Carb Acid Deriv
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Transcript of Carb Acid Deriv
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DERIVATIVES OF
CARBOXYLIC ACIDS
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CARBOXYLIC ACID DERIVATIVES
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Introduction to Nucleophilic Acyl
Substitution
leaving group
♦ Carboxylic acid derivatives (RCOZ) react with nucleophiles because they
contain an electrophilic, unhindered carbonyl carbon.♦ Substitution occurs, not addition, because carboxylic acid derivatives(RCOZ) have a leaving group Z on the carbonyl carbon.
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The Mechanism
The general mechanism for nucleophilic acyl substitution is a two-step
process: nucleophilic attack followed by loss of the leaving group.
The overall result of addition of a nucleophile and elimination of a leaving
group is substitution of the nucleophile for the leaving group.
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Nucleophiles
Nucleophilic acyl substitution using heteroatomic nucleophiles results in the
conversion of one carboxylic acid derivative into another.
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most reactive
C
O
ClR
More reactive acyl compounds (acid chlorides and anhydrides) can be
converted to less reactive ones (carboxylic acids, esters, and amide).
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Reactions of Acid Chloride
Cl-
Acid chlorides readily react with nucleophiles to
form nucleophilic substitution products with HCl
usually formed as a reaction by-product. A weak
base like pyridine is added to the reaction mixture to
remove this strong acid, forming an ammonium salt.
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Acid chlorides react with oxygen nucleophiles to form anhydrides,
carboxylic acids, and esters
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Mechanisms
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Acid chlorides also react with ammonia and 1o and 2o amines to
form 1
o
, 2
o
, and 3
o
amides respectively. Two equivalents of NH3 or amine are used.
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(CH3CH2)2NH2
Cl
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Review of other reactions of acid chlorides
1. Reduction to aldehydes
2. Conversion to ketones
3. Friedel-Crafts Acylation
R-COCl
Acid chloride
+ R'2CuLi R-CO-R'
Ketone
R-COCl
Acid chloride
+
Benzene
AlCl3
Acybenzene
COR
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Reactions of Anhydrides
Less reactive than acid chlorides, anhydrides nonetheless readily react
with most nucleophiles to form substitution products. Nucleophilic
attack occurs at one carbonyl group, while the second carbonyl
becomes part of the leaving group.
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Anhydrides can't be used to make acid chlorides!
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Mechanism
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acetylsalicylic acid
(aspirin)
acetaminophen
(the active ingredient in Tylenol)
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-Heroin-
Acetylation of Morphine
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• Esters can be converted into carboxylic acids and amides.
Reactions of Esters
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Ester Hydrolysis in Aqueous Acid
The hydrolysis of esters in aqueous acid is a reversible equilibrium reaction
that is driven to the right by using a large excess of water.
The first step in acid-catalyzed ester hydrolysis is protonation on oxygen,
the same first step of any mechanism involving an oxygen-containing
starting material and an acid.
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Mechanism
Acid-Catalyzed Hydrolysis of an Ester to a Carboxylic Acid
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Problem
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Ester Hydrolysis in Aqueous Base
Esters are hydrolyzed in aqueous base to form carboxylate anions. Basic
hydrolysis of an ester is called saponification.
The mechanism for this reaction has the usual two steps of the general
mechanism for nucleophilic acyl substitution—addition of the nucleophile
followed by loss of a leaving group—plus an additional step involving protontransfer.
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Mechanism
Base-Promoted Hydrolysis of an Ester to a Carboxylic Acid
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Problem
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Saponification
The word saponification comes from the Latin
“sapo” meaning soap. Soap is prepared by
hydrolyzing esters in fats with aqueous base.
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Reactions of AmidesBecause amides have the poorest leaving group of all the carboxylic acidderivatives. They are the least reactive. In fact, they have only one useful
reaction. Under strenuous reaction conditions, amides are hydrolyzed in acid
or base to form carboxylic acids or carboxylate anion.
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Mechanism Amide Hydrolysis in Base
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Nitriles
Nitriles are readily prepared by SN2 substitution reactions of unhinderedmethyl and 1o alkyl halides with -CN. This reaction adds one carbon to the
alkyl halide and forms a new carbon-carbon bond
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Hydrolysis of Nitriles
Nitriles are hydrolyzed with water in the presence of acid or base to yield
carboxylic acids or carboxylate anions. In this reaction, the three C-N
bonds are replaced by three C-0 bonds.
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Mechanism Hydrolysis of a Nitrile in Base
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Reduction of Nitriles
Nitriles are reduced with metal hydride reagents to form either 1o amines
or aldehydes, depending on the reducing agent.
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Mechanism Reduction of a Nitrile with LiAIH4
Mechanism Reduction of a Nitrile with DIBAL-H
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Addition of Grignard and Organolithium Reagents to Nitriles
Both Grignard and organolithium reagents react with nitriles to form
ketones with a new carbon-carbon bond.
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MechanismAddition of Grignard and Organolithium Reagents (R-M)
to Nitriles
PROBLEM: Draw the products of each reaction.