WWU-Chemistry The Amides WWU-Chemistry Carboxylic acids can be converted directly to the corresponding amides by the reaction of an acid with the appropriate

WWU-ChemistryWWU-Chemistry

The AmidesThe Amides


•Carboxylic acids can be converted directly to the corresponding amides by the reaction of an acid with the appropriate amine.

•The amine used in this reaction can be ammonia, a primary amine, or a secondary amine, depending on the degree of nitrogen substitution expected.


Preparation of AmidesPreparation of Amides(“C+ Method”)(“C+ Method”)

+ +R NH2O

HH

COH

O

RC

O

R NHR

While this is not the best method of preparing amides, it has the advantage of being simple. It also serves to introduce the amides as a class of compounds.


Preparation of AmidesPreparation of Amides(“A Method”)(“A Method”)

R C Cl

O

+ N H

H

H

R C N

O

H

H

R C Cl

O

+ N R

H

H

R C N

O

H

R

R C Cl

O

+ N R

R

H

R C N

O

R

R


• REMEMBER: The previous image neglects to account for the H-Cl produced in the reaction.

• In each of the previous reactions, two equivalents of amine are required -- one to act as nucleophile and the second to act as a base. The second equivalent of amine reacts with the H-Cl to form the corresponding amine hydrochloride.


Peptides and ProteinsPeptides and Proteins


Amino acids have the general structure:

C

R

HH2N

O OH

•The correct Fischer projection for naturally-occurring amino acids is shown here.

•The R group is variable.


•As can be seen, the amino acids possess both functional groups required to form an amide. Each amino acid is both a carboxylic acid and an amine simultaneously.

•Therefore, it should be possible to link amino acids together through the formation of amides.


Peptide bond(an amide linkage)

H2N CH C

R1

OH

O

H2N CH C

R2

OH

O

H2N CH C

R3

OH

O

H2N CH C

R1

O

HN CH C

R2

O

HN CH C

R3

OH

O


PeptidesPeptides

• When amino acids are linked together by amide linkages (biochemists call these “peptide bonds”), the resulting molecule is called a peptide.

• A peptide is a polymer formed from individual amino acid units.


PeptidesPeptides

• Peptides are named according to the number of amino acids that are linked:– dipeptide: two amino acids– tripeptide: three amino acids– tetrapeptide: four amino acids– etc.

• The term oligopeptide refers an amino acid polymer with a moderate number of repeating amino acid units.


Peptides and ProteinsPeptides and Proteins

• When a peptide grows to a length of about 70 amino acid units (molecular weight = approximately 10,000), the molecule begins to coil onto itself and assume a particular secondary structure.

• At this point, we no longer refer to the molecule as a “peptide”; we begin to call it a protein.


alphaalpha-Helix-Helix


Chateau de ChambordChateau de Chambord


Chambord – Double Staircase by Chambord – Double Staircase by Leonardo DaVinciLeonardo DaVinci


Other Amide PolymersOther Amide Polymers

H2NCH2

CH2

CH2CH2

CH2CH2

NH2Cl

CCH2

CH2CH2

CH2C

Cl

O

O

H2NCH2

CH2

CH2CH2

CH2CH2

NHC

CH2CH2

CH2CH2

CCl

O

O

NH (CH2)6 NH C

O

(CH2)4 C NH

O

(CH2)6 NH C

O

(CH2)4 C

O

+

repeat

NYLON!!!


Hydrolysis of AmidesHydrolysis of Amides

• The most important reaction of amides is hydrolysis.

• The products of amide hydrolysis are the carboxylic acid and the amine.



R C N

R

RO

O

HH+acid

heatR C OH

O

+

H N

R

R

This reaction can also be run under basic conditions.



• In living organisms, the hydrolysis of peptides is accomplished through catalysis by enzymes.

• The enzyme-catalyzed hydrolysis of peptides and proteins is what happens to protein when we eat it.

• The protein is hydrolyzed into individual amino acids, which are then used to build new proteins.


ExampleExample

C

N

O

H

CH3

+ H2OH+

C

OH

O

+ CH3 NH3


Reduction of AmidesReduction of Amides

R C N

R2

R1O

LiAlH4 H2OR CH2 N

R2

R1

•If either R1 or R2 is hydrogen in the amide, the corresponding R groups will be hydrogen in the amine product. Notice that the carbonyl group is reduced to a methylene group.

•NaBH4 cannot reduce amides


ExamplesExamples

CH3 CH2 CH2 C NH2

O

CH3 CH2 CH2 CH2 NH2

CH3 CH2 CH2 C NH CH3

O

CH3 CH2 CH2 CH2 NH CH3

1) LiAlH4

2) H2O

1) LiAlH4

2) H2O

CH3 CH2 CH2 C N

O

CH3 CH2 CH2 CH2 N1) LiAlH4

2) H2OCH3

CH3

CH3

CH3

a primary amine

a secondary amine

a tertiary amine


NitrilesNitriles


Formation of NitrilesFormation of Nitriles

+_: : +R CH2 Cl C N Cl R CH2 C N

This is an SN2 reaction. It works best with primary alkyl halides.


Hydrolysis of NitrilesHydrolysis of Nitriles

+ H2O + NH4+

R CH2 C OH

O

R CH2 C N

The reaction can be conducted The reaction can be conducted in either acidic or basic in either acidic or basic solution.solution.


ExampleExample

CH2 C N CH2 C OH

O

+ H2OH2SO4

heat


ExampleExample

CH3 CH2 CH2 CH2 C N

+

NaOH

H2O

CH3CH2OH heat

CH3 CH2 CH2 CH2 C O

O

Na

H2O

H+

CH3 CH2 CH2 CH2 C OH

O


Base-Promoted Hydrolysis of a Nitrile (Part One)Base-Promoted Hydrolysis of a Nitrile (Part One)

1)

:..

..

_

slow :.. _

: ..

2)..

_:

..

:

+ H2O

:..

.. + OH_

3):

..

..

:....

C N:R

CR

NH

OH

CR

NH2

O

C NR

O H

CR

N

OH

Tautomerism

O H

CR

NH

OH


Base-Promoted Hydrolysis of a Nitrile (Part Two)Base-Promoted Hydrolysis of a Nitrile (Part Two)

4)

5)

6)

: :..

:..

..

_

: :.. _

..

:..

: :.. _

..

:..

: :

:..

+ NH2:..

_

: :..

.. + NH2:

.._

: :..

.. :_

+ NH3

..

O

CR NH2

O H

R C NH2

O

O H

R C NH2

O

O H

O

CR

O H

O

CR OH

O

CR O


Acid-catalyzed Hydrolysis of a Nitrile (Part One)Acid-catalyzed Hydrolysis of a Nitrile (Part One)

1)

2)

3)

+fast + +

+

: :

slow ..

:+

..

:+

..

: :+

3 resonance forms

C N:R H+

C NR H C NR H

C NR H

OHH

C NR H

O

H

H

C NR H

O

H

H

C NR

O

H

H

H


Acid-catalyzed Hydrolysis of a Nitrile (Part Two)Acid-catalyzed Hydrolysis of a Nitrile (Part Two)

4)

5)

6)

:..

+

: ::

:..

+

:

:..

+

:

:

..

+

:

:..

+

..

:

:..

+

..

+ NH4

+

O

CR NH2

H

OH H

O

CR NH2

H

O H

H

O

CR NH2

H

O H

H

O

CR NH2

H

O H

HO

CR NH2

H

O H

H

O

CR NH3

H

O H

O

CR OH


Reduction of NitrilesReduction of Nitriles

R C N1) LiAlH4

2) H2OR CH2 NH2

NaBH4 does not reduce nitriles.


Also:Also:

R C N + 2 H2

Ni

140°R CH2 NH2

(pressure)

CAUTION!!!


ExampleExample

CH2 C N CH2 CH2 NH2

+ 2 H2 (pressure)

Ni

140°C


ExampleExample

CH3 CH2 CH2 C NLiAlH4

etherCH3 CH2 CH2 CH2 NH2


Reduction of a Nitrile to an Reduction of a Nitrile to an AldehydeAldehyde

O

O

C N

DIBALH H2O

H+

O

O

C O

H

85% yield

-78°

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WWU-Chemistry The Amides WWU-Chemistry Carboxylic acids can be converted directly to the corresponding amides by the reaction of an acid with the appropriate