The presence of electron donating and electron withdrawing groups on the substrates also effect the rate of reaction. For an SN1 reaction, electron donating groups stabilize the carbocation and thus it increases the rate of reaction while electron withdrawing groups tend to reduce it. In SN2 reactions, however, no simplistic trend could be observed. This is because both the bond forming and bond breaking processes, which act in opposite directions, are important in an SN2 reaction in the same step.
The strength of a nucleophile can be made to dictate whether a reaction will proceed through SN1 or SN2 pathway. A stronger nucleophile will favour SN2 as compared to SN1 pathway. Thus changing the nucleophile from CH3COOH to CH3COO− will probably shift the pathway towards SN2 provided all other factors favour this change.
Since the departure of the leaving group is involved in the rate determining step of both SN2 and SN1 pathways, the strength of the carbon- leaving group(C-L) bond, the polarizibility of this bond and the stability of leaving group (L−) as well as its degree of solvation by the solvent are key factors for the rate of reactions. In the series of alkyl halides it has been observed that the rate falls on going from alkyl iodides to alkyl bromides to alkyl chlorides. Alkyl fluorides are the most unreactive. This is not only in accordance to the order of the strength and polarizibilty of the bond but also follows the order of the relative acid strengths of the conjugate acids of the leaving groups. The effect of the strength of conjugate acid is an important factor in the determination of the effectiveness of an “oxygen acid” such as acetate or triflate to act as a leaving group.
Since a SN1 pathway involves the formation of a carbocation, it may lead to rearrangement to more stable carbocation (1° to 2° or 2° to 3°) before being attacked by the nucleophile to give the product. Thus, when neopentyl bromide (1-bromo-2,2-dimethylpropane) is subjected to solvolysis in ethanol, it gives ethyl- t -pentyl ether (2-ethoxy-2-methylbutane) along with other rearrangement products (Scheme 6).
Scheme 6
With regard to the stereochemical implications of aliphatic nucleophilic substitution, it must be noted that SN2 reactions proceed with an inversion of configuration at the attacking carbon, while a SN1 pathway understandably leads to racemization. The proof of complete inversion of configuration for SN2 reactions is obtained from an ingenious experiment where (+)-2-iodooctane was treated with isotopically labelled iodine (Scheme 7). If SN2 pathway leads to inversion of configuration, as postulated, then optical activity should fall to zero due to formation of a racemate. Thus, the observed rate of racemization will be double the rate of inversion. The reaction was monitored polarimetrically and it was found that the rate of inversion is same as the rate of the reaction.
Scheme 7
As for SN1 reaction, the formation of carbocation in the slow rate limiting step should lead to racemization of the product. This is because, once the carbocation is formed there is an equal probability of attack on both sides by the nucleophile thereby leading to a 1:1 mixture of both enantiomers. However, when (+)-(1-chloroethyl)benzene was subjected to solvolysis in 4:1 acetone water mixture, 98% racemization was observed while when water alone was used 80% racemization was observed. This result can be explained by the effect of solvent in solvating the ions formed in this reaction. The rate limiting ionization of SN1 is assumed to proceed in the following manner:
Here, (11) is an intimate ion pair where the ions are in close association with each other with no solvent molecules between them, (12) is a solvent separated ion-pair while the latter are completely separated ion pair. Thus, the degree of racemization is dependent on the fact that at what stage does the nucleophile attacks the carbocation predominantly. If the attack takes place in (11) then it has to be from one direction only. However, if the nucleophile attacks in (12), then this would lead to racemization. Now, the more stable a carbocation is, it will reach the state represented by (12) and thus more will be racemization. However, more nucleophilic is the solvent more will be the attack in the state represented by (11) leading to inversion. This explains the results stated above.
A third kind of nucleophilic substitution pathway is also known. In some nucleophilic substitutions, the reaction proceeds with retention of configuration. The pathway for these reactions is known as SNi (Substitution Nucleophillic Internal). One reaction where this mechanism is found to operate is the chlorination of ( S )-1-phenylethanol with thionyl chloride (Scheme 8).
Scheme 8