Download 100 Chapter 21. Carboxylic Acid Derivatives and Nucleophilic Acyl

Chapter 21. Carboxylic Acid Derivatives and
Nucleophilic Acyl Substitution Reactions
General mechanism:
O
acyl
group
R
C
leaving
group
Y
R
O
O
C
C
Y
R
O
Nu
R
C
+
Y:
Nu
Y
:Nu
tetrahedral
intermediate
Carboxylic acid derivatives:
Increasing reactivity
R
O
O
O
O
O
C
C
C
C
C
OH
R
carboxylic
acid
R
N
R
OR'
parent
function group
R
R'
acid
anhydride
ester
amide
O
O
O
O
C
C
SR'
R
R
Cl
acid
chloride
O
O
P
O
O
Chapter 21.8
please read
acyl phosphate
thioester
C
197
21.1 Naming Carboxylic Acid Derivatives: (Please read)
Acid Chlorides:
Derived from the carboxylic acid name by replacing the
-ic acid ending with -yl choride or replacing the -carboxylic
acid ending with -carbonyl chloride
O
O
H3C
C
C
O
C
Cl
Cl
Cl
acetyl chloride
(from acetic acid)
benzoyl chloride
(from benzoic acid)
Cyclohexancarbonyl chloride
(from cyclohexane carboxylic acid)
Acid Anhydrides:
Name symmetrical anhydrides as the carboxylic acid
except the word acid is replaced with anhydride
O
O
H3C
C
O
O
C
C
O
O
C
CH3
acetic anhydride
benzoic anhydride
198
100
Amides:
Primary amides (RCONH2) are named as the
carboxylic acid except the -ic acid ending is replaced
with -amide or the -carboxylic acid ending is replaced
with -carboxamide.
O
O
H3C
C
C
O
C
NH2
NH2
NH2
acetamide
(from acetic acid)
Cyclohexancarboxamide
(from cyclohexane carboxylic acid)
benzamide
(from benzoic acid)
Substituted amides are named by first identifying the
substituent(s) with an N- in front of it, then naming the
parent amide
O
O
H3C
C
N
H
C
CH3
O
N
CH2CH3
C
CH3
N-methylacetamide
N
CH2CH3
CH2CH3
N-ethyl-N-methylbenzamide
N,N-diethylcyclohexancarboxamide
199
Esters:
Esters are named by first identify the group on the
carboxylate oxygen, then identifying the carboxylic acids
and replacing the -oic acid with -ate.
O
O
H3C
C
C
OCH2CH3
ethyl acetate
O
O
CH3
C
methyl benzoate
OC(CH3)3
tert-butylcyclohexancarboxylate
21.2 Nucleophilic acyl substitution reactions
R
O
O
C
C
Y
R
:Nu
O
Nu
Y
R
C
+
Nu
Y:
Y = a leaving group
-OH, -OR’, -NR2, -Cl,
-O2CR’, -SR’,-OPO32-
tetrahedral
intermediate
200
101
Relative reactivity of carboxylic acid derivatives:
The mechanism of nucleophilic acyl substitution involves
two critical steps that can influence the rate of the overall
reaction: 1) the initial addition to the carbonyl groups, and
2) the elimination of the leaving group.
The nature of the acyl group:
The rate of addition to the carbonyl carbon is slower as
the steric demands of the R group increase. Branching
at the α-carbon has the largest effect.
Increasing reactivity
O
R
R
C
C
O
Y
<
R
R
C
R
C
R
H
C
C
O
Y
<
H
C
H
H
C
Y
H
-CH3
ΔG°= 7.6 KJ/mol
-CH2CH3
8.0
-CH(CH3)2
9.2
-C(CH3)3
> 18
-CH2C(CH3)3
8.4
-C6H 5
12.6
R
H
R
Y
H
Recall from Chapter 4:
Keq
O
<
H
201
Nature of the leaving group (Y):
In general, the reactivity of acyl derivatives correlate with
leaving group ability.
Increasing reactivity
O
R
C
O
O
<
N
amide
R
C
OR'
ester
<
R
C
O
O
C
O
R'
acid anhydride
<
R
C
Cl
acid chloride
What makes a good leaving group?
R’2N-H
R’O-H
R’CO2-H
pKa: 30-40
16-18
4-5
Cl-H
-7
The reactivity of the acyl derivative inversely correlates
with their resonance electron-donating ability
O
O
R
C
NH2
R
C
NH2
Resonance effect of the Y atom reduces the
electrophilicity of the carbonyl carbon.
Partial double bond character of the C-N bond
makes it harder to break.
202
102
All acyl derivatives are prepared directly from the carboxylic acid
Less reactive acyl derivative (amides and esters) are more
readily prepared from more reactive acyl derivatives
(acid chlorides and anhydrides)
acid chloride
acid anhydride
ester
amide
carboxylic
acid
ester
Increasing reactivity
acid anhydride
amide
ester
amide
amide
203
Nucleophilic acyl substitution reactions
O
hydrolysis
Y= -Cl, -O2CR', -OR', -NR'2
C
R
H2O
OH
carboxylic acid
O
aminolysis
C
R
R'2NH
Y= -OH, -Cl, -O2CR', -OR'
NR'2
amide
O
R
C
Y
O
alcoholysis
Carboxylic acid
derivative
R'OH
Y= -OH, -Cl, -O2CR',
-OR', -NR'2
reduction
H
C
R
Y= -OH, -Cl, -O2CR'
OR'
ester
O
R
C
H
H H
C
OH
H H
C
R
NR2
O
R''-M
R
C
R''
Y= -OH, -Cl, -O2CR', -OR'
R
Y= -NR2
R'' R''
C
R
OH
R''-M = R''2CuLi R''-M = R''-MgBr, R''-Li
Y= -Cl, -OR'
Y= -Cl
204
103
21.3 Nucleophilic acyl substitution reactions of carboxylic acids
Nucleophilic acyl substitution of carboxylic acids are slow
because -OH is a poor leaving group
Reactivity is enhanced by converting the -OH into a better
leaving groups
However, acid chlorides, anhydrides, esters and amides can be
prepared directly from carboxylic acids
O
R
C
OH
carboxylic acid
O
R
C
O
O
Cl
R
C
O
O
R'
R
acid anhydride
acid chloride
C
O
OR'
R
C
NR'2
amide
ester
205
Conversion of carboxylic acids into acid chlorides
Reagent: SOCl2 (thionyl chloride)
R
O
C
SOCl2, !"
OH
R
O
C
+
Cl
SO2
+
HCl
Recall the conversion of 1° and 2° alcohols to alkyl chlorides
Mechanism (p. 780), please read
206
104
Conversion of carboxylic acids into acid anhydrides (please read)
Reagent: heat
Reaction is best for the preparation of cyclic anhydrides from
di-carboxylic acids
Conversion of carboxylic acids into esters
1. Reaction of a carboxylate salt with 1° or
2° alkyl halides
XXX
Reagents: NaH, R’-X, THF
O
C
OH
NaH, THF
O
C
H3CH2C Br
O
O
C
SN2
O CH2CH3
Na
Note the similarity to the Williamson ether synthesis
(Chapter 18.3)
207
Conversion of carboxylic acids into esters
2. Fisher esterification reaction: acid-catalyzed reaction of
carboxylic acids with 1° or 2° alcohols to give esters
Reagents: ROH (usually solvent), HCl (strong acid)
HO H
C
OH
C
O
H3CH2C OH
HCl
Mandelic acid
HO H
C
OCH2CH3
C
O
+
H2O
Ethyl mandelate
Mechanism: (Fig. 21.5, p. 782)
208
105
Conversion of carboxylic acids into amides
Not a particularly good reaction for the preparation of amides.
Amines are organic bases; the major reaction between a
carboxylic acid and an amine is an acid-base reaction
(proton transfer)
21.4: Chemistry of Acid Halides
Preparation of acid halides (Chapter 21.3)
Reaction of a carboxylic acid with thionyl chloride (SOCl2)
R
O
C
SOCl2, !"
OH
R
O
C
+
Cl
SO2
+
HCl
209
Reactions of acid halides
Friedel-Crafts acylation (Chapter 16.4): reaction of an acid
chloride with a benzene derivative to give an aryl alkyl
ketone.
O
C
R
OH
carboxylic acid
SOCl2
O
C
R
Cl
acid chloride
O
C
AlCl3
R
+ HCl
Nucleophilic acyl addition reactions of acid halides
1. hydrolysis
O
O
H2O
C
NaHCO3
R
Cl
-oracid chloride
NaOH
C
R
OH
carboxylic acid
210
106
2. Alcoholysis: Acid chlorides react with alcohols to give esters.
reactivity: 1° alcohols react faster than 2° alcohols, which
react faster than 3° alcohols
O
C
R
Cl
acid chloride
+
OH
O
C
pyridine
R
Cl
+
N
H
O
ester
3. Aminolysis: Reaction of acid chlorides with ammonia,
1° or 2° amines gives amides.
O
C
R
Cl
acid chloride
HNR2
+
R
amine
(two equiv)
O
C
+
NR2
H2NR2 Cl
ester
211
4. Reduction: Acid chlorides are reduced to primary alcohols
with lithium aluminium hydride (LiAlH4)
5. Reaction of acid chlorides with organometallic reagents:
Reacts with two equivalents of a Grignard reagent to give
a 3° alcohols (recall reaction with esters)
R
O
C
Cl
acid chloride
+ H3C
MgX
a) THF
b) H3O+
Grignard reagent
(two equiv.)
OH
C CH
R CH 3
3
3° alcohol
+
MgXCl
212
107
Reaction of acid halides with diorganocopper reagents
R
O
C
a) ether
b) H3O+
+ (H3C)2 CuLi
Cl
R
diorganocopper
reagent
acid chloride
O
C
CH3
ketone
Mechanism (page 787), not typical, specific to diorganocopper
reagents. please look it over if you like
Diorganocopper reagent can be alkyl, aryl or vinyl
H
2
a) 4 Li(0)
b) CuI
H
C C
H
H
H
Br
C
H3CH2CH2C
C
H
O
C
Cl
H3CH2CH2C
Cu Li
2
O
C
C
H
H
C
H
Fill in the reagents:
O
OH
O
O
O
OCH2CH3
OCH2CH3
O
O
O
Cl
OH
Ch. 21.6
OCH2CH3
CH2CH3
213
21.5 Chemistry of acid anhydrides
Preparation of acid anhydrides
Na O
C
+
R
Cl
O
R'
acid chloride
sodium
carboxylate
O
C
O
C
R
O
Cl
O
C
R'
R
O
C
O
O
C
R'
+ NaCl
acid anhydride
Reactions of acid anhydrides
Acid anhydrides are slightly less reactive reactive that
acid chlorides; however, the overall reactions are nearly
identical and they can often be used interchangeably.
They do not react with diorganocopper reagents to
give ketone
214
108
21.6 Chemistry of esters
Preparation of esters
Na
O
O
1.
NaH, THF
R
2.
R
3.
R
C
O
C
O
C
OH
R
C
H3CH2C-OH
OH
R
HCl
SOCl2
OH
R
O
C
Cl
O
C
H3C
HC OH
H3C
pyridine
O CH3
Limited to 1° alkyl halides
and tosylates
Limited to simple 1° and 2°
alcohols (used as solvent)
R
O
C
Very general method, 1°, 2° and
3° alcohols usually work fine
CH3
CH
O
CH3
O
C
R
OR'
ester
O
C
R
OH
carboxylic acid
O
C
O CH2CH3
R'2NH
O
C
R
SN2
Reactions of esters
H2O
(NaOH, H2O or H3O+)
H3C I
O
RMgX
R
NR'2
amide
OH
C R''
R R''
3° alcohol
HO
C
R
H
aldehyde
H-
H H
C
R
OH
1° alcohol
215
Hydrolysis of esters: esters can be hydrolyzed to the carboxylic
acids with aqueous hydroxide (saponification) or aqueous
acid.
Mechanism of the base-promoted hydrolysis (Figure 21.9)
R
O
C
OCH3
ester
a) NaOH, H2O
b) H3O+
O
C
R
OH
carboxylic acid
216
109
Acid-catalyzed hydrolysis of esters (Figure 21.10, p. 793)
(reverse of the Fischer esterification)
R
O
C
O
C
H3O+
R
OH
carboxylic acid
OCH3
ester
217
Aminolysis: Conversion of esters to amides
R
O
C
HN
OCH3
ester
R
O
C
N
amide
Reduction of esters
LiAlH4 reduces esters to primary alcohols
R
H
O
C
LiAlH4
OCH3
O
R C OCH3
H
R
O
C
LiAlH4
H
fast
H H
C
OH
R
218
110
Reduction of esters
Diisobutylaluminium hydride (DIBAH) can reduce an
ester to aldehyde
iBu
R
O
C
Al
iBu
O
R C OCH3
H
DIBAH
OCH3
H
O
R C OCH3
H
H3O+
R
O
C
H
Esters do not react with NaBH4 or BH3
Reaction of esters with Grignard reagents: Esters will react with
two equivalents of a Grignard reagent to give 3° alcohols
1) 2 H3CMgBr
2) H3O+
O
C
H3C
HO
OCH2CH3
CH3
CH3
_
H3CMgBr
the H3O+
MgX
_
O
CH3
C
OCH2CH3
_
- CH3CH2O
O
C
H3C
_
CH3
The Grignard reagent can be alkyl, vinyl or aryl
219
21.7 Chemistry of Amides
Preparation of amides: amides are prepared from the reaction of
an acid chloride with ammonia, 1° or 2° amines
O
SOCl2
C
R
OH
carboxylic acid
NH3
R
O
C
R
Cl
acid chloride
R'NH2
O
C
NH2
unsubstitiuted
(1°) amide
R
R'2NH
O
C
N
H
R'
mono-substitiuted
(2°) amide
O
C
R'
N
R'
di-substitiuted
(3°) amide
R
Reactions of amides: Amides bonds are very stable do to
resonance between the nitrogen lone pair and the
π-bond of the carbonyl
220
111
Hydrolysis- Amides are hydrolyzed to the carboxylic acids and
amine with either aqueous acid or aqueous hydroxide.
Acid promoted mechanism:
R
O
C
H3O+
NH2
R
O
C
+
OH
NH3
Base promoted mechanism
R
O
C
NaOH, H2O
NH2
R
O
C
+
NH3
OH
221
Proteases: catalyzes the hydrolysis of amide bonds of peptides
O
H3N
R
N
H
O
H
N
O
R
R
N
H
O
H
N
O
R
protease
N
H
CO2
H2O
O
H3N
R
N
H
O
H
N
O
R
O
R
Asp–Arg–Val–Tyr–Ile–His–Pro–Phe–His–Leu–Val–Ile–His–Asn
angiotensinogen
aspartyl
protease
O
H
N
+ H N
3
O
R
N
H
CO2
ACE inhibitors
renin
N N
O
N NH
Asp–Arg–Val–Tyr–Ile–His–Pro–Phe–His–Leu
angiotensin I
(little biological activity)
N
CO2H
Diovan
HS
Zn2+
protease
angiotensin converting
enzyme (ACE)
Asp–Arg–Val–Tyr–Ile–His–Pro–Phe
angiotensin II
(vasoconstriction → high blood pressure)
O
HO2C
N
Captopril
222
112
Reduction of amides to primary amines: amides can be reduced
by LiAlH4 or BH3 (but not NaBH4) to give primary amines
Mechanism:
R
O
C
SOCl2
OH
R
O
C
H3C-NH2
R
Cl
O
C
N
H
CH3
LiAlH4
H H
C
CH3
N
H
R
21.8 Thioesters and Acyl Phosphates: Biological Carboxylic
AcidDerivatives
(please read)
21.9 Polyamides and Polyesters: Step-Growth Polymers
(please read)
223
21.10 Spectroscopy of Carboxylic Acid Derivatives
IR: typical C=O stretching frequencies for:
carboxylic acid: 1710 cm-1
ester: 1735 cm-1
amide: 1690 cm-1
aldehyde: 1730 cm-1
ketone 1715 cm-1
Conjugation (C=C π-bond or an aromatic ring) moves the C=O
absorption to lower
energy (right)
by ~15 cm-1 O
O
O
OCH3
aliphatic ester
1735 cm-1
O
conjugated ester
1725 cm-1
aliphatic amide
1690 cm-1
aromatic ester
1725 cm-1
O
O
NH2
OCH3
OCH3
NH2
conjugated amide
1675 cm-1
NH2
aromatic amide
1675 cm-1
224
113
1H
NMR:
Protons on the α-carbon (next to the C=O) of esters and amides
have a typical chemical shift range of δ 2.0 - 2.5 ppm
Proton on the carbon attached to the ester oxygen atom have a
typical chemical shift range of δ 3.5 - 4.5 ppm
δ 1.2
3H, t,
J= 7.1
δ 2.0
3H, s
δ 4.1
2H, q,
J= 7.1
δ 2.0
3H, s
O
H3C C N CH2CH3
δ 1.1
3H, t, J= 7.0
H
δ 3.4
2H, q, J= 7.0
NH
225
13C
NMR: very useful for determining the presence and nature
of carbonyl groups. The typical chemical shift range
for C=O carbon is δ160 - 220 ppm
Aldehydes and ketones: δ 190 - 220 ppm
Carboxylic acids, esters and amides: δ 160 - 185 ppm
O
H3C C O CH2CH3
14.2
60.3
170.9
21.0
CDCl3
21.0
O
H3C C N CH2CH3
170.4
14.8
34.4
H
CDCl3
226
114
C11H12O2
1H
NMR
δ 7.5 δ 7.3
2H, m 3H, m
δ 6.4
1H, d,
J= 15.0
δ 7.7
1H, d,
J= 15.0
δ 4.2
2H, q,
J= 7.0
δ 1.3
3H, t,
J= 7.0
IR
13C
NMR
130.2
128.8
127.9
144.5
134.9
166.9
60.5
118.2
CDCl3
14.3
TMS
227
115