{getToc} $title={Table of Contents}
Introduction
Benzene is a nucleophile. This is why it can undergo electrophilic aromatic substitution reactions. However, what about nucleophilic aromatic substitution reactions?
Today, we will be learning about their mechanisms, of which many (surprisingly?) exist. The most discussed mechanism is of course the aryne or benzyne mechanism, but other mechanisms exist as well. That forms the crux of what we will explain and discuss today.
There are, in general, six types of aromatic substitution reactions, the last two of which will only be discussed briefly, because they are not as established. We may have heard of the four more established mechanisms before; these are the SNAr, SN1, SRN1 and benzyne mechanisms.
We will firstly take a look at a simple mechanism, the SNAr mechanism. Why do we say it is simple? This is because the mechanism is extremely similar to what we have previously learnt before, the arenium ion mechanism, in terms of factors including the rates of the reactions.
So without further ado, let us begin the discussion of these four mechanisms.
SNAr Mechanism
The SNAr mechanism is special because, as we mentioned, it is highly similar to its electrophilic counterpart, the arenium ion mechanism. This mechanism will not take place for benzene itself, but will only occur for substituted benzenes, and there is a clear reason for this.
In benzene, the leaving group for SNAr mechanisms would be a hydrogen atom. It is primarily expected that aromatic carbons are nucleophilic, and for nucleophilic substitution to occur on these carbons, something must be employed to ‘force’ the reaction and make it more energetically favorable.
For the SNAr mechanism, a good leaving group would aid the reaction and make it more energetically favorable. This also means that ipso attack must occur on substituted benzenes, where attack occurs on the carbon directly bonded to the leaving group.
Now, we will take a look at the steps of the SNAr mechanism. Because of its similarities to the arenium ion mechanism, it also involves two steps. In the first step, there is an attack on the ipso carbon (Fig. 1), which results in the formation of a negatively-charged intermediate.
This intermediate can be stabilized by several factors, including by the addition of a positively-charged counterion, forming what is known as a Meisenheimer complex. In fact, the isolation of such complexes provide strong proof for the existence of this mechanism, something that will be explained later. But for now, let us move on to look at the second part of this mechanism.
Fig. 1: First step of the SNAr mechanism.
The second step of the SNAr mechanism is very similar to the second step of the arenium ion mechanism. The overall concept behind these is rearomatization. Since aromatic compounds are highly stable, the transition of the intermediates, whether from the SNAr or arenium ion mechanism, to the final compound, will be driven by rearomatization.
In both mechanisms, the loss of the leaving group is inevitable. For the arenium ion mechanism, a hydrogen is lost, while for the SNAr mechanism, the leaving group is lost.
Fig. 2: Second step of the SNAr mechanism.
Just as the leaving group is key, it is also similarly not involved in the consideration of the rates of both mechanisms. In the two mechanisms, the rate-determining step is the first one. This means that the leaving group, which only departs in the second step, will not be involved in the overall rate equation.
Logically, though, since the leaving group is bonded to the site of attack it will still be able to affect the rate of the reaction, albeit by very little. There are two main examples of this: 1. Steric hindrance, where the leaving group blocks the site of attack preventing reaction. 2. Inductive effects, where the leaving group withdraws or donates electron density to the site of attack.
SN1 Mechanism
Next, we will take a look at the SN1 mechanism. As suggested by the name, it is very similar to the SN1 mechanism of aliphatics (nonaromatic compounds). It cannot occur to all aromatics; only active ones may participate.
Interestingly, unimolecular SN1 mechanisms may occur as well, although this is much rarer. A commonly cited example for general aromatic SN1 reactions is with diazonium salts. This is logical because diazonium salts contain the diazo group, which is an excellent leaving group, perfect for the requirements of the SN1 mechanism.
The mechanism is exactly the same as its aliphatic counterpart, thus we will not show any images for this mechanism; images for aliphatic SN1 reactions are shown here.
There are two steps in the reaction. In the first step, the diazo cation leaves, resulting in the formation of the cyclohexadienyl cation. This cation, obviously, is unstable, and rearomatization becomes favorable. This is what happens in the second step; an attack by a negatively-charged nucleophile is able to resolve the positive charge and reform the neutral, aromatic compound. As with the aliphatic SN1 mechanism, the rate-determining step is the first step.
The rate of the reaction, being dictated by the first step, is only affected by the substrate. And since the substrate involves the leaving group, the effect of the leaving group matters here as well. We can take advantage of the rate equation to prove the mechanism; for example, by demonstrating that the reaction is first order with respect to the substrate.
Another proof is possible and this is given by reversible cleavage (Fig. 3). This describes the instance where the product of the first step, a cyclohexadienyl cation, is able to reform the bond with the stable molecule N2 to form the starting material, the diazonium salt. This means that the first step is reversible.
Fig. 3: Illustration of reversible cleavage.
Usually, the diazonium should not be selective enough such that the rate equation of the first step becomes more complicated, as we have explored for aliphatic SN1 reactions. Nevertheless, there will inevitably be some amount of reversible cleavage. How do we use this to our advantage as evidence for aromatic SN1 mechanisms?
Well, we can utilize isotopic labeling to our advantage. First, we label just one of the nitrogens on the diazo group. This nitrogen would be the one not directly bonded to the aromatic carbon.
If we observe that some diazonium salts in the reaction mixture have the labeled nitrogen instead bonded to the aromatic carbon, it indicates that the orientation of the diazo group has been swapped, and this means that reversible cleavage must have taken place. This has indeed been observed, providing strong proof for the existence of the aromatic SN1 mechanism.
Benzyne Mechanism
Before we look at the SRN1 mechanism, it is important for us to understand the benzyne mechanism. Like the previous two mechanisms we have already encountered, the benzyne mechanism also features two steps.
In some part, the benzyne mechanism’s first step is similar to an E2 mechanism. Typically, one substituent (for example, a chloride) is present on the benzene. That substituent is removed along with a substituent on the adjacent carbon, which is usually a hydrogen. The net result of this is that a new pi bond is formed.This will form the benzyne (Fig. 4).
Fig. 4: Conformations of benzyne by UCLA.
Strictly speaking, however, it is not possible for such a triple bond to form. Such a structure is a resonance hybrid of the structures on the left and right in Fig. 3. A more accurate depiction of benzyne has two adjacent carbons possessing one electron each in their orbitals (left of Fig. 3). For convenience’ sake, however, the benzyne depicted in the middle of Fig. 3 is usually employed.
Now, let us move on to the second step of the reaction. The pi bond in the benzyne is attacked by a nucleophile, which breaks this pi bond and forms the final product. It is important to note that there are two positions for attack, at each of the carbons forming the ‘triple bond’. This means that two products may be formed and regioselectivity exists.
When a separate substituent exists on the benzene, it is likely that one of the products formed will predominate, because of the directing effects of that substituent.
The structure of benzyne is interesting and deserves to be explored more. Strong evidence for the existence of the benzyne mechanism was given by the isolation of the benzyne, although this was performed at very low temperatures. Interestingly, benzyne is still aromatic; however, it is still highly reactive.
SRN1 Mechanism
This next mechanism appears to have a rather similar name to the SN1 mechanism. It can be considered a subset of the SN1 mechanism, because it has almost exactly the same mechanism, except that the reactants are slightly different. As we may have guessed from the name, the ‘R’ refers to the fact that radicals are present as reactants.
In certain reactions that were previously thought to occur by the benzyne mechanism, it was observed that the two products were formed in near equal proportions, yet regioselectivity for the benzyne mechanism predicted that just one would predominate.
This suggests that another mechanism operates. Since the products are formed in equal proportions, it means that the attacking reagent is impartial to either of the attacking sites. A good candidate would be free radicals. And thus, the SRN1 mechanism was proposed.
The SRN1 mechanism operates in two steps. In the first step, dissociation of the substrate is catalyzed by the presence of an electron donor (Fig. 5). Dissociation results in the formation of a negatively-charged leaving group as well as a phenyl radical.
Fig. 5: First step of the SRN1 mechanism.
The next step is much more complicated. In the second step, the phenyl radical will further react with a nucleophile to form a negatively-charged radical species. This radical species reacts with a neutral compound to form the final, substituted product (Fig. 6). Note that this also results in the formation of another radical. The termination step will then eventually occur to stop the reaction. Wikipedia also has an article on the SRN1 mechanism.
Fig. 6: Second step of the SRN1 mechanism.
There is much evidence for the presence of this mechanism. One of such evidences is the isolation of many side products that should not have been formed by the benzyne mechanism.
Other Mechanisms
Earlier, we mentioned that two more mechanisms have been demonstrated other than the four we have previously discussed. The first of these is known as the ANRORC mechanism involving three steps. Firstly, addition of a nucleophile in the first step causes a ring-opening reaction to occur in the next step. Ring-closure then occurs to form the final, substituted product.
The reaction is rather interesting because the ring-opening can occur to even aromatic rings, and this has been prominently identified for pyrimidines especially. It has applications in medicinal chemistry. Literature on this seems to be lacking, but I recommend the Wikipedia article’s cited links and also this article.
The final type of mechanism is known as vicarious nucleophilic substitution and may be considered a subset of the SNAr mechanism, which we have discussed. In this mechanism, the variation is that the leaving group is a hydrogen, and not a substituent like in the SNAr mechanism.
As expected, it can only occur for special types of reagents, particularly nitroarenes. Notably, the expected meta-directing effect is not observed (again, refer to the regioselectivity article on this). The original article on this mechanism’s discovery is here.