chapter 18 functional derivatives of carboxylic acids
DESCRIPTION
Carboxyl Derivatives In this chapter, we study five classes of organic compounds. under the structural formula of each is a drawing to help you see its relationship to the carboxyl group.TRANSCRIPT
18-18-11
FunctionalFunctionalDerivatives ofDerivatives ofCarboxylic AcidsCarboxylic Acids
Chapter 18Chapter 18
18-18-22
Carboxyl DerivativesCarboxyl Derivatives In this chapter, we study five classes of organic
compounds.• under the structural formula of each is a drawing
to help you see its relationship to the carboxyl group.
H-NH2H-Cl H-OR'RC-OHO
H-OCR'O
RC=NHO H
RC-OHO
RC-OHO
RC-OHO
-H2O -H2O -H2O -H2O -H2O
RC NRCNH2O
RCClO
RCOR'O
RCOCR'O O
The enol ofan amide
An acidchloride
An esterAn acidanhydride
An amide A nitrile
18-18-33
18.1 18.1 A.A. Structure: Acid ChloridesStructure: Acid Chlorides 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-ic acid to -yl halide.-yl halide.
CH3CClOO
RC- Cl
OCl
OCl
O
Benzoyl chlorideEthanoyl chloride(Acetyl chloride)
An acyl group
Hexanedioyl chloride(Adipoyl chloride)
18-18-44
Sulfonyl ChloridesSulfonyl Chlorides• replacement of -OH in a sulfonic acid by -Cl gives
a sulfonyl chloride.
SOHH3CO
O
CH3SOHO
O
SClH3CO
O
CH3SClO
O
Methanesulfonicacid
p-Toluenesulfonic acid
Methanesulfonyl chloride(Mesyl chloride, MsCl)
p-Toluenesulfonyl chloride (Tosyl chloride, TsCl)
18-18-55
B.B. Acid Anhydrides Acid Anhydrides The functional group of an acid anhydride has
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 acidacid of the parent acid by
anhydride.anhydride.
COCO O
CH3COCCH3
O O
Benzoic anhydrideAcetic anhydride
ethanoic anhydride
18-18-66
Acid AnhydridesAcid Anhydrides
Cyclic anhydrides are named from the dicarboxylic acids from which they are derived.
Maleic anhydride
O
O
OPhthalic
anhydrideSuccinic
anhydride
O
O
O
O
O
O
18-18-77
Phosphoric AnhydridesPhosphoric Anhydrides A phosphoric anhydride contains two phosphoryl
groups bonded to an oxygen atom.
Triphosphoric acid
Diphosphate ion(Pyrophosphate ion)
Diphosphoric acid(Pyrophosphoric acid)
HO-P-O-P-OH -O-P-O-P-O-
HO-P-O-P-O-P-OH -O-P-O-P-O-P-O-
Triphosphate ion
OH
O
OH
O
O-
O
O-
O
O-
O
O-
O
O-
O
O-
O
O- O-
OO
18-18-88
C.C. Esters 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-ic acid to –ate.–ate.
O
OEtO
O
OEtO
O
O
Ethyl ethanoate(Ethyl acetate)
Diethyl butanedioate(Diethyl succinate)
Isopropyl benzoate
18-18-99
Esters Esters Cyclic esters are called lactones.lactones. name the parent carboxylic acid, drop the
suffix -ic acid-ic acid and add –olactone.–olactone.
4-Butanolactone-Butyrolactone)
3-Butanolactone-Butyrolactone)
O OO O
H3C23
1213 4
6-Hexanolactone-Caprolactone)
O
O2 13
45 6
4-hydroxybutanoic acid lactone
18-18-1010
Esters of Phosphoric AcidEsters of Phosphoric Acid• phosphoric acid forms mono-, di-, and triesters.• name by giving the name of the alkyl or aryl
group(s) bonded to oxygen followed by the word phosphate.phosphate.
• in more complex phosphoric esters, it is common to name the organic molecule and then indicate the presence of the phosphoric ester by the word phosphatephosphate or the prefix phospho-.phospho-.
OCH3
CH3OPOHO C-H
CH2-O-P-O-
CHOHO
O-
O
N
HO
H3C
CH2O-P-O-
O-
CHO OCO-
CCH2
O P O-
O-
OO
Dimethylphosphate
Glyceraldehyde3-phosphate
Pyridoxal phosphate Phosphoenol-pyruvate
18-18-1111
D.D. Amides Amides The functional group of an amide is an acyl
group bonded to a nitrogen atom.• IUPAC: drop -oic acidoic acid from the name of the parent
acid and add –amide.–amide.• if the amide nitrogen is bonded to an alkyl or aryl
group, name the group and show its location on nitrogen by NN-.-.
CH3CNH2O
CH3C-NH
CH3
OH-C-N
CH3
CH3
O
N-Methylacetamide(a 2° amide)
Acetamide(a 1° amide)
N,N-Dimethyl-formamide (DMF)
(a 3° amide)
18-18-1212
AmidesAmides Cyclic amides are called lactams.lactams.
• name the parent carboxylic acid, drop the suffix --ic acidic acid and add –lactam.–lactam.
6-Hexanolactam-Caprolactam)
H3C
O
NH
O
NH1
2 123
45 63
3-Butanolactam-Butyrolactam)
18-18-1313
PenicillinsPenicillins• the penicillins are a family of -lactam antibiotics.
NHH2N
HHHO
N
S
COOHO
Amoxicillin(a -lactam antibiotic)
The penicillinsdiffer in thegroup bondedto the acyl carbon
-lactam
O
18-18-1414
CephalosporinsCephalosporins
• the cephalosporins are also -lactam antibiotics.
N
S
MeCOOH
O
O
NHNH2
HH
The cephalosporins differ in thegroup bonded to the acyl carbon andthe side chain of the thiazine ring
Cephalexin(Keflex)
-lactam
18-18-1515
ImidesImides The functional group of an imide is two acyl
groups bonded to nitrogen.• both succinimide and phthalimide are cyclic
imides.
PhthalimideSuccinimide
NH NH
O O
OO
18-18-1616
E.E. Nitriles Nitriles The functional group of a nitrile is a cyano group.
• IUPAC names: name as an alkanenitrile..alkanenitrile..• common names: drop the -ic acid-ic acid and add -onitrile-onitrile
CH3C N C N CH2C N
Ethanenitrile(Acetonitrile)
Benzonitrile Phenylethanenitrile(Phenylacetonitrile)
18-18-1717
Naming SummaryNaming Summary
Open chain Cyclic
•pentanoic acid cyclopentanecarboxylic acid•pentanoyl chloride cyclopentanecarbonyl chloride•pentanoic anhydride cyclopentanecarboxylic acid•ethanoic methanoic anhydride butandioic anhydride•ethyl pentanoate ethyl cyclopentanecarboxylate•pentanamide cyclopentanecarboxamide•pentanenitrile cyclopentanecarbonitrile
4-aminopentanoic acid lactam
4-hydroxypentanoic acid lactone
18-18-1818
18.2 18.2 Acidity of N-H bondsAcidity of N-H bonds 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.
CH3CNH2
O
O
OSNH2 NH
O
O
NH
O
O
pKa 8.3pKa 9.7pKa 10PhthalimideSuccinimideBenzenesulfonamideAcetamide
pKa 15-17
18-18-1919
Acidity of N-H bondsAcidity 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 N
O
OA resonance-stabilized anion
N
O
O
18-18-2020
Acidity of N-HAcidity of N-H
• imides such as phthalimide readily dissolve in aqueous NaOH as water-soluble salts.
(stronger acid)
(weakeracid)
(weakerbase)
(strongerbase)
pKa 15.7pKa 8.3
++
O
O
NH N- Na+
O
O
NaOH H2O
18-18-2121
18.3 18.3 Characteristic ReactionsCharacteristic Reactions
Nucleophilic acyl substitution:Nucleophilic acyl substitution: an addition-elimination sequence resulting in substitution of one nucleophile for another.
Tetrahedral carbonyladdition intermediate
-
++ CNuR
CY R
CNuR
O
Y
O O
:Nu- :Y-
Substitution product
:
18-18-2222
Characteristic ReactionsCharacteristic Reactions
• in the general reaction, we showed the leaving group as an anion to illustrate an important point about them: the weaker the base, the better the leaving group.
R2N- RO-O
RCO- X-
Increasing basicity
Increasing leaving ability
18-18-2323
Characteristic ReactionsCharacteristic Reactions• halide ion is the weakest base and the best
leaving group; acid halides are the most reactive toward nucleophilic acyl substitution.
• amide ion is the strongest base and the poorest leaving group; amides are the least reactive toward nucleophilic acyl substitution.
18-18-2424
18.4 A. 18.4 A. Reaction with HReaction with H22O - Acid ChloridesO - 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.
CH3CClO
H2O CH3COHO
HCl++Acetyl chloride
18-18-2525
B.B. Reaction with H Reaction with H22O - AnhydridesO - 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.
CH3COCCH3O O
H2O CH3COHO
HOCCH3O
++Acetic anhydride
18-18-2626
Reaction with HReaction with H22O - AnhydridesO - Anhydrides
• Step 1: addition of H2O to give a TCAI.
• Step 2: protonation followed collapse of the TCAI.
O
CH3 -C-O-C-CH3
H
HO-H
O
O HH
CH3 -C-O-C-CH3
H
HO-H
CH3 -C-O-C-CH3O
OH
H
H-O-HH
++
+
Tetrahedral carbonyladdition intermediate
+OO
OCH3-C-O-C-CH3
O
HOH
H+ O
H H
CH3 CO
OO C
OCH3
H
HOH
H+
CH3 C OO
OC CH3
OH
H
H
H
H+ H
+O
O
18-18-2727
C.C. Reaction with H Reaction with H22O - EstersO - 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.
18-18-2828
Reaction with HReaction with H22O - EstersO - Esters
Acid-catalyzed ester hydrolysis.
R OCH3CO
H2O H+ OHC
ROCH3
OHH+
R OHCO
CH3OH+ +
Tetrahedral carbonyladdition intermediate
18-18-2929
Reaction with HReaction with H22O - EstersO - Esters Hydrolysis of an esters in aqueous base is often
called saponification.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.
• hydrolysis of an ester in aqueous base involves formation of a tetrahedral carbonyl addition intermediate followed by its collapse and proton transfer.
ORCOCH3 NaOH
H2O ORCO- Na+ CH3OH++
18-18-3030
Reaction with HReaction with H22O - EstersO - 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.
R-C-OCH3
OOH R-C
O
OHOCH3 R-C
O
O H
OCH3 R-CO
OHOCH3
(1)+
(2) (3)+ +
18-18-3131
D.D. Reaction with H Reaction with H22O - AmidesO - Amides Hydrolysis of an amide in aqueous acid requires
1 mole of acid per mole of amide.• reaction is driven to completion by the acid-base
reaction between the amine or ammonia and the acid.
2-Phenylbutanoic acid2-Phenylbutanamide
++ + heatH2 O HClH2 O
NH4+ Cl-
PhNH2
O
PhOH
O
18-18-3232
Reaction with HReaction with H22O - AmidesO - 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.
CH3CNHO
NaOH H2O CH3CO-Na+O
H2N
AnilineSodiumacetate
N-Phenylethanamide(N-Phenylacetamide, Acetanilide)
++heat
18-18-3333
Reaction with HReaction with H22O - AmidesO - Amides• Step1: protonation of the carbonyl oxygen gives a
resonance-stabilized cation intermediate.
R CO
NH2 OH HH
OC NH2R
HOC NH2R
H
CO
NH2R
H
H2O
Resonance-stabilized cation intermediate
+
+
++
++
18-18-3434
Reaction with HReaction with H22O - AmidesO - Amides• Step 2: addition of water (a nucleophile) to the
carbonyl carbon (an electrophile) followed by proton transfer gives a TCAI.
• Step 3: collapse of the TCAI and proton transfer.
++ O
HH C
OHNH2R
OH H
COH
NH3+R
O
+COH
NH2R
H
proton transfer from
O to N
R COH
C OHRNH3
H
C
O
NH3+R
OHNH4
+++O
+O
H
18-18-3535
E.E. Reaction with H Reaction with H22O - NitrilesO - Nitriles The cyano group is hydrolyzed in aqueous acid
to a carboxyl group and ammonium ion.
• protonation of the cyano nitrogen gives a cation that reacts with water to give an imidic acid
• keto-enol tautomerism gives the amide.
Ph CH2C N 2H2O H2SO4H2O Ph CH2COH
ONH4
+HSO4-
Ammoniumhydrogen sulfate
Phenylaceticacid
Phenylacetonitrile+
heat++
R-C N H2O H+NH
OHR-C R-C-NH2
O
An imidic acid(enol of an amide)
+An amide
18-18-3636
Reaction with HReaction with H22O - NitrilesO - 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)9C NNaOH, H2O
OCH3(CH2)9COH
CH3(CH2)9CO-Na+O
HCl H2O
NaCl
NH3
NH4Cl
Sodium undecanoate Undecanenitrile+heat
Undecanoic acid+ +
18-18-3737
Reaction with HReaction with H22O - NitrilesO - Nitriles• hydrolysis of nitriles is a valuable route to
carboxylic acids.
CH3(CH2)8CH2Cl KCN CH3(CH2)9C NH2SO4, H2O
CH3(CH2)9COHO
Undecanenitrileheat
Undecanoic acid1-Chlorodecane ethanol, water
CHO HCN, KCN CN
OHH2SO4, H2O COOH
OH
heat
Benzaldehyde Benzaldehyde cyanohydrin(Mandelonitrile)
(racemic)
2-Hydroxyphenylacetic acid(Mandelic acid)
(racemic)
ethanol,water
18-18-3838
18.5 18.5 A.A. Reaction with AlcoholsReaction 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.
Butanoylchloride
Cyclohexyl butanoate
+
Cyclohexanol
HO HClCl
O+ O
O
18-18-3939
Reaction with AlcoholsReaction with Alcohols• sulfonic acid esters are prepared by the reaction
of an alkane- or arenesulfonyl chloride (Section 18.1A) with an alcohol or phenol.
• the key point here is that OH- (a poor leaving group) is transformed into a sulfonic ester (a good leaving group) with retention of configuration at the chiral center.
OHTsCl
OTs
(R)-2-Octanol p-Toluenesulfonylchloride
(Tosyl chloride)
(R)-2-Octyl p-toluenesulfonate[(R)-2-Octyl tosylate]
+ pyridine
18-18-4040
B.B. Reaction with Alcohols Reaction with Alcohols Acid anhydrides react with alcohols to give one
mole of ester and one mole of carboxylic acid.
• cyclic anhydrides react with alcohols to give one ester group and one carboxyl group.
CH3COCCH3O
HOCH2CH3 CH3COCH2CH3
OCH3COH
O
Acetic acidEthyl acetateEthanolAcetic anhydride++
(sec-Butyl hydrogenphthalate
2-Butanol(sec-Butyl alcohol)
+
Phthalicanhydride
O
O
O
OOHHO
O
O
O
18-18-4141
Reaction with AlcoholsReaction with Alcohols• aspirin is synthesized by treating salicylic acid
with acetic anhydride.
Acetylsalicylic acid (Aspirin)
2-Hydroxybenzoic acid
(Salicylic acid)
+
+
Acetic acid
Acetic anhydride
CH3COH
CH3COCCH3
OOCOOH
CH3
O
OHCOOH
O O
18-18-4242
C.C. Reaction with Alcohols Reaction with Alcohols Esters react with alcohols in the presence of an
acid catalyst in an equilibrium reaction called transesterification.transesterification.
Butyl propenoate(Butyl acrylate)
(bp 147°C)
1-Butanol(bp 117°C)
Methyl propenoate(Methyl acrylate)
(bp 81°C)
+
+ HCl
CH3OHMethanol(bp 65°C)
OCH3
OHO
OO
D. Amides are the least reactive acid derivativesD. Amides are the least reactive acid derivatives
18-18-4343
18.6 18.6 A.A. Reaction with Ammonia, etc.Reaction with Ammonia, etc.
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.
ClO
2NH3 NH2
ONH4
+Cl-+ +Hexanoylchloride
Ammonia Hexanamide Ammoniumchloride
18-18-4444
B.B. Reaction with Ammonia, etc. Reaction with Ammonia, etc.
Acid anhydrides react with ammonia, and 1° and 2° amines to form amides.• 2 moles of ammonia or amine are required.
CH3COCCH3
O O2NH3 CH3CNH2
OCH3CO-NH4
+O
+ +
Aceticanhydride
Ammonia Acetamide Ammoniumacetate
18-18-4545
C.C. Reaction with Ammonia, etc. Reaction with Ammonia, etc. Esters react with ammonia, and 1° and 2° amines
to form amides.• esters are less reactive than either acid halides or
acid anhydrides.
D. Amides do not react with ammonia, or 1° or 2° amines.
Ph OEtO
NH3 Ph NH2
OEtOH
PhenylacetamideEthyl phenylacetate
+ +
Ethanol
18-18-4646
D.D. Reaction of Amides Reaction of Amides An unsubstituted amide can be converted into a
nitrile using POCl3.• POCl3 is a dehydrating agent that removes water
from the amide.
2-Phenylbutanenitrile2-Phenylbutanamide
+heatPOCl3
PhNH2
O
Ph
C N
18-18-4747
18.7 18.7 Acid Chlorides with SaltsAcid Chlorides with Salts
Acid chlorides react with salts of carboxylic acids to give anhydrides. • most commonly used are sodium or potassium
salts.
+
Acetyl chloride
Sodium benzoate Acetic benzoicanhydride
+CH3 CCl -OC CH3 COC Na+Cl -Na+O O O O
18-18-4848
18.8 18.8 Interconversions, Fig. 18.1Interconversions, Fig. 18.1
18-18-4949
18.9 18.9 A.A. Reaction with Grignard ReagentsReaction with Grignard Reagents
• treating a formic ester with 2 moles of Grignard reagent followed by hydrolysis in aqueous acid gives a 2° alcohol.
HCOCH3O
2RMgX H2O, HCl HC-RR
OHCH3OH+
magnesium alkoxide salt
A 2° alcoholAn ester offormic acid
+
18-18-5050
Reaction with Grignard ReagentsReaction with Grignard Reagents
• treating an ester other than formic with a Grignard reagent followed by hydrolysis in aqueous acid gives a 3° alcohol.
CH3COCH3O
2RMgX H2O, HCl CH3C-RR
OHCH3OH
magnesium alkoxide salt
+
A 3° alcohol An ester of any acidother than formic acid
+
18-18-5151
Reaction with Grignard ReagentsReaction with Grignard Reagents
1. addition of 1 mole of RMgX to the carbonyl carbon gives a TCAI.
2. collapse of the TCAI gives a ketone (an aldehyde from a formic ester).
OCH3-C-OCH3 R MgX
O
ROCH3CH3-C
[MgX]+
CH3-CR
OCH3O -[MgX]+
1
1+
-
+
A magnesium salt(a tetrahedral carbonyladdition intermediate)
A ketone
2
2
18-18-5252
Reaction with Grignard ReagentsReaction with Grignard Reagents
3. reaction of the ketone with a 2nd mole of RMgX gives a second TCAI.
4. treatment with aqueous acid gives the alcohol.
CH3-CO
RR MgX CH3-C-R
R
O - [MgX]+
H2O, HCl CH3-C-RR
OH
Magnesium saltA ketone
+
A 3° alcohol
33
(4)
18-18-5353
B.B. Reactions with RLi Reactions with RLi
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.
RCOCH31. 2R'Li2. H2O, HCl
R-C-R'O
R'
OH+ CH3OH
18-18-5454
C.C. Gilman Reagents Gilman 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.
• See Chapter 15 for formation of Gilman reagent.
1. (CH3)2CuLi, ether, -78°C2. H2O
Pentanoyl chloride 2-HexanoneCl
O O
18-18-5555
Gilman ReagentsGilman Reagents
• Gilman reagents react only with acid chlorides.• they do not react with acid anhydrides, esters,
amides, or nitriles under the conditions described.
1. (CH3)2CuLi, ether, -78°C2. H2O
O
H3CO Cl
O
O
H3COO
18-18-5656
18.10 18.10 Reduction: RCOCl by LiAlHReduction: RCOCl by LiAlH44
Most reductions of carbonyl compounds now use hydride reducing agents.• Acid chlorides are reduced by LiAlH4 alcohols.
2-Phenyl-1-propanolMethyl 2-phenyl-
propanoate
1. LiAlH4 , ether2. H2O, HCl
Ph Cl
O Ph OH
18-18-5757
18.10 18.10 Reduction: using Li(tBuO)Reduction: using Li(tBuO)33AlHAlH
Specialized hydride reagents can provide specific reductions. • an acid chloride is reduced by Li(tBuO)3AlH to an
aldehyde.
2-Phenyl-1-propanolMethyl 2-phenyl-
propanoate
1. Li(tBuO)AlH, Et2O
2. H2O, HClPh Cl
O Ph CHO
18-18-5858
18.10 18.10 A.A. Reduction: Esters by LiAlHReduction: Esters by LiAlH44
Esters are reduced by LiAlH4 to two alcohols.The alcohol derived from the carbonyl group is
primary.
Methanol2-Phenyl-1-propanolMethyl 2-phenyl-
propanoate
+1. LiAlH4 , ether2. H2O, HCl
CH3OHPh OCH3
O Ph OH
18-18-5959
Reduction: Esters by LiAlHReduction: Esters by LiAlH44
Reduction occurs in three steps plus workup.• Steps 1 and 2 reduce the ester to an aldehyde.
• Step 3 reduction of the aldehyde followed by work up gives a 1° alcohol.
A tetrahedral carbonyladdition intermediate
(1)R C OR'O
+ H R C OR'O
HR C
H
O(2) OR'+
A 1° alcohol
R CH
O+ H (3) R C H
O
H
(4) R C HOH
H
18-18-6060
Reduction: Esters by NaBHReduction: Esters by NaBH44
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.
OEt
O O NaBH4EtOH OEt
OH O
(racemic)
18-18-6161
Reduction: Esters by DIBAlHReduction: 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.
Hexanal
Methyl hexanoate
+
1. DIBALH, toluene, -78°C2. H2O, HCl
CH3OH
OCH3
O
H
O
18-18-6262
B.B. Reduction: Amides by LiAlH Reduction: Amides by LiAlH44
LiAlH4 reduction of an amide gives a 1°, 2°, or 3° amine, depending on the degree of substitution of the amide.
NH2
O1. LiAlH42. H2O
1. LiAlH42. H2O
NMe2
ONMe2
NH2
Octanamide 1-Octanamine
N,N-Dimethylbenzamide N,N-Dimethylbenzylamine
18-18-6363
Reduction: Amides by LiAlHReduction: Amides by LiAlH44
The mechanism is divided into 4 steps.• Step 2: a Lewis acid-base reaction and formation
of an oxygen-aluminum bond.• Step 1: transfer of a hydride ion to the carbonyl
carbon.
R C NH2
O+H AlH3 R C NH2
O
HAlH3
(1) R C NH2
O
H
(2)AlH3
+
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Reduction: Amides by LiAlHReduction: Amides by LiAlH44
• Step 3: redistribution of electrons and ejection of H3AlO- gives an iminium ion.
• Step 4: transfer of a second hydride ion to the iminium ion completes the reduction to the amine.
R C NO
H
AlH3
HH
H
R C NH
HH
R-CH2-NH2
An iminium ion
(3) (4)
A 1° amine
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InterconversionsInterconversionsProblem:Problem: show reagents and experimental conditions to bring about each reaction.
Ph OH
O
OMe
OPh
Ph OH
Ph Cl
O
Ph NH2
Ph NH2
O
Phenylacetic acid
(a) (b) (c)
(d) (e)
(f)
(g) (h)
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C.C. Reduction - Nitriles by LiAlH Reduction - Nitriles by LiAlH44
The cyano group of a nitrile is reduced by LiAlH4 to a 1° amine.
6-Octenenitrile
6-Octen-1-amine
CH3CH=CH(CH2)4C 1. LiAlH42. H2O
CH3CH=CH(CH2)4CH2NH2
N
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IR SpectroscopyIR Spectroscopy
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Derivatives of Derivatives of Carboxylic AcidsCarboxylic Acids
End Chapter 18End Chapter 18