Solvent Effects and SN2 and SN1 reactions: Nucleophilic Substitution

S_N2 reactions and solvent effects

Polar aprotic solvents – solvents that do not have acidic proton such as DMSO, DMF, CH₃CN, HMPA - accelerate the rate of  S_N2 reactions by solvating the cation thus making the nucleophile more available to react.

On the contrary, protic solvents such as alcohols or amines decrease the rate of S_N2 reactions since they tend to solvate nucleophiles (Fig. 1). The partial positive charge that exists in the O-H hydrogens solvate the negative charge of the nucleophile (Nu:^-). Solvated nucleophiles are held tightly and  are unable to react with the electrophilic substrates – compounds that have leaving group.

Fig. 1: Partially positively charged hydrogens from polar O-H bonds solvate partially negative charge of the nucleophile. Solvated nucleophiles – as the one shown above – are unable to react with electrophilic substrates.

The effect of solvents on the rate of S_N2 nucleophilic substitution reactions is shown in Fig. 2.

Fig. 2: Solvents and S_N2 reactions rates.

The same electrophile -  especially compounds having a leaving group in a secondary carbon – can react under S_N2 or S_N1 conditions by simply changing the solvent and the nucleophile. Under S_N2 conditions and when a chiral carbon exists an inversion is observed in the product while under S_N1 conditions a racemic mixture is produced (Fig. 3).

 

Fig. 3: The secondary substrate shown above reacts with CN^- - a strong nucleophile - in a polar aprotic solvent acetone under  S_N2 conditions giving an inverted product at the secondary carbon. The same substrate reacts with OH^- - a weak nucleophile – in a polar protic solvent like methanol under S_N1 conditions giving a racemic mixture.

S_N1 reactions and solvent effects

S_N1 reactionsproceed more rapidly with more stable carbocations, therefore the rate of reactivity is correlated to carbocation stability. Polar protic solvents, such as water and alcohols, organic acids and inorganic acids (H₂SO₄, H₃PO₄), stabilize the transition state by solvating the carbocation intermediate and therefore increase the reaction rate even more.

In general, polar protic solvents are able to solvate both cations and anions through hydrogen bonds. For example they dissolve salts such as NaBr by hydrogen bonding to the anion Br^- and electron donation to the cation Na⁺.

By choosing a polar protic solvent such as methanol, the substrate shown in Fig. 4 gives a racemic mixture reacting under S_N1 conditions. The intermediate in the reaction is a carbocation that rearranges to form a tertiary carbocation before reacting with methanol.

The same substrate when it reacts with methoxide CH₃O^- in the presence of acetone – an aprotic solvent – gives a single product with inversion at the carbon atom having the Br group.

Fig. 4: The secondary substrate shown above reacts with CH₃OH - a protic solvent and weak nucleophile – in an S_N1 fashion to produce two products – a racemic mixture. The same substrate in the presence of methoxide in acetone – an aprotic solvent – reacts in an S_N2 fashion to give a single product with inversion at the C atom attached to the Br.

References

1. L. Sun et al., J.A.C.S., 123, 5753 (2001)

2. R. Bruckner, “Advanced Organic Chemistry – Reaction Mechanisms”, 2^nd Edition, Elsevier, 2002

3. M.B. Smith & J. March “March’s Advanced Organic Chemistry”, 6^thEdition, Wiley-Interscience, 2007

4. P. Muller, J. Mareda in G.A. Olah “Cage Hydrocarbons”, Wiley, 1990