Chapter 24: Amines
Amines: Nitrogen containing organic compounds
Organic derivatives of ammonia, NH3,
Nitrogen atom have a lone pair of electrons, which potentially
make amines both basic and nucleophilic
There are many naturally occurring organic compounds that
contain nitrogen (alkaloids)
H3 C
N
O
CO2 CH3
Ph
O
H3C
O
N
NH
N
H3 CO
N
CH3
H
NH2
H3 CO
CH3 CH3
physostigmine
HO
cocaine
HO2C
CH3
O
HO
OCH3
H
N
H3 CO
mescaline
H
N
O
N
NH
H
CH3
N
quinine
N
H
CH3
N
H
coniine
HO
nicotine
lysergic acid
286
morphine
24.1: Naming Amines
Alkyl-substituted (alkylamines) or aryl-substituted (arylamines)
H
H
N
C N
H
H
sp3
alkylamines
arylamines
Classified: 1° (RNH2), 2° (R2NH), 3° (R3N) and 4° (R4N+)
NH2
H
H3CH2C
H3C N
N
N
H
H
primary (1°)
amines
N
CH2CH3
N
CH2CH3
H
secondary (2°)
amines
tertiary (4°)
amines
quarternary (4°)
ammonium ion
Although the terminology is the same, this designation of amines
is different from that of alcohols.
H
H
H
H
H
1° carbon
methanol
R
C O
C O
C O
H
R
R
H
primary
R
H
C O
H
2° carbon
secondary
R
R
H
3° carbon
tertiary
287
145
Amine nomenclature:
The nomenclature for primary amines is similar to that of alcohols,
the suffix -amine can be used in place of the final -ol
Consider the -NH2 group as an amino substituent on the parent
chain
CH3CH2CH2CH3
CH3CH2CH2CH2OH
NH2
OH
butane
1-butanol
CO2H
cyclohexanamine
(cyclohexylamine)
CH3CH2CH2CH2NH2
NH2
1-butanamine
(butylamine)
2-amino-3-phenylpropanoic acid
2-butanamine
(2-aminobutane)
NH2
H2N
NH2
2-butanol
H2N
1,4-diaminobutane
NH2
1,5-diaminopentane
(putrescine)
(cadaverine)
288
Symmetrical secondary and tertiary amines are named by
adding the prefix di- or tri- to the alkyl group
Unsymmetrical secondary and tertiary amines are named as
N-substituted primary amines. The largest alkyl group
is the parent name, and other alkyl groups are
considered N-substituents.
H
H3CH2C
N
N
H
diphenylamine
N
H3C
CH2CH3
N
CH3
CH3
N
CH2CH2CH3
CH2CH3
diisopropylamine triethylamine
N,N-dimethylpropylamine
CH2CH3
N-ethyl-N-methylcyclohexylamine
Many arylamines go by non-systematic nomenclature
NH2
CH3
aniline
NH2
NH2
o-toluidine
H2N
p-phenylenediamine
289
146
The nomenclature of heterocyclic amines is highly specialized
and often non-systematic
N
N
N
N
N
N
H
pyridine
pyrrole
H
quinoline
imidazole
indole
24.2
N
quinoxoline
pyrimidine
O
N
N
H
N
N
N
H
H
pyrrolidine
piperidine
N
H
morpholine
Structure and Bonding in Amines
The nitrogen of alkylamines is sp3 hybridized and
tetrahedral
290
In principle an amine with three different substituents on the
nitrogen is chiral with the lone pair of electrons being the
fourth substituent; however, for most amines the pyramidal
inversion of nitrogen is a racemization mechanism
The barrier to nitrogen inversion is about 25 KJ/mol (very rapid
at room temperature).
291
147
24.3
Properties and Aources of Amines
Primary and secondary amines, likes water and alcohols,
can be hydrogen bond donors (N-H) and hydrogen bond
acceptors (the lone pair)
24.5
Basicity of Amines
The chemistry of amines is dominated by the basicity of
the nitrogen lone pair
O
N
+
H
O
O
R
N H
+
O
R
292
Alkyl amines are stronger bases than water, alcohols or ethers
R3N:
Kb =
+
H2 O
+
R3NH
[R3NH+] [HO-]
[R3N]
+
HO
-
pKb = - log Kb
pKb values are rarely used. Amines basicity is measured by
the pKa of the conjugate acid. (pKb + pKa = 14)
The conjugate base of a weak acid is a strong base:
Higher pKa = weaker acid = stronger conjugate base
The conjugate base of a strong acid is a weak base
Lower pKa = stronger acid = weaker conjugate base
R3NH+ + H2 O
higher pKa
R3NH+ less acidic
R3N more basic
+
H3O + R3N:
lower pKa
R3NH+ more acidic
R3N less basic
293
148
Table 24.1 (p. 899): pKa values of ammonium ions
Alkyl ammonium ions, R3NH+ X-, have pKa values in the range
of 10-11 (ammonium ion, H4N+ X-, has a pKa ~ 9.25)
The ammonium ions of aryl amines and heterocyclic aromatic
amines are considerably less basic than alkyl amines
(pKa ~ 5 or less). The nitrogen lone pair is less basic if
it is in an sp2 hybridized orbital (versus an sp3)
+
NH3
NH4+
pKa= 9.26
(H3CH2C)NH3+
10.8
(H3CH2C)2NH2+
10.7
(H3CH2C)3
NH+
pKa= 4.6
+
N H
11.0
+ H
N
H
+
NH2
5.2
0.4
7.0
O
+
NH3
24.5
- 1.0
294
Basicity of Substituted Arylamines
The lone pair of electrons on the nitrogen of aniline are
conjugated to the π-electrons of the aromatic ring
and are therefore less available for acid-base
chemistry. Protonation disrupts the conjugation.
Substituents can greatly influence the basicity of the aniline.
The effect is dependent upon the nature and position of
the subtituent (recall the acidity of substituted phenols)
295
149
Electron-donating substituents (-CH3, -OH, -OCH3) make the
substituted aniline more basic than aniline itself (the pKa
of the anilinium ion is higher than 4.6)
Electron-withdrawing substituents (-Cl, -NO2) make the
substituted aniline less basic than aniline itself (the pKa
of the anilinium ion is lower than 4.6)
See Table 24.2 (p. 903)
+
NH3
Y
NH2
Y
+ H2O
Y= -NH2
-OCH3
-CH3
-H
-Cl
-CN
-NO2
pKa= 6.15
pKa= 5.34
pKa= 5.08
pKa= 4.63
pKa= 3.98
pKa= 1.74
pKa= 1.00
+
+ H3O
less acidic
(more basic)
more acidic
(less basic)
296
Problem 24.4: Which compound is more basic?
a)
b)
O
H3CH2C NH2
-orH3CH2C
C
NaOH
-or-
c)
H3C NH2
(CH3)2NH
-or-
N
NH2
Problem 24.6: Rank the following in order of increasing basicity?
a)
b)
c)
O
O2N
NH2
,
NH2
Br
NH2
H3C
NH2
NH2 H2FC
,
NH2
H
,
O
Cl
F3C
NH2
,
NH2 H3C
,
NH2
,
297
150
24.6 Synthesis of Amines
Reduction of Nitriles, Amides and Nitro Compounds
R-Br
NaCN
R C
N
LiAlH4
R
ether
N
C
LiAlH4
H
2
N
C H
R
H
H3O+
R
1° amine
H3O+
-orNaOH, H2O
R-Br
Mg(0), CO2
then H3O+
R
O
C
SOCl2
OH
NH2
C H
H
R
O
C
H3C-NH2
R
Cl
O
C
N
H
CH3
LiAlH4
-orBH3
H H
C
CH3
N
H
R
1°, 2° or 3°
amine
HNO3, H2SO4
H2O
NO2
H2, Pd/C
-orSnCl2
NH2
1° arylamines
298
SN2 reaction of alkyl halides and tosylates
Ammonia and other alkylamines are good nucleophiles and
react with 1° and 2° alkyl halides or tosylates via
and SN2 reaction to give alkyl amines.
1°, 2°, and 3° amines all have similar reactivity; the initially
formed monoalkylation product can undergo further
reaction to yield a mixture of alkylated products
299
151
Synthesis of primary amines from the reaction of alkyl halides
or tosylates with “ammonia equivalents”
Azide ion is a very strong nucleophile and react with 1° or 2°
alkyl halides or tosylates via an SN2 reaction. The resulting
azide can be reduced to a 1° amine.
H
N N N
R2
azide
C X
H
H
SN2
N N N C
R1
N3 C
R2
H
H2N C
-orLiAlH4
R1
R1
1° or 2° alkyl halide
or tosylate
H2, Pd/C
R2
Alkyl azide
R2
R1
1° amine
Gabriel amine synthesis: reaction of potassium phthalimide with
alkyl halides or tosylates via an SN2 reaction. The resulting
N-substituted phthalimide can be hydrolyzed to a 1° amine.
O K+
O
N H
N
EtOH
O
Potassium
phthalimide
O
Phthalimide
O
H
KOH
H
H
C X
NaOH/H2O
N C
R1
O
N-substituted
phthalimide
H
R1
H
H2N C
R2
R1
1° amine
300
Reductive amination: synthesis of an amine by the reduction of
an imine from the condenstion of an aldehyde or ketone
with ammonia, 1° or 2° amine.
O
+ H3N
3-phenyl-2-propanone (P2P)
-H2O
NH
H2/ Pd/C
H
+ H3CNH2
-H2O
N
CH3
CH3
HN
H2/ Pd/C
H
1° amine
2° amine
methamphetamine
H3C + CH3
N
O
+ (H3C)2NH
1° amine
amphetamine
ammonia
O
NH2
-H2O
H3C
H2/ Pd/C
CH3
N
H
3° amine
2° amine
301
152
Sodium cyanoborohydride, Na+ N≡C-BH3– : the cyano ligand
makes cyanoborohydride a weak hydride source and it
will react with only the most easily reduced functional
groups. such as an imine. Does not reduce ketones and
reduced aldehydes slowly
Reductive amination with NaB(CN)H3: one-pot reaction
CHO
+ H3C-NH2
H
H
NaB(CN)H3
C
N
N
C
CH3
H H
CH3
H
H
H
NH2
+ H2C=O
N
NaB(CN)H3
C
CH2
N
CH3
H H
practice problem 24.1 (p. 908)
Hoffmann and Curtius rearrangements (please read)
302
24.7: Reactions of Amines
Acylation: ammonia, 1° and 2° amines react with acid chlorides
and anhydrides to give amides (Chapt. 21.4, 21.5 & 21.8)
NH3
R
R
O
C
SOCl2
OH
carboxylic acid
R
O
C
O
C
R'NH2
R
Cl
NH2
O
C
acid chloride
R'2NH
R
O
C
N
H
N
R'
unsubstitiuted
(1°) amide
R' mono-substitiuted
(2°) amide
R'
di-substitiuted
(3°) amide
303
153
Hofmann elimination: E2 elimination of a trimethyl ammonium
group to give an alkene
NH2
No reaction (H2N- is a very poor leaving group)
+ (H3C)3CO - K+
H3C-I
N(CH3)3 I
+
+ (H3C)3CO - K+
(major)
(minor)
Hofmann elimination gives the less substituted alkene, where
E2 elimination of an alkyl halide or tosylate will follow
Zaitsev rule to give the more substituted alkene
304
24.8
Reactions of Arylamines
Electrophilic aromatic substitution: an amino group is a
very strong activating group and an ortho/para
director.
The amino group is incompatible with the Friedel-Crafts
reactions (Ch. 16.3).
Electrophilic aromatic substitution of phenyl acetamides
(amides of aniline).
O
NH2
CH3
(H3CCO)2O,
pyridine
HN
O
CH3
HN
Br2
CH3
Br
NH2
CH3
Br
NaOH, H2O
CH3
CH3
The acetamide group is still a strong activator and an ortho/para
director. (see Fig. 16.10, page 541)
305
154
Advantages of the acetamide over the amino group for
electrophilic aromatic substitution:
Anilines are so activated that multiple substitution
reactions can be a problem. The reactivity of the
acetamide is attenuated so that mono substitution
NH
NH
is achieved.
Br
Br
2
2
Br2, H2O
Br
The acetamide group is compatiable with the FriedelCrafts reactions. NH
2
(H3CCO)2O,
pyridine
O
NH2
O
O
NaOH,
H2O
HN
CH3
(H3C)3C-Cl
HN
CH3
H3CCOCl
AlCl3
HN
CH3
NH2
NaOH,
H2O
AlCl3
O
O
CH3
CH3
306
Diazonium salts: The Sandmeyer reaction
primary arylamines (anilines) react with nitrous acid (HNO2,
generated from the reaction of NaNO2 and H2SO4) to form
a stable aryl diazonium salt.
OH
N
OH2
H+
N
- H2O
H2N
H
N
-H
N
O
O
O
O
N
N
N
OH
N
H+
N
N
OH2
N
HSO3
Aryl diazonium salts react with nucleophiles in a substitution
reaction. N2 is one of the best leaving groups.
N
N
Nu
+
+ Nu:
What is the mechanism?
N
N
N N
rate= k [Ar-N≡N+]
N
N
+
N
N
307
155
Some reactions of aryl diazonium salts
I
NaI
- N2
N
N
F
HBF4
- N2
H
H3PO2
- N2
Synthesize 3,5-dibromotoluene from bromobenzene or toluene
CH3
CH3
Br
Br
Br
308
Some more reactions of aryl diazonium substitution reactions
promoted by Cu(I) salts (Sandmeyer reaction).
HCl, CuCl
Cl
- N2
HBr, CuBr
N
N
Br
- N2
Cu(CN)
CN
- N2
Cu2O, H2O
OH
- N2
The mechanism of the Sandmeyer reaction (Cu+ promoted)
involves an aryl radical intermediate.
309
156
Synthesize 2-iodoethylbenzene from benzene:
I
CH2CH3
Diazonium coupling reaction (please read)
24.9
Tetraalkylammonium Salts as Phase-Transfer
Catalysts (please read)
310
24.10 Spectroscopy of Amines
IR: N-H stretches in the range of 3300 - 3500 cm-1
same range as O-H stretch, but N-H stretches are sharper
and less intense.
O
H
311
157
Mass Spectrum:
Nitrogen rule: small organic compounds with an odd number of
nitrogen atoms have an odd mass; compounds with an
even number of nitrogen atoms have an even mass
NMR: Hydrogens on the carbon attached to a nitrogen of an
amine have a chemical shift of δ 2.2 - 3.0
CH2 N CH2CH3
H
5H, m
C6H5-
3H, t
-CH2-CH3
2H, s
Ph-CH2-N-
2H, q
-N-CH2-CH3
1H, m
-NH
312
13C
NMR: Carbons attached to a nitrogen of an amine are
deshielded about 20 ppm downfield from where they
would absorb in an alkane
CH2 N CH2CH3
H
128.3
128.0
54.0
43.7
15.3
126.8
140.6
CDCl3
CH2 CH2 CH3
38.2
24.2
13.7
313
158
C9H13NO
[α]D +23°
3.60 (1H, dd,
J= 10.7, 4.1)
3.38 (1H, dd,
J= 10.7, 7.0)
3.05-3.12
(1H, m)
2.77 (1H, dd,
J= 13.3, 5.0)
2.49 (1H, dd,
J= 13.3, 8.8)
2.35-2.45
(3H, br s)
7.21-7.32 (m, 2H)
7.15-7.21 (m, 3H)
13C
NMR: 138.6, 129.1, 128.5, 126.3, 65.9, 54.2, 40.6
IR:
314
159