Chapter 21.

Carboxylic Acid
Derivatives: Nucleophilic Acyl
Substitution Reactions
羧酸衍生物 : 親核醯基取代反應

Based on McMurry’s Organic Chemistry, 9th edition

Carboxylic Acid Derivatives 羧酸衍生物
 Acyl group bonded to X, an electronegative atom or
leaving group
 Includes: X = halide (acid halides), acyloxy (anhydrides),
alkoxy (esters), amine (amides), thiolate (thioesters),
phosphate (acyl phosphates)
羧酸中的羥基被其他的原子取代的生成物稱作羧酸衍生物

酸酐 酯
醯鹵

醯胺 硫酯 醯磷酸 2
 General Reaction Pattern
 Nucleophilic acyl substitution

Why this Chapter?


Carboxylic acids are among the most widespread of molecules.

A study of them and their primary reaction “nucleophilic acyl substitution” is fundamental to understanding organic chemistry

3
 21.1 Naming Carboxylic Acid Derivatives
 Acid Halides, RCOX
 Derived from the carboxylic acid name by replacing the -ic acid ending

with -yl halide

 the -carboxylic acid ending with –carbonyl and specifying the halide

(from cyclohexanecarboxylic acid)

(from acetic acid) (from benzoic acid)
4
 Naming Acid Anhydrides, RCO2COR'
 If symmetrical anhydrides and cyclic anhydrides replace
“acid” with “anhydride” based on the related carboxylic acid
 Unsymmetrical anhydrides, listing the two acids
alphabetically and then adding anhydride

O
HO
OH
O

Succinic acid

5
 Naming Esters, RCO2R’
 Esters, RCO2R’
 Identifying alkyl group R’ attached to oxygen and the
carboxylic acid, replacing –ic acid with “-ate”

RCO2 R’

Common names

(from acetic acid)

IUPAC
Ethyl ethanoate
(from ethanoic 6
 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

O
HCN(CH3 ) 2
N,N-Dimethylformamide
(DMF)
7
 Naming Thioester, RCOSR’
 IUPAC name, the ester, with the “-oate” or 'carboxylate"
ending replaced by “-thioate” or "carbothioate"
 Common name, thio+(carboxylate common name)

Common names

IUPAC
Methyl ethanethioate

8
Naming Acyl Phosphates, RCO2PO3-

 Acyl phosphates, RCO2PO32- and RCO2PO3R’–

 Named by citing the acyl group and adding the
word phosphate
 Identified after acyl group, if an alkyl is attached
to the phosphate oxygen

9
10
 21.2 Nucleophilic Acyl Substitution
 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 nucleophilic acyl substitution

Nucleophilic Acyl Substitution Nucleophilic Addition

11
The General Mechanisms of Nucleophilic Addition
and Nucleophilic Acyl Substitution Reactions

addition

addition
elimination

12
*
Characteristic Reactions
 Nucleophilic acyl substitution 親核醯基取代反應 : an
addition-elimination 加成－脫去 sequence
resulting in substitution of one nucleophile for
another

羧酸衍生物的親核醯基取代反應實際上是經歷 (1) 親核加成

(2) 脫去兩步反應。

O :O- O
addition elimination
C + :N u- C C + :Y-
R Y R Nu R Nu
Y
Tetrahedral carbonyl Substitution
addition intermediate product

13
Mechanism of Nucleophilic Acyl Substitution

addition

tetrahedral addition
intermediate

elimination

14
Relative reactivity of carboxylic acid derivatives
羧酸衍生物相對反應活性

Steric and Electronic factor:

 Relative reactivity of carboxylic acid derivatives
 Nucleophiles react more readily with unhindered
carbonyl groups

Steric factor
Relative reactivity of carboxylic acid derivatives
• 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
• The weaker the base , the better the leaving group

離去基能力 : －
Cl ＞－ OCOR ＞－ OR ＞－ NH2
Basicity: －
Cl < －
OCOR < －
OR < －
NH2
Electronic factor
從共振效應看， L 上的孤電子對與 C ＝ O 共振，使羰
基碳正電性降低而穩定。共振效應愈大，碳正電性愈穩
定，反應活性愈低，而四種衍生物共振效應的強弱為：

　　　　 － NH2 ＞ － OR’ ＞ － OCOR ＞ － Cl

O O O
R C R C R C
L L L

17
 Reactivity 羧酸衍生物相對反應活性
 Reactivity decreases as leaving group becomes more basic.
 The weaker the base , the better the leaving group

離去基能力 : －
Cl ＞－ OCOR ＞－ OR’ ＞－ NH2 18
 Interconversion of Acid Derivatives
 A more reactive acid derivative can be converted into a less
reactive one
 Acid halides and acid anhydrides react rapidly with water
Interconversion of Derivatives
 More reactive derivatives can be
converted to less reactive
derivatives.

 Reactions in the opposite

direction are possible but require
more complex approaches

 Direct nucleophilic acyl

substitution of a carboxylic acid
is difficult because -OH group
is a poor leaving group.
Reactivity is enhanced by
converting -OH into better
leaving group

20
General Reactions of Carboxylic Acid Derivatives
 Hydrolysis 水解 - Water is used as a reagent to
make carboxylic acids
 Alcoholysis 醇解– Alcohol is used as reagent
to make esters
 Aminolysis 胺解 - Ammonia or an amine is used
to make an amide
 Reduction - Hydride source is used to make an
aldehyde or an alcohol
 Grignard reaction - Organometallic reagent is
used to make a ketone or an alcohol
Some General Reactions of Carboxylic Acid
Derivatives
 21.3 Reactions of Carboxylic Acids
 –OH is a poor leaving group
 Direct nucleophilic acyl substitution of a
carboxylic acid is difficult
 Reactivity of the acid can be increased by:
 Using a strong acid catalyst to protonate the
carboxyl
 Converting –OH into a better leaving group
 Specific reagents such as acid chlorides,
anhydrides, esters, and amides can be
prepared from carboxylic acids
O - O
Y
C C
R OH R Y
Acid Derivatives
Conversion of Carboxylic Acids into Acid Chlorides
 Conversion of carboxylic acids into acid chlorides
 Reaction with thionyl chloride 亞硫醯氯 , SOCl
2

24
 Mechanism of Thionyl Chloride Reaction
 Nucleophilic acyl substitution pathway
 Carboxylic acid is converted into a chlorosulfite intermediate which replaces
the –OH of the acid with a much better leaving group, then reacts with chloride

addition elimination

25
Conversion of Carboxylic Acids into Acid
Anhydrides
 Conversion of carboxylic acids into acid anhydrides
 Acid anhydrides can be derived from two molecules
of carboxylic acid by heating to remove water

26
Conversion of Carboxylic Acids into Esters
 Conversion of carboxylic acids into esters
 Through reaction of a carboxylate anion with a primary alkyl halide

27
 Fischer Esterification
 Fischer esterification reaction: Synthesis of esters by an acid-catalyzed nucleophilic acyl
substitution reaction of a carboxylic acid with an alcohol
 Acid + alcohol yields ester + water.
 Acid catalyzed for weak nucleophile alcohol.
 All steps are reversible.

28
 Mechanism of the Fischer Esterification

 Evidence of Mechanism:
18O-label CH O*H react with benzoic acid
3
 When 18O-labeled methanol reacts with benzoic acid,
the methyl benzoate produced is 18O-labeled but the
water produced is unlabeled

29
Key mechanism: Fischer Esterification
Nucleophilic acyl substitution

addition

elimination

*
30
(CH 2) Protonation of Carboxylic acid:
protonated carbonyl or protonated hydroxyl?
 For acetic acid, protonation cccurs on the doubly bonded
oxygen bause that product is stabilized by two resonance
forms

31
 Fischer Mechanism (1)
Addition:
Acid-catalized protonation of carbonyl and attack of
alcohol, a weak nucleophile.

+ +
O H OH OH

COH COH COH

+
OH OH
H COH
COH
O
CH3CH2OH O+ H R
O

CH2CH3 CH2CH3

ester hydrate

羧酸衍生物的親核醯基取代反應實際上是經歷
(1) 親核加成 (2) 脫去兩步反應
32
Fischer Mechanism (2)
Elimination:
Acid-catalized protonation of -OH and loss of water.

+
H +
H OH OH H
+
C OH O C O
COH C OH R
O O
O O
CH2CH3 CH2CH3
CH2CH3 CH2CH3

ester
Key mechanism:
• addition-elimination mechanicm of nucleophilic acyl substitution

try to write this entire mechanism without having to

•

memorize it!
33
 Fischer Esterification
 a key intermediate in Fischer esterification is the
tetrahedral carbonyl addition intermediate (TCAI)
or tetrahedral intermediate formed by addition of
ROH to the C=O group

H TCAI
O
R C OCH3
O
H
H + H+
O O
R C OH + HOCH3 R C OCH3 + HOH

34
 Fischer Esterification
 Fischer esterification is an equilibrium reaction
 by careful control of experimental conditions, it
is possible to prepare esters in high yield
 if the alcohol is inexpensive relative to the
carboxylic acid, it can be used in excess to
drive the equilibrium to the right
 alternatively, water can be removed by
azeotropic distillation

+ H2O

35
 Conversion of Carboxylic Acids into Amides
•
Conversion of carboxylic acids into amides
• difficult to prepare by direct reaction of carboxylic

Acids with amines

• prepared by activating with dicyclohexylcarbodiimide

(DCC), followed by react with amine

 Dicyclohexylcarbodiimide (DCC )
 coupling reagent 偶合試劑

N C N
36
Mechanism of
amide formation
by reaction of a
carboxylic acid
and an amine with
dicyclohexylcarbo
addition
diimide (DCC).

elimination

Fig. 21-5, p. 798

37
Conversion of Carboxylic Acids into Alcohols -Reduction
 Carboxylic acid is very resistant to reduction
 it is not affected by catalytic hydrogenation under conditions that
easily reduce aldehydes and ketones to alcohols, and reduce
alkenes and alkynes to alkanes
 it is not reduced by NaBH4
羧酸的羰基 比醛、酮的羰基活性低，較難還原。
 Carboxylic acid is reduced by strong reducing agent, LiAlH4.
to give primary alcohols
(CH 17.4)

38
Conversion of Carboxylic Acids into Alcohols

Reduction is a nucleophilic acyl substitution reaction in
which –H replaces –OH to give an aldehyde
addition elimination

Aldehyde reduces primary alcohol by nucleophilic

addition
addition

39
*
Conversion of Carboxylic Acids into Alcohols
 Borane 硼烷 reacts with carboxylic acids faster than any
other functional groups.
 Borane, BH3 in THF, reduces carboxylic acid to
alcohol, but does not reduce nitro group.

40
 21.4 Chemistry of Acid Halides
 Preparation of acid halides 醯鹵
 Acid chlorides 醯氯 are prepared from carboxylic acids by

reaction with SOCl2

 Reaction of a carboxylic acid with PBr yields the acid bromide
3
醯溴

41
 Reactions of Acid Halides
 Nucleophilic acyl substitution mechanisms
 Halogen replaced by OH, by OR, or by NH2
 Reduction yields a primary alcohol
 Grignard reagent yields a tertiary alcohol

42
Interconversion of Derivatives

 More reactive derivatives

can be converted to less
reactive derivatives.

43
Hydrolysis: Conversion of Acid Halides into Acids

 Hydrolysis 水解 : Acid chlorides react with water to

yield carboxylic acids
 HCl is generated during the hydrolysis: a base is
added to remove the HCl

44
 Conversion of Acid Halides into Anhydrides
 Conversion of acid halides into anhydrides
 Nucleophilic acyl substitution reaction of acid chloride
with a carboxylate anion gives acid anhydride

Compare with p.26

45
 Conversion of Acid Halides to Esters
 Alcoholysis 醇解 : Esters are produced in the
reaction of acid chlorides with alcohols in the
presence of pyridine or NaOH.
 The reaction is strongly affected by steric hindrance

10 ROH> 20 ROH > 30 ROH

46
Aminolysis: Conversion of Acid Halides into Amides

 Aminolysis 胺解 : Amides result from the reaction of acid chlorides

with NH3, primary (RNH2) and secondary amines (R2NH)
 The reaction with tertiary amines (R3N) gives an unstable species
that cannot be isolated
 Two equivalent of amine must be used or one equivalent added
base to neutralize HCl

47
Conversion of Acid Halides into Amides

鎮靜劑 48
Reduction: Conversion of Acid Chlorides into Alcohols
 Conversion of acid chlorides into alcohols: Reduction and Grignard reaction
 LiAlH4 reduces acid chlorides to yield aldehydes and then primary alcohols
 Reduction occurs via nucleophilic acyl substitution mechanism

49
 Reaction of Acid Chlorides with Grignard Reagents
 Grignard reagents react with acid chlorides to yield tertiary
alcohols with two identical substituent
 Reduction occurs via nucleophilic acyl substitution mechanism

50
 Formation of Ketones from Acid Chlorides
 Conversion of acid chlorides into ketones: Diorganocopper reaction
 Reaction of an acid chloride with a lithium diorganocopper (Gilman) reagent, Li+ R2Cu
 Addition produces an acyl diorganocopper intermediate, followed by loss of RCu and
formation of the ketone
 RCOOH, RCOR', RCO2COR' ,RCONH2 do not react

oxidative reductive
addition elimination

51
 21.5 Chemistry of Acid Anhydrides

 Preparation of acid anhydrides

 Nucleophilic acyl substitution of a carboxylate with
an acid chloride

52
 Reactions of Acid Anhydrides
 Similar to acid chlorides in reactivity

53
Interconversion of Derivatives

 More reactive derivatives

can be converted to less
reactive derivatives.

54
 Conversion of Acid Anhydrides to Esters
 Conversion of acid anhydrides into esters
 Acetic anhydride forms acetate esters
(Acetylation) from alcohols

阿斯匹林 55
 Conversion of Acid Anhydrides to Amides
 Conversion of acid anhydrides into amides
 Acetic anhydride forms N-substituted acetamides from
amines

乙醯胺酚

Panadol （普拿疼） 56
 21.6 Chemistry of Esters
 Many esters are pleasant-smelling liquids: fragrant odors
of fruits and flowers
 Also present in fats and vegetable oils

• Industrially used esters include:

• Ethyl acetate 乙酸乙酯 , common solvent
• Dialkyl phthalates, plasticizer 塑化劑 鄰苯二甲酸二丁酯

57
 Preparation of esters
Preparation of Esters

Esters are usually prepared from carboxylic acids

 Acid chlorides are converted into esters by treatment with an alcohol in the presence of base

58
 Reactions of Esters
 Reactions of Esters
 Less reactive toward nucleophiles than are

acid chlorides or anhydrides

 Cyclic esters are called lactones 內酯 and

react similarly to acyclic esters

59
 Hydrolysis: Conversion of Esters into
Carboxylic Acids
 Hydrolysis 水解 : An ester is hydrolyzed by aqueous base or
aqueous acid to yield a carboxylic acid plus an alcohol
 Saponification 皂化 : Ester hydrolysis in basic solution

60
 Mechanism of Base-induced Ester Hydrolysis
nucleophilic acyl substitution
 Hydroxide catalysis
via an addition
intermediate addition

tetrahedral addition
intermediate

elimination

61
Mechanism of
acid-catalyzed
ester hydrolysis

addition

tetrahedral addition
intermediate

elimination

62
 Ester hydrolysis in biological chemistry

Ester hydrolysis in biological chemistry : digestion of fat and oil

63
Conversion of Esters into Aamides : Aminolysis

 Aminolysis : Conversion of esters into amides 

 Ammonia reacts with esters to form amides

64
Leaving Groups in Nucleophilic Acyl 補充

Substitution

-
OCH3 leave in an
exothermic step.

 A strong base, such as methoxide

(-OCH3), is not usually a leaving group, except
in an exothermic step. 65
 Leaving Groups 補充

SN2
Endothermic:
the reaction rate
is sensitive to
leaving group

Acyl
substitution
Exothermic:
the reaction rate is
not sensitive to
leaving group
66

 In the nucleophilic acyl substitution, the elimination

of the alkoxide is highly exothermic, converting the
tetrahedral intermediate into a stable molecule.
Conversion of Esters into Alcohols : Reduction
 Reduction : Conversion of esters into alcohols
 Reaction with LiAlH yields primary alcohols
4

67
 Mechanism of Reduction of Esters

 Hydride ion adds to the carbonyl group, followed by

elimination of alkoxide ion to yield an aldehyde
 Reduction of the aldehyde gives the primary alcohol

68
Reduction Of Esters With Reducing Agent DIBAL
 Partial reduction of ester with 1 equivalent of
weaker reducing agent diisobutylaluminum
hydride (DIBAL or DIBAH) to yield an aldehyde

69
 Reaction of Esters with Grignard Reagents
 Conversion of esters into alcohols: Grignard reaction
 Esters react with 2 equivalents of a Grignard reagent to yield a tertiary alcohol

70
 21.7 Chemistry of Amides
 Amides are abundant in living organisms
 Proteins, nucleic acids, and other pharmaceuticals
have amide functional groups
 Amides are the least reactive of the common acid
derivative

a cyclic amide,
lactam 內醯胺 Uracil
71
 Preparation of Amides

 Prepared by reaction of an acid chloride with

ammonia, monosubstituted amines, or disubstituted
amines

72
 Reactions of Amides
 Conversion of Amides into Carboxylic Acids: Hydrolysis
 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

nucleophilic acyl substitution

addition

elimination

73
 Basic Hydrolysis of Amides
• Basic hydrolysis is difficult in comparison to
analogous acid-catalyzed reaction because amide
ion is a very poor leaving group
• Addition of hydroxide and loss of amide ion

addition elimination

74
 Amide hydrolysis In biological chemistry

 Amide hydrolysis in biological chemistry is common

 digestion of protein

75
 Conversion of Amides into Amines : Reduction
 Conversion of amides into amines: Reduction
 Reduced by LiAlH
4 to an amine rather than an alcohol
 Converts C=O  CH2

76
 Mechanism of Reduction
 Addition of hydride to carbonyl group
 Loss of the oxygen as an aluminate anion to give
an iminium ion intermediate which is reduced to
the amine

77
 Uses of Reduction of Amides
 The reaction is effective with both acyclic and cyclic amides, or
lactams 內醯胺
 Good route for preparing cyclic amines

78
 21.8 Chemistry of Thioesters and Acyl Phosphates:
Biological Carboxylic Acid Derivatives
 Nucleophilic carboxyl substitution in nature often
involves a thioester 硫酯 or acyl phosphate 醯磷酸
 Acetyl CoA’s are most common thioesters in nature

79
.
•
Acetyl CoA whose thioesters serve as a biochemical acyl
transfer reagents. Acetyl CoA transfers an acetyl group to a
nucleophile, with coenzyme A serving as the leaving group.

葡萄糖胺
乙醯葡萄糖胺
‘ 維骨力’

結締組織成分
關節滑液囊的潤滑液
80
Resonance Overlap in Ester and Thioesters
Thioesters are more reactive than esters because:
 - S-R is a better leaving group than -O-R
 The resonance overlap in a thioester is not as
effective as that in an ester.

2p 3p
2p 2p
 21.9 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 (nylon)
 A diol with a diacid leads to a polyester

82
 Polyamides (Nylons)
 Polyamides (Nylons)
 Heating a diamine with a diacid produces a polyamide called nylon
 Example - Nylon 66 尼龍 66 is prepared from adipic acid 己二酸 and
hexamethylene-diamine 己二胺 at 280°C

 Used in engineering applications and in making fibers

 Polyesters
 The polyester from dimethyl terephthalate 對苯二甲酸二甲酯 and ethylene glycol
is called Dacron® 達克龍 to make clothing fibers 纖維
 Tensile strength of poly(ethylene terephthalate) film is nearly equal to that of
steel

84
 Polyesters
 The polyester from diphenyl carbonate 碳酸二苯酯 and
bisphenol 雙酚 is called Lexan® ( 聚碳酸酯 Polycarbonate PC, 熱塑
性材料 )

85
 Biodegradable Polymers
• Sutures and biodegradable polymers
• Common biodegradable polymers include:
• Poly(glycolic acid) (PGA)

• Poly(lactic acid) (PLA)

• Poly(hydroxybutyrate) (PHB)

• Susceptible to hydrolysis of their ester links

PGA PLA PHB 86

21.10 Spectroscopy of Carboxylic Acid Derivatives
 Infrared Spectroscopy
 Acid chlorides absorb near 1800 cm 1

 Acid anhydrides absorb at 1820 cm 1 and

also at 1760 cm1

 Esters absorb at 1735 cm1, higher than

aldehydes or ketones
 Amides absorb near the low end of the

carbonyl region (1640-1680 cm-1)

87
88
Nuclear Magnetic Resonance Spectroscopy
 Hydrogens on the carbon next to a C=O are near 2~3
in the 1H NMR spectrum.
 All acid derivatives absorb in the same range so NMR
does not distinguish them from each other

89
 13
C NMR

 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

90
 Summary
 Carboxylic acid derivatives are compounds in which
the –OH group of a carboxylic acid has been
replaced by another substituent
 Acid halides, acid anhydrides, esters, and amides
are the most common
 Thioesters and acyl phosphates are common in
biological molecules
 Nucleophilic acyl substitution reaction dominates the
chemistry of carboxylic acid derivatives
 Step-growth polymers are prepared by reactions
between difunctional molecules