Thermodynamic control Friedel-Crafts

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. 

Thus ring acylation of phenols is observed under Friedel-Crafts conditions because the presence of aluminum chloride causes that reaction to be subject to thermodynamic (equi librium) control... 

A good deal of experimental care is often required to ensure that the product mixture at the end of a Friedel-Crafts reaction is determined by kinetic control. The strong Lewis acid catalysts can catalyze the isomerization of alkylbenzenes, and if isomerization takes place, the product composition is not informative about the position selectivity of electrophilic attack. Isomerization increases the amount of the meta isomer in the case of dialkylbenzenes, because this isomer is thermodynamically the most stable. ... 

A Wagner-Meerwein rearrangement can be part of the isomerization of an alkyl halide (Figure 14.4). For example, 1 -bromopropane isomerizes quantitatively to 2-bromopropane under Friedel-Crafts conditions. The [l,2]-shift A — B involved in this reaction again is an H atom shift. In contrast to the thermoneutral isomerization between carbenium ions A and B of Figure 14.3, in the present case an energy gain is associated with the formation of a secondary carbenium ion from a primary carbenium ion. Note, however, that the different stabilities of the carbenium ions are not responsible for the complete isomerization of 1-bromopropane into 2-bromopropane. The position of this isomerization equilibrium is determined by thermodynamic control at the level of the alkyl halides. 2-Bromopropane is more stable than 1-bromopropane and therefore formed exclusively. 

A significant advance in the use of Friedel-Crafts acylation of alkenes to prepare divinyl ketones was the employment of vinylsilanes to control the site of electrophilic substitution. Two groups have developed this approach to cyclopentenone annulation using slightly different strategies. In the method described by Magnus the reagent vinyltrimethylsilane (80) is used primarily as an ethylene equivalent (equation 44). The construction of bicyclic systems followed readily as Nazarov cyclization proceeded under the reaction conditions. Tin(lV) chloride was found to be the most effective promoter of the overall transformation. As expected the position of the double bond is thermodynamically controlled. 

Similarly, reaction of chlorobenzene with isopropyl chloride imder Friedel—Crafts conditions produced primarily the ortho and para alkylation products after a short reaction period. Allowing the reaction mixture to stand for a week before workup, however, produced primarily the meta product. In both of these cases, the product isolated after a short time is said to be the product of kinetic control of the product distribution, since the product isolated is the one that is formed faster. The product isolated after a longer time is said to be the product of thermodynamic control of product distribution, since it is the more stable product. ... 

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