Chapter 12.Carboxylic Acid Derivatives

（羧酸衍生物）

Text 1: chapter 21

Test 2: 第 13 章

esters

酯 R

O

OR'

acid anhydride

酸酐 R

O

O R

O

acid halides

酰卤 R

O

Cl

amides

酰胺 R

O

NR1R2

nitriles

腈R CN

Acid or base

waterCarboxylic acids

12.1 Nomenclature

Esters -yl (-oic acid)-ate× 酸 ×酯

CH3COCH2CH3

O

CH3COCH=CH2

O

CH3CH2COC(CH3)3

O

ethyl acetate ethyl ethanoate乙酸乙酯

vinyl acetate ethenyl ethanoate乙酸乙烯酯

tert-butyl propanoate丙酸叔丁酯

CH3COCH2CH2CH(CH3)2

OCH3CH2CH2CH2C

O

OCH2CH2CHCH3

CH3isopentyl acetate(used in synthetic banana flavor)乙酸异戊酯

isopentyl pentanoate(used in synthetic apple flavor)戊酸异戊酯

CO

OCH3 CO

OCH3Cl

methyl benzoate苯甲酸甲酯

methyl p-chlorobenzoate对 - 氯苯甲酸甲酯

CH3CH2OOCCH2COOCH2CH3

diethyl malonate丙二酸二乙酯

Cyclic Esters Are Known as Lactones

6-methyl-tetrahydropyran-2-one

5-hydroxyhexanoic acid lactone

OHO H

CH2OH

Vitamin CH

HOOH

άÉúËØ C

O

O

O

OHHO

H

O

OH

O

O

O

O

HO

N(CH3)2

CH3

CH3OH

CH3

OCH3

Erythromycin A ºì ùËØ

acid anhydrides酸酐

CO

O

O

H3C

H3C CO

O

O

H2C

H2C

CO

O

O

HC

HCO

O

O

--oic acid ——— --oic anhydride

acetic anhydride乙酐醋酐

succinic anhydride环丁酐丁二酸酐琥珀酸酐

maleic anhydride环丁烯酐顺丁烯二酸酐马来酐

phthalic anhydride邻苯二甲酸酐

acyl chlorides (acid chlorides酰氯 )

R C

O

CH3C

O

Cl CH3CH2C

O

Cl C

O

Cl

Acyl group酰基

acetyl chloride乙酰氯

propanoyl chloride丙酰氯

benzoyl chloride苯甲酰氯

--ic acid ——--yl chloride

amides --ic acid——--amide

CH3C

O

NH2CH3CH2C

O

NH2 C

O

NH2

acetamide酰胺

propanamide丙酰胺 benzamide

苯甲酰胺

HC

O

N(CH3)2

N,N-dimethylformamideN,N- 二甲基甲酰胺DMF

N-phenylacetamideN- 苯基乙酰胺

CH3C

O

NH C6H5

primary amide 伯酰胺 secondary amide 仲酰胺 tertiary amide 叔酰胺

Cyclic Amides Are Known as Lactams( 内酰胺 )

-valerolactam- 戊内酰胺

-butyrolactam- 丁内酰胺

-propiolactam- 丙内酰胺

NH

O

NH

O

NH

O

N

SNHC

O

R

OCH3

CH3

COOH

R = C6H5CH2 -

R =

NH2

R = C6H5OCH2 -

( penicillin G)

(ampicillin)

(penicillin V)

(ÇàùËØ G)

( penicillin)

C6H5CH

Nitriles alkanenitrile

CH3 C N CH3CH2CH2C N H2C CH C N

ethanenitrile(acetonitrile)乙腈

butanenitrile丁腈

propenenitrile丙烯腈

C N C N

benzenecarbonitrile(benzonitrile)苯甲腈

cyclohexanecarbonitrile环己基甲腈

Functional group Name as main group Name as substituent

carboxylic acids 羧酸

-oic acid carboxy( 羧基 )

esters 酯 -oate alkoxycarbonyl( 烷氧羰基 )

amides 酰胺 -amide amido( 酰氨基 )

nitriles 腈 -nitrile cyano( 氰基 )

aldehydes 醛 -al formyl( 甲酰基 )

ketones 酮 -one oxo( 氧代 )

alcohols 醇 -ol hydroxy( 羟基 )

amines 胺 -amine amino( 氨基 )

alkenes 烯 -ene alkenyl( 烯基 )

alkynes 炔 -yne alkynyl( 炔基 )

alkanes 烷 -ane alkyl( 烷基 )

ethers 醚 alkoxy( 烷氧基 )

halides 卤代烷 halo( 卤 )

Main groups in order of decreasing priority

12.2 Structure and physical properties

CN

OC

N

O

bp, mp: (Figure 21-2, p 948)

amide > acid > nitrile > alcohol > ester≈acid chloride ≈alkane

amide: primary > secondary > tertiary

CN

O

HO

N

H

Solubility: (Table 21-2)

All are soluble in common organic solvents.

Some are common organic solvents.

ethyl acetate (EtOAc ，乙酸乙酯， bp 77 , 10%℃ )

acetonitrile (CH3CN ， 乙腈， bp 82 ℃， misible with water)

DMF (N,N-dimethylformamide, N,N- 二甲基甲酰胺， bp 153 , misible with water,℃ )

IR

12.3 Spectroscopy

Compounds Stretching frequency of C=O (cm-1)

RCOCl(RCO)2O

RCO2R

RCONH2

RC≡N

1815~17851850~1800 and 1780~174017351680~16302210~2260

Esters ，Carboxylic acid ， anhydrides

1310 ~1050 cm-1 C－ O－ C

Amides 3500 ~3200 cm-1 N–H

Ring strain in a lactone or lactam increases the carbonyl streching frequency.

NH

O

NH

O

NH

O

1670 1700 1745 （ cm-1 ） .

O

O

O

O

O

O

1735 1770 1800 （ cm-1 ） .

1743

1827 1766

33483173 1681

CH3C

O

L RCH2C N

α - H δ: 2 ~ 3 ppm

1H NMR

13C NMR

C Nδ: ~120 ppm

N - H δ: 5 ~8 ppm

Amide:

C=O

δ: ~ 170 ppm

1H NMR:

13C NMR:

CH3

O

O

H2C

H3C 1.25

2.05

4.15

CH3

O

O

H2C

H3C

171

60

20

14

12.4 Interconversion of acid derivatives by nucleophilic acyl substitution ( 亲核酰基取代 )

Reactivity and interconversion of acid derivatives:

More reactive Less reactive

R C

O

Cl R C

O

O R C

O

OR'C

O

R R C

O

NH2 R C

O

O

R C

O

Cl + R'OH + HClR C

O

OR'

R C

O

Cl + R'NH2 + HClR C

O

NHR'

R C

O

Cl + + HClR C

O

OR' C

O

OH C

O

R'

R C

O

O +C

O

R R C

O

OR'R'OH R C

O

OH+

R C

O

O +C

O

R R C

O

NHR'R'NH2 R C

O

OH+

R C

O

OR' +

R C

O

OR' + + ROHR"NH2 R C

O

NHR"

R"OH + R'OHR C

O

OR"

transesterification酯交换反应

ammonolysis酯氨解反应

acid chlorides and anhydrides are used as acylation reagents.( 酰化试剂 )

Mechanism: nucleophilic acyl substitution （亲核酰基取代）

addition elimination deprotonation

R C

O

L + NuH R C

O

L

NuH

R C

ONu + HLR C

O

NuH

+ L

acid-catalyzed mechanism: protonation of carbonyl oxygen, addition, elimination

base-catalyzed mechanism ： addition, elimination

Acid-catalyzed transesterification 酸催化的酯交换反应

RC

O

OR'

H+

RC

OH

OR'

HOR"R C

OH

OR'

OR"H

R C

OH

OR'

OR"

- H+

R C

OH

OR'

OR"

H+

R C

OH

OR'

OR"

H

RC

OH- HOR'

OR"

- H+

RC

O

OR"

RC

O

OR'

OR"R C

O

OR'

OR"

- OR'

RC

O

OR"

Base-catalyzed transesterification 碱催化的酯交换反应

12.5 Hydrolysis of acid derivatives

Neutral hydrolysis

Acid-catalyzed hydrolysis

Base-catalyzed hydrolysis

Mechanism: nucleophilic acyl substitution

1. Hydrolysis of acid halides and anhydrides

Acid chlorides and anhydrides hydrolyze under neutral condition.

R C

O

Cl + R C

O

Cl

OH2

R C

OOH +R C

O

OH2

+ ClH2O HCl

R C

O

O + R C

OOHH2OC

O

R 2

2. Hydrolysis of esters

Acid–catalyzed hydrolysis of esters is the reverse of the Fisher esterification, is a equilibrium.

Base–catalyzed hydrolysis of esters is also called saponification ( 皂化反应 ), avoids the equilibrium of the Fisher esterification.

RCO

OR'

OHR C

O

OR'OH

- OR'

RC

O

OH

OR'

RC

O

O+ ROH

3. Hydrolysis of amides

Acid–catalyzed hydrolysis of amides: 6 mol/L HCl

RC

O

NH2

H+

RC

OH

NH2

HOHR C

OH

NH2

OHH

R C

OH

NH2

OH

- H+

R C

OH

NH2

OH

H+

R C

OH

NH2

OH

H

RC

OH- NH3

OH RC

O

OH

NH3

+ NH4

Base–catalyzed hydrolysis of amides: 40% aqueous NaOH

RCO

NH2

OHR C

O

NH2

OH

- NH2

RC

O

O RC

O

O+ NH3

NH2

H

4. Hydrolysis of nitriles

R C NH+

R C NH R C NHHOH

R C

OH

NH

H

R C

OH

NH- H+

Acid–catalyzed hydrolysis of nitriles

amides

Amides can be hydrolyzed to carboxylic acid under stronger conditions.

R C

OH

NHH+

R C

OH

NH2 R C

OH

NH2- H+

R C

OH

NH2 R C

O

NH2

Base–catalyzed hydrolysis of nitriles

R C N R C

OH

NOH OH

R C

OH

NH OH+H

R C

O

NH R C

O

NH R C

O

NH R C

O

NH2

OHH

H O HOH+

amides

Amides can be hydrolyzed to carboxylic acid under stronger conditions.

12.6 Reduction of acid derivatives

1. Reduction to alcohols

estersacid chloridescarboxylic acid

aldehydes 1° alcoholsLiAlH4 LiAlH4

2. Reduction to aldehydes

LiAl(OC(CH3)3)Hacid chlorides aldehydes

RCOClLiAl[OC(CH3)3]3H

RCHO

3. Reduction to amines

amidesnitriles

aminesLiAlH4

R C N R CH2 NH2

i. LiAlH4

ii. H2O

R C

O

NH2

i. LiAlH4

ii. H2OR C

O

NHR'

R C

O

NR'2

R CH2 NH2

R CH2 NHR'

R CH2 NR'2

12.7 Reaction of acid derivatives with organometallic reagents

O

COR'R

O

CClR

i. R"MgX

ii. H3O+ R R"

OHR"

esters:

acid chlorides:

tertiary alcohols三级醇

nitriles:i. R"MgX

ii. H3O+R C NR

C

O

R"

amides: NO reaction.

1. Synthesis of acyl chlorides

12.8 The chemistry of acyl chlorides

R C

O

OH

SOCl2

R C

O

Clor PCl3or PCl5

or (CO)2Cl2

2. Reactions of acyl chlorides

Acyl chloride

R C

O

Cl

R'COONa

(- NaCl)R'COOOCRAnhydride

R'OH, Base

(-HCl)RCOOR'

Ester

R'R''NHRCONR'R''amide

(R'=H, alkyl

(R', R"=H, alkyl(-HCl)

Acid chloride is important acylation reagent ( 酰化试剂 )

O

CClR

i. R"MgX

ii. H3O+ R R"

OHR"

i. LiAlH4

ii. H2O

LiAl[OC(CH3)3]3HRCHO

RCH2OH

R'2CuLi O

CR'R

Z

AlCl3Z

C

O

R

Z = H, alkyl, activating groups

1. Synthesis of carboxylic acid anhydrides

12.9 The chemistry of acid anhydrides

HO C

O

R'

Acyl chloride

õ£ÂÈ

R C

O

Cl +N

R C

O

O C

O

R' +N+H

Cl-

NaO C

O

R'

Acyl chloride

õ£ÂÈ

R C

O

Cl + R C

O

O C

O

R'(- NaCl)

HOOCCH2(CH2)nCOOH O

O

On

heatn=0, 1

2. The reactions of acid anhydride

R CO

O

R'OHRCOOR' + RCOOH

Esteracid, R' = H

RCONR'R''R'R''NH

amideCO

R

Z

AlCl3Z

C

O

R

Z = H, alkyl, activating groups

(R', R"=H, alkyl

Useful anhydrides:

acetic anhydrides( 醋酐 ) acetic formic anhydrides （甲乙酐）

cyclic anhydrides （环状酸酐）

H3CC

O

O

CCH3

O

H3CC

O

O

CH

O

ORC

H

O

H3CC

O

O

CH

O

+ ROH + CH3COOH

+ ROHCO

OC

O

H2C

H2C CO

C

O

H2C

H2C OR

OH

CO

OC

O

H2C

H2C

12.10 The chemistry of esters

• 1. Synthesis of esters

C

O

Cl + HOCH2CH3 C

O

OCH2CH3

Ethyl benzoate(80%)

Benzoyl chloride

Py

O

O

O

+ CH3CHCH2CH3

OH

C

C

O

O

OH

OCHCH2CH3

CH3

R C

O

OH

carboxylic acidR C

O

OCH3+ CH2N2

diazomethane methyl ester+ N2

R C

O

OH + HOR'H+

R C

O

OR' + H2OEster

2. The reactions of esters

R C

O

OR'i. R"MgX

ii. H3O+ R R"

OHR"

i. LiAlH4

ii. H2ORCH2OH

H2O

H+, or HO- R C

O

OH R C

O

Oor

R"OHRCOOR"

R'R''NH RCONR'R'' (R', R"=H, alkyl

H+, or RO-

+ R'OH

12.11 The chemistry of amides

1. Synthesis of amides

RCOClHNR'R" R C

O

NR'R"or anhydridesor acids (R', R"=H, alkyl

or esters

H2O

H+, or HO- R C

O

NH2R C N

2. The reactions of amides

R C

O

NH2

H2O

H+, or HO-

R C N

i. LiAlH4

ii. H2ORCH2NH2

R C

O

OH R C

O

Oor

or P2O5, or Ac2O

Br2, -OHRNH2

POCl3 only primary amides

Hoffmann rearrangement( 霍夫曼重排，霍夫曼降解 )only primary amides

Polyamides （聚酰胺）

NH

O

H2O-OC(CH2)5NH2

O

C

O

(CH2)5NH C

O

(CH2)5NHn

+ n H2N (CH2)6NH2HO C

O

(CH2)4 C

O

OHn

NH C

O

(CH2)4 C

O

NH (CH2)6(H2C)6 NHHNn

Nylon 6

Nylon 6,6

12.12 The chemistry of Nitriles

1. Synthesis of nitriles

R C

O

NH2 R C Nor P2O5, or Ac2O

POCl3

R X (1 °)NaCN

R C N

R C

O

R'HCN

KCNR C

OH

R'

CN

2. The reactions of nitriles

H2O

H+, or HO- R C

O

NH2

R C N

H2O

H+, or HO-

i. LiAlH4

ii. H2O RCH2NH2

R C

O

OH R C

O

Oor

i. R"MgX

ii. H3O+ RC

O

R"

12.13 Thioesters ( 硫酯 ) 21-15, p 988

R C

O

OH + HSR' R C

O

SR' + H2O

thiol硫醇

thioesters硫酯

Reactivity as acylating reagents:

acid chlorides > acid anhydrides > thioesters > esters

Thioesters are common acylating reagents in living systems.

常用来代替在水中不稳定的酰氯和酸酐作酰化试剂。

12.14 Derivatives of carbonic acid（碳酸的衍生物）

HO C

O

OH

carbonic acid碳酸

Cl C

O

Cl RO C

O

OR H2N C

O

NH2

carbonyl dichloridephosgene

碳酰氯，光气

carbonate esters碳酸酯

urea尿素，脲

RHN C

O

OH RHN C

O

OR'

carbamic acid氨基甲酸unstable

carbamate ， urethane氨基甲酸酯

Cl C

O

Cl + CH3CH2OCOCH2CH3

O

Diethyl carbonate

+ 2 HCl

2 H2O

HO C

O

OH + 2 HCl

air

2 HOCH2CH3

Cl C

O

Cl + 4 NH3 H2N C

O

NH2 +

Urea

2 NH4Cl

Assignments

Text 1: 48, 49, 50, 53, 55, 57