Recap
The previous article was very recent, and some advanced concepts building on the foundational ones were raised. In this article, we will no longer simply stick to the discussion of concepts; rather, we will begin taking a look at the many electrophilic aromatic substitution reactions of benzenes. Before that, we will take a look at the concepts that we have discussed in the previous article. The first of these concepts was the ortho-para ratio. Usually, ortho-para directing substituents will not produce the ortho and para product in equal amounts, as there are usually factors at play which favor one of the products over the other. The factors which may dictate whether a ortho or para product will be of a larger volume include the fact that there are two ortho positions available for attack, which is contrasted by the fact that only one para position is present, as well as the charge distributions of the molecule which may dictate favorability (the higher the charge distribution, the easier to stabilize the carbocation that is formed in the arenium ion mechanism). Furthermore, other factors such as steric hindrance and many more may also have an effect on the favorability of the different products. Notably, the example of the cyclodextrin (the ball-and-stick model of which is shown in Fig. 1) was also raised as an example of an artificial way to trigger the favorability of one product over another.
Fig. 1: Space-filling model of a cyclodextrin.
In the final part of the previous article, we also considered the regioselectivity of disubstituted benzenes. We have already understood the regioselectivity at play in monosubstituted benzenes, but disubstituted benzenes are likely to often put opposing factors together, creating problems when scientists attempt to predict the major product formed. There are a few general guidelines that have been devised to aid these scientists. The first guideline is that the stronger activating group on the disubstituted benzene will always control the products formed, no matter whether the other substituent is activating or deactivating. The second rule relates to steric hindrance, and suggests that if two attacking positions are possible, with one adjacent to both substituents on the disubstituted benzene, that position will not be favored due to destabilizing steric hindrance, particularly if the attacking species is a large one. The final rule relates to the third ortho effect and refers to the special case where the ortho-para directing group is meta to the meta-directing group, which compels the attacking species to attack on the carbon ortho relative to the meta-directing group.
Electrophilic Aromatic Substitutions
Now, it is time for us to take a look at the various reactions that may occur with benzenes or other aromatic systems, which are typically electrophilic aromatic substitutions. The first class of reactions are substitution reactions in which hydrogen is the electrophile. We only mention one reaction in this class of reactions, which is hydrogen exchange. Of course, this cannot be observed in reactions between ArH and H+; instead, the isotope, D+, is employed as the electrophile instead. The mechanism of such a reaction follows the arenium ion mechanism, evidence of which is given by the isolation of the corresponding intermediates. However, the mechanism may change if a strong base is added, in which the SE1 mechanism operates instead. In such cases, deprotonation of ArH occurs first resulting in the Ar- anion which may be attacked by an electrophile.
Let us move on to consider reactions in which nitrogen is the electrophile instead. The first such reaction we will discuss is also relatively common and can occur to a large variety of aromatics. It is the nitration of benzene (Fig. 1). This is done by reacting benzene with HNO3 (nitric acid) in H2SO4 (sulfuric acid). For more active substrates however, nitric acid alone can usually nitrate the ring successfully. Such compounds include phenols or pyrrholes, where the same mixture of HNO3 and H2SO4 would cause the generation of side products from oxidation, and milder conditions are usually needed for such substrates. Alternatively, instead of using nitric acid, nitrate esters in triflic acid may also be used, and the ortho product is usually generated in large amounts.
Fig. 1: Nitration of benzene.
Furthermore, the reaction is also easy to carry out and stop because the NO2+ group (formed after nitration) is deactivating. This means that the more the number of nitro groups added onto the ring, the slower the subsequent nitration will be. For multiple nitrations, drastic reaction conditions have to be applied, such as heating at high temperature or the usage of much stronger nitrating agents. Usually the attacking electrophile will be NO2+, which can be generated in a few ways. Firstly, nitric acid may undergo an acid-base reaction with sulfuric acid, where nitric acid acts as the base; in such cases, protonation will force the departure of a molecule of H3O+ (after double protonation of HNO3) as well as yield the positively-charged electrophile NO2+. The second path can occur with nitric acid (concentrated) alone, where an autoionization occurs, with one HNO3 molecule acting as an acid and the other acting as a base, and this also results in formation of NO2+. Alternatively it is also possible to use N2O5 (in CCl4), which may undergo dissociation, or nitronium salts, which also dissociate into the NO2+ ion.
The next reaction also similarly involves nitrogen, but this time it is the nitrosation of benzene. There are only two classes of aromatic benzene derivatives that are able to undergo this reaction; they are the phenols and specifically tertiary aromatic amines. When such compounds are treated with nitrous acid, there is the electrophilic substitution of the -N=O group onto the molecule. Nitrosation may only take place with activated substrates, which includes aromatic amines and phenols. Primary aromatic amines yield diazonium products, whereas for secondary aromatic amines, the nitrosation tends to happen on the nitrogen (on the secondary amine substituent) rather than on a carbon. As for the mechanism of this reaction, it is generally not well understood. The observed attacking entity seems to be NO+ in some cases, while NOCl or NOBr are also seen in other cases (these are carriers of NO+). NO+ itself is quite stable so after an arenium ion is formed, it can easily be cleaved to reform the starting material. For phenols, the problem seems to be circumvented, with attack first occurring on the OH group, before rearrangement takes place to nitrosate the carbon.
The next class of reactions we will discuss is of diazonium coupling, which involves the connection between two aryls through a N=N moiety. This, however, can only be done with active substrates, which, as we have discussed previously, include amines and phenols. The reactants of the diazonium coupling are active benzene derivatives (ArH) as well as an aryl diazonium salt (or ion). Typically the coupling occurs on the para carbon, because of steric hindrance caused by the two large aryl groups, but ortho coupling may occur as well if the para position is occupied. The reaction conditions are able to influence the rates of reaction, and this is particularly demonstrated by changes in the pH. If the derivative is an amine, the acidity cannot be too high because that would cause protonation of most of the amine substituents, preventing reaction. Generally mild acidity or neutrality is favored for amines. For phenols, a slightly basic (alkaline) solution is needed, because the conversion of phenols to phenoxide ions (more reactive) is needed to drive the coupling reaction. Yet, the more basic the solution, the more likely the formation of a side product, diazo hydroxide. Interestingly, it appears that in some cases even aliphatics may couple with the aryl diazonium salt, although this is rare and requires specific aliphatics.
Having discussed diazonium coupling, let us also explain the formation of aryl diazonium salts, which may be formed by direct introduction of the diazonium group onto a benzene. Again, since the reaction involves a direct introduction, it only applies to amines or phenols. The reactants are the benzene, which reacts with two equivalents of nitrous acid in hydrogen halide to form the aryl diazonium salt (in which the counterion would be the negatively-charged X- halide anion). We notice that the main reactants in such a reaction still remain essentially the same as in the nitrosation reaction, and this means that the products of the nitrosation, which are nitroso compounds, will form first. However, in excess nitrous acid, these nitroso substituents will react further and undergo conversion to the diazonium ion.
Next, we have the amination of benzenes. The conversion of aromatic compounds to primary amines is performed by hydrazoic acid, HN3, in the presence of either AlCl3 or H2SO4 as catalysts. For secondary or tertiary amines, the chlorodialkylamine (R2N+HCl) is employed for the amination, along with a metal ion catalyst. The reasoning behind this is because the metal ion is a good reducing agent, reducing the chlorodialkylamine into a R2N+H radical and a chloride anion. The radical then acts as the attacking species and may undergo electrophilic aromatic substitution as expected. We would think that the radical will attack the benzene in a mechanism different from the typical arenium ion mechanism, but this is not true, because the radical still possesses a positive charge and thus will behave normally similarly to a positively-charged species. It is possible for substitution to occur for alkyl groups, replacing the alkyl group with the amine.
Interestingly, it may be possible for the generation of meta products even when an ortho-para directing group is present on the molecule. In such a reaction, toluene (methylbenzene, where the methyl is ortho-para directing) reacts with NCl3 with AlCl3 resulting in amination on the meta position. This may seem unusual, but let us first take a look at the mechanism of the reaction. The first electrophilic attack is not by the nitrogen, but rather by the chloride cation, which attacks at the para position resulting in the formation of an arenium ion intermediate. Subsequently, this is attacked by the nitrogen nucleophile on the meta position, and note that this is not an electrophilic aromatic substitution, but a simple nucleophilic addition. In the last step, there is then elimination of a molecule of HCl to rearomatize the ring, forming the final meta-aminated product.