Industrial Organic Chemistry

Chapter 20.

Carboxylic Acids and Nitriles

Instructor: Prof. Junhwan Choi

 Introduction
• Carboxylic acids, RCO2H, occupy a central place among carbonyl compounds.
• They are valuable in themselves, and they also serve as starting materials for
preparing numerous carboxylic acid derivatives such as acid chlorides, esters,
amides, and thioesters.
 20-1. Naming Carboxylic Acids and Nitriles
Carboxylic Acids, RCO2H
• Simple carboxylic acids are named by replacing the terminal –e with –oic acid.
• 2

• 2H group bonded to a ring are named using the

suffix –carboxylic acid 2H group is carboxyl group.
 20-1. Naming Carboxylic Acids and Nitriles
• Several common names exist for carboxylic acids such as formic (methanoic)
acid and acetic (ethanoic) acid.
• The names of acyl groups is derived from the parent acids.
 20-1. Naming Carboxylic Acids and Nitriles

• nitriles and can

undergo some chemistry similar to that of carboxylic acids.
• Simple nitriles are named by adding –nitrile

•
–onitrile or –carbonitrile.
• cyano– is used.
 20-2. Structure and Properties of Carboxylic Acids
•
• sp2-hybridized and carboxylic acid groups are planar with
approximately 120°.

• hydrogen-bonding.
• Most carboxylic acids exist as cyclic dimers held together by two hydrogen
bonding.
• This strong hydrogen-bonding has a noticeable effect on boiling points (acetic
° °
 20-2. Structure and Properties of Carboxylic Acids
• acidic ) to give

2 M+.

• H3O+ and the carboxylate anions,

RCO2 . The extent of dissociation is given by an acidity constant, Ka.
 20-2. Structure and Properties of Carboxylic Acids
• For most carboxylic acids, Ka -4 -5.

•
stronger acids than alcohols
and phenols.
 20-2. Structure and Properties of Carboxylic Acids
• Why are carboxylic acids so much more acidic than alcohols?

• Alcohol: dissociates to give an alkoxide ion, in which the negative charge is

localized on a single electronegative atom.
 20-2. Structure and Properties of Carboxylic Acids
• Carboxylic acid: gives a carboxylate ion, in which the negative charge is
delocalized over two equivalent oxygen atoms (resonance-stabilization).

• From X-ray crystallographic studies, it is

equivalent).
20-3. Biological Acids and the Henderson-Hasselbalch Eq.
• In acidic solution (at low pH), a carboxylic acid is completely undissociated

2H.

• In basic solution (at high pH), a carboxylic acid is completely dissociated and

2 .

• If the pKa
percentages of dissociated and undissociated forms can be calculated using the
Henderson-Hasselbalch equation.
20-3. Biological Acids and the Henderson-Hasselbalch Eq.
• In what form do carboxylic acids exist inside cells?
• pKa

• Solving the equations gives [A × - M.

•

• Inside cells, carboxylic acids are almost entirely dissociated.

 20-4. Substituent Effects on Acidity
• The dissociation of a carboxylic acid is an equilibrium process: any factor that
stabilizes the carboxylate anion will drive the equilibrium toward increased
dissociation (increased acidity).
• For example, three electron-withdrawing fluorine atoms delocalize the
negative charge in the trifluoroacetate anion, stabilizing the ion and increasing
the acidity of CF3CO2H.

• 2 2H, pKa
acid because of electronegative oxygen atom.
 20-4. Substituent Effects on Acidity
• Because inductive effects operate through bonds and are dependent on
distance, the effect of halogen substitution decreases as the substituent moves
farther from the carboxyl group.

• Recall: aromatic rings with electron-donating groups are activated toward further
electrophilic substitution, and aromatic rings with electron-withdrawing groups
 20-4. Substituent Effects on Acidity
• An electron-donating (activating) group decreases acidity by destabilizing
the carboxylate anion.
• An electron-withdrawing (deactivating) group increases acidity by
stabilizing the carboxylate anion.
 20-4. Substituent Effects on Acidity

• It is much easier to measure the acidity than it is to determine the relative

reactivity toward electrophilic substitution.
• electrophilic reactivity,
we can simply find the acidity of the corresponding benzoic acid.
 20-4. Substituent Effects on Acidity
• The pKa of p-
substituent an activating or deactivating group in electrophilic aromatic
substitution?

• The pKa
• If the pKa of the aromatic carboxylic acid is lower (higher) than that of benzoic
acid, which means it is more (less) acidic, the substituent is deactivating
(activating) group.
 20-4. Substituent Effects on Acidity
• The pKa of p-
substituent an activating or deactivating group in electrophilic aromatic
substitution?

• The pKa
• If the pKa of the aromatic carboxylic acid is lower (higher) than that of benzoic
acid, which means it is more (less) acidic, the substituent is deactivating
(activating) group.

The pKa of p-(trifluoromethyl)benzoic acid is lower than that of benzoic acid.

(The trifluoromethyl substituent favors dissociation by stabilizing the negative charge)
Therefore, the trifluoromethyl substituent is deactivating group.
 20-4. Substituent Effects on Acidity
• Which would you expect to be a stronger acid, the lactic acid found in

• There is electron-withdrawing inductive effect of the hydroxyl group in lactic acid,

which can 1 stabilize the lactate anion.
-
> 더 강한 산일 것이다 .
 20-4. Substituent Effects on Acidity
• Which would you expect to be a stronger acid, the lactic acid found in

• There is electron-withdrawing inductive effect of the hydroxyl group in lactic acid,

which can stabilize the lactate anion.
• The lactic acid is expected to be a stronger acid than acetic acid.
 20-5. Preparing Carboxylic Acids
Methods for preparing carboxylic acids in previous chapters.
• Oxidation of a substituted alkylbenzene 4 2 2 gives a

can be oxidized, but tertiary groups are not affected.

• Oxidation of a primary alcohol or an aldehyde yields a carboxylic acid.

 20-5. Preparing Carboxylic Acids
Hydrolysis of Nitriles
• heating with aqueous acid or
base (hydrolysis) and nitriles are made by S 2 reaction of a primary and
.

• Two-step sequence:
cyanide displacement
(SN2 reaction) followed
by nitrile hydrolysis is a
 20-5. Preparing Carboxylic Acids
Carboxylation of Grignard Reagents
• 2 yields a metal carboxylate, followed
by protonation to give a carboxylic acid: carboxylation reaction.
• The organomagnesium 2 in a typical
nucleophilic carbonyl addition reaction.
• Protonation of the carboxylate
acid.
 20-5. Preparing Carboxylic Acids
• How 2 2H) from benzyl

2Br)?

•
2 reaction, so it is
limited to use with primary and some secondary alkyl halides.
(2) Formation of Grignard reagent followed by carboxylation: formation of
Grignard reagent is limited to use with organic halides that have no acidic
hydrogens or reactive functional groups.
 20-5. Preparing Carboxylic Acids
• How 2 2H) from benzyl

2Br)?

?
 20-6. Reactions of Carboxylic Acids: An Overview
• deprotonated to give anion, which are good
nucleophiles in S 2 reactions.
• reduced to yield alcohols.
• addition of nucleophiles to the carbonyl group (acyl
substitution, substitution).
 20-6. Reactions of Carboxylic Acids: An Overview
• How might you prepare 2-phenylethanol from benzyl bromide? More
than one step is needed.

• The final product is alcohol: reduction of carboxylic acid.

•
ion displacement or (2) Grignard reaction.
 20-6. Reactions of Carboxylic Acids: An Overview
• How might you prepare 2-phenylethanol from benzyl bromide? More
than one step is needed.
 20-7. Chemistry of Nitriles
•
• Both have a carbon atom with three bonds to an electronegative atom (including
bond). Both undergo nucleophilic addition reactions.

Preparation of Nitriles
• The simplest method is SN2 reaction of CN with a primary or secondary alkyl
halides -5).
 20-7. Chemistry of Nitriles
• Another method for preparing nitriles: dehydration of a primary amide,
RCONH2 2).

• 2 on the nucleophilic amide oxygen atom, followed by

deprotonation and a subsequent E2-like elimination reaction.

• The synthesis from amides is not limited by steric hinderance.

 20-7. Chemistry of Nitriles
Reactions of Nitriles
• A nitrile group is strongly polarized and has an electrophilic carbon atom,
therefore react with nucleophiles to yield sp2-hybiridized imine anions.
 20-7. Chemistry of Nitriles
• Some general reactions of nitriles:

(1) Hydrolysis: conversion of nitriles into carboxylic acids

• The reaction occurs in either basic or acidic aqueous solution.
 20-7. Chemistry of Nitriles
• Nucleophilic addition of
hydroxide ion (base) to the

imine anion (similar process

to the nucleophilic addition to

• Protonation gives a hydroxy

imine.
• A hydroxy imine tautomerizes
to an amide.
• Further hydrolysis gives a
carboxylate ion.
 20-7. Chemistry of Nitriles
• nucleophilic
addition of hydroxide ion to the amide carbonyl group, which yield tetrahedral
alkoxide ion.
• Expulsion of amide ion, NH2 , as leaving group gives the carboxylate ion

• Subsequent acidification in a separate step yields the carboxylic acid.

 20-7. Chemistry of Nitriles
(2) Reduction: conversion of nitriles into amines
• Reduction of a nitrile with LiAlH4 2.

• Nucleophilic addition of hydride ion imine

anion.
• An imine anion still contains a C=N bond and therefore undergoes a second
nucleophilic addition of hydride to give a dianion (Monoanion and dianions
are stabilized by Lewis acid-base complexation).
• Protonation of the dianion by addition of water gives the amine.
 20-7. Chemistry of Nitriles
(3) Reaction of nitriles with Grignard reagents
• Grignard reagents add to a nitrile to give an intermediate imine anion.
• The imine anion is hydrolyzed by addition of water to yield a ketone

• This reaction is similar to the reduction of a nitrile, except that only one
carbanion (R: ) nucleophile addition occurs rather than two hydride ion.
 20-7. Chemistry of Nitriles
• How would you prepare 2-methyl- -pentanone from a nitrile?

•
and the other will come from the nitrile.
 20-7. Chemistry of Nitriles
• How would you prepare 2-methyl- -pentanone from a nitrile?
 Summary of Chapter 20
• Carboxylic acids: carbonyl carbon atom is sp2-hybridized, carboxylic acids are
associated through hydrogen-bonding and therefore have high boiling points.
•
carboxylate ions are stabilized by resonance between two equivalent forms.
• electron-withdrawing (electron donating)
groups are more (less) acidic and have a lower (higher) pKa because their
carboxylate ions are stabilized (destabilized).
• The extent of dissociation of a carboxylic acid in a buffered solution of a given
pH can be calculated with the Henderson-Hasselbalch equation.
 Summary of Chapter 20
• Synthesis for carboxylic acids include (1) oxidation of alkylbenzene, (2)
oxidation of primary alcohols or aldehydes

2 (carboxylation) and (4) hydrolysis of nitriles.

• General reaction of carboxylic acids include (1) loss of the acidic proton, (2)
reduction, (3) nucleophilic acyl substitution and (4) substitution on the
carbon
• Nitriles are similar in some respects to carboxylic acids.
• SN2 reaction of an alkyl halide with cyanide ion
or by dehydration of an amide.
• nucleophilic addition
hydrolysis to carboxylic acids, reduction to primary amines and reaction
with Grignard reagents