Polyalkylation, Friedel-Crafts

Alkylation of furan and thiophene has been effected with alkenes and catalysts such as phosphoric acid and boron trifluoride. In general, Friedel-Crafts alkylation of furans or thiophenes is not preparatively useful, partly because of polymerization by the catalyst and partly because of polyalkylation. 

It should be noted that Scheme 5.1-44 shows idealized Friedel-Crafts allcylation reactions. In practice, there are a number of problems associated with the reaction. These include polyalkylation reactions, since the products of a Friedel-Crafts alkylation reaction are often more reactive than the starting material. Also, isomerization and rearrangement reactions can occur, and can result in a large number of products [74, 75]. The mechanism of Friedel-Crafts reactions is not straightforward, and it is possible to propose two or more different mechanisms for a given reaction. Examples of the typical processes occurring in a Friedel-Crafts alkylation reaction are given in Scheme 5.1-45 for the reaction between 1-chloropropane and benzene. 

Many variations of the reaction can be carried out, including halogenation, nitration, and sulfonation. Friedel-Crafts alkylation and acylation reactions, which involve reaction of an aromatic ling with carbocation electrophiles, are particularly useful. They are limited, however, by the fact that the aromatic ring must be at least as reactive as a halobenzene. In addition, polyalkylation and carbocation rearrangements often occur in Friedel-Crafts alkylation. 

Thus, a polyester with the ring in the backbone can be prepared by the Friedel-Crafts polyalkylation of vinyl 2-furoate. BF3 Et20 gave similar results at room temperature in methylene chloride. Structure 30 was arrived at by spectroscopy and by alcoholysis of the polymers. 

The Friedel-Crafts alkylation reaction does not proceed successfully with aromatic reactants having EWG substituents. Another limitation is that each alkyl group that is introduced increases the reactivity of the ring toward further substitution, so polyalkylation can be a problem. Polyalkylation can be minimized by using the aromatic... 

Apart from the possibility of rearrangement, the main drawback in the preparative use of this Friedel-Crafts reaction is polyalkylation (cf. p. 153). The presence of an electron-withdrawing substituent is generally sufficient to inhibit Friedel-Crafts alkylation thus nitrobenzene is often used as a solvent for the reaction because A1C13 dissolves readily in it, thus avoiding a heterogeneous reaction. 

Gold-catalyzed direct C-H functionalizations enable the formation of polyalkylated arenes under mild conditions. In many cases, branched products are obtained. Two mechanisms are thought to operate with electron-rich arenes, an S si2-type mechanism via Au(lll) leads to the linear product. The branched product is obtained via a Friedel-Craft-type alkylation. A silver salt is often added and is believed to generate a more electrophilic Au(m) species. Often regioselectivities are poor and symmetric arenes are employed. Intramolecular variants as well as Michael additions are also known (Equations (72)-(74)).71,71a,71b... 

Friedel-Crafts-type polyalkylations of alkyl-substituted benzenes with Ic become less difficult as the number of electron-donating methyl groups on the benzene ring increases. This is consistent with the fact that the alkylation occurs via an electrophilic substitution. The tendency of starting methylbenzenes to form rearranged products also increases in the same order from toluene to mesitylene. 

The low yields in Friedel-Crafts reactions are due to the polyalkylation of aromatic compounds, the production of racemic mixtures, and forming other undesirable products. 

Friedel-Crafts polyalkylation (Scheme 34) has been used to incorporate 8-hydroxyquino-line (122) into polymers. The polymers formed were found to be similar in properties, although of somewhat lower molecular weight, to those prepared by acid-catalyzed condensation of monomer (122) with formaldehyde or ethylene glycol (79MI11107), respectively. 

The Friedel-Crafts Alkylation may give polyalkylated products, so the Friedel-Crafts Acylation is a valuable alternative. The acylated products may easily be converted to the corresponding alkanes via Clemmensen Reduction or Wolff-Kishner Reduction. 

This Lewis acid-catalyzed electrophilic aromatic substitution allows the synthesis of alkylated products via the reaction of arenes with alkyl halides or alkenes. Since alkyl substituents activate the arene substrate, polyalkylation may occur. A valuable, two-step alternative is Friedel-Crafts Acylation followed by a carbonyl reduction. 

Polyalkylation was an advantage in the synthesis of BHT 13 it is the rearrangement that is chiefly unacceptable here. Friedel-Crafts acylation avoids both problems. The acyl group does not rearrange and the product is deactivated towards further electrophilic attack by the electron-withdrawing carbonyl group. We have an extra step reduction of the ketone to a CH2 group. There are various ways to do this (see chapter 24)—here the Clemmensen reduction is satisfactory.4... 

Friedel-Crafts alkylation. Reaction of arenes with acid chlorides in CH2C12 with AICI3 (1 equiv.) and (C2H5)3SiH (2.5-3 equiv.) results in the alkylated arene by deoxygenation of the intermediate acylated arene. Yields of 95% are obtainable, and this procedure avoids the problem of polyalkylation observed in regular Friedel-Crafts reactions.3... 

In the laboratory, we must often alkylate aromatic compounds that are more expensive than benzene. Because we cannot afford to use a large excess of the starting material, a more selective method is needed. Fortunately, the Friedel-Crafts acylation, discussed in Section 17-11, introduces just one group without danger of polyalkylation or rearrangement. 

Ferrocene reacts with acetyl chloride and aluminum chloride to afford the acylated product (287) (Scheme 84). The Friedel-Crafts acylation of (284) is about 3.3 x 10 times faster than that of benzene. Use of these conditions it is difficult to avoid the formation of a disubstituted product unless only a stoichiometric amount of AlCft is used. Thus, while the acyl substituent present in (287) is somewhat deactivating, the relative rate of acylation of (287) is still rapid (1.9 x 10 faster than benzene). Formation of the diacylated product may be avoided by use of acetic anhydride and BF3-Et20. Electrophilic substitution of (284) under Vilsmeyer formylation, Maimich aminomethylation, or acetoxymercuration conditions gives (288), (289), and (290/291), respectively, in good yields. Racemic amine (289) (also available in two steps from (287)) is readily resolved, providing the classic entry to enantiomerically pure ferrocene derivatives that possess central chirality and/or planar chirality. Friedel Crafts alkylation of (284) proceeds with the formation of a mixture of mono- and polyalkyl-substituted ferrocenes. The reaction of (284) with other... 

Three common procedures are available for the transformation of aldehydes and ketones to hydrocarbons (1) reduction by zinc and hydrochloric acid (Clemmensen), (2) reduction by hydrazine in the presence of a base (Wolff-Kishner), and (3) catalytic hydrogenation. In view of the complicated mixtures obtained by the polyalkylation of benzene by the Friedel-Crafts reaction (method 1), reduction of alkyl aryl ketones is the most reliable method for the preparation of di- and poly-alkylbenzenes. 

A third limitation to the Friedel-Crafts alkylation is that it s often difficult to stop the reaction after a single substitution. Once the first alkyl group is on the ring, a second substitution reaction is facilitated for reasons we ll discuss in the nc.xt section. Thus, we often observe polyalkylation. Reaction of benzene with 1 mol equivalent of 2-chloro-2-inethylpropane, for example, yieldsp-di-A"t-butvlbenzene as the major product, along with small amounts of fc//-butyl-benzene and unreacted benzene. A high yield of monoalkylation product is obtained only when a large excess of benzene is used. 

Carbonium ions can be generated at a variety of oxidation levels. The alkyl carbocation can be generated from alkyl halides by reaction with a Lewis acid (RCl + AICI3) or by protonation of alcohols or alkenes. The reaction of an alkyl halide and aluminium trichloride with an aromatic ring is known as the Friedel-Crafts alkylation. The order of stability of a carbocation is tertiary > secondary > primary. Since many alkylation processes are slower than rearrangements, a secondary or tertiary carbocation may be formed before aromatic substitution occurs. Alkylation of benzene with 1-chloropropane in the presence of aluminium trichloride at 35 °C for 5 hours gave a 2 3 mixture of n- and isopropylbenzene (Scheme 4.5). Since the alkylbenzenes such as toluene and the xylenes (dimethylbenzenes) are more electron rich than benzene itself, it is difficult to prevent polysubsiitution and consequently mixtures of polyalkylated benzenes may be obtained. On the other hand, nitro compounds are sufficiently deactivated for the reaction to be unsuccessful. 

Another limitation of the Friedel-Crafts alkylation arises because of polyalkylation. Treatment of benzene with an alkyl halide and AICI3 places an electron-donor R group on the ring. Because R groups activate a ring, the alkylated product (CeHsR) is now more reactive than benzene itself towards further substitution, and it reacts again with RCl to give products of polyalkylation. 

Next ask yourself, What is an immediate precursor ofp-bromotolueneT Perhaps toluene is an immediate precursor because the methyl group would direct bromination to the ortho and para positions, and the isomeric products could be separated. Alternatively, bromobenzene might be an imme ate precursor because we could carry out a Friedel-Crafts methylation li obtain para product. Both answers are satisfactory, although, in view of 1 difficulties often observed with polyalkylation in Friedel-Crafts reactions, bromination of toluene may be the better route. ... 

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