Download Functional Derivatives of Carboxylic Acids

Organic Lecture Series
Functional
Derivatives of
Carboxylic Acids
1
Organic acid derivatives
Organic Lecture Series
• There are five classes of organic acid derivatives
• Each arises from a dehydration reaction, usually a
condensation
• Therefore, each derivative can also be hydrolyzed
O
RCCl
A n acid
chloride
-H2 O
O
RC-OH H-Cl
O O
RCOCR'
An acid
anhydride
-H2 O
O
O
RC-OH H-OCR'
O
RCOR'
An ester
-H2 O
O
RC-OH H-OR'
O
RCNH2
An amide
-H2 O
O
RC-OH H-NH2
RC N
A nitrile
-H2 O
HO H
RC=N
Th e enol of
an amide
2
Organic Lecture Series
Acid halides
• The functional group of an acid halide
is an acyl group bonded to a halogen
– the most common are the acid chlorides
– to name, change the suffix -ic acid to -yl
halide
O
O
RC-
O
CH3 CCl
An acyl
group
O
Cl
Cl
Ethan oyl ch loride Benzoyl chloride
(Acetyl ch loride)
Cl
O
Hexan edioyl ch loride
(Adip oyl chloride)
3
Organic Lecture Series
Sulfonyl Chlorides
– replacement of -OH in a sulfonic acid by -Cl
gives a sulfonyl chloride
O
O
CH3 SOH
O
Methanes ulfon ic
acid
CH3 SCl
O
Methanes ulfonyl ch loride
(Mesyl ch loride, MsCl)
O
H3 C
SOH
O
p-Toluen esulfon ic
acid TsOH
O
H3 C
SCl
O
p-Toluen esulfon yl chloride
(Tosyl chlorid e, TsCl)
4
Organic Lecture Series
Acid Anhydrides
• The functional group of an acid anhydride
is two acyl groups bonded to an oxygen
atom
– the anhydride may be symmetrical (two
identical acyl groups) or mixed (two different
acyl groups)
– to name, replace acid of the parent acid by
anhydride
O O
O O
CH3 COCCH3
COC
A cetic an h ydrid e
Ben zoic anh ydrid e
5
Organic Lecture Series
Acid Anhydrides
• Cyclic anhydrides are named from the
dicarboxylic acids from which they are
derived
O
O
O
O
O
Succinic
anhydride
O
O
O
O
Maleic
anhydride
Phthalic
anhydride
6
Organic Lecture Series
Esters
• The functional group of an ester is an acyl
group bonded to -OR or -OAr
– name the alkyl or aryl group bonded to
oxygen followed by the name of the acid
– change the suffix -ic acid to -ate
O
O
O
O
O
Ethyl ethan oate
(Ethyl acetate)
Is op ropyl
ben zoate
OEt
EtO
O
D iethyl butaned ioate
(D ieth yl s uccin ate)
7
Organic Lecture Series
Esters
• Cyclic esters are called lactones
– name the parent carboxylic acid, drop
the suffix -ic acid and add -olactone
O
O
α
2
1
β3 O
H3 C
3-Bu tanolactone
(β -Butyrolactone)
α
1
2
O
3 4
β γ
4-Bu tanolactone
(γ-Bu tyrolacton e)
α
β
γ
3
4
2
O
1
O
5 6
δ
ε
6-Hexan olacton e
(ε -Cap rolactone)
8
Organic Lecture Series
Amides
• The functional group of an amide is an
acyl group bonded to a nitrogen atom
– IUPAC: drop -oic acid from the name of the
parent acid and add -amide
– if the amide nitrogen is bonded to an alkyl or
aryl group, name the group and show its
location on nitrogen by NO
CH3 CNH2
A cetamide
(a 1° amide)
O CH3
H-C-N
CH3
O H
CH3 C-N
CH3
N-Methylacetamide N ,N-D imethyl(a 2° amid e)
formamid e (DMF)
(a 3° amide)
9
Organic Lecture Series
Amides
• Cyclic amides are called lactams
– name the parent carboxylic acid, drop the
suffix -ic acid and add -lactam
α
O
α
2
β3
H3 C
1
NH
3-Butanolactam
(β-Butyrolactam)
penam –old term for β-lactam
β
γ
O
2
3
4
5
1
6
NH
δ
ε
6-Hexan olactam
(ε-Caprolactam)
10
Organic Lecture Series
Penicillins
the penicillins are a family of β-lactam antibiotics
The compound is an exceptional
“acylating” agent because of the
ring strain of the lactam.
Inhibit cell wall synthesis by acylating
and de-activating the required enzymes.
11
Organic Lecture Series
Penicillins
the penicillins are a family of β-lactam antibiotics
HO
The penicillin s
differ in the
grou p bond ed
to the acyl carb on
O
H
H
S
NH
H2 N
β-lactam
O
N
COOH
Amoxicillin
(a β-lactam an tib iotic)
12
Cephalosporins
Organic Lecture Series
the cephalosporins are also β-lactam antibiotics
The cephalosporins d iffer in the
group bonded to the acyl carbon an d
the s ide chain of the thiazin e rin g
O
NH2
H H
N
H
O
N
β-lactam
Cep halexin
(Keflex)
S
Me
COOH
Bacteria develop resistance by producing β-lactamases-enzymes,
which can hydrolyze the lactam before it can inhibit cell wall synthesis.
13
Meropenem
Organic Lecture Series
Highly resistant to degradation by beta-lactamases or
cephalosporinases.
14
Organic Lecture Series
Imides
• The functional group of an imide is
two acyl groups bonded to nitrogen
– both succinimide and phthalimide are
cyclic imides
O
O
NH
NH
O
Succinimide
O
Phthalimide
15
Acidity of N-H bonds
Organic Lecture Series
• Amides are comparable in acidity to alcohols
– water-insoluble amides do not react with NaOH or
other alkali metal hydroxides to form water-soluble
salts
• Sulfonamides and imides are more acidic than
amides
O
CH3 CNH2
Acetamide
pKa 15-17
O
SNH2
O
NH
O
NH
O
O
O
Ben zenesu lfonamide Succinimide Phth alimide
pK a 10
p Ka 9.7
p Ka 8.3
Sulfonamides are the class of “sulfa antibiotics”
16
Organic Lecture Series
Sulfanilamide
As an antibiotic, it functions by
competitively inhibiting (i.e. by acting as a
substrate analogue) enzymatic reactions
involving para-aminobenzoic acid (PABA).
PABA is needed in enzymatic reactions that
produce folic acid which acts as a
coenzyme in the synthesis of purine,
pyrimidine and other amino acids.
17
Organic Lecture Series
Sulfanilamide tragedy of 1937:
Elixir sulfanilamide was an improperly
prepared sulfanilamide medicine that
caused mass poisoning in the United
States in 1937.
The preparation used diethylene glycol
as the solvent and caused the deaths of
more than 100 people.
The public outcry caused by this
incident and other similar disasters led
to the passing of the 1938 Federal
Food, Drug, and Cosmetic Act.
18
Organic Lecture Series
Acidity of N-H bonds
Imides are more acidic than amides because:
1. the electron-withdrawing inductive of the two
adjacent C=O groups weakens the N-H bond,
and
2. the imide anion is stabilized by resonance
delocalization of the negative charge
O
O
N
O
N
O
N
O
O
A resonance-stabilized an ion
19
Organic Lecture Series
Acidity of N-H bonds
– imides such as phthalimide readily dissolve in
aqueous NaOH as water-soluble salts
O
O
NH + NaOH
O
pK a 8.3
(stronger
acid)
-
+
N Na +
H2 O
O
(stronger
base)
(weaker
base)
pK a 15.7
(weaker
acid)
This property is used to render
pharmaceutical agents water soluble:
20
Organic Lecture Series
Thalidomide-sedative, hypnotic
Barbituric Acid
Acidity of this H is used to
Make the derivatives soluble
1. Sedative was used in pregnant women
from 1956~1962 in Europe/Africa
1. Never approved in US
2. Caused birth defects (teratogen)
3. Later found use in leprosy treatment
21
Organic Lecture Series
Barbituric Acid
Sodium Pentothal® -Sodium thiopental
S Na
HN
N
Phenobarbital
O
HN
O
O
H 3C
NH
CH2
H 3C
CH3
O
O
CH2
H 3C
Anticonvulsant, hypnotic, anxiolytic
22
Organic Lecture Series
Characteristic Reactions
• Nucleophilic acyl substitution: an
addition-elimination sequence resulting in
substitution of one nucleophile for another
-:
O
R
+
C
-
:Nu
R
Y
O
O
C
C
R
Nu
Y
Tetrah edral carbonyl
addition in termediate
+
Nu
-
:Y
S ubs titu tion
p rodu ct
23
Organic Lecture Series
Fischer Esterifications
O
O
R'OH
C
R
OH
Carboxylic Acid
+
H
+ HOH
C
(cat)
R
OR'
Ester
24
Organic Lecture Series
Characteristic Reactions
– in the general reaction, the leaving
group, as an anion, illustrates an
important point:
– the weaker the base, the better the
leaving group
O
R2 N
-
-
RO
-
RCO
-
X
Increasin g leaving ability
Increasin g b asicity
25
Organic Lecture Series
Reaction with H2O - Acid Chlorides
– low-molecular-weight acid chlorides react
rapidly with water
– higher molecular-weight acid chlorides are
less soluble in water and react less readily
O
CH3 CCl + H2 O
Acetyl chlorid e
O
CH3 COH + HCl
These are hydrolysis reactions- “breaking of bonds with water”
26
Organic Lecture Series
Reaction with H2O - Acid Chlorides
• Step 1: Make a new bond between a
nucleophile and an electrophile. Water attacks
the carbonyl carbon directly to give a tetrahedral
carbonyl addition intermediate.
27
Organic Lecture Series
Reaction with H2O - Acid Chlorides
• Step 2: Take a proton away. Proton
transfer is rapid and reversible.
28
Organic Lecture Series
Reaction with H2O - Acid Chlorides
• Step 3: Break a bond to give stable
molecules or ions. Collapse of the tetrahedral
intermediate and expulsion of chloride ion gives
the carboxylic acid.
29
Organic Lecture Series
Reaction with H2O - Anhydrides
– low-molecular-weight acid anhydrides react
readily with water to give two molecules of
carboxylic acid
– higher-molecular-weight acid anhydrides also
react with water, but less readily
O O
CH3 COCCH3 + H2 O
Acetic an hydrid e
O
O
CH3 COH + HOCCH3
30
Organic Lecture Series
–Step 1: addition of H2O to give a TCAI
H +
O
H
O
O
CH3 -C-O-C-CH3
O
CH3 -C-O-C-CH3
+
O H
H
O-H
O-H
H
H
H
O O
+
CH3 -C-O-C-CH3 + H-O-H
O
H
H
Tetrah edral carbonyl
addition intermediate
31
Organic Lecture Series
–Step 2: protonation followed collapse of
the TCAI
H
H
H
+O
H
H
H
O
O
O
O
CH3 -C-O-C-CH3
O
H
H
H
+O
H
+ H
O
CH3 C O C CH3
H
H
H
O
CH3
O
O
C + O C
O
CH 3
H
32
Organic Lecture Series
Reaction with H2O - Esters
• Esters are hydrolyzed only slowly, even in
boiling water
– hydrolysis becomes more rapid if they are heated with
either aqueous acid or base
• Hydrolysis in aqueous acid is the reverse of
Fischer esterification
– the role of the acid catalyst is to protonate the
carbonyl oxygen and increase its electrophilic
character toward attack by water (a weak nucleophile)
to form a tetrahedral carbonyl addition intermediate
– collapse of this intermediate gives the carboxylic acid
and alcohol
33
Organic Lecture Series
hydrolysis reactions-
(Go to worksheet)
34
Organic Lecture Series
Reaction with H2O - Esters
• Acid-catalyzed ester hydrolysis
R
O
C
OH
C
+
+
OCH3
H2 O
H
R
H
+
OH
R
O
C
+
OH
CH3 OH
OCH3
Tetrahed ral carbonyl
ad dition intermed iate
35
Organic Lecture Series
Reaction with H2O - Esters
• Hydrolysis of an esters in aqueous base is often
called saponification
– each mole of ester hydrolyzed requires 1 mole of
base
– for this reason, ester hydrolysis in aqueous base is
said to be base promoted
O
RCOCH3 + NaOH
H2 O
O
-
RCO Na
+
+
CH3 OH
– hydrolysis of an ester in aqueous base involves
formation of a tetrahedral carbonyl addition
intermediate followed by its collapse and proton
transfer
36
Organic Lecture Series
Reaction with H2O - Esters
– Step 1: attack of hydroxide ion (a nucleophile)
on the carbonyl carbon (an electrophile)
– Step 2: collapse of the TCAI
– Step 3: proton transfer to the alkoxide ion; this
step is irreversible and drives saponification
to completion
O
(1)
R-C-OCH3 + OH
O
O
O
(2)
(3)
R-C + OCH3
R-C + HOCH3
R-C OCH3
O
O
OH
H
37
Organic Lecture Series
Reaction with H2O - Amides
Hydrolysis of an amide in aqueous acid
requires 1 mole of acid per mole of amide
– reaction is driven to completion by the acidbase reaction between the amine or ammonia
and the acid
O
O
N H2 + H2 O + HCl
Ph
2-Phenylbutanamide
H2 O
heat
OH + N H4
+
Cl
-
Ph
2-Phenylbutanoic acid
38
Organic Lecture Series
The “big picture”
39
Organic Lecture Series
hydrolysis reactions-
40
Organic Lecture Series
Reaction with H2O – Amides in Acid
– Step1: Add a proton. Protonation of the
carbonyl oxygen gives a resonance-stabilized
cation intermediate and increases the
electrophilic character of the carbonyl carbon.
41
Organic Lecture Series
Reaction with H2O – Amides in Acid
– Step 2: Make a new bond between a
nucleophile and an electrophile. Addition of
water to the carbonyl carbon.
42
Organic Lecture Series
Reaction with H2O – Amides in Acid
• Step 3: Take a proton away/add a
proton. Proton transfer between O and N
gives a tetrahedral carbonyl addition
intermediate.
43
Organic Lecture Series
Reaction with H2O – Amides in Acid
• Step 4: Break a bond to make stable
molecules or ions. Note that the leaving
group is a neutral amine (a weaker base),
a far better leaving group.
44
Organic Lecture Series
Reaction with H2O - Amides
Hydrolysis of an amide in aqueous base
requires 1 mole of base per mole of amide
– reaction is driven to completion by the
irreversible formation of the carboxylate sale
O
CH3 CNH
N-Phen yleth anamide
(N-Phen ylacetamid e,
Acetan ilide)
+ NaOH
H2 O
heat
O
CH3 CO- Na+ + H2 N
Sodiu m
acetate
A niline
45
Organic Lecture Series
Reaction with H2O – Amides in Base
• Step 1: Make a bond between a nucleophile
and an electrophile. Addition of hydroxide ion
to the carbonyl carbon gives a tetrahedral
carbonyl addition intermediate.
46
Organic Lecture Series
Reaction with H2O – Amides in Base
• Step 2: Take proton away. This step creates a
dianionic intermediate, which has enough
negative charge to expel the amide anion.
47
Organic Lecture Series
Reaction with H2O – Amides in Base
• Step 3: Break a bond to give stable
molecules or ions/add a proton. The amide
anion has so little lifetime in water because it is
so basic; therefore, it will be instantly protonated
by water.
48
Organic Lecture Series
hydrolysis reactions-
49
Organic Lecture Series
Reaction with H2O - Nitriles
• The cyano group is hydrolyzed in aqueous acid
to a carboxyl group and ammonium ion
Ph CH2 C N + 2 H2 O + H2 SO4
Phenylacetonitrile
H2 O
heat
O
+
Ph CH2 COH + NH4 HSO4
Ph enylacetic
Ammoniu m
acid
hydrogen s ulfate
– protonation of the cyano nitrogen gives a cation that
reacts with water to give an imidic acid
– keto-enol tautomerism gives the amide
+
R-C N + H2 O
H
OH
R-C NH
A n imidic acid
(en ol of an amide)
O
R-C-NH2
An amide
Can stop at the amide if: 1 mol H2O and cat H2SO4 is used.
50
Organic Lecture Series
Reaction with H2O - Nitriles
OH
+
R-C N + H2 O
O
R-C-NH2
An amide
H
R-C NH
A n imidic acid
(en ol of an amide)
Note: In excess aqueous acid- the amide
continues to undergo hydrolysis to give
the carboxylic acid:
O
+
R-C-NH2 + H2 O
An amide
H
∆
O
R-C- OH
NH4+
+
Carboxylic Acid
51
Organic Lecture Series
Reaction with H2O - Nitriles
– hydrolysis of a cyano group in aqueous base
gives a carboxylic anion and ammonia;
acidification converts the carboxylic anion to
the carboxylic acid
CH3 ( CH2 ) 9 C N
Un decan enitrile
NaOH, H2 O
h eat
O
-
+
CH3 ( CH 2 ) 9 CO Na + NH3
S od ium und ecanoate
HCl H2 O
O
CH3 ( CH2 ) 9 COH + NaCl + NH4 Cl
Und ecanoic acid
52
Organic Lecture Series
Reaction with H2O - Nitriles
– hydrolysis of nitriles is a valuable route
to carboxylic acids
– Molar excess of aqueous acid MUST be
used:
KCN
CH3 ( CH2 ) 8 CH2 Cl
ethan ol,
1-Ch lorod ecan e
w ater
CH3 (CH 2 ) 9 C N
H2 SO4 , H2 O
Und ecanen itrile
OH
heat
O
CH3 ( CH2 ) 9 COH
Und ecanoic acid
OH
CHO HCN, KCN
CN H2 SO4 , H2 O
COOH
eth anol,
heat
w ater
Benzaldeh yd e
Benzald ehyde cyanohydrin 2-Hydroxyp henylacetic acid
(Mandelonitrile)
(Mand elic acid )
(racemic)
(racemic)
See worksheet
53
Organic Lecture Series
Acylation Reactions to form Esters:
54
Organic Lecture Series
Reaction with Alcohols
• Acid halides react with alcohols to give
esters
– acid halides are so reactive toward even
weak nucleophiles such as alcohols that no
catalyst is necessary
– where the alcohol or resulting ester is
sensitive to HCl, reaction is carried out in the
presence of a 3°amine to neutralize the acid
O
O
Butanoyl
chloride
+
O
Cl + HO
Cyclohexan ol
HCl
Cyclohexyl butan oate
55
Organic Lecture Series
Reaction with Alcohols
• Acid anhydrides react with alcohols to give one
mole of ester and one mole of carboxylic acid
O O
CH3 COCCH3 + HOCH2 CH3
Acetic anhydride Ethanol
O
O
CH3 COCH2 CH 3 + CH3 COH
Ethyl acetate
Acetic acid
– cyclic anhydrides react with alcohols to give one ester
group and one carboxyl group
O
O
O
O
Phth alic
anh yd rid e
+
O
OH
HO
O
2-Butan ol
(sec-Butyl alcohol)
(s ec-Bu tyl h yd rogen
phth alate
56
Organic Lecture Series
Use in Practice
– aspirin is synthesized by treating salicylic acid
with acetic anhydride
COOH
OH
O O
+ CH COCCH
3
3
Acetic
2-Hydroxybenzoic anhydride
acid
COOH
(Salicylic acid)
O
CH 3
+
O
O
CH 3 COH
Acetic acid
Acetylsalicylic acid
(Aspirin)
57
Organic Lecture Series
Use in Practice
Both Acid anhydrides or acid chlorides can be
used as acylating agents:
O
HO
O
H 3C
O
O
O
H 3C
O
CH3
O
O
N CH3
N CH3
H 3C
HO
M o rp h in e
Cl
O
H 3C
O
D ia c e ty l-m o rp h in e
(H e ro in )
58
Organic Lecture Series
Reaction with Alcohols
• Esters react with alcohols in the presence
of an acid catalyst in an equilibrium
reaction called transesterification
O
OCH 3 +
Methyl propenoate
(Methyl acrylate)
(bp 81°C)
HCl
HO
1-Butanol
(bp 117°C)
O
O
+ CH 3 OH
Methanol
Butyl propenoate
(bp 65°C)
(Butyl acrylate)
(bp 147°C)
59
Organic Lecture Series
Acylation Reactions to form Amides:
60
Organic Lecture Series
Reaction with Ammonia
Acid halides react with ammonia, 1°amines,
and 2°amines to form amides
– 2 moles of the amine are required per mole of
acid chloride
O
Cl + 2 NH3
Hexanoyl
Ammon ia
chloride
O
+
-
NH2 + NH4 Cl
Hexan amid e
Ammon ium
chloride
61
Organic Lecture Series
Reaction with Ammonia
Acid anhydrides react with ammonia,
and 1°and 2°amines to form amides
– 2 moles of ammonia or amine are
required
O O
CH3 COCCH3 + 2 NH3
Acetic
Ammon ia
anh yd rid e
O
O
+
CH3 CNH2 + CH3 CO NH4
Acetamid e Ammon ium
acetate
62
Organic Lecture Series
Reaction with Ammonia
• Esters react with ammonia, and 1°and 2°
amines to form amides
– esters are less reactive than either acid
halides or acid anhydrides
O
Ph
O
OEt + NH3
Ethyl p henylacetate
Ph
NH2 +
Phenylacetamide
Et OH
Ethanol
• Amides do not react with ammonia, or 1°
or 2°amines
63
Organic Lecture Series
Acid Chlorides with Salts
Acid chlorides react with salts of carboxylic
acids to give anhydrides
– most commonly used are sodium or
potassium salts
O
O
+ +
CH3 CCl
Na
OC
Acetyl
chloride
Sodium benzoate
O O
CH3 COC
A cetic benzoic
anhydride
+
N a+ Cl
-
64
Organic Lecture Series
Reactions with Organometallic Reagents:
O
O
1) (R')2CuLi
C
R
Cl
Acid Chloride
2) H3O+
C
R
R'
Ketones
65
Organic Lecture Series
Reactions with Grignard Reagents
–treating a formic ester with 2 moles
of Grignard reagent followed by
hydrolysis in aqueous acid gives a
2°alcohol
O
HCOCH3 + 2 RMgX
An ester of
formic acid
OH
magn esium H O, HCl
2
alkoxide
HC-R + CH3 OH
salt
R
A 2° alcohol
66
Organic Lecture Series
Reactions with Grignard Reagents
– treating other esters with a Grignard
reagent followed by hydrolysis in
aqueous acid gives a 3°alcohol
O
CH3 COCH 3 + 2 RMgX
An ester of an y acid
other than formic acid
magnesiu m
H2 O, HCl
alk oxid e
salt
OH
CH3 C-R + CH3 OH
R
A 3° alcohol
67
Organic Lecture Series
Reactions with Grignard Reagents
– Step 1: Make a new bond between a nucleophile and
an electrophile. Reaction of the ester with one mole of
Grignard reagent forms a tetrahedral carbonyl addition
intermediate.
68
Organic Lecture Series
Reactions with Grignard Reagents
• Step 2: Break a bond to give stable
molecules or ions. Collapse of the intermediate
and expulsion of alkoxide ion gives a ketone and
a magnesium alkoxide.
69
Organic Lecture Series
Reactions with Grignard Reagents
• Step 3: Make a new bond between a nucleophile and
an electrophile. The ketone reacts with a second mole
of Grignard reagent to give a second tetrahedral
carbonyl addition intermediate.
70
Organic Lecture Series
Reactions with Grignard Reagents
• Step 4: Add a proton. The resulting hydrolysis
gives a tertiary alcohol.
71
Organic Lecture Series
Reactions with Organolithium
Organolithium compounds are even more
powerful nucleophiles than Grignard
reagents
– they react with esters to give the same types
of 2°and 3°alcohols as do Grignard reagents
– and often in higher yields
O
RCOCH3
1 . 2 R' Li
2 . H2 O, HCl
OH
R- C-R' + CH 3 OH
R'
72
Organic Lecture Series
Reactions with Organocuprate Reagents
Acid chlorides at -78°C react with Gilman
reagents to give ketones
– under these conditions, the TCAI is stable, and it
is not until acid hydrolysis that the ketone is
liberated
O
O
1 . ( CH 3 ) 2 CuLi, ether, -78°C
Cl 2 . H O
2
Pentanoyl chloride
2-Hexanone
This is analogous to Gilman coupling with alkyl halides.
73
Organic Lecture Series
Reactions with Organocuprate Reagents
Gilman reagents react only with acid
chlorides they do not react with acid
anhydrides, esters, amides, or nitriles
under the conditions described
O
H 3 CO
O
1 . ( CH3 ) 2 CuLi, eth er, -78°C
Cl 2 . H2 O
O
H 3 CO
O
74
Organic Lecture Series
Reductions:
O
OH
1) LAH
C
R
2) H3O+
OR'
Ester
C
R
H
H
1o Alcohol
75
Organic Lecture Series
Reduction - Esters by LiAlH4
Most reductions of carbonyl compounds now
use hydride reducing agents
– esters are reduced by LiAlH4 to two alcohols
– the alcohol derived from the carbonyl group is
primary
O
Ph
OCH 3
Methyl 2-phenylpropanoate
1 . LiAlH4 , et her
2 . H 2 O, HCl
Ph
OH + CH3 OH
2-Phenyl-1propanol
M ethanol
76
Organic Lecture Series
Reduction - Esters & NaBH4
• NaBH4 does not normally reduce
esters, but it does reduce aldehydes and
ketones
• Selective reduction is often possible by the
proper choice of reducing agents and
experimental conditions
O
O
OEt
NaBH4
OH O
EtOH
*
OEt
(racemic)
77
Organic Lecture Series
Reduction - Esters by DIBAlH
• Diisobutylaluminum hydride (DIBAlH) at -78°C
selectively reduces an ester to an aldehyde
– at -78°C, the TCAI does not collapse and it is not until
hydrolysis in aqueous acid that the carbonyl group of
the aldehyde is liberated
O
OCH3
Methyl hexanoate
1 . DIBALH , toluen e, -78°C
2 . H2 O, HCl
O
H + CH3 OH
Hex anal
78
Organic Lecture Series
Reduction - Amides by LiAlH4
• LiAlH4 reduction of an amide gives a 1°,
2°, or 3°amine, depending on the degree
of substitution of the amide
O
1 . LiAlH4
NH2
2 . H2 O
Octanamide
NH2
1-Octanamine
O
NMe2
NMe2 1 . LiAlH4
2 . H2 O
N ,N-D imeth ylb enzylamine
N,N -D imethylben zamide
79
Organic Lecture Series
Reduction - Nitriles by LiAlH4
• The cyano group of a nitrile is reduced by
LiAlH4 to a 1°amine
1 . LiA lH4
CH3 CH= CH( CH 2 ) 4 C N
2 . H2 O
6-Octenenitrile
CH3 CH= CH ( CH2 ) 4 CH2 N H2
6-Octen-1-amine
80