Enantiomers and Diastereomers Compared

Enantiomers are stereoisomers that are non-superimposable mirror images of each other and have identical physical properties except for the sign of their optical rotation, whereas diastereomers are stereoisomers that are not mirror images and have different physical properties. In brief: (2R,3R)-tartaric acid and (2S,3S)-tartaric acid are enantiomers (both melt at 170 °C, with rotations of +12.0° and −12.0°), while the meso isomer (2R,3S) is a diastereomer of both, and melts at 140 °C.

Once a molecule has more than one stereocenter, there are several kinds of stereoisomers, and it is important to know how they are related, because it determines how easily they can be separated and how they behave in reactions. This article defines enantiomers and diastereomers, shows how the relation can be worked out from the configurations of the stereocenters, compares their properties in a table, uses tartaric acid and other real examples, and explains why diastereomers can be separated and enantiomers cannot, at least by ordinary methods.

What are enantiomers?

Enantiomers are a pair of stereoisomers that are mirror images of each other and cannot be superimposed. Every stereocenter has the opposite configuration in the two enantiomers: (R) becomes (S), and vice versa. In an achiral environment (an ordinary solvent, with achiral reagents, or at a given temperature), enantiomers have identical melting points, boiling points, densities, solubilities, spectra and chemical reactivity. They differ in two ways:

• Optical rotation: they rotate the plane of polarized light by equal amounts in opposite directions. The (+) form is dextrorotatory, and the (−) form levorotatory.
• Interaction with other chiral substances: they react at different rates with chiral reagents or catalysts, and are recognized differently by enzymes and receptors, and have different odors or tastes.

What are diastereomers?

Diastereomers are stereoisomers that are not mirror images of each other. They arise when a molecule has two or more stereocenters, and the configuration is different at some but not all of them. Cis–trans (geometric) isomers are also diastereomers. Unlike enantiomers, diastereomers have different physical properties (melting and boiling points, solubility, spectra, chromatographic retention) and different chemical reactivity, so they are, in principle, easy to separate by crystallization, distillation or chromatography.

How do you work out the relationship?

Compare the configuration (R or S) of each stereocenter in the two molecules:

• All centers opposite (R↔S at every center): enantiomers.
• Some centers the same, some opposite: diastereomers.
• All centers the same: identical compounds.

Each stereoisomer has exactly one enantiomer (or none, for a meso form), but it can have many diastereomers. For n stereocenters, there are up to 2ⁿ stereoisomers, with 2ⁿ⁻¹ pairs of enantiomers. Each isomer has 2ⁿ − 2 diastereomers.

Example: the stereoisomers of tartaric acid

Tartaric acid, HOOC–CH(OH)–CH(OH)–COOH, has two stereocenters with identical sets of groups, so there are three stereoisomers: the enantiomeric pair (2R,3R) and (2S,3S), and the achiral meso form (2R,3S). The racemic mixture of the two enantiomers is a fourth substance, which is a mixture and not a compound.

The enantiomers have identical melting points and equal and opposite rotations. The meso form differs in its melting point (and solubility, density and acidity), because it is a diastereomer. The racemate has a different melting point from the pure enantiomers, because in the crystal the two enantiomers pack together to form a different solid.

Comparison of enantiomers and diastereomers

How are the stereoisomers separated?

Diastereomers can be separated by conventional methods such as recrystallization, distillation or chromatography. Enantiomers cannot, because their physical properties are the same. The separation of a racemate into its enantiomers (resolution) uses the trick of converting them to diastereomers: the racemic acid is combined with a single enantiomer of a chiral base (for example brucine or (S)-1-phenylethylamine) to give two diastereomeric salts, which have different solubilities and can be separated by crystallization. After separation, the acid is liberated from each salt. Another method is chromatography on a chiral stationary phase, which interacts differently with the two enantiomers.

Worked examples

Example 1: classify the relationship

• (2R,3R)-2,3-dibromobutane and (2S,3S)-2,3-dibromobutane: all centers opposite, so enantiomers.
• (2R,3R)-2,3-dibromobutane and (2R,3S)-2,3-dibromobutane: one center the same and one opposite, so diastereomers (the (2R,3S) compound is meso).
• (2R,3S)-2-bromo-3-chlorobutane and (2S,3S)-2-bromo-3-chlorobutane: one center changed, so diastereomers.

Example 2: ephedrine and pseudoephedrine

(−)-Ephedrine is (1R,2S) and (+)-pseudoephedrine is (1S,2S). One center is the same and the other opposite, so they are diastereomers. They are different compounds, with different melting points (ephedrine 34–40 °C, pseudoephedrine 118–120 °C) and different pharmacological effects: both are decongestants, but with different potency and side effects.

Example 3: sugars

D-Glucose and L-glucose are enantiomers (all four stereocenters are inverted). D-Glucose and D-galactose differ only at C4: they are diastereomers (and called epimers, since they differ at only one center). D-Glucose and D-mannose are C2 epimers.

Example 4: counting for threonine

Threonine, CH₃CH(OH)CH(NH₂)COOH, has two different stereocenters (C2 and C3), so there are 4 stereoisomers: two pairs of enantiomers. The natural amino acid L-threonine is (2S,3R); its enantiomer is D-threonine (2R,3S), and the two diastereomers are L-allo-threonine (2S,3S) and D-allo-threonine (2R,3R).

Example 5: different properties used in an analysis

A chemist has a mixture of 2R,3R and 2R,3S compounds (diastereomers). Because they have different retention times on a normal silica column, the two can be separated on the column and quantified. If she had a mixture of (R,R) and (S,S) enantiomers, a normal column would show one peak, and a chiral column would be needed.

Who discovered the difference?

Louis Pasteur’s work on tartaric acid in 1848–1853 identified all four forms: the two optically active enantiomers, the meso form (which he called “inactive tartaric acid”, not resolvable), and the racemic acid, which was resolvable. In 1853 he developed the resolution of racemic acid with the chiral base cinchonine, the first example of the separation through diastereomeric salts. The names enantiomer and diastereomer came into use in the late 19th and early 20th centuries, when Emil Fischer’s work on the sugars showed how many stereoisomers a molecule with several stereocenters can have.

Which mistakes are common?

• Treating any two stereoisomers as enantiomers: they must be mirror images.
• Assuming that diastereomers have equal and opposite properties: only enantiomers’ rotations are equal and opposite.
• Forgetting meso compounds: they are achiral and have no enantiomer.
• Thinking that enantiomers react differently with all reagents: only with chiral ones.
• Trying to separate enantiomers by distillation or ordinary crystallization: it does not work.