O
RCCl
Chapter 15
Carboxylic Acid Derivatives
Nucleophilic Acyl Substitution
Acyl chloride
O O
Carboxylic
Acid
Derivatives
RCOCR
Anhydride
O
RCOR'
RCOR
Ester
O
RCNR'2
O
RCCl
O
RCCl
Acyl chloride
O O
Decreasing
Reactivity
(Nucleophilic Acyl
Substitution)
RCOCR
Anhydride
Ester
O
RCNR'2
Acyl chloride
O O
O
RCOR'
RCOR
Amide
Increasing
stabilization
of C=O
RCOCR
Anhydride
O
RCOR'
RCOR
Ester
O
Amide
RCNR'2
Amide
most reactive
O
RCCl
O O
RCOCR'
O
a carboxylic acid
derivative can be
RCOR'
converted by
nucleophilic acyl
substitution to any other
type that lies below it in
this table
Spectroscopic Analysis of
Carboxylic Acid Derivatives
O
RCNR'
RC
NR'2
O
RCO–
least reactive
Infrared Spectroscopy
Infrared Spectroscopy
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
C O
unit, the other from an antisymmetrical stretch.
C=O stretching frequency ν
C=O stretching frequency ν
O
O O
CH3CCl
CH3COCCH3
1822 cm-1
1748
and
1815 cm-1
O
O
CH3COCH3 CH3CNH2
1736 cm-1
1694 cm-1
O O
CH3COCCH3
1748
1748
and
and -1
1815
1815cm
cm-1
Infrared Spectroscopy
Infrared Spectroscopy
Amides show different NN-H stretching peaks depending
on the number of hydrogens present:
A primary amide ((--CONH2) shows two peaks
A secondary amide ((--CONHR) shows one peaks
A tertiary amide ((--CONR2) shows no NN-H stretching
Infrared Spectroscopy
Nitriles are readily identified by absorption due to
carbon--nitrogen triple bond stretching in the 2210carbon
22102260 cm-1 region.
1H
NMR
1H
NMR readily
y distinguishes
g
between isomeric
esters of the type:
O
RCO
COR'
R'
O
and
R'CO
R'
COR
R
O
O
C
H
is less shielded than C
C
H
O
O
1H
NMR
CH3CH2CO
COCH
CH3
CH3CO
COCH
CH2CH3
For example:
O
O
CH3COCH2CH3
and
CH3CH2COCH3
Both have a triplet
triplet--quartet pattern for an ethyl
group and a methyl singlet. They can be
identified, however, on the basis of chemical
shifts.
5.0
4.0
3.0
2.0
1.0
0
5.0
Chemical shift (δ
(δ, ppm)
13C
NMR
Carbonyl carbon is at low field (δ
(δ 160
160--180
ppm), but not as deshielded as the carbonyl
carbon of an aldehyde or ketone (δ
(δ 190
190--215
ppm).
The carbon of a CN group appears near δ 120
ppm.
Acid halides
4.0
3.0
2.0
1.0
0
Acyl Halides
Acyl Halides
O
RC
O
X
acetyl chloride
CH3CCl
Name the acyl group after the carboxylic acid and
substitute -ic acid by -yl chloride,
chloride, fluoride
fluoride,, bromide
bromide,,
or iodide as appropriate
acyl chlorides are, by far, the most frequently
encountered of the acyl halides
O
H2C
CHCH2CCl
3-butenoyl chloride
O
F
CBr
p-fluorobenzoyl bromide
Preparation of Acyl Chlorides
From carboxylic
y acids and thionyl
y chloride
O
(CH3)2CHC
CHCOH
OH
O
SOCl2
heat
CHCCl
Cl + SO2 + HCl
(CH3)2CHC
(90%)
The same reaction can be carried out with PCl3
Reactions of Acid Chlorides:
Nucleophilic Substitution
Reactions of Acyl Chlorides
General Mechanism for Nucleophilic Acyl Substitution
O
involves formation and dissociation
off a tetrahedral
t t h d l intermediate
i t
di t
RCCl
RC
Cl
O O
RCOCR'
OH
••
O ••
R
C
HY
O ••
- HX
R
C
X
O
••
Y
R
C
RCOR'
O
Y
RCNR'
RC
NR'2
O
X
RCO–
Reactions of Acyl Chlorides
Reactions of Acyl Chlorides
Acyl chlorides react with water to give
carboxylic acids (carboxylate
(carboxylate ion in base):
O
RCCl
RC
Cl + H2O
Acyl chlorides react with water to give
carboxylic acids (carboxylate
(carboxylate ion in base):
O
RCO
RC
OH
O
O
+
HCl
RCCl
RC
Cl + H2O
RCO
RC
OH
H
O
2HO
O–
RCCl
RC
Cl + 2H
O
O
RCO
RC
O–
+
Cl–
+ H2O
via:
R
C
Cl
OH
+
HCl
Example
Reactions of Acyl Chlorides
Acyl chlorides react with carboxylic acids to give
acid anhydrides:
O
O
C6H5CH2COH + HCl
C6H5CH2CCl + H2O
O
O O
O
R'CO
OH
RCCl
RC
Cl + R'C
Reactions of Acyl Chlorides
O O
O
RCCl
RC
Cl + R'COH
RCOCR'
H
via:
R
O
O
C
OCR'
Cl
+
Example
Acyl chlorides react with carboxylic acids to give
acid anhydrides:
O
RCO
RC
OCR'
O
O
CH3(CH2)5CCl +
CH3(CH2)5COH
pyridine
+
HCl
O O
CH3(CH2)5COC(CH2)5CH3
(78--83%)
(78
HCl
Reactions of Acyl Chlorides
Reactions of Acyl Chlorides
Acyl chlorides react with alcohols to give esters:
Acyl chlorides react with alcohols to give esters:
O
O
R'O
OH
RCCl
RC
Cl + R'
O
O
RCO
RC
OR'
+
HCl
R'O
OH
RCCl
RC
Cl + R'
RCO
RC
OR'
+
HCl
H
O
via:
R
C
OR'
Cl
Example
Reactions of Acyl Chlorides
O
O
C6H5CCl + (CH3)3COH
pyridine
C6H5COC(CH3)3
(80%)
Acyl chlorides react with ammonia and amines
to give amides:
O
RCCl
RC
Cl + R'2NH + HO–
O
RCN
RC
NR'2 + H2O
+ Cl–
Reactions of Acyl Chlorides
Example
Acyl chlorides react with ammonia and amines
to give amides:
RCCl + R'2NH + HO–
C6H5CN
C
(87--91%)
(87
+ Cl–
O
R
H2O
RCNR'2 + H2O
H
via:
NaOH
C6H5CCl + HN
O
O
O
O
NR'2
Cl
Friedel-Crafts Acylation of Benzene
Reaction with Grignard reagents
O
O
O
H
AlCl3
+ CH3CH2CCl
O
R'MgX
C
CCH2CH3
R
OH
1. R'MgX
C
Cl
R
R'
2. H+, H2O
R
C
R'
+ HCl
Example:
El t hil iis an acyll cation
Electrophile
ti
O
C
+
CH3CH2C
••
O ••
CH3CH2C
+
O ••
Cl
1. 2 CH3MgCl
2. H+, H2O
C(CH3)2
OH
R'
R
Lithium diorganocuprates are used to
form C—C bonds
Example: Lithium dimethylcuprate
(CH3)2Cu
CuLi
Li + CH3(CH2)8CH2COCl
O
R2Cu
CuLi
Li +
R‘CX
R‘C
X
O
R‘CX
X
Ar2Cu
CuLi
Li + R‘C
O
diethyl ether
LiX
X
R C R' + RCu + Li
O
LiX
X
Ar C R' + Ar
ArCu
Cu + Li
Example: Lithium diphenylcuprate
CH3(CH2)8CH2CO
COCH
CH3
Reduction of
Acyl Chlorides
(C6H5)2Cu
CuLi
Li + CH3(CH2)6CH2COCl
O
LiAlH(O
( tBu))3
CH
O
diethyl ether
CCl
Or
CH3(CH2)6CH2CO
COC
C6H5
R
O
CCl
LiAlH(OtBu)3
O
R
CH
Reaction with LiAlH4, yields a primary alcohol RCH2OH
α-Halogenation of Carboxylic Acids
O
O
R2CCOH + X2
α-Halogenation of Carboxylic Acids:
The HellHell-Volhard
Volhard--Zelinsky Reaction
R2CCOH
H
+ HX
X
analogous
g
to α-halogenation
g
of aldehydes
y
and
ketones
key question: Is enol content of carboxylic
acids high enough to permit reaction to occur
at reasonable rate? (Answer is NO)
Example
But...
O
O
R2CCOH + X2
CH2COH + Br2
O
PX3
R2CCOH
+ HX
H
X
When a small amount of phosphorus trihalide is
added to the reaction mixture the reaction proceeds
faster.
PX3 will convert carboxylic acid to acyl halide
this combination is called the HellHell-Volhard
Volhard-Zelinsky reaction
PCl3 benzene
80°°C
80
O
CHCOH
Br
(60--62%)
(60
Value
Value
O
CH3CH2CH2COH
O
Br2
P
CH3CH2CHCOH
O
CH3CH2CH2COH
O
Br2
P
CH3CH2CHCOH
Br
Br
(77%)
(77%)
α-Halogen
g can be replaced
p
by
y nucleophilic
p
substitution
O
CH3CH2CHCOH
K2CO3
H2O
heat
OH
(69%)
Synthesis of α-Amino Acids
O
(CH3)2CHCH2COH
O
Br2
PCl3
(CH3)2CHCHCOH
Br
O
(CH3)2CHCHCOH
NH2
(48%)
NH3
H2O
(88%)
Anhydrides of Carboxylic Acids
Acid Anhydrides
Acid Anhydrides
O O
O O
RCOCR'
CH3COCCH3
when both acyl groups are the same, name the
acid and add the word anhydride
when
h th
the groups are diff
different,
t list
li t th
the names off th
the
corresponding acids in alphabetical order and add
the word anhydride
acetic anhydride
O O
C6H5COCC6H5
benzoic anhydride
O O
C6H5COC(CH2)5CH3
benzoic heptanoic anhydride
Some anhydrides are industrial chemicals
O O
Preparation of
Carboxylic Acid Anhydrides
O
O
CH3COCCH3
O
O
O
O
Prepared from Acyl Halides
(see the previous section)
Acetic
anhydride
Phthalic
anhydride
Maleic
anhydride
From dicarboxylic acids
Cyclic anhydrides with 5
5-- and 66-membered
rings can be prepared by dehydration of
dicarboxylic acids
O
H
COH
C
H
C
O
H
tetrachloroethane
O
130°°C
130
H
COH
O
Reactions of
Carboxylic Acid Anhydrides
+ H2O
O
(89%)
Reactions of Anhydrides
Reactions of Acid Anhydrides
Carboxylic acid anhydrides react with alcohols
to give esters:
O O
RCOCR'
O O
O
RCOR'
R'O
OH
RCO
RC
OCR + R'
O
O
RCO
RC
OR'
O
+ RCOH
normally,
y, symmetrical
y
anhydrides
y
are used
(both R groups the same)
RCNR'
RC
NR'2
O
RCO–
reaction can be carried out in presence of
pyridine (a base) or it can be catalyzed by acids
Reactions of Acid Anhydrides
Example
O O
Carboxylic acid anhydrides react with alcohols
to give esters:
O
O O
R'O
OH
RCO
RC
OCR + R'
RCO
RC
OR'
+ CH3CHCH2CH3
CH3COCCH3
O
OH
+ RCOH
H2SO4
H
O
via:
R
O
OR'
C
CH3COCHCH2CH3
OCR
CH3
O
Reactions of Acid Anhydrides
Reactions of Acid Anhydrides
Acid anhydrides react with ammonia and amines
to give amides:
O
O O
RCO
RC
OCR
+ 2R'2NH
(60%)
O
RCN
RC
NR'2 + RCO–
Acid anhydrides react with ammonia and amines
to give amides:
O
O O
RCO
RC
OCR
+ 2R'2NH
RCN
RC
NR'2 + RCO–
H
+
R'2NH2
+
R'2NH2
O
via:
O
R
NR'2
C
OCR
O
Example
Reactions of Acid Anhydrides
O O
CH3COCCH3
+ H2N
CH(CH3)2
Acid anhydrides react with water to give
carboxylic acids (carboxylate ion in base):
O O
O
+ H2O
RCO
RC
OCR
2RCO
2RC
OH
O
O O
CH3CNH
CH(CH3)2
O
RCO
RC
OCR + 2H
2HO
O–
2RCO–
+
H2O
(98%)
Reactions of Acid Anhydrides
Acid anhydrides react with water to give
carboxylic acids (carboxylate ion in base):
Example
O
O
COH
O O
RCO
RC
OCR
O
+ H2O
2RCO
2RC
OH
H
O
R
OCR
O
COH
O
O
OH
C
O + H2O
Friedel-Crafts Acylation of Benzene
Friedel-Crafts Acylation of Benzene
O
O
H
+ (RCO)2O
AlCl3
CR O
+ RCOH
O
AlCl3
+ (CH3CO)2O
CCH3
O
+ CH3COOH
Esters
O
RCOR'
Esters of Carboxylic Acids
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
Esters
O
CH3CO
COCH
CH2CH3
ethyl acetate
Sources of Esters
O
CH3CH2CO
COCH
CH3
methyl propanoate
O
COCH
CO
CH2CH2Cl
2-chloroethyl benzoate
Esters are very common natural products
Esters of Glycerol
O
O
CH3COCH2CH2CH(CH3)2
3-methylbutyl acetate
also
l called
ll d "i
"isopentyl
t l acetate"
t t " and
d "isoamyl
"i
l
acetate"
contributes to characteristic odor of bananas
O CH2OCR'
RCOCH
CH2OCR"
O
R, R', and R" can be the same or different
called "triacylglycerols," "glyceryl triesters," or
"triglycerides"
fats and oils are mixtures of glyceryl triesters
Esters of Glycerol
Preparation of Esters
O
O CH2OC(CH2)16CH3
CH3(CH2)16COCH
Fischer esterification
from acyl chlorides
CH2OC(CH2)16CH3
O
from carboxylic acid anhydrides
Baeyer--Villiger oxidation of ketones
Baeyer
Tristearin: found in many
animal and vegetable fats
Reactions of Esters:
Preparation of Tertiary Alcohols
From Esters and Grignard Reagents
Grignard reagents react with esters
δ– R
R'
Grignard reagents react with esters
R'
••
diethyl
ether
δ+ OCH
3
••
C
R
MgX O ••
••
C
••
OCH3
••
•• O •• + MgX
•• –
but species formed is unstable and
dissociates under the reaction
conditions to form a ketone
δ– R
R'
••
δ+ OCH
3
••
C
R'
diethyl
ether
R
MgX O ••
••
this ketone then goes on
to react with a second
mole of the Grignard
reagent to give a tertiary
alcohol
C
••
•• O •• + MgX
•• –
–CH3OMgX
R
R'
C
O ••
••
Example
O
CHCOCH
OCH3
2 CH3MgBr + (CH3)2CHC
1. diethyl ether
2. H3O+
OH
(CH3)2CHC
CHCCH
CH3
CH3
(73%)
Preparation of Alcohols By Reduction
of Esters
Two of the groups
attached to the tertiary
carbon come from the
Grignard reagent
••
OCH3
Example: Reduction of a Carboxylic Acid
O
COCH2CH2CH3
1. LiAlH4
diethyl ether
Acid--Catalyzed Ester Hydrolysis
Acid
2. H2O
CH2OH +
CH3CH2CH2OH
(90%)
Example
Acid--Catalyzed Ester Hydrolysis
Acid
O
iss the
t e reverse
e e se o
of Fischer
sc e este
esterification
cat o
O
RCO
RC
OR'
+
H+
H2O
O
CHCO
CHC
OCH2CH3 + H2O
Cl
HCl, heat
R'OH
RCOH + R'O
O
maximize conversion to ester by removing water
maximize ester hydrolysis by having large excess of water
CHCOH
equilibrium is closely balanced because carbonyl group of
ester and of carboxylic acid are comparably stabilized
Cl
(80--82%)
(80
+ CH3CH2OH
Mechanism of Acid
Acid--Catalyzed
Ester Hydrolysis
First stage: formation of tetrahedral intermediate
O
Is the reverse of the mechanism for acidacidcatalyzed esterification.
Like the mechanism of esterification, it involves
two stages:
1) formation of tetrahedral intermediate
(3 steps)
2) dissociation of tetrahedral intermediate
(3 steps)
RCO
RC
OR' + H2O
H+
OH
RC
OR'
water adds to the
carbonyl group of the
ester
this stage is
analogous to the acidacidcatalyzed addition of
water to a ketone
OH
Second stage: cleavage of tetrahedral
intermediate
O
+ R'
R'O
OH
RCOH
H+
OH
RC
OH
OR'
Mechanism of formation
of
tetrahedral intermediate
Step 1
Step 1
H
••
O ••
H
O•
+•
H
RC
•• O
••
H
••
O ••
O•
+•
H
H
RC
•• O
••
R'
••
+O
R'
H
H
•• O •
•
H
RC
Step 1
••
•• O
•• O
••
R'
••
+O
H
Step 2
H
RC
+O
R'
••
+O
H
••
RC
•• O
••
carbonyl oxygen is
protonated because
cation produced is
stabilized by electron
delocalization
(resonance)
•• O •
•
RC
R'
•• O
••
H
R'
H
Step 2
Step 3
••
•• OH
••
•• OH
H
+
O ••
RC
RC
H
•• OR'
••
••
+O
•• OR'
••
H
H
+
O ••
H
H
•• O •
•
H
•• O •
•
RC
•• O
••
R'
H
Step 3
••
•• OH
RC
H
+
O ••
H
•• OR'
••
•• OR'
••
•• O •
•
H
••
•
• OH
RC
H
H
O ••
••
+
H O ••
H
H
Cleavage of tetrahedral
intermediate
H
Step 4
Step 4
••
•• OH
••
R'
••
•• OH
RC
R'
H
OH
RC
+
O
••
••
•• O •
•
H
H
••
•• OH
••
OH
H
••
O ••
••
H
Step 5
O•
+•
••
RC
R'
OH
H
••
O ••
••
O•
+•
H
H
H
Step 5
••
••
•• OH
•• OH
RC
R'
+
O
••
••
OH
••
H
••
OH
RC
R'
+
O
••
••
H
••
•• OH
RC
+ ••
OH
••
+
••
R'
O
••
H
Step 5
Step 6
H
••
O ••
••
O+
H
H
H
••
O
RC
••
••
••
•• OH
RC
+ ••
OH
••
••
+ OH
OH
••
••
+O
H
RC
RC
••
OH
••
••
OH
••
Key Features of Mechanism
Activation of carbonyl group by protonation of
carbonyl oxygen
Nucleophilic addition of water to carbonyl group
forms tetrahedral intermediate
Eli i ti off alcohol
Elimination
l h l from
f
tetrahedral
t t h d l intermediate
i t
di t
restores carbonyl group
Ester Hydrolysis in Base:
Saponification
H
Ester Hydrolysis in Aqueous Base
O
O
RCO
RC
OR'
+
HO–
R'O
OH
RCO– + R'
Ester Hydrolysis in Aqueous Base
O
O
RCO
RC
OR'
+
HO–
R'O
OH
RCO– + R'
H+
is called saponification
is irreversible,
irreversible because of strong stabilization of carboxylate
ion
O
if carboxylic acid is desired product, saponification is followed
by a separate acidification step (simply a pH adjustment)
Example
RCOH
Example
O
H2C
CH2OCCH3
CH3
O
+
NaOH
CCOCH3
CH3
1. NaOH, H2O, heat
water--methanol, heat
water
2. H2SO4
O
O
CH2OH
(95--97%)
(95
CH3
+
CH3CONa
H2C
(87%)
CCOH
CH3
+
CH3OH
Soap--Making
Soap
Basic hydrolysis
of the glyceryl
triesters ((from
fats and oils)
gives salts of
long--chain
long
carboxylic acids.
These salts are
soaps.
O
CH2OC(CH2)xCH3
O
CH3(CH2)yCOCH
CH2OC(CH2)zCH3
O
K2CO3, H2O, heat
O
O
CH3(CH2)xCOK
CH3(CH2)yCOK
Mechanism of Ester Hydrolysis
in Base
Involves two stages:
1) formation of tetrahedral intermediate
2) dissociation of tetrahedral intermediate
O
CH3(CH2)zCOK
First stage: formation of tetrahedral intermediate
O
Second stage: cleavage of tetrahedral
intermediate
O
RCO
RC
OR' + H2O
HO–
OH
RC
OH
OR'
+ R'
R'O
OH
RCOH
water adds to the
carbonyl group of the
ester
this stage is
analogous to the
base--catalyzed
base
addition of water to a
ketone
HO–
OH
RC
OH
OR'
Step 1
••
O ••
Mechanism of formation
of
tetrahedral intermediate
Step 1
H
•• O •
•
•• –
RC
•• OR'
••
Step 2
••
O ••
H
•• O •
•
•• –
RC
•• OR'
••
– ••
• O ••
•
RC
H
O ••
••
•• O
H
H
– ••
• O ••
•
RC
••
•• OR'
••
H
O ••
••
•• OR'
••
Step 2
••
O ••
H
H
–
•• •
•• O
•
••
H
••
•• O
O ••
RC
Dissociation of
tetrahedral intermediate
•• OR'
••
H
H
– ••
•• O ••
H
O ••
RC
••
•• OR'
••
Step 3
Step 3
••
H
•• •–
•• O
•
H
O ••
RC
••
O ••
H
H
•• •–
•• O
•
O ••
••
••
•• O
H
O ••
••
H
•• OR'
••
RC
H
•• OR'
••
H
••
O ••
RC
•• O
••
H
– ••
•• OR'
••
Step 4
Key Features of Mechanism
••
O ••
Nucleophilic addition of hydroxide ion to carbonyl
group in first step
RC
•• O •• –
••
HO–
Tetrahedral intermediate formed in first stage
H
••
O ••
••
Hydroxide-induced dissociation of tetrahedral
Hydroxideintermediate in second stage
g
H2O
RC
•• O
••
••
OR'
H
– ••
•• OR'
••
Acid--Catalyzed Transesterification
Acid
Transeterification
O
RCO
RC
OR'
+
H+
R”OH
O
R'O
OH
RCOR”+ R'
Base--catalyzed Transesterification
Base
O
RCO
RC
OR'
O
+
R”O–
R'O
ORCOR”+ R'
Reactions of Esters
with Ammonia and Amines
Reactions of Esters
Reactions of Esters
Esters react with ammonia and amines
to give amides:
O
O
RCO
RC
OR'
O
RCOR'
O
RCNR'2
O
RCO–
+ R'2NH
RCN
RC
NR'2 +
R'O
R'
OH
Reactions of Esters
Example
Esters react with ammonia and amines
to give amides:
O
H2C
O
O
RCO
RC
OR'
+ R'2NH
RCN
RC
NR'2 +
CCOCH3 +
CH3
R'O
R'
OH
H2O
H
O
via:
NH3
R
O
NR'2
C
H2C
OR'
(75%)
CCNH2
+
CH3OH
CH3
Example
O
FCH2COCH2CH3
+
NH2
Intramolecular Ester Formation:
Lactones
heat
O
FCH2CNH
(61%)
+
CH3CH2OH
Examples
Lactones
O
Lactones are cyclic esters
O
+
HOCH2CH2CH2COH
Formed by intramolecular esterification in a
compound that contains a hydroxyl group and
a carboxylic acid function
O
4-hydroxybutanoic acid
4-butanolide
IUPAC nomenclature: replace the -oic acid
ending of the carboxylic acid by -olide
identify the oxygenated carbon by number
Examples
Common names
HOCH2CH2CH2COH
4-hydroxybutanoic acid
O
+
O
H2O
5-hydroxypentanoic acid
O
β
γ
4-butanolide
O
HOCH2CH2CH2CH2COH
β
α
O
O + H2O
O
5-pentanolide
O
γ-butyrolactone
α
γ
O
δ
O
δ-valerolactone
Ring size is designated by Greek letter
corresponding to oxygenated carbon
A γ lactone has a five
five--membered ring
A δ lactone has a sixsix-membered ring
H2O
Step-growth polymers, also called condensation
Steppolymers, are made by combining two molecules by
removing a small molecule
Polyesters
Amides having an NH2 group
O
RCN
RC
NH2
Amides
identify the corresponding carboxylic acid
replace the -ic acid or -oic acid ending by -amide.
Amides having an NH2 group
Amides having substituents on N
O
O
acetamide
CH3CNH2
O
RCN
RC
NHR'
O
and
RCN
RC
NR'2
name the amide as before
3-methylbutanamide
(CH3)2CHCH2CNH2
O
benzamide
CNH2
precede the name of the amide with the name of
th appropriate
the
i t group or groups
precede the names of the groups by the letter N(standing for nitrogen and used as a locant)
Amides having substituents on N
O
N-methyl
methylacetamide
acetamide
CH3CNHCH3
Preparation of Amides
O
CN(CH2CH3)2
N,N-diethyl
diethylbenzamide
benzamide
O
CH3CH2CH2CNCH(CH3)2
CH3
N-isopropyl
isopropyl--N-methyl
methylbutanamide
butanamide
Preparation of Amides
Amides are prepared from amines by acylation
with:
ith
acyl chlorides
Hydrolysis of Amides
anhydrides
esters
Hydrolysis of Amides
Hydrolysis of amides is irreversible. In acid
sol tion the amine prod
solution
product
ct is protonated to
give an ammonium salt.
O
RCN
RC
NHR' + H2O + H
O
+
+
R'N
NH3
RCOH + R'
Hydrolysis of Amides
In basic solution the carboxylic acid product
is deprotonated to gi
give
e a carbo
carboxylate
late ion
ion.
O
RCN
RC
NHR'
O
–
+ HO
–
RCO
+ R'
R'N
NH2
Example: Acid Hydrolysis
O
Example: Basic Hydrolysis
O
CH3CH2CHCNH2
O
CH3CH2CHCOH
NH2
CH3CNH
O
H2O
H2SO4
heat
KOH
+
+ NH4 HSO4–
(88--90%)
(88
H2O
heat
Br
CH3COK +
Br
(95%)
Mechanism of Acid
Acid--Catalyzed
Amide Hydrolysis
First stage: formation of tetrahedral intermediate
O
Acid-catalyzed amide hydrolysis proceeds via
Acidthe customary two stages:
1) formation of tetrahedral intermediate
2) dissociation of tetrahedral intermediate
RCN
RC
NH2 + H2O
H+
OH
RC
OH
NH2
water adds to the
carbonyl group of the
amide
this stage is
analogous to the acidacidcatalyzed addition of
water to a ketone
Second stage: cleavage of tetrahedral
intermediate
O
Mechanism of formation
of
tetrahedral intermediate
+
+ NH4
RCOH
H+
OH
NH2
RC
OH
Step 1
Step 1
H
••
O ••
RC
•• NH2
H
H
••
O ••
O•
+•
H
H
O•
+•
H
RC
•• NH2
••
+O
RC
•• NH2
H
H
•• O •
•
H
Step 1
••
•• O
Step 2
H
RC
+ NH2
••
+O
H
carbonyl oxygen is
protonated because
cation produced is
stabilized by electron
delocalization
(resonance)
••
+O
RC
H
RC
•• NH2
H
•• NH2
Step 2
H
•• O •
•
Step 3
••
•• OH
••
•• OH
H
+
O ••
RC
•• NH2
••
+O
RC
•• NH2
RC
H
H
+
O ••
•• NH2
H
H
•• O •
•
H
H
H
•• O •
•
H
Step 3
••
•• OH
RC
H
+
O ••
•• O •
•
H
•• NH2
H
••
•
• OH
RC
Cleavage of tetrahedral
intermediate
H
H
O ••
+
H O ••
••
•• NH2
H
H
Step 4
Step 4
••
•• OH
••
H2N
••
•• OH
RC
H2N ••
+
••
O ••
H
••
H
O•
+•
RC
H2N ••
H
•• O •
•
H
••
•• OH
H
H
OH
RC
H
H
O ••
H
••
H
O•
+•
H
Step 5
Step 5
••
•• OH
••
OH
RC
H2N
••
•• OH
+
••
RC
••
H2N
H
OH
+
••
H
••
•• OH
RC
+ ••
OH
+
•• NH3
••
Step 6
Step 6
••
•• OH
••
RC
H2N
OH
+
••
H
+ NH
••
•• OH
RC
+ ••
OH
••
+
H3O
+
•• NH3
4
••
•• OH
RC
+ ••
OH
••
••
+ OH
RC
••
OH
••
Step 6
H
••
O+
Mechanism of Amide Hydrolysis
in Base
H
H
••
O ••
H
••
O
RC
H
Involves two stages:
1) formation of tetrahedral intermediate
2) dissociation of tetrahedral intermediate
••
••
OH
••
••
+O
H
RC
••
OH
••
First stage: formation of tetrahedral intermediate
O
Second stage: cleavage of tetrahedral
intermediate
O
–
RCO
RCN
RC
NH2 + H2O
HO–
OH
RC
OH
NH2
water adds to the
carbonyl group of the
amide
this stage is
analogous to the
base--catalyzed
base
addition of water to a
ketone
+ NH3
HO–
OH
RC
OH
NH2
Step 1
••
O ••
Mechanism of formation
of
tetrahedral intermediate
Step 1
H
•• O •
•
•• –
RC
•• NH2
Step 2
••
O ••
H
•• O •
•
•• –
RC
•• NH2
– ••
• O ••
•
RC
•• NH2
H
O ••
••
••
•• O
H
H
– ••
• O ••
•
RC
•• NH2
H
O ••
••
Step 2
••
O ••
H
•• –
•• O ••
O ••
RC
H
••
•• O
H
••
Dissociation of
tetrahedral intermediate
•• NH2
H
H
– ••
•• O ••
RC
H
O ••
••
•• NH2
Step 3
Step 3
••
•• OH
••
H2N
••
•• OH
RC
H2N ••
+
••
O ••
H
••
H
O ••
••
RC
H2N ••
•• O •
•• • –
H
••
•• OH
H
H
OH
RC
H
O ••
H
••
H
O ••
••
Step 4
Step 4
••
H
•• –
•• O •
•
H
••
H
O ••
•• –
•• O •
•
••
RC
O ••
OH
••
H
H3N +
••
•• O
OH
••
H3N +
H
H
••
O ••
RC
•• O
••
Step 5
••
RC
H
•• NH3
Reduction of Amides give Amines
••
O ••
RC
O
•• O •• –
••
HO–
CN(CH3)2
2. H2O
CH2N(CH3)2
(88%)
••
O ••
RC
•• O
••
1. LiAlH4
H
•• NH3
Lactams
Lactams are cyclic amides. Some are industrial
chemicals others occur
chemicals,
occ r naturally.
nat rall
γ
Lactams
β
α
δ
ε
N
O
ε-Caprolactam*: used to
prepare a type of nylon
H
*Caproic acid is the common name for hexanoic acid.
Lactams
Lactams are cyclic amides. Some are industrial
chemicals others occur
chemicals,
occ r naturally.
nat rall
O
Imides
C6H5CH2CNH
α
O
β
N
S
CH3
CH3
CO2H
Penicillin G: a β-lactam antibiotic
Imides
Imides have 2 acyl groups attached to the
nitrogen.
nitrogen
Imides
The most common examples
p
are cyclic
y
imides.
O
O
O O
RCN
RC
NCR
R'
NH
O
Succinimide
NH
O
Phthalimide
Nylon 6 is an example of a stepstep-growth polymer formed
by a monomer with two different functional groups
Polyamides
A urethane (carbamate
(carbamate)) is a compound that has an
OR group and an NHR group bonded to the same
carbonyl compound
Polyurethanes
Nitriles
RC
Nitriles
N
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)
Nitriles
CH3C
ethanenitrile
or: acetonitrile
or: methyl cyanide
N
Preparation of Nitriles
C6H5C
benzonitrile
N
CH3CHCH3
C
2-methylpropanenitrile
or: isopropyl cyanide
N
Example
Example
O
KCN
CH3(CH2)8CH2Cl
CH3(CH2)8CH2C
ethanolethanolwater
SN2
OH
KCN
(95%)
N
CH3CH2CCH2CH3
H+
CH3CH2CCH2CH3
C
N
(75%)
Preparation of Nitriles
By dehydration of amides
uses the reagent P4O10 (often written as P2O5)
Hydrolysis of Nitriles
O
P4O10
((CH3)2CH
CHCN
CNH
H2
200°°C
200
((CH3)2CH
CHC
C
N
(69--86%)
(69
Hydrolysis of Nitriles
Hydrolysis of nitriles resembles the hydrolysis
of amides. The reaction is irreversible
irreversible..
Ammonia is produced and is protonated to
ammonium ion in acid solution.
O
RCN
RC
N + 2H2O + H
+
+
RCOH + NH4
Hydrolysis of Nitriles
In basic solution the carboxylic acid product
is deprotonated to give a carboxylate ion.
O
RCN
RC
N
–
+ H2O + HO
–
RCO
+ NH3
Example: Acid Hydrolysis
Example: Basic Hydrolysis
O
CH2CN
CH2COH
O
H2O
CH3(CH2)9CN
H2SO4
heat
h t
NO2
1. KOH, H2O, heat
2. H+
CH3(CH2)9COH
(80%)
NO2
(92--95%)
(92
Mechanism of Hydrolysis of Nitriles
O
RC
N
H2O
RCN
RC
NH2
Mechanism of Hydrolysis of Nitriles
OH
O
H2O
RCOH
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.
RC
N
H2O
RC
O
NH
RCN
RC
NH2
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.
carbon
The product of this addition is the nitrogen
analog of an enol. It is transformed to an amide
under the reaction conditions.
Step 1
Step 1
H
H
–
RC
H
–
•• O •
•
••
•• O •
•
••
N ••
• O ••
•
N ••
RC
RC
•• N ••
–
Step 2
Step 2
H
H
•• O ••
•• O ••
RC
RC
H
•• N ••
–
H
O ••
••
H
•• N ••
H
–
O ••
••
RC
•• N
H
H
•O •
– • •• •
H
O ••
••
Step 3
Step 3
H
•• O ••
H
H
•O •
– • •• •
•O •
– • •• •
H
H
•• •
O
•
H
O ••
–
O ••
••
•• N
••
••
RC
•• N
RC
H
RC
•• N
H
Step 4
H
Step 4
•• •
O
•
•• •
O
•
RC
•• •
O
•
RC
–
•• N
••
•• N
H
H
RC
••
O ••
H
H
H
–
– ••
•• O ••
H
•• N
••
H
H
••
O ••
H
Reduction of Nitriles yield Amines
CH3CH2CH2CH2CN
nitriles may also be
reduced by lithium
aluminum hydride
H2 (100 atm), Ni
CH3CH2CH2CH2CH2NH2
(56%)