Substitution and Elimination Reactions

Substitution and elimination mechanism pathways

Substitution and elimination reactions of alkyl halides and alcohols proceed through a small set of limiting mechanisms, which are distinguished by the molecularity of the rate-determining step, the strength of the nucleophile or base, the leaving group, and the solvent. SN2 is a one-step bimolecular substitution in which the nucleophile attacks from the back side of the leaving group, so the rate law is k[\text{RX}][\text{Nu}^-] and a stereocentre is inverted. SN1 is unimolecular: ionisation to a planar carbocation is the rate-determining step, and the nucleophile then adds to either face, so a chiral product is formed largely as a racemate. E1 shares the carbocation intermediate with SN1, but a weak base removes a proton from a neighbouring carbon to give an alkene. E2 is a concerted bimolecular elimination that needs a strong base and an antiperiplanar β-hydrogen. Polar protic solvents such as water, alcohols and carboxylic acids stabilise carbocations and leaving groups, so they favour SN1 and E1. Polar aprotic solvents such as acetone and DMSO leave anionic nucleophiles unsolvated and highly reactive, so they favour SN2. For example, a secondary bromide treated with iodide in acetone is expected to undergo SN2 with inversion, whereas the same bromide ionising in aqueous alcohol gives a racemic product. A carbocation formed in an E1 process can be reprotonated at the alkene, which regenerates the same cation. Rotation about the single bond in that cation then allows interconversion of E and Z alkenes, and deprotonation usually gives the thermodynamically more stable isomer. This is isomerisation through a carbocation, and it is an example of how an E1 pathway can be reversible.

Grignard reagents RMgX are strongly nucleophilic and basic carbanion equivalents. They add to the carbonyl carbon of aldehydes, ketones and esters, and the product is an alcohol after aqueous work-up. Formaldehyde gives a primary alcohol, an aldehyde gives a secondary alcohol, and a ketone gives a tertiary alcohol. With esters, the first addition gives a ketone after loss of the alkoxy group. This ketone is more reactive than the ester, so a second equivalent of the Grignard reagent adds to it, and excess reagent gives a tertiary alcohol carrying two identical groups from the reagent. Because the product depends only on which carbon bonds to which, different combinations of carbonyl compound and Grignard reagent can give the same alcohol, so it is necessary to trace the carbon skeleton of the product before judging which product is major.

E2 elimination regioselectivity

The regiochemistry of E2 elimination is controlled by the base, the leaving group and the steric environment. With a small, unhindered base such as ethoxide and a normal leaving group such as bromide, the Zaitsev product, which is the more substituted and more stable alkene, predominates. For example, 2-bromopentane with ethoxide gives mainly pent-2-ene. A quaternary ammonium group is a bulky leaving group, and in its elimination the base removes the less hindered β-hydrogen, so the Hofmann product, the less substituted alkene, becomes the major one. The trimethylammonium analogue of 2-pentyl bromide with ethoxide therefore gives mainly pent-1-ene. The rule to remember is that a small leaving group with a small base gives the Zaitsev alkene, while a large leaving group or a bulky base gives the Hofmann alkene.

E2 also has a strict stereoelectronic requirement. The leaving group and the β-hydrogen must lie in the same plane and be antiperiplanar, which in a cyclohexane chair means both must be axial and trans-diaxial. A substituent that is equatorial in the most stable chair therefore cannot undergo E2 until the ring flips to put the leaving group axial. A bulky group such as tert-butyl strongly prefers the equatorial position, so if the leaving group must be axial, the reactive conformer may be energetically inaccessible and the rate falls. In contrast, a cis isomer with a leaving group that is axial in its most stable chair has an antiperiplanar β-hydrogen immediately available and reacts quickly. Thus the rate constant depends on the population of the reactive conformer, not on the stability of the ground state alone.