Derivatives of Carboxylic Acid

:O:
C

: O:
R C

.. _ O: ..

.. Cl : ..

carboxylate

acid chloride

: O:
R C

.. OH ..

C
nitrile

N:

:O:
R C

.. O ..

: O:
C R

:O:
R C

:O:

acid anhydride

.. O ..

..
N

H H
1

ester

amide

Nomenclature of Acid Halides

IUPAC: alkanoic acid alkanoyl halide Common: alkanic acid alkanyl halide
NH2 CH2 CH2 O C Cl NO2 H3C CH CH2 CH2 O C Cl

: O:
R C

Cl : ..

..

I: 3-aminopropanoyl chloride c: b-aminopropionyl chloride

I: 4-nitropentanoyl chloride c: g-nitrovaleryl chloride

O Cl C CH2
4

O C Cl

I: hexanedioyl chloride

c: adipoyl chloride

Rings: (IUPAC only): ringcarbonyl halide

C Cl O
I: 3-cylcopentenecarbonyl chloride

O C Br
I: benzenecarbonyl bromide c: benzoyl bromide
2

Nomenclature of Acid Anhydrides

:O:
R C

.. O ..

: O:
C R

Acid anhydrides are prepared by dehydrating carboxylic acids

O CH3 C OH + O H O C CH3 - H2O CH3 O O

C O C CH3

acetic acid

ethanoic acid
O O

acetic anhydride ethanoic anhydride

O C OH - H2O O C O C O

O HO C

C O C

I: benzenecarboxylic anhydride c: benzoic andhydride

I: butanedioic acid c: succinic acid

I: butanedioic anhydride c: succinic anhydride

Some unsymmetrical anhydrides

I: cis-butenedioic anhydride c: maleic anhydride
O C O C O
O O
CH3 O C O O C H

C O C H

I: benzoic methanoic anhydride c: benzoic formic anhydride

I: ethanoic methanoic anhydride c: acetic formic anhydride

3

Nomenclature of Esters
Esters occur when carboxylic acids react with alcohols
alkyl I: alkanoate c: alkanate O
O O C H
: O:
R C

.. OH ..

.. O ..
alcohol

H2O H+ R

:O:
C ester

..
O .. R

carboxylic acid

O C O C(CH3)3

CH3 O C CH3

I: methyl ethanoate c: methyl acetate

O C O CH(CH3)2

I: phenyl methanoate c: phenyl formate

I: t-butyl benzenecarboxylate c: t-butyl benzoate

O O C CH(CH3)2

O O CH3 O C C O CH3

I: isobutyl cyclobutanecarboxylate c: none I: cyclobutyl 2-methylpropanoate c: cyclobutyl a-methylpropionate

I: dimethyl ethanedioate c: dimethyl oxalate

Nomenclature of Cyclic Esters, Lactones

O C CH2 CH2 OH H O CH2 - H2O H+ CH2 CH2 O C O CH2

O C O

Cyclic esters, lactones, form when an open chain hydroxyacid reacts intramolecularly. 5 to 7membered rings are most stable.

I: 4-hydroxybutanoic acid c: g-hydroxybutyric acid

I: 4-hydroxybutanoic acid lactone c: g-butyrolactone

lactone is added to the end of the IUPAC acid name. olactone replaces the ic acid of the common name and hydroxy is dropped but its locant must be included. O I: 5-hydroxypentanoic acid lactone O O c: d-valerolactone I: 4-hydroxypentanoic acid lactone O c: g-valerolactone
CH3
O O H3C

I: 3-hydroxypentanoic acid lactone c: b-valerolactone

O

I: 6-hydroxy-3-methylhexanoic acid lactone c: b-methyl-e-caprolactone

Nomenclature of Amides
1 amide
O R C N H H H 2 amide R C N R N-substituted amide O O 3 amide R R C N N,N-disubstituted amide R

1 amides: alkanoic acid + amide alkanamide a ring is named ringcarboxamide

O CH3CH2CH2 C N H H
Cl O C N

O
H H

NO2

C N

H H

I: butanamide c: butyramide

I: 3-chlorocyclopentanecarboxamide c: none

I: p-nitrobenzenecarboxamide c: p-nitrobenzamide

2 and 3 amides are N-substituted amides I: N,2-dimethylpropanamide c: N,a-dimethylpropionamide

O

I: N-phenylethanamide c: N-phenylacetamide c: acetanilide

C N CH3 CH2CH3

CH3 O CH3CH C N

CH3 H

O H3C C N H

I: N-ethyl-N-methylcyclobutanecarboxamide c: none

Nomenclature of Cyclic Amides, Lactams

O C CH2 CH2 OH H N CH2 H

O C CH2 - H2O CH2 NH CH2

O NH

Cyclic amides, lactams, form when an open chain aminoacid reacts intramolecularly. 5 to 7membered rings are most stable.

I: 4-aminobutanoic acid c: g-aminobutyric acid

I: 4-aminobutanoic acid lactam c: g-butyrolactam

lactam is added to the end of the IUPAC acid name. olactam replaces the ic acid of the common name and amino is dropped but its locant must be included.
O NH CH3
O NH H3C
NH

I: 3-amino-2-bromopropanoic acid lactam c: a-bromo-b-propionolactam

Br O

I: 5-aminohexanoic acid lactam c: d-caprolactam

I: 4-amino-3-methylbutanoic acid lactam c: b-methyl-g-butyrolactam

7

Nomenclature of Nitriles
O R C N H H POCl3 R C N - H2O

Nitriles are produced when 1 amides are dehydrated with reagents like POCl3

IUPAC: alkane + nitrile alkanenitrile IUPAC rings: ringcarbonitrile Common: alkanic acid + onitrile alkanonitrile
CH3 C N N C CH2CH2CH2 I
HS CN

I: ethanenitrile c: acetonitrile

I: 4-iodobutanenitrile c: g-iodobutyronitrile

I: p-thiobenzenecarbonitrile c: p-mercaptobenzonitrile

CH3O

CN

COOH CN

I: 3-methoxycyclohexanecarbonitrile c: none

I: 2-cyanocyclopentanecarboxylic acid c: none

Nomenclature Practice Exercise

CN

O CH3 C O CH2Br

O CH3 C O- Na+

I: cyclobutanecarbonitrile c: none

I: bromomethyl ethanoate c: bromomethyl acetate

I: sodium ethanoate c: sodium acetate

I: 3-bromo-N-methylpentanamide c: b-bromo-N-methylvaleramide
NHCH3 Br O

CH3 C CH2 C Cl

I: pentanedioic anhydride c: glutaric anhydride

O O

I: 3-oxobutanoyl chloride c: b-oxobutyryl chloride

O

NH Cl

I: 2-ethyl-5-hydroxypentanoic acid lactone c: a-ethyl-d-valerolactone

I: 6-amino-6-chlorohexanoic acid lactam c: e-chloro-e-caprolactam

9

Relative Reactivity of Carbonyl Carbons

Nucleophiles (electron donors), like OH-, bond with the sp2 hybridized carbonyl carbon. The order of reactivity is shown.

:O:
R C

.. O ..

: O:
C R

acid chloride acid anhydride

: O:
R C

.. Cl : ..

most
reactive

: O:
R C R

aldehyde
R

: O:
C H

ketone ester carboxylic acid amide

R
R

:O:
C

: O:
R C

.. OH ..

.. O ..

:O:
C

..
N

H H

C N:

nitrile carboxylate
R

:O:
C

least

.. _ O: ..

reactive
10

Nucleophilic Addition to Aldehydes and Ketones

Recall that electron donors (Nu: -s) add to the electrophilic carbonyl C in aldehydes and ketones. The C=O p bond breaks and the pair of electrons are stabilized on the electronegative O atom. R (alkyl groups) and hydrogens (H) bonded to the C=O carbon remain in place. R- and H- are too reactive (pKb of 40 and -21). R and H are not leaving groups, so the carbonyl group becomes an alkoxide as the sp2 C becomes a tetrahedral sp3 C.
O R C H CH3 MgBr
O R C H CH3

tetrahedral alkoxide with sp3 carbon.

A second addition of a nucleophile cannot occur since alkoxides are not nucleophilic. The reaction is usually completed by protonation of the alkoxide with H3O+ forming an alcohol. This later reaction is simply an acid/base reaction. The characteristic reaction of aldehydes and ketones is thus nucleophilic addition.
O H + H O+H
O H R C H CH3

R C H CH3

O H

11

Nucleophilic Acyl Substitution in Acid Derivatives

Carboxylic acid derivatives commonly undergo nucleophilic substitution at the carbonyl carbon rather than addition. The first step of the mechanism is the same. The C=O p bond breaks and the pair of electrons are stabilized on the electronegative O atom. A tetrahedral alkoxide is temporarily formed.
O R C Cl CH3 MgBr

O R C CH3 +

R C Cl CH3

Cl

Chlorine is a fair leaving group.

sp2 carbonyl reforms

sp2 carbonyl C

alkoxide C js sp3

In carboxylic acid derivates, one of the groups that was bonded to the carbonyl C is a leaving group. When this group leaves, the sp3 tetrahedral alkoxide reverts back to an sp2 C=O group. Thus substitution occurs instead of addition. In many cases, the substitution product contains a carbonyl that can react again.
O

H H O+H

O H R C CH3 + H O H CH3

R C CH3 R C CH3 CH3 MgBr CH3

Note that because the C=O group reforms, the nucleophile can react a second time.

12

Nucleophilic Acyl Substitution in Acid Derivatives

In carboxylic acid derivatives, the acyl group (RCO) is bonded to a leaving group (-Y).
O R C

O R C Y Nu:-

O Nu

O R C Nu +
Y:-

R C Y

acyl group

Draw the mechanism.

The leaving group (-Y) becomes a base (Y:-) . The acid derivative is reactive If the base formed is weak (unreactive). Weak bases are formed from good leaving groups. For the carboxylic acid derivatives shown, circle the leaving group. Then draw the structure of the base formed, give its pKb, and describe it as a strong or weak base.
acid derivative
O R C Cl O O R C O C R O R C O R O -

leaving group
Cl
O O C R

pKb

strength as base

+21
+9 -2 -21

non basic weak base strong base v. strong base

13

O R
NH2

R C NH2

Nucleophilic Acyl Substitution in Acid Derivatives

We will study the reaction of only a few nucleophiles with various carboxylic acid derivatives and we will see that the same kinds of reactions occur repeatedly.

Hydrolysis: Reaction with water to produce a carboxylic acid Alcoholysis: Reaction with an alcohol to produce an ester Aminolysis: Reaction with ammonia or an amine to produce an amide Grignard Reaction: Reaction with an organometallic to produce a ketone or alcohol Reduction: Reaction with a hydride reducing agent to produce an aldehyde or alcohol

Draw the structures of the expected products of these nucleophilic substitution reactions, then circle the group that has replaced the leaving group (-Y)
O R C Y + O R C Y + O R C Y + O R C Y + O R C Y +
H OH H OR

hydrolysis alcoholysis aminolysis Grignard reduction hydride reduction

O R C O H O R C O R

H NH2
R MgX

O R C NH2
O H R C R R O H R C H H

LiAlH3 H

14

Nucleophilic Acyl Substitution of Carboxylic Acids

O R C O H O R C Y

Nucleophilic acyl substitution converts carboxylic acids into carboxylic acid derivatives, i.e., acid chlorides, anhydrides, esters and amides.

: O:
R C

.. Cl : ..
.. O ..
: O:
C

SOCl2

: O:
R C

.. OH ..

NH3,, -H2O

:O:
R C
amide

..
N

H H

acid chloride

:O:
R C

-H2O
R

ROH H+

:O:
R C

.. O ..

acid anhydride

ester

15

Conversion of Carboxylic Acids to Acid Halides

The S atom in SOCl2 is a very strong electrophile. S is electron deficient because it is bonded to 3 electronegative atoms (Cl and O). Cl is a leaving group. The hydroxyl O atom in a carboxylic acid has non bonded pairs of electrons, making it a nucleophile. This O atom bonds with S (replacing a Cl) and forming a chlorosulfite intermediate. The chlorosulfite group is a very good leaving group. It is easily displaced by a Cl- ion via an SN2 mechanism yielding an acid chloride. Use curved arrows to draw the initial steps of the mechanism shown below.
1
:O: R C .. OH ..

1
+ Cl

:O : S Cl

2
R - HCl

:O : C

.. O ..

:O : S Cl H
+

:O: R C Cl + SO2 + HCl

2 thionyl chloride

chlorosulfite intermediate

H3C

PBr3 will substitute Br for OH converting a carboxylic acid to an acid bromide Draw and name the products of the following reactions.
O C OH SOCl2 HCl + SO2 + H3C O C Cl
I: p-methylbenzenecarbonyl chloride

c: p-methylbenzoyl chloride I: ethanoyl chloride c: acetyl chloride

O H3C C O H

SOCl2 HCl

O + SO2 + H3C C Cl

16

Conversion of Carboxylic Acids to Acid Anhydrides

High temperature dehydration of carboxylic acids results in two molecules of the acid combining and eliminating one molecule of water.
O CH3 C OH + O H O C CH3 - H2O CH3 O O C O C CH3
acetic anhydride ethanoic anhydride

acetic acid
ethanoic acid

Cyclic anhydrides with 5 or 6-membered rings are prepared by dehydration of diacids.

O C
2HC 2HC

OH OH C O

- H2O

2HC 2HC

C O C O

I: butanedioic acid c: succinic acid

I: butanedioic anhydride c: succinic anhydride

Draw a reaction showing the preparation of cyclohexanecarboxylic anhydride.

O O
2 - H2O O C O H

C O C

17

Conversion of Carboxylic Acids to Esters

Two methods are used: SN2 reaction of a carboxylate and Fischer Esterification 1. SN2 reaction of a carboxylate with a methyl halide or 1 alkyl halide is straightforward. 2 and 3 alkyl halides are not used because carboxylate is only a fair nucleophile and is basic enough (pKb = 9) that elimination of HX from the alkyl halide will compete with substitution. The carboxylate will be protonated and the alkyl halide eliminates HX becoming an alkene.
: O:
CH3CH2 C

.. O ..

Na OH H _ H2O

: O:
CH3CH2 C

.. O: ..

_ Na+

CH3

I CH3CH2

: O:
C

O ..

..

CH3

+ NaI

propanoic acid

SN2

acid/base

: O:
CH3CH2 C

.. O: ..

_ Na+ + H3C

CH3 C CH3 I

E2

O CH3CH2C OH

+ +

NaI CH3 CH2 C CH3 isobutylene

sodium propionoate
O O H CH2Br NaOH

O Na+ O CH2 Br

O O - NaBr CH2

O O

- H2O I: 5-bromopentanoic acid c: d-bromovaleric acid

I: sodium 5-bromopentanoate c: sodium d-bromovalerate

I: 5-hydroxypentanoic acid lactone c: d-valerolactone 18

Conversion of Carboxylic Acids to Esters

alkyl halide (substrate) Me 1 2 3 good Nu nonbasic
e.g., bromide
-

good Nu strong base

e.g., ethoxide

good Nu

strong bulky base e.g., t-butoxide

very poor Nu nonbasic CH3COOH

Br

C2H5O

(CH3)3CO

e.g., acetic acid

SN2

SN2 SN2 E2 E2
v. gd. .. Numoderate base ..

SN2

no reaction

SN2
SN2 SN1
v. gd. .. Numoderate . .base

E2 (SN2)
E2 E2
-

no reaction
SN1, E1 SN1, E1
HI HBr HCl

alkyl halide (substrate)

fair .. Nu weak .. base

e.g., cyanide

CN

e.g., alkyl sulfide

e.g., carboxylate

RS , also HS

4.7 pkb =
Me 1 2 3

6.0 / 7.0 pkb = SN2 SN2 SN2 E2

RCOO 9 pkb =

alcohol (substrate)

SN2 SN2 SN2 E2

SN2 SN2

Me 1 2 3

SN2 SN2

E2
E2

SN1
SN1 19

Conversion of Carboxylic Acids to Esters

2. Fischer Esterification: (RCOOH RCOOR) Esters are produced from carboxylic acids by nucleophilic acyl substitution by a methyl or 1 alcohol. Heating the acid and alcohol in the presence of a small quantity of acid catalyst (H2SO4 or HCl (g)) causes ester formation (esterification) along with dehydration. The equilibrium constant is not large (Keq ~ 1) but high yields can be obtained by adding a large excess of one of the reactants and removing the H2O formed. The reaction is reversible. A large excess of H2O favors the reverse reaction. Bulky (sterically hindered) reagents reduce yields.

Since alcohols are weak nucleophiles, acid catalyst is used to protonate the carbonyl oxygen which makes the carbonyl C a better electrophile for nucleophilic attack by ROH. Proton transfer from the alcohol to the hydroxyl creates a better leaving group (HOH). Learn the mechanism since it is common to other reactions.
H HSO4
+ -

: O:
R

..
OH

H : O+ R C

: O:

..

.. OH ..
R' '

C +

.. OH ..

: O:
R C + R' .. O

..
OH .. H

: O:
R R' C O .. :

HSO4

: O:
R

..
+OH H

.. OH ..

proton transfer

C OR' .. + H2O + H2 SO4

..

The net effect of Fischer esterification is substitution of the OH group of a carboxylic acid with the OR group of a methyl or 1 alcohol.

20

Conversion of Carboxylic Acids to Esters

Draw and name the products of the following reactions.
O O HO CCH2C OH 2 CH3CH2 OH H+
O O CH3CH2O CCH2C OCH2CH3 I: diethyl propanedioate c: diethyl malonate

I: propanedioic acid c: malonic acid

O C OH 2. CH2Br 1. NaOH

O C OCH2

cyclopentylmethyl benzoate

Draw the reagents that will react to produce the following ester.
O H3C CH3 HC C OCH H3C CH3

H+

CH3 HOCH CH3

O H3C HC C OH H3C

Why will an SN2 reaction of a carboxylate and an alkyl halide not work here? Isopropyl bromide is a 2 alkyl halide and would undergo an E2 rather than SN2 reaction.

I: isopropyl 2-methylpropanoate c: isopropyl isobutyrate

Draw the complete mechanism for Fischer esterification of benzoic acid with methanol.
21

Conversion of Carboxylic Acids to Amides

Amides are difficult to prepare by direct reaction of carboxylic acids with amines (RNH2) because amines are bases that convert carboxylic acids to non electrophilic carboxylate anions and themselves are protonated to non nucleophilic amine cations, (RNH3+)
: O:
CH3 C

.. O ..

..
H + CH3NH2

: O:
H3C C

.. O: ..

+ NH3CH3

: O:
H2O CH3 C

..
NH2

High temperatures are required to dehydrate these quaternary amine salts and form amides. This is a useful industrial method but poor laboratory method. In the lab amides are often prepared from acid chloride after converting the carboxylic acid to the acid chloride. Explain why methylamine is a Bronsted base. Explain why methylamine is a Lewis base. Explain why methylamine is not an Arrhenius base Proton (H+) acceptor Electron pair donor Has no OH- group

22

Synthesis Problems Involving Carboxylic Acids

Write equations showing how the following transformations can be carried out. Form a carboxylic acid at some point in each question.
? H3C CH3 O HO C Cl O C OH O C O C Cl

KMnO4

SOCl2
MgBr
Mg ether

1. CO2 2. H3O+

O C OH - H2O

Br
? O C O CH3 C O CH3 O O C OH C OH O
2 CH3OH H+
NaCN

C O C
- H2O

CN

H2O H+

C OH

KMnO4

23

Chemistry of Acid Halides

In the same way that acid chlorides are produced by reacting a carboxylic acid with thionyl chloride (SOCl2), acid bromides are produced by reacting a carboxylic acid with phosphorus tribromide (PBr3).
: O:
R C

..
OH

(or PCl3) + SOCl2 R

O C O Cl + SO2 + HCl

: O:
R C

..
OH

PBr3

Br

PBr2OH

Reactions of Acid Halides:

Acid halides are among the most reactive of the carboxylic acid derivatives and are readily converted to other compounds. Recall that acid chlorides add to aromatic rings via electrophilic aromatic substitution (EAS) reactions called Friedel-Crafts Acylation with the aid of Friedel-Crafts catalysts.
O R C R Cl ...... AlCl3 + .. O C .. R + O C .. + AlCl4-

acyl cation = acylium ion

O

O R Cl
-

+ C O

C H +

R +

HCl

24

Chemistry of Acid Halides

Draw a reaction showing how propylbenzene can be produced by a Friedel Crafts acylation reaction. O O
Cl CCH2CH3 AlCl3
CCH2CH3 H2/Pt
CH2CH2CH3

I: 1-phenyl-1-propanone c: ethyl phenyl ketone

Most acid halide reactions occur by a nucleophilic acyl substitution mechanism. The halogen can be replaced by -OH to produce an acid, -OR to produce an ester, -NH2 to produce an amide. Hydride reduction produces a 1 alcohol, and Grignard reaction produces a 3 alcohol.
: O:
R acid C O R ROH C Cl NH3 R [H] R':- MgBr+ R O C R' ketone R':- MgBr+ H aldehyde RCH2OH 1 alcohol OH R C [H] R'

..
OH

H2O

: O:
R C ester

: O:
C

.. OR ..

: O:
R

..

C NH2 amide

R' 3 alcohol

25

Hydrolysis: Conversion of Acid Halides into Acids

Acid chlorides react via nucleophilic attack by H2O producing carboxylic acids and HCl.
: O:
R C Cl H2O

: O:

..

_ _ Cl + H Cl
-

: O:
R C + H O: H

Cl

: O:
R + C HCl

.. ..

C O

..
OH

..

Tertiary amines, such as pyridine, are sometimes used to scavenge the HCl byproduct and drive the reaction forward. 3 amines will not compete with water as a nucleophile because their reaction with acid halide stops at the intermediate stage (there is no leaving group). Eventually, water will displace the amine from the tetrahedral intermediate, regenerating the 3 amine and forming the carboxylic acid. .. _ .. _ : O:
: O:
C R Cl +

..
R'3N

: O:
C

: O:
C

Cl

+ NR'3

C +O H

+ NR'3 H

R'3N +

.. H2O ..

..

..
R'3N N: pyridine

+ HCl

: O:
R'3NH Cl + +

.. ..
OH R

: O:
C

..
O +

H H

R'3N

Draw the mechanism of the reaction of cyclopentanecarbonyl chloride with water.

26

Alcoholysis: Conversion of Acid Halides into Esters

Acid chlorides react with alcohols producing esters and byproduct HCl by the same mechanism as hydrolysis above. Draw and name the products of the following reaction.
O H3C C Cl + HO CH CH3 CH3 O H3C C O CH CH3 I: isopropyl ethanoate c: isopropyl acetate CH3 + HCl

I: ethanoyl chloride c: acetyl chloride

Draw the mechanism of the reaction of benzoyl chloride and ethanol.

Once again, 3 amines such as pyridine may be used to scavenge the HCl byproduct or for water insoluble acid halides, aqueous NaOH can be used to scavenge HCl since it will not enter the organic layer and attack the electrophile (thus it cannot compete with the alcohol as the nucleophile).

NaOH, H2O

O R C Cl

HCl

CH2Cl2 ROH
27

Practice on Synthesis of Esters

Write equations showing all the ways that benzyl benzoate can be produced. Consider Fischer esterification, SN2 reaction of a carboxylate with an alkyl halide, and alcoholysis of an acid chloride.
O C O CH2
H2SO4 O CH2OH + C OH

O CH2Br + C O-Na+

N CH2OH +

O C Cl

Answer the same question as above but for t-butyl butanoate

O CH3 CH3
N O CH3 CH3

CH3CH2CH2C O C CH3

CH3CH2CH2C Cl + HO C CH3

This is the only method that will work.

Explain why the other methods will fail.

28

Aminolysis: Conversion of Acid Halides into Amides

Acid chlorides react rapidly with ammonia or 1 or 2 but not 3 amines producing amides. Since HCl is formed during the reaction, 2 equivalents of the amine are used. 1 equivalent is used for formation of the amide and a second equivalent to react with the liberated HCl, forming an ammonium chloride salt. Alternately, the second equivalent of amine can be replaced by a 3 amine or an inexpensive base such as NaOH (provided it is not soluble in the organic layer). Using NaOH in an aminolysis reaction is referred to as the Schotten-Baumann reaction.
:O:
C Cl + 2 NH(CH3)2 demethyl amine

..

O C

H +

Cl-

.. NH(CH3)2

O CH3 C N CH3

N CH3 CH3

+ NH2(CH3)2 Cl-

benzoyl chloride

I: N,N-dimethylbenzenecarboxamide c: N,N-dimethylbenzamide

Write equations showing how the following products can be made from an acid chloride. N-methylacetamide
O CH3 C NHCH3
N

O CH3 C Cl + NH2CH3

propanamide

O CH3CH2C NH2

O CH3CH2C Cl + NH3

29

Reduction of Acid Chlorides to Alcohols with Hydride

Acid chlorides are reduced by LiAlH4 to produce 1 alcohols. The alcohols can of course be produced by reduction of the carboxylic acid directly. The mechanism is typical nucleophilic acyl substitution in which a hydride (H:-) attacks the carbonyl C, yielding a tetrahedral intermediate, which expels Cl-. The result is substitution of -Cl by -H to yield an aldehyde, which is then immediately reduced by LiAlH4 in a second step to yield a 1 alcohol.
O R C Cl

Cl
1. LiAlH4

O R C H
LiAlH4

O H

R C H

2. H3O+

O H R C H + H2O H

Draw the reaction and name the product when 2,2-dimethylpropanoyl chloride is reduced with LiAlH4
CH3 O H3C C CH3 C Cl excess 1. LiAlH4 2. H3O
+

CH3 H3C C CH3 CH2OH

I: 2,2-dimethyl-1-propanol c: neopentyl alcohol

30

Reduction of Acid Chlorides to Aldehydes with Hydride

The aldehyde cannot be isolated if LiAlH4 (and NaBH4) are used. Both are too strongly nucleophilic. However, the reaction will stop at the aldehyde if exactly 1 equivalent of a weaker hydride is used, i.e., diisobutylaluminum hydride (DIBAH) at a low temperature (-78C). Under these conditions, even nitro groups are not reduced.
CH3 CH3CHCH2 H Al CH3 CH2CHCH3 CH3 CH3CHCH2 _
H Al H H aluminum hydride

+ Al

CH3 CH2CHCH3

H:

diisobutyl aluminum hydride (DIBAH)

DIBAH is weaker than LiAlH4. DIBAH is neutral; LiAlH4 is ionic. DIBAH is similar to AlH3 but is hindered by its bulky isobutyl groups. Only one mole of H:- is released per mole of DIBAH.
- 78C 1 equiv. 1. DIBAH 2. H3O
+

O NO2 C Cl

O NO2 C H

p-nitrobenzaldehyde
31

Reduction of Acid Chlorides to Alcohols with Grignards

Grignard reagents react with acid chlorides producing 3 alcohols in which 2 alkyl group substituents are the same. The mechanism is the same as with LiAlH4 reduction. The 1st equivalent of Grignard reagent adds to the acid chloride, loss of Cl- from the tetrahedral intermediate yields a ketone, and a 2nd equivalent of Grignard immediately adds to the ketone to produce an alcohol.
O C Cl CH3 MgBr O C CH3 CH3 MgBr

H3O+

O H C CH3 CH3

C CH3 CH3

I: 2-phenyl-2-propanol The ketone intermediate cant be isolated with Grignard reaction but can be with Gilman reagent (diorganocopper), R2CuLi. Only 1 equivalent of Gilman is used at -78C to prevent reaction with the ketone product. Recall the preparation of ketones (Ch. 19). This reagent does not react other carbonyl compounds (although it does replace halogens in alkyl halides near 0C)
1 equiv. O 1. Li(CH3)2Cu H3C - 78C CH C Cl H3C 2. H3O+
H3C H3C O CH C CH3

I: 3-methyl-2-butanone c: isopropyl methyl ketone

32

Practice Questions for Acid Chloride Reductions

Draw the reagents that can be used to prepare the following products from an acid chloride by reduction with hydrides, Grignards and Gilman reagent. Draw all possible combinations. I: ethanoyl chloride excess OH 1. O I: 1,1-dicyclopentylethanol MgBr CH C
3

H3C C Cl 2.
O C CH2CH3

H3O+
2CuLi

CH3CH2 2CuLi 1. 1 equiv. - 78C 2. H3O+

CH3 O H3C C 2. H3O+ CH3

O C Cl
or

1. 2.

O 1 equiv. - 78C CH3CH2 C Cl + H3O

CH3 OH H3C C CH3 CH2

excess 1. LiAlH4

I: 1-phenyl-1-propanone
c: ethyl phenyl ketone I: 2,2-dimethylpropanoyl chloride I: 2,2-dimethyl-1-propanol
O C Cl

C Cl

O C H

1. 2.

DIBAH 1 equiv. - 78C H3O+

I: cyclohexanecarbonyl chloride I: cyclohexanecarbaldehyde

33

Preparations of Acid Anhydrides

:O:
R C

.. O ..

: O:
C R

Preparation of Acid Anhydrides: Dehydration of carboxylic acids as previously discussed is difficult and therefore limited to a few cases. O O O O CH3 C OH + H O C CH3 CH3 C O C CH3 - H2O acetic anhydride acetic acid A more versatile method is by nucleophilic acyl substitution of an acid chloride with a carboxylate anion. Both symmetrical and unsymmetrical anhydrides can be prepared this way.
: O:
H C

: O:
+ O : Na ..

..

ether 25C CH3 SN2

: O:
H C

Cl

.. O ..

: O:
C CH3 + NaCl

sodium formate

acetyl chloride

acetic formic anhydride

Draw all sets of reactants that will produce the anhydride shown with an acid chloride.
O
O O

O Cl C
O + Na+ -O C

CH3 C O- Na+ +
O CH3 C Cl

CH3 C O C

34

Reactions of Acid Anhydrides

:O:
R C

.. O ..

: O:
C R

The chemistry of acid anhydrides is similar to that of acid chlorides except that anhydrides react more slowly. Acid anhydrides react with HOH to form acids, with ROH to form esters, with amines to form amides, with LiAlH4 to form 1 alcohols and with Grignards to form 3 alcohols. Note that of the anhydride is wasted so that acid chlorides are more often used to acylate compounds. Acetic anhydride is one exception in that it is a very common acetylating agent. O
O

: O:
2 R C acid

H2O

..
OH

R [H]

R':- MgBr+ R

O C R' ketone

: O:
R ester + acid C

.. O R' ..
:O:
C R

R'OH

NH3 2 R

: O:
C [H] H aldehyde 2 RCH2OH 1 alcohol

R':- MgBr+ OH R C R'

: O:
R

..

..
HO

C NH2 amide

R' 3 alcohol

Write the mechanism for the following reactions and name all products: aniline with acetic anhydride (2 moles aniline are needed or use 1 mole + aq. NaOH) cyclopentanol with acetic formic anhydride (the formic carbonyl is more reactive). methyl magnesium bromide with acetic propanoic anhydride (Grignards are not nucleophilic enough to react with carboxylate by products) lithium aluminum hydride with acetic formic anhydride (LiAlH4 is so powerful a nucleophile that it will reduce even carboxylates).
35

Practice Questions for Acid Anhydrides

Show the product of methanol reacting with phthalic anhydride
O C O + CH3OH C O C OH O O C OCH3

2-(methoxycarbonyl)benzoic acid

Draw acetominophen; formed when p-hydroxyaniline reacts with acetic anhydride

O HO O

O HO

NH2 + CH3 C O C CH3

N C CH3 + CH3 C OH H

N-(4-hydroxyphenyl)acetamide

36

Chemistry of Esters
Esters are among the most widespread of all naturally occurring compounds. Most have pleasant odors and are responsible for the fragrance of fruits and flowers. Write chemical formulas for the following esters Flavor pineapple bananas apple rum oil of wintergreen nail polish remover Name methyl butanoate isopentyl acetate isopentyl pentanoate isobutyl propanoate methyl salicylate [methyl 2-hydroxybenzoate) ethyl acetate Structure

O CH3CH2CH2C OCH3
O CH3C CH3 OCH2CH2CHCH3

O
O
O C O CH3 OH
O

CH3
CH3

CH3(CH2)3COCH2CH2CHCH3
CH2CH2C OCH2CHCH3

O CH3C OCH2CH3

new car smell (plasticizer for PVC)

dibutyl phthalate

C O (CH2)3CH3 C O (CH2)3CH3 O

37

Preparation of Esters
1. SN2 reaction of a carboxylate anion with a methyl or 1 alkyl halide

: O:
R C

.. _ O: ..

: O:
Na+ + R' Br R SN2 C

.. O R' ..

2. Fischer esterification of a carboxylic acid + alcohol + acid catalyst

: O:
R C

..
OH +

H R' OH

: O:
R C

..
O R' ..

3. Acid chlorides react with alcohols in basic media

: O:
Cl + R' OH R C

O R C

.. O R' ..

HCl

38

Reactions of Esters
Esters react like acid halides and anhydrides but are less reactive toward nucleophiles because the carbonyl C is less electrophilic. Both acyclic esters and cyclic esters (lactones) react similarly. Esters are hydrolyzed by HOH to carboxylic acids, react with amines to amides, are reduced by hydrides to aldehydes, then to 1alcohols, and react with Grignards to 3 alcohols.
: O:
R H2O C

..
O R' .. [H]

R':- MgBr+ R

O C R' ketone

: O:
R C acid

..
OH

NH3

: O:
R C [H] + R'OH 1 alcohols H aldehyde RCH2OH

R':- MgBr+ OH R C R'

: O:
R

..

C NH2 amide

R' 3 alcohol

39

Base Hydrolysis of Esters

Esters are hydrolyzed (broken down by water) to carboxylic acids or carboxylates by heating in acidic or basic media, respectively. Base-promoted ester hydrolysis is called saponification (Latin soap-making). Boiling animal fat (which contains ester groups) in an aqueous solution of a strong base (NaOH, KOH, etc.) makes soap. A soap is long hydrocarbon chain with an ionic end group. I: sodium dodecanoate c: sodium laurate bar soap
O C O- Na+

The mechanism of base hydrolysis is nucleophilic acyl substitution in which OH- adds to the ester carbonyl group producing a tetrahedral intermediate. The carbonyl group reforms as the alkoxide ion leaves, yielding a carboxylate.
O CH3(CH2)10C O CH3 K+OH-

c: potassium laurate
OCH3 O

O CH3(CH2)10C O

liquid soap
-

CH3(CH2)10C O H

K+

CH3OH

The leaving group, methoxide (OCH3-), like all alkoxides, is a strong base (pKb = -2). It will deprotonate the carboxylic acid intermediate converting it to a carboxylate. The alkoxide, when neutralized, becomes an alcohol.
40

Acid Hydrolysis of Esters

Acidic hydrolysis of an ester yields a carboxylic acid (and an alcohol). The mechanism of acidic ester hydrolysis is the reverse of Fischer esterification. The ester is protonated by acid then attacked by the nucleophile HOH. Transfer of a proton and elimination of ROH yields the carboxylic acid. The reaction is not favorable. It requires at least 30 minutes of refluxing. Draw the complete mechanism of acid hydrolysis of methyl cyclopentanecarboxylate.

..
O C OCH3 H2O H+
+

O H C OCH3

O H C OCH3 O H
+

..

O H C OCH3 + H O H

H2O

O C OH + H3O+ + CH3OH

Acid hydrolysis of an ester can be reversed by adding excess alcohol. The reverse reaction is called Fischer Esterification. Explain why base hydrolysis of an ester is not reversible.
41

Alcoholysis of Esters
:O:
R C ester

.. O ..

.. O ..
alcohol

:O:
R' H
+

C ester

.. O ..

R'

.. O ..
alcohol

Nucleophilic acyl substitution of an ester with an alcohol produces a different ester. The mechanism is the same as acid hydrolysis of esters except that that the nucleophile is an alcohol rather than water. A dry acid catalyst must be used, e.g., HCl(g) or H2SO4. If water is present, it will compete with the alcohol as the nucleophile producing some carboxylic acid in place of the ester product. The process is also called Ester Exchange or Transesterification

O O C H2SO4

O C O 2 CH3CH2OH
O O C OCH2CH3 + 2 OH

dicyclobutyl 1,4-benzenedicarboxylate dicyclobutyl terephthalate

diethyl 1,4-benzenedicarboxylate

CH3CH2O C

diethyl terephthalate cyclobutanol

42

Aminolysis of Esters
Amines can react with esters via nucleophilic acyl substitution yielding amides but the reaction is difficult, requiring a long reflux period. Aminolysis of acid chlorides is preferred. Draw the mechanism aminolysis of methyl isobutyroxide with ammonia.
O CH C OCH3 H3C

H3C

OCH3

NH3

H CH C N H + H3C H H3C

H3C

O + CH3OH

CH C N H H3C H

I: 2-methylpropanamide c: a-methylpropionamide

Write an equation showing how the following amide can be prepared from an ester.
O (CH3)2N C O C N(CH3)2 O CH3O C O C OCH3 + 2 NH(CH3)2

Note that the amide intermediate must deprotonate to form a stable, neutral amide. Thus the amine must have at least one H. NH3, 1 and 2 amines will work but not 3.

43

Hydride Reduction of Esters

Esters are easily reduced with LiAlH4 to yield 1 alcohols. The mechanism is similar to that of acid chloride reduction. A hydride ion first adds to the carbonyl carbon temporarily forming a tetrahedral alkoxide intermediate. Loss of the OR group reforms the carbonyl creating an aldehyde and an OR - ion. Further addition of H: - to aldehyde gives the 1 alcohol. Draw the mechanism and show all products.
O R C O R' LiAlH4

O R C H

LiAlH4

O H

H3O+

O H R C H H + R'OH

R C H

OR'

Draw and name the products. O I: 4-hydroxybutanoic acid lactone c: g-butyrolactone

O

excess 1. LiAlH4 2. H3O+

CH2OH OH

I: 1,4-butanediol c: none

The hydride intermediate can be isolated if DIBAH is used as a reducing agent instead of LiAlH4. 1 equivalent of DIBAH is used at very low temp. (-78 C).
O O O 1. DIBAH 1 equiv. - 78C H3O+

I: 4-hydroxypentanoic acid lactone

c: g-valerolactone

I: 4-hydroxypentanal H c: g-hydroxyvaleraldehyde
OH CH3

CH3 2.

44

Grignard Reduction of Esters

Esters and lactones react with 2 equivalents of Grignard reagent to yield 3 alcohols in which the 2 substituents are identical. The reaction occurs by the usual nucleophilic substitution mechanism to give an intermediate ketone, which reacts further with the Grignard to yield a 3 alcohol.
O C OCH3
-

MgBr

O C

MgBr

triphenylmethoxide O
C

methyl benzoate

OCH3

H O C

H3O+

benzophenone

+ CH3OH

triphenylmethanol
O

O
CH3 MgBr CH3 O
-

O O

CH3 CH3 O
-

OH H3O+

CH3 MgBr

CH3

CH3 OH

I: 4-hydroxybutanoic acid lactone c: g-butyrolactone

4-methyl-1,4-pentanediol 45

Practice with Esters

What ester and Grignards will combine to produce the following

2-phenyl-2-propanol
CH3 C OH CH3
C O + OR 1. 2 CH3MgBr 2. H3O+

1,1-diphenylethanol
OH C CH3
O RO C CH3 + 1. 2 CH3MgBr 2. H3O+

46

Chemistry of Amides
Amides are usually prepared by reaction of an acid chloride with an amine. Ammonia, monosubstituted and disubstituted amines (but not trisubstituted amines) all react.
..
O R C NH2 O R C NHR R NH3 R O C Cl NHR2 2 amine O C NR2 3 amide NR3 3 amine no reaction

1 amide

NH2R 1 amine

2 amide

Amides are much less reactive than acid chlorides, acid anhydrides, or esters. Amides undergo hydrolysis to yield a carboxylic acids plus an amine on heating in either aqueous acid or aqueous base. Basic hydrolysis occurs by nucleophilic addition of OH- to the amide carbonyl, followed by elimination of the amide ion, NH2-,(a very reactive base a difficult step requiring reflux)
O C NH2 aq Na+ OH- - NH2 O C O H
O C O -

Na+

+ NH3

I: sodium cyclohexanecarboxamide 47

Hydrolysis of Amides
Acidic hydrolysis occurs by nucleophilic addition of HOH to the protonated amide, followed by loss of a neutral amine (after a proton transfer to nitrogen).
O C N H
H2O

CH3

H3O+

O H CH 3 C N + H
H
+

O H CH 3 C N + H O H
H3O+

O H CH 3 + C N H O H H
O NH2CH3 +

H2O

N-methylcyclohexanecarboxamide
NH3CH3

C O H

cyclohexanecarboxylic acid
O ONH2

NaOH H2O

O NH H3O+

O OH NH3
+

5-aminopentanoic acid lactam d-valerolactam

48

Alcoholysis of Amides (to Esters)

Alcoholysis of amides occurs by the same acid catalyzed mechanism as acid hydrolysis except that the amido group of the amide is replaced with by an alcohol rather than water. Dry acid, e.g., HCl(g) or H2SO4 must be used otherwise water would compete with the alcohol as the nucleophile producing some carboxylic acid product in place of an ester.

The reaction will require a long reflux period because amides are weak electrophiles and alcohols are weak nucleophiles.
O C N(CH3)2 OH CH3CHCH2CH3 H2SO4

O C O CH3CHCH2CH3 + NH2(CH3)2
+

N,N-dimethylcyclopentanecarboxamide

sec-butyl cyclopentanecarboxylate

Write a mechanism for this reaction. Refer to acid hydrolysis mechanism if necessary.

49

Hydride Reduction of Amides

Amides are reduced by LiAlH4. The product is an amine rather than an alcohol. The amide carbonyl group is converted to a methylene group (-C=O -CH2). This is unusual. It occurs only with amides and nitriles. Initial hydride attack on the amide carbonyl eliminates the oxygen. A second hydride ion is added to yield the amine. The reaction works with lactams as well as acyclic amides. H - H
Al
O C N CH3 CH3 Li
+

AlH3 O C N CH3 H CH3

H O C N CH3 H CH3
H AlH2O+ C N CH3 H CH3

H AlH3

N,N-dimethylcyclopentanecarboxamide
O C Cl ? O C NHCH3

Write equations showing how the above transformation can be carried out.
O C Cl

NH2CH3
N

O C NHCH3

1. LiAlH4 2. H3O
+

H C NHCH3 H

benzoyl chloride

N-methylbenzamide 50

Grignard Reduction of Amides

Grignards deprotonate 1 and 2 amides and are not reactive enough to add to the imide ion product. N-H protons are acidic enough (pKa = 17) to be abstracted by Grignards.
: O:
R C

..
N

H R

:CH3 MgBr R _ CH 4

.. _ : O:
C

..
N

R :CH3 +MgBr

2 amide

imide anion

Write equations showing how the following transformation can be carried out.
Mg, ether

Br

? CH2 N(CH3)2
SOCl2

1. LiAlH4
O

2. H3O+

1. CO2
MgBr

O C OH

O C Cl

NH(CH3)2

C N(CH3)2

2. H3O+
O H C N CH2CH3
H2O H or OH
+ -

CH2OH

1. LiAlH4
O C OH

2. H3O+

51

Chemistry of Nitriles

d C

dN:

The carbon atom in the nitrile group is electrophilic because it is bonded to an electronegative N atom and a p bond in the nitrile is easily broken, i.e., as if it were providing a leaving group.

Preparation of Nitrile:
1. Nitriles are easily prepared by SN2 reaction of cyanide ion (CN-) with methyl halides or a 1 alkyl halide. 2 alkyl halides also work but some E2 product also forms. 3 alkyl halides will result in mostly an alkene (E2) product instead of a nitrile. (pKb of CN - = 4.7)
bromoethane ethyl bromide
CH3CH2 Br SN2 Na+ CN-

CH3CH2 C N

propanenitrile

2. Another method of preparing nitriles is by dehydration of a 1 amide using any suitable dehydrating agent such as SOCl2, POCl3, P2O5, or acetic anhydride. Initially, SOCl2 reacts with the amide oxygen atom and elimination follows. This method is not limited by steric hindrance. O
C NH2 SOCl2 , benzene 80C
R Cl POCl3 in pyridine _ H2O

SO2

2 HCl

SOCl2 Recall: R OH PBr3

OH R Br

52

Reactions of Nitriles

d C

dN:

Like carbonyl groups, the nitrile group is strongly polarized and the nitrile C is electrophilic. Nucleophiles thus attack yielding an sp2 hybridized imine anion.
: O: : O: sp 2 C C
E
+

..

products

Nu:-

Nu

sp 3
d+ C dN: Nu:-

..
R C Nu

_ products

R sp

N:

sp 2 imine anion

Nitriles are hydrolyzed by HOH to amides and subsequently to carboxylic acids, reduced by hydrides to amines or aldehydes, and by Grignards to ketones.
H2O O R C NH2 _HO 2 POCl3 R CH2 1 amine NH2 R [H] O C H R C N: RMgX R [H] O C ketone R

1 amide

aldehyde

53

Hydrolysis of Nitriles into Carboxylic Acids

d C

dN:

Nitriles are hydrolyzed in either acidic or basic aqueous solution to yield carboxylic acids plus ammonia or an amine.
H2O R C N H or OH
+ -

O R C O H + NH3

In acid media, protonation of N produces a cation that reacts with water to give an imidic acid (an enol of an amide). Keto-enol isomerization of the imidic acid gives an amide. The amide is then hydrolyzed to a carboxylic acid and ammonium ion. It is possible to stop the reaction at the amide stage by using only 1 mole of HOH per mole of nitrile. Excess HOH forces carboxylic acid formation.
H3O+ R C N: R C + N

..
H R C + N H R C +O H

..
N H H

:O ..
H

..

H2O

.. ..

: O:
R

..

H3O+ R

: O:
C amide

..
NH2

..
R C N H

C OH acid

: O:
hydroxyimine H

54

Hydrolysis of Nitriles into Carboxylate Salts

d C

dN:

In basic media, hydrolysis of a nitrile to a carboxylic acid is driven to completion by the reaction of the carboxylic acid with base. The mechanism involves nucleophilic attack by hydroxide ion on the electrophilic C producing a hydroxy imine, which rapidly isomerizes to an amide. Further hydrolysis yields the carboxylate salt.
H OH R C N:
-

:O .. .. _ N:
H _ OH-

: O:
R C

: O:

..
R

: O:
C amide

H N R C hydroxy imine

..
NH2

: O:
NH3 + R C

.. _ + O : Na ..

OHH2O

Show how the following transformation can be carried out without using a Grignard.
Br
Na+CNSN2
CN

O C OH

H3O+
H3O+ O C NH2
55

Reduction of Nitriles

d C

dN:

Alcoholysis of Nitriles doesnt work. Alcohols are weak nucleophiles and nitriles are weak electrophiles Aminolysis of Nitriles doesnt work. Amines are weak nucleophiles and nitriles are weak electrophiles. Reduction with Hydrides: Reduction of nitriles with 2 equivalents of LiAlH4 gives 1 amines. LiAlH4 is a very good nucleophile and can break 2 p bonds forming a dianion.
H 1. H:R C N: R C H

.. _ N:

R H:
-

C H dianion

.. _ 2 N: ..

H 2. H2O R H2O C H + 2 OH-

..
NH2

If less powerful DIBAH is used, only 1 equivalent of hydride can add. Subsequent addition of HOH yields the aldehyde.
1. LiAlH4 C N 2. CH3 o-methylbenzonitrile H2O

CH2NH2 CH3

1 equiv. 1. DIBAH , toluene , -78C 2. H2O or H3O+

O C H

2-methylbenzaldehyde
CH3

56

Reduction of Nitriles with Grignards

d C

dN:

Grignards add to nitriles giving intermediate imine anions which when hydrolyzed yield ketones. The mechanism is similar to hydride reduction except that the attacking nucleophile is a carbanion (R-). Grignards are not as strongly nucleophilic as LiAlH4 and so can only add once a dianion is not formed.
1. R C N: R:- MgBr+ R R C

.. _ N:

2.

H3O+ R

..
C N H

.. R H C +O H N .. H H

imine anion

NH4 + H3O +
NH3 + R

:O ..
R H

..

: O:
C R R

..
C N H H H

: O:

1. CH3CH3 MgBr 2. H3O

+

O C CH2CH3

1-phenyl-1-propanone ethyl phenyl ketone

benzonitrile

57

Multistep Synthesis Problems

Write equations to show how the following transformations can be carried out.
Br ? CH2NH2

Na+ CN-

CN

1. LiAlH4 2. H3O+
O
DIBAH 1 equiv. - 78C H3O+ from above

Br

C H

1. 2.

CN

O Br ? C

1. 2.

MgBr ether H3O+

CN

O H2O H+ C OH

from above

2 equiv.
Br HO ? C

SOCl2 O C Cl

1. 2.

MgBr ether H3O+

58