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more hydrogen atoms have been replaced by alkyl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.