chapter 18 carboxylic acid derivatives

Chapter 18 Carboxylic Acid Derivatives

Lecture 24

Chem 30B

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.

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 NRCNH2

ORCClO

RCOR'O

RCOCR'O O

The enol ofan amide

An acidchloride

An esterAn acidanhydride

An amide A nitrile

Structure: 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

O

Cl

O

Benzoyl chlorideEthanoyl chloride(Acetyl chloride)

An acyl group

Hexanedioyl chloride(Adipoyl chloride)

Sulfonyl 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)

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 acidacid of the parent acid by anhydrideanhydride.

COC

O O

CH3COCCH3

O O

Benzoic anhydrideAcetic anhydride

Acid 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

Phosphoric 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

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

Esters

• LactoneLactone: A cyclic ester.– name the parent carboxylic acid, drop the

suffix -ic acid-ic acid and add -olactone-olactone.

4-Butanolactone-Butyrolactone)

3-Butanolactone-Butyrolactone)

O O

OO

H3C

23

12

1

3 4

6-Hexanolactone-Caprolactone)

O

O2

134

5 6

Esters 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 phosphatephosphate.

• 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

CH3OPOH

OC-H

CH2-O-P-O-

CHO

HO

O-

O

N

HO

H3C

CH2O-P-O-

O-

CHO OCO-

CCH2

O P O-

O-

OO

Dimethylphosphate

Glyceraldehyde3-phosphate

Pyridoxal phosphate Phosphoenol-pyruvate

Amides

• IUPAC: drop -oic acidoic acid from the name of the parent acid and add -amide-amide. For the common name, drop

-ic ic of the parent name 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--.

CH3CNH2

OCH3C-N

H

CH3

OH-C-N

CH3

CH3

O

N-Methylacetamide(a 2° amide)

Acetamide(a 1° amide)

N,N-Dimethyl-formamide (DMF)

(a 3° amide)

Amides

• Lactams: A cyclic amides are called lactams.– Name the parent carboxylic acid, drop the

suffix -ic acid-ic acid and add -lactam-lactam.

6-Hexanolactam-Caprolactam)

H3C

O

NH

O

NH1

2 1

234

5 63

3-Butanolactam-Butyrolactam)

Penicillins

– The penicillins are a family of -lactam antibiotics.

NH

H2N

HH

HO

N

S

COOHO

Amoxicillin(a -lactam antibiotic)

The penicillinsdiffer in thegroup bondedto the acyl carbon

-lactam

O

Cephalosporins

– 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

Imides

• 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

Nitriles

• The functional group of a nitrile is a cyano group– IUPAC names: name as an alkanenitrilealkanenitrile.– common names: drop the -ic acid-ic acid and add

-onitrile-onitrile.

CH3C N C N CH2C N

Ethanenitrile(Acetonitrile)

Benzonitrile Phenylethanenitrile(Phenylacetonitrile)

Acidity 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

O

SNH2 NH

O

O

NH

O

O

pKa 8.3pKa 9.7pKa 10PhthalimideSuccinimideBenzenesulfonamideAcetamide

pKa 15-17

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

2. the imide anion is stabilized by resonance delocalization of the negative charge.

O

O

N N

O

O

A resonance-stabilized anion

N

O

O

Acidity 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

Acidity of N-H

• Saccharin, an artificial sweetener, is an imide.The imide is sufficiently acidic that it reacts with NaOH and aqueous NH3 to form water-soluble salts. The ammonium salt is used to make liquid Saccharin. Saccharin in solid form is the Ca2+ salt.

SNH

O

OOSaccharin

+ NH3 H2O SN- NH4

+

O

OOSaccharin

A water-solubleammonium salt

Characteristic 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

:Nu :Y

Substitution product

O

Characteristic 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

Characteristic 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.

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.

CH3CClO

H2O CH3COHO

HCl++

Acetyl chloride

Reaction with H2O - Anhydrides

– Low-molecular-weight anhydrides react readily with water to give two molecules of carboxylic acid.

– Higher-molecular-weight anhydrides also react with water, but less readily.

CH3COCCH3

O OH2O CH3COH

OHOCCH3

O++

Acetic anhydride

Reaction with H2O - Anhydrides

– Step 1: Addition of H2O to give a TCAI.

O

CH3-C-O-C-CH3

H

H

O-H

O

O HH

CH3-C-O-C-CH3

H

H

O-H

CH3-C-O-C-CH3

O

OH

H

H-O-HH

++

+

Tetrahedral carbonyladdition intermediate

+

OO

Reaction with H2O - Anhydrides

O

CH3-C-O-C-CH3

O

HOH

H+ O

H H

CH3 C

O

O

O C

O

CH3

H

HOH

H+

CH3 C O

O

O

C CH3

OH

H

H

H

H+ H

+O

–Step 2: Protonation followed collapse of the TCAI.

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.

Reaction with H2O - Esters

• Acid-catalyzed ester hydrolysis

R OCH3

CO

H2OH+

OHC

ROCH3

OHH+

R OHCO

CH3OH+ +

Tetrahedral carbonyladdition intermediate

Reaction with H2O - Esters

• SaponificationSaponification: The hydrolysis of an esters in aqueous base.– 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++

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.

R-C-OCH3

O

OH R-C

O

OHOCH3

R-C

O

OH

R-C

O

O

HOCH3(1)

+(2) (3)+ +OCH3

Reaction with H2O - Amides

• Hydrolysis of an amide in aqueous acid requires one 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

++ +heat

H2 O HClH2 O

NH4+ Cl

-

PhNH2

O

PhOH

O

Reaction with H2O - Amides

• Hydrolysis of an amide in aqueous base requires one mole of base per mole of amide.– Reaction is driven to completion by the

irreversible formation of the carboxylate salt.

CH3CNH

O

NaOHH2O

CH3CO-Na+

OH2N

AnilineSodiumacetate

N-Phenylethanamide(N-Phenylacetamide, Acetanilide)

++heat

Reaction with H2O - Amides

– Step1: Protonation of the carbonyl oxygen gives a resonance-stabilized cation intermediate.

R C

O

NH2 OH H

H

O

C NH2R

HO

C NH2R

H

C

O

NH2R

H

H2O

Resonance-stabilized cation intermediate

+

+

++

++

Reaction with H2O - Amides

– Step 2: Addition of water to the carbonyl carbon followed by proton transfer gives a TCAI.

– Step 3: Collapse of the TCAI and proton transfer.

R C

OH

C OHRNH3

H

C

O

NH3+R

OH

NH4+++

O+

OH

++ O

H

H C

OH

NH2RO

H H

C

OH

NH3+R

O

+C

OH

NH2R

H

proton transfer from

O to N

Reaction with H2O - 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

O

NH4+HSO4

-

Ammoniumhydrogen sulfate

Phenylaceticacid

Phenylacetonitrile

+heat

++

R-C N H2O H+

NH

OH

R-C R-C-NH2

O

An imidic acid(enol of an amide)

+

An amide

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)9C NNaOH, H2O

O

CH3(CH2)9COH

CH3(CH2)9CO-Na

+O

HCl H2O

NaCl

NH3

NH4Cl

Sodium undecanoate Undecanenitrile

+heat

Undecanoic acid

+ +

Reaction with H2O - Nitriles

Hydrolysis of nitriles is a valuable route to carboxylic acids.

CHO HCN, KCN CN

OH

H2 SO4, H2O COOH

OH

heat

Benzaldehyde Benzaldehyde cyanohydrin(Mandelonitrile)

(racemic)

2-Hydroxyphenylacetic acid(Mandelic acid)

(racemic)

ethanol,water

CH3(CH2)8CH2Cl KCN H2SO4, H2OCH3(CH2)9COH

heatethanol, water

O

CH3(CH2)9C N1-Chlorodecane Undecanenitrile Undecanoic acid

Chapter 18 Carboxylic Acid Derivatives

Lecture 25

Chem 30B

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.

– If the alcohol or resulting ester is sensitive to HCl, the reaction is carried out in the presence of a 3° amine to neutralize the acid.

Butanoylchloride

Cyclohexyl butanoate

+

Cyclohexanol

HO HClCl

O

+ O

O

Reaction with Alcohols

– Sulfonic acid esters are prepared by the reaction of an alkane- or arenesulfonyl chloride with an alcohol or phenol.

– The key point here is that OH- is transformed into a sulfonic ester (a good leaving group) with retention of configuration at the chiral center.

(R)-2-Octanolp-Toluenesulfonylchloride

(Tosyl chloride)

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

OH

+ TsCl pyridineOTs

Reaction with Alcohols• Acid anhydrides react with alcohols to give one

mole of ester and one mole of a carboxylic acid.

– Cyclic anhydrides react with alcohols to give one ester group and one carboxyl group.

(sec-Butyl hydrogenphthalate

2-Butanol(sec-Butyl alcohol)

+

Phthalicanhydride

O

O

O

OOHHO

O

O

Acetic acidEthyl acetateEthanolAcetic anhydride

++CH3COCCH3 HOCH2CH3 CH3COCH2CH3 CH3COHO O OO

Reaction 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

Reaction with Alcohols

• Esters react with alcohols in the presence of an acid catalyst in an equilibrium reaction called transesterificationtransesterification.

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

Reaction with Ammonia, etc.

• Acid halides react with ammonia, 1° amines, and 2° amines to form amides.– Two moles of the amine are required per mole of

acid chloride.

Cl

O

2NH3 NH2

O

NH4+Cl

-+ +

Hexanoylchloride

Ammonia Hexanamide Ammoniumchloride

Reaction with Ammonia, etc.

• Acid anhydrides react with ammonia, and 1° and 2° amines to form amides.– Two moles of ammonia or amine are required.

CH3COCCH3

O O2NH3 CH3CNH2

OCH3CO-NH4

+O

+ +

Aceticanhydride

Ammonia Acetamide Ammoniumacetate

Reaction with Ammonia, etc.

• Esters react with ammonia and with 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 with 1° or 2° amines.

PhOEt

O

NH3Ph

NH2

O

EtOH

PhenylacetamideEthyl phenylacetate

+ +

Ethanol

Acid Chlorides with Salts

• Acid chlorides react with salts of carboxylic acids to give anhydrides. – Most commonly used are sodium or potassium

salts.

+ +CH3 CCl -OC CH3 COC Na+Cl -Na

+O O O O

Acetylchloride

Sodiumbenzoate

Acetic benzoicanhydride

Chapter 18 Carboxylic Acid Derivatives

Lecture 26

Chem 30B

Interconversions of Acid Derivatives

Reaction with Grignard Reagents

1. Addition of 1 mole of RMgX to the carbonyl carbon of an ester gives a TCAI.

2. Collapse of the TCAI gives a ketone (an aldehyde from a formic ester).

O

CH3-C-OCH3 R MgX

O

R

OCH3CH3-C

[MgX]+

CH3-C

R

O

CH3O -[MgX]+

1

1

+

-

+

A magnesium salt(a tetrahedral carbonyladdition intermediate)

A ketone

2

2

Reaction with Grignard Reagents

– Treating a formic ester with two moles of Grignard reagent followed by hydrolysis in aqueous acid gives a 2° alcohol.

HCOCH3

O2RMgX

H2O, HClHC-R

R

OHCH3OH+

magnesium alkoxide salt

A 2° alcoholAn ester offormic acid

+

Reaction with Grignard Reagents

– Treating an ester other than formic with a Grignard reagent followed by hydrolysis in aqueous acid gives a 3° alcohol.

CH3COCH3

O2RMgX

H2O, HClCH3C-R

R

OHCH3OH

magnesium alkoxide salt

+

A 3° alcohol An ester of any acidother than formic acid

+

Reaction with Grignard Reagents

3. Reaction of the ketone with a second mole of RMgX gives a second TCAI.

4. Treatment with aqueous acid gives the alcohol.

CH3-C

O

R

R MgX CH3-C-R

R

O - [MgX]

+

H2O, HClCH3-C-R

R

OH

Magnesium saltA ketone

+

A 3° alcohol

33

(4)

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.

RCOCH3

1. 2R'Li

2. H2O, HClR-C-R'

O

R'

OH

+ CH3OH

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.

1. (CH3)2CuLi, ether, -78°C

2. H2OPentanoyl chloride 2-Hexanone

Cl

O O

Gilman 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

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.

Methanol2-Phenyl-1-propanol(racemic)

Methyl 2-phenyl-propanoate(racemic)

+1. LiAlH4 , ether

2. H2O, HCl

CH3OHPhOCH3

O PhOH

Reduction - Esters by LiAlH4

• 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 derived from the carbonyl group.

A 1° alcohol

R C

H

O+ H

(3)R C H

O

H

(4)R C H

OH

H

A tetrahedral carbonyladdition intermediate

(1)R C OR'

O

+ H R C OR'

O

H

R C

H

O(2)

OR'+

Reduction - Esters by 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.

OEt

O O NaBH4

EtOH OEt

OH O

(racemic)

Reduction - Esters by DIBALH

• Diisobutylaluminum hydride 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

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.

NH2

O1. LiAlH42. H2O

1. LiAlH4

2. H2ONMe2

ONMe2

NH2

Octanamide 1-Octanamine

N,N-Dimethylbenzamide N,N-Dimethylbenzylamine

Reduction - Amides by LiAlH4

• The mechanism is divided into 4 steps:– Step 1: Transfer of a hydride ion to the

carbonyl carbon.– Step 2: A Lewis acid-base reaction and

formation of an oxygen-aluminum bond.

R C NH2

O

+H AlH3 R C NH2

O

HAlH3

(1)R C NH2

O

H

(2)AlH3

+

Reduction - Amides by LiAlH4

– 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 N

O

H

AlH3

HH

H

R C NH

HH

R-CH2-NH2

An iminium ion

(3) (4)

A 1° amine

Reduction - Nitriles by LiAlH4

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

Interconversions

Problem:Problem: Show reagents and experimental conditions to bring about each reaction.

PhOH

O

OMe

OPh

PhOH

PhCl

O

PhNH2

PhNH2

O

Phenylacetic acid

(a) (b) (c)

(d) (e)

(f)

(g) (h)