Stereochemistry

An object is chiral if it cannot be superimposed on its mirror image. Your left and right hands are the classic example — they are mirror images but not identical; no matter how you rotate one, it will not match the other. A molecule is chiral for the same reason. The most common source of chirality in organic molecules is a chiral centre (also called a stereocentre or asymmetric carbon): a carbon atom bonded to four different groups.

If any two of the four groups are the same, the carbon is achiral — you can superimpose its mirror image on itself. Glycine (H₂N–CH₂–COOH) has two H atoms on the α-carbon, so it is achiral. But alanine (H₂N–CH(CH₃)–COOH) has four different groups on the α-carbon (–NH₂, –COOH, –H, –CH₃), making it chiral. A molecule can have multiple chiral centres; the maximum number of stereoisomers for a molecule with n chiral centres is 2ⁿ (though meso compounds reduce this).

The R/S system (Cahn-Ingold-Prelog, CIP) assigns an absolute configuration to each chiral centre. The process is simple in principle: rank the four substituents by atomic number (highest priority = 1), position the lowest-priority group pointing away from you, then read the remaining three groups in priority order. If they go clockwise, the configuration is R (rectus = right); if counterclockwise, it is S (sinister = left).

The D/L system is older than R/S and is still used for amino acids and sugars (see Ch8 §8.3 and Ch9 §9.3). It compares configurations to the reference compound glyceraldehyde. In a Fischer projection with the carbon chain vertical (most oxidised carbon at top): D-configuration = reference –OH (or –NH₂ for amino acids) on the right; L-configuration = on the left.

D/L does not tell you R or S directly — the two systems are independent naming conventions. Most naturally occurring amino acids are L (and happen to be S, except cysteine which is L but R due to the sulfur atom's high priority in CIP). Most biological sugars are D.

Enantiomers are non-superimposable mirror images of each other. They differ in configuration at every chiral centre simultaneously. Two molecules can only be enantiomers if they are mirror images — a pair. Key point: enantiomers have identical physical properties (same boiling point, melting point, solubility, density, spectroscopic data) except for two things: they rotate plane-polarised light in opposite directions, and they interact differently with other chiral molecules (enzymes, receptors).

This last point — different interaction with chiral biological molecules — is why enantiomers can have completely different pharmacological effects. Enzymes are chiral; they have a chiral active site. Just as a left-hand glove fits a left hand but not a right hand, an enzyme fits one enantiomer but not the other. This is the molecular basis of drug chirality and why pharmaceutical companies now develop single-enantiomer drugs when possible.

Diastereomers are stereoisomers that are NOT mirror images of each other. They arise when a molecule has two or more chiral centres and the configurations differ at some but not all centres. While enantiomers have identical physical properties, diastereomers have different physical properties — different melting points, boiling points, solubilities, and spectroscopic data. This makes diastereomers separable by ordinary physical means (chromatography, crystallisation), while enantiomers require chiral methods to separate.

Consider 2-bromo-3-chlorobutane: it has two chiral centres. The (2R,3R) and (2S,3S) forms are enantiomers. But (2R,3S) and (2S,3R) are also enantiomers of each other — and both pairs are diastereomers of the first pair. The relationship “enantiomers vs diastereomers” is about how many chiral centres differ: all = enantiomers; some but not all = diastereomers.

A meso compound has two or more chiral centres but is achiral overall due to an internal mirror plane (plane of symmetry). The two halves of the molecule are mirror images of each other, so the optical activities cancel out. Despite having chiral centres, a meso compound is superimposable on its mirror image — it is its own mirror image.

The classic example is meso-tartaric acid (2,3-dihydroxybutanedioic acid with (2R,3S) configuration). C-2 is R and C-3 is S — opposite configurations. A horizontal plane through the middle of the molecule is a mirror plane: the top half (R) is the mirror image of the bottom half (S). The molecule is achiral. This is why meso-tartaric acid does not rotate polarised light, while the (2R,2R) and (2S,2S) tartaric acid forms are enantiomers that do rotate light.

Chiral molecules interact with plane-polarised light: they rotate the plane of polarisation. A compound that rotates it clockwise (to the right) is dextrorotatory (+) or (d); one that rotates it counterclockwise is levorotatory (–) or (l). This rotation is measured with a polarimeter. The optical rotation observed depends on concentration, path length, temperature, and solvent — so rotation is standardised as specific rotation [α], defined as the rotation at a concentration of 1 g/mL in a 1 dm tube.

A racemic mixture (or racemate) contains equal amounts of both enantiomers. Because the two enantiomers rotate light in equal and opposite amounts, they cancel out — the racemic mixture has zero optical rotation and is optically inactive. Many drug syntheses produce racemic mixtures (total synthesis from achiral starting materials always gives a racemate), and separating them — resolution — is one of the most important operations in pharmaceutical chemistry.

Resolution works by temporarily converting enantiomers into diastereomers (which have different physical properties and can be separated). One method: react the racemate with a single pure enantiomer of a chiral reagent (a resolving agent such as a chiral acid or base) to form diastereomeric salts, separate by crystallisation, then remove the resolving agent to recover each pure enantiomer. Modern resolution also uses chiral HPLC columns or enzymatic resolution (enzymes react with only one enantiomer).