Preparation

1
Preparation

• We have already covered these methods
• nucleophilic ring opening of epoxides by ammonia
  and amines.
• addition of nitrogen nucleophiles to aldehydes
  and ketones to form imines
• reduction of imines to amines
• reduction of amides to amines by LiAlH4
• reduction of nitriles to a 1 amine
• nitration of arenes followed by reduction of the
  NO2 group to a 1 amine

2
Preparation

• Alkylation of ammonia and amines by SN2
  substitution.
• Unfortunately, such alkylations give mixtures of
  products through a series of proton transfer and
  nucleophilic substitution reactions.

polyalkylations
3
Preparation via Azides

• Alkylation of azide ion.

Overall Alkyl Halide ? Alkyl amine
4
Example Preparation via Azides

• Alkylation of azide ion.

Note retention of configuration, trans ? trans
5
Reaction with HNO2

• Nitrous acid, a weak acid, is most commonly
  prepared by treating NaNO2 with aqueous H2SO4 or
  HCl.
• In its reactions with amines, nitrous acid
• Participates in proton-transfer reactions.
• A source of the nitrosyl cation, NO, a weak
  electrophile.

6
Reaction with HNO2

• NO is formed in the following way.
• Step 1 Protonation of HONO.
• Step 2 Loss of H2O.
• We study the reactions of HNO2 with 1, 2, and
  3 aliphatic and aromatic amines.

7
Tertiary Amines with HNO2

• 3 Aliphatic amines, whether water-soluble or
  water-insoluble, are protonated to form
  water-soluble salts.
• 3 Aromatic amines NO is a weak electrophile
  and participates in Electrophilic Aromatic
  Substitution.

8
Secondary Amines with HNO2

• 2 Aliphatic and aromatic amines react with NO
  to give N-nitrosamines.

carcinogens
9
Amines with HNO2

• Reaction of a 2 amine to give an N-nitrosamine.
• Step 1 Reaction of the 2 amine (a nucleophile)
  with the nitrosyl cation (an electrophile).
• Step 2 Proton transfer.

10
RNH2 with HNO2

• 1 aliphatic amines give a mixture of
  unrearranged and rearranged substitution and
  elimination products, all of which are produced
  by way of a diazonium ion and its loss of N2 to
  give a carbocation.
• Diazonium ion An RN2 or ArN2 ion

11
1 RNH2 with HNO2

• Formation of a diazonium ion.
• Step 1 Reaction of a 1 amine with the nitrosyl
  cation.
• Step 2 Protonation followed by loss of water.

12
1 RNH2 with HNO2

• Aliphatic diazonium ions are unstable and lose N2
  to give a carbocation which may
• 1. Lose a proton to give an alkene.
• 2. React with a nucleophile to give a
  substitution product.
• 3. Rearrange and then react by Steps 1 and/or 2.

13
1 RNH2 with HNO2

• Tiffeneau-Demjanov reaction Treatment of a
  ?-aminoalcohol with HNO2 gives a ketone and N2.

14
Mechanism of Tiffeneau-Demjanov

• Reaction with NO gives a diazonium ion.
• Concerted loss of N2 and rearrangement followed
  by proton transfer gives the ketone.

Similar to pinacol rearrangement
15
Pinacol Rearrangement an example of
stabilization of a carbocation by an adjacent
lone pair.
Overall
16
Mechanism
Reversible protonation.
Elimination of water to yield tertiary
carbocation.
This is a protonated ketone!
1,2 rearrangement to yield resonance stabilized
cation.
Deprotonation.
17
1 ArNH2 with HNO2

• The -N2 group of an arenediazonium salt can be
  replaced in a regioselective manner by these
  groups.

18
1 ArNH2 with HNO2

• A 1 aromatic amine converted to a phenol.

19
1 ArNH2 with HNO2

• Problem What reagents and experimental
  conditions will bring about this conversion?

20
1 ArNH2 with HNO2

• Problem Show how to bring about each conversion.

21
Hofmann Elimination

• Hofmann elimination Thermal decomposition of a
  quaternary ammonium hydroxide to give an alkene.
• Step 1 Formation of a 4 ammonium hydroxide.

22
Hofmann Elimination

• Step 2 Thermal decomposition of the 4 ammonium
  hydroxide.

23
Hofmann Elimination

• Hofmann elimination is regioselective - the major
  product is the least substituted alkene.
• Hofmanns rule Any ?-elimination that occurs
  preferentially to give the least substituted
  alkene as the major product is said to follow
  Hofmanns rule.

24
Hofmann Elimination

• The regioselectivity of Hofmann elimination is
  determined largely by steric factors, namely the
  bulk of the -NR3 group.
• Hydroxide ion preferentially approaches and
  removes the least hindered hydrogen and, thus,
  gives the least substituted alkene.
• Bulky bases such as (CH3)3CO-K give largely
  Hofmann elimination with haloalkanes.

25
Cope Elimination

• Cope elimination Thermal decomposition of an
  amine oxide.
• Step 1 Oxidation of a 3 amine gives an amine
  oxide.
• Step 2 If the amine oxide has at least one
  ?-hydrogen, it undergoes thermal decomposition to
  give an alkene.

26
Cope Elimination

• Cope elimination shows syn stereoselectivity but
  little or no regioselectivity.
• Mechanism a cyclic flow of electrons in a
  six-membered transition state.