CHEM 213 Exam 4 Part 1
Professor Kelly Boebinger Chapter 20: Carboxylic Acids and Nitriles The Importance of Carboxylic Acids
(RCO2H) Carboxylic acids and their derivatives are carbonyl compounds in which the acyl group is bonded to electronegative atom such as oxygen, halogen, nitrogen, or sulfur. In contrast to aldehydes and ketones, the acyl group bonded to the substituent that can act as a leaving group in substitution reactions. Starting materials for acyl derivatives (esters, amides, and acid chlorides) Abundant in nature from oxidation of aldehydes and alcohols in metabolism
3 20.1 Naming Carboxylic Acids
Carboxylic Acids, RCO2H If derived from open-chain alkanes, replace the terminal -e of the alkane name with -oic acid The carboxyl carbon atom is C1
4 Alternative Names
Compounds with CO2H bonded to a ring are named using the suffix -carboxylic acid
The CO2H carbon is not itself numbered in this system
Use common names for formic acid (HCOOH) and acetic acid (CH3COOH) – see Table 20.1 5 Problems: Draw the structures for the following
A. 2,3-dimethylhexanoic acid B. 2-cyclohexenecarboxylic acid C. butanedioic acid
D. 2-aminopropanoic acid (alanine) (amino = NH2) E. 2-hydroxypropanoic acid (lactic acid)
A. B. C.
E. D.
6 Give the IUPAC name
A. CH3CH=CHCH2CH2COOH
B. (CH3)2CHCH2COOH
C. CH3CH(Br)CH2CH2COOH
A. B. C.
7 20.2 Structure and Physical Properties of Carboxylic Acids Carboxyl carbon sp2 hybridized: planar, 120° Carboxylic acids form hydrogen bonds, existing as cyclic dimers held together by two hydrogen bonds
Strong hydrogen bonding causes much higher
boiling points than the corresponding alcohols 8 20.3 Dissociation of Carboxylic Acids Carboxylic acids are proton donors toward weak and strong bases, producing metal + carboxylate salts, RCO2 M
Carboxylic acids with more than six carbons are only slightly soluble in water, but their conjugate base salts are water-soluble 9 Acidity Constant and pKa
Carboxylic acids transfer a proton to water to give + + H3O and carboxylate anions, RCO2 , but H3O is a much stronger acid -5 The acidity constant, Ka,, is about 10 for a typical carboxylic acid (pKa ~ 5) Weaker acids than mineral acids but stronger than alcohols. Weak acids slightly dissociate.
10 20.4 Substituent Effects on Acidity
Electronegative substituents promote formation of the carboxylate ion
11 Substituent Effects
Carboxylic acids differ in acid strength. Electron-withdrawing groups stabilize carboxylate anions and increase acidity. An electron-withdrawing group attached to the α-carbon of a carboxylic acid inductively withdraws electron density, thereby delocalizing the negative charge, thus stabilizes the carboxylate anion thus increasing acidity.
An electron-donating group destabilizes the carboxylate anion and decreases acidity 12 Examples of Inductive Effects on Acidity Fluoroacetic, chloroacetic, bromoacetic, and iodoacetic acids are stronger acids than acetic acid since more of the acid is in the dissociated form.
13 20.5 Substituent Effects in Substituted Benzoic Acids .Groups that are deactivating in electrophilic aromatic substitution reactions increase the acidity of substituted benzoic acids. .The acidity of benzoic acids can be used to predict electrophilic reactivity, since measuring acidity is easier.
14 20.6 Preparation of Carboxylic Acids
Oxidation of a substituted alkylbenzene with KMnO4 or Na2Cr2O7 gives a substituted benzoic acid (see Section 16.10) 1° and 2° alkyl groups can be oxidized, but NOT 3o
15 From Alkenes
Oxidative cleavage of an alkene with KMnO4 gives a carboxylic acid if the alkene has at least one vinylic hydrogen (see Section 7.8)
O O O O KMnO4 H3C CH CH C OH H3C C OH HO C C OH + + H3O
16 From Alcohols & Aldehydes
Oxidation of a primary alcohol or an aldehyde H CrO O R C OH 3 R C OH + H H3O
O O Ag2O R C H R C OH NH4OH
17 Hydrolysis of Nitriles (RCN)
Conversion of an alkyl halide to a nitrile (with cyanide ion) followed by hydrolysis produces a carboxylic acid with one more carbon (RBr RCN RCO2H) Best with primary halides because elimination reactions occur with secondary or tertiary alkyl halides
18 Carboxylation of Grignard Reagents
Grignard reagents react with dry CO2 to yield a metal carboxylate Limited to alkyl halides that can form Grignard reagents (see 17.6)
O ether 1. CO2, ether o R-Br + Mg R-Mg-Br R C OH + 2. H3O
19 20.7 Reactions of Carboxylic Acids: A Preview
Carboxylic acids transfer a proton to a base to give anions, which are good nucleophiles in SN2 reactions Like ketones, carboxylic acids undergo addition of nucleophiles to the carbonyl group In addition, carboxylic acids undergo other reactions characteristic of neither alcohols nor ketones
20 20.7 Reactions of Carboxylic Acids: A Preview
21 20.8 Reduction of Carboxylic Acids
Reduced by to yield primary alcohols Carboxylic acids can be reduced to primary alcohols with either LiAIH4 or BH3 (but not by NaBH4). LiAlH4 is difficult and often requires heating in tetrahydrofuran solvent to go to completion H O 1. LiAlH4, THF, ∆ R C OH R C OH + 2. H3O H
BH3 is a more selective reagent, since the reaction occurs rapidly at room temperature. H O 1. BH3, THF R C OH R C OH + 2. H3O 22 H Nitriles, RCN (Covered in chapter 21.8 McMurry 5th ed.)
Closely related to carboxylic acids named by adding -nitrile as a suffix to the alkane name, with the nitrile carbon as C1
Complex nitriles are named as derivatives of carboxylic acids. Replace -ic acid or -oic acid ending with -onitrile
23 20.9 Chemistry of Nitriles RC≡N
Nitriles and carboxylic acids both have a carbon atom with three σ bonds to an electronegative atom, and both contain a bond Both both are electrophiles
Preparation of Nitriles by Dehydration
Reaction of primary amides RCONH2 with SOCl2 or POCl3 (or other dehydrating agents) Not limited by steric hindrance or side reactions (as is the reaction of alkyl halides with NaCN)
O SOCl2, benzene
R C N + SO2 + 2 HCl R C NH2 80 °C 24 Reactions of Nitriles
25 Reactions of Nitriles RC≡N
Hydrolysis: Conversion of Nitriles into Carboxylic Acids Hydrolyzed in with acid or base catalysis to a carboxylic acid and ammonia or an amine
Reaction of Nitriles with Organometallic Reagents Grignard reagents add to give an intermediate imine anion that is hydrolyzed by addition of water to yield a ketone
26 Reactions of Nitriles RC≡N
Reduction: of a nitrile with LiAlH4 gives a primary amine
Mechanism Nucleophilic addition of hydride ion to the polar CN bond, yields an imine anion The C=N bond undergoes a second nucleophilic addition of hydride to give a dianion, which is protonated by water
27 20.10 Spectroscopy of Carboxylic Acids and Nitriles. Infrared Spectroscopy
O–H bond of the carboxyl group gives a very broad absorption 2500 to 3300 cm1 C=O bond absorbs sharply between 1710 and 1760 cm1 Free carboxyl groups absorb at 1760 cm1 Commonly encountered dimeric carboxyl groups absorb in a broad band centered around 1710 cm1
Nitriles show an intense CN bond absorption near 2250 cm1 for saturated compounds and 2230 cm1 for aromatic and conjugated molecules 28 13CNMR
Carboxyl 13COOH signals are at 165 to 185 Aromatic and ,b-unsaturated acids are near 165 and saturated aliphatic acids are near 185 13C N signal 115 to 130
29 1HNMR
The acidic CO2H proton is a singlet near 12 When D2O is added to the sample the CO2H proton is replaced by D causing the absorption to disappear from the NMR spectrum Note that the carboxyl proton absorption occurs at 12.0
30 CHEM 213 Exam 4 Part 2
Professor Kelly Boebinger Chapter 21. Carboxylic Acid Derivatives and Nucleophilic Acyl Substitution Reactions Carboxylic Compounds
General reaction pattern: Nucleophilic acyl substitution
33 21.1 Naming Carboxylic Acid Derivatives Acid Halides, RCOX Derived from the carboxylic acid name by replacing the -ic acid ending with -yl or the - carboxylic acid ending with –carbonyl and specifying the halide
34 Naming Acid Anhydrides, RCO2COR'
If symnmetrical replace “acid” with “anhydride” based on the related carboxylic acid (for symmetrical anhydrides)
Unsymmetrical anhydrides— cite the two acids alphabetically From substituted monocarboxylic acids: use bis- ahead of the acid name
35 Naming Amides, RCONH2
With unsubstituted NH2 group. replace -oic acid or -ic acid with -amide, or by replacing the -carboxylic acid ending with –carboxamide
If the N is further substituted, identify the substituent groups (preceded by “N”) and then the parent amide
36 Naming Esters, RCO2R
Name R’ and then, after a space, the carboxylic acid (RCOOH), with the “-ic acid” ending replaced by “- ate”
37 Name the following
B. C. A. O O CH3 CH3 O C H3C C Br CH CH CH C O CH Cl 3 2 2 3
D. O O A. acetyl bromide B. benzoyl chloride CH3 CH2 CH2 C O C CH3 C. methyl 2,3-dimethylbutanoate D. butanoic ethanoic anhydride E. E. 2-butenenitrile CH3 CH CH C N F. butanamide O F. CH CH CH C NH2 3 2 2 38 Give the structure of the following
A. A. methyl ethanoate B. (methyl acetate) B. propanoic anhydride C. benzamide C. (benzenecarboxamide) D. D. N,N-dimethylformamide E. 1-methylcyclobutanecarboxamide E. F. ethyl benzoate G. 2-chlorobutanoyl chloride
F. G.
39 Reactions of Carboxylic Acids
40 21.2 Nucleophilic Acyl Substitution
The substitution of a nucleophile to a polar C=O bond is a key step in 3 of the major 4 reactions of carbonyl groups. Carboxylic acid derivatives have an acyl carbon bonded to a group Y that can leave A tetrahedral intermediate is formed and the leaving group is expelled to generate a new carbonyl compound, leading to substitution
O O O + :Nu- (or :Nu-H) + :Y- C C C R Nu R1 Y 1 R1 Nu Y Y is a leaving group
= -OR, -NR2, -Cl
41 Relative Reactivity of Carboxylic Acid Derivatives
Nucleophiles react more readily with unhindered carbonyl groups
More electrophilic carbonyl groups are more reactive to addition (acyl halides are most reactive, amides are least) The intermediate with the best leaving group decomposes fastest
42 Substitution in Synthesis
It is possible to convert a more reactive acid derivative into a less reactive one
43 General Reactions of Carboxylic Acid Derivatives
Hydrolysis: reaction with water to yield a carboxylic acid. O HOH O HY R C Y R C OH +
Alcoholysis: reaction with an alcohol to yield an ester. 1o ROH is most reactive O R'OH O HY R C Y R C OR' + Aminolysis: reaction with ammonia or an amine to yield an amide.
O NH3 O HY R C Y + R C NH2 44 General Reactions of Carboxylic Acid Derivatives
Reduction: Reaction with a hydride reducing agent
yields an aldehyde or an alcohol. LiAlH(OC(CH3)3)3 reduces to RCHO. LiAlH4 reduces to ROH - - OH O [H ] O [H ] R C H R C Y R C H H Amides are reduced to yield amines. - H O [H ]
R C NH2 R C NH2 H 45 General Reactions of Carboxylic Acid Derivatives Grignard reaction: Reaction with organometallic reagent to yield a ketone or an alcohol. O O OH ether ether R C Y + R'MgX R C R' + R''MgX R C R'' R' Gilman reaction: Reaction with organometallic reagent to yield a ketone. O O ether ether OH - + - + R C Y + R'Cu Li R C R' + R"Cu Li R C R' R"
46 21.3 Nucleophilic Acyl Substitution Reactions of Carboxylic Acids
Convert -OH into a better leaving group to enhance reactivity. Acid halides are made from reaction of carboxylic acid with
thionyl chloride, SOCl2, (or PBr3) O O SOCl2 R C OH R C Cl
O O PBr3 R C OH R C Br ether
Acid anhydride made from 2 molecules of carboxylic acid by
heating to remove 1 equivalent of H2O. (symmetrical only) O O O 2 + H2O R C OH R C O C R 47 21.3 Nucleophilic Acyl Substitution Reactions of Carboxylic Acids
Fischer Esterification: Esters can be produced by the acid-catalyzed reaction of a carboxylic acid and an alcohol. Acid makes the acyl carbon more reactive toward the alcohol. All steps are reversible. The reaction can be driven to completion by removing water or by using a large excess of alcohol. O ethanol O R'OH + HOH R C OH + HCl R C O R'
Amides are difficult to form from carboxylic acids because amines convert carboxylic acids to carboxylate salts that no longer have electrophilic carbons.
48 21.4 Reactions of Acid Halides
49 21.5 Chemistry of Acid Anhydrides
Most general method, can be symmetrical or unsymmetrical anhydrides.
O O ether O O R C ONa + Cl C R 25 °C R C O C R
Heating cyclic dicarboxylic acids can form five- or six-membered rings Acyclic anhydrides are not generally formed this way - they are usually made from acid chlorides and carboxylic acids
50 21.5 Reactions of Acid Anhydrides
Similar to acid chlorides in reactivity
51 21.6 Chemistry of Esters
Many esters are pleasant-smelling liquids: fragrant odors of fruits and flowers Also present in fats and vegetable oils
52 21.6 Chemistry of Esters
Esters are usually prepared from carboxylic acids
Fisher Esterification 53 Mechanism of the Fischer Esterification The reaction is an acid-catalyzed, nucleophilic acyl substitution of a carboxylic acid When 18O-labeled methanol reacts with benzoic acid, the methyl benzoate produced is 18O-labeled but the water produced is unlabeled
54 21.6 Reactions of Esters
Less reactive toward nucleophiles than are acid chlorides or anhydrides Cyclic esters are called lactones and react similarly to acyclic esters Aminolysis: Esters can be converted to amides by heating with ammonia/amines, but it's easier to start with an acid chloride.
NH O 3 O
R C O R ether R C NH2 + ROH
Hydrolysis: Ester hydrolysis in basic solution (saponification) occurs through a nucleophilic acyl substitution mechanism.
H O, NaOH O 2 O
R C O R + R C OH + ROH or H3O 55 21.6 Reactions of Esters
Reduction: LiAlH4 reduces esters to primary alcohols by a route similar to that described for acid chlorides.
1. LiAlH , ether O 4 OH
R C O R + R C H + HOR 2. H3O 2
If DIBAH at -78°C is used, reduction yields an aldehyde. Low temperature to avoid further reduction to the alcohol. DIBAH = [(CH3)2CHCH2]2AlH
O 1. DIBAH in toluene O R C O R + R C H + HOR 2. H3O
56 21.6 Reactions of Esters
Reaction with Grignard reagents: Esters react twice with Grignard reagents to produce tertiary alcohols containing two identical substituents.
O 1. 2 R'MgBr in ether OH R C O R + R C R' + HOR 2. H3O R'
57 21.7 Chemistry of Amides
Prepared by reaction of an acid chloride with ammonia, monosubstituted amines, or disubstituted amines. All R’s can be Hydrogen
O R2'NH O + HCl R C Cl R C NR' 2
58 Hydrolysis Reactions of Amides
Heating in either aqueous acid or aqueous base produces a carboxylic acid and amine Acidic hydrolysis by nucleophilic addition of water to the protonated amide, followed by loss of ammonia
O + O H3O C + C + NH4 R NH2 R OH
Basic hydrolysis of Amides by addition of hydroxide and loss of amide ion O OH- O - C C NH R NH - + 2 2 R O 59 Reduction: Conversion of Amides into Amines
Reduced by LiAlH4 to an amine rather than an alcohol (Converts C=O CH2) O 1. LiAlH4, ether R CH NR' 2 R C NR' 2 2 2. H2O Uses of Reduction of Amides Works with cyclic and acyclic, good route to cyclic
amines H O 1. LiAlH4, ether H 2. H O N 2 N
NOTE: 21.8 Chemistry of nitriles covered in Chapter 20 60 21.9 Thioesters and Acyl Phosphates: Biological Carboxylic Acid Derivatives
Nucleophilic carboxyl substitution in nature often involves a thioester or acyl phosphate These have unique binding properties and are readily activated by enzymes
61 21.10 Polyamides and Polyesters: Step- Growth Polymers
Reactions occur in distinct linear steps, not as chain reactions Reaction of a diamine and a diacid chloride gives an ongoing cycle that produces a polyamide
A diol with a diacid leads to a polyester
62 Polyamides (Nylons)
Heating a diamine with a diacid produces a polyamide called Nylon® Nylon 66® is from adipic acid and hexamethylene- diamine at 280°C
63 Polyesters
The polyester from dimethyl terephthalate and ethylene glycol is called Dacron® and Mylar® to make fibers
64 21.11 Spectroscopy of Carboxylic Acid Derivatives
Infrared Spectroscopy Acid chlorides absorb near 1800 cm1 Acid anhydrides absorb at 1820 cm1 and also at 1760 cm1 Esters absorb at 1735 cm1, higher than aldehydes or ketones
Amides absorb near the low end of the carbonyl region65 Nuclear Magnetic Resonance Spectroscopy Hydrogens on the carbon next to a C=O are near 2 in the 1H NMR spectrum. All acid derivatives absorb in the same range so NMR does not distinguish them from each other
13C NMR is useful for determining the presence or absence of a carbonyl group in a molecule of unknown structure Carbonyl carbon atoms of the various acid derivatives absorb from 160 to 180
66 CHEM 213 Exam 4 Part 3
Professor Kelly Boebinger Chapter 22. Carbonyl Alpha-Substitution Reactions The Position
The carbon next to the carbonyl group is designated as being in the position Electrophilic substitution occurs at this position through either an enol or enolate ion
69 22.1 Keto–Enol Tautomerism
A carbonyl compound with a hydrogen atom on its carbon rapidly equilibrates with its corresponding enol Compounds that differ only by the position of a moveable proton are called tautomers The enol tautomer is usually present to a very small extent and cannot be isolated However, since it is formed rapidly, it can serve as a reaction intermediate
70 Tautomers Are Not Resonance Forms
Tautomers are structural isomers Resonance forms are representations of contributors to a single structure Tautomers interconvert rapidly while ordinary isomers do not
71 Mechanism of Tautomerism
Only hydrogens at the position are acidic.
Acid Catalysis Brønsted acids catalyze keto-enol tautomerization by protonating the carbonyl and activating the protons 72 Base Catalysis of Enolization
Brønsted bases catalyze keto-enol tautomerization The hydrogens on the carbon are weakly acidic and transfer to water is slow In the reverse direction there is also a barrier to the addition of the proton from water to
enolate carbon 73 22.2 Reactivity of Enols: The Mechanism of Alpha-Substitution Reactions
Enols behave as nucleophiles and react with electrophiles because the double bonds are electron-rich compared to alkenes
74 22.3 Alpha Halogenation of Aldehydes and Ketones
Aldehydes and ketones can be halogenated at their
positions by reaction with Cl2, Br2, or I2 in acidic solution O CH COOH O H 3 C X HX X2 C + R C + R C
Halogen isn't involved in the rate-limiting step: the rate doesn't depend on the identity of the halogen, but only on [ketone] and [H+].
75 Elimination Reactions of -Bromoketones α-Bromo ketones are useful in syntheses because they can be dehydrobrominated by base treatment to form α, β-unsaturated ketones.
76 22.4 Alpha Bromination of Carboxylic Acids: The Hell–Volhard–Zelinskii (HVZ) Reaction
Carboxylic acids do not react with Br2 (Unlike aldehydes and ketones)
They are brominated by a mixture of Br2 and PBr3 (HVZ) O O 1. Br2, PBr3 H Br C C HO C 2. H2O HO C
77 Mechanism of Bromination
PBr3 converts -COOH to –COBr, which can enolize and add Br2
78 22.5 Acidity of Alpha Hydrogen Atoms: Enolate Ion Formation Hydrogens α to a carbonyl group are weakly acidic. This stability is due to overlap of a vacant p orbital with the carbonyl group p orbitals, allowing the carbonyl group to stabilize the negative charge by resonance.
The two resonance forms aren't equivalent; the form with the negative charge on oxygen is of lower energy.
79 Reagents for Enolate Formation
Ketones are weaker acids than the OH of alcohols so a a more powerful base than an alkoxide is needed to form the enolate Sodium hydride (NaH) or lithium diisopropylamide
[LiN(i-C3H7)2] (LDA) are strong enough to form the enolate
80 b-Dicarbonyls Are More Acidic
When a hydrogen atom is flanked by two carbonyl groups, its acidity is enhanced. Both carbonyl groups can stabilize the negative charge.
81 Table 22.1: Acidities of Organic Compounds
82 22.6 Reactivity of Enolate Ions
The carbon atom of an enolate ion is electron-rich and highly reactive toward electrophiles (enols are not as reactive) Enolates are more useful than enols, unlike enols, stable solutions of enolates are easily prepared.
83 Two Reactions Sites on Enolates
Reaction on oxygen yields an enol derivative Reaction on carbon yields an -substituted carbonyl compound
84 22.7 Halogenation of Enolate Ions: The Haloform Reaction Base-promoted reaction occurs through an enolate ion intermediate
This proceeds readily because each halogen added makes the carbonyl compound more reactive. Consequently, poly halogenated compounds are usually produced.
85 Further Reaction: Cleavage
In presence of excess base and halogen, a methyl ketone is triply halogenated (X = Cl, Br, I) and then cleaved by a base.
O O X2 C C - + CHX3 R CH3 NaOH R O
This reaction is only useful with methyl ketones, which form HCX3 when reacted with halogens. The HCX3 is a solid that can be identified.
86 22.8 Alkylation of Enolate Ions
Alkylation occurs when the nucleophilic enolate ion reacts with the electrophilic tosylate or alkyl halide and displaces the leaving group
Alkylations are useful because they form a new C-C bond. Alkylations have the same limitations as SN2 reactions; the alkyl groups must be methyl, primary, allylic or benzylic. Secondary halides react poorly, and tertiary halides don't react at all because of competing elimination
87 The Malonic Ester Synthesis
For preparing a carboxylic acid from an alkyl halide while lengthening the carbon chain by two atoms
88 Formation of Enolate and Alkylation
Malonic ester (diethyl propanedioate) is easily converted into its enolate ion by reaction with sodium ethoxide in ethanol The enolate is a good nucleophile that reacts rapidly with an alkyl halide to give an -substituted malonic ester
89 Dialkylation
The product has an acidic -hydrogen, allowing the alkylation process to be repeated
90 Hydrolysis and Decarboxylation
The malonic ester derivative hydrolyzes in acid and loses CO2 (“decarboxylation”) to yield a substituted monoacid
91 Decarboxylation of b-Ketoacids
Decarboxylation requires a carbonyl group two atoms away from the CO2H The second carbonyl permit delocalization of the resulting enol The reaction can be rationalized by an internal acid- base reaction
92 Preparation Cycloalkane Carboxylic Acids
1,4-dibromobutane reacts twice, giving a cyclic product Three-, four-, five-, and six-membered rings can be prepared in this way
93 The Acetoacetic Ester Synthesis
The acetoacetic ester synthesis is used for converting an alkyl halide to a methyl ketone, while lengthening the carbon chain by 3 atoms.
As with malonic ester, acetoacetic ester has two acidic hydrogens, which are flanked by a ketone and an ester, and two alkylations can take place.
H O 1. Na+ O- Et H O 1. Na+ O- Et R' O H C C CH3 R C C CH3 R C C CH3 2. RX 2. R'X CO2Et CO2Et CO2Et
94 Generalization: b-Keto Esters
Heating in aqueous HCl hydrolyzes the ester and decarboxylates the acid to yield the ketone. All β- keto esters can undergo this type of reaction. The sequence: enolate ion formation, alkylation, hydrolysis/decarboxylation is applicable to b-keto esters in general Cyclic b-keto esters give 2-substituted cyclohexanones
95 Direct Alkylation of: Ketones, Esters, & Nitriles
LDA in a nonprotic solvent can be used to convert the above compounds to their enolates. Alkylation of an unsymmetrical ketone leads to a mixture of products, but the major product is alkylated at the less hindered position. Ketone
O O O H3C H H3C 1. LDA in THF H3C CH3 H H + H3C 2. CH3I major product minor product
96 Direct Alkylation of: Ketones, Esters, & Nitriles
Ester O O H R' R C 1. LDA in THF R C O C O C 2. R'X
Nitrile H 1. LDA in THF R N C C N C C 2. RX
97 CHEM 213 Exam 4 Part 4
Professor Kelly Boebinger Chapter 23. Carbonyl Condensation Reactions Condensation Reactions
Carbonyl compounds are both the electrophile and nucleophile in carbonyl condensation reactions
100 23.1 Mechanism of Carbonyl Condensation Reactions Carbonyl condensation reactions take place between two carbonyl components. Many kinds of carbonyl compounds undergo carbonyl condensation reactions. One component (the nucleophilic donor) is converted to its enolate and undergoes an α-substitution reaction. The other component (the electrophilic acceptor) undergoes nucleophilic addition. electrophile O O O - O base O
- - H nucleophile O 101 23.2 Condensations of Aldehydes and Ketones: The Aldol Reaction
The aldol condensation is a base-catalyzed dimerization of two aldehydes or ketones that have α hydrogens. Acetaldehyde reacts in basic solution (NaOEt, NaOH) with another molecule of acetaldhyde The b-hydroxy aldehyde product is aldol (aldehyde + alcohol)
Problem: Show the Aldol reaction of propanal O O + - OH O O O NaNa+OO-EtEt OH O
CCHH3CHCH2CHCH CHCH2CHCH CCHH3CHCH2CHCHCHCHCHCH 3 2 ++ 2 EtOHEtOH 3 2 CH CH 102 CH3 3 CH3 3 Aldehydes and the Aldol Equilibrium
For monosubstituted aldehydes, the equilibrium favors products, but for other aldehydes and ketones, the equilibrium favors reactants.
103 Ketones and the Aldol Equilibrium
104 Mechanism of Aldol Reactions
Aldol reactions, like all carbonyl condensations, occur by nucleophilic addition of the enolate ion of the donor molecule to the carbonyl group of the acceptor molecule The addition intermediate is protonated to give an alcohol product
CH H ++ CH H CH base CH33 H H CH33 H CH33 base H - OO CC O - C C H HO C C H - O C C H HO C C H H H C - H H H22C H CC HH CC HH CC OO HH OO HH OO Intermediate
105 Conditions for Condensations
Carbonyl condensation reactions require only a catalytic amount of base. Not all carbonyl compound is converted. – After the condensation, the basic catalyst ( OCH3 or –OCH2CH3) is regenerated
0.05 equiv O + - O CH CH CH OH O Na OCH3 3 2 CH3OH CH3CH2 CH CH3CH2 CH CHCH methanol CH3 Alpha-substitution reactions, on the other hand, use one equivalent of base. Reactions are accomplished by converting all of the carbonyl compound to enolate form so it is not an electrophile O O
1 equiv, LDA Add CH3I CH3 THF, -78 °C 106 23.4 Dehydration of Aldol Products: Synthesis of Enones Aldol products are easily dehydrated. The b-hydroxy carbonyl products dehydrate to yield conjugated enones The term “condensation” refers to the net loss of water and combination of 2 molecules
107 Dehydration of b-Hydoxy Ketones and Aldehydes
The hydrogen is removed by a base, yielding an enolate ion that expels the OH leaving group
Under acidic conditions the OH group is protonated and water is expelled
108 23.5 Using Aldol Reactions in Synthesis If a desired molecule contains either a b-hydroxy carbonyl or a conjugated enone, it might come from an aldol reaction
109 Extending the Synthesis
Subsequent transformations can be carried out on the aldol products A saturated ketone might be prepared by catalytic hydrogenation of the enone product Example: The synthesis of 1-butanol using an aldol reaction of ethanal.
OO OOHH OO O 1.1. NaBH NaBH OH O 1. 1.NaOH,1. NaOH, NaOH, EtOH EtOH EtOH 1. NaBH4 44 CHCCHHCH33CHCHCHCHCHCHCHCH ++ CHCCHHCH33CHCHCHCHCHCHCHCH22 2 H22HCH33CCCHCHCH 2. 2.heat2. heat heat 3 2.2. H H+OO 3 2 3 2. H3O33 HH, ,Pd Pd H2, Pd22
OHOOHH CCHH CHCH CHCHCHCH CH3 CH33 2 CH22 2CH222 22 110 23.6 Mixed Aldol Reactions
A mixed aldol reaction between two similar aldehyde or ketone partners leads to a mixture of four possible products. This is not useful
111 Practical Mixed Aldols
A single product can be formed from two different components: If one of the carbonyl partners contains no hydrogens and the carbonyl is unhindered (such as benzaldehyde and formaldehyde) it is a good electrophile and can react with enolates then a mixed aldol reaction is likely to be successful 2-methylcyclohexanone gives the mixed aldol product on reaction with benzaldehyde
112 Mixed Aldols With Acidic Carbonyl Compounds
A single product can be formed from two different components: if one carbonyl compound is more acidic. Ethyl acetoacetate is completely converted into its enolate ion under less basic conditions than monocarbonyl partners Aldol condensations with ethyl acetoacetate occurs preferentially to give the mixed product
113 23.7 Intramolecular Aldol Reactions
Treatment of certain dicarbonyl compounds with base produces cyclic products by intramolecular reaction
114 23.8 The Claisen Condensation Reaction Reaction of an ester having an hydrogen with 1 equivalent of a base to yield a b-keto ester
As in aldol condensation, writing the two Claisen components in the correct orientation makes it easier to predict the product. O O O O O O O O + - 1. Na+1.O -NaEt O Et CH3 CH2 C CH C O Et EtOH CH3 CH2 C O Et + H2C C O Et CH3 CH2 C CH C O Et EtO+ H CH3 CH2 C O Et + H2C C O Et + + 2.+ H O 2. H O 3 CH3 CH3 3 CH3 CH3 115 Problems: Show the reactions of Claisen condensation of the following. O
CH2C A. (CH3)2CHCH2CO2Et O Et B. ethyl cyclohexylacetate
A.
B.
116 23.9 Mixed Claisen Condensations
Successful when one of the two ester act as the electrophilic acceptor in reactions with other ester anions to give mixed b-keto esters One component has no hydrogens.
No hydrogen hydrogen
117 Esters and Ketones
Reactions between esters and ketones, resulting in b-diketones Best when the ester component has no hydrogens and can't act as the nucleophilic donor
118 23.10 Intramolecular Claisen Condensations: The Dieckmann Cyclization
1,6-diesters form 5-membered rings. (b- ketoester)
O O 1 Et + - O 2 1. Na OEt, EtOH O 1 5 C EtOH 2. H O+ 2 + 3 O 3 O Et 5 C 4 3 4 O Et 1,7-diesters form 6-membered rings (b- ketoester) O 1 O O Et 1. Na+ -OEt, EtOH 2 O 1 O 6 C Et EtOH + 2 3 2. H3O O + 6 C 4 5 O Et 3 5 119 4 Mechanism of the Dieckmann Cyclization
120 Alkylation of Dieckmann Product
The cyclic b-keto ester can be further alkylated and decarboxylated as in the acetoacetic ester synthesis
121 23.11 The Michael Reaction
The Michael reaction is the conjugate addition of an enolate to an α, β -unsaturated carbonyl compound. Occurs with a variety of ,b-unsaturated carbonyl compounds (aldehydes, esters, nitriles, amides, and nitro compounds) Donors include b-diketones, b-keto esters, malonic esters, b-keto nitriles, and nitro compounds
122 Best Conditions for the Michael Reaction When a particularly stable enolate ion Example: Enolate from a b-keto ester or other 1,3-dicarbonyl compound adding to an unhindered ,b-unsaturated ketone
123 Mechanism of the Michael Reaction
Nucleophilic addition of a enolate ion donor to the b carbon of an ,b-unsaturated carbonyl acceptor
H+
124 23.12 The Stork Enamine Reaction
Enamines are equivalent to enolates in their reactions and can be used to accomplish the transformations under milder conditions
Predict the product
Enamines are prepared from a ketone and a secondary amine
125 Why Enamines Are Nucleophilic
Overlap of the nitrogen lone-pair orbital with the double-bond π orbitals increases electron density on the carbon atom
126 23.13 Carbonyl Condensation Reactions in Synthesis: The Robinson Annulation Reaction
A two-step process: combines a Michael reaction with an intramolecular aldol reaction The product is a substituted 2-cyclohexenone
127 23.14 Biological Carbonyl Condensation Reactions
The acetyl CoA molecule as the major building block for synthesis in living systems (Two-carbon acetyl group and large CoA group is connected as thiol ester Acetyl CoA is an electrophilic acceptor, and can become a nucleophilic donor by loss of its hydrogen
128 The Role of Acetyl CoA
Acetyl CoA is a source of an acetyl enolate nucleophile in enzyme-catalyzed Claisen-like condensations in the biosynthesis of lipids and in sugar metabolism
129