nucleophilic substitution of an alkyl halide with OH or H2O (9.6) · Hydration of an alkene (10.12) · Hydroboration–oxidation of an alkene (10.16)

· Reduction of an epoxide with LiAlH4 (12.6) · Reduction of an aldehyde or ketone (20.4)

· Hydrogenation of an α,β-unsaturated carbonyl compound with H2 + Pd-C (20.4C) · Enantioselective reduction of an aldehyde or ketone with the chiral CBS reagent (20.6)

· Reduction of an acid chloride with LiAlH4 (20.7)

· Reduction of an ester with LiAlH4 (20.7)

· Reduction of a carboxylic acid with LiAlH4 (20.7) · Reaction of an aldehyde or ketone with a Grignard or organolithium reagent (20.10) · Reaction of an acid chloride with a Grignard or organolithium reagent (20.13) · Reaction of an ester with a Grignard or organolithium reagent (20.13) · Reaction of an organometallic reagent with an epoxide (20.14B) Aldehydes · Hydroboration–oxidation of a terminal alkyne (11.10)

· Oxidative cleavage of an alkene with O3 followed by Zn or (CH3)2S (12.10) · Oxidation of a 1° alcohol with PCC (12.12) – · Oxidation of a 1° alcohol with HCrO4 , Amberlyst A-26 resin (12.13)

· Reduction of an acid chloride with LiAlH[OC(CH3)3]3 (20.7) · Reduction of an ester with DIBAL-H (20.7) · Hydrolysis of an acetal (21.14B) · Hydrolysis of an imine or enamine (21.12B) · Reduction of a nitrile (22.18B) Alkanes · Catalytic hydrogenation of an alkene with H2 + Pd-C (12.3)

· Catalytic hydrogenation of an alkyne with two equivalents of H2 + Pd-C (12.5A)

· Reduction of an alkyl halide with LiAlH4 (12.6)

A-15

smi75625_apps_1180-1197.indd 1194 11/13/09 10:57:48 AM Appendix H How to Synthesize Particular Functional Groups A-16

· Reduction of a ketone to a methylene group (CH2)—the Wolff–Kishner or Clemmensen reaction (18.14B)

· Protonation of an organometallic reagent with H2O, ROH, or acid (20.9)

· Coupling of an organocuprate reagent (R2CuLi) with an alkyl halide, R'X (26.1)

· Simmons–Smith reaction of an alkene with CH2I2 and Zn(Cu) to form a cyclopropane (26.5) Alkenes · Dehydrohalogenation of an alkyl halide with base (8.3) · Dehydration of an alcohol with acid (9.8)

· Dehydration of an alcohol using POCl3 and pyridine (9.10) · β Elimination of an alkyl tosylate with base (9.13)

· Catalytic hydrogenation of an alkyne with H2 + Lindlar catalyst to form a cis alkene (12.5B)

· Dissolving metal reduction of an alkyne with Na, NH3 to form a trans alkene (12.5C) · Wittig reaction (21.10)

· β Elimination of an α-halo carbonyl compound with Li2CO3, LiBr, and DMF (23.7C) · Hofmann elimination of an amine (25.12)

· Coupling of an organocuprate reagent (R2CuLi) with an organic halide, R'X (26.1) · The palladium-catalyzed Suzuki reaction of a vinyl or aryl halide with a vinyl- or arylborane (26.2) · The palladium-catalyzed Heck reaction of a vinyl or aryl halide with an alkene (26.3) · Olefi n metathesis (26.6) Alkyl halides · Reaction of an alcohol with HX (9.11)

· Reaction of an alcohol with SOCl2 or PBr3 (9.12) · Cleavage of an ether with HBr or HI (9.14) · Hydrohalogenation of an alkene with HX (10.9)

· Halogenation of an alkene with X2 (10.13) · Hydrohalogenation of an alkyne with two equivalents of HX (11.7)

· Halogenation of an alkyne with two equivalents of X2 (11.8) · Radical halogenation of an alkane (15.3) · Radical halogenation at an allylic carbon (15.10) · Radical addition of HBr to an alkene (15.13) · Electrophilic addition of HX to a 1,3-diene (16.10) · Radical halogenation of an alkyl benzene (18.13) · Halogenation α to a carbonyl group (23.7) · Addition of a dihalocarbene to an alkene to form a dihalocyclopropane (26.4) Alkynes · Dehydrohalogenation of an alkyl dihalide with base (11.5) – – · SN2 reaction of an alkyl halide with an acetylide anion, C – CR (11.11) Amides · Reaction of an acid chloride with NH3 or an amine (22.8)

· Reaction of an anhydride with NH3 or an amine (22.9)

· Reaction of a carboxylic acid with NH3 or an amine and DCC (22.10)

· Reaction of an ester with NH3 or an amine (22.11)

smi75625_apps_1180-1197.indd 1195 11/13/09 10:57:49 AM A-17 Appendix H How to Synthesize Particular Functional Groups

Amines · Reduction of a nitro group (18.14C)

· Reduction of an amide with LiAlH4 (20.7B) · Reduction of a nitrile (22.18B)

· SN2 reaction using NH3 or an amine (25.7A) · Gabriel synthesis (25.7A) · Reductive amination of an aldehyde or ketone (25.7C) Amino acids · SN2 reaction of an α-halo carboxylic acid with excess NH3 (28.2A) · Alkylation of diethyl acetamidomalonate (28.2B) · Strecker synthesis (28.2C) · Enantioselective hydrogenation using a chiral catalyst (28.4) Anhydrides · Reaction of an acid chloride with a carboxylate anion (22.8) · Dehydration of a dicarboxylic acid (22.10) Aryl halides · Halogenation of benzene with X2 + FeX3 (18.3)

· Reaction of a diazonium salt with CuCl, CuBr, HBF4, NaI, or KI (25.14A) Carboxylic acids · Oxidative cleavage of an alkyne with ozone (12.11) 6+ · Oxidation of a 1° alcohol with CrO3 (or a similar Cr reagent), H2O, H2SO4 (12.12B)

· Oxidation of an alkyl benzene with KMnO4 (18.14A) · Oxidation of an aldehyde (20.8)

· Reaction of a Grignard reagent with CO2 (20.14A) · Hydrolysis of a cyanohydrin (21.9) · Hydrolysis of an acid chloride (22.8) · Hydrolysis of an anhydride (22.9) · Hydrolysis of an ester (22.11) · Hydrolysis of an amide (22.13) · Hydrolysis of a nitrile (22.18A) · Malonic ester synthesis (23.9) Cyanohydrins · Addition of HCN to an aldehyde or ketone (21.9) 1,2-Diols · Anti dihydroxylation of an alkene with a peroxyacid, followed by ring opening with –OH or H2O (12.9A)

· Syn dihydroxylation of an alkene with KMnO4 or OsO4 (12.9B) Enamines · Reaction of an aldehyde or ketone with a 2° amine (21.12) Epoxides · Intramolecular SN2 reaction of a halohydrin using base (9.6) · Epoxidation of an alkene with mCPBA (12.8) · Enantioselective epoxidation of an allylic alcohol with the Sharpless reagent (12.15)

smi75625_apps_1180-1197.indd 1196 11/13/09 10:57:49 AM Appendix H How to Synthesize Particular Functional Groups A-18

Esters – · SN2 reaction of an alkyl halide with a carboxylate anion, RCOO (7.19) · Reaction of an acid chloride with an alcohol (22.8) · Reaction of an anhydride with an alcohol (22.9) · Fischer esterifi cation of a carboxylic acid with an alcohol (22.10) Ethers – · Williamson ether synthesis—SN2 reaction of an alkyl halide with an alkoxide, OR (9.6) · Reaction of an alkyl tosylate with an alkoxide, –OR (9.13) · Addition of an alcohol to an alkene in the presence of acid (10.12) · Anionic polymerization of epoxides to form polyethers (30.3) Halohydrins · Reaction of an epoxide with HX (9.15) · Addition of X and OH to an alkene (10.15) Imine · Reaction of an aldehyde or ketone with a 1° amine (21.11) Ketones · Hydration of an alkyne with H2O, H2SO4, and HgSO4 (11.9)

· Oxidative cleavage of an alkene with O3 followed by Zn or (CH3)2S (12.10) · Oxidation of a 2° alcohol with any Cr6+ reagent (12.12, 12.13) · Friedel–Crafts acylation (18.5) · Reaction of an acid chloride with an organocuprate reagent (20.13) · Hydrolysis of an imine or enamine (21.12B) · Hydrolysis of an acetal (21.14B) · Reaction of a nitrile with a Grignard or organolithium reagent (22.18C) · Acetoacetic ester synthesis (23.10) Nitriles · SN2 reaction of an alkyl halide with NaCN (7.19, 22.18) · Reaction of an aryl diazonium salt with CuCN (25.14A) Phenols · Reaction of an aryl diazonium salt with H2O (25.14A)

smi75625_apps_1180-1197.indd 1197 11/13/09 10:57:49 AM Glossary

Addition polymer (Section 30.1): A polymer prepared by a chain A reaction that adds a monomer to the growing end of a polymer Absolute confi guration (Section 27.11): The exact three-dimensional chain. Addition polymers are also called chain-growth polymers. arrangement of the stereogenic centers in a molecule. Addition reaction (Sections 6.2C, 10.8): A reaction in which ele- Acetal (Section 21.14): A compound having the general structure ments are added to a starting material. In an addition reaction, a π R2C(OR')2, where R = H, alkyl, or aryl. Acetals are used as pro- bond is broken and two σ bonds are formed. tecting groups for aldehydes and ketones. Aglycon (Section 27.7C): The alcohol formed from hydrolysis of a Acetoacetic ester synthesis (Section 23.10): A stepwise method that glycoside. converts ethyl acetoacetate into a ketone having one or two car- Alcohol (Section 9.1): A compound having the general structure α bons bonded to the carbon. ROH. An alcohol contains a hydroxy group (OH group) bonded to Acetylation (Section 22.9): A reaction that transfers an acetyl group an sp3 hybridized carbon atom. – (CH3CO ) from one atom to another. Aldaric acid (Section 27.9B): The dicarboxylic acid formed by the Acetyl coenzyme A (Section 22.17): A biochemical thioester that oxidation of the aldehyde and the primary alcohol of an aldose. acts as an acetylating reagent. Acetyl coenzyme A is often referred Aldehyde (Section 11.10): A compound having the general structure to as acetyl CoA. RCHO, where R = H, alkyl, or aryl. Acetyl group (Section 21.2E): A substituent having the structure Alditol (Section 27.9A): A compound formed by the reduction of the – COCH3. aldehyde of an aldose to a primary alcohol. Acetylide anion (Sections 11.11, 20.9B): An anion formed by treat- Aldol condensation (Section 24.1B): An aldol reaction in which the ing a terminal alkyne with a strong base. Acetylide anions have the initially formed β-hydroxy carbonyl compound loses water by – – – general structure R C – C . dehydration. Achiral molecule (Section 5.3): A molecule that is superimposable Aldol reaction (Section 24.1A): A reaction in which two molecules upon its mirror image. An achiral molecule is not chiral. of an aldehyde or ketone react with each other in the presence of Acid chloride (Sections 20.1, 22.1): A compound having the general base to form a β-hydroxy carbonyl compound. structure RCOCl. Aldonic acid (Section 27.9B): A compound formed by the oxidation Acidity constant (Section 2.3): A value symbolized by Ka that repre- of the aldehyde of an aldose to a carboxylic acid. sents the strength of an acid (HA). The larger the Ka, the stronger Aldose (Section 27.2): A monosaccharide comprised of a polyhy- the acid. droxy aldehyde. [H O+][A –] Aliphatic (Section 3.2A): A compound or portion of a compound K = 3 made up of C – C σ and π bonds but not aromatic bonds. a [H A] Alkaloid (Section 25.6A): A basic, nitrogen-containing compound Active site (Section 6.11): The region of an enzyme that binds the isolated from a plant source. substrate. Alkane (Section 4.1): An aliphatic hydrocarbon having only C – C Acyclic alkane (Section 4.1): A compound with the general formula and C – H σ bonds. CnH2n + 2. Acyclic alkanes are also called saturated hydrocarbons Alkene (Section 8.2A): An aliphatic hydrocarbon that contains a because they contain the maximum number of hydrogen atoms carbon–carbon double bond. per carbon. Alkoxide (Sections 8.1, 9.6): An anion having the general structure Acylation (Sections 18.5A, 22.17): A reaction that transfers an acyl RO–, formed by deprotonating an alcohol with a base. group from one atom to another. Alkoxy group (Section 9.3B): A substituent containing an alkyl Acyl chloride (Section 18.5A): A compound having the general group bonded to an oxygen (RO group). structure RCOCl. Acyl chlorides are also called acid chlorides. Alkylation (Section 23.8): A reaction that transfers an alkyl group Acyl group (Section 18.5A): A substituent having the general struc- from one atom to another. ture RCO – . Alkyl group (Section 4.4A): A group formed by removing one hydro- Acylium ion (Section 18.5B): A positively charged electrophile gen from an alkane. Alkyl groups are named by replacing the suf- having the general structure (R – C – O)+, formed when the fi x -ane of the parent alkane with -yl. Lewis acid AlCl3 ionizes the carbon–halogen bond of an acid Alkyl halide (Section 7.1): A compound containing a halogen atom chloride. bonded to an sp3 hybridized carbon atom. Alkyl halides have the Acyl transfer reaction (Section 22.17): A reaction that transfers an general molecular formula CnH2n + 1X. acyl group from one atom to another. 1,2-Alkyl shift (Section 9.9): The rearrangement of a less stable car- 1,2-Addition (Sections 16.10, 20.15): An addition reaction to a con- bocation to a more stable carbocation by the shift of an alkyl group jugated system that adds groups across two adjacent atoms. from one carbon atom to an adjacent carbon atom. 1,4-Addition (Sections 16.10, 20.15): An addition reaction that adds Alkyl tosylate (Section 9.13): A compound having the general struc- groups to the atoms in the 1 and 4 positions of a conjugated sys- ture ROSO2C6H4CH3. Alkyl tosylates are also called tosylates and tem. 1,4-Addition is also called conjugate addition. are abbreviated as ROTs.

G-1

smi75625_glossary_1198-1215.indd1198 1198 11/13/09 11:07:17 AM Glossary G-2

Alkyne (Section 8.10): An aliphatic hydrocarbon that contains a In a d monosaccharide, the hydroxy group on the anomeric carbon carbon–carbon triple bond. is drawn down. Allyl carbocation (Section 16.1B): A carbocation that has a positive a Anomer (Section 27.6): The stereoisomer of a cyclic monosaccha- charge on the atom adjacent to a carbon–carbon double bond. An ride in which the anomeric OH and the CH2OH groups are cis. In allyl carbocation is resonance stabilized. a d monosaccharide, the hydroxy group on the anomeric carbon Allyl group (Section 10.3C): A substituent having the structure is drawn up. – – CH2 – CH – CH2. Anomeric carbon (Section 27.6): The stereogenic center at the hemi- Allylic bromination (Section 15.10A): A radical substitution reac- acetal carbon of a cyclic monosaccharide. tion in which bromine replaces a hydrogen atom on the carbon Anti addition (Section 10.8): An addition reaction in which the two adjacent to a carbon–carbon double bond. parts of a reagent are added from opposite sides of a double bond. Allylic carbon (Section 15.10): A carbon atom bonded to a carbon– Antiaromatic compound (Section 17.7): An organic compound that carbon double bond. is cyclic, planar, completely conjugated, and has 4n π electrons. Allylic halide (Section 7.1): A molecule containing a halogen atom Antibonding molecular orbital (Section 17.9A): A high-energy bonded to the carbon atom adjacent to a carbon–carbon double molecular orbital formed when two atomic orbitals of opposite bond. phase overlap. Allyl radical (Section 15.10): A radical that has an unpaired electron Anti conformation (Section 4.10): A staggered conformation in on the carbon adjacent to a carbon–carbon double bond. An allyl which the two larger groups on adjacent carbon atoms have a dihe- radical is resonance stabilized. dral angle of 180°. Alpha (`) carbon (Sections 8.1, 19.2B): In an elimination reaction, X the carbon that is bonded to the leaving group. In a carbonyl compound, the carbon that is bonded to the carbonyl carbon. Ambident nucleophile (Section 23.3C): A nucleophile that has two X reactive sites. Amide (Sections 20.1, 22.1): A compound having the general struc- Anti dihydroxylation (Section 12.9A): The addition of two hydroxy ture RCONR'2, where R' = H or alkyl. groups to opposite faces of a double bond. Amide base (Sections 8.10, 23.3B): A nitrogen-containing base Antioxidant (Section 15.12): A compound that stops an oxidation formed by deprotonating an amine or ammonia. from occurring. Amine (Sections 21.11, 25.1): A basic organic nitrogen compound Anti periplanar (Section 8.8A): In an elimination reaction, a geom- having the general structure RNH2, R2NH, or R3N. An amine has a etry where the β hydrogen and the leaving group are on opposite nonbonded pair of electrons on the nitrogen atom. sides of the molecule. `-Amino acid (Sections 19.14A, 28.1): A compound having the gen- Aromatic compound (Section 17.1): A planar, cyclic organic com- α eral structure RCH(NH2)COOH. -Amino acids are the building pound that has p orbitals on all ring atoms and a total of 4n + 2 π blocks of proteins. electrons in the orbitals. Amino acid residue (Section 28.5): The individual amino acids in Aryl group (Section 17.3D): A substituent formed by removing one peptides and proteins. hydrogen atom from an aromatic ring. Amino group (Section 25.3D): A substituent having the structure Aryl halide (Sections 7.1, 18.3): A molecule such as C6H5X, contain- – NH2. ing a halogen atom X bonded to an aromatic ring. `-Amino nitrile (Section 28.2C): A compound having the general Asymmetric carbon (Section 5.3): A carbon atom that is bonded – structure RCH(NH2)C – N. to four different groups. An asymmetric carbon is also called a Amino sugar (Section 27.14A): A carbohydrate that contains an NH2 stereogenic center, a chiral center, or a chirality center. group instead of a hydroxy group at a non-anomeric carbon. Asymmetric reaction (Sections 12.15, 20.6A, 28.4): A reaction Ammonium salt (Section 25.1): A compound containing a positively that converts an achiral starting material into predominantly one σ + – charged nitrogen with four bonds; for example, R4N X . enantiomer. Angle strain (Section 4.11): An increase in the energy of a molecule Atactic polymer (Section 30.4): A polymer having the substituents 3 resulting when the bond angles of the sp hybridized atoms devi- randomly oriented along the carbon backbone of an elongated ate from the optimum tetrahedral angle of 109.5°. polymer chain. Angular methyl group (Section 29.8A): A methyl group located at Atomic number (Section 1.1): The number of protons in the nucleus the ring junction of two fused rings of the steroid skeleton. of an element. Anhydride (Section 22.1): A compound having the general structure Atomic weight (Section 1.1): The weighted average of the mass of all (RCO)2O. isotopes of a particular element. The atomic weight is reported in Aniline (Section 25.3C): A compound having the structure atomic mass units (amu). C6H5NH2. Axial bonds (Section 4.12A): Bonds located above or below and per- Anion (Section 1.2): A negatively charged ion that results from a neu- pendicular to the plane of the chair conformation of cyclohexane. tral atom gaining one or more electrons. Three axial bonds point upwards (on the up carbons) and three Anionic polymerization (Section 30.2C): Chain-growth polymeriza- axial bonds point downwards (on the down carbons). tion of alkenes substituted by electron-withdrawing groups that stabilize intermediate anions. Annulation (Section 24.9): A reaction that forms a new ring. Annulene (Section 17.8A): A hydrocarbon containing a single ring with alternating double and single bonds. ` Anomer (Section 27.6): The stereoisomer of a cyclic monosaccha- Azo compound (Section 25.15): A compound having the general – ride in which the anomeric OH and the CH2OH groups are trans. structure RN – NR'.

smi75625_glossary_1198-1215.indd1199 1199 11/13/09 11:07:18 AM G-3 Glossary

Bromohydrin (Section 10.15): A compound having a bromine and a B hydroxy group on adjacent carbon atoms. Backside attack (Section 7.11C): Approach of a nucleophile from Brønsted–Lowry acid (Section 2.1): A proton donor, symbolized by the side opposite the leaving group. HA. A Brønsted–Lowry acid must contain a hydrogen atom. Barrier to rotation (Section 4.10): The energy difference between Brønsted–Lowry base (Section 2.1): A proton acceptor, symbolized the lowest and highest energy conformations of a molecule. by :B. A Brønsted–Lowry base must be able to form a bond to a Base peak (Section 13.1): The peak in the mass spectrum having the proton by donating an available electron pair. greatest abundance value. Basicity (Section 7.8): A measure of how readily an atom donates its C electron pair to a proton. 13C NMR spectroscopy (Section 14.1): A form of nuclear magnetic Benedict’s reagent (Section 27.9B): A reagent for oxidizing alde- 2+ resonance spectroscopy used to determine the type of carbon hydes to carboxylic acids using a Cu salt, forming brick-red atoms in a molecule. Cu2O as a side product. Cahn–Ingold–Prelog system of nomenclature (Section 5.6): The Benzoyl group (Section 21.2E): A substituent having the structure system of designating a stereogenic center as either R or S accord- – COC6H5. ing to the arrangement of the four groups attached to the center. Benzyl group (Section 17.3D): A substituent having the structure Carbamate (Sections 28.7, 30.6): A functional group containing a – C6H5CH2 . carbonyl group bonded to both an oxygen and a nitrogen atom. A Benzylic halide (Sections 7.1, 18.13): A compound such as carbamate is also called a urethane. C6H5CH2X, containing a halogen atom X bonded to a carbon that Carbanion (Section 2.5D): An ion with a negative charge on a car- is bonded to a benzene ring. bon atom. Beta (a) carbon (Sections 8.1, 19.2B): In an elimination reaction, Carbene (Section 26.4): A neutral reactive intermediate having the the carbon adjacent to the carbon with the leaving group. In a car- general structure :CR2. A carbene contains a divalent carbon sur- bonyl compound, the carbon located two carbons from the car- rounded by six electrons, making it a highly reactive electrophile bonyl carbon. that adds to C – C double bonds. Bimolecular reaction (Sections 6.9B, 7.10, 7.13A): A reaction in Carbinolamine (Section 21.7B): An unstable intermediate having a which the concentration of both reactants affects the reaction hydroxy group and an amine group on the same carbon. A carbi- rate and both terms appear in the rate equation. In a bimolecular nolamine is formed during the addition of an amine to a carbonyl reaction, two reactants are involved in the only step or the rate- group. determining step. Carbocation (Section 7.13C): A positively charged carbon atom. A Biodegradable polymer (Section 30.9B): A polymer that can carbocation is sp2 hybridized and trigonal planar, and contains a be degraded by microorganisms naturally present in the vacant p orbital. environment. Carbohydrate (Sections 21.17, 27.1): A polyhydroxy aldehyde or Biomolecule (Section 3.9): An organic compound found in a biologi- ketone or a compound that can be hydrolyzed to a polyhydroxy cal system. aldehyde or ketone. Boat conformation of cyclohexane (Section 4.12B): An unstable Carbonate (Section 30.6D): A compound having the general struc- conformation adopted by cyclohexane that resembles a boat. – ture (RO)2C – O. The instability of the boat conformation results from torsional Carbon backbone (Section 3.1): The C – C and C – H σ bond frame- strain and steric strain. The boat conformation of cyclohexane is work that makes up the skeleton of an organic molecule. 30 kJ/mol less stable than the chair conformation. Carbon NMR spectroscopy (Section 14.1): A form of nuclear magnetic resonance spectroscopy used to determine the type of carbon atoms in a molecule. Carbonyl group (Sections 3.2C, 11.9, 20.1): A functional group that Boiling point (Section 3.4A): The temperature at which molecules contains a carbon–oxygen double bond (C – O). The polar carbon– in the liquid phase are converted to the gas phase. Molecules with oxygen bond makes the carbonyl carbon electrophilic. stronger intermolecular forces have higher boiling points. Boiling Carboxy group (Section 19.1): A functional group having the struc- point is abbreviated as bp. ture COOH. Bond dissociation energy (Section 6.4): The amount of energy Carboxylate anion (Section 19.2C): An anion having the general needed to homolytically cleave a covalent bond. structure RCOO–, formed by deprotonating a carboxylic acid with Bonding (Section 1.2): The joining of two atoms in a stable arrange- a Brønsted–Lowry base. ment. Bonding is a favorable process that leads to lowered energy Carboxylation (Section 20.14): The reaction of an organometallic and increased stability. reagent with CO2 to form a carboxylic acid after protonation. Bonding molecular orbital (Section 17.9A): A low-energy molecular Carboxylic acid (Section 19.1): A compound having the general orbital formed when two atomic orbitals of similar phase overlap. structure RCOOH. Bond length (Section 1.6A): The average distance between the cen- Carboxylic acid derivatives (Section 20.1): Compounds having the ters of two bonded nuclei. Bond lengths are reported in picometers general structure RCOZ, which can be synthesized from carbox- (pm). ylic acids. Common carboxylic acid derivatives include acid chlo- Branched-chain alkane (Section 4.1A): An acyclic alkane that has rides, anhydrides, esters, and amides. alkyl substituents bonded to the parent carbon chain. Catalyst (Section 6.10): A substance that speeds up the rate of a reac- Bridged ring system (Section 16.13D): A bicyclic ring system in tion, but is recovered unchanged at the end of the reaction and which the two rings share non-adjacent carbon atoms. does not appear in the product. Bromination (Sections 10.13, 15.6, 18.3): The reaction of a com- Catalytic hydrogenation (Section 12.3): A reduction reaction involving pound with bromine. the addition of H2 to a π bond in the presence of a metal catalyst.

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Cation (Section 1.2): A positively charged ion that results from a Combustion (Section 4.14B): An oxidation–reduction reaction, in neutral atom losing one or more electrons. which an alkane or other organic compound reacts with oxygen to Cationic polymerization (Section 30.2C): Chain-growth polymer- form CO2 and H2O, releasing energy. ization of alkene monomers involving carbocation intermediates. Common name (Section 4.6): The name of a molecule that was CBS reagent (Section 20.6A): A chiral reducing agent formed by adopted prior to and therefore does not follow the IUPAC system reacting an oxazaborolidine with BH3. CBS reagents predictably of nomenclature. give one enantiomer as the major product of ketone reduction. Compound (Section 1.2): The structure that results when two or Cephalin (Section 29.4A): A phosphoacylglycerol in which the phos- more elements are joined together in a stable arrangement. + phodiester alkyl group is – CH2CH2NH3 . Cephalins are also Concerted reaction (Sections 6.3, 7.11B): A reaction in which all called phosphatidylethanolamines. bond forming and bond breaking occurs in one step. Chain-growth polymer (Section 30.1): A polymer prepared by a chain Condensation polymer (Sections 22.16A, 30.1): A polymer formed reaction that adds a monomer to the growing end of a polymer when monomers containing two functional groups come together chain. Chain-growth polymers are also called addition polymers. with loss of a small molecule such as water or HCl. Condensation Chain mechanism (Section 15.4A): A reaction mechanism that polymers are also called step-growth polymers. involves repeating steps. Condensation reaction (Section 24.1B): A reaction in which a small Chair conformation of cyclohexane (Section 4.12A): A stable con- molecule, often water, is eliminated during the reaction process. formation adopted by cyclohexane that resembles a chair. The sta- Condensed structure (Section 1.7A): A shorthand representation of bility of the chair conformation results from the elimination of the structure of a compound in which all atoms are drawn in but angle strain (all C – C – C bond angles are 109.5°) and torsional bonds and lone pairs are usually omitted. Parentheses are used to strain (all groups on adjacent carbon atoms are staggered). denote similar groups bonded to the same atom. Confi guration (Section 5.2): A particular three-dimensional arrangement of atoms. Conformations (Section 4.9): The different arrangements of atoms Chemical shift (Section 14.1B): The position of an absorption signal that are interconverted by rotation about single bonds. on the x axis in an NMR spectrum relative to the reference signal Conjugate acid (Section 2.2): The compound that results when a of tetramethylsilane. base gains a proton in a proton transfer reaction. Chirality center (Section 5.3): A carbon atom bonded to four dif- Conjugate addition (Sections 16.10, 20.15): An addition reaction ferent groups. A chirality center is also called a chiral center, a that adds groups to the atoms in the 1 and 4 positions of a conju- stereogenic center, and an asymmetric center. gated system. Conjugate addition is also called 1,4-addition. Chiral molecule (Section 5.3): A molecule that is not superimpos- Conjugate base (Section 2.2): The compound that results when an able upon its mirror image. acid loses a proton in a proton transfer reaction. Chlorination (Sections 10.14, 15.5, 18.3): The reaction of a com- Conjugated diene (Section 16.1A): A compound that contains two pound with chlorine. carbon–carbon double bonds joined by a single σ bond. Pi (π) Chlorofl uorocarbons (Sections 7.4, 15.9): Synthetic alkyl halides electrons are delocalized over both double bonds. Conjugated having the general molecular formula CFxCl4 – x. Chlorofl uo- dienes are also called 1,3-dienes. rocarbons, abbreviated as CFCs, were used as refrigerants and Conjugated protein (Section 28.10C): A structure composed of a aerosol propellants and contribute to the destruction of the ozone protein unit and a non-protein molecule. layer. Conjugation (Section 16.1): The overlap of p orbitals on three or Chlorohydrin (Section 10.15): A compound having a chlorine and a more adjacent atoms. hydroxy group on adjacent carbon atoms. Constitutional isomers (Sections 1.4A, 4.1A, 5.2): Two compounds Chromate ester (Section 12.12A): An intermediate in the chromium- that have the same molecular formula, but differ in the way the mediated oxidation of an alcohol having the general structure atoms are connected to each other. Constitutional isomers are also R – O – CrO3H. called structural isomers. s-Cis (Sections 16.6, 28.5B): The conformation of a 1,3-diene that Coordination polymerization (Section 30.4): A polymerization has the two double bonds on the same side of the single bond that reaction that uses a homogeneous catalyst that is soluble in the joins them. reaction solvents typically used. Cis isomer (Sections 4.13B, 8.2B): An isomer of a ring or double bond Copolymer (Section 30.2D): A polymer prepared by joining two or that has two groups on the same side of the ring or double bond. more different monomers together. Claisen reaction (Section 24.5): A reaction between two molecules Core electrons (Section 1.1): The electrons in the inner shells of of an ester in the presence of base to form a β-keto ester. orbitals. Core electrons are not usually involved in the chemistry ` Cleavage (Section 13.3B): A fragmentation in mass spectrometry of a particular element. that results in cleavage of a carbon–carbon bond. With aldehydes Counterion (Section 2.1): An ion that does not take part in a reaction and ketones, α cleavage results in breaking the bond between the and is opposite in charge to the ion that does take part in the reac- carbonyl carbon and the carbon adjacent to it. With alcohols, α tion. A counterion is also called a spectator ion. cleavage occurs by breaking a bond between an alkyl group and Coupling constant (Section 14.6A): The frequency difference, mea- the carbon that bears the OH group. sured in Hz, between the peaks in a split NMR signal. Clemmensen reduction (Section 18.14B): A method to reduce aryl Coupling reaction (Section 25.15): A reaction that forms a bond ketones to alkyl benzenes using Zn(Hg) in the presence of a strong between two discrete molecules. acid. Covalent bond (Section 1.2): A bond that results from the sharing of Coenzyme (Section 12.13): A compound that acts with an enzyme to electrons between two nuclei. A covalent bond is a two-electron carry out a biochemical process. bond.

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Crossed aldol reaction (Section 24.2): An aldol reaction in which together by an N-glycosidic linkage, and a phosphate bonded to a the two reacting carbonyl compounds are different. A crossed hydroxy group of the sugar nucleus. aldol reaction is also called a mixed aldol reaction. Deprotection (Section 20.12): A reaction that removes a protecting Crossed Claisen reaction (Section 24.6): A Claisen reaction in which group, regenerating a functional group. the two reacting esters are different. Deshielding effects (Section 14.3A): An effect in NMR caused by Crown ether (Section 3.7B): A cyclic ether containing multiple oxy- a decrease in electron density, thus increasing the strength of the gen atoms. Crown ethers bind specifi c cations depending on the magnetic fi eld felt by the nucleus. Deshielding shifts an absorp- size of their central cavity. tion downfi eld. Curved arrow notation (Section 1.5A): A convention that shows Dextrorotatory (Section 5.12A): Rotating plane-polarized light in the movement of an electron pair. The tail of the arrow begins at the clockwise direction. The rotation is labeled d or (+). the electron pair and the head points to where the electron pair 1,3-Diacid (Section 23.9A): A compound containing two carbox- moves. ylic acids separated by a single carbon atom. 1,3-Diacids are also Cyanide anion (Section 21.9A): An anion having the structure called β-diacids. –C – N. Dialkylamide (Section 23.3B): An amide base having the general – Cyano group (Section 22.1): A functional group consisting of a structure R2N . carbon–nitrogen triple bond (C – N). Diastereomers (Section 5.7): Stereoisomers that are not mirror Cyanohydrin (Section 21.9): A compound having the general struc- images of each other. Diastereomers have the same R,S designa- ture RCH(OH)C – N. A cyanohydrin results from the addition of tion for at least one stereogenic center and the opposite R,S desig- HCN across the carbonyl of an aldehyde or a ketone. nation for at least one of the other stereogenic centers. Cycloalkane (Sections 4.1, 4.2): A compound that contains carbons Diastereotopic protons (Section 14.2C): Two hydrogen atoms on joined in one or more rings. Cycloalkanes with one ring have the the same carbon such that substitution of either hydrogen with a general formula CnH2n. group Z forms diastereomers. The two hydrogen atoms are not Cyclopropanation (Section 26.4): An addition reaction to a carbon– equivalent and give two NMR signals. carbon double bond that forms a cyclopropane. 1,3-Diaxial interaction (Section 4.13A): A steric interaction between two axial substituents of the chair form of cyclohexane. Larger D axial substituents create unfavorable 1,3-diaxial interactions, d-Sugar (Section 27.2C): A sugar with the hydroxy group on the ste- destabilizing a cyclohexane conformation. reogenic center farthest from the carbonyl on the right side in the Diazonium salt (Section 25.13A): An ionic salt having the general Fischer projection formula. structure (R – N – N)+Cl–. Decalin (Section 29.8A): Two fused six-membered rings. cis- Diazotization reaction (Section 25.13A): A reaction that converts 1° Decalin has the hydrogen atoms at the ring fusion on the same side alkylamines and arylamines to diazonium salts. of the rings, whereas trans-decalin has the hydrogen atoms at the 1,3-Dicarbonyl compound (Section 23.2): A compound containing ring fusion on opposite sides of the rings. two carbonyl groups separated by a single carbon atom. 1,4-Dicarbonyl compound (Section 24.4): A dicarbonyl compound H H in which the carbonyl groups are separated by three single bonds. 1,4-Dicarbonyl compounds can undergo intramolecular reactions to form fi ve-membered rings. H H 1,5-Dicarbonyl compound (Section 24.4): A dicarbonyl compound cis trans in which the carbonyl groups are separated by four single bonds. 1,5-Dicarbonyl compounds can undergo intramolecular reactions Decarboxylation (Section 23.9A): Loss of CO2 through cleavage of to form six-membered rings. a carbon–carbon bond. Dieckmann reaction (Section 24.7): An intramolecular Claisen Degenerate orbitals (Section 17.9B): Orbitals (either atomic or reaction of a diester to form a ring, typically a fi ve- or six- molecular) having the same energy. membered ring. Degree of unsaturation (Section 10.2): A ring or a π bond in a mol- Diels–Alder reaction (Section 16.12): An addition reaction ecule. The number of degrees of unsaturation compares the num- between a 1,3-diene and a dienophile to form a cyclohexene ber of hydrogens in a compound to that of a saturated hydrocarbon ring. containing the same number of carbons. 1,3-Diene (Section 16.1A): A compound containing two carbon– Dehydration (Sections 9.8, 22.10B): A reaction that results in the carbon double bonds joined by a single σ bond. Pi (π) electrons loss of the elements of water from the reaction components. are delocalized over both double bonds. 1,3-Dienes are also called Dehydrohalogenation (Section 8.1): An elimination reaction in conjugated dienes. which the elements of hydrogen and halogen are lost from a start- Dienophile (Section 16.12): The alkene component in a Diels–Alder ing material. reaction that reacts with a 1,3-diene. Delta (c) scale (Section 14.1B): A common scale of chemical Dihedral angle (Section 4.9): The angle that separates a bond on one shifts used in NMR spectroscopy in which the absorption due to atom from a bond on an adjacent atom. tetramethylsilane (TMS) occurs at zero parts per million. Dihydroxylation (Section 12.9): Addition of two hydroxy groups to Deoxy (Section 27.14B): A prefi x that means without oxygen. a double bond to form a 1,2-diol. Deoxyribonucleoside (Section 27.14B): An N-glycoside formed by Diol (Section 9.3A): A compound possessing two hydroxy groups. the reaction of d-2-deoxyribose with certain amine heterocycles. Diols are also called glycols. Deoxyribonucleotide (Section 27.14B): A DNA building block hav- Dipeptide (Section 28.5): Two amino acids joined together by one ing a deoxyribose and either a purine or pyrimidine base joined amide bond.

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Diphosphate (Section 29.7B): A good leaving group that is often the N-terminal end, the identity of the amino acid determined, and used in biological systems. Diphosphate is abbreviated as OPP. the process repeated until the entire sequence is known. Dipole (Section 1.11): A separation of electronic charge. Eicosanoids (Section 29.6): A group of biologically active compounds Dipole–dipole interaction (Section 3.3B): An attractive intermolecu- containing 20 carbon atoms derived from arachidonic acid. lar interaction between the permanent dipoles of polar molecules. Elastomer (Section 30.5): A polymer that stretches when stressed but The dipoles of adjacent molecules align so that the partial positive then returns to its original shape. and partial negative charges are in close proximity. Electromagnetic radiation (Section 13.5): Radiant energy having Directed aldol reaction (Section 24.3): A crossed aldol reaction in dual properties of both waves and particles. The electromagnetic which the enolate of one carbonyl compound is formed, followed spectrum contains the complete range of electromagnetic radia- by addition of the second carbonyl compound. tion, arbitrarily divided into different regions. Disaccharide (Section 27.12): A carbohydrate containing two mono- Electron-donating inductive effect (Section 7.14A): An induc- saccharide units joined together by a glycosidic linkage. tive effect in which an electropositive atom or polarizable group Disproportionation (Section 30.2): A method of chain termination in donates electron density through σ bonds to another atom. radical polymerization involving the transfer of a hydrogen atom Electronegativity (Section 1.11): A measure of an atom’s attraction from one polymer radical to another, forming a new C – H bond for electrons in a bond. Electronegativity indicates how much a on one polymer chain and a new double bond on the other. particular atom “wants” electrons. Dissolving metal reduction (Section 12.2): A reduction reaction Electron-withdrawing inductive effect (Sections 2.5, 7.14A): An using alkali metals as a source of electrons and liquid ammonia as inductive effect in which a nearby electronegative atom pulls elec- a source of protons. tron density towards itself through σ bonds. Disubstituted alkene (Section 8.2A): An alkene that has two alkyl Electrophile (Section 2.8): An electron-defi cient compound, often groups and two hydrogens bonded to the carbons of the double symbolized by E+, which can accept a pair of electrons from an – – bond (R2C – CH2 or RCH – CHR). electron-rich compound, forming a covalent bond. Lewis acids are Disulfi de (Section 28.5C): A compound having the general struc- electrophiles. ture RSSR', often formed between the side chain of two cysteine Electrophilic addition reaction (Section 10.9): An addition reaction residues. in which the fi rst step of the mechanism involves addition of the Diterpene (Section 29.7A): A terpene that contains 20 carbons and electrophilic end of a reagent to a π bond. four isoprene units. Electrophilic aromatic substitution (Section 18.1): A characteris- Doublet (Section 14.6): An NMR signal that is split into two peaks of tic reaction of benzene in which a hydrogen atom on the ring is equal area, caused by one nearby nonequivalent proton. replaced by an electrophile. Doublet of doublets (Section 14.8): A splitting pattern of four peaks Electrospray ionization (Section 13.4C): A method for ionizing observed when a signal is split by two different nonequivalent large biomolecules in a mass spectrometer. Electrospray ioniza- protons. tion is abbreviated as ESI. Downfi eld shift (Section 14.1B): In an NMR spectrum, a term used Electrostatic potential map (Section 1.11): A color-coded map to describe the relative location of an absorption signal. A down- that illustrates the distribution of electron density in a molecule. fi eld shift means the signal is shifted to the left in the spectrum to Electron-rich regions are indicated in red and electron-defi cient higher chemical shift on the δ scale. regions are indicated in blue. Regions of intermediate electron density are shown in orange, yellow, and green. E ` Elimination (Section 26.4): An elimination reaction involving the E,Z System of nomenclature (Section 10.3B): A system for unam- loss of two elements from the same atom. biguously naming alkene stereoisomers by assigning priorities to a Elimination (Section 8.1): An elimination reaction involving the the two groups on each carbon of the double bond. The E isomer loss of elements from two adjacent atoms. has the two higher priority groups on opposite sides of the double Elimination reaction (Sections 6.2B, 8.1): A chemical reaction in which bond, and the Z isomer has them on the same side. elements of the starting material are “lost” and a π bond is formed. E1 mechanism (Sections 8.3, 8.6): An elimination mechanism that Enamine (Section 21.12): A compound having an amine nitrogen – goes by a two-step process involving a carbocation intermediate. atom bonded to a carbon–carbon double bond [R2C – CH(NR'2)]. E1 is an abbreviation for “Elimination Unimolecular.” Enantiomeric excess (Section 5.12D): A measurement of how much E1cB mechanism (Section 24.1B): A two-step elimination mecha- one enantiomer is present in excess of the racemic mixture. Enan- nism that goes by a carbanion intermediate. E1cB stands for tiomeric excess (ee) is also called optical purity; ee = % of one “Elimination Unimolecular, Conjugate Base.” enantiomer – % of the other enantiomer. E2 mechanism (Sections 8.3, 8.4): An elimination mechanism that Enantiomers (Section 5.3): Stereoisomers that are mirror images but goes by a one-step concerted process, in which both reactants are are not superimposable upon each other. Enantiomers have the involved in the transition state. E2 is an abbreviation for “ Elimi- exact opposite R,S designation at every stereogenic center. nation Bimolecular.” Enantioselective reaction (Sections 12.15, 20.6A, 28.4): A reaction Eclipsed conformation (Section 4.9): A conformation of a molecule that affords predominantly or exclusively one enantiomer. Enanti- where the bonds on one carbon are directly aligned with the bonds oselective reactions are also called asymmetric reactions. on the adjacent carbon. Enantiotopic protons (Section 14.2C): Two hydrogen atoms on the same carbon such that substitution of either hydrogen with a group Z forms enantiomers. The two hydrogen atoms are equivalent and give a single NMR signal. Endo position (Section 16.13D): A position of a substituent on a Edman degradation (Section 28.6B): A procedure used in peptide bridged bicyclic compound in which the substituent is closer to the sequencing in which amino acids are cleaved one at a time from longer bridge that joins the two carbons common to both rings.

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Endothermic reaction (Section 6.4): A reaction in which the energy of Excited state (Sections 1.8B, 16.15A): A high-energy electronic state the products is higher than the energy of the reactants. In an endother- in which one or more electrons have been promoted to a higher mic reaction, energy is absorbed and the ∆H° is a positive value. energy orbital by absorption of energy. Energy diagram (Section 6.7): A schematic representation of the Exo position (Section 16.13D): A position of a substituent on a energy changes that take place as reactants are converted to prod- bridged bicyclic compound in which the substituent is closer to the ucts. An energy diagram indicates how readily a reaction pro- shorter bridge that joins the two carbons common to both rings. ceeds, how many steps are involved, and how the energies of the Exothermic reaction (Section 6.4): A reaction in which the energy of reactants, products, and intermediates compare. the products is lower than the energy of the reactants. In an exother- Energy of activation (Section 6.7): The energy difference between mic reaction, energy is released and the ∆H° is a negative value. the transition state and the starting material. The energy of activa- Extraction (Section 19.12): A laboratory method to separate and tion, symbolized by Ea, is the minimum amount of energy needed purify a mixture of compounds using solubility differences and to break bonds in the reactants. acid–base principles. Enolate (Sections 20.15, 23.3): A resonance-stabilized anion formed when a base removes an α hydrogen from the α carbon to a car- F bonyl group. Fat (Sections 10.6B, 29.3): A triacylglycerol that is solid at room Enol tautomer (Sections 9.1, 11.9, 20.15): A compound having a temperature and composed of fatty acid side chains with a high hydroxy group bonded to a carbon–carbon double bond. An enol degree of saturation. – tautomer [such as CH2 – C(OH)CH3] is in equilibrium with its Fatty acid (Sections 10.6A, 19.6): A long-chain carboxylic acid hav- – keto tautomer [(CH3)2C – O]. ing between 12 and 20 carbon atoms. Enthalpy change (Section 6.4): The energy absorbed or released in a Fehling’s reagent (Section 27.9B): A reagent for oxidizing aldehydes reaction. Enthalpy change is symbolized by ∆H° and is also called to carboxylic acids using a Cu2+ salt as an oxidizing agent, form- the heat of reaction. ing brick-red Cu2O as a by-product. Entropy (Section 6.6): A measure of the randomness in a system. Fibrous proteins (Section 28.10): Long linear polypeptide chains The more freedom of motion or the more disorder present, the that are bundled together to form rods or sheets. higher the entropy. Entropy is denoted by the symbol S°. Fingerprint region (Section 13.6B): The region in an IR spectrum at Entropy change (Section 6.6): The change in the amount of disorder < 1500 cm–1. The region often contains a complex set of peaks and between reactants and products in a reaction. The entropy change is unique for every compound. is denoted by the symbol ∆S°. ∆S° = S°products – S°reactants. First-order rate equation (Sections 6.9B, 7.10): A rate equation in Enzyme (Section 6.11): A biochemical catalyst composed of at least which the reaction rate depends on the concentration of only one one chain of amino acids held together in a very specifi c three- reactant. dimensional shape. Fischer esterifi cation (Section 22.10C): An acid-catalyzed esterifi - Enzyme–substrate complex (Section 6.11): A structure having a cation reaction between a carboxylic acid and an alcohol to form substrate bonded to the active site of an enzyme. an ester. Epoxidation (Section 12.8): Addition of a single oxygen atom to an Fischer projection formula (Section 27.2A): A method for repre- alkene to form an epoxide. senting stereogenic centers with the stereogenic carbon at the Epoxide (Section 9.1): A cyclic ether having the oxygen atom as part intersection of vertical and horizontal lines. Fischer projections of a three-membered ring. Epoxides are also called oxiranes. are also called cross formulas. Epoxy resin (Section 30.6E): A step-growth polymer formed from a W W fl uid prepolymer and a hardener that cross-links polymer chains Z C X = ZX together. Equatorial bonds (Section 4.12A): Bonds located in the plane of the Y Y chair conformation of cyclohexane (around the equator). Three equa- Fishhook (Section 6.3B): A half-headed curved arrow used in a reac- torial bonds point slightly upward (on the down carbons) and three tion mechanism to denote the movement of a single electron. equatorial bonds point slightly downward (on the up carbons). Flagpole hydrogens (Section 4.12B): Hydrogens in the boat conformation of cyclohexane that are on either end of the “boat” and are forced into close proximity to each other. Formal charge (Section 1.3C): The electronic charge assigned to individual atoms in a Lewis structure. The formal charge is cal- Equilibrium constant (Section 6.5A): A mathematical expression, culated by subtracting an atom’s unshared electrons and half of denoted by the symbol Keq, which relates the amount of starting its shared electrons from the number of valence electrons that a material and product at equilibrium. Keq = [products]/[starting neutral atom would possess. materials]. Formyl group (Section 21.2E): A substituent having the structure Essential oil (Section 29.7): A class of terpenes isolated from plant – CHO. sources by distillation. Four-centered transition state (Section 10.16): A transition state Ester (Sections 20.1, 22.1): A compound having the general structure that involves four atoms. RCOOR'. Fragment (Section 13.1): Radicals and cations formed by the decom- Esterifi cation (Section 22.10C): A reaction that converts a carbox- position of the molecular ion in a mass spectrometer. ylic acid or a derivative of a carboxylic acid to an ester. Freons (Sections 7.4, 15.9): Chlorofl uorocarbons consisting of sim- Ether (Section 9.1): A functional group having the general structure ple halogen-containing organic compounds that were once com- ROR'. monly used as refrigerants. Ethynyl group (Section 11.2): An alkynyl substituent having the Frequency (Section 13.5): The number of waves passing a point per structure – C – C – H. unit time. Frequency is reported in cycles per second (s–1), which

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is also called hertz (Hz). Frequency is abbreviated with the Greek Glycosidic linkage (Section 27.12): An acetal linkage formed letter nu (ν). between an OH group on one monosaccharide and the anomeric Friedel–Crafts acylation (Section 18.5A): An electrophilic aromatic carbon on a second monosaccharide. substitution reaction in which benzene reacts with an acid chloride Green chemistry (Sections 12.13, 30.8): The use of environmentally in the presence of a Lewis acid to give a ketone. benign methods to synthesize compounds. Friedel–Crafts alkylation (Section 18.5A): An electrophilic aro- Grignard reagent (Section 20.9): An organometallic reagent having matic substitution reaction in which benzene reacts with an alkyl the general structure RMgX. halide in the presence of a Lewis acid to give an alkyl benzene. Ground state (Sections 1.8B, 16.15A): The lowest energy arrange- Frontside attack (Section 7.11C): Approach of a nucleophile from ment of electrons for an atom. the same side as the leaving group. Group number (Section 1.1): The number above a particular column Full-headed curved arrow (Section 6.3B): An arrow used in a reac- in the periodic table. Group numbers are represented by either an tion mechanism to denote the movement of a pair of electrons. Arabic (1 to 8) or Roman (I to VIII) numeral followed by the letter Functional group (Section 3.1): An atom or group of atoms with A or B. The group number of a second-row element is equal to the characteristic chemical and physical properties. The functional number of valence electrons in that element. group is the reactive part of the molecule. Grubbs catalyst (Section 26.6): A widely used ruthenium catalyst – Functional group interconversion (Section 11.12): A reaction that for olefi n metathesis that has the structure Cl2(Cy3P)2Ru – CHPh. converts one functional group into another. Guest molecule (Section 9.5B): A small molecule that can bind to a Functional group region (Section 13.6B): The region in an IR spec- larger host molecule. trum at ≥ 1500 cm–1. Common functional groups show one or two peaks in this region, at a characteristic frequency. H Furanose (Section 27.6): A cyclic fi ve-membered ring of a monosac- 1H NMR spectroscopy (Section 14.1): A form of nuclear magnetic charide containing an oxygen atom. resonance spectroscopy used to determine the number and type Fused ring system (Section 16.13D): A bicyclic ring system in which of hydrogen atoms in a molecule. 1H NMR is also called proton the two rings share one bond and two adjacent atoms. NMR spectroscopy. Half-headed curved arrow (Section 6.3B): An arrow used in a reac- G tion mechanism to denote the movement of a single electron. A Gabriel synthesis (Section 25.7A): A two-step method that converts half-headed curved arrow is also called a fi shhook. an alkyl halide into a primary amine using a nucleophile derived `-Halo aldehyde or ketone (Section 23.7): An aldehyde or ketone from phthalimide. with a halogen atom bonded to the α carbon. Gas chromatography (Section 13.4B): An analytical technique that Haloform reaction (Section 23.7B): A halogenation reaction of a separates the components of a mixture based on their boiling points methyl ketone (RCOCH3) with excess halogen, which results in – and the rate at which their vapors travel through a column. formation of RCOO and CHX3 (haloform). Gauche conformation (Section 4.10): A staggered conformation in Halogenation (Sections 10.13, 15.3, 18.3): The reaction of a com- which the two larger groups on adjacent carbon atoms have a dihe- pound with a halogen. dral angle of 60°. Halohydrin (Sections 9.6, 10.15): A compound that has a hydroxy group and a halogen atom on adjacent carbon atoms. X Halonium ion (Section 10.13): A positively charged halogen atom. X A bridged halonium ion contains a three-membered ring and is formed in the addition of a halogen (X2) to an alkene. GC–MS (Section 13.4B): An analytical instrument that combines Hammond postulate (Section 7.15): A postulate that states that the a gas chromatograph (GC) and a mass spectrometer (MS) in transition state of a reaction resembles the structure of the species sequence. (reactant or product) to which it is closer in energy. gem-Diol (Section 21.13): A compound having the general structure Haworth projection (Section 27.6A): A representation of the cyclic R2C(OH)2. gem-Diols are also called hydrates. form of a monosaccharide in which the ring is drawn fl at. Geminal dihalide (Section 8.10): A compound that has two halogen Head-to-tail polymerization (Section 15.14B): A mechanism of atoms on the same carbon atom. radical polymerization in which the more substituted radical of the Gibbs free energy (Section 6.5A): The free energy of a molecule. growing polymer chain always adds to the less substituted end of Gibbs free energy is denoted by the symbol G°. the new monomer. Gibbs free energy change (Section 6.5A): The overall energy differ- Heat of hydrogenation (Section 12.3A): The ∆H° of a catalytic ence between reactants and products. The Gibbs free energy change hydrogenation reaction equal to the amount of energy released by π is denoted by the symbol ∆G°. ∆G° = G°products – G°reactants. hydrogenating a bond. Globular proteins (Section 28.10): Polypeptide chains that are Heat of reaction (Section 6.4): The energy absorbed or released in a coiled into compact shapes with hydrophilic outer surfaces that reaction. Heat of reaction is symbolized by ∆H° and is also called make them water soluble. the change in enthalpy. Glycol (Section 9.3A): A compound possessing two hydroxy groups. Heck reaction (Section 26.3): The palladium-catalyzed coupling of Glycols are also called diols. a vinyl or aryl halide with an alkene to form a more highly substi- Glycosidase (Section 27.13B): An enzyme that hydrolyzes glycosidic tuted alkene with a new carbon–carbon bond. linkages. An α-glycosidase hydrolyzes only α-glycosidic linkages. `-Helix (Section 28.9B): A secondary structure of a protein formed Glycoside (Section 27.7A): A monosaccharide with an alkoxy group when a peptide chain twists into a right-handed or clockwise bonded to the anomeric carbon. spiral. N-Glycoside (Section 27.14B): A monosaccharide containing a nitro- Heme (Section 28.10C): A complex organic compound containing an gen bonded to the anomeric carbon. Fe2+ ion coordinated with a porphyrin.

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Hemiacetal (Section 21.14A): A compound that contains an alkoxy Hydrogen bonding (Section 3.3B): An attractive intermolecular group and a hydroxy group bonded to the same carbon atom. interaction that occurs when a hydrogen atom bonded to an O, N, Hertz (Section 13.5): A unit of frequency measuring the number of or F atom is electrostatically attracted to a lone pair of electrons on waves passing a point per second. an O, N, or F atom in another molecule. Heteroatom (Section 3.1): An atom other than carbon or hydrogen. Hydrogenolysis (Section 28.7): A reaction that cleaves a σ bond Common heteroatoms in organic chemistry are nitrogen, oxygen, using H2 in the presence of a metal catalyst. sulfur, phosphorus, and the halogens. ` Hydrogens (Section 23.1): The hydrogen atoms on the carbon Heterocycle (Section 9.3B): A cyclic compound containing a hetero- bonded to the carbonyl carbon atom (the α carbon). atom as part of the ring. Hydrohalogenation (Section 10.9): An electrophilic addition of Heterolysis (Section 6.3A): The breaking of a covalent bond by hydrogen halide (HX) to an alkene or alkyne. unequally dividing the electrons between the two atoms in the Hydrolysis (Section 21.9A): A cleavage reaction with water. bond. Heterolysis generates charged intermediates. Heterolysis is Hydroperoxide (Section 15.11): An organic compound having the also called heterolytic cleavage. general structure ROOH. Hexose (Section 27.2): A monosaccharide containing six carbons. Hydrophilic (Section 3.4C): Attracted to water. The polar portion of a Highest occupied molecular orbital (Section 17.4B): The molecu- molecule that interacts with polar water molecules is hydrophilic. lar orbital with the highest energy that also contains electrons. The Hydrophobic (Section 3.4C): Not attracted to water. The nonpolar highest occupied molecular orbital is abbreviated as HOMO. portion of a molecule that is not attracted to polar water molecules High-resolution mass spectrometer (Section 13.4A): A mass spec- is hydrophobic. trometer that can measure mass-to-charge ratios to four or more a-Hydroxy carbonyl compound (Section 24.1A): An organic com- decimal places. High-resolution mass spectra are used to deter- pound having a hydroxy group on the carbon β to the carbonyl mine the molecular formula of a compound. group. Hofmann elimination (Section 25.12): An E2 elimination reaction Hydroxy group (Section 9.1): The OH functional group. that converts an amine into a quaternary ammonium salt as the Hyperconjugation (Section 7.14B): The overlap of an empty p leaving group. The Hofmann elimination gives the less substituted orbital with an adjacent σ bond. alkene as the major product. Homologous series (Section 4.1B): A group of compounds that differ I by only a CH2 group in the chain. Imide (Section 25.7A): A compound having a nitrogen atom between Homolysis (Section 6.3A): The breaking of a covalent bond by two carbonyl groups. equally dividing the electrons between the two atoms in the bond. Imine (Sections 21.7B, 21.11A): A compound with the general struc- – Homolysis generates uncharged radical intermediates. Homolysis ture R2C – NR'. Imines are also called Schiff bases. is also called homolytic cleavage. Iminium ion (Section 21.11A): A resonance-stabilized cation having – + Homopolymer (Section 30.2D): A polymer prepared from a single the general structure (R2C – NR'2) , where R' = H or alkyl. monomer. Inductive effect (Sections 2.5B, 7.14A): The pull of electron density Hooke’s law (Section 13.7): A physical law that can be used to cal- through σ bonds caused by electronegativity differences of atoms. culate the frequency of a bond vibration from the strength of the Infrared (IR) spectroscopy (Section 13.6): An analytical technique bond and the masses of the atoms attached to it. used to identify the functional groups in a molecule based on their Host–guest complex (Section 9.5B): The complex that is formed absorption of electromagnetic radiation in the infrared region. when a small guest molecule binds to a larger host molecule. Initiation (Section 15.4A): The initial step in a chain mechanism that Host molecule (Section 9.5B): A large molecule that can bind a forms a reactive intermediate by cleavage of a bond. smaller guest molecule. Inscribed polygon method (Section 17.10): A method to predict Hückel’s rule (Section 17.7): A principle that states for a compound the relative energies of cyclic, completely conjugated compounds to be aromatic, it must be cyclic, planar, completely conjugated, to determine which molecular orbitals are fi lled or empty. The and have 4n + 2 π electrons. inscribed polygon is also called a Frost circle. Hybridization (Section 1.8B): The mathematical combination of two Integration (Section 14.5): The area under an NMR signal that is or more atomic orbitals (having different shapes) to form the same proportional to the number of absorbing nuclei that give rise to number of hybrid orbitals (all having the same shape). the signal. Hybrid orbital (Section 1.8B): A new orbital that results from the Intermolecular forces (Section 3.3): The types of interactions that mathematical combination of two or more atomic orbitals. The exist between molecules. Functional groups determine the type hybrid orbital is intermediate in energy compared to the atomic and strength of these forces. Intermolecular forces are also called orbitals that were combined to form it. noncovalent interactions or nonbonded interactions. Hydrate (Sections 12.12B, 21.13): A compound having the general Internal alkene (Section 10.1): An alkene that has at least one carbon structure R2C(OH)2. Hydrates are also called gem-diols. atom bonded to each end of the double bond. Hydration (Sections 10.12, 21.9A): Addition of the elements of Internal alkyne (Section 11.1): An alkyne that has one carbon atom water to a molecule. bonded to each end of the triple bond. Hydride (Section 12.2): A negatively charged hydrogen ion (H:–). Inversion of confi guration (Section 7.11C): The opposite relative 1,2-Hydride shift (Section 9.9): Rearrangement of a less stable car- stereochemistry of a stereogenic center in the starting material and bocation to a more stable carbocation by the shift of a hydrogen product of a chemical reaction. In a nucleophilic substitution reac- atom from one carbon atom to an adjacent carbon atom. tion, inversion results when the nucleophile and leaving group are in Hydroboration (Section 10.16): The addition of the elements of the opposite position relative to the three other groups on carbon. borane (BH3) to an alkene or alkyne. Iodoform test (Section 23.7B): A test for the presence of methyl Hydrocarbon (Sections 3.2A, 4.1): A compound made up of only the ketones, indicated by the formation of the yellow precipitate, elements of carbon and hydrogen. CHI3, via the haloform reaction.

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Ionic bond (Section 1.2): A bond that results from the transfer of elec- Kinetic resolution (Section 28.3B): The separation of two enantio- trons from one element to another. Ionic bonds result from strong mers by a chemical reaction that selectively occurs for only one electrostatic interactions between ions with opposite charges. The of the enantiomers. transfer of electrons forms stable salts composed of cations and Kinetics (Section 6.5): The study of chemical reaction rates. anions. Ionophore (Section 3.7B): An organic molecule that can form a com- L plex with cations so they may be transported across a cell mem- l-Sugar (Section 27.2C): A sugar with the hydroxy group on the ste- brane. Ionophores have a hydrophobic exterior and a hydrophilic reogenic center farthest from the carbonyl on the left side in the central cavity that complexes the cation. Fischer projection formula. Isocyanate (Section 30.6C): A compound having the general struc- Lactam (Section 22.1): A cyclic amide in which the carbonyl ture RN – C – O. carbon–nitrogen σ bond is part of a ring. A β-lactam contains the Isoelectric point (Sections 19.14C, 28.1A): The pH at which an carbon–nitrogen σ bond in a four-membered ring. amino acid exists primarily in its neutral zwitterionic form. Iso- Lactol (Section 21.16): A cyclic hemiacetal. electric point is abbreviated as pI. Lactone (Section 22.1): A cyclic ester in which the carbonyl Isolated diene (Section 16.1A): A compound containing two carbon– carbon–oxygen σ bond is part of a ring. carbon double bonds joined by more than one σ bond. Le Châtelier’s principle (Section 9.8D): The principle that a sys- Isomers (Sections 1.4A, 4.1A, 5.1): Two different compounds that tem at equilibrium will react to counteract any disturbance to the have the same molecular formula. equilibrium. Isoprene unit (Section 29.7): A fi ve-carbon unit with four carbons in Leaving group (Section 7.6): An atom or group of atoms (Z) that is a row and a one-carbon branch on one of the middle carbons. able to accept the electron density of the C – Z bond during a sub- Isotactic polymer (Section 30.4): A polymer having all the substit- stitution or elimination reaction. uents on the same side of the carbon backbone of an elongated Leaving group ability (Section 7.7): A measure of how readily a polymer chain. leaving group (Z) can accept the electron density of the C – Z bond Isotope (Section 1.1): Two or more atoms of the same element having during a substitution or elimination reaction. the same number of protons in the nucleus but a different number Lecithin (Section 29.4A): A phosphoacylglycerol in which the phos- + of neutrons. Isotopes have the same atomic number but different phodiester alkyl group is – CH2CH2N(CH3)3 . Lecithins are also mass numbers. called phosphatidylcholines. IUPAC system of nomenclature (Section 4.3): A systematic method Leukotriene (Section 9.16): An unstable and potent biomole- for naming compounds developed by the International Union of cule synthesized in cells by the oxidation of arachidonic acid. Pure and Applied Chemistry. Leukotrienes are responsible for biological conditions such as asthma. K Levorotatory (Section 5.12A): Rotating plane-polarized light in the Ka (Section 2.3): The symbol that represents the acidity constant of an counterclockwise direction. The rotation is labeled l or (–). acid HA. The larger the Ka, the stronger the acid. Lewis acid (Section 2.8): An electron pair acceptor. Lewis acid–base reaction (Section 2.8): A reaction that results when [H O+][A –] a Lewis base donates an electron pair to a Lewis acid. K = 3 a [H A] Lewis base (Section 2.8): An electron pair donor. Lewis structure (Section 1.3): A representation of a molecule that Keq (Section 2.3): The equilibrium constant. Keq = [products]/[starting shows the position of covalent bonds and nonbonding electrons. In materials]. Lewis structures, unshared electrons are represented by dots and Kekulé structures (Section 17.1): Two equilibrating structures for a two-electron covalent bond is represented by a solid line. Lewis benzene. Each structure contains a six-membered ring and three π structures are also called electron dot structures. bonds alternating with σ bonds around the ring. Ligand (Section 26.2A): A group coordinated to a metal, which Ketal (Section 21.14): A compound having the general structure donates electron density to or sometimes withdraws electron den- R2C(OR')2, where R = alkyl or aryl. Ketals are derived from sity from the metal. ketones and constitute a subclass of acetals. “Like dissolves like” (Section 3.4C): The principle that compounds a-Keto ester (Section 23.10): A compound containing a ketone car- dissolve in solvents having similar kinds of intermolecular forces; bonyl on the carbon β to the ester carbonyl group. that is, polar compounds dissolve in polar solvents and nonpolar Ketone (Section 11.9): A compound with two alkyl groups bonded to the compounds dissolve in nonpolar solvents. – – C – O carbon atom, having the general structures R2C – O or RCOR'. Lindlar catalyst (Section 12.5B): A catalyst for the hydrogenation of Ketose (Section 27.2): A monosaccharide comprised of a polyhy- an alkyne to a cis alkene. The Lindlar catalyst is Pd adsorbed onto droxy ketone. CaCO3 with lead(II) acetate and quinoline. Keto tautomer (Section 11.9): A tautomer of a ketone that has a Lipid (Sections 4.15, 29.1): A biomolecule with a large number of C – O and a hydrogen bonded to the α carbon. The keto tautomer C – C and C – H σ bonds that is soluble in organic solvents and is in equilibrium with the enol tautomer. insoluble in water. Kiliani–Fischer synthesis (Section 27.10B): A reaction that length- Lone pair of electrons (Section 1.2): A pair of valence electrons that ens the carbon chain of an aldose by adding one carbon to the is not shared with another atom in a covalent bond. Lone pairs are carbonyl end. also called unshared or nonbonded pairs of electrons. Kinetic enolate (Section 23.4): The enolate that is formed the Lowest unoccupied molecular orbital (Section 17.9B): The molec- fastest—generally the less substituted enolate. ular orbital with the lowest energy that does not contain electrons. Kinetic product (Section 16.11): In a reaction that can give more The lowest unoccupied molecular orbital is abbreviated as the than one product, the product that is formed the fastest. LUMO.

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Micelles (Section 3.6): Spherical droplets formed by soap molecules M having the ionic heads on the surface and the nonpolar tails packed M peak (Section 13.1): The peak in the mass spectrum that corre- together in the interior. Grease and oil dissolve in the interior non- sponds to the mass of the molecular ion. The M peak is also called polar region. the molecular ion peak or the parent peak. Michael acceptor (Section 24.8): The α,β-unsaturated carbonyl M + 1 peak (Section 13.1): The peak in the mass spectrum that cor- compound in a Michael reaction. responds to the mass of the molecular ion plus one. The M + 1 Michael reaction (Section 24.8): A reaction in which a resonance- peak is caused by the presence of isotopes that increase the mass stabilized carbanion (usually an enolate) adds to the β carbon of of the molecular ion. an α,β-unsaturated carbonyl compound. M + 2 peak (Section 13.2): The peak in the mass spectrum that cor- Mixed aldol reaction (Section 24.2): An aldol reaction between two responds to the mass of the molecular ion plus two. The M + 2 different carbonyl compounds. A mixed aldol reaction is also peak is caused by the presence of isotopes, typically of a chlorine called a crossed aldol reaction. or a bromine atom. Mixed anhydride (Section 22.1): An anhydride with two different Macrocyclic lactone (Section 22.6A): A cyclic ester contained in a alkyl groups bonded to the carbonyl carbon atoms. large ring. Macrocyclic lactones are also called macrolides. Molecular ion (Section 13.1): The radical cation having the general Macrolide (Section 22.6A): A cyclic ester contained in a large ring. structure M+•, formed by the removal of an electron from an organic Macrolides are also called macrocyclic lactones. molecule. The molecular ion is also called the parent ion. Magnetic resonance imaging (MRI) (Section 14.12): A form of Molecular orbital theory (Section 17.9A): A theory that describes NMR spectroscopy used in medicine. bonds as the mathematical combination of atomic orbitals to form Malonic ester synthesis (Section 23.9A): A stepwise method that a new set of orbitals called molecular orbitals. Molecular orbital converts diethyl malonate into a carboxylic acid having one or two theory is also called MO theory. α carbons bonded to the carbon. Molecular recognition (Section 9.5B): The ability of a host molecule Markovnikov’s rule (Section 10.10): The rule that states in the addi- to recognize and bind specifi c guest molecules. tion of HX to an unsymmetrical alkene, the H atom bonds to the Molecule (Section 1.2): A compound containing two or more atoms less substituted carbon atom. bonded together with covalent bonds. Mass number (Section 1.1): The total number of protons and neu- Monomers (Sections 5.1, 15.14): Small organic compounds that can trons in the nucleus of a particular atom. be covalently bonded to each other (polymerized) in a repeating Mass spectrometry (Section 13.1): An analytical technique used for pattern. measuring the molecular weight and determining the molecular Monosaccharide (Section 27.2): A simple sugar having three to formula of an organic molecule. seven carbon atoms. Mass-to-charge ratio (Section 13.1): A ratio of the mass to the Monosubstituted alkene (Section 8.2A): An alkene that has one charge of a molecular ion or fragment. Mass-to-charge ratio is alkyl group and three hydrogens bonded to the carbons of the dou- abbreviated as m/z. – ble bond (RCH – CH2). Megahertz (Section 14.1A): A unit used for the frequency of the Monoterpene (Section 29.7A): A terpene that contains 10 carbons RF radiation in NMR spectroscopy. Megahertz is abbreviated as 6 and two isoprene units. MHz; 1 MHz = 10 Hz. Multiplet (Section 14.6C): An NMR signal that is split into more Melting point (Section 3.4B): The temperature at which molecules than seven peaks. in the solid phase are converted to the liquid phase. Molecules Mutarotation (Section 27.6A): The process by which a pure anomer with stronger intermolecular forces and higher symmetry have of a monosaccharide equilibrates to a mixture of both anomers higher melting points. Melting point is abbreviated as mp. when placed in solution. Merrifi eld method (Section 28.8): A method for synthesizing polypeptides using insoluble polymer supports. Meso compound (Section 5.8): An achiral compound that contains N two or more tetrahedral stereogenic centers. n + 1 rule (Section 14.6C): The rule that an NMR signal for a pro- Meta director (Section 18.7): A substituent on a benzene ring that ton with n nearby nonequivalent protons will be split into n + 1 directs a new group to the meta position during electrophilic aro- peaks. matic substitution. Natural product (Section 7.19): A compound isolated from a natural Meta isomer (Section 17.3B): A 1,3-disubstituted benzene ring. Meta source. substitution is abbreviated as m-. Newman projection (Section 4.9): An end-on representation of the Metal hydride reagent (Section 12.2): A reagent containing a polar conformation of a molecule. The Newman projection shows the metal–hydrogen bond that places a partial negative charge on the three groups bonded to each carbon atom in a particular C – C hydrogen and acts as a source of hydride ions (H:–). bond, as well as the dihedral angle that separates the groups on Metathesis (Section 26.6): A reaction between two alkene mole- each carbon. cules that results in the interchange of the carbons of their double bonds. or Methylation (Section 7.12): A reaction in which a CH3 group is transferred from one compound to another. Methylene group (Sections 4.1B, 10.3C): A CH2 group bonded to a Nitration (Section 18.4): An electrophilic aromatic substitution reac- – + carbon chain ( – CH2 – ) or part of a double bond (CH2 – ). tion in which benzene reacts with NO2 to give nitrobenzene, 1,2-Methyl shift (Section 9.9): Rearrangement of a less stable carbo- C6H5NO2. cation to a more stable carbocation by the shift of a methyl group Nitrile (Sections 22.1, 22.18): A compound having the general struc- from one carbon atom to an adjacent carbon atom. ture RC – N.

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Nitronium ion (Section 18.4): An electrophile having the structure Octet rule (Section 1.2): The general rule governing the bonding pro- + NO2. cess for second-row elements. Through bonding, second-row ele- N-Nitrosamine (Sections 7.16, 25.13B): A compound having the ments attain a complete outer shell of eight valence electrons. – general structure R2N – N – O. Nitrosamines are formed by the Oil (Sections 10.6B, 29.3): A triacylglycerol that is liquid at room reaction of a secondary amine with +NO. temperature and composed of fatty acid side chains with a high Nitrosonium ion (Section 25.13): An electrophile having the struc- degree of unsaturation. ture +NO. Olefi n (Section 10.1): An alkene; a compound possessing a carbon– NMR peak (Section 14.6A): The individual absorptions in a split carbon double bond. NMR signal due to nonequivalent nearby protons. Optically active (Section 5.12A): Able to rotate the plane of plane- NMR signal (Section 14.6A): The entire absorption due to a particu- polarized light as it passes through a solution of a compound. lar kind of proton in an NMR spectrum. Optically inactive (Section 5.12A): Not able to rotate the plane of NMR spectrometer (Section 14.1A): An analytical instrument that plane-polarized light as it passes through a solution of a compound. measures the absorption of RF radiation by certain atomic nuclei Optical purity (Section 5.12D): A measurement of how much one when placed in a strong magnetic fi eld. enantiomer is present in excess of the racemic mixture. Optical Nonbonded pair of electrons (Section 1.2): A pair of valence elec- purity is also called enantiomeric excess (ee); ee = % of one enan- trons that is not shared with another atom in a covalent bond. tiomer – % of the other enantiomer. Nonbonded electrons are also called unshared or lone pairs of Orbital (Section 1.1): A region of space around the nucleus of an electrons. atom that is high in electron density. There are four different kinds Nonbonding molecular orbital (Section 17.10): A molecular orbital of orbitals, called s, p, d, and f. having the same energy as the atomic orbitals that formed it. Order of a rate equation (Section 6.9B): The sum of the exponents Nonnucleophilic base (Section 7.8B): A base that is a poor nucleo- of the concentration terms in the rate equation of a reaction. phile due to steric hindrance resulting from the presence of bulky Organoborane (Section 10.16): A compound that contains a carbon– groups. boron bond. Organoboranes have the general structure RBH2, Nonpolar bond (Section 1.11): A covalent bond in which the elec- R2BH, or R3B. trons are equally shared between the two atoms. Organocopper reagent (Section 20.9): An organometallic reagent Nonpolar molecule (Section 1.12): A molecule that has no net dipole. having the general structure R2CuLi. Organocopper reagents are A nonpolar molecule has either no polar bonds or multiple polar also called organocuprates. bonds whose dipoles cancel. Organolithium reagent (Section 20.9): An organometallic reagent Nonreducing sugar (Section 27.9B): A carbohydrate that cannot be having the general structure RLi. oxidized by Tollens, Benedict’s, or Fehling’s reagent. Organomagnesium reagent (Section 20.9): An organometallic Normal alkane (Section 4.1A): An acyclic alkane that has all of its reagent having the general structure RMgX. Organomagnesium carbons in a row. A normal alkane is an “n-alkane” or a straight- reagents are also called Grignard reagents. chain alkane. Organometallic reagent (Section 20.9): A reagent that contains a Nuclear magnetic resonance spectroscopy (Section 14.1): A power- carbon atom bonded to a metal. ful analytical tool that can help identify the carbon and hydrogen Organopalladium compound (Section 26.2): An organometallic framework of an organic molecule. compound that contains a carbon–palladium bond. Nucleophile (Sections 2.8, 7.6): An electron-rich compound, symbol- Organophosphorus reagent (Section 21.10A): A reagent that con- ized by :Nu–, which donates a pair of electrons to an electron- tains a carbon–phosphorus bond. defi cient compound, forming a covalent bond. Lewis bases are Ortho isomer (Section 17.3B): A 1,2-disubstituted benzene ring. nucleophiles. Ortho substitution is abbreviated as o-. Nucleophilic acyl substitution (Sections 20.2B, 22.1): Substitution Ortho, para director (Section 18.7): A substituent on a benzene ring of a leaving group by a nucleophile at a carbonyl carbon. that directs a new group to the ortho and para positions during Nucleophilic addition (Section 20.2A): Addition of a nucleophile to electrophilic aromatic substitution. the electrophilic carbon of a carbonyl group followed by proton- Oxaphosphetane (Section 21.10B): An intermediate in the ation of the oxygen. Wittig reaction consisting of a four-membered ring containing a Nucleophilicity (Section 7.8A): A measure of how readily an atom phosphorus–oxygen bond. donates an electron pair to other atoms. Oxazaborolidine (Section 20.6A): A heterocycle possessing a boron, Nucleophilic substitution (Section 7.6): A reaction in which a a nitrogen, and an oxygen. An oxazaborolidine can be used to nucleophile replaces the leaving group in a molecule. form a chiral reducing agent. Nucleoside (Section 27.14B): A biomolecule having a sugar and either Oxidation (Sections 4.14A, 12.1): A process that results in a loss of a purine or pyrimidine base joined together by an N-glycosidic electrons. For organic compounds, oxidation results in an increase linkage. in the number of C – Z bonds or a decrease in the number of Nucleotide (Section 27.14B): A biomolecule having a sugar and either C – H bonds; Z = an element more electronegative than carbon. a purine or pyrimidine base joined together by an N-glycosidic Oxidative addition (Section 26.2A): The addition of a reagent to a metal, linkage, and a phosphate bonded to a hydroxy group of the sugar often increasing the number of groups around the metal by two. nucleus. Oxidative cleavage (Section 12.10): An oxidation reaction that breaks both the σ and π bonds of a multiple bond to form two oxidized products. O Oxime (Section 27.10A): A compound having the general structure – Observed rotation (Section 5.12A): The angle that a sample of an R2C – NOH. optically active compound rotates plane-polarized light. The angle Oxirane (Section 9.1): A cyclic ether having the oxygen atom as part is denoted by the symbol α and is measured in degrees (°). of a three-membered ring. Oxiranes are also called epoxides.

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Ozonolysis (Section 12.10): An oxidative cleavage reaction in which axis joining the two nuclei. Pi (π) bonds are generally weaker than a multiple bond reacts with ozone (O3) as the oxidant. σ bonds. pKa (Section 2.3): A logarithmic scale of acid strength. pKa = –log Ka. P The smaller the pKa, the stronger the acid. Para isomer (Section 17.3B): A 1,4-disubstituted benzene ring. Para Plane of symmetry (Section 5.3): A mirror plane that cuts a molecule substitution is abbreviated as p-. in half, so that one half of the molecule is the mirror refl ection of Parent ion (Section 13.1): The radical cation having the general struc- the other half. ture M+•, formed by the removal of an electron from an organic Plane-polarized light (Section 5.12A): Light that has an electric molecule. The parent ion is also called the molecular ion. vector that oscillates in a single plane. Plane-polarized light, also Parent name (Section 4.4): The portion of the IUPAC name of an called polarized light, arises from passing ordinary light through organic compound that indicates the number of carbons in the a polarizer. longest continuous chain in the molecule. Plasticizer (Section 30.7): A low molecular weight compound added Pentose (Section 27.2): A monosaccharide containing fi ve carbons. to a polymer to give it fl exibility. Peptide bond (Section 28.5): The amide bond in peptides and a-Pleated sheet (Section 28.9B): A secondary structure of a protein proteins. formed when two or more peptide chains line up side by side. Peptides (Sections 22.6B, 28.5): Low molecular weight polymers of Poisoned catalyst (Section 12.5B): A hydrogenation catalyst with less than 40 amino acids joined together by amide linkages. reduced activity that allows selective reactions to occur. The Lind- Percent s-character (Section 1.10B): The fraction of a hybrid orbital lar catalyst is a poisoned Pd catalyst that converts alkynes to cis due to the s orbital used to form it. As the percent s-character alkenes. increases, a bond becomes shorter and stronger. Polar aprotic solvent (Section 7.8C): A polar solvent that is incapa- Percent transmittance (Section 13.6B): A measure of how much ble of intermolecular hydrogen bonding because it does not con- electromagnetic radiation passes through a sample of a compound tain an O – H or N – H bond. and how much is absorbed. Polar bond (Section 1.11): A covalent bond in which the electrons Peroxide (Section 15.2): A reactive organic compound with the gen- are unequally shared between the two atoms. Unequal sharing of eral structure ROOR. Peroxides are used as radical initiators by electrons results from bonding between atoms of different electro- homolysis of the weak O – O bond. negativity values, usually with a difference of ≥ 0.5 units. Peroxyacid (Section 12.7): An oxidizing agent having the general Polarimeter (Section 5.12A): An instrument that measures the degree structure RCO3H. that a compound rotates plane-polarized light. Peroxy radical (Section 15.11): A radical having the general struc- Polarity (Section 1.11): A characteristic that results from a dipole. The ture ROO·. polarity of a bond is indicated by an arrow with the head of the arrow Petroleum (Section 4.7): A fossil fuel containing a complex mix- pointing toward the negative end of the dipole and the tail with a per- ture of compounds, primarily hydrocarbons with 1 to 40 carbon pendicular line through it at the positive end of the dipole. The polar- atoms. ity of a bond can also be indicated by the symbols δ+ and δ–. Phenol (Sections 9.1, 15.12): A compound such as C6H5OH, which Polarizability (Section 3.3B): A measure of how the electron contains a hydroxy group bonded to a benzene ring. cloud around an atom responds to changes in its electronic Phenyl group (Section 17.3D): A group formed by removal of one environment. hydrogen from benzene, abbreviated as C6H5 – or Ph – . Polar molecule (Section 1.12): A molecule that has a net dipole. A Pheromone (Section 4.1): A chemical substance used for communi- polar molecule has either one polar bond or multiple polar bonds cation in an animal or insect species. whose dipoles reinforce. Phosphatidylcholine (Section 29.4A): A phosphoacylglycerol in Polar protic solvent (Section 7.8C): A polar solvent that is capable + which the phosphodiester alkyl group is – CH2CH2N(CH3)3 . of intermolecular hydrogen bonding because it contains an O – H Phosphatidylcholines are also called lecithins. or N – H bond. Phosphatidylethanolamine (Section 29.4A): A phosphoacylglycerol Polyamide (Sections 22.16A, 30.6A): A step-growth polymer that con- + in which the phosphodiester alkyl group is – CH2CH2NH3 . Phos- tains many amide bonds. Nylon 6,6 and nylon 6 are polyamides. phatidylethanolamines are also called cephalins. Polycarbonate (Section 30.6C): A step-growth polymer that contains Phosphoacylglycerols (Section 29.4A): A lipid having a glycerol many – OC( – O)O – bonds in its backbone, often formed by – backbone with two of the hydroxy groups esterifi ed with fatty reaction of Cl2C – O with a diol. acids and the third hydroxy group as part of a phosphodiester. Polycyclic aromatic hydrocarbon (Sections 9.17, 17.5): An aro- Phosphodiester (Section 29.4): A functional group having the gen- matic hydrocarbon containing two or more benzene rings that eral formula ROPO2OR' formed by replacing two of the H atoms share carbon–carbon bonds. Polycyclic aromatic hydrocarbons are in phosphoric acid (H3PO4) with alkyl groups. abbreviated as PAHs. Phospholipid (Sections 3.7A, 29.4): A hydrolyzable lipid that con- Polyene (Section 16.7): A compound that contains three or more tains a phosphorus atom. double bonds. Phosphonium salt (Section 21.10A): An organophosphorus reagent Polyester (Sections 22.16B, 30.6B): A step-growth polymer consist- with a positively charged phosphorus and a suitable counterion; ing of many ester bonds between diols and dicarboxylic acids. + – for example, R4P X . Phosphonium salts are converted to ylides Polyether (Sections 9.5B, 30.3): A compound that contains two or upon treatment with a strong base. more ether linkages. Phosphorane (Section 21.10A): A phosphorus ylide; for example, Polymer (Sections 5.1, 15.14): A large molecule composed of smaller – Ph3P – CR2. monomer units covalently bonded to each other in a repeating Photon (Section 13.5): A particle of electromagnetic radiation. pattern. Pi (o) bond (Section 1.9B): A bond formed by side-by-side overlap Polymerization (Section 15.14A): The chemical process that joins of two p orbitals where electron density is not concentrated on the together monomers to make polymers.

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Polysaccharide (Section 27.13): A carbohydrate containing three or more monosaccharide units joined together by glycosidic linkages. Q Polyurethane (Section 30.6C): A step-growth polymer that contains Quantum (Section 13.5): The discrete amount of energy associated many – NHC( – O)O – bonds in its backbone, formed by reaction with a particle of electromagnetic radiation (i.e., a photon). of a diisocyanate and a diol. Quartet (Section 14.6C): An NMR signal that is split into four peaks Porphyrin (Section 28.10C): A nitrogen-containing heterocycle that having a relative area of 1:3:3:1, caused by three nearby nonequiv- can complex metal ions. alent protons. Primary (1°) alcohol (Section 9.1): An alcohol having the general Quaternary (4°) carbon (Section 4.1A): A carbon atom that is bonded to four other carbon atoms. structure RCH2OH. Primary (1°) alkyl halide (Section 7.1): An alkyl halide having the Quaternary protein structure (Section 28.9C): The shape adopted when two or more folded polypeptide chains aggregate into one general structure RCH2X. Primary (1°) amide (Section 22.1): An amide having the general protein complex. Quintet (Section 14.6C): An NMR signal that is split into fi ve peaks structure RCONH2. Primary (1°) amine (Sections 21.11, 25.1): An amine having the caused by four nearby nonequivalent protons. general structure RNH2. Primary (1°) carbocation (Section 7.14): A carbocation having the R + R,S System of nomenclature (Section 5.6): A system of nomencla- general structure RCH2 . Primary (1°) carbon (Section 4.1A): A carbon atom that is bonded ture that distinguishes the stereochemistry at a tetrahedral stereo- to one other carbon atom. genic center by assigning a priority to each group connected to Primary (1°) hydrogen (Section 4.1A): A hydrogen that is bonded the stereogenic center. R indicates a clockwise orientation of the to a 1° carbon. three highest priority groups and S indicates a counterclockwise Primary protein structure (Section 28.9A): The particular sequence orientation of the three highest groups. The system is also called of amino acids joined together by peptide bonds. the Cahn–Ingold–Prelog system. Primary (1°) radical (Section 15.1): A radical having the general Racemic mixture (Section 5.12B): An equal mixture of two enantiomers. A racemic mixture, also called a racemate, is optically structure RCH2·. Propagation (Section 15.4A): The middle part of a chain mechanism inactive. in which one reactive particle is consumed and another is gener- Racemization (Section 7.13C): The formation of equal amounts of ated. Propagation repeats until a termination step occurs. two enantiomers from an enantiomerically pure starting material. Prostaglandin (Section 4.15): A class of lipids containing 20 car- Radical (Sections 6.3B, 15.1): A reactive intermediate with a single bons, a fi ve-membered ring, and a COOH group. Prostaglandins unpaired electron, formed by homolysis of a covalent bond. possess a wide range of biological activities. Radical anion (Section 12.5C): A reactive intermediate containing Prosthetic group (Section 28.10C): The non-protein unit of a conju- both a negative charge and an unpaired electron. gated protein. Radical cation (Section 13.1): A species with an unpaired electron Protecting group (Section 20.12): A blocking group that renders a and a positive charge, formed in a mass spectrometer by the bom- reactive functional group unreactive so that it does not interfere bardment of a molecule with an electron beam. with another reaction. Radical inhibitor (Section 15.2): A compound that prevents radical Protection (Section 20.12): The reaction that blocks a reactive func- reactions from occurring. Radical inhibitors are also called radical tional group with a protecting group. scavengers. Proteins (Sections 22.6B, 28.5): High molecular weight polymers of Radical initiator (Section 15.2): A compound that contains an espe- 40 or more amino acids joined together by amide linkages. cially weak bond that serves as a source of radicals. Proton (Section 2.1): A positively charged hydrogen ion (H+). Radical polymerization (Section 15.14B): A radical chain reaction Proton NMR spectroscopy (Section 14.1): A form of nuclear mag- involving the polymerization of alkene monomers by adding a π netic resonance spectroscopy used to determine the number and radical to a bond. type of hydrogen atoms in a molecule. Radical scavenger (Section 15.2): A compound that prevents radical Proton transfer reaction (Section 2.2): A Brønsted–Lowry acid– reactions from occurring. Radical scavengers are also called radi- base reaction; a reaction that results in the transfer of a proton cal inhibitors. from an acid to a base. Rate constant (Section 6.9B): A constant that is a fundamental char- Purine (Section 27.14B): A bicyclic aromatic heterocycle having two acteristic of a reaction. The rate constant, symbolized by k, is a nitrogens in each of the rings. complex mathematical term that takes into account the dependence of a reaction rate on temperature and the energy of activation. N N Rate-determining step (Section 6.8): In a multistep reaction mechanism, the step with the highest energy transition state. N N Rate equation (Section 6.9B): An equation that shows the relation- H ship between the rate of a reaction and the concentration of the Pyranose (Section 27.6): A cyclic six-membered ring of a monosac- reactants. The rate equation depends on the mechanism of the charide containing an oxygen atom. reaction and is also called the rate law. Pyrimidine (Section 27.14B): A six-membered aromatic heterocycle Reaction coordinate (Section 6.7): The x axis in an energy diagram having two nitrogens in the ring. that represents the progress of a reaction as it proceeds from reactant to product. N Reaction mechanism (Section 6.3): A detailed description of how bonds are broken and formed as a starting material is converted N to a product.

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Reactive intermediate (Sections 6.3, 10.18): A high-energy unstable Ring-opening metathesis polymerization (Problem 26.29): An ole- intermediate formed during the conversion of a stable starting fi n metathesis reaction that forms a high molecular weight poly- material to a stable product. mer from certain cyclic alkenes. Reactivity–selectivity principle (Section 15.6): The chemical prin- Robinson annulation (Section 24.9): A ring-forming reaction that ciple that less reactive reagents are generally more selective, typi- combines a Michael reaction with an intramolecular aldol reaction cally yielding one major product. to form a 2-cyclohexenone. Reciprocal centimeter (Section 13.6A): The unit for wavenumber, Rule of endo addition (Section 16.13D): The rule that the endo prod- which is used to report frequency in IR spectroscopy. uct is preferred in a Diels–Alder reaction. Reducing sugar (Section 27.9B): A carbohydrate that can be oxidized by Tollens, Benedict’s, or Fehling’s reagent. S Reduction (Sections 4.14A, 12.1): A process that results in the gain of Sandmeyer reaction (Section 25.14A): A reaction between an aryl electrons. For organic compounds, reduction results in a decrease in diazonium salt and a copper(I) halide to form an aryl halide the number of C – Z bonds or an increase in the number of C – H (C6H5Cl or C6H5Br). bonds; Z = an element more electronegative than carbon. Saponifi cation (Section 22.11B): Basic hydrolysis of an ester to form Reductive amination (Section 25.7C): A two-step method that con- an alcohol and a carboxylate anion. verts aldehydes and ketones into amines. Saturated fatty acid (Section 10.6A): A fatty acid having no carbon– Reductive elimination (Section 26.2A): The elimination of two carbon double bonds in its long hydrocarbon chain. groups that surround a metal, often forming new carbon–hydrogen Saturated hydrocarbon (Section 4.1): A compound that contains or carbon–carbon bonds. only C – C and C – H σ bonds and no rings, thus having the maxi- Regioselective reaction (Section 8.5): A reaction that yields predom- mum number of hydrogen atoms per carbon. inantly or exclusively one constitutional isomer when more than Schiff base (Section 21.11A): A compound having the general struc- – one constitutional isomer is possible. ture R2C – NR'. A Schiff base is also called an imine. Resolution (Section 28.3): The separation of a racemic mixture into Secondary (2°) alcohol (Section 9.1): An alcohol having the general its component enantiomers. structure R2CHOH. Resonance (Section 14.1A): In NMR spectroscopy, when an atomic Secondary (2°) alkyl halide (Section 7.1): An alkyl halide having the nucleus absorbs RF radiation and spin fl ips to a higher energy state. general structure R2CHX. Resonance hybrid (Sections 1.5C, 16.4): A structure that is a Secondary (2°) amide (Section 22.1): An amide having the general weighted composite of all possible resonance structures. The structure RCONHR'. resonance hybrid shows the delocalization of electron density Secondary (2°) amine (Sections 21.11, 25.1): An amine having the due to the different locations of electrons in individual resonance general structure R2NH. structures. Secondary (2°) carbocation (Section 7.14): A carbocation having + Resonance structures (Sections 1.5, 16.2): Two or more structures of the general structure R2CH . a molecule that differ in the placement of π bonds and nonbonded Secondary (2°) carbon (Section 4.1A): A carbon atom that is bonded electrons. The placement of atoms and σ bonds stays the same. to two other carbon atoms. Retention of confi guration (Section 7.11C): The same relative ste- Secondary (2°) hydrogen (Section 4.1A): A hydrogen that is attached reochemistry of a stereogenic center in the reactant and the prod- to a 2° carbon. uct of a chemical reaction. Secondary protein structure (Section 28.9B): The three- Retention time (Section 13.4B): The length of time required for dimensional conformations of localized regions of a protein. a component of a mixture to travel through a chromatography Secondary (2°) radical (Section 15.1): A radical having the general column. structure R2CH·. Retro Diels–Alder reaction (Section 16.14B): The reverse of a Second-order rate equation (Sections 6.9B, 7.10): A rate equation Diels–Alder reaction in which a cyclohexene is cleaved to give a in which the reaction rate depends on the concentration of two 1,3-diene and an alkene. reactants. Retrosynthetic analysis (Section 10.18): Working backwards from a Separatory funnel (Section 19.12): An item of laboratory glassware product to determine the starting material from which it is made. used for extractions. RF radiation (Section 14.1A): Radiation in the radiofrequency Septet (Section 14.6C): An NMR signal that is split into seven peaks region of the electromagnetic spectrum, characterized by long caused by six nearby nonequivalent protons. wavelength and low frequency and energy. Sesquiterpene (Section 29.7A): A terpene that contains 15 carbons Ribonucleoside (Section 27.14B): An N-glycoside formed by the and three isoprene units. reaction of d-ribose with certain amine heterocycles. Sesterterpene (Section 29.7A): A terpene that contains 25 carbons Ribonucleotide (Section 27.14B): An RNA building block having a and fi ve isoprene units. ribose and either a purine or pyrimidine base joined together by an Sextet (Section 14.6C): An NMR signal that is split into six peaks N-glycosidic linkage, and a phosphate bonded to a hydroxy group caused by fi ve nearby nonequivalent protons. of the sugar nucleus. Sharpless asymmetric epoxidation (Section 12.15): An enantioselec- Ring-closing metathesis (Section 26.6): An intramolecular olefi n tive oxidation reaction that converts the double bond of an allylic metathesis reaction using a diene starting material, which results alcohol to a predictable enantiomerically enriched epoxide. in ring closure. Sharpless reagent (Section 12.15): The reagent used in the Sharpless Ring current (Section 14.4): A circulation of π electrons in an aro- asymmetric epoxidation. The Sharpless reagent consists of tert- matic ring caused by the presence of an external magnetic fi eld. butyl hydroperoxide, a titanium catalyst, and one enantiomer of Ring fl ipping (Section 4.12B): A stepwise process in which one chair diethyl tartrate. conformation of cyclohexane interconverts with a second chair Shielding effects (Section 14.3A): An effect in NMR caused by small conformation. induced magnetic fi elds of electrons in the opposite direction to

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the applied magnetic fi eld. Shielding decreases the strength of Staggered conformation (Section 4.9): A conformation of a mole- the magnetic fi eld felt by the nucleus and shifts an absorption cule in which the bonds on one carbon bisect the R – C – R bond upfi eld. angle on the adjacent carbon. 1,2-Shift (Section 9.9): Rearrangement of a less stable carbocation to a more stable carbocation by the shift of a hydrogen atom or an alkyl group from one carbon atom to an adjacent carbon atom. Sigma (r) bond (Section 1.8A): A cylindrically symmetrical bond Step-growth polymer (Sections 22.16A, 30.1): A polymer formed that concentrates the electron density on the axis that joins two when monomers containing two functional groups come together nuclei. All single bonds are σ bonds. with loss of a small molecule such as water or HCl. Step-growth Silyl ether (Section 20.12): A common protecting group for an alco- polymers are also called condensation polymers. hol in which the O – H bond is replaced by an O – Si bond. Stereochemistry (Sections 4.9, 5.1): The three-dimensional structure Simmons–Smith reaction (Section 26.5): Reaction of an alkene with of molecules. CH I and Zn(Cu) to form a cyclopropane. 2 2 Stereogenic center (Section 5.3): A site in a molecule at which the Singlet (Section 14.6A): An NMR signal that occurs as a single interchange of two groups forms a stereoisomer. A carbon bonded peak. to four different groups is a tetrahedral stereogenic center. A tetra- Skeletal structure (Section 1.7B): A shorthand representation of the hedral stereogenic center is also called a chirality center, a chiral structure of an organic compound in which carbon atoms and the center, or an asymmetric center. hydrogen atoms bonded to them are omitted. All heteroatoms and Stereoisomers (Sections 4.13B, 5.1): Two isomers that differ only in the hydrogens bonded to them are drawn in. Carbon atoms are the way the atoms are oriented in space. assumed to be at the junction of any two lines or at the end of a Stereoselective reaction (Section 8.5): A reaction that yields pre- line. dominantly or exclusively one stereoisomer when two or more S 1 mechanism (Sections 7.10, 7.13): A nucleophilic substitution N stereoisomers are possible. mechanism that goes by a two-step process involving a carboca- Stereospecifi c reaction (Section 10.14): A reaction in which each of tion intermediate. S 1 is an abbreviation for “Substitution Nucleo- N two stereoisomers of a starting material yields a particular stereo- philic Unimolecular.” isomer of a product. S 2 mechanism (Sections 7.10, 7.11): A nucleophilic substitution N Steric hindrance (Section 7.8B): A decrease in reactivity resulting mechanism that goes by a one-step concerted process, where both from the presence of bulky groups at the site of a reaction. reactants are involved in the transition state. S 2 is an abbreviation N Steric strain (Section 4.10): An increase in energy resulting when for “Substitution Nucleophilic Bimolecular.” atoms in a molecule are forced too close to one another. Soap (Sections 3.6, 22.12B): The carboxylate salts of long-chain Steroid (Sections 16.14C, 29.8): A tetracyclic lipid composed of fatty acids prepared by the basic hydrolysis or saponifi cation of three six-membered rings and one fi ve-membered ring. a triacylglycerol. Solubility (Section 3.4C): A measure of the extent to which a compound dissolves in a liquid. Solute (Section 3.4C): The compound that is dissolved in a liquid solvent. Solvent (Section 3.4C): The liquid component into which the solute is dissolved. Straight-chain alkane (Section 4.1A): An acyclic alkane that has all Specifi c rotation (Section 5.12C): A standardized physical constant of its carbons in a row. Straight-chain alkanes are also called nor- for the amount that a chiral compound rotates plane-polarized mal alkanes. light. Specifi c rotation is denoted by the symbol [α] and defi ned Strecker amino acid synthesis (Section 28.2C): A reaction that converts using a specifi c sample tube length (l in dm), concentration an aldehyde into an α-amino acid by way of an α-amino nitrile. (c in g/mL), temperature (25 °C), and wavelength (589 nm). Structural isomers (Sections 4.1A, 5.2): Two compounds that have [α] = α/(l × c) the same molecular formula but differ in the way the atoms are Spectator ion (Section 2.1): An ion that does not take part in a reac- connected to each other. Structural isomers are also called consti- tion and is opposite in charge to the ion that does take part in a tutional isomers. reaction. A spectator ion is also called a counterion. Substituent (Section 4.4): A group or branch attached to the longest Spectroscopy (Section 13.1): An analytical method using the inter- continuous chain of carbons in an organic molecule. action of electromagnetic radiation with molecules to determine Substitution reaction (Section 6.2A): A reaction in which an atom or molecular structure. a group of atoms is replaced by another atom or group of atoms. Sphingomyelin (Section 29.4B): A hydrolyzable phospholipid Substitution reactions involve σ bonds: one σ bond breaks and derived from sphingosine. another is formed at the same atom. Spin fl ip (Section 14.1A): In NMR spectroscopy, when an atomic Substrate (Section 6.11): An organic molecule that is transformed by nucleus absorbs RF radiation and its magnetic fi eld fl ips relative to the action of an enzyme. the external magnetic fi eld. Sulfonate anion (Section 19.13): An anion having the general structure Spin–spin splitting (Section 14.6): Splitting of an NMR signal into – RSO3 , formed by deprotonating a sulfonic acid with a Brønsted– peaks caused by nonequivalent protons on the same carbon or Lowry base. adjacent carbons. Sulfonation (Section 18.4): An electrophilic aromatic substitution Spiro ring system (Problem 23.63, Appendix B): A compound hav- + reaction in which benzene reacts with SO3H to give a benzene- ing two rings that share a single carbon atom. sulfonic acid, C6H5SO3H.

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Sulfonic acid (Section 19.13): A compound having the general struc- Tesla (Section 14.1A): A unit used to measure the strength of a mag- ture RSO3H. netic fi eld. Tesla is denoted with the symbol “T.” Suzuki reaction (Section 26.2): The palladium-catalyzed coupling of Tetramethylsilane (Section 14.1B): An internal standard used as a an organic halide (R'X) with an organoborane (RBY2) to form a reference in NMR spectroscopy. The tetramethylsilane (TMS) ref- product R – R'. erence peak occurs at 0 ppm on the δ scale. Symmetrical anhydride (Section 22.1): An anhydride that has two Tetrasubstituted alkene (Section 8.2A): An alkene that has four identical alkyl groups bonded to the carbonyl carbon atoms. alkyl groups and no hydrogens bonded to the carbons of the dou- – Symmetrical ether (Section 9.1): An ether with two identical alkyl ble bond (R2C – CR2). groups bonded to the oxygen. Tetraterpene (Section 29.7A): A terpene that contains 40 carbons Syn addition (Section 10.8): An addition reaction in which two parts and eight isoprene units. of a reagent are added from the same side of a double bond. Tetrose (Section 27.2): A monosaccharide containing four carbons. Syn dihydroxylation (Section 12.9B): The addition of two hydroxy Thermodynamic enolate (Section 23.4): The enolate that is lower in groups to the same face of a double bond. energy—generally the more substituted enolate. Syndiotactic polymer (Section 30.4): A polymer having the substitu- Thermodynamic product (Section 16.11): In a reaction that can ents alternating from one side of the backbone of an elongated give more than one product, the product that predominates at polymer chain to the other. equilibrium. Syn periplanar (Section 8.8): In an elimination reaction, a geometry Thermodynamics (Section 6.5): A study of the energy and equilib- in which the β hydrogen and the leaving group are on the same rium of a chemical reaction. side of the molecule. Thermoplastics (Section 30.7): Polymers that can be melted and then Systematic name (Section 4.3): The name of a molecule indicating molded into shapes that are retained when the polymer is cooled. the compound’s chemical structure. The systematic name is also Thermosetting polymer (Section 30.7): A complex network of called the IUPAC name. cross-linked polymer chains that cannot be re-melted to form a liquid phase. T Thioester (Section 22.17): A compound with the general structure Target compound (Section 11.12): The fi nal product of a synthetic RCOSR'. scheme. Tollens reagent (Sections 20.8, 27.9B): A reagent that oxidizes alde- Tautomerization (Sections 11.9, 23.2A): The process of converting hydes, and consists of silver(I) oxide in aqueous ammonium hydrox- one tautomer into another. ide. A Tollens test is used to detect the presence of an aldehyde. Tautomers (Section 11.9): Constitutional isomers that are in equilib- p-Toluenesulfonate (Section 9.13): A very good leaving group hav- – – rium and differ in the location of a double bond and a hydrogen ing the general structure CH3C6H4SO3 and abbreviated as TsO . atom. Compounds containing a p-toluenesulfonate leaving group are Terminal alkene (Section 10.1): An alkene that has the double bond called alkyl tosylates and are abbreviated ROTs. at the end of the carbon chain. Torsional energy (Section 4.9): The energy difference between the Terminal alkyne (Section 11.1): An alkyne that has the triple bond at staggered and eclipsed conformations of a molecule. the end of the carbon chain. Torsional strain (Section 4.9): An increase in the energy of a mol- C-Terminal amino acid (Section 28.5A): The amino acid at the end ecule caused by eclipsing interactions between groups attached to of a peptide chain with a free carboxy group. adjacent carbon atoms. N-Terminal amino acid (Section 28.5A): The amino acid at the end Tosylate (Section 9.13): A very good leaving group having the gen- – – of a peptide chain with a free amino group. eral structure CH3C6H4SO3 , and abbreviated as TsO . Termination (Section 15.4A): The fi nal step of a chain reaction. In s-Trans (Sections 16.6, 28.5B): The conformation of a 1,3-diene that a radical chain mechanism, two radicals combine to form a stable has the two double bonds on opposite sides of the single bond that bond. joins them. Terpene (Section 29.7): A lipid composed of repeating fi ve-carbon Trans diaxial (Section 8.8B): In an elimination reaction of a cyclo- isoprene units. hexane, a geometry in which the β hydrogen and the leaving group Tertiary (3°) alcohol (Section 9.1): An alcohol having the general are trans with both in the axial position. structure R3COH. Trans isomer (Sections 4.13B, 8.3B): An isomer of a ring or double Tertiary (3°) alkyl halide (Section 7.1): An alkyl halide having the bond that has two groups on opposite sides of the ring or double general structure R3CX. bond. Tertiary (3°) amide (Section 22.1): An amide having the general Transition state (Section 6.7): An unstable energy maximum as a structure RCONR'2. chemical reaction proceeds from reactants to products. The transi- Tertiary (3°) amine (Sections 21.11, 25.1): An amine having the tion state is at the top of an energy “hill” and can never be isolated. general structure R3N. Triacylglycerol (Sections 10.6, 22.12A, 29.3): A lipid consisting of Tertiary (3°) carbocation (Section 7.14): A carbocation having the the triester of glycerol with three long-chain fatty acids. Triacyl- + general structure R3C . glycerols are the lipids that comprise animal fats and vegetable Tertiary (3°) carbon (Section 4.1A): A carbon atom that is bonded to oils. Triacylglycerols are also called triglycerides. three other carbon atoms. Triose (Section 27.2): A monosaccharide containing three carbons. Tertiary (3°) hydrogen (Section 4.1A): A hydrogen that is attached Triplet (Section 14.6): An NMR signal that is split into three peaks to a 3° carbon. having a relative area of 1:2:1, caused by two nearby nonequiva- Tertiary protein structure (Section 28.9C): The three-dimensional lent protons. shape adopted by an entire peptide chain. Trisubstituted alkene (Section 8.2A): An alkene that has three alkyl Tertiary (3°) radical (Section 15.1): A radical having the general groups and one hydrogen bonded to the carbons of the double – structure R3C·. bond (R2C – CHR).

smi75625_glossary_1198-1215.indd1214 1214 11/13/09 11:07:24 AM Glossary G-18

Triterpene (Section 29.7A): A terpene that contains 30 carbons and Vitamins (Sections 3.5, 29.5): Organic compounds needed in small six isoprene units. amounts by biological systems for normal cell function. VSEPR theory (Section 1.6B): Valence shell electron pair repulsion U theory. A theory that determines the three-dimensional shape of Ultraviolet (UV) light (Section 16.15): Electromagnetic radiation a molecule by the number of groups surrounding a central atom. with a wavelength from 200–400 nm. The most stable arrangement keeps the groups as far away from Unimolecular reaction (Sections 6.9B, 7.10, 7.13A): A reaction that each other as possible. has only one reactant involved in the rate-determining step, so the concentration of only one reactant appears in the rate equation. W `,a-Unsaturated carbonyl compound (Section 20.15): A con- Walden inversion (Section 7.11C): The inversion of a stereogenic jugated compound containing a carbonyl group and a carbon– center involved in an SN2 reaction. carbon double bond separated by a single σ bond. Wavelength (Section 13.5): The distance from one point of a wave Unsaturated fatty acid (Section 10.6A): A fatty acid having one to the same point on the adjacent wave. Wavelength is abbreviated or more carbon–carbon double bonds in its hydrocarbon chain. with the Greek letter lambda (λ). In natural fatty acids, the double bonds generally have the Z Wavenumber (Section 13.6A): A unit for the frequency of electro- confi guration. magnetic radiation that is inversely proportional to wavelength. Unsaturated hydrocarbon (Section 10.2): A hydrocarbon that has Wavenumber, reported in reciprocal centimeters (cm–1), is used fewer than the maximum number of hydrogen atoms per carbon for frequency in IR spectroscopy. atom. Hydrocarbons with π bonds or rings are unsaturated. Wax (Sections 4.15, 29.2): A hydrolyzable lipid consisting of an ester Unsymmetrical ether (Section 9.1): An ether in which the two alkyl formed from a high molecular weight alcohol and a fatty acid. groups bonded to the oxygen are different. Williamson ether synthesis (Section 9.6): A method for preparing Upfi eld shift (Section 14.1B): In an NMR spectrum, a term used to ethers by reacting an alkoxide (RO–) with a methyl or primary describe the relative location of an absorption signal. An upfi eld alkyl halide. shift means a signal is shifted to the right in the spectrum to lower Wittig reaction (Section 21.10): A reaction of a carbonyl group and chemical shift. an organophosphorus reagent that forms an alkene. Urethane (Section 30.6C): A compound that contains a carbonyl Wittig reagent (Section 21.10A): An organophosphorus reagent hav- – group bonded to both an OR group and an NHR (or NR2) group. A ing the general structure Ph3P – CR2. urethane is also called a carbamate. Wohl degradation (Section 27.10A): A reaction that shortens the carbon chain of an aldose by removing one carbon from the alde- V hyde end. Valence bond theory (Section 17.9A): A theory that describes cova- Wolff–Kishner reduction (Section 18.14B): A method to reduce aryl lent bonding as the overlap of two atomic orbitals with the elec- ketones to alkyl benzenes using hydrazine (NH2NH2) and strong tron pair in the resulting bond being shared by both atoms. base (KOH). Valence electrons (Section 1.1): The electrons in the outermost shell of orbitals. Valence electrons determine the properties of a given Y element. Valence electrons are more loosely held than the core Ylide (Section 21.10A): A chemical species that contains two oppo- electrons and thus participate in chemical reactions. sitely charged atoms bonded to each other, and both atoms have van der Waals forces (Section 3.3B): Very weak intermolecular inter- octets of electrons. actions caused by momentary changes in electron density in molecules. The changes in electron density cause temporary dipoles, Z which are attracted to temporary dipoles in adjacent molecules. Zaitsev rule (Section 8.5): In a β elimination reaction, a rule that van der Waals forces are also called London forces. states that the major product is the alkene with the most substi- Vicinal dihalide (Section 8.10): A compound that has two halogen tuted double bond. atoms on adjacent carbon atoms. Ziegler–Natta catalysts (Section 30.4): Polymerization catalysts Vinyl group (Section 10.3C): An alkene substituent having the struc- prepared from an organoaluminum compound and a Lewis acid – ture – CH – CH2. such as TiCl4, which afford polymer chains without signifi cant Vinyl halide (Section 7.1): A molecule containing a halogen atom branching and with controlled stereochemistry. bonded to the sp2 hybridized carbon of a carbon–carbon double Zwitterion (Sections 19.14B, 28.1B): A neutral compound that con- bond. tains both a positive and negative charge.

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smi75625_credits_1216-1217.indd 1217 11/19/09 9:24:10 AM Index

Page numbers followed by f indicate fi gures; those followed by t indicate tables. An A– before page numbers indicates appendix pages.

ABS, 1174 Acetophenone, 731, 913, 946, 996 as proton donors, 55 butane, 134–137, 134f, 136f Acebutolol, 110 aldol reaction of, 919 reaction of ethers with strong, 341–343 ethane, 129–134, 132f, 133f Acetal(s) structure of, 778 strength, 58–70 constitutional isomers, 115–117, conversion to hemiacetals, 807–808 N-Acetyl amino acids, 1082 sulfonic, 709–710 118t cyclic, 804 Acetylation, 845 Acid–base reactions having more than fi ve carbon atoms, in carbohydrates, 812–813 Acetyl chloride, 226, 1046 Brønsted–Lowry, 56–58, 254 117–118, 118t conversion of cyclic hemiacetal to, structure of, 826, 830 description, 56–58 having one to fi ve carbon atoms, 811–812 Acetylcholine, 861 Lewis, 73–74, 235 114–117, 118t glycosides, 1043–1045 Acetyl CoA, 860–862, 1134, 1140 organometallic reagents and, 741 homologous series, 117, 118t hydrolysis of, 807–808 1-Acetylcyclohexene, 909 predicting outcome of, 61–62 molecular formula, 114, 118, 118t as protecting groups, 808–809 1-Acetylcyclopentene, 945 Acid chlorides normal (n) (straight-chain), 117–118, structure of, 1042 Acetylene acidity/basicity of, 829, 829t 118t synthesis of, 820 acetylide anion formation from, boiling point of, 834t structure, 114–115 addition of alcohols to aldehydes 418–419 functional group in, 86t torsional and steric strain energies and ketones, 804–807 in acid–base reactions, 61–62 IR spectra of, 835, 835t in, 136t from hemiacetals, 805–806, acidity of, 67–68, 69f leaving group, 725 Acylases, 1084 811–812 bond dissociation energies of, melting point of, 834t Acylation terminology of, 804 400–401 NMR spectra of, 836 defi nition of, 648 Acetaldehyde, 820 bonds in, 38, 39, 39f, 40f nomenclature of, 830, 833, 833t Friedel–Crafts. See Friedel–Crafts aldol reaction of, 917, 919, 922 combustion of, 402 nucleophilic substitution reactions, 725 acylation ethanol oxidized to, 451 deprotonation of, 418 odor of, 842 Acyl derivatives, 722 structure of, 777 disparlure synthesis from, 441, 442f physical properties of, 834t Acyl group, 648, 830 Acetamide, structure of, 826, 831 electrostatic potential map of, 405, pKa, 829t naming, 779 Acetaminophen, 845, 856, 874, 999, 405f reactions of, 842–843, 858t Acylium ion, 471–472, 649–650 1132 functional group in, 83, 84t with ammonia or amines to form Acyl transfer reactions, 860–862, 861f Acetanilide, 717 Lewis structure, 15 amides, 975–976 Addition polymers. See Chain-growth Acetate molecular shape of, 24, 26f conversion to amides, 842 polymers formation from acetaldehyde oxidation, nomenclature, 402 conversion to anhydrides, 842, 843 Addition reactions 451 N-Acetyl-d-glucosamine (NAG), 862, conversion to carboxylic acids, in alkenes, 370–390, A–14 as nucleophile, 243–245, 252 1061–1062 842, 843 anti addition, 371, 377, 378t, 380, resonance structures of, 67–68, 67f, Acetyl group, 1046 conversion to esters, 842 382, 384 575–576, 701, 703f abbreviation for, 1006 Friedel–Crafts acylation reactions, halogenation, 371f, 379–383, 382f Acetate (fabric), 1060 structure, 779 648 halohydrin formation, 371f, Acetic acid, 107, 695, 716, 872 Acetylide anions, 61–62 with organometallic reagents, 383–385, 385f, 385t acidity of, 66–67, 70, 701, 704 conversion of terminal alkynes to, 414 750–753 hydration, 371f, 378–379, 390 as Brønsted–Lowry acid, 55f formation by deprotonation of terminal reduction of, 734 hydroboration–oxidation, 371f, electrostatic potential plot of, 67f, alkynes, 405–406 solubility of, 834t 385–390, 387f, 388f, 389f, 689, 689f as organometallic compounds, 740 stability of, 829 389t in ethyl acetate formation, 218–219 reactions with alkyl halides, 414–416 structure and bonding of, 722, 826, hydrohalogenation, 371–378, 371f, glacial, 695 reactions with epoxides, 416–417 828–829 372f, 373f, 374f, 377f, 378t halogenation of carbonyl compounds retrosynthetic analysis with, 418–419 synthesis from carboxylic acids, overview of, 370–371, 371f in, 893 synthesis from acetylene, 418–419 845–847, 846f stereochemistry of, 371, 376–378, melting point of, 93 in synthesis of disparlure, 441, 442f Acidity 378t NMR spectrum of, 523 Acetylsalicylic acid, 54, 696, 856. See basicity, inverse relationship with, syn addition, 371, 377, 378t, 386, pKa of, 701 also Aspirin 59, 59t 388–389 as polar protic solvent, 240f Achiral carbocation, 376 of carbon–hydrogen bonds, 64 allylic bromination, 554 resonance structures, 578 Achiral enolate, 891 of carboxylic acids, 689, 699, 700–705, anti additions, 434, 436, 442, 443 structure of, 691t, 826 Achiral epoxides, 443 703f carbene addition, 1013 Acetic anhydride, 826, 830, 1046 Achiral intermediate, 381 determining relative acidity of protons, conjugate, 934 Acetic benzoic anhydride, 830 Achiral meso compound, 178, 382, 382f 69–70 in conjugated dienes Acetoacetic ester synthesis, 900, 903–905, Achiral molecules, 164–166, 165f electronegativity and, 63–66 Diels–Alder reaction, 588–597, 932 halogenation of, 549–550 factors affecting, 62–70 589f Acetone, 566 optical inactivity of, 182–183 element effects, 63–65, 69f electrophilic, 584–586 acidity of, 67 Achiral product, 376 hybridization effects, 67–68, 68f, kinetic versus thermodynamic aldol reactions of, 922 Achiral reactant, 344, 376 69f product, 586–588 as Brønsted–Lowry base, 55f, 56 Acid(s) inductive effects, 65–66, 66f, 69f description of, 199 dipoles in adjacent molecules, 89 amino. See Amino acids resonance effects, 66–67, 67f, 69f dihydroxylation, 442–444 odor of, 783 Brønsted–Lowry periodic trends in, 63–65 epoxidation, 439–442, 451–454 as polar aprotic solvent, 241, 241f carboxylic acids, 699–703 Acidity constant (Ka), 58–59 exothermic reactions, 372, 372f solubility of, 94–95 description of, 55–56 Acid rain, 70 oxidative, 1006, 1008, 1011 structure and bonding of, 39, 778, reactions of, 56–58 Acrolein, 591f radical reactions, 554, 558–560 783 carboxylic. See Carboxylic acid(s) Acrylic acid, 561 syn additions, 434, 440, 442, 442f, surface area and boiling point of, 91f as catalysts, 218–219 Acrylonitrile, 1155f 443–444, 1013 uses of, 783 common, 70 Activation energy. See Energy of Adenine, 1064, 1065f Acetone enolate, 885, 891f conjugate, 56–58, 236–237, 237t activation (Ea) S-Adenosylmethionine (SAM), 250 Acetonitrile dehydration of alcohols to alkenes in Active methylene compounds, 923–924, ADHD, 191. See also Attention defi cit acidity of, 67 strong, 325–330 934 hyperactivity disorder deprotonation of, 62 as electron pair acceptors, 55, 58, 72 Active site, enzyme, 219, 220f -adiene (suffi x), 362 as polar aprotic solvent, 241f in epoxide ring opening reactions, Acyclic alkanes Adipic acid, 875, 1160 structure of, 832f 345–347 branched-chain, 115 Adipoyl chloride, 859 p-Acetophenetidin, 874 Lewis, 72–74 conformations of, 129–137 Adrenal cortical steroids, 1141, 1142 I-1

smi75625_index_1218-1246.indd 1218 11/24/09 12:13:30 PM Index I-2

Adrenaline, 228 from nucleophilic addition to -aldehyde (suffi x), 777 reduction of esters, 734 structure of, 958 aldehydes, 735 Aldehyde dehydrogenase, 451 reduction of nitriles, 865 synthesis of, 228, 251, 251f oxidation to carboxylic acids, 447, Aldehyde group, as electron-withdrawing unreactivity to nucleophilic Advair. See Fluticasone 448–450, 698 group, 655–656 substitution, 725–726 Advil. See Ibuprofen from reactions of aldehydes Aldehydes. See also Carbonyl Wittig reaction, 792–797 Aerosol propellant, 233, 551 with organometallic reagents, compounds Alditol, 1047 Agent Orange, 646f 742–743 aldol reactions of, 917–919, 922–923, Aldohexoses, 1053–1056 Aglycon, 1045 from reduction of acid chlorides, 925–926 d-aldohexoses, 1034–1035, 1035f, -al (suffi x), 776 734 boiling point of, 780t 1054f Alanine, 105 from reduction of aldehydes, 432, carbohydrates, 812–813 Haworth projections of, 1039–1040 abbreviation for, 711t 727, 728, 729 electrostatic potential map of, 723, pyranose ring of, 1037 acid–base reactions of, 712, 712f from reduction of carboxylic acid 723f stereogenic centers of, 1032, 1034 in dipeptide synthesis, 1094–1098 derivatives, 727 fragmentation pattern in mass Aldol reactions enantiomers of, 168f from reduction of carboxylic acids, spectrum, 471 crossed, 921–924 N-acetyl, 1082–1084 735 functional group in, 86t synthetically useful reactions, isoelectric point of, 713, 1078t from reduction of esters, 734 hydration of, 802–804 922–924, 923f in peptide formation, 1086–1087 from reduction of monosaccharides, kinetics of hydrate formation, useful transformations of aldol pKa values for, 1078t 1047 803–804 products, 924, 924f structure of, 104f, 1076f reactions of thermodynamics of hydrate dehydration of aldol product, 919–920 Albuterol, 167, 347, 347f, 819, 1001 conversion to alkyl halides with formation, 802–803 directed, 925–926, 925f Alcohol dehydrogenase, 451 HX, 331–335, 337t hydroxy features of, 917–919, 918f Alcoholic beverages, 319, 426 conversion to alkyl halides with cyclization of, 810, 813 intramolecular, 926–928, 928f Alcohols, 312–357, 449–450, 449f thionyl chloride and phosphorus β-hydroxy, synthesis in aldol in Robinson annulation, 936–939 alkene preparation by acid-catalyzed tribromide, 335–337, 337t reactions, 917–928 mechanism of, 917–918 dehydration, 369–370 conversion to alkyl tosylates, intramolecular cyclization of, 810, retrosynthetic analysis using, 920–921 allylic, epoxidation of, 452–453 338–340 813 Aldonic acid, 1047–1048 boiling point of, 318t elimination reactions, 323–331 melting point of, 780t d-Aldopentoses, 1034, 1035f, 1053, 1054f bonding in, 314 general features, 323–324 nomenclature, 776–777, 779 Aldoses classifi cation of, 313 nucleophilic substitution reactions, common names, 777, 777f d-aldose family, 1034–1035, 1035f dehydration reactions of, 324–331 323–324, 331–338 IUPAC system, 776, 777f in Kiliani–Fischer synthesis, 1049, alkene synthesis in, 324–331 summary of, 341, 341f nucleophilic addition reactions, 724, 1051–1056 carbocation rearrangements in, secondary (2°), 390 774–813 oxidation of, 1047–1049 328–330 classifi cation as, 313 acid-catalyzed, 787 reduction of, 1047 dehydration to alkenes, 324–331, conversion to alkyl halides with carbanion addition, 789–790 structure of, 1028–1029 327f, 331f HX, 332–334, 337t cyanide addition, 790–791 in Wohl degradation, 1049, 1050 E1 mechanism in, 326 conversion to alkyl halides with hydride addition, 789 Aldosterone, 1142 E2 mechanism in, 327, 330–331 phosphorus tribromide, 336, mechanism of, 786–787 Aldotetroses enthalpy change in, 327, 327f 337t nucleophiles in, 787–788, 788f d-aldotetroses, 1034, 1034f, 1035f, of β-hydroxy carbonyl compounds, conversion to alkyl halides with primary amine addition, 797–799, 1052 919–920 thionyl chloride, 335–336, 337t 801f stereoisomers of, 1034, 1034f Le Châtelier’s principle in, dehydration by E1 mechanism, secondary amine addition, 800–801, Aldrin, 604 327–328 326 801f Alendronic acid (Fosamax), 18 in phosphorus oxychloride and hydrogen bonding extent, 318 odors of, 783, 783f Aleve. See Naproxen pyridine, 330–331 oxidation to ketones, 447, 448, 450 oxidation reactions, 726–727, Aliphatic carboxylic acids, 703–704 in strong acid, 325–330 from reactions of aldehydes 738–739 Aliphatic hydrocarbons, 83, 114. See also electrostatic potential maps, 314f with organometallic reagents, to carboxylic acids, 1047–1048 Alkanes; Alkenes; Alkynes elimination reactions, 341 742–743 physical properties of, 779, 780t Aliskiren, 167 ether formation from, 378, 379 from reduction of ketones, 432, pKa, 886t Alizarin, 988 fragmentation pattern in mass 727, 728, 729 polyhydroxy, 812–813 Alizarine yellow R, 989 spectrum, 471 solubility, 318t protecting groups for, 808–809 Alkaloids, 957, 957f Friedel–Crafts alkylation of, 652 structure of, 313, 314 reactions of Alkanes, 113–158 functional group, 83, 85t substitution reactions, 341 with amines, 975 acyclic β-hydroxy carbonyl compounds, synthesis of, 321–322 at α carbon, 785–786 branched-chain, 115 917–928 from alkyl halides, 321–322 at carbonyl carbon, 785, 786 conformations of, 129–137, 132f, infrared (IR) spectra of, 482 hydration of alkenes, 378–379 halogenation at α carbon, 892–895, 133f, 134f, 136f interesting examples, 319, 320f hydroboration–oxidation of alkenes, 895f constitutional isomers, 115–117, leaving groups of, 324, 330–332, 385–390 with organometallic reagents, 118t 335–336, 338–339 by nucleophilic substitution 742–745, 745f, 789–790 having more than fi ve carbon atoms, melting point of, 318t reaction, 321–322 reactivity of, 724 117–118, 118t NMR spectra of, 518, 519 reactions of organometallic reagents reduction of, 789–790 having one to fi ve carbon atoms, nomenclature, 314–316 with aldehydes and ketones, to alcohols, 432, 727, 728, 729 114–117, 118t common names, 315–316 742–743, 789–790 reductive amination to amines, homologous series, 117, 118t for cyclic alcohols, 315, 315f reactions of organometallic reagents 963–966 molecular formula, 114, 118, 118t IUPAC system, 314–316 with epoxides, 754–755 solubility of, 780t normal (n) (straight-chain), 117– nucleophilicity of, 263 reduction of epoxides, 437–438, structure of, 722, 775 118, 118t oxidation of, 439f, 447–450, 451 438f synthesis of, 784 structure of, 114–115 patchouli, 331f tertiary (3°) alcohol oxidation, 447, 448–449, torsional and steric strain energies physical properties of, 318–319, 318t classifi cation as, 313 450 in, 136t as polar protic solvents, 240, 240f, 264 conversion to alkyl halides with carboxylic acid reduction, 727 boiling point of, 129, 130t primary (1°), 390 HX, 332–334, 337t hydroboration–oxidation of alkynes, combustion of, 148–149 classifi cation as, 313 dehydration by E1 mechanism, 326 412–413, 784 cycloalkanes conversion to alkyl halides with hydrogen bonding extent, 318 hydrolysis of acetals, 807–808 molecular formula, 114, 118 HX, 332–334, 337t from reaction of esters and acid hydrolysis of imines and enamines, naming, 125–127, 126f, 127f conversion to alkyl halides with chlorides with organometallic 801 structure, 114, 118 phosphorus tribromide, 336, reagents, 750–752 oxidation of primary alcohols, 784 substituted, 141–147, 143f, 146f 337t from reaction of ketones with oxidative cleavage of alkenes, fossil fuels, 128–129 conversion to alkyl halides with organometallic reagents, 444–446, 785 halogenation, 541–551 thionyl chloride, 335–336, 337t 742–743 reduction of acid chlorides, 734 of achiral starting material, dehydration by E2 mechanism, 327 Aldaric acids, 1047, 1049, 1054–1056 reduction of acid chlorides and 549–550, 549t hydrogen bonding extent, 318 d-aldaric acids, 1052 esters, 784 bromination, 546–547, 547f

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Alkanes (continued) mechanism of catalytic synthesis of example of, 229f halogenation (continued) hydrogenation, 430–431 Friedel–Crafts alkylation, 643f, SN2 substitution reactions, 248, 262, of chiral starting material, 549t, 550 infrared (IR) spectra of, 481 647–648 262f, 302f chlorination, 544–548, 544f, 545f, interesting examples, 366, 366f, 367f by reduction of aryl ketones, synthesis of, 332, 335, 336 548f, 549–551 internal, 359 672–673 reaction mechanism, determining type energy changes during, 544, 544f, lipids, 366–369 Alkylboranes of, 300–304 545f melting point of, 365, 368, 368t formation by hydroboration, 385–387, reduction of, 437–438, 438f mechanism of, 542–544 metathesis, 1015–1019, 1016f, 1018f 387f secondary (2°) in organic synthesis, 548–549 molecular formula of, 360 oxidation of, 388–389 acetylide anion reactions with, stereochemistry of, 549–551, 549t monomers in polymerization, 561–563, Alkyl bromides 414–415 infrared (IR) spectra of, 481 562t mass spectrum of, 469, 469f classifi cation as, 229–230 melting point of, 129, 130t monosubstituted, 281, 281f, 288 synthesis of, 558–560 E1 elimination reactions, 292, 303f nomenclature, 119–128, 123f NMR spectra of, 499–500, 516–517, Alkyl chlorides E2 elimination reactions, 287, common names, 127–128, 128f 516f, 517f in Friedel–Crafts alkylation reactions, 302f–303f IUPAC system, 121–127, 123f nomenclature, 362–365 648–649, 651 example of, 229f substituents, 120–121 common names, 365, 365f mass spectrum of, 468, 469f SN1 substitution reactions, 255, 262, nonreactivity of, 84 IUPAC system, 362–363 Alkyl diazonium salts, 981 262f, 303f oxidation of, 147–149 for stereoisomers, 363–364 Alkyl group, 120, 121, 231, 235, 365, SN2 substitution reactions, 248, 262, radical reactions, 541 organic synthesis, 391–392 647, 830 262f, 302f reduction of an alkyne to, 434–435 oxidative cleavage of, 444–446, 785 in alkyl tosylates, 338 synthesis of, 332, 335, 336 solubility of, 129, 130t physical properties of, 365–366, carbon radical stability and, 539–540, synthesis of synthesis of 368t 540f halogenation of alkanes, 541–549 reduction of alkenes, 427, 428–432, polymerization of, 1150–1156, 1153, as electron-donating group, 655, 656 hydrohalogenation of alkenes, 428f 1157–1158 in ethers, 313 371–378, 371f, 372f, 373f, 378t reduction of alkyl halides, 437–438, radical reactions, 541, 558–560 nomenclature tertiary (3°) 438f, 741 reduction of, 427, 428–432, 428f in alcohols, 315 acetylide anion reaction with, 414 reduction of alkynes, 428f, 434–435 solubility of, 365 for branched substituents, A–3–4 classifi cation as, 229–230 Alkene oxides, 317 stability of, 283–284, 429–430, 430f in ethers, 316 E1 elimination reactions, 292, 294, Alkenes, 358–398 stereoisomers of, 282–284 stabilization of carbonyl group by, 802 302f addition reactions, 370–390 alkyne reduction and, 434–436 Alkyl halides E2 elimination reactions, 287, 288, anti addition, 371, 377, 378t, 380, synthesis of, 369–370 acetylide anion reactions with, 302f 382, 384 amine conversion, 977–980 414–416 example of, 229f halogenation, 371f, 379–383, 382f comparison of methods, 796–797 alkane formation from, 741 SN1 substitution reactions, 255, 262, halohydrin formation, 371f, dehydration of alcohols, 369–370 allylic halides, 229, 229f 262f, 302f 383–385, 385f, 385t dehydrohalogenation of alkyl aryl halides, 229, 229f, 267 synthesis of, 332, 334–335 hydration, 371f, 378–379, 390 halides with strong base, 369, benzylic halides, 229, 229f unreactive, 229, 229f hydroboration–oxidation, 371f, 370 classifi cation of, 229–230, 229f, 301 vinyl halides, 229, 229f, 267 385–390, 387f, 388f, 389f, 389t by elimination reactions, 279–280, conversion of alcohols to, 331–337 1,2-Alkyl shift, 328 hydrohalogenation, 371–378, 371f, 369–370 with HX, 331–335, 337t Alkylthio group, 85t 372f, 373f, 374f, 377f, 378t by Hofmann elimination reaction, importance of, 337–338 Alkyl titanium compound, 1157 overview of, 370–371, 371f 977–980 with thionyl chloride and Alkyl tosylates, 338–340, 341f, 369 stereochemistry of, 371, 376–378, reduction of alkynes to cis alkenes, phosphorus tribromide, conversion of alcohols to, 338–339, 378t 434, 435 331–335, 337t 340 syn addition, 371, 377, 378t, 386, reduction of alkynes to trans conversion to carboxylic acids, 754 reactions of, 339–340 388–389 alkenes, 434, 436 conversion to primary amines, 962 Alkynes, 399–425 amino acid synthesis from, 1085–1086 substituted alkene in Heck reaction, coupling reaction with organocuprates, addition reactions boiling point of, 365–366 1009–1010 1003 halogenation, 406f, 409 classifi cation of, 281–282, 281f Wittig reaction, 792–797 dehydrohalogenation with strong base, hydration, 406f, 409–412 constitutional isomers of, 325 terminal, 359 369, 370 hydroboration–oxidation, 406f, conversion to alkynes, 404–405 tetrasubstituted, 281 in direct enolate alkylation, 897–899 412–413 conversion to cyclopropanes, trisubstituted, 281, 281f, 289–290, 293, elimination reactions, 234, 278–311 hydrohalogenation, 406–408, 406f 1012–1014 297–298 E1 mechanism, 300–304 overview of, 405 in coupling reactions with organic Alkenols, 363 E2 mechanism, 287, 288t, 295, boiling point of, 402 halides (Heck reaction), 1003, Alkoxides, 280 300–304, 979–980, 979f bond dissociation energies of, 400–401 1009–1011 electrostatic potential plot, 885, 885t examples, 229f, 232–234, 233f cycloalkynes, 401 cyclopropane synthesis in Simmons– in ether synthesis, 322 functional group, 85t degrees of unsaturation, 400 Smith reaction, 1014–1015 protonation of, 730, 733, 743, 751, mass spectrometry of, 468, 469, 469f deprotonation of, 405–406, 406t degrees of unsaturation, calculating, 754–755 molecular formula of, 229 functional group in, 83, 84t 360–361, 431–432 Alkoxy group, 85t, 316 nomenclature, 230–231, 231f hydroboration of, 1007, 1009 dehydration of alcohols to, 324–331 Alkylamines common names, 231 hydroboration–oxidation of, 406f, diastereoisomers of, 282–283 basicity of, 969–972, 973t, 974t IUPAC, 230, 231f 412–413 dihydroxylation of, 442–444 reaction with nitrous acid, 980–981 nucleophiles, reactions with, 103 infrared (IR) spectra of, 481 disubstituted, 281, 281f, 288, 289–290, Alkylation reactions nucleophilic substitution reactions, interesting examples, 402–404, 293, 297–298 in acetoacetic ester synthesis, 900, 234–269 402f–404f double bonds in, 281–283, 359, 360t 903–905 alcohol synthesis, 321–322 internal restricted rotation around, 282–283, of diethyl malonate derivative, alkyl halide structure and, 248, 255, defi nition of, 400 282f 1079–1080, 1081f 262, 262f hydration of, 410 electrophiles, reactions with, 103 of enolates, 897–899 with ammonia or amines to form hydroboration–oxidation of, electrostatic potential plots, 370, 370f general features of, 897–899 amines, 960 412–413 epoxidation of, 439–442, 439f tamoxifen synthesis, 899 ether synthesis, 321–322 oxidative cleavage of, 446–447, 698 fatty acids, 358, 367–369, 368f, 368t of unsymmetrical ketones, SN1 mechanism, 300–304 synthesis in acetylide anion Friedel–Crafts alkylation with, 652 898–899 SN2 mechanism, 300–304 reactions with alkyl halides, functional group in, 83, 84t Friedel–Crafts. See Friedel–Crafts physical properties, 231–232, 232t 414–416 hybrid orbitals in, 281, 284 alkylation polar carbon–halogen bond, 234 melting point of, 402 hydrogenation of, 429–434 in malonic ester synthesis, 900–903 primary (1°) molecular formula of, 400 alkene stability and, 429–430, 430f polyalkylation, 666 acetylide anion reactions with, nomenclature, 401–402 degrees of unsaturation, Alkyl benzenes 414–415 oxidative cleavage of, 446–447, 698 determination of, 431–432 electron density of, 655 classifi cation as, 229–230 physical properties of, 402 cis and trans isomers compared, halogenation of, 669–671 E2 elimination reactions, 287, 288, reduction of, 427, 428f, 434–437 429–430 oxidation of, 671–672, 698 302f to alkanes, 428f, 434–435

smi75625_index_1218-1246.indd 1220 11/24/09 12:13:31 PM Index I-4

to cis alkenes, 434, 435 nitrogen bases, 70, 71f reactions with acid chlorides and N-terminal, 1087–1088 to trans alkenes, 434, 436 NMR spectra of, 836 anhydrides, 975–976 peptide synthesis from, 1091–1100, solubility of, 402 nomenclature, 831–832, 833t reactions with aldehydes and 1101f structure of, 400–401 nucleophilic substitution reactions, 725 ketones, 975 pKa values, 1077, 1078, 1078t synthesis of, 404–405, 417–419 physical properties of, 834, 834f, 834t reactions with nitrous acid, 980–981 representative examples, 711t from alkenes, 404–405 pKa, 829t, 886t from reduction of amides, 963 resolution of by dehydrohalogenation, 299–300, polyamides, 825, 829 from reduction of nitriles, 865, 962 by conversion to diastereomers, 300f primary (1°), 827, 831, 834–836, 842, from reduction of nitro compounds, 1081–1084, 1082f from dihalides, 404–405 844, 850 962 kinetic, using enzymes, 1084 E2 elimination reactions, 279, tautomers, 863 structure of, 950 separation of, 1081–1084 299–300, 300f as protecting group for an amine, 977f protecting group for, 976, 977f stereogenic center of, 1075 multistep, 418–419 proteins, 837 reactions of structure of, 710, 1075, 1075f, 1076f, terminology and conventions, reduction to amines, 736–737, 963 with acid chlorides, 842, 975–976 1077 417–418 secondary (2°), 827, 831–832, with aldehydes and ketones, 975 synthesis of, 1078–1081 terminal 834–836, 842, 844, 850 with anhydrides, 844, 845, 975–976 alkylation of diethyl malonate conversion to acetylide anions, solubility of, 834t with carboxylic acids, 846f, derivative, 1079–1080, 1081f 414–415 stability of, 829 849–850 enantioselective hydrogenation, defi nition of, 400 structure and bonding of, 722, 826, conversion to alkenes, 977–980 1085–1086 hydration of, 410 827, 828–829 conversion to amides, 975–976 reaction of α-halo acids with hydroboration–oxidation, 412–413 synthesis of with esters, 850 ammonia, 1078–1079, 1081f oxidative cleavage of, 446–447, 698 from acid chlorides, 842, 975–976 general features, 966 Strecker synthesis, 1080–1081, reaction as an acid, 405–406 from anhydrides, 844–845, 975–976 Hofmann elimination, 977–980 1081f triple bond of, 400–401 from carboxylic acids, 846f, with monosaccharides, 1062 zwitterion form, 711–712, 1077 d-Allaric acid, 1049 849–850 with nitrous acid, 980–982 Aminobenzene. See Aniline Allegra. See Fexofenadine from esters, 850 secondary (2°) p-Aminobenzoic acid (PABA), 599, Allenes, 195 tautomers, 863–864 addition to aldehydes and ketones, 990–991 Allicin, 119 term usage, 887 800–801, 801f Aminoglycoside antibiotics, 1062 d-Allonic acid, 1071 tertiary (3°), 827, 831–832, 842, 844, from direct nucleophilic Amino group, 85t, 665–666, 953 d-Allose, 1035f, 1049 850 substitution, 960 as electron-donating group, 654–656, Allyl group, 365 enolate formation from, 885–886 IR spectra of, 955, 955f 656f Allylic alcohol Amide tautomer, 863–864 nomenclature, 952–953 inductive effect of, 654 epoxidation of, 452–453 Amikacin, 1062 proline, 1077 nitro reduction to, 673–674 synthesis from α,β-unsaturated -amine (suffi x), 952–953 reactions with acid chlorides and as ortho, para director, 662–663 carbonyl compounds, 756 Amine oxide, 444 anhydrides, 975–976 resonance effect of, 654 synthesis from aldol reactions, 924, Amines, 949–991 reactions with aldehydes and 6-Aminohexanoic acid, 1161 924f aromatic ketones, 975 α-Amino nitrile, 1080–1081 Allylic carbocations, 585 basicity of heterocyclic, 972, 973t, reaction with nitrous acid, 981–982 Amino sugars, 1061–1062 as conjugated system, 572, 573–574 974t from reduction of amides, 963 Ammonia electrostatic potential plot, 574, 574f nomenclature, 953 structure of, 950 basicity of, 969 NMR spectra of, 575, 575f basicity of, 950, 966–975 separation from other organic boiling point, 436 resonance of, 574–576 aromaticity effects on, 972, 973t compounds, 967–968, 967f in dissolving metal reductions, 428, Allylic carbon hybridization effects on, 972–973, solubility of, 954t 436 oxidation of, 433, 433f 973t spectroscopic properties of, 955–956, hybrid orbitals in, 35, 35f radical halogenation at, 552–555 inductive effects on, 969, 973t 955f molecular shape, 26, 26f bromination, 553–554 pKa values, 966, 968–969, 974t structure and bonding of, 950–952 pKa of, 60 product mixtures in, 555 relative to other compounds, synthesis of, 960–966 reactions with in triacylglycerols, 433, 433f 968–975, 974t direct nucleophilic substitution acid chlorides, 842, 975–976 Allylic halides, 229, 229f resonance effects of, 973t reactions, 960–961 alkyl halides to form amines, Allylic substitution, 554 boiling point of, 954t Gabriel synthesis, 961–962 960–961 Allyl radical, 552–555 classifi cation of, 950 reduction of amides, 736–737, 963 anhydrides, 844, 975–976 Alpha (α) carbon, 279–280, 691, 694, 710 electrostatic potential plots of, 951, reduction of nitriles, 962 esters, 850 of aldehydes and ketones, 777, 951f reduction of nitro compounds, 962 α-halo acids, 1078–1079 785–786 functional group, 85t reductive amination of aldehydes Ammonium cation, of amino acids, 712 substitution reactions of carbonyl general molecular formula for, 955 and ketones, 963–966 Ammonium salt compounds at the α carbon, infrared (IR) spectra of, 483 tertiary (3°) in amine extraction process, 967–968 880–906 interesting examples, 956–959 from direct nucleophilic enantiomers, 951 Alpha (α) cleavage, 471–472 derivatives of 2-phenylethy lamine, substitution, 960 in Hofmann elimination reaction, Alpha (α) elimination reaction, 1012 958–959, 959f IR spectra of, 955, 955f 977–978 Alpha (α) helix, 1101–1104, 1102f, 1105f, histamine and antihistamines, nomenclature, 952–953 synthesis of, 950–951, 960–961 1107f 957–958 reactions with acid chlorides and Amoxicillin, 3, 52, 192, 838 Alpha (α) hydrogens, 881, 922, 925 simple amines and alkaloids, anhydrides, 975–976 Amphetamine, 72, 76, 191, 964 Altocid. See Methoprene 956–957, 957f from reduction of amides, 963 Amygdalin, 194, 791–792 d-Altrose, 1035f, 1069 IR spectra of, 955, 955f structure of, 950 Amylopectin, 1060–1061 Aluminum chloride, in Friedel–Crafts mass spectra of, 955, 955f Amino acids, 104–105, 710–713. See also Amylose, 1060–1061 alkylations, 647–653, 665–666 melting point of, 954t Peptides; Proteins β-Amyrin, 1145 Alzheimer’s disease, 85, 926, 975 nitrosamine formation, 261 abbreviations for, 711t, 1076f Anabolic steroids, 1142 Amberlyst A-26 resin, 450–451 NMR spectra of, 956, 956f N-acetyl, 1082–1084 Analgesics, 696, 845, 898, 906 Ambident nucleophile, 888 nomenclature of, 952–954 acid–base behavior of, 711–712, 712f, Anastrozole, 862 -amide (suffi x), 831–832, 833t as nucleophiles, 950, 975–977 1077–1078, 1077f, 1078t Androsterone, 1141t, 1147 Amide bond in peptides, 1086, 1101 odors of, 956–957 α-amino acids, 710, 1075, 1075f -ane (suffi x), 117, 120, 121, 127, 362 Amides physical properties of, 954, 954t d-amino acids, 710–711, 1075, 1075f Anesthetics, 84, 233f, 320, 673 basicity of, 829t, 971–972, 973t, 974t primary (1°) l-amino acids, 710–711, 1075, 1075f Angiotensin, 1116 boiling point of, 834t addition to aldehydes and ketones, analysis of peptide composition, 1091 Angle strain, 137–139 cyclic, 827 797–799, 799f, 801f C-terminal, 1087–1088 in epoxide, 314 functional group in, 86t amino acids, 1077 enantiomers of, 1075, 1075f Angstrom (Å), 23 hydrolysis of, 855–856 from direct nucleophilic separation of, 1081–1084 Angular methyl groups, 1138–1139 interesting examples, 837–838 substitution, 960–961 essential, 711, 1077 Anhydrides IR spectra of, 835, 835t Gabriel synthesis, 961–962 general features of, 1075, 1075f, 1077 acidity/basicity of, 829t leaving group, 725 IR spectra of, 955, 955f isoelectric points, 713 boiling point of, 834t melting point of, 834t nomenclature, 952 naturally occurring, 1075, 1076f cyclic, 826–827, 847

smi75625_index_1218-1246.indd 1221 11/24/09 12:13:31 PM I-5 Index

Anhydrides (continued) epothilone A, 1018f open, 417 Automated peptide synthesis, 1099–1100, derivation of term, 830 illudin-S, 905 use in describing organic reactions, 1101f IR spectra of, 835, 835t imatinib mesylate, 837 202–203, 202t Avobenzone, 30, 931 melting point of, 834t tamoxifen, 880, 899 Artemisinin, 194, 389, 389f Axial bond, 160 mixed, 826–827 Anti conformation, 134f, 135–137, 136f Artifi cial sweeteners, 1058, 1059f, 1090 Axial hydrogens, 139–140, 139f, 141f NMR spectra of, 836 Antidepressant, 250, 646f, 653, 913, 958 Arylamines Azo compound nomenclature, 830, 833t Antifreeze, 319f basicity of, 969–971, 973t, 974t applications of, 988–991 physical properties of, 834t Antihistamines, 610, 646f, 957–958, reaction with nitrous acid, 980–981 dyes, 988–991 pKa, 829t 968, 975 Arylboranes, 1007 sulfa drugs, 990–991, 991f reactions of, 844–845, 858t Anti-infl ammatory drugs Aryl bromides, synthesis from aryl formation of, 982, 986–988 acetylation, 845 aspirin, 54, 71–72, 215, 268, 269f, 696, diazonium salts, 983 Azo coupling, 982, 986–988 with ammonia or amines to form 697, 1131–1132 Aryl chlorides AZT (azidodeoxythymidine), 4 amides, 975–976 fl uticasone, 230 examples of biologically active, 646f Azulene, 635 conversion to amides, 844–845 ibuprofen, 119, 150, 187, 673, 730f, synthesis from aryl diazonium salts, conversion to carboxylic acids, 844 916, 932, 1131–1132 983 Backside attack, in nucleophilic conversion to esters, 844–845 nabumetone, 906 Aryl diazonium salt, 980–988 substitution reactions, solubility of, 834t naproxen, 159, 187, 898 Aryl fl uorides, synthesis from aryl 245±246 stability of, 829 nonsteroidal anti-infl ammatory drugs diazonium salts, 983 Baekeland, Leo, 1166 structure and bonding of, 826–827, (NSAIDs), 1131–1132 Aryl groups, 612 Baeyer strain theory, 137 828–829 Antimalarial drugs, 289f, 389, 389f, 624, Aryl halides, 229, 229f, 267 Bakelite, 1165, 1166f symmetrical, 826–827, 830 896, 974, 975 coupling reactions Ball-and-stick model synthesis of Antioxidants, 557, 571 with alkenes, 1009–1011 of acyclic alkanes, 114–115 from acid chlorides, 842, 843 Anti periplanar geometry, 295–298, with organoboranes, 1006–1007 of molecular shape, 24–26 dehydration of dicarboxylic acids, 295f with organocuprates, 1003 Barbituric acid, 119 847 Antiseptics, 236 examples of biologically active, 646f Barrier to rotation, 136 Aniline, 970 Antiviral agents, 86, 1018f reactivity of, 650 Base(s) basicity of, 969–970 APC (aspirin, phenacetin, caffeine), 877 synthesis of for alkyne deprotonation, 405–406, electrophilic aromatic substitution Aprotic solvents, polar, 241, 241f, 264, from aryl diazonium salts, 983 406t reaction, 663 265, 265t, 287, 288t, 889–890 halogenation of benzene, 643f, for alkyne synthesis by dehydro- electrostatic potential plot of, 656f, Arabinose, 1054–1055 645 halogenation, 299–300, 300f 971f d-arabinose, 1034, 1035f, 1051 Aryl iodides, synthesis from aryl Brønsted–Lowry nomenclature and, 612 Arachidic acid, 1122t diazonium salts, 983 description of, 55–56 polyhalogenation of, 665 Arachidonic acid, 568, 570 Aryl ketones, reduction to alkyl benzenes, reactions of, 56–58 resonance structures, 654 leukotriene synthesis by oxidation 672–673 substitution reactions with alkyl structure of, 611, 953 of, 348 Ascorbic acid. See Vitamin C halides, 234 synthesis of prostaglandin synthesis from, 697 Asparagine common, 70–71 electrophilic aromatic substitution structure of, 97, 1122t isoelectric point for, 1078t conjugate, 56–58 β reaction, 646 synthesis of eicosanoids from, 1130, pKa values for, 1078t dehydration of -hydroxy carbonyl by nitrobenzene reduction, 673 1131f structure of, 1076f compounds with, 920 Anionic polymerization, 1154–1155, Arene, 608 Asparagopsis taxiformis, 232 as electron pair donors, 55, 58, 72–73 1155f Arene oxide, 157 Aspartame, 109, 872, 1058, 1059f, 1090 in elimination reactions, 279–280, of epoxides, 1156–1157 Arginine Aspartic acid, 1077, 1171 280t Anions isoelectric point for, 1078t isoelectric point for, 1078t in E1 elimination reactions, 291, acetate, 66–67, 67f pKa values for, 1078t pKa values for, 1078t 293, 293t, 298 carbanion, 68, 201–202, 201f structure of, 1076f structure of, 1076f in E2 elimination reactions, 286, cyclopentadienyl, 624–625, 630, 630f Aricept. See Donepezil Aspirin, 54, 71–72, 873 286f, 288t, 298 defi nition of, 7 Arimidex. See Anastrozole crossing of cell membrane, 72 enolate formation with, 887–888, enolate, 21 Aripiprazole, 995 derivation of word, 696 887t naked, 241 Aromatase inhibitors, 862 mechanism of action, 215, 697, hydrides, 70, 71f radical, 436 Aromatic compounds, 607–640 1131–1132 Lewis, 72–74 salt formation, 10–11 background on, 608 proton transfer reaction, 71–72 nitrogen-containing, 70, 71f solvation by hydrogen bonding, 240 bonding and antibonding orbitals, structure, 696 nonnucleophilic, 239 Anisole, 343, 492 627–628 synthesis of, 268, 269f, 696 organometallic reagents, 739, 741 Annulation buckminsterfullerene, 632 Asthma, 347–348 oxygen-containing, 70, 71f origin of word, 936 charged, 634–626 Asymmetric carbon. See Stereogenic as proton acceptors, 55 Robinson, 936–939 electrophilic substitution. See centers strong, 70–71 Annulenes, 620–621 Electrophilic aromatic Asymmetric reaction, 452 used to deprotonate carboxylic acids, 18-annulene, 537 substitution reactions Asymmetric reduction, 731 700, 700t Anomeric carbon, 1037–1040, 1042, examples, 620–626 Atactic polymer, 1157–1158 weak as good leaving group in 1044, 1056–1058, 1063 charged compounds, 624–626 -ate (suffi x), 692, 830–831, 833t nucleophilic substitution Anomers, 1037–1040 heterocycles, 621–624, 623f Atenolol, 78, 85 reactions, 236–238 Antabuse, 451 multiple rings, 621 Atherosclerosis, 861f, 862 Base pairs, 1064, 1065f Anthracene, 621 single ring, 620–621 Atmosphere Base peak, in mass spectrum, 465 Anti addition, 371, 377, 378t, 380, 382, Hückel’s rule, 617–620 carbon dioxide concentration in, 149, Bases, nucleoside, 1063–1065, 1065f 384, 434, 436, 442, 443 basis of, 626–629 149f Basicity Antiaromatic compounds, 618, 619, 625, interesting, 614–615, 614f ozone layer destruction, 233 acidity, inverse relationship with, 626 molecular orbitals, 627–629, 628f Atomic mass unit (amu), 7 59, 59t Antibiotics nomenclature, 610–613 Atomic number, 7 of amines, 950, 966–975 aminoglycoside, 1062 predicting aromaticity using the Atomic symbol, 7 of carboxylic acid derivatives, cephalosporins, 838 inscribed polygon method, Atomic weight, 7 828–829, 829t chloramphenicol, 167 629–631, 630f, 631f Atom mass, infrared (IR) absorption and, of carboxylic acids, 699 ionophores, 101–102 spectroscopic properties, 613–614, 478–479, 479f leaving group ability and, 236–238 β-lactam, 463, 485, 838, 856–857 613f, 613t Atoms nucleophilicity compared to, 239, penicillin(s), 463, 485, 838, 856–857 Aromaticity, effect on basicity of amines, components of, 7 240, 241 sulfa drugs, 990–991, 991f 972, 973t excited state, 32 periodic trends in, 63–65 Antibonding molecular orbital, 627, 628f, Arrows ground state, 32 Basketane, 128f 629–631 curved, 20–21, 56, 201, 235 Atorvastatin, 1140, 1141f Beeswax, 150, 150f Anticancer drugs double-headed, 18, 56–57, 202t Atropine, 957, 957f Benadryl, 968 aromatase inhibitors, 862 equilibrium, 56–57 Attention defi cit hyperactivity disorder, Benazepril, 995 doxorubicin, 1029f half-headed, 539 191. See also ADHD Benedict’s reagent, 1048

smi75625_index_1218-1246.indd 1222 11/24/09 12:13:31 PM Index I-6

Bent molecular shape electrophilic aromatic substitution, Bimolecular elimination. See E2 Bond dissociation energy, 203–206 alcohols, 314 657–660, 660f, 665–666 elimination reactions in alkynes, 400–401 description of, 26 electrostatic potential plot of, 656, Bimolecular reactions for benzylic C–H bond, 670 ethers, 314 656f elimination reactions, 285 bond length and, 205 polarity and, 44 Friedel–Crafts acylation of, in nucleophilic substitution reactions, bond strength and, 204–206 Benzaldehyde, 492 665–666 243–244 carbon radical stability and, 539–540 aldol reactions of, 922, 923, 923f Friedel–Crafts alkylation of, organic reactions, 217 of common bonds, 204t, A–7–8 electron density of, 656, 656f 665–666 Biocatalyst, 1167, 1168f defi nition of, 203 resonance structures of, 655 halogenation of, 665 Biodegradable polymers, 1170–1171 enthalpy change calculation from, secondary alcohol formed from, 743 inductive effects on, 654–656 Biofuels, 1125 205–206 structure of, 777 multistep synthesis of, 675–677 Biomolecules, 104–105, 104f, 1028. limitations of, 206 Benzalkonium chloride, 276 orientation effects on, 661–664 See also Carbohydrates; DNA; periodic table trend in, 204–205 Benzamide, structure of, 831 oxidation of, 671–672 Lipids; Proteins Bonded (shared) electrons, 12–14, 12f Benzene, 52, 83, 84t, 108, 157, 607–640 reduction of, 672–674 defi nition of, 104 Bonding molecular orbital, 627, 628f, as annulene, 620 resonance effects on, 654–656 families of, 104 629–631, 630f, 631f background on, 608 synthesis of, 668–669, 675–677 mass spectra of, 474 Bond length in BTX mixture, 614 with diazonium salts, 984–986 2,2'-Bis(diphenylphosphino)-1,1'- average for common bonds, 23t p-chlorostyrene synthesis from, trisubstituted, synthesis of, 676–677 binaphthyl (BINAP), 1085–1086 bond dissociation energy and, 205 675–676 Benzene ring Bisphenol A (BPA), 683, 1163, 1164f, bond strength and, 40–42, 41t conjugation of, 618 of arylamines, 969 1168 in conjugated dienes, 581–582 degrees of unsaturation, 608 NMR spectra of, 505, 506f, 506t, Blattellaquinone, 843, 844 percent s-character and, 41–42, 582 electrostatic potential plot of, 610, 518–519, 519f Bloch, Konrad, 1140 periodic trends in, 23 610f, 656f Benzenesulfonic acid, 643f, 646 Blood alcohol content, measurement of, Bond polarity, 43–44, 45f Friedel–Crafts acylation of, 643f, Benzo[a]pyrene, 349, 614, 614f 449–450, 449f, 485 Bond strength 647–653, 672–673 Benzo[a]pyrene derivative, 97 Boat form, of cyclohexane, 141, 141f bond dissociation energy and, 204–206 Friedel–Crafts alkylation of, 643f, Benzocaine, 673, 874 Boc (tert-butoxycarbonyl protecting bond length and, 40–42, 41t 647–653, 672–673 Benzoic acid group), 1096–1098 infrared (IR) absorption and, 478–479, halogenation of, 643f, 645, 668 acidity of, 705–707, 706f Boiling point 479f, 480 heat of hydrogenation, 616–617, 616f separation from cyclohexanol by of alcohols, 318t percent s-character and, 41–42 hybridization and orbitals, 609–610 extraction procedure, 707–709, of aldehydes and ketones, 780t Bongkrekic acid, 395 lack of addition reactivity, 608, 617, 709f of alkanes, 129, 130t 9-Borabicyclo[3.3.1]nonane (9-BBN), 387 642 structure of, 691t of alkenes, 365, 366 Borane, 731 molecular orbitals of, 628–630, 628f substituted, 705–707, 706f of alkyl halides, 232t addition to alkene, 386–387, 387f, 388f nitration of, 643f, 646–647, 669 synthesis of of alkynes, 402 hydroboration–oxidation of alkynes, p-nitrobenzoic acid synthesis from, 675 by oxidation of alkyl benzenes, of amines, 954t 412–413 NMR spectrum of, 505, 506f, 506t, 671, 698 of carboxylic acids, 693t Boron, octet rule exceptions in, 18 619–620 Benzonitriles, synthesis from aryl defi nition of, 90 Boron trifl uoride, molecular shape of, pi (π) electrons of, 618, 626, 642 diazonium salts, 492, 983 of enantiomers, 182, 184, 184t 24–25, 26f resonance, 609 Benzophenone, structure of, 778 of epoxides, 318t hybrid orbitals in, 35 resonance structures, 576 Benzoquinone, 591f of ethers, 318t BPA (bisphenol A), 683, 1163, 1164f, stability, 615–617, 619 Benzoyl group, 779 intermolecular forces and, 90–92 1168 structure of, 609–610 Benzphetamine, 996 polarizability and, 91 Bradykinin, 1089 substitution reactions, 608, 617, Benzylamine, 994, 996 of racemic mixtures, 184, 184t Brevicomin, 823 642–687. See also Electrophilic Benzyl bromide, 683 separation of liquids based on, 92, 92f Bridged bicyclic ring system, 593, 593f aromatic substitution reactions Benzyl ester, 1097 surface area and, 91 Bridged halonium ion, 380–382, 383–384, sulfonation of, 643f, 646–647 Benzyl group, 612 Bombykol, 1002, 1008, 1008f 385t, 409 synthesis from aryl diazonium salts, Benzylic bromination, 670–671 Bond(s) and bonding, 10–12. See also Bridgehead carbons, A–6 983–984 Benzylic C–H bond, 669–670, 698 specifi c bond types Bromination synthesis of m-bromoaniline from, 674 Benzylic halides, 229, 229f, 670–671 bond angle, 24–27, 26f of alkanes, 546–547, 547f synthesis of p-bromonitrobenzene Benzylic radical, 669–671, 1151–1152 bond length, 23, 23t, 40–42, 41t of alkenes, 558–560 from, 668–669 Benzyl methyl ether, 683 breaking and making in organic at allylic C–H bonds, 553–555 synthesis of o-nitrotoluene from, 669 Benzyl salicylate, 1177 reactions, 200–203, 201f with NBS, 553–555 synthesis of 1,3,5-tribromo benzene Bergstrom, Sune, 697 covalent, 10, 11–12 product mixtures in, 555 from, 984, 984f Beryllium, octet rule exceptions in, 18 defi nition of, 10 selective, 553–554 trisubstituted benzene synthesis from, Beryllium hydride double, 15 substitution versus addition, 554 676–677 hybrid orbitals in, 35 ionic, 10–11 of benzene, 645, 668 Benzenecarbaldehyde. See Benzaldehyde molecular shape of, 24, 26f Lewis structures, 12–18 benzylic, 670–671 Benzene derivatives Beta (β) blocker, 85 in nucleophilic substitution reactions, chlorination compared, 546–547 disubstituted, 666–668 Beta (β) carbon, 279–280, 296, 691 242–243, 252 as endothermic reaction, 547, 547f electrophilic aromatic substitution Beta (β) elimination reactions. See also octet rule, 10 polybromination, 665 reactions of, 666–668 Elimination reactions π (pi), 37–40, 38f, 39f, 40f of substituted benzenes, 665 halogenation of, 666–667 of alcohols, 323–331 polar, 43, 44, 45f as test for pi (π) bond, 380 nitration of, 667–668 dehydrohalogenation as, 279 rotation, 36 Bromine, isotopes of, 469 synthesis of, 668–669 Zaitsev rule, 288–291 σ (sigma), 32, 33, 36–40, 38f, 39f, α-Bromoacetone, 893 drugs containing benzene rings, 615f Beta (β) lactam(s), 311, 827, 838, 40f 3-Bromoacetophenone, 779f interesting examples, 614–615, 614f 856–857 triple, 15 m-Bromoacetophenone, 779f NMR spectra, 518–519, 519f Beta (β) lactam family of antibiotics, Bond angles m-Bromoaniline, 674 nomenclature, 610–613 463, 485 in alkynes, 400 o-Bromoaniline, 953 aromatic rings as substituents, Bextra. See Valdecoxib four groups around an atom, 24, 25–26, p-Bromobenzaldehyde, synthesis of, 612–613 BHA (butylated hydroxy anisole), 568 26f, 40f 985–986 disubstituted, 611 BHT (butylated hydroxy toluene), 557 molecular shape and, 24–27, 26f Bromobenzene, 343, 645 monosubstituted, 611 Biaryls, 1025 three groups around an atom, 24–25, 4-Bromobutanal, 819 polysubstituted, 611–612 Bicyclic compounds, naming, A–5–6 26f, 40f 1-Bromobutane, 288, 874 spectroscopic properties, 613–614, Bicyclic product, 592–593 two groups around an atom, 24, 26f, 2-Bromobutane, 280, 550–551 613f, 613t Bicyclic ring system, bridged, 593, 593f 40f 3-Bromo-1-butene, 555, 587, 588f substituted “Big Six” synthetic polymers, 1169, 1169t Bond cleavage 1-Bromo-2-butene, 555, 587, 588f activating and deactivating Bile acid, 158 heterolytic, 200–202, 201f cis-1-Bromo-4-tert-butylcyclohexane, 309 substituents, 657–661, 660f Bile salt, 158 homolytic, 200–202, 201f trans-1-Bromo-4-tert-butylcyclohexane, directing effects of substituents, Bilobalide, 153 in nucleophilic substitution reactions, 309 657–664, 664f Bimatoprost, 697 242–243, 252 o-Bromochlorobenzene, 611

smi75625_index_1218-1246.indd 1223 11/24/09 12:13:32 PM I-7 Index

1-Bromo-1-chloroethylene, NMR constitutional isomers of, 118t tert-Butyl methyl ether (MTBE), 95 secondary (2°), 256 spectrum of, 500 eclipsed conformation, 282f formation of, 378–379 in SN1 substitution reactions, 252–260, Bromocyclodecane, 308 halogenation of, 549–550 as fuel additive, 378, 497 260f Bromocyclohexane, 376 molecular formula of, 118t NMR spectrum of, 497, 499 tertiary (3°), 256, 649, 651–652 2-Bromocyclohexanone, 896 as propellant, 551 5-tert-Butyl-3-methylnonane, 124 trigonal planar, 253–254, 376 1-Bromocyclohexene, 1005 rotation about carbon–carbon single tert-Butyl pentyl ether, 492 vinyl, 267, 407–408, 411 1-Bromo-3,3-dimethylbutane, 567 bonds of, 282, 282f 1-Butyne, 424 Carbocation intermediates, 558 2-Bromo-2,3-dimethylbutane, 567 solubility of, 94–95 addition reactions of, 405, 406f Carbocation rearrangements (5R)-6-Bromo-2,5-dimethylnonane, 275 structure of, 115 hydrohalogenation of, 406f, 407 conversions of alcohols to alkyl (6R)-6-Bromo-2,6-dimethylnonane, 275 Butanedioic acid, 692 2-Butyne, 424 halides, 334–335 1-Bromohexane, 874 2,3-Butanediol, 345 hydration of, 410f, 411 in dehydration of alcohols, 328–330 3-Bromohexane, 166 2,3-Butanedione, addition to margarine infrared (IR) spectrum, 480 Friedel–Crafts alkylation, 651–652 enantiomers of, 168f of, 432 Butyric acid, structure of, 691t in hydration reactions, 378 6-Bromo-2-hexanone, 823 Butanenitrile, synthesis from 1-propanol, γ-Butyrolactone, 719, 872 1,2-shifts, 328–330 trans-1-Bromo-1-hexene, 1004 337–338 1,2-hydride shift, 651 1-Bromo-2-hexene, 274 Butanoic acid, 695 Cadaverine, 956–957 1,2-methyl shift, 328–329 Bromohydrins, 383–384 IR spectrum of, 694f Caffeine, 109, 529, 949 in SN1 reactions, 334–335 Bromomethane, in nucleophilic synthesis of, 901–902 Cahn–Ingold–Prelog system, 170 Carbocation stability substitution reactions, 243–245, 1-Butanol Calcitriol, 581, 581f of allylic carbocations, 573–574 248, 248f, 249f boiling point of, 91, 108, 352 Calorie (cal), 40 conjugation and, 573 2-Bromo-2-methylbutane, 289–290 intermolecular forces in, 90 Camphene, 1147 in electrophilic aromatic substitution cis-1-Bromo-4-methylcyclohexane, 263 melting point of, 93 Camphor, 1134 reaction, 659–660 1-Bromo-1-methylcyclopentane, 293 naming, 315 Cancer. See also Anticancer drugs Hammond postulate and, 258–261 2-Bromo-2-methylpropane, 280, 288, 414 2-Butanol nitrosamines and, 261 hyperconjugation and, 257–258 p-Bromonitrobenzene, 668–669 (2R)-2-Butanol, 873 polycyclic aromatic hydrocarbons inductive effects and, 256–257 Bromonium ion, 554 (2S)-2-butanol, conversion to its and, 349 1,2-shifts and, 328 1-Bromopentane, 492 tosylate, 338–339 Capnellene, 416, 416f Carbohydrates, 812–813, 1027–1073 2-Bromopentane, in E2 elimination enantiomers of, 171–173, 729–730 Caproic acid, 688, 691t amino sugars, 1061–1062 reaction, 979 infrared (IR) spectrum, 482 ε-Caprolactam, 1161, 1170 cellulose, 160–162, 161f, 162f, 858, 1-Bromopropane stereogenic center of, 168 ε-Caprolactone, 1177 858f, 1029f, 1059–1060 NMR spectrum of, 514–515, 515f synthesis using Grignard reaction, 747 Capsaicin, 4, 49, 485, 529, 607, 914 disaccharides, 1056–1058, 1058f, synthesis of, 558 tert-Butanol, as polar protic solvent, 240f Caraway, odor of, 188 1059f 2-Bromopropane, 310, 322 2-Butanone, 422 Carbamate, 870, 1095–1096, 1162 energy in, 1028 mass spectrum of, 469, 469f boiling point of, 779 Carbanions examples of, 1028, 1029f NMR spectrum of, 513, 513f infrared (IR) spectrum, 482 addition to aldehydes and ketones, glycosides, 1042–1046 synthesis of, 547, 558 reduction of, 729–730 789 N-glycosides, 1062–1065, 1065f α-Bromopropiophenone, 894 structure of, 778 electrostatic potential plots, 68, 68f molecular formula of, 1028 (Z)-2-Bromostyrene, 1009, 1024 synthesis of, 905 formation in alkyne reduction, 436 monosaccharides. See N-Bromosuccinimide (NBS), 383–384, 1-Butene, 306, 360t, 363f, 1021 nucleophilic addition with, 724, 789 Monosaccharides 553–555 halogenation of, 555 nucleophilic substitution with, 725 natural fi bers, 858, 858f p-Bromotoluene, 611 2-Butene vinyl, 436 nomenclature, 1028, 1029, 1034 Brompheniramine, 975 cis-2-butene, 306, 360t, 365, 382, 382f Carbenes polysaccharides, 1059–1061 Bronchodilator, 167, 321, 347, 347f carbene addition to, 1013 intermediates in cyclopropane starch, 160–161, 161f, 162f, 319, 320f, Brønsted–Lowry acid epoxidation of, 440 synthesis, 1012–1014 1060–1061 carboxylic acids, 699–703 hydrogenation of, 429–430 metal–carbene intermediates in Carbon description of, 55–56 trans-2-butene, 360t, 365, 382, 382f, metathesis, 1017 alpha (α), 279–280, 691, 694, 710 reactions of, 56–58 384 preparation of dihalocarbenes, of aldehydes and ketones, 777, Brønsted–Lowry base carbene addition to, 1014 1012–1013 785–786 alkyl halide and elimination reactions, epoxidation of, 440 structure of, 1012 substitution reactions of carbonyl 234 hydrogenation of, 429–430 Carbenoid, 1015 compounds at the α carbon, description of, 55–56 stereoisomers of, 282–284, 282f Carbinolamines, 788, 797, 800, 975 880–906 in elimination reactions with alkyl tert-Butoxide, nucleophilicity of, 239 Carbocation(s), 20 beta (β), 279–280, 296, 691 halides, 279 tert-Butoxycarbonyl protecting group achiral, 376 bonding of, 11, 12f, 15, 17t, 32–33 reactions of, 56–58 (Boc), 1096–1098 allylic charged atom, 31 Brucine, 1115 tert-Butoxy group, 316 as conjugated system, 572, chiral. See Stereogenic centers BTX mixture, 83, 614 Butter, 369, 432 573–574 delta (δ), 691 Buckminsterfullerene, 632 oxidation of lipids in, 215 electrostatic potential plot, 574, electron-defi cient, 65, 82, 84, 85, 103, Bufotenin, 958–959 Butylamine, mass spectrum of, 955, 955f 574f 202, 234, 234f Bufo toads, 958 (R)-sec-Butylamine, 195 NMR spectra of, 575, 575f electronegativity value, 739 Bupropion, 646f, 686, 913 Butylated hydroxy anisole (BHA), 568 resonance of, 574–576 electrophilic, 234, 234f 1,2-Butadiene, 424 Butylated hydroxy toluene (BHT), 557 classifi cation, 256 elemental forms of, 632 1,3-Butadiene, 397 Butylbenzene, 677 in electrophilic addition reactions, excited state, 32 conformations of, 1088 tert-Butylbenzene, 611 372–376 formal charge of, 17t conjugation in, 572–573, 573f Butylcyclohexane, 126f, 460 in electrophilic aromatic substitution gamma (γ), 691 electrostatic potential plot for, 573, tert-Butylcyclohexane, 143f reactions, 643–644, 659–660 ground state, 32 573f tert-Butyl cyclohexanecarboxylate, 831 electrostatic potential maps, 257, 257f isotopes of, 7, 8f, 472t HBr addition to, 584–588, 588f cis-4-tert-Butylcyclohexanol, 773 energy diagram for formation of, 260f mass of, 472t polymerization of, 1156, 1160 4-tert-Butylcyclohexanone, 773 formation in Lewis acid–base periodic table entry, 8 resonance structures, 576, 582 tert-Butylcyclopentane, 125 reactions, 74 primary (1°), 116 sigma (σ) bond length in, 581–582 tert-Butyldimethylsilyl ether (TBDMS), Hammond postulate, 374–375, 374f quaternary (4°), 116 stability of, 619 749, 750 as Lewis acid, 372 radicals, 539–540, 540f ultraviolet absorption, 598 Butyl group, 121 localized versus delocalized, 574f secondary (2°), 116 Butanal, 944 sec-butyl group, 121 in nucleophilic substitution reactions, tertiary (3°), 116 boiling point of, 91 tert-butyl group, 121, 143 243 tetravalence of, 4, 25, 27 intermolecular forces in, 90 tert-Butyl hydroperoxide, 438, 452 planar, 254, 263, 377, 1043–1044 valence electrons of, 32 melting point of, 93 tert-Butyl iodide, 231 primary (1°), 256 Carbonate, 1163 Butane Butyllithium, 71, 423, 794, 888 as reactive intermediate, 330 Carbon backbone (skeleton), 82 alkene conversion to, 429 Butylmagnesium chloride, 759 resonance-stabilized, 408, 410, 411, Carbon–carbon bonds anti conformation, 282f 1-sec-Butyl-3-methylcyclohexane, 127f 471, 574–575, 574f, 575f, bond length and bond strength, 40–41, conformations of, 134–137, 134f, 136f sec-Butyl methyl ether, 316 584–585, 587, 643 41t

smi75625_index_1218-1246.indd 1224 11/24/09 12:13:32 PM Index I-8

double. See also Double bonds reactions at α carbon, 880–906 interesting examples, 694–696 reactivity with nucleophiles, 725 in alkenes, 281–283. See also acetoacetic ester synthesis, 900, intermolecular forces, 692, 693f, 693t reduction of, 727 Alkenes 903–905 IR spectra of, 693–694, 694f resonance structures of, 828 properties of, 360t enolate alkylation, 897–899 leaving group, 725 solubility of, 834, 834t radical reactions, 541, 558–560 halogenation, 892–895, 895f melting point of, 693t stability of, 829 restricted rotation around, malonic ester synthesis, 900–903 NMR spectra of, 694, 695f structure and bonding of, 722, 826–829 282–283, 282f racemization, 891, 891f nomenclature of, 690–692 Carboxypeptidase, 1093, 1093t NMR spectra of, 505, 506f, 506t reactions of, 723–726 common names, 691–692, 691t, Carcinogen, 349 nonpolar nature of, 43 nucleophilic addition, 724 692f Cardinol, 1169 reactions forming, 1002–1026, A–9 nucleophilic substitution, 724, IUPAC system, 690–692 Carnauba wax, 1121 coupling reactions of 725–726 nucleophilic acyl substitution reactions, Carotatoxin, 109 organocuprates, 1003–1005 with organometallic reagents, 845–850, 846f, 858t β-Carotene, 97–98, 367f, 795, 795f cyclopropane synthesis, 712–745, 748–750, 749f conversion to acid chlorides, addition to margarine, 432 1012–1014 oxidation, 726–727, 738–739 845–847, 846f Carson, Rachel, 233 Heck reaction, 1003, 1009–1011 reduction, 726–738 conversion to amides, 846f, Carvacrol, 640 metathesis, 1015–1019, 1016f, reduction of, 726–738 849–850 Carvone, 188, 640, 1145 1018f biological, 732–733 conversion to cyclic anhydrides, Catalysts. See also specifi c catalysts Simmons–Smith reaction, carboxylic acids and derivatives, 846f, 847 acids as, 218–219 1014–1015 733–738 conversion to esters, 846f, 847–849 biocatalyst, 1167, 1168f Suzuki reaction, 1002, 1003, by catalytic hydrogenation, 729 nucleophilic substitution reactions, 725 chiral, 1085–1086 1005–1009, 1008f enantioselective, 731–733, 732f oxidation of aldehydes, 727, 738–739 defi nition of, 218 rotation around, 129, 131 with metal hydride reagents, physical properties, 692–693, 834, 834t energy of activation lowered by, 219, Carbon dioxide 728–729, 730f, 738t pKa of, 700–704, 829t 219f atmospheric concentration of, 149, stereochemistry of, 729–731 protonation of, 699 enzymes, 219–220, 220f 149f synthesis by hydroboration–oxidation reactions of homogeneous, 1159 electrostatic potential plot for, 45f of alkynes, 412–413 ester synthesis, 846f, 847–849 hydrogenation, 429 global warming, role in, 149 tautomers, 863–864 general features, 699 Lewis acid, 333 as nonpolar molecule, 44 α,β-unsaturated compounds, 755–758 nucleophilic acyl substitution Lindlar, 435 reaction of Grignard reagents with, unsymmetrical, enolates of, 889 reactions, 845–850, 846f, 858t metal, 218–219, 429 753–754 Carbonyl condensation reactions, reduction, 726, 735 palladium, 219, 729. See also release in combustion reactions, 148 916–939 resonance stabilization of, 701–702, Palladium-catalyzed reactions Carbon–halogen bond, polar, 234, 234f aldol reactions, 917–928. See also 702f, 703f Ziegler–Natta, 1157–1159, 1160 Carbon–hydrogen bonds Aldol reactions salts of, 696 Catalytic amount, 219 acidity of, 63, 64 Claisen reaction, 928–932, 929f separation from other organic Catalytic hydrogenation, 429–431 benzylic, 669–670 Dieckmann reaction, 932–933 compounds, 707–709, 709f of aldehydes and ketones, 729 bond length and bond strength, 41–42 Michael reaction, 934–936, 935f solubility of, 693t Catecholborane, 1007, 1009 halogenation of, 552–555 Robinson annulation, 936–939 spectroscopic properties, 693–694, Cation(s) nonpolar nature of, 43 Carbonyl groups, 409, 722 694f carbocation. See Carbocation(s) radical reaction with, 540–541 conjugated, 780–781 stability of, 829 counterions, 55 Carbon monoxide, 1110 as electron-withdrawing group, 591 structure and bonding of, 689, 722, cyclopentadienyl, 625 Carbon NMR, 495, 522–526 features of, 828 826, 828–829 defi nition of, 7 of aldehydes, 782, 782f formation by oxidative cleavage of substituted benzoic acids, 705–707, radical, 465 of amines, 956 alkenes, 444–446 706f salt formation, 10–11 basis of, 522–523 as functional group, 85, 86t synthesis of, 697–699 solvation by ion–dipole interactions, of benzene derivatives, 613–614, 613f, hydrogenation of, 432 conversion of acid chlorides, 842, 240, 241, 264–265 613t IR absorption of, 693, 694f, 780–781, 843 spectator ions, 55 of carbocations, 575, 575f 781f conversion of anhydrides, 844 tropylium, 625–626, 630, 630f of carboxylic acid derivatives, 836 of monosaccharides, 1028 hydrolysis of amides, 855–856 Cationic polymerization, 1153–1154, of carboxylic acids, 694, 695f nucleophilic addition to, 786–788, hydrolysis of esters, 850–852 1155f characteristic absorptions, A–12 788f hydrolysis of nitriles, 863–864 CBS reagent, 731–732, 732f chemical shifts in, 523, 524, 525t, reactivity of, 85 malonic ester synthesis, 900–903 Cedrol, 1133f 575, 575f stabilization by alkyl groups, 802 oxidation of aldehydes, 738 Celecoxib (Celebrex), 1132 examples of spectra, 526f tautomers of, 881–883 oxidation of alkyl benzenes, 698 Cell membrane of ketones, 782 Carboxy, derivation of term, 689 oxidation of alkynes, 698 cholesterol in, 150, 150f, 1140 of nitriles, 836 Carboxy group, 86t, 689 oxidation of primary (1°) alcohols, functions, 100 number of signals in, 523–524 of benzene derivatives, 671–672 447, 448–450, 698 phospholipids in, 1126–1128 position of signals in, 524–526 Carboxylate anion oxidative cleavage of alkynes, structure of, 100, 101f reference signal, 523 of amino acids, 712 446–447 transport across, 100–102, 102f Carbon–oxygen bonds, polar nature of, formation of, 700 reaction of organometallic reagents Cellobiose, 1058 43 metal salt of, 692, 693f with carbon dioxide, 753–754 Cells, 100 Carbon skeleton (backbone), 82 synthesis of -carboxylic acid (suffi x), 860 Cellulose, 858, 858f Carbon tetrachloride, 232 hydrolysis of amides, 855–856 Carboxylic acid derivatives. See also Acid hydrolysis of, 160, 161f, 1060 as solvent, 94 hydrolysis of esters, 850, 851–852 chlorides; Amides; Anhydrides; solubility of, 162 -carbonyl chloride (suffi x), 830, 833t hydrolysis of nitriles, 863–864 Esters structure of, 160–161, 161f, 162f, Carbonyl compounds. See also specifi c Carboxylation, 753–754 acidity/basicity of, 828–829, 829t 1029f, 1059–1060 classes Carboxylic acid(s), 688–709 boiling point of, 834, 834t Cellulose acetate, 1060 classes of, 722 acidity of, 689, 699, 700–705, 703f, IR spectra of, 835, 835t Cembrene, 601 condensation reactions, 916–939 829t, 845 leaving groups of, 827, 828, 829t, Cephalexin, 838 conversion of ozonides to, 445–446 aliphatic, inductive effects in, 703–704 838–840 Cephalin, 1126 electron defi ciency of, 723 aspirin as, 696–697 melting point of, 834, 834t Cephalosporins, 838 electrostatic potential map of, 723, basicity of, 699 NMR spectra of, 836 Cetylpyridinium chloride (CPC), 236 723f benzene derivatives, 671–672 nomenclature of, 830–834, 833t CFCs. See Chlorofl uorocarbons (CFCs) formation by oxidation of alcohols, boiling point of, 693t nucleophilic acyl substitution reactions Chain branching, in polymerization, 447 deprotonation of, 700, 700t of, 725, 838–839 1152–1153 β-hydroxy diacids, 692, 900 mechanism of, 838–839 Chain-growth polymerization, synthesis of, in aldol reactions, as dimers, 692, 693f relative reactivity, 839–841, 859 1150–1157 917–928 dipole–dipole interactions of, 692 summary of, 857–858, 858t anionic, 1154–1155, 1155f, useful transformations of, 924, 924f electrostatic potential plot, 689, 689f physical properties of, 834, 834t 1156–1157 leaving groups of, 722, 724, 725–726 functional group in, 86t reaction of organometallic reagents cationic, 1153–1154, 1155f pKa, 884–885, 885t, 886t hydrogen bonding, 692, 693f with, 750–753 chain branching in, 1152–1153

smi75625_index_1218-1246.indd 1225 11/24/09 12:13:33 PM I-9 Index

Chain-growth polymerization (continued) Chlorocyclopentane, 96 Citronellal, 783f monosubstituted cyclohexane, copolymers, 1156 Chlorocyclopropane, NMR spectrum Citronellol, 493 141–143, 143f of epoxides, 1156–1157 of, 500 Claisen reactions, 928–929, 929f ring-fl ipping, 140–141, 141f ionic, 1153–1156, 1155f Chloroethane, 51, 84, 231 crossed, 930–932 defi nition of, 131 radical, 1151–1152, 1151f, 1153–1156, NMR spectrum of, 524 intramolecular, 932–933 eclipsed, 131–137, 132f, 133f, 134f, 1155f Chloroethylene, NMR spectrum of, 500 Claritin. See Loratadine 136f, 136t, 295f Chain-growth polymers, 1149, 4-Chloro-1-ethyl-2-propylbenzene, 612 Clemmensen reduction, 672 free energy change and, 208–209 1150–1157 Chlorofl uorocarbons (CFCs), 3, 233, Clomiphene, 394 gauche, 134f, 135, 136f Chain mechanism, 544, 551 551–552, 552f Clopidogrel, 175, 912 staggered, 131–137, 132f, 133f, 134f, Chain termination, 1152 Chloroform, 232 Clostridium botulinum, 261 136f, 295, 295f Chair conformation dichlorocarbene preparation from, 13C NMR. See Carbon NMR Congo red, 989, 990 of cyclohexanes, 138–147, 139f 1012–1013 Cocaine, 78, 110, 836, 957 Coniine, 957, 957f of glucose, 1041 Chlorohydrin, estrone synthesis from, Cocoa butter, 1125 Conjugate acid, 56–58, 236–237, 237t Chantix. See Varenicline 385f Coconut oil, 369, 1123, 1124 Conjugate addition, 584, 934 Charge Chloromethane, 233f. See also Methyl Codeine, 716, 959 Conjugate base, 56–58 Brønsted–Lowry acids and bases, chloride Coenzyme, 451 Conjugated dienes, 580–599 55f, 56 1-Chloro-1-methylcyclohexane, 375 NADH, 733 addition reactions on carbon atom, 31 1-Chloro-2-methylcyclohexane Coffee, decaffeinated, 233f Diels–Alder reaction, 588–597, dipole, 43, 44, 45f cis-1-chloro-2-methylcyclo hexane, Collagen, 81, 1075 589f formal, 15–16, 17t 296 structure of, 1108–1109, 1109f electrophilic, 584–586 in resonance hybrid, 22 trans-1-chloro-2-methylcyclo hexane, Column, in periodic table, 8 kinetic versus thermodynamic Charged ion, 7 296 Combustion product, 586–588 Chauvin, Yves, 1015 1-Chloro-3-methylcyclohexane, 375 of acetylene, 402 carbon–carbon bond length in, Chemical shift 1-Chloro-1-methylcyclopropane, 307 of alkanes, 148–149 581–582 in 13C NMR, 523–524, 525t, 575, 2-Chloro-5-methylheptane, 230 defi nition of, 148 conformation of 575f 3-Chloro-3-methylhexane, 376 of triacylglycerols, 1125 s-cis, 580 in 1H NMR (3R)-1-Chloro-3-methylpentane, 310 Common names s-trans, 580 equation for, 498 1-Chloro-2-methylpropane, 231f of alcohols, 315–316 electrostatic potential plot for, 573, predicting values of, 503–504 meta-Chloroperoxybenzoic acid, 438f, of aldehydes, 777, 777f 573f protons on benzene rings, 505, 439–441 of alkanes, 127–128, 128f hydrogenation of, 583–584 506t 2-Chloropropanal, 777f of alkenes, 365, 365f interesting examples of, 581 protons on carbon–carbon double 1-Chloropropane, 374, 673 of alkyl halides, 231 numbering of carbons in, 584 bonds, 505, 506t 2-Chloropropane, 374 of amines, 952–953 stability of, 583–584, 583f protons on carbon–carbon triple mass spectrum of, 468, 469f of benzene derivatives, 610–612 stereoisomers of, 580 bonds, 505, 506t 2-Chloropropene, 407 of carbohydrates, 1029 synthesis in Suzuki reaction, 1006–1009 scale, 497 3-Chloropropenoic acid, NMR spectra of, of carboxylic acid derivatives, 830 ultraviolet (UV) light absorption, values for common bonds, 504t 516, 516f of carboxylic acids, 691–692, 691t, 597–599, 598f Chiral catalysts, 1085–1086 α-Chloropropionaldehyde, 777f 692f Conjugated double bond, 920 Chiral drugs, 187 Chloroquine, 974 of epoxides, 317 Conjugated proteins, 1109 Chirality p-Chlorostyrene, 675–676 of ethers, 316 Conjugated systems basic principles of, 165f Chlorpheniramine, 646f of ketones, 778, 779f allylic carbocation, 572, 573–574 of naturally occurring objects, 166 Cholesterol, 596, 861–862, 861f, 1119, of nitriles, 832, 832f 1,3-dienes, 572–573, 573f in substituted cycloalkanes, 180 1139–1141 Compounds Conjugation, 571–606 test for, 164 biosynthesis of, 1140, 1140f examples of, 10 defi nition of, 572 Chirality center, 165. See also Stereogenic in cell membranes, 150, 150f, 1140 formation of, 10 derivation of word, 572 centers cholesterol-lowering drugs, 1140, ionic, 11 β-dicarbonyl compounds, 882 Chiral molecules, 163–166, 165f 1141f Concentration, reaction rate and, 216, effect on carbonyl group IR absorption, halogenation of, 550–551 trans fats and, 433 217–218 780–781 optical activity of, 183 solubility of, 95, 150 Concerted reaction, 200, 285 Hückel’s rule and, 618 Chiral reagent, 1084, 1085 specifi c rotation of, 185 Condensation polymer. See also Step- Constitutional isomers Chiral reducing agent, 731 structure of, 150, 150f, 170, 1139 growth polymers of alkanes, 115–117, 118t Chitin, 1061–1062 synthesis stimulation by saturated nylon, 859 of alkenes, 325 Chloral, 802 fats, 369 polyesters, 859–860 defi nition of, 17 Chloral hydrate, 802, 803 Cholesteryl esters, 861, 861f Condensation reactions of dipeptides, 1087 Chloramphenicol, 167 Cholic acid, 158 carbonyl, 916–939 in elimination reactions, 280 Chlorination Choline, 861 defi nition of, 919 features of, 162 of alkanes, 544–548, 544f, 545f, 548f, Chromate ester, 448 Condensed structures, 27–29, 28f ketone and aldehyde, 413 549–551 Chromium Confi guration of monosaccharides, 1029 of benzene, 645 in oxidizing agents, 438–439, 448–450, inversion of stereoisomers compared, 163f bromination compared to, 546–548, 738–739 in alkyl tosylate reactions, 339–340 tautomers, 410 548f Chromium(VI) oxide, 438–439 retention of Copolymers, 1156 of ethane, 543–544, 544f, 545f Churchane, 128f in conversion of alcohols to alkyl Copper as exothermic reaction, 544, 544f, Churchill, Winston, 233 tosylates, 338–339, 340 electronegativity value of, 739 547–548, 548f Chymotrypsin, 1093, 1093t in oxidation of alkylboranes, organocuprate reagents, 739–740, mechanism of, 543–544 Ciguatoxin (CTX3C), 735–736, 736f 388–389 1003–005 Chlorine Cimetidine, 957, 958 in SN2 reactions, 246–247, 247f, 263 Copper(I) cyanide, 983 isotopes of, 468 Cinnamaldehyde, 783f, 922 of stereoisomers, 162 Core electrons, 9 mass spectra of alkyl chlorides, 468, Cis-fused, 592 Conformations Corey, E. J., 5, 348 469f Cis geometry of acyclic alkanes, 129–137 Corn 2-Chloroacetamide, 879 alkenes, 359, 360t, 363 butane, 134–137, 134f, 136f ethanol production from, 319, 320f 2-Chloroacetic acid, 704 cycloalkenes, 359 ethane, 129–134, 132f, 133f use in green polymer synthesis, Chlorobenzene, 611, 645 Cis isomers anti, 134f, 135–137, 136f 1167–1168, 1168f 2-Chloro-1,3-butadiene, polymerization of 2-butene, 282–283, 282f of cycloalkanes, 137–147 Coronary artery disease, 150, 175, 369 of, 1160 of cycloalkanes, 144–147 disubstituted, 143–147 Cortisol, 314, 1142 1-Chlorobutane, synthesis of, 549–550 defi nition of, 144, 282, 377 monosubstituted, 141–143 Cortisone, 783, 1142 2-Chlorobutane of disubstituted cycloalkanes, 180 of cyclohexane(s), 138–147 Diels–Alder reactions, 596–597 NMR spectrum of, 501 Cis protons, 516, 517f boat, 141, 141f Cotton synthesis of, 549–550 Citral, 1133f chair, 138–147, 139f binding dyes to, 990 Chlorocyclohexane, chair conformation Citric acid, as Brønsted–Lowry acid, disubstituted cyclohexane, 144–147, cellulose in, 1059 of, 296–297 50, 55f 146f structure of, 858, 858f

smi75625_index_1218-1246.indd 1226 11/24/09 12:13:33 PM Index I-10

Coumarin, 946 Cycloalkenes Cyclohexylamine, 952 E1 mechanism in, 326 Counterions, 55 cis and trans geometry of, 359 ammonium salt of, 967–968, 967f E2 mechanism in, 327, 330–331 Coupling constant, 510, 516 nomenclature, 363, 363f in Hofmann elimination reaction, 978 enthalpy change in, 327, 327f Coupling reactions Cycloalkynes, 401 separation from cyclohexanol, Le Châtelier’s principle in, alkenes with organic halides (Heck Cyclobutadiene, 618–619, 626, 631 967–968, 967f 327–328 reaction), 1003, 1009–1011 Cyclobutane Cyclononatetraene, 637 with phosphorus oxychloride and of aryl diazonium salts, 982, 986–988 conformation, 137 Cyclooctane, 187 pyridine, 330–331 of organocuprate reagents, 1003–1005 structure of, 118, 138f Cyclooctatetraene, 618, 637 in strong acid, 325–330 Covalent bonding 1-Cyclobutylhexane, 126f NMR spectrum of, 619–620 of aldol product, 919–920 description of, 10, 11–12 Cyclodecane, structure of, 138f Cyclooctene, cis and trans isomers of, 359 dicarboxylic acid conversion to cyclic in Lewis structures, 12–15 α-Cyclogeraniol, 398 Cyclooctyne, 401 anhydrides, 847 Covalent molecules Cycloheptane, structure of, 138f Cyclooxygenase, 697, 1130, 1131–1132, as β-elimination reaction, 325 boiling points of, 91 1,3,5-Cycloheptatriene, 618, 625 1131f fragmentation pattern in mass intermolecular forces, 87–90, 88f, 90t 1,3-Cyclohexadiene, 618 Cyclopentadiene, 593, 595–596, 625, 636 spectrum, 471 solubility of, 96f heat of hydrogenation, 616 Cyclopentadienyl anion, 624–625 Dehydrohalogenation COX-1, 1131–1132, 1131f stability of, 619 Cyclopentadienyl cation, 625 alkene synthesis by, 279 COX-2, 1131–1132, 1131f ultraviolet absorption, 598 Cyclopentadienyl radical, 625 of alkyl halides with strong base, 369, COX-3, 1132 Cyclohexanamine. See Cyclohexylamine Cyclopentane, structure of, 118, 138f 370 CPC (cetylpyridinium chloride), 236 Cyclohexane(s) Cyclopentanecarboxylic acid, 902 alkyne synthesis by, 299–300, 300f Cracking, 366 conformations of, 138–147 1,2-Cyclopentanediol bases commonly used in, 280, 280t Crafts, James, 643 boat, 141, 141f cis isomer of, 443 drawing products of, 280 CRCs (chlorofl uorocarbons), 233, chair, 138–147, 139f, 296–297 trans isomer of, 316 E1 mechanism of, 291 551–552, 552f disubstituted cyclohexane, 144–147, Cyclopentanol, 96 E2 mechanism of, 285, 290 p-Cresol, 686, 1176 146f Cyclopentanone, 422, 819 16,17-Dehydroprogesterone, 1146 Crossed aldol reactions, 921–924 free energy change and, 208 Cyclopentene, chlorination of, 381 Delocalization, resonance, 67 synthetically useful reactions, monosubstituted cyclohexane, Cyclopropane(s) Delta (δ) carbon, 691 922–924, 923f 141–143, 143f conformation, 137 Delta (δ) scale, 497 with two different aldehydes, both ring-fl ipping, 140–141, 141f dihalo to dialkyl conversion, 1014 Dementia, 85, 926 having α H atoms, 922 conversion to cyclohexene, 549 NMR spectrum of, 500 Demerol. See Meperidine useful transformations of aldol E2 elimination in, 297 structure of, 118 Dendrobates histrionicus (poison dart products, 924, 924f in mango, 114 synthesis of frog), 404, 404f Crossed Claisen reactions, 930–932 NMR spectrum, 518 in Simmons–Smith reaction, Deoxy (prefi x), 1063 Cross formula, 1030 skeletal structures, 29 1014–1015 2-Deoxyadenosine, 1063 Crown ethers, 101–102, 320–321, 321f structure of, 114, 118, 125 using carbene intermediates, Deoxyadenosine monophosphate, 104f, Crude oil, 128 Cyclohexanecarbonyl chloride, structure 1012–1014 105, 1029f, 1064 Crutzen, Paul, 551 of, 830 Cyclopropenone, 821 2-Deoxy-d-ribose, 1063 Crystallites, 1165 cis-1,2-Cyclohexanediol, 443 Cysteine, 190 Deoxyribonucleic acid (DNA), 104f, 105, CTX3C (ciguatoxin), 735–736, 736f Cyclohexanediols, 443, 1175 abbreviation for, 711t 1064–1065, 1065f Cubane, 128f, 138 1,3-Cyclohexanedione, 717 isoelectric point for, 1078t Deoxyribonucleosides, 1063–1064 Cucumber aldehyde, 779 Cyclohexanol, 819 in peptide formation, 1086–1087 Deoxyribonucleotides, 1064 Curcumin, 639 cyclohexene formation from, 392 pKa values for, 1078t Deprotection, 748 Curved arrow notation, 20–21, 56, 201, dehydration of, 330–331, 392 structure of, 1076f Deprotonation 235 1,2-dibromocyclohexane synthesis Cytidine, 1063 in acetoacetic ester synthesis, 904 Cyanide from, 391–392 Cytidine monophosphate, 1064 of alkyne, 405–406, 406t addition to aldehydes and ketones, separation from benzoic acid by Cytosine, 1064, 1065f of carboxylic acids, 700, 700t 790–791 extraction procedure, 707–709, of diethyl acetamidomalonate, 1079 addition to imines, 1080 709f 2,4-D (2,4-dichlorophenoxyacetic acid), in direct enolate alkylation, 897 α-Cyano carbonyl compounds, 923–924 separation of cyclohexylamine from, 646f in glycoside formation, 1043 2-Cyanocyclohexanone, structure of, 832f 967–968, 967f Darvon (propoxyphene), 106, 166–167 in halogenation at α carbon of carbonyl Cyano group, 791, 832 synthesis from cyclohexene, 378–379 DBN (1,5-diazabicyclo[4.3.0]non-5-ene), compounds, 893–895 of nitriles, 827 Cyclohexanone, 566, 760, 821 286, 286f, 300 in malonic ester synthesis, 901 Cyanohydrins aldol reactions of, 924, 924f DBU (1,8-diazabicyclo[5.4.0]undec-7- racemization at α carbon of carbonyl in Kiliani–Fischer synthesis, 1049, alkylation of, 898 ene), 286, 300 compounds, 891 1051 conversion to alkene, 796–797 DCC. See Dicyclohexylcarbodiimide Deshielding effects, in NMR, 502–503, naturally occurring derivatives, enolate formation from, 884 d (dextrorotatory) compounds, 183 502f, 503f, 506f, 506t 791–792 halogenation of, 896 DDE (dichlorodiphenyldichloro ethylene), DET (diethyl tartrate), 452–453 synthesis by cyanide addition to nucleophilic addition reactions, 788, 278, 280 Detergents, 100 aldehydes and ketones, 790–791 788f DDT (dichlorodiphenyltrichloro ethane), 4, Deuterium, 7 in Wohl degradation, 1049, 1050 tertiary alcohol formed from, 743 109, 215, 233, 683 Deuterochloroform, 496f Cyclic anhydrides, 826–827, 847 Cyclohexene biological effects of, 278 Dextropimaric acid, 1145 Cyclic compounds addition reactions of, 371f, 376, DDE formed from, 278 Dextrorotatory, 1033 entropy decrease with formation of, 378–379, 380 degradation of, 280 Dextrorotatory (d) compounds, 183 209 bromination of, 554 Dean–Stark trap, 804, 805f Di- (prefi x), 123 stereogenic centers in, 168–170 1,2-dibromocyclohexane synthesis Decalin, 158, 460, 1138, 1139f Diabetes, 783 Cyclic esters, 837 from, 392 Decamethrin, 1012 Diacids, 692, 900 Cyclic ethers, 317 heat of hydrogenation, 616 Decane, 113 formation from monosaccharide Cyclization, of hydroxy aldehyde, 810, as Lewis base, 74 constitutional isomers of, 118t oxidation, 1049 813 stereoisomers, 592 molecular formula of, 118t in nylon synthesis, 859, 1160 Cyclo- (prefi x), 118, 125 synthesis Decarboxylation, 1079 Diacon. See Methoprene Cycloalkanes cyclohexane conversion, 549 of β-diacids, 900 Dialkylborane, 387, 387f conformations of, 137–147 from cyclohexanol, 392 of β-keto acids, 901 Diamine, in nylon synthesis, 859, 1160 disubstituted, 143–147 by dehydration of cyclohexanol, in malonic ester synthesis, 900–902 1,4-Diaminobenzene, 1161 monosubstituted, 141–143 330–331 DEET, 842–843 1,6-Diaminohexane, 1160, 1167, 1167f disubstituted, 180–181 as synthetic intermediate, 392 Dehydrating agent, 849–850 Diamond, 632 molecular formula, 114, 118 2-Cyclohexen-1-ol, 356 Dehydration reactions Diastereomers, 175–177, 177f naming, 125–127, 126f, 127f 2-Cyclohexenone, 493, 821, 928 of alcohols to alkenes, 324–331, alkenes, 360t, 363–364 NMR spectra, 499–500 formation in Robinson annulation, 369–370 of 2-butene, 282–284, 282f stereoisomers, 144–147 936–939 alkene synthesis in, 324–331 defi nition of, 177 structure of, 114, 118 reduction of, 729 carbocation rearrangements in, disubstituted cycloalkanes, 180–181 substituted, 141–147, 143f, 146f synthesis of, 896 328–330 epimers, 1035

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Diastereomers (continued) Dicyclohexylcarbodiimide (DCC), 846f, Dihydroxyacetone, 1029, 1035, 1036f gem-diol, 802–804 of glucose, 1038, 1038f 849–850, 1095, 1098, 1100 1,4-Dihydroxybenzene, 1164 p-Dioxanone, 1177 halogenation reactions and, 550–551 Dicyclohexylurea, 849 Dihydroxylation, 442–444 Dioxybenzone, 109 of monosaccharides, 1035 Dicyclopentadiene, 595–596 anti, 442, 443 Dipeptides NMR spectrum of, 500–502 Didrex. See Benzphetamine syn, 442, 443–444 constitutional isomers of, 1087 nucleophilic substitution reactions Dieckmann reaction, 932–933 1,4-Dihydroxymethylcyclohexane, 860 synthesis of, 1086–1087, 1094–1098 and, 263 Diels–Alder reaction, 588–597 6,7-Dihydroxy-2-nonanone, 823 Diphenhydramine, 275, 610, 968 physical properties of, 185–186, 186f diene reactivity in, 590–591 Diisobutylaluminum hydride (DIBAL-H), Diphenyl carbonate, 1163, 1168 separation of amino acid enantiomers dienophile reactivity in, 591 734, 735, 736f, 738t, 865–866 Diphosphate, as leaving group, into, 1081–1083, 1082f drawing product of, 590 Diisopropylamine, 888, 952 1134–1137 1,3-Diaxial interactions, 143 features of, 589 β-Diketone, pKa of, 886t Dipole, 43, 44, 45f Diazepam, structure, 615f retro, 595–596 Dimers, carboxylic acids as, 692, 693f in alkenes, 365 Diazomethane, 1014 retrosynthetic analysis of product, 595 2,2-Dimethoxy-1,3-cyclopentanedi- temporary, 87–88 Diazonium ions, 261 rule of endo addition, 593–594 carbaldehyde, 785 Dipole–dipole interactions, 89, 90t Diazonium salts rules governing, 590–594, 593–594 5,5-Dimethoxy-2-pentanone, 820 of aldehydes and ketones, 779 alkyl, 981 stereospecifi city of, 592 Dimethylacetylene carboxylate, 606 of alkyl halides, 231 aryl, 980–988 in steroid synthesis, 596–597 Dimethylallyl diphosphate, 1134–1135, of carbonyl compounds, 834 coupling reactions of, 982, 986–988 tetrodotoxin synthesis, 589, 589f 1135f of carboxylic acids, 692 explosiveness of, 981 as thermal reaction, 589 4-(N,N-Dimethylamino)pyridine, 973 of nitriles, 834 formation from primary amines, Dienes, 362 N,N-Dimethylbenzamide, 832 in polar aprotic solvents, 241, 265 980–981 conjugated. See Conjugated dienes 1,3-Dimethylbenzene, 667 Dipole moment, infrared (IR) absorption substitution reactions of, 982–986 isolated, 572, 573f, 583, 583f, 584 2,3-Dimethylbutanal, 776 and, 480 synthesis of aryl chlorides and in metathesis, 1017–1019 3,3-Dimethyl-2-butanol, 328, 329 Directed aldol reactions, 925–926, 925f bromides, 983 ozonolysis of, 446 3,3-Dimethyl-2-butanone, 536 Disaccharides, 1056–1058 synthesis of aryl fl uorides, 983 1,3-Dienes, 572–573, 604. See also 2,2-Dimethyl-3-butenal, 779 artifi cial sweeteners, 1058, 1059f synthesis of aryl iodides, 983 Conjugated dienes 2,3-Dimethyl-1-butene, 397 general features, 1056 synthesis of benzene, 983–984 polymerization of, 1160 3,3-Dimethyl-1-butene, 567 lactose, 1027, 1057–1058 synthesis of benzonitriles, 983 synthesis in Suzuki reaction, 2,3-Dimethyl-2-butene, 397 maltose, 1057 synthesis of phenols, 982 1006–1009 Dimethyl carbonate, 769 sucrose, 1058, 1058f uses in synthesis, 984–986 Dienophiles (1E,4R)-1,4-Dimethylcyclodecene, 395 Discodermolide, 195 Diazotization, 980–981, 984 cis, 590–591, 592 1,2-Dimethylcyclohexane, 127f Disorder, entropy as measure of, 209 DIBAL-H (diisobutylaluminum hydride), common, 594f 1,3-Dimethylcyclohexane, 126 Disparlure, synthesis of, 441, 442f 734, 735, 736f, 738t, 865–866 cyclic, 590–591, 592 1,4-Dimethylcyclohexane, 144–146, 146f Disproportionation, 1152 Dibromobenzene Diels–Alder reaction, 588–596 2,2-Dimethyl-1,3-cyclohexanedione, 909 Dissolving metal reductions, 428, 436 meta-, 610, 613f reactivity of, 591 5,5-Dimethyl-1,3-cyclohexanedione, 909 Distillation, of crude petroleum, 129 ortho-, 610, 613f stereochemistry, 592 2,2-Dimethylcyclohexanone, 898, 899 Distillation apparatus, 92, 92f para-, 610, 613f trans, 590–591, 592 2,6-Dimethylcyclohexanone, 898 trans-1,2-Disubstituted cycloalkanes, 345 1,4-Dibromobutane, 902 Diesel fuel, composition of hydrocarbons 1,2-Dimethylcyclohexene, 377, 377f Disulfi de bonds 2,2-Dibromobutane, 407–408, 424 in, 128 1,6-Dimethylcyclohexene, 363f in α-keratins, 1108 2,3-Dibromobutane, 166, 177–179, 179f, Diesters 1,2-Dimethylcyclopentane, 144 in peptides, 1089 309 in Dieckmann reaction, 932–933 cis isomer, 163f in tertiary structure of proteins, 1105, Dibromocarbene, 1014 1,3-diesters, pKa of, 886t trans isomer, 163f 1106f 1,2-Dibromocyclohexane, synthesis from 1,6-diesters, in Dieckmann reaction, 1,3-Dimethylcyclopentane, 186 in vulcanized rubber, 1159, 1159f cyclohexanol, 391–392 932 3,3-Dimethylcyclopentene, 353 Diynes, 401 1,3-Dibromocyclopentane, 180–181 1,7-diesters, in Dieckmann reaction, Dimethylcyclopropanes, 194, 1026 DMAP, 973 1,2-Dibromoethane, 395 933 Dimethyl ether DMF. See Dimethylformamide 4,5-Dibromooctane, 396 β-diesters isomers of, 17, 78 DMSO. See Dimethyl sulfoxide 2,3-Dibromopentane, stereoisomers of, as active methylene compounds, NMR spectrum of, 524 DNA, 104f, 105, 1064–1065, 1065f 176–177, 177f, 179 924 Dimethylformamide (DMF), 537 Dobutamine, 952 Di-tert-butyl dicarbonate, 1096 synthesis in crossed Claisen boiling point of, 92 Docetaxel, 876 Dibutyl phthalate, 1165–1166, 1174 reaction, 931–932 as solvent, 241f, 896 Docosanoic acid, 460 Dicarbonyl compounds, 445 Diethyl acetamidomalonate, 1079 2,5-Dimethyl-3-heptyne, 402f Dodecahedrane, 127, 138, 606 aldol reactions with, 926–928 Diethylamine, solubility of, 96 4,5-Dimethylhexanoic acid, 690 Domagk, Gerhard, 990 1,4-dicarbonyl compounds, 926 Diethyl carbonate, in crossed Claisen 2,4-Dimethyl-3-hexanone, 760 Donepezil, 85, 926 1,5-dicarbonyl compounds, 927, 928f reaction, 931 2,4-Dimethylhexanoyl chloride, 833 l-Dopa (levodopa), 6, 45, 191, 1115 in Robinson annulation, 936–937 1,2-Diethylcyclohexane, 155 6,6-Dimethyl-3-octyne, 402 Dopamine, 820, 958, 959f synthesis of, 935, 936±937 cis-1,2-Diethylcyclopropane, 1015 2,2-Dimethyloxirane, 317, 346 Double bonds. See also Alkenes β-dicarbonyl compounds, 923, 923f Diethyl ether, 84, 108 2,3-Dimethyloxirane, 345 in alkenes, 83, 84t

pKa values, 886, 886t as anesthetic, 233f, 320 2,3-Dimethylpentane, 123f in alkyl halides, 229, 229f synthesis in crossed Claisen boiling point of, 779 mass spectrum of, 470±471 bond length and bond strength, 41, 41t reactions, 931 in extraction procedures, 707 2,2-Dimethylpropane, 116 components of carbon–carbon, 37, tautomers, 882 infrared (IR) spectrum, 482 2,2-Dimethylpropanoic acid, 704 38f 2,5-Dichloroaniline, 612 naming, 316 Dimethyl sulfi de, conversion of ozonide to in condensed structures, 28 4,4'-Dichlorobiphenyl, 95 solubility of, 96 carbonyl compounds, 445–446 conjugated, 576, 920 Dichlorocarbene, 1012 as solvent, 94, 341, 707 Dimethyl sulfoxide (DMSO), 266 degrees of unsaturation, calculating, 1,2-Dichlorocyclopentane, 381 Diethyl maleate, 1026 aqueous, 383–384 431–432 Dichlorodifl uoromethane, 551 Diethyl malonate, 910, 923, 932 as polar aprotic solvent, 241f effect on melting point of fatty acids, Dichlorodiphenyldichloroethylene. See alkylation of derivatives, 1079–1080, as solvent for alkyne synthesis, 299, 368, 368t DDE 1081f 300f in functional group, 83, 84t Dichlorodiphenyltrichloroethane. See conversion to a carboxylic acid, Dimethyl terephthalate, 1162, 1170 hydrogenation of, 432–433, 433f DDT 900–903 1,3-Dinitriles Lewis structure, 15 1,1-Dichloroethylene, NMR spectrum Diethyl oxalate, 946 active methylene compounds, nitrogen–nitrogen, 986 of, 500 Diethyl tartrate (DET), 452–453 923–924 NMR spectra of, 505, 506f, 506t π Dichloromethane, 233f, 448 N,N-Diethyl-m-toluamide, 842–843 pKa, 886t pi ( ) bonds, 82 as solvent in extraction procedure, Diethyl tartrate (DET), 452–453 Dinoprostone, 1130 planar, 376–377, 381, 386, 388 707–708, 708f, 709f Digoxin, 812 -dioic acid (suffi x), 692 radical reactions with, 541, 558–560 2,4-Dichlorophenoxyacetic acid herbicide Dihalides, 299 -diol (suffi x), 315 in resonance hybrid, 22 (2,4-D), 646f alkyne synthesis from, 404–405 Diols, 315 resonance structures trans-1,3-Dichloropropene, 517 Dihalocarbenes, 1012–1014 1,2-diol formation by dihydroxylation, conjugated, 576 Dictyopterene D', 460 Dihedral angle, 131, 132f, 135, 136f, 295 442–444 major contributor, 577–578, 582

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minor contributors, 577–578, 582 syn periplanar geometry in, 295, 295f Markovnikov’s rule on, 374–375, Enals, 779 with one atom more electronegative Zaitsev rule, 288–291, 297 374f, 378t Enamines than the other, 576, 577 Effexor. See Venlafaxine stereochemistry of, 376–378, 377f, hydrolysis of, 801 rotation restriction, 37, 360t E-85 fuel, 319, 320f 378t synthesis of in triacylglycerols, 369, 1122–1124, Ehrlich, Paul, 990 Electrophilic aromatic substitution from aldehydes and ketones, 1122t Eicosane reactions, 641–687, A–13 800–801, 801f in unsaturated fatty acids, 358, 368 constitutional isomers of, 118t azo coupling, 986–987 amine reaction with aldehydes and Z confi guration, 368 molecular formula, 118t energy changes in, 644, 644f ketones, 975 Double dagger notation, 211 Eicosanoids, 1129–1132 examples of, 643f Enanthotoxin, 25 Double-headed arrow, 18, 56–57, 202t biological activity of, 1130, 1130t Friedel–Crafts acylation, 643f, Enantiomeric excess, 184–185, 453, 732 Doublet, NMR spectrum, 509–510, 511t, biosynthesis of, 1130–1132, 1131f 647–653, 653f, 665–666, Enantiomers 512, 512t, 513 derivation of word, 1129 672–673, 677 of amino acids, 710–711, 1075, 1075f Doublet of doublets, NMR spectrum, E isomer, 364 Friedel–Crafts alkylation, 643f, separation of, 1081–1084, 1082f 516, 516f Elaidic acid, 395 647–653, 665–666, 672–673, of an ammonium salt, 951 Doxorubicin, 1029f Elastomer, 1159 675–676 in carbonyl reductions, 729–730 Dyes Electromagnetic radiation, 474–476, 475f halogenation, 643f, 644–645, 646f, chemical properties of, 186–188 azo compounds, 987, 988–991 Electromagnetic spectrum, 475, 475f 665, 666–667 chiral drugs, 187 binding to fabric, 989–990 Electron cloud, 7 mechanism of, 642–644 of cyclic compounds, 169 direct, 989 Electron-defi cient sites/species, 58, 82, 84, nitration, 643f, 646–647, 667–668 defi nition of, 164 natural and synthetic, 988–989 85, 102–103, 202, 723 of substituted benzenes, 657–660, 660f drawing, 168, 168f sulfa drugs, 990–991 Electron density, delocalization, 67 disubstituted benzenes, 666–668 in electrophilic addition to alkenes, Dyneema, 1159 Electron-donating groups, 256, 654–657, limitations on reactions, 665–666 376–377, 377f 660, 703–706, 706f rate of reactions, 660, 660f enatioselective reactions, 452–453 E,Z system of nomenclature, 364 Electron dot representation. See Lewis sulfonation, 643f, 646–647 in enolate alkylation, 898 E1cB elimination reactions, 920 structures Electrophilic carbon, in alkyl halides, 234 from epoxidation of alkenes, 440, 441 Eclipsed conformation, 131–137, 132f, Electronegativity Electrospray ionization (ESI), 474 in epoxide ring opening reactions, 133f, 134f, 136f, 136t, 295f acidity trends and, 63–66 Electrostatic interactions, between ions, 344–345 Edman degradation, 1091–1092 bond polarity and, 43, 44 10–11 formation in halogenation of alkenes, E1 elimination reactions defi nition of, 42 Electrostatic potential plot 380, 381, 382 acid-catalyzed dehydration of alcohols, inductive effects on substituted of acetic acid, 67f, 689, 689f halogenation reactions and, 549–551 369–370 benzenes, 654 of acetylene, 405, 405f in halohydrin formation, 384 base in, 291, 293, 293t, 298 oxidation and, 147 of an alcohol, 314f in hydroboration–oxidation reactions, characteristics of, 293t periodic trends in, 42, 42f of an alkoxide, 885, 885f 389 dehydration of secondary and tertiary values for common elements, 42f of amines, 951, 951f labeling stereogenic centers with R or alcohols, 326 Electron pair acceptor, 55, 72 of benzene, 610, 610f S, 170–175, 172f, 175f, 179–180 E2 mechanism compared, 298–299, Electron pair donor, 55, 72–73 of carbanions, 68f of monosaccharides, 1030, 1033–1034, 298t, 300–304, 302f–303f Electron pairs of carbocations, 257, 257f 1034f, 1036 energy diagram for, 292, 292f in Brønsted–Lowry acid–base localized and delocalized, 574, 574f in nucleophilic substitution reactions, kinetics of, 291, 293t defi nition, 55, 56 carbon dioxide, 45f 246, 254–255 leaving group in, 292, 293t Lewis acids and bases, 72–74 description of, 43–44 optical purity, 184–185 rate of reaction, 292–293, 293t movement of, 56, 201 of dienes, 573, 573f physical properties, 182–186, 184t, regioselectivity of, 293 Electron-poor sites/species, 73 of an enolate, 885, 885f 186f SN1 substitution reactions compared, Electron-rich sites/species, 58, 73, of an epoxide, 314f racemic mixture of, 183–184, 184t, 294, 300–304, 302f–303f 102–103, 370 of ethanol, 66f, 67f 376 SN2 substitution reactions compared, Electrons of an ether, 314f sense of smell and, 187–188, 188f 300–304, 302f–303f bonded (shared), 12 of ethylene, 370, 370f three-dimensional representations solvent for, 293t core, 9 of formaldehyde, 723, 723f for, 168f two-step mechanism, 291–292, 293t delocalized, 18, 22, 578–579, 609 of halomethanes, 234f Enantioselective reactions, 452–453 E2 elimination reactions density of, 8–9, 32, 43–44, 44f of methyl chloride, 44, 44f amino acid synthesis, 1085–1086 acetylide anion reactions with alkyl excited state, 597–598 of pyridine and pyrrole, 622, 623f biological reduction, 732–733 halides, 414–415 ground state, 597–598 of substituted anilines, 971, 971f carbonyl reductions, 731–733, 732f alkyl halide identity in, 287–288, 288t in Lewis structure, 12–14 of 2,2,2-trifl uoroethanol, 66f Enantiotopic protons, NMR signals of, alkyl tosylates reactions, 339 lone pairs, 21 of vitamins A and E, 1128, 1129f 500–502 alkyne synthesis, 299–300, 404–405 nonbonded (unshared), 12–14, 12f of water, 45f Enclomiphene, 394 anti periplanar geometry in, 295–298, number of, 7, 9 Elements, periodic table, 8–10, 8f Endergonic reaction, 210 295f in resonance structures, 18–23 Eleostearic acid, 395 Endo addition, 593–594, 594f base in, 286, 286f, 288t, 298 unpaired, 200–201 Elimination reactions, A–14 Endothermic reaction characteristics of, 288t valence, 10–16, 12–16, 17t of alcohols, 323–331 bond breaking and, 203–204 dehydration of alcohols, 327, Electron-withdrawing groups, 256, alkene synthesis, 279–280, 369–370 bromination, 547, 547f 330–331 591, 654–657, 660–661, 665, of alkyl halides, 234, 278–311 dehydration of alcohols, 327f dehydrohalogenation of alkyl halides, 703–707, 706f alkyne synthesis, 279, 404–405 energy diagram of, 212f 369, 370 Electrophiles, 85 alpha (α), 1012 enthalpy change and, 210 trans diaxial geometry in, 296–298, alkyne reactions with, 405 beta (β), 279 reaction rate, 259 296f carbocations as, 201, 202 bimolecular, 285. See also E2 transition state in, 258–259, 259f E1 mechanism compared, 298–299, Lewis acid, 73 elimination reactions -ene (suffi x), 362 298t, 300–304, 302f–303f meaning of term, 73 description of, 198 Energy energy diagram of, 285, 286f radicals as, 202 elimination, unimolecular, conjugate nonrenewable, 129 in Hofmann elimination, 978, 979, reactivity of, 102–103 base (E1cB) mechanism, 920 of photons, 474, 475–476 979f Electrophilic addition reactions, A–14 features of, 279–280 release in bond formation, 202 kinetics of, 285, 288t of conjugated dienes mechanisms of, 285 torsional, 133–134 leaving group in, 287, 288t kinetic versus thermodynamic E1. See E1 elimination reactions units of measurement, 40 one-step mechanism, 285–287, 288t products, 586–588, 587f, 588f E2. See E2 elimination reactions Energy barrier, 211, 213–214, 215, 285, organic synthesis examples, 289f 1,2- versus 1,4-addition, 584–586 E1 and E2 compared, 298–299, 292 rate of reaction, 287 energy diagram for, 372, 373f 298t, 300–304, 302f–303f Energy change, during the chlorination of regioselectivity of, 290 halogenation of alkynes, 409 reductive, 1006, 1008, 1011 ethane, 544, 544f, 545f SN1 and SN2 substitution reactions hydration of alkenes, 378–379, 390 stereochemistry, 295–298 Energy diagrams, 210–215, 212f, 215f compared, 300–304, 302f–303f hydrohalogenation of alkenes, unimolecular, 285. See also E1 for carbocation formation, 260f solvent for, 287, 288t 371–378, 372f, 373f, 374f, elimination reactions for chlorination of ethane, 545f stereochemistry of, 295–298, 295f 377f, 378t Zaitsev rule on, 288–291 for E1 elimination reactions, 292, 292f stereoselectivity of, 290 hydrohalogenation of alkynes, 407–408 Enalapril, 191 for E2 elimination reactions, 285, 286f

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Energy diagrams (continued) -enyne (suffi x), A–5 l-Erythrose, 1034, 1034f chlorination of, 543–544, 544f, 545f for electrophilic addition of HBr to Enynes, 401 d-Erythrulose, 1036f conformations of, 129–134, 132f, 1,3-butadiene, 587, 588f Enzymes, 219–220, 220f, 1075 ESI (electrospray ionization), 474 133f for electrophilic additions, 372, 373f active site of, 219, 220f Esmolol, 79 formation from ethylene and hydrogen, for electrophilic aromatic substitution, catalytic action of, 219–220, 220f Essential amino acids, 711, 1076f, 1077 218–219 644, 644f in kinetic resolution of amino acids, Essential fatty acids, 368, 369 molecular formula, 114, 115, 118t rate of electrophilic aromatic 1084 Essential oils, 1132 nonreactivity of, 82, 83 substitution of substituted in oxidation reactions, 451 Esterifi cation, 227 structure of, 82, 83, 114 benzenes, 660, 660f in peptide sequencing, 1093, 1093t Esterifi cation, Fischer, 847–848, 859–860 Ethanedioic acid, 692 for SN1 substitution reactions, 253, Enzyme–substrate complex, 219–220, Esters 1,2-Ethanediol, 316 253f, 260f 220f acidity/basicity of, 829t Ethanol, 110, 227 for SN2 substitution reactions, 245, Ephedrine, 166–167, 192 boiling point of, 834t in acid–base reactions, 61–62 245f, 249f Epi-aristolochene, 1147 cholesteryl, 861, 861f acidity of, 61–62, 65, 66, 67, 701, for two-step reaction mechanisms, Epichlorohydrin, 356, 1163, 1164f chromate, 448 703f 213–215, 215f Epimers cyclic, 837 in alcoholic beverages, 319, 426 Energy of activation (Ea) defi nition of, 1035 enolates from, 885–886 description, 2–3 catalysts and, 219, 219f of monosaccharides, 1051, 1053–1054 functional group in, 86t electrostatic potential plot, 66f, 67f defi nition of, 211 Epinephrine, 228 general structure of, 367 in ethyl acetate formation, 218–219 energy barrier height determined by, structure of, 958 interesting examples, 836–837 isomers of, 17, 78 211 synthesis of, 228, 251, 251f IR spectra of, 835, 835t NMR spectrum of, 518, 518f in energy diagrams, 211–215, 212f, Eplerenone, 321 leaving group, 725 oxidation of, 451 215f Epoxidation, 439–442, 439f melting point of, 834t pKa of, 701, 703f in exothermic reactions, 259, 260f in anti dihydroxylation, 443 NMR spectra of, 836 as polar protic solvent, 240f rate constant, relationship to, 217 Sharpless, 451–454 nomenclature of, 830–831, 833, 833t preparation from ethylene, 366f reaction rate and, 215–217 of squalene, 1140, 1140f nucleophilic substitution reactions, production by fermentation of transition state energy effect on, 259 stereochemistry of, 440 725 carbohydrates, 319, 320f Enol(s), 881–884 in synthesis of disparlure, 441, 442f odors of, 836 reactivity of, 82 hydroxy group of, 313 Epoxides, 277 physical properties of, 834t as renewable fuel source, 319, 320f reaction mechanism, 883–884 achiral, 443 pKa, 829t, 886t sodium ethoxide production from, resonance structures, 883–884 anionic polymerization of, 1156–1157 polyesters, 859–860 322 synthesis of, 755 applications, 347–349 reactions of, 850–855, 855f, 858t solubility of, 95 hydration of alkyne, 409–412 boiling point of, 318t with ammonia and amines to form structure, 82, 83 hydroboration–oxidation of alkynes, bonding, 314 amides, 850 Ethene, 365. See also Ethylene 412–413 electrostatic potential plot of, 314f carboxylic acid preparation by Ethers tautomers, 881–883 interesting examples, 321 malonic ester synthesis, boiling point of, 318t -enol (suffi x), A–5 melting point of, 318t 900–903 bonding of, 314 Enolate(s), 21, 884–891 nomenclature, 317–318 Claisen reaction, 928–932, 929f crown, 101–102, 320–321, 321f achiral, 891 physical properties of, 318–319, 318t hydrolysis to carboxylic acids, cyclic, 317 in aldol reactions, 918, 918f, 920, 922, reactions of, 343–347 850–852 electrostatic potential maps, 314f 923, 923f, 925, 927 with acetylide anions, 416–417 lipid hydrolysis, 853–855 formation by alcohol addition to alkylation, 897–899 with acids HZ, 345, 346f, 347 methyl ketone preparation by alkenes, 378–379 general features of, 897–899 general features, 324 acetoacetic ester synthesis, 900, functional group, 85t tamoxifen synthesis, 899 with organometallic reagents, 903–905 infrared (IR) spectra of, 482 of unsymmetrical ketones, 898–899 754–755 reaction with organometallic reagents, interesting examples, 320–321, 321f in Claisen reactions, 928–932 reduction, 437–438, 438f 750–752 melting point of, 318t electrostatic potential plot of, 885, with strong nucleophiles, 343–345 reduction of, 734 nomenclature, 316–317 885f reduction of, 437–438, 438f solubility of, 834t physical properties of, 318–319, 318t examples, 885–886 ring opening reactions, 1156–1157 stability of, 829 preparation by nucleophilic kinetic, 889–890, 898, 925 with acids, 345–347 structure and bonding of, 722, 826, substitution reaction, 269 in Michael reaction, 934–936, 935f enantiomers in, 344–345 828–829 reactions of reactions of, 888–889, 892, 897–899 nucleophilic substitution reactions, synthesis of alkyl halide formation, 341–343 resonance-stabilized, 920, 929, 935 343–347 from acid chlorides, 842 general features, 324 resonance structures, 884 regioselectivity of, 345–346 from anhydrides, 844–845 with strong acid, 341–343 in Robinson annulation, 936–939 solubility of, 318t from carboxylic acids, 846f, simple and complex, 316 synthesis of, 755 structure of, 313, 314 847–849 solubility of, 318t with bases, 887–888, 887t synthesis of, 322–323 from monosaccharides, 1046 structure of, 313, 314 from carbonyl compounds, 884 from alkenes, 439–441 thioesters, 860–861 symmetrical, 313, 322 from esters, 885–886 from halohydrins, 323 in triacylglycerols, 366, 367 synthesis of from tertiary amides, 885–886 Epoxy (prefi x), 317 waxes, 1121 from alkyl halides, 321–322 thermodynamic, 890–891, 899 Epoxyalkane, 317 Estradiol, 770 from monosaccharides, 1046 of unsymmetrical carbonyl compounds, 1,2-Epoxycyclohexane, 317, 344 analogs of, 402, 403 by nucleophilic substitution 889–891 1,2-Epoxy-2-methylpropane, 317 function in body, 1141t reactions, 321–322 Enol tautomers, 410–412, 882–883 cis-2,3-Epoxypentane, 317 structure of, 49, 157, 403, 1141t Williamson ether synthesis, 322 -enone (suffi x), A–5 Epoxy resins, 1163–1164, 1164f synthesis of, 288, 289f unsymmetrical, 313, 322 Enones, 779 Equal. See Aspartame Estragole, 684 Ethoxide, 61–62, 66, 701, 703f Entacapone, 52 Equations for organic reactions, writing, Estrogens, 1141, 1141t nucleophilicity of, 239 Enthalpy change (∆H°), 203–206 197, 197f Estrone Ethoxy group, 316 calculation from bond dissociation Equatorial bond, 160 function in the body, 1141t 4-Ethoxyoctane, 317 energies, 205–206 Equatorial hydrogens, 139–140, 139f, structure of, 117, 750, 935t, 1141t Ethyl acetate, 227 in dehydration of alcohols, 327, 327f 141f synthesis of, 687 in Claisen reaction, 928 E1 elimination reactions, 292, 292f Equilibrium, 206–208, 207f, 208t from a chlorohydrin, 385f formation from acetic acid and ethanol, in energy diagrams, 211–215, 212f, acid–base reactions, 61–62 in Diels–Alder reactions, 596–597 218–219 215f direction of, 216 using the Michael reaction, 935, as solvent, 847 free energy change, relation to, nucleophilic substitution and, 238 935f structure of, 831 209–210 Equilibrium arrows, 56–57, 202t Ethambutol, 49 synthesis of, 847 negative, 203, 210 Equilibrium constant (Keq), 206–209, Ethanal. See Acetaldehyde Ethyl acetoacetate, 888, 908, 914 positive, 203, 210 207f, 208t, 216 Ethane conversion to ketone, 903–905 Entropy (S°), 209 Ergot, 641 acidity of, 67–68, 69f synthesis in Claisen reaction, 928 Entropy change (∆S°), 209–210 Erlotinib, 421 bonds in, 36, 40f Ethyl p-aminobenzoate, 673 Environmental Protection Agency, 450 d-Erythrose, 193, 1034, 1034f, 1035f carbon–carbon bond length in, 581 N-Ethylaniline, 953, 996

smi75625_index_1218-1246.indd 1230 11/24/09 12:13:35 PM Index I-14

Ethylbenzene, 611 Etoposide, 817 Fischer proof of the structure of glucose, general features of, 647–648 bromination of, 670 Excited state 1053–1056, 1054f intramolecular reactions, 653 styrene synthesis from, 671 of atom, 32 Fishhook notation, 201 limitations in, 665–666 Ethyl benzoate, in crossed Claisen of electron, 597–598 Five-membered rings, synthesis of mechanism of, 648–649 reactions, 879, 930–931 Exergonic reaction, 210 in Dieckmann reaction, 932–933 polyalkylation, 666 Ethyl butanoate, 78, 836 Exo product, 593–594, 594f in intramolecular aldol reactions, unreactive halides, 650 Ethyl chloride, 84, 231, 524 Exothermic reactions 926–928 Frontalin, 454, 454f Ethyl chloroformate, in crossed Claisen addition reaction, 372, 372f FK506, 837 Frontside attack, in nucleophilic reaction, 931 bond formation and, 203–204, 206 Flagpole hydrogens, 141, 141f substitution reactions, 245–246 Ethyl chrysanthemate, 873 chlorination, 544, 544f, 547–548, Flat helical ribbon, shorthand for α-helix, Frost circle, 629 Ethyl α-cyanoacrylate, 1155f 548f 1103–1104 Fructofuranose ring, 1058 Ethylcyclobutane, 127f energy diagram of, 211, 212f Flat wide arrow, shorthand for β-pleated Fructose N-Ethylcyclohexanamine, 965 hydrogenation, 429 sheet, 1104 d-fructose, 1029, 1035, 1036f 2-Ethylcyclohexanecarbaldehyde, 776 reaction rate, 259 Fleming, Sir Alexander, 463, 857 stereogenic centers, 166–167 2-Ethylcyclohexanone, 898 transition state in, 258, 259f, 260f Flexibilene, 1146 in sucrose, 1058 4-Ethyl-3,4-dimethyloctane, 123f Exponent, 59 Flonase. See Fluticasone Fuels, renewable, 319, 320f 5-Ethyl-2,6-dimethyloctane, 123f Extraction, 707–709, 708f, 709f Flosal, 923 Full-headed curved arrow, 201, 202t Ethylcyclopentane, 489 for separation of amines, 967–968, 9-Fluorenylmethoxycarbonyl protecting Fumaric acid, 112, 592 Ethylene, 365 967f group (Fmoc), 1096, 1099–1100 Functional groups, 82–87. See also acidity of, 67–68, 69f Fluorine specifi c functional groups bond dissociation energies, 400–401 Fabric, binding of dyes to, 989–990 polarizability, 88–89 compounds containing a C=O group, bonds of, 36–38, 38f, 40f, 359 Farnesene, 306, 367f, 601 valence electrons of, 11 84, 85t bromine addition to, 608 Farnesol, 1133f, 1136 Fluoromethane, polarizability and boiling compounds containing a C–Z σ bond, as Brønsted–Lowry base, 55f, 56 Farnesyl diphosphate, 1135–1136, 1135f, point of, 91f 84, 85t electrostatic potential plot, 370f 1147 m-Fluoronitrobenzene, 611 defi nition of, 82 ethane formation from, 218–219 Fats, 369, 432–433, 853, 854 Fluoxetine, 3, 76, 187, 250, 250f, 732, 958 drawing connection to carbon skeleton, functional group in, 83, 84t body content of, 1125 Fluticasone, 230 82 in Heck reaction, 1009–1010 degree of unsaturation, 432 Fmoc (9-fl uorenylmethoxycarbonyl fragmentation pattern in mass as industrial starting material, 366, fatty acid composition, 1123, 1123t protecting group), 1096, spectrum, 471–472 366f melting point of, 369, 1122–1123 1099–1100 grouping organic compounds by, 83 Lewis structure, 14–15 saturated, 369 Folic acid, 990–991 hydrocarbons, 83–84, 84t molecular shape of, 24–25, 26f trans, 433 Formal charge, 15–16, 17t importance of, 86 monomers in polymerization, 561 Fat-soluble vitamins, 97, 1128, 1129f Formaldehyde infrared (IR) spectroscopy and, 477, pKa of, 60 Fatty acids aldol reactions of, 922 478, 478f, 479, 479f, 480t polymerization of, 1153, 1158 characteristics of, 1122 Bakelite preparation from, 1165 intermolecular forces and, 87 preparation from petroleum, 366 composition in fats and oils, 1123, electrostatic potential map of, 723, nomenclature of, A–4 structure of, 1151f 1123t 723f nucleophilic substitutions and, 267, synthesis from alkyl tosylates, 339 essential, 368, 369, 1122 formation from methanol oxidation, 268t Ethylene glycol, 155, 451, 807, 1176 melting point of, 368, 368f 451 reactivity and, 102–104 acetal formation from, 804 omega-3, 368, 369 hydration of, 802 synthesis of, A–15–18 in antifreeze, 319f oxidation of, 853 primary alcohol formed from, 743 Funk, Casimir, 97 formation from PET recycling, 1170 saturated, 358, 368, 433, 1122, 1122t, structure of, 777, 783 Funnel, separatory, 707, 708f naming, 316 1123, 1123t uses of, 783 Furan, 636, 1037 in polyester synthesis, 860 synthesis in lipid hydrolysis, 853, Formaldehyde hydrate, 802 Furanose rings, 1037, 1041–1042 in polyethylene terephthalate (PET), 854–855 Formalin, 783 Fused ring system, 592–593, 593f 1148, 1150f, 1161–1162 thioesters of, 861 Formic acid, 60, 119, 451, 691t, 694 in polyurethane synthesis, 1162 trans, 433 Formyl group, 779 Gabapentin, 170 preparation from ethylene, 366f triacylglycerol formation and, 105 Fosamax (alendronic acid), 18 Gabriel synthesis, 961–962 structure of, 319f in triacylglycerols, 367, 369, Fossil fuels, 70, 128–129, 149 Galactose, 156, 1057 Ethylene oxide, 317 1122–1125, 1122t Four-centered transition state, 386 d-galactose, 1035f, 1050 polymerization of, 1156–1157 unsaturated, 358, 368, 1122, 1122t, Fragmentation, 465, 469–472, 470f in lactose, 219, 220f ring opening of, 1156–1157 1123, 1123t, 1124 Free energy change (∆G°), 206–209, Wohl degradation, 1050 1-Ethyl-2-fl uorocyclopentane, 231f hydrogenation of, 1124 207f, 208t Gamma (γ) carbon, 691 N-Ethylformamide, 832 oxidation of, 1124 Frequency Garlic, 119 Ethyl formate, in crossed Claisen Feedstock, 1166 of electromagnetic radiation, 474–476, Gas chromatography–mass spectrometry reactions, 930–931 Fehling’s reagent, 1048 475f (GC–MS), 473–474, 473f, 474f Ethyl group, 121 Femara. See Letrozole of infrared radiation, 476–477 Gasohol, 319, 320f 2-Ethyl-1-heptene, 362 Fenfl uramine, 76 Friedel, Charles, 643 Gasoline Ethyl 2,4-hexadienoate, 946 Fenn, Dr. John, 474 Friedel–Crafts acylation, 643f, 647–653, additives 1-Ethyl-3-isopropylcyclohexane, 155 Fermentation, alcohol production by, 677 benzene, 83 Ethyl isopropyl ketone, 779f 319, 320f alkyl benzene synthesis, 672–673, 672f BTX mixture, 614 1-Ethyl-3-methylcyclohexane, 126 Ferulic acid, 605 of benzene, 643f ethanol, 319 N-Ethyl-N-methylcyclopentanamine, Fexofenadine, 49, 957, 958 electrophilic aromatic substitution high-octane, 497, 614 953 Fibers reaction, 643f MTBE, 95 N-Ethyl-N-methylcyclopentylamine, 953 natural, 858, 858f general features of, 647–648 combustion of, 148 Ethyl methyl ether, synthesis from alkyl synthetic, 825, 858–860 intramolecular, 653, 653f composition of hydrocarbons in, 128, tosylates, 339 Fibrinogen, 1075 ketone synthesis, 643f, 648, 672–673 129 3-Ethyl-3-methylheptane, 489 Fibrous proteins, 1106 limitations of, 665–666 isooctane in, 196, 216 Ethyl methyl ketone, 778 Fingerprint, of IR spectrum, 477, 478, mechanism of, 649–650 octane rating, 83 4-Ethyl-5-methyloctane, 123f 478f, 479, 479f Friedel–Crafts alkylation, 643f, 647–653, oxidation of isooctane, 196 Ethyl p-nitrobenzoate, 673 First-order kinetics, 217 675–676 Gauche conformation, 134f, 135, 136f 3-Ethylpentane, bromination of, 546 of E1 elimination reactions, 291, 293t of alcohols, 652 GC–MS (gas chromatography–mass 2-Ethyl-1-pentene, 376 of nucleophilic substitution reactions, of alkenes, 652 spectrometry), 473–474, 473f, Ethyl phenylacetate, 875 243–244 in alkyl benzene synthesis, 647–648, 474f Ethyl tosylate, 339 of SN1 substitution reactions, 252 672–673, 672f Geckos, 88 Ethyne, 402. See also Acetylene First-order rate equation, 217, 243, 244 of benzene, 643f Geminal dichloride, 404 Ethynylcyclohexane, 402f, 1021 Fischer, Emil, 1053 carbocations and rearrangements, Geminal dihalide, 299 Ethynylestradiol, 399f, 402–403, 403f, Fischer esterifi cation, 847–848, 859–860 650–652 alkyne synthesis from, 404–405 745, 745f, 750, 1142 Fischer projection formulas, 1030–1033, electrophilic aromatic substitution synthesis in hydrohalogenation of Ethynyl group, 402 1033f reaction, 643f alkynes, 406

smi75625_index_1218-1246.indd 1231 11/24/09 12:13:35 PM I-15 Index

Geminal protons, 516, 517f (S)-glyceraldehyde, 1030, 1033 methyl features of, 258–259 Generic name, 119 optical activity, 183 coupling reaction with SN1 substitution reactions, 258, Geranial, 306, 783f Glycerol organocuprates, 1003 260–261 Geraniol, 454, 1134, 1136 naming, 316 SN2 substitution reactions, 248, 262 Handedness, 160, 163, 166 Geranyl diphosphate, 1134–1137, 1135f, synthesis in lipid hydrolysis, 853, organic Hansen’s disease (leprosy), 169, 990 1136–1137 854–855 coupling reaction with Hardener, 1163–1164, 1164f GHB (γ-hydroxybutyric acid), 696, 872 in triacylglycerols, 367 organocuprate reagents, Hardening, 432, 1124 Gibberellic acid, 945 Glycine, 80, 710–711 1003–1005 Haworth projections, 1038, 1039–1041 Gibbs free energy (G°), 207 abbreviation for, 711t coupling with alkenes (Heck HCFCs (hydrochlorofl uorocarbons), 552 Ginkgo biloba, 4–5, 688 in dipeptide synthesis, 1094–1098 reaction), 1003, 1009–1011 HDL particles (high density lipoproteins), Ginkgolide B, 4–5 isoelectric point for, 1078t coupling with organoboron reagents 862 Glacial acetic acid, 695 pKa values for, 1078t (Suzuki reaction), 1003, HDPE (high-density polyethylene), 561, Gleevec, 837 structure of, 1075f, 1076f 1005–1009 1152, 1169t, 1170 Global warming, 149 Glycogen, 1061 unreactive, 650 Heat of hydrogenation, 429–430, Globular proteins, 1106 Glycolic acid, 66 α-Halo aldehyde or ketone, synthesis of, 583–584 d-Glucaric acid, 1049 copolymerization with lactic acid, 892–895 benzene, 616–617, 616f Glucitol, 1047 1161 Halo alkane, 230. See also Alkyl halides Heat of reaction, 203. See also Enthalpy Glucopyranose Glycols, 315 α-Halo carbonyl compounds change α-d-glucopyranose, 1038, 1048f formation by dihydroxylation, 442 reactions of, 896 Heck reaction, 1003, 1009–1011 β-d-glucopyranose, 1038, 1062 Glycopeptide transpeptidase, 857 synthesis of, 892–895 Helicene, 614–615 Glucosamine, 862 Glycoside(s) α-Halo carboxylic acids, amino acid Helminthosporal, 947 d-glucosamine, 1061 formation, 1043–1044 synthesis from, 1078–1079, Heme, 1109, 1110 Glucose, 156, 812–813 α glycoside, 1043–1044 1081f Hemiacetal(s) acyclic aldehyde, 1038–139, 1038f β glycoside, 1043–1044 Halocyclohexanes, E2 elimination in, in carbohydrates, 812–813 anomers of, 1038, 1038f, 1040, hydrolysis of, 1044–1045 296–298 conversion to acetals, 805–806 1041f naturally occurring, 1045 Haloform, 894–895, 895f conversion to carbonyl compounds, in complex carbohydrates, 105 N-Glycoside(s), 1062–1065, 1065f Haloform reaction, 894–895, 895f 808 conversion to ester, 1046 α-N-glycoside, 1062 Halogenation cyclic conversion to ether, 1046 β-N-glycoside, 1062 of alkanes, 541–551 conversion to cyclic acetals, diastereomers of, 1038, 1038f Glycosidic bond/linkage of achiral starting material, 811–812 drawing as cyclic hemiacetal, in disaccharides, 1056–1058 549–550, 549t structure, 809 1037–139, 1038f α-glycosidic linkage, 1058, 1060–1061 bromination, 546–547, 547f synthesis of, 810–811 energy in, 1028 1→4-α-glycosidic bond, 1057, of chiral starting material, 549t, monosaccharides, 1036–1046 Fischer projection of, 1032, 1033f 1060–1061 550 structure of, 809 Fischer proof of structure of, 1→6-α-glycosidic bond, 1060–1061 chlorination, 544–548, 544f, 545f, synthesis of, 805–806, 807 1053–1056, 1054f β-glycosidic linkage, 1063 548f, 549–551 Hemibrevetoxin B, 84 d-glucose, 1029, 1032, 1033, 1033f, 1→4-β-glycosidic bond, 1057, energy changes during, 544, 544f, Hemoglobin, 1075 1035, 1035f, 1037–1038, 1041f, 1059, 1062 545f sickle cell, 1110 1047, 1049–1051, 1053, 1071, in polysaccharides, 1059–1061 mechanism of, 542–544 structure, 1105, 1109–1110, 1109f 1167 Goodyear, Charles, 1159 in organic synthesis, 548–549 Heptalene, 635 α-d-glucose, 813, 1038, 1038f, Grandisol, 1134 stereochemistry of, 549–551, 549t Heptanal, 923 1043–1044, 1046, 1057, 1060 Graphite, 632 of alkenes, 371f, 379–383, 382f Heptane β-d-glucose, 812–813, 823, 1029f, Green chemistry of alkyl benzenes, 669–671 constitutional isomers of, 118t 1038, 1038f, 1041, 1043–1044, Amberlyst A-26 resin and, 450–451 of alkynes, 409 molecular formula, 118t 1046, 1057, 1060 defi nition of, 450 of benzene, 643f, 645, 668 2,6-Heptanedione, 926 l-glucose, 1033 green polymer synthesis, 946, of carbonyl compounds, at α carbon, 2-Heptanone, synthesis of, 905 glycoside formation from, 1043–1044 1166–1169, 1167f, 1168f 892–895, 895f trans-2-Heptene, 1004 in honey, 1042 Grignard products, retrosynthetic analysis in acid, 892–893, 895f Herbicides, 646, 646f from hydrolysis of, 746–748 in base, 892, 893–895, 895f Heroin, 192, 490, 845 of cellulose, 1060 Grignard reagents, 739–740 electrophilic aromatic substitution Heteroatom(s), 4 of glycosides, 1044 addition to nitriles, 866 reaction, 643f, 644–645, 646f, in condensed structures, 27–28 of maltose, 1057 organic synthesis with, 759–761 665, 666–667 defi nition of, 82 of starch, 160, 1061 preparation of, 740 haloform reaction, 894–895, 895f in functional groups, 82, 102–103 in lactose, 219, 220f reaction as base, 741 monohalogenation, 542 in skeletal structures, 29, 30 oxidation of, 196, 206, 1048–1049 reaction with α,β-unsaturated carbonyl polyhalogenation, 665 stereogenic centers, 167 reduction of carbonyl group, 1047 compounds, 757 stereochemistry of, 381–383 Heterocycle(s), 317 structure, 104f, 161f reaction with aldehydes and ketones, transition states in, 546–548, 547f, 548 aromatic, 621–624, 623f synthesis and metabolism of, 1028 742–745, 789 Halogens nitrogen, 953 three-dimensional representations for reaction with carbon dioxide, 753–754 in alkyl halides. See Alkyl halides Heterocyclic aromatic amines, basicity of, d-glucose, 1041, 1041f reaction with epoxides, 754–755 as electron-withdrawing groups, 972, 973t, 974t Wohl degradation, 1050 reaction with esters and acid chlorides, 655–656, 661 Heterogeneous reaction mixture, 429 Glucosidase 750–753 polarizable, 380 Heterolysis (heterolytic cleavage) α-glucosidase, 1061 Grignard, Victor, 739 Halo group, 85t carbocation formation, 252, 260 β-glucosidase, 1060 Ground state Halohydrin description, 200 Glutamic acid, 720 of atom, 32 epoxide synthesis from, 323 in E1 elimination reactions, 291 abbreviation for, 711t of electron, 597–598 synthesis from alkenes, 371f, 383–385, reactive intermediates of, 201–202, isoelectric point for, 1078t Group, in periodic table, 8 385f, 385t 201f

pKa values for, 1078t Group number, 8, 10 mechanism of, 383–384, 385t in two-step reaction mechanism, 213 structure of, 1076f Grubbs catalyst, 1015–1019 regioselectivity of, 384–385, 385t Hexachloroethane, 187 Glutamine Grubbs, Robert, 1015 stereochemistry of, 384–385, 385t 2,4-Hexadiene, 580, 619 isoelectric point for, 1078t Guanine, 1064, 1065f use in organic synthesis, 385 (2Z,4Z)-2,4-Hexadienoic acid, 1167 pKa values for, 1078t d-Gulose, 1035f, 1069 Halomethanes, electrostatic potential map 1,3-Hexadiyne, 402f structure of, 1076f Gutta-percha, 1159, 1160, 1175 of, 234f Hexamethylenediamine, 859, 875 Glutathione, 1090 Gypsy moth, 441 Halonium ion, bridged, 380–382, Hexamethylphosphoramide (HMPA), Glutaric acid, 683 383–384, 385t, 409 241f Glyceraldehyde Half-headed curved arrow, 201, 202t, 539 Halothane, 49, 233f, 320 Hexane, 113 enantiomers of, 1030–1031, 1033 Halides. See also Alkyl halides; Aryl Hammond postulate, 258–261, 293, constitutional isomers of, 118t d-glyceraldehyde, 1029, 1033, 1034 halides; Hydrogen halides; Vinyl 374–375, 374f, 408, 546–547 infrared (IR) spectrum, 481 l-glyceraldehyde, 1033 halides electrophilic aromatic substitution mass spectrum of, 466, 466f, 469–470, (R)-glyceraldehyde, 1030, 1033 allylic, 229, 229f reaction, 659 470f

smi75625_index_1218-1246.indd 1232 11/24/09 12:13:35 PM Index I-16

molecular formula, 118t in alkenes, 283–284 Hydrogenation partial, of peptides, 1092–1093 skeletal structures, 29 percent s-character, 68 of aldehydes and ketones, 729 of starch, 319, 320f as solvent, 94 superscripts, meaning of, 34 of alkenes, 429–434 of triacylglycerols, 1124 solvent in extraction procedure, 707 Hydrates alkene stability and, 429–430, 430f Hydronium ion, formal charge on, 16 2,5-Hexanedione, aldol reactions of, oxidation of, 449 cis and trans isomers compared, Hydroperoxide, 1124 926–927 synthesis from aldehydes and ketones, 429–430 5-Hydroperoxyeicosatetraenoic acid Hexanoic acid, 688, 717 802–804 degrees of unsaturation, (5-HPETE), 348, 573 2-Hexanol, conversion to other kinetics, 803–804 determination of, 431–432 Hydrophilic, 95, 97 compounds, 759 thermodynamics, 802–803 mechanism of catalytic Hydrophobic, 95, 97, 150, 1121 3-Hexanone, 425 Hydration hydrogenation, 430–431 Hydroxide 1,3,5-Hexatriene, 617, 619 of aldehydes and ketones, 802–804 alkene stability and, 429–430, 430f nucleophile in alcohol synthesis, 322 1-Hexene, infrared (IR) spectrum of, 481 kinetics, 803–804 catalytic, 429–431 oxygen bases, 70, 71f 3-Hexene thermodynamics, 802–803 of conjugated dienes, 583–584 α-Hydroxy acids, 66 cis-3-hexene, 363, 396, 1015 of alkenes, 371f, 378–379, 390 enantioselective synthesis of amino Hydroxy aldehyde trans-3-hexene, 363, 396 defi nition of, 791 acids, 1085–1086 cyclization of, 810, 813 1-Hexyne, 1009 hydroboration–oxidation compared, as exothermic reactions, 429 β-Hydroxy, synthesis in aldol infrared (IR) spectrum, 481 390 heat of, 429–430, 583–584, 616–617, reactions, 917–928 HFCs (hydrofl uorocarbons), 552 Hydrazine, in Wolff–Kishner reduction, 616f intramolecular cyclization of, 810, 813 High density lipoproteins (HDLs), 862 672 of oils, 432–434, 433f o-hydroxybenzaldehyde, 946 High-density polyethylene (HDPE), 561, Hydrides of unsaturated fatty acids, 1124 Hydroxybenzene. See Phenol 1152, 1158, 1169t, 1170 as base, 70, 71f Hydrogen bonding o-Hydroxybenzoic acid, 720 Highest occupied molecular orbital metal hydride reagents in alcohols, 318 p-Hydroxybenzoic acid, 720 (HOMO), 629 reducing agents, 428, 727–731, in amides, 834, 834f 3-Hydroxybutanal, 917 High-performance liquid chromatography 733–738, 738t in amines, 954 4-Hydroxybutanal, 810 (HPLC), 1091 reduction of aldehydes and ketones, anion solvation by, 240 2-Hydroxybutanedioic acid, 720 Hinckley, Robert, 320 727–729 in carboxylic acids, 692, 693f 4-Hydroxybutanoic acid, 696 Histamine, 622–623, 957–958, 995 reduction of nitriles, 865 in DNA, 104f, 105, 1064, 1065f 3-Hydroxy-2-butanone, addition to Histidine nucleophilic addition with, 724, 728 intramolecular in β-dicarbonyl margarine, 432 isoelectric point for, 1078t nucleophilic substitution with, 725 compounds, 882 3-Hydroxybutyric acid, 1170–1171 γ pKa values for, 1078t reduction of ketones and aldehydes, in polar protic solvents, 240, 265 -Hydroxybutyric acid (GHB), 696 structure of, 1076f 728–729, 730f, 738t, 789 solubility and, 94, 95 β-Hydroxy carbonyl compounds Histrionicotoxin, 106, 404, 404f 1,2-Hydride shift, 328–330, 651 strength of, 89, 90t synthesis of, in aldol reactions, HMPA (hexamethylphosphoramide), 241f Hydroboration in water, 89 917–928 1H NMR. See Proton NMR of alkenes, 386–387, 387f, 388f Hydrogen bromide, for removal of Boc useful transformations of, 924, 924f Hoffman, Felix, 696 of alkynes, 1007, 1009 protecting group, 1096 3-Hydroxy carboxylic acids, 1170–1171 Hofmann elimination, 977–980 defi nition of, 386 Hydrogen chloride. See Hydrochloric Hydroxy group, 85t Homogeneous catalysts, 1159 mechanism of, 386–387 acid of alcohols, 313, 324 Homologous series, 117, 118t regioselectivity of, 387 Hydrogen cyanide, 792 of enols, 313 Homolysis (homolytic cleavage) Hydroboration–oxidation reactions Hydrogen fl uoride, 12 of ethanol, 82–83 of allylic C–H bond, 552–553 of alkenes, 371f, 385–390 Hydrogen halides hydrophilic nature of, 95 bond dissociation energy for, 203 mechanism of, 385–387 addition to alkenes, 371–378, 371f, IR absorption, 482, 693, 694f chlorination of alkanes, 543, 545 regioselectivity of, 387, 389t 372f, 373f, 378t of monosaccharides, 1028, 1046–1047 endothermic nature of, 203 stereochemistry of, 388–389, 389t addition to alkynes, 406–408, 406f NMR absorption, 694, 695f entropy increase with, 209 hydration compared, 390 alcohol conversion to alkyl halides OH proton, NMR spectra of, 517–518, Honey, 1042 synthesis of artemisinin, 389, 389f with, 331–335 518f Honeycomb, 150 Hydrocarbons reactivity of, 333 of phenols, 313 Hooke’s law, 478, 479f aliphatic, 83, 114 Hydrogen ions (H+), Brønsted–Lowry acid 6-Hydroxy-2-hexanone, 808 Hormones. See also specifi c hormones aromatic, 83 defi nition and, 55 β-Hydroxy ketone, synthesis of, 919 local mediators distinct from, 1130 defi nition of, 83 Hydrogenolysis Hydroxylamine, 1050 peptide, 1089, 1090f functional groups in, 83–84, 84t of benzyl esters, 1097 5-Hydroxypentanal, 810, 813 sex, 1141–1142, 1141t infrared (IR) absorptions in, 480 in peptide synthesis, 1097–1098 5-Hydroxy-2-pentanone, 748, 749f, 750 Host–guest complex, 320 oxidation and reduction of, 427, 428f Hydrogen peroxide, as oxidizing agent, N-Hydroxysuccinimide, 1117 Housane, 128f polycyclic aromatic (PAH), 349 438 3-Hydroxyvaleric acid, 1170–1171 5-HPETE (5-hydroperoxyeicosate traenoic saturated, 114 Hydrohalogenation Hyperconjugation, 257–258 acid), 348, 568, 573 synthesis in organocuprate couplings, of alkenes, 371–378 Hypertension, 85 Hückel, Erich, 618 1004–1005 Markovnikov’s rule, 374–375, Hypophosphorous acid, 983 Hückel’s rule, 617–620 unsaturated, 360. See also Alkenes 374f, 378t basis of, 626–629 Hydrochloric acid, 70 mechanism of, 371–373, 372f, Ibufenac, 684 Humulene, 1008, 1008f, 1145 elimination in nylon synthesis, 859 373f, 378t Ibuprofen Hybridization, 32–40, 609–610 in epoxide ring opening reactions, stereochemistry of, 376–377, 377f, anti-infl ammatory action of, 150, 916 conjugated systems and, 578–579 345, 346 378t enantiomers, 187, 909 defi nition of, 33 as Lewis acid, 74 of alkynes, 406–408, 406f mode of action, 1131–1132 Hybridization effects for removal of Boc protecting group, Markovnikov’s rule, 407, 408 structure of, 78, 106 on acidity, 67–68, 68f, 69f 1096 Hydrolysis synthesis of, 673, 730f, 911, 916, 932 on basicity of amines, 972–973, 973t pKa of, 62 of acetals, 807–808 systematic name of, 119 Hybrid orbitals, 32–40 Hydrochloride salts, 968 in acetoacetic ester synthesis, 904, 905 -ic acid (suffi x), 691, 831, 832, 860 percent s-character, 41–42, 68, 284 Hydrochlorofl uorocarbons (HCFCs), 552 of amides, 855–856 -ide (suffi x), 231 sp orbitals, 34–35, 34f, 38–39, 40f Hydrofl uorocarbons (HFCs), 552 in amino acid synthesis, 1079 d-Idose, 1035f in alkynes, 400, 401, 405 Hydrogen base-promoted, 852 Illudin-S, 905 percent s-character, 68 covalent bond formation by, 11–12 defi nition of, 791 Imatinib mesylate, 837 sp2 orbitals, 34–35, 34f, 37, 39f, 40f isotopes of, 7, 472t of esters, 850–855 Imidazole, 749, 750, 870 in alkenes, 281, 283–284 mass of, 472t acid-catalyzed, 851 Imides, in Gabriel synthesis of primary in aromatic heterocycles, 621–623, octet rule exceptions, 17 applications of, 853–855 amines, 961 623f primary (1°), 116–117 base-promoted, 851–852 Imidic acid tautomer, 863–864 carbon radical, 539 as reducing agent, 428. See also glucose formation by, 1044, 1057, Imines carboxy group, 689 Hydrogenation 1060, 1061 hydrolysis of, 801 percent s-character, 68 secondary (2°), 116–117 of imines and enamines, 801 reduction to amines, 963 sp3 orbitals, 33–34, 33f, 35, 35f, 36, sigma (σ) bond in molecular hydrogen, of lipids, 853–855 synthesis of 36f, 39f, 40f 32 in malonic ester synthesis, 901 from aldehydes and ketones, in acyclic alkanes, 114 tertiary (3°), 116–117 of nitriles, 863–864 797–799, 799f, 801f, 975, 1080

smi75625_index_1218-1246.indd 1233 11/24/09 12:13:36 PM I-17 Index

Imines (continued) Intramolecular cyclization, of hydroxy Isoleucine Ketal, 804 synthesis of (continued) aldehydes, 810, 813 isoelectric point for, 1078t Ketamine, 191 from nucleophilic addition Intramolecular hydrogen bonding, in pKa values for, 1078t Ketene, 50 reactions, 788, 788f β-dicarbonyl compounds, 882 structure of, 1076f, 1077 Keto–enol tautomers, 410, 881–883 reduction of nitriles, 865–866 Intramolecular malonic ester synthesis, Isomers β-Keto esters Iminium ion, 798, 800–801, 801f 902 constitutional. See Constitutional as active methylene compounds, 924 Immunosuppressants, 837 Intramolecular reactions isomers conversion to ketones, 903–905 Indene, 636 aldol reactions, 926–928, 928f defi nition of, 17, 162 pKa, 886t Indigo, 988 Robinson annulation, 936–939 infrared (IR) spectroscopy of, 484 synthesis of Inductive effects Friedel–Crafts reactions, 652–653, Lewis structures, 17 Claisen reaction, 928–932, 929f on acidity, 65–66, 66f, 69f 653f ortho and para, 668–669 Michael reaction, 935, 936–937 in aliphatic carboxylic acids, 703–704 intramolecular Claisen (Diekmann resonance structures compared, 19 d-Ketohexoses, 1035, 1036f on basicity of amines, 969, 973t reaction), 932–933 stereoisomers. See Stereoisomers Ketones. See also Carbonyl compounds in carbocation stability, 256–257 Inversion of confi guration, 263 types of, 181, 181f aldol reactions of, 917–919, 922–923, defi nition of, 65 in alkyl tosylate reactions, 339–340 Isoniazid, 995 925–926 electron-donating, 654–656 in SN2 substitution reaction, 246–247, Isooctane boiling point of, 780t electron-withdrawing, 65, 654–656 247f, 263 combustion of, 148 carbohydrates, 812–813 on substituted benzenes, 654–657 Invirase. See Saquinavir oxidation of, 196, 206, 216 in crossed Claisen reactions, 931 -ine (suffi x), 230–231 Iodine, polarizability of, 88–89 Isopentane, 127 fragmentation pattern in mass Infl uenza, 86 Iodoform, 894–895 melting point of, 93 spectrum, 471 Infrared (IR) absorptions/spectra Iodoform test, 894 structure, 116 functional group in, 86t of aldehydes, 780–781, 781f Iodomethane, polarizability and boiling Isopentenyl diphosphate, 1134–1136, hydration of, 802–804 of amines, 955, 955f point of, 91f 1135f, 1138 kinetics of hydrate formation, atom mass and, 478–479, 479f 1-Iodo-1-methylcyclohexane, 289 Isophorone, 948 803–804 of benzene derivatives, 613 Ion(s) Isoprene, 581, 605, 1145, 1159 thermodynamics of hydrate bond strength and, 478–479, 479f, 480 anions Isoprene unit, 1132–1138 formation, 802–803 of carboxylic acid derivatives, 835, acetate, 66–67, 67f Isopropyl alcohol, 315 interesting examples, 783 835t carbanion, 68, 201–202, 201f Isopropylamine, 356, 952, 963 iodoform test of, 894 of carboxylic acids, 693–694, 694f cyclopentadienyl, 624–625, 630, Isopropylbenzene IR spectra of, 482, 780–781 characteristic frequencies, A–10 630f oxidation to benzoic acid, 671 melting point of, 780t functional groups and, 478, 479, 479f, defi nition of, 7 structure of, 673 NMR spectra of, 782, 782f 480t, 481–485 enolate, 21 synthesis from benzene, 673 nomenclature, 777–778, 779 of hydrocarbons, 481 naked, 241 Isopropylcyclopentane, 761 common names, 778, 779f important, 479, 480t radical, 436 Isopropyl group, 120 IUPAC system, 777–778, 779f of ketones, 780–781 salt formation, 10–11 3-Isopropyl-4-methylcyclohexanone, nucleophilic addition reactions, 724, of nitriles, 835 solvation by hydrogen bonding, 778 774–813 of nitrogen-containing compounds, 240 Isopropyl methyl ether, 322 acid catalyzed, 787 483 bond formation by, 202 Isopropyl 2-methylpentanoate, 833 carbanion addition, 789–790 of oxygen-containing compounds, 482 cations (R)-Isoproterenol, 768 cyanide addition, 790–791 percent s-character and, 480 carbocation. See Carbocation(s) Isopulegone, 493 hydride addition, 789 vibration of bonds and, 476–477, counterions, 55 Isotactic polymer, 1157–1158 mechanism of, 786–787 478–480 cyclopentadienyl, 625 Isotopes, 7, 8f nucleophiles in, 787–788, 788f wavenumber scale of, 476 defi nition of, 7 of bromine, 469 primary amine addition, 797–799, Infrared (IR) spectroscopy, 464, 474, radical, 465 of carbon, 7, 8f, 472t 801f 476–487 salt formation, 10–11 of chlorine, 468 secondary amine addition, 800–801, background on, 476–477 solvation by ion–dipole interactions, defi nition of, 7 801f functional group identifi cation, 476, 240, 241, 264–265 masses of common, 472t physical properties, 779, 780t 477 spectator ions, 55 of nitrogen, 472t pKa, 886t IR inactive vibration, 480 tropylium, 625–626, 630, 630f of oxygen, 472t protecting groups for, 808–809 isomers distinguished by, 484 counterions, 55 IUPAC nomenclature reactions of structure determination in, 485–487 polyatomic, 16 of alcohols, 314–316, 315f aldol reactions, 917–919, 922–923, vibration modes, 476–477 spectator ions, 55 of aldehydes, 776, 777f 925–926 wavenumber scale, 476 transport across cell membranes, of alkanes, 121–127, 123f, 126f, 127f with amines, 975 Infrared (IR) spectrum 100–102, 102f of alkenes, 362–363 at α carbon, 785–786 characteristics of, 477–478, 478f Ion–dipole interactions of alkyl halides, 230–231, 231f at carbonyl carbon, 785, 786 fi ngerprint region, 477, 478, 478f, cation solvation by, 240, 241, 264–265 of alkynes, 401–402 crossed Claisen reactions, 931 479, 479f description of, 94, 94f of benzene derivatives, 610–613 halogenation at α carbon, 892–895, functional group region, 477, 478, Ionic bonding, 10–11 of carboxylic acids, 690–692 895f 478f, 479, 479f, 480t Ionic compounds of cycloalkanes, 125–127, 126f, 127f hydration, 802–804 Inorganic compounds, 1 boiling points of, 91 of epoxides, 317–318 nucleophilic addition reactions, 724, Inscribed polygon method for predicting formation of, 10–11 of ethers, 316–317 774–813 aromaticity, 629–631, 630f, intermolecular forces, 87, 90t of ketones, 777–778, 779f with organometallic reagents, 631f melting points of, 93 742–745, 745f, 789–790 Insecticide, 233, 1012 solubility of, 94, 96f Jack-o’-lantern mushroom, 905 reactivity of, 724 Inspra. See Eplerenone Ionic intermediates, 554 Januvia. See Sitagliptin reduction of, 789–790 Insulin, 1075, 1105, 1106f Ionic polymerization, 1153–1156, 1155f cis-Jasmone, 435 to alcohols, 727, 728, 729 Integral, NMR spectrum, 507–508 Ion–ion interactions, 87, 90t Johnson, W. S., 928 of aryl ketones to alkyl benzenes, Intermolecular forces, 87–90 Ionophores, 100–102, 102f Joule (J), 40 672–673 of aldehydes and ketones, 779, 780t IR spectroscopy. See Infrared (IR) Juvenile hormones, 721, 745, 745f, 1004 reductive amination to amines, boiling point and, 90–92, 91f spectroscopy mimics of, 745 963–966 in carboxylic acids, 692, 693f, 693t Iso- (prefi x), 120 to secondary alcohols, 432 dipole–dipole interactions, 89, 90t Isoamyl acetate, 836 Kavain, 364 solubility of, 780t hydrogen bonding, 89, 90t, 954 Isobutane, 115 Kefl ex. See Cephalexin structure of, 722, 775 ion–ion interactions, 87, 90t p-Isobutylbenzaldehyde, 911 Kekulé, August, 608 synthesis of melting point and, 92–93 Isobutyl chloride, 231f Kekulé structures, 608, 609 acetotacetic ester synthesis, 900, solubility and, 93–96, 94f, 96f Isobutylene, 1155 Kelsey, Frances Oldham, 170 903–905 van der Waals forces, 87–89, 88f, 90t Isobutyl group, 121 Keratins, 1075 alcohol oxidation, 447, 448, 450 International Union of Pure and Applied Isocyanate, 1162 α-keratins, 1107–1108, 1108f Friedel–Crafts acylation, 643f, 648, Chemistry, 119. See also IUPAC Isoelectric point (pI), for amino acids, Kerosene, composition of hydrocarbons 672–673, 784 nomenclature 713, 1078, 1078t in, 128 hydration of alkynes, 409–412, 784

smi75625_index_1218-1246.indd 1234 11/24/09 12:13:36 PM Index I-18

hydroboration–oxidation of alkynes, of carboxylic acid derivatives, 827, Lipases, 853 LSD, 606, 641 412–413 828, 829t, 838–840 Lipid bilayer, 100, 101f, 102, 102f, intramolecular Friedel–Crafts acylation hydrolysis of acetals, 807–808 in E2 elimination reactions, 287, 288t 1126–1127, 1128 in the synthesis of, 653, 653f hydrolysis of imines and enamines, in nucleophilic acyl substitution Lipids, 149–151, 1119–1147 structure of, 959 801 reactions, 827, 838–840 bonding in, 1120 synthesis of, 641 oxidation of secondary alcohols, in nucleophilic substitution reactions, defi nition of, 149 LTC 4, 1130f 784 235–236, 264 eicosanoids, 1129–1132, 1130t, LUMO (lowest unoccupied molecular oxidative cleavage of alkenes, good, 237t 1131f orbital), 629 444–446, 785 periodic trends in ability, 236–237 energy in, 151, 1125 Lycopene, 571, 581, 598, 598f, 1145 reactions of acid chlorides with poor, 237t examples of, 150, 150f, 1120f Lycra. See Spandex organocuprates, 784 reaction rate and, 264 fat-soluble vitamins, 1128, 1129f Lyrica. See Pregabalin tautomers, 864 weak bases, 236–238 hydrolysis of, 853–855, 1121 Lynen, Feodor, 1140 unreactivity to nucleophilic in terpene biosynthesis, 1134–1137 hydrolyzable, 1121 Lysergic acid diethyl amide. See LSD substitution, 725 Le Châtelier’s principle, 327–328, 1042 metabolism of, 1125 Lysine, 720 unsymmetrical, alkylation of, 898–899 Lecithin, 1126, 1127f nonhydrolyzable, 1121 abbreviation for, 711t Wittig reaction, 792–797 Length, units used to report wavelength, origin of word, 1120 ionizable side chain of, 1077, 1078t Ketoprofen, 70, 191 474 oxidation of, 215, 556–557, 556f isoelectric point for, 1078t Ketoses Letrozole, 862 phospholipids. See Phospholipids pKa values for, 1078t d-ketose family, 1035–1036, 1036f Leucine, 191 solubility of, 149, 1120 structure of, 1076f structure, 1028–1029 isoelectric point for, 1078t steroids. See Steroids Lysozyme, 1104, 1104f Keto tautomers, 882–883 pKa values for, 1078t structure of, 150f d-Lyxose, 1034, 1035f, 1050 Kevlar, 1161, 1174 structure of, 1076f terpenes, 1132–1138, 1133f, 1133t, Kiliani–Fischer synthesis, 1049, Leukotrienes, 1129–1130, 1130t, 1131f 1135f Macrocyclic lactone, 837 1051–1056 biological activity of, 348 triacylglycerols. See Triacylglycerols Macrolide, 837 Kinetic enolates, 889–890, 898 leukotriene A4, 348 unsaturated, oxidation of, 556–557, Magnesium, electronegativity value of, Kinetic product, in electrophilic addition leukotriene C4, 348, 568 556f 739 reactions of conjugated dienes, synthesis of, 348 waxes, 1121 Magnesium monoperoxyphthalate 586–588, 587f, 588f Levonorgestrel, 403 Lipitor. See Atorvastatin (MMPP), 438f Kinetic resolution, of amino acids using Levorotatory (l) compounds, 183, 1033 Lipoprotein, 861f, 862 Magnetic resonance imaging (MRI), 527, enzymes, 1084 Lewis acid, 72–74 Lipoxygenase, 348, 1130 527f Kinetics alkenes as, 372 Lithium Ma huang, 166, 192 defi nition of, 206, 215 borane as, 386 electronegativity value of, 739 Malaria, 289, 974 E1 elimination reactions, 291, 293t carbocation as, 372 valence electrons of, 11 Maleic acid, 112, 592, 603 E2 elimination reactions, 285 catalyst, 333 Lithium acetylide, 740–741, 745 Maleic anhydride, 591f fi rst-order, 217 Lewis acid–base reactions, 73–74, Lithium aluminum hydride (LiAlH4), Malonic acid, 79, 692 rate equations, 216–218 235. See also Nucleophilic 727–730, 733–738, 738t Malonic acid synthesis second-order, 217 substitution reactions as reducing agent, 428 intramolecular, 902 SN1 substitution reactions, 252, 256t electrophilic addition, 372 reduction of aldehydes and ketones, retrosynthetic analysis of, 902–903 SN2 substitution reactions, 244, 249t SN1 substitution reactions, 252 789 step in, 901–902 Lewis base, 72–74 reduction of alkyl halides, 437–438, Malonic ester synthesis, 900–903 Lactams, 827 nucleophile as, 238 438f Maltose, 824, 1057 β-Lactam(s), 311, 827, 838, 856–857 tetrahydrofuran (THF) as, 386 reduction of a nitrile, 865 Mandelic acid, 194, 1115 β-Lactam family of antibiotics, 463, 485 Lewis structures, 12–18 reduction of epoxides, 437–438, 438f Manganese, in oxidizing agents, 438, 439 Lactase, 219, 220f, 1027, 1058 of acyclic alkanes, 114–115 reduction of nitriles to primary amines, Mannose Lactate dehydrogenase, 733 condensed formula conversion to, 962 in Fischer proof, 1053–1056 Lactic acid, 29, 696, 733 28–29 Lithium diisopropylamide (LDA), 898, d-mannose, 1035, 1035f, 1051 copolymerization with glycolic acid, drawing of, 12–14 925 Haworth projections of, 1039–1040 1161 formal charge, 15–16, 17t enolate formation with, 887–888, Manoalide, 1134 optical activity of, 183 isomers, 17 889–890 Margarine, 432–433 specifi c rotation of, 185 molecular shape determination, 23–27 pKa, 887t Markovnikov’s rule, 374–375, 374f, 378t, Lactide, 1168 multiple bonds in, 14–15 preparation of, 888 407, 408, 584 Lactols, 809, 810 octet rule exceptions, 17–18 Lithium dimethylcuprate, 492, 1014 in cationic polymerization, 1153 Lactone(s), 398, 827 resonance structures, 18–23 Lithium fl uoride, 11 Mass number, 7 macrocyclic, 837 skeletal structure conversion to, 29–31 Lithium tri-tert-butoxyaluminum hydride, Mass spectrometer synthesis by esterifi cation of carboxylic Lexan, 1149f, 1163, 1168 734, 735, 738t features of, 464 acids, 848 Ligands, in palladium-catalyzed reactions, Lithium tri-sec-butylborohydride, 773 high-resolution, 472 Lactose, 812, 1027, 1057–1058 1005–1006 Living polymerization, 1155 schematic of, 464f breakdown of, 219, 220f Light Local anesthetic, 673 Mass spectrometry (MS) Lactose intolerance, 1027, 1058 polarized, 182–183 Local mediators, 1130 of alkyl halides, 468–469, 469f Laetrile, 792 speed of, 475 Log, 59, 60 of amines, 955, 955f Lanolin, 1121 Limonene, 50, 446, 1137 London forces, 87. See also van der analysis of unknowns using molecular Lanosterol, 1140, 1140f (R)-limonene, 367f Waals forces ion, 466–468 Lard, 369 (S)-limonene, 366 Lone pairs base peak, 465 Latanoprost, 697 Linalool, 747 in aromatic heterocycles, 621–623 of biomolecules, 474 Latex, 1159, 1160 Linalyl diphosphate, 1137 Brønsted–Lowry bases and, 55–56, 55f defi nition of, 464 Lauric acid, 1122t, 1125 Linamarin, 791–792 in carbanions, 202 electrospray ionization (ESI), 474 Lavandulol, 747 Lindlar catalyst, 435 in heteroatoms, 82, 103 features of, 464–466 l (levorotatory) compounds, 183, 1033 Linear molecule, 24, 26f, 44 in Lewis structures, 12–15 fragmentation in, 465, 469–472, 470f LDA. See Lithium diisopropylamide alkynes, 400 of negatively charged carbon atoms, 31 gas chromatography and, 473–474, (LDA) Linen, 858, 858f number of, 31 473f, 474f LDL particles (low density lipoproteins), Linoleic acid, 459, 1122, 1122t in resonance structures, 19, 21, 67, 576 high-resolution, 472 862 as essential fatty acid, 368, 369 second-row elements and, 12 M peak, 465, 468–469 l-Dopa (levodopa), 6, 45, 191, 1115 melting point, 368t Long, Dr. Crawford, 320 M + 1 peak, 466 LDPE (low-density polyethylene), 561, structure, 368f, 368t Loratadine, 615f M + 2 peak, 468–469 1152 Linolenic acid, 1122, 1122t Lotensin. See Benazepril Mass spectrum, 465 Leaving group as essential fatty acid, 368 Low density lipoproteins (LDLs), 862 Mass-to-charge (m/z) ratio, 464f, 465 of alcohols, 324, 330–332, 335–336, melting point, 368t Low-density polyethylene (LDPE), 1152, Mauveine, 988–989 338–339 as omega-3 fatty acid, 368 1169t Maytansine, 1025 of carbonyl compounds, 722, 724, sources of, 369 Lowest unoccupied molecular orbital mCPBA (meta-chloroperoxybenzoic acid), 725–726 structure, 368f, 368t (LUMO), 629 438f, 439–441

smi75625_index_1218-1246.indd 1235 11/24/09 12:13:37 PM I-19 Index

MDMA (3,4-methylenedioxymeth- in natural gas, 128 2-Methylcyclopentanamine, in Hofmann Miscibility, 95 amphetamine), 998 oxidation of, 427, 427f reaction, 979 Misoprostol, 1131 Mefl oquine, 194 pKa of, 62, 63 Methylcyclopentane, 169 Mixed aldol reaction. See Crossed aldol Melamine, 1177 structure of, 114 2-Methylcyclopentanecarboxamide, reactions Melanin, 599 whole-number mass of, 465 structure of, 831 MMPP (magnesium Melatonin, 494, 522 Methanesulfonic acid, 710, 837 (3R)-3-Methylcyclopentanone, 790 monoperoxyphthalate), 438f Melmac, 1177 Methanethiol, 128 1-Methylcyclopentene, 363f, 928 Molecular formula Melting point Methanol Methyl dimethylphosphonate, 537 of acyclic alkanes, 114, 118, 118t of alcohols, 318t ether formation by addition to alkenes, Methylene, 1014 of alkenes, 360 of aldehydes and ketones, 780t 378, 379 α-Methylene-γ-butyrolactone, 899 of alkyl halides, 229 of alkanes, 129, 130t hybrid orbitals in, 35 Methylene chloride, 233f of alkynes, 400 of alkenes, 365, 368, 368t Lewis structure, 14 Methylenecyclohexane, 365, 796 of amines, 955 of alkyl halides, 232t oxidation of, 451 3,4-Methylenedioxymethamphetamine of butane, 118t of alkynes, 402 as polar protic solvent, 240f (MDMA), 998 of carbohydrates, 1028 of amines, 954t structure of, 319f Methylene group, 117, 365 of cycloalkanes, 114, 118 of carboxylic acids, 693t toxicity of, 319f Methyl ester, 1097 of decane, 118t defi nition of, 92 Methenolone, 1146 3-Methylfentanyl, 467–468 of eicosane, 118t of enantiomers, 182, 184, 184t Methionine Methyl α-d-glucopyranoside, 1044, of ethane, 114, 115, 118t of epoxides, 318t abbreviation for, 711t 1048f of heptane, 118t of ethers, 318t isoelectric point for, 1078t Methyl group, 121 of hexane, 118t of fats, 369, 1122–1123 pKa values for, 1078t angular, 1138–1139 of methane, 114, 115, 118t intermolecular forces and, 92–93 structure of, 1076f as electron-donating group, 657 of nonane, 118t of monosaccharides, 1036 synthesis of, 1081f inductive effect of, 654 of octane, 118t of oils, 369, 1122–1123 Methoprene, 745 as ortho, para director, 657, 662, of pentane, 118t of racemic mixtures, 184, 184t Methoxide, as Brønsted–Lowry base, 666–668 of propane, 114, 115, 118t of triacylglycerols, 433f 55f, 56 Methyl halides Molecular ion, 465, 466–468 Membrane proteins, 1075 p-Methoxybenzoic acid, 706 coupling reaction with organocuprates, Molecular orbitals (MOs), 627–629, 628f Menthol, 49, 108, 156, 1132–1133 Methoxychlor, 234 1003 antibonding, 627, 628f, 629–630 Menthone, 108 Methoxycyclohexane, conformations SN2 substitution reactions, 248, 262 bonding, 627, 628f, 629–631, 630f, Meperidine, 950 of, 209 6-Methyl-6-hepten-2-ol, 363 631f Mercapto group, 85t Methoxy group, 316 2-Methylhexanoic acid, synthesis of, 903 degenerate, 629 Mercury, in Clemmensen reduction, Methoxy methyl ether, 819 5-Methyl-3-hexanol, 315 highest occupied MO (HOMO), 629 672–673 p-Methoxyphenyl ester, 1117 5-Methyl-4-hexen-1-yne, 402f lowest unoccupied MO (LUMO), 629 Merrifi eld method, of peptide synthesis, Methyl acetate, 226 Methyl 5-hydroxyhexanoate, 808 patterns for cyclic, completely 1099 formation of, 243 N-Methylisopropylamine, 952 conjugated systems, 631f Merrifi eld, R. Bruce, 1099 NMR spectrum of, 524, 526f Methyl ketones, 410 prediction/determination of relative Mescaline, 958, 999 structure of, 826 halogenation of, 894–895, 895f energies of, 629–631, 630f, Mesityl oxide, 773 Methyl acrylate, 591f synthesis in acetoacetic ester synthesis, 631f Meso compounds, 177–179 Methylamine, 952 900, 903–905 Molecular orbital (MO) theory, 627 achiral compounds, 178, 180–181, 382, as Brønsted–Lowry base, 55f, 56 Methyllithium, 740 Molecular recognition, 320 382f, 592, 1013 electrostatic potential plot of, 951, Methylmagnesium bromide, 740 Molecular shape carbene addition and, 1013 951f Methylmagnesium chloride, 748 bent, 26, 44 disubstituted cycloalkanes, 180–181 N-Methylaniline, NMR spectrum of, 956, Methyl 2-methylbutanoate, 836 determining from epoxidation of alkenes, 440 956f N-Methylmorpholine N-oxide (NMO), bond angle, 24–27, 26f plane of symmetry, 178 p-Methylaniline 444 bond length, 23, 23t Mestranol, 109, 770 basicity of, 970 4-Methyl-2-nonene, 395 four groups around an atom, 25–27 Meta (prefi x), 611 electrostatic potential plot of, 971f Methyl orange, 987, 989–990 linear, 24, 26f, 44 Metabolite, 157 Methyl anthranilate, 875 3-Methylpentanal, 777f tetrahedral, 25–26, 26f Meta director, 657, 658, 661, 663–664, Methylation, with SAM, 250 4-Methyl-1-pentanamine, 953 three groups around an atom, 24–25 664f, 665, 666, 668–669, 674 Methylbenzene. See Toluene 2-Methylpentane, 163f trigonal planar, 24–25, 26f Metal–carbenes, 1017 Methyl benzoate, synthesis of, 847 3-Methylpentane, 163f trigonal pyramid, 26 Metal catalyst, 218–219, 429 (R)-α-Methylbenzylamine, 1082–1084 4-Methyl-1,4-pentanediol, 748, 749f, 750 two groups around an atom, 24 Metal hydride reagents 2-Methyl-1,3-butadiene, 581, 1159 2-Methyl-3-pentanone, 779f Molecules reducing agents, 428, 727–731, 2-Methylbutane, 116, 127 3-Methyl-2-pentanone, 778 defi nition of, 11 733–738, 738t 2-Methylbutanenitrile, structure of, 3-Methyl-2-pentene, 364 polarity of, 44, 45f reduction of aldehydes and ketones, 832f (2E)-3-methyl-2-pentene, 364 Molina, Mario, 551 727–729 2-Methyl-2-butanol, 325 (2Z)-3-methyl-2-pentene, 364 Molozonide, 445 reduction of nitriles, 865 2-Methylbutanoyl chloride, structure 4-Methyl-3-penten-2-one, 779 Molybdenum, 1015 Metals of, 830 Methylphenidate, 191 Monensin, 812 as catalysts, 218–219 (R)-α-Methylbutyrophenone, 909 1-Methyl-4-phenyl-4-propionoxy- Monohalogenation, 542 in oxidizing agents, 438–439 2-Methyl-CBS-oxazaborolidine, 731 piperidine, 467–468 Monomers, 1149 Metathesis, 1015–1019, 1016f, 1018f Methyl chloride, electrostatic potential N-Methyl-2-propanamine, 952 Monosaccharides, 1028–1056 derivation of word, 1015 plot for, 44, 44f. See also 2-Methyl-1-propanol, 269 d-aldoses, family of, 1034–1035, drawing products of, 1016, 1016f Chloromethane 2-Methylpropene, 396, 686, 1014, 1155 1035f mechanism, 1017 Methyl trans-chrysanthemate, 1023 2-Methylpropene oxide, 1175 common names of, 1029, 1034 ring-closing (RCM), 1018–1019, 7-Methyl-1,3,5-cycloheptatriene, 636 2-[4-(2-Methylpropyl)phenyl]propanoic constitutional isomers of, 1029 1018f 3-Methylcycloheptene, 363f acid, 119 conversion to esters, 1046–1047 Met-enkephalin, 837 Methylcyclohexane, 125, 142, 143f 4-Methylpyridine, 948 conversion to ethers, 1046–1047 Methamphetamine, 65, 958, 964, 964f 2-Methyl-1,3-cyclohexanedione, 936 Methyltriphenylphosphonium bromide, cyclic forms, 1036–1042 Methanal. See Formaldehyde 1-Methylcyclohexanol, 352 794 anomers, 1037–1042, 1041, 1041f Methanamine. See Methylamine 3-Methylcyclohexanol, 315f β-Methylvaleraldehyde, 777f chair form, 1040 Methane cis-3-methylcyclohexanol, 340 Methyl vinyl ketone, 591f, 936 drawing glucose as a cyclic bonding in, 32–33, 33f trans-4-Methylcyclohexanol, 263 Metoprolol, 78 hemiacetal, 1037–1038, 1038f combustion of, 148 2-Methylcyclohexanone, 412, 925 Mevalonic acid, 157 furanoses, 1041–1042 description, 2 alkylation of, 898–899 Micelles, 99 Haworth projections, 1038, halogenation of, 542f enolates formed from, 889 Michael acceptor, 934 1039–1041 Lewis structure, 13 1-Methylcyclohexene, 760, 1005 Michael reaction, 934–936, 935f three-dimensional representations mass spectrum of, 465–466 3-Methylcyclohexene, 375 Mifepristone, 403 for d-glucose, 1041, 1041f molecular formula, 114, 115, 118t stereogenic center, 169 Mineral oil, 158 determining structure of unknown, molecular shape of, 25 5-Methyl-1,3-cyclopentadiene, 636 Mirror images, 160, 163–165, 177 1052–1053

smi75625_index_1218-1246.indd 1236 11/24/09 12:13:37 PM Index I-20

examples of, 1029 NBS (N-bromosuccinimide), 383–384 Nitrosonium ion, 980–982 scale, 497 Fischer projection formulas of, Nelfi navir, 615f N-Nitrosopyrrolidine, 261 signal versus peak, 509 1030–1033, 1033f Neopentane o-Nitrotoluene, synthesis from benzene, spectrometers, 496, 496f Fischer proof of glucose structure, melting point of, 93 669 variables in, 496–497 1053–1056, 1054f structure, 116 p-Nitrotoluene, 666 Nucleophiles, 85, 238–242 glycosides van der Waals forces, 88, 88f Nitrous acid, reaction of amines with, acetylide anions as, 406 formation, 1043–1044 Neral, 779, 1145 980–982 addition to carbonyl groups, 787–788, hydrolysis, 1044–1045 Nerol, 398 NMO (N-methylmorpholine N-oxide), 788f naturally occurring, 1045 Neryl diphosphate, 1137, 1145 444 alkyl halide substitution reactions isomers (d and l) of, 1033–1034 Neurotoxin, 84 NMR. See Nuclear magnetic resonance with, 234 d-ketoses, family of, 1035–1036, Neurotransmitter (NMR) spectroscopy ambident, 888 1036f acetylcholine, 861 NMR spectrometers, 496, 496f attack of electron-defi cient atoms melting point of, 1036 dopamine, 958, 959f Noble gases, stability of, 10 by, 238 physical properties of, 1036 serotonin, 958 Node of electron density, 8–9 biological, 261 reactions at carbonyl group, Neutrons, 7 Nomenclature, A–3–6. See also Common carbanions as, 201, 202 1047–1053 Newman projection, 131–132, 132f, names; IUPAC nomenclature common, table of, 242t addition or removal of one carbon, 133f of acid chlorides, 830, 833, 833t enolates as, 888–889, 892 1049–1053 Niacin, 98 of alcohols, 314–316, 315f hydroxide, in alcohol synthesis, 322 Kiliani–Fischer synthesis, 1049, Nickel, as catalyst, 219 of aldehydes, 776–777, 777f, 779 Lewis base, 73 1051–1056 Nicotinamide adenine dinucleotide of alkanes, 119–128 meaning of term, 73 oxidation, 1047–1049, 1048f (NADH), 732–733 common names, 127–128, 128f negatively charged, 242t reduction, 1047 Nicotine, 52, 252, 275, 957, 957f, 973 IUPAC system, 121–127, 123f neutral, 242t Wohl degradation, 1049, 1050 Niphatoxin B, 416, 416f substituents, 120–121 opening of epoxide rings, 343–345 reactions at hydroxy groups, Nitration of alkenes, 362–365 organometallic reagents as, 739, 1046–1047 of benzene, 643f, 646–647, 669 of alkyl halides, 230–231, 231f 741–742 solubility of, 1036, 1047 electrophilic aromatic substitution of alkyl substituents that contain pi (π) bonds and, 82, 103 stereogenic centers in, 1030–1034 reactions, 643f, 646–647, branching, A–3–4 reactivity of, 102–103 d and l designations, 1033–1034 667–668 of alkynes, 401–402 strength, 239–242 multiple, 1032 Nitriles, 862–866 of amides, 831–832, 833t strong, 263 structure of, 1028 acidity of, 885–886 of amines, 952–954 in substitution reactions, 235–236. See sweetness of, 1036 addition of organometallic reagents, of anhydrides, 830, 833t also Nucleophilic substitution Monosodium glutamate (MSG), specifi c 863, 866 of bicyclic compounds, A–5–6 reactions rotation of, 185 dipole–dipole interactions of, 834 of carboxylic acids, 690–692, 691t weak, 263 Morphine, 55–56, 597, 845, 957 hydrolysis of, 863–864, 1081 E,Z system, 364 Nucleophile strength. See Nucleophilicity Morton, Dr. William, 320 infrared (IR) spectra of, 483, 835 of epoxides, 317–318 Nucleophilic acyl substitution reactions, Motrin. See Ibuprofen NMR spectra of, 836 of esters, 830–831, 833, 833t 725, 838–858, A–13 M peak, in mass spectrum, 465, 468–469 nomenclature, 832, 832f, 833t of ethers, 316–317 biological, 860–862, 861f M + 1 peak, in mass spectrum, 466 physical properties, 834 generic name, 119 general reaction of, 881 M + 2 peak, in mass spectrum, 468–469 pKa of, 886, 886t of ketones, 777–778, 779, 779f leaving groups in, 827 MPPP, 467–468 reduction of, 863, 865–866 of monosaccharides, 1028–1029 mechanism of, 838–839 MRI (magnetic resonance imaging), 527, reduction to primary amines, 962 of nitriles, 33t, 831–832, 832, 832f, polyester synthesis, 1161–1162 527f structure and bonding of, 827, 829, 833t reactions of acid chlorides, 842–843, MS. See Mass spectrometry (MS) 862–863 of polyfunctional compounds, A–4–5 858t MSG (monosodium glutamate), specifi c synthesis of, 862 systematic name, 119 reactions of amides, 855–857, 858t rotation of, 185 Nitrite preservatives, 261 trade name, 119 reactions of anhydrides, 844–845, 858t MTBE. See tert-Butyl methyl ether p-Nitroaniline Nomex, 1174 reactions of carboxylic acids, 845–850, (MTBE) basicity of, 970 Nonactin, 101, 102 846f, 858t Multiple bond electrostatic potential plot of, 971f Nonane conversion to acid chlorides, in condensed structures, 27–28 Nitrobenzene, 643f, 646, 647, 657, 663 constitutional isomers of, 118t 845–847, 846f Lewis structures, 14–15 reduction to aniline, 673 molecular formula, 118t conversion to amides, 846f, position of, 22 p-Nitrobenzoic acid, 707 Nonbonded (unshared) electrons, 12 849–850 Multiplet, NMR spectrum, 511, 511t, Nitrogen Nonnucleophilic bases, 239 conversion to cyclic anhydrides, 514, 514f in aromatic heterocycles, 621–624, Nonpolar bond, 43 846f, 847 α-Multistriatin, 454, 454f 623f Nonpolar molecule conversion to esters, 846f, 847–849 Muscalure, 276, 460 bonding patterns and formal charge, description of, 44, 45f reactions of esters, 850–855, 855f, Muscone, 730f 17t solubility of, 94 858t Mushroom infrared (IR) absorptions in nitrogen- Nonreducing sugars, 1048, 1048f, 1058 reactivity of carboxylic acids and jack-o’-lantern, 905 containing compounds, 483 Nonsteroidal anti-infl ammatory drugs derivatives in, 839–841 Psilocybe, 959 isotopes, 472t (NSAIDs), 1131–1132 summary of reactions, 857–858, 858t Musk deer, 730 mass of, 472t Noradrenaline (norepinephrine) Nucleophilic addition reactions Mutarotation, 1039, 1044, 1057 Nitrogen heterocycles, 953 structure of, 958 aldehydes and ketones, 724, A–14 Mycomycin, 195 Nitrogen–nitrogen double bond, 986 synthesis of, 251, 251f aldol reactions. See Aldol reactions Myelin sheath, 1128 Nitrogen rule, 467 Norethindrone, 97, 192, 402–403, 403f, of carbonyl compounds, 881 Myoglobin, 1074, 1109–1110, 1109f Nitro group 1142 Michael reaction, 934–935 Myrcene, 49, 1132–1133 as electron-withdrawing group, 657 Novadex. See Tamoxifen of nitriles, 863 Myristic acid, 1122t in Friedel–Crafts reactions, 665 Novocain. See Procaine organometallic reagents with as meta director, 657, 663–664, 666, Noyori, Ryoji, 1085 aldehydes and ketones, Nabumetone, 906, 941 668, 674 NSAIDs (nonsteroidal anti-infl ammatory 742–745, 745f NADH (nicotinamide adenine reduction of, 673–674, 962 drugs), 150, 1131–1132 polyurethane synthesis, 1162 dinucleotide), 732–733 Nitromethane, 78 Nuclear magnetic resonance (NMR) α,β-unsaturated carbonyl compounds, NAG (N-acetyl-d-glucosamine), 862, Nitronium ion, 646 spectroscopy, 464, 474, 755–758 1061–1062 o-Nitrophenol, 611 494–537 Nucleophilicity Nandrolone, 1142 Nitrosamines basis of, 495–497 basicity compared to, 239, 240, 241 Naphthalene, 614, 621, 683 in foods, 261 13C (carbon), 495, 522–526. See also periodic trends in, 239, 240, 241 1-Naphthol, 356 formation of, 261 Carbon NMR SN1 versus SN2 substitution reactions, Naprosyn. See Naproxen N-nitrosamine from primary 1H (proton), 495, 497–522. See also 262–264 Naproxen, 76, 159, 187, 898 amines, 981 Proton NMR solvent effects, 240–242 Natta, Giulio, 1158 N-nitrosamine from secondary medical uses of, 527, 527f polar aprotic solvents, 241, 241f Natural gas, 128 amines, 980, 981–982 nuclear spin in, 495–497 polar protic solvents, 240, 240f Natural product, 268 N-Nitrosodimethylamine, 261 reference signal, 497, 523 steric effects and, 239

smi75625_index_1218-1246.indd 1237 11/24/09 12:13:37 PM I-21 Index

Nucleophilic substitution reactions, -oic acid (suffi x), 690, 831 bimolecular, 217 reactions A–13 Oil(s), 369 bond breaking and bond making, with aldehydes and ketones, 742, acetylide anion reactions with alkyl crude, 128 200–203, 201f 789 halides, 414–415 degree of unsaturation, 432 bond dissociation energy, 203–206, as base, 741 adrenaline synthesis, 228, 251, 251f essential, 1132 204t with esters, 752 of alcohols, 323–324, 331–338 fatty acid composition, 1123, 1123t catalysts, 218–219, 219f with α,β-unsaturated carbonyl alcohol synthesis by, 321–322 fi sh, 1123 endergonic, 210 compounds, 757 of alkyl halides, 234–269 hardening, 1124 endothermic, 203–204 Organomagnesium reagents, 739–740. See amine formation by, 960–962 hydrogenation of, 432–434, 433f, energy diagrams for, 210–215, 212f, also Grignard reagents bimolecular, 243–244 1124 215f Organometallic reagents, 739–761. See of carbonyl compounds, 724, 725–726, melting points of, 369, 1122–1123 energy of activation, 211–216, 212f, also specifi c reagents 881 oxidation of, 556 215f, 219, 219f acetylide anions, 740–741 Claisen reaction, 929–932, 929f partial hydrogenation of, 432–433, enthalpy change in, 203–206, defi nition of, 739 components of, 235 433f 209–210 organic synthesis with, 759–761 crown ether use in, 321, 321f rancid, 1124 entropy change in, 209–210 preparation of, 740 epoxide ring opening reactions, unsaturated, 369 enzymes in, 219–220, 220f protecting groups and, 748–750, 749f 343–347 vegetable, 835, 854, 855, 1123, 1124 equations for, 197, 197f reactions equilibrium and, 238 Oil of ginger, 367f equilibrium constants for, 206–209, acid–base, 748 ethers with strong acids, 341–343 Oil refi nery, 128f 207f, 208t with acid chlorides, 750–753 ether synthesis by, 321–322 Oil spill, 129 exergonic, 210 with aldehydes, 742–745, 745f, features of, 235–236 Olefi n metathesis, 1015–1019, 1016f, exothermic, 203–204, 206 789–790 fi rst-order rate equation, 243, 244 1018f free energy changes in, 206–209, 207f, as base, 739, 741 leaving groups in, 235–238, 237t, Olefi ns, 359. See also Alkenes 208t with carbon dioxide, 753–754 264 Oleic acid, 358, 485, 1122t general types, A–13–14 with carbonyl compounds, mechanisms, 242–269 melting point, 368t kinetics of, 215–218 742–745, 748–750, 749f distinguishing between SN1 and structure, 104f, 368f, 368t learning details of, 390–391 with carboxylic acid derivatives, SN2, 262–266, 262f, 265t triacylglycerol formation, 105 mechanisms of. See Reaction 750–753 one-step, 243, 244–245, 249t Olestra, 854 mechanism with epoxides, 754–755 order of bond breaking and bond Olfactory receptors, 187, 188f multistep, 214 with esters, 750–752 making, 242–243, 252 Olive oil, 369 oxidation and reduction reactions, with ketones, 742–745, 745f, SN1, 252–261, 253f, 255f, 256t, Omega carbon, 691 147–148, 148f 789–790 260f Omega-3 fatty acids, 368 polar, 201, 201f as nucleophile, 739, 741–742 SN2, 244–252, 245f, 247f, 248f, -one (suffi x), 777 radical, 201, 201f summary of, 758 249f, 249t, 250f, 251f, 268t -onitrile (suffi x), 832, 833t rate of. See Reaction rate with α,β-unsaturated carbonyl two-step, 243, 244, 252–253, 256t Open arrow, 417 sequential, 197 compounds, 755–758 nucleophile strength (nucleophilicity), Opium, 845 thermodynamics of, 206–209, 207f, Organophosphorus reagents, 793–794 239–242, 262–264 Opsin, 799, 799f 208t Organosodium reagents, 740 organic synthesis by, 267–269, 268t, Optical activity, 182–183 types of, 198–199. See also specifi c Ortho (prefi x), 611 272f of chiral compounds, 183 types of reactions Ortho, para activator, 658 in polycarbonate synthesis, 1163 dextrorotatory (d) and levorotatory (l) unimolecular, 217 Ortho, para deactivator, 658 rate-determining step in, 243, 244 compounds, 183 Organic synthesis Ortho, para director, 657–658, 661, second-order rate equation, 243, 244 enantiomeric excess, 184–185 alkenes in, 391–392 662–663, 664f, 666–668, solvent effects on, 240–242, 241f, of racemic mixtures, 183 of aspirin, 268, 269f 669, 984 264–265, 265t specifi c rotation, 184, 185 carbon–carbon bond-forming reactions -ose (suffi x), 1029 unimolecular, 244, 252 Optical purity, 184–185 in, 1002–1026 Oseltamivir, 86, 872 vinyl halides and, 267 Orajel. See Benzocaine defi nition of, 267 Osmium tetroxide Nucleotides, 104–105, 104f Oral contraceptives, 399f, 402–403, 403f halogenation reactions, 548–549 as oxidizing agent, 439 Nucleus, atomic, 7 Orbitals. See also Hybrid orbitals; halohydrin use in, 385 in syn dihydroxylation, 443–444 Nylon Molecular orbitals (MOs); by nucleophilic substitution reactions, Osprey, 278 history of, 825, 859 specifi c orbitals 267–269, 268t Oxalic acid, 696 nylon 6, 1161, 1170 description, 8–9 reactions with organometallic reagents, Oxaphosphetane, 794 nylon 6,6, 825, 859, 1149f, 1150, number of electrons in, 9 759–761 Oxazaborolidine, 731 1160, 1167, 1167f Order, of a rate equation, 217 retrosynthetic analysis, 417–419 Oxetane, 772 synthesis of, 859, 1160–1161 Organic chemistry sodium borohydride reductions used Oxidation, 147–148, 148f, 426–462 defi nition of, 1 in, 730f of alcohols, 439f, 447–450, 451 -o (suffi x), 230 importance of, 1, 2f of taxol, 268 of aldehydes, 726–727, 738–739 Occidentalol, 606 Organic halides. See also Alkyl halides Organoaluminum compounds, 1157 of aldoses, 1047–1049 Octane, 1021 coupling reaction with organocuprate Organoborane of alkanes, 147–149 constitutional isomers of, 118t reagents, 1003–1005 defi nition of, 387 of alkenes, 428f, 439f, 444–446 molecular formula, 118t coupling with alkenes (Heck reaction), in Suzuki reaction, 1003, 1006–1009 of alkyl benzenes, 671–672 Octanenitrile, infrared (IR) spectrum 1003, 1009–1011 synthesis of, 1007 of alkylboranes, 388–389 of, 483 coupling with organoboron reagents Organocopper reagents. See of alkynes, 428f, 439f, 446–447 Octane rating, of gasoline, 83 (Suzuki reaction), 1003, Organocuprate reagents of carbonyl compounds, 726–727 4-Octene, 396 1005–1009 Organocuprate reagents, 739–740 carboxylic acid synthesis 1-Octen-3-ol, 769 Organic molecules coupling reactions of, 1003–1005 from alkyl benzenes, 698 Octet rule, exceptions to, 17–18 aromatic compounds, 607–640 general features of, 1003–1004 from alkynes, 698 Octinoxate, 30, 852, 947 common features of, 4 hydrocarbon synthesis in, from primary alcohols, 698 Octylamine, infrared (IR) spectrum of, drawing structures of, 3, 27–31 1004–1005 defi nition of, 147, 427 483 condensed structures, 27–29, 28f stereospecifi city of, 1004 dihydroxylation, 442–444 Octyl salicylate, 852 skeletal structures, 27–31, 29f preparation of, 740 anti, 442, 443 1-Octyne, 741 examples of, 2–4 reactions with α,β-unsaturated syn, 442, 443–444 Odor(s) grouping by functional group, 83 carbonyl compounds, 757 energy released by, 206 of acetone, 783 shape. See Molecular shape reactions with acid chlorides, 752 epoxidation, 439–442, 439f of acid chlorides, 842 solubility of, 94–95 Organolithium reagents, 739–740 Sharpless, 451–454 of aldehydes, 783, 783f Organic reactions, 196–227. See also addition to nitriles, 866 stereochemistry of, 440 of amines, 956–957 specifi c types of reactions in anionic polymerization, 1154 in synthesis of disparlure, 441, 442f of caraway, 188 acid–base, 56–58, 61–62 arylborane synthesis, 1007 of ethanol, 451 of esters, 836 arrows used in describing, 202–203, in ethynylestradiol synthesis, 745 of fatty acids, 853 of spearmint, 188 202t in lithium diisopropylamide general scheme for, 427f OH proton, NMR spectra, 517–518, 518f asymmetric, 452 preparation, 888 green chemistry, 450–451

smi75625_index_1218-1246.indd 1238 11/24/09 12:13:38 PM Index I-22

hydroboration–oxidation reactions, Parent ion. See Molecular ion third-row elements, 18 Phosphatidylethanolamine, 1126 371f, 385–390, 387f, 388f, 389f, Parent name, 120 trends Phosphine, in palladium-catalyzed 389t, 412–413 Parkinson’s disease, treatment of, 6, 45, acidity, 63–65 reactions, 1005 of hydrocarbons, 427, 428f 191, 958, 959f electronegativity, 42, 42f Phosphoacylglycerols, 1126–1127, 1127f, of lipids, 151, 215 Paroxetine (Paxil), 78 Periodic trends 1128f oxidative cleavage Patchouli alcohol, 331f, 1145 in bond dissociation energies, 204–205 Phosphodiester, 1126, 1127, 1128f of alkenes, 444–446 PCB (polychlorinated biphenyl), 95–96 in leaving group ability, 236–237 Phospholipids of alkynes, 446–447 PCC (pyridinium chlorochromate), nucleophilicity, 239, 240, 241 in cell membranes, 100, 101f, 102, in haloform reaction, 894–895, 895f 438–439, 448 Periplanone B, 486, 925, 925f, 1145 102f, 1126–1128 of polycyclic aromatic hydrocarbons Peanut butter, 432 Perkin, William Henry, 988–989 phosphoacylglycerols, 1126–1127, (PAHs), 349 PEG (polyethylene glycol), 109, 1157 Perlon. See Nylon, Nylon 6 1127f, 1128f reduction, relationship to, 427 Penicillamine, 1113 Peroxide, as radical initiator, 540 sphingomyelins, 1127–1128, 1128f of substituted benzenes, 671–672 Penicillin(s), 838, 856–857 Peroxyacetic acid, 438f, 439 structure of, 100, 101f, 111, 1126 of unsaturated fatty acids, 1124 discovery of, 463 Peroxyacids Phosphoric acid, 1126 of unsaturated lipids, 556–557, 556f penicillin G, 106, 158, 463, 485 in epoxidation, 439–441 Phosphoric acid diester, 1126 Oxidation and reduction reactions, 1,4-Pentadiene, 572, 573f as oxidizing agents, 438, 438f Phosphorus, octet rule exceptions in, 18 147–148 hydrogenation of, 583 Peroxy radical, 1151 Phosphorus oxychloride, dehydration of Oxidative addition (3E)-1,3-Pentadiene, hydrogenation of, Pesticide, 233 alcohols using, 330–331 in Heck reaction, 1011 583 PET. See Polyethylene terephthalate (PET) Phosphorus tribromide, conversion of in palladium-catalyzed reactions, 1006, Pentalene, 635 Petroleum, 113, 128–129, 129f alcohols to alkyl halides with, 1008, 1011 2-Pentanamine, in E2 elimination reaction, alkenes prepared from, 562 335, 336–337 in Suzuki reactions, 1008 979–980, 979f ethylene preparation from, 366 Photons, 474–476 Oxidative cleavage Pentane, 466–467 as feedstock of polymer synthesis, Photosynthesis, 1028 of alkenes, 444–446 boiling point, 91 1167 Phthalic acid, 672 of alkynes, 446–447, 698 constitutional isomers of, 118t Ph- (abbreviation), 612 Phthalimide, 961 in haloform reaction, 894–895, 895f melting point of, 93 PHAs (polyhydroxyalkanoates), Phylloquinone, 98 Oxidized state, 147 molecular formula, 118t 1170–1171 Physical properties. See Boiling point; Oxidizing agents, 438–439. See also structure, 116 PHB (polyhydroxybutyrate), 1171 Melting point; Solubility specifi c agents van der Waals forces, 88, 88f, 90 PHBV, 1171 Pi* (π*) antibonding molecular orbital, NAD+, 733 2,4-Pentanedione, 882, 886, 908, 909 α-Phellandrene, 1133f 627, 628f peroxyacids, 438, 438f Pentanoic anhydride, 870 Phenacetin, 877 Pi (π) bond, 37–40, 38f, 39f, 40f Oxime, 1050 3-Pentanol, 746 Phenanthrene, 621, 636, 640 in alkene double bond, 281 Oxiranes, 317. See also Epoxides 2-Pentanone, 910 Phenol(s), 151, 227, 611, 717 in alkenes, 359, 360, 370–373, 391 6-Oxoheptanal, 945 mass spectrum of, 472 acidity of, 701, 703f in alkynes, 299, 300f, 400–401, -oxy (suffi x), 316 preparation from an acid chloride and as antioxidants, 557 405–406 Oxycodone, 490 an organocuprate reagent, 753 in aspirin synthesis, 268, 269f in aromatic compounds, 83, 608, 609 Oxygen 3-Pentanone, boiling point of, 91, 91f, 914 Bakelite preparation from, 1165 breaking in addition reactions, 199, bonding patterns and formal charge, Pentanoyl chloride, 492, 870 conjugate base of, 701–702, 702f, 703f 359, 370–373, 371f, 378, 379, 17t 1-Pentene, 466–467 formation from anisole, 343 380, 383, 390, 391 in condensed structures, 28 2-Pentylcinnamaldehyde, 923 hydroxy group of, 313 bromination as test for, 380 infrared (IR) absorptions in oxygen- 1-Pentyne, 466–467 naming, 612 Brønsted–Lowry bases and, 55–56, 55f containing compounds, 482 Peptide bonds, 1086, 1088–1089 pKa of, 701, 703f in carbonyl group, 85, 722–723, 724 isotopes of, 472t s-cis conformation, 1088 polyhalogenation of, 665 degrees of unsaturation and, 360 mass of, 472t planar geometry of, 1088–1089 synthesis from aryl diazonium salts, delocalized, 583 as radical scavenger, 541 s-trans conformation, 1088–1089 982 formation in elimination reactions, 198, Oxytocin, 828, 1089, 1090f, 1105 Peptides, 837, 1086–1101 Phenoxide, 701–702, 702f, 703f 279–280, 291, 294, 299, 300f -oyl (suffi x), 779 constitutional isomers, 1087 Phentermine, 76 in functional groups, 82, 102–103 Ozone interesting examples, 1089–1090, Phenylacetaldehyde, 777f, 884 in Lewis base, 72, 74 destruction of atmospheric, 233, 1090f Phenylacetamide, 871 in polyenes, 580, 581 551–552, 552f N- and C-terminal amino acids, 1087 Phenylacetic acid, 871 radical reactions with, 541, 562 as oxidizing agent, 438, 445–447 peptide bond in, 1088–1089 Phenylacetonitrile, 871 in resonance structure, 67 synthesis of, 551 sequencing, 1090–1094 Phenylalanine strength, 359 Ozonide, 445, 447 amino acid analysis, 1091 abbreviation for, 711t Pi (π) bonding molecular orbital, 627, Edman degradation, 1091–1092 N-acetyl, 1086 628f PABA (para-aminobenzoic acid), 599, partial hydrolysis of peptide, isoelectric point for, 1078t Picometer (pm), 23 π 684, 990–991 1092–1093, 1093t pKa values for, 1078t Pi ( ) electrons Pacifi c yew tree, 268 simple, 1086–1088 structure of, 1076f in aromatic compounds, 613, 617, Padimate O, 599 synthesis of, 1094–1101 synthesis of, 1080, 1086 618–619, 619t PAHs. See Polycyclic aromatic automated, 1099–1100, 1101f 4-Phenyl-2-butanone, 998 in benzene, 609, 610 hydrocarbons (PAHs) protecting groups in, 1094–1098 Phenylcyclohexane Hückel’s rule and, 618–619, 619t, Pain relievers, 906. See also Analgesics solid phase technique, 1099–1100 conformations of, 208 626–629 Palladium-catalyzed reactions, 219 Percent s-character, 41, 68 phenyl group in, 83 in NMR spectroscopy, 505–506, 506t alkene reduction, 429 bond length and, 582 Phenylethanal. See Phenylacetaldehyde Pinacol, 357 alkyne reduction, 434–435 effect on basicity of amines, 972–973 2-Phenylethylamine, 965 Pinacolone, 357 general features of, 1005–1006 hybrid orbital in alkenes, 284 derivatives of, 958–959 α-Pinene, 1145 Heck reaction, 1003, 1009–1011 infrared (IR) absorption and, 480 in Hofmann elimination reaction, 978 Piperidine hydrogenation of aldehydes and Percent transmittance, 477 Phenyl group, 83, 84t, 612 basicity of, 972–973, 973t ketones, 729 Perfume, 435 (1E)-1-Phenyl-1-hexene, 1024 structure, 953 oxidative addition in, 1006, 1008, 1011 Period, in periodic table, 8 Phenyl isothiocyanate, 1091–1092 Pitocin. See Oxytocin in peptide synthesis, 1097–1098 Periodic table, 7–10 (1Z,3E)-1-Phenyl-1,3-octadiene, 1009 Pivalic acid, 60 reductive elimination in, 1006, 1008, bond length trends, 23 3-Phenyl-1-propanamine, 995 pKa values, 59–68, A–1–2 1011 element location and bonding type, 10 Phenylpropanoic acid, 195 acid strength and, 59–60 Suzuki reactions, 1003, 1005–1009 of elements common in organic N-Phenylthiohydantoin (PTH), of amines, 966, 968–969, 974t Palmitic acid, 1122, 1122t chemistry, 8f 1091–1092, 1118 for amino acids, 1077, 1078, 1078t Palmitoleic acid, 1122t fi rst-row elements, 8f, 9 N-Phenylthiourea, 1091–1092 of carbonyl compounds, 884–885, Palm oil, 1123 organization of, 8 Pheromones, 114, 115, 441, 442f, 454, 885t, 886t Palytoxin, 312, 356 second-row elements, 8f, 9–10 454f, 843, 844, 925, 925f, 1008 defi nition, 59 Para (prefi x), 611 bonding of, 12 Phomallenic acid C, 421 of leaving groups in nucleophilic Paracyclophane, 639 exceptions to octet rule, 18 Phosgene, 1163 substitution reactions, 237 Para red, 989 shape arrangements, 24 Phosphatidylcholine, 1126 logarithmic scale of, 60

smi75625_index_1218-1246.indd 1239 11/24/09 12:13:38 PM I-23 Index

pKa values (continued) Polymerization, 560–563 Potassium tert-butoxide, 239 Primary (1°) amines of selected organic compounds, 59t anionic, 1154–1155, 1155f in dehydrohalogenation reactions, addition to aldehydes and ketones, of strong acids, 70 of epoxides, 1156–1157 280, 280t 797–799, 799f, 801f of strong bases, 71 cationic, 1153–1154, 1155f Potassium dichromate, 438, 448, 449, amino acids, 1077 PLA (polylactic acid), 860 chain branching in, 1152–1153 449f from direct nucleophilic substitution, Planar carbocation, 377, 1043–1044 coordination, 1159 Potassium hydroxide, in dehydrohalo- 960–961 Planar double bond, 376–377, 381, 386, defi nition of, 561, 1149 genation reactions, 280t Gabriel synthesis, 961–962 388 feedstock for, 1166–1167 Potassium iodide, 10, 983 IR spectra of, 955, 955f Planar molecule head-to-tail, 563 Potassium permanganate (KMnO4) nomenclature, 952 benzene, 609–610 ionic, 1153–1156, 1155f as oxidizing agent, 71–672, 439, 675, reactions with acid chlorides and Plan B, 403 living, 1155 738 anhydrides, 975–976 Plane of symmetry, 165–166, 165f radical, 562–563, 1151–1152, 1151f, in syn dihydroxylation, 443–444 reactions with aldehydes and ketones, in disubstituted cycloalkanes, 180 1153 Potassium propanoate, 692 975 of meso compound, 178 Ziegler–Natta, 1157–1159 Potassium sorbate, 696 reactions with nitrous acid, 980–981 Plane-polarized light, 182–183 Polymers, 560–562, 560–563, Precor. See Methoprene from reduction of amides, 963 Plaque, atherosclerotic, 861f, 862 1148–1178 Prednisone, 783 from reduction of nitriles, 962 Plastic, polyethylene, 84 alternating, 1156 Prefi x, 120 from reduction of nitro compounds, Plasticizers, 96, 1165–1166 amorphous regions of, 1164–1165 cis, 363 962 Platinum, as catalyst, 219 atatic, 1157–1158 cyclo-, 118, 125 structure of, 950 Plavix. See Clopidogrel “Big Six,” 1169, 1169t deoxy, 1063 synthesis from reduction of nitriles, β-Pleated sheet, 1101–1104, 1103f, biodegradable, 1170–1171 di-, 123 865 1105f, 1107f chain-growth, 1149, 1150–1157 E, 363 Primary (1°) carbocations, 256 PMMA [Poly(methyl methacrylate)], in consumer products, 1149, 1149f epoxy, 317 Primary carbon (1°), 116 568 copolymers, 1156 iso-, 120 Primary hydrogen (1°), 116–117 Poison ivy, 707 crystalline regions of, 1164–1165 meta-, 611 Primary structure, of proteins, 1101, Polar aprotic solvents, 241, 241f, defi nition of, 160, 1149 ortho-, 611 1107f 264, 265, 265t, 287, 288t, derivation of word, 1149 para-, 611 Primobolan, 1146 889–890 green synthesis of, 1166–1169, 1167f, R, 170–175, 179–180 Procaine, 615f Polar bond 1168f S, 170–175, 179–180 Progesterone carbon–halogen, 234, 234f insoluble, 1099 sec-, 120 analogs of, 402, 403 description of, 43, 44, 45f isotactic, 1157–1158 tert-, 120, 121 function in body, 1141t Polarimeter, 182 in medicine and dentistry, 561, 562t tetra-, 123 structure of, 403, 1120f, 1141t Polarity, of carboxylic acids, 699 molecular weights of, 1150 trans, 363 synthesis of, 928 Polarizability natural and synthetic fi bers, 858–860, tri-, 123 Progestins, 1141 boiling point and, 91f 858f Z, 363 Prograf. See FK506 inductive effects on substituted nylon, 825, 859, 1149f, 1150, Pregabalin, 106 Proline, 719 benzenes, 654 1160–1161, 1167, 1167f, 1170 Preparations, 697 isoelectric point for, 1078t van der Waals forces and, 88–89 physical properties of, 1164–1166 Prepolymer, 1163–1164, 1164f pKa values for, 1078t Polarized light, 182–183 polyesters, 859–860 Preservatives, 261 structure of, 1076f, 1077 Polar molecule random, 1156 Primary (1°) alcohols, 390 Prontosil, 990 description, 44, 45f recycling of, 1148, 1169–1170, 1169t classifi cation as, 313 Propanal solubility of, 94 shorthand representation of, 1150, conversion to alkyl halides with HX, aldol reaction of, 918–919, 922 Polar protic solvents, 240, 240f, 1150f 332–334, 337t enolate formation from, 884 264–265, 265t, 293t, 890 step-growth, 1150, 1160–1164 conversion to alkyl halides with IR spectrum of, 780, 781f Polar reactions, 201, 201f stereochemistry of, 1157–1159 phosphorus tribromide, 336, NMR spectra of, 782, 782f Poly- (prefi x), 1155 structure of, 1149, 1164–1166 337t Propanamide Poly(acrylic acid), 561, 1171 syndiotactic, 1157–1158 conversion to alkyl halides with thionyl boiling point of, 92 Polyacrylonitrile, 1155f synthetic, 1148–1178. See also chloride, 335–336, 337t infrared (IR) spectrum of, 483 Polyalkylation, 666 Synthetic polymers dehydration by E2 mechanism, 327 2-Propanamine, 952 Polyamides, 825, 859, 1160–1161 Poly(methyl methacrylate) (PMMA), 568 hydrogen bonding extent, 318 Propane, 224 PolyAspirin, 1177 Polypropylene, 562t, 1169t from nucleophilic addition to aldehyde, bromination of, 546–547, 547f Polyatomic ion, 16 Polysaccharides, 1059–1061 735 chlorination of, 546–548, 548f Polycaprolactone, 1177 cellulose, 1059–1060 oxidation to carboxylic acids, 447, molecular formula of, 114, 115, 118t Polycarbonates, 1163 glycogen, 1061 448–450, 698 as propellant, 551 Polychlorinated biphenyl (PCB), 95–96 starch, 1060–1061 from reactions of aldehydes with structure of, 114–115 Polycyclic aromatic hydrocarbons Polystyrene, 96, 538, 562, 1150f, 1169t organometallic reagents, torsional energy of, 134 (PAHs), 349, 614, 614f, 621 preparation from ethylene, 366f 742–743 Propanedioic acid, 692 Polydioxanone, 1177 Polystyrene derivative, 1099 from reduction of acid chlorides, 734 1,2-Propanediol, 352 Polyenes, 580, 581 Polytetrafl uoroethylene (Tefl on), 562t from reduction of aldehydes, 432, 727, 1,3-Propanediol, 352, 1167, 1168f, ultraviolet absorption, 598 Poly(trimethylene terephthalate) (PTT), 728, 729 1176 Polyesters, 859–860, 1161–1162 1167, 1168f from reduction of carboxylic acid 1,2,3-Propanetriol, 316 Polyethers, 320, 1156 Polytulipalin, 946 derivatives, 727 Propanil, 999 Poly(ethyl acrylate), 568 Polyurethanes, 1162 from reduction of carboxylic acids, Propanoic acid Poly(ethyl α-cyanoacrylate), 1155f Poly(vinyl acetate), 562, 1155f 735 NMR spectra of, 695f Polyethylene, 84, 366, 366f, 561, 1149f, preparation from ethylene, 366f from reduction of esters, 734 pKa of, 77 1152–1153, 1158, 1159 Poly(vinyl alcohol), 1176 from reduction of monosaccharides, 1-Propanol Poly(ethylene glycol) (PEG), 109, 1157 Poly(vinyl butyral), 1176 1047 conversion to butanenitrile, 337–338 Polyethylene terephthalate (PET), 719, Poly(vinyl chloride) (PVC), 109, 232, Primary (1°) alkyl halides IR spectrum of, 477 859–860, 1148, 1150f, 562t, 1149, 1165, 1169t acetylide anion reactions with, NMR spectrum of, 524, 526f 1161–1162, 1169t, 1170, 1174 preparation from ethylene, 366f 414–415 Proparacaine, 684, 1001 Polyfunctional compounds, nomenclature p Orbitals classifi cation as, 229–230 Propene of, A–4–5 description, 8–9 E2 elimination reactions, 287, 288, borane addition to, 387 Polyhalogenation, 665 hybridization of, 33–40, 33f–35f, 302f hydrohalogenation, 374 Polyhydroxyalkanoates (PHAs), 38f–40f example of, 229f monomers in polymerization, 562t 1170–1171 hyperconjugation, 257 SN2 substitution reactions, 248, 262, radical halogenation, 552–553 Polyhydroxybutyrate (PHB), 1171 overlap of, 572–573, 578–579, 582, 262f, 302f synthesis from propylamine, Poly(hydroxyethyl methacrylate), 568 610, 610f synthesis of, 332, 335, 336 977–978 Polyhydroxyvalerate, 1171 2p orbitals, 9, 32–35, 34f Primary (1°) amides, 827, 831, 834–836, 2-Propen-1-ol, 363 Polyisobutylene, 568, 1155f in alkenes, 281 842, 844, 850 Propiolic acid, 77 Poly(lactic acid) (PLA), 860, 1167–1168 in alkynes, 400, 401, 405 tautomers, 863 Propionic acid, structure of, 691t

smi75625_index_1218-1246.indd 1240 11/24/09 12:13:39 PM Index I-24

Propiophenone, 732 of cyclohexane conformations, 518 Qinghao, 389 general features of, 540–541 halogenation of, 893–894 general principles Quantum, 474 halogenation at allylic carbon, 552–555 Propoxyphene (Darvon), 106, 166–167 chemical shifts, 497–498 Quartet, NMR spectrum, 511t, 512t, 518 bromination, 553–554 Propranolol, 70, 356 downfi eld signals, 497–498 Quaternary ammonium salt. See also product mixtures in, 555 Propylamine, conversion to propene, reference signal, 497 Ammonium salt halogenation of alkanes, 541–551 977–978 scale, 497 in Hofmann elimination reaction, of achiral starting material, Propylbenzene, 227, 673 signal intensity, 497 977–978 549–550, 549t Propyl group, 120 upfi eld signals, 497–498 synthesis of, 960–961 bromination, 546–547, 547f Prostacyclins, 1129–1130, 1130t, 1131f identifi cation of an unknown, 519–522 Quaternary carbon (4°), 116 of chiral starting material, 549t, 550 Prostaglandins, 150, 150f, 215, integrals, 507–508 Quaternary structure, of proteins, 1105, chlorination, 544–548, 544f, 545f, 1129–1131 intensity of signals, 507–508 1107f 548f, 549–551 analogues, 1131 of ketones, 782 Quiana, 1174 energy changes during, 544, 544f, biological functions, 697 number of signals, 498–502 Quinine, 194 545f inhibitors of synthesis, 1131–1132 enantiotopic and diastereotopic as natural alkaloid, 957 mechanism of, 542–544 PGA2, synthesis of, 286, 933 protons, 500–502 source of, 289 in organic synthesis, 548–549 PGE1, 768, 1131 equivalent protons in alkenes and structure of, 624, 975 stereochemistry of, 549–551, 549t PGE2, 1130 cycloalkanes, 499–500 synthesis of, 288, 289f, 896, 896f halogenation of alkyl benzenes, PGF2α, 150, 150f, 223, 306, 398, 570, general principles, 498–499 Quinoline, 435 669–671 697, 1120f, 1130f, 1144 OH proton, 517–518, 518f Quintet, NMR spectrum, 511t inhibitors of, 541 PGG2, 570, 697 position of signals, 502–504 Quinuclidine, 277 polymerization, 560–563, 562t PGI2, 1130f chemical shift values, 503–504, two radicals reacting with each other, synthesis of, 697, 1130, 1131f 504t R (prefi x), 170–175, 179–180 541 Protecting groups, 748–750 shielding and deshielding effects, Racemic mixture (racemate), 183–184, 184t Radical scavenger, 541 acetals as, 808–809 502–503, 502f, 503f, 506f, 506t of alcohols from hydroboration– Radical substitution reaction, 541, A–13 amide for amines, 977 regions of spectra, 506, 506f oxidation of alkenes, 389 Randomness, entropy as measure of, 209 in amino acid synthesis, 1094–1098 spin–spin splitting, 508–517 alkene halogenation, 381 Rate constant (k), 216–217 general strategy for using, 749f in alkenes, 516–517, 516f, 517f of alkyl chlorides, 334 Rate-determining step Proteins, 1086, 1101–1110. See also common patterns of, 512t of amino acids, separation of, in chlorination of ethane, 544, 545f, Peptides complex examples of, 513–515 1081–1084, 1082f 548 amide linkages in, 837, 855–856 how a doublet arises, 509–510 in carbene addition, 1014 E1 elimination reactions, 292 conjugated, 1109 how a triplet arises, 510 in enolate alkylation, 898 electrophilic additions, 373, 373f, 374 fi brous, 1106 overview of, 508–509 from epoxidation of alkenes, 440 in halogenation reactions, 546–548 globular, 1106 rules and examples, 510–513 in epoxide ring opening reactions, 344 bromination, 547 important examples, 1106–1110, Protons formation by hydrohalogenation, 376 chlorination, 548 1108f, 1109f description of, 7 halogenation reactions and, 381, halogenation of alkenes, 382 membrane, 1075 relative acidity of, determining, 69–70 549–550 in a multistep mechanism, 214–215, natural fi bers, 858, 858f Proton transfer reaction in hydride reduction of ketones, 730 217 stability of, 855–856 aspirin and, 71–72 SN1 substitution reactions and, in nucleophilic substitution reactions, structure, 1101–1106 description of, 56–58 254–255, 255f 243, 244 primary, 1101, 1107f Proventil. See Albuterol Racemic switch, 187 rate equation for, 217 quaternary, 1105, 1107f Proximity effect, 587 Racemization SN1 substitution reactions, 260 secondary, 1101–1104, 1102f, Prozac. See Fluoxetine at α carbon of carbonyl compounds, Rate equation, 216–218 1103f, 1105f, 1107f d-Pscicose, 1036f 891 fi rst-order, 217, 243, 244 tertiary, 1104–1105, 1107f Pseudoephedrine, 65, 192, 966, 999 defi nition of, 254 for nucleophilic substitution reactions, subunits, 1105 Psilocin, 958–959 in SN1 substitution reactions, 254–255, 243–244 Protic solvents, polar, 240, 240f, Psilocybe mushroom, 959 255f second-order, 217, 243, 244 264–265, 265t, 293t, 890 PTH (N-phenylthiohydantoin), Radiation Rate law, 216–218 Proton acceptor, 55 1091–1092 electromagnetic, 474–476, 475f RCM (ring-closing metathesis), Protonation PTT. See Poly(trimethylene terephthalate) infrared, 476–477 1018–1019, 1018f in acid-catalyzed ester hydrolysis, Puffer fi sh, 589, 589f RF (radiofrequency), 495–496, 527 Reaction arrow, 197, 202t 851 Purifi cation procedures ultraviolet, 599 curved, 201, 202, 202t in aldehyde/ketone nucleophilic extraction, 707–709, 708f, 709f Radical(s) double, 202t addition reactions, 786–787 Purine, 635, 1063–1064 bond formation from, 202 Reaction coordinate, 210, 211, 212f, 215f of carboxylic acids, 699 Putrescine, 956–957 defi nition of, 539 Reaction mechanism in glycoside formation, 1043–1044 PVC. See Poly(vinyl chloride) as electrophile, 202 bond cleavage, 200–202 in glycoside hydrolysis, 1044 Pyran, 1037 as reactive intermediate, 201–202, 201f bond formation, 202 in nucleophilic addition to aldehydes Pyranose ring, 1037, 1056 resonance-stabilized, 555 concerted, 200 and ketones, 724 Pyrethrin I, 106, 1012, 1023 stability of, 539–540, 540f defi nition of, 200 tautomerization in acid, 410–412 Pyridine, 71, 369–370, 621–622, 687, 842 Radical anion, 436 energy diagram for a two-step, Proton donor, 55 alcohol conversion to alkyl tosylates in, Radical cation, 465 213–215, 215f Proton NMR, 495, 497–522 338–340, 341f Radical inhibitor, 541 rate equations and, 216–218 of aldehydes, 782, 782f basicity of, 972–973, 973t, 974t Radical initiator, 540 stepwise, 200, 213–215, 217 of amines, 956, 956f conversion of alcohols to alkyl halides, Radical intermediates, 539, 554, 558 Reaction rate of aromatic compounds, 619–620 335–336 Radical polymerization, 1151–1152 catalysts and, 218–219, 219f of benzene derivatives, 518–519, 519f, conversion of monosaccharides to chain branching in, 1153 concentration effect on, 216, 217–218 613–614, 613t esters using, 1046 chain termination in, 1152 of endothermic reactions, 212f, 259 of carboxylic acid derivatives, 836 dehydration of alcohols using, 330–331 monomers used in, 1151, 1151f energy of activation (Ea) and, 215–217 of carboxylic acids, 694, 695f electrostatic potential plot of, 622, 623f Radical reactions, 201, 201f, 538–570. See of exothermic reactions, 212f, 259 characteristic absorptions, A–11–12 structure of, 953 also specifi c reactions nucleophilic substitution reactions, chemical shift Pyridinium chlorochromate (PCC), of alkanes, 541–551 264–265 equation for, 498 438–439, 448 of alkenes, 541, 558–560 rate-determining step, 214–215, 217 predicting values of, 503–504 Pyridoxine, 109 applications of temperature effect on, 216 protons on benzene rings, 505, 506t Pyrimidine, 1063–1064 antioxidants, 557 Reactions. See Organic reactions protons on carbon–carbon double α-Pyrone, 635 oxidation of unsaturated lipids, Reactive intermediate bonds, 505, 506t Pyrrole, 622, 636, 687, 995 556–557, 556f carbanion, 201–202, 201f protons on carbon–carbon triple basicity of, 972, 973t, 974t ozone destruction by CFCs, carbocation, 201–202, 201f, 252–253, bonds, 505, 506t electrostatic potential plot of, 622, 623f 551–552, 552f 330 scale, 497 structure of, 953 carbon–hydrogen bond, reaction of description of, 200 values for common bonds, 504t Pyrrolidine, structure of, 953, 995 radical with, 540–541 radicals, 201–202, 201f coupled protons, 510 Pyruvic acid, 733 double bonds, addition to, 541, 558–560 synthetic intermediate compared, 392

smi75625_index_1218-1246.indd 1241 11/24/09 12:13:39 PM I-25 Index

Reactivity, functional groups and, Resolving agent, 1082 in substituted benzene syntheses, 674, Seaweed, 232 102–104 Resonance, 18–23 675–677 Sebacic acid, 1177 Reactivity–selectivity principle, 546 of allylic carbocations, 574–575, 574f synthesis of m-bromoaniline from Sebacoyl chloride, 1177 Reagent, 197, 197f allyl type, 575–576 benzene, 674 sec- (prefi x), 120 Rebaudioside A, 1045 benzene, 609 using aldol reaction, 920–921 Secondary (2°) alcohols, 390 Receptors, chiral, 187 examples of, 575–577 using malonic ester synthesis, classifi cation as, 313 Recycling of polymers, 1148, 1169–1170, theory/principles, 18 902–903 conversion to alkyl halides with HX, 1169t usage of term, 574 Wittig reaction, 795–796 332–334, 337t Red seaweed (Asparagopsis taxiformis), Resonance delocalization, 67 RF radiation, 495–496, 527 conversion to alkyl halides with 232 Resonance effects R group, 82, 120 phosphorus tribromide, 336, Reduced state, 147 on acidity, 66–67, 67f, 69f identity in SN2 substitution reactions, 337t Reducing agents, 428. See also specifi c on basicity of amines, 973t 248–249, 249t conversion to alkyl halides with thionyl agents electron-donating, 654–656 Rhodium, 1085 chloride, 335–336, 337t chiral, 731 electron-withdrawing, 654–656 Rhodopsin, 799, 799f dehydration by E1 mechanism, 326 metal hydride reagents, 428, 727–731, on substituted benzenes, 654–657 Ribbon diagrams, 1104 hydrogen bonding extent, 318 733–738, 738t Resonance hybrid, 18, 22–23 α-d-Ribofuranose, 1042, 1062 oxidation to ketones, 447, 448, 450 NADH, 732–733 of benzene, 609 β-d-Ribofuranose, 1042 from reactions of aldehydes with Reducing sugars, 1048, 1048f, 1057 drawing, 22 Ribonucleosides, 1063–1064 organometallic reagents, Reduction, 147–148, 148f, 426–462 electron delocalization, hybridization, Ribonucleotides, 1064 742–743 of acid chlorides and esters, 734–735 and geometry, 578–579 d-Ribose, 1034, 1035f, 1063 from reduction of ketones, 432, 727, of alkenes, 427, 428–432, 428f major contributor to, 577–578 d-Ribulose, 1036f 728, 729 of alkyl halides, 437–438, 438f minor contributors to, 577–578 Rimantadine, 966 Secondary (2°) alkyl halides of alkynes, 427, 428f, 434–437, 437f Resonance stabilization, of carboxylic Ring-closing metathesis (RCM), acetylide anion reactions with, to alkanes, 428f, 434–435 acids, 701–702, 702f, 703f 1018–1019, 1018f 414–415 to cis alkenes, 434, 435 Resonance-stabilized allyl carbocation, Ring-fl ipping, 140–141, 141f classifi cation as, 229–230 to trans alkenes, 434, 436 574–575, 574f, 575f Ring formation, in Robinson annulation, E1 elimination reactions, 292, 303f of amides to amines, 736–737, 963 Resonance-stabilized carbocation, 936–939 E2 elimination reactions, 287, of aryl ketones to alkyl benzenes, 584–585, 587 Ring-opening metathesis polymerization 302f–303f 672–673 in electrophilic aromatic substitution (ROMP), 1022 example of, 229f asymmetric, 731 reaction, 643 Ritalin. See Methylphenidate SN1 substitution reactions, 255, 262, of carbonyl compounds, 726–738 in glycoside formation, 1043–1044 RNA, 1064, 1065f 262f, 303f biological, 732–733 in glycoside hydrolysis, 1044 Robinson, Sir Robert, 936 SN2 substitution reactions, 248, 262, carboxylic acids and derivatives, Resonance-stabilized radical, 555 Robinson annulation, 936–939 262f, 302f 733–738 Resonance structures, 18–23, 574–579 Rocaltrol. See Calcitriol synthesis of, 332, 335, 336 by catalytic hydrogenation, 729 of acetate, 701, 703f Rofecoxib, 1132 Secondary (2°) amides, 827, 831–832, enantioselective, 731–733, 732f acidity and, 66–67 Row, in periodic table, 8 834–836, 842, 844, 850 with metal hydride reagents, of allyl radical, 553 Rowland, F. Sherwood, 551 Secondary (2°) amines 728–729, 730f, 738t of benzylic radical, 669 RU 486, 403 addition to aldehydes and ketones, stereochemistry of, 729–731 of carboxylic acid derivatives, 828 Rubber, 1149f, 1159–1160, 1159f 800–801, 801f of the carbonyl group of cations with positive charge adjacent to Rubbing alcohol, 319f from direct nucleophilic substitution, monosaccharides, 1047 lone pair, 576 Ruthenium, 1015 960 Clemmensen, 672 conjugated allyl carbocation, 574 IR spectra of, 955, 955f defi nition of, 147, 427 of conjugated dienes, 582, 583 S (prefi x), 170–175, 179–180 nomenclature, 952–953 dissolving metal, 428, 436 double bond Saccharide, origin of word, 1028 proline, 1077 of epoxides, 437–438, 438f conjugated, 576 Saccharin, 1058, 1059f reactions with acid chlorides and general scheme for, 427f major contributor, 577–578, 582 Saffl ower oil, 369 anhydrides, 975–976 of hydrocarbons, 427, 428f minor contributors, 577–578, 582 Safrole, 998 reactions with aldehydes and hydrogenation, 429–434 with one atom more electronegative Salicin, 71, 195, 696, 1045 ketones, 975 of ketones to amines, 963–966 than the other, 576, 577 Salicylamide, 874 reactions with nitrous acid, 981–982 of nitriles, 863, 865–866 drawing, 19–22 Salicylates, 71 from reduction of amides, 963 of nitriles to amines, 962 of enolates, 884 Salicylic acid, 696, 873 structure of, 950 of nitro groups, 673–674 of enols, 883–884 Salmeterol, 347, 347f, 732f, 772 Secondary carbon (2°), 116 oxidation, relationship to, 427 isomers compared to, 19 Salsolinol, 820 Secondary hydrogen (2°), 116–117 of polar C–X sigma (σ) bonds, of naphthalene, 621 Salts Secondary structure, of proteins, 437–438 of phenoxide, 701–702, 702f, 703f Brønsted–Lowry bases and, 55 1101–1104, 1102f, 1103f, of triple bonds, 437–437, 437f stability of, 577–578 of carboxylic acids, 696 1105f, 1107f Wolff–Kishner, 672 of substituted benzenes, 654–655 formation of, 10–11 Second-order kinetics, 217 Reductive amination, of aldehydes and three atom allyl system, 575–576, 577 negatively charged nucleophile, 235 of E2 elimination reactions, 285 ketones to amines, 963–966 of α,β-unsaturated carbonyl SAM (S-Adenosylmethionine), 250 in nucleophilic substitution reactions, Reductive elimination compound, 934 SAMe, 250 243–244 in Heck reaction, 1011 of Wittig reagent, 793 Samuelsson, Bengt, 697 Second-order rate equation, 217, 243, in palladium-catalyzed reactions, 1006, Retention of confi guration Sandmeyer reaction, 983 244 1008, 1011 in conversion of alcohols to alkyl Santalbic acid, 401 L-Selectride, 773 in Suzuki reactions, 1008 tosylates, 338–339, 340 Saponifi cation, 851, 854–855 Selective serotonin reuptake inhibitors Refi ning, 128–129, 129f in oxidation of alkylboranes, 388–389 Saponins, 98 (SSRIs), 958 Refrigerant, 233 in SN2 substitution reactions, 246 Saquinavir, 195 Separation, of amino acids, 1081–1084 Regioselectivity Retention time, in gas chromatography, Saran, 1156 Separatory funnel, 707, 708f of alcohol dehydrations, 325 473–474 Saturated fats, 369 Septet, NMR spectrum, 511t, 513 of E1 elimination reactions, 293 Retinal, 799, 799f Saturated fatty acid, 358 Serevent. See Salmeterol of E2 elimination reactions, 289, 296 Retinol, 97 Saturated hydrocarbons, 114 Serine of electrophilic addition of hydrogen Retro Diels–Alder reaction, 595–596 Saytzeff rule, 289 abbreviation for, 711t halides, 374 Retrosynthetic analysis, 392, 417–419 SBR (styrene–butadiene rubber), isoelectric point for, 1078t of epoxide ring opening reactions, in acetoacetic ester synthesis, 904 polymerization of, 1156 pKa values for, 1078t 345–346 in benzene derivative synthesis, 985 Sch38516, 1018f structure of, 1076f of halohydrin formation, 384–385, 385t of Diels–Alder product, 595 s-character, of hybrid orbitals, 68 Serotonin, 874, 958 of Hofmann elimination, 979 of disparlure, 441 Schiff base, 797 Sertraline, 615f, 653 of hydroboration, 387 of Grignard products, 746–748 Schrock, Richard, 1015 Sex hormones, 1141–1142, 1141t. See Reserpine, 879 of Heck reaction, 1010 s-cis conformation, 580 also specifi c hormones Resolution, of amino acids, 1081–1084, organometallic reagent reactions, Scombroid fi sh poisoning, 622 Sex pheromone, 486, 1002 1082f 760–761 Seashells, chiral helical, 166 Sextet, NMR spectrum, 511t, 515f

smi75625_index_1218-1246.indd 1242 11/24/09 12:13:39 PM Index I-26

Sharpless epoxidation, 451–454, 1085 solvent effects on, 264–265 Sodium dichromate, 438, 448 sp2 hybrid orbitals, 34–35, 34f, 37, 39f, Sharpless, K. Barry, 452 stereochemistry, 253–255, 255f, 256t Sodium ethoxide, 322 40f, 257, 267, 313, 365 Sharpless reagent, 452 transition state in, 253, 253f, 264 in dehydrohalogenation reactions, in alkenes, 281, 283–284, 359 Shell, of electrons, 8–9 two-step mechanism for, 252–253, 280t of alkyl halides, 229, 229f, 267 Shielding effects, in NMR, 502–503, 256t Sodium hydroxide in aromatic heterocycles, 621–623, 502f, 503f, 506f, 506t SN2 substitution reactions, 244–252 in dehydrohalogenation reactions, 623f 1,2-Shifts, 328–330 in acetoacetic ester synthesis, 904, 905 280, 280t carbon radical, 539 Shikimic acid, 86 acetylide anion reactions with alkyl use in extraction procedure, 707–708, carboxy group, 689 Sickle cell anemia, 1110 halides, 414–415 709f percent s-character, 41, 68 Sickle cell hemoglobin, 1110 acetylide anion reaction with epoxides, Sodium hypochlorite, 451 sp3 hybrid orbitals, 33–34, 33f, 35, 35f, Side chain, of amino acid, 1075, 1077, 416–417 Sodium iodide, 983 36, 36f, 39f, 40f, 242, 313, 365 1078t alcohol conversion to alkyl halides, Sodium methoxide, 322 in acyclic alkanes, 114 Sigma (σ) bond, 32, 33, 36–40, 38f, 39f, 336–337 in dehydrohalogenation reactions, in alkenes, 283–284 40f with HX, 332–334 280t of alkyl halides, 229, 229f in alkanes, 83 with phosphorus tribromide, Sodium nitrite, 261 in nucleophilic substitution reactions, in alkenes, 281, 359, 428–429 336–337 Sodium salicylate, 696 235–236 in alkynes, 400–401 with thionyl chloride, 335–336 Sodium trichloroacetate, 1023 percent s-character, 41, 68 breaking in addition reactions, 199 alcohol synthesis from alkyl halides, Soft coral (Capnella imbricata), 416 Spiriva. See Tiotropium bromide carbon–oxygen, 313 321–322 Solanine, 1045 Spiro ring system, A–6 formation in addition reactions, 370, alkyl halide identity in, 262, 262f Solid phase technique, of amino acid Splenda. See Sucralose 371, 371f, 372 alkyl halide with ammonia or amine, synthesis, 1099–1100 Squalene, 157, 459, 1133f, 1135–1136, formation in elimination reactions, 960–961 Solubility, 93–96 1135f, 1140, 1140f 198 alkyl tosylate reactions, 339–340 of alcohols, 318t Squalene oxide, 1140, 1140f functional groups that contain C–Z applications of, 250–252, 250f, 251f of aldehydes and ketones, 780t Stachyose, 1072 σ bonds, 84, 85t in automated peptide synthesis, 1099 of alkanes, 129, 130t Staggered conformation, 131–137, 132f, hyperconjugation, 257 backside attack in, 245–247, 263 of alkenes, 365 133f, 134f, 136f, 295, 295f inductive effect and, 65, 256 direct enolate alkylation, 897 of alkynes, 402 Stanozolol, 639, 1142 length in conjugated dienes, 581–582 E1 elimination reactions compared, of amines, 954t Starch radical reactions with, 540 300–304, 302f–303f of carboxylic acids, 693t hydrolysis of, 160, 161, 161f, 319, rotation around, 129 E2 elimination reactions compared, defi nition of, 93 320f, 1061 in substitution reactions, 198, 242 300–304, 302f–303f of enantiomers, 182 structure of, 160–161, 161f, 162f, Sildenafi l, 615f energy diagrams for, 245, 245f, 249f of epoxides, 318t 1060–1061 Silent Spring, 233 epoxide ring opening reactions, of ethers, 318t Stearic acid, 358, 1122, 1122t Silk, 858, 858f 343–345 intermolecular forces and, 93–96, 94f melting point, 368t binding of dyes to, 989–990 epoxide synthesis from halohydrin, 323 “like dissolves like,” 94 structure, 368f, 368t structure of, 1104, 1105f epoxy resin synthesis, 1163 of lipids, 149, 1120 Stearidonic acid, 368–369, 457 Silver(I) oxide ethers with strong acids, 341–342 of monosaccharides, 1036, 1047 Step-growth polymers, 1150, 1160–1164 in aqueous ammonium hydroxide, ether synthesis from alkyl halides, Solute, 93 epoxy resins, 1163–1164, 1164f 738 321–322 Solvent effects, on nucleophilic polyamides, 1160–1161 as oxidizing agent, 439 features of, 244, 249t substitution reactions, 240–242, polycarbonates, 1163 Silyl ether, 749 frontside attack in, 245–246 240f, 241f, 264–265, 265t polyesters, 1161–1162 Simmons, H. E., 1014 of α-halo acids with ammonia, Solvents, 93 polyurethanes, 1162 Simmons–Smith reaction, 1014–1015 1078–1079, 1081f alkyl halides, 232 Stepwise reaction, 200 Simmons–Smith reagent, 1015 of α-halo carbonyl compounds, 896, in E1 elimination reactions, 293t Stereocenter. See Stereogenic centers Simvastatin, 170, 581, 581f, 1140, 1141f 896f in E2 elimination reactions, 287, 288t Stereochemistry, 129, 159–195 α-Sinensal, 723 kinetics of, 244, 249t for extraction procedure, 707–709, of addition reactions, 371, 376–378, Singlet, NMR spectrum, 508, 511t, 518 leaving group in, 264 708f, 709f 377f, 378t Sirenin, 1024 in malonic ester synthesis, 901 liquid, 197 of carbonyl reduction, 729–731 Sitagliptin, 624 nitrile synthesis, 862 nonpolar, 94 chemical properties of enantiomers, Six-membered ring, synthesis of nucleophile strength in, 262–264 nucleophilicity and, 240–242, 265 186–188 in aldol reaction, 928 one-step mechanism for, 244–245, organic, 94 chiral and achiral molecules, 163–166, in Dieckmann reaction, 933 249t polar, 94 165f in Robinson annulation, 936–939 organic synthesis, 267, 268t, 269 polar aprotic, 241, 241f, 264, 265, diastereomers, 175–177, 185–186, Skeletal structures, 29–31, 29f reduction of alkyl halides, 437–438, 265t, 287, 288t, 889–890 186f with charged carbon atoms, 31 438f polar protic, 240, 240f, 264–265, 265t, of Diels–Alder reaction, 592 Smith, R. D., 1014 reduction of epoxides, 437–438, 438f 293t, 890 of dienophiles, 592 SN1 substitution reactions, 252–261 R group in, 248–249, 249t s Orbitals of dihydroxylation, 442–444 alcohol conversion to alkyl halide, SN1 reactions compared, 262–266, description, 8–9 of disubstituted cycloalkanes, 180–181 332–334 262f, 265t, 300–304, 302f–303f hybridization of, 33–40, 33f–35f, of E2 elimination reactions, 295–298, alkyl halide identity in, 262, 262f solvent effects on, 264–265 38f–40f 295f applications of, 261 stereochemistry of, 245–248, 247f, 1s orbital, 9, 32 of electrophilic addition reactions, carbocation stability, 256–258 249t 2s orbital, 9, 32–34, 34f 376–378, 378t Hammond postulate and, 258–261 steric hindrance and, 248–249, 248f, Sorbitol, 179, 180, 1047 of enolate alkylation, 898 hyperconjugation and, 257–258 249t d-Sorbose, 1036f of epoxidation, 440 inductive effects and, 256–257 transition state, 245, 245f, 246, 247f, Sorona, 1167, 1168f of halogenation reactions, 381–383, E1 elimination reaction compared, 294, 264 Spam, 261 549–551, 549t 300–304, 302f–303f Soap, 98–99, 99f, 851, 854–855 Spandex, 1162 of halohydrin formation, 384–385, E2 elimination reaction compared, Sodium, in dissolving metal reductions, Spearmint, odor of, 188 385t 300–304, 302f–303f 428, 436 Specifi c rotation, 184, 185 of hydroboration–oxidation reactions, energy diagram for, 253, 253f, 260f Sodium acetate, 93, 692 Spectator ions, 55 388–389, 389t ethers with strong acids, 341–342 Sodium amide, for alkyne synthesis by Spectrometer, NMR, 496, 496f meso compounds, 177–179, 177f features of, 252 dehydrohalogenation, 299, 300f Spectroscopy, 465 physical properties of stereoisomers, kinetics of, 252, 256t Sodium benzoate, 696, 708 Spermaceti wax, 1121 182–186, 184t, 186f leaving group in, 264 Sodium bisulfi te, 443–444 Spermine, 950 polymer, 1157–1159 nucleophile strength in, 262–264 Sodium borohydride, 428, 727–731, 730f, SPF rating (sun protection factor), 599 reactions of organometallic reagents, racemization in, 254–255, 255f 738, 738t, 789, 1047 Sphingomyelins, 1127–1128, 1128f 744 rate-determining step, 260 Sodium chloride, 10–11 Sphingosine, 1127 of SN2 substitution reactions, 245–248, R group in, 255–256, 256t Sodium cyanoborohydride, for reductive sp hybrid orbitals, 34–35, 34f, 38–39, 40f 247f, 249t SN2 reactions compared, 262–266, amination of aldehydes and in alkynes, 400, 401, 405 of SN1 substitution reactions, 253–255, 262f, 265t, 300–304, 302f–303f ketones, 964 percent s-character, 41, 68 255f, 256t

smi75625_index_1218-1246.indd 1243 11/24/09 12:13:39 PM I-27 Index

Stereochemistry (continued) Stone, Reverand Edmund, 71 Sulfi de (functional group), 85t Talose of starch and cellulose, 160–162, 161f, Strain Sulfi soxazole, 991f d-talose, 1035f, 1050 162f angle, 137–139, 314 Sulfonate anion, 710 Wohl degradation, 1050 stereogenic centers, 166–180, 168f, Baeyer strain theory, 137 Sulfonation Tamifl u, 86 172f steric, 135, 136t, 138, 239 of benzene, 643f, 646–647 Tamoxifen, 880, 899 Stereogenic centers, 166–180 torsional, 133–134, 136t, 137, 138 electrophilic aromatic substitution Tandem ring-opening–ring-closing in amines, 951–952 s-trans conformation, 580 reaction, 643f, 646–647 metathesis, 1026 in amino acids, 710–711, 1075, 1077 Strecker synthesis, 1080–1081, 1081f Sulfonic acids, 709–710 Target compound, 417 on carbon atoms not part of ring, Strong electrostatic interactions, in ionic Sulfur Tartaric acid, stereoisomers of, 185–186, 166–167 compounds, 87 in fossil fuels, 70 186f in cyclic compounds, 168–170 Strychnine, 1084 octet rule exceptions in, 18 Tautomerization defi nition of, 164 Styrene, 538, 562, 671, 1016, 1016f, Sulfuric acid, 70 in acid, 410–411, 883 in diastereomers, 175–177 1021 dehydration of alcohols in, 325–330, of amides, 863–864 drawing enantiomers, 168, 168f polymerization of, 1150f, 1151, 327f in base, 883 formation from hydrohalogenation, 1153, 1156 in epoxide ring opening reactions, of carbonyl compounds, 863–864, 376, 377 structure of, 1150f, 1151f 345 881–883, 893 halogenation reactions and, 549–551 Styrene–butadiene rubber (SBR), 1156 in nitration and sulfonation reactions mechanism of, 883 inversion of confi guration around, Substituents, naming, 120–121, 611–612 of benzene, 646–647 Tautomers 246–247, 247f naming aromatic rings as, 612 Sulfur nucleophile, 348 defi nition of, 410 labeling with R or S, 170–175, 172f, Substitution reactions, A–13 Sulfur oxides, 70 enol, 410–412, 864, 882–883 175f, 179–180 alcohols, 323–324, 331–338 Sulfur trioxide, 646–647 keto, 410–412, 864, 882–883 in meso compounds, 177–179 allylic, 554 Sunscreen, 30, 599 Taxol, 170, 268, 726 in monosaccharides, 1030–1034 of aryl diazonium salts, 982–986 Supercoil, 1108, 1108f Taxotere, 876 number in a molecule, 165 at α-carbon of carbonyl compounds, Superhelix, 1108–1109 TBDMS (tert-butyldimethylsilyl), 749, priority assignment, 170–174, 172f 880–906 Surface area 750 retention of confi guration around, description of, 198 boiling point and, 91f Tefl on. See Polytetrafl uoroethylene 246 electrophilic aromatic. See van der Waals forces and, 88, 88f (Tefl on) tetrahedral, 164–165, 166, 168, 169, Electrophilic aromatic Suzuki reaction, 1002, 1003, 1005–1009, Temperature, reaction rate and, 216 178 substitution reactions 1008f Teratogen, 169 Stereoisomers. See also Enantiomers Heck reaction, 1003, 1009–1011 Sweeteners, artifi cial, 1058, 1059f, 1090 Terephthalic acid, 860, 1148, 1150f, in alkenes, 360t nucleophilic, 235–269 Sweetness, of monosaccharides, 1036 1161, 1176 chemical properties of, 186–188 radical, 541 Sweet’n Low. See Saccharin Terpenes, 1132–1138 cis, 144–147 Substrate, 219–220, 220f Symbol, atomic, 7 biosynthesis of, 1134–1138, 1135f confi guration of, 162 Succinic acid, 692 Symmetrical anhydrides, 826–827, 830 classes of, 1133t of conjugated dienes, 580 Sucralose, 1058, 1059f Symmetry examples of, 1133f constitutional isomers compared, Sucrose, 109, 157, 1058, 1058f melting points and, 93 locating isoprene units in, 1132–1134, 163f olestra synthesis from, 854 plane of, 165–166, 165f, 178 1133f of cycloalkanes, 144–147 stereogenic centers, 170 Syn additions, 371, 377, 378t, 386, rubber, 1159 defi nition of, 144 structure of, 1058f 388–389, 434, 440, 442, 442f, α-Terpinene, 1138 diastereomers, 175–177, 177f, Sudafed, 65. See also Pseudoephedrine 443–444, 1013 α-Terpineol, 398, 1137 185–186, 186f Suffi x, 120 Syndiotactic polymer, 1157–1158 tert- (prefi x), 120, 121 disubstituted cycloalkanes, 180–181 -adiene, 362 Syn periplanar geometry, 295, 295f Tertiary (3°) alcohols enantiomers, 164 -al, 776 Synthetic intermediate, 392 classifi cation as, 313 of monosaccharides, 1032–1036, -aldehyde, 777 Synthetic polymers, 560–562, conversion to alkyl halides with HX, 1034f -amide, 831–832, 833t 1148–1178 332–334, 337t nomenclature for alkenes, 363–364 -amine, 952–953 amorphous regions of, 1164–1165 dehydration by E1 mechanism, 326 number of, maximum, 175 -ane, 117, 120, 121, 127, 362 atatic, 1157–1158 hydrogen bonding extent, 318 physical properties of, 182–186, 184t, -ate, 692, 830–831, 833t “Big Six,” 1169, 1169t from reaction of esters and acid 186f -carbonyl chloride, 830, 833t biodegradable, 1170–1171 chlorides with organometallic starch and cellulose, 160–162 -carboxylic acid, 830 chain-growth, 1149, 1150–1157 reagents, 750–752 trans, 144–147 -dioic acid, 692 in consumer products, 1149, 1149f from reaction of ketones with Stereoselective reaction -diol, 315 crystalline regions of, 1164–1165 organometallic reagents, dissolving metal reduction of alkynes, -ene, 362 disposal of, 1169–1171 742–743 436 -enol, A–5 green synthesis of, 1166–1169, 1167f, Tertiary (3°) alkyl halides of E2 elimination reactions, 290 -enone, A–5 1168f acetylide anion reaction with, 414 Stereospecifi c reactions -enyne, A–5 isotactic, 1157–1158 classifi cation as, 229–230 carbene addition, 1013–1014 -ic acid, 691, 830, 831, 832 molecular weights of, 1150 E1 elimination reactions, 292, 294, coupling reactions with -ide, 231 nylon, 825, 859 302f organocuprates, 1004 -ine, 230–231 physical properties of, 1164–1166 E2 elimination reactions, 287, 288, defi nition of, 382 -o, 230 plasticizer addition to, 1165–1166 302f epoxidation, 440 -oic acid, 690, 831 polyesters, 859–860 example of, 229f

halogenation of alkenes, 382 -one, 777 recycling of, 1148, 1169–1170, 1169t SN1 substitution reactions, 255, 262, Heck reaction, 1009–1010 -onitrile, 832, 833t shorthand representation of, 1150, 262f, 302f Simmons–Smith reaction, 1015 -ose, 1029 1150f synthesis of, 332, 334–335 Suzuki reaction, 1006 -oxy, 316 step-growth, 1150, 1160–1164 Tertiary (3°) amides, 827, 831–832, 842, Steric effects, nucleophilicity and, 239 -oyl, 779 stereochemistry of, 1157–1159 844, 850 Steric hindrance, 239 -yl, 120, 316 structure of, 1149, 1164–1166 enolates formation from, 885–886 in alcohols, 318 -yl chloride, 833, 833t, 860 syndiotactic, 1157–1158 Tertiary (3°) amines in hydroboration reactions, 387 -ylic acid, 831 thermoplastics, 1165 from direct nucleophilic substitution, SN2 substitution reactions and, -yne, 401 thermosetting, 1165 960 248–249, 248f, 249t Sugar, simple, 104–105. See also Systematic name, 119. See also IUPAC IR spectra of, 955, 955f Steric strain, 135, 136t, 138, 239 Monosaccharides nomenclature nomenclature, 952–953 Steroids, 1138–1142 Sugars. See also Carbohydrates of amines, 952–953 reactions with acid chlorides and adrenal cortical, 1142 amino, 1061–1062 anhydrides, 975–976 anabolic, 1142 nonreducing, 1048, 1048f, 1058 2,4,5-T (2,4,5-trichlorophenoxyacetic from reduction of amides, 963 cholesterol. See Cholesterol reducing, 1048, 1048f, 1057 acid), 646f structure of, 950 sex hormones, 1141–1142, 1141t simple. See Monosaccharides Tacrine, 975 Tertiary carbon (3°), 116 structure of, 1138–1139, 1139f Sulfa drugs, 990–991 Tacrolimus. See FK506 Tertiary hydrogen (3°), 116–117 synthesis in Diels–Alder reaction, Sulfamethoxazole, 991f Tagamet. See Cimetidine Tertiary structure, of proteins, 1104–1105, 596–597 Sulfanilamide, 990–991 d-Tagatose, 1036f 1107f

smi75625_index_1218-1246.indd 1244 11/24/09 12:13:40 PM Index I-28

Testosterone, 1141t dehydration of alcohols to alkenes in, 1,2,4-Triethylcyclopentane, 127f Undecane, 114 Tetra- (prefi x), 123 325, 331f Trifl uoroacetic acid, for removal of Boc Unimolecular elimination. See E1 Tetrabutylammonium fl uoride, 749 p-Toluenesulfonyl chloride (TsCl), protecting group, 1096 elimination reactions Tetrachloromethane, 232 338–340, 340, 341f 2,2,2-Trifl uoroethanol, 65–66, 66f Unimolecular reaction Tetrafl uoroethylene, monomers in p-Toluidine Trifl uoromethanesulfonic acid, 710 in nucleophilic substitution reactions, polymerization, 562t basicity of, 970 Trigonal planar carbocation, 253–254, 244, 252 Tetrahalide, 409 electrostatic potential plot of, 971f 376 organic reactions, 217 Tetrahedral arrangement, 25–26, 26f Torsional energy, 133–134 Trigonal planar carbon radical, 539 Unknown Tetrahedral geometry, of acyclic alkanes, Torsional strain, 133–134, 136t, 137, 138 Trigonal planar double bond, 281 analysis using mass spectrometry, 114–115 Tosic acid, 710 Trigonal planar molecule, 24–25, 26, 26f 466–468 Tetrahedral oxygen, 314 Tosylate, 338–340, 341f carbonyl group, 722–723 using 1H NMR to identify an, 519–522 Tetrahedral stereogenic center, 164–165, Tosyl group, 338, 710 carboxy group, 689 α,β-Unsaturated carbonyl compounds, 166, 169, 178 TPA (thermal polyaspartate), 1171 Trigonal pyramidal molecule 755–758 Tetrahedrane, 138 Trade name, 119 amines, 950–951 1,2-addition to, 755–756 Tetrahydrocannabinol (THC) Trans diaxial geometry, 296–298, 296f Trihalomethanes, 1012 1,4-addition to, 755–756 mass spectrum of, 474, 474f Trans dihalide, 409 Trimethylamine, 956 in Michael reaction, 934–936, 935f structure of, 70 Trans fats, 433 electrostatic potential plot of, 951, resonance structures, 934 Tetrahydrofuran (THF), 317, 888, Trans geometry 951f in Robinson annulation, 936–939 889–890, 898 alkenes, 359, 360t, 363 Trimethyl borate, 1007 synthesis of complexed with borane, 386 cycloalkenes, 359 1,3,5-Trimethylcyclohexane, 156 in dehydration of aldol product, as solvent, 241f, 341 Trans isomers 2,5,5-Trimethylcyclohexane carboxylic 919–920, 922, 924f Tetrahydrogestrinone, 1142 of 2-butene, 282–283, 282f acid, 690 from α-halo carbonyl α-Tetralone, 653 of cycloalkanes, 144–147 2,5,5-Trimethylcyclohexanol, 315f compounds, 896 2,3,4,6-Tetra-O-methyl-d-galactose, defi nition of, 144, 282, 377 2,3,5-Trimethyl-2-hexene, 362 Unsaturated fatty acid. See Fatty acids, 1073 of disubstituted cycloalkanes, 180 1,3,6-Tri-O-methyl-d-fructose, 1073 unsaturated Tetramethyl α-d-glucopyranose, 1048f Transition state 2,3,4-Tri-O-methyl-d-glucose, 1073 Unsaturation, degrees of Tetramethylsilane (TMS), 497, 523 defi nition of, 210–211 2,2,4-Trimethylpentane, combustion of, in alkenes, 431–432 Tetravalent carbon, 4, 25, 27 drawing structure of, 211 148 benzene, 608 Tetrodotoxin, synthesis of, 589, 589f of E1 elimination reactions, 292, 2,3,5-Trimethyl-4-propylheptane, 123f calculation of, 360–361, 431–432 Thalidomide, 169 292f Triols, 315 hydrogenation data and, 431–432 THC. See Tetrahydrocannabinol (THC) of E2 elimination reactions, 285–286, Tripeptide, 1086–1088 in triacylglycerols, 432 Thermodynamic enolates, 890–891, 899 286f, 287, 289, 295 Triphenylene, 640 Uracil, 1063–1064, 1065f Thermodynamic product, in electrophilic in energy diagrams, 210–215, 215f Triphenylphosphine, 793, 1005 Urethanes, 1162, 1175 addition reactions of conjugated four-centered, 386 Triphenylphosphine oxide, 792, 794 Urushiols, 707 dienes, 586–588, 587f, 588f in halogenation reactions, 546–548, Triple bonds Thermodynamics, 206–209, 207f, 208t 547f, 548f in alkynes, 83, 84t, 400–401 Valdecoxib, 1132 of hydrate formation, 802–803 Hammond postulate and, 258–261, bond length and bond strength, 41, Valence bond theory, 627 Thermoplastics, 1165 259f, 260f, 546–547 41t Valence electrons, 10–16, 17t, 32 Thermosetting polymers, 1165 SN1 substitution reactions, 264 components of carbon–carbon, 39 Valence shell electron pair repulsion THF. See Tetrahydrofuran (THF) SN2 substitution reactions, 264 as functional group, 83, 84t (VSEPR) theory, 24 Thiazolinone, 1091–1092, 1118 in two-step reactions, 213–215, 215f Lewis structure, 15 Valeric acid, structure of, 691t Thioester, 860–861 Trans protons, 516, 517f NMR spectra of, 505, 506f, 506t Valine Thiol (functional group), 85t Tri- (prefi x), 123 reduction of, 434–437, 437f isoelectric point for, 1078t Thionyl chloride Triacylglycerols, 1122–1125 Triple helix, of collagen, 1108–1109, pKa values for, 1078t conversion of alcohols to alkyl halides combustion of, 1125 1109f structure of, 1076f with, 335–336 common fatty acids in, 1122t Triplet, NMR spectrum, 509, 510, 511t, Valinomycin, 101 conversion of carboxylic acids to acid degrees of unsaturation in, 432 512, 512t, 515f, 518 Valium. See Diazepam chlorides, 846–847, 846f energy storage in, 1125 Tri(o-tolyl)phosphine, 1005 Valproic acid, 78, 910 Three-dimensional representation, of fats and oils, 369 Triynes, 401 Vancomycin, 111 acyclic alkanes, 114–115 formation of, 105 Tropylium cation, 625–626 van der Waals forces, 87–89, 88f, 90t Threonine, 719 hydrogenation of, 432–434, 433f, Truvia. See Rebaudioside A in alkanes, 129 isoelectric point for, 1078t 1124 Trypsin, 1093, 1093t surface area and, 88, 88f pKa values for, 1078t hydrolysis of, 367, 853, 854–855, Tryptophan, 720 Vane, John, 697 structure of, 1076f, 1077 1124 isoelectric point for, 1078t Vanillin, 30, 529, 783f Threose, 190 melting point of, 1122–1123 pKa values for, 1078t Vanilloids, 4 d-threose, 1034, 1034f, 1035f mixed, 1122 structure of, 1076f Varenicline, 995 l-threose, 1034, 1034f olestra as a substitute for, 854 TsCl (p-Toluenesulfonyl chloride), Vasopressin, 1089, 1090f, 1105 Thrombin, 1075 oxidation of, 556, 556f, 1124 338–340, 341f Vasotec. See Enalapril Thromboxanes, 1129–1130, 1130t, physical properties of, 369 TsOH. See p-Toluenesulfonic acid Vegetable oil, 835, 854, 855 1131f saponifi cation of, 854–855 (TsOH) partial hydrogenation of, 432–433, Thymine, 1063–1064, 1065f saturated, 853, 853f, 1122–1123, Tuberculosis, 250 433f Thymol, 529, 638 1122t, 1123f Tulipalin A, 946 Venlafaxine, 748, 773 Tiotropium bromide, 321 simple, 1122 Tungsten, 1015 Ventolin. See Albuterol Titanium(IV) isopropoxide, 452 structure of, 366–367, 853, 853f, ar-Turmerone, 926 β-Vetivone, 913, 915, 943 Toads (Bufo), 958 1120f, 1122–1123, 1122t, 1123f, Twistofl ex, 614–615 Viagra. See Sildenafi l Tobacco, 614f 1128f Two-step reaction mechanism, 213–215, Vibration of bonds, infrared spectroscopy Tobramycin, 1062 unsaturated, 1122–1123, 1122t, 1123f, 215f, 217 and, 476–477, 478–480 Tollens reagent, 738, 1048 1124 TXA2, 1130f Vicinal dibromide, 404, 405 Toluene, 108 Trialkylborane, 387, 387f Tylenol. See Acetaminophen Vicinal dihalides, 299, 379 in BTX mixture, 614 Triarylphosphine, 1009 Tyrian purple, 988 alkyne synthesis from, 404–405 electrophilic aromatic substitution 1,3,5-Tribromobenzene, synthesis of, Tyrosine Vinegar, 695 reaction, 657, 662 984, 984f isoelectric point for, 1078t Vinyl acetate oxidation to benzoic acid, 671 Tributyltin hydride, 570 pKa values for, 1078t NMR spectrum of, 517f structure of, 611 Trichlorofl uoromethane, 3, 233, 551 structure of, 1076f polymerization of, 1152, 1155f synthesis by Friedel–Crafts alkylation, Trichloromethane, 232 Tyvek, 1170 structure of, 1151f 675 2,4,5-Trichlorophenoxyacetic acid Vinylboranes, 1007, 1009 Toluene 2,6-diisocyanate, 1162 herbicide (2,4,5-T), 646f Ultraviolet light trans vinylborane, 1006–1007 p-Toluenensulfonate. See Tosylate Tricyclohexylphosphine, 1005 absorption by conjugated dienes, Vinyl bromide, 1009 p-Toluenesulfonic acid (TsOH), 70, Trienes, 362 597–599, 598f Vinyl carbanion, 436 709–710, 804 Triethylamine, 71, 277, 952, 1009 skin damage from, 599 Vinyl carbocation, 407, 408

smi75625_index_1218-1246.indd 1245 11/24/09 12:13:40 PM I-29 Index

Vinyl chloride Vitamin C (ascorbic acid), 80, 81, 568 hybrid orbitals in, 35, 35f Xalatan. See Latanoprost bond strength, 51 solubility of, 98 hydration of alkynes, 406f, 409–412 X-ray crystallography, 1053 monomers in polymerization, 562t sources of, 98 hydrogen bonding, 89 m-Xylene, 667 polymerization of, 1149, 1156 structure of, 98, 836 as Lewis base, 73 p-Xylene, 614 structure of, 1149, 1151f Vitamin D3, 581 Markovnikov addition of, 410 d-Xylose, 1034, 1035f 1-Vinylcyclohexene, 365 defi ciency, 1129f molecular shape of, 26, 26f d-Xylulose, 1036f Vinyl group, 365 role in the body, 1129f nucleophilicity of, 73, 263 Vinyl halides, 229, 229f, 267 sources of, 1128 pKa of, 59t, 62, 63 -yl (suffi x), 120, 316, 779 coupling reactions with structure of, 282, 1129f as polar molecule, 44 -yl chloride (suffi x), 833, 833t, 860 alkenes, 1009–1011 Vitamin E, 109 removing from reaction mixture using -ylic acid (suffi x), 831 organoboranes, 1006–1007 as antioxidant, 557 Dean–Stark trap, 804, 805f Ylide, 793 organocuprates, 1003–1004 defi ciency, 1129f as solvent, 94–96, 240, 240f, 264 -yne (suffi x), 401 reactivity of, 650 electrostatic potential plot of, 1128, in extraction procedure, 707, 708f synthesis in hydrohalogenation of 1129f Wavelength Zaitsev rule, 288–291, 293, 297, 980 alkynes, 406–407 as radical scavenger, 541 defi nition of, 474 Z confi guration, of double bonds, 368 Vinylidene chloride, polymerization of, role in the body, 1129f electromagnetic spectrum and, Zidovudine. See AZT 1156 sources of, 1128 474–476, 475f (azidodeoxythymidine) Vinyl iodide, 1010–1011 structure of, 557, 1129f length units for, 474 Ziegler, Karl, 1158 Vioxx. See Rofecoxib Vitamin K (phylloquinone), 98 Wavenumber, 476 Ziegler–Natta catalysts, 1157–1158, 1160 Viracept. See Nelfi navir defi ciency, 1129f Waxes, 150, 150f, 1121 Zigzag skeletal structures, 137 Vitamin(s), 97–98 role in the body, 1129f Wedges, in Fischer projection formula, Zileuton, 348 defi nition of, 97, 1128 sources of, 1128 1032 Zinc fat-soluble, 97, 149, 1128, 1129f structure of, 1129f Wellbutrin. See Bupropion in Clemmensen reduction, 672–673 origin of term, 97 VSEPR (valence shell electron pair Williamson ether synthesis, 322 conversion of ozonide to carbonyl water-soluble, 97–98 repulsion) theory, 24 Willow tree, 71 compounds, 445 Vitamin A, 97–98, 331f Vulcanization, 1159, 1159f Wittig, Georg, 792 Zinc chloride, 333 β-carotene conversion to, 97–98 Wittig reaction Zinc–copper couple, 1014–1015 defi ciency, 97, 1129f Wald, George, 799 mechanism of, 794 Zingerone, 50 electrostatic potential plot of, 1128, Walden, Dr. Paul, 246 retrosynthetic analysis using, 795–796 Zingiberene, 367f, 459, 601, 1133f 1129f Walden inversion, 246 Wittig reagent, 792–797 Z isomer, 364 role in the body, 1129f Wang resin, 1118 Wohl degradation, 1049, 1050 Zocor. See Simvastatin solubility, 97 Water Wolff–Kishner reduction, 672 Zoloft. See Sertraline sources, 1128, 1129f as achiral molecule, 164 Wood alcohol, 319f. See also Methanol Zuclomiphene, 394 structure, 97, 282, 1129f, 1134 electrophilic addition of, 378–379, Wool Zwitterion, 80, 711–712, 1077 Vitamin B3, 98 390 binding of dyes to, 989–990 Zyban. See Bupropion Vitamin B6, 109 electrostatic potential plot for, 45f structure of, 858, 858f Zyfl o. See Zileuton

smi75625_index_1218-1246.indd 1246 11/24/09 12:13:40 PM Common Abbreviations, Arrows, and Symbols

Abbreviations

Ac acetyl, CH3CO– BBN 9-borabicyclo[3.3.1]nonane BINAP 2,2©-bis(diphenylphosphino)-1,1©-binaphthyl Boc tert-butoxycarbonyl, (CH3)3COCO– bp boiling point Bu butyl, CH3CH2CH2CH2– CBS reagent Corey±Bakshi±Shibata reagent DBN 1,5-diazabicyclo[4.3.0]non-5-ene DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCC dicyclohexylcarbodiimide DET diethyl tartrate DIBAL-H diisobutylaluminum hydride, [(CH3)2CHCH2]2AlH DMF dimethylformamide, HCON(CH3)2 DMSO dimethyl sulfoxide, (CH3)2S – O ee enantiomeric excess Et ethyl, CH3CH2– Fmoc 9-¯ uorenylmethoxycarbonyl HMPA hexamethylphosphoramide, [(CH3)2N]3P – O HOMO highest occupied molecular orbital IR infrared LDA lithium diisopropylamide, LiN[CH(CH3)2]2 LUMO lowest unoccupied molecular orbital m- meta mCPBA m-chloroperoxybenzoic acid Me methyl, CH3– MO molecular orbital mp melting point MS mass spectrometry MW molecular weight NBS N-bromosuccinimide NMO N-methylmorpholine N-oxide NMR nuclear magnetic resonance o- ortho p- para PCC pyridinium chlorochromate Ph phenyl, C6H5– ppm parts per million Pr propyl, CH3CH2CH2– RCM ring-closing metathesis ROMP ring-opening metathesis polymerization TBDMS tert-butyldimethylsilyl THF tetrahydrofuran TMS tetramethylsilane, (CH3)4Si Ts tosyl, p-toluenesulfonyl, CH3C6H4SO2– TsOH p-toluenesulfonic acid, CH3C6H4SO3H UV ultraviolet

smi75625_endppBACK.indd 2 12/2/09 10:13:14 AM Arrows reaction arrow equilibrium arrows double-headed arrow, used between resonance structures full-headed curved arrow, showing the movement of an electron pair half-headed curved arrow (® shhook), showing the movement of an electron retrosynthetic arrow no reaction

Symbols dipole hν light ∆ heat δ+ partial positive charge δ± partial negative charge λ wavelength ν frequency ~ν wavenumber HA Brùnsted±Lowry acid B: Brùnsted±Lowry base :Nu± nucleophile E+ electrophile X halogen bond oriented forward bond oriented behind partial bond [ ]³ transition state [O] oxidation [H] reduction

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