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45.4.2.1.1.1 Variation 1: Lewis Acid Catalyzed Friedel–Crafts Alkylation of Arenes with Alkyl Halides

DOI: 10.1055/sos-SD-045-00097

Zysman-Colman, E.Science of Synthesis, (201045159.

Throughout the 140-year history of FriedelCrafts alkylation chemistry, two Lewis acid catalysts have become preeminent (Scheme 2). Despite its limited solubility in apolar solvents, anhydrous aluminum trichloride, first introduced by Friedel and Crafts, remains a first-choice catalyst. Boron trifluoride and related complexes have also had widespread appeal since the 1920s.

Scheme 2 General Schematic of Lewis Acid Catalyzed FriedelCrafts Alkylation

All manner of alkyl halides, be they fluoride, chloride, bromide, or iodide, can be used in FriedelCrafts alkylation protocols. Even bulky alkyl halides such as 1-chloronorbornane, 3-chloroadamantane, and fluorocubane couple in moderate yields (ca. 50%) using aluminum trichloride as a catalyst.[‌17‌] A primary disadvantage of FriedelCrafts alkylations, alluded to in Section 45.4.2.1.1, is the potential for isomerized product formation that results from migration of the carbenium ion intermediate. Isomerization of alkyl halides with Lewis acids such as aluminum trichloride occurs readily, even at low temperatures (20°C). These isomerizations naturally tend toward formation of the most stabilized carbenium ion, which can be confirmed by alkylated product ratio analysis. Such isomerizations can be minimized somewhat, but are case specific. One solution is to have the arene present in solution with the alkyl halide when the catalyst is added.[‌18‌] Mollifying the catalytic activity of aluminum trichloride by addition of nitromethane slows isomerization when the substrate electrophile is either an alkyl halide or an alkene.[‌19‌] This depression of catalytic activity by solvent should not be generalized. A second disadvantage to using catalysts such as aluminum trichloride is that they are usually used stoichiometrically, with a necessary concomitant removal of aluminum hydroxide byproducts during workup. Aluminum trichloride is also not very functional group tolerant, thus limiting its applicability in FriedelCrafts alkylation reactions.

Since the mid-1950s, following the discovery of trifluoromethanesulfonic acid, metal trifluoromethanesulfonate use has come to the fore. FriedelCrafts alkylation can proceed in moderate yields at room temperature using a boron, aluminum, or gallium tris(trifluoromethanesulfonate) complex.[‌20‌] These have the particular advantage of being much less volatile than boron trifluoride or aluminum trichloride without significant loss in catalytic activity. Though less thermally stable, given the increased solubility of boron tris(trifluoromethanesulfonate) in weakly coordinating solvents such as dichloromethane, it remains the catalyst of choice of the three for solution-phase FriedelCrafts alkylation. Alkyl chlorides, fluorides, and bromides can all be used, although the last affords decreased yields. Dialkylation can be minimized through the use of an excess of arene to alkyl halide.

The regioselectivity of alkylation onto substituted arenes is governed largely by the temperature, the nature and the stoichiometry of the catalyst, and the solvent polarity.[‌21‌] Though the regiochemistry of the initial alkylation can be effectively directed by the substituents on the arene, over time, under thermodynamic control,[‌22‌] regiochemical scrambling will occur via a sequence of [1,2]-alkyl and [1,2]-H WagnerMeerwein shifts. This is particularly evident when the substituent is alkyl. As an example, room temperature boron tris(trifluoromethanesulfonate) catalyzed isomerization of each of the isomeric ethyl­(methyl)benzenes affords after 2hours in each case a mixture of the three regioisomers, with 1-ethyl-3-methylbenzene the major product observed. A weakness of this methodology is the need for 50mol% catalyst loading and the necessity that the reaction be run under strictly anhydrous conditions, owing to the hygroscopicity of the catalyst.

The use of transition metal catalysts is one way to modulate the acidity of the Lewis acid. Rhenium catalysts such as bromopentacarbonylrhenium(I) have been demonstrated to effectively catalyze the monoalkylation of tert-butyl chloride onto arenes in 1,2-dichloroethane to give alkylarenes 1 in excellent yield (Scheme 3).[‌23‌] As is usually the case, a slight modification in the reaction conditions results in dramatic changes in product distribution. Changing the solvent to chloroform, using anisole as a substrate and at slightly reduced reaction temperatures, results in a 22:78 ratio of monoalkylated/dialkylated material compared to a 92:8 ratio in 1,2-dichloroethane. Alkyl chlorides as electrophiles provide higher yields of alkylarenes compared to their bromide or iodide congeners. Analogously, benzyl fluorides are more reactive than benzyl chlorides, which themselves are more reactive than benzyl bromides.[‌24‌] In general, activated arenes such as anisole react faster (ca. 30 minutes) and afforded higher yields of mixtures of mono- and dialkylated products than less activated arenes. Even at elevated temperatures (120°C) over 8hours, the total yield of tert-butyl- and di-tert-butylbenzenes reaches only 43%.

Scheme 3 Rhenium(I)-Catalyzed FriedelCrafts Alkylation Using Alkyl Halides[‌23‌]

Other transition metal Lewis acids, such as gallium(III) chloride, titanium(IV) chloride, antimony(V) fluoride, iron(III) chloride, tin(IV) chloride, gold(III) chloride, and zirconium(IV) chloride, also catalyze the alkylation of arenes.[‌24‌] Depending upon the reaction time and the choice of Lewis acid, different ratios of regioisomeric products can be obtained. Although a single Lewis acid cannot be identified as being optimal for all substrates, through judicious choice of Lewis acid, positional control as well as chemoselectivity amongst competing arenes can be augmented, albeit moderately.

A common problem with Lewis acid catalysts is that they cannot be recovered to be reused after aqueous workup. There are additional environmental issues that need to be considered, including the inevitable disposal of metal hydroxide salts frequently created during aqueous workup. A potential solution is the use of lanthanide catalysts, which can be recycled from the aqueous layer during workup by evaporation to dryness in the presence of catalytic hydrochloric acid. Although there are conflicting reports[‌24‌] as to the efficacy of lanthanide(III) chlorides as catalysts in FriedelCrafts alkylations, it has been found that, under heterogeneous conditions at slightly elevated temperatures (75°C, toluene), most lanthanide(III) chlorides, and particularly the late lanthanides [e.g., lutetium(III) chloride and thulium(III) chloride], efficiently catalyze the alkylation of arenes;[‌25‌] scandium(III) chloride and lanthanum(III) chloride are exceptions. Yields for alkylarenes are good and usually hover around 60%. Critical to their reactivity is that water be excluded from the reaction mixture. Lanthanide hydrates needed to be copiously dried in order to obtain high yields. Reactions are rapid and usually are complete in only 30 minutes. Although the reaction conditions are chemoselective for monoalkylated products, as is frequently the case, one obtains mixtures of regioisomeric products about the arene.

Experimental Procedure

Alkylbenzenes 1; General Procedure:[‌23‌]

A three-necked, round-bottomed flask was charged with the arene (2mmol), alkyl halide (6mmol), and ReBr(CO)5 (0.02mmol) in 1,2-dichloroethane (3.5mL). The mixture was heated to 84°C for 0.515h, depending on the arene. Upon cooling to rt and evaporation of the solvent, the products were purified by chromatography; yield: 999%.

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