19.1619.16αα--Halogenation of Carboxylic Acids:Halogenation of Carboxylic Acids:The HellThe Hell--VolhardVolhard--Zelinsky ReactionZelinsky Reaction

analogous to analogous to αα--halogenation of aldehydes and halogenation of aldehydes and ketonesketones

key question: Is enol content of carboxylic key question: Is enol content of carboxylic acids high enough to permit reaction to occur acids high enough to permit reaction to occur at reasonable rate?at reasonable rate? (Answer is NO)(Answer is NO)

αα--Halogenation of Carboxylic AcidsHalogenation of Carboxylic Acids

++ XX22 ++ HHXXRR22CCOHCCOH

OO

HH

RR22CCOHCCOH

OO

XX

reaction works well if a small amount ofreaction works well if a small amount ofphosphorus or a phosphorus trihalide is added tophosphorus or a phosphorus trihalide is added tothe reaction mixturethe reaction mixture

this combination is called the Hellthis combination is called the Hell--VolhardVolhard--Zelinsky reactionZelinsky reaction

But...But...

++ XX22 ++ HHXXRR22CCOHCCOH

OO

HH

RR22CCOHCCOH

OO

XX

P or PXP or PX33

ExampleExample

CHCH22COHCOH

OO

PClPCl33 benzenebenzene80°C80°C

CHCOHCHCOH

OO

BrBr

(60(60--62%)62%)

++ BrBr22

ValueValue

CHCH33CHCH22CHCH22COHCOH

OOBrBr22

PPCHCH33CHCH22CHCOHCHCOH

OO

BrBr

(77%)(77%)

αα--Halogen can be replaced by nucleophilic Halogen can be replaced by nucleophilic substitutionsubstitution

ValueValue

CHCH33CHCH22CHCH22COHCOH

OOBrBr22

PPCHCH33CHCH22CHCOHCHCOH

OO

BrBr

CHCH33CHCH22CHCOHCHCOH

OO

OHOH

(77%)(77%)

(69%)(69%)

KK22COCO33

HH22OOheatheat

Synthesis of Synthesis of αα--Amino AcidsAmino Acids

(CH(CH33))22CHCHCHCH22COHCOH

OOBrBr22

PClPCl33(CH(CH33))22CHCHCOHCHCHCOH

OO

BrBr

(CH(CH33))22CHCHCOHCHCHCOH

OO

NHNH22

(88%)(88%)

(48%)(48%)

NHNH33

HH22OO

19.1719.17Decarboxylation of Malonic AcidDecarboxylation of Malonic Acid

and Related Compoundsand Related Compounds

Decarboxylation of Carboxylic AcidsDecarboxylation of Carboxylic Acids

Simple carboxylic acids do not decarboxylateSimple carboxylic acids do not decarboxylatereadily.readily.

RHRH ++ COCO22RCOHRCOH

OO

Decarboxylation of Carboxylic AcidsDecarboxylation of Carboxylic Acids

Simple carboxylic acids do not decarboxylateSimple carboxylic acids do not decarboxylatereadily.readily.

But malonic acid does.But malonic acid does.

RHRH ++ COCO22RCOHRCOH

OO

150°C150°CCHCH33COHCOH

OO

++ COCO22HOCCHHOCCH22COHCOH

OO OO

Mechanism of Decarboxylation of Malonic AcidMechanism of Decarboxylation of Malonic Acid

One carboxyl group assists the loss of the other.One carboxyl group assists the loss of the other. OO OO

OHOHHOHO

HH HH

OO

HOHO OO

OO

HH HH

HH

Mechanism of Decarboxylation of Malonic AcidMechanism of Decarboxylation of Malonic Acid

This compound is This compound is the enol form of the enol form of acetic acid.acetic acid.

OO OO

OHOHHOHO

HH HH

HH

HH

OHOH

HOHO

OO

HOHO OO

OO

HH HH

HH

++ CC

OO

OO

One carboxyl group assists the loss of the other.One carboxyl group assists the loss of the other.

Mechanism of Decarboxylation of Malonic AcidMechanism of Decarboxylation of Malonic Acid

OO OO

OHOHHOHO

HH HH

HH

HH

OHOH

HOHO

OO

HOHO OO

OO

HH HH

HH

++ CC

OO

OO

One carboxyl group assists the loss of the other.One carboxyl group assists the loss of the other.

HOCCHHOCCH33

OO

Mechanism of Decarboxylation of Malonic AcidMechanism of Decarboxylation of Malonic Acid

OO OO

OHOHHOHO

HH HH

HH

HH

OHOH

HOHO

OO

HOHO OO

OO

HH HH

HH

++ CC

OO

OO

One carboxyl group assists the loss of the other.One carboxyl group assists the loss of the other.

HOCCHHOCCH33

OO

These hydrogens play no role.These hydrogens play no role.

Mechanism of Decarboxylation of Malonic AcidMechanism of Decarboxylation of Malonic Acid

OO OO

OHOHHOHO

RR R'R'

RR

R'R'

OHOH

HOHO

OO

HOHO OO

OO

RR R'R'

HH

++ CC

OO

OO

One carboxyl group assists the loss of the other.One carboxyl group assists the loss of the other.

HOCCHHOCCHR'R'

OO

Groups other than H may be present.Groups other than H may be present.

RR

185°C185°C

Decarboxylation is a general reactionDecarboxylation is a general reactionfor 1,3for 1,3--dicarboxylic acidsdicarboxylic acids

160°C160°C

COCO22HH

COCO22HH

COCO22HH

HH

(74%)(74%)

(96(96--99%)99%)

CH(COCH(CO22H)H)22

CHCH22COCO22HH

Mechanism of Decarboxylation of Malonic AcidMechanism of Decarboxylation of Malonic Acid

OO OO

OHOHHOHO

RR R'R'

RR

R'R'

OHOH

HOHO

OO

HOHO OO

OO

RR R'R'

HH

++ CC

OO

OO

One carboxyl group assists the loss of the other.One carboxyl group assists the loss of the other.

This OH group plays no role.This OH group plays no role.

HOCCHHOCCHR'R'

OO

RR

Mechanism of Decarboxylation of Malonic AcidMechanism of Decarboxylation of Malonic Acid

OO OO

OHOHR"R"

RR R'R'

RR

CC

OO

OO

One carboxyl group assists the loss of the other.One carboxyl group assists the loss of the other.

Groups other than OH may be present.Groups other than OH may be present.

R"R"CCHCCHR'R'

OO

RR

OO

OO

OO

RR R'R'

HH

R"R"

R'R'

OHOH

++R"R"

Mechanism of Decarboxylation of Malonic AcidMechanism of Decarboxylation of Malonic Acid

OO OO

OHOHR"R"

RR R'R'

This kind of compoundThis kind of compoundis called a is called a ββ--keto acid.keto acid.

ααββ

R"R"CCHCCHR'R'

OO

RR

Decarboxylation of a Decarboxylation of a ββ--keto acid gives a keto acid gives a ketone.ketone.

Decarboxylation of a Decarboxylation of a ββ--Keto AcidKeto Acid

CCCHCH33CC

OO

CHCH33

CHCH33

COCO22HH25°C25°C

COCO22

CCCHCH33CC

OO

CHCH33

CHCH33

HH

++