Chemistry for Biology 2 (ChB2)

Dr. Stewart Kirton (F153) s.b.kirton3@herts.ac.uk Stereoisomerism

Lecture Overview
Definition of Isomerism Subdivision of Isomers
Constitutional Isomers Stereoisomers
Geometric Isomers Diastereoisomers Enantiomers and chirality

Biological Importance of Chirality

What does ISOMER mean?

Isobar, Isotherm, Isoyhet connect stuff which is the same. Isomer translates as same unit Chemical Compounds which have same atoms (exactly same number of exactly same type) Differ due to arrangement of atoms in 3D space. Often but not always have identical physical and chemical properties.

A Handy Reference Guide

Constitutional Isomers
Also called Structural Isomers. Same molecular formula, but different arrangements of atoms in space. Different Connectivities May result in different physical and chemical properties.

Question Time
How many Constitutional Isomers are there for a substance with the chemical formula: C5H12 ?
A: 1 B: 2 C: 3 D: 4 E: 5

Pentane

2-methylbutane

2,2 -dimethylpropane

Stereoisomers
All atoms are the same all bonds are the same, but how they are arranged in space is different. Look at several different types Geometric Diastereomers Enatiomers

Geometric Isomerism
Considering molecules which have double bonds. Cannot rotate freely about double bond, therefore position is fixed in space. Gives rise to cis and trans isomerism

CIS

TRANS

CIS = On the same side as TRANS = Across From

E-Z Isomerism

Can we assign whether this molecule is cis or trans? Assign E or Z status instead When multiple functional groups substituted on double bond assign the group with highest priority at each atom of the double bond. Group with highest priority is the one with biggest atomic number. If groups on same side say the molecule has Z configuration. If groups on opposite sides of double bond molecule has E configuration.

Enantiomers
Compounds have identical atoms Compounds have identical bonds. They tend to have identical physical properties therefore difficult to separate They are non superimposable mirror images of one another Exist as pairs of molecules (enantiomeric pairs)

Chirality
For enantiomers to exist there must be at least one chiral atom. Focus on Chiral Carbon atoms For Carbon to be chiral it must be connected to 4 different atoms. If a molecule has a plane of symmetry it cannot be chiral (there cannot be any enantiomers).

Which of these molecules is chiral?

How do we define the differences between enantiomers?

Enantiomeric compounds only differ in the arrangement of their molecules in space. So how do we communicate these differences in configuration as scientists? Use chiral nomenclature.

Cahn-Ingold-Prelog (CIP) Rules

Draw the compound in 3-Dimensions and assign configuration of the chiral centre (i.e. the carbon atom attached to 4 different groups)
Tetravalent Carbon Drawn as a tetrahedron 2 4
Going behind page away from you
Cl H

3
CH 3

1. Assign Priorities based on Atomic Number 2. Redraw structure so that lowest priority is pointing away from you 3. Starting at 1 and moving from 2 to 3 draw arrows on your structure

4 1
Coming out of page towards you

Br H

Br Cl

1 2

If your arrows travel in an clockwise direction your chiral centre has r (rectus) configuration If your arrows travel in an anti-clockwise direction your chiral centre has s (sinister) configuration

Question Time
Assign the configuration of the molecule given below according to CIP rules and draw the other half of the enantiomeric pair.
H H3 C CH3 OH

Question Time - Workthrough

4
H

1
CH3 OH

3 2 1
H3 C

OH H CH3

4 3

Add Arrows Anti Clockwise s-butan-2-ol

H3 C

Assign Priorities

Redraw Structure Draw alternative enantiomer Swap groups 2 and 3

1
OH H

H3 C

CH3

Clockwise r-butan-2-ol

Enantiomers as Optical Isomers

Enantiomers are virtually identical in terms of physical properties. However a given enantiomer will rotate the plane of planepolarised light in the opposite direction to the other molecule of the enantiomeric pair. Used as a test to distinguish between enantiomeric forms. 2 Other forms of Nomenclature +/- enantiomers D or L enantiomers

D and L Nomenclature
D is shorthand for dextrorotatory i.e. the enantiomer rotates the plane of plane polarised light in clockwise direction L is shothand for levorotatory i.e. the enantiomer rotates the plane of plane polarised light in an anti-clockwise direction Used frequently in biological systems (CIP is more prevalent in chemistry) in conjunction with Fischer Projections of sugars.

Fischer Projection: D form OH on chiral atom on the right. L form OH on chiral atom on the left.

Chirality in Action - Limonene

Unusual Compound: Nature normally produces a single enantiomer. Where is the chiral carbon?

Relevance of Chirality in Biology

Our body contains chiral biological receptors. Enzymes, in particular are chiral receptors and as such they will only respond to compounds with the correct chirality. A chiral lock needs a chiral key.

Importance of Chirality in Medicine

Drug enantiomers also produce different responses in biological systems Virtually all drugs are chiral Only one enantiomer is usually biologically active

Methadone R enantiomer-potent analgesic S enantiomer-no biological activity

Thalidomide

Further Reading
Chemistry for the Biosciences, the essential concepts, Crowe Bradshaw and Monk (Chpt.12) Chemistry, Timberlake (Chpt.12.6)

Learning Outcomes
Introduction to the concept of isomerism Define the terms constitutional isomer, geometric isomer, diastereoisomer and enantiomer. Able to distinguish between, and draw, cis and trans, E and Z geometric isomers Understand the concept of chirality and its importance in medicine Use Cahn-Ingold-Prelog rules to determine chirality of a molecule. Appreciate the use of alternative chiral nomenclatures e.g. +/- or D/L.