Recap
In the previous article, which was quite a while ago, we discussed a few important and key things about electrophilic aromatic substitution reactions. That article has discussed the foundation of electrophilic aromatic substitution; thus, in this and the following articles, we will focus on some of the concepts that simply build on these foundations. We will also give some examples of electrophilic aromatic substitution reactions, although the reactions will mostly follow the arenium ion mechanism and not the SE1 mechanism. Before we begin delving into some of these advanced concepts, let us first recap the foundational concepts so that we will not forget them when we learn about the more advanced ones. Firstly, let us only recap the main and most common mechanism for electrophilic aromatic substitution, which is the arenium ion mechanism. Generally, most reactions will follow this mechanism, while there are very few exceptions.
The arenium ion mechanism occurs via a two-step process. There is usually some confusion about whether it is the electrophile that attacks or the nucleophile that attacks, and in this case we will treat the electrophile as the attacking reagent and the benzene ring or other aromatic system (which is nucleophilic) as the substrate. In the first step of the arenium ion mechanism, the electrophile first attacks the aromatic ring, which of course makes the ring lose its aromaticity, as one of the double bonds is broken. This forms the reaction intermediate, which is known as an arenium ion or Wheland intermediate (Fig. 1). The aromatic compound is much more stable than this intermediate, and this means that the rearomatization of the ring is energetically favorable. Now, there are two ways to achieve rearomatization, which is either by departure of the electrophile (which has attacked) or a proton. Therefore the first step of the arenium ion mechanism is reversible. The reaction can be made faster by addition of a base.
Fig. 1: Structure of the arenium ion.
We also will consider where the electrophilic substituent will add to on the benzene ring. For benzene itself this is not a problem, because attack at any carbon atom would still yield the same product. However, the problem exists for monosubstituted benzenes (discussed previously) as well as disubstituted benzenes (discussed in this article). For monosubstituted benzenes, the nomenclature (Fig. 2) is that the 2-carbon, 3-carbon and 4-carbon are ortho, meta and para to the carbon bonded to the electrophilic substitution (also the 1-carbon). Different substituents will direct to different positions; activating groups, generally electron-donating groups, will direct to the ortho and para positions, while deactivating groups, generally electron-withdrawing groups, will direct to the meta positions. The reason behind the activation and deactivation is that the resonance of the arenium ion will bring the positive charge onto the carbon bonded to the electrophilic substituent largely in the ortho and para positions. When this electrophilic substituent is electron-donating, it will stabilize the carbocationic positive charge (which can only happen in the ortho and para positions) and this will speed up the reaction and explain the attack at these positions. When the electrophilic substituent is electron-withdrawing instead, the ortho and para attack is disfavored because it brings the carbocation in contact with this substituent, which is destabilizing. Thus the meta attack is favored. Since there is no stabilization, the group is deactivating.
However, it is also possible for some groups, which although are electron-withdrawing, still direct ortho-para, because they possess a lone pair of electrons. When the carbocation moves to delocalize over the carbon this electrophilic substituent is bonded to, the substituent may form a pi bond with the carbon, effectively removing the positive charge and granting all atoms on the molecule a full octet of electrons, and this is a highly stabilizing phenomenon. The direct result of this is that ortho and para attack will be favored due to the stabilization; furthermore, these electron-withdrawing substituents will also act as activating groups, as the resonance provided by the presence of the lone pair is able to outweigh the inductive effects (electron withdrawal or donation) of the electrophilic substituent.
Fig. 2: Explanation of the ortho, meta and para positions.
Ortho And Para Products
In the last article, we noted that electron-donating groups and some electron-withdrawing groups with lone pairs are able to direct ortho and para, and thus form a majority of the ortho and para products. Yet, we have failed to consider whether the products formed will be equimolar or in some ratio. Before we even start the discussion, we will have noted that there is only one para position available for attack, yet two ortho positions are available. This means that with all other conditions being equal, there would be twice as many ortho products as para products. However, of course, the conditions are almost always not equal, and even small factors such as charge distributions of monosubstituted benzenes are able to play a part in the dictation of whether the reaction proceeds with greater formations of the ortho or para product. In general, the largest charge distribution is present on the para position, with the ortho position coming in at a close second; thus the para attack is more stabilizing.
An excellent candidate, perhaps, for understanding the ratio of ortho and para products is the hydrogen exchange reaction of benzene, where usually a hydrogen atom on the benzene is substituted with a deuterium ion (D+). Technically hydrogen exchanges may happen between a proton (H+) and the benzene as well; however, it should not be observable. Since there are almost no factors affecting the reactivity of the benzene, it should be easy for us to identify the ortho and para ratio as similar to the one predicted by the charge distributions (were it correct). And this indeed proves to be the case, with the ratio of the ortho and para products formed by hydrogen exchange highly similar to the ratio of the charge distributions.
We will note one final factor which has a say in the regioselectivity of the electrophilic substituent. This is steric hindrance. Where the substituent on the benzene is simultaneously a large one and also ortho-para directing, it is likely for a higher percentage of the para product to form, because of unfavorable steric interactions created by the electrophilic substituent’s addition onto the ortho position. This is also true if the attacking species is large. Because of steric hindrance, the larger the attacking species or the ortho-para directing group, the lower the percentage of the ortho product formed. Note that if the attacking species is very large, there would be a smaller yield overall, but since a substituent exists adjacent to the ortho position, there would be even more steric hindrance than if the attack were at the para position, thus there would be a lower percentage of the ortho product. Another form of steric hindrance may exist if the benzene is encased in a cyclodextrin (Fig. 3), which is a very large cylinder-shaped macrocycle. In such cases, only the ‘ends’ of the benzene ring will be exposed (i.e. the para position) allowing for a much higher yield of the para product.
Fig. 3: Structure of a cyclodextrin.
Regioselectivity in Disubstituted Benzenes
Finally for this article, we will be taking a look at disubstituted benzenes, which are a more complicated case than monosubstituted benzenes, as the directing of groups may be different and constantly in opposition with one another. Usually, there will be no opposition between substituents, and they will instead reinforce each other’s effects, typical at a single carbon (that carbon will then be the most likely to participate in nucleophilic attack). However, there may be problems when there are two opposing groups instead. In such cases, a few rules have been established so as to allow us to predict which products are formed in such cases. The first rule is that a stronger activating group substituent will always control the products formed when the other substituent is weaker (i.e. weakly activating, weakly deactivating or strongly deactivating). We should note, however, that there would be less products formed than if there were only the stronger activating group on the aromatic ring, as some opposition, though miniscule, continues to exist.
The second rule is that if the direction of a group is onto a carbon that is adjacent to two other carbons both with substituents, the resulting product would be the least likely to form. The explanation for this is usually attributed to steric hindrance, which is posed by the two substituents, which makes it difficult for electrophiles to approach the carbon, however favored, for attack. The size of the attacking species also matters as well, though the focus would be on the disubstituted benzene. The third and last rule is the most interesting one as it dictates a highly specific case. It is known as the third ortho effect (the first and second ortho effects refer to the acidities and basicities of benzoic acids and anilines). It states that when there is an ortho-para directing group meta relative to a meta-directing group, the attacking group will most likely attack on the carbon which is ortho relative to the meta-directing group. Of course, the attack tends to be on the non-sterically hindered side, as established by the second rule. An application of the second and third rules is shown in Fig. 4.
Fig. 4: Application of the third ortho effect.
Part 1 of this article is here.
Part 3 of this article will be here on Dec 5.