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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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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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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(+)
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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
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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
21
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