Chapter 18

Carboxylic Acids and Their

Derivatives. Nucleophilic
AdditionElimination at the Acyl
Carbon
Introduction
The carboxyl group (-CO2H) is the parent group of a family of
compounds called acyl compounds or carboxylic acid derivatives
Structure Name Structure Name
O
O
C Acyl (or acid) chloride
R Cl C
R NH2
O O
C C Acid anhydride O
R O R' C Amide
O R NH R'

C R' Ester
R O O
C -
R C N Nitrile R N R' R''

Chapter 18 2
Nomenclature and Physical Properties
In IUPAC nomenclature, the name of a carboxylic acid is obtained
by changing the -e of the corresponding parent alkane to -oic acid
-The carboxyl carbon is assigned position 1 and need not be explicitly numbered

O O
6 5 4 3 2 6 5 4 3 2
H3CCH2 CH CH2CH2 C OH H3C CH CH CH2CH2 C OH

CH3
4-Hexenoic acid
4-Methylhexanoic acid (or hex-4-enoic acid)

The common names for many carboxylic acids remain in use

-Methanoic and ethanoic acid are usually referred to as formic and acetic acid
Carboxylic acids can form strong hydrogen bonds with each other
and with water
-Carboxylic acids with up to 4 carbons are miscible with water in all proportions

Chapter 18 3
 Water Solubility
(g 100 mL -1 H2O),
Structure Systematic name Common Name mp(0C) bp(0C) pKa
250C
HCO2 H Methanoic acid Formic acid 8 100.5 oo 3.75
CH3 CO2 H Ethanoic acid Aceptic acid 16.6 118 oo 4.76
CH3 CH2 CO2 H Propranoic acid Propionic acid -21 141 oo 4.87
CH3 (CH2 )2 CO2 H Butanoic acid Butyric acid -6 164 oo 4.81
CH3 (CH2 )3 CO2 H Pentanoic acid Valeric acid -34 187 4.97 4.82
CH3 (CH2 )4 CO2 H Hexanoic acid Caproic acid -3 205 1.08 4.84
Octanoic acid Caprylic acid 16 239 0.07 4.89
CH3 (CH2 )6 CO2 H
Decanoic acid Capric acid 31 269 0.015 4.84
CH3 (CH2 )8 CO2 H
Dodecanoic acid Lauric acid 44 17918 0.006 5.30
CH3 (CH2 )10 CO2 H
Tetradecanoicacid Myristic acid 59 0.002
CH3 (CH2 )12 CO2 H 20020
Hexadecanoic acid Palmitic acid 63 0.0007 6.46
CH3 (CH2 )14 CO2 H Octadecanoic acid Stearic acid 70 21917 0.0003
CH3 (CH2 )16 CO2 H Chloroethenanoic acid Chloroacetic acid 63 383 Very soluble 2.86
CH2 ClCO2 H Dichloroethenanoic acid Dichloroacetic acid 10.8 189 Very sloluble 1.48
CHCl2 CO2 H Trochloroethenanoic acid Trichloroaceticacid 56.3 192 Very soluble 0.70
CCl3 CO2 H 2-Chloropropanoic acid -Chloropropionic acid 198 Soluble 2.83
CH3 CHClCO2 H 3-Chloropropanoic acid Chloropropionic acid 61 186 Soluble 3.98
CH2 ClCH2 CO2 H Bezoic acid Benzoic acid 122 204 0.34 4.19
C6 H5 CO2 H 4-Methylbenzoic acid p-Toluic acid 180 250 0.03 4.36
4-Chlorobenzoic acid p-Chlorobenzoic acid 242 275 0.009 3.98
p-CH3 C6 H4 CO2 H
4-Nitrobenzoic acid p-Nitrobenzoic acid 242 0.03 3.41
p-ClC6 H4 CO2 H
1-Naphthoic acid
p-NO2 C6 H4 CO2 H 300 3.70
-Napthoic acid 160 Insoluble
CO 2H 1- Napththoic acid

CO 2CH
1- Napththoic acid 300 Insolule 4.17
aphthoic acid 185

Chapter 18 4
Acidity of Carboxylic Acids
The carboxyl proton of most carboxylic acids has a pKa = 4 - 5
-Carboxylic acids are readily deprotonated by sodium hydroxide or sodium
bicarbonate to form carboxylate salts
-Carboxylate salts are more water soluble than the corresponding carboxylic acid
O
O
H2O
COH
+ Na OH
CO
-
Na
+
+ H 2O

Benzoic acid Stronger Weaker

Sodium benzoate
(water insoluble) acid
base (water soluble)
Stronger

O Weaker base
O
H2O
COH
+ Na OH
CO
-
Na
+
+ CO 2
+ H 2O

CH4
(water insoluble) Stronger H2CO3
(water soluble)
Stronger
base Weaker
Weaker base
acid
Electron-withdrawing groups near the carboxyl group increase the
carboxylic acid’s acidity
-They stabilize the carboxylate anion by inductive delocalization of charge
Cl
Cl Cl Cl

Cl C CO 2 H > Cl C CO 2 H > Cl C CO 2 H > Cl C CO 2 H

Cl Cl Cl Cl

pKa 0.70 1.48 2.86 4.76

Chapter 18 5
Dicarboxylic Acids
Dicarboxylic acids are named as alkanedioic acids in the IUPAC
system
-Common names are often used for simple dicarboxylic acids
pKa
(at 25oC)
Structure Common Name mp(oC) pK1 pK2

HO2C-CO2H Oxalic acid 189dec 1.2 4.2

HO2CCHCO2H Malonic acid 136 2.9 5.7
Succinic acid 187 4.2 5.6
HO2C(CH2)2CO2H Glutaric acid 98 4.3 5.4
HO2C(CH2)3CO2H Adipic acid 153 4.4 5.6
HO2C(CH2)4CO2H Maleic acid 131 1.9 6.1
Fumaric acid 287 3.0 4.4
cis HO2C-CH=CH-CO2H
Phinalic acid 206-208dec 2.9 6.5
trans HO2C-CH=CH-CO2H
H H
CO 2

CO
H 2H
Isophthalic acid 345-348 3.5 4.6
H H
CO 2

CO
H 2H 3.5 4.8
Sublimes
H H Terephthalic acid
CO 2

COH2H

Chapter 18 6
Esters
The names of esters are derived from the names of the
corresponding carboxylic acid and alcohol from which the ester
would be made
-The alcohol portion is named first and has the ending -yl
-The carboxylic acid portion follows and its name ends with -ate or -oate

O C H3
O O

CH 3C OCH2 CH3 CH 2 CH 3 C OC C H3 H3C C O CH CH2

Ethyl acetate or C H3 Vinyl acetate or

ethyl ethanoate tert-Betyl propanoate
ethanoate ethanoate

O
O O
Cl COCH 3
CH3CH2 O CCH2 C O CH2 CH3

Methyl p-chlorobenzoate Diethyl malonate

Esters cannot hydrogen bond to each other and therefore have

lower boiling points than carboxylic acids
-Esters can hydrogen bond to water and have appreciable water solubility

Chapter 18 7
 Solubility
in water

Name Structure mp(oC) bp(oC) (g 100 mL-1 at 20oC)

Methyl formate HCO2CH3 31.5 Very soluble

-99
Ethyl formate HCO2CH2CH3 54 57 Soluble
-79
Methyl acetate CH3CO2CH3 -99 77 24.4 7.39
o
Ethyl acetate CH3CO2CH2CH3 -82 102 (25 C) 1.89
Propyl acetate CH3CO2CH2CH2CH3 -93 125 1.0 (22oC)
Butyl acetate CH3CO2CH2(CH2)CH3 -74 99
Ethyl propanoate 1.75 0.51
CH3CH2CO2CH2CH3 -73 120
Ethyl butanoate 0.22
CH3(CH2)2CO2CH2CH3 -93 145
Ethyl pentanoate 0.063
CH3(CH2)3CO2CH2CH3 -91 168
Ethyl hexanoate 0.15
CH3(CH2)4CO2CH2CH3 -68 199
Methyl benzoate 0.08
C6H5CO2CH3 -12 213
Ethyl benzoate Slightly soluble
C6H5CO2CH2CH3 -35 196
Phenyl acetate 0.74 (30oC)
CH3CO2C6H5 223
Methyl salicylate o-HOC6H4CO2CH3 -9

Chapter 18 8
Acid Anhydrides
Most anhydrides are named by dropping the word acid from the
carboxylic acid name and adding the word anhydride
O O O O

H3C C C C HC C
H2C
O O O O
H2C HC
H3C C C
C
C

O O O O

Acetic anhydride Succinic Maleic anhydride

anhydride Phthalic anhydride
(ethnoic anhydride)
mp 530C
mp-730C mp 121 C 0 mp 1310C

Acid Chlorides
Acid chlorides are named by dropping the -ic acid from the name
of the carboxylic acid and adding -yl chloride
O O
O

CH3C Cl
CH3CH2 C Cl
C 6 H 5C Cl
Acetyl chloride Propanoyl chloride Benzoyl cloride
mp-940C;800C mp-10C;bp1970 C
(ethanoyl cloride)
mp -1120C;bp510C

Chapter 18 9
Amides
Amides with no substituents on nitrogen are named by replacing
-ic acid in the name with amide
-Groups on the nitrogen are named as substitutents and are given the locants N- or
N,N- O O O
C H3
CH3C NH2 C H3 C N
CH3C NHC2H5
C H3
Acetamide
N,N-Dimethylacetamide N-Ethylacitamide
(ethanamide)
mp-200C;bp 1660C
mp 820C;bp 2110C bp2050C

O O
C6H5
CH 3C N
C NH2
CH 2 CH 2CH 3

Benzamide
N-Phenyl-N-propylacitamide
mp1300C;bp2900C
mp 490C;bp 2660C at 712 torr

Amides with one or two hydrogens on nitrogen form very strong

hydrogen bonds and have high melting and boiling points
-N,N-disubstituted amides cannot form hydrogen bonds to each other and have
lower melting and boiling points

Chapter 18 10
 Hydrogen bonding between amides in proteins and peptides is an
important factor in determining their 3-dimensional shape

( )
O H R2 O H R4 O
O
H N N NH
H3C N N
R N CH3
R O H R3 O H R5
R1
+ H

)
 R5 H O R3 H O O

(
R1
O H3C N N
1 N CH3
NH N N
R
RH N R4 H O R2 H
O R2 O

H
Hydrogen bonding (red dots)
between amide molecules Hydrogen bonding between amide groups of peptide
chains. This interaction between chains (called a  seet)
is important to the structure of many proteins.
Nitriles
Acyclic nitriles are named by adding the suffix -nitrile to the
alkane name
-The nitrile carbon is assigned position 1
-Ethanenitrile is usually called acetonitrile

H 3C C N H 2C CH C N
Ethanenitrile Propenenitrile
(acetonitrile) (acrylonitrile)

Chapter 18 11
Preparation of Carboxylic Acids
By Oxidation of Alkanes (1) KMnO4, OH
-

R CH CH R'
heat
R CO2H + R' CO2H
+
(2) H3O

(1) O3
R CH CH R'
heat
R CO2H + R' CO2H

(2) H2O2

By Oxidation of Aldehydes and Primary Alcohols

+ -
(1) Ag2O, or Ag(NH3)2 OH
R CHO +
R CO2H
(2) H3O

-
(1) KMnO4, OH
R CH2OH R CO2H
heat
(2) +
H3O

H2CrO4
R CHO or R CH2OH R CO2H

By Oxidation of Alkylbenzenes
-
(1) KMnO4, OH
CH3 CO2H
heat
(2) +
H3O

Chapter 18 12
By Oxidation of the Benzene Ring
O
(1) O3, CH3CO2H
R C 6H 5 R COH
(2) H2O2

By Oxidation of Methyl Ketones (The Haloform Reaction)

O O

C
(1) X 2/NaOH
C + CHX3
+
(2) H3O
Ar CH3 Ar OH

By Hydrolysis of Cyanohydrins and Other Nitriles

-Hydrolysis of a cyanohydrin yields an a-hydroxy acid

OH
R R OH
HA
C O + HCN C H2O R C CO2H

R' R' CN R'

Chapter 18 13
 -Primary alkyl halides can react with cyanide to form nitriles and these can be
hydrolyzed to carboxylic acids
-
NaCN (1) OH , H2O
H2COH CH2 Cl H2COH CH2 CN H2COH CH2 CO2H
(80%) +
(2) H3O
3-Hydroxy- (75-80%) 3-Hydroxypopanoic
acid
propanenitrile

+
NaCN H3O
Br CH2CH2 CH2Br CNCH2CH2 CH2CN HO2CCH2CH2 CH2CO2H
(77-80%) (77-86%)

Pentanitrile Glutaric acid

By Carbonation of Grignard Reagents

CH3 CH3 CH3
(1) CO2
Mg CH3C CO2H
CH3 C Cl CH3CMg Cl +
Et2O (2) H3O

CH3 CH3
CH3
2,2-Dimethylpropanoic acid
(79-80% overall)
(1) CO2
CH3CH2CH2CH2 Cl CH3CH2CH2CH2 MgCl CH3CH2CH2CH2 CO2H
(2) H O+
3 Pentanoic acid
Butyl chloride
(85%)

Mg (1) CO2
Br MgBr CO2H
Et2O (2) H O+
3
Benzoic acid
(85%)
Chapter 18 14
Nucleophilic Addition-Elimination at the Acyl
Carbon
Recall that aldehydes and ketones undergo nucleophilic addition
to the carbon-oxygen double bond Nu
R' Nu
- – H Nu -
C O + Nu R' C O R' C O H + Nu

R R R
Aldehyde or
ketone

Nucleophilic addition

The carbonyl group of carboxylic acids and their derivatives

undergo nucleophilic addition-elimination
-The nucleophile reacts at the carbonyl group to form a tetrahedral intermediate
-The tetrahedral intermediate eliminates a leaving group (L)
-The carbonyl group is regenerated; the net effect is an acyl substitution
H
+ +
R Nu Nu
Nu
– –
C O + Nu H C O C O C O + HL
R R
L
L HL R
An acyl compound Another acyl
+
Tetrahedral intermediate compound

Nucleophilic addition Elimination

Chapter 18 15
 To undergo nucleophilic addition-elimination the acyl compound
must have a good leaving group or a group that can be converted
into a good leaving group
-Acid chlorides react with loss of chloride ion
-Anhydrides react with loss of a carboxylate ion

Spesific Example –
O
O O
+ –
R C + O H R C O H R C
+ Cl
+
Cl H H O H
Cl
H
Loss of the
chloride ion
as a leaving
H2O
group
O
+
R C + H3O

O H

Chapter 18 16
Esters, carboxylic acids and amides generally react with loss of
the leaving groups alcohol, water and amine, respectively
-These leaving groups are generated by protonation of the acyl compound
Aldehydes and ketones cannot react by this mechanism because
they lack a good leaving group

–
O O
–
R C Nu R C + H

H Nu Hydride
ion These reactions
– rarely occur.
O O

R C Nu R C + -
R

R Nu Alkanide
ion

Chapter 18 17
Relative Reactivity of Acyl Compounds
The relative reactivity of carboxylic acids and their derivatives is
as follows:
O O O O

R C > R C > R C > R C

Cl O O R' NH2
R' C

O
Acyl Acid Ester Amide
chloride anhydride

In general, reactivity can be related to the ability of the leaving

group (L) to depart
-Leaving group ability is inversely related to basicity
-Chloride is the weakest base and the best leaving group
-Amines are the strongest bases and the worst leaving groups
As a general rule, less reactive acyl compounds can be
synthesized from more reactive ones
-Synthesis of more reactive acyl derivatives from less reactive ones is difficult and
requires special reagents (if at all possible)

Chapter 18 18
Acid Chlorides
Synthesis of Acid Chlorides
Acid chlorides are made from carboxylic acids by reaction with
thionyl chloride, phosphorus trichloride or phosphorus
pentachloride
-These reagents work because they turn the hydroxyl group of the carboxylic acid
into an excellent leaving group

O O

R C OH + SOCl2 R C Cl + SO2 + HCl

Thionyl chloride

O O

3 R C OH + PCl3 3 R C Cl + H3PO3
Phosphorus
trichloride

O O

R C OH + PCl5 R C Cl + POCl3 + HCl

Phosphorus
pentachloride

Chapter 18 19
 .. ..
. ..

..
.. O Cl

..
..
O Cl..
C .. -
+
..
H S O S O
..

..
C .. +
..

..
.. R O
O Cl Cl

..
.. ..

..
R ..

..
H

..
O .. .. - .. ..
..

Cl O Cl

..
..
..
..

..
Cl

..
..

..
O

..
..
C .. + ..
S
R C O S
.. C + O S

..
.. + .. H ..O ..
R Cl Cl

..
..

..
O .. R .. O

..
..
O
.. H

.. H
-
Cl
..

..
..

Protonated acyl
HCl + SO2
chlorosulfite

Reactions of Acyl Chlorides

Acyl chlorides are the most reactive acyl compounds and can be
used to make any of the other derivatives
Since acyl chlorides are easily made from carboxylic acids they
provide a way to synthesize any acyl compound from a carboxylic
acid
Acyl chlorides react readily with water, but this is not a
synthetically useful reaction
Chapter 18 20
 O O
- +
R'CO Na
(-Na+Cl-) RC O CR'
Anhydride

O
R'OH, base RCCR'
(-HCL)
Ester

SOCl2
O O O
or
PCl3 NH3
RCOH RCNH2
RCCl
or (-NH4+Cl-)
PCl3 Amide

O
R'NH2
RCNHR'
(-R'NH3+Cl-
N-Substituted amide

O
R'R'NH
RCNR'R''
(-R'RNNH2+Cl-
N,N-Disubstituted amide
O
RCOH
+ HCl
O H 2O

RCCl O
Acyl chloride
OH -/H
2 O RCO
- + Cl-

Chapter 18 21
Carboxylic Acid Anhydrides
Synthesis of Carboxylic Acid Anhydrides
Acid chlorides react with carboxylic acids to form mixed or
symmetrical anhydrides
-It is necessary to use a base such as pyridine

O O
O O
C C
C + +
C + +
N
R OH R' Cl N R O R'
H

Sodium carboxylates react readily with acid chlorides to form

anhydrides
O O
O O
+ C C + Na+Cl-
C C
- +
R O Na R' Cl R O R'

Chapter 18 22
 Cyclic anhydrides with 5- and 6-membered rings can be
synthesized by heating the appropriate diacid
O O O
O
C C C C
H2C OH O
300 C H2C OH 230OC
+ H2O O + H2O
H2C O OH
OH H2C C C
C
C
O O O
O

Succinic
acid Succinic anhydride Phthalic acid Phthalic anhydride (~100%)

Reactions of Carboxylic Acid Anhydrides

Carboxylic acid anhydrides are very reactive and can be used to
synthesize esters and amides
-Hydrolysis of an anhydride yields the corresponding carboxylic acids

Chapter 18 23
 O O
R'OH
RCOR' + RCO H

Ester

O O
NH3
RCNH2 + -
RCO NH3
+

O O Amide
RC O CR
Anhydride
O O
R'NH2
RCNHR' + RCO R'NH3
- +

N-Substituted
amide

O O
N
R'R NH
RCNR'R'' + -
RCO R'R''NH2
+

N,N-Disubstituted By-products
amide
O O

RCOH + H OCR'
O O H 2O
RC O CR' O O
OH -
Anhydride /H
2O RCO
-
+ -
OCR'

Chapter 18 24
Esters
Synthesis of Esters: Esterification
Acid catalyzed reaction of alcohols and carboxylic acids to form
esters is called Fischer esterification
Fischer esterification is an equilibrium process
-Ester formation is favored by use of a large excess of either the alcohol or
carboxylic acid
-Ester formation is also favored by removal of water

O O
HA
C + R' OH C
+ H2O
R OH R OR'

O O
HA
CH 3COH + OH 2CH 3C H CH 3COCH 2CH 3 + H 2O

Acetic acid Ethanol Ethyl acetate

O O
HA
CH 5C 6OH + CH 3OH CH 5C 6OCH 3 + H2O

Benzoic acid Methanol Methyl benzoate

Chapter 18 25
 Esterification with labeled methanol gives a product labeled only
at the oxygen atom bonded to the methyl group
-A mechanism consistent with this observation is shown below
O
O
HA 18
C6 H5 C OH + H3C
18
O H C6 H5 C OCH3 + H2O

H +
+ O O
H O H

H C C H O H
+CH 3 -OH
+
H5C6 O H H5C6 O H H5C6 C O CH3
-CH 3 -OH

The carboxylic acid

O H
accepts a proton from The alcohol attacks the
A proton is lost at one
the strong acid catalyst. protonated carbonyl
oxygen atom and
group to give a
gained at another.
tetrahedral intermediate.

H O H O +
H O O
H 5C 6 C O CH 3 H +
C -H3 O
+ C
O H H5C6 O CH3 +H3O
+
H5C6 O CH3
H
Loss of a molecule of Transfer of a proton to
water gives a a base leads to the ester.
protonated ester.

Chapter 18 26
 The reverse reaction is acid-catalyzed ester hydrolysis
-Ester hydrolysis is favored by use of dilute aqueous acid

O +
O
H3O
C
+ H 2O + R' OH

R OR' R OH

Esters from Acid Chlorides

-Acid chlorides react readily with alcohols in the presence of a base (e.g. pyridine)
to form esters
.. ..
O ..
O
..

..
-HCl
R C + R' O
.. H R C ..
O
.. R'
Cl
..

..
..

O
O

CH5C6 Cl + CH3CH2OH + CH5C6 OCH2CH3 + Cl-

+
N
.N
.
H
Ethyl benzoate
Benzoyl chloride (80%)

Chapter 18 27
Esters from Carboxylic Acid Anhydrides
-Alcohols react readily with anhydrides to form esters
O
RC O O
O + R' OH RC + R COH
RC O R'

O O

H 3C C 2 O + H5C6CH2 OH H 3C C O CH2 C 6H 5 + H 3C CO 2 H

Acetic Benzyl Benzyl acetate

Anhydride Alcohol

O O
H3C
C C
o
110 C O CHCH2 CH3
O + H3C CHCH2CH3 OH
C HO C

O O
Phthalic sec-Butyl hydrogen phthalate
sec-Butyl alcohol (97%)
Anhydride

Chapter 18 28
Base-Promoted Hydrolysis of Esters: Saponification
Reaction of an ester with sodium hydroxide results in the
formation of a sodium carboxylate and an alcohol
O O
H2O -
O R' + +
RC NaOH RC O Na + R' OH
Ester
Sodium carboxylate Alcohol

The mechanism is reversible until the alcohol product is formed

Protonation of the alkoxide by the initially formed carboxylic acid
is irreversible
-This step draws the overall equilibrium toward completion of the hydrolysis
-
O - O
O H slow
C R C O H
R O R' O R'
A hydroxide ion attacks The tetrahedral intermediate
the carbonyl carbon atom. expels an alkoxide ion.

O O
C C
- -
R O H + O R' R O + H O R'

Transfer of a proton leads

to the products of the reaction.
Chapter 18 29
Lactones
- or -Hydroxyacids undergo acid catalyzed reaction to give
cyclic esters known as - or -lactones, respectively
A H O H
O H
O +
H
    O H O
R HC CH2 CH2 CH2 C OH + H
O H O
O

H R R
A -hydroxy acid

+
O H O

O H + -
O + O + H O H + A
H H
R
R
A -lactone

Chapter 18 30
Lactones can be hydrolyzed with aqueous base
-Acidification of the carboxylate product can lead back to the original lactone if too
much acid is added

O
OH O
OH- / H2O
O -
H5C 6 CH CH2 CH2 C O
HA, slight excess

0oC HA, exactly one

C 6H 5 equivalent

OH O
H5C 6 CH CH2 CH2 C OH

Chapter 18 31
 Amides
Synthesis of Amides
Amides From Acyl Chlorides
-Ammonia, primary or secondary amines react with acid chlorides to form amides
-An excess of amine is added to neutralize the HCl formed in the reaction
-Carboxylic acids can be converted to amides via the corresponding acid chloride

-
O O O O
C R''
R C Cl C
+ -
C R' + R' R''NH2 + Cl
-
R Cl + R N R' Cl
R N
H N R''
H R'
HN R'R'' R'
HN R'R''

Reactant Product
Ammonia; R', R'' = H Unsubstituted amide; R', R'' = H
1o Amine; R' = H, R'' = alkyl, aryl N-Substituted amide; R' = H, R'' = alkyl, aryl
N,N-Disubstituted amide; R', R'' = alkyl, aryl
2o Amine; R', R'' = alkyl, aryl

Chapter 18 32
Amides from Carboxylic Anhydrides
-Anhydrides react with 2 equivalents of amine to produce an amide and an
ammonium carboxylate
O O
- +
RC O + 2 R' NH RC N R' + R CO2 R' R''NH2
2

R'' R''
R', R'' can be H, alkyl or aryl

-Reaction of a cyclic anhydride with an amine, followed by acidification yields a

product containing both amide and carboxylic acid functional groups
-Heating this product results in the formation of a cyclic imide
O O O
C C H3O
+ C
H2O NH2
NH2
O + 2 NH3 - + +
warm O NH3 ( - NH4 ) OH
C C C
O O O
Phthalic Ammonium Phthalamic
anhydride phthalamate acid
(94%) (81%)
O
O
C
NH2 o
150 - 160 C C
OH N H + H2O
C
C
O
O
Phthalamic acid Phthalamide
(~100%)
Chapter 18 33
Amides from Carboxylic Acids and Ammonium Carboxylates
-Direct reaction of carboxylic acids and ammonia yields ammonium salts

O O
+ NH3 C
C - +
R OH R O NH3
An ammonium
carboxylate

-Some ammonium salts of carboxylic acids can be dehydrated to the amide at high
temperatures
-This is generally a poor method of amide synthesis

C O
heat
R
-
O NH3
+ R C + H2O
(solid)
NH2

-A good way to synthesize an amide is to convert a carboxylic acid to an acid

chloride and to then to react the acid chloride with ammonia or an amine

Chapter 18 34
 -Dicylohexylcarbodiimide (DCC) is a reagent used to form amides from carboxylic
acids and amines
-DCC activates the carbonyl group of a carboxylic acid toward nucleophilic
addition-elimination
C 6 H 11

R N C6H11 R N C6H11
N
O +
C O C C O C
R C + C - + -
H O N H O N
O H
N
C6H11 C6H11
C 6 H 11
Dicyclohexyl- Proton
carbodiimide transfer
(DCC) O
N C6H11
C R' NH2
R O C
NHC6H11
Reactive
intermediate
-
O N C6H11
O NHC6H11
R C O C
R C + O C
+ Collapse of the
H2N NHC6H11 tetrahedral NHC6H11
NH R'
intermediate
and proton An amide N,N'-Dicyclohexylurea
R'
transfer
Chapter 18 35
Hydrolysis of Amides
Heating an amide in concentrated aqueous acid or base causes
hydrolysis
-Hydrolysis of an amide is slower than hydrolysis of an ester

O O
H2O
+
C + H3O + C + NH4
heat
R NH2 R OH

O O
+ - H2O
C + Na OH C + NH
heat 3
R NH2 R O Na+

Chapter 18 36
 O O H
H O+ H
C + H OH2 +
O+ H C R C OH2
R NH2
R NH2
The amide carbonyl accepts
NH2
A water molecule
a proton from the attacks the protonated A proton is
aqueous acid. carbonyl to give lost at
a tetrahedral one oxygen
intermediate. and gained
at the
nitrogen.

O H
O+ H O

R C O H C + NH C +
3 + NH 4

NH3 R O H R OH
+
Loss of a molecule Transfer of
of ammonia gives a proton to
a protonated ammonia leads
carboxylic acid. to the carboxylic
acid and an
ammonium ion.

Chapter 18 37
 _ _
O O O
_ OH
C + OH _
R C O H R C O
R NH2
NH2 NH2
A hydroxide ion
attacks the acyl A hydroxide ion
carbon of the removes a proton
amide. to give a dianion. H OH
The dianion loses a
molecule of ammonia
(or an amine); this
step is syncronized
with a proton transfer
from water due to
the basicity of NH2-

O
_
C _ + NH3 + OH
R O

Chapter 18 38
Nitriles from the Dehydration of Amides
A nitrile can be formed by reaction of an amide with phosphorous
pentoxide or boiling acetic anhydride
O
P4O10 or (CH3CO)2O
R C R C N + H3PO4 or CH3CO2H
heat A nitrile
NH2 (_- H2O)

Hydrolysis of Nitriles
A nitrile is the synthetic equivalent of a carboxylic acid because it
can be converted to a carboxylic acid by hydrolysis

eat R CO2H
, h
H 2O
H3O,
R C NO
H -,
HO
2 ,
hea
t RCO2-

Chapter 18 39
 H H
+ + slow
R C N + H O+ H R C NH R C NH + O H

Protonated nitrile
H
H
O+ H O
C H
OH2 C
R NH R NH + H O+ H
Amide tautomer

H H +
O O
several steps +
C C ( amide
RCO2H + NH4
R NH2 R NH2 hydrolysis)
+

Protonated amide

Chapter 18 40
 _
N NH
_ H OH _
R C N + O H C C + O H
R OH R OH
Amide
tautomer

_
OH O H O
_ H OH -
R C NH OH HOH
-
OH
R C NH2 R C NH2
H2O -
OH
OH OH O H
_
O O
H OH
R C NH2 C _ +NH3 + OH-
_ R O
O Carboxylate
anion

Chapter 18 41
Decarboxylation of Carboxylic Acids
-Keto carboxylic acids and their salts decarboxylate readily when
heated
-Some even decarboxylate slowly at room temperature

O O O
100 - 150 oC
RCCH2 COH RCCH3 + CO2
A  - keto acid

The mechanism of -keto acid decarboxylation proceeds through

a 6-membered ring transition state
H H
O O O O
-CO2
C C C
CH2 C
R O R CH2 R CH3
 -Keto acid Enol Ketone

Chapter 18 42
Carboxylate anions decarboxylate rapidly because they form a
resonance-stabilized enolate
O
R C O O O
HA
CH2 C R C R C
_ -CO2 _
O CH2 CH3
Acylacetate ion

_
O
R C
CH2
Resonance-stabilized
anion

Malonic acids also decarboxylate readily

O R O R O
- o
100 150 C
HOC C COH H C COH + CO2
R R
A malonic acid

Chapter 18 43