Nucleophilic Substitution

One of the most common reactions of alkyl halides and related substances is nucleophilic substitution. The carbon-halogen (C-X) bond in an alkyl halide is polarised, with a partial positive charge on the carbon and a partial negative charge on the halogen.

This makes the carbon atom susceptible to attack by a nucleophile (a reagent that brings a pair of electrons) and the halogen leaves as the halide ion (X^–), taking the two electrons from the C-X bond. The nucleophile is usually neutral or negatively charged. Some examples are HO^–, H₂O, MeOH, EtO^–. The general equation for a nucleophilic substitution by a nucleophile Y is shown below.

There are 2 nucleophilic substitution mechanisms: S_N2 and S_N1.

The S_N2 mechanism

S_N2 denotes Substitution by a Nucleophile, Bimolecular. The rate law for an S_N2 reaction is:

Rate = k [RX] [Nuc]

(k is the rate constant, [RX] is the concentration of the alkyl halide and [Nuc] is the concentration of the nucleophile)

The reaction rate is second-order overall and the reaction is bimolecular, i.e. two species are involved in the rate-determining step. Below is the proposed mechanism which fits with these kinetics:

If the substitution occurs at a chiral carbon, does the reaction proceed with retention, inversion or loss of stereochemistry? The answer to this question lies in the direction of attack of the incoming nucleophile. Attack on the same side as the halogen would result in retention of stereochemistry. Attack from the opposite side to the halogen would result in inversion of stereochemistry.

A mixture of these two possibilities would lead to loss of stereochemical integrity at the chiral carbon. Experimentally, it is found that a purely S_N2 reaction at a chiral carbon proceeds with inversion of stereochemistry. This means that the nucleophile attacks from the opposite side to the halogen.

The S_N1 mechanism

S_N1 denotes Substitution by a Nucleophile, Unimolecular. The rate law for an S_N1 reaction is:

Rate = k [RX]

The S_N1 reaction is first-order and the rate is proportional to only the concentration of the alkyl halide. The rate of reaction is independent with respect to the concentration of the nucleophile i.e. the nucleophile does not take part in the rate-determining step. The reaction is unimolecular.

Any proposed mechanism for the reaction must have the alkyl halide undergoing some change without the aid of the nucleophile. The first step must therefore be cleavage of the C-X bond to form a carbocation, followed by reaction with the nucleophile to give the substitution product.

This mechanism is clearly different from the S_N2 pathway and the stereochemical outcome should also differ. Carbocations are sp² hybridised, planar species – at first glance it would appear that the nucleophile, Y^– could attack from either face of the carbocation, with an equal probability. We would predict that this should lead to complete racemisation if the starting alkyl halide were optically pure. In practice, complete racemisation is rarely observed, and usually, a minor excess (up to ~20%) of inversion is observed. One explanation for this was provided by Winstein, an eminent physical organic chemist. It was proposed that an ion-pair between the carbocation and the leaving group X^– is present, which partly blocks attack of the nucleophile from one face. This means inversion slightly dominates.

Factors which influence the reaction pathway

S_N2

Steric Effects: The transition state in the S_N2 reaction involves partial bonding between the nucleophile and the substrate. The bulkier the substrate, the more difficult it is for the transition state to be reached. The reactivity order is 1^o > 2^o > 3^o.

The Nucleophile: By definition, a nucleophile must have an unshared pair of electrons, whether it is charged or neutral.

Nucleophilicity usually increases going down a group in the periodic table. The reactivity order of the more common nucleophiles is: CN^– > I^– > MeO^– > HO^– > Cl^– > H₂O.

The Leaving Group: The leaving group is normally ejected with a negative charge, so the best leaving groups are those which can best stabilise a negative charge. Weak bases (TsO^–, I^–, Br^–) are generally good leaving groups, whereas strong bases (F^–, HO^–, RO^–) are generally poor leaving groups.

The Solvent: Polar aprotic solvents are best for S_N2 reactions. These include acetonitrile (CH₃CN), dimethyl sulfoxide (Me₂SO) and N,N-dimethylformamide (Me₂NCHO). Protic solvents tend to form a ‘cage’ around the nucleophile, decreasing its reactivity.

S_N1

The Substrate: Substrates which can form relatively stable carbocation intermediates favour S_N1 reactions. The order of stability of carbocations is: 3^o > 2^o > benzyl > allyl > 1^o.

The Nucleophile: The nucleophile is not involved in the rate-determining step in an S_N1 reaction but the S_N1 pathway is more likely to be followed if the nucleophile is poor, e.g. H₂O.

The Leaving Group: The leaving group is also involved in the rate-determining step for an S_N1 reaction, so the same reactivity order as for S_N2 is followed.

The Solvent: The solvent can have an effect on the rate of the S_N1 reaction, but for different reasons. Solvent effects arise from stabilisation of the transition state and not the reactants themselves. The rate of S_N1 reactions is increased in a polar protic solvent such as water or aqueous ethanol.

Practice

To practice drawing nucleophilic substitution mechanisms, go to curlyarrows.org and select ‘Nucleophilic Substitution’, then select from either ‘S_N1′ or ‘S_N2′.

There are 10 S_N2 and S_N1 reactions, and each set of 10 has 1 introductory question.

The introductory questions test your knowledge of the general mechanisms and the questions that follow show specific reactants. If you don’t recognise the reactants, don’t panic. Identify the nucleophile and the electrophile and show how one attacks the other.

Remember that a nucleophile is electron-rich and an electrophile is electron-poor. The curly arrow should go from the source of electrons to the destination of the electrons, so from the nucleophile to the electrophile.

The SN2 mechanism

The SN1 mechanism