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John E. McMurry
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Chapter 15
Carboxylic Acids and Nitriles
Richard Morrison • University of Georgia, Athens
Carboxylic Acids and Nitriles
Carboxylic acids (-CO2H)
are present in most
biological pathways and
are the biological starting
materials from which
other acyl derivatives are
made
Cholic acid is a major
component of human bile
15.1 Naming Carboxylic Acids and Nitriles
Carboxylic acids named by replacing –e of the corresponding
alkane name with –oic acid
• –CO2H carbon atom is numbered C1
Naming Carboxylic Acids and Nitriles
• Name compounds with –CO2H group bonded to a ring
using the suffix –carboxylic acid
Naming Carboxylic Acids and Nitriles
Naming Carboxylic Acids and Nitriles
Naming Carboxylic Acids and Nitriles
Compounds containing
functional group are called
nitriles
C N
• Named by adding –nitrile as a suffix to the alkane name
• Nitrile carbon numbered C1
Naming Carboxylic Acids and Nitriles
Nitriles also named as carboxylic acid derivatives by replacing
–ic acid or –oic acid ending with –onitrile or by replacing the
–carboxylic acid ending with –carbonitrile
15.2 Structure and Properties of Carboxylic
Acids
• Carboxyl carbon is sp2-hybridized
• Carboxylic acids are strongly associated because of
hydrogen bonding
•
Hydrogen bonding significantly increases boiling point
• Most carboxylic acids exist as cyclic dimers
Structure and Properties of Carboxylic Acids
• Carboxylic acids react with bases to give metal (M+)
carboxylate salts, RCO - M+
2
• Carboxylic acids slightly ionize in water
Structure and Properties of Carboxylic Acids
Structure and Properties of Carboxylic Acids
Carboxylic acids are much weaker acids than mineral acids but
much stronger acids than alcohols
Structure and Properties of Carboxylic Acids
Carboxylic acids ionize to give resonance stabilized
carboxylate ions
Structure and Properties of Carboxylic Acids
Both carbon-oxygen bonds in sodium formate are 127 pm in
length, midway between the C=O bond (120 pm) and the CO bond (134 pm) of formic acid
15.3 Biological Acids and the HendersonHasselbalch Equation
At pH = 7.3, a value known as physiological pH, both the
carboxylic acid and its conjugate base are present
•
The conjugate base form predominates at pH = 7.3
• Percentages of carboxylic acid and conjugate base can be
calculated from the pKa and the pH of the medium
A
H3O+   A - 


+

pK a = - log
= - log H3O  - log
HA 
HA 
 A - 
pH = pK a + log
HA 
Henderson - Hasselbalch equation
Biological Acids and the Henderson-Hasselbalch
Equation
The percent dissociation of a 0.0010 M solution of acetic acid (pKa = 4.76)
can be calculated from the Henderson-Hasselbalch equation
A- 
log   = pH - pKa = 7.3 - 4.76 = 2.54
HA 


A- 
  = antilog 2.54 = 3.5 × 102 ; so  A -  = 3.5 × 102 HA 


 
HA 




 A -  + HA  = 0.0010 M

  
Solving the two simultaneous equations gives  A -  = 0.0010 M and
HA  = 3 × 10-8. Therefore, at physiological pH of 7.3, essentially 100%


of acetic acid molecules in a 0.0010 M solution are dissociated to
the acetate ion
15.4 Substituent Effects of Acidity
Substituents that stabilize the carboxylate anion relative to the
undissociated carboxylic acid will drive the equilibrium
toward increased dissociation and result in increased acidity
Substituent Effects of Acidity
Effects of electron-donating and electron-withdrawing
substituents on the acidity of benzoic acid
Substituent Effects of Acidity
The electron-donating or electron-withdrawing effect
of a certain substituent on electrophilic reactivity can
be found by measuring the acidity of the
corresponding benzoic acid
Worked Example 15.1
Predicting the Effect of a Substituent on the Reactivity of
an Aromatic Ring toward Electrophilic Substitution
The pKa of p-(trifluoromethyl)benzoic acid is 3.6. Is
the trifluoromethyl substituent an activating or
deactivating group in electrophilic aromatic
substitution?
Worked Example 15.1
Predicting the Effect of a Substituent on the Reactivity of
an Aromatic Ring toward Electrophilic Substitution
Strategy
• Decide whether p-(trifluoromethyl)benzoic acid is
stronger or weaker than benzoic acid. A
substituent that strengthens the acid is a
deactivating group because it withdraws electrons,
and a substituent that weakens the acid is an
activating group because it donates electrons.
Worked Example 15.1
Predicting the Effect of a Substituent on the Reactivity of
an Aromatic Ring toward Electrophilic Substitution
Solution
• A pKa of 3.6 means that p-(trifluoromethyl)benzoic acid
is stronger than benzoic acid, whose pKa is 4.19. Thus,
the trifluoromethyl substituent favors ionization by
helping stabilize the negative charge. Trifluoromethyl
must therefore be an electron-withdrawing, deactivating
group.
15.5 Preparing Carboxylic Acids
Preparation of carboxylic acids:
•
Oxidation of substituted alkyl benzenes
•
Oxidation of primary alcohols or aldehydes
Preparing Carboxylic Acids
•
Hydrolysis of nitriles
•
•
•
•
Nitriles hydrolyzed in hot aqueous acid or base
Nitrile hydrolysis is used in synthesis of ibuprofen
RX
RC≡N
RCO2H
Product carboxylic acid contains one more carbon atom than
starting alkyl halide
Preparing Carboxylic Acids
• Carboxylation of Grignard Reagents by CO2
Preparing Carboxylic Acids
• Biological carboxylation of Acetyl CoA to give Malonyl
CoA
Worked Example 15.2
Devising a Synthesis Route for a Carboxylic Acid
How would you prepare phenylacetic acid
(PhCH2CO2H) from benzyl bromide (PhCH2Br)?
Worked Example 15.2
Devising a Synthesis Route for a Carboxylic Acid
Strategy
We’ve seen two methods for preparing carboxylic acids from
alkyl halides:
1.
2.
Cyanide ion displacement followed by hydrolysis, and
Formation of a Grignard reagent followed by carboxylation.
The first method involves an SN2 reaction and is therefore
limited to use with primary and some secondary alkyl halides.
The second method involves formation of a Grignard reagent
and is therefore limited to use with organic halides that have
no acidic hydrogens or reactive functional groups. In the
present instance, either method would work well.
Worked Example 15.2
Devising a Synthesis Route for a Carboxylic Acid
Solution
15.6 Reactions of Carboxylic Acids:
An Overview
Reactions of carboxylic acids can be grouped into four
categories:
15.7 Chemistry of Nitriles
Nitriles exhibit similar chemistry to carboxylic acids because
both have a carbon atom with three bonds to an
electronegative atom containing p bonds
Chemistry of Nitriles
Nitriles are known but not abundant in living organisms
• Cyanocycline A is an antimicrobial and antitumor agent
• Lotaustralin is poisonous to herbivores
Chemistry of Nitriles
Laboratory preparations of nitriles:
•
SN2 reaction of CN- with primary or secondary alkyl halide
(Section 15.5)
• Dehydration of primary amide, RCONH2
•
Occurs by initial reaction of SOCl2 on the nucleophilic amide oxygen
atom, followed by deprotonation and E2-like elimination
Chemistry of Nitriles
Nucleophilic reactions of carbonyls and nitriles:
Chemistry of Nitriles
• Hydrolysis
Chemistry of Nitriles
•
Mechanism of basic hydrolysis
• Proceeds through amide
Chemistry of Nitriles
•
At higher reaction temperatures, the amide undergoes further
hydrolysis to give a carboxylic acid by a nucleophilic acyl
substitution mechanism
Chemistry of Nitriles
• Reduction of nitriles with LiAlH4 yields an amine via two
successive hydride additions
Chemistry of Nitriles
•
Reduction of nitriles with Grignard reagents gives an intermediate
imine anion that hydrolyzes to a ketone
•
Grignard reaction of ethyl magnesium bromide with
benzonitrile to give propiophenone
15.8 Spectroscopy of Carboxylic Acids and
Nitriles
Infrared Spectroscopy
•
Carboxylic acids have two characteristic absorptions:
•
•
Broad –OH absorption over 2500 to 3300 cm-1 range
Strong C=O absorption between 1710 and 1760 cm-1
Spectroscopy of Carboxylic Acids and Nitriles
Nuclear Magnetic Resonance Spectroscopy
•
13C
•
NMR
Carboxyl carbon atoms absorb in the 165 to 185 d range
•
•
•
Aromatic and a,b-unsaturated carboxyl carbon atoms absorb
near upfield end (~ 165 d)
Carboxyl carbon atoms of saturated aliphatic acids absorb near
the downfield end (~ 185 d)
Nitrile carbons absorb in range 115 to 130 d
Spectroscopy of Carboxylic Acids and Nitriles
1H
NMR
• – CO2H proton normally absorbs as a singlet near 12 d