Download 21_Lecture

Organic Chemistry
6th Edition
Paula Yurkanis Bruice
Chapter 21
More About Amines
Heterocyclic
Compounds
1
© 2011 Pearson Education, Inc.
Nomenclature of Heterocycles
Cyclic amines (the names in quotes are preferred):
Nitrogen is #1 when numbering the ring
2
© 2011 Pearson Education, Inc.
Heterocycles with oxygen and sulfur heteroatoms
(the names in quotes are preferred):
3
© 2011 Pearson Education, Inc.
Acid–Base Properties of Amines
Amines are the most common organic bases:
4
© 2011 Pearson Education, Inc.
Saturated amine heterocycles containing five or more
atoms have physical and chemical properties typical of
acyclic amines:
5
© 2011 Pearson Education, Inc.
Amines React as Bases and as Nucleophiles
The lone-pair electron on the nitrogen of an amine
causes it to be nucleophilic as well as basic:
6
© 2011 Pearson Education, Inc.
Reactions of Amines
Nucleophilic substitution reactions:
Nucleophilic acyl substitution reactions:
7
© 2011 Pearson Education, Inc.
Nucleophilic addition–elimination reactions:
8
© 2011 Pearson Education, Inc.
Conjugate addition reactions:
9
© 2011 Pearson Education, Inc.
Reactions of Quaternary Ammonium Hydroxides
The Hofmann elimination is an E2 reaction:
D
The leaving group of a quaternary ammonium ion has
about the same leaving tendency as a protonated amino
group
10
© 2011 Pearson Education, Inc.
The hydrogen is removed from the b-carbon bonded to
the most hydrogens:
The least-substituted alkene elimination product is often
called the Hofmann product
11
© 2011 Pearson Education, Inc.
Quaternary ammonium ions, like alkyl fluorides, are
poor leaving groups:
12
© 2011 Pearson Education, Inc.
Hofmann elimination requires exhaustive methylation
of the amine, followed by elimination:
A strong base, such as hydroxide ion, must be used in
the elimination reaction
13
© 2011 Pearson Education, Inc.
Quaternary ammonium salts are used as phase transfer
catalysts in facilitating the reactions between certain
ionic and organic reactants:
14
© 2011 Pearson Education, Inc.
Consider the reaction between sodium cyanide and an
alkyl halide:
15
© 2011 Pearson Education, Inc.
Oxidation of Amines
Mechanism:
16
© 2011 Pearson Education, Inc.
Tertiary Amine Oxides Undergo a
Cope Elimination Reaction
The proton is removed from the b-carbon bonded to the
most hydrogens
17
© 2011 Pearson Education, Inc.
Synthesis of Amines
Because ammonia and amines are good nucleophiles,
they readily undergo SN2 reactions with RX:
It is difficult to control the desired number of alkyl
substituents placed on the nitrogen
18
© 2011 Pearson Education, Inc.
The Gabriel Synthesis of Primary Amines
19
© 2011 Pearson Education, Inc.
Other Methods for Synthesizing Amines
20
© 2011 Pearson Education, Inc.
Reduction of amides with LiAlH4:
21
© 2011 Pearson Education, Inc.
Aromatic Five-Membered Heterocycles
22
© 2011 Pearson Education, Inc.
Pyrrole is an extremely weak base:
23
© 2011 Pearson Education, Inc.
The dipole moment in pyrrolidine (left) is attributed to
the electron-withdrawing property of the nitrogen atom:
24
© 2011 Pearson Education, Inc.
25
© 2011 Pearson Education, Inc.
Pyrrole, furan, and thiophene undergo electrophilic
substitution, preferentially at C-2:
26
© 2011 Pearson Education, Inc.
Electrophilic aromatic substitution reactions:
27
© 2011 Pearson Education, Inc.
Structures of the intermediates that can be formed from
the reaction of an electrophile with pyrrole at C-2 and C-3
Three resonance structures: more stable
Two resonance
structures: less
stable
28
© 2011 Pearson Education, Inc.
If both positions adjacent to the heteroatom are
occupied, electrophilic substitution occurs at C-3:
29
© 2011 Pearson Education, Inc.
Why? Because of cation stabilization by lone-pair
resonance release:
30
© 2011 Pearson Education, Inc.
The relative reactivities of the five-membered
heterocycles in Friedel–Crafts reaction:
31
© 2011 Pearson Education, Inc.
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:
32
© 2011 Pearson Education, Inc.
Pyrrole is more acidic than pyrrolidine because of
stabilization of its conjugated base by resonance
Five resonance
structures for the anion
Localized anion
33
© 2011 Pearson Education, Inc.
34
© 2011 Pearson Education, Inc.
Indole, benzofuran, and benzothiophene all contain a
five-membered aromatic ring fused to a benzene ring:
35
© 2011 Pearson Education, Inc.
Aromatic Six-Membered-Ring Heterocycles
36
© 2011 Pearson Education, Inc.
The pyridinium ion is a stronger acid than a typical
ammonium ion
Pyridine reacts like a tertiary amine:
37
© 2011 Pearson Education, Inc.
Pyridine Is Aromatic
• The nitrogen lone pair is not released into the
aromatic system because it is perpendicular to
the  system.
• The nitrogen withdraws electrons by resonance,
resulting in an electron-deficient ring system.
38
© 2011 Pearson Education, Inc.
Pyridine undergoes electrophilic aromatic substitution at
C-3:
39
© 2011 Pearson Education, Inc.
40
© 2011 Pearson Education, Inc.
The pyridine nitrogen is a meta director:
41
© 2011 Pearson Education, Inc.
Pyridine is reactive toward nucleophilic aromatic
substitution because of the presence of the
electronegative nitrogen:
42
© 2011 Pearson Education, Inc.
Pyridine undergoes nucleophilic aromatic substitution at
C-2 and C-4:
43
© 2011 Pearson Education, Inc.
If the leaving groups at C-2 and C-4 are different, the
incoming nucleophile will preferentially substitute for
the weaker base:
44
© 2011 Pearson Education, Inc.
Bromination and Oxidation of
Substituted Pyridine
45
© 2011 Pearson Education, Inc.
Diazotization of Aminopyridine
46
© 2011 Pearson Education, Inc.
The a-hydrogens of alkyl substituents can be
removed by base to generate anionic nucleophiles:
Pyridine a-hydrogen acidity is similar to that of
ketone a-hydrogens
47
© 2011 Pearson Education, Inc.
Reactions of pyridine-based anionic nucleophiles:
48
© 2011 Pearson Education, Inc.
Quinoline and isoquinoline are ring-fused pyridine
derivatives:
49
© 2011 Pearson Education, Inc.
Some Biologically Important Heterocycles
Imidazole
50
© 2011 Pearson Education, Inc.
51
© 2011 Pearson Education, Inc.
52
© 2011 Pearson Education, Inc.
Purine and Pyrimidine
53
© 2011 Pearson Education, Inc.
Porphyrin
54
© 2011 Pearson Education, Inc.