22'6 Reactions of Amines: A Review and a Preview

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22.6Reactions of AminesA Review and a Preview
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Preparation of Amines

• Two questions to answer
• 1) How is the CN bond to be formed?
• 2) How do we obtain the correct oxidation state
  of nitrogen (and carbon)?

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Methods for CN Bond Formation

• Nucleophilic substitution by azide ion (N3)
  (Section 8.1, 8.13)
• Nitration of arenes (Section 12.3)
• Nucleophilic ring opening of epoxides by ammonia
  (Section 16.12)
• Nucleophilic addition of amines to aldehydes and
  ketones (Sections 17.10, 17.11)
• Nucleophilic substitution by ammonia on a-halo
  acids (Section 19.16)
• Nucleophilic acyl substitution (Sections 20.4,
  20.6, and 20.12)

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22.7Preparation of Aminesby Alkylation of
Ammonia
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Alkylation of Ammonia
Desired reaction is

2 NH3

RX
RNH2
NH4X
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Alkylation of Ammonia
But the method doesn't work well in
practice.Usually gives a mixture of primary,
secondary,and tertiary amines, plus the
quaternary salt.
RX
RX
NH3
RNH2
R2NH
RX
RX
R3N
7
Example
NH3
CH3(CH2)6CH2Br
CH3(CH2)6CH2NH2
(45)

• As octylamine is formed, it competes with ammonia
  for the remaining 1-bromooctane. Reaction of
  octylamine with 1-bromooctane gives
  N,N-dioctylamine.

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22.8The Gabriel Synthesis of Primary Alkylamines
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Gabriel Synthesis

• gives primary amines without formation
  ofsecondary, etc. amines as byproducts
• uses an SN2 reaction on an alkyl halide to
  formthe CN bond
• the nitrogen-containing nucleophileis
  N-potassiophthalimide

10
Gabriel Synthesis

• gives primary amines without formation
  ofsecondary, etc. amines as byproducts
• uses an SN2 reaction on an alkyl halide to
  formthe CN bond
• the nitrogen-containing nucleophileis
  N-potassiophthalimide

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N-Potassiophthalimide

• the pKa of phthalimide is 8.3
• N-potassiophthalimide is easily prepared bythe
  reaction of phthalimide with KOH

O
KOH

O
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N-Potassiophthalimide as a nucleophile
O
SN2


N


O
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Cleavage of Alkylated Phthalimide

• imide hydrolysis is nucleophilic acyl substitution

acid or base

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Cleavage of Alkylated Phthalimide

• hydrazinolysis is an alternative method of
  releasing the amine from its phthalimide
  derivative

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Example

C6H5CH2Cl
DMF
16
Example

(97)
C6H5CH2NH2
H2NNH2
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22.9Preparation of Amines by Reduction
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Preparation of Amines by Reduction

• almost any nitrogen-containing compound canbe
  reduced to an amine, including
• azides nitriles nitro-substituted benzene
  derivatives amides

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Synthesis of Amines via Azides

• SN2 reaction, followed by reduction, gives a
  primary alkylamine.

NaN3
(74)
azides may also bereduced by catalytichydrogenat
ion
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Synthesis of Amines via Nitriles

• SN2 reaction, followed by reduction, gives a
  primary alkylamine.

NaCN
CH3CH2CH2CH2Br
CH3CH2CH2CH2CN
(69)
nitriles may also bereduced by lithiumaluminum
hydride
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Synthesis of Amines via Nitriles

• SN2 reaction, followed by reduction, gives a
  primary alkylamine.

NaCN
CH3CH2CH2CH2Br
CH3CH2CH2CH2CN
(69)
the reduction alsoworks with cyanohydrins
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Synthesis of Amines via Nitroarenes
HNO3
Cl
H2SO4
nitro groups may alsobe reduced with tin (Sn)
HCl or by catalytichydrogenation
(88-95)
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Synthesis of Amines via Amides
1. SOCl2
2. (CH3)2NH
(86-89)
only LiAlH4 is anappropriate reducingagent for
this reaction
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22.10Reductive Amination
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Synthesis of Amines via Reductive Amination
In reductive amination, an aldehyde or ketoneis
subjected to catalytic hydrogenation in
thepresence of ammonia or an amine.
fast


NH3
H2O

• The aldehyde or ketone equilibrates with
  theimine faster than hydrogenation occurs.

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Synthesis of Amines via Reductive Amination
The imine undergoes hydrogenation fasterthan the
aldehyde or ketone. An amine is the product.
fast


NH3
H2O
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Example Ammonia gives a primary amine.
H2, Ni

NH3
ethanol
(80)
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Example Primary amines give secondary amines
H2, Ni
ethanol
(65)
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Example Secondary amines give tertiary amines

H2, Ni, ethanol
(93)
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Example Secondary amines give tertiary amines
possible intermediates include
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22.11Reactions of AminesA Review and a Preview
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Reactions of Amines
Reactions of amines almost always involve
thenitrogen lone pair.
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Reactions of Amines
Reactions already discussed

• basicity (Section 22.4)
• reaction with aldehydes and ketones
  (Sections17.10, 17.11)
• reaction with acyl chlorides (Section
  20.4),anhydrides (Section 20.6), and esters
  (Section 20.12)

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22.12Reactions of Amines with Alkyl Halides
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Reaction with Alkyl Halides
Amines act as nucleophiles toward alkyl halides.



X



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Example excess amine

(4 mol)
(1 mol)
NaHCO3
90C
(85-87)
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Example excess alkyl halide

3CH3I
methanol
heat

(99)
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22.13The Hofmann Elimination
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The Hofmann Elimination

• a quaternary ammonium hydroxide is the
  reactantand an alkene is the product
• is an anti elimination
• the leaving group is a trialkylamine
• the regioselectivity is opposite to the Zaitsev
  rule.

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Quaternary Ammonium Hydroxides
are prepared by treating quaternary
ammmoniumhalides with moist silver oxide
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The Hofmann Elimination
on being heated, quaternary ammonium hydroxides
undergo elimination
160C


HO
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Mechanism
H
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Regioselectivity
Elimination occurs in the direction that gives
the less-substituted double bond. This is
called the Hofmann rule.
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Regioselectivity
Steric factors seem to control the
regioselectivity.The transition state that leads
to 1-butene isless crowded than the one leading
to cisor trans-2-butene.
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Regioselectivity
largest group is between two H atoms
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Regioselectivity
H
CH3
H
CH3
H

largest group is between anH atom and a methyl
group
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22.14Electrophilic Aromatic Substitutionin
Arylamines
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Nitration of Anililne

• NH2 is a very strongly activating group
• NH2 not only activates the ring toward
  electrophilic aromatic substitution, it also
  makes it more easily oxidized
• attemped nitration of aniline fails because
  nitric acid oxidizes aniline to a black tar

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Nitration of Anililne

• Strategy decrease the reactivity of aniline by
  converting the NH2 group to an amide

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Nitration of Anililne

• Strategy nitrate the amide formed in the first
  step

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Nitration of Anililne

• Strategy remove the acyl group from the amide
  by hydrolysis

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Halogenation of Arylamines

• occurs readily without necessity of protecting
  amino group, but difficult to limit it to
  monohalogenation

(82)
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Monohalogenation of Arylamines

• Decreasing the reactivity of the arylamine by
  converting the NH2 group to an amide allows
  halogenation to be limited to monosubstitution

(74)
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Friedel-Crafts Reactions

• The amino group of an arylamine must be protected
  as an amide when carrying out a Friedel-Crafts
  reaction.

O
NHCCH3
CH3
(57)