8. Isomers

Question 1

What are isomers?

Answer 1

Isomers are molecules that have
the same molecular formula but
atoms are arranged differently.

he word comes from the Greek words ‘isos’
meaning ‘equal’, and ‘meros’ meaning ‘part’.

Question 2

Isomers can be classified as follows:

Answer 2

ISOMERS

STRUCTURAL ISOMERS
CHAIN POSITIONAL FUNCTIONAL

STEREOISOMERS
ENANTIOMERS CIS-TRANS

Question 3

What are structural isomers?

x4 types

Answer 3

These are compounds that have
the same molecular formula
but different chemical structures
(i.e. their atoms are arranged differently).

There are four main forms of structural isomers:

1
> Chain isomers – 
carbon skeleton varies but 
the functional group remains
 in the same position

2
> Positional isomers –
carbon skeleton remains the same
but the functional group varies position

3
> Functional –
carbon skeleton remains the same but the functional group changes

4
> Tautomers – see below.

Question 4

What is tautomerism?

Answer 4

This is a form of dynamic isomerism
where two structural isomers (known as tautomers) exist in equilibrium.

The position of the equilibrium between
the two forms depends on the conditions of the surrounding environment.

> Midazolam, which has a seven-membered ring:

• pH <4.0 – ring open and water soluble
• pH >4.0 – ring closed and lipid soluble.

> Thiopentone isomers alternate between ketone and enol states.

> Morphine isomers alternate between ketone and enol states.

Question 5

What are stereoisomers?

Answer 5

These are compounds that have the
same molecular formula and chemical structure
but different spatial arrangements.

There are two main forms of stereoisomers:

• enantiomers and diastereoisomers (optical isomers)
• cis–trans isomers (geometric isomers).

Enantiomers (previously called ‘optical isomers’):

• They possess a single chiral centre

(usually carbon or nitrogen atom)
to which four other atoms are bonded.

• They form the mirror image
of each other but cannot be superimposed upon each other.

• They have identical physical and chemical properties.

• They rotate polarised light
equally but in opposite directions
(they used to be classified as laevo–
or dextro– depending on which way they rotated light).

• Each enantiomer is either the R (rectus) or S (sinister) form.

This reflects the direction of ascending
atomic number of the atoms attached to the chiral centre.

If the numbers descend in a clockwise direction, the isomer is the R form, if anti-clockwise, it is an S isomer).

• Examples include 
levobupivacaine and S-bupivacaine, 
zopiclone and eszopiclone, 
citalopram and escitalopram, 
and ketamine and S-ketamine.

Question 6

Diastereoisomers:

Answer 6

• They possess more than one chiral centre and so they cannot form mirror images of each other.

• Examples include atracurium,
which has four chiral centres.

Question 7

Cis–trans isomers (previously called ‘geometric isomers’):

Answer 7

• They possess a double bond around which the attached atoms cannot rotate.
• Cis-form – the groups are arranged on the same side of the double bond.
• Trans-form – the groups are arranged on opposite sides of the double bond.

An example is mivacurium where
36% is cis–trans,
58% trans–trans and
6% cis–cis.

• The cis–trans nomenclature only works if the two groups around the double bond are identical.

Question 8

What is the clinical relevance of isomerism?

Answer 8

Isomers may have the same molecular formulae and physical properties

(e.g. melting points, pKa, solubility, etc.),

but the altered arrangement of
atoms confers different
pharmacodynamic/kinetic properties.

1. • Comparing S-ketamine

(also called esketamine)
with racemic ketamine,
S-ketamine has greater affinity
for the NMDA receptor,

it is twice as potent,

patients report a more pleasant experience
at doses causing the same effect and
recovery of mental function is quicker.

• Comparing esomeprazole with omeprazole,
it has higher bioavailability.

• Comparing S-warfarin with R-warfarin
it is more highly protein bound,
its volume of distribution is lower,
it is more potent and its half-life is only
32 hours compared to 54 hours for R-warfarin.

• Halothane, enflurane and isoflurane are chiral isomers with differing anaesthetic potency.
• Sotalol is formulated as a racemic mixture but only the L-isomer has any beta-blocking activity.

• Some isomers are unsafe for clinical use, e.g. R-thalidomide is sedative while S-thalidomide is teratogenic;
L-dopa is used to treat Parkinson’s
disease, while D-dopa is not because it causes neutropenia.