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Reactions of Aromatic
Compounds
15.1 2-2
catalyst E
+ E + H
FeBr 3 Br
+ Br–Br
Br
+ Br–Br F
Br
X2, FeX 3 X
+ HX
X = Cl, Br
NO 2
HNO 3
+ H 2O
H 2SO 4
SO 3 SO 3H
H 2SO 4
RCl R
+ HCl
AlCl3
O
ROCl R
+ HCl
AlCl3
15.2 2-4
H
+ E
E A + A
H
E
E
+ A + H–A
H
E
E
+ E A + H–A
+ A
15.3 2-6
Halogenation of Benzene
FeCl 3 Cl
+ Cl–Cl
25°C
F
FeBr 3 Br
+ Br–Br
heat
Mechanism:
Nitration of Benzene
HNO 3, H 2SO 4 NO 2
F
50°C
Mechanism:
15.5 2-8
Sulfonation of Benzene
SO 3, H 2SO 4 SO 3H
F
Mechanism:
Friedel-Crafts Alkylation
AlCl3 R
+ R X F
Mechanism:
2-10
HF
+ F
0°C
OH BF 3
+ F
60°C
Friedel-Crafts Acylation
O
O
AlCl3 F
+
Cl
acetophenone
Mechanism:
15.7 2-12
O
O O O
1. AlCl3 F
+ +
O OH
2. H 2O
acetic anhydride
Mechanism:
AlCl3
+ Br + F
36% 64%
AlCl3
+
Cl
Cl AlCl3
+
15.8 2-14
O
AlCl3
H Cl
O OH O R
NO 2 N(CH 3)3 CF3 SO 3H NH 2
Cl
AlCl3
+
15.8 2-16
Clemmensen Reduction
Problem (slide 2-13):
AlCl3
+ Br +
36% 64%
O
O
AlCl3
+
Cl
O
Zn(Hg)/HCl
reflux F
Note: only arylketones (or aldehydes) are reduced (e.g. carboxylic acids remain unaffected)
a) tert-butyl benzene:
b) 1-phenyl-2-methylbutane:
2-18
Problem: Propose a synthesis of -tetralone starting from benzene and succinic anhydride:
O O
+ O
OCH3 CH3 H Cl NO 2
activation deactivation
Alkyl substituents:
59% 4% 37%
NH 2 NH 2
Br 2 Br Br
H 2O
aniline Br
>99%
Because this step is endothermic, there is a strong resemblance between the arenium
cation and the transition state leading to it (Hammond-Lefer postulate)
H
+ E
E A + A
Q Q
H Br H Br H Br
H Br H Br H Br
para attack:
H E H E H E
meta attack:
E E E
H H H
Stabilization of the arenium ion intermediate yields a lower activation barrier and thus
the fastest reaction pathway for ortho and para substitution.
CHEM 2312 Spring 2016 Notes: C.J. Fahrni
15.10, 15.11 2-25
OH OH OH OH
para attack:
H E H E H E H E
OH OH OH OH
H H H H
ortho attack: E E E E
OH OH OH
meta attack:
E E E
H H H
NO 2 NO 2 NO 2 NO 2
HNO 3 NO 2
+ +
H 2SO 4
NO 2
nitrobenzene NO 2
6% 93% 1%
O O O O O O
N N N
H
E
E
H E H
para attack:
H E H E H E
meta attack:
E E E
H H H
Meta substitution yields the least destabilized intermediate and therefore the fastest
reaction pathway.
Cl Cl Cl Cl
Cl2 Cl
+ +
FeCl 3
Cl
chlorobenzene Cl
39% 6% 55%
Cl Cl Cl Cl
HNO 3 NO 2
+ +
H 2SO 4
NO 2
chlorobenzene NO 2
30% 0% 70%
Cl Cl Cl Cl
para attack:
H E H E H E H E
Cl Cl Cl Cl
H H H H
ortho attack: E E E E
Cl Cl Cl
meta attack:
E E E
H H H
Weakly deactivating:
–F, –Cl, –Br, –I
F
Examples: OCH3
Br 2
AlBr3
CF3
HNO 3
H 2SO 4
O
Br 2
FeBr 3
O
CH3COCl
AlCl3
CH3I
AlCl3
15.14B 2-32
AlCl3 F
CH3 CH3
CH3 CH3
Br 2
F
FeBr 3
NO 2 NO 2
CH3 CH3
HNO 3
H 2SO 4 F
C(CH3)3 C(CH3)3
CH3 CH3
HNO 3
F
H 2SO 4
CH3 CH3
OCH3 OCH3
Br 2
F
HOAc
CH3 CH3
CHO CHO
HNO 3
F
H 2SO 4
OCH3 OCH3
15.14A 2-34
NH 2
HNO 3
F
H 2SO 4
Solution:
NH 2
CH3COCl
F
pyridine
NBS, light
F
CCl4
HBr
F
peroxides
HBr
(no peroxides) F
15.13 2-36
Alkyl, alkynyl, and acyl benzenes are also degraded to benzoic acid:
CH2R
CH3
1. HNO 3/H2SO 4 NO 2
2. CH3COCl/AlCl3
3. Zn(Hg)/HCl
3. Br 2, FeBr 3
Br
15.14 2-38
Synthetic Strategies
R
R = –Cl, –Br, –I, SO 3H, –NO2, –COR, –alkyl
NH 2 HN HN NH 2
1. H 2O, H 2SO 4
CH3COCl heat
base 2. NaOH
R R
2-40
2-42
20.4B 2-44
NO 2 NH 2
reducing
HNO 3 reagent
F
H 2SO 4
reducing reagents
a) (1) Fe, HCl; (2) NaOH
b) (1) Zn, HCl; (2) NaOH
c) SnCl2
d) H 2/Pt (catalyst)
e) H 2S, NH 3, EtOH
Anilines react with nitrous acid to form diazonium salts, which can be converted F
to a wide range of derivatives:
HBF 4, heat F
CuCl Cl
CuBr Br
N
NH 2 NaNO 2 N KI I
HCl
CuCN CN
H 3PO 2 H
Cu2O, Cu2+ OH
20.6 2-46
Mechanism of diazotization:
N
NH 2 NaNO 2 N
HCl
OH
Cl
2-48
Br Br
Cl G
N
N G
+ N
N
G = –NR2 or –OH
20.8 2-50
N N N
N COONa N N
O
O2N N O S
Alizarine Yellow R Methyl orange NH 2 Prontosil
(pH Indicator) (pH Indicator) (antibiotic )
OH NO 2
COOEt N
N
N SO 3Na
N SO 3Na SO 3Na
N
N
N
O N
NaO 3S SO 3Na OH
OH
Orange B Orange G Eriochrome Black T
(food dye) (histological stain) (complexometric Indicator)
NH 2 H 2N
OH HO
NaO 3S SO 3Na
N N
N N
SO 3Na NaO 3S
Trypan Blue
(vital stain to selectively color dead cells)
The Trypan Blue exclusion assay
identies dead cells
CHEM 2312 Spring 2016 Notes: C.J. Fahrni
21.1 2-51
Phenols
Nomenclature:
OH OH OH
OH
Cl
phenol m-chlorophenol 1-naphthol 2-naphthol
F
OH OH OH
CH3
CH3
CH3
p-cresol m-cresol o-cresol
OH OH OH
OH
OH
OH
hydroquinone resorcinol catechol
21.5 2-52
Phenols: Acidity
OH O
+ H 2O + H 3O pK a = 9.89
OH OH OH OH OH OH
NO 2 O2N NO 2
CH3 Cl NO 2 NO 2 NO 2
A– + H3O+
reaction
coordinate
21.5 2-54
pK a = 7.15
N
O O
pK a = 8.28
O
N
O
OH OH OH
NH N N
21.4 2-56
Phenols: Synthesis
1. Hydrolysis of aryldiazonium salts (slide 2-45)
N OH
NH 2 NaNO 2 N Cu2O, Cu2+
HCl H 2O
2. Industrial syntheses:
Cl NaOH O –Na +
Cl2
F
Fe 350°C
high pressure
OOH
O2 H 2SO 4 OH
Phenols: Reactions
1. Phenol oxygen as nucleophile:
O
OH
Cl
pyridine
O O
F
OH
O
pyridine
OH
1. NaOH, H 2O conc. HBr
F
2. R–Br
21.8 2-58
OH
excess Br 2
OH
HNO 3
H 2SO 4
OH
conc. H 2SO 4
Kolbe Reaction:
OH O OH O
1. NaOH 2. CO2 3. H 3O+
O
Mechanism:
2-60
O O
OH Aspirin
Acetaminophen
NH
21.9 2-62
OH O OH
Br
heat F
NaOH
H 2O
Cl r.t. OH
Cl H 2O
r.t.
Aryl halides undergo substitution only under more drastic reaction conditions:
Cl NaOH OH
F
350°C
Cl KNH 2 NH 2
F
21.11B 2-64
Labeling experiment:
14 Cl K +NH 2– 14 NH 2 14 H
C C C
+
NH 3 (l)
NH 2
Br Br
F
H
130°C
Cl OH
NO 2 NaOH NO 2
F
100°C
NO 2 NO 2
Cl OH
O2N NO 2 NaOH O2N NO 2
35°C
NO 2 NO 2
21.11A 2-66
Addition-Elimination Mechanism:
Cl
+ OH
N
O O
Problem: Rank the following compounds in descending order of reactivity toward hydroxide ion:
Br Br Br Br Br
NO 2 NO 2
NO 2 NO 2
NO 2 NO 2 NO 2
I II III IV V
2-68
NO 2
OH NaOCH 3 O
H 3C S H 3C SO2
O O NO
2
Na
NO 2
Cl
Cl NO 2 NaOCH 3
CH3OH
NO 2
Cl
LiNEt 2
HNEt 2
CH3
2-70
Problem (21.19) The following scheme outlines the synthesis of the -blocker toliprolol. Give the
structures of the intermediates and the nal product.
OH O
Cl
OH NH 2
C10H13 O2Cl C10H12 O2 C13H 21NO 2
toliprolol
CH3