Unless otherwise stated, all images in this file have been reproduced from:
Blackman, Bottle, Schmid, Mocerino and Wille,
Chemistry, 2012 (John Wiley & Sons)
ISBN: 9 78047081 0866
1
Nucleophilic acyl
substitution (again!)
Lecture 12 Lecture 13 Lecture 14
More oxidation & More nucleophilic acyl Organic reaction
reduction substitution overview
Nucleophilic acyl Synthetic strategies
substitution
One mechanism to rule them all – step 3
Mechanism: Nucleophilic Acyl Substitution – with H-Nu
Step 1: nucleophilic
addition to electrophilic
carbon of acid chloride …
gives a tetrahedral
intermediate
Step 2: acid/base reaction
(deprotonation of the
tetrahedral intermediate)
Step 3: collapse of the
tetrahedral intermediate
to regenerate the C=O p
bond with elimination of
chloride anion as the
leaving group
Worksheet – Q1a,b 3
Carboxylic acids …
1. Are acidic
2. Can be reduced
3. Can be activated as acyl chlorides
Reduction of organic molecules decreases their O content or increases their H
content. 4
There are many nucleophilic acyl substitution reactions
Step 1: nucleophilic
addition to electrophilic
carbon of carboxylic acid
derivative … gives a
tetrahedral intermediate
Step 2: acid/base reaction
(deprotonation of the
tetrahedral intermediate)
Step 3: collapse of the
tetrahedral intermediate
to regenerate the C=O p
bond with elimination of
‘X’ anion as the leaving
group
Worksheet – Q1-c,e 5
There are many nucleophilic acyl substitution reactions
• Most of the reactions we’ve seen so far start with the acid chloride to form an ester or amide but it is
possible to form an ester directly from the carboxylic acid by addition of an alcohol using an acid catalyst.
H HO OH
O H O
R
O
OH OH HO R H
H
HO OH Tetrahedral
R intermediate
O
H2O
H
H H
O
O
HO O H
OR R
OR O
• The mechanism looks complicated, but the reaction proceeds through the same tetrahedral intermediate
as the other nucleophilic acyl substitution reactions we’ve seen. 6
Reactions of carboxylic acid derivatives
Carboxylic acid derivatives can be hydrolysed back to the parent acid with
water
acid chloride acid anhydride ester amide
O O O O O
C C C C R' C R"
R Cl R O R R O R N
R'
+ H2O + H2O + H2O + H2O
O O O O
C C C C
R OH R OH R OH R OH
acid acid acid acid
+ + O + +
H R"
H Cl H C H R' N
O R O
R'
Worksheet – Q1f hydrochloric acid acid alcohol amine 7
Reactivity of carboxylic acid derivatives
8
Recap: Acid-base reactions
Carboxylic acids react with dilute base (e.g. NaOH or NaHCO3) to form a water
soluble carboxylate ion
O O
C acid - base C
OH + Na OH reaction O Na + H2O
benzoic acid sodium benzoate
soluble in diethyl ether insoluble in diethyl ether
(soluble in NaOH solution)
The carboxylate anion is a base (proton acceptor) and so reacts with dilute acid
to give the corresponding carboxylic acid
O acid - base O
C reaction
+ H Cl C
O OH + Cl
9
Hydrolysis reactions
HCl (acid chloride)
or O
O R C OH (anhydride)
or
H /H2O R C OH + R'OH (ester)
O
or
R C Y
R'2NH2 (amide)
acid derivative
OH /H2O
Cl (acid chloride)
or O
O
R C O R C O (anhydride)
+ or
R'OH (ester)
or
R'2NH (amide)
Worksheet – Q2 10
Learning outcomes
After this lecture you should be able to:
• Recognise carboxylic acid derivative functional groups
• Understand the different reactivity of these derivatives
• Predict conditions for hydrolysis and interconversion of
carboxylic acid derivatives
Further reading: Blackman 23.4-23.5
11
