Friedel-Crafts selectivity

This is not a concerted rearrangement mechanism of the usual cationic sort, like the pinacol (Chapter 2), but a normal ionic reaction. The Lewis acid catalyses the breakdown of the ester 8 into an acylium ion and a metal complex of the phenol which remain associated as an ion pair 9 in non-polar solvents. This naturally tends to give the ortho product as the acylium ion is held close to the ortho position by electrostatic interactions. In polar solvents, the ion pair is separated into two independent ions which show the normal Friedel-Crafts selectivity, that is high preference for the para product. 

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. 

Alkyl halides and sulfonates are the most frequently used alkylating acceptor synthons. The carbonyl group is used as the classical a -synthon. O-Silylated hemithioacetals (T.H. Chan, 1976) and fomic acid orthoesters are examples for less common a -synthons. In most synthetic reactions carbon atoms with a partial positive charge (= positively polarized carbon) are involved. More reactive, "free carbocations as occurring in Friedel-Crafts type alkylations and acylations are of comparably limited synthetic value, because they tend to react non-selectively. 

Tertiary, benzyl, and aHyhc nitro compounds can also be used as Friedel-Crafts alkylating agents eg, reaction of (CH2)3CN02 (2-nitro-2-methyl propane [594-70-7]) with anisole in the presence of SnCl gives 4-/-butylanisole [5396-38-3] (7). SoHd acids, such as perfluorodecanesulfonic acid [335-77-3], and perfluorooctanesulfonic acid [1763-23-1] have been used as catalysts for regio-selective alkylations (8). 

Preformed Carbocationic Intermediates. Propargyl cations stabilized by hexacarbonyl dicobalt have been used to effect Friedel-Crafts alkylation of electron-rich aromatics, such as anisole, /V, /V- dim ethyl a n il in e and 1,2,4,-trimethoxybenzene (24). Intramolecular reactions have been found to be regio and stereo-selective, and have been used ia the preparatioa of derivatives of 9JT- uoreaes and dibenzofurans (25). 

Akylsilanes are more reactive than vinylskanes in Friedel-Crafts reactions, as shown in the selective acylation of 2,3-disilylalkenes. The akylsilanes, a-skyloxyakyltrialkylsilanes, have been used as enolate equivalents in the preparation of 1,4-diketones (178). The mild reaction conditions required for these reactions tolerate many other functional groups, providing valuable synthetic routes. 

Friedel-Crafts catalysts are electron acceptors, ie, Lewis acids. The alkylating ability of ben2yl chloride was selected to evaluate the relative catalytic activity of a large number of Lewis acid haUdes. The results of this study suggest four categories of catalyst activity (200) (Table 1). 

G-5 Aliphatic Petroleum Resins. Carbocationic polymerization of C-5 feedstreams has been accomptished with various Friedel-Crafts catalyst systems. Table 3 compares the efficiencies of selected Lewis acids ia the polymerization of a typical C-5 stream containing 43 wt % C-5—C-6 diolefias and 47 wt % C-5—C-6 olefins (20). Based on weight percent yield of resia at equimolar coaceatratioas of catalyst (5.62 mmol/100 g), efficieacy follows AICI3 AlBr3 > BF3etherate-H20 > TiCfy > SnCl. The most commonly used catalyst in petroleum resin synthesis is AlCl. ... 

Short-chain alkylated biphenyls are the principal biphenyl derivatives in commercial use. They are generally produced by Hquid-phase Friedel-Crafts alkylation of biphenyl with ethylene, propylene, or mixed butenes. A series of mixed ethylated biphenyl heat-transfer fluids (trademarked Therm S-600, 700, 800) is marketed by Nippon Steel. A mixed diethylbenzene—ethylbiphenyl heat-transfer fluid is also available from Dow (63). Monoisopropylbiphenyl [25640-78-2] largely as a mixture of meta- and para-isomers is produced by Koch Chemical Co. Monoisopropylbiphenyl (MIPB) was selected by Westinghouse (64,65) as a PCB replacement in capacitors and this is its primary appHcation today. For a time MIPB was also employed as a PCB replacement in pressure sensitive copy paper, but this outlet has since given way to other dye solvents. A similar product consisting of a mixture of j -butylbiphenyl isomers [38784-93-9] (66) is currently the favored dye solvent for pressure sensitive copy paper (67) manufactured in the United States. 

Another important use of BCl is as a Ftiedel-Crafts catalyst ia various polymerisation, alkylation, and acylation reactions, and ia other organic syntheses (see Friedel-Crafts reaction). Examples include conversion of cyclophosphasenes to polymers (81,82) polymerisation of olefins such as ethylene (75,83—88) graft polymerisation of vinyl chloride and isobutylene (89) stereospecific polymerisation of propylene (90) copolymerisation of isobutylene and styrene (91,92), and other unsaturated aromatics with maleic anhydride (93) polymerisation of norhornene (94), butadiene (95) preparation of electrically conducting epoxy resins (96), and polymers containing B and N (97) and selective demethylation of methoxy groups ortho to OH groups (98). 

Absolute rate data for Friedel-Crafts reactions are difficult to obtain. The reaction is complicated by sensitivity to 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 reagents. The product ratio establishes the relative reactivity. These studies reveal low substrate and position selectivity. 

A study of alkylations with a group of substituted benzyl halides and a range of Friedel-Crafts catalysts has provided insight into the trends in selectivity and orientation that accompany changes in both the alkyl group and the catalysts. There is a marked increase in substrate selectivity on going from / -nitrobenzyl chloride to /i-methoxybenzyl chloride. For example, with titanium tetrachloride as the catalyst, Aitoi Abenz increases from 2.5 to 97. This increase in substrate selectivity is accompanied by an increasing preference for para substitution. With /i-nitrobenzyl chloride, the ortho para ratio is 2 1 (the... 

Table 10.9. Substrate and Position Selectivity in Friedel-Crafts Alkylation Reactions...

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. ... 

The most selective 4-substitution is obtained in the Friedel-Crafts isopropylation of 2-acetylthiophene, which under certain conditions gives as much as 99% of this isomer and 1% of the 5-isomer. An--other case of selective 4-substitution is the bromination of 2-thienyl alkyl ketones using the swamping catalyst effect (i.e., brominating in the presence of excess AlCb without solvent), which yields 43-63% of apparently isomer-free 4-bromo-2-thienyl alkyl ketones. Gold-farb et al. also have applied this method to the chloromethylation of... 

As a demonstration of the complete synthesis of a pharmaceutical in an ionic liquid, Pravadoline was selected, as the synthesis combines a Friedel-Crafts reaction and a nucleophilic displacement reaction (Scheme 5.1-24) [53]. The allcylation of 2-methylindole with l-(N-morpholino)-2-chloroethane occurs readily in [BMIM][PF6] and [BMMIM][PF6] (BMMIM = l-butyl-2,3-dimethylimida2olium), in 95-99 % yields, with potassium hydroxide as the base. The Friedel-Crafts acylation step in [BMIM][PF6] at 150 °C occurs in 95 % yield and requires no catalyst. 

The LAB production process (process 1) is mainly developed and licensed by UOP. The N-paraffins are partially converted to internal /z-olefins by a catalytic dehydrogenation. The resulting mixture of /z-paraffins and n-olefins is selectively hydrogenated to reduce diolefins and then fed into an alkylation reactor, together with an excess benzene and with concentrated hydrofluoric acid (HF) which acts as the catalyst in a Friedel-Crafts reaction. In successive sections of the plant the HF, benzene, and unconverted /z-paraffins are recovered and recycled to the previous reaction stages. In the final stage of distillation, the LAB is separated from the heavy alkylates. 

See Davister, M. Laszlo, P. Tetrahedron Lett., 1993, 34, 533 for examples of paradoxical selectivity in Friedel-Crafts alkylation. 

Another SBU with open metal sites is the tri-p-oxo carboxylate cluster (see Section 4.2.2 and Figure 4.2). The tri-p-oxo Fe " clusters in MIL-100 are able to catalyze Friedel-Crafts benzylation reactions [44]. The tri-p-oxo Cr " clusters of MIL-101 are active for the cyanosilylation of benzaldehyde. This reaction is a popular test reaction in the MOF Hterature as a probe for catalytic activity an example has already been given above for [Cu3(BTC)2] [15]. In fact, the very first demonstration of the catalytic potential of MOFs had aheady been given in 1994 for a two-dimensional Cd bipyridine lattice that catalyzes the cyanosilylation of aldehydes [56]. A continuation of this work in 2004 for reactions with imines showed that the hydrophobic surroundings of the framework enhance the reaction in comparison with homogeneous Cd(pyridine) complexes [57]. The activity of MIL-lOl(Cr) is much higher than that of the Cd lattices, but in subsequent reaction rans the activity decreases [58]. A MOF with two different types of open Mn sites with pores of 7 and 10 A catalyzes the cyanosilylation of aromatic aldehydes and ketones with a remarkable reactant shape selectivity. This MOF also catalyzes the more demanding Mukaiyama-aldol reaction [59]. 

Furthermore, Jana et al. developed a FeCl3-catalyzed C3-selective Friedel-Crafts alkylation of indoles, using allylic, benzylic, and propargylic alcohols in nitromethane as solvent at room temperature. This method can also be used for the alkylation of pyrrole (Scheme 4). The reactions were complete within 2-3 h without the need of an inert gas atmosphere leading to the C-3-substitution product exclusively in moderate to good yields [20]. 

Olah et al. (1999) have been able to realize selective cyclisation of o-benzoyl benzoic acid to anthraquinone using dichlorobenzene as a solvent and Nafion-H as a catalyst. This may lead to avoidance of the Friedel-Crafts reaction using a stoichiometric amount of aluminium chloride and resulting in a lot of wa,ste. Many other examples of similar reactions have been reported. 

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