Carboxylic Acid Derivatives

LEARNING OUTCOMES

• By the end of this session, the student should be able to:

• Describe the structure of carboxylic acids derivatives.

• Name carboxylic derivatives according to IUPAC System.

• Understand the properties of Carboxylic Acid derivatives

• Outline the synthesis and some reactions of the Carboxylic Acid derivatives
Carboxylic acid Derivatives

3
 Structure and Reactivity of Carboxylic Acid Derivatives
Increasing reactivity
O O O O O
C C C C < C
R N < R OR' < R O R' R Cl

amide ester acid anhydride acid chloride

All acyl derivatives acid chloride

are prepared directly acid anhydride ester amide

from the carboxylic acid.
Less reactive acyl acid anhydride
derivative (amides
carboxylic
and esters) are more acid ester amide
readily prepared from ester
more reactive acyl
derivatives (acid amide
chlorides and anhydrides)
amide
4
• The important features of the carboxylic acid derivatives that influence their
reactivity are governed by this substituent in the following ways:
•   the effect the substituent has on the electrophilicity of the carbonyl C
• if the substituent is electron donating, then the electrophilicity is reduced, \
less reactive
• if the substituent is electron withdrawing, the electrophilicity is increased, \
more reactive
• the ability of the substituent to function as a leaving group.
• There are 3 resonance structures to consider for carboxylic acid derivatives.
Reactivity of Carboxylic Acid Derivatives

• In carboxylic acid derivatives , where a lone pair on the heteroatom Z is able to

donate electrons to the adjacent positive center the reactivity is affected.

• The stronger this electron donation from Z the less positive the carbonyl C and
the less electrophilic the carbonyl group.

•   The ability of Z to donate electrons is linked to its electronegativity...the more

electronegative Z is, the less the stabilizing effect and the better it is as a leaving
group.
Reactivity of Carboxylic Acid Derivatives
 Reactivity of Carboxylic Acid Derivatives

The reactivity of the acid derivative is related to it resonance stabilization.

The C-N bond of amides is significantly stabilized through resonance and is
consequently, the least reactive acid derivative.

The C-Cl bond of acid chlorides is the least stabilized by resonance and is
the most reactive acid derivative.
O O

C C
R N R OR'

ester
amide

O O O
C C C
R O R' R Cl
9
acid anhydride acid chloride
Reactivity of Carboxylic Acid Derivatives

acyl halides > anhydrides > aldehydes > ketones > esters = carboxylic acids > amides
Reactivity of Carboxylic Acid Derivatives
Nomenclature for esters
• Thinking of an ester in terms of an “alcohol portion” and a “carboxylic acid portion” is
important for naming esters using the IUPAC system:
1. The name for the alcohol portion comes first: name the alkyl part of the alcohol
(e.g., for the ester shown below, the first part of the ester’s name is methyl (alcohol
part comes from methanol). Present the alkyl name separate from the remainder of
the ester name.
2. The carboxylic acid portion is named as if it were deprotonated, changing the “-ic
acid” part of that name to “-ate”
Methyl propanoate
O

CH3 CH2 C O CH3 O

derives from derives from

CH3 CH2 C O CH3
propanoic acid methanol

This part would be called “propanoate”

Nomenclature for esters
• Some other examples:
O

CH2 C CH2 Ethyl butanoate

CH3 CH2 O CH3

O
b
g a Ethyl 2-methylbutanoate
O Ethyl a-methylbutyrate

2-Methylpropyl butanoate
O Isobutyl butanoate

O
2-Butyl butanoate
O
Sec-Butyl butanoate
ESTERS

•Commonly found in nature

• Many of the fragrances of flowers & fruits are due to esters
Selected common esters
• Flavor/fragrance agents
Selected common esters
• Pheromones:
O
O CH3

CH3 C O CH3
CH3 C O CH2 CH2 CH CH3

alarm pheromone for honeybee sexual attractant for canines

• Medications:
O

O
OH

H 2N C O CH2 CH3

O C CH3

benzocaine Aspirin O
Selected common esters
• Synthesis of Aspirin
O
O

OH
OH O +
H
+ + H2O
C heat O C CH3
OH HO CH3

salicylic acid acetic acid Aspirin O

• Synthesis of oil of wintergreen:

O
O

CH3
CH3
O
OH HO
H+
+ + H2O
Methanol heat OH
OH

Aspirin
salicylic acid
Nomenclature for Cyclic Esters
• Systematic names (IUPAC) - cyclic esters are named as“2-oxacycloalkanones”.
• Replace “alk”-part with amount of C’s in ring
• “oxa” = Used to designate the O atom
• Examples:
 Cyclic Esters

 Reaction of —OH and —COOH on same molecule

produces a cyclic ester called lactone.
 To name, add the word lactone to the IUPAC acid
name or replace the -ic acid of common name with
-olactone.

Chapter 21 5
Name the following:
Amides

• Amino acids are linked together by

• amide bonds to form peptides & proteins.

• Caffeine: Naturally occurring amide

• found in cocoa & coffee beans.

• Penicillin G (‘normal’ penicillin):

• Compound with two amide bonds
 Amide Structure

 Amides are the product of the reaction of a carboxylic

acid with ammonia or an amine.
 Not basic because the lone pair on nitrogen is
delocalized by resonance.
 The C—N bond has double-bond character.

Chapter 21 6
 Protonation of Amides

 Under acidic conditions, the double-bonded

oxygen will get protonated.

Chapter 21 7
Structure of Amides

• Amides (R-CONH2) have a −NH2, −NHR or −NR2 group in place of the −OH
group of a carboxylic acid (R-COOH)
• Amides can be cyclic or acyclic
• Amide classification:
• primary (1°) = 1 x C group bonded to amide N atom
• secondary (2°) = 2 x C groups bonded to amide N atom
• tertiary (3°) = 3 x C groups bonded to amide N atom
 Classes of Amides

3º amide 2º amide 1º amide

 1 amide has one C—N bond (two N—H).

 2 amide or N-substituted amide has two C—N bonds
(one N—H).
 3 amide or N,N-disubstituted amide has three C—N
bonds (no N—H).
Chapter 21 8
 Nomenclature of Amides
O CH3
N-ethyl-N-methyl-2-dimethylpropanamide
CH3CHC N CH2CH3 (N-ethyl-N-methylisobutyramide)
CH3

 For 1 amide, drop -ic or -oic acid from the

carboxylic acid name, add -amide.
 Alkyl groups bonded to nitrogen are named
with N-alkyl to indicate their attachment to
the nitrogen atom.
Chapter 21 9
Nomenclature of Amides

• Common & Systematic names (IUPAC) - use the acid name,replacing “oic
acid” or “ic acid” with “amide.”
• For acids ending with “carboxylic acid,” “ylic acid” is replaced with “amide”
• Entire name – written as one word!
• Examples:
For acids ending with “carboxylic acid,” “ylic acid” is replaced with “amide”
When the amide group is on a ring, replace the –carboxylic acid ending with
carboxamide
Nomenclature of Amides

• For substituents bonded to the -N -, name of the substituent is

stated 1st followed by the name of the amide.

• - If there is more than 1 substituent bonded to the N, they are stated

Alphabetically.

• Name of each substituent bonded to N is preceded by an“N” (in

• italics) indicating that the group is bonded to a N rather than to a C
 Nomenclature of Amides

• Examples:

• Try
Nomenclature of Amides

• - Cyclic amides are called “lactams” in common nomenclature

• - Nomenclature is similar to that of lactones
 Cyclic Amides

 Cyclic amides are called lactams.

 To name, add the word lactam to the IUPAC
acid name or replace the -ic acid of common
name with -olactam.
Chapter 21 10
Nomenclature of Amides

• Named as “2-azacycloalkanones” in systematic nomenclature

• - “aza” = Used to designate the N atom.
Examples:
Acid Halides
• Acyl halides – not commonly found in nature, because of their high reactivity
• Acyl halides (R-COX) have a −X in place of the −OH group of a carboxylic acid
(R-COOH)
• Acyl chlorides & acyl bromides - most common acyl halides
• Common & Systematic names (IUPAC) - named by using the acid name &
replacing “ic acid” with “yl chloride”(or “yl bromide”)
• - Acids ending with “carboxylic acid” – replace “carboxylic acid” with
“carbonyl chloride” (or “bromide”)
• Examples:
Reactivity of Acid halides

• Acyl halides = activated derivatives of carboxylic acids

• Halogen atom (X) of an acyl halide inductively withdraws e- density
• from carbonyl C, enhancing its electrophilic nature
• This makes acyl halides particularly reactive toward nucleophilic
• acyl substitution
• Halide ion - serves as a good leaving group
Reactivity of Acid halides

Nucleophilic acyl substitution

Acid Anhydrides

• Acid anhydrides – not commonly found in nature, because of

• their high reactivity
• Loss of H2O from 2 carboxylic acid molecules -Acid anhydride
• ((R-CO)2-O)
• “Anhydride” means “without water”
• Types of acid anhydrides:
• Symmetrical anhydride - the 2 COOH molecules forming the
• acid anhydride are the same
• Mixed anhydride - the 2 COOH molecules forming the acid
• anhydride are different.
Nomenclature of anhydrides

• Symmetrical anhydrides:Named by using the acid name and

• replacing “acid” with “anhydride”

• - Mixed anhydrides:Named by stating the names of both acids in

• alphabetical order, followed by “anhydride”
 O O O
H3C C
O O O
H3C C
O O O

ethanoic anhydride phthalic anhydride maleic anhydride

acetic anhydride
• Acid anhydrides = activated derivatives of carboxylic acids (like acyl halides).

• However, acid anhydrides are not as reactive as acyl halides.

• In acyl chloride - Cl atom activates carbonyl (C=O) group and serves as a

leaving group.

• In acid anhydride - carboxylate group serves these functions

Nitirles

• Nitriles – compounds that contain a cyano (C=N) functional

• group
• – considered carboxylic acid derivatives because, like all
• Class I carbonyl compounds, they react with H2O
• (hydrolyse) to form carboxylic acids
• Common & Systematic names (IUPAC)
• - Common names:The suffix “-ic acid” is replaced by the suffix
• “-onitrile”
• - Systematic names: Constructed from the alkane name, with the
• suffix “-nitrile” added
• Substituent nomenclature: If it is seen as a substituent in a
• molecule, it is called “cyano”
 Multifunctional Compounds
 The functional group with the highest priority
determines the parent name.

OH
CH3 CH2 CH C N

2-hydroxybutanenitrile

acid > ester > amide > nitrile > aldehyde > ketone >
alcohol > amine > alkene > alkyne
Chapter 21 18
Properties of Carboxylic Acid Derivatives
• The relatively high boiling point of carboxylic acids is due to extensive hydrogen bonded
dimerization.

• Similar hydrogen bonding occurs between molecules of 1º and 2º-amides (amides having
at least one N–H bond), and the first three compounds in the table serve as hydrogen
bonding examples.

• The last nine entries in the above table cannot function as hydrogen bond donors, so
hydrogen bonded dimers and aggregates are not possible.

• The relatively high boiling points of equivalent 3º-amides and nitriles are probably due to
the high polarity of these functions.

• Indeed, if hydrogen bonding is not present, the boiling points of comparable sized
compounds correlate reasonably well with their dipole moments.
• Small esters have boiling points which are similar to those of aldehydes and ketones with
the same number of carbon atoms.

• Esters, like aldehydes and ketones, are polar molecules and so have

dipole-dipole interactions as well as van der Waals dispersion forces.

• However, they do not form ester-ester hydrogen bonds, so their boiling points are
significantly lower than those of an acid with the same number of carbon atoms.
• Because they don’t possess OH groups, esters cannot form H-bonds with other ester
molecules. As a result, esters have lower boiling points than carboxylic acids and
alcohols that have approximately the same molar mass.

• Water molecules can H-bond to esters, at the oxygen atoms. This makes low molecule
weight esters water-soluble.
• The reason for this trend in solubility is that although esters cannot hydrogen bond with
each other, they can hydrogen bond with water molecules.

• One of the partially-positive hydrogen atoms in a water molecule can be sufficiently

attracted to one of the lone pairs on one of the oxygen atoms in an ester, forming a
hydrogen bond. Dispersion forces and dipole-dipole attractions are also present.

• Forming these intermolecular attractions releases some of the energy needed to solvate
the ester.
• As chain length increases, the hydrocarbon portion forces itself between water molecules,
breaking the relatively strong hydrogen bonds between water molecules without offering
an energetic compensation; furthermore, the water molecules are forced into an ordered
alignment along the chain, decreasing the entropy in the system.

• This makes the process thermodynamically less favorable, and so solubility decreases.
57
Structures of Carboxylic Acids and
Carboxylic Acid Derivatives

58
Two major resonance contributors in esters,
carboxylic acids, and amides:

59
Carboxylic acids have relatively high boiling points
because…

Amides have the highest boiling points:

60
The reactivity of carbonyl compounds resides in the
polarity of the carbonyl group:

61
The tetrahedral intermediate is a transient species that
eliminates the leaving group Y– or the nucleophile Z–:

This is a nucleophilic acyl substitution reaction

62
Z– will be expelled if it is a much weaker base than Y –;
that is, Z– is a better leaving group than Y– (k–1 >> k2):

63
Y– will be expelled if it is a weaker base than Z–; that is,
Y– is a better leaving group than Z– (k2 >> k–1):

64
Both reactant and product will be present if Y– and Z–
have similar leaving abilities:

65
The reactivity of a carboxylic acid derivative depends on
the basicity of the substituent attached to the acyl group:

66
Electron withdrawal increases the carbonyl carbon’s
susceptibility to nucleophilic attack:

The weaker the basicity of Y, the greater the reactivity:

67
Inductive electron withdrawal by Y increases the electrophilic character of the carbonyl
carbon, and increases its reactivity toward nucleophiles.

Thus, acyl chlorides (Y = Cl) are the most reactive of the derivatives. Resonance electron
donation by Y decreases the electrophilic character of the carbonyl carbon.

The strongest resonance effect occurs in amides, which exhibit substantial carbon-nitrogen
double bond character and are the least reactive of the derivatives.
Weak bases are easier to expel when the tetrahedral
intermediate collapses:

69
A carboxylic acid derivative can be converted only into a
less reactive carboxylic acid derivative:

70
The tetrahedral intermediate eliminates the weaker base:

71
If the nucleophile is neutral…

72
Reactivity : -
O
(2)
O R C O O O

R C > O > R C > R C > R C

Cl 'R C OH O R' NH 2

Reasons : -

(i) Ease of leaving(Stability of bases) : -

Cl > RCOO > HO > RO > H2N > R > H

∵ Strength of bases : -
Cl < RCOO < HO < RO < H2N < R < H
Reasons : -
(ii) Resonance effect : -

O (2p) O

Increasing resonance
Less stable R C
R C (2p)
More reactive
Cl (3p) Cl

effect
O(2p) O
More stable R C
R C (2p)
Less reactive
O/N (2p) O/N

Efficiency of orbital overlap : 2p/2p > 3p/2p

Reactivity : -
O
(2)
O R C O O O

R C > O > R C > R C > R C

Cl 'R C OH O R' NH 2

The less reactive derivatives can be prepared

from the more reactive derivative via
nucleophilic substitution reactions.
All Acid Derivatives can be Hydrolyzed
O O

(CH3)2CHO OCH(CH3)2
diisopropyl pimelate
Hydrolysis
+
H3O or
in base
O O

HO OH
+ 2 (CH3)2CHOH
What are the 3 Hydrolysis Products?
O
C N(CH2CH3)2
+
O H3O

O products are carboxylic acid(s)

+ conjugate acid of the LGs
Two hydrolyzable groups
O
C N(CH2CH3)2 CO2H
+ OH
O H3O

+ HN(CH2CH3)2
O
HO
+
O
Draw the Hydrolysis Products

O
CH2CNH +
H3O
S
N CH3
O CH3
- +
penicillin G CO2 K
Hydrolysis of Penicillin

O
CH2CNH +
CH2CO2H
H3O
S NH2
N CH3 S
O CH3 CO2H N
- +
penicillin G CO2 K H
CO2H
 Aspartame
O O O
O O
HOCCH2CHCNHCHCOCH3
+
H3O HOCCH2CHCOH
NH2 CH2 HOCH3
NH2 O
aspartic acid methanol
H2NCHCOH

phenylalanine CH2
Hydrolysis of an Acid Chloride

HCl is generated during the hydrolysis: a base is added to

remove the HCl

Acyl chlorides must therefore be stored in anhydrous conditions as they hydrolyze

rapidly in the presence of even a trace amount of water.

Amides, on the other hand, react with water only in the presence of strong acid or base
catalysts and external heating.
 Preparation of Acid Chlorides
• When carboxylic acid is reacted with a chlorine-rich compound such as
phosphorous pentachloride (PCl5) or thionyl chloride (SOCl2) or phosphorus
trichloride (PCl3) at room temperature , an acyl chloride is formed.
• A white fume of hydrogen chloride is given off as side product.
• In the case of benzoic acid, the reaction mixture is heated.
• The reaction is a nucleophilic substitution reaction.
 Acyl chlorides in synthesis
Acyl chlorides react with nucleophiles
 O O

(3) R C > C

Cl Cl

C – O  bond of benzoyl chloride has

less mesomeric effect
 Carbonyl C of benzoyl chloride is
less positive O

 Less susceptible to nucleophilic C

attack
Cl
 O 


(4) R C + > + C Cl

Cl

The carbonyl C is attached to TWO electron-

withdrawing atoms
 more positive

 more susceptible to electrophilic attacks

 O 


(4) R C + > + C Cl

Cl

Also, the nucleophile experiences less steric hindrance

with acyl chloride because the reaction site is planar
Preparation of acid Halides

89
O O
COH CCl
SOCl2
+ SO2
in N
+ HCl
O O

SOCl2, pyridine CCl

OH
+ HCl
+ SO2
O
S
Cl Cl O
O S
O Cl
C OH
C O
Cl

O O
O
S S
S Cl O Cl
O O Cl
Cl C
C OH C OH pyr: O
Cl
The goal is to convert the OH group into a better leaving
group:

91
• Examples:
 1. Acid chloride with high b.p. (>170C)

Phosphorus
O O oxychloride
R C + PCl5 R C + POCl3 + HCl(g)
(s) (l)
Cl
OH
sublimes at 160℃ b.p. = 106℃

Higher b.p. than acid removed first by

chloride due to fractional distillation
intermolecular H-bonds
2. Acid chloride with high/intermediate/low b.p.
(85C < b.p. < 170C) or b.p. < 65C

O O

R C + SOCl2 + SO2(g) + HCl(g)

(l) R C

OH
b.p. = 74.6℃ Cl
can be removed
easily
Most useful
 3. Acid chloride with low b.p.(< 69C)

O O

3 R C + PCl3 3 R C + H3PO3(s)
(l)
OH b.p. = 79℃ Cl decomposes
at 200℃

Removed first by
fractional
distillation
 s.t.=160C heat b.p.=106C
COOH + PCl5(s) COCl + POCl3(l) + HCl(g)

b.p.=249C b.p.=197.2C

heat
COOH + SOCl2(l) COCl + SO2(g) + HCl(g)

b.p.=74.6C
 O O
heat
H3C C + PCl3(l) H3C C + H3PO3(l)

OH b.p.=76C Cl d.c.200C
b.p.=118C b.p.51C

Removed first
by fractional
distillation
Preparation of acid anhydrides
• - reaction of carboxylic acid with an acid chloride in the presence of pyridine.
• - pyridine, C5H5N (base) is added to neutralize the HCl formed in the reaction to
prevent unnecessary side reaction
Note that with acid chlorides, due to their high reactivity a catalyst may not be needed in
their use in synthesizing anhydrides.
 O
HO
Cl
O
addition
O O H

O
Cl
elimination O O H
Cl

O
deprotonation
O O + HCl

O
Chemistry of Acid Anhydrides
• Prepared by nucleophilic acyl substitution of a
carboxylate with an acid chloride

103
 Preparation of Acid Anhydrides Cont’d O

(1) O R C
O
pyridine
R C + 'R C O + HCl

Cl OH 'R C

Reaction is carried out in pyridine which neutralizes the HCl

R  R’  unsymmetrical anhydride

R = R’  symmetrical anhydride
 Preparation of Acid Anhydrides Cont’d
O

(1) O R C
O
pyridine
R C + 'R C O + HCl

Cl OH 'R C

N + HCl NH Cl

pyridine

Equilibrium position shifts to the right

Yield 
 Preparation of Acid Anhydrides Cont’d
O

(2) O R C
O
pyridine
R C + 'R C O + NaCl(s)
Cl O Na 'R C

O
R  R’  unsymmetrical anhydride

R = R’  symmetrical anhydride

NaCl(s) produced is removed by precipitation

 Equilibrium position shifts to the right
 Yield 
 Preparation of Acid Anhydrides Cont’d
O

(3) O
dehydrating agent R C
P2O5
2R C O + H2O
heat
OH R C
P4O10 = P2O5
O

Non-SN reaction
Only suitable for preparing symmetrical anhydrides
It gives a mixture of three acid anhydrides.

RCOOH + R’COOH

heat P4O10
O O O

R C R C 'R C

O + O + O

'R C R C 'R C

O O O
• Symmetrical anhydride is formed when two carboxylic acid is heated with
phosphorus pentoxide (P2O5) (dehydration reaction) or heating with ZnO.
Preparation of Esters
• Esters are usually prepared from carboxylic acids

111
Preparation of Esters
• Methods include reaction of a carboxylate anion with a
primary alkyl halide

112
Transesterification
a Methanolysis
Transesterification is the conversion of a carboxylic acid ester into a different carboxylic
acid ester.When in ester is placed in a large excess of an alcohol along with presence of
either an acid or a base there can be an exchange of alkoxy groups.

The large excess of alcohol is used to drive the reaction forward. The most common
method of transesterification is the reaction of the ester with an alcohol in the presence of
an acid catalyst eg:
 
O O
+
OCH2C6H5 CH3OH, H
OCH3
+ C6H5CH2OH
O H
+ O
+
OCH2C6H5 CH3OH, H
OCH3
+ C6H5CH2OH

O
H CH3OH O H

OCH2C6H5 OCH3
HOCH3

OH OH
H
+
H trans. OCH2C6H5
OCH2C6H5
OCH3 OCH3
H
Synthesis of Amides

• Amides can be synthesised directly from carboxylic acids, but the yield is poor.
• A better method of synthesising amides is by using acid chlorides.
• When ammonium carboxylates are heated in the presence of the free acid,
dehydration occurs to form the primary amide.
• Ammonium carboxylates are obtained by the reaction of carboxylic acids with
ammonia (poor method).
• Secondary and tertiary amides can be synthesised by using primary amines and
secondary amines respectively.
Other method: reaction of acid chloride with ammonia or amines
Amide Preparation from an Acid Chloride
Amide from Anhydride
General Reactions of Carboxylic Acid Derivatives
• water carboxylic acid
• alcohols esters
• ammonia or an amine an amide
• hydride source an aldehyde or an
alcohol
• Grignard reagent a ketone or
an alcohol

122
Reactions of Esters

123
Reactions of Esters
• Less reactive toward nucleophiles than are acid
chlorides or anhydrides

• Cyclic esters are called lactones and react similarly

to acyclic esters

124
Hydrolysis: Conversion of Esters into Carboxylic
Acids
• An ester is hydrolyzed by aqueous base or aqueous acid to
yield a carboxylic acid plus an alcohol

125
Mechanism of Ester Hydrolysis
• Hydroxide catalysis via an addition intermediate

126
Aminolysis of Esters
• Ammonia reacts with esters to form amides

127
128
Reduction: Conversion of Esters into Alcohols
• Reaction with LiAlH4 yields primary alcohols

129
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

130
Reaction of Esters with Grignard Reagents
• React with 2 equivalents of a Grignard reagent to yield a
tertiary alcohol

131
Hydrolysis of an ester with primary or secondary alkyl
groups can be catalyzed by an acid

132
• Excess water will force the equilibrium to the right
• Alcohols that have low boiling points can be removed by distillation as they
are formed

133
Esters with tertiary alkyl groups undergo hydrolysis much
more rapidly than do others.

134
O
LiAlH4 Reductions
CCl CH2OH
+ HCl
O O
COCCH3 CH2OH
+ CH3CH2OH

CO2H 1) LiAlH 4 CH2OH

+ + H 2O
2) H3O
O
COCH3 CH2OH
+ CH3OH
O
CNH2 CH2NH2
Reduction of Esters with
LiAlH4
•Carboxylic esters are reduced give 2 alcohols, one from the alcohol portion of the
ester and a 1o alcohol from the reduction of the carboxylate portion.
•Esters are less reactive towards Nu than aldehydes or ketones.
•They can only be reduced by LiAlH4 but NOT by the less reactive NaBH4
•The reaction requires that 2 hydrides (H-) be added to the carbonyl group of the ester
•The mechanism is an example of the reactive system type.
•The reaction proceeds via a aldehyde intermediate which then reacts with the
second equivalent of the hydride reagent (review)
•Since the aldehyde is more reactive than the ester, the reaction is not normally used
as a preparation of aldehydes .
 Reactions of Amides

Amides are very unreactive carboxylative derivatives

139
Amides can react with water and alcohols if an acid catalyst is present to
form carboxylic acid and ester respectively:

140
 Dehydration of an Amide

Dehydration reagents commonly used are SOCl2, P2O5,

or POCl3

141
An acid catalyst can make the amine a better leaving
group:

142
The need for an acid catalyst…
Ammonia anion
Ammonia is an is a very poor
excellent leaving leaving group
group

143
Basic Hydrolysis of an Amide
Mechanism
O O
CN(CH2CH3)2 C
NaOH, H2O O Na
+
OH H carb.
acid
+ HN(CH2CH3)2

O
O
C
C N(CH2CH3)2 OH
OH + N(CH2CH3)2
Reduction of Amides with LiAlH4
•Amides, RCONR'2, can be reduced to the amine, RCH2NR'2 by conversion of the C=O to -CH2-

•Amides can be reduced by LiAlH4 but NOT the less reactive NaBH4

•Typical reagents :  LiAlH4  / ether solvent followedby aqueous work-up.

•Note that this reaction is different to that of other C=Ocompounds which reduce to alcohols
•The nature of the amine obtained depends on the substituents present on the original amide.
Note that the bonds of the N substituents in the following
examples doesn’t change
Reaction of Anhydrides
Reactions of Acid Anhydrides
• Similar to acid chlorides in reactivity

150
Acetylation
• Acetic anhydride forms acetate esters from
alcohols and N-substituted acetamides from amines

151
Anhydride reactions are facilitated by acid or base catalysts

152
Mechanism for the conversion of an acid
anhydride into an ester (and a carboxylic acid):
Elimination
Addition facilitated facilitated by
by protonation protonation

In the absence of an acid catalyst, the reaction is

sluggish, but the reaction speeds up as acid
products are formed
153
Formation of Paracetamol
 Aspirin Synthesis

CO2H CO2H O
O O
OH OCCH3
CH3COCCH3
H2SO4 (aq) + CH3CO2H
 H
O O
CH3COCCH3
+
CO 2H H CO 2H O
O O
OH OCCH3
CH3COCCH3
+ CH3CO2H
H2SO4 (aq)

H OH2
CO 2H O
OCCH3
+ CH3CO2H

H
OH
CO 2H O CO 2H O O
+
OCOCCH3 H transf. OC OCCH3
H CH3 CH3 H
Reaction of Acid Chlorides
Reactions of Acid Halides
• Nucleophilic acyl substitution
• Halogen replaced by OH, by OR, or by NH2
• Reduction yields a primary alcohol
• Grignard reagent yields a tertiary alcohol

158
The acyl halide can be used to prepare other carboxylic
acid derivatives:

TEA

159
 Acyl chlorides  Carboxylic acids and Esters
Carboxylic acids using water

Water

Esters using alcohols

Alcohol
 Acyl chlorides  Amides
Primary amides using ammonia

Ammonia

Secondary amides using primary amines

Primary amine
Conversion of Acid Halides to Esters
• Esters are produced in the reaction of acid chlorides with
alcohols in the presence of pyridine or NaOH. This is called
Alcoholysis
• The reaction is better with less steric bulk

162
Aminolysis: Conversion of Acid Halides into
Amides
• 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
• HCl is neutralized by the amine or an added base

163
Reduction: Conversion of Acid Chlorides into
Alcohols
• LiAlH4 reduces acid chlorides to yield aldehydes and then
primary alcohols

164
Reaction of Acid Chlorides with Organometallic
Reagents
• Grignard reagents react with acid chlorides to yield tertiary
alcohols in which two of the substituents are the same

165
Formation of Ketones from Acid Chlorides
• 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

166
Summary of Reactions of Carboxylic Acid Derivatives.

+
R'OH / H RCOOR' Ester

NH3
RCONH 2 Amide

SOCl 2
RCOOH RCOCl Acid Chloride

1) PCl 5
- + RCOOCOR" Anhydride
2) R''COO Na
 Reactions of Acid Chlorides

O
H2O R C + HCl
OH
O
R'OH R C + HCl
OR'
O
HCl
O
NH3 R C +
NH2
R C + O
Cl
NH 2R' R C + HCl
NHR'
O
AlCl 3 HCl
R C +
1) LiAlH 4
+ R CH 2OH
2) H 3O
 Reactions of Esters
O + O
H
R C + H2O R C + R'OH
OR' OH
O + O
H
R C + R''OH R C + R'OH
OR' OR"
O + O
H
R C + NH3 R C + R'OH
OR' NH2

O
1) LiAlH 4
R C
2) H 3O
+ R CH2 OH + R'OH
OR'

R"
O
1) Dry ether
R C + 2 R"MgX
2) H 3O
+ R C OH + R'OH
OR'
R"
Reactions of Amides
O + O
H3O
R C R C + NH3
NH2 OH

O O
NaOH/ heat
R C R C + NH3
NH2 ONa

O
1) LiAlH 4
R C R CH2 NH2
+
NH2 2) H 3O

O
1) LiAlH 4
R C R CH2 NHR'
+
NHR' 2) H 3O

O
P 2O 5
R C R C N
- H 2O
NH2

O
Br 2 / NaOH
R C R NH2
NH2 or NaOBr
 Reactions of Acid anhydride

O
H2O R C + R'COOH
OH
O
R'OH R C + R'COOH
OR'
O
R'COOH
O O NH3 R C +
NH2
R C O C R' + O
NH 2R' R C + R'COOH
NHR'
O
AlCl 3
R C + R'COOH

1) LiAlH 4

2) H 3O
+ R CH 2OH + R'CH 2OH