Beruflich Dokumente
Kultur Dokumente
Reactions
H2 , EtOH
E+Z
Pd-C
H2 , EtOH
Ni(R)
H2 , EtOH
Pd-C
or say E+Z
H2 , EtOH
Pd-BaSO4
quinoline
H2 , EtOH
O
OH
PtO2
H2 , EtOH
N.R.
Me3C
Na , NH3 (-33C)
H
Me3COH
55
O-H
Me3C
59
The mechanism involves transfer of a single electron from sodium metal to the carbonyl unit
of the ketone to give a new type of intermediate, a radical-anion.
In this case, the radical-anion is 56A and it is generically known as a ketyl.
This ketyl is a resonance stabilized species and it can be drawn with the negative charge on
either oxygen (56A) or carbon (56B), and the single electron (the radical) can be drawn on
either oxygen or carbon.
The resonance form that has the negative charge on carbon (56B) functions as a carbanion
base, and removes a proton from either ammonia or the alcohol in an acid-base reaction.
Me3C
Na
Me3C
56A
55
56B
O
Na
57
O-H
ROH
H
Me3C
HOR
Me3C
Me3C
58
Me3C
H
59
C3H7
C
60
C3H7
Na , NH3 , EtOH
C3H7
C
H 64
H
C
C3H7
C3H7
Na
C3H7
60
EtOH
C3H7
C
C3H7
62
C3H7
C3H7
Na
C3H7
C
61A
C3H7
61B
C3H7
C
EtOH
C3H7
63
C3H7
C
H
C
C3H7
64
Na , NH3
EtOH , 33C
65
66
Initial electron transfer from sodium metal to benzene leads to radical anion 67.
Resonance delocalization as shown should favor the resonance contributor 67B due to charge
separation.
If 67B reacts with the acid (ethanol), reduction gives 68. A second electron transfer from
additional sodium metal converts radical 68 to carbanion 69, which quickly reacts with the
acidic proton of ethanol to give the final product 66.
The non-conjugated diene unit is determined by charge separation in 67 at the time of the
initial electron transfer.
This reduction of benzene and its derivatives is commonly known as Birch reduction.
H-OEt
Na
67A
65
68
67B
Na
H-OEt
69
66
I
C24H49
70
Zn , HCl
C24H49
71
68%
Clemmensen
Bu
Zn(Hg) , HCl
Bu
CHO
77
78
NH2NH2 , KOH
CHO
Bu
Wolff-Kishner
77
78
NH2NH2
KOH
80
10
11
When hexadecanenitrile (81) is treated with SnCl2 and HCl, the HCl
adds to the CN unit to give a chloro-imine, 82.
The chlorine is subsequently reduced, and in the acidic medium
chlorine is replaced with hydrogen to give imine 83.
In the aqueous acid solution, the imine is converted to an aldehyde, 84.
In one reported experiment, 81 is converted to hexadecanal (84) in
quantitative yield.
C!N
SnCl2 , HCl
Cl
H3
C14H29
O
C14H29
C14H29
82
N-H
N-H
C14H29
81
O+
83
84
12
Reactions
Na , NH3 , EtOH
OH
Na , NH3 , EtOH
Na , NH3 , EtOH
CHO
1. N2H4 , KOH
CH3
2. aq. H+
CN
CHO
13
14
The basic rules of nomenclature for alcohols, amines, aldehydes and ketones,
carboxylic acids, and carboxylic acid derivatives. (chapter 5, sections 5.6, 5.9.B,
5.9.C and chapter 16, section 16.4)
The basic rules of nomenclature for carboxylic acid derivatives. (chapter 16,
section 16.7)
Nomenclature of dicarboxylic acids. (chapter 16, section 16.5)
Nomenclature for imines and nitriles. (chapter 5, section 5.9.D)
The CIP rules for prioritizing substituents, groups and atoms. (chapter 9, section
9.3)
Identification and nomenclature for E- and Z-isomers. (chapter 9, section 9.4)
Bond polarization. (chapter 3, section 3.7)
The fundamentals of acyl addition. (chapter 16, section 16.3 and also chapter 18,
section 18.1)
The fundamentals of acyl substitution and a tetrahedral intermediate. (chapter
16, section 16.8)
The acid-base reactions of the carbonyl group and formation of oxocarbenium
ions. (chapter 18, sections 18.1 and 18.5)
How to identify a good leaving group. (chapter 11, sections 11.1, 11.2)
How to identify relative nucleophilic strength. (chapter 11, section 11.2 and
chapter 18, sections 18.3-18.7)
Characteristics and reactivity of Grignard reagents, organolithium reagents.
(chapter 15, sections 15.1, 14.5)
15
16
Many acid derivatives can be generated by "replacing" the OH unit of a carboxylic acid
(COOH) with another atom or group; -Cl, -Br, -O2CR, -OR, -NR2. Common acid
derivatives are acid chloride, acid anhydrides, esters, and amides.
Acid or base hydrolysis of acid chlorides, acid anhydrides, esters, or amides regenerates
the "parent" carboxylic acid.
Acid chlorides are prepared by reaction of a carboxylic acid with a halogenating agent
lc
such as thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosgene, or
oxalyl chloride.
Acid anhydrides can be prepared by reaction of an acid chloride with a carboxylic acid
or by the dehydration of two carboxylic acids that leads to coupling.
Esters can be prepared by the reaction of an acid chloride or acid anhydride with an
alcohol as well as by direct reaction of an acid and an alcohol, with an acid catalyst, or by
using a dehydrating agent such as DCC. Lactones are cyclic esters.
Amides can be prepared by the reaction of an acid chloride, acid anhydride, or an ester
with ammonia or an amine. Acids and amines can be coupled in the presence of a
dehydrating agent such as DCC. Amines react with carboxylic acids to give ammonium
salts. Heating these salts to around 200C will usually give the amide. Lactams are cyclic
amides.
Imides are formed by the reaction of amides with other acid derivatives. Cyclic
anhydrides and cyclic imides can be prepared from dicarboxylic acids or acid dichlorides.
Acid derivatives react with Grignard reagents and organolithium reagents to give
ketones, but this initial product reacts with a second equivalent of Grignard reagent or
organolithium reagent to give a tertiary alcohol.
17
18
Acyl Substitution
Acid derivatives (2, X = OR, Cl, O2CR, NR2) react with an acid
such as sulfuric acid, HCl or p-toluenesulfonic acid to form an
oxocarbenium ion, 3.
The electrophilic carbon subsequently reacts with a nucleophile
to generate a tetrahedral intermediate that has a leaving group
attached (see 4).
Loss of the leaving group regenerates the carbonyl in a new
carboxylic acid derivative or a carboxylic acid, 5.
This reaction of an acid derivative with a nucleophile is known as
nucleophilic acyl substitution.
O
O
R
C
X
O
2
S
O
H
H
R
O
HSO4 X
R
O
:Y
R
O
C
4 X
R
C
Y
Y
O
5
19
Carboxylic Acids
O
H-O-H
O-H
7
O Na+
8
20
Compound 11 is the key tetrahedral intermediate and it has two leaving groups, OH (from the
water nucleophile) and Cl (from the acid chloride).
Chlorine is a superior leaving group when compared to OH.
O
C3H7
+ H+
C3H7
Cl
Cl
9
8
- Cl-
H
C3H7
H2O
O
OH
C3H7
12
OH
+ H2O
C3H7
C3H7
Cl
H2O
- H+
O
OH
C3H7
OH
7
Cl
O
10
OH
- H+
C3H7
H
Cl
O
11
21
Hydroxide is a strong base (it is the conjugate base of water), but it is also a nucleophile in
reactions with carboxylic acid derivatives.
If the basic OH ion reacts with acid chloride 8, attack at the carbonyl carbon gives tetrahedral
intermediate 13 directly. The alkoxide unit can donate electrons back to the carbon and
regenerate the C=O unit, but there are two leaving groups.
Loss of chloride ion from 13 leads directly to the acid, 7.
Once the acid is formed it is in a solution of hydroxide, which is a strong base (as mentioned
above). The acid and the base react immediately to give the anionic salt of the carboxylic acid,
14. Carboxylate anion 14 is the final product of this reaction.
In order to isolate 7, an acid must be added to 14 that is significantly stronger than 7 (a mineral
acid such as HCl for example) in a second chemical step. Therefore, treatment of 14 with
aqueous HCl (shown as H3O+) gives 7.
O
O
C3H7
Cl
8
- Cl
OH C3H7
13
Cl
OH
C3H7
OH
7
OH
C3H7
O
14
H3O+
C3H7
OH
7
22
Hydrolysis: anhydrides
The base-induced reaction of the symmetrical dipropanoic anhydride (15) illustrates the
mechanism of base hydrolysis with anhydrides, in a reaction that gives two equivalents of
propanoic acid.
Acyl addition of the nucleophilic hydroxide gives tetrahedral intermediate 16. In this case, the
best leaving group is the carboxylate anion 18, which gives propanoic acid, 17.
Since 17 is formed in a basic solution, reaction with hydroxide gives 18.
A second step is required to convert 17 to 18, using aqueous acid (aqueous sulfuric acid or
aqueous HCl).
O
O
O
Et
Et
O
15
Et
OH
Et
OH
O
16
Et
O
OH
17
O
Et
OH
18
Et
+
O
18
H3O+
O
Et
17
OH
23
Hydrolysis: esters
For basic hydrolysis conditions, the experiment requires two steps to convert the ester to the
acid.
Isopropyl acetate (19), for example, is heated to reflux in aqueous NaOH and then neutralized
with aqueous sulfuric acid to give a quantitative yield of two products, acetic acid (15) and 2propanol (isopropanol).
This reaction is explained by addition of hydroxide (in blue) to the acyl carbon of 19 to give
tetrahedral intermediate 20.
In water and with an excess of hydroxide ion loss of OiPr (isopropoxide, in green) is more
facile, and this generates the acid (acetic acid, 21).
Since it is formed in the presence of hydroxide (isopropoxide is also present), the acid-base
reaction leads to the final product of the first chemical step, carboxylate ion 22.
To isolate acid 21, 22 is treated with aqueous acid as shown, in a second chemical step.
O
Me
OH
OCHMe2
19
O
Me
OH
20
Me2CHO
OCHMe2
O
H3O+
HO
HOCHMe2
Me Me
21
O
22
Me
OH
21
24
Hydrolysis: esters
O
Me
19
1. aq. NaOH
OCHMe2
2. dilute
H3O+
+
Me
OH
21
Me2CHOH
25
Hydrolysis: esters
O
C3H7
H+
OEt
C3H7
29
OH
O
OEt C3H7
+ H2O
C3H7
OEt
30
OH
Et
C3H7
OH
OH
33
- EtOH
OH
C3H7
O
31
O
OH
12
C3H7
OEt
OH
H+
C3H7
H
H
OH
OH
32
- H+
+ H+
OEt
O
C3H7
OH
7
26
Hydrolysis: amides
Amides react under both acidic and basic conditions to give the parent carboxylic acid and an
amine for secondary and tertiary amides, or ammonia from a primary amide.
The mechanisms are essentially the same as those shown for the other acid derivatives, except
that the tetrahedral intermediate will have NH2 and OH as leaving groups.
The NH2 group (amide group) is a much worse leaving group when compared with the other
groups in this section, and experimentally the hydrolysis of an amide requires much more
vigorous conditions than the other acid derivatives.
It is more difficult to hydrolyze an amide when compared to other acid derivatives.
The acid catalyzed hydrolysis of butanamide proceeds as expected to give butanoic acid.
An example is the acid catalyzed hydrolysis of the tertiary amide N,N-diethyl-3phenylpentanamide (34) to give 3-phenylpentanoic acid (35).
Ph
34
aq. H
NEt2
Ph
O
+
35
OH
H
H
N
36
Hydrolysis: reactivity
27
O
R
28
Carboxylic acids react with thionyl chloride (38) to give an acid chloride.
Heating butanoic acid (7) on a water bath with SOCl2 (38) and then distilling the product gives
butanoyl chloride (8) in 86% yield.
Careful analysis shows that sulfur dioxide (SO2) and HCl are also produced as products during
the reaction.
SOCl2
OH
7
Cl
heat on a
water bath
O
O
C3H7
O
OH Cl
S
38
C3H7
Cl
O
H
39
O
C3H7
40
S
O
O
- H+
Cl
Cl
- Cl-
Cl
O
86%
C3H7
Cl
8
+ O=S=O + HCl
29
Cl
Cl
Cl
Cl
Cl
41
O
Cl
Cl
42
CO2H
45
Cl
P
Cl
43
Cl
Br
Br
Br
Br
Br
Br
PBr3
44
SOBr2
46
Br
Br
Br
P
Br
PBr5
Br
30
Heptanoyl chloride (50) reacts with heptanoic acid (51), with benzene as a solvent and in the
presence of pyridine (53), to give the symmetrical heptanoic anhydride (53) in 83% isolated
yield.
Unsymmetrical anhydrides are prepared by choosing which half of the anhydride comes from
the acid chloride, and which comes from the carboxylic acid.
If heptanoyl chloride (50) and butanoic acid (7) react in the presence of triethylamine as the
base, anhydride 54 is formed.
Anhydride 54 can also be prepared by the reaction of butanoyl chloride with hexanoic acid.
C5H11
CO2H
51
C5H11
C5H11
Cl
N:
, benzene
O
C5H11
7
Cl
50
C5H11
O
53
52
50
CO2H
NEt3 , benzene
O
C5H11
O
O
54
31
excess Ac2O
2
OH
17
O
O
55
+ CH3COOH
+ Ac2O
(excess)
32
Preparation of esters
O
HO
Cl
60
O
Cl
CH3
59
NMe2 H
61
CH3
O
63
Cl
Cl
CH3
CH3
O
64
62
33
Preparation of esters
O
OH
59
O
O
CH3
+ CH3CO2H
reflux
62 O
34
Preparation of esters
O
H3C
OH
O
H3C
Me
H
O
+ H+
Me
21
67
OH
65
OH
OH
OH
+ H+
OBu
OH
Bu
+ BuOH
Me
OH
Me
O
70
21
69%
Me
H
OBu
H
68
Me
OH
O
- H2O
Me
H
+ BuOH
OBu
69
Me
OH
66
- H+
OH
OBu
H
O
- H+
Me
OBu
70
35
Transesterification
O
C3H7
+ H+
OMe
C3H7
71
O
OMe
72
OH
C3H7
O
74 Me
O
75
OEt
Me
OMe
O
- MeOH
C3H7
+EtOH
C3H7
+EtOH
OEt C3H7
76
- H+
Et
C3H7
O
MeO
73
OH
+ H+
OEt
C3H7
OH
OH
OEt
- H+
C3H7
OEt
29
36
DCC Coupling
A carbodiimide is a unique chemical entity that is effectively a "di-imine, and it has the
generic structure shown for 81.
Carbodiimides serve as "dehydration agents" for various OH-bearing compounds, including
carboxylic acids.
One specialized and readily available carbodiimide called dicyclohexylcarbodiimide (usually
abbreviated DCC) will be used to illustrate this transformation, and it has structure 78.
When 3-methylbutanoic acid (77; isobutyric acid) is stirred with tert-butanol in the presence
of a catalytic amount of 4-pyrrolidinopyridine (79), for example, tert-butyl 3-methylbutanoate
(80) is isolated in 65% yield. In addition to the ester, one molar equivalent of dicyclohexyl
urea (see 87) is also isolated.
Urea is 82.
R
N
77
81
78
OH
O
O
cat. N
79
O
OH
80
H2N
82
NH2
37
DCC Coupling
!+
!+
N C N
N C N
CHMe2
84
78
Me2HC
N C N
H
83
Me2HC
85
CHMe2
O 77
O
N C N
H
Me2HC
86
O
O
O
H
CHMe2
N
H
C N
O
O
CHMe2
87
In effect the DCC unit "activates" the acyl carbon (derived from
butanoic acid) to attack by the weak nucleophile, ethanol.
CHMe2
80
38
Lactones
O
88
O
89
90
Cyclic esters in which the acyl carbon and the "alcohol" oxygen are constituent members of a
ring, as in 88-90, are called lactones.
The common names for structurally simple lactones arise by using the suffix for the open
chain carboxylic acid precursor and the word lactone.
Compound 88 is -butyrolactone and 89 is -valerolactone where the name is taken from the
common names for the four-carbon acid (butyric acid) and the five-carbon acid (valeric acid).
The IUPAC names are based on the cyclic ether, so 88 is 2-oxoolane and 89 is 2-oxooxane.
The fourteen-membered ring lactone (90) does not have a simple name derived from the
parent acid and is named as a hydroxy-acid: 14-hydroxytetradecanoic acid lactone.
39
Amides
Primary amides (92) have two hydrogen atoms that can hydrogen
bond.
A secondary amide (93) has only one N-H unit.
A tertiary amide (94) has no N-H units.
O
R
O
N
92 H
O
N
93
R1
N
94
R2
R1
40
O
NH3
17
OH
95
CO2H
Me2NH
97
O NH4
O
O
98
NH2Me2
41
O
NH3
17
OH
95
CO2H
Me2NH
97
200C
O NH4
NH2
96
O
O
98
200C
NH2Me2
NMe2
99
42
2 :NH3
C4H9
100
O
Me
Cl
101
O
O
C4H9
O
:NH2Et
Me
Me
NH3/EtOH
OEt
103
102
NHEt
O
O
Ph
NH2
175C
Ph
NH2
75%
104
43
Ph
107
C6H13
C6H13
N
108 H
DCC
78
N
Ph
Ph
O 109
Et
44
Lactams
Cyclic amides (see 113-15) are called lactams, and they are
characterized by an acyl carbon and a nitrogen atom as constituent atoms
of a ring.
Lactam 113 is -butyrolactam and 114 is -valerolactam (from butyric
acid and valeric acid).
Lactams containing a four-membered ring (such as 115) are commonly
called -lactams. The IUPAC name for a four-membered ring
containing nitrogen is azetidine.
115 is formally named azetidin-2-one.
N
H
N
113
H 114
N
H
O
115
45
Imides
O
117
118
Reactions
46
47
Grignard reagents
O BuMgBr
- Cl
Cl
119
BuMgBr
C7H15
Cl
Bu
120
C7H15
Bu C7H15
121
Bu
122
H3O
Bu
OH
C7H15
Bu
123
Bu
organolithium reagents
48
49
Li
Br
Cu
10C
126
Li
Bu2CuLi
ether , 10C
127
1. Li , ether
2. 0.5 CuI , ether , 10C
Br
50
Li
ether , 10C
Cl
CO2H
128
1. SOCl2
2. Et2CuLi , ether
10C
129
51
Dialkylcadmium reagents
CdCl2
R2Cd
130
2 Et-MgX
Me
+
Cl
O 131
CdCl2
1. Et2Cd
Et2Cd
Me
2. H3O+
O
132
52
2-Chlorobutane reacts with Mg metal in ether to give the Grignard reagent, 133.
The ether solution containing the Grignard reagent is poured carefully onto crushed dry ice
(CO2), and this slurry is then poured onto crushed ice containing concentrated HCl.
This reaction sequence gives 2-methylbutanoic acid (135) in 79% yield.
Nucleophilic acyl addition of the Grignard reagent to a C=O unit in carbon dioxide to
generates 134, which is a carboxylate anion.
Acid hydrolysis (134 is the base and hydronium ion is the acid) gives the carboxylic acid, 135
(the conjugate acid of 134).
This reaction makes a carbon-carbon bond and extends the carbon chain by one carbon.
Mg , ether
Cl
C
CH3
MgCl !"
O
C
CH3
133
!+
C
H
CH3
O
H3O+
O
H
134
CH3
OH
135
OH MeMgBr
97
OH
136
+ Me-H
97
139
MgBr
OH
Li
Li O
137
138
OH
- H2O
Me
via enol
Me-H
O Li MeLi
MeLi
53
Me
140
O
Me
H3O+
54
N:
EtMgBr
MgBr H O+
3
C!N
141
Et
142
H
H3O+
Et
143
144
Et
55
Dicarboxylic acids
Structure
!HOOC-COOH!
!HOOC-CH2-COOH!
!HOOC-(CH2)2-COOH!
!HOOC-(CH2)3-COOH
!HOOC-(CH2)4-COOH!
!HOOC-(CH2)5-COOH!
!HOOC-(CH2)6-COOH!
!HOOC-(CH2)7-COOH!
!HOOC-(CH2)8-COOH!
Common Name
oxalic acid!
malonic acid!
succinic acid!
glutaric acid!
adipic acid!
pimelic acid!
suberic acid!
azelaic acid!
sebacic acid!
IUPAC Name
1,2-ethanedioic acid
1,3-propanedioic acid
1,4-butanedioic acid
1,5-pentanedioic acid
1,6-hexanedioic acid
1,7-heptanedioic acid
1,8-octanedioic acid
1,9-nonanedioic acid
1,10-decanedioic acid
56
(CH2)n
OH
145
Cl
Cl
O
OH
OH
O
149
146
(CH2)n
(CH2)n
OH
OR
147
O
Cl
2 SOCl2
OR
Cl
Cl
OH
Cl
O 150
151
(CH2)n
major
148
OR
57
OH
excess EtOH
OEt
OEt
OH
cat. H+
OEt
OH
major
O
O
O 153
152
O
Cl
155
excess MeNH2
Cl
O 154
O
MeHN
NHMe
156
58
Oxalyl Chloride
O
OH
45
+ Cl
157
Cl
O
NEt3
Cl
158
59
O
OH
heat
OEt
OEt
OH
O 152
cat. H+ , EtOH
159
NH3 , heat
153
O
N
160
O
Cl
O 161
N
O
Br
162
60
Baeyer-Villiger Oxidation
Peroxyacids also react with ketones to form esters in what is known as the BaeyerVilliger reaction.
When 3-pentanone (163) reacts with peroxyacetic acid (164), the products are
ethyl propanoate (165) and acetic acid.
The second oxygen atom in ester 165 (relative to ketone 163) must come from the
peroxyacid, which means that 164 must react with 163, probably by an acyl addition.
There is a skeletal rearrangement in which one of the groups flanking the acyl
carbon has migrated (rearranged) to an oxygen.
This analysis suggests that ketones react with peroxyacids to give esters via a C
O rearrangement.
O
O
163
H3C
164
O
O
H
165
O
CH3
61
Baeyer-Villiger Oxidation
Mechanism of the Baeyer-Villiger reaction.
Et
H+
Et
Et
Et
Et
H+
CH3
Et
CH3
O
O
O
O
H
O
H3C
Et
H
O
O
O
O
Et
O
Et 169
O
Et
H
CH3
O
167
Et
H
166
Et
168
Et
O 164
Et
163
Et
O
H
Et
CH3
H+
Et
165
Et
62
Baeyer-Villiger Oxidation
When 2-methyl-3-pentanone (170) reacts with peroxyacetic acid, the key intermediate is
171.
The major product is 173, so the secondary carbon group migrates in preference to the
primary alkyl group. The order of migration for groups in unsymmetrical ketones is
tert-alkyl > cyclohexyl 2 alkyl benzyl
The preference for group migration is consistent with the ability of each carbon to support a
positive charge.
The group that can best form a carbocation migrates. T
herefore, a tertiary carbon migrates faster than a secondary, which migrates faster than a
primary.
This guide helps to predict that the product of a Baeyer-Villiger reaction of 170 to be 173
and not 174.
O
Et migration
164
O
170
H
CH3
171 O
O
O
172
Et
CHMe2 migration
O
173
63
Baeyer-Villiger Oxidation
164
O
O
174
64
Sulfonyl Chlorides
Sulfonyl halides have the generic structure 175.
The reaction of thionyl chloride, 38, with a sulfonic acid such as butanesulfonic
acid (176) gives the analogous acid chloride, butanesulfonyl chloride (177).
This reaction is rather general, and benzenesulfonic acid (PhSO3H) is converted to
benzenesulfonyl chloride (PhSO2Cl) just as methanesulfonic acid (MeSO3H) is
converted to methanesulfonyl chloride (MeSO2Cl, 178).
Sulfonyl chloride 178 also has the common name of mesyl chloride.
4-Methylbenzenesulfonyl chloride (179) is also called para-toluenesulfonyl
chloride (also called tosyl chloride).
O
R
O
X
O
175
C4H9
176
O
OH +
Cl
178 O
S
38
Cl
O
Me
NEt3
Cl
Cl
O
Me
179
O
C4H9
177
Cl
65
Sulfonate Esters
Cl
S
177
OH
NEt3
O
180
66
Sulfonate Esters
H
OH +
+H
OH
+ EtOH
182
H
S
OH
O
O
Et
185
183
O
O
- H2O
S
O
186
O
S
181
H
OH
H
O
-H
S
O
Et
184
O
- H+
OEt
Et
187
+
OH + H
O
Et
67
Sulfonamides
Sulfonamides are the sulfonic acid analogs of carboxylic acid amides, formed by reaction of
sulfonyl chlorides or sulfonate esters with amines or ammonia.
2-Methylbutanesulfonyl chloride (188) reacts with ammonia, for example, to give 2methylbutanesulfonamide (189). Amines reacts to give N-substituted sulfonamides.
A base is usually added to this reaction to drive it towards the sulfonamide product. When
the base is hydroxide and the reaction is done in water,
Sulfonamides are prepared from sulfonate esters.
An example is the reaction of ethyl butanesulfonate (190) with ammonia to give
butanesulfonamide, 191.
SO2Cl
SO2NH2
189
188
O
S
190
NH3
S
OEt
191
NH2
68
There are derivatives of the mineral acids nitric acid, sulfuric acid
and phosphoric acid.
For the most part, such acid derivatives are used sparingly in organic
chemical transformations.
Phosphorus derivatives are widely observed in biological systems,
however.
The structure of nitric acid is 194, sulfuric acid is 195, and
phosphoric acid is 196.
O
O
N
OH
HO
O
OH
O
194
195
HO
P
OH
196
OH
69
O
N
OR
O
197
ONO2
ONO2
198
O
HO
O
Cl
HO
O
NH2
RO
O
OH
RO
199
200
201
202
OR
70
Phosphate Esters
O
OH
RO
OH
203
O
OH
RO
OR
204
P
OR
205
O
OR
HO
P
OH
OH
206
OH
71
Phosphate Esters
+ excess EtOH
HO
O
OEt
HO
207 OH
O
EtO
O
P
hydrolysis
OEt
H2O
OEt
208 OEt
O
HO
208
P
OEt
OEt
72
Phosphate Esters
HO
H O H
H
OH
NH2
HO
N
N
H O H
H
O
H
OH 211
OH
O
P
O-
213
H
OH
212
P
O
-O
P
O-
NH2
O
P
-O
O
H O H
H O H
OH
210
HO
H O H
H
OH
NH2
OH
H
OH
N
N
214
73
Nitriles
Nitriles are indeed acid derivatives because (a) nitriles are formed by
dehydration reactions of amides and (b) acid hydrolysis of nitriles leads
to either an amide or a carboxylic acid.
O
215
P2O5 , heat
C!N
NH2
216
O
OH
219
6N HCl
H2O
C!N
100C
217
1N HCl
H2O
NH2
218
74
75
76
77
78
79
Substituents such as alkene units, alkyne units, and carbonyls can be reduced by
catalytic hydrogenation.
Lithium aluminum hydride reduces many heteroatom
substituents, including nitrile and acid derivatives.
Polycyclic aromatic compounds such as naphthalene, anthracene, and phenanthrene give
electrophilic aromatic substitution reactions, with the major product determined by the
number of resonance stabilized intermediates for attack at a given carbon, and the
lc
number of fully aromatic rings (intact rings) in the resonance structures.
Aniline react with nitrous acid to give benzenediazonium salts, which react with a
variety of reagents via a substitution reaction. These reagents include cuprous salts,
aqueous acid, iodide, hypophosphorous acid, and activated benzene derivatives.
Nucleophilic substitution at the sp2 carbon of a halo-benzene derivative does not occur
unless high heat and pressure are used. Electron withdrawing substituents on the benzene
ring significantly lower the temperature required for the reaction. Nucleophiles for this
nucleophilic aromatic substitution reaction include water, hydroxide, alkoxide, and
amines.
When halobenzene derivatives are heated with powerful bases such as sodium amide,
deprotonation is followed by elimination to give a benzyne, which reacts rapidly with the
nucleophile.
80
Benzene
The usual representation of benzene is 1A or 1B but neither adequately describes its structure.
If benzene looked like either 1A or 1B it should have three longer carbon-carbon single bonds and three
shorter C=C units. It would then be called cyclohexatriene.
It is not called cyclohextatriene, but rather benzene.
The C-C bond length in ethane is 1.53 (153 pm), and it is 1.536 (153.6 pm) in cyclohexane. The bond
distance for the C=C bond in ethene is 1.34 (134 pm).
A C=C unit has a shorter bond distance than a CC unit.
In benzene, all six carbon-carbon bonds have a measured bond distance of 1.397 (139.7 pm), a value that
lies in between those for the C-C bond in an alkane and the C=C unit of an alkene.
This means that the carbon-carbon bonds in benzene are not single bonds, nor are they alkene-type bonds
where the -electrons are localized between two carbons in a -bond.
Each carbon in benzene is sp2 hybridized, which means each has a trigonal planar geometry.
1A
1B
81
Benzene
Each carbon in benzene is sp2 hybridized, which means each has a trigonal planar geometry (see 1C and
molecular model 1F).
Each carbon atom has a p-orbital that is perpendicular to the plane of the carbon and hydrogen atoms, and
there is one -electron associated with each p-orbital.
In 1C, the p-orbitals are contiguous (one p-orbital on every carbon of the ring) and all are parallel, so there
are a total of six p-orbitals and six -electrons. These six-electrons are delocalized by resonance in the six porbitals.
1D shows the large -cloud of electrons above and below the plane of the atoms in benzene.
Electron density is concentrated above and below the plane of the carbon and hydrogen atoms.
In the electron density map 1G, the red area in the center of the ring indicates an area of high electron
density, consistent with the -cloud shown in cartoon form in 1C and 1D.
H
H
C
C
-cloud
H
H
H
H
C
C
1C
H
1E
1D
1F
1G
82
Kekul Structures
The bonding in benzene is not properly described by either 1A or 1B, but rather by both
structures.
Each of these two resonance contributors is known as a Kekul structure, and each is a sixmembered ring with a C=C unit on alternate carbon atoms.
When two Kekul structures (1) are drawn, each structure is taken to be a resonance
contributor, and together they represent the resonance delocalization of the p-electrons shown for
1D and in 1G.
Benzene is sometimes drawn as a single six-membered ring with a circle in it (see 1E), but it is
more common that one of the Kekul structures is used to represent benzene.
When one Kekul structure is drawn, it is meant to represent the true resonance delocalized
structure and the single structure is drawn for the sake of convenience.
1A
1B
Hckels Rule
83
84
Br
2
Br
5
HBr
the !-bond acts as a base
Br
6
3
HBr
No Reaction
1
Br
Nomenclature: Arenes
Arenes are named using the alkyl name of the substituent with benzene, so an arene
becomes an alkyl benzene.
Compound 8 is named methylbenzene but its common name is toluene, a common
constituent of paint solvents.
Similarly, compound 9 is ethylbenzene.
Is the parent compound of 10 benzene, or is benzene a substituent? I
n general, if a benzene ring is attached to an alkane carbon chain of five or more
carbon atoms, the benzene ring is treated as a substituent.
Therefore, 10 is named 2-phenylpentane.
10
85
86
Nomenclature: Arenes
Three dimethylbenzene derivatives are known: 1,2-dimethylbenzene (11), 1,3dimethylbenzene (12), and 1,4-dimethylbenzene (13).
The common name for the dimethylbenzenes is xylene.
In the common nomenclature, two substituents with a 1,2-relationship are said to be
ortho-; those with a 1,3-relationship are said to be meta-, and those with a 1,4-relationship
are said to be para-.
Using this system, 11 is called ortho-xylene (or o-xylene), 12 is called meta-xylene (or mxylene) and 13 is called para-xylene (or p-xylene).
CH3
CH3
CH3
CH3
CH3
11
12
CH3
13
14
Arene 14 is 1,2,4-trimethylbenzene.
Nomenclature: Arenes
15
16
C
17
87
88
(18) is bromobenzene.
19 is named benzenol using the IUPAC system. The common name of 19 is phenol.
20 is 4-chlorobenzenol.
21 is called methoxybenzene .
22 is ethoxybenzene.
There are also common names for these compounds, so 21 is known an anisole and 22 is
phenetole.
Cl
Br
18
OH
19
OCH3
OH
20
21
OCH2CH3
22
NH2
23
NH2
CH3
24
NHEt
25
89
90
O
N
H3C
26
OH
27
C!N
28
91
CH3
H3C
CH3
29
30
31
32
CH3
33
Br
92
OH
CO2H
OH
34
CHO
CO2H
35
CHO
36
93
Benzene as a Base
It is known that benzene does not react directly with bromine, so it is easy to
conclude that it is a weak Lewis base as well as a weak Brnsted-Lowry base.
It is known that diatomic bromine reacts with a Lewis acid such as ferric bromide
to generate an ate complex Br+ FeBr4.
If benzene is mixed with Br2, in the presence of ferric bromide (FeBr3), there is a
reaction and bromobenzene (18) is formed in good yield, along with HBr.
Br2
1
Br
Br2 , FeBr3
No Reaction
1
18
Experiments have shown that the reaction proceeds by a cation intermediate (an
electrophilic reaction), and it clearly involves an aromatic species such as benzene.
If benzene reacts with bromine via Br+, and there is a cation intermediate, it is
reasonable to conclude that the hydrogen atom is lost in a subsequent step.
This type of reaction is labeled electrophilic aromatic substitution and it accounts
for most of the chemistry of benzene and its derivatives.
94
The reaction of diatomic bromine with aluminum chloride (AlCl3) gives complex
Br+AlCl3Br as the product before there is any reaction with benzene.
This cationic bromine atom is so reactive, however, that even a weak base like benzene will
react to form a carbocation, 40.
This high energy intermediate is called a Wheland intermediate or an arenium ions
40 is reasonable stabilized as shown in 40A, which leads to sufficient stability that the
reaction generates this intermediate.
40 is resonance stabilized but not aromatic.
!+
Br
39
Br+ AlCl3Br
AlCl3
BrBr
Br+
Br
Br
40A
Br
AlCl3Br
Br
H
Br
AlCl3Br
40B
40C
H+
18
95
Br
39
Br+ AlCl3Br
AlCl3
BrBr
Br+
Br
Br
40A
Br
AlCl3Br
Br
H
Br
AlCl3Br
40B
40C
H+
18
96
BrBr
Br+ AlCl3Br
AlCl3
H
H
Br+
Br
Br
40A
AlCl3Br
Br
H+
18
Br
97
Nitrobenzene
The nitronium ion, NO2+, is formed when nitric acid is mixed with the stronger
sulfuric acid, nitric acid functions as a base.
Benzene reacts as a Lewis base with the nitronium ion to give resonance stabilized
arenium ion intermediate, 41.
The second step is the E1 reaction and loss of a proton to give nitrobenzene, 42.
O
N
O
H
+
O
O
O
S
O
acid
H base
O
H
N
O
nitronium ion
O
O
O
H
+ H3O+
H
NO2
NO2
1
H2SO4
NO2
41
H
NO2
NO2
-H
42
98
Friedel-Crafts Alkylation
Cl
0.4 AlCl3
0-20C
45
benzyl chloride
59%
99
Friedel-Crafts Alkylation
AlCl3Br 46
H
47
48
100
Friedel-Crafts Acylation
When benzene reacts with butanoyl chloride (49), in the presence of AlCl3, the
isolated product is a ketone; butyrophenone (1-phenyl-1-butanone, 50) in 51% yield.
It is known that benzene does not react with 49 without the presence of aluminum
chloride.
The acyl unit has reacted with benzene to form the new carbon-carbon bond, with
loss of the chlorine atom of 49, but there must be a prior reaction between AlCl3 and
the acid chloride.
This is an aromatic substitution, and based on knowledge of benzene there must be
an arenium ion intermediate.
O
O
AlCl3
+
49
Cl
50
101
Friedel-Crafts Acylation
The chlorine atom reacts as a Lewis base with the aluminum atom to form AlCl4.
When the O=CCl bond is broken, a new type of carbocation is formed, an acyl cation that is
known as an acylium ion.
Specifically, when 49 reacts with AlCl3 acylium ion 51 is formed, which is resonance
stabilized.
An acylium ion is sufficiently stable that it does not rearrange, but it is reactive enough to
react with benzene.
Acylium ion 51 reacts with benzene via electrophilic aromatic substitution as it would any
other cation to give arenium ion 52. Loss of a proton from 52 leads to the final product, 1phenyl-1-butanone (50).
The net result of this reaction is electrophilic aromatic substitution of a hydrogen atom on
benzene with an acyl group, and it is called Friedel-Crafts acylation.
O
O
C3H7
AlCl3
AlCl4
Cl
49
C3H7
C3H7
51 C3H7
O
52
C3H7
50
102
Friedel-Crafts Alkylation
When benzene reacts with 2-bromopropane and AlCl3 it gives a mixture of 53 (1methylethylbenzene or isopropylbenzene, also known as cumene), which is the
expected product, but it also gives the disubstituted product 54.
The reaction with alkyl halides may lead to polyalkylation of the benzene ring, and
this is the second of the two problems noted above for Friedel-Crafts alkylation.
The only way to explain formation of 54 is via a Friedel-Crafts alkylation of the
initially formed product 53 with 2-bromopropane.
This result suggests that 53 must react faster with the carbocation derived from 2bromopropane than does benzene.
Br
+
AlCl3
53
54
Friedel-Crafts Alkylation
103
Friedel-Crafts Alkylation
104
105
Reaction of Toluene
NO2
H2SO4
8
CH3
CH3
55
56
NO2
O2N
CH3
57
106
Reaction of Nitrobenzene
Nitrobenzene (40) reacts with bromine and ferric bromide, the major
product of the reaction is the meta- product 3-bromonitrobenzene (58)
with only trace amounts of 2-bromonitrobenzene (59) and 4bromonitrobenzene (60).
Experimental results also show that this reaction is much slower
than the nitration or bromination of benzene, and almost 106 slower
than nitration of toluene.
This means that nitrobenzene reacts slower than benzene, and much
slower than toluene, and formation of 60 is faster than formation of 58
and 59.
NO2
Br2 , FeBr3
Br
NO2
NO2
NO2
major
minor
40
58
minor
Br
59
Br
60
107
Faster or Slower
The results of these two experiments are explained by noting that when the
electron-releasing group is attached to the benzene ring, the products are ortho/para
and the reaction is faster than when compared to nitration of benzene.
This contrasts with the presence of an electron-withdrawing group on the benzene
ring that gives a meta product and the reaction is slower than the comparable
bromination reaction of benzene.
CH3
CH3
CH3
HNO3
NO2
55
56
NO2
NO2
Br2 , FeBr3
Br
CH3
NO2
57
Slower
NO2
NO2
O2N
H2SO4
Faster
major
minor
40
58
minor
Br
59
Br
60
108
X
H
X
H
Br
Br
Br
Br
62
ipso carbon
Br+
61
Br
Br
H
Br
X
65
() or !
electron
releasing
(stabilizing)
Br
63
64
Br
Br
Br
X
H
X
66
(+) or !+
electron
withdrawing
(destabilizing)
109
X
H
X
H
Br
Br
Br
Br
62
ipso carbon
Br+
61
Br
Br
H
Br
X
65
() or !
electron
releasing
(stabilizing)
Br
63
64
Br
Br
Br
X
H
X
66
(+) or !+
electron
withdrawing
(destabilizing)
110
X
H
X
H
Br
Br
Br
Br
62
ipso carbon
Br+
61
Br
Br
H
Br
X
65
() or !
electron
releasing
(stabilizing)
Br
63
64
Br
Br
Br
X
H
X
66
(+) or !+
electron
withdrawing
(destabilizing)
The rate of reaction for generating the ortho and para products is
faster than the rate for generating the meta product, so when X is
electron releasing the major products should be ortho and para.
Based on this simple analysis, assume that the ortho and para
arenium ions are about equal in energy, thee ortho and para
products should be formed in roughly equal amounts in the absence
of other mitigating factors.
When the substituent X has unshared electrons (O, N. halogen), it is
possible to draw a fourth resonance contributor if there is a resonance
contributor with the positive charge on the ipso carbon (ortho/para
attack).
The fourth resonance contributor is an indication of greater
charge delocalization and greater stability for those arenium ions.
111
112
>
O
!
Z
R
H (or R)
> alkyl
slower rate of reaction
<
O
R
<
O
OH
<
O
Cl
< NO2
slower rate of reaction
113
114
OMe
OMe
H
Br
OMe
OMe
Br
Br
Br
Br+
OMe
OMe
67A
67D
67C
OMe
67B
OMe
Br+
H
21
68A
Br
H
68B
OMe
Br
OMe
H
Br
62C
OMe
OMe
Br+
Br
H
69A
Br
H
69B
Br
H
69C
Br
H
69D
115
CH3
HNO3
NO2
H2SO4
55
NO2
CH3
CH3
56
NO2
CH3
57
116
NO2
Br
O
H
Br
Br
Br+
O
70A
70B
NO2
70C
NO2
NO2
Br+
H
Br
40
Br
71A
71B
NO2
NO2
Br+
Br
H
72A
Br
H
72B
Br
O
Br
71C
O
H
72C
117
O
O
AlCl3
+
49
Cl
50
118
!+ Br
Br
Br
Br
!
Br+
18
Br
H
73A
Br
H
73B
Br
H
73C
Br
H
73D
119
AlHBr3
NH2
+
23
AlBr3
H
74
120
HN
CH3
Br2 , FeBr3
Ac2O
23
NHAc
26
Br
75
Br
76
121
Polysubstitution
H3C
OMe
Cl2 , FeCl3
77
OMe
OMe
HO3S
major
SO3 , H2SO4
NO2
79
OMe
78
OMe
NO2
H3C
80
major
Cl
OMe
SO3H
minor
NO2
SO3H 81
NO2
82
Br
HO2C
NO2
84
Br2 , AlCl3
HO2C
85
NO2
122
Reduction: Hydrogenation
Addition of one molar equivalent of hydrogen (H-H) will generate a diene and addition
of two molar equivalents of H-H) will give an alkene.
Complete reduction of benzene to cyclohexane (addition of three molar equivalents of HH) typically requires the use of an excess of hydrogen.
The aromatic character of the benzene ring makes the reduction more difficult, so a
hydrogenation reaction requires more vigorous conditions when compared to
hydrogenation of an alkene.
This means that higher temperatures and/or higher pressures of hydrogen gas are
necessary.
When benzene reacts with three molar equivalents of hydrogen gas in the presence of a
Raney nickel catalyst, abbreviated Ni(R), reduction to cyclohexane occurs if the reaction is
heated.
Hydrogenation of benzene is also possible using a palladium catalyst or a rhodium (Rh)
catalyst.
3 H2 , Ni(R)
1 eq. H2 , Ni(R)
3
123
The two hydrogen atoms are incorporated into the benzene ring with a net reduction
of one C=C unit.
The two hydrogen atoms are incorporated from the solvent, and that the remaining
C=C units are not conjugated (they are not directly attached one to the other; see this
concept in chapter 23).
Na
86B
86A
H
EtOH
86C
H
H
EtOH
Na
87
88
H
89
124
Na
86B
86A
H
EtOH
86C
H
H
EtOH
Na
87
88
H
89
125
In 91, the negative charge on the ipso carbon leads to electron repulsion that greatly
destabilizes that resonance contributor.
Electronic repulsion is minimized and the intermediate is more stable (it will form faster)
when the negative charge does not reside on the ipso carbon, as in 90.
!" OMe
!" OMe
OMe
Na
OMe
or
21
90
92
91
In 94 the negative charge is on the ipso carbon adjacent to the positively charged nitrogen atom
of the nitro group.
The attraction of positive and negative charges is stabilizing and this intermediate is more stable
and formed faster than the alternative 93, where the negative and positive charges are never
adjacent to each other.
O
N
NO2
94
95
Na
or
40
93
126
!" OMe
OMe
Na
or
21
O
N
90
O
92
91
NO2
94
95
Na
or
40
OMe
93
127
Reduction: Substituents
H2
heat
Pd-C
excess H2 , Ni(R)
15
CHO
96
H2 , PtO2
OH
29
NH2
97
NO2
H2 , Pd-C
1. LiAlH4 , THF
2. dil. aq. H+
40
23
98
H2 , Pd-C
C!N
or
NH2
1. LiAlH4 , THF
2. dil. aq. H+
28
99
128
Reduction: Substituents
CO2H
1. LiAlH4 , THF
OH
2. dil. aq. H+
27
C!N
NH2
P2O5 , heat
28
97
104
99
49
Cl
Clemmensen
Zn(Hg), HCl
50
NH2NH2 , KOH
Wolff-Kishner
105
129
Aromaticity
Hckel's rule states that for planar, monocyclic hydrocarbons containing
completely conjugated sp2 hybridized atoms, the presence of (4n+2) -electrons
leads to aromaticity (n is an integer in the series 0, 1, 2, 3, etc.).
For aromaticity there must be a ring, so there is a requirement for cyclic polyenes. If
the number of -electrons does not equal 4n+2, then aromaticity does not exist and the
system is rather unstable (this is sometimes called an anti-aromatic system).
If Hckel's rule or the "4n+2 rule" as it is called is used, the presence of 2, 6, 10, 14,
18, etc. -electrons in a ring where every atom is sp2 hybridized is characteristic of an
aromatic compound.
aromatic
6!
electrons
14 !
electrons
18 !
electrons
111
112
anti-aromatic
4!
electrons
8!
electrons
113
114
130
Anti-Aromaticity
There are another set of cyclic polyenes that have (4n) -electrons such as cyclobutadiene (113;
4 -electrons) and cyclooctatetraene (114; 8 -electrons), so they do not adhere to the Hckel
rule.
Both 113 and 114 do not satisfy the Hckel rule it is not aromatic.
These compounds are not aromatic, and it is also true that they are also very unstable and
difficult to prepare.
Cyclic compounds such as this with 4n -electrons are called anti-aromatic compounds.
Assume that such compounds cannot be prepared (in fact, they can if extremely low
temperatures and specialized conditions are used).
aromatic
6!
electrons
14 !
electrons
18 !
electrons
111
112
anti-aromatic
4!
electrons
8!
electrons
113
114
131
Intermediates
2 ! electrons
aromatic
6 ! electrons
aromatic
115
4 ! electrons
not aromatic
116
6 ! electrons
aromatic
117
8 ! electrons
not aromatic
118
119
The cyclopentadienyl anion (118) has six -electrons and it is aromatic, very easy to form
and is quite stable.
Formation of 118 from cyclopentadiene (120) is an acid-base reaction. The pKa of
cyclopentadiene is 14-15 (compare that with a pKa of 15.8 for water).
The cycloheptatrienyl anion (119), which has 4n -electrons, is not aromatic and is
particularly unstable and difficult to form.
The pKa of 121 is about 36, which reflects the great difficulty in forming the anti-aromatic
conjugate base.
base
base
H
H
120
pKa = 14-15
pKa = 36
H
118
H
121
119
132
8
2
1
5
6
3
6
4
6
5
10
10
7
9
122
123
124
Naphthalene is a bicyclic aromatic compound with the formula C10H8 and structure
122.
Naphthalene is planar, with 10 -electrons in a -cloud above and below the plane
of the ten carbon atoms and, like benzene, it is aromatic and particularly stable.
Another polycyclic aromatic compound has three rings are fused together as in 123,
and this aromatic molecule (14 -electrons) is called anthracene (formula, C14H10).
There is an isomer of anthracene called phenanthrene, in which the point of
attachment of the "third ring" on the "middle ring" is different. Phenanthrene has the
same empirical formula but its structure is 124.
122
126
133
134
Chlorination of naphthalene at C1 leads to the five resonance structures shown for arenium ion intermediate
127.
Similar attack at C2 gives arenium ion 128, which also has five resonance structures shown.
Note that 127A and 127B have a fully aromatic benzene rings (an "intact benzene ring"), which means that
there is an additional Kekul structure for each intact ring.
Therefore, 127 has a total of seven resonance structures, but 128 has only six resonance contributors.
This observation indicates that 127 is more stable than 128, and it will form faster and lead to the major
product, 1-chloronaphthalene.
intact benzene rings (2 Kekule structures for each)
Cl+
1
2
122
Cl
Cl
Cl
Cl
Cl
127A
127B
127D
127C
127E
Cl+
1
2
122
Cl
128A
Cl
128B
Cl
128C
Cl
128D
Cl
128E
135
Phenanthrene
6
7
Br2
CCl4
Br
10
8
124
129
Br
136
Diazonium Salts
N!N
131
- N2
137
Diazonium Salts
Aromatic amines, however, generate diazonium intermediates that are more stable
(in many cases) and several interesting chemical transformations are possible.
When aniline (23) reacts with NaNO2/HCl, the HONO generated in situ gives
benzenediazonium chloride, 145 (in situ means that HONO is formed in the reaction
mixture where reaction with amine occurs, and it is not isolated).
Diazonium salt 145 (benzenediazonium chloride) is relatively stable in aqueous
solution, and it will stay in solution long enough to give predictable chemical
reactions.
It is important to note that this reaction is restricted to primary amines (-NH2) such
as aniline.
NH2
N2+ Cl-
NaNO2
HCl
23
145
138
NH2
23
N2+ Cl160C
aq. H2SO4
NaNO2 , HCl
132
OH
19
139
N2+ ClCuBr
132
Br
Me
18
C!N
Me
24
134
140
KI , heat
132
135
O2N
NH2
O2N
100-150C
NaNO2 , HBF4
136
137
NHAc
Br2 , FeBr3
139
NHAc
140
Br
138
Br
141
141
NMe2
N!N+
Cl-
NMe2
142
N
N
132
143
142
Cl
Cl
OH
Cl
OH
HO-
OH
- Cl-
aq. H+
- H+
heat
pressure
149
Cl
OH
150
151
19
This is the aromatic SN2 reaction (termed SNAr) in which Cl is replaced with OH.
143
SO3H
O S
3
HO
HO
152
42
OH
OH
-SO3-2
OH
H3O+
153
154
19
When bromobenzene (18) is heated with ethylamine (EtNH2) in aqueous solution (to about
300C) the aromatic SN2 reaction is slow, but the product is N-ethylaniline, 25.
The reactions are much faster when tertiary amide solvents such as dimethylformamide
(DMF, 155) or dimethylacetamide (156) are used.
The reaction of 18 with ethylamine, for example, gives a good yield 25 at a reaction
temperature of only 160-200C when DMF is used as the solvent.
Br
H
18
25
NHEt
Me
155 Me
H3C
N
156
Me
Me
144
O2N
O
N
Cl
O
Cl
O2N
Cl
O2N
Cl
OH
O2N
OH
N
NO2
NO2
NO2
157
OH
O
O2N
NO2
OH
NO2
NO2
Cl
O
O
Cl
N
O
NO2
NO2
NO2
159
NO2
158
NO2
NO2
O2N
145
Benzyne Formation
An acid-base reaction removes the hydrogen atom ortho- to the bromine to give 161.
The ortho hydrogen is a weak acid. Although this fact is not necessarily obvious, this
mechanism is supported by many experiments.
Once 161A is formed, it is highly reactive and the electrons of the carbanion unit
expel the leaving group bromide, in an aromatic elimination reaction, to form a new bond in a molecule with the unusual structure shown for 162A.
OMe
OMe
NH2
NH2
OMe
OMe
OMe
Br
NH2
H
160
Br
+ H+
- Br-
+ NH2
165
OMe
163
OMe
161A
162A
164
NH2
166
NH2
146
Benzyne Formation
Once 161A is formed, it is highly reactive and the electrons of the carbanion unit expel the
leaving group bromide, in an aromatic elimination reaction, to form a new -bond in a
molecule with the unusual structure shown for 162A.
The new -bond is formed that is orthogonal to the aromatic -cloud (see 162B).
This benzene ring with a triple bond is known as a benzyne and it is highly susceptible to
accepting electrons fro a suitable nucleophile.
Benzyne itself is 167A, and the electron density map (see 167B) clearly shows the red areas
(higher electron density) in the middle of the ring, consistent with the usual aromatic cloud, but
there is a region of high electron density perpendicular to the aromatic cloud consistent with
the extra -bond.
H
OMe
!
- Br-
OMe
167A
Br
161B
162B
167B
147
Benzyne Formation
A nucleophile such as amide (NH2) attacks the orthogonal -bond to form two different
carbanions, 163 and 164.
When 163 reacts with ammonia (which functions as an acid in the presence of this
carbanionic base) the product is 165 and when 164 reacts with ammonia, the product is 166.
The major product of this reaction is 165.
In 164, the negative charge is closer to the electronegative OMe unit, which is destabilizing.
This destabilization is much less in 163 because the negative charge on the ring is further away
from the OMe unit, and 163 leads to the major product.
OMe
OMe
NH2
NH2
OMe
OMe
OMe
Br
NH2
H
160
Br
+ H+
- Br-
+ NH2
165
OMe
163
OMe
161A
162A
164
NH2
166
NH2