Friedel-Crafts alkylations

One of the most common examples of an electrophilic aromatic substitution is Friedel-Crafts alkylation [40], These days, many important industrial processes are based on this type of Friedel-Crafts-chemistry [41]. The manufacture of high-octane gasoline, ethylbenzene, synthetic rubber, plastics and detergent alkylates are examples. Moreover, the Friedel-Crafts alkylation is among the most fundamental and convenient processes for C—C bond formation on arenes, especially for the synthesis of fine chemicals and agrochemicals containing functionalized arenes and heteroarenes. 

Through the interaction of an alkylating agent, a hydrogen atom of the aromatic core, in the case of alkylation of arenes, is replaced by an alkyl group driven by a Friedel-Crafts catalyst. A variety of alkylating agents (e.g. alkyl halides, alcohols, 

The first general iron-catalyzed arylation of benzyl alcohols and benzyl carboxylates was published by our group in 2005 [56]. A practical synthesis of a multitude of 

Notably, this reaction shows a high tolerance towards a wide variety of functional groups, such as CHO, C02R, I, Br, Cl, F, OH and OMe, and also thiophene and furan derivatives, which is a rare feature in Friedel-Crafts-type chemistry. In the reaction with o-xylene, various alcohols were successfully used as benzylation agents, forming the corresponding products in high yield and selectivity (Table 6.1). 

In these transformations, water is the only by-produced, so this arylation method is a state-of-the-art green route to diarylmethanes via Friedel-Crafts chemistry. 

The metal-catalyzed addition of aromatic substrates to a- or 7r-systems, also known as Friedel-Crafts alkylation, belongs to one of the most powerful strategies for the formation of C-C bonds [75-77]. Nevertheless, relatively few enantioselective catalytic approaches have been reported that use this reaction manifold, despite the widespread availability of electron-rich aromatics and the chemical relevance of the resulting products. 

Based on the mechanistic rationales discussed earlier, it is clear that 7r-facial selectivity and reaction rates of cycloaddition reactions result exclusively from the association of imidazolidinone catalysts to the electrophilic enal component. It is, therefore, conceivable that this platform should be amenable to a range of reactions of a,/ -unsaturated carbonyl compounds, regardless of the nature of the HOMO-donor component. 

The use of other nucleophilic species to perform Friedel-Crafts alkylations to a,/ -unsaturated aldehydes has also been investigated, with success. For example, indoles [14, 83] and anilines [18, 84] have been added to a,/ -unsaturated aldehydes, providing 1,4-addition products in good yields and excellent enantioselec-tivities. Again, the importance of such an approach is demonstrated by the suc- 

The sulfonic acid resins such as Dowex-50 and Amberlyst-15 have been used to promote the alkylation of the more active aromatic rings but attempts to increase their acidity generally resulted in the degradation of the solid. 2 The more strongly acidic perfluorinated resin sulfonic acid, Nafion-H,2 3 has, however, been used to promote the alkylation of benzene and other aromatic compounds. Nafion-H catalyzed the vapor phase reaction between toluene and methanol. When nm at 185°C a 12% yield of the isomeric xylenes was obtained with the ortho isomer the major product. 0 Methylation of phenol at 205°C over this catalyst gave, at 63% conversion. 37% anisole and 10% of a mixture of the ortho and para cresols in a 2 1 ratio. Reaction of anisole with methanol under these conditions resulted in a 14% selectivity to the methyl anisoles at 40% conversion, with the ortho and para isomers formed in nearly equal amounts.  

The alkylation of toluene with methtmol at 400°C over H-ZSM-5 gave, at 36% conversion, a 69% selectivity for xylene formation, of which 27% was the para isomer. 2 Aluminum phosphate based molecular sieve catalysts such as CoAPO gave a lower conversion but higher selectivities for p-xylene formation. 2 Metallosilicates such as As-silicate having a ZSM-5 structure produced an 82% selectivity for p-xylene at 21% conversion. 

With a vermiculite catalyst, the alkylation of benzene with p-methyl benzyl chloride (1) at 80°C gave the mono-alkylated product, 2, in greater than 90% yield. No dialkylated product was formed (Eqn. 22.1). With a montmorillonite catalyst the reaction proceeded to give a 50% yield of this product and then stopped.  

When alkyl chloroformates were used as the alkylating agents in Nafion catalyzed reactions, better yields of the alkylated benzene were obtained. The liquid phase reaction of toluene with iso-propyl chloroformate at 100°C gave a mixture of the ortho, meta and para cymenes ( 7, 3, and 4) in a 42 21 37 ratio at 

80% conversion. The corresponding vapor phase reaction run at 190°C gave 7, 3, and 4 in a 4 66 30 ratio at 76% conversion (Eqn. 22.3). Dialkyl oxalates could also be used as alkylating agents in this reaction. 

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We will show here the classification procedure with a specific dataset [28]. A reaction center, the addition of a C-H bond to a C=C double bond, was chosen that comprised a variety of different reaction types such as Michael additions, Friedel-Crafts alkylation of aromatic compounds by alkenes, or photochemical reactions. We wanted to see whether these different reaction types can be discerned by this... 

Other catalysts which may be used in the Friedel - Crafts alkylation reaction include ferric chloride, antimony pentachloride, zirconium tetrachloride, boron trifluoride, zinc chloride and hydrogen fluoride but these are generally not so effective in academic laboratories. The alkylating agents include alkyl halides, alcohols and olefines. 

It should be noted that the Friedel-Crafts acylation differs from the Friedel-Crafts alkylation (compare Sections IV,3-4 and discussion preceding Section IV,1) in one important respect. The alkylation requires catal3d.ic quantities of aluminium chloride, but for acylation a molecular equivalent of aluminium chloride is necessary for each carbonyl group present in the acylating agent. This is because aluminium chloride is capable of forming rather stable complexes with the carbonyl group these complexes probably possess an oxonium... 

The formation of the (X-delocalized norbornyl cation via ionization of 2-norbornyl precusors in low-nucleophilicity, superacidic media, as mentioned, can be considered an analog of an intramolecnlar Friedel-Crafts alkylation in a saturated system. Indeed, deprotonation gives nortricyclane,... 

Synthesis This route has been carried out successfully (Rec. Trav. Chem., 1958, 77, 854). Note that no AICI3 is needed for Friedel-Crafts alkylation with easily formed t-alkyl compounds. 

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. 

Nitration in sulphuric acid is a reaction for which the nature and concentrations of the electrophile, the nitronium ion, are well established. In these solutions compounds reacting one or two orders of magnitude faster than benzene do so at the rate of encounter of the aromatic molecules and the nitronium ion ( 2.5). If there were a connection between selectivity and reactivity in electrophilic aromatic substitutions, then electrophiles such as those operating in mercuration and Friedel-Crafts alkylation should be subject to control by encounter at a lower threshold of substrate reactivity than in nitration this does not appear to occur. 

All attempts to prepare selenazole derivatives by the Gatterman (for-mylation) or Friedel-Crafts (alkylation) methods failed (19, 26). indicating that the electrophilic reactivity of the 5-position is less than that of benzene or toluene. 

Friedel-Crafts alkylation Alkyl halides react with benzene in the presence of alu minum chloride to yield alkylbenzenes... 

One drawback to Fnedel-Crafts alkylation is that rearrangements can occur espe cially when primary alkyl halides are used For example Friedel-Crafts alkylation of benzene with isobutyl chloride (a primary alkyl halide) yields only tert butylbenzene... 

FIGURE 12 7 The mechanism of Friedel-Crafts alkylation The molecular model depicts the cyclohexadienyl cation intermediate formed in step 1... 

Because acylation of an aromatic ring can be accomplished without rearrangement it is frequently used as the first step m a procedure for the alkylation of aromatic compounds by acylation-reduction As we saw m Section 12 6 Friedel-Crafts alkylation of ben zene with primary alkyl halides normally yields products having rearranged alkyl groups as substituents When a compound of the type ArCH2R is desired a two step sequence IS used m which the first step is a Friedel-Crafts acylation... 

Neither Friedel-Crafts acylation nor alkylation reactions can be earned out on mtroben zene The presence of a strongly deactivating substituent such as a nitro group on an aromatic ring so depresses its reactivity that Friedel-Crafts reactions do not take place Nitrobenzene is so unreactive that it is sometimes used as a solvent m Friedel-Crafts reactions The practical limit for Friedel-Crafts alkylation and acylation reactions is effectively a monohalobenzene An aromatic ring more deactivated than a mono halobenzene cannot be alkylated or acylated under Friedel-Crafts conditions... 

It IS sometimes difficult to limit Friedel-Crafts alkylation to monoalkylation... 

Isopropylbenzene is prepared by the Friedel-Crafts alkylation of benzene y using isopropyl chloride and aluminum chloride (Section 12 6) j... 

Other typical electrophilic aromatic substitution reactions—nitration (second entry) sul fonation (fourth entry) and Friedel-Crafts alkylation and acylation (fifth and sixth entnes)—take place readily and are synthetically useful Phenols also undergo elec trophilic substitution reactions that are limited to only the most active aromatic com pounds these include mtrosation (third entry) and coupling with diazomum salts (sev enth entry)... 

Friedel-Crafts alkylation (Section 12 6) An electrophilic aro matic substitution in which an aromatic compound reacts with an alkyl halide in the presence of aluminum chloride An alkyl group becomes bonded to the nng... 

Friedel-Crafts alkylation [FRIEDEL-CRAFTSREACTIONS] (Volll)... 

Friedel-Crafts alkylation pRIEDEL-CRAFTS REACTIONS] (Vol 11)... 

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