1

R CO

ClR C

O

OC

OR

R CO

OR'

R CO

NR'

R"

acid halide acid anhydride an ester an amide

Carboxylic Acid Derivatives

The most important derivatives of carboxylic acids are —

Although not direct derivatives, nitriles, R-CN, are relatedto carboxylic acids. They can be hydrolyzed to carboxylicacids and they can be prepared from carboxylic acids viadehydration of the amide.

2

R CO

Y

:Nu-

R CO-

YNuR C

O

Nu

trigonal tetrahedral trigonal

less crowded more crowded+ Y-

slowstep

The typical reaction type of carboxylic acid derivatives isnucleophilic substitution at the carbonyl carbon.[Aldehydes and ketones usually undergo nucleophilicaddition because they do not contain reasonable leavinggroups: R- and H- are poor leaving groups.] A generalizedreaction mechanism under basic conditions, BAC2 (basic,acyl, bimolecular) looks like this:

[If :Nu is neutral, the intermediate will be a neutral betaine(-O-, -Nu+), and the product will carry a + charge unlessthe -Nu+ expells an H+.]

3

R CO

Y

H

:Nu-H

R CO

YNu-H

H

R CO

Nu

H

trigonal tetrahedral

trigonal

less crowded more crowded

+ Y-H

R CO

YH+

R CO

Y-HNu

H

tetrahedralR C

O

Nu+ H+

slowstep

A generalized reaction mechanism under acidicconditions, AAC2 (acidic, acyl, bimolecular) looks like this:

Since the intermediate is more crowded than the reactant,bulky R-groups slow down the reaction: for a given Nu andY, the rate of reaction is usually in the order: 1o > 2o > 3o.

4

The more electronegative Y the faster the reaction: for agiven R and Nu, the rate of reaction is usually in the order: Cl > OCOR > OR' > NR'R". The reason for this dependson the reaction type.

> If it is BAC2 with Nu-, the intermediate carries anegative charge and it (and the transition state leading toit) are stabilized by an electronegative group. Thereacting molecule, on the other hand, is destabilized byelectronegative groups because of the δ+ charge on thecarbonyl carbon. These effects work together causingelectronegative groups to reduce ∆G‡.

> If it is BAC2 with Nu, the intermediate is neutral, but thestarting material is destabilized by electronegative groupsbecause of the δ+ charge on the carbonyl carbon, thusreducing ∆G‡.

> If it is AAC2 (with Nu), the intermediate and reactant(the protonated starting material) are both positivelycharged. Electronegative groups would destabilize both. However, the effect may be greater on the reactantbecause the positive charge is transferred to the carbonylcarbon by both an inductive and resonance effect, while inthe intermediate there is only an inductive effect. If thereactant is more destabilized than the intermediate, ∆G‡ isreduced.

5

R CO

OH

SOCl2

PCl5

ClCOCOClR C

O

Cl

R CO

OHSOCl2

R CO

Cl

+ R CO

O SO

Cl+ H

+ Cl-

R CO

O SO

ClCl

+ O S O + Cl

A consequence of this reactivity order is that acidchlorides can be directly converted into the other derivatesand anhydrides can be directly converted into esters andamides, but directly converting the less reactivederivatives into the more reactive ones is difficult.

To convert acarboxylic acid intoan ester or amide, itis usually convertedto a chloride first.

Mechanism (using thionyl chloride) —

6

RCCl

O+ R'OH

or Ar or Ar'RCOR'

O

+ HCl

R, R' = 1o, 2o, 3o

RC

O

Cl N+ RC

O

Cl

NRC

O

N

HOR'+

RC

O

OR'

H

+ N

RC

O

OR'

+N

HRC

O

OR'

H

N

-Cl

Esters: Preparation

Reaction of an Acid Chloride with an Alcohol or Phenol—

This reaction is catalyzed by pyridine —

7

R CO

OH+ HOR' R C

O

OR'+ H2O

H+

Dean-Stark Apparatus

Fisher Esterification —

The equilibrium constant for aFisher Esterification istypically about 1. However,when phenols are employedKeq is usually much less than1; phenols are not usuallyacylated by the Fisheresterification.

This reaction can be driven inthe forward direction by usingthe alcohol as the solvent orby removal of water. Removal of water is oftenaccomplished by use of aDean-Stark trap.

This reaction can be driven inthe reverse direction(hydrolysis of an ester) byuse of an excess of water.

8

C

O

OH

H18OCH3

+ H3O+ C

OH

OH C

OH

OH

C

OH

OH

H18OCH3

C

OH2

OH18OCH3

2 steps

H2O - H2O

C OH18OCH3

C OH18OCH3

C O18OCH3

+ H+

Mechanism of the Fisher Esterification (and AcidCatalyzed Hydrolysis of an Ester), AAC2 —

9

CO

OCH3

+ OH-

C

O

OCH3

OH

CO

OH+ OCH3 C

O

O+ HOCH3

Esters: Reactions

Hydrolysis: Conversion to Carboxylic Acids —

> Acidic: see Fisher Esterification.

> Basic: typical nucleophilic acyl substitution via atetrahedral intermediate, BAC2 —

10

R CO

OR'

+ OH-

R C

O

OR'

OHR C

O

OH+ OR' R C

O

O+ HOR'

1.

2.

R CO

OR'

+ OH-

slow

slow R CO

OH+ OR' R C

O

O+ HOR'

3. SN2

R CO

OR' + OH-

slow R CO

O+ HOR'

Evidence for this Mechanism for the Alkaline Hydrolysis ofEsters —

rate = k2[ester][OH-], suggesting —

11

Ph C

O

Cl + H O CC2H5

CH3H(S)-2-butanol

O CC2H5

CH3HO

CPh

configuration retained: S

OH-,H2O Ph C

O

O- + H O CC2H5

CH3H(S)-2-butanol

C2H5 C

O18OC2H5 + OH- C2H5 C

O

O- + H18OC2H5

Narrowing down the field —

> If 1 or 2 is correct, inversion of configuration is notexpected in R', since the O-R' bond is not broken. However, if 3 (an SN2 mechanism) is correct, a Waldeninversion is predicted. Experiment and observation:

Configuration is retained: mechanism 3 (SN2) is incorrect. This is confirmed by an isotopic tracer experiment—

12

R C OR'

18O+ OH- R C OH

18O+ OR'-

> To distinguish between 1 and 2 (ie, is there atetrahedral intermediate?) —

Treat with OH- and recover some ester beforeR C OR'

18O

it is all consumed. If mechanism 2 is correct we wouldexpect all of the ester to be labeled, even if the reaction isreversible:

13

R C OR'

18O+ OH- R C OH

18O+ OR'-R C OR'

18O-

OH

R C O-

18O

+ HOR'-

R C O

18O-

H2OOH-

R C OR'

18OH

OH

H2O OH-

R C OR'

18OH

O-

R C 18OH

O+ OR'-

R C OR'

O

18OH-+unlabeled ester

However, if mechanism 1 is correct, we might expect torecover ester, part of which is unlabeled, via the followingmechanism —

When unreacted ester is recovered, some is unlabeled. This rules out mechanism 2.

14

Saponification —

Hydrolysis of esters under basic conditions is known assaponification.

Soap is made by saponification of oil or fat. Most soap ismade from fat; Castile soap is made from olive oil.

Oils and fats are triglycerides, ie triesters of glycerol andfatty acids. Fatty acids are straight chain carboxylic acids,having an even number of carbons ranging from ~10 to~20. The alkyl portion may be saturated or unsaturated; ifunsaturated the double bond(s) are usually cis and thereare usually not more than 3.

15

O C

O

RCH2

CH

CH2

O C

O C

O

R'O

R"

H2Oheat

O C

O

RCH2OH

CHOH

CH2OH

O C

O

R'

O C

O

R"

+ 3 NaOH

Na

Na

Na

a triglyceride glycerol sodium soap

S

O

O

O- Na+

a branched alkyl sulfonate, not biodegradable

When triglycerides are saponified, soap and glycerol areproduced —

Sodium soap is a surfactant; it disperses into water in theform of micelles and is able to emulsify grease.

Hard water contains Ca+2, Mg+2 or iron ions. Sodium soapreacts with these ions forming an insoluble magnesium orcalcium soap, soap scum. This problem can be remediedby replacing soap by a synthetic detergent which does notprecipitate in the presence of the "hard water" ions.

Sodium sulfonates,having long alkyl chains,are sometimes used asdetergents and areeffective in hard water. Often the sulfonic acidgroup is on an aromatic ring which also holds the longalkyl group.

16

CO

OCH3 OCH3

OC 1. LiAlH4, ether

2. H3O+CH2OHHOCH2

CO

H

OC

HC

O

OCH3 OCH3

OC

2. H3O+1. DIBAH, toluene, -78 o

DIBAH = [(CH3)2CHCH2]2AlH

C

O

OCH3 MgBr+ 2 H3O+

C OH

HC

O

OCH3 MgBr+ 2 H3O+

C OH

H

Reduction —> to Primary Alcohols:

> to Aldehydes:

> to 2o or 3o Alcohols via Grignard Reagents:

17

R C

O

Cl + HNR'R" :B R C

O

NR'R" HB+ Cl-+

HN

H

O

NO

n

Cl ClO

OH N N

HH

H+

+ HCl

base

Amides: Preparation

Amides can be prepared from acid chlorides by reactionwith ammonia, NH3, primary amines, NH2R', andsecondary amines, NHR'R" —

When a base, such as pyridine, is added to promote thisreaction, it is known as the Schotten-Baumann reaction.

Nylon 6.10 can be made by interfacial polymerization ofdecanedioyl dichloride in petroleum ether andhexamethylenediamine and NaOH in water —

18

R C

O

OH + HNR'R"

R C

O

NR'R"

R C

O

O- + H2NR'R"

+ H2Oheat

R C

O

OH

+ HNR'R"R C

O

NR'R"R C

O

O-

+ H2NR'R"

+ H2OheatH3O+

OH-

heat

Sometimes, amides can be formed by reacting acarboxylic acid with a primary or secondary amine to formthe salt and then heating this salt to expel water —

Reactions of Amides

Hydrolysis —

19

H2NN

NN

NN

OH

R8

O R15

O R3

O R20

O R3

O R17

OH

H

H

H

H

H2NN

NN

NN

OH

R8

O R15

O R3

O R20

O R3

O R17

OH

H

H

H

H

H2N

R8

O

OH

N

R15

OH

H OH

N

R3

OH

OHH

N

R20

OH

OHH

N

R3

OH

OHH

NOH

R17

OH

H

HCl,H2O heat

Polypeptide...

...showing cleavagesites at peptide (amide)bonds between aminoacid residues.

Soup of amino acids afterhydrolysis; can be analyzedby chromatography.

R C

O

NR'R" 1. LiAlH4

2. H2OR CH2 NR'R"

Acid hydrolysis is used to determine which amino acidresidues are present in a polypeptide or protein.

Reduction to Amines —

20

R X + C N R C N + X

C OR'

R+ K

+ -C N H3O+R' C

OH

CN

R

R C

O

NH2or Ar

SOCl2or POCl3or P2O5

R C Nor Ar

Nitriles

Preparation —

Reaction of cyanide ion with alkyl halides (usually SN2):

Works best for 1o R.

Cyanohydrin synthesis from aldehydes and unhinderedketones:

Dehydration of primary amides:

21

Ar NH2NaNO2HCl

Ar N N CuCN Ar C NCl

R C N 1. LiAlH42. H2O

R CH2 NH2

R C N 1. DIBAH, -78o2. H2O

R C

O

H

a primary amine

R C N1. R'MgX2. H2O

R C

O

R'

Diazotization of primary aromatic amines, followed by theSandmeyer reaction:

Reactions —

Acidic or basic hydrolysis to give carboxylic acids ---discussed earlier.

Reduction —

Reaction with Grignard reagents to give ketones —