• 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 (NNitrosoamine)
• 3°-Amines + HONO (cold acidic solution) A Clear Solution
(Ammonium Salt Formation)
=>
1
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.
=>
2
Sandmeyer Reaction
3
Schiemann Reaction
4
5
6
7
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.
C6H5–N(CH3)3(+) Br(–) + R-S(–) Na(+)
R-S-CH3 + C6H5–N(CH3)2 + NaBr
8
Hofmann Elimination
Hofmann Mechanism (1)
• N-H protons of amide are abstracted.
• Rearrangement forms an isocyanate.
=>
9
Hofmann Mechanism (2)
Isocyanate reacts with water to form
carbamic acid, which loses CO2.
=>
•
•
•
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.
10
Oxidation States of Nitrogen
Oxidation
State
_3
Formulas R3N
names Amines
R4N(+)
Ammoniu
C=N–R
Imines
_2
_1
0
+1
+3
R2N–NR2
Hydrazine
RN=NR
azo cpd.
N2
nitrogen
R–N=O
nitroso
R-NO2
C=N–NR2
R2NOH
Hydrazones hydroxyl
amine
R–N2(+)
diazonium
Nitro
RO–N=O
nitrite
ester
R3NO
amine oxide
C≡N
nitriles
Amine Oxides
• Amine oxides are prepared by oxidizing
3º-amines or pyridines with hydrogen
peroxide or peracids
• Cope Elimination
11
http://www.iupac.org/goldbook/E02212.pdf
Aromatic Five-Membered Heterocycles
12
Pyrrole is an extremely weak base
The dipole moment in pyrrolidine (left) is attributed to
the electron-withdrawing property of the nitrogen atom
13
Pyrrole, furan, and thiophene undergo electrophilic
substitution preferentially at C-2
14
Electrophilic aromatic substitution reactions
Structures of the intermediates that can be formed from
the reaction of an electrophile with pyrrole at C-2 and C-3
15
If both positions adjacent to the heteroatom are
occupied, electrophilic substitution occurs at C-3
16
The relative reactivities of the five-membered-ring
heterocycles in Friedel–Crafts reaction
The resonance hybrid of pyrrole indicates that there is a
partial positive charge on the nitrogen
Pyrrole is unstable in strongly acid solution because the
protonated pyrrole polymerizes
17
Pyrrole is more acidic than the analogous saturated
Its acidity is increased due to its conjugated base
being stabilized by resonance !!!!!!!!!!!!!
18
Aromatic Six-Membered-Ring Heterocycles
The pyridinium ion is a stronger acid than a typical
ammonium ion
19
Pyridine Reacts Like a Tertiary Amine
Pyridine Is Aromatic
20
Pyridine undergoes electrophilic aromatic substitution at
C-3
21
Protonation of pyridine decreases its reactivity
22
Pyridine is less reactive than benzene toward
electrophilic aromatic substitution, but is more reactive
toward nucleophilic aromatic substitution
Pyridine undergoes nucleophilic aromatic substitution at
C-2 and C-4
23
If the leaving groups at C-2 and C-4 are different, the
incoming nucleophile will preferentially substitute for
the weaker base
Bromination and Oxidation of
Substituted Pyridine
24
Diazotization of Aminopyridine
25
The α-hydrogens of alkyl substituents can be removed by
base to generate nucleophiles
Quinoline and isoquinoline are known as benzopyridines
26
Some Biologically Important Heterocycles
Imidazole
27
Purine and Pyrimidine
28
Porphyrin
29