Stereochemistry in mechanisms: inversion, retention, syn and anti
The three-dimensional outcome of a reaction is not an optional extra. It is a direct consequence of the mechanism, and often the best clue to which mechanism is operating.
Substitution
- SN2: inversion. The nucleophile attacks from the side opposite the leaving group (backside attack), so a stereocentre is inverted, like an umbrella flipping in the wind. An (R) alkyl halide gives the (S) product when priorities stay the same. See SN2.
- SN1: racemisation. The planar carbocation can be attacked from either face. In practice, ion-pairing means a slight excess of inversion is common, so you may see partial racemisation. See SN1.
- Neighbouring-group participation: retention. If a nearby group first displaces the leaving group (one inversion) and is then displaced by the incoming nucleophile (a second inversion), the net result is retention of configuration. Sulfur, nitrogen, and carboxylate groups can do this.
Elimination
E2 needs the leaving group and the β-hydrogen to be anti-periplanar (180° apart). In cyclohexanes this means both must be axial. This is why menthyl chloride eliminates slowly to give one alkene, while neomenthyl chloride eliminates quickly to give another. E1, which goes through a cation, has no such requirement.
Addition to alkenes
| Reaction | Stereochemistry | Reason |
|---|---|---|
| Catalytic hydrogenation (Catalytic hydrogenation of an alkene (Pd/C, H₂)) | Syn | Both H atoms delivered from the metal surface |
| Hydroboration–oxidation (Hydroboration-oxidation of propene) | Syn | Concerted four-centre addition of B–H |
| Halogenation (Br₂ addition to an alkene (vicinal dihalide)) | Anti | Cyclic halonium ion opened from the back |
| Halohydrin formation (Halohydrin formation from an alkene + Br₂/H₂O) | Anti | Same halonium opening by water |
| Epoxide opening (Base-catalyzed epoxide opening with methoxide, Acid-catalyzed epoxide opening with methanol) | Anti (trans) | Backside attack on the epoxide carbon |
| Dihydroxylation with OsO₄ (Sharpless asymmetric dihydroxylation) | Syn | Concerted [3+2] addition of Os–O |
Carbonyl additions
A planar C=O can be attacked from either face. If a stereocentre is nearby, the faces are not equal: the Felkin–Anh model predicts the major diastereomer by placing the largest group perpendicular to the carbonyl and having the nucleophile approach near the smallest group. Chiral auxiliaries and catalysts exploit this idea deliberately, as in the Evans aldol and the CBS reduction.
Pericyclic reactions
- Diels–Alder: stereospecific. The dienophile's cis or trans relationship is kept in the product, and the endo product is usually favoured kinetically. See Diels-Alder.
- Electrocyclisation: the sense of ring closing (conrotatory or disrotatory) depends on the electron count and on heat or light. See Thermal 6π electrocyclic ring closure.
- [3,3] sigmatropic rearrangements: usually go through a chair transition state, which transfers stereochemistry predictably. See Claisen rearrangement and Cope rearrangement of 1,5-hexadiene.
Asymmetric catalysis
When a reaction creates a new stereocentre from a flat starting material, a chiral catalyst can make one face more reactive than the other. Examples include Sharpless epoxidation, Noyori hydrogenation, Jacobsen epoxidation and MacMillan organocatalysis.
Using stereochemistry as a clue
If an exam question tells you the product is a single inverted enantiomer, think SN2. If it is racemic, think a planar intermediate (cation, enol, radical). If a trans-diol appears from an alkene, think epoxide then ring opening. The outcome tells you the path.
Practise in the interactive app Browse all 345 reactions
More study guides
- How to learn reaction mechanisms (without memorising everything)A practical method for learning organic reaction mechanisms: understand electron flow, group reactions into a few patterns, and practise by drawing.
- Curved-arrow notation: rules and the mistakes students makeHow to read and draw curved arrows in organic mechanisms: where they start and end, full-headed versus fish-hook arrows, and the most common errors.
- SN1, SN2, E1 or E2? How to decide which mechanism winsA clear decision guide for substitution versus elimination: substrate, nucleophile or base strength, solvent and temperature, with examples.
- Nucleophiles, electrophiles and leaving groups: what makes a reaction goWhat decides how reactive a nucleophile, an electrophile or a leaving group is, and how solvent, charge, size and resonance change reactivity.