NITROGEN CONTAINING
COMPOUNDS
Amines
Amines are derivatives of ammonia (NH)) in which one or
more hydrogen atoms have been replaced by alkyl
groups.
This classification is different from that of alkyl halides
or alcohols. Their classification is based on the number of
groups attached to the carbon that has the halide or
hydroxyl group.
Amines are classified as Primary (1°), Secondary (2"), or
Tertiary (3°), according to the number of alkyl groups
attached to the nitrogen atom.
Aprimary amine has only one alkyl group directly attached
to the nitrogen. A secondary amine has two alkyl groups
directly attached to the nitrogen, A tertiary amine has three
alkyl groups directly attached to the nitrogen.
This classification is different from that of alkyl halides or
alcohols. Their classification is based on the number of
groups attached to the carbon that has the halide or
hydroxyl group.
METHODS OF PREPARATION
(1) Gabriel Phthalimide Method. This involves the
treatment of phthalimide with potassium hydroxide to form
the potassium salt. The salt is then heated with an alkyl
halide to give N-alkylphthalimide, which in turn reacts with
potassium hydroxide to form a potassium phthalate salt
and a pure primary amine.
Phthalimide is prepared by heating phthalic anhydride with
ammonia. The potassium salt is made by treating
phthalimide with KOH. Usually, a proton cannot be
removed from an amide nitrogen so easily. However, like
other B-dicarbonyl compounds, imides are acidic because
the anion is resonance-stabilized.
MECHANISM. Following steps are involved : (1) Base (-
OH) abstracts a proton from the nitrogen of the imide to
form anion. (2) The imide anion reacts with alkyl halide to
form an alkyl imide (S 2 Reaction). (3) Subsequent basic-
hydrolysis gives the l° amine product.
This is an excellent method for making primary amines.
Only 1o alkyl halides can be used in this reaction. The
reaction is generally carried out in a polar solvent
(Dimethylformamide, DMF)
(2) Reduction of Nitroalkanes. Primary amines can be
obtained by reduction of nitroalkanes with H, + Pt (or Ni) or
lithium aluminium hydride.
(3)Reduction of Nitriles. Primary amines can be
prepared by reduction of nitriles (alkyl cyanides) vith H, +
Ni or lithium aluminium hydride.
(4) Reductive Amination of Aldehydes and Ketones.
Primary amines may be obtained by passing aldehyde or
ketone, hydrogen, and ammonia over nickel catalyst at
high temperature. The reaction probably goes through the
formation of an imine. and tertiary amines can also be
synthesized by reductive amination if a primary and
secondary amine is used instead of ammonia Tertiary
amines do not give this reaction.
The overall reaction can be broken down into two stages.
(a) The reaction between nitrogen compounds (NH, and 2°
amines) and ketones or aldehydes to form a carbon-
nitrogen double bond (an imine or iminium ion).
(b) The imine compound is reduced with hydrogen and a
catalyst (e.g., Ni, Pd). Sodium cyanoborohydride (NaBH
CN) can also be used as the reducing agent.
Depending on the type of nitrogen substrate, different
types of amine products are formed.
MECHANISM. The mechanism for 1° amine synthesis is
described below; the mechanisms for 2° and 3° amine
synthesis are very similar to that of l amine synthesis.
Overall, the reaction can be divided into two steps :
Step 1. Conversion of a ketone/aldehyde to an imine
(a) Nucleophilic attack by ammonia on the carbonyl
carbon atom.
(b) Proton transfer from the nitrogen to the oxygen atom.
(c) Loss of hydroxide ion forms an iminium ion
intermediate.
(d) (i) When NH, and 1° amines are the nitrogen substrate,
a proton is lost from the iminium ion intermediate to form
the imine and water. (ii) When 2° amines are the nitrogen
substrate, there is no proton loss from the iminium ion
intermediate. The intermediate can be reduced directly to
form an amine product.
Step 2 Reduction of the amine with H, and the
catalyst to form the amine.
(5) Hofmann's Degradation of Amides. This is a
good laboratory method for the conversion of an
amide to a pure primary amine. The amide is
warmed with bromine and concentrated aqueous
NaOH solution.
This reaction is also called Hofmann's
Rearrangement. Notice that the overall result is the
removal of the carbonyl group from the amide. The
product contains one carbon less than the original
amide. The method provides a useful technique for
the descent of a homologous series.
MECHANISM. The Hofmann's degradation of
amides proceeds through the following
Steps
Physical properties
(1) Lower amines are gases or low-boiling liquids
and possess a characteristic ammonia like
(2) Primary and secondary amines are capable of
intermolecular hydrogen bonding, because they
contain N-H bonds. Because nitrogen is less
electronegative than oxygen, however,
intermolecular hydrogen bonds between N and H
are weaker than those between O and H.
(3) Primary (1°) and secondary (2°) amines have
higher boiling points than similar compounds (like
ethers) incapable of hydrogen bonding, but lower
boiling points than alcohols that have stronger
intermolecular hydrog en bonds.
(4) Tertiary (3°) amines have lower boiling points
than 1° and 2° amines of comparable molecular
weight, because they have no N H bonds and are
incapable of hydrogen bonding.
(5) Amines are soluble in organic solvents
regardless of size. All amines having S 5C's arc H.
O soluble because they can hydrogen bond with H,
O. Amines. having > 5C's are H, O insoluble
because the nonpolar alkyl portion is too large to
dissolve in the polar H, O solvent.
CHEMICAL PROPERTIES
The main reactions of amines are due to the lone
pair of electrons on nitrogen. This lone pair of
electrons is available for donation to electron-
seeking reagents. Amines are nucleophilic reagents.
(1) Salt Formation. Amines are bases. They react
with mineral acids to form ammonium salts.
Conversion of amines to salts is a useful reaction
because the ammonium salts are soluble in water
but insoluble in organic solvents such as ethyl ether.
Thus, it is possible to separate an amine ICI from
nonbasic organic compounds by converting the
amine to an ammonium salt with aqueous HCL and
extracting the salt in water. Treatment of the
aqueous phase with a strong base (NaOH) releases
the free amine. For example, the separation of a
mixture of an amine and a water-insoluble but ether-
soluble ketone can be accomplished by the following
scheme.
Consider the separation of cyclohexylamine and
cyclohexanol. When cyclohexylamine is treated with
aqueous HCL, it is protonated, forming an
ammonium salt. Because the ammonium salt is
ionic, it is soluble in water, but insoluble in organic
solvents like CH CI, A similar acid-base reaction
does not occur with cyclohexanol, which is much
less basic.
Thus cyclohexylamine and cyclohexanol can be
separated by the following three steps :
Step I. Dissolve cyclohexylamine and cyclohexanol
in CH2CI2Both compounds dissolve in the organic
solvent CH2CI2,
Step 2. Add 10% HC1 solution to form two layers
Adding 10% aqueous HCl solution forms two layers.
When the two layers are mixed, the HCI protonates
the amine (RNH2) to form RNH+2CI-2 which dissolves
in the aqueous layer. The cyclohexanol remains in
the CH2CI2layer.
Step 3. Separate the layers. Draining the lower layer
out the bottom stopcock separates the two layers,
and the separation is complete. Cyclohexanol
(dissolved in CH2CI2) is in the flask. The ammonium
salt (dissolved in water) is in the funnel.
2. Reaction with Nitrous Acid. Nitrous acid (HONO)
is an unstable substance and is prepared in situ by
the reaction of sodium nitrite with dilute HCl at 0°C.
(a) Primary amines react with nitrous acid to form
nitrogen gas (seen as bubbles) and other products.
Primary amines react with nitrous acid (NaNO2/HCl
at O°C) to form diazonium salts. Alkyldiazonium
salts are unstable and decompose to give a mixture
of alcohol and alkene products along with nitrogen
gas (seen as bubbles). The decomposition yields a
carbocation.
(b) Secondary amines react with nitrous acid to form
N-nitrosamines which are water-insoluble yellow oils.
(c) Tertiary amines react with nitrous acid to form
trialkylammonium nitrite salts which are soluble in
water.
This reaction is used as the basis of a test to
distinguish between primary, secondary, and tertiary
amines. The test is known as the Nitrous Acid Test.
To summarize this test :
(a) Primary amines react with nitrous acid to produce
nitrogen gas (seen as bubbles).
b) Secondary amines react with nitrous acid to
produce a yellow oily layer.
(c) Tertiary amines react with nitrous acid to form
soluble nitrite salts. There is no visible sign of
reaction.
Separation of mixture of amines
When the mixture contains salts of primary,
secondary. and tertiary amines along with the
quaternary salt, it is first distilled with KOH solution.
The mixture of the three amines (1°. 2° and 3°)
distils over. The quaternary salt does not react with
KOH and being non-volatile is left behind.
2° and 3° Amine salts also react in this way.
The distillate contains the mixture of primary,
secondary, and tertiary amines. It may be separated
by the following methods :
(1) Fractional Distillation. The mixture of primary,
secondary, and tertiary amines may be separated by
fractional distillation because their boiling points are
quite different. This method is extensively used in
industry.
(2) Hofmann Method. This involves the treatment of
the mixture with diethyl oxalate.
(i) The primary amine forms a dialkyloxamide, which
is a solid.
(ii) The secondary amine forms a dialkyloxamic
ester, which is an oily liquid.
(iii) The tertiary amine does not react at all.
The reaction mixture is now fractionally distille1. The
tertiary amine distils over and forms the first fraction.
This is followed by the oxamic ester which forms the
second fraction. The oxamide remains behind in the
distillation flask.
The oxamide and the oxamic ester separated as
above are hydrolyzed with KOH to give back the
amines which are distilled off.
(3) Hinsberg Method. This involves the treatment
of the mixture with benzenesulfonyl chloride
(Hinsberg reagent). The solution is then made
alkaline with aqueous NaOH.
(1) The primary amine gives N-
alkylbenzenesulfonamide. This forms salt with
NaOH, which is soluble in water.
(ii) The secondary amine gives N, N-
dialkylbenzenesulforamide. This does not form salt
with NaOH (No acidic hydrogens) and is insoluble in
alkali solution.
(iii) The tertiary amine does not react. The
resulting alkaline solution is distilled when the
tertiary amine passes over and the remaining
mixture is filtered. The filtrate on acidification gives
the sulfonamide of the primary amine, while the solid
residue is the sulfonamide of the secondary amine.
The two sulfonamides thus isolated are hydrolyzed
with conc. HCl and distilled over NaOH to yield the
respective amines.
Nowadays benzenesulfonyl chloride has been
replaced by p-toluenesulfonyl chloride CH3 – C6H4
–SO2Cl, since the substituted sulfonamides thus
formed are stable solids which can be easily
recrystallized.
Stereochemistry of Amines
The amines of the type R R2R3N (three different
alkyl groups attached to chiral N) exist in the form of
racemic mixture that cannot be resolved into
enantiomers because of rapid inversion of an
enantiomer to its mirror image. This inversion is
called amine inversion, nitrogen inversion or
flipping.
ELECTROPHILIC SUBSTITUTION
REACTION OF ANILINE
Aromatic amines give the aromatic substitution
reactions as given by benzene. Aniline is more
reactive then benzene. The presence of amino
group activates the aromatic ring and directs the
incoming group preferably to ortho and para
positions. This ia clear from the following structures
in which electron density is more at and para
(structures III to IV).
Therefore, subatitution mainly occurs at ortho
and para positions. Due to strong activating effect of
-NH,, aromatic amines undergo electrophilic
substitution reactions readily. Therefore, it is difficult
to stop the reaction to monosubstitution stage.
However, in order to stop the reaction to
monosubstitution stage, the activating effect of the
amino group has to be reduced. This can be done
by acetylation with acetic anhydride in the presence
of pyridine. Acetyl group is electron withdrawing
group and therefore, the electron pair of N-atom is
withdrawn towards the carbonyl group as shown by
the following resonating structures :
Therefore, the lone pair of electrons on nitrogen
is less available and the activating power of –NH2
Group is decreased This method is called the
protection of the amino group by acetylation and
can be used to control of electrophilic substitution
reaction. This also prevents the formation of di and
tri substituted products.
The acetyl group is then removed by hydrolysis to
get back the amine. Some of these reactions are
given below :
(i) Halogenation. Aniline reacts with bromine water
readily to give a white precipitate of 2, 4, 6-
tribromoant
This reaction is used as a test for aniline.
However, if monosubstituted derivative is desired,
aniline is first acetylated with acetyl chloride and the
halogenation is carried out. After halogenation, the
acetyl group is removed by hydrolysis and only
halogen derivative is oblained.
It may be noted that - NH, group directs the
attacking group at o- and p-positions and therefore,
o- and p-derivatives are obtained.
As already explained acetylation deactivates the
ring and controls the reaction to monosubetitution
(2) Nitration. Aromatic amines cannot be nitrated
directly because they are readily oxidized. This is
because, ENO, is a strong oxidising agent and in
partial oxidation of the ring to form a black mass.
However. Under controlled conditions, nitration of
aniline gives unexpectedly 47% m-nitro aniline in
addition to o- and p-nitroaniline.
The reason for the formation of large amount of m-
nitroaniline is that under strongly acidic conditions
aniline geta protonated to anilinium ion (-NH group).
This is deactivating group and is meta directing.
Therefore, to solve this problem, nitration in carried
out by protecting the NH, group by acetylation. The
acetylation deactivates the rim ring and therefore,
controls the reaction The of nitroscetanilides
removes the and gives back amines.
(3) Sulphonation. Sulphonation of aniline is carried
out by heating aniline with sulphuric acid. The
product formed is anilinium hydrogen sulphate which
on heating gives sulphanilic acid.
The sulphanilic acid exists as a dipolar ion (structure
II) which has acidic and basic groups in the same
molecule.Such ions are called Zwitter ions or inner
salts.
Aniline does not undergo Friedel Craft reaction
(alkylation and acetylation) because of the salt
formation with
aluminium chloride (Lewis acid which is used as a
catalyst).
As a result, nitrogen of aniline aquires positive
charge and hence acts as a strong deactivating
group for further reaction.
preparation of diazonium salts
Aromatic diazonium salts are prepared by
heating an ice cold solution of aromatic primary
amine in mineral acid like HC1 or H2SO4 with an ice
cold solution of nitrite dissolved in water. The
temperature maintained between 273-278 K
because most of the diazonium salta decompose at
higher temperature.
The diazonium salt so formed remains in the
solution. Since the diazonium salts are unstable and
eral substances, they are not isolated in solid form
but are used directly in the solution.
Nitrite esters formed from alcohols and nitrous acid
are also used to form diazonium salta on treatment
aromatic primary amines.
For example, benzene diazonium chloride is
prepared by treating an ice-cold solution of aniline in
hydrochloric with an ice cold solution of sodium
nitrite at about 0°C. The reaction of converting
aromatic primary and diazonium salt is called
diazotisation.
Diazotisation of amines
The of amines is believed to occur by the following
mechanism. Nitrous acid formed by the reaction of
soidum nitrite and mineral acid, takes up a proton
from the acid and undergoes to form nitrosonium
ion.
The electrophilie nitrosonium ion reacts with the
nitrogen of the amine and combines with the lone
pairs of electrons at N to form N-nitroso derivative,
which by protonic shift rearranges to diazohydroxide.
The diazohydroxide in acidic solution takes up a
proton and by the elimination of water molecule
forms ion. which may take up acid anion X to form
diazonium salt.
Stability of Diazonium salt
Aromatic diazonium salts are stable due to the
dispersal of positive charge over the benzene ring
as ahown below.
PHYSICAL PROPERTIES OF DIAZONIUM SALTS
The general physical properties af diazonium
salts are :
(1) Diazonium salts are generally colourlese,
crystalline solids.
(2) These are readily soluble in water and are
stable in cold but react with water when warmed.
They are less soluble in alcohol.
(3) They are unstable and explode in dry state.
Therefore, they are generally used in solution state.
(4 ) Certain diazonium salts such as fluoroborates
are water insoluble and are stable enough to be
dried and stored.
(5) Their aqueous molutions are neutral to litmus
and conduct electricity due to the presence of iona
chemical properties of diazonium
salts
The reactions of benzene diazonium salts can be
broadly divided into two types :
a. Reactions involving displacement of nitrogen
b. Reactions retention of diazo group
a. Reactions Involving displacement of nitrogen
Diazo group being a very good leaving group, is
readily substituted or replaced by other groups. In
these reections of diazonium salts in lont an N, and
different groups are introduced in its place. Some of
the importas ment reactions are :
1) Replacement by - OH group. When an aqueous
of diazonium salt in boiled (upto 283 K) or ste
diazonium group is replaced by -OH group.
2) Replacement by hydrogen. When diazonium
salt is treated with mild reducing agents such an
hypophorous acid) or ethanol, benzene is obtained.
The hypophosphorous acid or ethanol are
themselves get oxidized acid and ethanal
respectively.
This complete process involving diazotisation amine
followed by reduction of diazonium salt or
replacement diazo group of hydrogen is called
deamination.
3) Replacement by Cl and Br group. When a
diazonium salt solution warmed with cuprous
chloride in chloric acid or cuprous bromide in
hydrobromic acid the corresponding halide is
formed.
This reaction is called Sandmeyer reaction.
When the diazonium salt solution is warmed with
copper powder and the corresponding halogen acid,
the respective talogen is introduced. The reaction is
a modified form of Sandmeyer reaction and is known
as Gattermann reaction.
The yield of Sandmeyer reaction is found to be
better than Gattermann reaction.
(4) Replacement by iodo (-I) group. When
aqueous solution of benzene diazonium salt is
warmed with of potassium iodide, aryl iodide is
formed.
lodine is not easily introduced into the benzene ring
directly, therefore, this reaction provides an indirect
method fot preparing iodo compounds.
(5) Replacement by fluoro (-F) group. When
diazonium salt is treated with acid (HBF4 ) benzene
diazonium is precipitated, which on heating
decomposes to fluorobenzene. This reaction is
called Balz Schiemann reaction.
(6) Replacement by cyano (-CN) group. When
benzene diazonium salt is treated with copper cyan
cyanobenzene is formed.
This method of preparing carboxylic acids is
more useful than carbonation of Grignard reagents.
(7) Replacement by nitro (-NO2) group.
Nitrobenzene is prepared by heating diazonium
fluoroborate will aqueous NaNO2 in the presence of
copper powder.
Alternatively, nitro compounds may be prepared by
treating diazonium salt with nitrous acid in the
presence of grous oxide.
(8) Replacement by thio (-SH) group. When
diazonium salt is treated with potassium
hydrosulphide, is produced.
B. Reactions involving retention of
diazo group
Azo Coupling Reactions. The second general
reaction of diazonium salts is coupling. a diazonium
salt is treated with an aromatic compound that
contains a strong electron-donor group, the two
rings join together to form an azo compound, a
compound with a nitrogen-nitrogen double bond.
Azo compounds are highly conjugated,
rendering them coloned. Many of these compounds,
such as the azo compound "butter yellow, " are
synthetic dyes. Butter yellow was once used to color
margarine.
This reaction is another example of electrophilic
aromatic substitution, with the diazonium salt acting
as the electrophile. Like all electrophilic
substitutions, the mechanism has two steps :
addition of the electrophile (the diazonium ion) to
form a resonance-stabilized carbocation, followed by
deprotonation.
MECHANISM All azo coupling reactions take place
by the following steps :
Step 1. Electrophilic diazonium ion resonance -
stabilized carbocation.
Step 2. Loss of proton regenerates the aromatic
ring.
Because a diazonium salt is only weakly
electrophilic, the reaction occurs only when the
benzene ring has a strong electron-donor group Y,
where Y = NH2, NHR, NR2, or OH. Although these
groups activate both the ortho and para positions,
substitution occurs unless the para positions,
already has another substituent present.
To determine what starting materials are needed to
synthesize a particular azo compound, always divide
the molecule into two components : one has a
benzene with a diazonium ion, and one has a
benzene ring with a very strong electron-donor
group.
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