Chapter 14 Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution

14.1 Carboxylic Acid Derivatives and Nomenclature14.2 Structure of carboxylic acid derivatives14.3 Preparation of carboxylic acid derivatives14.4 Nucleophilic substitution at the acyl carbon14.4.1 Hydrolysis14.4.2 Reactions with alcohols 14.4.3 Reactions with amines

14. 5 Reduction 14.5.1 Reduction by LiAlH4 (LAH) and its derivatives14.5.2 Reduction by Na14.5.3 Reaction with Grignard reagents14.6 Reactions of amides14.6.1 Dehydration of amides14.6.2 The Hofmann Rearrangement14.7 Spectroscopic analysis of carboxylic acid derivatives

RC

O

LCH3CH2C

O

ClCH3CH2C

O

Cl

Propanoyl chloride丙酰氯

Acyl halides酰卤

CH3C O CCH3

O OCH3C O CCH3

O O

Acetic anhydride乙酸酐

Carboxylic acid anhydrides

酸 酐

Propanoic acid

CO

OC2H5CH3CO

OC2H5CH3

Esters酯

Acetic acid

Ethyl acetate乙酸乙酯

Acetic acid

Propanoyl chloride

Acetic anhydride

Ethyl acetate

P309,10.1P309,10.1

C

O

OCH2CH3C

O

OCH2CH3

Benzoic acidEthyl benzoate（苯甲酸乙酯）

14.1 Carboxylic Acid Derivatives and Nomenclatures

CH3C

O

NH2

C6H5C

O

NHCH3

HC

O

NCH3

CH3

Acetamide乙 酰胺

N-MethylbenzamideN- 甲基苯甲 酰胺

N,N-Dimethylform-amide (DMF)

N, N- 二甲基甲 酰胺

Amides酰胺

Acetic acidAcetamide

PhC N

Nitrile腈

Benzonitrile苄腈

Phenyl cyanide苯基氰

Benzoic acidBenzonitrile

CH3CHCH2CH2CN

CH3

4-Methylpentanenitrile4- 甲基戊腈

R

O L

A common feature of carboxylic acid derivatives:

CH3C

O

L + H2O CH3C

O

OH + HL

Hydrolysis to carboxylic acids

PhC N + H2O PhCOOHH+

+ NH4+

14.2 Structure of carboxylic acid derivatives

R CO

LR C

O

LR C

O

L

p - π Conjugation

L: X < OCR' < OR' < NHR'O

+C Effect:

14.3 Preparation of Carboxylic Acid Derivatives14.3.1 Preparation of Acyl Halides

RC

O

OH

SOCl2

PBr3

RC

O

Cl

EtherRC

O

Br

SOCl2(Thionyl chloride)PBr3(Phosphorous tribromide)14.3.2 Preparation of Acid Anhydride

RC

O

Cl R'C

O

OH+N

RC

O

O CR'

O

+ + N

H

Cl

RC

O

Cl R'C

O

ONa+ RC

O

O CR'

O

14.3.3 Preparation of Esters

RC

O

OH + R'OHH+

RC

O

O R'

RC

O

Cl R'OH+Pyridine

RC

O

O R'

14.3.4 Preparation of Amides

RC

O

Cl +

NH3

R'NH2

R'2NH

RC

O

NH2

RC

ONHR'

RC

ONR'2

14.4 Nucleophilic substitution at the acyl carbon

14.4.1 Hydrolysis

(C6H5)2CHCH2CCl

O

+ H2ONa2CO3

0¡æ, 65%(C6H5)2CHCH2COH

O

CH3 CH

CH

C

C

O

OO

H2O, ¡÷

94%

CH3 CH

CH

C

C

O

O

OH

OH

O O

H2O, NaOH

90% OH

CO

OH

P318,10.5P318,10.5

Ch.P390Ch.P390

RC

O

L + Nu:RC

O

L R C

O

Nu

L RC

O

NuAddition Elimination + L

CH3C

O

NH Br C2H5OH-H2O, KOH95%

CH3C

O

O-K+

+ NH2 Br ¡÷£¬Mechanism:

Saponification( 皂 化 反应 )

Step 1 Nucleophilic addition of hydroxide ion to carbonyl group.

R CO

O R'+ O H R C

O R'

O H

O

Base-promoted hydrolysis of ester

Hydrolysis of Acyl halides is catalyzed by a base.

Hydrolysis of Acid anhydridesEstersAmides

Catalyzed by a acid or a base.

P331P331

R C

O R'

O H

OR C

O

O H+ R' O

Step 2 Elimination of leaving group to restore carbonyl group:

Step 3 Proton transfer to yield alcohol and carboxylate ion:

CO

O H+ R' OR C

O

OR + R' O H

RCO

X>RC

ORC

O

OR'RC

O

NH2> >

RCO

O

14.4.2 Reactions with alcoholsAcyl halides

Acid anhydridesEstersNitriles

Alcohols orphenols

Esters

Hydrolysis of Nitriles: P320P320

R C N

H3O+,heat R COOH

R COOHO, H2O

heat

Reactivity of carboxylic acid derivatives:

CO

Cl+ C

O

OCH2CH3CH3CH2OH

N+ N

H

Cl

Benzoyl chloride Ethyl benzoate(80%)

2 (CH3CO)2O

O

+ HO OHH2SO4 CH3C

O

O O CCH3

O

+ 2 CH3COOH93%

Esters Alcohols Esters (Exchange of esters)

O

OHOH

+ CH3COCCH3

O OPyridine

O

OHOCCH3

O

+ CH3COO

Salicylic acid( 水杨酸 )

Asprin( 阿司匹林 )

CH2 CH C

O

OC2H5 + CH3CH2CH2CH2OHH+, 94%

Methyl acrylate（丙烯酸甲酯）

Butyl alcohol（丁醇）

CH2 CH C

O

OCH2CH2CH2CH3 + C2H5OH

Butyl acrylate ( 丙烯酸丁酯 )

(94%)

CH3CH2CH2COOCH3

CH3C

O

OCH2CH2CH(CH3)2

CH3CN + C2H5OHHCl,H2O

CH3COOC2H5

Alcoholysis of Nitriles: Ch.P391Ch.P391

C6H5CO

Cl + HNNaOH

H2O C6H5CO

N

Benzoylchloride

Piperidine （哌啶）

N-Benzoyl-Piperidine

（ N- 苯甲酰哌啶）（ 87-91% ）

FCH2C

OOCH2CH3 + NH3

H2O FCH2C

ONH2 + CH3CH2OH

Ethyl Floroacetate

（氟乙酸乙酯）Floroacetamide（氟乙酸酰胺）

(90%)

14.4.3 Reactions with aminesAcyl halides

Carboxylic acid anhydridesEsters

Ammoniaor amines Amides

14. 5 Reduction14.5.1 Reduction by LiAlH4 (LAH) and its derivatives

C16H15CCl

O¢ÙLiAlH4, Et2O

¢Ú H2O,98%C16H15CH2OH

C

C

O

O

O¢ÙLiAlH4, Et2O

¢Ú H2O,87%

CH2OH

CH2OH

CH3CH CHCH2COOCH3¢ÙLiAlH4, Et2O

¢Ú H2O,75%CH3CH CHCH2CH2OH

+ CH3OH

CN(CH3)2

O¢ÙLiAlH4, Et2O

¢Ú Reflux,88%CH2N(CH3)2

F3C CH2CN¢ÙLiAlH4, Et2O

¢Ú H2O,53%F3C CH2CH2NH2

1) LiAlH(OR)3Acyl halidesAmides 2) H2O

Aldehydes

AmidesNitriles

AminesLiAlH4

Acryl halidesCarboxylic acidAcid anhydrides

Esters

Primaryalcohols

LiAlH4

14.4.2 Reduction by NaBouveault - Blanc reduction

Esters NaEthanolButanolPentanol

reflux Primary alcohols

CH3(CH2)7CH CH(CH2)7COOC2H5Na,C2H5OH

50%

CH3(CH2)7CH CH(CH2)7CH2OHEthyl oleate油酸乙酯 Oleic alcohol

油醇 The unique method for the preparation of unsaturated primary alcohols in industry

Ch. P393Ch. P393

14.5.3 Reaction with Grignard reagents

C6H5 C

O

OC2H5 + C6H5:MgBr 醚或苯Reflux

C6H5 C

O

OC2H5

C6H5

C6H5 C

O

C6H5

MgBr

MgBrOC2H5

C6H5:MgBr C6H5 C

O

C6H5

C6H5

MgBrH2O

NH4ClC6H5 C

OH

C6H5

C6H5

CH3C

O

Cl + CH3CH2CH2CH2MgCl醚£¬FeCl3-70¡æ,72%

CH3C

O

CH2CH2CH2CH3

1 mol RMgX Low temperature

RMgX Ketones Tertiaryalcohols

Carboxylic acidderivatives

RMgX

CH3CH2C N + C6H5MgBr CH3CH2C NMgBr

C6H5H3+O

¡÷ , 91%CH3CH2C O

C6H5

Et2O

Reactions of nitriles with Grignard reagents

Addition

1. RMgX Imine亚胺

Nitriles2. H2O

HydrolysisKetones

RLi reacts in the same way and are often used instead of RMgX

14.6 Reactions of amides14.6.1 The dehydration of amides

AmidesDehydrating agents: P4O10 (P2O5), （脱水剂） (CH3CO)2O Heating To form nitrils

(CH3)2CHC

O

NH2P4O10

200¡æ(CH3)2CHC N

2-Methylpropanamide2- 甲基丙酰胺

2-Methylpropanenitrile2- 甲基丙腈

（ 69-86% ）

Br2 / OH －

Carbonyl group had been plucked out

CH2CNH2

O

+ Br2 + 4NaOH94%

CH2NH2 + 2NaBr

+ Na2CO3 + 2H2O

14.6.2 The Hofmann Rearrangement （ Hofmann 降解反应） N-unsubstituted amides

to form primary amines having one less carbon atom than amide

Mechanism:Step 1 Formation of an N-bromo amide intermediate:

R C

O

N H

H

OHR C

O

N

H

Br Br R C

O

N Br + Br

H

Deprotonation of amideAmide nitrogen anionas a nucleophile

Ch.P396,( 丙 )

Ch.P396,( 丙 )

Step 2 Rearrangement of the N-bromo amide to an isocyanate （异氰酸酯）

R C

O

N Br

H

OHR C

O

N Br £ Br

O C N R

Deprotonation of N-bromo amide, the group R migrates from C atom to N atom to form an isocyanate.Step 3 Hydrolysis of isocyanate by base-catalyzed

N C OR N C OHROH

NH2 + CO3 + H2O

H2O

ROH

Carbamic acid ( 异氰酸 )dissociates to an amine and CO2

The features of Hofmann rearrangement:1. N-unsubstituted amides as substrates2. Rearrangement proceeds with retention of configuration at migrating group

C

HPhCH2

H3CC

ONH2

Br2, NaOHH2O

C

HPhCH2

H3CNH2

(S)-2-Methyl-3-Phenylpropanamide

(S)-1-Phenyl-2-propanamine

14. 7 Spectroscopic analysis of carboxylic acid derivatives

Table 1. The stretching frequency of C=OIR:

RC N : The stretching frequency of C N:2210~2260 cm-1

CompoundsStretching frequency of C=O

(cm-1)

RCOCl(RCO)2ORCO2RRCONH2

1815~17851850~1800 and 1780~1740

17351680~1630

EstersCarboxylic acid

anhydrides

Stretching frequency of C － O:1310 ~1050 cm-1

Amides: Stretching frequency of N – H bond: 3500 ~3200 cm-1

CH3C

O

L RCH2C N

α - H δ: 2 ~ 3 ppm

1H NMR:

13C NMR:C N

δ: 120 ppmAmide: N - H δ: 5 ~8 ppm

Problems to chapter 14P 346 10.31 (a),(d),(e) 10.32(c)~(g) 10.33(b),(d),(g) 10.37 10.39 10.41 10.42 (a),(c) 10.45 10.46(a), (c) 10.47 10.55 10.56(b)

P 346 10.31 (a),(d),(e) 10.32(c)~(g) 10.33(b),(d),(g) 10.37 10.39 10.41 10.42 (a),(c) 10.45 10.46(a), (c) 10.47 10.55 10.56(b)

10.5710.5810.5910.6010.6110.62

10.5710.5810.5910.6010.6110.62