Beruflich Dokumente
Kultur Dokumente
Aromatic and heterocyclic amines are generally known by historical names. Phenylamine
is called aniline and its derivatives are named as derivatives of aniline.
The names and structures of some common heterocyclic amines are shown below:
Amines serve many functions in living organisms. Because of their high degree of
biological activity, many amines are used as drugs and medicines. The structures and uses
of some important biologically active amines are given below:
2. CLASSIFICATION OF AMINES
Amines are classified as primary (1), secondary (2) or tertiary (3) corresponding to
one, two or three alkyl groups attached to nitrogen. In secondary and tertiary amines, the
alkyl or aryl groups may be the same or different.
Quaternary ammonium salts have four alkyl or aryl groups attached to nitrogen atom.
Thus, the nitrogen atom bears a positive charge. The four groups joined to nitrogen in the
ammonium ion may be same or different. For example,
Primary Amines
Secondary and tertiary aliphatic amines are named in a similar way. We either designate
the alkyl/aryl groups individually if they are different or use prefixes dior tri- if they are
same. Some examples are given below:
Secondary Amines
Tertiary Amines
B. IUPAC Names
Under the IUPAC nomenclature, amines are named by adding the suffix -amine to the
name of the chain or ring system to which the amino group is attached with removal of the
final e.
Primary Amines
Tertliary Amines
Amines have higher boiling points than non-polar compounds of the same molecular
weight but lower boiling points than alcohols or carboxylic acids. Because nitrogen is less
electronegative than oxygen, the NH bond is less polar than the OH bond. Therefore,
amines form weaker hydrogen bonds than do alcohols of similar molecular weights. Primary
and secondary amines have boiling points that are lower than those of alcohols but higher
than those of ethers of similar molecular weights.
Hydrogen bonding is more important with 1 than with 2 amines. Therefore, primary
amines have higher boiling points than those of secondary amines. Tertiary amines have no
hydrogen bonding, they have lower boiling points than primary and secondary amines of
similar molecular weights. Table 1. gives melting points, boiling points and water
solubilities of some simple aliphatic and aromatic amines. All these properties increase with
increasing molecular weight as a result of the greater intermolecular attraction with the
larger members in the series.
Thus, we observe a primary amine always boils higher than a secondary amine of the
same molecular weight.
All amines, even tertiary ones, form hydrogen bonds with hydroxylic solvents such as
water and alcohols. Therefore, amines tend to be soluble in alcohols and lower molecular
weight amines (up to about six carbon atoms) are relatively soluble in water.
Primary Amines
Secondary Amines
Tertiary Amines
The most important property of amines is their characteristic odour of rotting fish. Some
of the diamines are particularly pungent. However, the methylamines and ethylamines
smell like ammonia.
Aromatic amines are generally very toxic. They are readily absorbed through the skin
often with fatal results. Aromatic amines are very easily oxidised by air. Most are colourless
when pure, they are often discoloured due to the presence of oxidation products.
As nitrogen is less electronegative than oxygen, amines are more basic than alcohols.
However, amines are stronger bases than water, but are far weaker bases than
hydroxide ions, alkoxide ions and carbanions.
Since amines are much more basic than water, aqueous solutions of amines have basic
properties. An amine can abstract a proton from water giving an ammonium ion and a
hydroxide ion.
The equilibrium constant for this reaction is called the base-dissociation constant
(basicity constant) and is denoted by Kb . Kb is given by the expression
+
[R - NH3 ][OH- ]
Kb =
[R - NH2 ]
water being in large excess, concentration of water is not included in the above expression.
This gives us a convenient method of comparing the relative basicities of amines. Values
of Kb for most amines are fairly small and the equilibrium for this dissociation constant lies
pKb = log Kb
The values of Kb, pKb and pKafor some amines are listed in Table 2.
The larger the value of Kb (or smaller the value of pKb), the greater is the tendency of
the amine to accept a proton from water and thus the greater will be theconcentrations of
+
R - NH3 and OH in the solution. Larger values of Kb are associated with those amines that
are stronger bases and smaller values of Kb are associated with those amines that are
weaker bases. Just the opposite is true for values of pK b.
The basicity constant for ammonia at 25C is 1.8 10 5, we can have its pKb as given
below:
[NH4+ ][OH- ]
K b= = 1.8 105
[NH2 ]
= 4.74
Another way to compare the basic strengths of amines is to compare the acidity
constants or pKa values of their conjugate acids, the alkylammonium ions. We have the
equilibrium as
[R - NH2 ][H3O+ ]
Kb =
[R - NH3+ ]
pKa = log Ka
Ka Kb = [H3O+] [OH]
= Kw = 1.0 1014
pKa + pKb = 14
pKb = 14 pKa
If the amine is strongly basic, the ammonium ion will hold the proton tightly, it will have
larger pKai.e., it will not be very acidic. On the otherhand, if the amine is weakly basic the
ammonium ion will not hold the proton tightly and will be much more acidic (it will have a
small pKa).
Primary Amines
Secondary Amines
Tertiary Amines
We can explain this on the basis of electron-releasing ability (+I effect) of an alkyl
group. An alkyl group has +I effect, it releases electrons and stabilises the alkyl ammonium
ion that results from the acid-base reaction.
This explanation is supported by measurements in the gas phase. The basicities of the
following amines increase with increasing methyl substitution.
We might expect secondary amines to be stronger than primary amines and tertiary
amines to be the strongest of all. This is not the order of basicity of these amines in
aqueous solution. In aqueous solution the order is
It is observed that the introduction of an alkyl group into ammonia increases the basic
strength markedly as expected. The introduction of second alkyl group further increases the
basic strength but the effect of introducing the second alkyl group is much less marked. The
introducing of a third alkyl group to yield a tertiary amine, however, decreases the basic
strength. It becomes even less basic than a primary amine. This is due to solvation effects.
The basicity of an amine in water is determined not only by the availability of electrons
on the nitrogen atom but also by the extent to which cation, formed by uptake of a proton,
stabilises by solvation. The more the number of hydrogen atoms attached to nitrogen in the
cation the greater is the possibility of solvation via. hydrogen bonding between these and
hydrogen.
Whereas their related pKa values in water are 10.61, 11.27 and 9.87. There is no
solvation of butylamines in chlorobenzene.
The effect of introducing electron-withdrawing groups e.g., Cl, NO2, close to the basic
centre NH 2 is to decrease the basicity due to their I effect. Thus, we observe the amine
is found to be virtually non basic due to the three powerful electron-withdrawing CF3
groups.
Amides are found to be very weakly basic in water. Thus, acetamide pK a ~ 0.5 is very
weak in comparison to ammonia pKa = 9.25. This is due to electronwithdrawing mesomeric
effect of C = O group.
The lone pair of electrons on the nitrogen are withdrawn by the adjacent C = O group.
If two C = O groups are present, the resultant imides are often sufficiently acidic to form
alkali metal salts, e.g., phthalimide is so acidic that on treatment with potassium hydroxide
it forms potassium phthalimide because the conjugate base can stabilise by resonance.
The cation is greatly stabilised with respect to the neutral molecule because the
structures are equivalent and there is no charge separation. Thus, protonation of guanidine
makes it energetically favourable and guanidine becomes an extremely strong base.
Urea has two amino groups joined to aC=O group. On protonation we get two equivalent
resonating structures. Therefore, it acts as a monoacidic base.
Aromatic amines are much weaker bases than the corresponding non aromatic amine,
cyclohexylamine. For example, aniline is a very weak base (pK a = 4.62) compared to
ammonia (pKa = 9.25) or cyclohexylamine (pKa = 10.68).
Anilinium ion has got only two resonating structures and consequently resonance does
not stabilise the anilinium ion to as extent as it does aniline itself. The aniline is thus
stabilised to a greater extent with respect to the anilinium cation and it is energetically
unfavourable for aniline to take a proton. Therefore, aniline acts as a weaker base (pKa =
4.62) compared to cyclohexylamine, pKa = 10.68.
Electrons on nitrogen atom are withdrawn by phenyl groups and are not available for
protonation.
Introduction of alkyl e.g., CH3 groups on to the nitrogen of aniline results in increase in
basic strength. Thus, dimethyl aniline is a stronger base than methylaniline which is
stronger than aniline.
Irregular effects of introduction of methyl group into o-, m-, and p-positions in aniline
have been observed. When a methyl group is attached to the benzene nucleus in aniline,
the basicity increases only if the group is at para position. Thus, we have
o-Nitroaniline is such a weak base that its salts are largely hydrolysed in aqueous
solution, while 2,4-dinitroaniline is insolube in aqueous acid and 2,4,6trinitroaniline behaves
as an amide, called picramide. It readily undergoes hydrolysis to picric acid.
We show below the conjugation of lone pair of electrons of OCH3 group with the
electrons of the benzene nucleus. This results in increasing basicity when OCH3 group is
there at the p-position.
We have seen difference between the basicities of dimethylaniline and aniline is very
little. However, the basicity of 2,4,6-trinitro-N,N-dimethyl aniline is about40,000times than
that
feresterically with the large NO2 groups in both the o-positions. As a result of this the
extended conjugation of the lone pair of electrons with NO2 groups is inhibited because
the p-orbitals on the N atoms are no longer parallel to the p-orbitals of the ring carbon
atoms. Thus the expected base weakening by mesomeric electron withdrawl does not take
6. PREPARATION OF AMINES
A.Direct alkylation of Ammonia-Ammolysis of Halides
We know that alkyl halides undergo nucleophilic substitution reactions. Salts of primary
amines can be prepared by the reaction of alkyl halides with ammonia by nucleophilic
substitution reactions. Subsequent treatment of the resulting aminium salts with base gives
primary amines
For example,
We give the general scheme of reactions where overalkylations may give a mixture of
products even when equivalent molar amounts of ammonia and alkyl halide are used.
Pure primary amines can be prepared in good yield by a method known as Gabriel
Synthesis. This method involves the alkylation of a protected form of ammonia.
Phthalimide, prepared from ammonia and phthalic acid, is converted into potassium
phthalimide. Alkylation of potassium phthalimide with any alkyl halide results in the
formation of N- alkyl phthalimide. Alkaline hydrolysis produces the desired primary amine
and phthalic acid, obtained as a byproduct is recycled again.
The phthalimide anion is a strong nucleophile and can enter into displacement reactions
with alkyl halides. It reacts with alkyl halides by SN2 mechanism displacing a halide ion.
Nitro compounds undergo ready reduction to yield primary amines. The method gives
the most general synthesis of aromatic amines because aromatic nitro compounds of a wide
This method cannot be used when some easily hydrogenated group is present in the
molecule.
Among the most common chemical reducing agents are metals and acid, usually, iron,
zinc or tin and dilute hydrochloric acid. In the laboratory, reduction of nitrobenzene to
aniline is generally carried out by using dilute hydrochloric acid and granulated tin. In the
acidic solution aniline is obtained as its salt.
The free amine is liberated from the solution by the addition of base and is
steamdistilled from the reaction mixture.
Stannous chloride, SnCl2, and hydrochloric acid are especially useful combination when
other reducible groups, such as carbonyl groups are present. For example,
Selective reduction of one nitro group of a dinitro compound can be achieved by using
sodium hydrogen sulphide in alcoholic solution.
It is not always possible to predict which nitro group will be reduced. However, treating
2,4-dinitrotoluene with H2S and ammonia results in reduction of the 4-nitro group.
On the other hand reduction of 2,4-dinitroaniline causes reduction of the 2-nitro group.
Amides, oximes and nitriles can be reduced to amines. Reduction of a nitrile or an oxime
yields a primary amine whereas reduction of an amide can yield a primary, secondary or
tertiary amine.
Nitriles can be prepared from alkyl halides and CN or from aldehydes and ketones as
cyanohydrins.
Oximes can be prepared from aldehydes and ketones by the reaction with
hydroxylamine. Amides can be prepared from acid chlorides, acid anhydrides or esters.
(i) Reduction of Nitriles
The side reaction may be suppressed by carrying out the hydrogenation in the presence
of excess ammonia.
Secondary amine formation may also be minimized by carrying out the reaction in acetic
anhydride as solvent. The primary amine produced is rapidly converted into the amide. The
amine may then be obtained by hydrolysis of the amide.
Since nitriles are easily available by several methods, many primary amines may be
synthesised by this procedure.
(ii) Reduction of Oximes
Oximes can be reduced to primary amines. Since oximes are easily generated in high
yield, this is a useful synthetic method. Reduction can be carried out with hydrogen and a
catalyst or with LiAlH4.
Oximes are also easily reduced with sodium in alcohol, which is a safer method than the
use of LiAlH4.
Amides are reduced by lithium aluminium hydride in refluxing ether. We can get
primary, secondary or tertiary amine depending upon the nature of the amide.
The reduction is unusual because a C=O group is reduced to CH2. Yields are generally
good.
Examples,
The reducing agents generally used are hydrogen and a catalyst (such as nickel) or
sodium cyanohydridoborate (NaBH3CN) or LiBH3CN. The reaction involves reduction of the
intermediate imine obtained from aldehyde or a ketone.
This side reaction may be minimized by using a large excess of ammonia in the reaction
medium.
However, reductive amination may also be used as a method for the synthesis of
secondary amines as shown by the following example:
When ammonia or a primary amine is used there are two possible pathways for the
formation of the product-via. an amino alcohol which is called hemiaminal or via. an imine.
When secondary amines are used, an imine cannot form and therefore, the pathway is
through the hemiaminal or through an iminium ion
Here R may be an alkyl oraryl group. If the alkyl group is of six or seven carbon atoms
low yields of the product are obtained.
When bromine and sodium methoxide are used instead of bromine and sodium
hydroxide, the product of addition to the isocyanate is the formation of a carbamate,which
is easily isolated and can be hydrolysed to the anime.
Mechanism
The mechanism of the reaction follows the following pattern:
The first step in the above reaction sequence is the formation of the N- bromoamide. A
proton is removed from the nitrogen atom. The deprotonated intermediate undergoes
simultaneous rearrangement with the migration of the alkyl group to give the formation of
the isocyanate.
N-Bromoamide is quite acidic and loses a proton to the base because of the presence of
two electron withdrawing groups acyl and bromine atom.
This has been established by isotopic labelling. When two amides are rearranged,
together no cross products are obtained. The isocyanate produced may be isolated in
anhydrous conditions but the reaction is generally carried out in aqueous or alcoholic
solution in which the isocyanate is converted into an amine or a urethane respectively.
In this case it is the nucleophilicity of the migrating group that facilitates the reaction.
Hofmann rearrangement provides an efficient route for making both aliphatic and
aromatic amines. Thus, we have
The Curtius rearrangement involves pyrolysis of acyl azides to yield isocyanates. The
reaction gives good yields of isocyanates since no water is present to hydrolyse them to
amines. However, they can be subsequently hydrolysed in the presence of water or alcohol.
The addition of water to isocyanate initially results in the formation of carbamic acid,
which is unstable and decarboxylates to give amines. With alcohols the corresponding
carbamates are obtained, which can be hydrolysed to give amines.
Azides may be treated with caution as they may decompose explosively. The isocyanate
may be isolated by carrying out the reaction in an aprotic solvent such as chloroform.
Generally, an alcoholic solvent is used with which the isocyanate reacts to form a urethane.
The amines formed contain one carbon atom less than the original acyl azide. It is due to
this reason that the reaction is sometimes referred to as Curtius degradation rather than
Curtius rearrangement.
Mechanism
Sulphuric acid is the most common catalyst, but Lewis acids have also been used. Good
results are obtained for aliphatic R groups. When R is aryl, the yields are variable.
It is almost a direct method of converting carboxylic acids into primary amines, but
conditions are more drastic. Under the acid conditions employed, the isocyanate is virtually
never isolated. However, Schmidt reaction is applicable if the acid does not contain other
groups that are sensitive to concentrated sulphuric acid.
REFERENCES:
1.Organic Chemistry by Morrison, R.T. and Boyd, R.N. Darling Kindersley (India) Pvt. Ltd.
(Pearson Education).
2. Organic Chemistry by Graham Solomons, T.W. John Wiley and Sons.
3. Introduction to organic chemistry by Andrew Streitwieser, Jr. and Claylon H. Heathcock
Macmillan Publishing Company.
4. Organic Chemistry by Seyhan Ege A.I.T.B.S. Publishers and Distributers J5/6, Krishan
Nagar, Delhi- 110051.
5. Advanced Organic Chemistry by Jerry March John Wiley and Sons.
6. Organic Chemistry by L.G. Wade, Jr. Pearson Education.
7. A Guide Book to Mechanism in Organic Chemistry by Peter Sykes Pearson Education.