Amines are organic bases . They are found widely in nature.
Trimethylamine occurs in animal tissue, and the distinctive odor of fish is due to amines. Amines isolated from plants are called alkaloids and many are pharmacologically important.
Amines are classified according to the number of R nitrogen.
(1
RNH
2
primary o ) amine
R
2
NH secondary
(2 o ) amine
R
3
N tertiary
(3 o ) amine
The R groups may be alkyl or aryl.
For the common name of simple aliphatic amines, name the alkyl group(s) on the nitrogen and attach "amine." Use the prefixes "di" and "tri" as needed.
N
H
Ethylmethylamine
N -Methylethanamine
N
Trimethylamine
N,N -Dimethylmethanamine
The systematic name is derived from the name of the longest alkane chain present by dropping the final "e" and adding the suffix "amine."
Then designate smaller alkyl groups as shown, using the italicized locant " N ."

1 o Amines
2 o Amines
NH
2
Cyclohexylamine
Cyclohexanamine
CH
3
CH
3
CNH
2
CH
3 tertButylamine
2-Methyl-2-propanamine
H
N
H
N
N -Methylpropanamine N -Methyl-2-propanamine
3 o Amines
N
N
Cyclopentyldimethylamine
N,N -Dimethylcyclopentanamine
Butylethylisopropylamine
N -EthylN -(1-methylethyl)-butanamine

When the amino function is not the principal group ,
it is designated by use of the prefix " amino ."
There is an established order of precedence of compound classes, which is used to determine which functional group is the principal one. A highly abbreviated list, in order of decreasing precedence, is:
Acids, aldehydes, ketones, alcohols, amines.
So in most polyfunctional compounds, an amine function will be designated by use of the prefix.
NH
2
O NH
2
OH
2-Amino-3-pentanol
NH
2
Aromatic amines are often named as derivatives of aniline .
Aniline
Benzenamine
CH
3
NH
NMethylaniline
N -Methylbenzenamine
NH
2
R
Additional unique common names:
When R = CH
3
, p -toluidine .
When R = OCH
3
, p -anisidine .
Examples
N N
N N
H H
Pyridine Pyrrole Piperidine Pyrrolidine

Amines are moderately polar compounds because of the greater electronegativity of nitrogen relative to carbon and hydrogen.
Since 1 o and 2 o amines have N-H bonds, they hydrogen bond intermolecularly causing their boiling points to be higher than those of alkanes of comparable molecular weight but lower than those of similar alcohols.
3 o Amines boil at lower temperatures than 1 o and 2 o , but all amines can hydrogen bond to water, making low-molecular-weight amines
A COMPARISON:
CH
3
NH
2
OH
Methylcyclohexane Cyclohexylamine Cyclohexanol
MW 98 99 100
BP 100 o C 134 o C 161.5 o C
Water solubility
Insoluble Slightly soluble 3.6 g/100 mL

The nitrogen atom in most amines is similar to that in ammonia and can be considered to be sp 3 hybridized. The nonbonding electron pair is in an sp 3 orbital.
The geometry is described
R
R'
N
R'' as trigonal pyramidal .
Bond angles are close to
109.5
o
.

When there are three (four, counting the unshared pair) different groups attached to the nitrogen, the structure is chiral . But because of very fast inversion at the stereocenter (the inversion rate in NH
3
is close to 10 11 s -1 ), it is not possible to resolve a chiral amine .
R'
R
N :
R'' fast
: N
R R'
R''
Interconversion of amine enantiomers by fast inversion at the nitrogen center
Quaternary ammonium salts (compounds of type R
4
N
+
X
-
) display stereochemical features similar to chiral tetravalent carbon. If they contain four different R groups, they are chiral and, being of stable, non-inverting form, can be resolved into their enantiomers.
R''
R'
N
+
R
R'''
R
+
N
R'R''
R'''
Chiral quaternary ammonium salts can be resolved.

The greater the basicity of an amine, the weaker the acidity of its conjugate acid, the cation in its salts.
3
+
2
2
3
+
a
[RNH
2
][H
3
O + ]
[RNH
3
+ ]
a
a
a
H N
+
H
H
9.26
CH
3
N
+
H
H
10.64
CH
3
CH
2
N
+
H
H
10.75
a

This stabilization of positive charge on nitrogen by alkylation is parallel to the stabilization of carbocations by alkylation. It is another example of the electron-releasing nature of alkyl groups.
R N
+
R C
+
This increase in the basicity of an amine by alkylation is slightly enhanced by introduction of a second alkyl group. Further alkylation of a 2 o amine the usual aqueous media, aminium ions from 1 o
and 2 o
amines are very effectively stabilized by hydrogen-bonding with water molecules. Aminium ions from 3 o
amines, with only one N-H bond per ion, are not as well stabilized, so 3 o amines in water cannot fully utilize their true basicity.
Order of increasing basicity in gas phase: NH
3
< RNH
2
< R
2
NH < R
3
N
Order of increasing basicity in water: NH
3
< R
3
N < RNH
2
< R
2
NH

+
NH
3
Anilinium ion
+
NH
3
Cyclohexylaminium ion
a
The greater acidity of the anilinium ion means that aniline is a markedly weaker base than is cyclohexylamine, a typical 1 o
alkylamine.
The decreased basicity of aniline is primarily due to the delocalization of
NH
2
NH
2
-
+
NH
2
+
NH
2
+
NH
2
-
-
These two general types of benzene resonance forms are the only ones available to stabilize the anilinium ion:
+
NH
3
+
NH
3

The smaller enthalpy change on protonation of cyclohexylamine ( ∆ H o
1
) than on protonation of aniline ( ∆ H o
2
) results from its net resonance stabilization and explains why the alkylamine is more basic than aniline.
Basicity of arylamines is also lowered by the sp 2 -hybridized carbon attached to the amino group; it is more electronegative than the sp
3
carbon of an alkyl group.

Substituents, especially those that are electron-withdrawing, influence the basicity of anilines. The substituent effect is important in both the aminium ion (conjugate acid) and free base (see the aniline discussion).
+
NH
3
NH
2
+ HO
+ H
2
O
G G
When G is electron-releasing, the conjugate acid is stabilized (i. e., base strength is increased) leading to a slightly larger value for its pK a
. E.g., when G is a p -methyl group , the pK a
increases from 4.58 for the parent aniline to 5.08.
When G is electron-withdrawing, the conjugate acid is destabilized (i. e., base strength is decreased) leading to a sometimes considerably smaller value for its pK a
. E. g., when G is a p -nitro group, the pK a
drops to 1.00.

Nonaromatic amines have basicities like those of acyclic amines: pK a
of aminium ion
N
Piperidine
H
11.20
N
Pyrrolidine
H
11.11
N
Diethylamine
H
10.98
similar to that of aniline: pK a
of aminium ion
N
Pyridine
5.23
N
N
N
H
Pyrimidine Pyrrole
2.70
0.40
NH
2
Aniline
4.58
The basicity of pyrrole is especially low because its nominally unshared pair electrons are tied up in the
"aromatic sextet" and delocalized about the ring.

Amides are much less basic than amines even though their structural formulas both show an unshared pair of electrons on the nitrogen.
R-NH
2
Amine pK a
(conjugate acid) ~ 10
(R = alkyl)
O
RC-NH
2
Amide
~ 0
The decreased base strength of amides is explained by both resonance and inductive influences , as with aryl amines.

Stabilization by π -electron delocalization is important in amides, but relatively unimportant in their conjugate acids, as illustrated in these resonance structures.
AMIDE
R
:O:
NH
2
R
:O:
-
+
NH
2
R
:O:
-
+
NH
2
Large resonance stabilization large contribution
PROTONATED
AMIDE
(conjugate acid)
R
:O:
+
NH
3
R
:O:
-
+
+
NH
3
Small resonance stabilization small contribution
Therefore, resonance lowers the energy of the free base more than that of the protonated state, giving this conjugate acid a smaller pK a
(about zero) in comparison with aliphatic aminium ions (about 10).

Under sufficiently acidic conditions, amides do become protonated but on the oxygen atom, not the nitrogen.
Protonation occurs on the carbonyl oxygen because that adduct is resonance stabilized:
R
+
:OH
NH
2
R
:OH
+
NH
2
R
:OH
+
NH
2 explained by comparing the electrostatic potential maps for ethylamine and acetamide, which show a shift of the high electron density from nitrogen in the amine to oxygen in the amide.

Protonation of primary, secondary or tertiary amines produces aminium salts .
. .
RNH
2
+ HX
R
2
. .
NH + HX
R
3
. .
N + HX
+
RNH
3
X
+
R
2
NH
2
X
-
-
+
R
3
NH X
-
Aminium salts
It is the formation of aminium salts that causes amines to dissolve in acidic aqueous media. Aminium salts are not basic because there is no
Aminum salts are weak acids . As conjugate acids of the free base amines, the general conjugate relationship applies in which pK a
+ pK b
= 14 .
The aminium salts of aliphatic amines (pK b
~ 4) have pK a values of ~ 10 (like phenols). The aminium salts of aryl amines
(pK b
~ 9) are about as acidic as carboxylic acids, pK a
~ 5.

When there are four R groups
(alkyl or aryl) attached to the nitrogen, the function is called a quaternary ammonium ion.
Quaternary ammonium salt
-
Quaternary ammonium salts are prepared by exhaustive N -alkylation of amines:
R-NH
2
R'X
- H X
R-NH
R'
R'X
- H X
R-NR'
R'
R'X
R'
+
R-NR'
R'
X
-
Quaternary ammonium halides, having no unshared pair on nitrogen, cannot act as bases. If, however, the halide ion is replaced with a hydroxide ion they are fully ionic, strong bases like NaOH or KOH.
Strong base ion exchange resins are of this hydroxide type, with the quaternary ammonium ion covalently bonded to the polymer matrix.

Because most aminium salts are soluble in water, it is possible to separate amines (whether they are water-soluble or water-insoluble) from other organic materials by extraction into an aqueous acid like dilute HCl.
R-N-R''
R'
+
Neutral and acidic
Extract with aq. acid
Neutral and acidic organics
(In the organic solvent layer)
Dry; then evaporate solvent
Separate the layers like ether)
(In aqueous layer)
(1) Neutralize
with aq. HO
-
(2) Extract with
organic solvent
R-N-R''
R'
(In organic solvent)
Dry; then evaporate solvent

A type of amine called alkaloids is available from plant sources.
Many are chiral and occur in single enantiomer form. Some of these compounds are pharmacologically important, e. g., quinine and atropine.
Others have dangerous natures, e. g., morphine and strychnine.
Some alkaloids have been used to separate the enantiomers of chiral carboxylic acids. This resolution is based on:
(1) Formation of the diastereomeric salts from an enantiomeric
alkaloid amine and a racemic carboxylic acid and
(2) Utilization of the differing physical properties of the
diastereomers.

α
R
COOH COOH
H
C
OH
C
6
H
5
HO
C
H
C
6
H
5
( R ) racemic form
( S )
-
H
C
C
6
H
OH
5
C
6
H
5
+
NH
C
CH
3
H
( R , R ) -Aminium salt
+ C
6
H
5
NH
2
C
H
Resolving agent
(
CH
3
R )
+
Formation of diastereomeric aminium salts
-
HO
C
H
C
6
H
5
C
6
H
5
+
NH
C
CH
3
H
( S , R ) -Aminium salt
H
3
O
+
COOH
C
H OH
C
6
H
5
R
Separation and recovery of carboxylic acids
H
3
O
+
COOH
HO
C
H
C
6
H
5
S

Amines are widely encountered in biological and pharmacological studies. Some important examples are the 2-phenylethylamines, some vitamins, antihistamines, tranquilizers, and neurotransmitters.
2-Phenylethylamines
NH
2
NH
2
HO
H OH
NH R
H
3
C H
Amphetamine
(Benzidrine)
HO
R = CH
3
, Adrenaline
R = H, Noradrenaline
HO
NH
2
HO NH
2
Serotonin
HO
Vitamins
OH
OH
HO
N
H
Pyridoxine
(Vitamin B
6
)
CH
3
Antihistamines
N
NH
2
Histamine
N
Cl
O
Chlorpheniramine
(an antihistamine)
H
OH
Nicotinic acid
(Niacin)
N
N
CH
3
CH
3

Tranquilizers These examples are both 1,4-benzodiazepine anxiolytics.
H
3
C
N
O
N
NHCH
3
Cl
N
Valium
(Diazepam)
Cl
N
+
O
-
Chlordiazepoxide
Neurotransmitters
Besides 2-phenylethylamines like noradrenaline, dopamine, and serotonin, the simpler amine-family compound acetylcholine is a neurotransmitter, one of great importance that acts at neuromuscular synapses.
H
3
C CH
3
O
O
N
+
CH
3
+ H
2
O
Acetylcholine
Acetylcholineesterase
O
OH
+
HO
H
3
C CH
3
N
+
CH
3
Choline
An essential feature of this system is that the esterase can almost immediately hydrolyze the neurotransmitter that has been received at the receptor site, freeing it to receive a later nerve impulse.

Medicinal chemists have long used structural features as a key to drug design.
The structural similarity between the amphetamines and the natural brain hormones (like adrenaline, noradrenaline, and dopamine) is an example.
Another example of structure-reactivity relationships appears to be the hallucinogenic effect of a number of compounds of the indole type.
HO
NH
2
HO
N(CH
3
)
2
O N
Indole system
N
H
N
N
H
CH
3
Harmala alkaloids
Found in plants in Peru, Ecuador,
Columbia and Brazil. Used as a hallucinogen by native indians.
N
Psilocin
H
A hallucinogenic alkaloid obtained from the "sacred" mushrooms of Central America,
Psilocybe mexicana.
N diethyl amide
(LSD)
CH
3
N
H
First synthesized by Albert Hofmann in 1938 at Sandoz Pharmaceutical Co. while working on derivatives of the hallucinogenic ergot alkaloids .

The nucleophilic substitution of alkyl halides with ammonia is a general synthesis of primary amines.
NH
3
+ R-X
+
RNH
3
X
aminium salt base
(- HX)
RNH
2
1 o amine
The reaction may be carried out in aqueous or alcoholic (to improve limitations of an S
N
2 reaction apply.
NH
3
CH
3
CH
2
CH
2
CH
2
Br
1 o Substitution
CH
3
CH
2
CH
2
CH
2
+
NH
3
Br
-
Butyl ammonium bromide
(butanaminium bromide)
While
CH
3
CH
3
CBr
3
CH
3 o
NH
3
Elimination
CH
3
C=CH
CH
3
Isobutene
2
+
+ NH
4
Br
-

o
A problem in synthesizing 1 o
amines by the direct alkylation reaction is the formation of more highly alkylated products from repetitive reaction.
RX
NH
3
+
RNH
3
X
-
1 o Aminium
NH
3
(- NH
4
X)
RNH
2
1 o Amine salt
The desired reaction is this alone.
RX
R
2
+
NH
2
X
-
2 o Aminium salt
NH
3
(- NH
4
X)
R
4
+
N X
-
Quaternary ammonium salt
RX
3 o Amine
NH
(- NH
4
X)
+
NH X
-
3 o Aminium salt
RX
2 o Amine
While the direct alkylation synthesis of 1 o amines is simple, the products are contaminated by the 2 o and 3 o amines and 4 o ammonium salts. By using a very large excess of ammonia, good results sometimes can be achieved.
A similar alkylation method that yields 1 o
amines free of higher order amines reacts azide ion (N
3
) with an alkyl halide to give an alkyl azide, which is then reduced to the 1 o
amine by use of Na/alcohol or LiAlH
4
.
Caution must be taken because azides are explosive.

o
The Gabriel synthesis is a good choice when 1 o amines are desired.
This synthesis utilizes the anion of phthalimide as a nucleophile in S
N
2 reaction with alkyl halides. Alkaline hydrolysis of the N -alkylated phthalimide yields the 1 o
amine free of 2 o
and 3 o
amines.
O
N H
KOH
- H
2
O
O
N
-
K
+
R-X
- KX
O
Phthalimide, pK a
= 9
O
1
2 o Amine
+
1
2 o Amine
CO
2
-
CO
2
alkaline hydrolysis
HO
-
, H
2
O
+
O
N
H
N
H
O
Phthalazine-1,4-dione
OR
NH
2
NH
2 in EtOH at reflux
O
N R
O
An N -alkyl phthalimide
The alternative of using hydrazine, NH
2
NH
2
, to release the 1 o amine often gives superior results.

Anilines may be prepared by reduction of nitrobenzenes. The overall synthetic sequence begins with nitration of the starting arene.
ArH nitration
HNO
3
H
2
SO
4
ArNO
2 reduction
[H]
ArNH
2
These reactions use metals such as iron, zinc and tin and typically are carried out at reflux in hydrochloric acid solution, sometimes with added acetic acid to help dissolve the aromatic compound.
EXAMPLE
NO
2
Fe
30% HCl, heat
NH
3
+
Cl
-
HO
-
H
2
O
NH
2
Nitrobenzene Anilinium chloride Aniline

A SECOND EXAMPLE
NO
2
CH
3 pNitrotoluene
Sn
HCl, heat
NH
3
+
Cl
-
HO -
H
2
O
CH
3
NH
2
CH
3 p -Toluidine
Anilines may also be prepared by catalyzed reaction of pre-formed hydrogen with nitroaromatics:
NO
2
NH
2
H
2
, Pt ethanol
CO
2
Et CO
2
Et
Ethyl p -nitrobenzoate Ethyl p -aminobenzoate

Aldehydes and ketones can be converted into amines by catalytic or chemical reduction in the presence of ammonia or a 1 o
or 2 o
amine.
The overall synthetic schemes are these:
[H]
NH
3
NH
2
RC H R'
1 o amine
O
R''NH
2
[H]
R''NH
R'''
RC H R'
R''N-R'''
RC H R'
3 o amine
These conversions can alternatively be viewed as reductive alkylations of the starting amines.

Reductive amination involves addition of the amine to the carbonyl followed by reduction via the immediate aminal or its dehydration product, an imine.
H O NHR''
- H
2
O
NR''
O
R
R'
+ H
2
NR''
1 o
Amine or NH
3
R R'
Hemiaminal
R R'
Imine
O
R
R'
+ HNR''R'''
2 o Amine
[H]
The reduction is carried out with H
2
/Ni or with NaBH
3
CN, sodium cyanoborohydride
H NHR''
R R'
H O NR''R'''
- H
2
O
R R'
Hemiaminal
+
R''NR'''
R R'
Iminium ion
[H]
R
H NR''R'''
o
R'

O
CH NH
3
H
2
, Ni pressure, heat
CH
2
NH
2
+ H
2
O
Benzaldehyde Benzylamine
Amination of aldehyde OR alkylation of ammonia
O
2-Pentanone
NaBH
3
CN
NH
2
2-Pentanamine
O
Cyclohexanone
(CH
3
)
2
NH
NaBH
3
CN
H
3
C
CH
3
N H
N,NDimethylcyclohexanamine

Reduction of any of these functional groups by catalytic hydrogenation or lithium aluminum hydride (LiAlH
4
) yields an amine.
[H]
RC N nitrile
RCH
2
NH
2
1 o amine
R' oxime
O
RC-N-R'
R'' amide
RCHNH
2
R'
(Oximes are often reduced with sodium metal in alcohol.)
[H]
RCH
2
N-R'
R''
1 o , 2 o , or 3 o amine

Examples
NOH
O
H
2
NOH, H +
(-H
2
O)
Cyclohexanone
CH
2
C N
H
2
, Ni
140 o
C
NH
3
H
2
, Ni
Na ethanol
NH
2
CH
2
CH
2
NH
2
1 o
Cyclohexanamine
1 o
2-Phenylethanamine
O
CCl
CH
3
CH
2
NH
2
Benzoyl chloride
O
CNHC
2
H
5
(1) LiAlH
4
/ether
(2) H
2
O 2 o
CH
2
NHC
2
H
5
Benzylethylamine

The Hofmann Rearrangement: Amines from Primary Amides
Primary amides are converted into amines by loss of the carbonyl group in aqueous basic solutions of Br
2
or Cl
2.
O
1
R C NH
2 o amide
+ X
2
+ 4 NaOH
1 o
RNH
2
+ 2 NaBr + Na
2
C O
3
+ 2 H
2
O
amine
The Hofmann rearrangement of 1 o amides provides 1 o amines exclusively, with no contamination from 2 o
or 3 o
amines.
This reaction also can be useful for shortening a carbon chain , which explains why it is sometimes referred to as a Hofmann degradation .

The proposed mechanism begins with base-promoted
N -bromination, analogous to α -bromination of enolizable ketones.
acid-base reaction
O
RCN H
2
+ HO
pK a
~ 25
O
-
RCNH low conc.
+ H
2
O nucleophilic attack: N-bromination step
-
RCNH + Br-Br RCNHBr + Br
-
The N -bromoamide is more acidic than the unsubstituted amide and deprotonation readily occurs:
O
RC-N-Br + HO
-
O
_
RC-N-Br
+ H
2
O
H anion is unstable pK a
<< 25

The Rearrangement Step molecular rearrangement of unstable anion to isocyanate
R
O
C
N
_
Br
(- Br
-
)
R-N=C=O isocyanate
The R group (alkyl or aryl) shifts from the carbonyl to the nitrogen with departure of the bromide ion. Formation of a π -bond produces the isocyanate.
ANOTHER VIEW:
R
C
O
N
..
-
Br
O C N
..
+ Br
-
The R group shifts with its pair of bonding electrons as the bromide ion departs. If the R-group carbon that is immediately attached to the carbonyl is chiral, its stereochemistry is preserved during the rearrangement.
The nitrogen atom undergoes a change in hybridization from sp
3 to sp 2 as a nonbonding electron pair on nitrogen forms a π -bond with the carbon center that has transformed from sp 2 to sp hybridization.

Isocyanates undergo nucleophilic addition reactions at the electropositive carbon center.
R-N=C=O + HO
-
-
OH
R-N-C=O fast
H
+ transposition
:O:
-
R-N-C=O
H carbamate ion unstable decarboxylation of carbamate anion
:O:
-
R-N C=O
H
+ H-O-H
1 o
RNH
2
amine
+ CO
2
+ HO
-
HCO
3
-

Some Features of the Hofmann Rearrangement the migrating group may be alkyl or aryl
O
Hexanamide
NH
2
Br
2
, NaOH
H
2
O
Pentanamine
NH
2
O
CNH
2
Br
2
, NaOH
H O
Benzamide the rearrangement is intramolecular
Aniline
NH
2
O O
C
6
H
4
D CNH
2
+ C
6
H
5
C
15
N H
2
Br
2
, NaOH
H
2
O
A double label experiment
C
6
H
4
D NH
2
+ C
6
H
5
15 N H
2
No crossover of isotope labels

stereocenters migrate with retention
[That is, neither complete inversion nor racemization is observed.]
( S
CH
3
H
C
C
6
H
5
O
CNH
2
Br
2
, NaOH
H
2
O
)-(+)-2-Phenylpropanamide
CH
3
H
C
C
6
H
5
NH
2
( S )-(-)-1-Phenylethanamine
H
C
6
H
5
C
*
O
C
CH
3
_
N:
Br
*
S
H
C
6
H
5
O
C
CH
C N:
δ -
3
Br
δ transition state
C
6
H
5
O=C=N
H
C * + Br
-
CH
3
*
S

This is a rearrangement of acyl azides that is analogous to the
Hofmann rearrangement.
O
R Cl
Acyl chloride
NaN
3
- NaCl R
O
-
+
N N N:
Acyl azide heat
- N
2
H
2
O
R NH
2
+ CO
2
R N C O
Isocyanate
The driving force for the rearrangement is the elimination of the thermodynamically super stable N
2
molecule. Similarly, the driving force for the decarboxylation is the elimination of the very stable CO
2
molecule.

The chemistry of amines is determined by the unshared electron pair on nitrogen. Amines are bases and nucleophiles.
base N: + H
+
+
N-H nucleophile
N: + R-X
H
O
N: + R-C-X
+
N-R + X
-
O
N-C-R + HX
The amino group as a substituent on a benzene ring is a powerful activating group and ortho-para director in electrophilic aromatic substitution:
NH
2
NH
2
E
+
E ortho and para
[This holds for reactions like bromination, but if the electrophile being used forms a stable aminium ion (as in the Friedel-Crafts reaction) by initial reaction with the basic amino group the benzene ring is very strongly deactivated.]

With alkyl amines, the only useful oxidation reaction is that of 3 o amines. By using hydrogen peroxide or peroxy acids, they can be converted to 3 o
amine oxides.
O
H
2
O
2
or RCO-OH
R
3
N: R
3
+
N O:
reaction, a useful alkene synthesis.
Arylamines are so electron rich that they readily undergo oxidation, but it occurs first on the ring and, as with 1 o
and 2 o
aliphatic amines, rarely gives useful products.

Nitrous acid, HNO
2
, is unstable and is prepared in the reaction mixture from a nitrite salt and an acid such as HCl or HBr in the presence of the amine.
Diazotization of 1 o Aliphatic Amines overall chemistry
RNH
2
+ NaNO
2
+ 2 HX sodium nitrite
H
2
O
+
R-N N: X
-
+ NaX + 2 H
2
O
- N
2 diazonium salt unstable
R
+
+ X
-
Alkenes, alcohols, alkyl halides
The complexity of the product mixture makes the reaction with 1 o
amines of no synthetic value.
Mechanism
Na
+
-
:O N=O
+
+ H-OH
2 sodium nitrite formation of nitrosonium ion
H-O N=O + Na
+
+ H
2
O nitrous acid
+
H-O N=O
+ H-OH
2
+
H-O N=O
H
+
N=O + H
2
O nitrosonium
ion

nitrosation of amine
R-NH
2
+ N=O
+
+
H
R-N-N=O
H
N-nitrosoamine dehydration of N-nitrosoamine
A series of deprotonation and reprotonation steps leads to dehydration:
+
H
R-N-N=O
H
H
+ H
R-N=N-O-H
+
(- H
2
O)
+
R-N=N
+
R-N N
Alkyl diazonium ions are unstable .
+
R-N N fast
R
+ + :N N:
The measurement of the released N
2 gas from diazotization of primary amines is used in some analytical procedures.

o
This most important reaction of amines with nitrous acid yields aryl diazonium ions , which have many replacement reaction uses in organic synthesis.
Aryl diazonium salts can be prepared and manipulated at 0 o C:
ArNH
2
+ NaNO
2
+ 2 HX sodium nitrite
+
Ar-N N: X
-
+ NaX + 2 H O aryl diazonium salt
(stable below 5 o C)
Note: Many dry aryl diazonium salts are explosive .
Therefore, these compounds are typically not isolated but prepared and then used in the same solution.

o
o
Secondary amines, both alkyl and aryl, and 2 o
amides are converted to N -nitroso derivatives on reaction with nitrous acid.
EXAMPLES: [HO-N O] + H
3
O
+ +
N O + 2 H
2
O
N H +
+
N O
Dimethylamine
- H
+
N N O
N -Nitrosodimethylamine a yellow oil
O
N
H
H
N -Methylaniline
+
N O
+
+
N O
N -Methylacetamide
N O
- H
+
N -NitrosoN -methylaniline a yellow oil
O
N O
N
- H
+
N -NitrosoN -methylacetamide a yellow crystalline solid
This compound, on reaction with aqueous NaOH, yields diazomethane, a powerful methylating agent
(but one which is poisonous and explosive, requiring special precautions ).

o
Aliphatic 3 o amines afford N -nitrosoammonium compounds,
R
3
+
N N O X
but these salts are of little importance.
Aryl 3 o
amines react with nitrous acid via their electron-rich aromatic rings, affording C -nitroso derivatives. This electrophilic aromatic substitution takes place almost exclusively at the para position or, if it is ortho position.
EXAMPLE: [HO-N O] + H
3
O
+ +
N O + 2 H
2
O
N +
+
N O
N,N -Dimethylaniline
O N N
4-NitrosoN,N -Dimethylaniline

Reaction of aryl diazonium salts with various reagents results in replacement of the diazonium group by other groups.
Cu
2
O, Cu
2+
H
2
O
ArOH phenol
CuX
ArX (Br or Cl)
Ar-NH
2
[HONO]
0-5 o C
Ar-N
2
+
CuCN
ArCN nitrile
KI
ArI aryl iodides
HBF
4
ArF
(fluoroboric acid)
H
3
PO
2
ArH
(hypophosphorus acid) aryl fluorides

When an aqueous solution of benzenediazonium chloride and KI is allowed to warm to room temperature, the benzenediazonium iodide produced decomposes with liberation of N
2
to give a good yield of iodobenzene.
+
N
2
Cl
+
N
2
I
-
I
+ KI warm
H
2
O (- N
2
)
A similar reaction does not occur with the aryldiazonium chlorides and bromides. But in 1884, the Swiss chemist Traugott Sandmeyer discovered that replacement reactions are catalyzed by cuprous salts. With Cu Cl ,
Cu Br , or Cu CN added, replacement reactions occur as the diazonium salt is allowed to warm to room temperature.
OCH
3
NH
2
NaNO
2
, HBr
H
2
O, 0-5 o C
OCH
3
N
+
2
Br
-
CuBr warm to 100 o C
OCH
3
Br oBromoanisole
NO
2
NH
2 NaNO
2
, HCl
H
2
O, 0-5 o
C
NO
2
N
+
2
Cl
-
CuCN warm to 100 o C
NO
2
CN oNitrobenzonitrile

When aryldiazonium salts are reacted with fluoroboric acid (HBF
4
), the aryldiazonium tetrafluoroborate salts often crystallize out and can be isolated. These salts are unique in their stability. When heated, they produce the aryl fluoride.
CH
3
(1) NaNO
2
, HX, cold
NH
2
(2) HBF
4
CH
3
+
N
2
BF
4 stable, can be isolated heat
CH
3
F
Fluorine cannot be introduced by direct electrophilic aromatic substitution of toluene. Even if it could, toluene would yield ortho and para substitution products.

The diazonium group can be replaced with a hydroxyl group by adding cuprous oxide to a dilute solution of the diazonium salt that contains a large excess of cupric nitrate:
N
2
+ HSO
4
-
Cu
2
O
OH p -Toluenediazonium hydrogen sulfate p
This variation of the Sandmeyer reaction was developed by T. Cohen of the
University of Pittsburgh. It is simpler and safer than an older procedure.

O
-
Arenediazonium salts react with hypophosphorous acid (H
3 to yield products in which the diazonium group has
PO
2
, HO-P-H)
H been replaced by a hydrogen atom.
NH
2
X
NaNO
2
, H
2
SO
4
H
2
O, 0-5 o C
+
N
2
X
HSO
4
-
H
3
PO
2
H
2
O, 25 o
C
(- N
2
)
X
Deamination refers to such a removal of the amino function. In synthetic design, the ortho para directing ability of the amino function can be exploited before it is removed (or replaced) by another group using diazotization chemistry.
m -Bromotoluene cannot be prepared by simple bromination of toluene because of the o / p directing nature of the methyl group.
Target compound
CH
3
Br mBromotoluene

CH
3
CH
3
CH
3
O O
CH
3
COCCH
3
(moderates reactivity
(1) Br
2
(2) HO
-
, H
2
O, heat p-
NH
2 of amino group)
Aminotoluene
NHCCH
3
O p -Methylacetanilide
Br
NH
2
4-Amino-3-bromotoluene
CH
3
NaNO
2
, H
2
SO
4
CH
3
H
3
PO
2
CH
3
N
2
+
HSO
4
-
(- N
2
)
NH
2
Extended Synthetic Sequence: nitration
HNO
3
H
2
SO
4
NO
2 reduction
[H] metadirecting
NH
2 deamination
(1) HONO o,pdirecting
(2) H
3
PO
2
H
When this sequence is carried out on substituted benzenes, it is possible to design synthetic routes to aromatics with a variety of substitution patterns.

Aryldiazonium ions are weak electrophiles that react with electron-rich aromatics such as phenols and N,N -disubstituted aryl amines to give azo compounds .
Electrophilic aromatic substitution
+
N N:
G +
G +
H
:N N
G = R
2
N-, HO+
N N resonance stabilized by substituent electrophile
- H +
G :N N an azo compound

Azo compounds are typically intensely colored because of their extended
π -electron systems that absorb radiation in the visible region. They are used commercially as dyes. Substituent groups such as -SO
3
-
Na
+ are introduced to make them water soluble and to promote their binding to polar fibers (wool, cotton, or nylon).
3
-
Na
+
H
2
N SO
3
-
Na
+ p -Aminobenzenesulfonic acid, sodium salt
OH
N=N
OH
2-Naphthol Orange II
A particularly brilliant example

Azo dyes are used as pH indicators because their π -electron systems change dramatically between the free base and conjugate acid forms, leading to different colors for the two forms.
Butter yellow , a dye once used to color margarine, is red below pH 3 (in the conjugate acid form) and yellow at and above pH 4 in the free base form).
CH
3
N
CH
3
H
N=N
+
+ H
+
CH
3
N
CH
3
N=N
- H
+
CH
3
N
CH
3
H
N=N
+ butter yellow
Protonation on the azo function is energetically favored because it produces a cation with more resonance stabilization than the cation produced by protonation on the amino nitrogen.
CH
3 +
N
CH
3
H
N N etc.
red form

The coupling reaction between N,N -dimethylaniline and diazonium ions occurs fastest in the intermediate pH range 5.5 to 7, as shown below.
(CH
3
)
2
N
+
+ N
2
-Ar (CH
3
)
2
N +
H
N
2
-Ar maximum rate
Reaction rate
2 3 4 5 6 7 8 9 10 11 12

The rate-determining step in the coupling reaction involves electrophilic attack by the diazonium ion on the N,N -dimethylaniline in its free base form :
(CH
3
)
2
N
+
+ N
2
-Ar
RDS
(CH
3
)
2
N +
H
N
2
-Ar
The concentrations of these two reactants depend on the pH of the solution because of the equilibria below.
(CH
3
)
2
+
N
HO
-
(CH
3
)
2
N pK a
= 5.15
Dominates at low pH reactive free base form
Dominates at high pH
The above equilibrium explains the rate increase as pH is raised to about 6.
The rate of coupling begins to decrease above pH 6-7 because of this second equilibrium that decreases the concentration of the electrophilic diazonium ion:
Ar-N=N
+
X
-
HO
-
H
+
Ar-N=N -OH + X
reactive electrophile does not undergo coupling
Dominates at low pH Dominates at high pH

Primary and secondary amines react readily with sulfonyl chlorides just as they do with acyl chlorides :
1 o
RNH
2
O
+ R'CCl acyl chloride
(- HCl)
O
RNH CR'
Nsubstituted amide
RNH
2
O
+ ArSCl
O sulfonyl chloride
(- HCl)
O
RNH SAr
O
Nsubstituted sulfonamide
Similarly,
O
RR'NH + R'CCl acyl chloride
(- HCl)
O
RR'N CR'
N,Ndisubstituted amide
2 o
O
RR'NH + ArSCl
(- HCl)
O sulfonyl chloride
O
RR'N SAr
O
N,Ndisubstituted sulfonamide
Tertiary amines do not give stable products.

Carboxamides (amides derived from carboxylic acids) hydrolyze under either acidic or basic conditions.
HCl
NH
3
+
+ COOH
H
2
O, heat
O
NHC
Benzanilide
( N -phenylbenzamide)
HO
-
H
2
O, heat
NH
2
+ CO
2
-
Sulfonamides hydrolyze much more slowly than carboxamides, but hydrolysis does occur under acidic conditions. Under basic conditions, the rapid formation of an anion ( derived from the acidic H on nitrogen ) inhibits nucleophilic attack and hydrolysis.
O
RN H SAr
O pK a
~10
HCl
H
2
O, heat
HO
-
H
2
O, heat
-
RNH
3
+ + ArSO
3
H aryl sulfonic acid
O
RN SAr
O
O
-
RN SAr
O
O
RN SAr
O
resists hydrolysis (resonance stabilized) etc.

o
o
o
This test, a classic method of distinguishing among the amine classes, was developed in 1890 by O. Hinsberg in his studies with benzenesulfonyl chloride.
The test reagent is benzenesulfonyl chloride in aqueous KOH. It is important to use excess amounts of KOH to avoid false results with primary amines.
primary amines
When a 1 o
amine is added to the test reagent, a sulfonamide product is formed initially that rapidly is deprotonated by hydroxide ion because of the acidic H on nitrogen. The sulfonamide salt is soluble in water so a clear solution is observed . When acid is added , the insoluble sulfonamide product precipitates .
O
RNH
2
+ C
6
H
5
SCl
O
KOH
H
2
O (- HCl)
H O
RN SC
6
H
5 pK
O a
~10 fast
HO
-
K
+
O
RN SC
6
H
5
O water soluble acidification
K
+
O
RN SC
6
H
5
O
H +
H O
RN SC
6
H
5 insoluble
O a 1 o
sulfonamide

secondary amines
Secondary amines form water insoluble sulfonamides. They do not have an acidic H on nitrogen, so salts are not formed in the basic solution.
O
RR'NH + C
6
H
5
SCl
O
KOH
H
2
O (- HCl)
O
RR'N SC
6
H
5 water insoluble ppt formed
O a 2 o
sulfonamide tertiary amines
With a 3 o amine, there is no visual sign of reaction with the test reagent. However, if the amine is water insoluble, it will dissolve
O
RR'R''N + C
6
H
5
SCl
O acidification
RR'R''N + H + A
-
KOH
H
2
O no reaction
RR'R''N H
+
A
water soluble a 3 o
aminium salt
Summary of Observations with the Hinsberg Test
RNH
2 clear solution, ppt with H +
RR'NH RR'R''N immediate ppt no reaction (but dissolves in acid)

Chemotherapy is the use of chemical agents to destroy infectious organisms without harming the host. Typically, chemotherapy is used to kill bacteria responsible for a disease.
Early in the 20th century, Paul Ehrlich (Nobel Prize 1908) discovered the first therapeutic chemicals. As a medical student, Ehrlich observed that certain dyes stained tissues selectively. He reasoned that staining was the result of selective chemical reactions between the dyes and the biological materials. He began a search for dyes with selective affinities for microorganisms hoping to find dyes that would be selectively lethal to specific microorganisms that cause disease...his "magic bullets."
H
Ehrlich discovered salvarsan as a treatment for syphilis in 1909.
HO
2
N
As=As
NH
2
OH salvarsan
Note that this compound is an arsenic analog of a diazo compound.
Recall that arsenic and nitrogen are both in Group VA of the Periodic
Table, which explains why they can be interchanged in many structures.

Between 1909 and 1935, thousands of chemicals, including many dyes, were screened for activity. Very few "magic bullets" were found until a desperate father tried to save the life of his sick daughter in 1935.
Gerhard Domagk was a doctor employed by a German dye manufacturer (I. G. Farbenindustrie) when his daughter contracted a streptococcal infection. She became very ill and was near death when in one final desperate act, Domagk gave her a dose of a dye called prontosil .
It was selected because tests at I. G. Farben had shown that prontosil inhibited the growth of streptococci in mice. The child recovered and a
In 1936, Ernest Fourneau of the Pasteur Institute in Paris showed that prontosil breaks down in the human body to produce sulfanilamide , the active agent.
NH
2
H
2
N N=N prontosil
O
S-NH
2
O
H
2
N
O
S-NH
2
O sulfanilamide the first sulfa drug
In the following years, many thousands of structural variations of sulfanilamide were synthesized in the search for additional drugs.

The sulfa drugs are broad spectrum antibacterial agents. They are effective against malaria, tuberculosis, leprosy, meningitis, pneumonia, scarlet fever, plague and a variety of respiratory infections.
NH
2
NH
2
NH
2 sulfa pyridine
N
N sulfa diazine
N
S sulfa thiazole
The classic synthetic route to these important compounds involves a key selective hydrolysis step that depends on the reactivity difference between carboxamides and sulfonamides.

NH
2
O O
CH
3
COCCH
3
Nacetylation
O
NHCCH
3
O
Cl-SOH
O chlorosulfonation
O
NHCCH
3
Acetanilide
RNH
2
O= S=O
Cl pAcetamidobenzene-
sulfonyl chloride
O
NHCCH
3
NH
2
SO
2
NHR
H
+
,
H
2
O selective hydrolysis
The success of this last step is dependent on the greater ease of hydrolysis of the carboxamide group than of the sulfonamide group.
SO
2
NHR

The sulfanilamides selectively kill bacteria but do not harm animal cells. Sulfanilamides function by blocking the enzymatic synthesis of folic acid in bacteria. Humans also need folic acid but derive it from their diet, so the action of sulfa drugs does not affect them.
H
2
N
N
N N
N
H
N-
O H
C N
CH
2 pAminobenzoic acid moiety
CH
2
CH
2
COOH
C H
COOH
Folic Acid
In 1940, D. D. Woods observed that the inhibition of growth of certain microorganisms by sulfanilamide is competitively overcome by p -aminobenzoic acid. He reasoned that sulfanilamide competes with p -aminobenzoic acid in an essential metabolic step. It is now generally accepted that sulfanilamide becomes incorporated into a "mock" folic acid that blocks further folic acid synthesis at the active site of an enzyme.

It is suggested that the similar functionality and dimensions of p aminobenzoic acid and sulfanilamide allow the latter to act at the active site of the enzyme that synthesizes folic acid, blocking or slowing folic acid synthesis. Such a compound is called an antimetabolite .
H H
N
H H
N o
6.7 A o
6.9 A
H-O C=O O= S=O
RNH o
2.3 A
Another example of an antimetabolite is methotrexate , a mock folic acid effective in treating some cancers.
H
2
N methotrexate
N
N N
N
CH
3
CH
2
N-
O H
C N
CH
2
CH
2
COOH
C H
COOH
NH
2
Because of its structural similarity to folic acid, it enters into similar reactions but cannot serve the same function. Methotrexate is toxic to all dividing cells, but it primarily acts against cancer cells because they divide more rapidly than normal cells.

Infrared Spectroscopy
1 o and 2 o Amines show sharp, characteristic absorption bands between
3300-3500 cm -1 from N-H stretch.
1 o Amines show two bands (symmetric and asymmetric stretches) while 2 o amines show a single band. 3 o Amines have, of course, no such bands.
Proton NMR Spectroscopy
N-H proton signals may appear anywhere between δ 0.5-5 . The signals may be broad and are influenced by solvent, concentration and other factors. Because of rapid proton exchange among nitrogen atoms, N-H protons usually do not spin-spin couple to H on adjacent carbon atoms.
They are best detected by adding D
2
O, which results in exchange of N-H for N-D, with disappearance of any N-H signals.
Protons on the α carbon of an aliphatic amine are deshielded and absorb typically at δ 2.2-2.9
.
13
C NMR Spectroscopy
The α carbon of an aliphatic amine is somewhat deshielded, appearing typically at δ 30-60 .
MS Spectra of Amines
If there is an odd number of nitrogen atoms present, the molecular ion peak has an odd number mass . Cleavage between the α and β carbons is a common mode of fragmentation.

The starting material for Hofmann elimination reactions is a quaternary ammonium hydroxide.
Exhaustive N -alkylation converts amines into quaternary ammonium salts:
RNH
2
R'X
(- HX)
RNH
R'
R'X
(- HX)
RN-R'
R'
R'X
R'
+
RN-R' X
-
R' quaternary
Treatment of a quaternary ammonium halide with an aqueous solution of silver oxide (actually AgOH), precipitates AgX and yields a solution containing the quaternary ammonium hydroxide.
R'
+
RN-R'
R'
X
-
Ag
2
O
H
2
O
R'
+
RN-R'
-
OH
R' quaternary ammonium hydroxide

In the late 19th century, the prominent German-born chemist, August
W. von Hofmann (1818-1895) , discovered that quaternary ammonium hydroxides on heating undergo an elimination reaction to produce an alkene. Hofmann made many important contributions to organic chemistry as a professor at the Royal College of Chemistry in London.
In the traditional Hofmann elimination, a primary amine with a β -H is exhaustively methylated to give a trimethylalkylammonium salt:
-C-C-NH
2
H
1 o amine with β -H
CH
3
-C-C-N
+
CH
3
H CH
3
trimethylalkylammonium iodide
Treatment with aqueous silver oxide produces the hydroxide salt:
CH
3
-C-C-N
+
CH
3
H CH
3
I
-
Ag
2
O
H
2
O
CH
3
-C-C-N
+
CH
3
H CH
3
-
OH trimethylalkylammonium hydroxide

The 4 o ammonium hydroxide is stable and may be isolated and purified.
When it is heated in the solid state or in solution to around 200 o
C an E2 reaction occurs. The availability of a β -H is, of course, a requirement for this reaction, and a trialkylamine (here trimethylamine) is the leaving group.
CH
3
-C-C-N
+
CH
3
H CH
3
-
OH heat
-C-C
H
HO
-
CH
3
N CH
3
CH
3
C=C + HOH + (CH
3
)
3
N
CH
2
+
N(CH
3
)
3
-
H
OH
Cyclohexylmethyltrimethylammonium hydroxide heat
CH
2
+ (CH
3
)
3
N + H
2
O
Methylenecyclohexane

In quaternary ammonium hydroxides that have two or more nonequivalent β -H's, the major product results from abstraction of the more or most acidic β -H . This is what is called the Hofmann rule.
Since alkyl groups are electron-donating relative to H, a β -H is more acidic the fewer alkyl substituents are on the carbon to which it is attached.
EXAMPLE CH
3
CH
3
C-CH-C H
3
H
N(CH
+
HO
3
-
)
3
N,N,N ,3-Tetramethylheat
2-butanaminium hydroxide
CH
3
CH
3
CHCH=CH
2
3-Methyl-1-butene major product
+ (CH
3
)
3
N + H
2
O
CH
3
CH
3
C-CH-C H
3
H less acidic
N(CH
3
+
)
3 more acidic
Recall that in eliminations involving neutral substrates, e. g., an alkyl bromide, the major product is that predicted by the Zaitsev rule : the most heavily substituted (the most stable) alkene possible. For example, if the leaving group above were bromide instead of (CH
3
)
3
N, the major product would involve loss of the alternative β -H and be 2-methyl-2-butene .
CH
3
CH
3
C CHCH
3

Essentially a variation of the Hofmann elimination, the Cope starts with a 3 o
amine oxide, another type of compound that has a positive charge on a fully substituted nitrogen just as the 4 o ammonium hydroxides that undergo
Hofmann elimination do. The Cope is a syn elimination that proceeds through a cyclic transition state:
R +
N
H :O:
R'
R''
150 o
C
R
An alkene
+ H O N
R'
A 3 o amine oxide
An N,N -dialkylhydroxylamine
+
CH
3
N CH
3
H O -
160 o C
+ (CH
3
)
2
NOH
Cyclohexylmethyldimethylamine oxide
Methylenecyclohexane
98%

Quiz 20.01
Provide both common and IUPAC names for these amines.
H
N
Methylpropylamine
N -Methylpropanamine
N
Cyclopentylethylmethylamine
N -EthylN -methylcyclopentanamine

O
N
-
K
+
+ C
6
H
5
CH
2
Br
O
CO
2
-
K +
CO
2
-
K
+
+
C
6
H
5
CH
2
NH
2
KOH
H
2
O, heat
O
N CH
2
C
6
H
5

Quiz 20.03
Provide the structures of the products of the following reactions.
NH
2
NO
2
(1) Fe, aq HCl, heat
(2) KOH, H
2
O
CH(CH
3
)
2
O
CCH
3 NH
3
H
2
/Ni, pressure, heat
CH(CH
3
)
2
NH
2
CHCH
3
N
H
2
/Ni heat
NH
2

Quiz 20.04
C
6
H
5
SOCl
2
H
C
CH
3
COOH retention
( R )-2-Phenylpropanoic acid
H
C
6
H
5
C
CH
3
COCl retention
NH
3
H
C
6
H
5
C
CH
3
NH
2
( R )-1-Phenylethanamine retention
Br
2
, NaOH
H
2
O
H
C
6
H
5
C
CH
3
CONH
2

NO
2
Br
2
, Fe
NO
2
(1) Fe, HCl
-
NH
2
Br
Br
(1) NaNO
2
, HBr,
H
2
O, 0 o
C
(2) CuBr, 100 o C

Quiz 20.06
Design a synthesis of the dye butter yellow from aniline.
NH
2
N(CH
3
)
2
NH
2
+ CH
3
I
2 eq
NH
2
NaNO
2
, HBr
H
2
O, 0 o C
N(CH
3
)
2
N=N-C
6
H
5
Butter yellow
N(CH
3
)
2 pH 5-6
+
N
2
Br
-
N=N-C
6
H
5

Quiz 20.07
An unknown amine is one of the three compounds below. When the
Hinsberg test is run, the unknown amine dissolves completely in the
Hinsberg reagent (C
6
H
5
SO
2
Cl, KOH, H
2
O), but a solid is formed when acid is added and the solution pH is adjusted to 7.
Circle the structure of the unknown amine.
3 2
3 p
3
3
N
p
N,N
p

Quiz 20.08
Exhaustive methylation of 3-methylpiperidine, followed by treatment with aqueous silver oxide and heating, yields an amine product, C
8
H
17
N. What is its structure?
CH
3
N
H
3-Methylpiperidine
(1) excess CH
3
I
(2) Ag
2
O, H
2
O
(3) heat
N
CH
3
CH
3
8
17
CH
3