WWU-Chemistry Acid Chlorides Preparation and Reactions.

WWU-ChemistryWWU-Chemistry

Acid ChloridesAcid ChloridesPreparation and ReactionsPreparation and Reactions


Preparation of an Acid ChloridePreparation of an Acid Chloride(“A” Method)(“A” Method)

+ SOCl2R C OH

O

R C Cl

O

+

+

O S O

H Clthionyl chloride

heat


ExampleExample

C OH

O

C Cl

O

+ SOCl2 + SO2 (gas) + HCl (gas)


Example #2Example #2

CH3

CH2CH2

CH2CH2

COH

O

CH3

CH2CH2

CH2CH2

CCl

O

SOCl2


Preparation of Acid ChloridesPreparation of Acid Chlorides(“C+” Method)(“C+” Method)

R C OH

O

R C Cl

O

+ PCl5

heat

+ POCl3 + HCl


Preparation of an Acid ChloridePreparation of an Acid Chloride(“C-” Method)(“C-” Method)

R C OH

O

+ PCl3

heatR C Cl

O

+ H3PO3

The single advantage to this method is that it does not produce HCl as a product. Use this method when your molecule can’t stand HCl.


Hydrolysis of an Acid ChlorideHydrolysis of an Acid Chloride

+ H2O +

O

CR Cl

O

CR OH H Cl

•Notice the direction of the equilibrium arrow.

•Explain why you can’t make an acid chloride by reacting a carboxylic acid with hydrogen chloride.

•This explains why acid chlorides are very moisture-sensitive and why it is difficult to store them.


Preparation of an EsterPreparation of an Ester(“A” Method)(“A” Method)

+

+

O

CR Cl

O

CR O R

H Cl

R OH

Because the ester is so much more stable than the acid chloride, this reaction proceeds at a rapid rate and in high yield.


ExampleExample

C Cl

O

+ CH3 OH

C O

O

CH3

+ H Cl


Preparation of an AmidePreparation of an Amide(“A” Method)(“A” Method)

+

+two equivalents " "

O

CR Cl

O

CR N

R

R

H Cl

H N

R

R

•Two equivalents of amine are required.

•The first equivalent acts as nucleophile to form the amide

•The second equivalent acts as a base and reacts with the HCl that is formed.


Example #1Example #1(Ammonia is the Nucleophile)(Ammonia is the Nucleophile)

C Cl

O

+ 2 NH3

C NH2

O

+ NH4+ Cl-

Because the amide is so much more stable than the acid chloride, this reaction proceeds rapidly and in high yield.


Example #2Example #2(Primary Amine is the Nucleophile)(Primary Amine is the Nucleophile)

CH3 CH2 C Cl

O

+ 2 CH3 NH2

CH2 C NH

O

+ CH3 NH3+ Cl-

CH3CH3


Example #3Example #3(Secondary Amine is the Nucleophile)(Secondary Amine is the Nucleophile)

H

C

O

Cl

+H

NCH2 CH2

CH3 CH32

H

C

O

NCH2

CH3

+

NH2CH2 CH2

CH3 CH3 Cl

CH2

CH3


Preparation of an Acid AnhydridePreparation of an Acid Anhydride

+

+

O

CR Cl

O

CR O C R

O

H Cl

O

CR OH

•This will also work with an acid chloride and a carboxylate anion.

•Because the acid chloride is less stable than the acid anhydride, this reaction proceeds rapidly and in good yield.


ExampleExample

CH3 C Cl

O

CH3 C O

O

+

CH3 C O C CH3

O O

+

Cl


Rosenmund ReductionRosenmund Reduction

+ H2

Pd/BaSO4

sulfurquinoline

R C Cl

O

R C H

O

Recall this from Chapter 17, Section 17.17


ExampleExample

CH3 CH2 C Cl

O

CH3 CH2 C H

O H2 Pd

sulfurboiling quinoline


Also...Also...

C Cl

O

C H

O

LiAlH[O-tert-Butyl]3


By contrast, lithium aluminum hydride reduces acid chlorides all the way to alchols.

R C Cl

O

LiAlH4R CH2 OH


ExampleExample

CH3

CH2CH2

CCl

O

1) LiAlH4

2) H2O CH3

CH2CH2

C

O

HH

H

Butanoyl chloride 1-Butanol


•Acid chlorides react with enamines to yield 1,3-dicarbonyl compounds

•In this reaction, the first step involves formation of the enamine

•see Chapter 16, Section 16.13

•The enamine, being highly nucleophilic, reacts with the acid chloride in a nucleophilic acyl substitution process.

•Hydrolysis of the resulting iminium salt yields the final product.


Acylation of an EnamineAcylation of an Enamine

1)

+

+

2) +

+ H2O

+

+

R C Cl

O

RCH C R

N

CH C R

N

C

R

R

O

CH C R

N

C

R

R

O

R C

O

CH C

R

R

O

N

HH

+


Acylation of an Enamine -- Acylation of an Enamine -- Mechanism (Part 1)Mechanism (Part 1)

: :

:

slow

+ +

:..

:_

: :

NC

R

CR

R

C

O

R Cl

C C

R

R R

N NC

R

CR

R

C

O

R

O

CR Cl

+ Cl


Acylation of an Enamine -- Acylation of an Enamine -- Mechanism -- Part 2Mechanism -- Part 2

+

: : : :

: :

:+

..NCCCR

O R

R

R

O

H

H

NCCCR

O R

R

R

OH H


Acylation of an Enamine -- Acylation of an Enamine -- Mechanism -- Part 3Mechanism -- Part 3

: :

:+

..: :

:..

+

: :

: :

+

+

..

CCCR

O R

R

R

O

NCCCR

O R

R

R

O

H

H

NCCCR

O R

R

R

O H

H

NH

H+


+HOTs

+ H2O..

:

:

+

+

+

+ H2O

+

+

..

R C C R

H

R

O

N

H

R C

O

C C

R

RR

N

C C

R

R R

N

C C

R

R R

N

R C Cl

O

R C

O

C C

R

RR

NR C

O

C C R

OR

RN

H

H+

Overall SequenceOverall Sequence


ExampleExample

O N

H

HOTs

N

CH3 C Cl

O

N

CCH3

O

H2OO

CCH3

O


Example #2Example #2

O

CCH3 CH3

N

O

H

HOTsN

O

CCH3 CH2

CH3 CH C Cl

O

CH3

N

O

CCH3 CH2

CCH

O

CH3

CH3

H2O

O

CCH3 CH2

CCH

O

CH3

CH3


Also review...Also review...

• Conversion of acid chlorides to ketones– review material in Chapter 17, Section 17.18


Using Dialkylcadmium ReagentsUsing Dialkylcadmium Reagents

CH3 C Cl

O

+

H3C Cd CH3

CH3 C CH3

O


Using Lithium DialkylcupratesUsing Lithium Dialkylcuprates

C

Cl

O

CH3 CH2 CH2 CH2

C

CH2

O

CH2

CH2 CH3

+

2CuLi

0 °C

ether

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WWU-Chemistry Acid Chlorides Preparation and Reactions.

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