18 18-1 OrganicChemistry William H. Brown & Christopher S. Foote.

1818

18-1

OrganicOrganic

ChemistryChemistryWilliam H. Brown &William H. Brown &

Christopher S. FooteChristopher S. Foote

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18-2

CarboxylCarboxyl

DerivativesDerivatives

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18-3

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

An acidchloride An ester

An acidanhydride

OO

RCCl RCOR'RCOCR'

O

RC-OH H-Cl

O

RC-OH H-OCR'

O

RC-OH H-OR'

O

O O

1818

18-4

Carboxyl DerivativesCarboxyl Derivatives• an amide is formally related to a carboxyl group by

loss of -OH from the carboxyl and -H from ammonia • loss of -OH and -H from an amide gives a nitrile

An amide A nitrile

O

RC NRCNH2

O

RC-OH H-NH2 RC=N

HO H

The enol ofan amide

1818

18-5

Structure: Acid ChloridesStructure: Acid Chlorides The functional group of an acid halide is an acyl

group bonded to a halogen• to name, change the suffix -ic acid-ic acid to -yl halide-yl halide

RC-

O

RCCl

O

CH3CCl

O

CCl

O

ClC(CH2)4CCl

OO

Benzoyl chloride

Ethanoyl chloride(Acetyl chloride)

An acyl chloride(An acid chloride)

An acyl group

Hexanedioyl chloride (Adipoyl chloride)

1818

18-6

Acid ChloridesAcid Chlorides• replacement of -OH in a sulfonic acid by -Cl gives a

sulfonyl chloride

SOHH3C

O

O

CH3SOH

O

O

SClH3C

O

O

CH3SCl

O

O

Methanesulfonicacid

p-Toluenesulfonic acid

Methanesulfonyl chloride(Mesyl chloride, MsCl)

p-Toluenesulfonyl chloride (Tosyl chloride, TsCl)

1818

18-7

Acid AnhydridesAcid 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 acidacid of the parent acid by anhydrideanhydride

Acetic benzoic anhydride

Benzoic anhydrideAcetic anhydride

COCCH3COCCH3CH3COC

OOOO OO

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18-8

Acid AnhydridesAcid Anhydrides Cyclic anhydrides are named from the

dicarboxylic acids from which they are derived

Maleic anhydride

O

O

O

Phthalic anhydride

Succinicanhydride

O

O

O

O

O

O

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18-9

Acid AnhydridesAcid Anhydrides A phosphoric acid 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

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18-10

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

Ethyl ethanoate(Ethyl acetate)

Diethyl butanedioate(Diethyl succinate)

O

OO

OO

O

O

O

Isopropyl benzoate

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18-11

Esters Esters Cyclic esters are called lactones

• name the parent carboxylic acid, drop the suffix -ic -ic acidacid, and add -olactone-olactone

5-Hexanolactone(δ-Caprolactone)

4-Butanolactone(γ-Butyrolactone)

3-Butanolactone(β-Butyrolactone)

δβ

α

γβ

αβ

α

γO O

OO O

O

H3C CH3

23 1

22 1

3

1

3 4 45

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18-12

AmidesAmides 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 N-N-

N-Methylacetamide(a 2° amide)

Acetamide(a 1° amide)

CH3CNH2 CH3CNHCH3 HCN(CH3)2

N,N-Dimethyl-formamide (DMF)

(a 3° amide)

O O O

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18-13

AmidesAmides Cyclic amides are called lactams Name the parent carboxylic acid, drop the suffix

-ic acid-ic acid and add -lactam-lactamα

β

γ

δ ε6-Hexanolactam(ε-Caprolactam)

α

βH3C

O

NH

O

NH1

2 1

234

5 63

3-Butanolactam(β-Butyrolactam)

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18-14

PenicillinsPenicillins The penicillins are a family of β-lactam

antibiotics

N

S CH3

CH3

COOHO

NC

H

O

CH2

Penicillin G

H H

the penicillins differin the group bondedto the acyl carbon

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18-15

PenicillinsPenicillins Amoxicillin

N

S

COOHO

HN

O

NH2

HH

HO

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18-16

CephalosporinsCephalosporins The cephalosporins are also β-lactam

antibiotics

NO

NC

H

N

S

COOHCH3

S

NH2N

Cefetamet

H

CH3O

H

the cephalosporins differin the group bonded to theacyl carbon and the side chainbonded to the thiazine ring

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18-17

CefetametCefetamet

NO

NC

H

N

S

COOHCH3

S

NH2N

H

OCH3

H

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18-18

NitrilesNitriles The functional group of a nitrile is a cyano group IUPAC: name as an alkanenitrilealkanenitrile Common: drop the -ic acid-ic acid and add -onitrile-onitrile

CH3C N C N CH2C N

Ethanenitrile(Acetonitrile)

Benzonitrile Phenylethanenitrile(Phenylacetonitrile)

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18-19

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

ONH

O

O

NH

O

OO

SNH2

O

pKa 8.3pKa 9.7pKa 10PhthalimideSuccinimideBenzenesulfonamideAcetamide

pKa 15-17

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18-20

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

Phthalimide A resonance-stabilized anion

+N-H

O

O O

O

N- N

O-

O

H3O++ H2O

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18-21

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 H2 O

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18-22

IR SpectroscopyIR SpectroscopyAdditional Stretchings (cm-1)

O-H at 2400-3400C-O at 1210-1320

(2° have one N-H peak)(1° have two N-H peaks)N-H at 3200 and 3400

C-O at 900-1300

C-O at 1000-1100and 1200-1250

(cm-1)C=O Stretch

1740-1760 and

1800-1850

1630-1680

1735-1800

1700-1725

O

O

O

O

RCOH

RCOCR

RCOR

RCNH2

Cmpd

O

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18-23

NMR SpectroscopyNMR Spectroscopy 1H-NMR

• H on the α-carbon to a C=O group are slightly deshielded and come into resonance at δ 2.1-2.6

• H on the carbon of the ester oxygen are more strongly deshielded and come into resonance at δ 3.7-4.7

13C-NMR • the carbonyl carbons of esters show characteristic

resonance at δ 160-180

Methyl propanoate

δ 3.68(s)δ 2.33(q)O

CH3-CH2-C-O-CH3

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18-24

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

Y

O O-

Nu Y

Substitution product

:

:

:R

CNu

O

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18-25

Characteristic ReactionsCharacteristic Reactions• in this general reaction, we have shown the leaving

group as an anion to illustrate an important point about them: the weaker the base, the better the leaving group

Increasing basicity

Increasing leaving ability

X-RO-R2N- RCO-O

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18-26

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

ORCXRCOCR'RCOR'RCNH2

Increasing reactivity toward nucleophilic acyl substitution

Amide Ester Anhydride Acid halide

OO OO

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18-27

Rexn with HRexn with H22O - RCOClO - RCOCl• low-molecular-weight acid chlorides react rapidly with

water • higher molecular-weight acid chlorides are less

soluble in water and react less readily

++

O O

CH3CCl H2O CH3COH HCl

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18-28

Rexn with HRexn with H22O - RCOO - RCO22OROR• 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

CH3COCCH3

O OH2O CH3COH

O O

HOCCH3++

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18-29

Rexn with HRexn 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 to form a tetrahedral carbonyl addition intermediate

• collapse of this intermediate gives the carboxylic acid and alcohol

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18-30

Rexn with HRexn with H22O - EstersO - Esters Acid-catalyzed ester hydrolysis

R OCH3

CO

H2OH+

OHC

ROCH3

OHH+

R OHCO

CH3OH+ +

Tetrahedral carbonyladdition intermediate

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18-31

Rexn with HRexn with H22O - EstersO - 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

• hydrolysis of an ester in aqueous base involves formation of a tetrahedral carbonyl addition intermediate followed by its collapse and proton transfer

O

RCOCH3 NaOHH2O

O

RCO- Na

+ CH3OH++

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18-32

Rexn with HRexn with H22O - AmidesO - Amides Hydrolysis of an amide in aqueous acid requires

1 mole of acid per mole of amide

2-Phenylbutanoic acid2-Phenylbutanamide

++ +heat

H2 O HClH2 O

NH4+ Cl

-

PhNH2

O

PhOH

O

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18-33

Rexn with HRexn with H22O - AmidesO - Amides Hydrolysis of an amide in aqueous base requires

1 mole of base per mole of amide

CH3CNH

O

NaOH H2O

CH3CO-Na+O

H2N

AnilineSodium acetate

N-Phenylethanamide(N-Phenylacetamide, Acetanilide)

+

+heat

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18-34

Rexn with HRexn with H22O - NitrilesO - Nitriles The cyano group is hydrolyzed in aqueous acid

to a carboxyl group and ammonium ion

Ammoniumhydrogen sulfate

Phenylacetic acid

Phenylacetonitrile

+

heat++CH2C

CH2COH

N 2H2 O H2 SO4H2 O

NH4+HSO4

-O

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18-35

Rexn with HRexn with H22O - NitrilesO - Nitriles• protonation of the cyano nitrogen gives a cation that

reacts with water to give an imidic acid• keto-enol tautomerism of the imidic acid gives the

amide

R-C N H2OH

+

R-C

OH

NH

O

R-C-NH2

An imidic acid(enol of an amide)

+

An amide

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18-36

Rexn with HRexn 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

Undecanenitrileheat

++CH3(CH2)9 C H2 O NaOHH2 O

Undecanoic acidSodium undecanoate

CH3(CH2)9 CO-Na

+ HCl

H2 OCH3(CH2)9 COH

OO

N

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18-37

Rexn with HRexn with H22O - NitrilesO - Nitriles Hydrolysis of nitriles is a valuable route to

carboxylic acids

heat

Benzaldehyde

Benzaldehyde cyanohydrin

(Mandelonitrile)

2-Hydroxyphenyl-acetic acid

(Mandelic acid)

CH

HO

CC

H

N CHCOHH2 SO4, H2O

ethanol, water

HCN, KCN

HO

O

O

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18-38

Rexn with AlcoholsRexn 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

Butanoyl chloride

Cyclohexyl butanoate

+

Cyclohexanol

HO

HCl

Cl

O

+

O

O

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18-39

Rexn with AlcoholsRexn with Alcohols• sulfonic acid esters are prepared by the reaction of an

alkane- or arenesulfonyl chloride with an alcohol or phenol

S-ClH3C

O

O

C OH

C6H13

H

H3C

O

O

CH3O-SC

C6H13

H

H3C

+

(R)-2-Octanolp-Toluenesulfonylchloride

(Tosyl chloride; TsCl)

pyridine

(R)-2-Octyl p-toluenesulfonate[(R)-2-Octyl tosylate]

1818

18-40

Rexn with AlcoholsRexn with Alcohols Acid anhydrides react with alcohols to give one

mole of ester and one mole of carboxylic acid

Acetic acidEthyl acetate

EthanolAcetic anhydride

+

+

O

OO

CH3COCCH3 HOCH2CH3

CH3COCH2CH3 CH3COH

O

1818

18-41

Rexn with AlcoholsRexn with Alcohols• cyclic anhydrides react with alcohols to give one ester

group and one carboxyl group

1-Methylpropyl hydrogen phthalate(sec-Butyl hydrogen phthalate)

2-Butanol(sec-Butyl alcohol)

+

Phthalicanhydride

O

O

O

O

O

O

OH

HO

1818

18-42

Rexn with AlcoholsRexn with Alcohols• aspirin is synthesized by treatment of 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

1818

18-43

Rexn with AlcoholsRexn with Alcohols Esters react with alcohols in the presence of an

acid catalyst in a reaction called transesterification, an equilibrium reaction

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

O

HO

O

O

1818

18-44

Rexn with Ammonia, etc.Rexn 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

+ +

Hexanoylchloride

Ammonia Hexanamide Ammoniumchloride

2NH3 NH4+Cl-Cl

O

NH2

O

1818

18-45

Rexn with Ammonia, etc.Rexn with Ammonia, etc. Acid anhydrides react with ammonia, and 1° and

2° amines to form amides.• 2 moles of ammonia or amine are required

Ammonia+

Ammoniumacetate

Ethanamide(Acetamide)

+

Aceticanhydride

O O OCH3COCCH3 2NH3 CH3CNH2 CH3CO

-NH4

+O

1818

18-46

Rexn with Ammonia, etc.Rexn 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

Amides do not react with ammonia, or 1° or 2° amines

PhenylacetamideEthyl phenylacetate

+ +NH3Ph

O

O

PhNH2

O

HO

Ethanol

1818

18-47

InterconversionsInterconversions

QuickTime™ and aPhoto - JPEG decompressor

are needed to see this picture.

1818

18-48

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

1818

18-49

Rexns with GrignardsRexns with Grignards• treatment of a formic ester with 2 moles of Grignard

reagent followed by hydrolysis with aqueous acid gives a 2° alcohol

+

magnesium alkoxide salt

A secondaryalcohol

An ester offormic acid

OH

R

HCOCH3 2RMgX

H2 O, HClHC-R + CH3OH

O

1818

18-50

Rexn with GrignardsRexn with Grignards• treatment of an ester other than formic with a

Grignard reagent followed by hydrolysis in aqueous acid gives a 3° alcohol

magnesium alkoxide salt

+

A tertiaryalcohol

An ester other than a formate

O

R

OH

CH3COCH3 2RMgX

H2 O, HClCH3C-R + CH3OH

1818

18-51

Rexns with GrignardsRexns with Grignards1. 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)

CH3-C-OCH3 R MgBr

O– [MgBr]+

CH3-C OCH3

R

O

R

CH3-C CH3O- [MgBr]+

+

+

A magnesium salt(a TCAI)

A ketone

O

1818

18-52

Reaction with GrignardsReaction with Grignards• 3. reaction of the ketone with a 2nd mole of RMgX

gives a second TCAI• 4. treatment with aqueous acid gives the alcohol

R

O

CH3-C R MgBr

R

O- [MgBr]+

CH3-C-RH2O, HCl

OH

R

CH3-C-R

Magnesium salt

A ketone

+

A tertiary alcohol

1818

18-53

Rexns with RLiRexns 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

RCOCH3

1. 2R'Li

2. H2O, HClR-C-R'

O

R'

OH

+ CH3OH

1818

18-54

Gilman ReagentsGilman 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

1. (CH3)2CuLi, ether, -78°C

2. H2OPentanoyl chloride 2-Hexanone

Cl

O O

1818

18-55

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°C

2. H2OO

H3COCl

O

O

H3COO

1818

18-56

Redn - Esters by LiAlHRedn - Esters by LiAlH44 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

Methanol2-Phenyl-1-propanolMethyl 2-phenyl-

propanoate

+1. LiAlH4 , ether

2. H2O, HCl

CH3OHPhOCH3

O PhOH

1818

18-57

Redn - Esters by LiAlHRedn - Esters by LiAlH44 Reduction occurs in three steps plus workup

:H- R-C-H

H

(3):

H2OR- C-H

H

OH

A primary alcohol

R-C

H

O +

(4)

O-

O

R-C-OR' :H- R-C-OR'

H

O–

R-C

H

O -:OR'+

An ester A tetrahedral carbonyladdition intermediate

+(1) (2)

An aldehyde

:

1818

18-58

Redn - Esters by LiAlHRedn - Esters by LiAlH44 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

NaBH4

EtOHO

O O

O

OH O

1818

18-59

Redn - Esters by DIBAlHRedn - 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°C

2. H2O, HCl

CH3OH

OCH3

O

H

O

1818

18-60

Redn - Amides by LiAlHRedn - Amides by LiAlH44 LiAlH4 reduction of an amide gives a 1°, 2°, or 3°

amine, depending on the degree of substitution of the amide

Octanamide 1-Octanamine

1. LiAlH42. H2ONH2

O

NH2

N,N-Dimethylbenzamide N,N-Dimethylbenzylamine

1. LiAlH4

2. H2ON

O

N

1818

18-61

Redn - Amides by LiAlHRedn - Amides by LiAlH44 The mechanism is divided into 4 steps

• Step 1: transfer of a hydride ion to the carbonyl carbon

• Step 2: formation of an oxygen-aluminum bond

CR NH2

O

CR

NH2

O

H

AlH3-

CR

NH2

O-

AlH3

H

HAlH3

-

:(1) (2)

1818

18-62

Redn - Amides by LiAlHRedn - Amides by LiAlH44• Step 3: redistribution of electrons gives an iminium

ion• Step 4: transfer of a second hydride ion completes the

reduction to the amine

:

CR

N

O

H

AlH3-

H H

CR

N

H

H H

H:-

CR

N

HH

H H

An iminium ion

(3) (4)

:

1818

18-63

Redn - Nitriles by LiAlHRedn - 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)4C1. LiAlH4

2. H2O

CH3CH=CH(CH2)4CH2NH2

N

1818

18-64

InterconversionsInterconversionsProblem:Problem: show reagents and experimental conditions to bring about each reaction

PhCH2COHO

PhCH2CClO

PhCH2COCH3

O

PhCH2CH2OH

PhCH2CNH2

O

PhCH2CHO

PhCH2CH2NH2

(a)

(c)

(b)

(d)

(f)

(e)

(g)

(j) (h) (i)

(k)

1818

18-65

Hofmann RearrangementHofmann Rearrangement When a 1° amide is treated with bromine or

chlorine in aqueous NaOH or KOH, • the carbonyl carbon is lost as carbonate ion, and• the amide is converted to an amine of one fewer

carbon atoms

PhNH2

H3C H

O

Br2 , NaOH

H2O

Ph NH2

H3C HNa2CO3

(S)-2-Phenyl-propanamide

+

(S)-1-Phenyl-ethanamine

1818

18-66

Hofmann RearrangementHofmann RearrangementStage 1: acid-base reaction gives an amide anion, which

reacts as a nucleophile with Br2

Stage 2: a 2nd acid-base reaction followed by elimination of Br- gives a nitrene, an electron-deficient species, that rearranges to an isocyanate

:: +-

An N-bromoamideAn amide anion

R C N H

H

O

N

H

CRBr Br

O

N

H

BrCRHO-

:Br-: :O

HO-

-H2OAn acyl nitrene

-:Br -R-C-N-Br

H

O :R-C-N-Br

O :: R-C-N

O ::

An isocyanate

R-N=C=O:

1818

18-67

Hofmann RearrangementHofmann Rearrangement• Stage 3: reaction of the isocyanate with water gives a

carbamic acid

• Stage 4: decarboxylation of the carbamic acid gives the primary amine

An isocyanateA carbamic acid

+ H2O R-N-C-OHH

OR-N=C=O

+ H2OR-N-C-OHH

OR-NH2

1818

18-68

Prob 18.19Prob 18.19Propose a structural formula for each compound.

1H-NMR 13C-NMR13C-NMR1H-NMR

22.4521.06

4.10 (t, 2H)2.09 (s, 3H)

0.92 (d, 6H)1.52 (m, 2H)1.70 (m, 1H)

25.05

37.31 63.12171.15161.11

70.01

27.71 19.008.08 (s, 1H)

3.95 (d, 2H)1.96 (m, 1H)0.96 (d, 6H)

(b)(a) C7H1 4O2C5H1 0O2

1818

18-69

Prob 18.19 (cont’d)Prob 18.19 (cont’d)Propose a structural formula for each compound.

13C-NMR1H-NMR

14.25

1.18 (d, 6H)1.26 (t, 3H)2.51 (m, 1H)

4.13 (q, 2H) 19.01

34.04 60.17177.16

(c) C6H1 2O2

1H-NMR 13C-NMR

1H-NMR 13C-NMR

13C-NMR1H-NMR2.29 (m, 2H)2.50 (t, 2H)4.36 (t, 2H)

22.17

27.79 68.58177.81

(f)

(d)

(e)

1.28 (t, 6H)3.36 (s, 2H)4.21 (q, 4H)

14.0741.69

61.43166.52

170.51 52.92 52.32

21.52

4.42 (q, 1H)3.80 (s, 3H)1.68 (d, 3H)

C4H7 ClO2

C7H1 2O4

C4H6 O2

1818

18-70

Prob 18.20Prob 18.20Draw a structural formula for the product formed on treatment of benzoyl chloride with each reagent.

(a) (b)OH OH, pyridine

(d)(c) (two equivalents)SH, pyridine NH2

(e) (f) (CH3)2CuLi, then H3O+O- Na+

O

(h)

(g) NH2, pyridineCH3O

(two equivalents), then H3O+C6H5 MgBr

1818

18-71

Prob 18.26Prob 18.26Draw a structural formula for the product of treating this αβ-unsaturated ketone with each reagent.

(a) (b)

(c)1. LiAlH4 , THF

2. H2O

H2 (1 mol)

Pd, EtOH

NaBH4

CH3OH

OEt

O O

(d)1. DIBALH, -78°

2. H2O

1818

18-72

Prob 18.28Prob 18.28Draw a structural formula for the product of treating this anhydride with each reagent.

heatheat(a) (b) (c)

H2 O, HCl H2 O, NaOH 1. LiAlH4

2. H2O

O

H

H

O

O

(e)(d) CH3OH NH3 (2 moles)

1818

18-73

Prob 18.31Prob 18.31Show how to bring about each step in this conversion of nicotinic acid to nicotinamide.

O

COH

NNicotinic acid (Niacin)

O

COCH2CH3

N

O

CNH2

NEthyl nicotinate Nicotinamide

? ?

1818

18-74

Prob 18.32Prob 18.32Complete these reactions.

CH3CCl

O

CH3COCH3

O

NH2

CH3O NH2

HN

HN

CH3(CH2)5CHO

CH3COCCH3

O O+(a)

+(b) 2

(d)

(c) +

+

1818

18-75

Prob 18.35Prob 18.35Draw structural formulas for the products of complete hydrolysis of each compound in hot aqueous acid.

Meprobamate

Pentobarbital

Phenobarbital

(a) (b)H2N O O NH2

O O

NH

HNO O

O

NH

HNO O

O

(c)

1818

18-76

Prob 18.36Prob 18.36Show reagents to bring about each step in this synthesis of anthranilic acid.

(3)

Phthalic anhydride

Anthranilic acid

(1) (2)

COH

CNH2

O

OCNH2

CO-NH4+O

O

COH

NH2

O

O

O

O

1818

18-77

Prob 18.37Prob 18.37Propose a mechanism for each step in this sequence.

A carbamateAn isocyanateA primaryamide

+

O O

RCNH2 Br2 RN=C=OCH3O

-Na

+

CH3OH

CH3OHRNHCOCH3

1818

18-78

Prob 18.38Prob 18.38Propose a mechanism for each step in this sequence.

CH3O-Na+O

COCH3

O

CH3OH

(R)-(+)-Pulegone

Br2

OBr

Br

1818

18-79

Prob 18.39Prob 18.39Show how to prepare the insect repellent DEET from 3-methyltoluic acid.

N,N-Diethyl-m-toluamideDEET)

3-Methylbenzoic acid(m-Toluic acid)

N

O

OH

O

1818

18-80

Prob 18.40Prob 18.40Show how to prepare isoniazid from 4-pyridinecarboxylic acid.

4-Pyridine-carboxylic acid

N COH?

N CNHNH2

4-Pyridine-carboxylic acid hydrazide

(Isoniazid)

OO

1818

18-81

Prob 18.41Prob 18.41Show how to bring about this conversion.

C CH2COCH2CH=CH2

Phenylacetylene Allyl phenylacetate

CH

O

1818

18-82

Prob 18.42Prob 18.42Propose a mechanism for the formation of this bromolactone, and account for the observed stereochemistry of each substituent on the cyclohexane ring.

CH3

COOH

COOH Br2

O

Br

CH3

O

COOH

O

HO

COOH

OH

A bromolactone

PGE1 (alprostadil)

manysteps

1818

18-83

Prob 18.43Prob 18.43Propose a mechanism for this reaction.

5,5-Diethylbarbituric acid (Barbital)

Diethyldiethylmalonate

Urea

+

12

3456

+

OH2N

H2N

NH

NH

O

O

O

1. EtO-Na

+

2. H2O

2EtOH

OEt

OEt

O

O

1818

18-84

Prob 18.44Prob 18.44Propose a synthesis of this β-chloroamine from anthranilic acid.

several steps

2-Aminobenzoic acid (Anthranilic acid)

+ 2NH2

COOH

O

O

N

O

Cl

1818

18-85

Prob 18.45Prob 18.45Show reagents for the synthesis of 5-nonanone from 1-bromobutane as the only organic starting material.

O

5-NonanoneOH

O

BrC N1-Bromobutane

1818

18-86

Prob 18.46Prob 18.46Describe a synthesis of procaine from the three named starting materials.

Procaine

+

+

4-Aminobenzoic acid

Ethylene oxideDiethylamine

ON

H2N

O

OH

H2N

O

HON

NH

O

1818

18-87

Prob 18.47Prob 18.47The following sequence converts (R)-2-octanol to (S)-2-octanol. Propose structural formulas for A and B, and specify the configuration of each.

(S)-2-Octanol

(R)-2-Octanol

pyridineC

H3C

OHH

C6H1 3

C

CH3

HOH

C6H1 3

CH3COO-Na

+

DMSO

1. LiAlH4

2. H2O

p-TsCl

B

A

1818

18-88

Prob 18.48Prob 18.48Propose a mechanism for this reaction.

+

+

Diethyl carbonateButylamine

Ethyl N-butylcarbamate

EtOH

EtO OEt

O

EtO NH

O

H2N

1818

18-89

Prob 18.49Prob 18.49Propose a mechanism for this reaction.

+

Tolbutamide(Oramide, Orinase)

Sodium salt of p-toluenesulfonamide

A carbamic ester

NH

SNH

H3C

O O O

EtO NH

ONH- Na+S

O O

1818

18-90

Prob 18.50Prob 18.50Show how each hypoglycemic drug can be synthesized by converting an appropriate amine to a carbamate ester, and then treating its sodium salt with a substituted benzenesufonamide.

Tolazamide(Tolamide, Tolinase)

Gliclazide(Diamicron)

(a) (b)NH

SNH

NO O O

NH

SNH

O O ON

1818

18-91

Prob 18.51Prob 18.51Propose a mechanism for Step 1, and reagents for Step 2 in the synthesis of the antiviral agent amantadine.

Brin H2SO4

CH3C N

NHCCH3

O

NH2(2)

(1)

1-Bromoadamantane

Amantadine

1818

18-92

Prob 18.52Prob 18.52• Propose structural formulas for intermediates A-F and

for the configuration of the bromoepoxide.

HOOCCOOH

H OH

1. CH3CH2OH, H+

O, H+

C (C9H18O4) D

5. NaBr, DMSO

4. TsCl, pyridine

3. LiAlH4, then H2O

A (C8H14O5)

F (C4H8OBr2)

7. KOH

B

6. H2O, CH3COOH

BrO

2.

1 2 3

4 5 E 6

7

(S)-Malic acid

A bromoepoxide

1818

18-93

Prob 18.53Prob 18.53Show reagents for the synthesis of (S)-Metolachlor from the named starting materials

NO

(S)-Metolachlor

ClO

HNO

NH2

+

2-Ethyl-6-methyl- aniline

Chloroacetic acid

Acetone

1 2

3

5

+

4CH3OH

Methanol+ OCH3

OCl

OO

NO

OHCl

O

1818

18-94

Derivatives of Derivatives of

Carboxylic Carboxylic AcidsAcids

End Chapter 18End Chapter 18