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• Reaction of Amines with Nitrous Acid (produced in situ

by mixing sodium nitrite, NaONO, with HCl)

– Qualitative testes:

• 1°-Amines + HONO (cold acidic solution) Nitrogen Gas Evolution

from a Clear Solution

• 2°-Amines + HONO (cold acidic solution) An Insoluble Oil (N-Nitrosoamine)

• 3°-Amines + HONO (cold acidic solution) A Clear Solution (Ammonium Salt Formation)

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2

Reactions of Aryl Diazonium Salts

Synthesis, 2007, 81-84

J. Org. Chem., 2006, 71, 3332-3334

Arenediazonium Salts• Stable in solution at 0°–10°C.

• The -+N≡N group is easily replaced by many different groups.

• Nitrogen gas, N2, is a by-product.

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3

Sandmeyer Reaction

4

Schiemann Reaction

5

6

7

8

Azo compounds

Substitution and Elimination Reactions of Amines

• Amine functions don’t usually act as

leaving groups in nucleophilic substitution

or base-catalyzed elimination reactions.

• tetraalkyl ammonium salts are efficient

leaving groups in eliminations and in some

SN2 substitutions.

R-S-CH3 + C6H5–N(CH3)2 + NaBrC6H5–N(CH3)3(+) Br(–) + R-S(–) Na(+)

9

Hofmann Elimination

Hofmann Mechanism (1)

• N-H protons of amide are abstracted.

• Rearrangement forms an isocyanate.

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Hofmann Mechanism (2)

Isocyanate reacts with water to form

carbamic acid, which loses CO2.

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• simple amines are easily converted to the necessary 4º-ammonium salts by exhaustive alkylation

• methyl has no beta-hydrogens and cannot compete in the elimination reaction.

• the major product may be the less substituted alkene.The tendency of Hofmann eliminations to give the less-substituted double bond isomer is commonly referred to as the Hofmann Rule, and contrasts strikingly with the Zaitsev Rule formulated for dehydrohalogenations and dehydrations.

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Oxidation States of Nitrogen

R-NO2

Nitro

RO–N=Onitrite ester

R–N=Onitroso

N2

nitrogen

R–N2(+)

diazonium

RN=NR azo cpd.

R2NOHhydroxyl

amine

R3NO amine oxide

R2N–NR2

Hydrazine

C=N–NR2

Hydrazones

R3NAmines

R4N(+)

Ammoniu

C=N–RImines

C≡Nnitriles

Formulas

names

+3+10_1_2_3Oxidation

State

Amine Oxides

• Amine oxides are prepared by oxidizing

3º-amines or pyridines with hydrogen

peroxide or peracids

• Cope Elimination

12

http://www.iupac.org/goldbook/E02212.pdf

Aromatic Five-Membered Heterocycles

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Pyrrole is an extremely weak base

The dipole moment in pyrrolidine (left) is attributed tothe electron-withdrawing property of the nitrogen atom

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Pyrrole, furan, and thiophene undergo electrophilicsubstitution preferentially at C-2

15

Electrophilic aromatic substitution reactions

Structures of the intermediates that can be formed fromthe reaction of an electrophile with pyrrole at C-2 and C-3

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If both positions adjacent to the heteroatom are occupied, electrophilic substitution occurs at C-3

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The relative reactivities of the five-membered-ring heterocycles in Friedel–Crafts reaction

The resonance hybrid of pyrrole indicates that there is apartial positive charge on the nitrogen

Pyrrole is unstable in strongly acid solution because theprotonated pyrrole polymerizes

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Pyrrole is more acidic than the analogous saturated

Its acidity is increased due to its conjugated basebeing stabilized by resonance !!!!!!!!!!!!!

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Aromatic Six-Membered-Ring Heterocycles

The pyridinium ion is a stronger acid than a typicalammonium ion

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Pyridine Reacts Like a Tertiary Amine

Pyridine Is Aromatic

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Pyridine undergoes electrophilic aromatic substitution atC-3

22

Protonation of pyridine decreases its reactivity

23

Pyridine is less reactive than benzene toward electrophilic aromatic substitution, but is more reactive toward nucleophilic aromatic substitution

Pyridine undergoes nucleophilic aromatic substitution atC-2 and C-4

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If the leaving groups at C-2 and C-4 are different, theincoming nucleophile will preferentially substitute for the weaker base

Bromination and Oxidation of

Substituted Pyridine

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Diazotization of Aminopyridine

26

The α-hydrogens of alkyl substituents can be removed bybase to generate nucleophiles

Quinoline and isoquinoline are known as benzopyridines

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Some Biologically Important Heterocycles

Imidazole

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Purine and Pyrimidine

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Porphyrin