Organic Chemistry

Home , Acyl halide, Cannizzaro reaction, Cycloaddition, Electrophilic addition, Geminal, Haloform reaction

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Reaction Mechanisms Pocket-Book

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● The key to building intuition is to develop the habit ALKANES of asking how each particular mechanism reﬂects Thermal Cracking - Pyrolysis ...... 1 general principles. Look for the concepts behind Combustion ...... 1 the chemistry to make organic chemistry more co- Free Radical Halogenation...... 2 herent and rewarding. ALKENES Electrophilic Addition of HX to Alkenes ...... 3 ● Acid Catalyzed Hydration of Alkenes ...... 4 Exothermic reactions tend to follow pathways Electrophilic Addition of Halogens to Alkenes ...... 5 where like charges can separate or where un- Halohydrin Formation ...... 6 like charges can come together. When reading Free Radical Addition of HX to Alkenes ...... 7 organic chemistry mechanisms, keep the elec- Catalytic Hydrogenation of Alkenes...... 8 tronegativities of the elements and their valence Oxidation of Alkenes to Vicinal Diols...... 9 electron conﬁgurations always in your mind. Try Oxidative Cleavage of Alkenes ...... 10 to nterpret electron movement in terms of energy Ozonolysis of Alkenes ...... 10 Allylic Halogenation ...... 11 to make the reactions easier to understand and Oxymercuration-Demercuration ...... 13 remember. Hydroboration of Alkenes ...... 14

ALKYNES ● For MCAT preparation, pay special attention to Electrophilic Addition of HX to Alkynes ...... 15 Hydration of Alkynes...... 15 reactions where the product hinges on regio- Free Radical Addition of HX to Alkynes ...... 16 and stereo-selectivity and reactions involving Electrophilic Halogenation of Alkynes...... 16 resonant intermediates, which are special favor- Hydroboration of Alkynes ...... 17 ites of the test-writers. Catalytic Hydrogenation of Alkynes...... 17 Reduction of Alkynes with Alkali Metal/Ammonia . . 18 Formation and Use of Acetylide Anion Nucleophiles . 19 Coupling of Alkyl Halides with Gilman Reagents . . . 20

ALYL HALIDES ALDEHYDES AND KETONES SN2 Mechanism with Alkyl Halides ...... 21 Reduction of Ketones and Aldehydes ...... 57 SN1 Mechanism with Alkyl Halides ...... 22 Reduction of Aryl Alkyl Ketones ...... 58 E2 Mechanism with Alkyl Halides ...... 23 Oxidation of Aldehydes and Ketones ...... 59 E1 Mechanism with Alkyl Halides ...... 24 Reaction with Grignard Reagents...... 60 The Wittig Reaction...... 61 ALLYLIC AND CONJUGATED STRUCTURES Acetal Formation...... 63 SN1 Mechanism with Allylic Cation Intermediate. . . 25 The Wolff-Kishner Reaction ...... 65 1,2 and 1,4 Addition to Conjugated Diene ...... 27 Reductive Amination ...... 67 Diels-Alder Reaction ...... 29 The Cannizzaro Reaction ...... 69 Acid or Base Catalyzed Enolization ...... 71 AROMATIC COMPOUNDS Alpha Halogenation ...... 73 Electrophilic Aromatic Substitution with Halogen . . 31 Haloform Reaction of Methyl Ketones...... 75 Electrophilic Aromatic Substitution - Nitration. . . . . 33 Aldol Condensation...... 77 Electrophilic Aromatic Substitution - Sulfonation . . 35 Claisen Condensation ...... 79 Friedel-Crafts Alkylation ...... 37 Conjugate Nucleophilic Addition ...... 81 Friedel-Crafts Acylation ...... 39 Conjugate Addition of Gilman Reagents ...... 83 Alkylbenzene Oxidation ...... 43 Alkylbenzene Halogenation ...... 44 CARBOXYLIC ACIDS AND DERIVATIVES Nucleophilic Aromatic Substitution ...... 41 Acid Halide Formation ...... 85 Fischer Esterification ...... 86 ALCOHOLS AND ETHERS Use of Carboxylate Anion Nucleophile to form Esters . 87 Dehydration of Alcohols ...... 45 Hydrolysis of Acid Halides ...... 88 Reaction of Alcohols with HX – Dehydrohalogenation. . 47 Reaction of Acyl Halide with Ammonia or Amine. . . 89 Reaction of Alcohols with Thionyl Chloride ...... 48 Esterification of Acid Halides ...... 90 Reaction of Alcohols with Phosphorus Tribromide. . . 49 Esterification of Acid Anhydrides ...... 91 Oxidation of Alcohols ...... 50 Saponification of Esters ...... 92 Alkoxide Ion Formation from Alcohols ...... 50 Nitrile Hydrolysis...... 93 Reaction of Alcohols to form Ethers...... 51 Nitrile Reduction ...... 94 Williamson Ether Synthesis ...... 52 Hofmann Rearrangement ...... 95 Acid Cleavage of Ethers ...... 53 Epoxidation of Halohydrins ...... 54 Acid Epoxide Ring Opening ...... 55 Thermal Cracking - Pyrolysis Alkanes

heat CH3(CH2)xCH3 CH3CH3 + CH4 + H2CCH2 + etc High carbon number Lower carbon number petroleum distillate cleavage product mixture

A process carried out on petroleum distillates at high temperature and pressure, thermal cracking yields lower carbon number product, probably by means of a radical (homeolytic) mechanism. The thermodynamics are dominated by the entropy change rather than the enthalpy change, especially if the volume is kept constant.

Combustion Alkanes

CnH2n + 2 + (3n + 1)/2 O2 nCO2 + (n + 1) H2O Hydrocarbon Oxygen Carbon dioxide Water

Many organic molecules can undergo combustion, forming carbon dioxide and water in an exothermic reaction. The heat released in the combustion reaction (the enthalpy change) can be used as an indicator of the relative stability of isomers. Combustion is more exothermic for unbranched alkanes, for example, than for their branched isomers, and we can infer that the branched isomer is the more stable. Such comparisons are often used in organic chemistry. For example, ketones are pointed out as more stable than their aldehyde isomers. The more stable the isomer, the lower the heat of combustion.

Free Radical Halogenation Alkanes

RCH3 + X2 RCH2X + HX Alkane Halogen Alkyl halide Hydrogen halide

hv Initiation X2 2 X. Halogen Halide radical

Propagation X. + RCH3 RCH2. + HX Halide radical Alkane Alkyl radical

X2 + RCH2. RCH2X + X. Halogen Alkyl radical Alkyl halide Halide radical

Termination X. + RCH2. RCH2X

X. + X. X2

RCH2. + RCH2. RCH2CH2R

Because of the relative stability of alkyl radical intermediates, selectivity in free radical halogenation favors tertiary over secondary over primary carbon radicals. Bromination, though, is more selective than chlorination, because the proton extraction step is more endothermic in bromination than chlorination. This follows from Hammond’s postulate, which governs the correlation between proximity in energy and proximity in structure among transition states and intermediates. Halogenation is the classic illustration of Hammond’s postulate. Because the activated complex prior to formation of the alkyl radical intermediate must have more radical character for bromination compared to chlorination, the effect of substitution in stabilizing radicals plays a greater roll with bromination leading to a higher degree of regioselectivity.

2 Electrophilic Addition of HX to Alkenes Alkenes

X H R R H + HX CC H CC H Hydrogen H Alkene halide H H Alkyl halide

δ- H Br R H δ+ CC + HBr R H H H H CC H Hydrogen Alkene halide

H Br H + R R + - H CC Br CC H H Carbocation H H H Intermediate Alkyl halide

Because tertiary and secondary carbocations are more stable than primary carbocations, Markovnikov addition is observed in the electrophilic addition of HX to alkenes, so the product formed is the one with the halogen substituent upon the more highly substituted carbon. Also, rearrangement (hydride or methyl shift to form a more stable carbocation) might occur, typical of reactions that have a carbocation intermediate. Remember that electrophilic addition will not be observed in the presence of peroxides. Peroxides initiate anti-Markovnikov addition via free-radical addition. An interesting fact about electrophilic addition of HX to alkenes, is that the more acidic the hydrogen halide, the more electrophilic it will be. HF, for example, only a weak acid, does not react.

Acid Catalyzed Hydration of Alkenes Alkenes

H O H R H H 0, H+ R CC 2 CC H H Aqueous Alkene H Sulfuric acid H H Alcohol

H δ+ H O H H + H H 0, H+ δ+ R R H 2 R H CC + O H CC H CC H H H H H Carbocation H Alkene intermediate

H H H O + H O H R R CC CC + H+ H H H H H H Oxonium ion Alcohol

Markovnikov’s rule is followed in hydration of alkenes. Therefore, in the alcohol product, the hydroxyl group is located upon the more highly substituted carbon. Watch for rearrangement of the carbocation intermediate, if methyl or hydride shift is probable. Note that this reaction is the reverse of acid catalyzed dehydration of alcohols.

4 Electrophilic Addition of Halogens to Alkenes Alkenes

X H R R H + X CC H CC H 2 H Alkene Halogen molecule H X Vicinal dihalide

δ- Br Br Br + R + - R H δ CC + Br CC + Br2 R H H H H H CC H H H Alkene + δ+ Br Br Br H - R CC + Br CC CC R H R H Br H H H H H H Cyclic halonium Br δ- Vicinal dihalide ion intermediate

In analysis of the addition of halogen to an alkene, the anti stereospeciﬁcity of the dihalide product serves as evidence that the mechanism occurs via a cyclic halonium ion intermediate. For problem solving, this anti stereospeciﬁcity is especially pertinent in the cases of addition to cyclic alkenes or where the product carbons are chiral.

Halohydrin Formation Alkenes

H X X R R H 2 CC + HX CC H H H H2O Alkene Halogen in OH H aqueous conditions Halohydrin

δ- Br Br Br + R + - R H δ CC + Br CC + Br2 R H H H H H CC H H Halogen H Alkene + + H Br Br Br Br- R - CC CC + Br CC H R H R H + O H H H H H HH Cyclic halonium O HH ion intermediate Br-

H Br R H Br CC R H CC + HBr + O H H OH H HH Halohydrin Br-

In aqueous solution, electrophilic addition of halogen results in the formation of halohydrin. Water performs the ring opening instead of halide ion, which opens the ring in non aqueous halogenation. Water addition is preferential for the more highly substituted carbon, which receives a bit more of the distributed positive charge in the halonium ion than the other carbon.

6 Free Radical Addition of HX to Alkenes Alkenes

H R Hydrogen halide Br H hv + R + HBr C C Br H C C H peroxide H Halide radical Alkene aqueous conditions are H H sufﬁcient to supply peroxide Alkyl halide

hv R O OR 2R O Peroxide Alkoxy radical initiator

Alkoxy RO + HBr ROH + Br Halide radical Hydrogen radical halide H Br H R R Br + C C C C Halide H H H Alkyl radical Alkene H radical

H H R Br Br R + Br C C H + HBr C C Halide Alkyl H radical radical H Hydrogen halide H H Alkyl halide

In the presence of a peroxide initiator, hydrogen halide adds to alkene via an anti-Markovnikov, free-radical mechanism. The carbanion radical product of the ﬁrst propagation step will be more stable if the carbon with the lone electron, the radical carbon, is highly substituted. For this reason, the halogen atom binds to the less substituted carbon, in other words, anti-Markovnikov addition.

Catalytic Hydrogenation of Alkenes Alkenes

catalyst RCH CH2 + HH RCH2CH3 Alkene Hydrogen Alkane

H H R H H H CC H C H H R C H H H H R H catalyst catalyst catalyst + CC HH

Hydrogenation of alkenes occurs in the presence of a metal catalyst, a syn addition process. The two hydrogen atoms add to the same face of the double bond. Furthermore, if one side is more hindered than the other, addition is stereoselective for the less hindered side. Hydrogenation is exothermic, and relative heats of hydrogenation can be used to infer the relative stability of double bonds in different contexts. The more stable the double bond, the lower the heat of hydrogenation will be.

8 Oxidation of Alkenes to Vicinal Diols Alkenes

- O O Mn OH OH Potassium permanganate KMnO H O R H in basic solution 4 O O 2 CC R H CC HH HH Vicinal diol Cyclic manganate R H or osmate intermediate H CC H Alkene O O Os OH OH Osmium tetroxide OsO4 NaHSO3 R H O O CC R H H2O CC HH Vicinal diol H H

Both of the above oxidation mechanisms proceed by syn addition. To accomplish anti hydroxylation of alkenes, the method to employ is hydrolysis of epoxides. As shown above, in basic conditions, oxidation of alkene with potassium permanganate results in formation of vicinal diol, but with acidic or neutral conditions, complete cleavage occurs to produce carboxylic acids or ketones (or carbon dioxide).

Oxidative Cleavage of Alkenes Alkenes

O R H KMnO4 + CO H CC H RC OH 2 H2O Alkene Potassium Carboxylic acids 2 permanganate (CO from terminal alkene carbon) in acid or neutral solution In basic conditions, treatment of alkene with potassium permanganate forms a vicinal diol. Oxidative cleavage by permanganate in neutral or acidic conditions, however, leads to cleavage to form carbonyl compounds by means of the same cyclic manganate ester intermediate. Where ozonolysis, another method of oxidative cleavage of alkenes, produces an aldehyde or formaldehyde, cleavage with permanganate produces a carboxylic acid or carbon dioxide respectively.

Ozonolysis of Alkenes O Alkenes OO R H O3 R H CC H H CH2Cl2 CC Alkene Molozonide Ozone HH

O O R O O H Zn CC + H H CH3COOH RC H HC H O Reducing Aldehyde mixture Ozonide agent If aldehyde product is desired over carboxylic acid, ozonolysis is preferred in cleavage of alkenes over potassium permanganate cleavage. Also, with terminal alkenes, the end carbon leads to formaldehyde molecule. Cleavage of such alkenes by potassium permanganate forms carbon dioxide.

10 Allylic Halogenation Alkenes

Br H H H C H C H Br2 H C H 3 C H 3 CC 3 CC or H CC H C hv H C H H Alkene H H H Halogen Br Allyl halide mixture

hv Br2 2 Br Halide radical Halogen

H H H3C H H3C H CC H CC + Br H C C H Alkene H H Halide radical Br H

H C H3C H H 3 C H Resonance stabilized allylic H CC C H CC H H H radical

Br H Br Br H Br2 H3C H3C H C H H H3C H3C H C H CC3 CC H CCC H or H CC H H C C H H CCC H H H H hv H HH HBr Br Br continued Br H 11 H C H H3C C H 3 CC or H CC + Br H C H H H hv Br Br2 2 Br

H H H3C H H3C H CC H CC C + Br H C H H H Br H

H C H3C H H 3 C H H CC C H CC H H H

Br Br H C H3C H H 3 C H H CC C H CC H H H

Br Br

Br H H C H H3C C H 3 CC or H CC + Br H C H H H Br Allyl halide mixture

At high temperatures chlorine and bromine react with alkenes larger than ethylene by free-radical substitution. (At low temperatures, electrophilic addition to produce vicinal dihalides occurs). Halogenation is selective for two particular carbons due to the resonance stabilization that can occur with an allylic radical intermediate.

12 Oxymercuration-Demercuration Alkenes

OH H R H 1. Hg(OAc)2 in THF, H2O R CC CC Alcohol H H 2. NaBH , OH- Alkene 4 H H H

O 3 CH OC 3 Hg CH H H OC R CC H + Hg(O2CCH3)2 H H O Mercuric R CC H Alkene acetate

O HH O O O H H + HgOCCH3 O O HgOCCH3 + HgOCCH3 H - + R R CC + OCCH H CC H 3 R CC H Mercuric acetate H H H H H carbocation Intermediate Oxonium Intermediate O - O O H3COC H H H H HgOCCH H HgOCCH O 3 O - O O + 3 R NaBH4, OH R R CC + CC CC H HOCCH3 H H H H H H H H Hydroxyalkyl mercuric acetate Alcohol

Oxymercuration-demercuration is usually preferred over acidic hydration to form Markovnikov alcohols from alkenes. The reaction begins with electrophilic approach onto the alkene by mercuric acetate to form a mercuric acetate carbocation derivative, which can rearrange. Hydration then occurs followed by a demercuration step with sodium borohydride.

Hydroboration of Alkenes Alkenes

H OH - H H H BH3 OH CC CC R H THF H2O2 H Alkene R H Alcohol

H δ- H H H B H H B H BH H -OH H 3 H H CC R CC H R CC H H THF δ+ H2O2 Alkene R H Alkylborane

H OH -OH H CC H2O2 H R H Alcohol

Hydroboration-oxidation of an alkene forms an alcohol by means of a mechanism leading to anti-Markovnikov regioselectivity. Furthermore, the geometry of the activated complex produces a syn addition product. Note as a point of general interest that borane derives its electrophilicity from a vacant p orbital.

14 Electrophilic Addition of HX to Alkynes Alkynes

X H X H HX HX R CCH R CCH R CCH no peroxides no peroxides Alkyne Vinyl Hydrogen halide Hydrogen X H halide halide Geminal dihalide

Electrophilic addition to alkynes is very similar to the analogous reactions upon alkenes, although two additions occur. Markovnikov addition is observed. Due to the greater instability of vinylic carbocations, however, alkynes are somewhat less reactive than alkenes.

Hydration of Alkynes Alkynes

OH H O H H2O, H2SO4 R CCH R CCH R CCH HgSO4 Alkyne Enol Ketone Aqueous sulfuric acid H with mercuric sulfate catalyst

The vinylic alcohol, or enol, intermediate forms when an alkyne is hydrated which immediately rearranges to form a ketone. This process of rearrangement is called keto-enol tautomerism. Due to decreased reactivity of alkynes for electrophilic addition compared to alkenes, acid catalyzed hydration of alkynes requires a mercuric sulfate catalyst.

Free Radical Addition of HX to Alkynes Alkynes

H X H X HX HX R CCH R CCH R CCH peroxides peroxides Alkyne Vinyl Hydrogen halide Hydrogen halide halide H X with peroxides with peroxides Geminal dihalide

As with alkenes, free radical addition occurs when hydrogen halide reacts with alkynes in the presence of peroxides. Two anti-Markovnikov additions occur leading to a geminal dihalide product.

Electrophilic Halogenation of Alkynes Alkynes

X R' X2 R X X2 X R CC R' CC ' CC CCl X R CCl X Alkyne 4 4 Vicinal vinylic R X Halogen dihalide molecule Tetrahaloalkane

Bromine and chlorine add with trans stereochemistry to an alkyne. The process may be concluded at the trans vinylic dihalide, or if excess halogen is employed, addition can be made to occur a second time.

16 Hydroboration of Alkynes Alkynes

H OH H O BH -OH R CCH 3 R CCH R CCH THF H2O2 Alkyne Alkyne Borane in tetrahydrofuran solution H Aldehyde followed by aqueous hydrogen peroxide in basic solution

Due to its anti-Markovnikov selectivity, hydroboration-oxidation of a terminal alkyne leads to an enol which rearranges to form a terminal aldehyde. The alternative method, hydration (either acidic hydration or oxymercuration-demercuration) applied to such an alkyne would result in a ketone.

Catalytic Hydrogenation of Alkynes Alkynes

catalyst RC CR' + HH R R' H CC H Alkyne Hydrogen Cis alkene

R' H R CC R' C H H R C H

+ R R' catalyst catalyst catalyst H CC H

Catalytic hydrogenation occurs by syn addition resulting in the formation of a cis alkene. Metal-ammonia reduction, an alternative hydrogenation method, yields trans alkenes.

Reduction of Alkynes with Alkali Metal/Ammonia Alkynes

1. Na, NH3 R H R CC R' CC 2. H O H R' Alkyne 2 Sodium or Lithium Trans alkene in Ammonia

R - + R CC R' + Na CC + Na R' Alkyne Sodium Alkenyl anion Sodium ion radical

R - R H - CC + H NH CC + NH R' 2 R' 2 Alkenyl anion Ammonia Alkenyl radical Amide ion radical

R H R H + CC + Na CC + Na R' - R' Alkenyl radical Sodium Alkenyl anion Sodium ion

R H R H - CC H NH CC + NH2 - R' 2 H R' Alkenyl anion Ammonia Trans alkene Amide ion

Of two alternative means of carrying out the hydrogenation of an alkyne, catalytic hydrogenation yields a cis alkene, while metal-ammonium reduction yields a trans alkene. The latter occurs due to the trans stereochemistry of the alkenyl anion radical intermediate in metal/ammonia reduction..

18 Formation and Use of Acetylide Anion Nucleophiles Alkynes

H H CH CH + CH CH NH2Na 2 3 R CC H 3 2 CBr R CC C Sodium amide Alkyne Alkylated alkyne H H Primary alkyl halide

- + - + R CC H + NH2Na R CC Na + NH3 Alkyne Sodium amide Acetylide anion Ammonia

+ H H Na - CH3CH2 CH2CH3 R CC CBr R CC C + NaBr Acetylide anion H H Alkylated alkyne Primary alkyl halide

An acetylide anion is formed by reaction of a terminal alkyne with sodium amide, which is a very strong base. The acetylide anion can then perform nucleophilic substitution upon methyl and primary alkyl halides. (Being a strong base, acetylide anion would react by elimination with secondary and tertiary alkyl halides, rather than by nucleophilic substitution).

Coupling of Alkyl Halides with Gilman Reagents Alkyl Halides

H CH H CH 3 R 3 CH CH - + CH3CH2 3 2 CC + CC Br Cu Li R H3C CH3 R Gilman reagent H3C CH3 Alkyl halide (Lithium dialkylcuprate) Alkyl substituted product

RX + 2 Li RLi + LiBr Formation of Gilman reagent R - + (Lithium dialkylcuprate) 2 RLi + CuI Cu Li + LiI R R - H CH3 Cu H CH3 R CH3CH2 CH CH - + CC R + 3 2 CC + Br Li Br Cu Li H3C CH3 H3C CH3 R Gilman reagent Alkyl halide Mechanism isn’t fully understood H CH3 CH CH 3 2 CC R H3C CH3 Alkyl substituted product

Lithium dialkylcuprates react with alkyl halides via a substitution mechanism which is not well understood. It appears that nucleophilic attack by the negatively charged copper atom leads to an intermediate which fragments to produce the alkane product. Reactions such as this which form new carbon-carbon bonds are extremely useful in organic synthesis.

20 SN2 Mechanism with Alkyl Halides Alkyl Halides

H - H H3C Nu C Br Nu C CH3 H H Alkyl halide Substitution product

H - H H H3C Nu H3C C Br - C Br Nu C Nu CH3 H H H

Nucleophilic bimolecular substitution (SN2) occurs mainly with primary and sometimes secondary alkyl halides. Be- cause of the geometry of the bimolecular mechanism, the reaction always takes place with inversion of conﬁguration. A polar aprotic solvent like DMSO is used, because a protic solvent like water will over-stabilize the nucleophile through solvation and promote E1 elimination instead, or the SN1 mechanism. Both E2 and SN2 prefer polar aprotic solvents. With primary alkyl halides, however, regardless of solvent, the SN2 mechanism almost always predominates. This occurs even if the nucleophile is a strong Bronsted base. With primary alkyl halides, only strong, bulky (hindered) base like tert-butoxide can cause elimination (E2) to occur rather than SN2 substitution. The SN2 mechanism is more difﬁcult to achieve with secondary alkyl halides than with primary. Instead of substitution, strong bases react by elimination (E2) with secondary alkyl halides. SN2 substitution is possible with secondary alkyl halides if the solvent is polar and aprotic and the nucleophile is a weak base, like cyanide ion or alcohol. SN2 substitution does not occur with tertiary alkyl halides, which are too hindered for nucleophilic attack, and it does not occur with vinylic or aryl halides.

SN1 Mechanism with Alkyl Halides Alkyl Halides

H C 3 - H3C H3C Nu H C C Br 3 C Nu

H3C Alkyl halide H3C Substitution product

H3C H3C - H C + H3C Nu 3 CH3 C Br C Br H3C C CH3 H C H3C Alkyl halide 3 Carbocation intermediate

H C - + 3 CH3 H3C Nu H3C C C Nu CH3 H3C attack from either side Attack from either side Substitution product

With secondary and tertiary alkyl halides, SN1 and E1 occur in protic solvents with weakly basic nucleophiles. The reactions occur more easily with tertiary alkyl halides, if the nucleophile is not a strong base. The SN1 mechanism is always in competition with E1 because both occur under the same reaction conditions. These conditions are as follows: the alkyl halide is secondary and tertiary (especially); the solvent is protic, to stabilize the intermediate stage (consisting of the carbocation and departed leaving group); and the nucleophile is a weak base. With a strong base, remember that E2, bimolecular elimination is favored, not SN1 or E1 (with both secondary and tertiary alkyl halides). The SN1 mechanism, because it proceeds through a trigonal planar carbocation intermediate, will not lead to a product that is composed of pure enantiomer, as would happen if only SN2 occurred. Although the nucleophile prefers the side of the carbocation opposite the leaving group, attack can occur onto either face of the carbocation, and also rearrangement can occur in the carbocation intermediate.

22 E2 Mechanism with Alkyl Halides Alkyl Halides

H H CH3 - H C H C C Base 3 C C H3C H3CH2C CH3 Alkene H3CH2C Br Alkyl halide

- Base H H H H CH3 - CH3 H C H C C Base 3 C C H3C C C H CH C CH H3C 3 2 3 H3CH2C Br H3CH2C Br

anti periplanar transition state

Strong bases react with secondary and tertiary alkyl halides by the E2 (bimolecular elimination) mechanism. As with SN2, the best solvent for E2 is polar and aprotic. While SN2 predominates with primary alkyl halides even if the nucleophile is a strong base, E2 will always predominate with a strong base on secondary and tertiary alkyl halides (if weak base is used with such alkyl halides, in protic solvent, E1 and SN1 will be favored.) Bimolecular elimination obeys Zaitsev’s rule, i.e. forming as highly substituted an alkene as possible. Also, in the activated complex of the E2 mechanism, the proton abstracted by the base is anti-periplanar to the leaving group. Such stereochemistry, in some instances, will determine whether product will be cis or trans, and with ring alkyl halides, the anti-periplanar geometry of the transition state will determine the conformation of alkene ring product. On rings, both the proton and leaving group must be axial to be also anti-periplanar.

E1 Mechanism with Alkyl Halides Alkyl Halides

H3C - H C H CH3 3 C Br Base C C H CH3 Alkyl halide Alkene H3C

H3C H3C - + H3C Base H3C CH3 C Br C Br H C C 3 CH Alkyl halide 3 H3C H3C Carbocation

- Base H H + CH H CH3 C C 3 C C CH H CH3 3 Alkene H

With secondary and tertiary alkyl halides, the E1 and SN1 mechanisms occur in protic solvents with weakly basic nucleophiles. The reactions occur more easily with tertiary alkyl halides if the nucleophile is not a strong base. The E1 mechanism is always in competition with SN1 because both occur under the same reaction conditions. These conditions are as follows: the alkyl halide is secondary and tertiary (especially); the solvent is protic, to stabilize the intermediate stage (consisting of the carbocation and departed leaving group); and the nucleophile is a weak base. With a strong base, remember that E2, bimolecular elimination, not E1 or SN1, is favored with both secondary and tertiary alkyl halides. E1 product is most often obtained in mixture with SN1, and with a very weak base. With a moderately vigorous nucleophile (like ethanol), SN1 will predominate.

24 SN1 Mechanism with Allylic Cation Intermediate Allylic and Conjugated Structures

H C H H 3 H HBr H C H H H3C 3 + C H H CC C H CC C CC OH H Br H H Alkene with allylic leaving group H Br Alkene mixture

H H H C H 3 CC H3C H HBr H C H CC C OH OH H Alkene with allylic H HBr leaving group

H H C H HH3C 3 CC H H H C H H H C HBr+ 3 CC H H H3C H O + H3C H C CCOxonium ion CC + C+ H H C H H H C O CC OH H HBr H H H Br + H C H C H 3 C H 3 CC H H CC Allylic carbocation H C H H intermediate + H

H H H3C H H C H HBr H CC C continued 3 CC + H C H COH H3C H 3 C H OHCC H H H CC 25 HH C HHBr H + H - H Br H C H H 3 CC H H C H H C + 3 CC H O + H C O + H H H C 3 H H H H H C H C H 3 CC + CC H C Br H H + H C H H H3C C 3 H H H CCBr C H H CC H + H

+ H C H3C H 3 C H CC H H CC H C H H + H - Br

H3C H H H C H C H 3 CC + CC H C H H H Br Br Alkene mixture

The departure of an allylic leaving group is eased by resonance stabilization within the allylic carbocation intermediate. Allyl halides, for example, are candidates for SN1 substitution, even if the carbon is primary.

26 1,2 and 1,4 Addition to Conjugated Diene Allylic and Conjugated Structures

Br Br 1,2 product H2C CH CH CH2 Br H C CH CH CH 2 + 2 2 Br Br Conjugated diene 1,4 product H2C CH CH CH2

Br Br

H C CH CH CH H C CH CH CH 2 2 + Br2 2 Br Br 2 Conjugated diene Halogen H2C CH CH CH2 Br H C CH CH CH 2 + 2 2 Br Br BrBr + + - + Br H2C CH CH CH2 H2C CH CH CH2 H2C CH CH CH2 Allylic carbocation intermediate

continued Br Br Br Br 27 + or + H2C CH CH CH2 H2C CH CH CHBr2 Br

H2C CH CH CH2 + Br2 H2C CH CH CH2 Br Br Br Br + H2C CH CH CH2 H2C CH CH CH2

Br Br + + - + Br H2C CH CH CH2 H2C CH CH CH2

Br Br Br Br + or + H2C CH CH CH2 H2C CH CH CH2

Br Br Br Br + H2C CH CH CH2 H2C CH CH CH2 1,2 product 1,4 product

Instead of forming the triangular halonium ion typical of electrophilic addition of halogen to alkene, halogen adds to a conjugated diene to form a resonance stabilized allylic carbocation intermediate. The two resonance forms of the resonance- stabilized allylic carbocation lead respectively to two different possible products, the 1,2 and 1,4 products of addition. A very interesting and signiﬁcant discussion arises from the fact that while the pathway to the 1,4 product occurs with greatest free energy decrease, the pathway to the 1,2 product is achieved with less activation energy. This means that formation of 1,4 product is favored thermodynamically, but 1,2 product is favored kinetically. Higher temperatures, ‘thermodynamic conditions’, promote the formation of 1,4 product, because if a larger fraction of the molecules possess activation energy for either pathway, as would occur at higher temperature, a large portion of diene concentration continuously moves down the 1,4 pathway and forms the more stable 1,4 product. Lower temperatures, however, are ‘kinetic conditions’. At lower temperatures, fewer reagent diene particles have enough energy to get over the activated complex energy hump to form the 1,4 product, so 1,2 addition predominates.

28 Diels-Alder Reaction Allylic and Conjugated Structures

H H CH2 H C N C N C C + C C H CH H 2 H3C H Conjugated diene Dienophile H3C Diels-Alder adduct

H C N H CH2 H C N C C + C C H CH2 H3C H H H3C

H C N

H H3C

A conjugated diene, such as 1,4 butadiene, combines with an alkene in the Diels-Alder reaction. Especially favored are those alkenes which are dienophiles (having electron withdrawing substituents). The Diels-Alder reaction is a pericyclic process. In other words, it occurs by means of a particular type of transition state in which electrons simultaneously re- distribute in a cyclic manner. The process starts with the bonding overlap of the terminal π lobes of the conjugated diene with those of the alkene. The stereochemistry of the Diels-Alder reaction is informed by concerns particular to pericyclic reactions. The overlap occurs between the HOMO of one of the species (Highest Occupied Molecular Orbital) and the LUMO of the other (lowest unoccupied molecular orbital). Cycloaddition reactions can be antarafacial or, suprafacial, which means that the reagents must rotate for orbital overlap or not, respectively. Diels-Alder is of the suprafacial type, so it takes place more easily, i.e. at lower temperatures. Note that if the alkene reagent is trans, the derived ring substituents will also be trans.

30 Electrophilic Aromatic Substitution with Halogen Aromatic Compounds

FeBr3 + Br2 Ferric bromide Halogen catalyst Aromatic ring Halogenated aromatic ring

Br Br

FeBr3 + Br2 Halogen Ferric Aromatic ring bromide catalyst

Br Br Br H H + H - Br +

Resonance stabilized + carbocation intermediate - Br Br Br H + HBr

+ Halogenated aromatic ring

Electrophilic aromatic substitution of bromine is assisted by a ferric bromide catalyst, ferric chloride for chlorination. Unlike electrophilic addition to alkenes, a catalyst is necessary to enhance the electrophilicity of the halogen to react with an aromatic ring because aromatic π electrons are more stable than vinylic π electrons, Electrophilic aromatic substitution begins with the addition of the electrophile into the aromatic π system of the ring. A conjugated, carbocation intermediate is formed, a resonance combination of three forms, concentrating positive charge at three locations, the two ortho positions and one para relative to the halide substituent. After this addition, a proton departs, completing the overall substitution with aromaticity restored.

Consider the case where electrophilic aromatic substitution is attempted on an aromatic ring that already contains an original halogen substituent. If electrophilic aromatic substitution is attempted upon rings that already contain substituents, the location of the next substitution depends on the characteristics of the original substituent. Whether the new substitution occurs ortho, para or meta to the original substituent depends on whether the original substituent either stabilizes or destabilizes a concentration of positive charge upon its carbon at the carbocation intermediate stage. If the substituent already present is electron donating, it will stabilize the carbocation by donating negative charge. New substitutions will occur ortho or para to such electron donating substituents already present on the ring. Electron withdrawing substituents destabilize a carbocation, so the new substitution will most likely be meta. Being electronegative, halide substituents are ring deactivating by induction. However, nonbonded pairs of electrons are present on the halide substituent which can donate by resonance. Because of these combined effects, a halide substituent, already present on the ring, is a ring deactivating, ortho-para director for further electrophilic aromatic substitution.

32 Electrophilic Aromatic Substitution - Nitration Aromatic Compounds

NO2

HNO3

H2SO4 Nitric acid/ Aromatic ring Nitrated ring sulfuric acid mixture

+ - HNO3 + H2SO4 NO2 + HSO4 + H2O Nitric acid Sulfuric acid Nitronium ion + NO2 + + NO2 Nitronium ion Aromatic ring

NO2 NO2 NO2 H H + H +

Resonance stabilized + carbocation intermediate H O NO2 NO2 H H + + H3O

+ Nitrated ring

+ The electrophile for the nitration reaction, the nitronium cation (NO2 ), is generated by reaction of nitric acid (HNO3) with sulfuric acid (H2SO4). Electrophilic aromatic substitution begins with the addition of the electrophile into the aromatic π system of the ring. A conjugated, carbocation intermediate is formed, a resonance combination of three forms, concentrating positive charge at three locations, the two ortho positions and one para. After this addition, a proton departs, completing the overall substitution with aromaticity restored.

Consider the case where electrophilic aromatic substitution is attempted on an aromatic ring that already contains an original nitro substituent. If electrophilic aromatic substitution is attempted upon rings that already contain substituents, the location of the next substitution depends on the characteristics of the original substituent. Whether the new substitution occurs ortho, para or meta to the original substituent depends on whether the original substituent either stabilizes or destabilizes a concentration of positive charge upon its carbon at the carbocation intermediate stage. If the substituent already present is electron donating, it will stabilize the carbocation by donating negative charge. New substitutions will occur ortho or para to such electron donating substituents already present on the ring. Electron withdrawing substituents destabilize a carbocation, so the new substitution will most likely be meta. Nitro is such a substituent. Containing only electronegative atoms, nitro is electron-withdrawing by induction. Furthermore, the nitrogen atom in nitro also has no electron pairs capable of donating into the ring by resonance. A nitro group, already present on the ring, is a ring deactivating, meta director for further electrophilic aromatic substitution.

(Some substituents, such as halogen or hydroxide, even though being electronegative (electron withdrawing inductively), will donate electron pairs to the ring by resonance and are still ortho para directing, though deactivating by induction.)

34 Electrophilic Aromatic Substitution - Sulfonation Aromatic Compounds

SO3H

SO3

H2SO4 Fuming sulfuric Aromatic ring Sulfonated ring acid

S OH + H2SO4 + SO3 O Sulfur trioxide Aromatic ring

SO3H SO3H SO3H H H + H +

Resonance stabilized + carbocation intermediate H O SO3H SO3H H H + + H3O

+ Sulfonated ring

Sulfur trioxide, the electrophile in sulfonation of benzene, is present in small amounts in normal sulfuric acid and sulfonation of benzene will occur with sulfuric acid. Frequently, though, a solution of sulfur trioxide and sulfuric acid is used (called oleum or fuming sulfuric acid). Electrophilic aromatic substitution begins with the addition of the electrophile into the aromatic π system of the ring. A conjugated, carbocation intermediate is formed, a resonance combination of three forms, concentrating positive charge at three locations, the two ortho positions and one para. After this addition, a proton departs, completing the overall substitution with aromaticity restored.

Consider the case where electrophilic aromatic substitution is attempted on an aromatic ring that already contains an original sulfonate substituent. If electrophilic aromatic substitution is attempted upon rings that already contain substituents, the location of the next substitution depends on the characteristics of the original substituent. Whether the new substitution occurs ortho, para or meta to the original substituent depends on whether the original substituent either stabilizes or destabilizes a concentration of positive charge upon its carbon at the carbocation intermediate stage. If the substituent already present is electron donating, it will stabilize the carbocation by donating negative charge. New substitutions will occur ortho or para to such electron donating substituents already present on the ring. Electron withdrawing substituents destabilize a carbocation, so the new substitution will most likely be meta. Sulfonate is such an electron withdrawing substituent. Containing only electronegative atoms, sulfonate is electron-withdrawing by induction. Furthermore, the sulfur atom has no lone electron pairs to donate into the ring in resonance. A sulfonate group, already present on the ring, is a ring deactivating, meta director for further electrophilic aromatic substitution.

36 Friedel-Crafts Alkylation Aromatic Compounds

CH(CH3)2 H3C H AlCl3 + C Cl Aluminum trichloride H3C Aromatic ring Alkylated ring Alkyl halide

H3C - AlCl CH3 H 3 HC AlCl4 C Cl + CH3 Aluminum H C 3 trichloride Carbocation Alkyl halide CH3 HC + CH3

CH3 + HC + CH3 Carbocation Aromatic ring

CH(CH3)2 CH(CH3)2 CH(CH3)2 H H + H +

Resonance stabilized + carbocation intermediate

CH(CH ) CH(CH3)2 3 2 H Cl + HCl

+ Alkylated ring

The aluminum chloride catalyst in Friedel-Crafts alkylation facilitates carbocation formation from an alkyl halide, preparing the species as an alkyl electrophile for electrophilic aromatic substitution. Electrophilic aromatic substitution begins with the addition of the electrophile into the aromatic π system of the ring. A conjugated, carbocation intermediate is formed, a resonance combination of three forms, concentrating positive charge at three locations, the two ortho positions and one para. After this addition, a proton departs, completing the overall substitution with aromaticity restored.

Consider the case where electrophilic aromatic substitution is attempted on an aromatic ring that already contains an original alkyl substituent. If electrophilic aromatic substitution is attempted upon rings that already contain substituents, the location of the next substitution depends on the characteristics of the original substituent. Whether the new substitution occurs ortho, para or meta to the original substituent depends on whether the original substituent either stabilizes or destabilizes a concentration of positive charge upon its carbon at the carbocation intermediate stage. If the substituent already present is electron donating, it will stabilize the carbocation by donating negative charge. New substitutions will occur ortho or para to such electron donating substituents already present on the ring. Electron withdrawing substituents destabilize a carbocation, so the new substitution will most likely be meta. Alkyl groups are electron-donating by induction. Because carbon is only moderately electronegative, alkyl groups have negative charge to share with the positive carbon in the ortho- para resonance form. An alkyl group, already present in the ring, is ring activating and ortho-para directing.

38 Friedel-Crafts Acylation Aromatic Compounds

O R C O + AlCl3 RC Cl Aluminum Acyl halide Aromatic ring trichloride Acylated ring

O + + - AlCl3 AlCl RC Cl ROC ROC + 4 Acylated ring Aluminum Carbocation Acyl cation trichloride + ROC + + ROC Acyl cation Aromatic ring O O O R R R C C C H H + H + + Resonance stabilized + carbocation intermediate O O R R C - C H Cl + HCl

Acylated ring

The same aluminum chloride catalyst used in Friedel-Crafts alkylation is also used for Friedel-Crafts acylation. In this context, aluminum chloride assists in the formation of an acyl cation from acid halide to serve as an electrophile for aromatic substitution. Unlike alkyl cation, acyl cation has the advantage of not rearranging. Electrophilic aromatic substitution begins with the addition of the electrophile into the aromatic π system of the ring. A conjugated, carbocation intermediate is formed, a resonance combination of three forms, concentrating positive charge at three locations, the two ortho positions and one para. Finally, the proton departs and substitution at the carbon is complete with aromaticity restored. Acylation is frequently followed by Clemmensen reduction in synthesis, which will transform the acylbenzene into an alkylbenzene.

Consider the case where electrophilic aromatic substitution is attempted on an aromatic ring that already contains an original acyl substituent. If electrophilic aromatic substitution is attempted upon rings that already contain substituents, the location of the next substitution depends on the characteristics of the original substituent. Whether the new substitution occurs ortho, para or meta to the original substituent depends on whether the original substituent either stabilizes or destabilizes a concentration of positive charge upon its carbon at the carbocation intermediate stage. If the substituent already present is electron donating, it will stabilize the carbocation by donating negative charge. New substitutions will occur ortho or para to such electron donating substituents already present on the ring. Electron withdrawing substituents destabilize a carbocation, so the new substitution will most likely be meta. Acyl group is electron withdrawing due to the electronegativity of the oxygen atom, which draws electron density toward itself and leaves the carbon electron poor. Acyl is a ring deactivating, meta director for further electrophilic aromatic substitution.

40 Nucleophilic Aromatic Substitution Aromatic Compounds

Br Br Nu Nu

NO2 - NO Nu 2 or or Aryl halide with electron Product with Ortho withdrawing substituent Para nucleophile ortho or para NO2 substituted for halogen NO2

- Br Br Nu NO - NO 2 Nu 2 Ortho Aryl halide with ortho electron-withdrawing substituent - Br Nu Br Nu O Br Nu Br Br + NO2 N Nu NO2 Nu - O - - NO2 - NO2 Resonance stabilized Nu carbanion intermediate or or Nu NO Ortho 2 Para NO2 NO2 Product with nucleophile substituted for halogen - Br Br Nu - Br - Br Nu Nu Para NO - NO continued 2 Nu 2 Ortho 41 NO2 NO2 - Br Nu Br Nu Br Nu Br Nu Br Nu Br Nu O Br Nu N+ - NO2 NO2 - - O - - - NO2 NO2 NO2 N Nu - O + O - Nu NO2

- Br Br Nu NO2 - Nu Para Br Aryl halide with para - Nu electron-withdrawing substituent NO Meta 2 NO2 NO Br Nu Br Nu 2 Br Nu Br Nu - - Resonance stabilized - carbanion intermediate NO2 NO2 NO2 N - O + O - Nu

Product with nucleophile substituted for halogen NO2 Br - Nu Meta NO Aryl halide with meta 2 electron-withdrawing substituent

Nucleophilic aromatic substitution (also called addition-elimination), requires an electron withdrawing substituent to be present on the ring ortho or para to the halide being substituted. The reaction is difﬁcult to achieve with aryl halides for which halogen is the lone ring substituent. If a strongly electron-withdrawing substituent is present, however, ortho or para to the halogen, the carbanion intermediate will be more stable. A substituent such as nitro, while deactivating electrophilic aromatic substitution (which forms a carbocation intermediate), activates ortho and para positions, if they contain halogen, for nucleophilic aromatic substitution. Basicity of the nucleophile also facilitates the reaction.

42 Alkylbenzene Oxidation Aromatic Compounds

H O KMnO4 C COH CH3 H Benzoic acid Aromatic ring with alkyl substituent

Potassium permanganate or chromic acid oxidize an alkyl side chain on an aromatic ring to form a carboxyl group. If the alkyl group has more than one carbon, cleavage occurs at the benzylic position.

Alkylbenzene Halogenation Aromatic Compounds

H Br Br2 C C + Br CH3 hv CH3 H Halogen H Halide radical Aromatic ring with Haloalkylbenzene alkyl substituent (Halogen at the alkyl position)

hv Br2 2 Br Halogen Halide radical

Br H H C + Br C CH3 CH3 H Halide radical H Aromatic ring with alkyl substituent Br Br

C CH3 C CH3 H H Benzyl radical

Br C + Br CH3 Haloalkylbenzene H Halide radical

Free-radical halogenation of alkylbenzene is selective for benzylic carbons because the benzylic radical is stabilized by resonance (like the allylic). Otherwise, the mechanism is completely analogous to the free-radical halogenation of alkanes.

44 Dehydration of Alcohols Alcohols and Ethers

CH H3C + CH3 2 CH3CH2 H COH CH3CH C + CH3CH2 C Acid catalysis CH3 CH3 H3C major product Alcohol Alkene mixture

H C H3C 3 CH CH + H CH3CH2 + H 3 2 COH + HO COH + HO H H H C H3C 3 Alcohol

CH H3C + CH3 2 H3C H H3C H H3C CH3CH2 H CH3CHCO2 H+ CH3CHCH2 3CH+ C + CH3CH+2 C CO CO CH3CH2 C H H CH3 H C CH3 H3C H3C H3C Carbocation 3 Alkyloxonium ion

H O 2 H continued H H H C CH3 + CH3C C CH3CH C 45 H C H3C 3 H C CH3 CH CH H H + H CH3CH2 + H 3 2 COH + HO COH + HO H H H H C H3C 3

H H H H C CH2 H C H H C H3C + H H O 3 3 CH3C C 2 CH3CH2 C CH3CH2 + CH3CH2 + + CO CO CH CH3CH2 C H H C H 3 H H H C H3C H H3C 3

H O 2 H H H H C CH3 + CH3C C CH3CH C CH H H C H 3 H

Alkene mixture

H H H H C CH2 + H O CH3C C 2 CH3CH2 C CH H H C H 3 H

Protonation in acidic conditions of the hydroxyl group of secondary and tertiary alcohols converts the hydroxyl group into a leaving group, which departs as water. The carbocation intermediate, which can rearrange, will then be deprotonated in an E1 elimination mechanism. This reaction is the reverse of acid-catalyzed hydration of alkenes.

46 Reaction of Alcohols with HX – Dehydrohalogenation Alcohols and Ethers

H3C H3C CH CH CH3CH2 + 3 2 COH HX CX + H2O Hydrogen H C H3C halide 3 Alcohol Alkyl halide

H C H3C 3 H3C H CH CH CH3CH2 CH3CH2 + 3 2 COH + HX COH + HCl CO Hydrogen H C H Alcohol H3C 3 H3C halide Alkyloxonium ion

H C H C H C 3 H 3 3 - CH3CH2 + + + CO CH3CH2 C +H2O + Cl- CH3CH2 C Cl Halide anion H3C H H3C H3C Carbocation

H3C CH CH 3 2 CCl H C 3 Alkyl halide

Dehydrohalogenation only takes place with secondary and tertiary alcohols. The reaction begins with protonation in acidic conditions of a hydroxyl group. The hydroxyl group is converted into a leaving group and it departs as water. The carbocation intermediate formed attracts a nucleophile, in this case a halide ion, completing the SN1 substitution. This reaction competes with acid-catalyzed dehydration (E1 elimination).

Reaction of Alcohols with Thionyl Chloride Alcohols and Ethers

H SOCl2 R RCH2OH Cl C Alcohol Thionyl chloride H Alkyl halide

H O O R SOCl2 C O S Cl RCH2OH RCH2 O S Cl + HCl - Cl Alcohol Thionyl Alkylsulfonyl Hydrochloric acid H chloride chloride

H R Cl C + SO2 + HCl H Alkyl halide

Reaction of alcohols with thionyl chloride followed by hydrochloric acid results in the replacement of the hydroxyl group of the alcohol with a chloride substituent, forming an alkyl chloride product. This mechanism does not, like dehydrohalogenation, pass through a carbocation intermediate. Therefore, rearrangement cannot occur in reaction with thionyl chloride. Note that thionyl chloride can also convert a carboxylic acid into an acid chloride.

48 Reaction of Alcohols with Phosphorus Tribromide Alcohols and Ethers

H PBr3 R RCH2OH Br C Alcohol Phosphorus Alkyl bromide tribromide H

H R PBr3 C O PBr RCH OH RCH O PBr + HBr - 2 2 2 2 Br H Alcohol Phosphorus Phosphobromide Hydrogen tribromide ether bromide

H R Br C + HOPBr2 H Alkyl bromide

Analogous to their reaction with thionyl chloride, reaction of alcohols with phosphorus tribromide followed by hydrobromic acid results in the replacement of the hydroxyl group of the alcohol with bromine, forming the alkyl bromide product. This mechanism does not, like dehydrohalogenation, pass through a carbocation intermediate. Therefore, rearrangement cannot occur in this reaction. A carboxylic acids can be converted to an acyl bromide with this reaction.

Oxidation of Alcohols Alcohols and Ethers O

ROCH2 H RC OH Primary alcohol Carboxylic acid O

ROCH2 H RC H Primary alcohol Aldehyde H O O R C R' RC R' Secondary alcohol H Ketone Oxidation of a primary alcohol yields an aldehyde or, under the most strong, vigorous oxidizing conditions, a carboxylic acid. The stronger oxidizing agents KMnO4 and K2Cr2O7 both mainly transform primary alcohols into carboxylic acids, while Collin’s reagent, PCC and PDC form aldehydes. Oxidation of a secondary alcohol yields a ketone. Extreme conditions are necessary to oxidize a tertiary alcohol, producing cleavage mixtures.

Alkoxide Ion Formation from Alcohols Alcohols and Ethers

- + ROH + NaH RO Na + H2 Alcohol Sodium hydride Alkoxide salt

Alkoxide ions can be formed by a very strong base such as sodium hydride. (The alkoxide ion may be later used to serve as an SN2 nucleophile upon a primary alcohol to produce an ether.)

50 Reaction of Alcohols to form Ethers Alcohols and Ethers

H2SO4 2 CH3CH2OH CH3CH2OCH2CH3 + H2O Acid catalyst 2 Alcohol Ether

+ H H H SO 2 4 + + 2 CH3CH2OH CH3CH2 O CH CH OH CH3CH2 O H 3 2 2 Alcohol Acid H Alcohol catalyst Oxonium ion CH3CH2OH

+ H OH2 H CC H H H H H CC H H CH3CH2OCH2CH3 CH3CH2OH H HOCH2CH3 Ether + Ether oxonium ion

With primary alcohols, acidic conditions prepare hydroxyl to leave in an SN2 reaction in which another alcohol serves as the nucleophile. In this condensation reaction, the product formed is an ether. Two alcohols have combined releasing water. (Note that the conversion of hydroxyl group into a leaving group with secondary and tertiary alcohols leads to E1 and SN1).

Williamson Ether Synthesis Alcohols and Ethers

+ RO-Na + R'I ROR' Alkoxide ion Alkyl halide Ether

H H - + CI O Na + CH3I - H Alkoxide ion Alkyl halide O

+ NaI OCH3

Ether

In the Williamson ether synthesis, alkoxide ion acts as an SN2 nucleophile upon a primary alkyl halide forming an ether. Williamson ether synthesis can be used to form asymmetrical ethers. The mechanism will not work upon secondary or tertiary alkyl halides because of competition from the E2 mechanism, which would form an alkene.

52 Acid Cleavage of Ethers Alcohols and Ethers

Hydrogen Ether Alcohol Alkyl halide halide

Ether Hydrogen halide

Dialkyl Halide ion oxonium ion

Alcohol Alkyl halide

Ethers are generally unreactive to most species. With strong acid, however, ethers undergo a cleavage through a process begun by protonation of the ether oxygen. HI and HBr are often used. The products separate in either an SN1 or SN2 style process, determined by the shape of the ether, the halide anion serving as nucleophile. Some of E1’s alkene product, as always, will be mixed in if SN1 occurs.

Epoxidation of Halohydrins Alcohols and Ethers

OH CH3 O CH3 NaOH CC CC H3C H2O H C CH Br 3 3 H3C Base H3C CH3 Halohydrin Epoxide

- OH H - OH CH3 O CH3 O CH3 CH CH CH CC 3 NaOH CC 3 CC 3 H3C H2O H3C H3C H3C Br Base H3C Br H3C Br Halohydrin Halohydrin anion

- O O CH3 CH3 CC CC H3C CH3 H3C H3C CH3 H C Br 3 Epoxide

Basic conditions activate a halohydrin to complete an intramolecular process to form an epoxide. The oxygen of the hydroxyl substituent displaces the halide through nucleophilic attack. This mechanism is essentially an intramolecular Williamson ether synthesis. The product formed is a triangular epoxide molecule. Epoxides are useful substances because of their own high reactivity toward nucleophiles in epoxide ring opening reactions.

54 Acid Epoxide Ring Opening Alcohols and Ethers

O R OH H+ H CC CC H H Nu- H H H Nu H Epoxide Alcohol with nucleophile as new substituent O OH H R CC CC H H Nu- H H H H Nu

H + O O R OH H+ H acid-induced with CC CC R CC normal nucleophile H H Nu- H H H H H H Nu H Nu- Alcohol with nucleophile as new substituent

O O OH H R CC CC basic nucleophile R CC H H Nu- H H H H H H H Nu Nu - 55

In epoxide ring opening reactions, the SN2 approach of a nucleophile on an epoxide results in cleavage of the epoxide. Nucleophilic attack occurs at the more highly substituted carbon in acidic conditions. In basic conditions, steric hindrance is the determining factor with nucleophilic attack occurring at the less substituted carbon.

56 Reduction of Ketones and Aldehydes Aldehydes and Ketones

O OH RC H R C Primary alcohol Aldehyde Reducing agent H H

O OH Secondary alcohol ' R C RC R R' Reducing agent Ketone H

NaBH4 and LiAlH4 are reducing agents commonly used for transforming an aldehyde or a ketone, respectively, into a primary or a secondary alcohol. Note that Wolff-Kishner and Clemmensen reduction reduce aldehydes and ketones further than NaBH4 and LiAlH4, all the way to alkanes. (Note the special case where catalytic hydrogenation may be used to reduce a benzylic carbonyl group to an alkane.) Remember of the sequence in oxidation states of carbon, from more reduced to more highly oxidized: alkyl, alcohol, aldehyde, ketone, carboxylic acid.

Reduction of Aryl Alkyl Ketones Aldehydes and Ketones

O H C CH CH 2 CH CH CH 2 3 catalyst 2 2 3 Alkyl aromatic Aryl alkyl ketone

O O OH H 2 H2 CH2 C CH3 catalystC CH CHCH2 C CH3 CH CH CH 2 3 catalyst 2 2 3

O OH H2 CH2 C CH3 catalyst CH2 C CH3

Reduction with hydrogen in the presence of a catalyst reduces a non-benzylic carbonyl group only to a hydroxyl group.

A carbonyl carbon located at the benzylic position may be reduced to become an alkyl carbon. It is not necessary to employ Wolff-Kishner reduction or Clemmensen reduction, which reduce even nonbenzylic carbons to this point. For benzylic carbonyl groups, the process can be carried out by catalytic hydrogenation. (The reducing agents NaBH4 and LiAlH4 reduce aldehydes or ketones only to alcohols, even if the carbonyl is benzylic.)

58 Oxidation of Aldehydes and Ketones Aldehydes and Ketones

O O - 1. KMNO4, OH RC H RC OH Aldehyde 2. H3O Carboxylic acid

O - O O 1. KMNO4, OH + + CO2 CH3 CCH2CH3 CH3 C OH CH3CH2 C OH 2. H3O + Ketone Potassium permanganate Carboxylic acid cleavage mixture (extreme conditions) (CO2 if methyl ketone)

Many of the stronger oxidizing agents such as KMnO4 will transform aldehydes into carboxylic acids. Tollens’ reagent (Ag2O) is frequently used. A shiny mirror of metallic silver is deposited through oxidation of aldehydes by Tollens’ reagent, so it is frequently used as a test for aldehydes. Aldehydes are themselves oxidation products of alcohols. A strong oxidizing agent like KMnO4 will oxidize a primary alcohol past the aldehyde all the way to the carboxylic acid oxidation state, while other, weaker oxidizing agents, like PCC, can be used to form aldehydes from alcohols, not oxidizing the aldehyde further. In general, normal ketones are not oxidized except under extreme conditions, with benzylic carbonyl group being an exception, which KMnO4 oxidizes easily.

Reaction of Grignard Reagents with Aldehydes and Ketones Aldehydes and Ketones

R'' O R' + R MgBr C OH C + ' '' Grignard reagent R R 2. H3O R Alcohol Aldehyde or ketone Acid only for clean-up after the initial reaction.

RBr + Mg RMgBr Alkyl halide Magnesium Grignard reagent

'' R'' R + O O ' ' C R H3O + RMgBr R C OMgBr C ' '' Grignard reagent R R RMgBr R Alkoxymagnesium Aldehyde or ketone halide '' + R H O R' 3 C OH R Alcohol

Grignard reagents, which are obtained by reaction of alkyl, aryl, acetylenic halides, are very important instruments of synthesis. A Grignard reagent provides a nucleophilic carbon which can be used for bonding to another carbon. (The carbon bonded to magnesium in the Grignard reagent is nucleophilic, being the more electronegative end of the bond with magnesium.) For example, Grignard reagent carbon reacts with electropositive carbonyl carbons. Grignard reagents also react to form new carbon-carbon bonds with esters, nitriles, epoxides, and carbon dioxide carbons. (Grignard reagents can’t be used in the presence of acidic protons. The acid in the mechanism above is only applied in the reaction’s last stage.)

60 The Wittig Reaction Aldehydes and Ketones

H O R R R'' Br + (C6H5)3P + ' CC ''' C C R R Triphenylphosphine R'' R''' R' Alkene Aldehyde or ketone Alkyl halide

H H H R O R (C6H5)3P + C Br C Br '' R (C6H5)3P R R TriphenylphosphineBr + (C6' H5)3P + ' ' CC ''' C R Alkyl halide C R R R R'' R''' R' H + - + - NaH R (C6H5)3P C Br (C6H5)3P C ' R or BuLi R R' Triphenylphosphonium ylide

+ - R O (C6H5)3P C ' + - R R +H '' C (C6H5)3P C ' H R '' R''' R R R R O C R''' (C6H5)3P + C BrTriphenylphosphonium C Br continued Aldehyde or ketone (C6H5)3P ylide R' R' + 61 + R R R (C H ) P H (C H ) P C (C H ) P C 6 5 3 C ' 6 5 3 R' + - 6 5 3 R' R + - NaH R - (C6H5)3P'' C Br - (C H ) ''P C '' R 6 5R3 R' R O C ''' R or BuLi O C ''' O C ''' R R' R R

+ - R (C H ) P C O R 6 5 3 R' (C6H5)3P C '+ - '' + R R R R + '' C (C6H5)3P C ' ' CC ''' R (C6H5)3P O '' R''' '' R R R R R O C R''' O C R'''

+ + R R R (C H ) P C (C6H5)3P C (C6H5)3P C 6 5 3 R' R' R' - '' - '' '' Unstable betaine R R R O C ''' O C ''' O C ''' intermediate R R R

R (C H ) P C 6 5 3 R' R R'' ' CC ''' + (C6H5)3P O R'' R R O C R''' Alkene

Phosphorus ylides are used in the Wittig reaction to convert aldehydes and ketones to alkenes. In the process a new carbon-carbon bond is formed. To prepare the triphenylphosphonium ylide reagent, an SN2 reaction is utilized between triphenylphosphine and an alkyl halide (followed by deprotonation). The ylide (an ylide is a dipolar substance with adjacent opposite charges) is then made to undergo a reaction with an aldehyde or ketone that is somewhat analogous to the reaction of aldehydes or ketones with Grignard reagents. The ylide carbanion electrons lead to bond formation with the positive carbon pole of the carbonyl group. A betaine is formed, which is unstable (a betaine is a dipolar substance with nonadjacent opposite charges.) Electron pair movement continues as oxygen departs its bond with carbon to bond with phosphorus. The two carbons of interest now possess a double bond between them. (Carbon-carbon bond forming reactions are of particular importance for organic synthesis. Other important reactions that form carbon-carbon bonds include the use of acetylide anion as an SN2 nucleophile, Grignard reagents, Gilman reagents, and the aldol & Claisen condensations.)

62 Acetal Formation Aldehydes and Ketones

O OR R' HCl '' R' C R'' + 2ROH C R Aldehyde or 2 equiv. Acid RO Ketone Alcohol Acetal

H HCl + O O O HCl ' '' + ROH R C OR R' C R'' OR R' C R'' Acid R' Aldehyde or Alcohol HCl '' Ketone' '' + C R R C R H 2ROH + O OH RO OH R' R' C R'' C R'' R' C R'' O O H R H H R + + O O H R H

+ OH HCl R' OH OH2 '' R' R' C R '' H'' C R HCl C + R O RO Hemiacetal O O HCl RO RO continued ' '' + ROH R C R R' C R'' R' C R'' R + + R 63 O OHH2 + ' + O R OH ' OH '' OC R'' R C R 'R' '' R' R C C RR'' C R'' R'ROC R'' O O O H R R H H H R + + O O R H RR H O O OR R' R' R' '' '' + '' COH R C R HCl C R ' OH OH R O O' H RO' 2 R +CH R'' R R+ H O R C R'' H C R'' RO RO RO

R + + R O OH2 + ' O R ' '' C R'' R C R R' C R'' RO O R H R R O O OR R' R' R' C R'' C R'' C R'' O O H RO H H O Acetal R + R + H

An aldehyde or a ketone reacts with alcohol in the presence of an acid catalyst to form a geminal diether product called an acetal. Acetal formation begins with protonation of the ketone or aldehyde carbonyl oxygen by an acid catalyst, increasing the attractiveness of the carbonyl group to the approaching alcohol nucleophile. A tetrahedral intermediate forms, which is typical of nucleophilic reactions with carbonyl compounds. After a subsequent protonation, the hydroxyl group leaves as water, forming a cation intermediate. This intermediate is approached by another alcohol nucleophile.

One interesting use of acetal formation is to protect carbonyl groups from hostile reaction conditions. Ethylene glycol is often used in this way to form a cyclic acetal, which can be converted back into the aldehyde or ketone at a later stage.

64 The Wolff-Kishner Reaction Aldehydes and Ketones

H O - H H OH + NN RC H +N N + H2O C ' H H R R Hydrazine ' R Alkane Aldehyde or Ketone

- O O R O ' H H -C H C R O + NN R ' C H H OH R + R R' H H +H NN HN + H O + HydrazineNN H HRC H 2 C H H NN H Aldehyde or KetoneR' H H N Tetrahedral R R' H intermediate - H O OH O R ' R R C R C R' C R' + H N H N N H H H N H N H H N H H - O O R O - H ' H H C C R H + NN H R OH' N C N HH H N H R H + - R HR' - H N H N H + OH N + HN + H + H2O + OH NN H H H C ' N C C R R H R R' R R' continued H Hydrazone - - O OH O H N OHR - 65 ' R R N - HC R H N C R' H N C R' + OH N + H O H + N N 2 C - H N HN N N R R' H H N H C H' C ' H H C ' R N R R R N O R H R H - H H - - H H HN OH H N OH N N H N H H H - - N + - - H N N + OH N + N + RC H +N N+ + HH2O2O OH+ OH RC RC ' C ' CH ' C H R R R R R R R' R' R' - H N OH H - O HH H N H N N - N + OH - + H2O - H N + N C - N RC H OH R R' RC H R' C C ' H ' C R R' R R O R R R' - H Hydrazone anion - H N OH H N - N - N + OH RC H +N N + H2O RC H RC H R' R' R' Carbanion

H O H H - - RC H + OH RC H R' ' R Alkane A ketone or an aldehyde is reacted with hydrazine in Wolff-Kishner reduction. The reaction begins with nucleophilic attack of hydrazine upon the carbonyl carbon. This is one of the more challenging mechanisms. Conceptual framing is helpful to learning. Wolff-Kishner belongs to the group of reactions that are possible between ketones/aldehydes and amines and amine derivatives. In these reactions, if the nucleophile is a primary amine, having two hydrogens to lose, reaction with a ketone or an aldehyde will produce an imine form, in which the carbon originally double bonded to oxygen will be double bonded to nitrogen. If the amine is secondary, the product is an enamine, in which the carbon-nitrogen bond is single, but the carbon is double bonded. In Wolff-Kishner, the tetrahedral intermediate formed by the nucleophilic attack, resolves itself by losing the original carbonyl oxygen as hydroxide, forming eventually a hydrazone, the structure of which is of the imine type (not enamine). Deprotonating with a strong base puts electrons on the move within the hydrazone in a manner similar to an elimination mechanism, except that here we have electrons moving into nitrogen-nitrogen bonds, not carbon-carbon, with resonance stability also. Two deprotonations occur moving two electron pairs between the nitrogens, displacing electrons onto the original carbonyl carbon, eventually turning the alkyl portion of the molecule into an E2 style leaving group, which, after departing, is protonated to form the alkane product.

66 Reductive Amination Aldehydes and Ketones

H R ' O 1. NH3 C R RC R' 2. H2 N Aldehyde Ammonia H or ketone then H Hydrogen Amine

- O O O R RC R' C R' + NH RC R' 3 H N + Ammonia H Aldehyde NH3 Tetrahedra H H intermediate or ketone R ' O 1. NH3 C R - ' 2. H H RCO R 2 N R OH O ' R H R C R C R' H C R' + H N N N H H H H H H Carbinolamine

- - continued O OH HH HH O O R NH N + - RC R'+ R' + H2 + + N C H2O 67 NH OH ' RC R' 3 + RC R RC R' RC R' H N NH H 3 H

H R - H H C OR' 2 R OH O ' R R N C R C R' C R' H+ HH N N N H H H H H H

- OH HH HH NH N + - + + H2 + N H2O OH RC R' RC R' RC R' Imine Conjugate acid of imine

H R ' H2 C R N H H Amine

Reductive amination is a means of converting an aldehyde or a ketone into an amine. The reaction begins with nucleophilic addition of ammonia or an amine to the carbonyl group of an aldehyde or a ketone. The imine or enamine derivative formed is subsequently reduced by hydrogen to form the amine product. If the nucleophile is ammonia, a primary amine will be formed in reductive amination. If the nucleophile is a primary amine, the product will be a secondary amine. With a secondary amine nucleophile, a tertiary amine product will be obtained. Recall that the nucleophilic addition of ammonia or primary amine results in imine formation and addition of a secondary amine to an aldehyde or ketone results in enamine formation. Both are ultimately reduced to form amines in reductive amination.

68 The Cannizzaro Reaction Aldehydes and Ketones

O O H C OH H C - H C 3 3 C 1. OH 3 C H3C H C OH CC 2 H3C C + H3C + 2. H3O H H3C H Two equivalents H3C H3C aldehyde Carboxylic acid Alcohol

O O - H C O H C - H C 3 3 C O OH 3 C O H3C 2 H C C H H C C H CC OH 3 -3 HH3C H3C Aldehyde H3C H C H3C C 1. OH H3C OH C H3C OH3 H - C OH TetrahedralCC 2 H3C C + H3C + intermediate 2. H3O H H3C H H3C H3C - O O H3C H C H C 3 C 3 OH - CC H3C C + H H Hydride ion H3C OH H3C Carboxylic acid

continued - O O O O O H-3C + H C H3C H3C O 69 3 C -- C H3C H3O H3C H H H3C C H H C CC H C C C + OH HC3C 3 H 2 H3 C C H H C C H CC 3 3 H3C H H H3C H3C H H C H C OH - H3C OH 3 3 -

OH + H3C - O H3O H3C O H3C H C H C CC 3 C 3 H OH - CC H3C C + H H3C HH H3C OH H3C

- O O O H3C + H C H3C H3C H O 3 C - C CC 3 H + H C H H3C C H3C H H3C H H C Aldehyde H3C H 3 - New tetrahedral intermediate

+ H3C OH H3O H3C CC H H3C H

The Cannizzaro reaction resembles the acyl exchange reactions among carboxylic acid derivatives, although it occurs with aldehyde. With aldehyes (or ketones) tetrahedral intermediate formation is not typically followed by the departure of an acyl type leaving group. Reactions of nucleophiles with aldehydes and ketones differ in this respect from reactions of carboxylic acids. Although sometimes the original carbonyl oxygen will depart (as in acetal or imine/enamine formation) the reaction of a nucleophile with an aldehydes most commonly results in a tetrahedral product) In the Cannizzaro reaction, a strong base reacts with an aldehyde having no α-hydrogens. The hydroxyl adds to the aldehyde to produce a typical tetrahedral intermediate, except that this intermediate resolves itself with hydride (hydride!) departing as an ‘acyl type’ leaving group, forming a carboxylic acid. The freshly departed hydride then acts as a nucleophile upon another aldehyde, producing a new tetrahedral intermediate, which, after protonation, becomes an alcohol. One equivalent of aldehyde becomes carboxylic acid and the other leads to the alcohol form.

70 Acid or Base Catalyzed Enolization Aldehydes and Ketones

+ H3O H H O CH3 O CH3 H3C or C C C - H3C C C C CH3 H 1. OH CH3 H CH3 Enol CH3 Aldehyde or Ketone 2. H2O Either Acidic or Basic conditions

H HO + H

+ H O CH3 H O CH H O 3 Acid H3C 3 + H C C C C 3 H3O C C C H Catalyzed CH3 CH Acid 3 H H O CHCH3 3 H CH3 O CH3 H3C Aldehyde or or C KetoneC C H3C H - H C C C +CH3 1. OH H CH H O CH 3 H HCHO3 CH3 3 H C + CH3 H3C 3 C C C 2. H2O C C C CH CH3 3 H CH H CH3 3 Resonant cation intermediate H H HO H + H H O CH3 O CH3 H HO3C CH + + H C C C3 C H 3O C CHC3 C H3O H H3C CH H3C CH C C C 3 C C C 3 H CH3 CH3 CH3 EnolCH3 H CH3 H CH3 continued H2O

H H + 71 H O CH3 H O CH3 H O CH3 H O CH3 - H3C + H3C H3C C C C H3C C C C OH C C C CH3 C C C CH3 CH3 CH H CH3 H 3 CH3 H CH3 H CH3 HO H - H

H O - CH3 O CH3 H C O+ CH3 O CH3 3 H3C- C C C H C C C H3C C C CH3 H3C C C CH3 H C H C H CH3CH3 CHCH33 CH3 CH3 H2O

HO H H H O CH H O CH 3 Base 3 - H C O CH3 O CH3 3 HHO3C - OH C C C Catalyzed 2 C C C H3C H3C CCH3C C C CHC3 C H H H CH3 CH3 H CH BaseCH3 3 CH3 CH3 Aldehyde or Ketone HO - - O O CH3 - CH3 H3C C C H3C C C H C H C CH3 CH3 CH3 Resonant Enolate anion CH3 intermediate

HO H H O O CH CH3 H O - 3 2 H3C C C H3C C C C H C H CH3 CH3 CH3 CH3 Enol

Keto-enol tautomerism is one of the most important aspects of the reactivity of aldehydes or ketones. The movement from an aldehyde or ketone to its enol isomer involves proton exchange between an α-carbon and the carbonyl oxygen of an aldehyde or ketone. Although continuous interchange between the carbonyl compound and its enol does exist normally in neutral conditions, keto-enol tautomerism can be catalyzed by the addition of either acid or base. The particular events differ between the cases, but the same net intramolecular process occurs with either acid or base catalyzed enol formation, the transfer of a proton from the α-carbon to the carbonyl oxygen, accompanied by the shifting of electron pairs up toward oxygen, forming the vinylic alcohol known as an enol. α halogenation, the haloform reaction, and aldol condensation, among other reactions, involve the reactivity of the enol form, which, in these processes, is approached by an electrophile at the α-carbon. In another instance, the presence of enolate anion intermediate contributes to the special reactivity of α-β unsaturated carbonyl compounds to nucleophiles at the β carbon.

72 Alpha Halogenation Aldehydes and Ketones

H O CH3 H O CH3 Br , HBr H3C 2 H3C C C C C C C CH3 CH3 H CH3 Br CH3 Aldehyde or Ketone

H Br

H O CH + H O CH 3 H 3 H3C H3C C C C C C C CH3 CH3 H CH3 H CH3 Aldehyde or Ketone H H H O CH3+ H O CH3 O H O CH3 H CHBr32, HBr H3C H3C H C + Br2, H3C 3 C C C C C C C C C C C C CH3 CH Resonant cation CH3 CH3 3 H CH H CHH 3 CH3 intermediate Br 3 CH3

H H

H O CH3 H BrO CH3 H C + 3 H3C C C C H C C C CH3 CH3 H O HCH3 CH + H O CH3 CH H C H3 H C 3 3 C - C 3 C C C Br C continued CH3 CH3 H CH3 H CH3 H H H + 73 H H H O CH3 H O CH3 O CH3 + H3C H O CH H3C + H C H O CH3 C C C 3 C C C 3 C C C H C + Br2, H H3C 3 CH3 CH3 CH3 C C C C C C Br CH Br CH3 CH CH 3 CH3 Br Br 3 3 H CH H CH3 3 - Br H H H + H O CH3 H O CH3 H O CH3 H3C O CH3 H3C C C C + HBr H3C + CH C CC C C C H3C C C C 3 CH3 H CH CH3 Br CH33 Br CH3 H CH3 CH3 - Br

H H H + H O CH3 H O CH3 O CH3 H3C H3C + C C C C C C H3C C C C H CH3 CH3 CH3 Br CH Br CH3 Resonant cation 3 Br Br CH3 intermediate - Br H + H O CH3 O H CH3 H3C H3C C C C + HBr C C C CH3 CH3 Br CH3 Br CH3 α-halo derivative

The process of acid catalyzed keto-enol tautomerism allows aldehydes and ketones with α-hydrogens to react with electrophiles. α-halogenation is a typical reaction of this type. In this reaction, the π electrons between the vinylic carbons of an enol form of the aldehyde or ketone are subject to electrophilic attack, leading to a new bond between the α−carbon and halogen.

74 Haloform Reaction of Methyl Ketones Aldehydes and Ketones

H O CH3 O CH3 H Br C C C 2 HO C C CH CH 3 OH - 3 H CH3 CH3 Methyl ketone Halogen with base Carboxylic acid

H H O CH O 3 H CH3 - H + H OH C C C C C C CH3 H O CHCH3 3 H OCH CH3 H CH Base 3 H 3 Br CMethylC ketone C 2 HO -HO C C CH CH 3 OH - - 3 H CH3 O CH CH3 O CH3 3 - H Br2 H C C C C C H C H CH CH3 3 Enolate anion CH CH3 3

- H O O CH3 H H CHO3 CH3 H O CH3 H Br2 H - H+ - H C C C OH C C CC C C + Br C C H C CH3 CH3 CH3 CH3 H CH3 BrCH3 CH3 H Br CHBr 3 continued HO -

-Br O CH3 - O CH - 75 O CH3 Br 3 OH -Above mechanism C C C Br OH H H 2 C repeatedC C twice C C C CH3 Br2 H CH H CH Br 3 CH3 3 CH CH3 3

Br O CH3 - - Br Br - Br O CH3 OH C C C O CH H C O CH 3CH3 C C 3 Br2 CH H CH - H Br 3 CBr C C 3 + H C C C O CH Br - O CH3 H CH3 3 H CH Br CH Br Br 3 3 - Br O CH Br O CH3 Br O 3CH3 - C -Br + - OH Above CmechanismC O CC CC C HCBrOH 3 CH CH3CH Br Brrepeated twice 3 3 2 O CH Br CH3CH H 3 3

Br O CH3 - - Br Br Br O CH3 OH C C C C CH3 C C Br CH3 Br CH3 O CH - O H 3 Tetrahedral H intermediate

- Br O CH Br O CH3 3 C - + C C O C C HCBr3 CH Br CH3 3 Haloform O CH CH3 H 3 Carboxylate anion

The haloform reaction is a variation of α-halogenation. Under basic conditions for enolate formation of a methyl ketone, halogenation of the α-carbon continues until its supply of hydrogens is exhausted. The resulting trihalo-derivative is unstable, undergoing an acyl type substitution resulting in formation of carboxylate and haloform. The iodoform version of this reaction is used as a qualitative test for methyl ketones. Yellow iodoform precipitate convincingly indicates upon reaction with iodine the presence of a methyl ketone.

76 Aldol Condensation Aldehydes and Ketones

H OH H3C CH3 C C H O CH3 - C 2 H3C 1. OH H H C C CH3 C C C 3 H CH CH3 3 2. H O O C H CH3 2 Aldehyde or Ketone C CH3 H3C CH3 Aldol addition product

H OH H O CH3 H O CH3 - H3C H3C CH3 2 H3C OH C C C C C C C C H O CH3 CH3 CH3 - C H HCH3 2 H3CH CH3 1. OH H C C CH3 C C C 3 H Aldehyde or Ketone CH HO - CH3 3 2. H O O C H CH3 2 - C CH3 O CH O CH 3 - H3C 3 H3C C C H3C C C CH3 H C H C CH3 CH3 CH3 CH3

Enolate anion - continued H O CH3 H O H3C H3C CH3 C C C C C 77 CH3 H O CH 3 C H2O H O CHH 3 CH - H C CH 3 H3C H3C H 3 2 H3C OH C C C CH C C O CH3 3 C - CH3 O C CH3 H3C C C C H CH3 H CHH3 C CH3 CH3 H3C CH3 HO - CH3 - OH O O H CH3 - CH3 H3C CH3 HC3C C C C H3C C C H C H C H O C CH3 - CH3 2 H C CHCH CH H3C H 3 3 + OH 3 CH3 O C - C CH3 H O CH3 H O H3C HCH3C H3C CH3 3 C C C C C CH3 C H O H CH H C CH 2 3 H3C H 3 O CH CH3 - 3 O C H3C C C C H C CH3 CH3 H3C CH3 CH3 Anion form of product H OH H3C CH3 C C H O C - 2 H C CH H3C H 3 + OH CH3 O C

C CH3 H3C CH3 Aldol addition product

Many of the reactions involving aldehydes or ketones fall into one of two categories. One set of reactions take place by means of nucleophilic attack upon the electropositive carbonyl carbon. The other set occurs by means of keto-enol tautomerism, a process that exposes an aldehyde or ketone to electrophilic attack at its α-carbon (as in α-halogenation). Aldol condensation, however, belongs to both categories. Aldol condensation occurs with bond formation between the carbonyl carbon of one equivalent of aldehyde or ketone and the α-carbon of another equivalent. Keto-enol tautomerism generates the enolate form from one molecule of the aldehyde or ketone, and the α-carbon of the enolate acts as a nucleophile, forming a bond with the carbonyl carbon of another aldehyde or ketone molecule.

78 Claisen Condensation Aldehydes and Ketones

H O - O O H 1. OH 2 C C O CH CH C CH C O CH + CH OH 3 + 3 2 3 3 2. H3O Claisen condensation product Alcohol H Ester

H O H O - H H OH C C O CH3 2 C C O CH3 Base H H Ester HO H O - O - O H 1. OH 2 C C O CH CH C CH C O CH + CH OH 3 - + 3 2 3 3 O 2. H O O H 3 - H H C O C O H C CH3 H C CH3 Enolate ester

- continued H O H O H H 79 C C O CH3 C C O O CH3 H H H C H O - H H H O OH H C C O OCHC3 2 C C O -CH H 3C O H C CH3 H O H HO - CH3 - H - O H O O C C - H O CH3 + H O O HC C CO CH3 C C O CH3 H H H H3OH CH C CH C O CH + CH OH O C 3 2 3 3 O

CH3 - H O H O H H C C O CH3 C C O CH3 H H C H H O O C - Tetrahedral H C C O CH H 3 O intermediate

CH3 - H O H C C O CH3 + O O H C H H H3O CH C CH C O CH + CH OH O C 3 2 3 3 Claisen condensation product Alcohol O

CH3

Claisen condensation of esters is very similar to aldol condensation (which is why we have included this methanism in this section, even though esters are carboxylic acid derivatives). In Claisen condensation, the enolate form of one ester molecule carries out nucleophilic attack on the carbonyl carbon of another ester molecule. How Claisen condensation differs from aldol condensation illustrates a general difference in the reactivity of esters vs. aldehydes and ketones. In Claisen condensation, the enolate form of one ester molecule approaches another, similarly to aldol condensation, but, in this case, the tetrahedral intermediate resolves itself along an acyl substitution pathway. Both the aldol and Claisen condensations begin with an α-substitution, but in aldol condensation the overall pathway corresponds to nucleophilic addition, while Claisen condensation resolves itself in the manner of an acyl substitution reaction with sp2-hybridization returning with the departure of the leaving group.

80 Conjugate Nucleophilic Addition Aldehydes and Ketones

O H O H C C Nu C - CH3CH2 C CH3CH2 CH CH2 + Nu H α,β – unsaturated Nucleophile H Product with nucleophile aldehyde or ketone having added at β position

O O C - C H + CH CH CH C CH3CH2 CH CH2 Nu 3 2 H - – unsaturated α,β Nucleophile Nu aldehyde or ketone - O H O H C - C Nu C C Nu CH3CH2 C H CH3CH2 C H H H

+ Resonance stabilized H enolate ion

O H H C C Nu CH3CH2 C H H Product with nucleophile added at β position

With α,β unsaturated carbonyl compounds (also called conjugated enones), some nucleophiles will approach and bond to the β-carbon, such as amines, cyanide, and Gilman reagents. Normally with aldehydes and ketones, a nucleophile will only approach and bond to the carbonyl carbon. Being in a polar bond with oxygen, carbonyl carbons are electropositive. However, with an α,β unsaturated carbonyl compound, the positive charge arising due to the polarity of the carbonyl group is shared between the carbonyl carbon and the β-carbon by means of allylic resonance. This is why the β-carbon of α,β unsaturated carbonyl compounds is attractive to nucleophiles.

82 Conjugate Addition of Gilman Reagents Aldehydes and Ketones

O O H R H C C C R + Li CH3CH2 CH CH2 Cu CH3CH2 C H α,β-unsaturated R Gilman reagent H aldehyde or ketone (lithium dialkylcuprate) Product with alkyl group added at β position

RX + 2 Li RLi + LiBr

Formation of O Gilman reagent O H R R+ H C - + LiI C C R 2 RLi + CuI Cu+ Li CH3CH2 CH CH2 Cu Li CH CH C R O 3 2 H R O C H H CH CH CH C R 3 2 H C - + R + - + CH3CH2 CH CH Cu Li 2 Cu Li α,β-unsaturated R Gilman reagent R aldehyde or ketone - continued O H O H R R C - C C C 83 CH3CH2 C H CH3CH2 C H RX + 2 Li RLi + LiBr H H

R + - + 2 RLi + CuI H Cu Li + LiI R O

O C H CH CH CH C O RH 3 2 H C - + R +H - + CH3CH2 CH CH2 C CCu RLi CH CH Cu Li 3 2 C R H R H - O H O H C - C R C C R CH3CH2 C CH3CH2 C H Resonance stabilized H H enolate ion H

+ H

O H H C C R CH3CH2 C H H Product with alkyl group added at β position

Gilman reagents (lithium dialkylcuprates) can be used to carry out nucleophilic addition upon α,β unsaturated carbonyl compounds, adding an alkyl group to the β-carbon. This is a useful reaction for organic synthesis.

84 Acid Halide Formation Carboxylic Acids and Derivatives

O O

CH3CH2 C OH + SOCl2 CH3CH2 C Cl Carboxylic acid Thionyl chloride Acid halide

O O O

CH3CH2 C OH + SOCl2 CH3CH2 C O S Cl + HCl Carboxylic acid Thionyl chloride Chlorosulﬁte O O - O O CH3CH2 C O S Cl CH CH C O S Cl - 3 2 Cl Cl Tetrahedral intermediate

- O O O - CH3CH2 C O S Cl CH3CH2 C Cl + SO2 + Cl Cl Acid halide

Thionyl chloride can be used to convert a carboxylic acid into an acid chloride. (Phosphorus tribromide will accomplish an analogous reaction, converting carboxylic acids to acid bromides.) The mechanism is composed of two successive nucleophilic acyl substitutions, the ﬁrst substitution converting the carboxylic acid into the reactive chlorosulﬁte form, which is then attacked by chlorine anion, resulting in the formation of the acid chloride product.

Fischer Esteriﬁcation Carboxylic Acids and Derivatives

O O HCl RC OH + R'OH RC OR' Acid Carboxylic acid Alcohol Ester

H + H O HCl + O O O RC OH HCl RC OH + R'OH RC OH RC OH Carboxylic Alcohol Acid ' O acid R H

OH OH R R OH H OH H C OH C OH R R C O + C O + ' O ' O R + H R + H R'O H R'O H Tetrahedral intermediate

H O H H H + + O O O + + H3O ' ' RC OR RC OR' RC OR Ester

Fischer esteriﬁcation involves the formation of an ester from a carboxylic acid and an alcohol. The mechanism is an acid promoted acyl substitution, which results in the substitution of an alkoxy group for the hydroxyl portion of the carboxyl group. (An alternate method of ester formation involves the use of the carboxylate anion as an SN2 nucleophile upon a primary alkyl halide.)

86 Use of Carboxylate Anion Nucleophile to form Esters Carboxylic Acids and Derivatives

O O 1. NaOH CH CH C OH CH3CH2 C OCH3 3 2 2. CH Br Carboxylic acid 3 Ester Base then Alkyl halide

O O - + CH3CH2 C OH + NaOH CH3CH2 C O Na + H2O Carboxylic acid Base Carboxylate anion

O O H - + - H + CH3CH2 C O Na CH3Br CH3CH2 C O C Br Carboxylate anion Alkyl halide H O

CH3CH2 C OCH3 + NaBr Ester

Titrating carboxylic acid with a strong base forms a carboxylate salt. The carboxylate anion can then serve as a nucleophile in an SN2 reaction upon a primary or secondary alkyl halide to form an ester. (Fischer esteriﬁcation is often the choice over this SN2 process to form esters from carboxylic acids, especially if the alkoxy portion is tertiary.)

Hydrolysis of Acid Halides Carboxylic Acids and Derivatives

O O H2O C C R Cl Water R OH Acid halide Carboxylic acid

O - O O C R R Cl C Cl C R Cl O O + Tetrahedral Acid halide HH HH intermediate - O O O - R - + Cl C Cl C + Cl C R OH2 R O H OH + + 2 H

O C R OH Carboxylic acid

A typical acyl substitution reaction is the hydrolysis of acyl halides to form carboxylic acids. The progression among acyl derivatives from highest to lowest enthalpy (toward greatest stability) is as follows: acid chloride, acid anhydride, ester, amide, and ﬁnally carboxylic acid. Therefore, thermodynamics favors the hydrolysis of an acid halide.

88 Reaction of Acyl Halide with Ammonia or Amine Carboxylic Acids and Derivatives

O O + - + 2 NH + C 3 C NH4 Cl R Cl 2 equiv. amine R NH2 Ammonium salt Acid halide Amide

O - O O C R R + NH Cl C Cl C 3 R Cl Amine N N + Tetrahedral Acid halide H H H H H H intermediate - O O O - R Cl C Cl C + - C R NH Cl R N H + 3 NH + + 3 H H

O O NH3 C + HCl C + + - R R NH4 Cl Ammonium NH2 Acid Ammonia NH2 Amide Amide salt

Among acyl derivatives, amides are next in stability to carboxylic acids, and both are more stable than acid halides. Just as water will easily hydrolyze an acid halide to form a carboxylic acid, ammonia will aminolyze an acid halide to form an amide. These types of reactions are characterized by the pattern of the electropositive acyl carbon accepting a pair of electrons from the nucleophile while shifting a bond pair over to oxygen, forming the tetrahedral intermediate. The amide product is formed after departure of the halide leaving group. The conjugate acid of the amide has formed, which is a stronger acid than hydrogen halide, so proton transfer occurs onto the halide ion. The amide product will therefore be accompanied by hydrogen halide. Thus two equivalents of ammonia are consumed in the reaction, one consumed in neutralizing the acidic hydrogen halide.

Esteriﬁcation of Acid Halides Carboxylic Acids and Derivatives

O O

RC Cl + R'OH RC OR' Acid halide Alcohol Ester

O - O O RC Cl R C Cl RC Cl + R'OH Acid halide Alcohol O Tetrahedral O R' + H R' H intermediate - O O R ' - C Cl R RC O + Cl O + H R' + H

O R' O RC O + HCl H - RC OR' + Cl Ester

Because of their relative thermodynamic instability, acyl halides are good starting points for the formation of the whole array of carboxylic acid derivatives (carboxylic acids, amides, esters, or acid anhydrides). An alcohol, like water or ammonia, begins the reaction by donating an electron pair to the acyl carbon. An ester is formed when an alcohol performs as the nucleophile in an acyl substitution reaction.

90 Esteriﬁcation of Acid Anhydrides Carboxylic Acids and Derivatives

O O O

RC O C R + R'OH R C OR' Acid anhydride Alcohol Ester

- O O O O O O R + R'OH RC OC R C O C R RC O C R Alcohol O Tetrahedral Acid anhydride R' H O + intermediate R' H - O O O O + R + R C O R' C OC R R C O R' H - O H Cl R' + H

O + HCl RC OR' Ester

Acid anhydrides are somewhat unstable carboxylic acid derivatives. Like acyl halides, which are also unstable, acid anhydrides may be hydrolyzed, aminolyzed, or esteriﬁed through acyl substitution.

Saponiﬁcation of Esters Carboxylic Acids and Derivatives

O - O OH ' C C - + R OH ' Base R OR R O Alcohol Ester Carboxylate anion

O - O O C - ' R OH R OR C OR' C ' Base - R OR OH OH Tetrahedral Ester intermediate - O O O - R OR' C OR' C + - ' C R OH OR R O H Alkoxide OH Carboxylic H anion acid O ' C - + R OH R O Alcohol Carboxylate anion

Refer to the order of stability among carboxylic acid derivatives to predict the ease of carrying out a given acyl transfer reaction. Among common derivatives, the acyl chloride form is the most unstable, followed in order by acid anhydride, ester, amide, and lastly carboxylate (or carboxylic acid), the most stable (lowest free energy). Reaction equilibrium favors the more stable form. For this reason it is a simple process to carry out the saponiﬁcation of an ester by a strong base and transform the relatively unstable ester molecule into a carboxylate anion. The most common use of this reaction is the saponiﬁcation of triglyceride to make soap.

92 Nitrile Hydrolysis Carboxylic Acids and Derivatives

- O 1. OH RC N C Nitrile + OH 2. H3O R Base then Carboxylic acid Acid

H - O - OH OH RC N C - H O RC N R N Nitrile 2 Base

- O H 1. OH H H O RCO N C O HH + O OH 2. H3O R C - C C R N R N H R N H

O - O O H C R - NH C NH C OH R 2 O 2 - NH R OH 2 - OH Tetrahedral RC N Amide RC N OH C - H2O R N intermediate continued - - O O O R - NH2 93 HC NH C H + NH HC 2O R OH 2 R O H O O OH HH O C - C C R N R N H R N H

O O + H3O - + NH O C - C 3 R OH O RO O C R NH C NH C R 2 2 R NH2 - OH OH

- - O O O R - NH2 C NH C + NH C 2 R OH 2 R O H OH Carboxylic Amine acid ion

O + O H3O - + C C NH3 OH R O R Ammonia Acid Carboxylate anion Carboxylic acid

The electropositive nitrile carbon is similar to a carbonyl carbon in that it can accept the approach of a nucleophile for addition, although the overall process is signiﬁcantly different with nitriles. Nitrile hydrolysis begins with the nucleophilic addition of hydroxide anion to the nitrile. The ﬁrst intermediate formed then takes a proton from water and subsequently undergoes an intramolecular rearrangement to form an amide. This amide is temporary, however, in a strong base environ- ment, becoming transformed through the acyl substitution hydrolysis to form the carboxylate anion.

Nitrile Reduction Carboxylic Acids and Derivatives

LiAlH4 RC N RCH2 NH2 Nitrile Reducing Amine agent

Nitrile is a highly oxidized form, and it will mine the reducing agent, LiAlH4, for its hydrides (H–). The reduction of a nitrile produces an amine.

94 Hofmann Rearrangement Carboxylic Acids and Derivatives

O - H C H OH, Br2 R N + CO N H 2 R H Carbon Amide H2O Amine dioxide Halogen in Aqueous Base

O O - O OH, Br2 C H C H N R N C - + R H H H H2O Halogen in R N Amide - OAqueous Base OH Conjugate base of amide - H C H OH, Br2 R N + CO N H 2 - R O H O H2O OH O C H C H R - N R N Br C H Br Br R N N-Bromo amide Br

O O - O O OH, Br C O H 2 H C + R N - ONC R + - R N C - H2O H C - C H + H2O Br H Br Br R N R N - R N N-Alkyl isocyanate Conjugate base OH of N-Bromo amide continued O R R - O N OH ONC R N O C 95 H C H + R - N -R C N+ H - C H O O O Br O C O H H R NH HH Br Br Br

- R O N O O O - + H O ONC R + Br C - C Br + H 2 C C R - Br C R O N O N R O N O H R HN H H H

R R N ONC R N H R N + CO + - C + H H 2 - C H O O O O O H H HH Betaine intermediate

- R N O O

C + H C R C R O N O N O O H H H H H N-Alkylcarbamic acid

H R N + CO H 2 Amine Carbon dioxide

Hofmann rearrangement converts an amide, with the loss of one carbon, into an amine. Beginning with the amide, strong base, and halogen, the strong base ionizes the amide to form an amide anion. Amide anions have certain characteristics in common with the enolate anions, and halogenation occurs in manner similar to the α-halogenation of aldehydes and ketones. Halogenation enhances the acidity of the remaining hydrogen, which the base removes easily. To assist the task of retaining in memory the formidable Hofmann rearrangement mechanism, imagine the point of view of nitrogen atom at this point. In the bromoamide anion, nitrogen has one bond to a carbonyl carbon, which has the strong electronegative pull of oxygen working across it, and another bond to bromine, which also pulls tenaciously on electrons. From the point of view of nitrogen, these are two greedy neighbors. Intramolecular electron pair migrations occur to stabilize the entire system as an alkyl shift occurs from the carbonyl carbon onto nitrogen and the departure of halide ion. Isocyanate results, which contains a very electropositive carbon that draws the approach of a nucleophilic water molecule. This leads to N-alkylcarbamic acid, which is still unstable. Decarboxylization occurs as the last major step, releasing carbon dioxide to leave the ﬁnal amine, with a new carbon-nitrogen bond.