Temperature control Friedel—Crafts reaction

This principal reaction mechanism is widely believed to apply to most S Ar reactions irrespective of the electrophilic reagent. There are however a number of experimental observations that indicate exceptions to this mechanism. There are examples of thermodynamically controlled Friedel-Crafts reactions, when using reaction conditions like polyphosphoric acid and elevated temperatures [27,28]. In iodination and some cases of Friedel-Crafts acylation, the last step of the reaction, the proton abstraction, has been shown to have a substantial kinetic isotope effect, which indicates that this step is at least partially rate limiting [29-31]. There are also still open questions regarding the exact nature of the reaction intermediates, and we will focus on these issues in the remaining part of the chapter. 

The chemistry of pyrrole is similar to that of activated benzene rings. In general, however, the heterocycles are more reactive toward electrophiles than benzene rings are, and low temperatures are often necessary to control the reactions. Halogenation, nitration, sulfonation, and Friedel-Crafts acylation can all be accomplished. For example ... 

The ene reaction,3 6360-365 the addition of a carbon-carbon or carbon-oxygen double bond with concomitant transfer of an allylic hydrogen, can allow for chirality transfer.366-369 The reaction has similarities to the Diels-Alder reaction in that a o-bond is formed at the expense of a 7t-bond. In addition, the use of a Lewis acid as a catalyst allows for control of the relative stereochemistry (Scheme 26.14).370-372 Large-scale reactions will be complicated by the need to use either high temperatures or Lewis acids. In addition, thermal and Friedel-Crafts-type degradation products may be problematic with the use of these conditions.361373... 

We see here a situation exactly analogous to one we have encountered several times before in 1,2- and 1,4-addition to conjugated dienes (Sec. 8.22), in Friedel-Crafts alkylation of toluene (Sec. 12.11), and in sulfonation of phenols (Problem 24.13, p. 803). At low temperatures the controlling factor is rate of reaction, at high temperatures, position of equilibrium,... 

Traditional Friedel-Crafts synthesis uses low temperatures and long reaction times to control the reaction. In many cases, reactions are performed over 24-72 h, which nevertheless produces a mixture of products that need separation to recover the desired product with appropriate purity. In the case of continuous flow reactors, however, higher temperatures are required than in a batch reactor because the residence time within small-volume reactors is comparatively low even so, high selectivities and conversions have still been achieved at these temperatures [48]. 

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