Chirality and Identifying Chiral Centers

A molecule is chiral if it cannot be superimposed on its mirror image, and the most common cause is a stereocenter: an sp³ carbon atom bonded to four different groups. In brief: in 2-butanol the carbon bearing the –OH group has four different groups (H, OH, CH₃, C₂H₅), so there are two mirror-image forms, while in propan-2-ol the central carbon has two identical methyl groups, and the molecule is achiral.

The word chirality comes from the Greek cheir, hand: your left and right hands are mirror images that cannot be superimposed. Chirality is one of the most important ideas in organic chemistry and biochemistry, as all amino acids (except glycine) and all sugars are chiral, and the molecules of life are present in only one of their mirror-image forms. This article explains chirality, shows how to find stereocenters, provides a table of examples, gives worked examples and describes why the property matters.

What does chiral mean?

An object is chiral if it is not superimposable on its mirror image. Hands, shoes, screws and spiral staircases are chiral. Objects such as a cup, a ball or a plain spoon are achiral: they are identical to their mirror images. The two mirror-image forms of a chiral molecule are enantiomers. A molecule is achiral if it has a plane of symmetry, a center of symmetry or an alternating axis of symmetry. In practice, a plane of symmetry is the most useful test: if you can cut the molecule into two halves that are mirror images of each other, it is achiral.

What is a chiral center?

A chiral center (stereocenter, stereogenic center, asymmetric carbon) is a tetrahedral carbon atom with four different groups. The four groups can be arranged in two ways in space, which are mirror images of each other. Switching two of the groups converts one enantiomer into the other. The carbon atoms in CH₄, CH₃Cl or CH₂Cl₂ are not stereocenters, since two or more groups are identical. A carbon with a double bond (sp²) is also not a stereocenter in the usual sense.

How do you find chiral centers?

1. Look at each sp³ carbon atom (a carbon with four single bonds).
2. List the four groups attached to it. Remember that a group is defined by the whole branch, not only the first atom. Two CH₂CH₃ groups are the same, but CH₂CH₃ and CH₂CH₂CH₃ are different (the difference appears further out).
3. If all four groups are different, the carbon is a stereocenter.
4. Mark all stereocenters, and look for symmetry that could make the whole molecule achiral (meso compounds).

Chiral and achiral molecules

How many stereoisomers can a molecule have?

A molecule with n stereocenters can have up to 2ⁿ stereoisomers. If the molecule has an internal symmetry, the actual number can be smaller (meso compounds). Examples: 2-butanol (1 center) has 2 stereoisomers; a molecule with 3 centers can have up to 8; the open-chain form of glucose (4 centers) has 16; cholesterol with 8 stereocenters has 256 possible, of which only one is made by living organisms; and a typical protein has hundreds of centers.

Can a molecule be chiral without a stereocenter?

Yes. Chirality is a property of the whole molecule, and not only of a single atom. Examples:

• Allenes with two different groups at each end (R(R′)C=C=C(R)R′).
• Biaryls with hindered rotation such as 6,6′-dinitro-2,2′-diphenic acid, and BINOL, a ligand in asymmetric catalysis.
• Helical molecules: the DNA double helix is right-handed, and helicenes are chiral because of their screw shape.
• Stereocenters on other atoms: a phosphorus, sulfur or nitrogen atom with four different groups and no easy inversion, such as in a sulfoxide or a phosphine.

Worked examples

Example 1: stereocenters in 2-methylbutan-1-ol

CH₃CH₂CH(CH₃)CH₂OH. Carbon 2 is bonded to H, CH₃, CH₂CH₃ and CH₂OH: four different groups, so it is a stereocenter. The other carbons have two identical hydrogens, or three (CH₃), so there is one stereocenter and 2 stereoisomers.

Example 2: stereocenters in a drug

Ibuprofen, (CH₃)₂CHCH₂C₆H₄CH(CH₃)COOH, has one stereocenter, the carbon with H, CH₃, COOH and the aryl group. Only the (S)-enantiomer has anti-inflammatory activity, but the body converts much of the (R)-form to the (S)-form, so ibuprofen is sold as the racemate.

Example 3: counting stereocenters

In 2,3-dibromobutane, CH₃CHBrCHBrCH₃, carbons 2 and 3 each have H, Br, CH₃ and CHBrCH₃, so there are two stereocenters and up to 4 stereoisomers. Since the molecule has a symmetric structure, two of them are identical to their mirror image combination (meso form), so only 3 distinct stereoisomers exist.

Example 4: is 3-methylpentane chiral?

CH₃CH₂CH(CH₃)CH₂CH₃. Carbon 3 has H, CH₃, and two identical CH₂CH₃ groups. It is not a stereocenter, and the molecule has a plane of symmetry: achiral.

Example 5: cyclic compounds

In 1,2-dimethylcyclohexane, carbons 1 and 2 each have H, CH₃, and two different ring paths, so they are stereocenters. The cis isomer has a plane of symmetry (in the average planar ring representation), and is achiral (meso), while the trans isomer is chiral and exists as a pair of enantiomers.

Why is chirality important?

• Biology: proteins are built from L-amino acids only, and carbohydrates from D-sugars. Enzymes and receptors are chiral, and distinguish between enantiomers like a hand in a glove.
• Drugs: the two enantiomers can have different effects. In the 1950s and 1960s, thalidomide, sold as the racemate, caused severe birth defects; the (S)-enantiomer is linked to the teratogenic effect, but the two forms interconvert in the body, so using a single enantiomer would not have prevented the harm. Since the 1990s, many drugs are marketed as single enantiomers, for example esomeprazole, the (S)-enantiomer of omeprazole.
• Smell and taste: (R)-carvone smells of spearmint, (S)-carvone of caraway; (R)-limonene smells of orange and (S)-limonene of lemon or turpentine.
• Materials: liquid crystals and some polymers use chiral molecules.

How was chirality discovered?

Jean-Baptiste Biot discovered in 1815 that quartz and some organic substances in solution rotate the plane of polarized light. Louis Pasteur separated the two mirror-image crystal forms of sodium ammonium tartrate in 1848 and showed that the solutions rotate light in opposite directions, with equal magnitude. Van ‘t Hoff and Le Bel linked this to the tetrahedral carbon in 1874. The term chirality was introduced by Lord Kelvin in 1893, who defined a figure as chiral if it cannot be brought into coincidence with its mirror image.

Which mistakes are common?

• Looking only at the atoms directly bonded: two groups may be the same at the first atom but different further out.
• Counting sp² or sp carbons as stereocenters: they have fewer than four different substituents.
• Assuming that each stereocenter doubles the number of distinct compounds: meso forms reduce the count.
• Saying that every molecule with a stereocenter is chiral: meso compounds are not.
• Forgetting chirality without stereocenters: helical or hindered molecules can be chiral.