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Carboxylic Acid DerivativesSynthesis and Reactions
Dr. Sapna Gupta
Reactivity of the Derivatives
Here are all derivatives and their relationship to carboxylic acid.
Carboxylic Acid Derivatives Synthesis and Reactions 2
H-NH2H-Cl H-OR'RC-OH
O
H-OCR'
O
RC=N
HO H
RC-OH
O
RC-OH
O
RC-OH
O-H2 O -H2 O -H2 O -H2 O
-H2 O
RC NRCNH2
O
RCCl
O
RCOR'
O
RCOCR'
O O
The enol ofan amide
An acidchloride
An esterAn acidanhydride
An amide A nitrile
Reactivity of the Derivatives
• Two kinds of reactions occur in acids: • Nucleophilic addition
• Nucleophilic substitution
In leaving group ability:
Carboxylic Acid Derivatives Synthesis and Reactions 3
Interconversions of Acid Derivatives
Least reactive
Most reactive R NH2
O
R Cl
O
R O
O
R
O
R OR
O
R OH
O
> > > >
Acyl Chlorides- Synthesis
Carboxylic Acid Derivatives Synthesis and Reactions 5
Acyl Chlorides - Reactions
•Acyl chlorides are the most reactive acyl compounds and can be used to make any of the other derivatives•Since acyl chlorides are easily made from carboxylic acids they provide a way to synthesize any acyl compound from a carboxylic acid•Acyl chlorides react readily with water, but this is not a synthetically useful reaction
Carboxylic Acid Derivatives Synthesis and Reactions 6
Anhydrides - Synthesis
1) Acid chlorides + carboxylic acids to form mixed or symmetrical anhydrides. It is necessary to use a base such as pyridine
3) Cyclic anhydrides with 5- and 6-membered rings can be synthesized by heating the appropriate diacid
2) Sodium carboxylates + acid chlorides to form anhydrides.
Carboxylic Acid Derivatives Synthesis and Reactions 7
Anhydrides - Reactions
Carboxylic Acid Derivatives Synthesis and Reactions 8
Esters - Synthesis
•Acid catalyzed reaction of alcohols and carboxylic acids to form esters is called Fischer esterification•Fischer esterification is an equilibrium process •Ester formation is favored by use of a large excess of either the alcohol or carboxylic acid and by removal of water.
From Acids
Carboxylic Acid Derivatives Synthesis and Reactions 9
Mechanism of Esterification
Carboxylic Acid Derivatives Synthesis and Reactions 10
Esters - Synthesis
From Acyl Chlorides
From Acid Anhydrides
Carboxylic Acid Derivatives Synthesis and Reactions 11
Lactones
Synthesis
Hydrolysis
Carboxylic Acid Derivatives Synthesis and Reactions 12
Esters - Reactions
Hydrolysis: Acids can be acid hydrolyzed to give acid and alcohol.
Transesterifcation: One ester can be converted to another in presence of an alcohol and a catalyst.
Write the mechanism on your own! (start with protonating the carbonyl of the ester; the OCH3 will be the leaving group.)
Saponification: Treatment of ester with strong base. Used mostly to prepare soaps.
Carboxylic Acid Derivatives Synthesis and Reactions 13
Butyl propenoate(Butyl acrylate)
(bp 147°C)
1-Butanol(bp 117°C)
Methyl propenoate(Methyl acrylate)
(bp 81°C)
+
+HCl
CH3 OH
Methanol(bp 65°C)
OCH3
O
HO
O
O
Butyl propenoate(Butyl acrylate)
(bp 147°C)
1-Butanol(bp 117°C)
Methyl propenoate(Methyl acrylate)
(bp 81°C)
+
+HCl
CH3 OH
Methanol(bp 65°C)
OCH3
O
HO
O
O
OEt
O
OH
O+ EtOH
H3O+
H2SO4
OEt
O
O-Na
+
O+ EtO-NaOH
Amides - Synthesis
(Note: do mechanism for lactams on your own)
From Acyl Chlorides
From Anhydrides
Carboxylic Acid Derivatives Synthesis and Reactions 14
Carboxylic Acid Derivatives Synthesis and Reactions 15
Amides - Synthesis
From Carboxylic Acid
Amides - Reactions
Hydrolysis
Carboxylic Acid Derivatives Synthesis and Reactions 16
Interconversions of Acid Derivatives
Least reactive
Most reactive R NH2
O
R Cl
O
R O
O
R
O
R OR
O
R OH
O
> > > >
Nitriles - Synthesis
• From Alkyl Halides (SN2 reaction)
• From Aldehydes and Ketones
• From dehydration of amides
Carboxylic Acid Derivatives Synthesis and Reactions 18
Reactions - Nitriles (as Acid Derivative)
• Hydrolysis gives carboxylic acid
Carboxylic Acid Derivatives Synthesis and Reactions 19
Other Reactions of Carboxylic Acid Derivatives – With Grignard Reagent
• With acyl chlorides – gives tertiary alcohols
• With esters – gives tertiary alcohols (write mechanism)
Carboxylic Acid Derivatives Synthesis and Reactions 20
Other Reactions of Carboxylic Acid Derivatives – With Grignard Reaction (Ester – Mechanism)
Carboxylic Acid Derivatives Synthesis and Reactions 21
Other Reactions of Carboxylic Acid Derivatives – with Copper Reagents
• Acyl chlorides – give ketones
Carboxylic Acid Derivatives Synthesis and Reactions 22
Other Reactions of Carboxylic Acid Derivatives - Reduction
Of Acyl chlorides
Give 1o alcohols
Of Amides
Give amines
Of Nitriles
Give amines
Carboxylic Acid Derivatives Synthesis and Reactions 23
CN CH2NH2LAH
Other Reactions of Carboxylic Acid Derivatives - Reduction
Of Esters
With strong reducing agent
Give 1o alcohols
Mechanism
Using a weak reducing agent
Give aldehydes
Carboxylic Acid Derivatives Synthesis and Reactions 24
All Reactions
Carboxylic Acid Derivatives Synthesis and Reactions 25
H2O
R"OH
NH3
R'R''NH
LAH
R'MgX
R'2CuLi
R OH
O
R NH2
O
R NR'R''
O
R H
OHH
R R'
OH
R'
R R'
O
R OR"
O
+ R"OH
+ R"OH
+ R"OH
+ R"OH
+ R"O-
H2O
LAH
R OH
O
R NH2
OHH
H2O
LAH
R OH
O
R NH2
HH
R OR'
O
R NH2
O
R CN
R Cl
O
R O
O
R'
O
H2O
R"OH
NH3
R'R''NH
LAH
R'MgX
R'2CuLi
R OH
O
R NH2
O
R NR'R''
O
R H
OHH
R R'
OH
R'
R R'
O
R OR"
O
+ R"OH
+ R"OH
+ R"OH
+ R"OH
+ R"O-
R O-Na
+
ONaOH
H2O
R'COO-
R'OH
NH3
R'R''NH
LAH
R'MgX
R'2CuLi
R OH
O
R OR'
O
R NH2
O
R NR'R''
O
R H
OHH
R R'
OH
R'
R R'
O
R O
O
R'
O
Interconversions - Practice
Problem: Show reagents and experimental conditions to bring about each reaction.
PhOH
O
OMe
O
Ph
PhOH
PhCl
O
PhNH2
PhNH2
O
Phenylacetic acid
(a) (b) (c)
(d) (e)
(f)
(g) (h)
Key Concepts
• Synthesis and Reactions of all derivatives
• Mechanism of esterification
Carboxylic Acid Derivatives Synthesis and Reactions 27
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