Chemistry

UNIT 9: AMINES AND AMINO ACIDS

Key unit competency:

The learner should be able to relate the chemical nature of the amines and

aminoacids to their properties, uses and reactivity.

Learning objectives

At the end of this unit, the students will be able to:

• Explain the zwitterion forms in the solution of different pH.

• Explain the isoelectric point in amino acids.

• Describe the physical properties and uses of amines.

• Describe the preparation methods of the amines.

• Describe the reactions of amino acids and amines with other substances.

• Classify amines as primary, secondary and tertiary amines.

• Compare and contrast the physical properties of the amino acids to those of

carboxylic acids and amines.

• Test the presence of amines and amino acids in the solution. 

9.1. Nomenclature and classification of amines

Amines are one of organic compounds containing nitrogen. They are one of the

most important classes of organic compounds which are obtained by replacing

one or more hydrogen atoms by an alkyl or aryl group in a molecule of ammonia

(NH₃). They are present in vitamins, proteins, hormones, etc. They are extensively

used in the manufacturing of many drugs and detergents.

9.1.1 Classification of amines

Nitrogen has 5 valence electrons and so is trivalent with a lone pair. As per VSEPR

theory, nitrogen present in amines is sp³ hybridized and due to the presence of lone pair, it is pyramidal in shape instead of tetrahedral shape which is a general structure for most sp3

 hybridized molecules. Each of the three sp³  hybridized orbitals of nitrogen overlap with orbitals of hydrogen or carbon depending upon the configuration of amines. Due to the presence of lone pair, the C-N-H angle in amines is less than 109 degrees which is characteristic angle of tetrahedral geometry. The angle in amines is near about 108 degrees.

9.1.2 Nomenclature of amines

In organic chemistry, the names of the compounds are given according to the

guidelines provided by IUPAC. In this regards, amines are named by ending with –

amine. The IUPAC system names amine functions as substituents on the largest alkyl

group. 

9.2 Physical properties, natural occurrences and uses of amines.

9.2.1 Physical properties of amines

Tertiary amines do not bond to each other by hydrogen bond and they have boiling

points similar to those of hydrocarbons of the same molecular weight. However,

primary, secondary and tertiary amines form hydrogen bond with water and amines

with low-molecular weight are generally soluble in water.

Generally the boiling point of amines increases as the molecular weight increase

and they boil at higher temperatures than alkanes but at lower temperatures than

alcohols of comparable molar mass.

The amines are soluble in organic solvent and the solubility decreases as the

molecular weight increases. The Table 9.3 summarizes some physical properties of

some amines.

9.2.2 Natural occurrence of amines and their usage

Natural amines occur in proteins, vitamins, hormones, etc. and they are also prepared

synthetically to make polymers, drugs and dyes.

Amines can be used as dyes (colorants) or as drugs: Primary aromatic amines are

used as a starting material for the manufacture of azo dyes. They react with nitrous

(II) acid to form diazonium salt which can undergo a coupling reaction in order to

form an azo compound. As azo compounds are highly coloured, they are widely

used in dyeing industries. Examples include Methyl orange and Direct brown 138.

In medicine, amines can be used as drugs. 

• Chlorpheniramine is an antihistamine that helps to relief allergic disorders

due to cold, hay fever, itchy skin, insect bites and stings.

• Diphenhydramine is the common antihistamine.

• Chlorpromazine is a tranquillizer that anaesthetizes without inducing sleep.

It is used to relieve anxiety, excitement, restlessness or even mental disorder.

• Acetaminophen is also known as paracetamol or p-acetaminophenol, it is

an analgesic that relieves pains such as headaches. It is believed to be less

corrosive to the stomach and is an alternative to aspirin.

Amines are widely encountered in biological and pharmacological studies. Some

important examples are the 2-phenylethylamines, some vitamins, antihistamines,

tranquilizers, and neurotransmitters (noradrenaline, dopamine and serotonin)

which act at neuromuscular synapses.

9.3 Preparation of amines.

The amines can be prepared based on the following reactions:

9.3.1 Alkylation of ammonia

9.3.2. Gabriel phthalimide synthesis

This procedure is used for the preparation of primary amines. Phthalimide on

treatment with ethanolic potassium hydroxide forms potassium salt of phthalimide

which on heating with alkyl halide followed by alkaline hydrolysis produces the

corresponding primary amine. However, primary aromatic amines cannot be

prepared by Gabriel phthalimide synthesis because aryl halides do not undergo

nucleophilic substitution with the anion formed by phthalimide.

9.3.3. Hoffmann bromamide degradation reaction

Hoffmann developed a method for the preparation of primary amines by treating an

amide with bromine in an aqueous or ethanolic solution of sodium hydroxide. This

is a degradation reaction with migration of an alkyl or aryl group taking place from

carbonyl carbon of the amide to the nitrogen atom.

The reaction is valid for the preparation of primary amines only, and it yields

uncontaminated compound with other amines. 

9.3.4 Reduction of amides

Similarly to reduction of amides, lithium aluminium hydride (LiAlH₄) reduces amides to amines. 

9.3.5 Reduction of nitriles

Nitriles are reduced to amines using hydrogen in the presence of a nickel catalyst, although acidic or alkaline conditions should not be used to avoid the possible hydrolysis of the -CN group. LiAlH₄ is more commonly employed for the reduction of nitriles on the laboratory scale.

9.3.6 Reduction of nitro compounds

Nitro compounds are reduced to amines by passing hydrogen gas in the presence

of finely divided nickel, palladium or platinum and also by reduction with metals

in acidic medium. Nitroalkanes can also be similarly reduced to the corresponding

alkanamines.

Reduction with iron scrap and hydrochloric acid is preferred because FeCl₂ formed gets hydrolysed to release hydrochloric acid during the reaction. Thus, only a small amount of hydrochloric acid is required to initiate the reaction.

9.4. Chemical properties of amines

Difference in electronegativity between nitrogen and hydrogen atoms and the

presence of unshared pair of electrons over the nitrogen atom makes amines

reactive. The number of hydrogen atoms attached to nitrogen atom also is involved

in the reaction of amines; that is why the reactivity of amines differ in many reactions.

Amines behave as nucleophiles due to the presence of unshared electron pair.

The chemical properties of amines are summarized in the reactions below.

9.4.1 Reactions of amines diluted with acids

Amines, like ammonia, are bases. Being basic in nature, they react with acids to form salts.

9.4.2 Reactions of amines (alkylation, acylation, and sulfonation)

Acyl chlorides and acid anhydrides react with primary and secondary amines to

form amides. Tertiary amines cannot be acylated due to the absence of a replaceable

hydrogen atom. 

9.4.3. Reaction with carboxylic acid

Because amines are basic, they neutralize carboxylic acids to form the corresponding

ammonium carboxylate salts. Upon heating at 200°C, the primary and secondary

amine salts dehydrate to form the corresponding amides.

9.4.4. Reaction with nitrous acid

Nitrous acid, HNO₂ is unstable. It is produced indirectly using a mixture of NaNO₂ and a strong acid such as HCl or H₂SO₄ in diluted solution. Primary aliphatic amines react with nitrous acid to produce a very unstable diazonium salts which spontaneously decomposes by losing N₂ to form a carbenium ion. Further, the carbonium ion is used to produce a mixture of alkenes, alkanols or alkyl halides, with alkanols as major product said above

Primary aromatic amines, such as aniline (phenylamine) forms a more stable

diazonium ion at 0^oC –5°C. Above 5°C, it will decompose to give phenol and N₂. Diazonium salts can be isolated in the crystalline form but are usually used in solution and immediately after preparation, due to its rapid decomposition.

9.4.5. Reactions with ketones and aldehydes

Primary amines react with carbonyl compounds to form imines. Specifically,

aldehydes become aldimines, and ketones become ketimines. In the case of

formaldehyde (R’ = H), the imine products are typically cyclic trimers.

Secondary amines react with ketones and aldehydes to form enamines. An

enamine contains a C=C double bond, where the second C is singly bonded to N as

part of an amine ligand.

9.4.6. Neutralization reactions

Tertiary amines (R₃N) react with strong acids such as hydroiodic acid (HI), hydrobromic acid (HBr) and hydrochloric acid (HCl) to give ammonium salts R₃NH⁺X^-.

9.5. General structure of amino acids and some common examples

9.5.1. General structure of amino acids

Amino acids are organic compounds containing amine (-NH₂) and carboxyl (-COOH)

functional groups, along with a side chain (R group) specific to each amino acid.

The key elements of an amino acid are carbon (C), hydrogen (H), oxygen (O), and

nitrogen (N). About 500 naturally occurring amino acids are known.

The general structure of amino acid is shown by the functional group (-NH₂) and

a carboxylic acid group (-COOH) attached to the same carbon and they are called

α-amino acids.

The R group is the part of the amino acid that can vary in different amino acids. It

can be a hydrogen (in that case, the amino acid is called Glycine) or a –CH₃ group (Alanine) or other radicals.

9.5.2. Common Amino Acids

Among the 500 known amino acids, there are 20 important α-amino acids, as shown

in the Table 9.4 below. Each amino acid has a common name. You will notice that

the names in common used for amino acids are not descriptive of their structural

formulas; but at least they have the advantage of being shorter than the systematic

names. The abbreviations (Gly, Glu, …) that are listed in table below, are particularly

useful in designating the sequences of amino acids in proteins and peptides. 

The first amino acid to be isolated was asparagine in 1806. It was obtained from

protein found in asparagus juice (hence the name). Glycine, the major amino acid

found in gelatin, was named for its sweet taste (Greek glykys, meaning “sweet”). In

some cases an amino acid found in a protein is actually a derivative of one of the

common 20 amino acids.

9.6. Comparison of physical properties of amino acids to those of carboxylic acids and amines

The amino acids, carboxylic acids and amines have different functional groups; this

is the base of their different physical properties as shown in the Table 9.5.

The first amino acid to be isolated was asparagine in 1806. It was obtained from protein found in asparagus juice (hence the name). Glycine, the major amino acid found in gelatin, was named for its sweet taste (Greek glykys, meaning “sweet”). In some cases an amino acid found in a protein is actually a derivative of one of the common 20 amino acids.

9.7. Chemical properties of amino acids

The reactivity of amino acids involves the reactions of both amines and carboxylic

acids. Some of these reactions are given below.

9.7.1. Acid–base properties of amino acids

As the name suggests, amino acids are organic compounds that contain both a

carboxylic acid group and an amine group. Amino acids are crystalline, high melting

point (>200°C) solids. Such high melting points are unusual for a substance with

molecules of this size — they are a result of internal ionisation. Even in the solid

state, amino acids exist as zwitterions in which a proton has been lost from the

carboxyl group and accepted by the nitrogen of the amine group:

So instead of hydrogen bonds between the amino acid molecules there are stronger

ionic (electrovalent) bonds. This is reflected in the relative lack of solubility of amino

acids in non- aqueous solvents compared with their solubility in water.

Zwitterions exhibit acid–base behaviour because they can accept and donate

protons. In acids a proton is accepted by the carboxylic acid anion, forming a unit

with an overall positive charge:

In alkalis the reverse occurs with the loss of a proton from the nitrogen atom: 

Carboxylic acids have acidic properties and react with bases. Amines have basic

properties and react with acids. It therefore follows that amino acids have both

acidic and basic properties.

9.7.2. Isoelectric point in aminoacids (pI)

The isoelectric point (pI), is the pH at which a particular molecule carries no net

electrical charge in the statistical mean. This means it is the pH at which the amino

acid is neutral, i.e. the zwitterion form is dominant. The pI is given by the average of

the pKa that involve the zwitterion, i.e. that give the boundaries to its existence.

The table below shows the pKa values and the isoelectronic point, pI, are given

below for the 20 α-amino acids (Table 9.6).

pKa₁= α-carboxyl group, pKa₂= α-ammonium ion, and pKa₃  = side chain group

There are 3 cases to consider: 

1. Neutral side chains

These amino acids are characterised by two pKa values: pKa₁ and pKa₂ for the

carboxylic acid and the amine respectively. The isoelectronic point will be halfway

between, or the average of, these two pKa values . This is most readily appreciated

when you realise that at very acidic pH (below pKa₁) the amino acid will have an

overall positive charge and at very basic pH (above pKa₂) the amino acid will have

an overall negative charge. 

The other two cases introduce other ionisable groups in the side chain “R” described

by a third acid dissociation constant, pKa₃

_{2. Acidic side chains}

The pI will be at a lower pH because the acidic side chain introduces an “extra” negative charge. So the neutral form exists under more acidic conditions when the extra -ve has been neutralised. For example, for aspartic acid shown below, the neutral form is dominant between pH 1.88 and 3.65, pI is halfway between these two values, i.e. pI = 1/2 (pKa₁ + pKa₃ ), so pI = 2.77

3. Basic side chains

The pI will be at a higher pH because the basic side chain introduces an “extra”

positive charge. So the neutral form exists under more basic conditions when the

extra positive has been neutralised. For example, for histidine, which has three acidic

groups of pKa’s 1.82 (carboxylic acid), 6.04 (pyrrole NH) and 9.17 (ammonium NH),

the neutral form is dominant between pH 6.04 and 9.17; pI is halfway between these

two values, i.e. , so pI = 7.60. 

_{9.7.3. Reaction with strong acids} 

_{In the following reaction, amino acids react with strong acids such as hydrochloric acid:}

9.7.4. Reaction with nitrous acid (deamination) 

The amine function of α-amino acids and esters reacts with nitrous acid in a similar manner to that described for primary amines. The diazonium ion intermediate loses molecular nitrogen in the case of the acid, but the diazonium ester loses a proton and forms a relatively stable diazo compound known as ethyl diazoethanoate:

The diazo ester is formed because of the loss of N₂ from the diazonium ion which

results in the formation of a quite unfavourable carbocation.

9.7.5. Reaction with sodium hydroxide

Amino acids react with strong bases such as sodium hydroxide:

9.7.6. Reaction of amino acids with sodium carbonate

Amino acids are instantly dissolved by strong hydrochloric acid but are in part

recovered unchanged on dilution and evaporation. They are not decomposed by

sodium carbonate but are easily decomposed by sodium hydroxide. (Dakin & West,

1928).

9.8. Optical isomers of amino acids

In chemistry, the term “isomer” means molecules that have the same molecular

formula, but have a different arrangement of the atoms in space.

Simple substances which show optical isomerism exist as two isomers known as

enantiomers. Where the atoms making up the various isomers are joined up in a

different order, this is known as structural isomerism. Structural isomerism is not

a form of stereoisomerism, which involve the atoms of the complex bonded in the

same order, but in different spatial arrangements. Optical isomerism is one form of

stereoisomerism; geometric isomers are a second type.

The general formula for an amino acid (apart from glycine, 2-aminoethanoic acid)

is shown below.The carbon at the centre of the structure has four different groups

attached. In glycine, the “R” group is another hydrogen atom.

The lack of a plane of symmetry means that there will be two stereoisomers of an

amino acid (apart from glycine) - one the non-superimposable mirror image of the

other.

For a general 2-amino acid, the isomers are:

The R group, usually referred to as a side chain, determines the properties of each

amino acid. Scientists classify amino acids into different categories based on the

nature of the side chain. A tetrahedral carbon atom with four distinct groups is

called chiral. The ability of a molecule to rotate plane polarized light to the left,

L (levorotary) or right, D (dextrorotary) gives it its optical and stereo chemical

fingerprint. 

All the naturally occurring amino acids have the right-hand structure in the

diagram above. This is known as the “L-” configuration. The other one is known as

the “D-” configuration.

When asymmetric carbon atoms are present in a molecular compound, there are

two ways in which the groups attached to that carbon can be arranged in the three

dimensions, as we have just shown with the two models above. Chemically, optical

isomers behave in the same way. Biologically, they do not. One will react properly,

but the other will not.

9.9. Peptides and polypeptides

9.9.1. Formation of peptide bonds

Amino acid molecules can also react with each other; the acidic –COOH group in one

molecule reacts with the basic –NH₂ group in another molecule. When two amino

acids react together, the resulting molecule is called a dipeptide, forming an amide

linkage (peptide bond), with the elimination of a water molecule.

Each amino acid possesses a carboxylic acid group and an amine group. The

possibilities for constructing polypeptides and proteins are enormous. Let us

consider two simple amino acids, glycine (2-aminoethanoic acid) and alanine

(2-aminopropanoic acid). The figures below show that these can be joined in two

ways:

Note the amide link between the two amino acids. An amide link between two

amino acid molecules is also called a peptide link. The reaction is a condensation

reaction as a small molecule. The dipeptide product still has an –NH₂ group at one

end and a –COOH group at the other end. Therefore the reaction can continue, to

form a tripeptide initially, and then ever-longer chains of amino acids. The longer

molecules become known as polypeptides, and then proteins as they get even

longer sequences of amino acids. A typical protein is formed from between 50 and

200 amino acids joined in a variety of sequences.

9.9.2. Structure of peptides and polypetides

A series of amino acids joined by peptide bonds form a polypeptide chain, and each

amino acid unit in a polypeptide is called a residue. A polypeptide chain has polarity

because its ends are different, with α-amino group at one end and α-carboxyl

group at the other. By convention, the amino end is taken to be the beginning of

a polypeptide chain, and so the sequence of amino acids in a polypeptide chain

is written starting with the aminoterminal residue. Thus, in the pentapeptide TyrGly-Gly-Phe-Leu (YGGFL), tyrosine is the amino-terminal (N-terminal) residue and

leucine is the carboxyl-terminal (C-terminal) residue Leu-Phe-Gly-Gly-Tyr (LFGGY) is

a different pentapeptide, with different chemical properties.

This above illustration of the pentapeptide Tyr-Gly-Gly-Phe-Leu (YGGFL) shows

the sequence from the amino terminus to the carboxyl terminus. This pentapeptide,

Leu-enkephalin, is an opioid peptide that modulates the perception of pain. The

reverse pentapeptide, Leu-Phe-Gly-Gly-Tyr (LFGGY), is a different molecule and

shows no such effects.

A polypeptide chain consists of a regularly repeating part, called the main chain

or backbone, and a variable part, comprising the distinctive side chains. The

polypeptide backbone is rich in hydrogen-bonding potential. Each residue contains

a carbonyl group, which is a good hydrogen-bond acceptor and, with the exception

of proline, an NH group, which is a good hydrogen-bond donor. These groups

interact with each other and with functional groups from side chains to stabilize

particular structures, as will be discussed later.

A polypeptide chain consists of a constant backbone (shown in blue) and variable

side chains (shown in green).

9.9.3. Uses of amino acids as building blocks of proteins

Like carbohydrates and lipids, proteins contain the elements carbon (C), hydrogen

(H) and oxygen (O), but in addition they also always contain nitrogen (N).sulphur(S)

is often present as well as iron (Fe) and phosphorus (P). Before understanding how

proteins are constructed, the structure of amino acids should be noted. 

The process of construction of proteins begins by amino acids bonding together, as

seen earlier, through peptide bonds. When many amino acids join together a long-chain polypeptide is produced. The linking of amino acids in this way takes place

during protein synthesis.

The simplest level of protein structure, primary structure, is simply the sequence of

amino acids in a polypeptide chain. The primary structure (Figure 9.2) of a protein

refers to its linear sequence of amino de (–S–S–) bridges. One of those sequences is:

–Gly–Ile–Val–Cyst–Glu–Gln–Ala–Ser–Leu–Asp–Arg–Asp–Arg–Cys–Val–Pro–

The primary structure is held together by peptide bonds that are made during the

process of protein biosynthesis. The two ends of the polypeptide chain are referred

to as the carboxyl terminus (C-terminus) and the amino terminus (N-terminus) based

on the nature of the free group on each extremity.

For example, the hormone insulin (Figure 9.3) has two polypeptide chains, A and B,

shown in diagram below. Each chain has its own set of amino acids, assembled in a

particular order. For instance, the sequence of the A chain starts with glycine at the

N-terminus and ends with asparagine at the C-terminus, and is different from the

sequence of the B chain. You may notice that the insulin chains are linked together

by sulfur-containing bonds between cysteines.