20.6 Sources of Esters

CH 3 COCH 2 CH 2 CH(CH 3 ) 2 O Esters are very common natural products 3-methylbutyl acetate also called "isopentyl acetate" and "isoamyl acetate" contributes to characteristic odor of bananas

Esters of Glycerol R, R', and R" can be the same or different called "triacylglycerols," "glyceryl triesters," or "triglycerides" fats and oils are mixtures of glyceryl triesters RCOCH CH 2 OCR' O CH 2 OCR" OO

Esters of Glycerol CH 3 (CH 2 ) 16 COCH CH 2 OC(CH 2 ) 16 CH 3 O OO Tristearin: found in many animal and vegetable fats

Cyclic Esters (Lactones) (Z)-5-Tetradecen-4-olide (sex pheromone of female Japanese beetle) OO H H CH 2 (CH 2 ) 6 CH 3

Fischer esterification (Sections 15.8 and 19.14) from acyl chlorides (Sections 15.8 and 20.3) from carboxylic acid anhydrides (Sections 15.8 and 20.5) Baeyer-Villiger oxidation of ketones (Section 17.16) Preparation of Esters

20.7 Physical Properties of Esters

Boiling Points Esters have higher boiling points than alkanes because they are more polar. Esters cannot form hydrogen bonds to other ester molecules, so have lower boiling points than alcohols. CH 3 CHCH 2 CH 3 CH 3 CH 3 COCH 3 O CH 3 CHCH 2 CH 3 OH28°C 57°C 99°C boiling point

Solubility in Water Esters can form hydrogen bonds to water, so low molecular weight esters have significant solubility in water. Solubility decreases with increasing number of carbons. CH 3 CHCH 2 CH 3 CH 3 CH 3 COCH 3 O CH 3 CHCH 2 CH 3 OH~ Solubility (g/100 g)

20.8 Reactions of Esters: A Review and a Preview

with Grignard reagents (Section 14.10) reduction with LiAlH 4 (Section 15.3) with ammonia and amines (Sections 20.13) hydrolysis (Sections 20.9 and 20.10) Reactions of Esters

20.9 Acid-Catalyzed Ester Hydrolysis

maximize conversion to ester by removing water maximize ester hydrolysis by having large excess of water equilibrium is closely balanced because carbonyl group of ester and of carboxylic acid are comparably stabilized Acid-Catalyzed Ester Hydrolysis RCOH O+ R'OH RCOR' O+ H2OH2OH2OH2O H+H+H+H+ is the reverse of Fischer esterification

Example HCl, heat + H2OH2OH2OH2OO CHCOCH 2 CH 3 Cl + CH 3 CH 2 OH OCHCOH Cl (80-82%)

Is the reverse of the mechanism for acid- catalyzed esterification. Like the mechanism of esterification, it involves two stages: 1)formation of tetrahedral intermediate (3 steps) 2)dissociation of tetrahedral intermediate (3 steps) Mechanism of Acid-Catalyzed Ester Hydrolysis

First stage: formation of tetrahedral intermediate RCOHOH OR' + H2OH2OH2OH2O RCOR' O H+H+H+H+ water adds to the carbonyl group of the ester this stage is analogous to the acid- catalyzed addition of water to a ketone

Second stage: cleavage of tetrahedral intermediate RCOHOH OR' + R'OH H+H+H+H+ RCOHO

Mechanism of formation of tetrahedral intermediate

Step 1 RC O OR' O + HHH

Step 1 RC O OR' O + HHH RC OOR' + H O HH

Step 1 RC O OR' + H carbonyl oxygen is protonated because cation produced is stabilized by electron delocalization (resonance) RC O OR' + H

Step 2 O HH RC O OR' + H

Step 2 O HH RC O OR' + H RC OH OR' O + H H

Step 3 O HH RC OH OR' O H H +

Step 3 O HH RC OH OR' O H H + O HH H + RC OH OR' O H

Cleavage of tetrahedral intermediate

Step 4 O HH H + RC OH O OH R'

Step 4 O HH H + RC OH O OH R' RC OH O OHOHOHOH R' H + O HH

Step 5 RC OH O OH R' H +

Step 5 RC OH O OH R' H + O R' H + RC OH OH +

Step 5 RC OHOH + RC OH OH +

Step 6 O H H RC OOH + H + O H HH RC OOH

Activation of carbonyl group by protonation of carbonyl oxygen Nucleophilic addition of water to carbonyl group forms tetrahedral intermediate Elimination of alcohol from tetrahedral intermediate restores carbonyl group Key Features of Mechanism

18 O Labeling Studies + H2OH2OH2OH2O COCH 2 CH 3 O O+ H2OH2OH2OH2O Ethyl benzoate, labeled with 18 O at the carbonyl oxygen, was subjected to acid- catalyzed hydrolysis. Ethyl benzoate, recovered before the reaction had gone to completion, had lost its 18 O label. This observation is consistent with a tetrahedral intermediate. H+H+H+H+

18 O Labeling Studies C OHOHOHOHOH OCH 2 CH 3 + H2OH2OH2OH2O COCH 2 CH 3 O H+H+H+H+ O+ H2OH2OH2OH2O H+H+H+H+

20.10 Ester Hydrolysis in Base: Saponification

is called saponification is irreversible, because of strong stabilization of carboxylate ion if carboxylic acid is desired product, saponification is followed by a separate acidification step (simply a pH adjustment) Ester Hydrolysis in Aqueous Base RCO – O+ R'OH RCOR' O+ HO –

Ester Hydrolysis in Aqueous Base RCO – O+ R'OH RCOR' O+ HO – H+H+H+H+ RCOH O

Example water-methanol, heat (95-97%) CH 2 OCCH 3 CH 3 O+ NaOH CH 2 OH CH 3 O CH 3 CONa +

Example (87%) + CCOH CH 3 O H2CH2CH2CH2C 1. NaOH, H 2 O, heat 2. H 2 SO 4 CH 3 OH CCOCH 3 CH 3 O H2CH2CH2CH2C

Soap-Making CH 3 (CH 2 ) y COCH CH 2 OC(CH 2 ) x CH 3 O CH 2 OC(CH 2 ) z CH 3 O O Basic hydrolysis of the glyceryl triesters (from fats and oils) gives salts of long-chain carboxylic acids. These salts are soaps. K 2 CO 3, H 2 O, heat CH 3 (CH 2 ) x COK O CH 3 (CH 2 ) y COK O CH 3 (CH 2 ) z COK O

Which bond is broken when esters are hydrolyzed in base? RCO O + R' – OH RCO O + R'OH – One possibility is an S N 2 attack by hydroxide on the alkyl group of the ester (alkyl-oxygen cleavage). Carboxylate is the leaving group.

Which bond is broken when esters are hydrolyzed in base? + –OH RC O OR' + OR' – A second possibility is nucleophilic acyl substitution (acyl-oxygen cleavage). RC O OH

18 O Labeling gives the answer 18 O retained in alcohol, not carboxylate; therefore nucleophilic acyl substitution (acyl- oxygen cleavage). CH 3 CH 2 COCH 2 CH 3 ONaOH + CH 3 CH 2 CONa O CH 3 CH 2 OH +

Stereochemistry gives the same answer alcohol has same configuration at stereogenic center as ester; therefore, nucleophilic acyl substitution (acyl- oxygen cleavage) not S N 2 CH 3 COK O+ CH 3 C O C OH C6H5C6H5C6H5C6H5 CH 3 C HOHOHOHOH C6H5C6H5C6H5C6H5 KOH, H 2 O

Does it proceed via a tetrahedral intermediate? + –OH RC O OR' + OR' – Does nucleophilic acyl substitution proceed in a single step, or is a tetrahedral intermediate involved? RC O OH

18 O Labeling Studies + H2OH2OH2OH2O COCH 2 CH 3 O O+ H2OH2OH2OH2O Ethyl benzoate, labeled with 18 O at the carbonyl oxygen, was subjected to hydrolysis in base. Ethyl benzoate, recovered before the reaction had gone to completion, had lost its 18 O label. This observation is consistent with a tetrahedral intermediate. HO –

18 O Labeling Studies C OHOHOHOHOH OCH 2 CH 3 + H2OH2OH2OH2O COCH 2 CH 3 O HO – COCH 2 CH 3 O+ H2OH2OH2OH2O HO –

Involves two stages: 1)formation of tetrahedral intermediate 2)dissociation of tetrahedral intermediate Mechanism of Ester Hydrolysis in Base

First stage: formation of tetrahedral intermediate RCOHOH OR' + H2OH2OH2OH2O RCOR' O water adds to the carbonyl group of the ester this stage is analogous to the base-catalyzed addition of water to a ketone HO –

Second stage: cleavage of tetrahedral intermediate RCOHOH OR' + R'OH RCOHO HO –

Mechanism of formation of tetrahedral intermediate

Step 1 RC O OR' O H –

Step 1 RC O OR' RC O OR' O H – O H –

Step 2 RC O OR' O H – HO H

Step 2 RC O OR' O H – HO H RC O OR' O H H – O H

Dissociation of tetrahedral intermediate

Step 3 RC O OR' O H H – O H

Step 3 HO H RC O OR' O H H – O H OR' – RC O O H

Step 4 OR' – RC O O H HO – RC O O – H OR' H2OH2OH2OH2O

Nucleophilic addition of hydroxide ion to carbonyl group in first step Tetrahedral intermediate formed in first stage Hydroxide-induced dissociation of tetrahedral intermediate in second stage Key Features of Mechanism

20.11 Reactions of Esters with Ammonia and Amines

RCOR'O RCNR' 2 O RCO – O Reactions of Esters

+ RCNR' 2 O+ Esters react with ammonia and amines to give amides: R' 2 NH RCOR' O R'OH

Reactions of Esters + RCNR' 2 O+ Esters react with ammonia and amines to give amides: R' 2 NH RCOR' O R'OH via: C R O OR' NR' 2 H

Example (75%) + CCNH 2 CH 3 O H2CH2CH2CH2C CH 3 OH CCOCH 3 CH 3 O H2CH2CH2CH2C + NH 3 H2OH2OH2OH2O

Example (61%) + FCH 2 COCH 2 CH 3 O NH 2 + CH 3 CH 2 OH FCH 2 CNH Oheat

20.12 Thioesters

Thioesters Thioesters are compounds of the type: RCSR' O Thioesters are intermediate in reactivity between anhydrides and esters. Thioester carbonyl group is less stabilized than oxygen analog because C—S bond is longer than C—O bond which reduces overlap of lone pair orbital and C=O  orbital

Thioesters Many biological nucleophilic acyl substitutions involve thioesters. RCSR' O+NuH RCNu O+ R'SH via: C R O SR' NuH