Chapter 25
Aryl Halides Nucleophilic Aromatic Substitution
Structure
Aryl halides are compounds containing halogen attached directly to an aromatic ring. Theyhavethe general formula ArX, where Ar is phenyl, substituted phenyl, or one of the other aryl groups that we shall study.
An aryl halide is not just any halogen compound containing an aromatic ring. Benzyl chloride, for example, is not an aryl halide, for halogen is not attached to the aromatic ring; in structure and properties it is simply a substituted alkyl halide and was studied with the compounds it closely resembles (Chap. 14).
We take up the aryl halides in a separate chapter because they differ so much from the alkyl halides in their preparation and properties. Aryl halides as a class are comparatively unreactive toward the nucleophilic substitution reactions so characteristic of the alkyl halides. The presence of certain other groups on the aromatic ring, however, greatly increases the reactivity of aryl halides; in the absence of such groups, reaction can still be brought about by very basic reagents or high temperatures. We shall find that nucleophilic aromatic substitution can follow two very different paths: the bimolecular displacement mechanism, for activated aryl halides; and the elimination-addition mechanism, which involves the remarkable intermediate called benzyne.It will be useful to compare aryl halides with certain other halides that are not aromatic at all: vinyl halides, compounds in which halogen is attached directly
to a doubly-bonded carbon. Vinyl halides, we have already seen, show an interesting parallel to aryl halides. Each kind of compound contains another functional group besides halogen: aryl halides contain a ring, which undergoes electrophilic substitution; vinyl halides contain a carbon-carbon double bond, which undergoes electrophilic addition. In each of these reactions, halogen exerts an anomalous influence on reactivity and orientation. In electrophilic substitution, halogen deactivates, yet directs ortho,para (Sec. 11.21); in electrophilic addition, halogen deactivates, yet causes Markovnikov orientation (Problem 11.13, p. 367). In both cases we attributed the influence of halogen to the working of opposing factors. Through its inductive effect, halogen withdraws electrons and deactivates the entire molecule toward electrophilic attack. Through its resonance effect, halogen releases electrons and tends to activate but only toward attack at certain positions.
Problem 25.1 Drawing all pertinent structures, account in detail for the fact that: (a) nitration of chlorobenzene is slower than that of benzene, yet occurs predominantly ortho,para\ (b) addition of hydrogen iodide to vinyl chloride is slower than to ethylene, yet yields predominantly 1-chloro-l-iodoethane.
The parallel between aryl and vinyl halides goes further: both are unreactive toward nucleophilic substitution and, as we shall see, for basically the same reason. Moreover, this low reactivity is caused partly, at least by the same structural feature that is responsible for their anomalous influence on electrophilic attack: partial double-bond character of the carbon-halogen
We must keep in mind that aryl halides are of *'low reactivity" only with respect to certain"sets of familiar reactions typical of the more widely studied alkyl halides. Before 1953, aryl halides appeared to undergo essentially only one reaction and that one, rather poorly. It is becoming increasingly evident that aryl halides are actually capable of doing many different things; as with the "unreactive" alkanes (Sec. 3.18), it is only necessary to provide the proper conditions and to have the ingenuity to observe what is going on. Of these reactions, we shall have time to take up only two. But we should be aware that there are others: free-radical reactions, for example, and what Joseph Bunnett (p. 478) has named the base-catalyzed halogen dance (Problem 23, p. 845).
Physical properties
Unless modified by the presence of some other functional group, the physical properties of the aryl halides are much like those of the corresponding alkyl halides. Chlorobenzene and bromobenzene, for example, have boiling points very nearly the same as those of /i-hexyl chloride and w-hexyl bromide; like the alkyl halides, the aryl halides are insoluble in water and soluble in organic solvents.
The physical constants listed in Table 25.1 illustrate very well a point previously made (Sec. 12.3) about the boiling points and melting points of ortho, meta, and para isomers. The isomeric dihalobenzenes, for example, have very nearly the same boiling points: between 173 and 180 for the dichlorobenzenes, 217 to 221 for the dibromobenzenes, and 285 to 287 for the diiodobenzenes. Yet the melting points of these same compounds show a considerable spread; in each case, the para isomer has a melting point that is some 70-100 degrees higher than the ortho or meta isomer. The physical constants of the halotoluenes show a similar relationship.
Here again we see that, having the most symmetrical structure, the para isomer fits better into a crystalline lattice and has the highest melting point. We can see how it is that a reaction product containing both ortho and para isomers frequently deposits crystals of only the para isomer upon cooling. Because of the strong intracrystalline forces, the higher melting para isomer also is less soluble in a given solvent than the ortho isomer, so that purification of the para isomer is often possible by recrystallization. The ortho isomer that remains in solution is generally heavily contaminated with the para isomer, and is difficult to purify.
Preparation
Aryl halides are most often prepared in the laboratory by the methods outlined below, and on an industrial scale by adaptations of these methods.
These methods, we notice, differ considerably from the methods of preparing alkyl halides. (a) Direct halogenation of the aromatic ring is more useful than direct halogenation of alkanes; although mixtures may be obtained (e.g., ortho + para], attack is not nearly so random as in the free-radical halogenation of aliphatic hydrocarbons. Furthermore, by use of bulky thallium acetate (Sec. 11.7) as the Lewis acid, one can direct bromination exclusively to the para position, (b) Alkyl halides are most often prepared from the corresponding alcohols; aryl halides are not prepared from the phenols. Instead, aryl halides are most commonly prepared by replacement of the nitrogen of a diazonium salt; as the sequence above shows, this ultimately comes from a nitro group which was itself introduced directly into the ring. From the standpoint of synthesis, then, the nitro compounds hear much the same relationship to aryl halides that alcohols do to alkyl halides. (These reactions of diazonium salts have been discussed in detail in Sees. 23.11- 23.12.)
The preparation of aryl halides from diazonium salts is more important than direct halogenation for several reasons. First of all, fluorides and iodides, which can seldom be prepared by direct halogenation, can be obtained from the diazonium salts. Second, where direct halogenation yields a mixture of ortho and para isomers, the ortho isomer, at least, is difficult to obtain pure. On the other hand, the ortho and para isomers of the corresponding nitro compounds, from which the diazonium salts ultimately come, can often be separated by fractional distillation (Sec. 11.7). For example, the o- and />bromotoluenes boil only three degrees apart: 182 and 185. The corresponding o- and p-nitrotoluenes, however, boil sixteen degrees apart: 222 and 238.
Aryl iodides can be prepared by simple treatment of arylthallium compounds with iodine. As in the synthesis of phenols (Sec. 24.5) the thallation route has the advantages of speed, high yield, and orientation control (sec Sees. 11.7 and 11.13)
Problem 25.2
Using a different approach in each case, outline all steps in the synthesis of the following from toluene: (a) p-bromotoluene; (b) /Modotoluenc; (c) w-bromotoluene; (d) /w-iodotoluene; (e) 0-bromotoluene.
Reactions
The typical reaction of alkyl halides, we have seen (Sec. 14.5), is nucleophilic substitution. Halogen is displaced as halide ion by such bases as OH", OR", NH3 , CN , etc., to yield alcohols, ethers, amines, nitriles, etc. Even FriedclCrafts alkylation is, from the standpoint of the alkyl halide, nucleophilic substitution by the basic aromatic ring.
It is typical ofvry\ halides that they undergo nucleophilic substitution only with extreme difficulty. Except for certain industrial processes where very severe conditions are feasible, one does not ordinarily prepare phenols ( ArOH), ethers (ArOR), amines (ArNH2), or nitriles (ArCN) by nucleophilic attack on aryl halides. We cannot use aryl halides as we use alkyl halides in the Friedel-Crafts reaction. However, aryl halides do undergo nucleophilic substitution readily Jf the aromatic ring contains, in addition to halogen, certain other properly placed groups: electron-withdrawing groups like NO2 , NO, or CN, located ortho or para to halogen. For aryl halides having this special kind of structure, nucleophilic substitution proceeds readily and can be used for synthetic purposes. The reactions of unactivated aryl halides with strong bases or at high temperatures, which proceed via benzyne, are finding increasing synthetic importance. The Dow process, which has been used for many years in the manufacture of phenol (Sec. 24.4), turns out to be what Bunnett (p. 478) calls "benzyne chemistry on the tonnage scale!" The aromatic ring to which halogen is attached can, of course, undergo the typical electrophilic aromatic substitution reactions: nitration, sulfonation, halogenation, Friedel-Crafts alkylation. Like any substituent, halogen affects the reactivity and orientation in these reactions. As we have seen (Sec. 11.5), halogen is unusual in being deactivating, yet ortho,para-dirccting.
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