04 Conformation and Stereochemistry

What stereochemistry describes

Stereochemistry concerns the three-dimensional arrangement of atoms. Stereoisomers have the same atom-to-atom connectivity but differ in spatial arrangement. Their differences may arise from rotation around single bonds or from arrangements that cannot interconvert through free rotation.

Conformations and molecular flexibility

A conformation is a spatial arrangement reached by rotation around a formally single bond; different arrangements are called conformers. Rotation is more favorable at some angles than others. Eclipsed bonds generally have higher energy than staggered bonds because of torsional strain.

• In ethane, the staggered conformation is more stable than the eclipsed conformation.

• In butane, the anti arrangement, with methyl groups separated by $180^\circ$, is more stable than the gauche arrangement, with methyl groups separated by $60^\circ$.

• Cyclohexane mainly adopts a puckered chair conformation. A chair flip exchanges each substituent’s axial and equatorial positions while preserving whether it points up or down. Larger substituents usually favor equatorial positions because axial positions create steric interactions.

Conformers usually interconvert without breaking bonds. By contrast, changing a molecule’s configuration generally requires breaking bonds or overcoming a barrier to free rotation, as in an alkene.

Chirality, enantiomers, and diastereomers

A molecule is chiral if it is not superimposable on its mirror image; otherwise, it is achiral. A common source of chirality is a tetrahedral carbon attached to four different groups, called a chirality center. Chirality is a property of the whole molecule, however, and a chiral molecule does not always need to contain such a carbon.

Two nonsuperimposable mirror-image stereoisomers are enantiomers. In an achiral environment, enantiomers have the same ordinary physical properties, but they rotate plane-polarized light in opposite directions and may behave differently in a chiral environment. The direction of optical rotation cannot be inferred from an $R$ or $S$ descriptor.

Diastereomers are stereoisomers that are not mirror images. They can differ in physical properties and chemical behavior, including in achiral environments. If two molecules have multiple chirality centers and differ at some—but not all—of them, they are diastereomers. For example, $(2R,3R)$- and $(2R,3S)$-2,3-dibromobutane are diastereomers.

A molecule with $n$ independent chirality centers has at most $2^n$ configurations, although symmetry can reduce the number. A meso compound has stereogenic centers but is achiral overall because of molecular symmetry.

Geometric isomers: cis–trans and E/Z

Restricted rotation can produce stereoisomers even when a molecule has no chirality center. In an alkene, the double bond prevents free rotation, allowing substituents to occupy distinct arrangements. Cis–trans terminology describes groups on the same or opposite sides of a reference plane; it is commonly used for simple alkenes and substituted rings.

For alkenes where cis–trans terminology is ambiguous or insufficient, use E/Z descriptors. Apply the Cahn–Ingold–Prelog (CIP) rules to rank the groups attached to each double-bond carbon. If the higher-priority groups are on the same side, the alkene is Z (zusammen, “together”); if they are on opposite sides, it is E (entgegen, “opposite”). In but-2-ene, the form with methyl groups on the same side is $(Z)$-but-2-ene, while the form with methyl groups on opposite sides is $(E)$-but-2-ene.

Assigning absolute configuration

The R/S system specifies the absolute configuration at a stereogenic center. Assign it using these steps:

1. Rank the four attached groups by CIP priority. At the first point of difference, the group whose atom has the higher atomic number takes precedence. If the first atoms tie, compare the atoms attached to them in decreasing atomic-number order.

2. Orient the lowest-priority group away from you.

3. Trace the path from priority 1 to 2 to 3. A clockwise path is R (rectus); a counterclockwise path is S (sinister).

If the lowest-priority group points toward you, reverse the result. For molecules with multiple stereogenic centers, provide a descriptor and locant for each center, as in $(2R,3S)$-... . These descriptors specify configuration, not the direction of optical rotation.

Putting the distinctions together

Use the type of molecular change to distinguish stereochemical relationships. Rotation around a single bond changes conformation; it does not usually change configuration. A mirror-image pair of nonsuperimposable structures consists of enantiomers, while stereoisomers that are not mirror images are diastereomers. Restricted rotation can create geometric isomers, which may be identified with cis–trans or E/Z terminology. CIP priority rules then provide a systematic way to assign R/S descriptors.