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1

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.

Dissolving Metal Reductions: aldehydes and ketones

When sodium metal is mixed with a ketone in liquid ammonia and an


alcohol, a reduction occurs to give an alcohol.
In one typical experiment, 4-tert-butylcyclohexanone is treated with
Na metal in liquid ammonia and tert-butanol to give 4-tertbutylcyclohexanol (59) in 98% yield.
The only way an alcohol may be formed is via transfer of a hydrogen
atom to both the carbon and the oxygen of the carbonyl unit.
The only source of hydrogen, however, is either the ammonia (NH3)
or the alcohol (t-BuOH).
O

Me3C

Na , NH3 (-33C)
H

Me3COH
55

O-H

Me3C

59

Dissolving Metal Reductions: aldehydes and ketones

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

Dissolving Metal Reductions: alkynes

Alkynes are reduced to alkenes in good yield using dissolving metal


conditions, and the experimental evidence shows that the E-alkene is
the major product.
In a typical example, 4-octyne (60) is treated with sodium in liquid
ammonia, and oct-4E-ene (64) is isolated in 90% yield.
None of the Z-alkene is observed in this reaction.

C3H7

C
60

C3H7

Na , NH3 , EtOH

C3H7
C
H 64

H
C
C3H7

Dissolving Metal Reductions: alkynes


Electron transfer from the sodium to one -bond of 60 leads to a radical-anion, 61.
Transfer of the electron will generate an anion (the orbital containing the two electrons of the
negative charge) and a radical either on the same side of the remaining double bond (as in
61A) or on opposite sides (as in 61B).
Formation of the observed E-product is most easily explained by minimizing the electronic
repulsion between the two orbitals, making 61B the lowest energy species.
The reaction of 61B reacts with ethanol leads to a vinyl radical, 62.
Another electron transfer to 62 from a second sodium atom leads to carbanion 63, and
protonation of 63 gives the final product, alkene 64.
As a general statement, dissolving metal reductions of alkynes give the E-alkene due to
minimized electronic repulsion in the ketyl intermediate.

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

Dissolving Metal Reductions: benzene

When benzene (65) is treated with sodium metal in a mixture of


liquid ammonia and ethanol, the product is 1,4-cyclohexadiene 66.
Note that the non-conjugated diene is formed.

Na , NH3
EtOH , 33C
65

66

Dissolving Metal Reductions: benzene

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

Dissolving Metal Reductions: alkyl halides


If a stronger proton transfer agent (i.e., a stronger acid) is used, other metals may be
used for reductions, including zinc and tin.
Zinc in acetic acid (ethanoic acid, CH3CO2H) is commonly used to reduce halides
in a reaction that replaces the halogen atom with a hydrogen atom.
The reaction of alkyl halides is slow in acetic acid, unless the halogen is conjugated
to a carbonyl, but Zn in HCl is more effective.
This is illustrated by the experiment in which 1-iodohexacosane (cetyl iodide, 70;
isolated from Chinese wax) reacts with Zn/HCl to give hexacosane (cerane, 71) in
68% yield.

I
C24H49
70

Zn , HCl

C24H49
71

68%

Dissolving Metal Reductions: Clemmensen reduction

Heptanal (77) is treated with zinc amalgam (Zn/Hg) in HCl to give


heptane (78) as the final product in 72% yield.
This reduction is known as Clemmensen reduction.
The starting material and the product must withstand the concentrated
HCl used in the reaction, but it is a very effective method for the
complete reduction of ketones to hydrocarbons.

Clemmensen
Bu

Zn(Hg) , HCl

Bu

CHO
77

78

Dissolving Metal Reductions: Wolff-Kishner reduction

An alternative reductive method that treats ketones or aldehydes with


hydrazine in aqueous KOH, and is called the Wolff-Kishner
reduction.
For the purpose of comparison with the Clemmensen reduction,
Wolff-Kishner reduction of heptanal (77) with hydrazine/KOH gives
heptane (78) in 54% yield.
Bu

NH2NH2 , KOH
CHO

Bu

Wolff-Kishner

77

78

Wolff-Kishner reduction of ketone 79, for example, leads to 80.


Wolff-Kishner
O
79

NH2NH2
KOH
80

10

11

Dissolving Metal Reductions: Stephen reduction

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

SnCl2 , HCl, H2O

CHO

Chapter 20: Carboxylic Acid


Derivatives and Acyl
Substitution
Although acid derivatives react with nucleophiles via attack at
the acyl carbon, the presence of a leaving group attached to the
acyl carbon leads to a subsequent reaction that is not possible
with aldehydes and ketones.
Acid derivatives react with nucleophiles via acyl
substitution.
This reaction pathway proceeds by an intermediate called a
tetrahedral intermediate.

13

To begin, you should know:

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)

To begin, you should know:

15

Characteristics and reactivity of organocuprates. (chapter 15, section 15.6)


Nucleophilic acyl addition of organometallic reagents to carbonyl compounds.
(chapter 18, section 18.4)
Acid catalyzed nucleophilic acyl addition of weak nucleophiles to carbonyl
compounds. (chapter 18, sections 18.5, 18.6)
The mechanism of acetal and ketal formation. (chapter 18, section 18.6)
Oxidation reactions of peroxyacids. (chapter 10, section 10.5 and chapter 17,
section 17.3)
Reagents for the conversion of alcohols to alkyl halides. (chapter 11, section
11.7)

When completed, you should know:

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.

When completed, you should know:

17

Grignard reagents and organolithium reagents react with cadmium chloride to


form dialkyl cadmium reagents, which react with acid chloride to give ketones.
Organolithium reagents react with copper(I) salts to give lithium dialkyl cuprates,
which react with acid chlorides to give ketones.
Grignard reagents and organolithium reagents react with carbon dioxide to give
lc
carboxylic acids.
Organolithium reagents react with carboxylic acids to give ketones.
Grignard reagents and organolithium reagents react with nitriles to give imine
anions, but aqueous acid hydrolysis usually convert the imine anion to a ketone
as the final product.
Peroxyacids react with ketones to give esters in the Baeyer-Villiger reaction.
Acid dichlorides are prepared by reaction of the diacid with a halogenating
agent. Diesters are prepared from dicarboxylic acids or diacid chlorides and
alcohols. Diamides are prepared from diesters or diacid chlorides and amines.
Sulfonic acids can be converted to sulfonic acid chlorides, sulfonate esters, and
sulfonamides, similar to reactions of carboxylic acids.
The ester derivatives of nitric acid, sulfuric acid and phosphoric acid are
important compounds, with some use in organic chemistry but greater use in
biology.
Nitriles are acid derivatives. Primary amides are dehydrated to nitriles, and
nitriles are hydrolyzed to either an amide or a carboxylic acid.

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

Remember that carboxylic acids are good Brnsted-Lowry acids,


with a pKa between 1-5 for the most derivatives.
Therefore, if an acid reacts with a nucleophile that is also basic
(sodium hydroxide, sodium methoxide, or sodium amide), the
acid-base reaction dominates and the product is the anionic salt of
a carboxylic acid.
Butanoic acid (7) reacts with sodium hydroxide, for example, to
give sodium butanoate (8) as the conjugate base, and water as
the conjugate acid.
This means that if a carboxylic acid is formed as a product in the
presence of a base such as sodium hydroxide, the initially formed
carboxylic acid is converted to the carboxylate salt.
O
Na+ OH

O
H-O-H

O-H
7

O Na+
8

20

Hydrolysis: acid chlorides

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

Hydrolysis: acid chlorides

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

This two-step process, shown in reaction form for 19 21 + 2-propanol,


is known as saponification.
saponification

O
Me

19

1. aq. NaOH
OCHMe2

2. dilute

H3O+

+
Me

OH
21

Me2CHOH

25

Hydrolysis: esters

Acid-catalyzed ester hydrolysis

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

There is an order of reactivity for acid derivatives:


acid chlorides acid anhydrides
>> esters >>> amides.
This order or reactivity with nucleophiles such as water can be
correlated to the ability of the "X" group to "leave."
Since chlorine is the best leaving group and NR2 is the poorest,
the fact that an acid chloride is the most reactive and an amide is
the least reactive is not surprising.
This order of reactivity correlates with the relative stability of
each acid derivative to acid or base hydrolysis.

O
R

28

Preparation of Acid Chlorides

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

Preparation of Acid chlorides and bromides

Three additional chlorinating reagents include phosphorus trichloride (41), phosphorus


pentachloride (42), and phosphorus oxychloride (43).
As with thionyl chloride, an amine such as triethylamine (NEt3) may be added as a base to react
with the HCl that is formed in the reaction.
Acid bromides are prepared by the reaction of carboxylic acids with brominating agents such as
thionyl bromide (44, SOBr2), phosphorus tribromide (PBr3) or phosphorus pentabromide (PBr5).
Cl

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

Preparation of acid anhydrides

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

Preparation of acid anhydrides

An alternative method is used to prepare symmetrical anhydrides that treats two


equivalents of a carboxylic acid such as propanoic acid (17) with an excess of acetic
anhydride.
Acetic anhydride reacts with the 17 to give an intermediate that reacts with a second
equivalent of 17 to give propanoic anhydride (55), along with acetic acid.

excess Ac2O

2
OH
17

O
O
55

+ CH3COOH
+ Ac2O
(excess)

32

Preparation of esters

One of the most efficient methods to prepare esters is the reaction of


an alcohol with an acid chloride.
2-Methyl-2-propanol (59; tert-butyl alcohol) dissolved in diethyl
ether, in the presence of dimethylaniline (61) as an amine base, is
heated to reflux and then treated with acetyl chloride (60) to give a
62% yield of 1,1-dimethylethyl ethanoate (tert-butyl acetate, 62)

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

Acid anhydrides also react with alcohols, in the presence of amine


bases, to give esters.

O
OH
59

O
O

CH3
+ CH3CO2H

reflux
62 O

34

Preparation of esters

Acid catalyzed reaction of an alcohol with an acid.


OH

O
H3C

OH

cat. H2SO4 , reflux

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

Transesterification is a very specific term that means exchanging the


alcohol unit of one ester with a different alcohol unit to make a new
ester.

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

Amides from carboxylic acids

When propanoic acid (17) is mixed with ammonia, ammonium


propanoate (95) is formed.
Similarly, dimethylamine (Me2NH) reacts with cyclohexanecarboxylic
acid (97) to give dimethylammonium cyclohexanecarboxylate (98).
Because of this acid-base reaction, mixing an amine or ammonia with
an acid (and no other added reagents) at normal temperatures does not
give an amide directly.
O

O
NH3

17

OH

95
CO2H
Me2NH
97

O NH4
O
O
98

NH2Me2

41

Amides from carboxylic acids

To prepare an amide after mixing an amine or ammonia with a


carboxylic acid, the initially formed ammonium salt must be heated to a
high temperature so that water is driven off (this is known as
dehydration).
Heating 95, typically to 180-220C, leads to propanamide (96), and
N,N-diethylcyclohexanecarboxamide (99) is obtained when similarly 98
is heated.
Note that 99 has the specialized name carboxamide because the amide
unit is appended on a six-membered ring.
O

O
NH3

17

OH

95
CO2H
Me2NH
97

200C

O NH4

NH2
96

O
O
98

200C

NH2Me2

NMe2
99

42

Amides from acid derivatives

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

It is not possible to convert an amide to an ester, and anhydride or an


acid chloride by acyl substitution.

43

Amides via DCC coupling

The reaction of N-ethyl-1-aminohexane (108) with 3,3-diphenylbutanoic


acid (107) gives 109.
Et
OH
Ph

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

Imides are a specialized class of compounds related to amides in that


there are two acyl groups attached to nitrogen, as in 117 and 118.
The name for such molecules is based on the longest chain carboxylic
acid parent.
For 117, there are two acyl portions, butanoic acid and ethanoic acid
(acetic acid). The name is N-ethanoylbutanoic acid amide (or, more
commonly, N-ethanoylbutanamide). It is also commonly called Nacetylbutanamide.
In cases where the imide is symmetrical (both acyl groups are
identical), the name can be simplified. Imide 118 is diacetamide
(diethanamide).
H
H
N
Me
Me
N
Me

O
117

118

Reactions

Acid derivatives react with many nucleophiles by acyl substitution,


including carbon nucleophiles.
There are complications in this latter reaction because, in some cases,
the compounds produced in the reaction are more reactive than the
starting materials, and they compete for reaction with the nucleophiles.
Experimentally, cyanide and alkyne anions are not the best partners
in this reaction, so the focus will be on Grignard reagents and
organolithium reagents.

46

47

Grignard reagents

If a Grignard reaction with an acid chloride is done at ambient or


higher temperatures, or with an excess of the Grignard reagent, an
alcohol is the major, if not the exclusive product.
The reaction of octanoyl chloride (119) and n-butylmagnesium
bromide does not give ketone 121 but rather tertiary alcohol 123 as the
major product.
The only way to form alcohol 123 is by reaction of the ketone product
(121) with unreacted butylmagnesium bromide.
O
C7H15

O BuMgBr

- Cl
Cl

119

BuMgBr
C7H15

Cl
Bu
120

C7H15

Bu C7H15
121

Bu
122

H3O
Bu

OH

C7H15
Bu
123

Although it is not obvious, a ketone reacts faster than an ester in most


cases.

Bu

organolithium reagents

48

Organolithium reagents are more reactive than Grignard reagents in


reactions with aldehydes and ketones, and also with acid derivatives.
It is even more difficult to isolate a ketone product from reaction with
an acid chloride, acid anhydride, or an ester. In general, this is correct.
Due to the difficulty in controlling this reaction, it is not used here to
prepare ketones but it is sometimes used to prepare alcohols when an
excess of the organolithium reagent is added.
This is a convenient reaction when the organolithium is commercially
available (methyllithium, butyllithium, tert-butyllithium, phenyllithium,
etc.).

49

Lithium dialkylcuprate reagents


Lithium dialkyl cuprates such as 126 are prepared from organolithium reagents and
Cu(I) compounds such as cuprous iodide.
The reaction of two molar equivalents of n-butyllithium and CuI gives lithium
dibutylcuprate (126), which is usually abbreviated as Bu2CuLi.
The reaction of 126 and benzyl bromide will give 127.
CuI , ether
2

Li
Br

Cu
10C

126

Li

Bu2CuLi
ether , 10C

127

1. Li , ether
2. 0.5 CuI , ether , 10C
Br

3. PhCH2Br , ether , 10C


127

50

Lithium dialkylcuprate reagents

Organocuprates also react with acid chlorides to form a ketone.


When 126 reacts with benzoyl chloride, for example, the product is
128.
This reaction is a preferred method for the conversion of carboxylic
acids to ketones.
A reaction sequence that begins with 3-methylpentanoic acid first
forms the acid chloride via reaction with thionyl chloride, and
subsequent reaction with lithium diethyl cuprate leads to the ketone,
129.
Cu
126

Li
ether , 10C

Cl

CO2H

128

1. SOCl2
2. Et2CuLi , ether
10C

129

51

Dialkylcadmium reagents

Cadmium chloride (CdCl2) reacts with Grignard reagents to form a


new organometallic reagent, a dialkylcadmium (130).
Simple Grignard reagents generally work well and the reaction of
CdCl2 with two equivalents of ethylmagnesium iodide leads to
diethylcadmium, Et2Cd.
Acetyl chloride (131) reacts with Et2Cd to give a 46% yield of 2butanone (132), with none of the tertiary alcohol (2-methyl-2-butanol).
2 R-MgX +

CdCl2

R2Cd
130

2 Et-MgX
Me

+
Cl

O 131

CdCl2
1. Et2Cd

Et2Cd
Me

2. H3O+
O

132

52

Grignard reagents with CO2

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

Grignard reagents & organolithium reagents


with carboxylic acids

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

Reaction with nitriles


When ethylmagnesium bromide is mixed with cyclopropylcyanide (141) the
product is identified as an iminium salt, 142.
The nitrogen atom of 142 is basic, and reaction with a suitable acid gives the
conjugate acid, imine 143.
Hydrolysis of this iminium salt gives ketone 144 in 68% yield rather than the imine
(143) expected by simple protonation of the nitrogen.

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

Dicarboxylic acid Derivatives


Derivatives with only one chlorine (a half-acid chloride 145) or two chlorine atoms
(a diacid dichloride; 146, actually called an acid dichloride) are possible.

Similarly, a half-ester can be formed (147) or a diester (148). In reactions of simple


dicarboxylic acids such as 1,3-propanedioic acid (malonic acid, 149) with thionyl
chloride, it can be difficult to generate only the half-acid chloride, 150 (malonyl
chloride).
Normally, the acid dichloride (151, malonyl dichloride) is formed by this reaction.
O

(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

Dicarboxylic acid Derivatives

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

There is one acid dichloride (acid dichloride) that is extremely useful,


oxalyl chloride (157).
When 157 reacts with a carboxylic acid such as pentanoic acid (45),
in the presence of an amine base (such as triethylamine), the acid is
converted to an acid chloride (in this case pentanoyl chloride, 158).
Reaction with oxalyl chloride is a very efficient and very mild
method for converting acids to acid chlorides.

O
OH
45

+ Cl
157

Cl
O

NEt3

Cl
158

59

Cyclic Anhydrides and Imides


O
O

O
OH

heat

OEt
OEt

OH
O 152

cat. H+ , EtOH

159

NH3 , heat

153

O
N

160
O

Imide 161 is known as N-chlorosuccinimide (NCS) and 162 is N-bromosuccinimide (NBS).


Imide 161 is used as a chlorinating reagent (converts a molecule to a chloride), and is
particularly useful in radical substitution reactions.
Similarly, 162 is used as a brominating reagent (converts a molecule to a bromide).
O
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

phenyl > vinylic > 1 alkyl > methyl

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

Cyclic ketones undergo Baeyer-Villiger reaction to give the


corresponding lactone.
The reaction of cyclopentanone with peroxyacetic acid (164), for
example, gives lactone 174.

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

Both sulfonic acids and sulfonyl chlorides react with alcohols to


form sulfonate esters.
When butanesulfonyl chloride (177) reacts with propanol, usually in
the presence of a base such as triethylamine, propyl butanesulfonate
(180) is formed.
A wide range of sulfonyl esters can be formed from an alcohol and a
sulfonic acid.
O

Cl

S
177

OH

NEt3
O

180

66

Sulfonate Esters

Acid-catalyzed conversion of sulfonic acids to 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

NH3 , aq. NaOH

189

188
O
S
190

NH3
S

OEt
191

NH2

68

Sulfate, Phosphate and Nitrate Esters

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

Sulfate and Nitrate Esters


Nitric acid gives a nitrate ester, 197. Nitrate esters are often unstable, and the trinitrate ester
of glycerol (198) is the well-known explosive nitroglycerin.
Amide derivatives O3N-NR2 are known as nitramides, but they will not be discussed.
Acid derivatives of sulfuric acids are more complicated because there are two acidic protons,
and two OH units.
If one OH unit is replaced with Cl, this is the acid chloride equivalent 199. However, the
name of this compound is chlorosulfonic acid, and the chemistry is related more to the
sulfonic acids.
The amide derivative 200 is known as sulfamic acid.
The ester derivatives of sulfuric acid include the monoester 201 and the diester 202.
When R = methyl, 201 is methyl sulfate and 202 is dimethyl sulfate.
ONO2

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

The acid chloride derivative of phosphoric acid is ClPO(OH)2,


chlorophosphoric acid, and the amide derivative is phosphoramic acid,
H2N-PO(OH)3.
There are three ester derivatives of phosphoric acid, a monoester
203, a diester 204, and a triester 205.
There are also derivatives of pyrophosphoric acid (diphosphoric acid
206), which include various esters.
O
RO

O
OH

RO

OH
203

O
OH

RO

OR
204

P
OR

205

O
OR

HO

P
OH

OH
206

OH

71

Phosphate Esters

The reaction of ethanol and P4O10 (the dimeric form of phosphorus


pentoxide), for example, gives a mixture of 207 and 208.
They are separable based on differences in solubility in alkaline earth
salts.
The hydrolysis of pyrophosphate esters such as 209 gives the
phosphate ester 208.
O
P4O10

+ excess EtOH

HO

O
OEt

HO

207 OH
O
EtO

O
P

OEt 209 OEt

hydrolysis
OEt

H2O

OEt

208 OEt
O

HO
208

P
OEt

OEt

72

Phosphate Esters

The phosphate ester of a nucleoside is called a nucleotide.


These are structural components used in DNA and RNA.
There are three possible monophosphate esters of adenosine (210): 211, 212, and 212.
The pyrophosphate (diphosphate) derivative is adenosine 5'-diphosphate (214).
The symbol A is used to designate an adenosine derivative in biology, so 211 is abbreviated 5AMP (adenosine 5-monophohpate) and 214 is 5-ADP (adenosine 5-diphosphate).
This information is explained in chapter 28, section 28.5.
NH2
NH2
N

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

Chapter 21: Aromatic


Compounds And Benzene
Derivatives
Benzene is a special hydrocarbon,
There are hydrocarbons related to benzene that have two, three, or
more rings fused together (polycyclic compounds).
The unifying concept of all these molecules is that they are aromatic,
which means that they are especially stable with respect to their
bonding and their structure.

74

To begin, you should know:

75

The concept of resonance and resonance stability. (chapter 5, section 5.9.C)


Identify the structure of benzene. (chapter 5, section 5.10)
Nomenclature and structure of alkenes, alkyl halides, alcohols, amines,
aldehydes and ketones. (chapter 5, sections 5.1, 5.6, 5.9)
Nomenclature and structure of carboxylic acids. (chapter 5, section 5.9.C and
chapter 16, section 16)
Nomenclature and structure of carboxylic acid derivatives. (chapter 16, section
16.7 and chapter 20, section 20.1, 20.3-20.6)
The structure and nature of a -bond. (chapter 5, section 5.1.A)
The fundamental reactivity of alkenes. (chapter 6, section 6.4.E and chapter 10,
section 10.1)
The formation, stability and reactivity of carbocations. (chapter 7, section 7.4.A
and chapter 10, section 10.2)
E2 elimination reactions of alkyl halides. (chapter 12, sections 12.1, 12.3)
E1 elimination reactions. (chapter 12, section 12.4)
Be able to draw resonance contributors. (chapter 5, section 5.9.C and chapter 16,
section 16.3)
The CIP rules for prioritizing substituents, groups and atoms. (chapter 9, section
9.3)
Recognize electron releasing and withdrawing substituents. (chapter 5, section
5.4 and chapter 6, section 6.2 and chapter 11, section 11.3)

To begin, you should know:

76

The Brnsted-Lowry acid-base reactions of alkenes. (chapter 10, sections 10.1,


10.2)
Factors that regulate carbocation stability. (chapter 10, section 10.2 and chapter
11, section 11.4)
How to identify a good leaving group. (chapter 11, section 11.2.D and chapter
16, section 16.8)
How to identify relative nucleophilic strength. (chapter 11, section 11.3)
Characteristics and reactivity of good Lewis acids. (chapter 6, section 6.5)
Rate of reaction. (chapter 7, section 7.11)
Oxidation of alcohols. (chapter 17, section 17.2)
Reduction of carbonyl derivatives. (chapter 19, sections 19.2, 19.3)

When completed, you should know:

77

Benzene is a simple hydrocarbon with a unique structure of carbon-carbon bonds of


equal length and strength. Overlap and delocalization of the -electrons in benzene,
coupled with its cyclic nature and continuous array of sp2 atoms leads to special stability
called aromaticity, and benzene is an aromatic molecule.
A molecule is aromatic if it is cyclic, has a continuous and contiguous array of sp2
hybridized atoms, and has 4n+2 -electrons (the Hckel rule).
lc
Monocyclic aromatic compounds are called annulenes.
Both anions and cations derived from cyclic hydrocarbons can be aromatic if they fit the
usual criteria.
Benzene derivatives with an alkyl substituent are called arenes. There are special names
for benzene derivatives bearing heteroatom substituents. These include phenol (OH),
aniline (NH2), anisole (OMe), benzoic acid (COOH), benzonitrile (CN), benzaldehyde
(CHO), acetophenone (COMe), and benzophenone (COPh).
Because it is aromatic, benzene does not react directly with reagents such as HBr or HCl,
or even with diatomic bromine or chlorine. Benzene reacts with cationic species to give a
resonance stabilized carbocation intermediate, which loses a hydrogen to give a
substitution product. This reaction is called electrophilic aromatic substitution. The most
common method for generating reactive cations in the presence of benzene is to treat
certain reagents with strong Lewis acids. Using Lewis acids or mixtures of strong acids,
benzene can be converted to chlorobenzene, bromobenzene, nitrobenzene or
benzenesulfonic acid.
The reaction of benzene with a carbocation leads to an arene in what is known as
Friedel-Crafts alkylation. The reaction of an alkyl halide with a strong Lewis acid gives a
carbocation, which is subject to rearrangement.

When completed, you should know:

78

Friedel-Crafts alkylation reactions are subject to polyalkylation because the arene is


more reactive than benzene.
The reaction of benzene with an acylium ion leads to a phenyl ketone in what is known
as Friedel-Crafts acylation. The reaction of an acid chloride with a strong Lewis acid gives
an acylium ion, which is not subject to rearrangement.
Substituents on benzene lead to either a mixture of ortho-/para- products or to a metalc
product. Substituents that give ortho-/para- products react faster than benzene and are
called activators, and substituents that give meta- products react slower than benzene and
are called deactivators.
Activating substituents are electron releasing and have excess electron density attached
to the ring. These include alkyl groups and heteroatoms with a negative charge or a atom. Activating substituents lead to a resonance stabilized intermediate with a positive
charge on a carbon atom that is adjacent to an electron releasing substituent, which
stabilizes the intermediate and makes the reaction proceed faster.
Deactivating substituents are electron withdrawing and have diminished electron
density attached to the ring. These include groups with a positive charge or a + atom.
Deactivating substituents lead to a resonance stabilized intermediate with a positive
charge on a carbon atom that is adjacent to an electron withdrawing substituent, which
destabilizes the intermediate and makes the reaction proceed slower.
Benzene reacts with hydrogen gas and a suitable catalyst to give cyclohexane
derivatives, and in some cases cyclohexene or cyclohexadiene derivatives.
Benzene reacts with sodium metal in liquid ammonia and ethanol to give non-conjugated
cyclohexadiene derivatives in what is known as the Birch reduction.

When completed, you should know:

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

Resonance leads to special stability for benzene, and benzene is said to


be aromatic. Benzene is an aromatic hydrocarbon.

Hckels Rule

83

Hckels 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.).
As the value on n changes in the series 0, 1, 2, 3, 4, etc, a new series of
numbers in generated by 4n+2: 2, 6, 10, 14, 18, 22, etc.
n other words, Hckels rule states that for a hydrocarbon to be
aromatic, the number of -electrons must be equal to one of the numbers
in the 4n+2 series.
Using Hckels rule, benzene has six -electrons that are confined to a
planar ring, and six -electrons corresponds to n = 1 in the 4n+2 series.
Six is a number in the Hckel series, 2, 6, 10, 14, etc.
When a hydrocarbon fits these criteria and has a number of electrons that is equal to a number in the 4n+2 series, it is aromatic
and particularly stable.

84

Aromaticity Makes Benzene a Weak Base

An aromatic hydrocarbon is also particularly stable.


This means that if electrons are not localized on a single atom, but rather delocalized
on several atoms, that structure tends to be more stable.
The extent of this stability can be evaluated for benzene when compared to
alkenes and dienes, based on chemical reactivity: acid-base reactions.
HBr

the !-bond acts as a base

Br
2

Br
5

HBr
the !-bond acts as a base

Br
6

3
HBr

benzene is not basic enough


to react with HBr

No Reaction
1

These results will help explain the chemical reactions of benzene

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 has an ethenyl group is known as ethenylbenzne, but the common


name is styrene.
Compound 16 is E-1,2-diphenylethene but it is commonly called
trans-stilbene.
Compound 17 is simply known as 1,2-diphenylethyne (or diphenyl
acetylene, although it has the common name of tolane).

15

16

C
17

87

88

Nomenclature: Functional Groups

(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

Nomenclature: Functional Groups

Compound 23 is named benzeneamine, but the common name is


aniline, which is also an acceptable name.
The name aniline or benzeneamine defines the class of compounds
bearing an -NR2 unit on a benzene ring. S
Substituents may appear on the benzene ring, as in 4-methylaniline
(24, 4-methylbenzeneamine), or on the nitrogen as in N-ethylaniline,
25 (N-ethylbenzeneamine).

NH2

23

NH2

CH3
24

NHEt

25

89

90

Nomenclature: Functional Groups

26 is known as N-acetylaniline (N-acetylbenzeneamine; note that the common name


is acetanilide).
Compound 27 is benzoic acid, the parent structure for this class, and the usual acid
derivatives such as esters (benzoates), acid chlorides (benzoyl chlorides), and amides
(benzamides) are all known.
There are also nitrile derivatives, and 28 is named benzonitrile.

O
N

H3C

26

OH

27

C!N

28

91

Nomenclature: Functional Groups


29 is named benzenal. The common name is benzaldehyde, and this name is widely used.
Acetophenone is the common name for 30, but the IUPAC name is 1-phenylethanone.
31 is named 1-phenyl-1-butanone.
An older system of nomenclature is available for such compounds, and 30 has been named
methyl phenyl ketone and 31 would be phenyl propyl ketone.
32is named benzophenone (if named as an aliphatic ketone, the name would be
diphenylmethanone).
When both benzene rings of benzophenone are substituted, the name becomes a bit more
complicated. The substituent in one ring is numbered 1,2,3. etc., but the substituents in the
other ring are numbered with a "prime," such as 1', 2', 3', etc.
Compound 33 is 4'-bromo-2,2',3-trimethylbenzophenone.

CH3

H3C

CH3
29

30

31

32

CH3

33

Br

92

Nomenclature: Functional Groups


(34) is named 1,2-benzenediol, but its common name is catechol.
The meta- compound is named 1,3-benzenediol (resorcinol) and the paracompound is named 1,4-benzenediol (hydroquinone).
1,2-Benzenedioc acid (phthalic acid, 35) has two carboxyl groups with an orthorelationship.
In 1,3-benzenedioc acid (isophthalic acid), the carboxyl groups are meta-, and in
1,4-benzenedioc acid (terephthalic acid) the carboxyl groups have a pararelationship.
1,2-benzenedial (phthaladehyde 36; also phthalic dicarboxaldehyde)
1,3-benzenedial (isophthalaldehyde; also isophthalic dicarboxaldehyde), and 1,4benzenedial (terephthalaldehyde; also terephthalic dicarboxaldehyde).

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

Electrophilic Aromatic Substitution

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

Electrophilic Aromatic Substitution

Arenium ion 40 is a resonance stabilized intermediate with the three


resonance contributors shown in 40A, and it is sometimes written in an
abbreviated form (40C) to represent the resonance.
It is known that the final product is 18, which requires loss of
hydrogen atom from 40.
!+

Br
39

Br+ AlCl3Br

AlCl3

BrBr

Br+

Br

Br
40A

Br

AlCl3Br
Br

H
Br
AlCl3Br
40B

40C

H+
18

96

Electrophilic Aromatic Substitution

The reaction of benzene and bromine in the presence of aluminum


chloride to give bromobenzene is an electrophilic aromatic
substitution reaction.
The mechanism of this reaction is formally a two-step process: (1)
Lewis-base-Lewis acid reaction between benzene and Br+, followed by
(2) an E1 reaction that leads to loss of a proton to regenerate the
aromatic benzene ring.
!+

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

If benzene reacts with a carbocation, a new carbon-carbon bond is formed, and


electrophilic aromatic substitution will give an arene.
The reaction of benzene and its derivatives with carbocations is generically called the
Friedel-Crafts reaction.
Friedel-Crafts alkylation involves formation of an alkyl carbocation in the presence of
benzene or a benzene derivative.
When benzene reacts with benzyl chloride in the presence of 0.4 equivalents of AlCl3,
diphenylmethane (45) is isolated in 59% yield.

Cl
0.4 AlCl3

0-20C
45
benzyl chloride

59%

99

Friedel-Crafts Alkylation

If a primary or secondary carbocation is formed, however,


rearrangement to a more stable cation may occur before the reaction
with benzene.
AlCl3
Br
AlCl3Br

AlCl3Br 46
H

47

48

Assume that primary cations obtained from primary halides will


always rearrange before they react with benzene.

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

An acylium ion is sufficiently stable that there is no


rearrangement of an acylium ion.

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

When a substituted benzene derivative reacts, it is


possible to generate different isomers: ortho, meta or
para.
Therefore, the issue of regioselectivity for this
reaction must be addressed.
In other words, when one group is attached to the
benzene ring where will the second group be placed
via electrophilic aromatic substitution?

103

Friedel-Crafts Alkylation

When a substituted benzene derivative reacts, it is


possible to generate different isomers: ortho, meta or
para.
Therefore, the issue of regioselectivity for this
reaction must be addressed.
In other words, when one group is attached to the
benzene ring where will the second group be placed
via electrophilic aromatic substitution?

104

105

Reaction of Toluene

In one experiment, toluene (8) is nitrated using HNO3/H2SO4.


Three products are isolated from this reaction: 43% of 2-nitrotoluene
(55), 4% of 3-nitrotoluene (56), and 53% of 4-nitrotoluene (57).
There are three products but clearly 55 and 57 are formed in nearly
equal amounts, to the near exclusion of the 56.
The reaction is regioselective.
The 1,2- (ortho-) and 1,4- (para-) products constitute the major
products with the 1,3-product (meta-) being minor.
Why is there a preference for the ortho and para products.
CH3
HNO3

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

The Ipso Carbon


The carbon of the benzene ring that is attached to the substituent is defined as the ipso carbon.
There are only three possible arenium ion intermediates for the reaction of any monosubstituted benzene
derivative 61 with an electrophile such as Br+, 62, 63 and 64.
62 & 63 have 4 resonance contributors but 64 has only 3.

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

Electron Releasing Groups and ortho/para


If X is an electron-releasing group that contains a heteroatom such as O or N (unshared electrons, or it
is polarized ), then the X group release electrons to an adjacent positive center, as in 65.
Releasing electrons to a positive center will stabilize the charge, and lead to a lower activation energy
for the formation of that intermediate.
In other words, that intermediate is easier to form and the reaction is faster.

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

Electron Withdrawing Groups and ortho/para


If X is an electron-withdrawing group that contains a group with a + or it is polarized +, then the X
group withdraw electrons to an adjacent positive center, as in 65.
Withdrawing electrons to a positive center will destabilize the charge, and lead to a higher activation
energy for the formation of that intermediate.
In other words, that intermediate is harder to form and the reaction is slower.

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)

Activating and Deactivating

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

Activating and Deactivating

activators (faster) and ortho/para directors.


deactivators (slower) and meta-directors.
Electron Releasing ability
react faster than
benzene

RO > HO > NHR > NH2 >

>
O

!
Z

R
H (or R)

Faster Rate of reaction

> alkyl
slower rate of reaction

Electron Releasing Groups


ortho, para products are major
BENZENE (reference Compound)
Halogens (F, Cl, Br,. I) react slower than benzene but give orth/para products
react slower than
benzene
!+
X

Electron withdrawing ability


O
H

<

O
R

<

O
OH

<

O
Cl

< SO3H < C"N

Faster Rate of reaction


meta products are major

Electron Withdrawing Groups

< NO2
slower rate of reaction

Activating and Deactivating

113

The classification of a group as deactivating simply means that the


rate of electrophilic aromatic substitution for a compound bearing that
group is slower than the reaction with benzene itself.
The category meta-director means that the major product of
electrophilic aromatic substitution is the meta product.
For activating substituents, the presence of an activating group (the
electron releasing group) on a benzene ring makes the rate of
electrophilic aromatic substitution faster than that of benzene.
Classification as an ortho-/para- director means that electrophilic
aromatic substitution gives a mixture of the ortho- and the paraproducts as the major products.

114

Activating and ortho/para directing

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

Activating and ortho/para directing

CH3
HNO3

NO2

H2SO4
55

NO2

CH3

CH3

56

NO2
CH3
57

55 is formed in 43% and 57 is formed in 53% yield, which is


consistent with the ortho/para prediction.
Other factors influence the actual percentages of products,
including the reaction time, temperature, etc..
For the purposes of this book, assume that these reactions give a
1:1 mixture,

116

Deactivating and meta directing


NO2

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

Deactivating and meta directing

O
O

AlCl3

+
49

Cl

50

Halobenzenes: Deactivating but ortho/para directors

118

Halogen substituents such as bromine are deactivating groups


because they are slightly electron withdrawing.
The halogens are polarizable.
The benzene ring is electron rich, leading to an induced positive
dipole of the adjacent halogen atom, as shown in 18.
Bromine will be polarized in the arenium ion intermediate, so
the ortho and para arenium ions are stabilized more than the meta.
Br

!+ Br

Br

Br

Br

!
Br+
18

Br

H
73A

Br

H
73B

The halogen is an ortho-/para- director

Br

H
73C

Br

H
73D

119

A problem with aniline


Aniline is a good Lewis base.
The amine unit is a much stronger Lewis base than the benzene ring, and when aniline is
mixed with Br2/AlBr3, the amine unit reacts preferentially with the Br+ cation to generate 74, a
Lewis acid/Lewis base ate complex.
If the aluminum bromide is tied up as the ate complex, no Br+ is formed to react with the
benzene ring.
The positive charge on nitrogen in 74 makes that group electron withdrawing, so the
benzene ring in 74 is deactivated.
Therefore, electrophilic aromatic bromination does not occur.
A limitation of electrophilic aromatic substitution is that the substituent on benzene
cannot be more basic than the benzene ring so that it reacts preferentially with the Lewis
acid.

AlHBr3

NH2
+
23

AlBr3

H
74

120

A problem with aniline


The problem relating to the basicity of aniline is largely counteracted by first
reacting aniline (23) with acetic anhydride to give the amide, N-acetyl aniline (26;
known as acetamide).
The acetyl group of the amide withdraws electron density from the nitrogen,
making the nitrogen much less basic.
The Lewis basicity of the nitrogen is diminished sufficiently that normal
electrophilic aromatic substitution reaction occur, and the NAc unit is electron
releasing, activating and ortho/para directing.
In effect, the acetyl group protects the nitrogen from reaction with the Lewis acid.
When 26 is treated with bromine and ferric bromide, the products are 2-bromo Nacetylaniline (75) and 4-bromo N-acetylaniline (76).
O
NHAc
NH2

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

Reduction: Birch Reduction


When benzene is treated with sodium and ethanol in liquid ammonia, the product is
1,4-cyclohexadiene, 89.

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

Reduction: Birch Reduction

Although there are three resonance contributors to 86, the lowest


energy resonance contributor will arise by separation of the two
electrons of the carbanion and the single electron of the radical in order
to diminish electronic repulsion.
This means that 86B represents the lowest energy electronic
distribution in the intermediate, and it will lead to the final product.

Na

86B

86A
H

EtOH

86C
H
H

EtOH
Na

87

88

H
89

125

Reduction: Birch Reduction

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

Reduction: Birch Reduction

An electron releasing group (including alkyl groups such as methyl


or ethyl) will be attached to an sp2 carbon in the final product,
whereas an electron withdrawing group will be attached to a sp3
carbon in the final product.
!" OMe

!" 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

NH2 1. LiAlH4 , THF


2. dil. aq. H+

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

Polynuclear Aromatic Hydrocarbons


3
8

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.

Electrophilic Aromatic Substitution


Cl
Cl2 , AlCl3

122

126

In naphthalene, it is important to recognize that there are only two


different positions, C1 and C2 (see 122).
This means that C1, C4, C5, and C8 are chemically identical and
that C2, C3, C6, and C7 are chemically identical.
In other words, if substitution occurs at C1, C4, C5, and C8 as
labeled in 122, only one product is formed, 1-chloronaphthalene
(121), which is the actual product isolated from the chlorination
reaction.

133

134

Electrophilic Aromatic Substitution

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

intact benzene ring (2 Kekule structures)

Cl+
1
2

122

Cl
128A

Cl
128B

Cl
128C

Cl
128D

Cl
128E

135

Phenanthrene

Electrophilic substitution of phenanthrene is more complicated since there is less difference in


the stability of the intermediate cations formed from each substitution position.
Nitration of phenanthrene (124) leads to five products.
The "middle" ring is not stabilized by aromaticity to the same extent as the others (as
mentioned above), making it susceptible to reactions not usually observed with aromatic systems.
For example, phenanthrene reacts with diatomic bromine in the absence of a Lewis acid, much
like a simple alkene, to give 129.
This reaction does not occur with benzene or naphthalene, and it is the distortion of -electrons
in 124 that is responsible for this reaction.
3
4

6
7

Br2
CCl4
Br

10
8

124

129

Br

136

Diazonium Salts

When hydrochloric acid is mixed with sodium nitrite (NaNO2), the


resulting reaction generates a transient and highly reactive acid known
as nitrous acid (HONO).
Nitrous acid reacts rapidly with amines to generate a highly reactive
product called a diazonium salt, which is also known as a diazo
compound.
An aliphatic primary amine such as 1-aminobutane (130) reacts to
give 131, but this diazonium salt is extremely unstable and it loses
nitrogen (N2 = NN) to give a carbocation.

NH2 NaNO2 , HCl


130

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

Diazonium Salts: Formation of Phenol

Treatment of aniline with HONO to give benzenediazonium chloride


(132), as noted above, and heating this salt in aqueous sulfuric acid (at
temperatures around 160C) leads to substitution of N2 by water to
give phenol, 19.
Note that N2 is an extraordinary leaving group and that this type of
substitution does not occur with other leaving groups on the benzene
ring except under special circumstances.
The reaction works quite well with substituted aniline derivatives to
produce substituted phenol derivatives.

NH2

23

N2+ Cl160C
aq. H2SO4

NaNO2 , HCl

132

OH

19

139

Diazonium Salts: Sandmeyer Reaction


The conversion to aryl halides by reaction with cuprous salts (CuX), in what is
known as the Sandmeyer reaction.
The Ar-NH2 ArX conversion is possible, where Ar = an aryl group.
When 132 is treated with cuprous bromide (CuBr), the product is bromobenzene
(18).
The reaction works with many other cuprous salts as well, including cuprous
chloride (CuCl).
A variation of this reaction treats the diazonium salt with cuprous cyanide (CuCN)
to give a nitrile: 4-methylaniline (24) is treated with HCl and NaNO2 and then with
CuCN to give 4-methyl-1-cyanobenzene (134).

N2+ ClCuBr

132

NH2 1. NaNO2 , HCl


2. CuCN

Br

Me
18

C!N

Me
24

134

140

Diazonium Salts: Sandmeyer Reaction


N2+ Cl-

KI , heat

132

135
O2N

NH2

N2+ BF4- O2N

O2N

100-150C

NaNO2 , HBF4
136

137

NHAc
Br2 , FeBr3

139

NHAc

140

Br

138

1. aq. OH2. aq. H+


3. NaNO2 , HCl
4. H3PO2

Br
141

141

Diazonium Salts: Azo Compounds

It is possible to make a series of highly colored and highly important


compounds known as azo dyes.
One example is the reaction of 132 with N,N-dimethylaniline (142) to
produce diazo compound 143.

NMe2
N!N+

Cl-

NMe2
142

N
N

132

143

142

Nucleophilic Aromatic Substitution


When chlorobenzene (149) is heated to 50C in aqueous hydroxide there is no reaction.
Hydroxide does not easily displace chloride by attack at the sp2 carbon, unless the reaction is
placed in a sealed reaction vessel and heated to 350C so that it is pressurized.
The hydroxide attacks the sp2 bearing the chlorine (called the ipso carbon) to generate a
carbanionic intermediate 150.
Chloride ion is rapidly expelled to initially form phenol (19), but phenol is a moderately
strong acid (pKa about 10) and it reacts with the aqueous hydroxide to form phenoxide, 151 as
the isolated product.
After the substitution is complete, the reaction is cooled and the basic phenoxide ion is
neutralized (an acid-base reaction) with dilute acid to regenerate phenol, 19.
This reaction is an example of an aromatic substitution process and is usually called
nucleophilic aromatic substitution.
O

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

Nucleophilic Aromatic Substitution


Another SNAr reaction heats benzenesulfonic acid (42) with aqueous sodium hydroxide (to
300C) in a reaction bomb to give phenol, 19.
SO3

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

EtNH2 , H2O , 300C

H
18

25

NHEt

Me

155 Me

H3C

N
156

Me

Me

144

Nucleophilic Aromatic Substitution


Aromatic substitution proceeds under very mild conditions when the carbanion intermediate
is particularly stable, but electron withdrawing groups must be attached to the benzene ring.
The reaction of 2,4,6-trinitrochlorobenzene (157) and aqueous hydroxide, for example,
occurs at room temperature to give the trinitrophenol, 159.
The intermediate is 158, and the negative charge is on a carbon atom that is adjacent to a
nitro group in several resonance contributors.
Cl

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