Introduction
In this article, we will be discussing electrophilic and nucleophilic aromatic substitution reactions. These reactions are generally discussed with benzene, the most well-known aromatic compound, as the reactant; however, it is important to note that these reactions can happen to any aromatic, not just benzene. Aromatic substitution is very interesting because both electrophilic and nucleophilic substitution can occur to the reactant (benzene); however, electrophilic substitution reactions happen much more regularly to aromatics. The reason for this is due to the high electron density in the aromatic ring, making benzene nucleophilic, and thus more attractive to electrophiles, allowing more electrophilic substitution reactions to occur. We begin the article by explaining the mechanisms proposed for electrophilic aromatic substitution reactions.
Mechanisms
In a previous article, where we explained nucleophilic aliphatic substitution reactions, it was noted that there were a very large number of possible mechanisms, all leading to the same product (i.e. SN1, SN2, SNi, just to name a few). Uniquely for electrophilic aromatic substitutions, there is usually only one mechanism, the arenium ion mechanism, but another interesting mechanism, the SE1 (substitution electrophilic unimolecular) can occur as well in certain specific cases, which will be discussed later. Let us first focus on the arenium ion mechanism (Fig. 1). The first step involves the benzene reactant acting as the nucleophile (with the delocalized pi electrons) attacking the electrophile. The process is also sometimes described as a Lewis acid-base reaction, with the benzene being the Lewis base and the electrophile being the Lewis acid. The product of this first step is an intermediate where one of the carbon atoms is bonded to the electrophile and a double bond breaks; this intermediate is known as an arenium ion or a Wheland intermediate.
Fig. 1: Arenium ion mechanism of electrophilic aromatic substitution.
The arenium ion formed is not as unstable as expected due to resonance from the two double bonds left, but it is not aromatic and thus not as stable as the reactants or the products. The loss of the proton to regain aromaticity is thus energetically favorable, and this occurs to form the final product. This makes the second step relatively faster, with the first step slower and therefore rate-determining. Note that it is possible for the arenium ion to undergo two reactions: firstly, the hydrogen can depart leading to the final product, or the electrophile can depart, resulting in the reformation of the reactant. To make the loss of the proton (hydrogen) more favorable (thus increasing the rate of product formation), the substitution reaction usually occurs in a basic solvent or with the presence of base.
Regarding the evidence for such a mechanism, much has been found. Since a C-H bond is broken in the mechanism, it should be possible to prove the mechanism by deuteration (isotope effect); we may think that it is not possible, because the rate-determining reaction is the first step, which does not involve the breakage or formation of a C-H bond. However, we must remember that the first step of the reaction is reversible, as loss of the bonded electrophile is always possible to reform the product, giving the reactant in the second step two options. For ArHY+ (‘normal’ hydrogen), it is likely that the formation of the product would be more energetically favorable than the reformation of the reactant, since the Ar-H bond is broken. For ArDY+, however, Ar-D is more difficult to break (empirically proven). This makes the backward reaction of the first step occur more frequently, resulting in the first step being slightly slower for the deuterated aryl. This, however, will not occur if the rate constant for the second step is much higher than the rate constant for the backward reaction in the first step, as the overwhelming favorability of the second step makes the isotope effect negligible. Furthermore, stronger evidence comes from the direct isolation of arenium ions as well, showing that the arenium ion indeed exists as an intermediate and thus proving the arenium ion mechanism.
The second mechanism that exists is known as the SE1 mechanism, and like its name suggests, it is quite analogous to its aliphatic counterpart, the SN1 mechanism. As such, it also involves two steps; the first step is the ionization of the reactant, forming the benzene anion as well as the leaving group cation, and the intermediate from the first step attacks an electrophile, forming the product. This mechanism is much rarer than the arenium ion mechanism, because the departure of a leaving group from an aromatic is not usually energetically favorable. In fact, there are only two cases where this second mechanism can take place. The first case is where a very strong base is present, since this would make the loss of a proton more energetically favorable. Secondly, it could be that a carbon is the leaving atom. However, we will not focus much on the SE1 mechanism since it rarely occurs.
Substituent Effects
A key part of electrophilic aromatic substitution stems from our analysis of monosubstituted benzene rings (i.e. a benzene ring in which one hydrogen is replaced by another substituent), as this substituent can either confer or withhold reactivity onto the aromatic ring, speeding up or slowing down electrophilic aromatic substitution reactions. Substituents which slow down these reactions are known as deactivating groups, while substituents that speed up these reactions are known as activating groups. Furthermore, these substituents can also direct substituents to different positions on a ring: the ortho, meta and para positions, which are relative to the substituent (R in Fig. 2). How do these directing groups function? We know that three different intermediates are formed depending on where the electrophilic substitution occurs. These intermediates are of varying stabilities; the more stable the intermediate, the more likely electrophilic substitution will occur at the position that results in the intermediate. As such, whichever intermediate is stabilized the most by the presence of the substituent will then be the most energetically favorable reaction.
As we know, all three intermediates possible will always end up with a positive charge delocalized throughout the ring, since there is the breakage of a double bond. As such, it would be sensible to predict that whichever substituent stabilizes the positive charge the most would then speed up all three reactions, making generally the rate of all three reactions faster. What stabilizes positive charges? The answer is electron-donating groups. The electron-donating group donates negatively-charged electrons to the positive center of the ring, thus stabilizing the positive charge. As such, electron-donating groups are activating groups (they speed up the electrophilic substitution reaction). In contrast, electron-withdrawing groups withdraw electron density from the positive center, where there is already a lack of electron density. This further destabilizes the molecule; as such, electron-withdrawing groups are also known as deactivating groups.
Fig. 2: Position of substituents on a benzene ring.
Fig. 3: Resonance forms for ortho, para and meta attack.
Additionally, we notice that when electrophilic attack at the ortho and para positions occurs, the positive charge will be delocalized over the carbon bonded to the substituent already on the ring; as such, electron-donating groups will stabilize the ortho and para attack intermediates more than that of the meta attack intermediate (although all three intermediates will be stabilized). For both the ortho and para positions, it is possible in some cases for an extra bond to be formed between the substituent and its carbon, especially where this substituent has an unshared pair of electrons available for bonding (such as the halogens), creating a new resonance structure. This resonance structure is relatively stable and contributes significantly to the resonance hybrid. As such, although halogens appear to be electron-withdrawing groups that should destabilize the molecule, it instead directs ortho-para and activates these positions for electrophilic attack (although it is still a deactivating group).
The last type of substituent involves groups that lack an unshared pair but are still ortho-para directing. These substituents are electron-donating and activate the benzene ring; examples of this include alkyl and COO-, as well as (notably) the aryl group. Although aryl groups are electron-withdrawing and lack lone pairs of electrons, it is interesting that the extra resonance form can still occur because of delocalization of electrons in the aryl. As for the alkyl group, the ortho-para effect observed can be attributed to hyperconjugation.
Part 2 of this article will be released here on 23 Nov.