Nucleophilic Substitution Reactions
One of the most common reactions of alkyl halides and related substances is nucleophilic substitution (or displacement). 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. Thus the carbon atom is susceptible to attack by a nucleophile (a reagent that brings a pair of electrons) and the halogen leaves as the halide ion (X-), taking on the two electrons from the C-X bond. The nucleophile is usually neutral or negatively charged and some examples are HO-, H2O, MeOH, EtO-, RS-. A general equation for a nucleophilic substitution by a nucleophile Y is shown below.
When the nucleophile is also used as the solvent for the reaction, the substitution reaction is called a solvolysis. This is a term which is used widely in mechanistic studies, especially in the older literature.
Nucleophilic substitution reactions (II) can be compared to a Brønsted-Lowry acid-base equilibrium (I):
The equilibria of these reactions generally lies far to the right. In the Brønsted reaction, hydroxide ion displaces bromide ion from HBr. In the organic reaction, hydroxide ion displaces bromide ion from ethyl bromide. Thus, by analogy, the equilibrium in nucleophilic substitution reactions favours the release of the weaker base. We can now see why the reverse reaction is disfavoured, i.e. iodide ion does not displace hydroxide ion. We say that hydroxide ion is a good nucleophile and iodide ion is a good leaving group. Nucleophilicity and leaving group ability can often be estimated by comparing pKa values of the species concerned.
The SN2 Reaction
Nucleophilic substitution reactions follow different rate laws, depending on the exact mechanism. The rate law for an SN2 reaction is: Rate = k [RX] [Nuc]
where k is the rate constant, RX is the alkyl halide and Nuc is the nucleophile.
The reaction rate is therefore second order overall. This also tells us that the reaction is bimolecular, i.e. two species are involved in the rate-determining step. If the kinetics are determined experimentally, it is possible to propose a mechanism which is consistent with the data:
This proposed mechanism for the SN2 reaction raises an interesting question: 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 SN2 reaction at a chiral carbon proceeds with inversion of stereochemistry.
In 1896, German chemist Paul Walden reported the conversion of enantiopure (+)-(R)-malic acid into the enantiomer (-)-(S)-malic acid, although he did not know at which step inversion was occurring. In the 1920s Kenyon and Philips investigated a similar process with 1-phenyl-2-propanol:
this and several other such cycles, Kenyon and Phillips concluded
that the nucleophilic substitution reaction of primary and secondary
alkyl halides and tosylates always proceeds with inversion of stereochemistry.
In the cycle above inversion takes place in the nucleophilic substitution
of tosylate ion by acetate ion.
The SN1 Reaction
The SN2 reaction is favoured by basic nucleophiles such as hydroxide ion and disfavoured by protic solvents such as alcohols and water. The reaction also depends on the nature of the substrate: primary substrates react rapidly, secondary substrates react more slowly and tertiary substrates are almost inert to SN2 reaction. In protic media with non-basic nucleophiles under neutral or acidic conditions, tertiary substrates can be orders of magnitude more reactive than their primary or secondary counterparts. The SN2 mechanism clearly cannot account for this and it can be concluded that a different mechanism can operate under these circumstances. This mechanism is called SN1 which denotes Substitution by a Nucleophile, Unimolecular. That is, only one species is involved in the rate-determining step.
The SN1 reaction is first order and the rate varies only as the concentration of the alkyl halide: Rate = k [RX]
rate of reaction is found to be independent with respect to the concentration
of the nucleophile. In other words, the nucleophile does not take
part in the rate-determining step.
Any proposed mechanism for the reaction must therefore 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.
mechanism is clearly different from the SN2 pathway above
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. Thus,
inversion slightly dominates.
Factors which Influence the Reaction Pathway
The problems in this section concentrate on the common substitution pathways. If some of the nucleophiles or electrophiles look unfamiliar, use the chemistry that you know to work out a realistic mechanism and remember, you are looking for a substitution (displacement) reaction overall.