Which substrate-nucleophile combination is most favorable for an SN2 reaction?

• A. Primary substrate with a strong nucleophile.
• B. Tertiary substrate with a weak nucleophile.
• C. Tertiary substrate with a strong nucleophile.
• D. Primary substrate with a weak nucleophile.

Answer: (A)

SN2 reactions run best when the electrophilic carbon is not crowded and the nucleophile is strong, because the bond-forming and bond-breaking happen in one concerted step with backside attack. A primary carbon presents far less steric hindrance than a tertiary one, so the nucleophile can approach and displace the leaving group more easily. A strong nucleophile is able to push electrons into the carbon center efficiently, speeding up the reaction. If the nucleophile is weak, the reaction proceeds much more slowly even with a relatively open (primary) substrate, and at a tertiary center the approach is hindered so SN2 becomes essentially unfeasible. So the most favorable combination is a primary substrate with a strong nucleophile.