CHAPTER 22
AMINES
N
itrogen-containing compounds are essential to life. Their ultimate source is atmo-
spheric nitrogen which, by a process known as nitrogen fixation, is reduced to
ammonia, then converted to organic nitrogen compounds. This chapter describes
the chemistry of amines, organic derivatives of ammonia. Alkylamines have their nitro-
gen attached to sp
3
-hybridized carbon; arylamines have their nitrogen attached to an
sp
2
-hybridized carbon of a benzene or benzene-like ring.
Amines, like ammonia, are weak bases. They are, however, the strongest uncharged
bases found in significant quantities under physiological conditions. Amines are usually
the bases involved in biological acid–base reactions; they are often the nucleophiles in
biological nucleophilic substitutions.
Our word “vitamin” was coined in 1912 in the belief that the substances present
in the diet that prevented scurvy, pellagra, beriberi, rickets, and other diseases were “vital
amines.” In many cases, that belief was confirmed; certain vitamins did prove to be
amines. In many other cases, however, vitamins were not amines. Nevertheless, the name
vitamin entered our language and stands as a reminder that early chemists recognized
the crucial place occupied by amines in biological processes.
R N
R H11005 alkyl group:
alkylamine
Ar N
Ar H11005 aryl group:
arylamine
858
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22.1 AMINE NOMENCLATURE
Unlike alcohols and alkyl halides, which are classified as primary, secondary, or tertiary
according to the degree of substitution at the carbon that bears the functional group,
amines are classified according to their degree of substitution at nitrogen. An amine with
one carbon attached to nitrogen is a primary amine, an amine with two is a secondary
amine, and an amine with three is a tertiary amine.
The groups attached to nitrogen may be any combination of alkyl or aryl groups.
Amines are named in two main ways, in the IUPAC system: either as alkylamines
or as alkanamines. When primary amines are named as alkylamines, the ending -amine
is added to the name of the alkyl group that bears the nitrogen. When named as alkan-
amines, the alkyl group is named as an alkane and the -e ending replaced by -amine.
PROBLEM 22.1 Give an acceptable alkylamine or alkanamine name for each of
the following amines:
(a) C
6
H
5
CH
2
CH
2
NH
2
(b)
(c) CH
2
?CHCH
2
NH
2
SAMPLE SOLUTION (a) The amino substituent is bonded to an ethyl group that
bears a phenyl substituent at C-2. The compound C
6
H
5
CH
2
CH
2
NH
2
may be named
as either 2-phenylethylamine or 2-phenylethanamine.
Aniline is the parent IUPAC name for amino-substituted derivatives of benzene.
Substituted derivatives of aniline are numbered beginning at the carbon that bears the
amino group. Substituents are listed in alphabetical order, and the direction of number-
ing is governed by the usual “first point of difference” rule.
Arylamines may also be named as arenamines. Thus, benzenamine is an alterna-
tive, but rarely used, name for aniline.
F
4
NH
2
1
p-Fluoroaniline
NH
2
CH
2
CH
3
Br
5
1
2
5-Bromo-2-ethylaniline
C
6
H
5
CHNH
2
CH
3
CH
3
CH
2
NH
2
Ethylamine
(ethanamine)
NH
2
Cyclohexylamine
(cyclohexanamine)
CH
3
CHCH
2
CH
2
CH
3
NH
2
1-Methylbutylamine
(2-pentanamine)
R N
H
H
Primary amine
N
RH11032
H
R
Secondary amine
N
RH11032
RH11033
R
Tertiary amine
22.1 Amine Nomenclature 859
Aniline was first isolated in
1826 as a degradation prod-
uct of indigo, a dark blue
dye obtained from the West
Indian plant Indigofera anil,
from which the name aniline
is derived.
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Compounds with two amino groups are named by adding the suffix -diamine to
the name of the corresponding alkane or arene. The final -e of the parent hydrocarbon
is retained.
Amino groups rank rather low in seniority when the parent compound is identified
for naming purposes. Hydroxyl groups and carbonyl groups outrank amino groups. In
these cases, the amino group is named as a substituent.
Secondary and tertiary amines are named as N-substituted derivatives of primary
amines. The parent primary amine is taken to be the one with the longest carbon chain.
The prefix N- is added as a locant to identify substituents on the amino nitrogen as
needed.
PROBLEM 22.2 Assign alkanamine names to N-methylethylamine and to N,N-
dimethylcycloheptylamine.
SAMPLE SOLUTION N-Methylethylamine (given as CH
3
NHCH
2
CH
3
in the pre-
ceding example) is an N-substituted derivative of ethanamine; it is N-
methylethanamine.
PROBLEM 22.3 Classify the following amine as primary, secondary, or tertiary,
and give it an acceptable IUPAC name.
A nitrogen that bears four substituents is positively charged and is named as an
ammonium ion. The anion that is associated with it is also identified in the name.
N(CH
3
)
2
CH
CH
2
CH
3
CH
3
CH
3
NHCH
2
CH
3
N-Methylethylamine
(a secondary amine)
NO
2
Cl
4
1
3
NHCH
2
CH
3
4-Chloro-N-ethyl-3-
nitroaniline
(a secondary amine)
N(CH
3
)
2
N,N-Dimethylcyclo-
heptylamine
(a tertiary amine)
HOCH
2
CH
2
NH
2
2-Aminoethanol
NH
2
HC
O
41
p-Aminobenzaldehyde
(4-Aminobenzenecarbaldehyde)
H
2
NCH
2
CHCH
3
NH
2
1,2-Propanediamine
H
2
NCH
2
CH
2
CH
2
CH
2
CH
2
CH
2
NH
2
1,6-Hexanediamine
NH
2
H
2
N
1,4-Benzenediamine
860 CHAPTER TWENTY-TWO Amines
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Ammonium salts that have four alkyl groups bonded to nitrogen are called quaternary
ammonium salts.
22.2 STRUCTURE AND BONDING
Alkylamines: As shown in Figure 22.1 methylamine, like ammonia, has a pyramidal
arrangement of bonds to nitrogen. Its H±N±H angles (106°) are slightly smaller than
the tetrahedral value of 109.5°, whereas the C±N±H angle (112°) is slightly larger.
The C±N bond distance of 147 pm lies between typical C±C bond distances in alkanes
(153 pm) and C±O bond distances in alcohols (143 pm).
An orbital hybridization description of bonding in methylamine is shown in Fig-
ure 22.2. Nitrogen and carbon are both sp
3
-hybridized and are joined by a H9268 bond. The
CH
3
NH
3
H11001
Cl
H11002
Methylammonium
chloride
NCH
2
CH
3
CH
3
H
H11001
CF
3
CO
2
H11002
N-Ethyl-N-methylcyclopentyl-
ammonium trifluoroacetate
C
6
H
5
CH
2
N(CH
3
)
3
H11001
I
H11002
Benzyltrimethyl-
ammonium iodide
(a quaternary ammonium
salt)
22.2 Structure and Bonding 861
147 ppm
112H11034
106H11034
NC
H
H
H
H
H
(a)(b)
FIGURE 22.1 A ball-
and-stick model of methyl-
amine showing the trigonal
pyramidal arrangement of
bonds to nitrogen. The most
stable conformation has the
staggered arrangement of
bonds shown. Other alkyl-
amines have similar geome-
tries.
FIGURE 22.2 Orbital hybridization description of bonding in methylamine. (a) Carbon has four
valence electrons; each of four equivalent sp
3
-hybridized orbitals contains one electron. Nitrogen
has five valence electrons. Three of its sp
3
hybrid orbitals contain one electron each; the fourth
sp
3
hybrid orbital contains two electrons. (b) Nitrogen and carbon are connected by a H9268 bond in
methylamine. This H9268 bond is formed by overlap of an sp
3
hybrid orbital on each atom. The five hy-
drogen atoms of methylamine are joined to carbon and nitrogen by H9268 bonds. The two remaining
electrons of nitrogen occupy an sp
3
-hybridized orbital.
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unshared electron pair on nitrogen occupies an sp
3
-hybridized orbital. This lone pair is
involved in reactions in which amines act as bases or nucleophiles. The graphic that
opened this chapter is an electrostatic potential map that clearly shows the concentration
of electron density at nitrogen in methylamine.
Arylamines: Aniline, like alkylamines, has a pyramidal arrangement of bonds around
nitrogen, but its pyramid is somewhat shallower. One measure of the extent of this flat-
tening is given by the angle between the carbon–nitrogen bond and the bisector of the
H±N±H angle.
For sp
3
-hybridized nitrogen, this angle (not the same as the C±N±H bond angle) is
125°, and the measured angles in simple alkylamines are close to that. The correspond-
ing angle for sp
2
hybridization at nitrogen with a planar arrangement of bonds, as in
amides, for example, is 180°. The measured value for this angle in aniline is 142.5°, sug-
gesting a hybridization somewhat closer to sp
3
than to sp
2
.
The structure of aniline reflects a compromise between two modes of binding the
nitrogen lone pair (Figure 22.3). The electrons are more strongly attracted to nitrogen
when they are in an orbital with some s character—an sp
3
-hybridized orbital, for exam-
ple—than when they are in a p orbital. On the other hand, delocalization of these elec-
trons into the aromatic H9266 system is better achieved if they occupy a p orbital. A p orbital
of nitrogen is better aligned for overlap with the p orbitals of the benzene ring to form
≈125H11034
Methylamine
(CH
3
NH
2
)
Aniline
(C
6
H
5
NH
2
)
Formamide
(O?CHNH
2
)
142.5H11034
180H11034
862 CHAPTER TWENTY-TWO Amines
The geometry at nitrogen in
amines is discussed in an arti-
cle entitled “What Is the
Geometry at Trigonal Nitro-
gen?” in the January 1998 is-
sue of the Journal of
Chemical Education, pp.
108–109.
(a) (b)
FIGURE 22.3 Electrostatic potential maps of the aniline in which the geometry at nitrogen
is (a) nonplanar and (b) planar. In the nonplanar geometry, the unshared pair occupies an sp
3
hy-
brid orbital of nitrogen. The region of highest electron density in (a) is associated with nitrogen.
In the planar geometry, nitrogen is sp
2
-hybridized and the electron pair is delocalized between a
p orbital of nitrogen and the H9266 system of the ring. The region of highest electron density in (b)
encompasses both the ring and nitrogen. The actual structure combines features of both; nitro-
gen adopts a hybridization state between sp
3
and sp
2
.
You can examine the
structure of methylamine, in-
cluding its electrostatic poten-
tial, in more detail on Learning
By Modeling.
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an extended H9266 system than is an sp
3
-hybridized orbital. As a result of these two oppos-
ing forces, nitrogen adopts an orbital hybridization that is between sp
3
and sp
2
.
The corresponding resonance description shows the delocalization of the nitrogen
lone-pair electrons in terms of contributions from dipolar structures.
The orbital and resonance models for bonding in arylamines are simply alternative
ways of describing the same phenomenon. Delocalization of the nitrogen lone pair
decreases the electron density at nitrogen while increasing it in the H9266 system of the aro-
matic ring. We’ve already seen one chemical consequence of this in the high level of
reactivity of aniline in electrophilic aromatic substitution reactions (Section 12.12). Other
ways in which electron delocalization affects the properties of arylamines are described
in later sections of this chapter.
PROBLEM 22.4 As the extent of electron delocalization into the ring increases,
the geometry at nitrogen flattens. p-Nitroaniline, for example, is planar. Write a
resonance form for p-nitroaniline that shows how the nitro group increases elec-
tron delocalization. Examine the electrostatic potential of the p-nitroaniline model
on Learning By Modeling. Where is the greatest concentration of negative charge?
22.3 PHYSICAL PROPERTIES
We have often seen that the polar nature of a substance can affect physical properties
such as boiling point. This is true for amines, which are more polar than alkanes but less
polar than alcohols. For similarly constituted compounds, alkylamines have boiling
points higher than those of alkanes but lower than those of alcohols.
Dipole–dipole interactions, especially hydrogen bonding, are present in amines but
absent in alkanes. The less polar nature of amines as compared with alcohols, however,
makes these intermolecular forces weaker in amines than in alcohols.
Among isomeric amines, primary amines have the highest boiling points, and ter-
tiary amines the lowest.
CH
3
CH
2
CH
2
NH
2
Propylamine
(a primary amine)
bp 50°C
CH
3
CH
2
NHCH
3
N-Methylethylamine
(a secondary amine)
bp 34°C
(CH
3
)
3
N
Trimethylamine
(a tertiary amine)
bp 3°C
CH
3
CH
2
CH
3
Propane
H9262 H11005 0 D
bp H1100242°C
CH
3
CH
2
NH
2
Ethylamine
H9262 H11005 1.2 D
bp 17°C
CH
3
CH
2
OH
Ethanol
H9262 H11005 1.7 D
bp 78°C
H
H
H
H
H
NH
2
Most stable
Lewis structure
for aniline
H
H
H
H
H
H11002
H11001
NH
2
H
H
H
H
H
H11002
H11001
NH
2
H
H
H
H
H
H11001
NH
2
H11002
Dipolar resonance forms of aniline
22.3 Physical Properties 863
A collection of physical prop-
erties of some representative
amines is given in Appendix
1. Most commonly encoun-
tered alkylamines are liquids
with unpleasant, “fishy”
odors.
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Primary and secondary amines can participate in intermolecular hydrogen bonding, but
tertiary amines cannot.
Amines that have fewer than six or seven carbon atoms are soluble in water. All
amines, even tertiary amines, can act as proton acceptors in hydrogen bonding to water
molecules.
The simplest arylamine, aniline, is a liquid at room temperature and has a boiling
point of 184°C. Almost all other arylamines have higher boiling points. Aniline is only
slightly soluble in water (3 g/100 mL). Substituted derivatives of aniline tend to be even
less water-soluble.
22.4 MEASURES OF AMINE BASICITY
Two conventions are used to measure the basicity of amines. One of them defines a
basicity constant K
b
for the amine acting as a proton acceptor from water:
K
b
H11005 and pK
b
H11005H11002log K
b
For ammonia, K
b
H11005 1.8 H11003 10
H110025
(pK
b
H11005 4.7). A typical amine such as methylamine
(CH
3
NH
2
) is a stronger base than ammonia and has K
b
H11005 4.4 H11003 10
H110024
(pK
b
H11005 3.3).
The other convention relates the basicity of an amine (R
3
N) to the acid dissocia-
tion constant K
a
of its conjugate acid (R
3
NH
H11001
):
where K
a
and pK
a
have their usual meaning:
K
a
H11005 and pK
a
H11005H11002log K
a
The conjugate acid of ammonia is ammonium ion (NH
4
H11001
), which has K
a
H11005 5.6 H11003 10
H1100210
(pK
a
H11005 9.3). The conjugate acid of methylamine is methylammonium ion (CH
3
NH
3
H11001
),
which has K
a
H11005 2 H11003 10
H1100211
(pK
a
H11005 10.7). The more basic the amine, the weaker is its
conjugate acid. Methylamine is a stronger base than ammonia; methylammonium ion is
a weaker acid than ammonium ion.
The relationship between the equilibrium constant K
b
for an amine (R
3
N) and K
a
for its conjugate acid (R
3
NH
H11001
) is:
K
a
K
b
H11005 10
H1100214
and pK
a
H11001 pK
b
H11005 14
PROBLEM 22.5 A chemistry handbook lists K
b
for quinine as 1 H11003 10
H110026
. What is
pK
b
for quinine? What are the values of K
a
and pK
a
for the conjugate acid of qui-
nine?
Citing amine basicity according to the acidity of the conjugate acid permits
acid–base reactions involving amines to be analyzed according to the usual Br?nsted
relationships. By comparing the acidity of an acid with the conjugate acid of an amine,
for example, we see that amines are converted to ammonium ions by acids even as weak
as acetic acid:
[H
H11001
][R
3
N]
[R
3
NH
H11001
]
R
3
NHR
3
N
H11001
H
H11001
H11001
[R
3
NH
H11001
][HO
H11002
]
[R
3
N]
R
3
N H11001 OHH HR
3
N
H11001
H11001 OH
H11002
864 CHAPTER TWENTY-TWO Amines
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Conversely, adding sodium hydroxide to an ammonium salt converts it to the free
amine:
PROBLEM 22.6 Apply the Henderson–Hasselbalch equation (see “Quantitative
Relationships Involving Carboxylic Acids,” the box accompanying Section 19.4) to
calculate the CH
3
NH
3
H11001
/CH
3
NH
2
ratio in water buffered at pH 7.
Their basicity provides a means by which amines may be separated from neutral
organic compounds. A mixture containing an amine is dissolved in diethyl ether and
shaken with dilute hydrochloric acid to convert the amine to an ammonium salt. The
ammonium salt, being ionic, dissolves in the aqueous phase, which is separated from the
ether layer. Adding sodium hydroxide to the aqueous layer converts the ammonium salt
back to the free amine, which is then removed from the aqueous phase by extraction
with a fresh portion of ether.
22.5 BASICITY OF AMINES
Amines are weak bases, but as a class, amines are the strongest bases of all neutral mol-
ecules. Table 22.1 lists basicity data for a number of amines. The most important rela-
tionships to be drawn from the data are
1. Alkylamines are slightly stronger bases than ammonia.
2. Alkylamines differ very little among themselves in basicity. Their basicities cover
a range of less than 10 in equilibrium constant (1 pK unit).
3. Arylamines are much weaker bases than ammonia and alkylamines. Their basicity
constants are on the order of 10
6
smaller than those of alkylamines (6 pK units).
The differences in basicity between ammonia, and primary, secondary, and tertiary
alkylamines result from the interplay between steric and electronic effects on the mole-
cules themselves and on the solvation of their conjugate acids. In total, the effects are
small, and most alkylamines are very similar in basicity.
Arylamines are a different story, however; most are about a million times weaker
as bases than ammonia and alkylamines.
As unfavorable as the equilibrium is for cyclohexylamine acting as a base in water,
CH
3
N
H11001
H
H
H
Methylammonium ion
(stronger acid; pK
a
H11005 10.7)
H11001 OH
H11002
Hydroxide ion
CH
3
NH
2
Methylamine
H11001 HOH
Water
(weaker acid; pK
a
H11005 15.7)
CH
3
NH
2
Methylamine
H11001 H OCCH
3
O
Acetic
acid
(stronger acid; pK
a
H11005 4.7)
CH
3
NH
3
H11001
Methylammonium
ion
(weaker acid; pK
a
H11005 10.7)
H11001 OCCH
3
O
H11002
Acetate
ion
22.5 Basicity of Amines 865
NH
2
Cyclohexylamine
H11001 H
2
O
Water
NH
3
H11001
Cyclohexylammonium
ion
H11001 HO
H11002
Hydroxide
ion
(K
b
4.4 H11003 10
H110024
; pK
b
3.4)
Recall from Section 4.6 that
acid–base reactions are char-
acterized by equilibrium con-
stants greater than unity
when the stronger acid is on
the left side of the equation
and the weaker acid on the
right.
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it is far less favorable for aniline.
Aniline is a much weaker base because its delocalized lone pair is more strongly held
than the nitrogen lone pair in cyclohexylamine. The more strongly held the electron pair,
the less able it is to abstract a proton.
When the proton donor is a strong acid, arylamines can be completely protonated.
Aniline is extracted from an ether solution into 1 M hydrochloric acid because it is con-
verted to a water-soluble anilinium ion salt under these conditions.
N
H
H
Aniline is stabilized by
delocalization of lone
pair into H9266 system of
ring, decreasing the electron
density at nitrogen.
H11001 H
2
O N
H11001
H
H
H H11001 HO
H11002
866 CHAPTER TWENTY-TWO Amines
TABLE 22.1
Base Strength of Amines As Measured by Their Basicity Constants and the Dissociation
Constants of Their Conjugate Acids*
Compound
*In water at 25°C.
Ammonia
Primary amines
Methylamine
Ethylamine
Isopropylamine
tert-Butylamine
Aniline
Secondary amines
Dimethylamine
Diethylamine
N-Methylaniline
K
b
1.8 H11003 10
H110025
4.4 H11003 10
H110024
5.6 H11003 10
H110024
4.3 H11003 10
H110024
2.8 H11003 10
H110024
3.8 H11003 10
H1100210
5.1 H11003 10
H110024
1.3 H11003 10
H110023
6.1 H11003 10
H1100210
5.3 H11003 10
H110025
5.6 H11003 10
H110024
1.2 H11003 10
H110029
pK
b
4.7
3.4
3.2
3.4
3.6
9.4
3.3
2.9
9.2
4.3
3.2
8.9
K
a
5.5 H11003 10
H1100210
2.3 H11003 10
H1100211
1.8 H11003 10
H1100211
2.3 H11003 10
H1100211
3.6 H11003 10
H1100211
2.6 H11003 10
H110025
2.0 H11003 10
H1100211
7.7 H11003 10
H1100212
1.6 H11003 10
H110025
1.9 H11003 10
H1100210
1.8 H11003 10
H1100211
8.3 H11003 10
H110026
pK
a
9.3
10.6
10.8
10.6
10.4
4.6
10.7
11.1
4.8
9.7
10.8
5.1
Structure
NH
3
CH
3
NH
2
CH
3
CH
2
NH
2
(CH
3
)
2
CHNH
2
(CH
3
)
3
CNH
2
C
6
H
5
NH
2
(CH
3
)
2
NH
(CH
3
CH
2
)
2
NH
C
6
H
5
NHCH
3
(CH
3
)
3
N
(CH
3
CH
2
)
3
N
C
6
H
5
N(CH
3
)
2
Tertiary amines
Trimethylamine
Triethylamine
N,N-Dimethylaniline
Basicity Acidity of conjugate acid
NH
2
Aniline
H11001 H
2
O
Water
NH
3
H11001
Anilinium ion
H11001 HO
H11002
Hydroxide
ion
(K
b
3.8 H11003 10
H1100210
; pK
b
9.4)
Compare the calculated
charge on nitrogen in cyclohex-
ylamine and aniline on Learning
By Modeling.
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PROBLEM 22.7 The two amines shown differ by a factor of 40,000 in their K
b
values. Which is the stronger base? Why? View their structures on Learning By
Modeling. What are the calculated charges on the two nitrogens?
Conjugation of the amino group of an arylamine with a second aromatic ring, then
a third, reduces its basicity even further. Diphenylamine is 6300 times less basic than
aniline, whereas triphenylamine is scarcely a base at all, being estimated as 10
8
times
less basic than aniline and 10
14
times less basic than ammonia.
In general, electron-donating substituents on the aromatic ring increase the basic-
ity of arylamines slightly. Thus, as shown in Table 22.2, an electron-donating methyl
group in the para position increases the basicity of aniline by a factor of only 5–6 (less
than 1 pK unit). Electron-withdrawing groups are base-weakening and exert larger
effects. A p-trifluoromethyl group decreases the basicity of aniline by a factor of 200
and a p-nitro group by a factor of 3800. In the case of p-nitroaniline a resonance inter-
action of the type shown provides for extensive delocalization of the unshared electron
pair of the amine group.
Just as aniline is much less basic than alkylamines because the unshared electron pair of
nitrogen is delocalized into the H9266 system of the ring, p-nitroaniline is even less basic
because the extent of this delocalization is greater and involves the oxygens of the nitro
group.
NNH
2
H11001
H11002
O
O
H11001
N
H11001
NH
2
H11002
O
H11002
O
Electron delocalization in p-nitroaniline
C
6
H
5
NH
2
Aniline
(K
b
3.8 H11003 10
H1100210
;
pK
b
9.4)
(C
6
H
5
)
2
NH
Diphenylamine
(K
b
6 H11003 10
H1100214
;
pK
b
13.2)
(C
6
H
5
)
3
N
Triphenylamine
(K
b
H11015 10
H1100219
;
pK
b
H11015 19)
N
H
Tetrahydroquinoline
NH
Tetrahydroisoquinoline
22.5 Basicity of Amines 867
TABLE 22.2 Effect of Substituents on the Basicity of Aniline
X
H
CH
3
CF
3
O
2
N
4 H11003 10
H1100210
2 H11003 10
H110029
2 H11003 10
H1100212
1 H11003 10
H1100213
K
b
9.4
8.7
11.5
13.0
pK
b
X NH
2
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868 CHAPTER TWENTY-TWO Amines
PROBLEM 22.8 Each of the following is a much weaker base than aniline. Pre-
sent a resonance argument to explain the effect of the substituent in each case.
(a) o-Cyanoaniline (c) p-Aminoacetophenone
(b)
SAMPLE SOLUTION (a) A cyano substituent is strongly electron-withdrawing.
When present at a position ortho to an amino group on an aromatic ring, a cyano
substituent increases the delocalization of the amine lone-pair electrons by a
direct resonance interaction.
This resonance stabilization is lost when the amine group becomes protonated,
and o-cyanoaniline is therefore a weaker base than aniline.
Multiple substitution by strongly electron-withdrawing groups diminishes the
basicity of arylamines still more. As just noted, aniline is 3800 times as strong a base
as p-nitroaniline; however, it is 10
9
times more basic than 2,4-dinitroaniline. A practical
consequence of this is that arylamines that bear two or more strongly electron-with-
drawing groups are often not capable of being extracted from ether solution into dilute
aqueous acid.
Nonaromatic heterocyclic compounds, piperidine, for example, are similar in basic-
ity to alkylamines. When nitrogen is part of an aromatic ring, however, its basicity
decreases markedly. Pyridine, for example, resembles arylamines in being almost 1 mil-
lion times less basic than piperidine.
Imidazole and its derivatives form an interesting and important class of hetero-
cyclic aromatic amines. Imidazole is approximately 100 times more basic than pyridine.
Protonation of imidazole yields an ion that is stabilized by the electron delocalization
represented in the resonance structures shown:
An imidazole ring is a structural unit in the amino acid histidine (Section 27.1) and is
involved in a large number of biological processes as a base and as a nucleophile.
H
N N
Imidazole
(K
b
H11005 1 H11003 10
H110027
; pK
b
H11005 7)
H11001
N
H H
N
H11001
H
N
H
N
Imidazolium ion
H11001 H
H11001
H
N
Piperidine
(K
b
H11005 1.6 H11003 10
H110023
; pK
b
H11005 2.8)
Pyridine
(K
b
H11005 1.4 H11003 10
H110029
; pK
b
H11005 8.8)
N
is more basic than
NH
2
N
C C
H11001
NH
2
H11002
N
C
6
H
5
NHCCH
3
O
Pyridine and imidazole were
two of the heterocyclic aro-
matic compounds described
in Section 11.21.
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22.5 Basicity of Amines 869
AMINES AS NATURAL PRODUCTS
The ease with which amines are extracted into aque-
ous acid, combined with their regeneration on treat-
ment with base, makes it a simple matter to separate
amines from other plant materials, and nitrogen-
containing natural products were among the earliest
organic compounds to be studied.
*
Their basic prop-
erties led amines obtained from plants to be called
alkaloids. The number of known alkaloids exceeds
5000. They are of special interest because most are
characterized by a high level of biological activity.
Some examples include cocaine, coniine, and mor-
phine.
Many alkaloids, such as nicotine and quinine,
contain two (or more) nitrogen atoms. The nitrogens
highlighted in yellow in quinine and nicotine are part
of a substituted quinoline and pyridine ring, respec-
tively.
CH
3
N
C
O
OCH
3
OCC
6
H
5
O
Cocaine
(A central nervous system
stimulant obtained from
the leaves of the coca plant.)
CH
2
CH
2
CH
3
N
H
Coniine
(Present along with other
alkaloids in the hemlock
extract used to poison
Socrates.)
HO
HO
NCH
3
O
H
Morphine
(An opium alkaloid. Although it is an excellent
analgesic, its use is restricted because
of the potential for addiction. Heroin is
the diacetate ester of morphine.)
Several naturally occurring amines mediate the
transmission of nerve impulses and are referred to as
neurotransmitters. Two examples are epinephrine
and serotonin. (Strictly speaking, these compounds
are not classified as alkaloids, because they are not
isolated from plants.)
CH
3
O
H
N
N
H
HO
Quinine
(Alkaloid of cinchona bark
used to treat malaria)
N
CH
3
N
Nicotine
(An alkaloid present in tobacco;
a very toxic compound sometimes
used as an insecticide)
—Cont.
* The isolation of alkaloids from plants is reviewed in the August 1991 issue of the Journal of Chemical Education, pp. 700–703.
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870 CHAPTER TWENTY-TWO Amines
Bioactive amines are also widespread in ani-
mals. A variety of structures and properties have been
found in substances isolated from frogs, for example.
One, called epibatidine, is a naturally occurring
painkiller isolated from the skin of an Ecuadoran frog.
Another family of frogs produces a toxic mixture of
several stereoisomeric amines, called dendrobines, on
their skin that protects them from attack.
Among the more important amine derivatives
found in the body are a group of compounds known
as polyamines, which contain two to four nitrogen
atoms separated by several methylene units:
These compounds are present in almost all mam-
malian cells, where they are believed to be involved
in cell differentiation and proliferation. Because each
nitrogen of a polyamine is protonated at physiologi-
cal pH (7.4), putrescine, spermidine, and spermine ex-
ist as cations with a charge of H11001 2, H11001 3, and H11001 4, re-
spectively, in body fluids. Structural studies suggest
that these polyammonium ions affect the conforma-
tion of biological macromolecules by electrostatic
binding to specific anionic sites—the negatively
charged phosphate groups of DNA, for example.
Dendrobine
(Isolated from frogs of the
Dendrobatidae family. Related
compounds have also been
isolated from certain ants.)
N
HH
H
N
Cl
HN
Epibatidine
(Once used as an arrow poison,
it is hundreds of times more
powerful than morphine in
relieving pain. It is too toxic
to be used as a drug, however.)
H
2
N
NH
2
Putrescine
H
N
H
2
N
NH
2
Spermidine
H
N
NH
2
H
2
N
N
H
Spermine
H
C
HO
HO
CH
2
NHCH
3
OH
Epinephrine
(Also called adrenaline; a
hormone secreted by the
adrenal gland that prepares
the organism for “flight or
fight.”)
HO
CH
2
CH
2
NH
2
N
H
Serotonin
(A hormone synthesized in
the pineal gland. Certain
mental disorders are be-
lieved to be related to sero-
tonin levels in the brain.)
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22.6 TETRAALKYLAMMONIUM SALTS AS PHASE-TRANSFER
CATALYSTS
In spite of being ionic, many quaternary ammonium salts dissolve in nonpolar media.
The four alkyl groups attached to nitrogen shield its positive charge and impart lipophilic
character to the tetraalkylammonium ion. The following two quaternary ammonium salts,
for example, are soluble in solvents of low polarity such as benzene, decane, and halo-
genated hydrocarbons:
This property of quaternary ammonium salts is used to advantage in an experi-
mental technique known as phase-transfer catalysis. Imagine that you wish to carry out
the reaction
Sodium cyanide does not dissolve in butyl bromide. The two reactants contact each other
only at the surface of the solid sodium cyanide, and the rate of reaction under these con-
ditions is too slow to be of synthetic value. Dissolving the sodium cyanide in water is
of little help, since butyl bromide is not soluble in water and reaction can occur only at
the interface between the two phases. Adding a small amount of benzyltrimethylammo-
nium chloride, however, causes pentanenitrile to form rapidly even at room temperature.
The quaternary ammonium salt is acting as a catalyst; it increases the reaction rate. How?
Quaternary ammonium salts catalyze the reaction between an anion and an organic
substrate by transferring the anion from the aqueous phase, where it cannot contact the
substrate, to the organic phase. In the example just cited, the first step occurs in the aque-
ous phase and is an exchange of the anionic partner of the quaternary ammonium salt
for cyanide ion:
The benzyltrimethylammonium ion migrates to the butyl bromide phase, carrying a
cyanide ion along with it.
Once in the organic phase, cyanide ion is only weakly solvated and is far more reactive
than it is in water or ethanol, where it is strongly solvated by hydrogen bonding. Nucle-
ophilic substitution takes place rapidly.
Benzyltrimethylammonium
cyanide
(aqueous)
CN
H11002
C
6
H
5
CH
2
N(CH
3
)
3
H11001
Benzyltrimethylammonium
cyanide
(in butyl bromide)
CN
H11002
C
6
H
5
CH
2
N(CH
3
)
3
H11001
fast
CN
H11002
Cyanide
ion
(aqueous)
Cl
H11002
Chloride
ion
(aqueous)
Benzyltrimethylammonium
chloride
(aqueous)
Cl
H11002
C
6
H
5
CH
2
N(CH
3
)
3
H11001
Benzyltrimethylammonium
cyanide
(aqueous)
CN
H11002
C
6
H
5
CH
2
N(CH
3
)
3
H11001
H11001H11001
fast
CH
3
CH
2
CH
2
CH
2
Br
Butyl bromide
CH
3
CH
2
CH
2
CH
2
CN
Pentanenitrile
NaCN
Sodium
cyanide
NaBr
Sodium
bromide
H11001H11001
CH
3
N(CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
3
)
3
H11001
Cl
H11002
Methyltrioctylammonium chloride
CH
2
N(CH
2
CH
3
)
3
H11001
Cl
H11002
Benzyltriethylammonium chloride
22.6 Tetraalkylammonium Salts as Phase-Transfer Catalysts 871
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The benzyltrimethylammonium bromide formed in this step returns to the aqueous phase,
where it can repeat the cycle.
Phase-transfer catalysis succeeds for two reasons. First, it provides a mechanism
for introducing an anion into the medium that contains the reactive substrate. More
important, the anion is introduced in a weakly solvated, highly reactive state. You’ve
already seen phase-transfer catalysis in another form in Section 16.4, where the metal-
complexing properties of crown ethers were described. Crown ethers permit metal salts
to dissolve in nonpolar solvents by surrounding the cation with a lipophilic cloak, leav-
ing the anion free to react without the encumbrance of strong solvation forces.
22.7 REACTIONS THAT LEAD TO AMINES: A REVIEW AND A
PREVIEW
Methods for preparing amines address either or both of the following questions:
1. How is the required carbon–nitrogen bond to be formed?
2. Given a nitrogen-containing organic compound such as an amide, a nitrile, or a
nitro compound, how is the correct oxidation state of the desired amine to be
achieved?
A number of reactions that lead to carbon–nitrogen bond formation were presented
in earlier chapters and are summarized in Table 22.3. Among the reactions in the table,
the nucleophilic ring opening of epoxides, reaction of H9251-halo acids with ammonia, and
the Hofmann rearrangement give amines directly. The other reactions in Table 22.3 yield
products that are converted to amines by some subsequent procedure. As these proce-
dures are described in the following sections, you will see that they are largely applica-
tions of principles that you’ve already learned. You will encounter some new reagents
and some new uses for familiar reagents, but very little in the way of new reaction types
is involved.
22.8 PREPARATION OF AMINES BY ALKYLATION OF AMMONIA
Alkylamines are, in principle, capable of being prepared by nucleophilic substitution
reactions of alkyl halides with ammonia.
Although this reaction is useful for preparing H9251-amino acids (Table 22.3, fifth entry), it
is not a general method for the synthesis of amines. Its major limitation is that the
expected primary amine product is itself a nucleophile and competes with ammonia for
the alkyl halide.
RX
Alkyl
halide
RNH
2
Primary
amine
2NH
3
Ammonia
NH
4
H11001
X
H11002
Ammonium
halide salt
H11001H11001
Benzyltrimethylammonium
bromide
(in butyl bromide)
Br
H11002
C
6
H
5
CH
2
N(CH
3
)
3
H11001
Benzyltrimethylammonium
cyanide
(in butyl bromide)
CN
H11002
C
6
H
5
CH
2
N(CH
3
)
3
H11001
CH
3
CH
2
CH
2
CH
2
Br
Butyl bromide
H11001
H11001CH
3
CH
2
CH
2
CH
2
CN
Pentanenitrile
(in butyl bromide)
872 CHAPTER TWENTY-TWO Amines
Phase-transfer catalysis is the
subject of an article in the
April 1978 issue of the Jour-
nal of Chemical Education
(pp. 235–238). This article in-
cludes examples of a variety
of reactions carried out un-
der phase-transfer condi-
tions.
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22.8 Preparation of Amines by Alkylation of Ammonia 873
TABLE 22.3 Methods for Carbon–Nitrogen Bond Formation Discussed in Earlier Chapters
Reaction (section) and comments
Nitration of arenes (Section 12.3) The
standard method for introducing a nitro-
gen atom as a substituent on an aromatic
ring is nitration with a mixture of nitric
acid and sulfuric acid. The reaction pro-
ceeds by electrophilic aromatic substitu-
tion.
Nucleophilic substitution by azide ion on
an alkyl halide (Sections 8.1, 8.13) Azide
ion is a very good nucleophile and reacts
with primary and secondary alkyl halides
to give alkyl azides. Phase-transfer cata-
lysts accelerate the rate of reaction.
Nucleophilic ring opening of epoxides by
ammonia (Section 16.12) The strained
ring of an epoxide is opened on nucleo-
philic attack by ammonia and amines to
give H9252-amino alcohols. Azide ion also
reacts with epoxides; the products are
H9252-azido alcohols.
Nucleophilic addition of amines to alde-
hydes and ketones (Sections 17.10,
17.11) Primary amines undergo nucleo-
philic addition to the carbonyl group of
aldehydes and ketones to form carbinol-
amines. These carbinolamines dehydrate
under the conditions of their formation
to give N-substituted imines. Secondary
amines yield enamines.
(Continued)
General equation and specific example
Pentyl azide (89%)
(1-azidopentane)
CH
3
CH
2
CH
2
CH
2
CH
2
N
3
NaN
3
phase-transfer
catalyst
CH
3
CH
2
CH
2
CH
2
CH
2
Br
Pentyl bromide
(1-bromopentane)
Nitroarene
ArNO
2
Water
H
2
O
H
2
SO
4
ArH
Arene
HNO
3
Nitric acid
H11001H11001
Primary
amine
RNH
2
Water
H
2
O
Aldehyde
or ketone
RH11032CRH11033
O
X
Imine
RH11032CRH11033
X
NR
H11001H11001
Methylamine
CH
3
NH
2
N-Benzylidenemethylamine
(70%)
C
6
H
5
CH?NCH
3
H11001
Benzaldehyde
C
6
H
5
CH
O
X
Alkyl azide
N?N?N±R
H11002
H11001
Alkyl halide
R±XX
H11002
Halide ion
H11001H11001
Azide ion
N?N?N
H11002H11002
H11001
HNO
3
H
2
SO
4
CH
O
X
Benzaldehyde
O
2
N
CH
O
X
m-Nitrobenzaldehyde
(75–84%)
H11001
Ammonia
H
3
N
Epoxide
R
2
C±CR
2
O
±
±
H9252-Amino alcohol
H
2
N±C±C±OH
W
W
W
W
R
R
R
R
H
3
C
H
H
3
C
H
O
(2R,3R)-2,3-Epoxybutane
CH
3
CH
3
OHH
HH
2
N
(2R,3S)-3-Amino-2-butanol (70%)
NH
3
H
2
O
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When 1-bromooctane, for example, is allowed to react with ammonia, both the primary
amine and the secondary amine are isolated in comparable amounts.
In a similar manner, competitive alkylation may continue, resulting in formation
of a trialkylamine.
CH
3
(CH
2
)
6
CH
2
Br
1-Bromooctane
(1 mol)
CH
3
(CH
2
)
6
CH
2
NH
2
Octylamine
(45%)
[CH
3
(CH
2
)
6
CH
2
]
2
NH
N,N-Dioctylamine
(43%)
H11001
NH
3
(2 mol)
RX
Alkyl
halide
RNH
2
Primary
amine
RNHR
Secondary
amine
NH
3
Ammonia
NH
4
H11001H11001 H11001
Ammonium
halide salt
X
H11002
H11001
874 CHAPTER TWENTY-TWO Amines
TABLE 22.3
Methods for Carbon–Nitrogen Bond Formation Discussed in Earlier Chapters
(Continued)
Reaction (section) and comments
Nucleophilic substitution by ammonia on
H9251-halo acids (Section 19.16) The H9251-halo
acids obtained by halogenation of car-
boxylic acids under conditions of the
Hell–Volhard–Zelinsky reaction are reac-
tive substrates in nucleophilic substitu-
tion processes. A standard method for
the preparation of H9251-amino acids is dis-
placement of halide from H9251-halo acids by
nucleophilic substitution using excess
aqueous ammonia.
Nucleophilic acyl substitution (Sections
20.3, 20.5, and 20.11) Acylation of ammo-
nia and amines by an acyl chloride, acid
anhydride, or ester is an exceptionally
effective method for the formation of
carbon–nitrogen bonds.
The Hofmann rearrangement (Section
20.17) Amides are converted to amines
by reaction with bromine in basic media.
An N-bromo amide is an intermediate; it
rearranges to an isocyanate. Hydrolysis of
the isocyanate yields an amine.
General equation and specific example
Ammonium
halide
NH
4
XH11001H11001
Ammonia
(excess)
H
3
N
H9251-Halo
carboxylic acid
RCHCO
2
H
W
X
H9251-Amino
acid
RCHCO
2
H11002
H11001
NH
3
W
2-Bromo-3-methylbutanoic
acid
(CH
3
)
2
CHCHCO
2
H
W
Br
NH
3
H
2
O
2-Amino-3-methylbutanoic
acid (47–48%)
(CH
3
)
2
CHCHCO
2
H11002
W
H11001
NH
3
Primary or
secondary
amine, or
ammonia
R
2
NH
Water
HXH11001H11001RH11032C
O
X
±
?
Acyl chloride, acid
anhydride, or ester
Amide
R
2
NCRH11032
O
X
H11001H11001NCCH
3
O
X
N-Acetylpyrrolidine
(79%)
2
N
H
Pyrrolidine
CH
3
CCl
O
X
Acetyl chloride
Cl
H11002
H11001
N
HH
Pyrrolidine
hydrochloride
Amine
RNH
2
Amide
RCNH
2
O
X
Br
2
, HO
H11002
H
2
O
tert-Butylamine (64%)
(CH
3
)
3
CNH
2
2,2-Dimethylpropanamide
(CH
3
)
3
CCNH
2
O
X
Br
2
, HO
H11002
H
2
O
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Even the tertiary amine competes with ammonia for the alkylating agent. The product is
a quaternary ammonium salt.
Because alkylation of ammonia can lead to a complex mixture of products, it is
used to prepare primary amines only when the starting alkyl halide is not particularly
expensive and the desired amine can be easily separated from the other components of
the reaction mixture.
PROBLEM 22.9 Alkylation of ammonia is sometimes employed in industrial
processes; the resulting mixture of amines is separated by distillation. The ultimate
starting materials for the industrial preparation of allylamine are propene, chlo-
rine, and ammonia. Write a series of equations showing the industrial preparation
of allylamine from these starting materials. (Allylamine has a number of uses,
including the preparation of the diuretic drugs meralluride and mercaptomerin.)
Aryl halides do not normally react with ammonia under these conditions. The few
exceptions are special cases and will be described in Section 23.5.
22.9 THE GABRIEL SYNTHESIS OF PRIMARY ALKYLAMINES
A method that achieves the same end result as that desired by alkylation of ammonia
but which avoids the formation of secondary and tertiary amines as byproducts is the
Gabriel synthesis. Alkyl halides are converted to primary alkylamines without contam-
ination by secondary or tertiary amines. The key reagent is the potassium salt of phthal-
imide, prepared by the reaction
Phthalimide, with a K
a
of 5 H11003 10
H110029
(pK
a
8.3), can be quantitatively converted to its
potassium salt with potassium hydroxide. The potassium salt of phthalimide has a neg-
atively charged nitrogen atom, which acts as a nucleophile toward primary alkyl halides
in a bimolecular nucleophilic substitution (S
N
2) process.
H11001 C
6
H
5
CH
2
Cl
Benzyl chloride
K
H11001
H11002
O
O
N
N-Potassiophthalimide
O
O
NCH
2
C
6
H
5
N-Benzylphthalimide
(74%)
H11001 KCl
Potassium
chloride
DMF
O
O
NH
Phthalimide
H11001 KOH K
H11001
H11002
O
O
N
N-Potassiophthalimide
H11001 H
2
O
Water
RX
Alkyl
halide
R
3
N
Tertiary
amine
H11001
Quaternary
ammonium salt
X
H11002
R
4
N
H11001
RX
Alkyl
halide
R
2
NH
Secondary
amine
R
3
N
Tertiary
amine
NH
3
Ammonia
H11001H11001 H11001NH
4
Ammonium
halide salt
X
H11002
H11001
22.9 The Gabriel Synthesis of Primary Alkylamines 875
The Gabriel synthesis is
based on work carried out by
Siegmund Gabriel at the Uni-
versity of Berlin in the 1880s.
A detailed discussion of each
step in the Gabriel synthesis
of benzylamine can be found
in the October 1975 Journal
of Chemical Education (pp.
670–671).
DMF is an abbreviation for
N,N-dimethylformamide,
. DMF is a polar
aprotic solvent (Section 8.12)
and an excellent medium for
S
N
2 reactions.
HCN(CH
3
)
2
O
X
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The product of this reaction is an imide (Section 20.15), a diacyl derivative of an
amine. Either aqueous acid or aqueous base can be used to hydrolyze its two amide
bonds and liberate the desired primary amine. A more effective method of cleaving the
two amide bonds is by acyl transfer to hydrazine:
Aryl halides cannot be converted to arylamines by the Gabriel synthesis, because
they do not undergo nucleophilic substitution with N-potassiophthalimide in the first step
of the procedure.
Among compounds other than simple alkyl halides, H9251-halo ketones and H9251-halo
esters have been employed as substrates in the Gabriel synthesis. Alkyl p-toluenesul-
fonate esters have also been used. Because phthalimide can undergo only a single alkyl-
ation, the formation of secondary and tertiary amines does not occur, and the Gabriel
synthesis is a valuable procedure for the laboratory preparation of primary amines.
PROBLEM 22.10 Which of the following amines can be prepared by the Gabriel
synthesis? Which ones cannot? Write equations showing the successful applica-
tions of this method.
(a) Butylamine (d) 2-Phenylethylamine
(b) Isobutylamine (e) N-Methylbenzylamine
(c) tert-Butylamine (f) Aniline
SAMPLE SOLUTION (a) The Gabriel synthesis is limited to preparation of amines
of the type RCH
2
NH
2
, that is, primary alkylamines in which the amino group is
bonded to a primary carbon. Butylamine may be prepared from butyl bromide by
this method.
CH
3
CH
2
CH
2
CH
2
Br
Butyl bromide
H11001
O
O
NK
N-Potassiophthalimide N-Butylphthalimide
O
O
NCH
2
CH
2
CH
2
CH
3
DMF
H
2
NNH
2
CH
3
CH
2
CH
2
CH
2
NH
2
Butylamine
H11001
NH
O
NH
O
Phthalhydrazide
H11001 H
2
NNH
2
Hydrazine
C
6
H
5
CH
2
NH
2
Benzylamine
(97%)
O
O
NCH
2
C
6
H
5
N-Benzylphthalimide
H11001
ethanol
Phthalhydrazide
NH
O
NH
O
876 CHAPTER TWENTY-TWO Amines
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22.10 PREPARATION OF AMINES BY REDUCTION
Almost any nitrogen-containing organic compound can be reduced to an amine. The syn-
thesis of amines then becomes a question of the availability of suitable precursors and
the choice of an appropriate reducing agent.
Alkyl azides, prepared by nucleophilic substitution of alkyl halides by sodium
azide, as shown in the first entry of Table 22.3, are reduced to alkylamines by a variety
of reagents, including lithium aluminum hydride.
Catalytic hydrogenation is also effective:
In its overall design, this procedure is similar to the Gabriel synthesis; a nitrogen nucle-
ophile is used in a carbon–nitrogen bond-forming operation and then converted to an
amino group in a subsequent transformation.
The same reduction methods may be applied to the conversion of nitriles to pri-
mary amines.
Since nitriles can be prepared from alkyl halides by nucleophilic substitution with
cyanide ion, the overall process RX → RCPN → RCH
2
NH
2
leads to primary amines
that have one more carbon atom than the starting alkyl halide.
Cyano groups in cyanohydrins (Section 17.7) are reduced under the same reaction
conditions.
Nitro groups are readily reduced to primary amines by a variety of methods. Cat-
alytic hydrogenation over platinum, palladium, or nickel is often used, as is reduction
by iron or tin in hydrochloric acid. The ease with which nitro groups are reduced is
LiAlH
4
or
H
2
, catalyst
RC N
Nitrile
RCH
2
NH
2
Primary amine
1. LiAlH
4
,
diethyl ether
2. H
2
O
F
3
CCH
2
CN
p-(Trifluoromethyl)benzyl
cyanide
F
3
CCH
2
CH
2
NH
2
2-(p-Trifluoromethyl)phenylethyl-
amine (53%)
H
2
(100 atm), Ni
diethyl ether
CH
3
CH
2
CH
2
CH
2
CN
Pentanenitrile 1-Pentanamine (56%)
CH
3
CH
2
CH
2
CH
2
CH
2
NH
2
NaN
3
dioxane–water
H
2
, Pt
O
1,2-Epoxycyclo-
hexane
OH
N
3
trans-2-Azidocyclo-
hexanol (61%)
OH
NH
2
trans-2-Aminocyclo-
hexanol (81%)
RNN
H11001
H11002
N
Alkyl azide
RNH
2
Primary amine
reduce
C
6
H
5
CH
2
CH
2
NH
2
2-Phenylethylamine (89%)
C
6
H
5
CH
2
CH
2
N
3
2-Phenylethyl azide
1. LiAlH
4
diethyl ether
2. H
2
O
22.10 Preparation of Amines by Reduction 877
The preparation of pen-
tanenitrile under phase-
transfer conditions was
described in Section 22.6.
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especially useful in the preparation of arylamines, where the sequence ArH → ArNO
2
→ ArNH
2
is the standard route to these compounds.
PROBLEM 22.11 Outline syntheses of each of the following arylamines from
benzene:
(a) o-Isopropylaniline (d) p-Chloroaniline
(b) p-Isopropylaniline (e) m-Aminoacetophenone
(c) 4-Isopropyl-1,3-benzenediamine
SAMPLE SOLUTION (a) The last step in the synthesis of o-isopropylaniline, the
reduction of the corresponding nitro compound by catalytic hydrogenation, is
given as one of the three preceding examples. The necessary nitroarene is
obtained by fractional distillation of the ortho–para mixture formed during nitra-
tion of isopropylbenzene.
As actually performed, a 62% yield of a mixture of ortho and para nitration prod-
ucts has been obtained with an ortho–para ratio of about 1:3.
Isopropylbenzene is prepared by the Friedel–Crafts alkylation of benzene
using isopropyl chloride and aluminum chloride (Section 12.6).
Reduction of an azide, a nitrile, or a nitro compound furnishes a primary amine.
A method that provides access to primary, secondary, or tertiary amines is reduction of
the carbonyl group of an amide by lithium aluminum hydride.
H11001
CH(CH
3
)
2
Isopropylbenzene
HNO
3
CH(CH
3
)
2
NO
2
o-Isopropylnitrobenzene
(bp 110°C)
CH(CH
3
)
2
NO
2
p-Isopropylnitrobenzene
(bp 131°C)
H
2
, Ni
methanol
NO
2
CH(CH
3
)
2
o-Isopropylnitrobenzene
NH
2
CH(CH
3
)
2
o-Isopropylaniline (92%)
1. Fe, HCl
2. NaOH
NO
2
Cl
p-Chloronitrobenzene
NH
2
Cl
p-Chloroaniline (95%)
1. Sn, HCl
2. NaOH
O
CCH
3
O
2
N
m-Nitroacetophenone
O
CCH
3
H
2
N
m-Aminoacetophenone (82%)
878 CHAPTER TWENTY-TWO Amines
For reductions carried out in
acidic media, a pH adjust-
ment with sodium hydroxide
is required in the last step in
order to convert ArNH
3
H11001
to
ArNH
2
.
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In this general equation, R and RH11032 may be either alkyl or aryl groups. When RH11032H11005H,
the product is a primary amine:
N-Substituted amides yield secondary amines:
N,N-Disubstituted amides yield tertiary amines:
Because amides are so easy to prepare, this is a versatile method for the prepara-
tion of amines.
The preparation of amines by the methods described in this section involves the
prior synthesis and isolation of some reducible material that has a carbon–nitrogen bond:
an azide, a nitrile, a nitro-substituted arene, or an amide. The following section describes
a method that combines the two steps of carbon–nitrogen bond formation and reduction
into a single operation. Like the reduction of amides, it offers the possibility of prepar-
ing primary, secondary, or tertiary amines by proper choice of starting materials.
22.11 REDUCTIVE AMINATION
A class of nitrogen-containing compounds that was omitted from the section just dis-
cussed includes imines and their derivatives. Imines are formed by the reaction of alde-
hydes and ketones with ammonia. Imines can be reduced to primary amines by catalytic
hydrogenation.
RCRH11032
O
Aldehyde
or ketone
RCRH11032
NH
Imine
RCHRH11032
NH
2
Primary amine
NH
3
Ammonia
H11001
H
2
catalyst
1. LiAlH
4
,
diethyl ether
2. H
2
O
CN(CH
3
)
2
O
N,N-Dimethylcyclohexane-
carboxamide
CH
2
N(CH
3
)
2
N,N-Dimethyl(cyclohexylmethyl)-
amine (88%)
1. LiAlH
4
,
diethyl ether
2. H
2
O
NHCCH
3
O
Acetanilide
NHCH
2
CH
3
N-Ethylaniline (92%)
C
6
H
5
CHCH
2
CNH
2
O
CH
3
3-Phenylbutanamide
C
6
H
5
CHCH
2
CH
2
NH
2
CH
3
3-Phenyl-1-butanamine (59%)
1. LiAlH
4
,
diethyl ether
2. H
2
O
RCNRH11032
2
O
Amide
1. LiAlH
4
2. H
2
O
RCH
2
NRH11032
2
Amine
22.11 Reductive Amination 879
Acetanilide is an acceptable
IUPAC synonym for N-
phenylethanamide.
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The overall reaction converts a carbonyl compound to an amine by carbon–nitro-
gen bond formation and reduction; it is commonly known as reductive amination.
What makes it a particularly valuable synthetic procedure is that it can be carried
out in a single operation by hydrogenation of a solution containing both ammonia
and the carbonyl compound along with a hydrogenation catalyst. The intermediate
imine is not isolated but undergoes reduction under the conditions of its formation.
Also, the reaction is broader in scope than implied by the preceding equation. All
classes of amines—primary, secondary, and tertiary—may be prepared by reductive
amination.
When primary amines are desired, the reaction is carried out as just described:
Secondary amines are prepared by hydrogenation of a carbonyl compound in
the presence of a primary amine. An N-substituted imine, or Schiff’s base, is an
intermediate:
Reductive amination has been successfully applied to the preparation of tertiary
amines from carbonyl compounds and secondary amines even though a neutral imine is
not possible in this case.
Presumably, the species that undergoes reduction here is a carbinolamine or an iminium
ion derived from it.
HO
H11002
OH
CH
3
CH
2
CH
2
CH N
Carbinolamine
CH
3
CH
2
CH
2
CH N
H11001
Iminium ion
H11001
H
2
, Ni
ethanol
H11001CH
3
CH
2
CH
2
CH
O
Butanal
N
H
Piperidine
CH
3
CH
2
CH
2
CH
2
N
N-Butylpiperidine (93%)
H
2
, Ni
ethanol
CH
3
(CH
2
)
5
CH
O
Heptanal
H11001 H
2
N
Aniline
CH
3
(CH
2
)
5
CH
2
NH
N-Heptylaniline (65%)
CH
3
(CH
2
)
5
CH Nvia
H
2
, Ni
ethanol
O
Cyclohexanone
H11001 NH
3
Ammonia
H
NH
2
Cyclohexylamine
(80%)
via
NH
880 CHAPTER TWENTY-TWO Amines
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PROBLEM 22.12 Show how you could prepare each of the following amines
from benzaldehyde by reductive amination:
(a) Benzylamine (c) N,N-Dimethylbenzylamine
(b) Dibenzylamine (d) N-Benzylpiperidine
SAMPLE SOLUTION (a) Since benzylamine is a primary amine, it is derived from
ammonia and benzaldehyde.
The reaction proceeds by initial formation of the imine C
6
H
5
CH?NH, followed by
its hydrogenation.
A variation of the classical reductive amination procedure uses sodium cyanoboro-
hydride (NaBH
3
CN) instead of hydrogen as the reducing agent and is better suited to
amine syntheses in which only a few grams of material are needed. All that is required
is to add sodium cyanoborohydride to an alcohol solution of the carbonyl compound and
an amine.
22.12 REACTIONS OF AMINES: A REVIEW AND A PREVIEW
The noteworthy properties of amines are their basicity and their nucleophilicity. The
basicity of amines has been discussed in Section 22.5. Several reactions in which amines
act as nucleophiles have already been encountered in earlier chapters. These are sum-
marized in Table 22.4.
Both the basicity and the nucleophilicity of amines originate in the unshared elec-
tron pair of nitrogen. When an amine acts as a base, this electron pair abstracts a pro-
ton from a Br?nsted acid. When an amine undergoes the reactions summarized in Table
22.4, the first step in each case is the attack of the unshared electron pair on the posi-
tively polarized carbon of a carbonyl group.
In addition to being more basic than arylamines, alkylamines are also more nucleophilic.
All the reactions in Table 22.4 take place faster with alkylamines than with arylamines.
The sections that follow introduce some additional reactions of amines. In all cases
our understanding of how these reactions take place starts with a consideration of the
role of the unshared electron pair of nitrogen.
We will begin with an examination of the reactivity of amines as nucleophiles in
S
N
2 reactions.
N H X
Amine acting as a base
CON
Amine acting as a nucleophile
C
6
H
5
CH
O
Benzaldehyde
CH
3
CH
2
NH
2
Ethylamine
C
6
H
5
CH
2
NHCH
2
CH
3
N-Ethylbenzylamine (91%)
H11001
NaBH
3
CN
methanol
Ni
Benzaldehyde
C
6
H
5
CH
O
Ammonia
NH
3
H11001
Hydrogen
H
2
H11001
Water
H
2
OH11001
Benzylamine
(89%)
C
6
H
5
CH
2
NH
2
22.12 Reactions of Amines: A Review and a Preview 881
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882 CHAPTER TWENTY-TWO Amines
TABLE 22.4 Reactions of Amines Discussed in Previous Chapters*
Reaction (section) and
comments
Reaction of secondary
amines with aldehydes
and ketones (Section
17.11) Enamines are
formed in the correspond-
ing reaction of secondary
amines with aldehydes
and ketones.
Reaction of primary
amines with aldehydes
and ketones (Section
17.10) Imines are formed
by nucleophilic addition
of a primary amine to the
carbonyl group of an
aldehyde or a ketone. The
key step is formation of a
carbinolamine intermedi-
ate, which then dehy-
drates to the imine.
Reaction of amines with
acyl chlorides (Section
20.3) Amines are convert-
ed to amides on reaction
with acyl chlorides. Other
acylating agents, such as
carboxylic acid anhydrides
and esters, may also be
used but are less reactive.
*Both alkylamines and arylamines undergo these reactions.
General equation and specific example
Benzaldehyde
C
6
H
5
CH
O
X
N-Benzylidenemethylamine
(70%)
C
6
H
5
CH?NCH
3
CH
3
NH
2
Methylamine
H
2
O
Water
H11001H11001
Aldehyde
or ketone
C?O
RH11032
RH11033
±
±
H11002H
2
O
Primary
amine
RNH
2
Carbinolamine
RNH±C±OH
W
W
RH11033
RH11032
Imine
RN?C
RH11032
RH11033
±
±
Aldehyde
or ketone
C?O
RH11032CH
2
RH11033
±
±
H11002H
2
O
Secondary
amine
R
2
NH
Carbinolamine
R
2
N±C±OH
W
W
RH11033
CH
2
RH11032
Enamine
CHRH11032
RH11033
±
?
R
2
N±C
H11001
H11001
H11001
H11001
N
H
Pyrrolidine
H
2
O
benzene
heat
N-(1-Cyclohexenyl)pyrrolidine (85–90%)
N
Cyclohexanone
O
H11002HCl
Primary or
secondary amine
R
2
NH
Tetrahedral
intermediate
R
2
N±CCl
W
W
RH11032
OH
Amide
R
2
NCRH11032
O
X
H11001
Acyl
chloride
RH11032CCl
O
X
Butylamine
CH
3
CH
2
CH
2
CH
2
NH
2
Pentanoyl chloride
CH
3
CH
2
CH
2
CH
2
CCl
O
X
N-Butylpentanamide (81%)
CH
3
CH
2
CH
2
CH
2
CNHCH
2
CH
2
CH
2
CH
3
O
X
H11001
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22.13 REACTION OF AMINES WITH ALKYL HALIDES
Nucleophilic substitution results when primary alkyl halides are treated with amines.
A second alkylation may follow, converting the secondary amine to a tertiary amine.
Alkylation need not stop there; the tertiary amine may itself be alkylated, giving a qua-
ternary ammonium salt.
Because of its high reactivity toward nucleophilic substitution, methyl iodide is the alkyl
halide most often used to prepare quaternary ammonium salts.
Quaternary ammonium salts, as we have seen, are useful in synthetic organic chem-
istry as phase-transfer catalysts. In another, more direct application, quaternary ammo-
nium hydroxides are used as substrates in an elimination reaction to form alkenes.
22.14 THE HOFMANN ELIMINATION
The halide anion of quaternary ammonium iodides may be replaced by hydroxide by
treatment with an aqueous slurry of silver oxide. Silver iodide precipitates, and a solu-
tion of the quaternary ammonium hydroxide is formed.
CH
2
N(CH
3
)
3
H11001
I
H11002
(Cyclohexylmethyl)trimethyl-
ammonium iodide
Ag
2
O
H
2
O, CH
3
OH
CH
2
N(CH
3
)
3
H11001
HO
H11002
(Cyclohexylmethyl)trimethylammonium
hydroxide
H11001
2(R
4
NI
H11002
)
Quaternary
ammonium iodide
H11001
2(R
4
N OH)
H11002
Quaternary
ammonium hydroxide
Ag
2
O
Silver
oxide
H11001 2AgI
Silver
iodide
H11001H
2
O
Water
H11001
methanol
heat
CH
2
NH
2
(Cyclohexylmethyl)-
amine
H11001 3CH
3
I
Methyl
iodide
CH
2
N(CH
3
)
3
H11001
I
H11002
(Cyclohexylmethyl)trimethyl-
ammonium iodide (99%)
RNH
2
Primary
amine
RNHCH
2
RH11032
Secondary
amine
RN(CH
2
RH11032)
2
Tertiary
amine
RN(CH
2
RH11032)
3
H11001
X
H11002
Quaternary
ammonium salt
RH11032CH
2
X RH11032CH
2
X RH11032CH
2
X
RNH
2
Primary
amine
H11001 RH11032CH
2
X
Primary
alkyl halide
RN
H
H
H11001
CH
2
RH11032 X
H11002
Ammonium
halide salt
RN
H
CH
2
RH11032
Secondary
amine
H11001 HX
Hydrogen
halide
C
6
H
5
NH
2
Aniline (4 mol)
C
6
H
5
CH
2
Cl
Benzyl chloride
(1 mol)
C
6
H
5
NHCH
2
C
6
H
5
N-Benzylaniline
(85–87%)
H11001
NaHCO
3
90°C
22.14 The Hofmann Elimination 883
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When quaternary ammonium hydroxides are heated, they undergo H9252-elimination to
form an alkene and an amine.
This reaction is known as the Hofmann elimination; it was developed by August W.
Hofmann in the middle of the nineteenth century and is both a synthetic method to pre-
pare alkenes and an analytical tool for structure determination.
A novel aspect of the Hofmann elimination is its regioselectivity. Elimination in
alkyltrimethylammonium hydroxides proceeds in the direction that gives the less substi-
tuted alkene.
The least sterically hindered H9252 hydrogen is removed by the base in Hofmann elim-
ination reactions. Methyl groups are deprotonated in preference to methylene groups, and
methylene groups are deprotonated in preference to methines. The regioselectivity of
Hofmann elimination is opposite to that predicted by the Zaitsev rule (Section 5.10).
Elimination reactions of alkyltrimethylammonium hydroxides are said to obey the
Hofmann rule; they yield the less substituted alkene.
PROBLEM 22.13 Give the structure of the major alkene formed when the
hydroxide of each of the following quaternary ammonium ions is heated.
(a) (c)
(b)
SAMPLE SOLUTION (a) Two alkenes are capable of being formed by H9252-elimina-
tion, methylenecyclopentane and 1-methylcyclopentene.
Methylenecyclopentane has the less substituted double bond and is the major
product. The reported isomer distribution is 91% methylenecyclopentane and 9%
1-methylcyclopentene.
H11001
heat
H11002H
2
O
H11002(CH
3
)
3
N
CH
3
N(CH
3
)
3
H11001
HO
H11002
(1-Methylcyclopentyl)trimethyl-
ammonium hydroxide
CH
2
Methylenecyclopentane
CH
3
1-Methylcyclopentene
(CH
3
)
3
CCH
2
C(CH
3
)
2
H11001
N(CH
3
)
3
CH
3
CH
2
NCH
2
CH
2
CH
2
CH
3
CH
3
CH
3
H11001
CH
3
N(CH
3
)
3
H11001
CH
3
CHCH
2
CH
3
H11001
N(CH
3
)
3
HO
H11002
sec-Butyltrimethylammonium
hydroxide
H11001
heat
H11002H
2
O
H11002(CH
3
)
3
N
1-Butene (95%)
CH
2
CHCH
2
CH
3
2-Butene (5%)
(cis and trans)
CH
3
CH CHCH
3
H11001
160°C
CH
2
H
H11001
N(CH
3
)
3
OH
H11002
(Cyclohexylmethyl)trimethyl-
ammonium hydroxide
CH
2
Methylenecyclohexane
(69%)
(CH
3
)
3
N
Trimethylamine
H11001 H
2
O
Water
884 CHAPTER TWENTY-TWO Amines
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We can understand the regioselectivity of the Hofmann elimination by comparing
steric effects in the E2 transition states for formation of 1-butene and trans-2-butene from
sec-butyltrimethylammonium hydroxide. In terms of its size, (trimethylam-
monio) is comparable to (CH
3
)
3
C± (tert-butyl). As Figure 22.4 illustrates, the E2 tran-
sition state requires an anti relationship between the proton that is removed and the
trimethylammonio group. No serious van der Waals repulsions are evident in the transi-
tion state geometry for formation of 1-butene. The conformation leading to trans-2-
butene, however, is destabilized by van der Waals strain between the trimethylammonio
group and a methyl group gauche to it. Thus, the activation energy for formation of
trans-2-butene exceeds that of 1-butene, which becomes the major product because it is
formed faster.
With a regioselectivity opposite to that of the Zaitsev rule, the Hofmann elimina-
tion is sometimes used in synthesis to prepare alkenes not accessible by dehydrohalo-
genation of alkyl halides. This application has decreased in importance since the Wittig
reaction (Section 17.12) became established as a synthetic method beginning in the
1950s. Similarly, most of the analytical applications of Hofmann elimination have been
replaced by spectroscopic methods.
(CH
3
)
3
N±
H11001
22.14 The Hofmann Elimination 885
H
CH
3
CH
2
CH
3
CH
2
N(CH
3
)
3
H
H
HO
H11002
H11001
(a) Less crowded: Conformation leading to 1-butene by anti elimination:
(b) More crowded: Conformation leading to trans-2-butene by anti elimination:
HH
H
H11002H
2
O
H11002(CH
3
)
3
N
H11002H
2
O
H11002(CH
3
)
3
N
1-Butene
(major product)
H
CH
3
H
CH
3
trans-2-Butene
(minor product)
These two groups
crowd each other
H
H
CH
3
N(CH
3
)
3
H
CH
3
HO
H11002
H11001
H
FIGURE 22.4 Newman projections showing the conformations leading to
(a) 1-butene and (b) trans-2-butene by Hofmann elimination of sec-butyltrimethyl-
ammonium hydroxide. The major product is 1-butene.
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22.15 ELECTROPHILIC AROMATIC SUBSTITUTION IN ARYLAMINES
Arylamines contain two functional groups, the amine group and the aromatic ring; they
are difunctional compounds. The reactivity of the amine group is affected by its aryl
substituent, and the reactivity of the ring is affected by its amine substituent. The same
electron delocalization that reduces the basicity and the nucleophilicity of an arylamine
nitrogen increases the electron density in the aromatic ring and makes arylamines
extremely reactive toward electrophilic aromatic substitution.
The reactivity of arylamines was noted in Section 12.12, where it was pointed out
that , , and are ortho, para-directing and exceedingly powerful
activating groups. These substituents are such powerful activators that electrophilic aro-
matic substitution is only rarely performed directly on arylamines.
Direct nitration of aniline and other arylamines, for example, is difficult to carry
out and is accompanied by oxidation that leads to the formation of dark-colored “tars.”
As a solution to this problem it is standard practice to first protect the amino group by
acylation with either acetyl chloride or acetic anhydride.
Amide resonance within the N-acetyl group competes with delocalization of the nitro-
gen lone pair into the ring.
Protecting the amino group of an arylamine in this way moderates its reactivity and per-
mits nitration of the ring to be achieved. The acetamido group is activating toward elec-
trophilic aromatic substitution and is ortho, para-directing.
After the N-acetyl-protecting group has served its purpose, it may be removed by
hydrolysis, liberating the amino group:
NH
2
CH(CH
3
)
2
p-Isopropylaniline
NHCCH
3
CH(CH
3
)
2
O
p-Isopropylacetanilide
(98%)
CH(CH
3
)
2
NO
2
NHCCH
3
O
4-Isopropyl-2-nitroacetanilide
(94%)
CH
3
COCCH
3
(protection
step)
O
X
C
O
X
C HNO
3
, 20°C
(nitration
step)
CCH
3
H
N
O
CCH
3
H
N
H11001
H11002
O
Amide resonance in acetanilide
ArNHCCH
3
O
N-Acetylarylamine
ArNH
2
Arylamine
CH
3
CCl
or
CH
3
COCCH
3
O
X
X
O
X
O
±NR
2
±NHR±NH
2
886 CHAPTER TWENTY-TWO Amines
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The net effect of the sequence protect–nitrate–deprotect is the same as if the substrate
had been nitrated directly. Because direct nitration is impossible, however, the indirect
route is the only practical method.
PROBLEM 22.14 Outline syntheses of each of the following from aniline and
any necessary organic or inorganic reagents:
(a) p-Nitroaniline (c) p-Aminoacetanilide
(b) 2,4-Dinitroaniline
SAMPLE SOLUTION (a) It has already been stated that direct nitration of ani-
line is not a practical reaction. The amino group must first be protected as its
N-acetyl derivative.
Nitration of acetanilide yields a mixture of ortho and para substitution products.
The para isomer is separated, then subjected to hydrolysis to give p-nitroaniline.
NHCCH
3
NO
2
O
p-Nitroacetanilide
NH
2
NO
2
p-Nitroaniline
H
2
O, HO
H11002
or
1. H
3
O
H11001
2. HO
H11002
H11001
HNO
3
H
2
SO
4
CH
3
COCCH
3
O
X
O
X
NH
2
Aniline
O
NHCCH
3
Acetanilide
NO
2
NHCCH
3
O
o-Nitroacetanilide
NHCCH
3
NO
2
O
p-Nitroacetanilide
ArNHCCH
3
O
N-Acetylarylamine
ArNH
2
Arylamine
H
2
O, HO
H11002
or
1. H
3
O
H11001
2. HO
H11002
CH(CH
3
)
2
NO
2
NHCCH
3
O
4-Isopropyl-2-nitroacetanilide
CH(CH
3
)
2
NO
2
NH
2
4-Isopropyl-2-nitroaniline
(100%)
KOH, ethanol
heat
(“deprotection” step)
22.15 Electrophilic Aromatic Substitution in Arylamines 887
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Unprotected arylamines are so reactive toward halogenation that it is difficult to
limit the reaction to monosubstitution. Generally, halogenation proceeds rapidly to
replace all the available hydrogens that are ortho or para to the amino group.
Decreasing the electron-donating ability of an amino group by acylation makes it possi-
ble to limit halogenation to monosubstitution.
Friedel–Crafts reactions are normally not successful when attempted on an aryl-
amine, but can be carried out readily once the amino group is protected.
22.16 NITROSATION OF ALKYLAMINES
When solutions of sodium nitrite (NaNO
2
) are acidified, a number of species are formed
that act as nitrosating agents. That is, they react as sources of nitrosyl cation, .
In order to simplify discussion, organic chemists group all these species together and
speak of the chemistry of one of them, nitrous acid, as a generalized precursor to nitro-
syl cation.
Nitrosation of amines is best illustrated by examining what happens when a sec-
ondary amine “reacts with nitrous acid.” The amine acts as a nucleophile, attacking the
nitrogen of nitrosyl cation.
NO O
H11002
Nitrite ion
(from sodium nitrite)
H
H11001
H
H11001
H11002H
2
O
HNO O
Nitrous acid
H
H
H11001
NO O N
H11001
O
Nitrosyl
cation
N?O
H11001
AlCl
3
CH
2
CH
3
NHCCH
3
O
2-Ethylacetanilide
H11001 CH
3
CCl
O
CH
2
CH
3
CH
3
C NHCCH
3
OO
4-Acetamido-3-ethylacetophenone (57%)
CH
3
NHCCH
3
O
2-Methylacetanilide
CH
3
NHCCH
3
O
Cl
4-Chloro-2-methylacetanilide (74%)
Cl
2
acetic acid
Br
2
acetic acid
NH
2
CO
2
H
p-Aminobenzoic acid
BrBr
NH
2
CO
2
H
4-Amino-3,5-dibromobenzoic acid
(82%)
888 CHAPTER TWENTY-TWO Amines
Nitrosyl cation is also called
nitrosonium ion. It can be
represented by the two reso-
nance structures
N?O
H11001
NPO
H11001
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The intermediate that is formed in the first step loses a proton to give an N-nitroso amine
as the isolated product.
PROBLEM 22.15 N-Nitroso amines are stabilized by electron delocalization.
Write the two most stable resonance forms of N-nitrosodimethylamine,
(CH
3
)
2
NNO.
N-Nitroso amines are more often called nitrosamines, and because many of them
are potent carcinogens, they have been the object of much recent investigation. We
encounter nitrosamines in the environment on a daily basis. A few of these, all of which
are known carcinogens, are:
Nitrosamines are formed whenever nitrosating agents come in contact with secondary
amines. Indeed, more nitrosamines are probably synthesized within our body than enter it
by environmental contamination. Enzyme-catalyzed reduction of nitrate (NO
3
H11002
) produces
nitrite (NO
2
H11002
), which combines with amines present in the body to form N-nitroso amines.
When primary amines are nitrosated, their N-nitroso compounds can’t be isolated
because they react further.
NaNO
2
H
H11001RNH
2
Primary
alkylamine
H
RN
N O
(Not isolable)
H
H11001
H11002H
H11001
R
H11001
H
N
N OH
(Not isolable)
H
H11001
H11002H
2
O
RN N
H11001
Alkyl diazonium
ion
RN N OH
2
H11001
(Not isolable)
RN N OH
(Not isolable)
H
3
C
N
O
H
3
C
N
N-Nitrosodimethylamine
(formed during
tanning of leather;
also found in beer
and herbicides)
N
N
O
N-Nitrosopyrrolidine
(formed when bacon
that has been cured
with sodium nitrite
is fried)
N
N
N
O
N-Nitrosonornicotine
(present in tobacco
smoke)
Dimethylamine
(CH
3
)
2
NH (CH
3
)
2
N N O
N-Nitrosodimethylamine
(88–90%)
NaNO
2
, HCl
H
2
O
H11002H
H11001
R
2
N
H
Secondary
alkylamine
H11001 R
2
N
H11001
H
N ON
H11001
O
Nitrosyl
cation
R
2
N N O
N-Nitroso
amine
22.16 Nitrosation of Alkylamines 889
Refer to the molecular
model of nitrosyl cation on
Learning By Modeling to verify
that the region of positive elec-
trostatic potential is concen-
trated at nitrogen.
The July 1977 issue of the
Journal of Chemical Educa-
tion contains an article enti-
tled “Formation of Nitrosa-
mines in Food and in the Di-
gestive System.”
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The product of this series of steps is an alkyl diazonium ion, and the amine is said to
have been diazotized. Alkyl diazonium ions are not very stable, decomposing rapidly
under the conditions of their formation. Molecular nitrogen is a leaving group par excel-
lence, and the reaction products arise by solvolysis of the diazonium ion. Usually, a car-
bocation intermediate is involved.
Figure 22.5 shows what happens when a typical primary alkylamine reacts with nitrous
acid.
Since nitrogen-free products result from the formation and decomposition of dia-
zonium ions, these reactions are often referred to as deamination reactions. Alkyl dia-
zonium ions are rarely used in synthetic work but have been studied extensively to probe
the behavior of carbocations generated under conditions in which the leaving group is
lost rapidly and irreversibly.
PROBLEM 22.16 Nitrous acid deamination of 2,2-dimethylpropylamine,
(CH
3
)
3
CCH
2
NH
2
, gives the same products as were indicated as being formed from
1,1-dimethylpropylamine in Figure 22.5. Suggest a mechanism for the formation
of these compounds from 2,2-dimethylpropylamine.
Aryl diazonium ions, prepared by nitrous acid diazotization of primary arylamines,
are substantially more stable than alkyl diazonium ions and are of enormous synthetic
value. Their use in the synthesis of substituted aromatic compounds is described in the
following two sections.
The nitrosation of tertiary alkylamines is rather complicated, and no generally use-
ful chemistry is associated with reactions of this type.
RN
H11001
N
Alkyl diazonium ion
R
H11001
Carbocation
H11001 NN
Nitrogen
890 CHAPTER TWENTY-TWO Amines
Recall from Section 8.14 that
decreasing basicity is associ-
ated with increasing leaving-
group ability. Molecular
nitrogen is an exceedingly
weak base and an excellent
leaving group.
Nitrogen
HONO
CH
3
CH
?
C(CH
3
)
2
H11001 CH
3
CH
2
C
?
CH
2
H11001 CH
3
CH
2
CCH
3
H11001
H11002H
H11001
H11001
1,1-Dimethylpropylamine 1,1-Dimethylpropyl
diazonium ion
1,1-Dimethylpropyl
cation
H
2
O
W
CH
3
2-Methyl-2-butene
(2%)
2-Methyl-1-butene
(3%)
2-Methyl-2-butanol
(80%)
CH
3
CH
2
CCH
3
CH
3
W
W
NH
2
CH
3
CH
2
CCH
3
CH
3
CH
2
CCH
3
CH
3
W
W
N
H11001
?
N
CH
3
W
N
P
N
CH
3
W
W
OH
FIGURE 22.5 The diazonium
ion generated by treatment
of a primary alkylamine with
nitrous acid loses nitrogen
to give a carbocation. The
isolated products are
derived from the carboca-
tion and include, in this
example, alkenes (by loss of
a proton) and an alcohol
(nucleophilic capture by
water).
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22.17 NITROSATION OF ARYLAMINES
We learned in the preceding section that different reactions are observed when the var-
ious classes of alkylamines—primary, secondary, and tertiary—react with nitrosating
agents. Although no useful chemistry attends the nitrosation of tertiary alkylamines, elec-
trophilic aromatic substitution by nitrosyl cation takes place with N,N-dialkyl-
arylamines.
Nitrosyl cation is a relatively weak electrophile and attacks only very strongly activated
aromatic rings.
N-Alkylarylamines resemble secondary alkylamines in that they form N-nitroso
compounds on reaction with nitrous acid.
Primary arylamines, like primary alkylamines, form diazonium ion salts on nitro-
sation. Aryl diazonium ions are considerably more stable than their alkyl counterparts.
Whereas alkyl diazonium ions decompose under the conditions of their formation, aryl
diazonium salts are stable enough to be stored in aqueous solution at 0–5°C for reason-
able periods of time. Loss of nitrogen from an aryl diazonium ion generates an unstable
aryl cation and is much slower than loss of nitrogen from an alkyl diazonium ion.
Aryl diazonium ions undergo a variety of reactions that make them versatile inter-
mediates for the preparation of a host of ring-substituted aromatic compounds. In these
reactions, summarized in Figure 22.6 and discussed individually in the following sec-
tion, molecular nitrogen acts as a leaving group and is replaced by another atom or group.
All the reactions are regiospecific; the entering group becomes bonded to precisely the
ring position from which nitrogen departs.
C
6
H
5
NH
2
Aniline
NaNO
2
, HCl
H
2
O, 0–5°C
Benzenediazonium chloride
NC
6
H
5
N
H11001
Cl
H11002
NaNO
2
, H
2
SO
4
H
2
O, 0–5°C
NH
2
(CH
3
)
2
CH
p-Isopropylaniline p-Isopropylbenzenediazonium
hydrogen sulfate
(CH
3
)
2
CH N
H11001
N HSO
4
H11002
C
6
H
5
NHCH
3
N-Methylaniline
NaNO
2
, HCl
H
2
O, 10°C
NC
6
H
5
N O
CH
3
N-Methyl-N-nitrosoaniline (87–93%)
N(CH
2
CH
3
)
2
N,N-Diethylaniline
N(CH
2
CH
3
)
2
N
O
N,N-Diethyl-p-nitrosoaniline (95%)
1. NaNO
2
, HCl, H
2
O, 8°C
2. HO
H11002
NPO()
H11001
22.17 Nitrosation of Arylamines 891
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22.18 SYNTHETIC TRANSFORMATIONS OF ARYL DIAZONIUM SALTS
An important reaction of aryl diazonium ions is their conversion to phenols by hydrolysis:
This is the most general method for preparing phenols. It is easily performed; the aqueous
acidic solution in which the diazonium salt is prepared is heated and gives the phenol directly.
An aryl cation is probably generated, which is then captured by water acting as a nucleophile.
Sulfuric acid is normally used instead of hydrochloric acid in the diazotization step so
as to minimize the competition with water for capture of the cationic intermediate.
Hydrogen sulfate anion (HSO
4
H11002
) is less nucleophilic than chloride.
PROBLEM 22.17 Design a synthesis of m-bromophenol from benzene.
The reaction of an aryl diazonium salt with potassium iodide is the standard method
for the preparation of aryl iodides. The diazonium salt is prepared from a primary aro-
matic amine in the usual way, a solution of potassium iodide is then added, and the reac-
tion mixture is brought to room temperature or heated to accelerate the reaction.
NH
2
Br
o-Bromoaniline
I
Br
o-Bromoiodobenzene (72–83%)
NaNO
2
, HCl, H
2
O, 0–5°C
KI, room temperature
Ar N
H11001
N
Aryl diazonium
ion
ArI
Aryl
iodide
I
H11002
Iodide
ion
H11001 H11001 NN
Nitrogen
1. NaNO
2
, H
2
SO
4
, H
2
O
2. H
2
O, heat
NH
2
(CH
3
)
2
CH
p-Isopropylaniline
(CH
3
)
2
CH OH
p-Isopropylphenol (73%)
ArN
H11001
N
Aryl diazonium ion
ArOH
A phenol
H
H11001
H
2
O
Water
H11001H11001H11001 NN
Nitrogen
892 CHAPTER TWENTY-TWO Amines
ArH ArNO
2
ArNH
2
H
2
O
KI
1. HBF
4
2. heat
Ar
±
N
P
N
:
+
Aryl
diazonium
ion
Schiemann
reaction
Sandmeyer
reactions
ArOH
ArI
ArF
ArCl
ArBr
ArCN
ArH
CuCl
CuCN
CuBr
H
3
PO
2
or
CH
3
CH
2
OH
FIGURE 22.6 Flowchart
showing the synthetic origin
of aryl diazonium ions and
their most useful transfor-
mations.
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PROBLEM 22.18 Show by a series of equations how you could prepare
m-bromoiodobenzene from benzene.
Diazonium salt chemistry provides the principal synthetic method for the prepara-
tion of aryl fluorides through a process known as the Schiemann reaction. In this pro-
cedure the aryl diazonium ion is isolated as its fluoroborate salt, which then yields the
desired aryl fluoride on being heated.
A standard way to form the aryl diazonium fluoroborate salt is to add fluoroboric acid
(HBF
4
) or a fluoroborate salt to the diazotization medium.
PROBLEM 22.19 Show the proper sequence of synthetic transformations in the
conversion of benzene to ethyl m-fluorophenyl ketone.
Although it is possible to prepare aryl chlorides and aryl bromides by electrophilic
aromatic substitution, it is often necessary to prepare these compounds from an aromatic
amine. The amine is converted to the corresponding diazonium salt and then treated with
copper(I) chloride or copper(I) bromide as appropriate.
ArX
Aryl chloride
or bromide
Aryl diazonium
ion
Ar N
H11001
N H11001 NN
Nitrogen
CuX
1. NaNO
2
, HCl, H
2
O, 0–5°C
2. CuCl, heat
NH
2
NO
2
m-Nitroaniline
Cl
NO
2
m-Chloronitrobenzene (68–71%)
1. NaNO
2
, HBr, H
2
O, 0–10°C
2. CuBr, heat
Cl
NH
2
o-Chloroaniline
Cl
Br
o-Bromochlorobenzene (89–95%)
1. NaNO
2
, H
2
O, HCl
2. HBF
4
3. heat
NH
2
O
CCH
2
CH
3
m-Aminophenyl ethyl ketone
F
O
CCH
2
CH
3
Ethyl m-fluorophenyl ketone (68%)
ArF
Aryl
fluoride
BF
3
Boron
trifluoride
Aryl diazonium
fluoroborate
Ar N
H11001
N BF
4
H11002
H11001 H11001 NN
Nitrogen
heat
22.18 Synthetic Transformations of Aryl Diazonium Salts 893
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Reactions that employ copper(I) salts as reagents for replacement of nitrogen in diazo-
nium salts are called Sandmeyer reactions. The Sandmeyer reaction using copper(I)
cyanide is a good method for the preparation of aromatic nitriles:
Since cyano groups may be hydrolyzed to carboxylic acids (Section 20.19), the Sand-
meyer preparation of aryl nitriles is a key step in the conversion of arylamines to sub-
stituted benzoic acids. In the example just cited, the o-methylbenzonitrile that was formed
was subsequently subjected to acid-catalyzed hydrolysis and gave o-methylbenzoic acid
in 80–89 percent yield.
The preparation of aryl chlorides, bromides, and cyanides by the Sandmeyer reac-
tion is mechanistically complicated and may involve arylcopper intermediates.
It is possible to replace amino substituents on an aromatic nucleus by hydrogen by
reducing a diazonium salt with hypophosphorous acid (H
3
PO
2
) or with ethanol. These
reductions are free-radical reactions in which ethanol or hypophosphorous acid acts as a
hydrogen atom donor:
Reactions of this type are called reductive deaminations.
Sodium borohydride has also been used to reduce aryl diazonium salts in reductive deam-
ination reactions.
NaNO
2
, H
2
SO
4
, H
2
O
H
3
PO
2
CH
3
NH
2
o-Toluidine
CH
3
Toluene (70–75%)
NaNO
2
, HCl, H
2
O
CH
3
CH
2
OH
CH(CH
3
)
2
NO
2
NH
2
4-Isopropyl-2-nitroaniline
CH(CH
3
)
2
NO
2
m-Isopropylnitrobenzene (59%)
ArH
AreneAryl diazonium
ion
Ar N
H11001
N H11001 NN
Nitrogen
H
3
PO
2
or
CH
3
CH
2
OH
ArCN
Aryl
nitrile
Aryl diazonium
ion
Ar N
H11001
N H11001 NN
Nitrogen
CuCN
1. NaNO
2
, HCl, H
2
O, 0°C
2. CuCN, heat
CH
3
NH
2
o-Toluidine
CH
3
CN
o-Methylbenzonitrile (64–70%)
894 CHAPTER TWENTY-TWO Amines
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PROBLEM 22.20 Cumene (isopropylbenzene) is a relatively inexpensive com-
mercially available starting material. Show how you could prepare m-isopropyl-
nitrobenzene from cumene.
The value of diazonium salts in synthetic organic chemistry rests on two main
points. Through the use of diazonium salt chemistry:
1. Substituents that are otherwise accessible only with difficulty, such as fluoro, iodo,
cyano, and hydroxyl, may be introduced onto a benzene ring.
2. Compounds that have substitution patterns not directly available by electrophilic
aromatic substitution can be prepared.
The first of these two features is readily apparent and is illustrated by Problems 22.17
to 22.19. If you have not done these problems yet, you are strongly encouraged to attempt
them now.
The second point is somewhat less obvious but is readily illustrated by the syn-
thesis of 1,3,5-tribromobenzene. This particular substitution pattern cannot be obtained
by direct bromination of benzene, because bromine is an ortho, para director. Instead,
advantage is taken of the powerful activating and ortho, para-directing effects of the
amino group in aniline. Bromination of aniline yields 2,4,6-tribromoaniline in quantita-
tive yield. Diazotization of the resulting 2,4,6-tribromoaniline and reduction of the dia-
zonium salt gives the desired 1,3,5-tribromobenzene.
To exploit the synthetic versatility of aryl diazonium salts, be prepared to reason
backward. When you see a fluorine substituent in a synthetic target, for example, real-
ize that it probably will have to be introduced by a Schiemann reaction of an arylamine;
realize that the required arylamine is derived from a nitroarene, and that the nitro group
is introduced by nitration. Be aware that an unsubstituted position of an aromatic ring
need not have always been that way. It might once have borne an amino group that was
used to control the orientation of electrophilic aromatic substitution reactions before
being removed by reductive deamination. The strategy of synthesis is intellectually
demanding, and a considerable sharpening of your reasoning power can be gained by
attacking the synthesis problems at the end of each chapter. Remember, plan your
sequence of accessible intermediates by reasoning backward from the target; then fill in
the details on how each transformation is to be carried out.
22.19 AZO COUPLING
A reaction of aryl diazonium salts that does not involve loss of nitrogen takes place when
they react with phenols and arylamines. Aryl diazonium ions are relatively weak
NaNO
2
, H
2
SO
4
,
H
2
O
CH
3
CH
2
OH
Br
2
H
2
O
NH
2
Aniline
NH
2
BrBr
Br
2,4,6-Tribromoaniline (100%)
BrBr
Br
1,3,5-Tribromobenzene
(74–77%)
22.19 Azo Coupling 895
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electrophiles but have sufficient reactivity to attack strongly activated aromatic rings. The
reaction is known as azo coupling; two aryl groups are joined together by an azo
(±N?N±) function.
Azo compounds are often highly colored, and many of them are used as dyes.
896 CHAPTER TWENTY-TWO Amines
H11002H
H11001
H
ERG
(ERG is a powerful
electron-releasing
group such as ±OH
or ±NR
2
)
N
H11001
NAr
Aryl
diazonium
ion
ERG
H
N
H11001
NAr
Intermediate in
electrophilic
aromatic
substitution
ERG
N NAr
Azo compound
FROM DYES TO SULFA DRUGS
T
he medicine cabinet was virtually bare of an-
tibacterial agents until sulfa drugs burst on the
scene in the 1930s. Before sulfa drugs became
available, bacterial infection might transform a small
cut or puncture wound to a life-threatening event.
The story of how sulfa drugs were developed is an in-
teresting example of being right for the wrong rea-
sons. It was known that many bacteria absorbed dyes,
and staining was a standard method for making bac-
teria more visible under the microscope. Might there
not be some dye that is both absorbed by bacteria
and toxic to them? Acting on this hypothesis, scien-
tists at the German dyestuff manufacturer I. G. Far-
benindustrie undertook a program to test the thou-
sands of compounds in their collection for their
antibacterial properties.
In general, in vitro testing of drugs precedes in
vivo testing. The two terms mean, respectively, “in
glass” and “in life.” In vitro testing of antibiotics is car-
ried out using bacterial cultures in test tubes or Petri
dishes. Drugs that are found to be active in vitro
progress to the stage of in vivo testing. In vivo testing
is carried out in living organisms: laboratory animals or
human volunteers. The I. G. Farben scientists found
that some dyes did possess antibacterial properties,
both in vitro and in vivo. Others were active in vitro
but were converted to inactive substances in vivo and
therefore of no use as drugs. Unexpectedly, an azo dye
called Prontosil was inactive in vitro but active in vivo.
In 1932, a member of the I. G. Farben research group,
Gerhard Domagk used Prontosil to treat a young child
suffering from a serious, potentially fatal staphylococ-
cal infection. According to many accounts, the child
was Domagk’s own daughter; her infection was cured
and her recovery was rapid and complete. Systematic
testing followed and Domagk was awarded the 1939
Nobel Prize in medicine or physiology.
In spite of the rationale on which the testing of
dyestuffs as antibiotics rested, subsequent research
revealed that the antibacterial properties of Prontosil
had nothing at all to do with its being a dye! In the
body, Prontosil undergoes a reductive cleavage of its
azo linkage to form sulfanilamide, which is the sub-
stance actually responsible for the observed biologi-
cal activity. This is why Prontosil is active in vivo, but
not in vitro.
NH
2
H
2
N NN SO
2
NH
2
Prontosil
in vivo
SO
2
NH
2
H
2
N
Sulfanilamide
—Cont.
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The colors of azo compounds vary with the nature of the aryl group, with its substituents,
and with pH. Substituents also affect the water-solubility of azo dyes and how well they
bind to a particular fabric. Countless combinations of diazonium salts and aromatic sub-
strates have been examined with a view toward obtaining azo dyes suitable for a par-
ticular application.
22.20 SPECTROSCOPIC ANALYSIS OF AMINES
Infrared: The absorptions of interest in the infrared spectra of amines are those asso-
ciated with N±H vibrations. Primary alkyl- and arylamines exhibit two peaks in the
range 3000–3500 cm
H110021
, which are due to symmetric and antisymmetric N±H stretch-
ing modes.
R
H
H
N R
H
H
N
Symmetric N±H
stretching of a
primary amine
Antisymmetric N±H
stretching of a
primary amine
OH
1-Naphthol
H11001 Cl
H11002
H11001
C
6
H
5
NN
Benzenediazonium
chloride
OH
N NC
6
H
5
2-(Phenylazo)-1-naphthol
22.20 Spectroscopic Analysis of Amines 897
We tend to take the efficacy of modern drugs
for granted. One comparison with the not-too-
distant past might put this view into better perspec-
tive. Once sulfa drugs were introduced in the United
States, the number of pneumonia deaths alone de-
creased by an estimated 25,000 per year. The sulfa
drugs are used less now than they were in the mid-
twentieth century. Not only are more-effective, less-
toxic antibiotics available, such as the penicillins and
tetracyclines, but many bacteria that were once sus-
ceptible to sulfa drugs have become resistant.
N
S
SO
2
NHH
2
N
Sulfathiazole
N
N
SO
2
NHH
2
N
Sulfadiazine
Bacteria require p-aminobenzoic acid in order to
biosynthesize folic acid, a growth factor. Structurally,
sulfanilamide resembles p-aminobenzoic acid and is
mistaken for it by the bacteria. Folic acid biosynthesis
is inhibited and bacterial growth is slowed sufficiently
to allow the body’s natural defenses to effect a cure.
Since animals do not biosynthesize folic acid but ob-
tain it in their food, sulfanilamide halts the growth of
bacteria without harm to the host.
Identification of the mechanism by which Pron-
tosil combats bacterial infections was an early tri-
umph of pharmacology, a branch of science at the in-
terface of physiology and biochemistry that studies
the mechanism of drug action. By recognizing that
sulfanilamide was the active agent, the task of
preparing structurally modified analogs with poten-
tially superior properties was considerably simplified.
Instead of preparing Prontosil analogs, chemists syn-
thesized sulfanilamide analogs. They did this with a
vengeance; over 5000 compounds related to sulfanil-
amide were prepared during the period 1935–1946.
Two of the most widely used sulfa drugs are sulfathi-
azole and sulfadiazine.
A number of pH indicators—
methyl red, for example—
are azo compounds.
The symmetric and anti-
symmetric stretching vibrations
of methylamine can be viewed
on Learning By Modeling.
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These two vibrations are clearly visible at 3270 and 3380 cm
H110021
in the infrared spec-
trum of butylamine, shown in Figure 22.7a. Secondary amines such as diethylamine, shown
in Figure 22.7b, exhibit only one peak, which is due to N±H stretching, at 3280 cm
H110021
.
Tertiary amines, of course, are transparent in this region, since they have no N±H bonds.
898 CHAPTER TWENTY-TWO Amines
Transmittance (%)Transmittance (%)
Wave number, cm
H110021
(a)
CH
3
CH
2
CH
2
CH
2
NH
2
(b)
(CH
3
CH
2
)
2
NH
4000 3500 3000 25004000 3500 3000 2500
CH
2
NH
2
W
ArH
CH
2
N
CH
3
NH
2
W
CH
3
6.0 5.0 4.0 3.0 2.0 1.0 07.08.09.0
(a)
Chemical shift (δ, ppm)
FIGURE 22.7 Portions
of the infrared spectrum of
(a) butylamine and (b) di-
ethylamine. Primary amines
exhibit two peaks due to
N±H stretching, whereas
secondary amines show only
one.
FIGURE 22.8 The 200-MHz
1
H NMR spectra of (a) 4-
methylbenzylamine and of
(b) 4-methylbenzyl alcohol.
The singlet corresponding to
CH
2
N in (a) is more shielded
than that of CH
2
O in (b).
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22.20 Spectroscopic Analysis of Amines 899
CH
2
OH
W
W
CH
3
ArH
CH
2
O
CH
3
OH
5.0 4.0 3.0 2.0 1.0 06.07.08.09.0
Chemical shift (δ, ppm)
(Figure 22.8b)
1
H NMR: Characteristics of the nuclear magnetic resonance spectra of amines may be
illustrated by comparing 4-methylbenzylamine (Figure 22.8a) with 4-methylbenzyl alco-
hol (Figure 22.8b). Nitrogen is less electronegative than oxygen and so shields neigh-
boring nuclei to a greater extent. The benzylic methylene group attached to nitrogen in
4-methylbenzylamine appears at higher field (H9254 3.8 ppm) than the benzylic methylene of
4-methylbenzyl alcohol (H9254 4.6 ppm). The N±H protons are somewhat more shielded
than the O±H protons of an alcohol. In 4-methylbenzylamine the protons of the amino
group correspond to the signal at H9254 1.5 ppm, whereas the hydroxyl proton signal of 4-
methylbenzyl alcohol is found at H9254 2.1 ppm. The chemical shifts of amino group pro-
tons, like those of hydroxyl protons, are variable and are sensitive to solvent, concen-
tration, and temperature.
13
C NMR: Similarly, carbons that are bonded to nitrogen are more shielded than those
bonded to oxygen, as revealed by comparing the
13
C chemical shifts of methylamine and
methanol.
UV-VIS: In the absence of any other chromophore, the UV-Vis spectrum of an alkyl-
amine is not very informative. The longest wavelength absorption involves promoting
one of the unshared electrons of nitrogen to an antibonding H9268 orbital (n → H9268*) with a
H9261
max
in the relatively inaccessible region near 200 nm. Arylamines are a different story.
26.9 ppm CH
3
NH
2
Methylamine
48.0 ppm CH
3
OH
Methanol
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There the interaction of the nitrogen lone pair with the H9266-electron system of the ring
shifts the ring’s absorptions to longer wavelength. Tying up the lone pair by protonation
causes the UV-Vis spectrum of anilinium ion to resemble benzene.
Mass Spectrometry: A number of features make amines easily identifiable by mass
spectrometry.
First, the peak for the molecular ion M
H11001
for all compounds that contain only car-
bon, hydrogen, and oxygen has an m/z value that is an even number. The presence of a
nitrogen atom in the molecule requires that the m/z value for the molecular ion be odd.
An odd number of nitrogens corresponds to an odd value of the molecular weight; an
even number of nitrogens corresponds to an even molecular weight.
Second, nitrogen is exceptionally good at stabilizing adjacent carbocation sites. The
fragmentation pattern seen in the mass spectra of amines is dominated by cleavage of
groups from the carbon atom attached to the nitrogen, as the data for the following pair
of constitutionally isomeric amines illustrate:
22.21 SUMMARY
Section 22.1 Alkylamines are compounds of the type shown, where R, RH11032, and RH11033 are
alkyl groups. One or more of these groups is an aryl group in arylamines.
Alkylamines are named in two ways. One method adds the ending -amine
to the name of the alkyl group. The other applies the principles of sub-
stitutive nomenclature by replacing the -e ending of an alkane name by
-amine and uses appropriate locants to identify the position of the amino
group. Arylamines are named as derivatives of aniline.
Section 22.2 Nitrogen’s unshared electron pair is of major importance in understand-
ing the structure and properties of amines. Alkylamines have a pyrami-
dal arrangement of bonds to nitrogen, and the unshared electron pair
N
R
H
H H
Primary amine
N
R
RH11032
Secondary amine
R
RH11032
RH11033
N
Tertiary amine
X
Benzene
Aniline
Anilinium ion
X
H
NH
2
NH
3
H11001
204, 256
230, 280
203, 254
H9261
max
, nm
900 CHAPTER TWENTY-TWO Amines
(CH
3
)
2
NCH
2
CH
2
CH
2
CH
3
N,N-Dimethyl-1-butanamine
e
H11002
(CH
3
)
2
N
H11001
CH
2
CH
2
CH
2
CH
3
M
H11001
(m/z 101)
CH
2
(CH
3
)
2
N
H11001
(m/z 58)
(most intense peak)
H11001 CH
2
CH
2
CH
3
e
H11002
CH
3
NH
H11001
CH
2
CH
2
CH(CH
3
)
2
M
H11001
(m/z 101)
CH
2
CH(CH
3
)
2
CH
3
NHCH
2
CH
2
CH(CH
3
)
2
N,3-Dimethyl-1-butanamine
CH
2
CH
3
NH
H11001
(m/z 44)
(most intense peak)
H11001
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resides in an sp
3
-hybridized orbital. The geometry at nitrogen in aryl-
amines is somewhat flatter than in alkylamines, and the unshared elec-
tron pair is delocalized into the H9266 system of the ring. Delocalization binds
the electron pair more strongly in arylamines than in alkylamines. Aryl-
amines are less basic and less nucleophilic than alkylamines.
Section 22.3 Amines are less polar than alcohols. Hydrogen bonding in amines is
weaker than in alcohols because nitrogen is less electronegative than oxy-
gen. Amines have lower boiling points than alcohols, but higher boiling
points than alkanes. Primary amines have higher boiling points than iso-
meric secondary amines; tertiary amines, which cannot form intermolec-
ular hydrogen bonds, have the lowest boiling points. Amines resemble
alcohols in their solubility in water.
Section 22.4 Basicity of amines is expressed either as a basicity constant K
b
(pK
b
) of
the amine or as a dissociation constant K
a
(pK
a
) of its conjugate acid.
Section 22.5 The basicity constants of alkylamines lie in the range 10
H110023
–10
H110025
. Aryl-
amines are much weaker bases, with K
b
values in the 10
H110029
–10
H1100211
range.
Section 22.6 Quaternary ammonium salts, compounds of the type R
4
N
H11001
X
H11002
, find
application in a technique called phase-transfer catalysis. A small
amount of a quaternary ammonium salt promotes the transfer of an anion
from aqueous solution, where it is highly solvated, to an organic solvent,
where it is much less solvated and much more reactive.
Sections Methods for the preparation of amines are summarized in Table 22.5.
22.7–22.11
CH
2
NH
2
Benzylamine
(alkylamine: pK
b
H11005 4.7)
NHCH
3
N-Methylaniline
(arylamine: pK
b
H11005 11.8)
R
3
N H11001 H
2
OR
3
NH
H11001
H11001 HO
H11002
K
b
H11005
[R
3
NH][HO
H11002
]
[R
3
N]
H11001
22.21 Summary 901
TABLE 22.5 Preparation of Amines
Reaction (section) and comments
Alkylation of ammonia (Section 22.8)
Ammonia can act as a nucleophile toward
primary and some secondary alkyl halides
to give primary alkylamines. Yields tend
to be modest because the primary amine
is itself a nucleophile and undergoes
alkylation. Alkylation of ammonia can
lead to a mixture containing a primary
amine, a secondary amine, a tertiary
amine, and a quaternary ammonium salt.
(Continued)
Alkylation methods
General equation and specific example
Alkylamine
RNH
2
Ammonium halide
NH
4
XRX
Alkyl
halide
2NH
3
Ammonia
H11001H11001
Dibenzylamine
(39%)
(C
6
H
5
CH
2
)
2
NH
NH
3
(8 mol)
C
6
H
5
CH
2
Cl
Benzyl chloride
(1 mol)
C
6
H
5
CH
2
NH
2
Benzylamine
(53%)
H11001
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902 CHAPTER TWENTY-TWO Amines
TABLE 22.5 Preparation of Amines (Continued)
Reaction (section) and comments
Alkylation of phthalimide. The Gabriel
synthesis (Section 22.9) The potassium
salt of phthalimide reacts with alkyl hal-
ides to give N-alkylphthalimide deriva-
tives. Hydrolysis or hydrazinolysis of this
derivative yields a primary alkylamine.
Reduction of alkyl azides (Section 22.10)
Alkyl azides, prepared by nucleophilic
substitution by azide ion in primary or
secondary alkyl halides, are reduced to
primary alkylamines by lithium aluminum
hydride or by catalytic hydrogenation.
Reduction of nitriles (Section 22.10)
Nitriles are reduced to primary amines by
lithium aluminum hydride or by catalytic
hydrogenation.
(Continued)
Reduction methods
General equation and specific example
1. N-potassiophthalimide, DMF
2. H
2
NNH
2
, ethanol
CH
3
CH?CHCH
2
Cl
1-Chloro-2-butene
CH
3
CH?CHCH
2
NH
2
2-Buten-1-amine (95%)
H11001RX
Alkyl
halide
O
O
N
H11002
K
H11001
N-Potassiophthalimide
O
O
NR
N-Alkylphthalimide
H11001H11001 H
2
NNH
2
Hydrazine
RNH
2
Primary
amine
O
O
NR
N-Alkylphthalimide Phthalhydrazide
NH
NH
O
O
Alkyl azide
RN?N?N
H11002
H11001
Primary amine
RNH
2
reduce
Nitrile
RCPN
Primary amine
RCH
2
NH
2
reduce
Ethyl 2-azido-4,4,4-
trifluorobutanoate
CF
3
CH
2
CHCO
2
CH
2
CH
3
W
N
3
Ethyl 2-amino-4,4,4-
trifluorobutanoate (96%)
CF
3
CH
2
CHCO
2
CH
2
CH
3
W
NH
2
H
2
, Pd
1. LiAlH
4
2. H
2
O
CN
Cyclopropyl cyanide
CH
2
NH
2
Cyclopropylmethanamine
(75%)
Reduction of aryl nitro compounds (Sec-
tion 22.10) The standard method for the
preparation of an arylamine is by nitra-
tion of an aromatic ring, followed by
reduction of the nitro group. Typical
reducing agents include iron or tin in
hydrochloric acid or catalytic hydrogena-
tion.
Nitroarene
ArNO
2
Arylamine
ArNH
2
reduce
Nitrobenzene
C
6
H
5
NO
2
Aniline (97%)
C
6
H
5
NH
2
1. Fe, HCl
2. HO
H11002
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Sections The reactions of amines are summarized in Tables 22.6 and 22.7.
22.12–22.19
Section 22.20 The N±H stretching frequency of primary and secondary amines appears
in the infrared in the 3000–3500 cm
H110021
region. In the NMR spectra of
amines, protons and carbons of the type H±C±N are more shielded
than H±C±O.
Amines have odd-numbered molecular weights, which helps identify
them by mass spectrometry. Fragmentation tends to be controlled by the
formation of a nitrogen-stabilized cation.
CN
H11001
N
H11001
C C H11001 C
H9254 3.8 ppm
H9254 47 ppm
CH
3
C NH
2
H
H
H9254 4.6 ppm
H9254 65 ppm
CH
3
C OH
H
H
22.21 Summary 903
TABLE 22.5 Preparation of Amines (Continued)
Reaction (section) and comments
Reduction of amides (Section 22.10) Lithi-
um aluminum hydride reduces the car-
bonyl group of an amide to a methylene
group. Primary, secondary, or tertiary
amines may be prepared by proper choice
of the starting amide. R and RH11032 may be
either alkyl or aryl.
Reductive amination (Section 22.11) Reac-
tion of ammonia or an amine with an
aldehyde or a ketone in the presence of a
reducing agent is an effective method for
the preparation of primary, secondary, or
tertiary amines. The reducing agent may
be either hydrogen in the presence of a
metal catalyst or sodium cyanoborohy-
dride. R, RH11032, and RH11033 may be either alkyl or
aryl.
General equation and specific example
Amine
RCH
2
NRH11032
2
Amide
RCNRH11032
2
O
X
reduce
Amine
RCRH11032
W
W
NRH11033
2
H
Aldehyde
or ketone
RCRH11032
O
X
Ammonia or
an amine
RH11033
2
NHH11001
reducing
agent
N-Ethyl-tert-butylamine (60%)
CH
3
CH
2
NHC(CH
3
)
3
N-tert-Butylacetamide
CH
3
CNHC(CH
3
)
3
O
X
1. LiAlH
4
2. H
2
O
Acetone
CH
3
CCH
3
O
X
H11001
NH
2
Cyclohexylamine
HNCH(CH
3
)
2
N-Isopropylcyclohexylamine
(79%)
H
2
, Pt
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904 CHAPTER TWENTY-TWO Amines
TABLE 22.6 Reactions of Amines Discussed in This Chapter
Reaction (section) and comments
Alkylation (Section 22.13) Amines
act as nucleophiles toward alkyl
halides. Primary amines yield sec-
ondary amines, secondary amines
yield tertiary amines, and tertiary
amines yield quaternary ammoni-
um salts.
Hofmann elimination (Section
22.14) Quaternary ammonium
hydroxides undergo elimination
on being heated. It is an anti elim-
ination of the E2 type. The regio-
selectivity of the Hofmann elimi-
nation is opposite to that of the
Zaitsev rule and leads to the less
highly substituted alkene.
Electrophilic aromatic substitution
(Section 22.15) Arylamines are
very reactive toward electrophilic
aromatic substitution. It is custom-
ary to protect arylamines as their
N-acyl derivatives before carrying
out ring nitration, chlorination,
bromination, sulfonation, or Frie-
del–Crafts reactions.
(Continued)
General equation and specific example
Arylamine
ArH
Product of electrophilic
aromatic substitution
ArE
Electrophile
E
H11001
Proton
H
H11001
H11001H11001
RH11032CH
2
X
RH11032CH
2
X
Primary amine
RNH
2
Secondary amine
RNHCH
2
RH11032
RH11032CH
2
X
Quaternary
ammonium salt
RN(CH
2
RH11032)
3
X
H11002
H11001
Tertiary amine
RN(CH
2
RH11032)
2
H11001
heat
2-(Pyrrolidinylmethyl)pyridine (93%)
N
N
CH
2
Pyrrolidine
HN
2-Chloromethylpyridine
N
CH
2
Cl
Water
H
2
OH11001H11001
Trimethylamine
N(CH
3
)
3
Alkyltrimethylammonium
hydroxide
RCH
2
CHRH11032 HO
H11002
H11001
N(CH
3
)
3
W
Alkene
RCH?CHRH11032
heat
heat
N(CH
3
)
3
HO
H11002
H11001
Cycloheptyltrimethylammonium
hydroxide
Cycloheptene (87%)
2Br
2
acetic acid
p-Nitroaniline
NH
2
NO
2
Br
NH
2
NO
2
Br
2,6-Dibromo-4-nitroaniline
(95%)
Nitrosation (Section 22.16) Nitro-
sation of amines occurs when
sodium nitrite is added to a solu-
tion containing an amine and an
acid. Primary amines yield alkyl
diazonium salts. Alkyl diazonium
salts are very unstable and yield
carbocation-derived products. Aryl
diazonium salts are exceedingly
useful synthetic intermediates.
Their reactions are described in
Table 22.7.
NaNO
2
H
H11001
, H
2
O
Primary amine
RNH
2
Diazonium ion
RNPN
H11001
NaNO
2
, H
2
SO
4
H
2
O, 0–5°C
HSO
4
H11002
NO
2
NPN
H11001
m-Nitrobenzenediazonium
hydrogen sulfate
NO
2
NH
2
m-Nitroaniline
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22.21 Summary 905
TABLE 22.6 Reactions of Amines Discussed in This Chapter (Continued)
Reaction (section) and comments
Secondary alkylamines and secon-
dary arylamines yield N-nitroso
amines.
Tertiary alkylamines illustrate no
useful chemistry on nitrosation.
Tertiary arylamines undergo nitro-
sation of the ring by electrophilic
aromatic substitution.
General equation and specific example
NaNO
2
, H
H11001
H
2
O
Secondary amine
R
2
NH
N-Nitroso amine
R
2
N±N?O
NaNO
2
, HCl
H
2
O
NO
CH
3
N CH
3
2,6-Dimethyl-N-
nitrosopiperidine (72%)
CH
3
N
H
CH
3
2,6-Dimethylpiperidine
NaNO
2
, HCl
H
2
O
(CH
3
)
2
N
N,N-Dimethylaniline
(CH
3
)
2
N N O
N,N-Dimethyl-4-nitrosoaniline
(80–89%)
TABLE 22.7 Synthetically Useful Transformations Involving Aryl Diazonium Ions
Reaction and comments
Preparation of phenols Heating its
aqueous acidic solution converts a
diazonium salt to a phenol. This is
the most general method for the
synthesis of phenols.
Preparation of aryl fluorides Addi-
tion of fluoroboric acid to a solu-
tion of a diazonium salt causes the
precipitation of an aryl diazonium
fluoroborate. When the dry aryl
diazonium fluoroborate is heated,
an aryl fluoride results. This is the
Schiemann reaction; it is the most
general method for the prepara-
tion of aryl fluorides.
(Continued)
General equation and specific example
1. NaNO
2
, H
2
SO
4
, H
2
O
2. H
2
O, heat
Primary
arylamine
ArNH
2
Phenol
ArOH
1. NaNO
2
, H
2
SO
4
, H
2
O
2. H
2
O, heat
NH
2
NO
2
m-Nitroaniline
OH
NO
2
m-Nitrophenol (81–86%)
Aryl diazonium
fluoroborate
BF
4
H11002
ArNPN
H11001
Primary
arylamine
ArNH
2
Aryl
fluoride
ArF
1. NaNO
2
, H
H11001
, H
2
O
2. HBF
4
heat
NH
2
CH
3
m-Toluidine
NPN
CH
3
H11001
BF
4
H11002
m-Methylbenzenediazonium
fluoroborate (76–84%)
1. NaNO
2
, HCl, H
2
O
2. HBF
4
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906 CHAPTER TWENTY-TWO Amines
TABLE 22.7 Synthetically Useful Transformations Involving Aryl Diazonium Ions (Continued)
Reaction and comments
Preparation of aryl chlorides In the
Sandmeyer reaction a solution con-
taining an aryl diazonium salt is
treated with copper(I) chloride to
give an aryl chloride.
Preparation of aryl bromides The
Sandmeyer reaction using cop-
per(I) bromide is applicable to the
conversion of primary arylamines
to aryl bromides.
General equation and specific example
Primary
arylamine
ArNH
2
Aryl chloride
ArCl
1. NaNO
2
, HCl, H
2
O
2. CuCl
Primary
arylamine
ArNH
2
Aryl bromide
ArBr
1. NaNO
2
, HBr, H
2
O
2. CuBr
o-Toluidine
NH
2
CH
3
o-Chlorotoluene
(74–79%)
Cl
CH
3
1. NaNO
2
, HCl, H
2
O
2. CuCl
m-Bromoaniline
NH
2
Br
m-Dibromobenzene
(80–87%)
Br
Br
1. NaNO
2
, HBr, H
2
O
2. CuBr
Preparation of aryl iodides Aryl
diazonium salts react with sodium
or potassium iodide to form aryl
iodides. This is the most general
method for the synthesis of aryl
iodides.
Primary
arylamine
ArNH
2
Aryl iodide
ArI
1. NaNO
2
, H
H11001
, H
2
O
2. NaI or KI
F
CH
3
m-Fluorotoluene (89%)
NPN
CH
3
H11001
BF
4
H11002
m-Methylbenzenediazonium
fluoroborate
heat
Br
NH
2
NO
2
Br
2,6-Dibromo-4-nitroaniline
Br
I
NO
2
Br
1,3-Dibromo-2-iodo-5-nitrobenzene
(84–88%)
1. NaNO
2
, H
2
SO
4
,
H
2
O
2. NaI
(Continued)
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Problems 907
TABLE 22.7 Synthetically Useful Transformations Involving Aryl Diazonium Ions (Continued)
Reaction and comments
Preparation of aryl nitriles Cop-
per(I) cyanide converts aryl diazo-
nium salts to aryl nitriles.
Reductive deamination of primary
arylamines The amino substituent
of an arylamine can be replaced by
hydrogen by treatment of its
derived diazonium salt with etha-
nol or with hypophosphorous acid.
General equation and specific example
Primary
arylamine
ArNH
2
Aryl nitrile
ArCN
Primary
arylamine
Arene
1. NaNO
2
, H
2
O
2. CuCN
ArNH
2
ArH
1. NaNO
2
, H
H11001
, H
2
O
2. CH
3
CH
2
OH or H
3
PO
2
o-Nitroaniline
NH
2
NO
2
o-Nitrobenzonitrile
(87%)
CN
NO
2
1. NaNO
2
, HCl, H
2
O
2. CuCN
4-Methyl-2-nitroaniline
NO
2
NH
2
CH
3
m-Nitrotoluene (80%)
NO
2
CH
3
1. NaNO
2
, HCl, H
2
O
2. H
3
PO
2
PROBLEMS
22.21 Write structural formulas or build molecular models for all the amines of molecular formula
C
4
H
11
N. Give an acceptable name for each one, and classify it as a primary, secondary, or tertiary
amine.
22.22 Provide a structural formula for each of the following compounds:
(a) 2-Ethyl-1-butanamine
(b) N-Ethyl-1-butanamine
(c) Dibenzylamine
(d) Tribenzylamine
(e) Tetraethylammonium hydroxide
(f) N-Allylcyclohexylamine
(g) N-Allylpiperidine
(h) Benzyl 2-aminopropanoate
(i) 4-(N,N-Dimethylamino)cyclohexanone
(j) 2,2-Dimethyl-1,3-propanediamine
22.23 Many naturally occurring nitrogen compounds and many nitrogen-containing drugs are bet-
ter known by common names than by their systematic names. A few of these follow. Write a struc-
tural formula for each one.
(a) trans-2-Phenylcyclopropylamine, better known as tranylcypromine: an antidepressant
drug
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(b) N-Benzyl-N-methyl-2-propynylamine, better known as pargyline: a drug used to treat
high blood pressure
(c) 1-Phenyl-2-propanamine, better known as amphetamine: a stimulant
(d) 1-(m-Hydroxyphenyl)-2-(methylamino)ethanol: better known as phenylephrine: a nasal
decongestant
22.24 (a) Give the structures or build molecular models and provide an acceptable name for all
the isomers of molecular formula C
7
H
9
N that contain a benzene ring.
(b) Which one of these isomers is the strongest base?
(c) Which, if any, of these isomers yield an N-nitroso amine on treatment with sodium
nitrite and hydrochloric acid?
(d) Which, if any, of these isomers undergo nitrosation of their benzene ring on treatment
with sodium nitrite and hydrochloric acid?
22.25 Arrange the following compounds or anions in each group in order of decreasing basicity:
(a) H
3
C
H11002
, H
2
N
H11002
, HO
H11002
, F
H11002
(b) H
2
O, NH
3
, HO
H11002
, H
2
N
H11002
(c)
(d)
22.26 Arrange the members of each group in order of decreasing basicity:
(a) Ammonia, aniline, methylamine
(b) Acetanilide, aniline, N-methylaniline
(c) 2,4-Dichloroaniline, 2,4-dimethylaniline, 2,4-dinitroaniline
(d) 3,4-Dichloroaniline, 4-chloro-2-nitroaniline, 4-chloro-3-nitroaniline
(e) Dimethylamine, diphenylamine, N-methylaniline
22.27 Physostigmine, an alkaloid obtained from a West African plant, is used in the treatment of
glaucoma. Treatment of physostigmine with methyl iodide gives a quaternary ammonium salt.
What is the structure of this salt?
22.28 Describe procedures for preparing each of the following compounds, using ethanol as the
source of all their carbon atoms. Once you prepare a compound, you need not repeat its synthe-
sis in a subsequent part of this problem.
(a) Ethylamine (b) N-Ethylacetamide
NN
CH
3
CH
3
OCNHCH
3
O
Physostigmine
N
H11002
,
O
O
N
H11002
,
O
N
H11002
HO
H11002
, H
2
N
H11002
,CPN , NO
3
H11002
H11002
908 CHAPTER TWENTY-TWO Amines
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(c) Diethylamine (e) Triethylamine
(d) N,N-Diethylacetamide (f) Tetraethylammonium bromide
22.29 Show by writing the appropriate sequence of equations how you could carry out each of
the following transformations:
(a) 1-Butanol to 1-pentanamine
(b) tert-Butyl chloride to 2,2-dimethyl-1-propanamine
(c) Cyclohexanol to N-methylcyclohexylamine
(d) Isopropyl alcohol to 1-amino-2-methyl-2-propanol
(e) Isopropyl alcohol to 1-amino-2-propanol
(f) Isopropyl alcohol to 1-(N,N-dimethylamino)-2-propanol
(g)
22.30 Each of the following dihaloalkanes gives an N-(haloalkyl)phthalimide on reaction with one
equivalent of the potassium salt of phthalimide. Write the structure of the phthalimide derivative
formed in each case and explain the basis for your answer.
(a) FCH
2
CH
2
Br
(b)
(c)
22.31 Give the structure of the expected product formed when benzylamine reacts with each of
the following reagents:
(a) Hydrogen bromide
(b) Sulfuric acid
(c) Acetic acid
(d) Acetyl chloride
(e) Acetic anhydride
(f) Acetone
(g) Acetone and hydrogen (nickel catalyst)
(h) Ethylene oxide
(i) 1,2-Epoxypropane
(j) Excess methyl iodide
(k) Sodium nitrite in dilute hydrochloric acid
22.32 Write the structure of the product formed on reaction of aniline with each of the following:
(a) Hydrogen bromide
(b) Excess methyl iodide
BrCH
2
CCH
2
CH
2
Br
CH
3
CH
3
BrCH
2
CH
2
CH
2
CHCH
3
Br
OO
C
6
H
5
CH
3
to
N
C
6
H
5
CHCH
3
Problems 909
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(c) Acetaldehyde
(d) Acetaldehyde and hydrogen (nickel catalyst)
(e) Acetic anhydride
(f) Benzoyl chloride
(g) Sodium nitrite, aqueous sulfuric acid, 0–5°C
(h) Product of part (g), heated in aqueous acid
(i) Product of part (g), treated with copper(I) chloride
(j) Product of part (g), treated with copper(I) bromide
(k) Product of part (g), treated with copper(I) cyanide
(l) Product of part (g), treated with hypophosphorous acid
(m) Product of part (g), treated with potassium iodide
(n) Product of part (g), treated with fluoroboric acid, then heated
(o) Product of part (g), treated with phenol
(p) Product of part (g), treated with N,N-dimethylaniline
22.33 Write the structure of the product formed on reaction of acetanilide with each of the fol-
lowing:
(a) Lithium aluminum hydride (e) tert-Butyl chloride, aluminum chloride
(b) Nitric acid and sulfuric acid (f) Acetyl chloride, aluminum chloride
(c) Sulfur trioxide and sulfuric acid (g) 6 M hydrochloric acid, reflux
(d) Bromine in acetic acid (h) Aqueous sodium hydroxide, reflux
22.34 Identify the principal organic products of each of the following reactions:
(a)
(b)
(c)
(d)
(e)
(f)
(g) (CH3)2CHNHCH(CH3)2
NaNO
2
HCl, H
2
O
heat
H
3
C
H
3
C
CH
3
N(CH
3
)
3
H11001
HO
H11002
triethylamine
THF
(C
6
H
5
CH
2
)
2
NH H11001
O
CH
3
CCH
2
Cl
(CH
3
)
2
CHNH
2
H11001
CH
3
O
OCH
3
CH
O
CH
2
C
6
H
5
CH
2
CH
2
CH
2
OH
1. p-toluenesulfonyl chloride,
pyridine
2. (CH
3
)
2
NH (excess)
1. LiAlH
4
2. H
2
O, HO
H11002
NCH
2
CH
3
O
Cyclohexanone cyclohexylamineH11001
H
2
, Ni
910 CHAPTER TWENTY-TWO Amines
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22.35 Each of the following reactions has been reported in the chemical literature and proceeds
in good yield. Identify the principal organic product of each reaction.
(a)
(b)
(c)
(d)
(e)
(f )
(g)
(h)
(i)
(j)
(k)
(l)
(m)
(n)
(o)
(p)
(q)
(r)
(s)
1. NaNO
2
, HCl, H
2
O
2. HO
H11002
(CH
3
)
2
N
CH
3
Aniline
1. NaNO
2
, H
2
SO
4
, H
2
O
2. 2,3,6-trimethylphenol
2-Amino-5-iodobenzoic acid
1. NaNO
2
, HCl, H
2
O
2. CH
3
CH
2
OH
2,4,6-Trinitroaniline
NaNO
2
, H
2
SO
4
H
2
O, H
3
PO
2
heat
N
H11001
N N
H11001
N 2BF
4
H11002
2,6-Diiodo-4-nitroaniline
1. NaNO
2
, H
2
SO
4
, H
2
O
2. KI
o-Nitroaniline
1. NaNO
2
, HCl, H
2
O
2. CuCN
m-Bromoaniline
1. NaNO
2
, HBr, H
2
O
2. CuBr
2,6-Dinitroaniline
1. NaNO
2
, H
2
SO
4
, H
2
O
2. CuCl
Product of part (i)
1. NaNO
2
, H
2
SO
4
, H
2
O
2. H
2
O, heat
Br NO
2
1. Fe, HCl
2. HO
H11002
Acetanilide H11001
O
ClCH
2
CCl
AlCl
3
Aniline heptanalH11001
H
2
, Ni
O
C
6
H
5
NHCCH
2
CH
2
CH
3
1. LiAlH
4
2. HO
H11002
Product of part (d) H11001 HCl
Product of part (c) H11001 (CH
3
CH
2
)
2
NH
Product of part (b) H11001
O
ClCH
2
CCl
1,3-Dimethyl-2-nitrobenzene
1. SnCl
2
, HCl
2. HO
H11002
1,2-Diethyl-4-nitrobenzene
H
2
, Pt
ethanol
Problems 911
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22.36 Provide a reasonable explanation for each of the following observations:
(a) 4-Methylpiperidine has a higher boiling point than N-methylpiperidine.
(b) Two isomeric quaternary ammonium salts are formed in comparable amounts when 4-
tert-butyl-N-methylpiperidine is treated with benzyl chloride. (Hint: Building a molec-
ular model will help.)
(c) When tetramethylammonium hydroxide is heated at 130°C, trimethylamine and
methanol are formed.
(d) The major product formed on treatment of 1-propanamine with sodium nitrite in
dilute hydrochloric acid is 2-propanol.
22.37 Give the structures, including stereochemistry, of compounds A through C.
22.38 Devise efficient syntheses of each of the following compounds from the designated starting
materials. You may also use any necessary organic or inorganic reagents.
(a) 3,3-Dimethyl-1-butanamine from 1-bromo-2,2-dimethylpropane
(b)
(c)
(d)
(e)
22.39 Each of the following compounds has been prepared from p-nitroaniline. Outline a reason-
able series of steps leading to each one.
(a) p-Nitrobenzonitrile (d) 3,5-Dibromoaniline
(b) 3,4,5-Trichloroaniline (e) p-Acetamidophenol (acetaminophen)
(c) 1,3-Dibromo-5-nitrobenzene
NC CH
2
N(CH
3
)
2
NC CH
3
from
NH
2
C
6
H
5
O C
6
H
5
OOH
from
CH(CH
2
)
8
CH
2
CH
2
N from 10-undecenoic acid and pyrrolidine
(S)-2-Octanol H11001 CH
3
SO
2
Cl
pyridine
1. LiAlH
4
2. HO
H11002
NaN
3
,
methanol–water
Compound A
Compound BCompound C
C(CH
3
)
3
CH
3
N
4-tert-Butyl-N-methylpiperidine
HN CH
3
4-Methylpiperidine
(bp 129°C)
CH
3
N
N-Methylpiperidine
(bp 106°C)
912 CHAPTER TWENTY-TWO Amines
C
6
H
5
CH
2
NHCH
3
BrCH
2
CH
2
CH
2
CNC
6
H
5
CH
2
NCH
2
CH
2
CH
2
CH
2
NH
2
CH
3
from and
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22.40 Each of the following compounds has been prepared from o-anisidine (o-methoxyaniline).
Outline a series of steps leading to each one.
(a) o-Bromoanisole (d) 3-Fluoro-4-methoxybenzonitrile
(b) o-Fluoroanisole (e) 3-Fluoro-4-methoxyphenol
(c) 3-Fluoro-4-methoxyacetophenone
22.41 Design syntheses of each of the following compounds from the indicated starting material
and any necessary organic or inorganic reagents:
(a) p-Aminobenzoic acid from p-methylaniline
(b)
(c) 1-Bromo-2-fluoro-3,5-dimethylbenzene from m-xylene
(d)
(e) o-BrC
6
H
4
C(CH
3
)
3
from p-O
2
NC
6
H
4
C(CH
3
)
3
(f) m-ClC
6
H
4
C(CH
3
)
3
from p-O
2
NC
6
H
4
C(CH
3
)
3
(g) 1-Bromo-3,5-diethylbenzene from m-diethylbenzene
(h)
(i)
22.42 Ammonia and amines undergo conjugate addition to H9251,H9252-unsaturated carbonyl compounds
(Section 18.12). On the basis of this information, predict the principal organic product of each of
the following reactions:
(a)
(b)
(c) C
6
H
5
CCH
O
CHC
6
H
5
H11001 HN O
O H11001 HN
(CH
3
)
2
C CHCCH
3
O
H11001 NH
3
CH
3
O
NH
CH
3
O
CH
2
COCH
3
CH
3
O
CH
3
O
O
O
2
N
from
CF
3
Br
I
from
H
2
N
CF
3
Br
NHCCH
3
O
Br
F
CH
3
from
NH
2
NO
2
CH
3
O
p-FC
6
H
4
CCH
2
CH
3
from benzene
Problems 913
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(d)
22.43 A number of compounds of the type represented by compound A were prepared for evalu-
ation as potential analgesic drugs. Their preparation is described in a retrosynthetic format as
shown.
On the basis of this retrosynthetic analysis, design a synthesis of N-methyl-4-phenylpiperidine
(compound A, where R H11005 CH
3
, RH11032H11005C
6
H
5
). Present your answer as a series of equations, show-
ing all necessary reagents and isolated intermediates.
22.44 Mescaline, a hallucinogenic amine obtained from the peyote cactus, has been synthesized
in two steps from 3,4,5-trimethoxybenzyl bromide. The first step is nucleophilic substitution by
sodium cyanide. The second step is a lithium aluminum hydride reduction. What is the structure
of mescaline?
22.45 Methamphetamine is a notorious street drug. One synthesis involves reductive amination of
benzyl methyl ketone with methylamine. What is the structure of methamphetamine?
22.46 The basicity constants of N,N-dimethylaniline and pyridine are almost the same, whereas
4-(N,N-dimethylamino)pyridine is considerably more basic than either.
Identify the more basic of the two nitrogens of 4-(N,N-dimethylamino)pyridine, and suggest an
explanation for its enhanced basicity as compared with pyridine and N,N-dimethylaniline. Refer
to Learning By Modeling and compare your prediction to one based on the calculated charge and
electrostatic potential of each nitrogen.
22.47 Compounds A and B are isomeric amines of molecular formula C
8
H
11
N. Identify each iso-
mer on the basis of the
1
H NMR spectra given in Figure 22.9.
N(CH
3
)
2
N,N-Dimethylaniline
K
b
1.3 H11003 10
H110029
pK
b
8.9
N
Pyridine
K
b
2 H11003 10
H110029
pK
b
8.7
N
N(CH
3
)
2
4-(N,N-Dimethylamino)pyridine
K
b
H11005 5 H11003 10
H110025
pK
b
4.3
RH11032
N
R
N
R
ORH11032
N
R
Compound A
H11001RNH
2
RN(CH
2
CH
2
CO
2
CH
2
CH
3
)
2
CH
2
CHCO
2
CH
2
CH
3
O
(CH
2
)
3
CH(CH
2
)
4
CH
3
NH
2
spontaneous
C
15
H
27
NO
914 CHAPTER TWENTY-TWO Amines
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Problems 915
4.0 3.8
1.01.21.41.6
5.06.07.08.09.010.0 4.0 3.0 2.0 1.0 0.0
Compound A
C
8
H
11
N
5
2
1
3
(a)
Chemical shift (δ, ppm)
2.72.82.93.03.1
5.06.07.08.09.010.0 4.0 3.0 2.0 1.0 0.0
Compound B
C
8
H
11
N
5
2
2
2
(b)
Chemical shift (δ, ppm)
FIGURE 22.9 The 200-MHz
1
H NMR spectra of (a) com-
pound A and (b) compound
B (Problem 22.47).
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22.48 The compound shown is a somewhat stronger base than ammonia. Which nitrogen do you think
is protonated when it is treated with an acid? Write a structural formula for the species that results.
Refer to Learning By Modeling, and compare your prediction to one based on the calculated charge
and electrostatic potential of each nitrogen.
22.49 Does the
13
C NMR spectrum shown in Figure 22.10 correspond to that of 1-amino-2-methyl-
2-propanol or to 2-amino-2-methyl-1-propanol? Could this compound be prepared by reaction of
an epoxide with ammonia?
CH
3
N
N
5-Methyl-H9253-carboline (pK
b
H11005 3.5)
916 CHAPTER TWENTY-TWO Amines
5060708090100 40 30 20 10
CH
2
C
CH
3
CDCl
3
Chemical shift (δ, ppm)
FIGURE 22.10 The
13
C NMR
spectrum of the compound
described in Problem 22.49.
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| 课件名称： | 有机化学（英文原版） |
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