Carboxylic Acids and Their Derivatives—Nucleophilic

Acyl Substitution
Carboxylic Acid Derivatives:

Chapter-2

O O O O
-H2O
OH + HO O

ANHYDRIDE 1
2
Types of anhydrides:

Types of amides:

3
Cyclic esters and amides:

Nitriles:

4
Structure and Bonding

The two most important features of the carbonyl group

are:

5
• Three resonance structures stabilize carboxylic acid
derivatives (RCOZ) by delocalizing electron density.
• The more resonance structures 2 and 3 contribute to the
resonance hybrid, the more stable RCOZ is.

6
7
• Because the basicity of Z determines the relative
stability of the carboxylic acid derivatives, the following
stability order results:

• In summary, as the basicity of Z increases, the stability

of RCOZ increases because of added resonance
stabilization.
8
• The structure and bonding of nitriles is very different from that
of other carboxylic acid derivatives, and resembles the C—C
triple bond of alkynes.

• The carbon atom on the CN group is sp hybridized, making it

linear with a bond angle of 180°.
• The triple bond consists of one  and two  bonds. 9
10
11
12
Introduction to Nucleophilic Acyl Substitution

• Nucleophilic acyl substitutions is the characteristic

reaction of carboxylic acid derivatives.
• This reaction occurs with both negatively charged
nucleophiles and neutral nucleophiles.

13
• Other nucleophiles that participate in this reaction include:

14
To draw any nucleophilic acyl product:

[1] Find the sp2 hybridized carbon with the leaving group.
[2] Identify the nucleophile.
[3] Substitute the nucleophile for the leaving group. With a neutral
nucleophile, the proton must be lost to obtain a neutral
substitution product.

15
Based on this order of reactivity, more reactive compounds can be
converted into less reactive ones. The reverse is not usually true.

16
Reactions of Acid Chlorides
• Acid chlorides react readily with nucleophiles to form
nucleophilic substitution products.
• HCl is usually formed as a by-product.
• A weak base like pyridine is added to the reaction
mixture to remove the strong acid (HCl), forming an
ammonium salt.

17
Acid chlorides react with oxygen nucleophiles to form
anhydrides, carboxylic acids and esters.

18
• Acid chlorides also react with ammonia and 1° and 2° amines to
form 1°, 2° and 3° amides respectively.
• Two equivalents of NH3 or amine are used.
• One equivalent acts as the nucleophile to replace Cl, while the
other reacts as a base with the HCl by-product to form an
ammonium salt.

19
• As an example, reaction of an acid chloride with
diethylamine forms the 30 amide N,N-diethyl-m-
toluamide, popularly known as DEET.
• DEET is the active ingredient in the most widely used
insect repellents, and is effective against mosquitoes,
fleas and ticks.

20
21
Reactions of Anhydrides
• Nucleophilic attack occurs at one carbonyl group, while
the second carbonyl becomes part of the leaving group.

22
• Besides the usual steps for nucleophilic addition and
elimination of the leaving group, the mechanism
involves an additional proton transfer.

23
Reactions of Carboxylic Acids

• Nucleophiles that are also strong bases react with

carboxylic acids by removing a proton first, before any
nucleophilic substitution reaction can take place.

24
 O
Cl S
Cl
thionyl chloride

Figure 22.2
Nucleophilic acyl substitution
reactions of carboxylic acids

N
C
N

dicyclohexylcarbodiimide

DCC
25
• Treatment of a carboxylic acid with thionyl chloride
(SOCl2) affords an acid chloride.
• This is possible because thionyl chloride converts the
OH group of the acid into a better leaving group, and
because it provides the nucleophile (Cl¯) to displace the
leaving group.

26
27
• Although carboxylic acids cannot readily be converted
into anhydrides, dicarboxylic acids can be converted to
cyclic anhydrides by heating to high temperatures.
• This is a dehydration reaction because a water molecule
is lost from the diacid.

28
• Treatment of a carboxylic acid with an alcohol in the
presence of an acid catalyst forms an ester.
• This reaction is called a Fischer esterification.
• The reaction is an equilibrium, so it is driven to the right
by using excess alcohol or by removing water as it is
formed.

29
30
• Esterification of a carboxylic acid occurs in the presence
of acid but not in the presence of base.
• Base removes a proton from the carboxylic acid, forming
the carboxylate anion, which does not react with an
electron-rich nucleophile.

31
• Intramolecular esterification of - and -hydroxyl
carboxylic acids forms five- and six-membered lactones.

32
• Carboxylic acids cannot be converted into amides by
reaction with NH3 or an amine because amines are
bases, and undergo an acid-base reaction to form an
ammonium salt before nucleophilic substitution occurs.
• However, heating the ammonium salt at high
temperature (>100°C) dehydrates the resulting
ammonium salt of the carboxylate anion to form an
amide, although the yield can be low.

33
• The overall conversion of RCOOH to RCONH2 requires
two steps:
[1] Acid-base reaction of RCOOH with NH3 to form an
ammonium salt.
[2] Dehydration at high temperature (>100°C).

34
• A carboxylic acid and an amine readily react to form an
amide in the presence of an additional reagent,
dicyclohexylcarbodimide (DCC), which is converted to
the by-product dicyclohexylurea in the course of the
reaction.

35
• DCC is a dehydrating agent.
• The dicyclohexylurea by-product is formed by adding
the elements of H2O to DCC.
• DCC promotes amide formation by converting the
carboxy group OH group into a better leaving group.

36
37
Reactions of Esters

• Esters are hydrolyzed with water in the presence of

either acid or base to form carboxylic acids or
carboxylate anions respectively.

• Esters react with NH3 and amines to form 1°, 2°, or 3°

amides.

38
39
• Basic hydrolysis of an ester is also called saponification.

• Hydrolysis is base promoted, not base catalyzed,

because the base (OH–) is the nucleophile that adds to
the ester and forms part of the product. It participates in
40
the reaction and is not regenerated later.
• The carboxylate anion is resonance stabilized, and this
drives the equilibrium in its favor.
• Once the reaction is complete and the anion is formed, it
can be protonated with strong acid to form the neutral
carboxylic acid.

41
Reactions of Amides

• Amides are the least reactive of the carboxylic acid derivatives.

• Amides are hydrolyzed in acid or base to form carboxylic acids
or carboxylate anions.

• In acid, the amine by-product is protonated as an ammonium ion,

whereas in base, a neutral amine forms.

42
• The mechanism of amide hydrolysis in acid is exactly the same
as the mechanism of ester hydrolysis in acid.
• The mechanism of amide hydrolysis in base has the usual two
steps in the general mechanism for nucleophilic acyl
substitution, plus an additional proton transfer.

43
Nitriles
• Nitriles have the general structural formula RCN. Two useful
biologically active nitriles are letrozole and anastrozole.

• Nitriles are prepared by SN2 reactions of unhindered methyl and

1° alkyl halides with ¯CN.

44
Reactions of Nitriles—Hydrolysis

• Nitriles are hydrolyzed with water in the presence of acid

or base to yield carboxylic acids or carboxylate anions.
• In this reaction, the three C—N bonds are replaced by
three C—O bonds.

45
• The mechanism of this reaction involves formation of an
amide tautomer. Two tautomers can be drawn for any
carbonyl compound, and those for a 1° amide are as
follows:

46
• The imidic acid and amide tautomers are interconverted
by treatment with acid or base, analogous to keto-enol
tautomers of other carbonyl compounds.

47
48
Reactions of Nitriles—Reduction
• Treatment of a nitrile with LiAlH4 followed by H2O adds two
equivalents of H2 across the triple bond, forming a 10 amine.

• Treatment of a nitrile with a milder reducing agent such as

DIBAL-H followed by water forms an aldehyde.

H-
Al+
Diisobutylaluminium hydride

DIBAL-H

49
• With LiAlH4, two equivalents of hydride are sequentially
added to yield a dianion which is then protonated with
H2O to form an amine.

50
• With DIBAL-H, nucleophilic addition of one equivalent of
hydride forms an anion which is protonated with water
to generate an imine. The imine is then hydrolyzed in
water to form an aldehyde.

51
Hydrolysis of an imine

H A
NH
H2O NH2
NH2

H2N
H2N

OH H
O
NH2 OH H
A

52
Reactions of Nitriles—Addition of Organometallic reagents

• Both Grignard and organolithium reagents react with

nitriles to form ketones with a new C—C bond.

53
• The reaction occurs by nucleophilic addition of the
organometallic reagent to the polarized C—N triple bond to
form an anion, which is protonated with water to form an
imine. Water then hydrolyzes the imine, replacing the C=N
with C=O. The final product is a ketone with a new C—C
bond.

54
22.49)
O O
a)
NaHCO3 + H2CO3
Ph
Ph
Na+ OH ONa
OH -
O
O
sodium bicarbonate
O
b)
NaOH + H2 O
Ph
ONa

c) O
SOCl2

Ph
Cl

55
 d) O

NaCl
Ph NO REACTION
OH

O
e) NH3
Ph
1 equiv. ONH4

O
f) NH3
Ph
heat
NH2

56
 O
g) CH3OH O
Ph
Ph H2SO4
OH OCH3

O
h) CH3OH Ph
NaOH
ONa

O
i) NaOH O

CH3COCl Ph O

57
j) O O
Ph
CH3NH2
Ph NHCH3
DCC
OH

O
k) Ph
SOCl2

CH3CH2CH2NH2 NHCH2CH2CH3

O
l) SOCl2 Ph

(CH3)2CHOH
OCH(CH3)2

58
22.50) O

a)
SOCl2 NO REACTION
H3CH2CH2C OCH2CH3

O
b) H3O+

H3CH2CH2C OH

O
c) H2O
NaOH + CH3CH2OH
H3CH2CH2C ONa

59
d) O
O

NH3 + CH3CH2OH
H3CH2CH2C OCH2CH3
H3CH2CH2C NH2

O
e)
CH3CH2NH2
+ CH3CH2OH
H3CH2CH2C NHCH2CH3

60
22.51)
a) O O
+
Ph H3O Ph

NH2 OH

b) H2O O
Ph
NaOH
ONa

61
22.52) O

a) C6H5H2C CN H3O+
C6H5H2C OH

O
H2O
b)
NaOH
C6H5H2C ONa

O
CH3MgBr
c)
H2O C6H5H2C

62
 O

d) C6H5H2C CN CH3CH2LI
H2 O C6H5H2C

O
e) DIBAL-H
H2 O
C6H5H2C H

f) LiAlH4
H2O
C6H5H2C NH2

63
Carboxylic acids, syntheses:
1. oxidation of primary alcohols
RCH2OH + K2Cr2O7  RCOOH
2. oxidation of arenes
ArR + KMnO4, heat  ArCOOH
3. carbonation of Grignard reagents
RMgX + CO2  RCO2MgX + H+ 
RCOOH
4. hydrolysis of nitriles
RCN + H2O, H+, heat  RCOOH
1. oxidation of 1o alcohols:

CH3CH2CH2CH2-OH + CrO3 
CH3CH2CH2CO2H
n-butyl alcohol butyric acid
1-butanol butanoic acid

CH3 CH3
CH3CHCH2-OH + KMnO4  CH3CHCOOH
isobutyl alcohol isobutyric acid
2-methyl-1-propanol` 2-methylpropanoic acid
2. oxidation of arenes:
KMnO4, heat
CH3 COOH

toluene benzoic acid

CH3 COOH note: aromatic

KMnO4, heat
acids only!

H3C HOOC

p-xylene terephthalic acid

KMnO4, heat
CH2CH3 COOH + CO2

ethylbenzene benzoic acid

3. carbonation of Grignard reagent:

Mg CO2 H+
R-X RMgX RCO2MgX RCOOH
Increases the carbon chain by one carbon.

Mg CO2 H+
CH3CH2CH2-Br CH CH2CH2MgBr
CH3CH2CH2COOH 3
n-propyl bromide butyric acid

H+
O O O
+
RMgX + C R C + MgX R C
O- OH
O
CH3 CH3 CH3
Mg CO2 H+

Br MgBr COOH

p-toluic acid

Br2, hv Mg
CH3 CH2Br CH2MgBr

CO2

H+

CH2 COOH

phenylacetic acid
4. Hydrolysis of a nitrile:

H2O, H+
R-CN R-CO2H
heat

H2O, OH-
R-CN R-CO2- + H+  R-CO2H
heat

R-X + NaCN  R-CN + H+, H2O, heat  RCOOH

1o alkyl halide

Adds one more carbon to the chain.

R-X must be 1o or CH3!
 Br2, hv NaCN
CH3 CH2Br CH2 CN

toluene
H2O, H+, heat

CH2 COOH

phenylacetic acid

KCN
CH3CH2CH2CH2CH2CH2-Br CH3CH2CH2CH2CH2CH2-CN
1-bromohexane
H2O, H+, heat

CH3CH2CH2CH2CH2CH2-COOH
heptanoic acid
CH2OH

KMnO4

CH3
KMnO4, heat
CO2H

Br MgBr
Mg
CO2; then H+

C N
H2O, H+, heat
carboxylic acids, reactions:
1. as acids
2. conversion into functional derivatives
a)  acid chlorides
b)  esters
c)  amides
3. reduction
4. alpha-halogenation
5. EAS
as acids:
a) with active metals
RCO2H + Na  RCO2-Na+ + H2(g)
b) with bases
RCO2H + NaOH  RCO2-Na+ + H2O
c) relative acid strength?
CH4 < NH3 < HCCH < ROH < HOH < H2CO3 < RCO2H <
HF
d) quantitative
HA + H2O  H3O+ + A- ionization in water
Ka = [H3O+] [A-] / [HA]
Ka for carboxylic acids  10-5
Why are carboxylic acids more acidic than alcohols?
ROH + H2O  H3O+ + RO-
RCOOH + H2O  H3O+ + RCOO-
ΔGo = -2.303 R T log Keq
The position of the equilibrium is determined by the free
energy change, ΔGo.
ΔGo = ΔH - TΔS
ΔGo  ΔH Ka is inversely related to ΔH, the potential
energy difference between the acid and its conjugate base.
The smaller the ΔH, the larger the Ka and the stronger the
acid.
Effect of substituent groups on acid strength of benzoic acids?

Electron withdrawing groups will stabilize the anion, decrease the ΔH, shift
the ionization to the right, increasing the Ka, increasing acid strength.

COO-

Electron donating groups will destabilize the anion, increase the ΔH, shift
the ionization in water to the left, decreasing the Ka, decreasing acid
strength.
COO-

G
-NH2, -NHR, -NR2
-OH
-OR electron donating
-NHCOCH3
-C6H5
-R
-H
-X
-CHO, -COR
-SO3H
-COOH, -COOR electron withdrawing
-CN
-NR3+
-NO2
Relative acid strength?
Ka
p-aminobenzoic acid 1.4 x 10-5
p-hydroxybenzoic acid 2.6 x 10-5
p-methoxybenzoic acid 3.3 x 10-5
p-toluic acid 4.2 x 10-5
benzoic acid 6.3 x 10-5
p-chlorobenzoic acid 10.3 x 10-5
p-nitrobenzoic acid 36 x 10-5
2. Conversion into functional derivatives:
a) acid chlorides

O SOCl2 O
R C R C
OH or PCl3 Cl
orPCl5

CO2H + SOCl2 COCl

O PCl3 O
CH3CH2CH2 C CH3CH2CH2 C
OH Cl
b) esters
“direct” esterification: H+
RCOOH + R´OH  RCO2R´ + H2O
-reversible and often does not favor the ester
-use an excess of the alcohol or acid to shift equilibrium
-or remove the products to shift equilibrium to
completion

“indirect” esterification:
RCOOH + PCl3  RCOCl + R´OH  RCO2R´
-convert the acid into the acid chloride first; not
reversible
 O H+ O
C + CH3OH C + H2O
OH O CH3

SOCl2

O CH3OH
C
Cl
c) amides
“indirect” only!
RCOOH + SOCl2  RCOCl + NH3  RCONH2
amide
O O
PCl3 NH3 O
OH Cl NH2
3-Methylbutanoic acid

Directly reacting ammonia with a carboxylic acid results

in an ammonium salt:
RCOOH + NH3  RCOO-NH4+
acid base
 O PCl3 O NH3 O
C C C
OH Cl NH2

amide

NH3

O
C ammonium salt
O NH4
 3. Reduction:
RCO2H + LiAlH4; then H+  RCH2OH
1o alcohol

LiAlH4 H+
CH3CH2CH2CH2CH2CH2CH2COOH
Octanoic acid
(Caprylic acid)
CH3CH2CH2CH2CH2CH2CH2CH2OH
1-Octanol

Carboxylic acids resist catalytic reduction under normal

conditions.
RCOOH + H2, Ni  NR
 O H2, Pt
CH2 C NR
OH

LiAlH4

H+

CH2CH2OH
4. Alpha-halogenation: (Hell-Volhard-Zelinsky reaction)

RCH2COOH + X2, P  RCHCOOH + HX

X
α-haloacid
X2 = Cl2, Br2

CH3CH2CH2CH2COOH + Br2,P CH3CH2CH2CHCOOH

pentanoic acid Br
2-bromopentanoic acid

COOH
Br2,P
NR (no alpha H)
RCH2COOH + Br2,P RCHCOOH + HBr
Br

NH3

RCHCOOH RCHCOOH
aminoacid
NH2
OH

KOH(alc)
RCH2CHCOOH RCH=CHCOOH
Br then H+
5. EAS: (-COOH is deactivating and meta- directing)
CO2H
HNO3,H2SO4

NO2

CO2H
H2SO4,SO3
CO2H

SO3H

CO2H
benzoic acid Br2,Fe

Br

CH3Cl,AlCl3
NR
spectroscopy:

IR: -COOH O—H stretch 2500 – 3000 cm-1 (b)

C=O stretch 1680 – 1725 (s)

nmr: -COOH 10.5 – 12 ppm

Carboxylic acids, syntheses:
1. oxidation of primary alcohols
RCH2OH + K2Cr2O7  RCOOH
2. oxidation of arenes
ArR + KMnO4, heat  ArCOOH
3. carbonation of Grignard reagents
RMgX + CO2  RCO2MgX + H+ 
RCOOH
4. hydrolysis of nitriles
RCN + H2O, H+, heat  RCOOH
carboxylic acids, reactions:
1. as acids
2. conversion into functional derivatives
a)  acid chlorides
b)  esters
c)  amides
3. reduction
4. alpha-halogenation
5. EAS