What Is an Isomer? Same Atoms, Different Molecule

Isomers divide into two broad families. Structural isomers differ in which atoms are bonded to which, so the connection pattern itself is different, and they can differ in chain arrangement, in the position of a functional group along a chain, or in the nature of the group entirely, which means two structural isomers may belong to different classes of compound and share nothing but a formula. Stereoisomers have identical connections and differ in how the atoms are arranged in space. Within those, some differ by rotation about a rigid double bond, giving arrangements with groups on the same side or on opposite sides. Others are mirror images of each other that cannot be superimposed, in the way a left hand cannot be placed onto a right, and those are the ones with the most dramatic consequences.

Mirror-image molecules behave identically in most respects and differently where handedness is involved:

• •They have the same melting point, boiling point and density, and are indistinguishable by most ordinary measurements
• •They rotate the plane of polarised light in opposite directions, which is how they were first detected
• •They interact differently with other handed molecules, and biological molecules are overwhelmingly handed
• •Enzymes and receptors are therefore selective, accepting one form and not the other
• •Taste and smell frequently differ, with two forms of the same compound smelling of different things entirely
• •Drug activity differs, with one form active and the other inactive, less active or harmful

The thalidomide disaster of the late 1950s and early 1960s is the episode usually cited, and the chemistry is more complicated than the standard telling. The drug was marketed as a mixture of both mirror forms, and it was subsequently found that the two differ in effect, with one form responsible for the sedative action and the other implicated in the birth defects. The complication is that the two forms interconvert in the body, so administering the pure beneficial form would not have prevented the harm, which is an important qualification to a story frequently told as a simple lesson about separating isomers. The episode nonetheless transformed drug regulation, introducing far stricter testing requirements and approval processes, and it made the handedness of pharmaceutical compounds a standard regulatory concern, with single-form drugs now common where mixtures were once the norm.

Mirror-image molecules smelling of different things is the most immediately convincing demonstration that handedness matters biologically, and the examples are familiar. One form of a particular compound smells of caraway and the other of spearmint, which is not a subtle difference and is detected by anyone. Another pair gives lemon and orange. A further pair differs in whether it smells pleasant at all. The explanation is that olfactory receptors are proteins built from handed amino acids, so the binding site has a shape that accommodates one form better than the other, and two forms therefore activate different combinations of receptors and are perceived as different smells. Taste works comparably, with one form of an amino acid tasting sweet and the other bitter. These cases are useful because they make an abstract structural point directly perceptible.

Because mirror forms share nearly every physical property, separating them is genuinely difficult and the methods are ingenious. The classical approach reacts the mixture with a handed compound obtained from a natural source, producing two products that are no longer mirror images and therefore differ in solubility, which allows crystallisation to separate them before the added compound is removed. Chromatography using a handed stationary phase separates them directly and is now standard. Enzymes can be used to react one form selectively, leaving the other. Avoiding the problem altogether by synthesising only the wanted form is the preferred modern route and requires handed catalysts, an achievement recognised with a Nobel Prize and one of the more consequential developments in industrial chemistry, since it made single-form drugs manufacturable at scale.

Structural isomers differ in which atoms connect to which and can belong to different classes of compound entirely, while stereoisomers differ only in spatial arrangement. Mirror forms share nearly every physical property and interact differently with the handed molecules of biology, which is why one can be a medicine and the other useless. Synthesising only the wanted form required handed catalysts.