Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution

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Carboxylic Acid DerivativesNucleophilic Acyl
Substitution
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NOMENCLATURE
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ACYL GROUPS
ACID HALIDES
IUPAC
an acyl group
-oyl
Common
oh-wheel
-yl
ethanoyl
acetyl
eel
butanoyl chloride
ethanoyl chloride
benzoyl chloride
butyryl chloride
acetyl chloride
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SALTS OF ACIDS
-oate
metal
oh-ate
sodium pentanoate
potassium benzoate
potassium benzenecarboxylate
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ESTERS
alkyl group
ethyl pentanoate
-oate
methyl 2-methylpropanoate methyl isobutyrate
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ESTERS
isopropyl benzenecarboxylate
isopropyl benzoate
tert-butyl phenylethanoate
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ESTERS
methyl cyclohexanecarboxylate
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Esters as Flavoring Substances
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an acyl group
ACYL FUNCTIONAL GROUP INTERCONVERSIONS
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SOME ACYL COMPOUNDS
ACID DERIVATIVES
carboxylic acid
acid chloride
primary secondary tertiary
amides
ester
anhydride
These compounds differ from aldehydes and
ketones in that they have a leaving group
-OH -Cl -OR -NH2 -O(CO)R
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COMPARISON OF CARBONYL COMPOUNDS
The typical reaction of an aldehyde or ketone
is addition, or an addition followed by loss of
water.
enamine
-H2O
imine
acetal
Nu-R
hemiacetal
Acid derivatives (acyl compounds) undergo
substitution reactions.

X
a leaving group
displacement
Nu-R
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Nucleophilic Acyl Substitution
SIMPLIFIED VIEW
-
addition of nucleophile
-
elimination of leaving group
-
carbonyl group forms again
most arent this simple, proton transfers are
usually required
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REACTIVITY OF CARBONYL COMPOUNDS
most reactive
least reactive
special case
( acidic H )
..
..
OH-
..
no catalyst required
acid catalyst required (base may be used for
hydrolysis)
acid catalyst required with weak
nucleophiles only
acid required (in the conjugate base CO is
deactivated)
Not acid derivatives different chemistry.
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REACTIVITY IS ALSO REFLECTED IN THE STABILITY
OF THE LEAVING GROUP
(not considering acid catalysis)
MOST REACTIVE
-
Cl
-
-
O-R
-
NH2
STRONGEST BASE
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PREPARATION OF ACID CHLORIDES
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QUICK REVIEW
Preparation of an Acid Chloride
benzene
or neat
thionyl chloride
( a liquid )
The same reagent that converts alcohols to halides
R-O-H
R-Cl
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CHLORIDES, BROMIDES AND IODIDES
In SN2 reactions you learned the rate sequence
R-I gt R-Br gt R-Cl and that iodides are better
substrates than chlorides.
This is true.
Based on this knowledge ..
many students assume that if acid chlorides are
good, the acid bromides and iodides must be
better.
However acid bromides and iodides are
difficult to prepare, and the iodides are quite
unstable
.. you should use the chlorides.
They are easily prepared from the acid by
R-COOH SOCl2
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REACTIONS THAT DO NOT REQUIRE CATALYSIS
ACID CHLORIDES ACID ANHYDRIDES
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REACTIONS OF ACID CHLORIDES
NO CATALYST REQUIRED
Hydrolysis
Acid
Ester
-

Amide
2 equivalents
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ACID CHLORIDES
d-
..
..
-



d
..
..



..
..
..
..
very reactive no catalyst needed
..
water or alcohol
..
..


..
..
..

..
..

..
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Preparations of an Acid Anhydride
best method
NaOH
P2O5
heat
The acid chloride and the acid may be reacted
directly to form the anhydride, but the reaction
usually gives a better yield if the carboxylate
salt is used (shown above).
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This method works best with small MW liquid acids
or diacids that can make a cyclic anhydride.
HCl
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Formation of Cyclic Anhydrides
heat

Geometry is important in forming
cyclic anhydrides.
phthalic acid
phthalic anhydride
Linear anhydrides are usually not made by
this method.
heat

maleic acid
maleic anhydride
cis
trans
fumaric acid
no reaction
heat
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ACID ANHYDRIDES ARE
ALMOST AS REACTIVE AS ACID CHLORIDES
NO CATALYST REQUIRED
2 equivalents
Hydrolysis


H-OH
Acid
R-OH


Ester
..
..
-

R2NH2
Amide
2 equivalents
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EVERYTHING CAN BE MADE FROM THE ACID (CHLORIDE)
RMgX CO2
NaOH
SOCl2
H2O
Na
ROH
ACID DERIVATIVES
NH3 NR2H
. or the anhydride
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REACTIONS THAT REQUIRE ACID CATALYSIS
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Acid-Catalyzed Nucleophilic Acyl
Substitution
SIMPLIFIED
..


..
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Functional Group Interconversions
Conversions that proceed via the acid chloride or
anhydride.
These Reactions Do Not Require Catalyst
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Functional Group Interconversions
ROH
H2O
NH3 NR2H
NH3 NR2H
ROH
H2O
These New Interconversions Are Also Possible
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Reactions That Do Not Go Via the Acid
Chloride or Anhydride
ROH
These pathways require acid catalysis, although
in the hydrolysis reactions (H2O) basic catalysis
(NaOH) may also be used. The basic product is
H2O
ROH
NH3 NR2H
NH3 NR2H
-

ROH
H2O
Na
instead of the acid.
Reactions Requiring Acid Catalysis
.. typically H2SO4
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Fischer Esterification
EQUILIBRIUM
The equilibrium position is usually about
50/50 unless shifted by using an excess of a
reactant or removing water.
ECONOMICS use an excess of the cheaper starting
reactant.
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Fischer Esterification
MECHANISM
H2SO4 2 ROH 2 ROH2 SO42-

..
..
..
..



2
H
..
..

RCOOH
..
slow
..

..
..
..
..
1
excess

..

..
..



..
..
..
..
H2O

..
lost
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Transesterification
mechanism is similar to the Fischer Esterification
EXAMPLE
heat
excess