Recap
In the previous article, we discussed the two simplest types of mechanisms for substitution reactions, which are the SN1 and SN2 mechanisms. SN1 mechanisms, as the name suggests, involve only a single molecule in the rate-determining step. This molecule is known as a substrate, which comprises the electrophilic portion of the molecule (which is to be attacked by the nucleophile) as well as the leaving group. In the SN1 reaction, the rate-determining step is solvolysis (the first step), where the substrate solvolyses into two different ions, the positively-charged electrophile and the negatively-charged leaving group. After this leaving group departs, only the electrophile is left, and in the second step the electrophile is attacked by the nucleophile. The rates of the SN1 reaction are interesting because the rate law can be both simple or complex. For more selective chemical species, the complex rate law, which takes into account that the first step of the reaction is reversible (Fig. 1), is usually employed.
Fig 1: Reversible first step of an SN1 reaction.
The SN2 mechanism (Fig. 2) is interesting because instead of being two-step like the SN1 reaction, it is only a single step reaction. This means that this one step has to be the rate-determining step. The SN2 mechanism’s name suggests that two molecules participate in the rate-determining step, and this is true, because the two molecules, the nucleophile and the substrate, will participate in this rate-determining step. The mechanism of the reaction involves nucleophilic attack by the nucleophile on the substrate, and this simultaneously causes the bond between the electrophilic portion of the molecule and the leaving group to break, forming the final substitution product. All this is captured in a transition state, which differs from an intermediate in that it cannot be isolated and is even more unstable. This transition state is pentavalent, with partial bonds to the leaving group and the nucleophile (OH and Br in the diagram below). Since the SN2 reaction involves one step only, the nucleophile can only attack on the opposite side of the molecule from the leaving group due to steric hindrance of the leaving group. This is known as ‘backside attack’, and results in a phenomenon, Walden inversion. As for the rate of the reaction, the rate law is second-order with respect to the concentrations of the substrate and nucleophile, because they are the molecules involved in the only step and rate-determining step of the reaction. There are no complications or exceptions.
Fig. 2: Mechanism of an SN2 reaction with Walden inversion.
In this article, we will be discussing two new types of mechanisms for nucleophilic substitution reactions. The first type of mechanism will be the neighboring-group mechanism, while the second type of mechanism will be the SET mechanism. We should note that both types of mechanisms are considerably rarer than that of the SN1 and SN2 mechanisms, and only occur in certain special cases.
Neighboring-Group Reactions
When we say ‘neighboring-group reactions’, what we really refer to are reactions that take place using the neighboring-group mechanism. Evidence of the neighboring-group mechanism include the fact that in some reactions that are previously ascertained to be SN2 reactions do not have the characteristics that are seen in the SN2 reactions. For example, one of these characteristics is the inversion of stereochemistry from the reactant to the product, known as Walden inversion. Some reactants and reagents which should be reacting by the SN2 mechanism display much faster rates of reactions than has been predicted, and there is a lack of Walden inversion. This suggests the possibility of another mechanism taking place. The mechanism is known as the neighboring-group mechanism, and it can only occur when there is a group with a lone pair of electrons on the beta-carbon with respect to the leaving group.
In the neighboring-group mechanism (Fig. 3), the neighboring group, which is nucleophilic, attacks the electrophilic atom intramolecularly, causing the leaving group to depart. This typically forms a positive charge on the molecule, which can attract the negatively-charged nucleophile, but attack on the electrophilic carbon is nevertheless preferred, which breaks the bond between the neighboring-group and the carbon, and forms the final carbon-nucleophile bond that ends the reaction. As we also note from Fig. 3, there are not one, but two electrophilic sites on the molecule upon attack by the sulfur neighboring group. However, since the molecule is symmetrical, attack on either carbon will nevertheless result in the same product, thus this does not have to be taken note of. The reason why the neighboring-group mechanism effectively speeds up the rate of the reaction as compared to the SN2 mechanism can be explained using a mechanistic treatment.
Fig. 3: Neighboring-group mechanism.
It is obvious that the first step of the reaction cannot be the rate-determining step, because this step should happen rapidly, as do many other intramolecular reactions. The reason for this is because intramolecular attacks do not require any collision of molecules; as such, it may happen at faster rates than other, intermolecular reactions. The rate-determining step would then be the second step. Meanwhile, the second step will be sped up by the presence of a formal charge on one of the atoms on the molecule. Of course, sulfur is quite electronegative and will not be that stable when it possesses a negative charge. Though of opposing charges, the nucleophile cannot attack the sulfur atom directly as that would form another bond to it, which would be undesirable. However, the presence of this charge on the substrate will still attract the nucleophile, which will then attack the electrophilic atom, and this would show up as a slight increase in the rate of a reaction.
Determination of the difference between the rates of the neighboring-group mechanism and the rates of the SN2 mechanism is not easy to do. If we compare the rates of reactions of a molecule without the neighboring group and a molecule with the neighboring group, such as HOCH2CH2Br and CH3CH2Br, we will not get accurate results, because the hydroxyl (OH) substituent will also affect the rate of the reactions in other ways other than lending antichimeric assistance (another term for neighboring-group mechanism), such as field effects. Furthermore, the hydroxyl substituent can also interact with the solvent, most prominently protic solvents, where hydrogen bonds can be formed between the hydroxyl group and the solvent. Measurements of the rate yielded that the rate for the molecule with the neighboring group was fifty times faster than the molecule without the neighboring group. Perhaps the strongest evidence will come from the observation of no Walden inversion, or inversion of stereochemistry, which should have been observed from an SN2 reaction.
So, what can act as neighboring groups? The definition for this is not clear. For example, carboxylates, ethers, hydroxyls and thiols are all able to act as neighboring groups. However, ‘non-conventional’ species, such as sigma and pi bonds, may also be able to act as neighboring groups in some cases. When such species act as neighboring groups, the mechanism does not feature ‘full’ cyclic intermediates, and there is instead a resonance hybrid in which each of the resonance forms will delocalize the charge onto the cyclic structure. Thus there will be partial bonds instead of full cyclics. The intermediate would then be known as a nonclassical or bridged carbocation. However, we will not discuss this in detail as it is not relevant to knowing the basic mechanism of the neighboring-group reaction.
Fig. 4: Structure of a nonclassical carbocation.
SET Reaction
The SET reaction refers to a nucleophilic substitution reaction which goes by the single-electron transfer mechanism. Both the SN1 or SN2 reactions will generally give similar products as compared to the SET mechanism, thus it is sometimes difficult to discern. This mechanism involves a free radical substitution, which makes it seem similar to nucleophilic substitution. The first step of the mechanism (Fig. 5) involves the transfer of a single electron by the nucleophile onto the substrate, where the nucleophilic is an anion (negatively-charged). This forms the radical RX- anion and the nucleophile radical. The second step (Fig. 6) involves cleavage of the RX- radical into the R radical and X anion. The final step would then be the recombination of the R and Y radicals into the RY neutral molecule (Fig. 7). The existence of the SET mechanism would be easy to prove, and we will attempt to do so in the below paragraph.
Fig. 5: The first step of an SET mechanism.
Fig. 6: The second step of an SET mechanism.
Fig. 7: The third step of an SET mechanism.
We should be aware that the radical can attack anywhere on the substrate, because there is no steric hindrance. Thus, it is likely that an equimolar mixture of products resulting from either attack from the front or backside attack will be formed, and this is known as a racemic mixture. This eliminates the possibility of it being an SN2 reaction. However, we still may consider that it could be an SN1 reaction. When the reaction is carried out at a bridgehead, it can take place successfully, suggesting that it is not likely that a carbocation intermediate is involved, ruling out the SN1 mechanism as well. Perhaps the strongest evidence for the SET mechanism is that the existence of radicals and radical ion intermediates has been detected, and this makes it highly likely that the SET mechanism indeed exists.
Part 1 of this article is here.
Part 3 of this article will be released on 17 Nov here.