Optical isomerism

Four different groups on one carbon

Butan-2-ol is CH₃CH(OH)CH₂CH₃. Its second carbon carries four different groups: a hydrogen atom, a hydroxyl group, a methyl group and an ethyl group. Those four groups sit at the corners of a tetrahedron, and there are exactly two ways to arrange four different things on the corners of a tetrahedron. The two arrangements are mirror images of each other.

A model kit shows the problem. Laid one on the other, the two models cannot be made to coincide: line up the OH and the H and the methyl and ethyl groups point the wrong way; swap those and the OH and H are wrong. No rotation makes them match, because turning a molecule cannot turn it into its reflection. A left and a right hand are related in just this way, and the word chiral comes from the Greek for hand.

Describe the drawing

Two drawings of 2-bromobutane either side of a vertical dashed mirror line. In each the chiral carbon C* has CH₃ straight up and C₂H₅ to one side as plain bonds in the plane of the page, Br on a solid wedge towards the viewer and H on a dashed wedge away from the viewer, both low on the other side. The right drawing is the exact reflection of the left, so the groups run the opposite way round and no rotation makes one drawing into the other.

The carbon carrying the four different groups is the chiral centre, sometimes called an asymmetric carbon, and it is marked with an asterisk in a structure. The two forms are enantiomers, and together they are an example of optical isomerism, a type of stereoisomerism: the structural formula is the same and only the arrangement in space differs.

Draw an enantiomer with two bonds in the plane of the paper as plain lines, one coming towards the reader as a solid wedge and one going away as a dashed wedge. Draw the second enantiomer as the reflection of the first in a vertical mirror line. A drawing that shows the four groups flat, at right angles, does not show chirality at all, because a flat drawing of a tetrahedral carbon loses the information about which group is in front.

Chiral centre

A carbon atom bonded to four different atoms or groups of atoms.

Enantiomers

Stereoisomers that are non-superimposable mirror images of each other.

Optical isomerism

Stereoisomerism that occurs when a molecule contains a chiral centre, giving two enantiomers.

Stereoisomers

Molecules with the same structural formula but a different arrangement of atoms in space.

Finding the chiral centre

Check each carbon in turn and ask what it is bonded to. Two kinds of carbon can be ruled out at once. A carbon in a CH₃ or CH₂ group has at least two identical hydrogens. A carbon in a double bond, C=C or C=O, has only three groups around it and is planar, so it has no mirror-image form.

For the carbons left, compare the four groups as whole groups, not as the first atom. In 3-methylhexane, CH₃CH₂CH(CH₃)CH₂CH₂CH₃, the third carbon carries H, CH₃, CH₂CH₃ and CH₂CH₂CH₃. Three of those begin with a carbon, but the groups differ further along, so all four are different and the carbon is chiral. In 3-methylpentane, CH₃CH₂CH(CH₃)CH₂CH₃, the same carbon carries two ethyl groups, and the molecule is not chiral.

Molecules with two or more chiral centres can have more than two stereoisomers. A question asks only that each chiral centre be identified, and one that asks how many chiral centres a drug molecule contains is answered by counting the carbons that pass the four-different-groups test, ring carbons included.

Amino acids are chiral too. Alanine, CH₃CH(NH₂)COOH, has H, NH₂, CH₃ and COOH on its central carbon. Every amino acid in a protein has a chiral centre except glycine, H₂NCH₂COOH, whose central carbon carries two hydrogens. Proteins are built from one enantiomer of each amino acid only, so the enzymes made from them are chiral too.

A ring carbon is tested by walking round the ring in each direction from it. If the two routes meet the same atoms in the same order, the two ring branches are identical groups and the carbon is not chiral; if they differ, they count as two different groups.

Plane-polarised light and racemic mixtures

Enantiomers have the same melting point, the same boiling point, the same density and the same reactions with ordinary reagents. Every bond is the same, so nothing that depends only on bonds can tell them apart. One physical property does differ, and it is the one that gave optical isomerism its name.

Light from a lamp vibrates in every plane at right angles to its direction of travel. A polarising filter lets through only the light vibrating in one plane, giving plane-polarised light. Pass that light through a solution of one enantiomer and the plane is turned, say 10° clockwise. A solution of the other enantiomer, at the same concentration in the same tube, turns it 10° anticlockwise. A substance that rotates the plane of plane-polarised light is optically active.

Describe the drawing

A beam of light runs left to right. Unpolarised light from a lamp, drawn as double-headed arrows in many planes, passes a polariser with vertical slits and leaves as one vertical plane of vibration. It passes a tube holding a solution of one enantiomer and leaves with the plane turned clockwise, marked 10 degrees, so the analyser beyond it is turned through the same angle before the light reaches the observer's eye. Below, the emerging plane for three samples: the (+) enantiomer turns it clockwise, the (−) enantiomer anticlockwise by the same angle, and a racemate not at all.

The instrument is a polarimeter. The rotation is measured by turning a second filter, the analyser, until the light passing through is brightest again. The size of the rotation depends on the concentration and the length of the tube; its direction depends only on which enantiomer is present. The enantiomer that turns the plane clockwise, seen by an observer looking towards the light source, is labelled (+); its mirror image is labelled (−). The sign is measured, not predicted from the drawing.

A mixture containing equal amounts of the two enantiomers is a racemic mixture, or racemate. For every molecule turning the plane one way, there is a molecule turning it the same amount the other way, so the rotations cancel and the mixture is optically inactive. A racemate still contains chiral molecules; the mixture as a whole shows no rotation.

Plane-polarised light

Light in which the vibrations occur in one plane only.

Optically active

Able to rotate the plane of plane-polarised light; the two enantiomers rotate it by equal amounts in opposite directions.

Racemic mixture

A mixture containing equal amounts of two enantiomers, which is optically inactive because their rotations cancel.

Why a carbonyl gives a racemate

Ethanal reacts with hydrogen cyanide to give 2-hydroxypropanenitrile, CH₃CH(OH)CN. The product's middle carbon carries H, OH, CH₃ and CN, so it is a chiral centre. The ethanal it came from has no chiral centre: its carbonyl carbon is bonded to only three groups, H, CH₃ and O, and those three lie in one plane with bond angles of 120°.

The cyanide ion attacks the carbonyl carbon from above or below that plane. Nothing in a flask of ethanal favours one face over the other, so attack from above and attack from below happen equally often. Attack from one face gives one enantiomer; attack from the other face gives its mirror image. Across the many millions of molecules in a flask the two are made in equal amounts, and the product is a racemic mixture with no optical activity.

Describe the drawing

Ethanal's carbonyl group drawn lying in a shaded flat plane seen at an angle, with δ+ on carbon and δ− on oxygen. A cyanide ion above the plane on the left and another below it on the right each send a curly arrow from the lone pair on carbon to the carbonyl carbon, with a second arrow from the C=O bond to oxygen. After H⁺ is added, attack from above gives one enantiomer of 2-hydroxypropanenitrile with CN pointing up, and attack from below gives its reflection in a dashed mirror line, CN pointing down. Both faces are equally likely, so the product is a 50 : 50 racemic mixture.

The same reasoning applies to any reaction in which a nucleophile adds to a planar carbonyl carbon and creates a chiral centre. Reduction of butanone by sodium tetrahydridoborate(III) gives racemic butan-2-ol, since its carbonyl carbon is planar too and the product carbon carries H, OH, CH₃ and C₂H₅. Where the carbonyl carbon already carries two identical groups, as in propanone, the product has no chiral centre and the question of a racemate does not arise.

Living cells behave differently. An enzyme's active site is itself chiral, so it holds the planar substrate with one face exposed and the other buried, and the product is a single enantiomer. Muscle makes only one form of lactic acid for this reason.

In an answer, the three points that earn the marks are the planar carbonyl group, attack equally likely from above and below the plane, and equal amounts of the two enantiomers. 'Random attack' alone does not say that both faces are equally open, and 'a mixture of isomers' does not say that the amounts are equal.

Drugs as single enantiomers

A drug acts by fitting a receptor or an enzyme, and those are chiral. The two enantiomers of a drug can fit differently, so one may be active and the other inactive, or harmful. A synthesis that goes through a planar carbonyl gives a racemate, and the unwanted enantiomer then has to be separated out or the route changed to make one enantiomer only, which is expensive.

Thalidomide was sold from 1957 as a racemate, prescribed as a sedative and against morning sickness. One enantiomer is a sedative. The other causes severe limb defects in a developing fetus, and around ten thousand children were born affected before the drug was withdrawn in 1961. Selling only the sedative enantiomer would not have prevented the harm, because the two interconvert in the body and the racemate forms again. Thalidomide is now used, under strict controls, to treat leprosy and some cancers.

Ibuprofen is also sold as a racemate. Only one enantiomer relieves pain and inflammation, but the body converts much of the other into the active form, so the racemate works. A single-enantiomer version exists, acts faster at a lower dose, and costs more to make. The decision to separate is therefore one of cost against benefit, made drug by drug.

Other boards: optical activity as evidence for a mechanism

Edexcel uses the polarimeter to show which mechanism a substitution followed; AQA does not. The test starts from one pure enantiomer of 2-bromobutane, which rotates plane-polarised light, warmed with aqueous sodium hydroxide. Both the SN2 and the SN1 mechanism give butan-2-ol, which is chiral, so the product's effect on the light is what tells the two routes apart.

In an SN2 reaction the hydroxide ion attacks the carbon from the side opposite the bromine, and the C–O bond forms as the C–Br bond breaks, in one step. The other three groups are pushed through to the far side, like an umbrella blown inside out, so the product has the opposite arrangement of groups to the reactant. This is inversion of configuration. Every molecule is inverted in the same way, so the product is a single enantiomer and the solution is still optically active.

In an SN1 reaction the C–Br bond breaks first and a carbocation forms. Its positive carbon is bonded to three groups and is planar, like a carbonyl carbon. The hydroxide ion then attacks either face with equal probability, the two enantiomers of butan-2-ol form in equal amounts, and the product is a racemic mixture that does not rotate the light, although the starting material did.

A tertiary halogenoalkane reacts by SN1 and a primary one by SN2. A secondary one such as 2-bromobutane can do both at once, and its product is then partly racemised: it still rotates the light, but by less than a pure enantiomer would.

Chiral

Describes a molecule that cannot be superimposed on its mirror image, usually because it contains a chiral centre.

Inversion of configuration

The reversal of the arrangement of groups around a chiral centre when a nucleophile attacks from the side opposite the leaving group, as in an SN2 reaction.