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Chem 212 B. R.

Kaafarani 1
Chapter 19
Carboxylic Acid Derivatives:
Nucleophilic Acyl Substitution
Chem 212 B. R. Kaafarani 2
RC
O
X
Acyl Halides
Name the acyl group and add the word chloride,
fluoride, bromide, or iodide as appropriate
Acyl chlorides are, by far, the most frequently
encountered of the acyl halides
19.1. Nomenclature of Carboxylic Acid
Derivatives
Chem 212 B. R. Kaafarani 3
CH
3
CCl
O
Acetyl chloride
3-Butenoyl chloride
O
H
2
C CHCH
2
CCl
O
CBr F p-Fluorobenzoyl bromide
Acyl Halides
Chem 212 B. R. Kaafarani 4
RCOCR'
O O
Acid Anhydrides
When both acyl groups are the same, name the acid
and add the word anhydride.
When the groups are different, list the names of the
corresponding acids in alphabetical order and add the
word anhydride.
Chem 212 B. R. Kaafarani 5
Acetic anhydride
Benzoic anhydride
Benzoic heptanoic anhydride
CH
3
COCCH
3
O O
C
6
H
5
COCC
6
H
5
O O
C
6
H
5
COC(CH
2
)
5
CH
3
O O
Acid Anhydrides
Chem 212 B. R. Kaafarani 6
RCOR'
O
Esters
Name as alkyl alkanoates.
Cite the alkyl group attached to oxygen first (R').
Name the acyl group second; substitute the
suffix -ate for the -ic ending of the corresponding
acid.
Chem 212 B. R. Kaafarani 7
CH
3
COCH
2
CH
3
O
Ethyl acetate
Methyl propanoate
2-Chloroethyl benzoate
O
CH
3
CH
2
COCH
3
COCH
2
CH
2
Cl
O
Esters
Chem 212 B. R. Kaafarani 8
RCNH
2
O
Amides having an NH
2
group
Identify the corresponding carboxylic acid.
Replace the -ic acid or -oic acid ending by amide.
Chem 212 B. R. Kaafarani 9
CH
3
CNH
2
O
Acetamide
3-Methylbutanamide
O
(CH
3
)
2
CHCH
2
CNH
2
CNH
2
O
Benzamide
Amides having an NH
2
group
Chem 212 B. R. Kaafarani 10
RCNHR'
O
and RCNR'
2
O
Amides having substituents on N
Name the amide as before.
Precede the name of the amide with the name of
the appropriate group or groups.
Precede the names of the groups by the letter N-
(standing for nitrogen and used as a locant).
Chem 212 B. R. Kaafarani 11
CH
3
CNHCH
3
O
N-Methylacetamide
N-Isopropyl-N-methylbutanamide
CN(CH
2
CH
3
)
2
O
N,N-Diethylbenzamide
O
CH
3
CH
2
CH
2
CNCH(CH
3
)
2
CH
3
Amides having substituents on N
Chem 212 B. R. Kaafarani 12
RC N
Nitriles
Add the suffix -nitrile to the name of the parent
hydrocarbon chain (including the triply bonded
carbon of CN).
Or: replace the -ic acid or -oic acid name of the
corresponding carboxylic acid by onitrile.
Or: name as an alkyl cyanide (functional class
name).
Chem 212 B. R. Kaafarani 13
CH
3
C N
Ethanenitrile
or: Acetonitrile
or: Methyl cyanide
C
6
H
5
C N
Benzonitrile
N C
CH
3
CHCH
3
2-Methylpropanenitrile
or: Isopropyl cyanide
Nitriles
Chem 212 B. R. Kaafarani 14
Figure 19.1
(page 816)
The key to managing the information in
this chapter is the same as always:
structure determines properties.
The key structural feature is how well the
carbonyl group is stabilized.
The key property is reactivity in nucleophilic
acyl substitution.
19.2. Structure and Reactivity
of Carboxylic Acid Derivatives
Chem 212 B. R. Kaafarani 15
CH
3
C
O
Cl
CH
3
C
O
OCCH
3
O
CH
3
C
O
SCH
2
CH
3
CH
3
C
O
OCH
2
CH
3
CH
3
C
O
NH
2
Most
reactive
Least
reactive
Least
stabilized
Most
stabilized
Chem 212 B. R. Kaafarani 16
RC
O
X


RC
O
X

+
RC
O
X

Electron Delocalization and the Carbonyl Group


The main structural feature that distinguishes acyl
chlorides, anhydrides, thioesters, esters, and amides is the
interaction of the substituent with the carbonyl group. It
can be represented in resonance terms as:
The extent to which the lone pair on X can be delocalized
into C=O depends on:
1) The electronegativity of X.
2) How well the lone pair orbital of X interacts with the t orbital
of C=O.
Chem 212 B. R. Kaafarani 17

C
O
R
Cl

C
O
R
Cl

Acyl chlorides have the least stabilized carbonyl


group.
Delocalization of lone pair of Cl into C=O group is
not effective because CCl bond is too long.
Acyl Chlorides
Chem 212 B. R. Kaafarani 18
RCOCR'
O O
RCCl
O
RCOR'
O
RCNR'
2
O
RCO

O
least stabilized C=O
most stabilized C=O
RCSR'
O
Chem 212 B. R. Kaafarani 19
Acid Anhydrides
C
R
O

C
O

R
O

C
R
O

C
R

Lone pair donation from oxygen stabilizes the
carbonyl group of an acid anhydride.
The other carbonyl group is stabilized in an
analogous manner by the lone pair.
Chem 212 B. R. Kaafarani 20
Thioesters

C
R
O

SR'

C
R
SR'


Sulfur (like chlorine) is a third-row element.
Electron donation to C=O from third-row elements
is not very effective.
Resonance stabilization of C=O in thioesters is
not significant.
Chem 212 B. R. Kaafarani 21
Esters

C
R
O

OR'

C
R
OR'


Lone pair donation from oxygen stabilizes the
carbonyl group of an ester.
Stabilization greater than comparable stabilization of
an anhydride or thioester.
Chem 212 B. R. Kaafarani 22
Amides

C
R
O

NR'
2
O

C
R
NR'
2

Lone pair donation from nitrogen stabilizes the carbonyl group
of an amide.
N is less electronegative than O; therefore, amides are
stabilized more than esters and anhydrides.
Amide resonance imparts significant double-bond character to
CN bond.
Activation energy for rotation about CN bond is 75-85 kJ/mol.
CN bond distance is 135 pm in amides versus normal single-
bond distance of 147 pm in amines.
Chem 212 B. R. Kaafarani 23
Carboxylate ions

C
R

C
R
O

O
Very efficient electron delocalization and dispersal
of negative charge.
Maximum stabilization.
Chem 212 B. R. Kaafarani 24
Reactivity is related to structure
RCOCR'
O O
RCCl
O
RCOR'
O
RCNR'
2
O
Stabilization
very small
small
large
moderate
Relative rate
of hydrolysis
10
11
10
7
< 10
-2
1.0
The more
stabilized the
carbonyl group, the
less reactive it is.
Chem 212 B. R. Kaafarani 25
In general:
O

C
R
X
+ HY
O

C
R
Y
+ HX
Reaction is feasible when a less stabilized carbonyl
is converted to a more stabilized one (more reactive to
less reactive).
19.3. General Mechanism
for Nucleophilic Acyl Substitution
Chem 212 B. R. Kaafarani 26
RCOCR'
O O RCCl
O
RCOR'
O
RCNR'
2
O
RCO

O
least stabilized C=O
most stabilized C=O
RCSR'
O
A carboxylic acid derivative
can be converted by
nucleophilic acyl substitution to
any other type that lies below it
in this table.
Chem 212 B. R. Kaafarani 27
O

C
R
X
HNu
C
R
OH
X
Nu
O

C
R
Nu
-HX
General Mechanism for Nucleophilic Acyl
Substitution
Involves formation and dissociation of a tetrahedral
intermediate.
Both stages can involve several elementary steps.
First stage of mechanism (formation of tetrahedral
intermediate) is analogous to nucleophilic addition to C=O of
aldehydes and ketones.
Second stage is restoration of C=O by elimination.
Chem 212 B. R. Kaafarani 28
The Tetrahedral Intermediate
Tetrahedral Intermediate (TI)
C
R
O
X
Nu

C
R
O
X
Nu

H
+
Conjugate acid of tetrahedral
intermediate (TI
+
)

C
R
X
Nu

Conjugate base of tetrahedral


intermediate (TI

)
Chem 212 B. R. Kaafarani 29
Dissociation of TIH
+

C
R
O
X
Nu

H
+
+
BH +
C
O
R Nu

+ X H

Chem 212 B. R. Kaafarani 30


Dissociation of Tl

C
R
O
X
Nu

+
BH +
C
O
R Nu

+ X

Chem 212 B. R. Kaafarani 31


Dissociation of TI

C
O
R Nu

+ X

C
R
O
X
Nu

Chem 212 B. R. Kaafarani 32


From carboxylic acids and thionyl chloride
(CH
3
)
2
CHCOH
O
SOCl
2
heat
(CH
3
)
2
CHCCl
O
+
SO
2
+
HCl
(90%)
Preparation of Acyl Chlorides
19.4. Nucleophilic Substitution
in Acyl Chlorides
Chem 212 B. R. Kaafarani 33
RCOCR'
O O
RCCl
O
RCOR'
O
RCNR'
2
O
RCO

O
Reactions of Acyl Chlorides
Chem 212 B. R. Kaafarani 34
RCCl
O
+
R'COH
O
RCOCR'
O O
+
HCl
Acyl chlorides react with carboxylic acids to give acid
anhydrides:
via:
C R
O
Cl
OCR'
H
O
Reactions of Acyl Chlorides
Chem 212 B. R. Kaafarani 35
RCCl
O
+
RCOR'
O
+
HCl
Acyl chlorides react with alcohols to give esters:
R'OH
via:
C R
O
Cl
OR'
H
Reactions of Acyl Chlorides
Chem 212 B. R. Kaafarani 36
RCCl
O
+
RCNR'
2
O
+
H
2
O
Acyl chlorides react with ammonia and amines to give
amides:
R'
2
NH + HO

+
Cl

via:
C R
O
Cl
NR'
2
H
Reactions of Acyl Chlorides
Chem 212 B. R. Kaafarani 37
RCCl
O
+
RCOH
O
+
HCl
Acyl chlorides react with water to give carboxylic
acids (carboxylate ion in base):
H
2
O
RCCl
O
+
RCO

O
+
Cl

2HO

+ H
2
O
Reactions of Acyl Chlorides
Chem 212 B. R. Kaafarani 38
via:
C R
O
Cl
OH
H
Reactions of Acyl Chlorides
Acyl chlorides react with water to give carboxylic
acids (carboxylate ion in base):
RCCl
O
+
RCOH
O
+
HCl H
2
O
Chem 212 B. R. Kaafarani 39
Reactivity
C
6
H
5
CCl
O
C
6
H
5
CH
2
Cl
Relative rates of
hydrolysis (25C)
1,000 1
Acyl chlorides undergo nucleophilic substitution
much faster than alkyl chlorides.
Chem 212 B. R. Kaafarani 40
Anhydrides can be prepared from acyl
chlorides as described in Table 19.1.
19.5
Nucleophilic Acyl Substitution in
Carboxylic Acid Anhydrides
Chem 212 B. R. Kaafarani 41
CH
3
COCCH
3
O O
Acetic
anhydride
O
O
O
O
O
O
Phthalic
anhydride
Maleic
anhydride
Some anhydrides are industrial chemicals
Chem 212 B. R. Kaafarani 42
C
C
H
H COH
COH
O
O
O
O
O
H
H
tetrachloroethane
130C
(89%)
+ H
2
O
From Dicarboxylic Acids
Cyclic anhydrides with 5- and 6-membered rings
can be prepared by dehydration of dicarboxylic acids.
Chem 212 B. R. Kaafarani 43
+
RCOR'
O
+
Carboxylic acid anhydrides react with alcohols to give
esters:
R'OH
RCOCR
O O
RCOH
O
Normally, symmetrical anhydrides are used (both R
groups the same).
Reaction can be carried out in presence of pyridine
(a base) or it can be catalyzed by acids.
Reactions of Acid Anhydrides
Chem 212 B. R. Kaafarani 44
+
RCOR'
O
+
Carboxylic acid anhydrides react with alcohols to
give esters:
R'OH
RCOCR
O O
RCOH
O
via:
C R
O
OCR
OR'
H
O
Reactions of Acid Anhydrides
Chem 212 B. R. Kaafarani 45
+
RCNR'
2
O
+
Acid anhydrides react with ammonia and amines to
give amides:
2R'
2
NH
RCOCR
O O
RCO

O
R'
2
NH
2
+
via:
C R
O
OCR
NR'
2
H
O
Reactions of Acid Anhydrides
Chem 212 B. R. Kaafarani 46
+
2RCOH
O
Acid anhydrides react with water to give carboxylic
acids (carboxylate ion in base):
H
2
O
+
2RCO

O
+
2HO

H
2
O
RCOCR
O O
RCOCR
O O
Reactions of Acid Anhydrides
Chem 212 B. R. Kaafarani 47
+
2RCOH
O
Acid anhydrides react with water to give carboxylic
acids (carboxylate ion in base):
H
2
O RCOCR
O O
C R
O
OCR
OH
H
O
Reactions of Acid Anhydrides
Chem 212 B. R. Kaafarani 48
Example
+
H
2
O
O
O
O

COH
O
COH
O
Chem 212 B. R. Kaafarani 49
CH
3
COCH
2
CH
2
CH(CH
3
)
2
O
3-methylbutyl acetate
Also called "isopentyl acetate" and "isoamyl acetate.
Contributes to characteristic odor of bananas.
Esters are very common natural products
19.6. Sources of Esters
Chem 212 B. R. Kaafarani 50
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"
O
O
Chem 212 B. R. Kaafarani 51
Preparation of Esters
Fischer esterification.
From acyl chlorides.
From carboxylic acid anhydrides.
Baeyer-Villiger oxidation of ketones.
Chem 212 B. R. Kaafarani 52
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
OH
28C
57C
99C
boiling
point
19.7. Physical Properties of Esters
Chem 212 B. R. Kaafarani 53
Solubility in Water
~0
33
12.5
Solubility
(g/100 g)
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
Chem 212 B. R. Kaafarani 54
19.8. Reactions of Esters:
A Review and a Preview
With Grignard reagents.
Reduction with LiAlH
4
.
With ammonia and amines.
Hydrolysis.
Chem 212 B. R. Kaafarani 55
RCOH
O
+
R'OH
RCOR'
O
+ H
2
O
H
+
is the reverse of Fischer esterification
19.9. 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.
Chem 212 B. R. Kaafarani 56
Example
HCl, heat
+
H
2
O

O
CHCOCH
2
CH
3
Cl
+
CH
3
CH
2
OH
O
CHCOH
Cl
(80-82%)
Chem 212 B. R. Kaafarani 57
Mechanism of Acid-Catalyzed
Ester Hydrolysis
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).
Chem 212 B. R. Kaafarani 58
RC
OH
OH
OR'
+
H
2
O RCOR'
O
H
+
First stage: formation of tetrahedral intermediate
Water adds to the
carbonyl group of the
ester.
This stage is
analogous to the acid-
catalyzed addition of
water to a ketone.
Chem 212 B. R. Kaafarani 59
+
R'OH
H
+
RCOH
O
Second stage: cleavage of tetrahedral intermediate
RC
OH
OH
OR'
Chem 212 B. R. Kaafarani 60
Key Features of Mechanism
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.
Chem 212 B. R. Kaafarani 61
18
O Labeling Studies
+
H
2
O
18

COCH
2
CH
3
O
18

COCH
2
CH
3
O
+
H
2
O
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
+
Chem 212 B. R. Kaafarani 62
C
18
OH
OH
OCH
2
CH
3

COCH
2
CH
3
O
18
H
+
+
H
2
O
+
H
2
O
18

COCH
2
CH
3
O
H
+
18
O Labeling Studies
Chem 212 B. R. Kaafarani 63
RCO

O
+
R'OH
RCOR'
O
+
HO

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).
19.10. Ester Hydrolysis in Base: Saponification
Chem 212 B. R. Kaafarani 64
Example
water-methanol, heat
(95-97%)

CH
2
OCCH
3
CH
3
O
+
NaOH
CH
2
OH
CH
3
O
CH
3
CONa
+
Chem 212 B. R. Kaafarani 65
Example
(87%)
+
CCOH
CH
3
O
H
2
C
1. NaOH, H
2
O, heat
2. H
2
SO
4
CH
3
OH
CCOCH
3
CH
3
O
H
2
C
Chem 212 B. R. Kaafarani 66
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
Chem 212 B. R. Kaafarani 67
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. Carboxylate is the
leaving group.
Which bond is broken when esters are
hydrolyzed in base?
Chem 212 B. R. Kaafarani 68
+

OH

RC
O
OR'

+
OR'

A second possibility is nucleophilic acyl substitution.


RC
O

OH
Which bond is broken when esters are
hydrolyzed in base?
Chem 212 B. R. Kaafarani 69
18
O Labeling gives the answer

18
O retained in alcohol, not carboxylate; therefore,
nucleophilic acyl substitution.
CH
3
CH
2
C
18
OCH
2
CH
3
O
NaOH
+
CH
3
CH
2
CONa
O
CH
3
CH
2
18
OH
+
Chem 212 B. R. Kaafarani 70
Stereochemistry gives the same answer
CH
3
COK
O
+ HO
CH
3
KOH, H
2
O
Alcohol has same
configuration at chirality
center as ester;
therefore, nucleophilic
acyl substitution.
Not S
N
2.
CH
3
C
O

C
O
H
C
6
H
5
18
C
H
C
6
H
5
CH
3
18
Chem 212 B. R. Kaafarani 71
Does nucleophilic acyl substitution proceed in a
single step, or is a tetrahedral intermediate involved?
Does it proceed via a tetrahedral
intermediate?
+

OH

RC
O
OR'

+
OR'


RC
O

OH
Chem 212 B. R. Kaafarani 72
18
O Labeling Studies
+
H
2
O
18

COCH
2
CH
3
O
18

COCH
2
CH
3
O
+
H
2
O
HO

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.
Chem 212 B. R. Kaafarani 73
C
18
OH
OH
OCH
2
CH
3
+
H
2
O
18

COCH
2
CH
3
O
18
HO


COCH
2
CH
3
O
+
H
2
O
HO

18
O Labeling Studies
Chem 212 B. R. Kaafarani 74
Amides are less reactive toward nucleophilic acyl
substitution than other acid derivatives.
C
O
H N
H
H
C
O
H N
H
H
C
O
H N
H
H
Formamide
Physical Properties of Amides
19.14. Amides
Chem 212 B. R. Kaafarani 75
Acyl chlorides.
Anhydrides.
Esters.
Amides are prepared from amines by acylation with:
Preparation of Amides
Chem 212 B. R. Kaafarani 76
Amines do not react with carboxylic acids to give amides.
The reaction that occurs is proton-transfer (acid-base).
RCOH
O
+
R'NH
2
RCO
O
+
R'NH
3
+

Preparation of Amides
RCNHR'
O
+
H
2
O
heat
If no heat-sensitive groups
are present, the resulting
ammonium carboxylate salts
can be converted to amides
by heating.
Chem 212 B. R. Kaafarani 77
Example

COH
O
+

H
2
N
225C
+
H
2
O
(80-84%)
CNH
O
Chem 212 B. R. Kaafarani 78
20.16. Lactams
Lactams are cyclic amides. Some are industrial
chemicals, others occur naturally.
c-Caprolactam: used to
prepare a type of nylon
(Caproic acid is the common
name for hexanoic acid).

N
H
O
o
|

o
c
o
|
CH
3
CH
3
S
CO
2
H
O
N
C
6
H
5
CH
2
CNH
O
Penicillin G: a |-
lactam antibiotic
Chem 212 B. R. Kaafarani 79
Hydrolysis of amides is irreversible. In acid solution the
amine product is protonated to give an ammonium salt.
+
R'NH
3
+
RCOH
O
RCNHR'
O
+
H
2
O H
+
+
19.15. Hydrolysis of Amides
In basic solution the carboxylic acid product is deprotonated
to give a carboxylate ion.
RCNHR'
O
+
R'NH
2

RCO
O
HO
+

Chem 212 B. R. Kaafarani 80


(88-90%)
CH
3
CH
2
CHCNH
2
O
CH
3
CH
2
CHCOH
O
H
2
O
H
2
SO
4
heat
+
NH
4
+
HSO
4

Example: Acid Hydrolysis


Chem 212 B. R. Kaafarani 81
(95%)
CH
3
COK
O
KOH
H
2
O
heat
+
CH
3
CNH
O
Br
NH
2
Br
Example: Basic Hydrolysis
Chem 212 B. R. Kaafarani 82
Mechanism of Acid-Catalyzed
Amide Hydrolysis
Acid-catalyzed amide hydrolysis proceeds via the
customary two stages:
1) Formation of tetrahedral intermediate.
2) Dissociation of tetrahedral intermediate.
Mechanism as before. Check your book.
Chem 212 B. R. Kaafarani 83
Involves two stages:
1) Formation of tetrahedral intermediate.
2) Dissociation of tetrahedral intermediate.
Mechanism of Amide Hydrolysis
in Base
Mechanism as before. Check your book.
Chem 212 B. R. Kaafarani 84
RC
OH
OH
NH
2
+
H
2
O RCNH
2
O
HO

First stage: formation of tetrahedral intermediate


Water adds to the carbonyl
group of the amide.
This stage is analogous to the
base-catalyzed addition of water
to a ketone.
Chem 212 B. R. Kaafarani 85
+
RCO
O
NH
3

HO

Second stage: cleavage of tetrahedral intermediate


RC
OH
OH
NH
2
Chem 212 B. R. Kaafarani 86
19.17. Preparation of Nitriles
Nitriles are prepared by:
Nucleophilic substitution by cyanide on alkyl
halides.
Canohydrin formation.
Dehydration of amides.
Chem 212 B. R. Kaafarani 87
Examples
(95%)
CH
3
(CH
2
)
8
CH
2
Cl
KCN
ethanol-
water
CH
3
(CH
2
)
8
CH
2
C N
S
N
2
(75%)
1. KCN
2. H
+
CH
3
CH
2
CCH
2
CH
3
O
CH
3
CH
2
CCH
2
CH
3
OH
C N
Chem 212 B. R. Kaafarani 88
By dehydration of amides:
(CH
3
)
2
CHCNH
2
O
P
4
O
10
200C
(CH
3
)
2
CHC N
(69-86%)
Preparation of Nitriles
Using the dehydration reagent phosphorus pentoxide
P
4
O
10
(often written as P
2
O
5
).
Chem 212 B. R. Kaafarani 89
19.18. Hydrolysis of Nitriles
Hydrolysis of nitriles resembles the hydrolysis
of amides. The reaction is irreversible.
Ammonia is produced and is protonated to
ammonium ion in acid solution.
+
NH
4
+
RCOH
O
RCN
+
2H
2
O H
+
+
Chem 212 B. R. Kaafarani 90
In basic solution the carboxylic acid product is
deprotonated to give a carboxylate ion.
+

RCO
O
HO
+

NH
3
RCN
+
H
2
O
Hydrolysis of Nitriles
Chem 212 B. R. Kaafarani 91
(92-95%)
O
H
2
O
H
2
SO
4
heat

CH
2
CN
NO
2

CH
2
COH
NO
2
Example: Acid Hydrolysis
Chem 212 B. R. Kaafarani 92
(80%)
CH
3
(CH
2
)
9
COH
O
CH
3
(CH
2
)
9
CN
1. KOH, H
2
O, heat
2. H
+
Example: Basic Hydrolysis
Chem 212 B. R. Kaafarani 93
RC N
H
2
O
RCNH
2
O
H
2
O
RCOH
O
Mechanism of Hydrolysis of Nitriles
Hydrolysis of nitriles proceeds via the corresponding
amide.
We already know the mechanism of amide hydrolysis.
Therefore, all we need to do is to see how amides are
formed from nitriles under the conditions of hydrolysis.
Chem 212 B. R. Kaafarani 94
RC N
H
2
O
RCNH
2
O
RC NH
OH
The mechanism of amide formation is analogous to that
of conversion of alkynes to ketones.
It begins with the addition of water across the carbon-
nitrogen triple bond.
The product of this addition is the nitrogen analog of an
enol. It is transformed to an amide under the reaction
conditions.
Mechanism of Hydrolysis of Nitriles
Chem 212 B. R. Kaafarani 95
Step 1 Step 1
O

RC N

RC
O
N

H

Chem 212 B. R. Kaafarani 96
Step 2 Step 2
RC
O
N

H
O

H
H

H
RC
O
N

H
H

Chem 212 B. R. Kaafarani 97


Step 3 Step 3

H
RC
O
N

H
H

RC
O
N

H
H
Chem 212 B. R. Kaafarani 98
Step 4 Step 4

RC
O
N

H
O

H
H

RC
O

H
H

Chem 212 B. R. Kaafarani 99


RC N
R'MgX
RCR'
NMgX
H
2
O
RCR'
NH
diethyl
ether
19.19. Addition of Grignard
Reagents to Nitriles
Grignard reagents add to carbon-nitrogen triple
bonds in the same way that they add to carbon-
oxygen double bonds.
The product of the reaction is an imine.
Chem 212 B. R. Kaafarani 100
RCR'
O
H
3
O
+
Imines are readily hydrolyzed to
ketones. Therefore, the reaction of
Grignard reagents with nitriles can be
used as a synthesis of ketones.
RC N
R'MgX
RCR'
NMgX
H
2
O
RCR'
NH
diethyl
ether
Addition of Grignard Reagents to Nitriles
Chem 212 B. R. Kaafarani 101
Example
(79%)

F
3
C
C N
+ CH
3
MgI
1. Diethyl ether
2. H
3
O
+
, heat
F
3
C
CCH
3
O
Chem 212 B. R. Kaafarani 102
Section 19.20
Spectroscopic Analysis of
Carboxylic Acid Derivatives
Chem 212 B. R. Kaafarani 103
Infrared Spectroscopy
1822 cm
-1
1748
and
1815 cm
-1
1736 cm
-1
1694 cm
-1
C=O stretching frequency v
C=O stretching frequency depends on whether the
compound is an acyl chloride, anhydride, ester, or amide.
Anhydrides have two peaks due to C=O stretching. One
results from symmetrical stretching of the C=O unit, the other
from an antisymmetrical stretch.
CH
3
CCl
O
CH
3
COCH
3
O
CH
3
COCCH
3
O O
CH
3
CNH
2
O
Chem 212 B. R. Kaafarani 104
Infrared Spectroscopy
Nitriles are readily identified by absorption due to carbon-
nitrogen triple bond stretching in the 2210-2260 cm
-1
region.
1
H NMR
RCOR'
O
and R'COR
O
O
C
H
is less shielded than
O
C
C
H

1
H NMR readily distinguishes between isomeric esters of the
type:
Chem 212 B. R. Kaafarani 105
CH
3
COCH
2
CH
3
O
and
For example:
CH
3
CH
2
COCH
3
O
Both have a triplet-quartet pattern for an ethyl
group and a methyl singlet. They can be identified,
however, on the basis of chemical shifts.
1
H NMR
Chem 212 B. R. Kaafarani 106
13
C NMR
UV-VIS
CH
3
CCl
O
235 nm
CH
3
COCH
3
O
225 nm
CH
3
COCCH
3
O O
207 nm
CH
3
CNH
2
O
214 nm
nt* absorption:
max
Carbonyl carbon is at low field (o 160-180 ppm), but not as
deshielded as the carbonyl carbon of an aldehyde or ketone (o
190-215 ppm).
The carbon of a CN group appears near o 120 ppm.
Chem 212 B. R. Kaafarani 107
Most carboxylic acid derivatives give a prominent
peak for an acylium ion derived by the fragmentation shown.
Mass Spectrometry
+
RCX

RCX
+
O

RC
O
+

X
Amides, however, cleave in the direction that gives a
nitrogen-stabilized cation.
+
R
RCNR'
2

+
RCNR'
2
O

+
O
C

NR'
2