Racemic Mixtures and Meso Compounds

A racemic mixture contains equal amounts of two enantiomers and is optically inactive because the rotations cancel (external compensation), whereas a meso compound is a single achiral molecule that has stereocenters but is optically inactive because of an internal plane of symmetry (internal compensation). In brief: tartaric acid has three stereoisomers: (R,R) and (S,S), which form a racemic pair, and the meso form (R,S), which is identical to its own mirror image.

Both racemic mixtures and meso compounds give no optical rotation, but for very different reasons, and the difference is important when counting stereoisomers or when a reaction forms a chiral product. This article explains both concepts, shows how to recognize a meso compound from its structure, gives a table of examples with the actual number of stereoisomers, describes how racemates arise and how they are resolved, and works through several examples.

What is a racemic mixture?

A racemic mixture (racemate) is a 1 : 1 mixture of two enantiomers. It is written with the prefix (±) or rac, or dl: (±)-2-butanol. It is optically inactive, because for each molecule of the (+) enantiomer there is a molecule of the (−) enantiomer that rotates light by an equal angle in the opposite direction. It is an external compensation: the molecules are chiral individually. The racemate may have different properties from the pure enantiomers: melting point, solubility and density, as the two enantiomers can pack together differently in the crystal. Racemic tartaric acid melts at 206 °C against 170 °C for each enantiomer. The enantiomeric excess (ee) of a racemate is zero. A mixture of 75 % (R) and 25 % (S) has ee = 50 %.

What is a meso compound?

A meso compound has two or more stereocenters but is achiral, because the molecule has an internal plane of symmetry (or a center of symmetry) that makes one half of the molecule the mirror image of the other half. It is superimposable on its own mirror image and so does not have an enantiomer. It does not rotate polarized light. Since the effects of the two halves are canceled inside one molecule, it is an internal compensation. The stereocenters have opposite configurations, for example (2R,3S). A meso compound is a single pure substance, whereas a racemate is a mixture that can in principle be separated.

How do you recognize a meso compound?

1. The molecule has two or more stereocenters.
2. The groups on the stereocenters are the same on both halves (a symmetrical structure).
3. In some conformation (usually the eclipsed one) there is a plane of symmetry passing through the middle of the molecule.
4. The configurations of the paired stereocenters are opposite: (R,S).

An easy check is to invert all the stereocenters: if the result is the same compound, the molecule is meso. For (2R,3S)-tartaric acid, inverting both centers gives (2S,3R), which is the same as (2R,3S) by symmetry (renumbering from the other end).

How many stereoisomers are there?

The reduction in number occurs only for molecules with symmetry, where the two ends of the molecule are the same.

How do racemic mixtures form?

• Synthesis from achiral starting materials with achiral reagents: if an achiral molecule is converted into a chiral product by an achiral reagent, the two enantiomers form at equal rates. For example, the addition of HBr to but-1-ene gives (±)-2-bromobutane, and the reduction of butanone with NaBH₄ gives (±)-butan-2-ol. The reagent attacks the flat carbonyl group from either face with equal probability.
• S_N1 reactions at a stereocenter, through a planar carbocation, lead to racemization.
• Racemization: a pure enantiomer can lose its optical activity if its stereocenter can interconvert, for example by enolization of a ketone next to the stereocenter, or by heating.

In nature, enzymes produce only one enantiomer, so natural products are usually enantiomerically pure. Laboratory syntheses, in contrast, give racemates unless chiral catalysts, reagents or starting materials are used (asymmetric synthesis).

How are racemates resolved?

• Diastereomeric salts: a racemic acid reacts with a single enantiomer of a chiral base to give two diastereomeric salts, which have different solubilities and are separated by crystallization. The pure acid is then recovered.
• Chiral chromatography: a column packed with a chiral stationary phase retains one enantiomer longer than the other.
• Kinetic resolution: a chiral catalyst or an enzyme (for example a lipase) reacts faster with one enantiomer.
• Spontaneous resolution: in a small number of cases (about 5–10 % of racemates), the two enantiomers crystallize separately, as a conglomerate of mirror-image crystals. This was the case for Pasteur’s sodium ammonium tartrate.

Worked examples

Example 1: is it meso?

• (2R,3S)-2,3-dibromobutane: the ends are identical (CH₃CHBr–), and the configurations are opposite, so it is meso.
• (2R,3R)-2,3-dibromobutane: both centers are the same, so it is chiral (its enantiomer is (2S,3S)).
• (2R,3S)-2-bromo-3-chlorobutane: the ends are not identical (one has Br, the other Cl), so there is no symmetry, and it is chiral.

Example 2: optical rotation of mixtures

Pure (+)-2-butanol has [α] = +13.9°. What rotation does a mixture of 60 % (+) and 40 % (−) show? ee = 60 − 40 = 20 %, so [α] = 0.20 × 13.9 = +2.8°. A racemate would show 0°.

Example 3: cis- and trans-1,2-dimethylcyclohexane

The cis isomer has a plane of symmetry (through the middle of the ring, between carbons 1 and 2) in the planar representation, and is meso, with configurations (1R,2S). The trans isomer has no plane of symmetry and is chiral: (1R,2R) and (1S,2S). So the three stereoisomers include one meso compound and a pair of enantiomers.

Example 4: addition of HBr to but-1-ene

But-1-ene (achiral) + HBr → 2-bromobutane, which has a stereocenter. The planar carbocation intermediate is attacked by Br⁻ equally from both faces, giving 50 % (R) and 50 % (S): the racemate. The product shows no optical rotation, although it consists of chiral molecules.

Example 5: Pasteur’s experiment

Racemic sodium ammonium tartrate crystallizes below 27 °C as two kinds of crystals that are mirror images. Pasteur separated them with tweezers, and the solutions of each rotated light in opposite directions. This is spontaneous resolution of a conglomerate, and required the right temperature, a lucky coincidence.

Why do they matter?

• Drug development: many drugs were originally sold as racemates, such as ibuprofen. The enantiomers may differ in activity and toxicity, so regulators require data on each, and single-enantiomer drugs are now common.
• Counting isomers: forgetting meso forms gives the wrong number of stereoisomers.
• Analysis: a lack of optical rotation can mean a racemate, a meso compound or an achiral compound, so more tests are needed.
• Sugars: many sugar acids and alcohols (such as xylitol and the aldaric acids) have meso forms.

What is the history?

The word racemic comes from the Latin racemus, a bunch of grapes: “racemic acid” was an optically inactive form of tartaric acid obtained from the deposits in wine barrels. Pasteur showed in 1848 that it is a mixture of equal amounts of the dextro- and levo-rotatory tartaric acids, and in 1853 he obtained the meso (inactive, non-resolvable) form by heating, so that all four known forms of tartaric acid were explained. The term meso is from the Greek for “middle”, and refers to the internal compensation.

Which mistakes are common?

• Mixing up racemic and meso: a racemate is a mixture of two compounds, a meso compound is one compound.
• Assuming that all compounds with stereocenters are chiral: meso compounds are not.
• Thinking that a racemate cannot be separated: it can, by resolution.
• Saying that no optical rotation means that there are no stereocenters: a racemate or a meso compound is also inactive.
• Counting 2ⁿ stereoisomers for a symmetrical molecule: the actual number is smaller.