Introduction
It is not easy to predict the rates of nucleophilic substitution reactions. Often, many factors are responsible for increasing or decreasing the rate of nucleophilic substitution reactions. Before we continue into the discussion of these factors, let us first explain what a nucleophilic substitution reaction is in the first place. The scope of the definition of a nucleophilic substitution reaction is quite large, but more or less, the ‘net’ reaction remains the same: it is a simple ‘substitution’ of a substituent on the reactant molecule with another substituent (Fig. 1). It is important to note that the rates of individual reactions depend on the mechanism by which the reaction takes place, because a different mechanism could mean that the reaction changes from first order to second order, or that it becomes dependent on the concentrations of different reactants and products instead. However, for all or most of these substitution reaction mechanisms in general, there are five factors that they are dependent on.
Fig. 1: Reactants and products of a substitution reaction.
Factor: Structure
Structure is a decently broad term, and it can refer to many concepts that all work to increase or decrease the rate of the reaction. The structure of the substrate and the nucleophile will both affect the rate of the reaction. The first structural factor we will consider would be branching at the site of nucleophilic attack and at the alpha atoms, meaning the atoms that are adjacent to the site of nucleophilic attack, respectively. Branching at these sites will prevent nucleophilic attack from occurring, mainly due to steric hindrance. When the substrate has large amounts of branching, it will be difficult for the nucleophile to approach the site for attack in both the SN1 and SN2 reactions (Fig. 2). Furthermore, in the SN2 reaction, where a transition state is formed (mechanisms of both the SN1 and the SN2 reactions are discussed in this article), the transition state will be unusually crowded which results in unfavorable steric interactions, and this also slows down the rate of the reaction. Carbocations prefer planarity in a large number of cases, and the presence of large groups may cause distortion, away from planarity, giving these carbocations a higher energy and therefore making them more unstable.
Fig. 2: Nucleophilic attack is unable to occur.
Another structural factor would be of resonance, and this is especially true for the SN1 mechanism. In the SN1 mechanism, the first step involves the formation of a carbocation. The more stable this carbocation, the faster and more energetically favorable the reaction will be; as such, structural factors may be those that stabilize the carbocation. Stabilization is possible through three main ways: the resonance, induction, and field effects. Where there are groups that can lend resonance to the formed carbocation, and delocalize the positive charge, the molecule will become more stable. Many examples of such groups do exist, but a prominent example is triphenylmethyl chloride, where there are three phenyl groups bonded to the site of nucleophilic attack (in this case, the carbon atom). The delocalization is very great in this case, with the positive charge delocalized over the three benzene rings.
Fig. 3: Structure of triphenylmethyl chloride.
Finally, there are some specific cases where nucleophilic substitution definitely does not occur or at least becomes slower (this is sometimes considered another factor, location, but in our case we will consider it as the same factor). Notably, where the site of nucleophilic attack is present in a cyclic molecule, it is rare for nucleophilic attack to occur. It is also likely for a ring-opening reaction to occur simultaneously with the departure of the leaving group. As such, it is unlikely for nucleophilic attack to occur unless the ring strain of the cyclic is very great, because the ring-opening would take a significant amount of energy to achieve. Closely related to the idea of cyclic substrates is bridgehead carbons, where only the SN1 mechanism may be achieved. In bridgehead carbons, the same idea of steric hindrance exists as well. Since the SN2 mechanism requires a backside attack, it is impossible for the nucleophile to attack via the SN2 mechanism, because the backside of the bridgehead carbon is blocked.
Factor: Nucleophilicity
Very obviously, the nucleophilicity (that is, how ‘strong’ the nucleophile is) of the nucleophile can and will affect the rate of the nucleophilic substitution reaction. What is key here is how we differentiate the nucleophilicities of different nucleophiles. There are four factors which dictate the nucleophilicities, but since they are not quantitative, it is only sufficient for us to compare two different nucleophiles. Firstly, and most simply, a nucleophile with a negative charge will always be stronger than its neutral counterpart. For example, OH- is a stronger nucleophile than H2O. This, however, does not serve as an effective comparison, especially between completely different nucleophiles. The usage of periodic table correlations is able to supplement this. Across a period of the periodic table, the nucleophilicity will increase with the basicity, although we should note that this does not imply that nucleophilicity is the same as basicity. This means that OH- is stronger than F- as a nucleophile. However, comparison between elements of the same group instead shows that the nucleophilicity increases as the basicity increases. It is not difficult to explain why. Solvent cages form around smaller nucleophiles, preventing reaction or making it slow and inefficient. For larger nucleophiles, it is more difficult to form solvent cages, allowing for faster nucleophilic attack to occur (Fig. 4).
Fig. 4: Formation of solvent cages.
Factor: Solvent
Obviously, because of the previous factor, we would know that the solvent also plays a part. In particular, we are referring to the difference between protic and aprotic solvents. For neutral substrates, hydrogen bonds may be formed between the substrate and the solvent molecule, allowing for rapid SN1 reactions. The hydrogen bonds stabilize and facilitate the departure of the leaving group, allowing for this leaving group to depart at a fast rate (Fig. 5). Note, however, that this will only greatly influence the rate of SN1 reactions, because in SN2 reactions, the nucleophilic attack happens simultaneously with the departure of the leaving group, while the departure of the leaving group solely happens in the rate-determining step of the SN1 reaction. We will also list some simple examples of protic and aprotic solvents. For protic solvents, commonly used are water, alcohols, or carboxylic acids. As for aprotic solvents, DMF (dimethylformamide) as well as DMSO (dimethyl sulfoxide) are the most commonly cited.
Fig. 5: Protic solvents facilitate substitution.
Factor: Electronegativity
The final factor for nucleophilic substitution reactions is the electronegativity of the leaving group. We will see why later. The leaving group also ties in to the factor of solvents, because the presence of hydrogen bonds to the leaving group makes it easier for the leaving group to depart. In any case, the leaving group will take away both bonding electrons, and this means that the leaving group should usually bear a negative charge as a free atom. To make the departure of the leaving group more energetically favorable, the leaving group should be stable as a free atom; the factor is thus how well the leaving group bears the negative charge. In many cases, there is only one thing that affects this factor: the electronegativity of the leaving group. The more electronegative the leaving group, the more it wants electrons, and thus the better it can bear electron density. As such, the more electronegative the leaving group, the faster the rate of the substitution reaction. This is why common substitution reactions involve electronegative leaving groups, most notably the halogens. In Fig. 6, we see similar molecules, with either a hydrogen or a chlorine as the leaving group. Obviously, only the molecule on the left, chloromethane, can participate in reaction, and that is because chlorine is more electronegative and thus a better leaving group than hydrogen.
Fig. 6: Electronegativity matters in substitution.
Factor: Activating Groups
We have already finished discussing all five (or four) factors relating to the rate of nucleophilic aliphatic (non-aromatic) substitution reactions. Now, let us begin looking at another common type of substitution reactions, which are electrophilic aromatic substitution reactions. Since electrophilic aromatic substitution reactions involve a completely different type of substrate, it is logical that there should be a completely new set of factors involved. This is precisely true for electrophilic aromatic substitution, where, for example, the nucleophilicity of the leaving group no longer matters because the leaving group is always the same (a hydrogen). Once again, the mechanism of electrophilic aromatic substitution reactions is explained here. The most obvious factor which affects the rate of these reactions is the presence of activating or deactivating groups. Activating groups are electron-donating groups, while deactivating groups are electron-withdrawing groups.
In the main mechanism of electrophilic aromatic substitution, the arenium ion mechanism, a carbocation is formed in the intermediate (arenium ion). As with what we previously discussed, if the benzene has another substituent on it, it may stabilize or destabilize the carbocation via inductive and field effects. If the substituent were electron-withdrawing, it would withdraw even more electron density from the already electron-deficient arenium ion ring, destabilizing it even more. This makes the electrophilic attack on the benzene less energetically favorable. As such, an electron-withdrawing group is a deactivating group which slows down the electrophilic substitution reaction. However, for electron-donating groups, it stabilizes the carbocation by donating electron density to it, making the reaction more energetically favorable. This means that the reaction will proceed faster, and an electron-donating group is also known as an activating group.
Factor: Steric Hindrance
Steric hindrance is much more clear-cut for electrophilic aromatic substitution reactions, because in this case there are only six possible positions (six carbon atoms) on the substrate for the substituent to be. The steric hindrance for benzenes is very simple: when substituents are present on the 1 and 3-carbons, electrophilic attack cannot or will rarely occur on the 2-carbon. Furthermore, if there is branching on those substituents on the 1 and 3-carbons, it would make electrophilic substitution even less likely. Another key idea that also matters is the size of the electrophile: if the electrophile were too large, it would sometimes be unable to attack even at minimally hindered positions. For example, for monosubstituted benzenes, large electrophiles are unable to attack at the 2 or the 6-carbons, because those positions are partially sterically hindered by the lone substituent on the benzene.
Conclusion
So, yes, there are a total of 7 factors affecting the rate of substitution reactions. This could be slightly misleading, because we have studied 5 factors affecting the rates of nucleophilic substitution reactions and 2 factors affecting the rates of electrophilic substitution reactions. Of course, it is likely that I could have missed out some factors, but that will be it for this article.