Organic Chemistry II
Carboxylic Acid Derivatives
Dr. Ralph C. Gatrone
Department of Chemistry and Physics
Virginia State University
Spring, 2011
1
Chapter Objectives
• Nomenclature
• Properties
• Preparation
• Reactions
• Spectroscopy
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Carboxylic Derivatives
• Functional Groups we will consider are:
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Carboxylic Derivatives
• Chemistry is similar
• Chemistry is dominated by one reaction
O
R
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O
Nu:
X
R
Nu
4
Nomenclature
Acid Halides RCOX
• Derived from the carboxylic acid name by
replacing the -ic acid ending with -yl or the carboxylic acid ending with –carbonyl and
specifying the halide
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Nomenclature
Acid Anhydrides, RCO2COR’
• If symmetrical replace “acid” with “anhydride” based on
the related carboxylic acid
•
• For substituted monocarboxylic acids: use bis- ahead of
the acid name
• Unsymmetrical anhydrides— cite the two acids
alphabetically
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Nomenclature
Esters, RCO2R
• Name R’ and then, after a space, the carboxylic
acid (RCOOH), with the “-ic acid” ending
replaced by “-ate”
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Nomenclature
Amides, RCONH2
• With unsubstituted NH2 group. replace -oic acid or -ic
acid with -amide, or by replacing the -carboxylic acid
ending with –carboxamide
• If the N is further substituted, identify the substituent
groups (preceded by “N”) and then the parent amide
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Examples
O
• Try these
O(CH2)7 CH3
O
CH3COCH3
O
O
Br
Br
O
Cl
O
O
N
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Examples
• Answers
O
O(CH2)7CH3
octyl crotonate
O
CH3COCH3
O
O
Br
methyl acetate
Br
O
Cl
bis-bromoacetic anhydride
pentanoyl chloride
O
O
N
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N-ethyl-N-isopropylacrylamide
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Properties
• Amides have higher boiling point than
other derivatives due to H-bonding
• Esters have pleasant odors associated with
fruits and flavors
• Acid halides have pungent odors due to
hydrolysis to HCl or HBr
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Stability
•
•
•
•
Amides more stable than
Esters, more stable than
Acid anhydrides, more stable than
Acid halides
• Esters and amides are commonly found in
•
•
natural materials.
Amides make up foundation of animals
Acid halides and anhydrides don’t exist in nature
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Stability
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Relative Reactivity of Carboxylic
Acid Derivatives
• Nucleophiles react
more readily with
unhindered carbonyl
groups
• More electrophilic
carbonyl groups are
more reactive to
addition (acyl halides
are most reactive,
amides are least)
• The intermediate with
the best leaving group
decomposes fastest
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General Reactions of Carboxylic
Acid Derivatives
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Reactions of Carboxylic Acids
• OH is poor leaving group
• Must enhance reactivity
• Specific reagents can produce acid chlorides,
anhydrides, esters, amides
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Acids to Acid Chlorides
• Reaction with thionyl chloride, SOCl2
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Acids to Acid Anhydrides
• Heat cyclic dicarboxylic acids that can form five•
or six-membered rings
Acyclic anhydrides are not generally formed this
way - they are usually made from acid chlorides
and carboxylic acids
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Acids to Esters
• Carboxylate anion with a primary alkyl halide
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Fischer Esterification
• Heating a carboxylic acid in an alcohol solvent
containing a small amount of strong acid
produces an ester from the alcohol and acid
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Esterification using Diazomethane
CH2N2
O
O
ETHER
CO2 H
CO2 CH3
Reaction only provides the methyl ester
Glassware must be polished (no ground glass joints)
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Acids to Amides
• Direct reaction cannot be done
base
CO2H
acid
(CH3)2NH
CO2
+
(CH3)2NH2
salt
• Due to acid base reaction that occurs first
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Acids to Amides
• Must make OH a better leaving group
• Generally done in the laboratory via the acyl halide
• Can also use dicyclohexylcarbodiimide to activate the
OH
O
R
O
O
R
N
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C
HN
O
O
N
RNH2
R
NHR
N
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Chemistry of Acid Halides
• Acid chlorides are prepared from carboxylic acids
•
by reaction with SOCl2
Reaction of a carboxylic acid with PBr3 yields the
acid bromide
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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
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Acid Halides into Acids
(Hydrolysis)
• Acid chlorides react with water to yield
•
carboxylic acids
HCl is generated during the hydrolysis: a base is
added to remove the HCl
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Acid Halides to Anhydrides
• Acid halides react with carboxylate anions
O
Cl
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CH3CH2C
O
O
O
O
O
CH2CH3
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Acid Halides to Esters
• Esters are produced in the reaction of acid
•
chlorides react with alcohols in the presence of
pyridine or NaOH
The reaction is better with less steric bulk
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Acid Halides into Amides
• Amides result from the reaction of acid chlorides
– with NH3,
– primary amines (RNH2)
– 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
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Acid Chlorides into Alcohols
• LiAlH4 reduces acid chlorides to yield primary
alcohols through the aldehyde (not isolated)
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Acid Halides with Organometallics
• Grignard reagents react with acid chlorides to
yield tertiary alcohols in which two of the
substituents are the same
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Acid Chlorides to Ketones
• Reaction of an acid chloride with a lithium
diorganocopper (Gilman) reagent, Li+ R2Cu
• Reaction of an acid chloride with organocadmium
reagent
O
R
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O
R2Cd
Cl
R
R
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Chemistry of Acid Anhydrides
• Prepared by carboxylate nucleophile with
an acid chloride
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Reactions of Acid Anhydrides
• Similar to acid chlorides in reactivity
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Anhydrides to Esters or Amides
• Anhydrides form esters with alcohols
• Anhydrides form amides with amines
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Anhydrides: More Selective than Acid
Halides
• Anhydrides react with amines in presence of
alcohols, Not so acid chlorides
O
O
NH2
NH2
N
H
Cl
HO
HO
H
N
NH2
HO
O
O
O
O
O
O
O
NH2
HO
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O
N
H
O
HO
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Chemistry of Esters
• Many esters are pleasant-smelling liquids:
•
fragrant odors of fruits and flowers
Also present in fats and vegetable oils
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Preparation of Esters
• Esters are usually prepared from carboxylic acids
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Reactions of Esters
• Less reactive toward nucleophiles than are acid
•
chlorides or anhydrides
Cyclic esters are called lactones and react
similarly to acyclic esters
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Esters into Carboxylic Acids
• An ester is hydrolyzed by aqueous base or
aqueous acid to yield a carboxylic acid plus an
alcohol
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Soap
• Ester (Fat) hydrolysis into carboxylate anion
O
R
O
O
O
R
O
NaOH
R
O
O
R
O
-
Na+
OH
HO
OH
soap
R = C11 to C17 hydrocarbon
triglyceride (animal fat)
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Esters to Amides
• Ammonia reacts with esters to form
amides
• Reaction is easier from the acid chloride
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Esters into Alcohols: Reduction
• Reaction with LiAlH4 yields primary alcohols
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Reduction of Esters
•
•
•
•
•
LAH is reducing agent of choice
NaBH4 does not reduce esters
H2 does not reduce esters
BH3 – THF does not reduce esters
DIBAH reduces esters to the aldehyde
O
O
OMe
DIBAH
H
toluene
DIBAH =
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Al
H
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Esters with Grignard Reagents
• Reacts with 2 equivalents of a Grignard reagent
to yield a tertiary alcohol
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Chemistry of Amides
• Prepared by reaction of an acid chloride with
•
ammonia, primary amines, or secondary amines
Amides are the least reactive of derivatives
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Reactions of Amides
• Heating in either aqueous acid or aqueous
base produces a carboxylic acid and the
amine
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Amides into Amines
• Reduced by LiAlH4 to an amine rather than an
•
alcohol
Converts C=O  CH2
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Reduction of Amides
• Works with cyclic and acyclic
• Good route to cyclic amines
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Amides to Nitriles
O
CN
NH2
SOCl2 or POCl3 can be used
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Amide to Amine
The Hoffmann Rearrangement
• Preparation of amine with loss of a carbon
O
NH2
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Br2/NaOH/H2O
NH2
+
CO2
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Infrared Spectroscopy
• Acid chlorides: 1800cm-1
• Acid anhydrides: 1820 and 1760cm-1
• Esters: 1735cm-1
• Amides: 1650 - 1690cm-1 depending on N
substitution
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NMR Spectroscopy
• Carbon-13 NMR
• Difficult to assign with certainty
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NMR Spectroscopy
• Proton NMR
• Protons adjacent to C=O resonate near 2d
• Identity of the C=O cannot be determined
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