Introduction
As we have already mentioned in previous articles, the definition of substitution reactions is unnecessarily broad and thus a large number of reactions and their mechanisms may be covered within this definition. In this article and a few later ones, we will be only discussing nucleophilic substitution reactions. The general nucleophilic substitution reaction has the following scheme in Fig. 1. Of the substitution reaction, there are a few mechanisms, usually involving the same key reactants and products, and having a ‘substitution’ of the substituents on the substrate with another. The presence of a few mechanisms suggests that there is more than one way to achieve this substitution. The mechanisms include the SN1, SN2, SN1cA, SN1cB, Borderline SN1 / SN2, SET, SNi, tetrahedral, elimination-addition and addition-elimination mechanisms. Of course, these are but a few of the mechanisms possible; the mechanisms we reflect here and explain later are only the most major types of nucleophilic substitution reactions that are possible. There may also be ‘isolated’ nucleophilic substitution reactions that cannot be grouped in a class but nevertheless is still considered a separate type of substitution reaction.
Fig. 1: Scheme of a general nucleophilic substitution reaction.
For those who are unfamiliar with the abbreviations in Fig. 1, we will be going through them now. Nu refers to the nucleophile, which is the namesake of the nucleophilic substitution reactions. R is simply a generalization and can refer to any alkyl group (which can have other functional groups on it, such as acyl or halide groups). Lastly, LG is an acronym that refers to the leaving group. What do all these terms mean? The nucleophile is very generic and can refer to any molecule with an atom that possesses a lone pair of electrons. A lot of molecules are nucleophilic, and simple examples can be raised such as the OH substituent (found in alcohols) or the OR, alkoxy substituent. A nucleophile uses this pair of electrons to form a bond with what we will term the substrate. In this article, the substrate will be considered R-LG in Fig. 1, unless otherwise indicated. When the nucleophile forms a bond with the substrate, we say that it uses its pair of electrons to attack the substrate.
Obviously, it is impossible for the nucleophile to attack any substrate. The substrate has to feature an R group bonded to the leaving group. Why is there a leaving group in the molecule? The answer to this question is best demonstrated when we regard the case of the carbon atom. As is well known, the carbon atom can only form four bonds.For the nucleophile to form a bond to a carbon that is already bonded to four different substituents, one of the bonds has to be broken, because unlike for other molecules such as nitrogen or oxygen, it is not possible for carbon to bond more than what it is typically ‘expected’ to. In general, the different mechanisms we have featured above provide us with different ways for the attack by the nucleophile and for the departure of the leaving group, though there are a few exceptions. For some mechanisms, they occur completely differently due to the broadness of the definition of a substitution reaction. For others, they may be considered unique subsets of the typical substitution reactions to explain a different type of product formed, or a product that is formed in greater proportion than another.
SN1 Reactions
The first of the two main types of nucleophilic substitution reactions would be SN1 reactions. SN1 stands for substitution nucleophilic unimolecular. These reactions have a very simple two-step mechanism (Fig. 2), although complexity may exist at times. For these two steps, only the first is the slow step and therefore rate-determining. The first step involves a slow ionization of the reactant molecule into a positively-charged electrophilic species and the leaving group. This ionization is facilitated by a solvent; as such, SN1 reactions usually do not take place in solventless conditions, unless temperatures are sufficiently high. Then, the second step is a fast step where the nucleophile attacks the electrophilic species and forms a bond with it, leading to the same outcome as in the SN2 reaction. Interestingly, the solvent may interact with the substrate molecule so as to facilitate ionization. Evidence of such occurrences are given kinetically, especially for protic solvents. These solvents are able to form hydrogen bonds, and thus form hydrogen bonds with the electronegative and partially negatively-charged leaving group. In the case of SN1 reactions, two of the solvent molecules form bonds with one substrate leaving group.
Fig. 2: Mechanism of the SN1 reaction.
The SN1 reaction itself is problematic because the mechanism is not necessarily as simple as what we have summed up in the earlier paragraph. For example, it is possible that the nucleophile needs to be deprotonated in the end step, such as in Fig. 2, which warrants an additional step and thus can no longer be considered a ‘conventional’ SN1 reaction. More commonly, the substrate exists but does not contain a leaving group unless protonation or deprotonation occurs. Usually, it is the former that will occur, because it is more likely that protonation will cause a substituent to become a better leaving group. This is especially demonstrated with alcohols, which are unable to react with the nucleophile in an SN1 manner until the leaving group departs, and in order for the leaving group to depart, it is necessary that the leaving group must be stable as a free atom; otherwise, the solvolysis will not be energetically favorable. In alcohols, the leaving group is the -OH substituent, which is not a good leaving group because it is not that stable as a free atom. However, when protonation occurs before the SN1 reaction, the -H2O+ substituent is formed instead, which is a much better leaving group; this makes the reaction much more energetically favorable and thus is likely to happen.
Having concluded our discussion on the mechanisms of the SN1 reaction, let us now take a look at how to predict the rate of the SN1 reaction. The simplicity of the rate-determining step is very deceptive. Because the rate-determining step involves simply a solvolysis, which is the separation of the substrate into the alkyl group and the leaving group in solvent, some may assume that the rate-determining step is first order with respect to the substrate. Indeed, this has been proven to be true for many substrates; however, for more selective substrates, the rate of the reaction may begin to depend on other factors. We have to remember that the rate-determining step, solvolysis, is reversible, because the solvolysis products may simply join back together to reform the substrate. In such cases, the concentration of the product (solvolysed components of the substrate) will matter, because the more the product formed, the more likely the backward reaction (reformation of the substrate) will occur. The more product molecules, the more likely collisions will happen with the product molecules and thus the more likely the backward reaction will occur. The opposite is true for a lower number of product molecules. However, we will not discuss the rates of SN1 and SN2 reactions here in detail, as we have already done so in this article.
SN2 Reactions
SN2 stands for substitution nucleophilic bimolecular. As the name suggests, the transformation involves two reactants; for SN1 reactions, it was unimolecular (like the name), as in the rate-determining step, only the reactant was involved in solvolysis. However, in the SN2 reaction there is only one step, and this step involves the simultaneous attack by the nucleophile on the substrate as well as the departure of the leaving group. Although there is a lack of an intermediate, there will nevertheless be a transition state that is pentavalent. It can arise by a carbon possessing partial bonds to both the nucleophilic atom and the leaving group. The nucleophile employs a backside attack and approaches the substrate from the opposite side of the leaving group, because there would be steric hindrance caused by approaching from the front side where the leaving group is present, and the vacant orbital that is filled by the two electrons from the nucleophile (from a molecular orbital point of view) is only present opposite to the leaving group. Despite how we always experience many exceptions in chemistry we discuss, there is never an exception to this rule of backside attack.
Fig. 3: Mechanism of the SN2 reaction.
Owing to the backside attack, there is an interesting phenomenon regarding the stereochemistry of the reactants and the products. The nucleophile will always attack on the opposite side of the leaving group, thus the stereochemistry of the nucleophile will also always be opposite. For example, if the leaving group were facing out of the page, the nucleophile would be facing into the page. This is a phenomenon known as Walden inversion. There is nothing much interesting regarding the rates of SN2 reactions, because they are almost always second order with respect to both the concentrations of the nucleophile and the substrate. Interestingly, however, it is not always that an SN2 reaction lacks an intermediate. Special cases have been reported where an intermediate is observed to exist. To prove that an intermediate exists, the energy diagram of a reaction must feature two peaks and three energy minima. These energy minima suggest the existence of a reactant, an intermediate and a product, because intermediates have a lower energy than the transition states between the reactants and the intermediate (first peak) and between the intermediate and the products (second peak).
One reaction in which an intermediate appears to exist is the Menshutkin reaction (Fig. 4). In this reaction, there is a tertiary amine (amine that has three alkyl groups bonded to it) and an alkyl halide. In the reaction, the amine nitrogen attacks the carbon bonded to the chloride substituent, forming a bond with it. This, of course, gives nitrogen a positive charge, and it is stabilized by the existence of the chloride anion. The product is then an ammonium salt. The formation of ionic products allows us to observe the effects of polar and nonpolar solvents on the reaction, and this is done commonly today.
Fig. 4: Example of Menshutkin reaction.
Part 2 of this article will be released here on 14 Nov.