Download Chapter 21: Carboxylic Acid Derivatives and Nucleophilic Acyl

Chapter 21: Carboxylic Acid Derivatives and
Nucleophilic Acyl Substitution Reactions
Nomenclature:
O
O
O
X
N
C
Ester
Carboxylic acid
O
O
O
OH
O
Acyl halide
Amide
Anhydride
O
oic acid
amide
oyl halide
oic anhydride
O
O
Cl
H3C
oate
ethanoyl chloride
(acetyl chloride)
O
Br
3,3-dimethylhex-5-enoyl bromide
H3C
O
O
O
CH3
ethanoyl anhydride
(acetic anhydride)
shorthand form:
CH3COCl or AcCl
H3C
O
O
CH2CH3
ethanoyl propanoyl anhydride
shorthand forms:
(CH3CO)2O
also Ac2O
O
O
H3C
NH2
O
N
CH3
CH3
ethanamide
(acetamide)
N,N-dimethybutanamide
shorthand forms:
CH3CONH2
CH3CH2CH2CONMe2
H3C
O
O
CH3
methyl ethanoate
(methyl acetate)
O
butyl propanoate
shorthand forms:
CH3COOCH3
CH3CO2CH3
1
Some naturally occurring lactones
Smells of some simple esters
O
H
O
O
HO
3-methylbutyl ethanoate
isoamyl acetate
banana / pear
HO
O
H
CH2OH
octyl ethanoate
octyl acetate
orange
O
O
O
methyl salicylate
wintergreen
erythromcyin A
(antibiotic)
H
N
HOOC
NH2
N
O
O
OH
OH
OH
COOH
O
OH
OH
HO
O
O
O
NMe2
O
O
OMe
O
OH
musk ambrette from the seeds
of Hibiscus abelmoschus
S
O
N
COOH
Penicillin G
OH
Reactions of acid derivatives – nucleophilic acyl substitution
Some naturally occurring lactams
S
OH
amphotericin B
(antibiotic)
OH
Me
O
OH
ethyl butanoate
pineapple
O
O
O
OH
O
O
H
N
HO
O
HO
O
OH
O
Vitamin C
O
NH2
O
O
OH
2-methylpropyl methanoate
isobutyl formate
raspberry
O
HO
O
COOH
O
Cephalosporin C
Relative reactivity – substituent effects
Relative reactivity – substituent effects
2
Relative reactivity – substituent effects
Z
R
C
Y
R
Z
R
O
attack of nucleophile
on electrophilic carbon
Z
O
Y
O
+ Y
loss of leaving
group
this could, conceivably, go either way
what makes it go only one way?
look at the tetrahedral intermediate – it has a choice of losing
either Y or Z
the important feature is the leaving group ability
how can we get a handle on this?
Here are the groups in order of decreasing reactivity:
O
O
Cl
O
O
O
Reactions of carboxylic acids. Conversion to:
Acyl halides
O
OR
NH2
Here are the intermediates, with the leaving group indicated in red:
Nu
O
Cl
Nu
O
O
O
Nu
O
OR
Nu
O
NH2
Cl
OCOR
O
O
These are the leaving groups:
OR
NH2
3
PBr3
OH
Br
3
+ H3PO3
90%
These are the acids corresponding to those leaving groups:
HCl
HOCOR
And these are the pKa values:
~5
pKa
-7
HOR
~ 16
NH3
36
O
O
Br
OH
PCl5
Br
Cl
+ POCl3 + HCl
70%
Reactions of carboxylic acids. Conversion to:
Acid anhydrides
95%
in reality, acid to anhydride only works well with cyclic systems
3
Reactions of carboxylic acids. Conversion to:
Esters
There are two ways:
The blue way:
O
R
O
we can make this bond
we can make this bond
I
+
O
O
HOAc
O
Na
O
100°
95%
O
Br
10
COOH
K2CO3
O
DMSO
100°
89%
The red way – known as Fischer esterification
OH
Ph
OH
EtOH
COOH
Ph
dry HCl
COOEt
86%
O
O
H2SO4
O
OH
HO
90%
Reactions of carboxylic acids. Conversion to:
Amides
Reactions of acyl halides. Conversion to:
Acids and esters
this one is quite difficult – the first tendency is acid + amine to give
a salt. This must then be strongly heated to drive off water.
O
O
∆
O
NH4
OH
H3N
reaction with alcohols gives esters – very easy reaction
NH2
O
+
HNMe2
COO
∆
reaction with water will get you back to the acid
why would you want to?
97%
O
∆
N
155°
84%
O
NH
86%
these reactions are often done in base to mop up the HCl
which is also being formed
There are easier ways!
4
Reactions of acyl halides. Conversion to:
Amides
OH
OCOCH3
CH3COCl
py
75%
OH
O
COCl
aq NaOH
+
O
97%
Reactions of acyl halides. Conversion to:
Alcohols - reduction
Reactions of acyl halides. Conversion to:
Alcohols – organometallic reactions
this is not usually seen;
reduction of the acid is
also possible, so why go
to the trouble of making
the acid halide?
cannot be controlled to add only one RLi or RMgX;
the intermediate ketone is too reactive
but – a selective reduction to aldehyde is useful:
O2N
LiAlH(Ot-Bu)3
1 equiv.
COCl
H2O
diglyme
-78°
O2N
CHO
81%
Reactions of acyl halides. Conversion to:
Alcohols – organometallic reactions
Reactions of acid anhydrides. Conversion to:
Esters and Amides
but, by changing the organometallic, we can get specificity
90%
Cl
O
O
2 CuLi
THF
-78°
H2O
CO2H
70%
NH2
L-leucine
PhCH2OCOCl
aq NaOH
CO2H
HN
O
Ph
90%
O
a carbobenzoxy group (cbz)
5
Reactions of esters.
Hydrolysis
Reactions of esters.
Hydrolysis
O
O
OCH3
O2N
20% NaOH
H3O+
∆
5-10 m
OH
+ CH3OH
O2N
96%
Cl
Cl
OEt
O
OH
HCl
H2O
∆
Reactions of esters.
Hydrolysis
O
+ CH3CH2OH
82%
Reactions of esters. Conversion to:
Amides
+
OEt
NC
O
Reactions of esters. Conversion to:
Alcohols – reduction
H
O
NH2
H
OEt
NH3
H2O
∆
∆
H
N
O
90%
NH2
NC
O
88%
Reactions of esters. Conversion to:
Alcohols – organometallics
6
Reactions of amides.
Hydrolysis
Br
Reactions of amides. Conversion to:
Amines
Br
HCl
NH
H2O
∆
O
OH H3N
HO
H2N
Br
O
67%
NO2
NO2
MeO
NHAc
KOH
MeOH, H2O
∆
MeO
NH2
+ KOAc
95%
What does Nature use?
7