Carboxyl Derivatives

Classes shown, formally, via dehydration.

O RCCl A n acid chloride -H2 O

O O RCOCR' An acid anhydride -H2 O O O RC-OH H-OCR'

O RCOR' An ester

O RCNH2 An amide

RC N A nitrile -H2 O HO H RC=N Th e enol of an amide

-H2 O O RC-OH H-OR'

-H2 O O RC-OH H-NH2

O RC-OH H-Cl

18-1

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 -oic acid to -oyl halide.
O O RCAn acyl group O CH3 CCl Cl Cl O Cl O Hexan edioyl ch loride (Adip oyl chloride)

Ethan oyl ch loride Benzoyl chloride (Acetyl ch loride)

18-2

Related: Sulfonyl Chlorides

Replacement of -OH in a sulfonic acid by -Cl gives a sulfonyl chloride.
O CH3 SOH O Methanes ulfon ic acid O H3 C SOH O p-Toluen esulfon ic acid H3 C O CH3 SCl O Methanes ulfonyl ch loride (Mesyl ch loride, MsCl) O SCl O p-Toluen esulfon yl chloride (Tosyl chlorid e, TsCl)

18-3

Structure: Acid Anhydrides

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 CH3 COCCH3 Acetic anhydride

O O COC Benzoic anhydride

18-4

Acid Anhydrides
Cyclic

anhydrides are named from the dicarboxylic acids from which they are derived.
O O O Succinic anhydride O O O Maleic anhydride O O O Phthalic anhydride

18-5

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 Ethyl ethan oate (Ethyl acetate) Is op ropyl ben zoate EtO O OEt O D iethyl butaned ioate (D ieth yl s uccin ate)

18-7

Esters; Lactones
Lactone:

A cyclic ester.

3 4 2 5 6 1

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

2 3 1

O O

O
1 2 O 3 4

O O

H3 C

3-Bu tanolactone -Butyrolactone)

4-Bu tanolactone -Bu tyrolacton e)

6-Hexan olacton e -Cap rolactone)

18-8

Amides
The

functional group of an amide is an acyl group bonded to a nitrogen atom.

drop -oic acid from the name of the parent acid and add -amide. (For the common acid name, drop -ic of the acid name and add -amide.) an alkyl or aryl group bonded to the N: name the group and show its location on nitrogen by N-.
O CH 3 CNH 2 A cetamide (a 1 amide) O H CH3 C-N CH3 O CH3 H-C-N CH3

ethanamide

N- Methylacetamide N ,N-D imethyl(a 2 amid e) formamid e (DMF) (a 3 amide)

18-10

Amides: resonance

18-11

Amides; Characteristics

18-12

Amides; Lactams
Lactams:

A cyclic amides are called lactams.

3 4 2 5 6 1

Name the parent carboxylic acid, drop the suffix -ic acid and add -lactam.

2 3 1

O NH

O NH

H3 C

3-Butanolactam -Butyrolactam)

6-He xanolactam -Caprolactam)

Indicates where the N is located.

18-13

Imides
The

functional group of an imide is two acyl groups bonded to nitrogen.

Both succinimide and phthalimide are cyclic imides.
O NH O Succinimide O NH O Phthalimide

18-14

Related: Nitriles
The

functional group of a nitrile is a cyano group

IUPAC names: name as an alkanenitrile. common names: drop the -ic acid and add -onitrile.

CH3 C N Ethanenitrile (Acetonitrile)

C N Benzonitrile

CH2 C N Phenylethanenitrile (Phenylacetonitrile)

18-15

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

O SNH2 O O NH O NH

amides.
O CH3 CNH2 Acetamide pKa 15-17

O O Ben zenesu lfonamide Succinimide Phth alimide pK a 10 p Ka 9.7 p Ka 8.3

18-16

Acidity of N-H bonds

Effect

of neighboring carbonyl groups.

1.0

18-17

Acidity of N-H
Imides such as phthalimide readily dissolve in aqueous NaOH as water-soluble salts.
O NH + O pK a 8.3 (s tronger acid) N aOH O N Na O (s tronger bas e) (we ak er bas e) pK a 15.7 (we ak er acid)
+

H2 O

18-18

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. More resonance delocalization of the negative charge.
O N O O N O A resonance-stabilized an ion O N O

18-19

Lab related: Sulfonamides (Hinsberg)

Experimental test to distinguish primary, secondary and tertiary amines. 1
soluble insoluble

2
insoluble

3
soluble

In base

In acid

Reaction replaces one H with the sulfonyl group. In 18-20 an H remains it is soluble in base.

Characteristic Reactions: Ketones & Aldehydes

Nucleophilic

acyl Addition:

Protonation makes carbonyl better electrophile. Ok with poor nucleophile.

Carbonyl weaker electrophile. Need good nucleophile.

18-21

Characteristic Reactions: Derivatives

Nucleophilic

acyl substitution: An additionelimination sequence resulting in substitution of one nucleophile for another.
O R C Y
+ :Nu

O C Nu

O R C Nu
+ :Y

Y Tetrahe dral carbonyl addition intermediate

Subs titution product

Dominant for derivatives due to good leaving group (Y), uncommon for ketones or aldehydes.
18-22

Characteristic Reactions
Poor bases make good leaving groups.
O R2 N RORCOX-

Increasin g leaving ability Increasin g b asicity

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.
18-23

Water and 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

18-24

Water and 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.
O O CH3 COCCH3 + H2 O Acetic an hydrid e O O CH3 COH + HOCCH3

18-25

Mechanism- Anhydrides
Step 1: Addition of H2O to give a TCAI. (Addition)
H + O CH3 -C- O-C- CH 3 O-H H H O CH3 -C- O-C- CH 3 + O H H O-H H O O O + CH3 -C- O-C- CH 3 + H- O-H O H H Tetrahe dral carbonyl addition intermediate H

Acid makes carbonyl better electrophile.

18-26

Mechanism- Anhydrides

Step 2: Protonation and collapse of the TCAI. (Elimination)

H H +O H O O H H O CH3 -C-O-C-CH3 H O H O O H + H O H H H +O H CH3 O O C + O C O H CH3

CH3 C O C CH3 H

Acid sets up better leaving group.

18-27

Water and 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.

acid catalyst protonates the carbonyl oxygen and increases 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.
18-28

Mechanism: Acid/H2O - Esters (1o and 2o alkoxy)

Acid-catalyzed
O C OCH3

ester hydrolysis.
H
+

H2 O

OH C R

H OH

O C OH

CH3 OH

Acid makes carbonyl Better electrophile.

OCH3 Tetrahed ral carbonyl ad dition intermed iate

Acid sets up leaving group.

18-29

Mechanism: Reaction with Acid/H2O Esters (3o alkoxy) But wait!!!!!!!

water
alcohol
18-30

Reaction with Base/H2O - Esters

Saponification:

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.
O RCOCH 3 + NaOH H2 O O RCO Na
+ +

CH3 OH

18-31

Mechanism of Reaction with Base/H2O Esters Step 1: Attack of hydroxide ion (a nucleophile) on the carbonyl carbon (an electrophile). (Addition) Step 2: Collapse of the TCAI. (Elimination) Step 3: Proton transfer to the alkoxide ion; this step is irreversible and drives saponification to completion.
O O (1) (2) R- C + R- C-OCH3+ OH R- C OCH3 O OH H O O OCH3 (3) R- C + HOCH3 O

18-32

Acidic 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.
O NH2 + H2 O + HCl H2 O
heat

O OH + NH4 Ph
+

Cl

Ph 2-Phenylbutanamide

2-Phenylbutanoic acid

18-33

Basic 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.
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

18-34

Mechanism: Acidic H2O - Amides

Step1: Protonation of the carbonyl oxygen gives a resonance-stabilized cation intermediate.
O + R C NH2 + H O H

H
+H O R C NH2 H O R C
+

H O NH2 R C + NH2 + H2 O

Reso nance-stabil ized catio n i ntermed iate

18-35

Acidic H2O - Amides

Step 2: Addition of water (a nucleophile) to the carbonyl carbon (an electrophile) followed by proton transfer gives a TCAI.
proton transfer from O to N

OH

R C N H2 +

OH O H H R C N H2 O+ H H

OH R C N H3 + H O

Step 3: Collapse of the TCAI and proton transfer. (Elimination)

H O R C NH3 + OH R

+
O C OH

NH3

O C

OH + NH4 +

18-36

Mechanism: Reaction with Basic H2O - Amides

Amide

hydroxide ion

Dianion!

18-37

Acidic H2O and Nitriles

The

cyano group is hydrolyzed in aqueous acid to a carboxyl group and ammonium ion.
H2 O
heat

O
+ Ph CH2 COH + NH4 HSO4 Ph enylacetic Ammoniu m acid hydrogen s ulfate

Ph CH2 C N + 2 H2 O + H2 SO4 Phenylacetonitrile

Protonation of the cyano nitrogen gives a cation that reacts with water to give an imidic acid. Keto-enol tautomerism gives the amide. Acid OH O + + H + H O R-C N R-C NH R-C-NH2 2 Ammonium A n imidic acid An amide ion (en ol of an amide)
18-38

Basic H2O and 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 ( CH2 ) 9 CO Na + NH3 S od ium und ecanoate HCl H2 O O CH3 ( CH2 ) 9 COH + NaCl + NH4 Cl Und ecanoic acid

18-39

Synthesis: Reaction with H2O - Nitriles

Hydrolysis of nitriles is a valuable route to carboxylic acids.
CH 3 ( CH2 ) 8 CH2 Cl 1-Chlorodecane KCN
ethanol, water

CH3 ( CH2 ) 9 C N Undecanenitrile

H2 SO 4 , H2 O
heat

O CH3 ( CH2 ) 9 COH Undecanoic acid

OH

OH

CHO HCN , KCN CN H2 SO 4 , H2 O COOH ethanol, heat water Benzaldehyde Benzaldehyde cyanohydrin 2-Hydroxyphenylacetic acid (Mandelonitrile) (Mandelic acid) (racemic) (racemic)

18-40

Synthesis: Grignards + Nitriles ->ketone 1

NMgX RC N

NH H2O RCR'

R'MgX
RCR' diethyl ether

Grignard

reagents add to carbon-nitrogen triple bonds in the same way that they add to carbonoxygen double bonds. The product of the reaction is an imine.
18-41

Synthesis: Grignards + Nitriles ->ketone 2

NMgX RC N

NH H2O RCR'

R'MgX
RCR' diethyl ether

H3O+
O RCR'

Imines hydrolyzed to ketones.

18-42

Reaction of Alcohols and Acid Halides

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 Cl + HO Butanoyl chloride Cyclohexan ol O O Cyclohexyl butan oate
+ HCl

18-43

Reaction with Alcohols, Sulfonic Esters

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- (a poor leaving group) is transformed into a sulfonic ester (a good leaving group) with retention of configuration at the chiral center.
OH
+

OT s T sCl

pyridine (R )-2-Octyl p-t oluenesulfonate [(R)-2-Octyl tos ylate]

(R )-2-Octanol

p- Toluenesulfonyl chloride (Tos yl chloride)

18-44

Reaction of Alcohols and Acid Anhydrides

Acid

anhydrides react with alcohols to give one mole of ester and one mole of a carboxylic acid.
O O CH3 COCCH3 + HOCH2 CH 3 Acetic anhydride Ethanol O O CH3 COCH2 CH3 + CH3 COH Acetic acid Ethyl acetate

Cyclic anhydrides react with alcohols to give one ester group and one carboxyl group.
O O O Phth alic anh yd rid e
+

O HO O 2-Butan ol (sec- Butyl alcohol) (s ec-Bu tyl h yd rogen phth alate O OH

18-45

Reaction of Alcohols and Esters

Esters

react with alcohols in the presence of an acid catalyst in an equilibrium reaction called transesterification.
O OCH3 Methyl propenoate (Methyl acrylate) (bp 81C)
+

HO 1-Butanol (bp 117C) O

HCl

O Butyl propenoate (Butyl acrylate ) (bp 147C)

CH3 OH Methanol (bp 65C)

18-46

Reaction of Ammonia, etc. and Acid Halides

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.
O 2 NH3 Cl Hexanoyl Ammon ia chloride
+

O NH 2 + NH4 Cl Hexan amid e Ammon ium chloride

+ -

18-47

Reaction of Ammonia, etc. and Anhydrides.

Acid

anhydrides react with ammonia, and 1 and 2 amines to form amides.

Two moles of ammonia or amine are required.
O O CH3 COCCH3 + 2 NH3 Acetic Ammon ia anh yd rid e O O + + CH CO NH CH3 CNH2 3 4 Acetamid e Ammon ium acetate

18-48

Ammonia, etc. and Esters

Esters

react with ammonia and with 1 and 2 amines to form amides.

Esters are less reactive than either acid halides or acid anhydrides.
O Ph OEt + NH3 Ph O NH2 + Et OH Ethanol

Ethyl phenylacetate
Amides

Phenylacetamide

do not react with ammonia or with 1 or 2 amines.

18-49

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 + N a - OC Acetyl chloride Sodium ben zoate O O CH3 COC Acetic be nzoic anhydride
+ N a + Cl -

18-50

Interconversions of Acid Derivatives

18-51

Grignard and an Ester. Look for two kinds of reactions.

OMgX

R-Mg-X
R' OEt R

R-Mg-X
R' R
R' R R

R'

OEt

Any alcohol will do here.

Substitution
EtOH

R'COCl

Acid chloride

But where does an ester come from?

R'

OH

R R

SOCl2 R'CO2H

Perhaps this carboxylic acid comes from the oxidation of a primary alcohol or reaction of a Grignard with CO2.

Addition

18-52

Grignard Reagents and Formic Esters

Treating a formic ester with two 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

18-53

Reactions with RLi

Organolithium

compounds are even more powerful nucleophiles than Grignard reagents.

O RCOCH3

1 . 2 R' Li 2 . H2 O, HCl

OH R- C-R' + CH3 OH R'

18-54

Gilman Reagents
Acid

chlorides at -78C react with Gilman reagents to give ketones.

O 1 . ( CH3 ) 2 CuLi, eth er, -78C 2-He xanone

Cl 2 . H O 2 Pentanoyl chloride

Gilman Reagents do not react with acid anhydrides, esters, amides or nitriles under these conditions. Selective reaction.
18-55

Synthesis: Reduction - Esters by LiAlH4

Most

reductions of carbonyl compounds use hydride reducing agents.

Esters are reduced by LiAlH4 to two alcohols. The alcohol derived from the carbonyl group is primary.
O Ph OCH3 1 . LiA lH4 , e t he r 2 . H2 O, HCl Ph OH + CH3 OH Methanol

Methyl 2-ph enylpropanoate (racemic)

2-Phenyl-1propanol (racemic)

18-56

Mechanism: Reduction - Esters by LiAlH4

Reduction

occurs in three steps plus workup:

O R C OR' H O R C H

Steps 1 and 2 reduce the ester to an aldehyde.

O R C OR' + H

(1)

(2)

OR'

A tetrahedral carbonyl addition inte rmediate

Step 3: Work-up gives a 1 alcohol derived from the carbonyl group.

O R C H + H (3) O R C H H OH (4) R C H H A 1 alcohol

18-57

Synthesis: Selective Reduction by NaBH4

NaBH4

reduces aldehydes and ketones. It does not normally reduce esters. LiAlH4 reduces all. Selective reduction is often possible by the proper choice of reducing agents and experimental conditions.
O O OEt NaBH4 EtOH OH O OEt (racemic)

18-58

Synthesis: Reduction - Esters by DIBAlH -> Aldehyde

Diisobutylaluminum

hydride (DIBAlH) at -78C selectively reduces an ester to an aldehyde.

At -78C, the TCAI does not collapse and it is not until hydrolysis in aqueous acid that the carbonyl group of the aldehyde is liberated.
O OCH 3 Methyl hexanoate 1 . DIBALH , toluen e, -78C 2 . H 2 O, HCl O H + CH 3 OH Hexanal

18-59

Synthesis: 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 NH2 Octanamide O NMe2 1 . LiAlH4 2 . H2 O N,N -D imethylben zamide NMe2 1 . LiAlH4 2 . H2 O NH2 1-Octanamine

N ,N-D imeth ylb enzylamine

18-60

Synthesis: Reduction - Nitriles by LiAlH4

The

cyano group of a nitrile is reduced by LiAlH4 to a 1 amine.

1 . LiAlH4 CH3 CH= CH( CH 2 ) 4 C N 2 . H2 O 6-Octene nitrile CH3 CH= CH( CH2 ) 4 CH2 NH2 6-Octen-1-amine

Can use catalytic hydrogenation also.

18-61

Interconversions
Problem: Show reagents and experimental conditions to bring about each reaction.
O Ph (a) O Ph OH Ph enylacetic acid (d ) Ph O OMe (g) (f) Ph OH Ph Cl (b ) (e) (c) O Ph NH2 (h ) NH2

18-62