Friedel-Crafts Alkylation and Related Reactions

There are relatively few kinetic data on the Friedel-Crafts reaction. Alkylation of benzene or toluene with methyl bromide or ethyl bromide with gallium bromide as the catalyst is first order in each reactant and in the catalyst. With aluminum bromide as the catalyst, the rate of reaction changes with time, apparently because of heterogeneity of the reaction mixture. The initial rate data fit the following kinetic expression  

The reaction rates of toluene and benzene with /-propyl chloride or r-butyl chloride in nitromethane can be fit to a third-order rate law. 

Rates that are independent of aromatic substrate concentration have been found for reaction of benzyl chloride catalyzed by TiC or SbF in nitromethane. This can be interpreted as resulting from rate-determining formation of the electrophile, presumably a benzyl ion pair. The reaction of benzyl chloride and toluene shows a second-order dependence on the titanium chloride concentration under conditions where there is a large excess of hydrocarbon. This is attributed to reaction through a 1 2 benzyl chloride-TiC complex, with the second TiC molecule assisting in the ionization reaction  

All these kinetic results can be accommodated by a general mechanistic scheme that incorporates the following fundamental components (1) complexation of the alkylating agent and the Lewis acid in some systems, there may be an ionization of the complex to yield a discrete carbocation (2) electrophilic attack on the aromatic reactant to form the cyclohexadienylium ion intermediate and (3) deprotonation. The formation of carbocations accounts for the fact that rearrangement of the alkyl group is observed frequently during Friedel-Crafts alkylation. 

Absolute rate data for the Friedel-Craft reactions are difficult to obtain. The reaction is very sensitive to the effects of moisture and heterogeneity. For this reason, most of the structure-reactivity trends have been developed using competitive methods, rather than by direct measurements. Relative rates are established by allowing the electrophile to compete for an excess of the two reactants. The product ratio establishes 

The Friedel-Crafts reaction is a very important method for introducing alkyl substituents on an aromatic ring. It involves generation of a carbocation or related electrophilic species. The most common method of generating these electrophiles involves reaction between an alkyl hahde and a Lewis acid. The usual Friedel-Crafts catalyst for preparative work is AICI3, but other Lewis acids such as SbFj, TiC, SnCl4, and BF3 can also promote reaction. Alternative routes to alkylating species include protonation of alcohols and aUcenes. 

A rate law of the same form pertains to /-butyl chloride.  

The same rate law pertains to t-butyl chloride. The reaction of benzyl chloride and toluene shows a second-order dependence on titanium chloride concentration under conditions where there is a large excess of hydrocarbon.  

Rates which are independent of aromatic substrate concentration have been found for reaction of benzyl chloride catalyzed by TiCU or SbFs in nitromethane. This can be interpreted as resulting from rate-determining formation of the electrophile, presumably an ion pair of the benzyl cation. 

Good kinetic results, in general, have been difficult to come by in the Friedel-Crafts reaction. With the common catalysts, the reactions are very fast and often complicated by other problems, including heterogeneity. For this reason, most studies of structure-reactivity trends have been done using competitive reactivity data, rather than direct rate measurements. 

Electrophilic reagents felol benz Toluene 0 p ratio Ref. 

Steric effects also play a major role in determining Xht o p ratio in Friedel-Crafts alkylations. The amount of ortho substitution of toluene decreases as the size of the entering alkyl group increases along the series methyl, ethyl, 2-propyl.No ortho-substitution product is found when the entering group is -butyl.  

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

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For a monograph, see Roberts, R.M. Khalaf, A.A. Friedel-Crafts Alkylation Chemistry Marcel Dekker NY, 1984. For a treatise on Friedel-Crafts reactions in general, see Olah, G.A. Friedel-Crafts and Related Reactions Wiley NY, 1963-1965. Volume 1 covers general aspects, such as catalyst activity, intermediate complexes, and so on. Volume 2 covers alkylation and related reactions. In this volume the various reagents are treated by the indicated authors as follows alkenes and alkanes, Patinkin, S.H. Friedman, B.S. p. 1 ... 

The dicyclopentadienyl metal compounds undergo Friedel-Crafts alkylation and acylation, sulfonation, metalation, arylation, and formyla-tion in the case of ferrocene, dicyclopentadienyl ruthenium, and dicyclopentadienyl osmium, whereas the others are unstable to such reactions ( ). Competition experiments (128) gave the order of electrophilic reactivity as ferrocene > ruthenocene > osmocene and the reverse for nucleophilic substitution of the first two by n-butyl lithium. A similar rate sequence applies to the acid-catalysed cleavage of the cyclopentadienyl silicon bonds in trimethylsilylferrocene and related compounds (129), a process known to occur by electrophilic substitution for aryl-silicon bonds (130). 

The mechanism of the chloromethylation reaction is related to that of Friedel-Crafts alkylation and acylation and probably involves an incipient chloro-methyl cation, CH2C1 ... 

The Friedel-Crafts alkylation and acylation are of very little, if any, synthetic interest when applied to heterocyclic aromatic bases the substitution of protonated heterocycles by nucleophilic carbon-centered radicals is instead successful. This reaction, because of the dominant polar effect which is mainly related to the charge-transfer character of the transition state (Scheme 1), reproduces most of the aspects of the Friedel-Crafts aromatic substitution, but reactivity and selectivity are the opposite. 

In aromatic substitution, rates of halogenations were correlated with higher r values than unity (Yukawa et al., 1966). Extensive use of the Y-T equation by Eabom and his coworkers demonstrated significant variations of r value in aromatic substitution, particularly, with r values lower than unity these observations have been comprehensively reviewed by Norman and Taylor (1965). The present authors were not involved directly in the further development of this field and therefore these reactions will not be covered in this review. However, neighbouring aryl-assisted reactions are mechanistically related to Friedel-Crafts alkylation, and /3-aryl assisted solvolyses will be a particular concern in this review. 

Schmerling, L., in "Friedel Crafts and Related Reactions in Alkylation and Related Reactions." Olah, G. A. (ed.). Interscience Publishers (1964). 

Friedel-Crafts Acylation, Alkylation, and Related Reactions. While a stoichiometric amount of AICI3 is needed in Friedel-Crafts acylations, a small amount of Sc(OTf)3 smoothly catalyzes the same reaction. In the acetylation of thioanisole and o- or m-dimethoxybenzene, a single acetylated product is formed in an excellent yield. In the benzoylation of anisole, both benzoic anhydride and benzoyl chloride are effective, while benzoic anhydride gives a slightly higher yield. Addition of lithium perchlorate (LiC104) as a cocatalyst improves the yield dramatically (eq 13). ... 

Olah, G.A. Friedel-Crafts and Related Reactions, II-Alkylation and Related Reactions Intersci. Publ., New York/London/Sydney (1964)... 

Friedel-Crafts acylation, alkylation and related reactions... 

In 1877, Charles Friedel and James Mason Crafts [30a, b] corporately discovered that treatment of amyl chloride with aluminum strips in benzene led to the formation of amylben-zene. This type of transformation was found to be general for alkyl halides and aromatics under the catalysis of Lewis acid. Along with the discovery of the closely related acylation [30c, d], these two men are best remembered by Friedel-Crafts reaction that bears their names. With various modem modifications that appeared in the Uterature, including enan-tioselective variants [31], Friedel-Crafts alkylation and acylation have already become one of the most powerful C—C bond forming reactions in organic chemistry [32]. These methods are recognized to date as of fundamental importance not only in acadania but also in industry [33]. As shown in Scheme 10.18, some heteroaromatics, instead of the aryl component or alcohol, and alkenes instead of halides can be used as suitable substrates. Also, other common Lewis acids like BFj, TiCl, SnCl, ScfOTOj, etc., and Brpnsted acids snch as HF, H SO, and superacids (e.g., HF SbFj, HS03-SbFj) can also used as catalysts. 

The selectivity of an electrophile, measured by the extent to which it discriminated either between benzene and toluene, or between the meta- and ara-positions in toluene, was considered to be related to its reactivity. Thus, powerful electrophiles, of which the species operating in Friedel-Crafts alkylation reactions were considered to be examples, would be less able to distinguish between compounds and positions than a weakly electrophilic reagent. The ultimate electrophilic species would be entirely insensitive to the differences between compounds and positions, and would bring about reaction in the statistical ratio of the various sites for substitution available to it. The idea has gained wide acceptance that the electrophiles operative in reactions which have low selectivity factors Sf) or reaction constants (p+), are intrinsically more reactive than the effective electrophiles in reactions which have higher values of these parameters. However, there are several aspects of this supposed relationship which merit discussion. 

In this section, the reactivities of organosilicon compounds for the Friedel-Crafts alkylation of aromatic compounds in the presence of aluminum chloride catalyst and the mechanism of the alkylation reactions will be discus.sed, along with the orientation and isomer distribution in the products and associated problems such as the decomposition of chloroalkylsilanes to chlorosilanes.. Side reactions such as transalkylation and reorientation of alkylated products will also be mentioned, and the insertion reaction of allylsilylation and other related reactions will be explained. 

G. A. Olah, ed., Friedel-Crafts and Related Reactions, Vols. 1-1V, Wiley-Interscience, New York, 1962-1964. R. M. Roberts and A. A. Khalaf, Friedel-Crafts Alkylation Chemistry, Marcel Dekker, New York, 1984. 

This first example of a Bi(OTf)3-catalyzed Friedel-Crafts alkylation originated in the following procedures, including benzylations of 2,4-pentanediones or hydroarylation and hydroalkylation reactions. A related procedure was simultaneously developed by Bonrath et al. [39]. The authors utilized Bi(OTf)3 in the synthesis of (all-rac)-a-tocopherol (Vitamin E) [39], Besides rare earth metal triflates, such as Ga(OTf)3, Hf(OTf)3, Sc(OTf)3 and Gd(OTf)3, Bi(OTf)3 was shown to be the most efficient catalyst for the Friedel-Crafts-type reaction between trimethylhydroquinone acetate 10b and isophytols 11a, b. With only 0.02 mol% Bi(OTf)3 (substrate to catalyst ratio 5,000 1) the desired a-tocopherols 12a and 12b were isolated in excellent yields (Scheme 10). 

Thus, the combination of increased acidity and increased solvent power can be exploited for cleaner acid-catalysed reactions of organic compounds, for example Friedel-Crafts alkylation, [31] or hydrolysis of esters [9,28]. The acidity of high-temperature D20 can be used to deuterate organic compounds but the process is more efficient with an additional heterogeneous acid catalyst [32]. A related application, but not a catalytic one, exploits the acidity of SC-H2O for the in situ generation of H2 from metallic Zn the H2 can then be used for the selective reduction of organic nitro-compounds [29,30], see Figure 9.1-2. 

Another catalytic methodology that is widely used for C-C bond formation is the Heck and related coupling reactions [86, 87]. The Heck reaction [88] involves the palladium-catalysed arylation of olefinic double bonds (Fig. 1.31) and provides an alternative to Friedel-Crafts alkylations or acylations for attaching carbon fragments to aromatic rings. The reaction has broad scope and is currently being widely applied in the pharmaceutical and fine chemical industries. For example, Albemarle has developed a new process for the synthesis of the anti-in-... 

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