Introduction of Alkyl Groups

A wide range of reactants, catalysts, solvents and reaction conditions can be used, making the Friedel-Crafts reaction a very valuable and versatile process. 

As well as alkyl halides, alcohols and alkenes are direct sources of alkyl groups. Acyl chlorides and anhydrides are additional sources, but these involve the subsequent reduction of a carbonyl group (C=0) to a methylene (CH,) unit. 

A variety of catalysts, including other Lewis acids such as FeC and BF3, and the protic acids HF, phosphoric acid and sulfuric acid, has been used. In reactions using alcohols, the favoured catalyst is BF3 HF is often used in reactions involving alkenes. 

The reaction can be very fast, but can be moderated by the use of an inert solvent such as nitrobenzene or carbon disulfide. The temperature at which the reaction is carried out can vary from below room temperature to about 200 °C. 

However, there are several drawbacks to this alkylation reaction. The use of longer alkyl chains than ethyl can be complicated by isomerization of the alkyl group arising from carbonium ion hydride shifts. It is therefore not uncommon for mixtures to be produced. In extreme cases, a completely different alkyl group from that of the starting material can be present in the product. 

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Cl Acid Gieen 25 [4403-90-1] (3) (Cl 61570) was also invented in 1894. This dye shows improved wetfastness, and is prepared from leucoquinizarin by reaction with 2 moles of i)-toluidine in a similat manner to the preparation of Cl Acid Violet 43 (134). Wetfastness and leveling properties may be altered by choosing the substituents of arylamines. The introduction of alkyl groups into aromatic amines improves the wetfastness and affinity in neutral or weekly acid baths. Examples ate Cl Acid Blue 80 [4474-24-27] (131) (Cl 61585) and Cl Acid Gieen 27 [6408-57-7] (132) (Cl 61580). 

The introduction of alkyl groups into steroids is generally achieved by means of the following types of reactions between Grignard reagents and ketones or epoxides. 

The reduction of 4-chloro-4-methyltetrahydropyran with triethylsilane requires more than a catalytic amount of aluminum chloride. No 4-methyltetrahydropyran is obtained after 20 hours at room temperature even when 0.75 equivalents of the catalyst is used, but a 92% yield is obtained after only 30 minutes when two equivalents of catalyst and three equivalents of triethylsilane are used.136 146 This is presumably a result of the ability of the Lewis acid to coordinate at the ring oxygen as well as at the chlorine. The introduction of alkyl groups at C2 appears to introduce enough steric hindrance near the ring oxygen to enable less than one equivalent of aluminum chloride to effect reduction, but also makes the products unstable to the reaction conditions so that the synthetic yields decline compared with the unsubstituted substrate.136... 

Akiba, K.-y., Matsuoka, H., and Wada, M., Regiospecific introduction of alkyl groups into 4-position of pyridine — novel synthesis of 4-substituted py-... 

Whereas the first reaction, which results in the synthesis of ketones, is much used because of the ease with which it usually proceeds, the introduction of alkyl groups proves much less satisfactory since, in the first place, the substitution goes further and, in the second, the alkyl groups may at the same time be partially split off again. The method of Fittig is usually to be preferred in this case. 

The combination of the photopromoted carbotelluration with the elimination reaction, provides a useful method for the introduction of alkyl groups to terminal acetylenes. 

The introduction of alkyl groups on pyrroles, indoles, isoindoles and carbazoles can usefully be subdivided according to the desired locus of substitution. There are three distinct... 

Recent efforts in the area of Friedel-Crafts alkylations have focused on the direct introduction of alkyl groups bearing functionalities, and on intramolecular alkylative cycliz-ations. The cyclization of the 2-substituted thiophene (55) to (56) has been achieved in 65% yield (80JOC3159). Similarly, the 3-substituted thiophene (57) has been cyclized to the isomeric (58). In both cases, detosylation of the product was achieved by treatment with diisobutylaluminum hydride (DIBAL). An elegant bis-cyclization of the diene (59) to the octahydrodibenzothiophene (60) has been reported (70CJC2587). 

Nucleophilic substitution at silicon in l,3-dichloro-l,3-disilacyclobutanes by Grignard reagents allows the introduction of alkyl groups onto the ring (Equation 18) <1997PSA3193>. 

IV. Two or more nitrogens attached to the same carbon destroy the tendency to combine stoichiometrically with hydrogen chloride for all except one of the nitrogens, except insofar as this may be compensated by the introduction of alkyl groups. 

The UV absorption spectrum of 1,3-dithiolylium perchlorate in ethanol/perchloric acid shows two bands, which are shifted to longer wavelength in perchloric add alone (Table 6). Introduction of alkyl groups, as in trimethyl-1,3-dithiolylium perchlorate, causes a bathochromic shift of the longest wavelength absorption to 305 nm (71T4705). 

The synthesis of Z-disubstituted double bond was accomplished by Zweifel. The Zweifel s (Z)-alkene synthesis involves the iodination of dialkylvinylboranes in the presence of sodium hydroxide which results in the transfer of an alkyl group from boron and the formation of the (Z)-alkene (Eq. 62) 117118>, although the introduction of alkyl groups is limited. 

The introduction of alkyl groups at the a-carbon of amino acids has been accomplished most efficiently by formation of imine esters. For example, the benzaldehyde imine of ethyl glycinate can be deproton-ated and alkylated (equation 39)." Other imines also have been used." Optical activity has been introduced by using chiral palla um ligands during the alkylation step, ° chiral alcohols to form the ester, and chiral ketones to form the imine." Alkylation of 2-pyrrole acetate esters has been accomplished in a similar fashion." ... 

Relatively inaccessible cycloalkylcarboxylic acids can be produced via these Favorskii rearrangements (for example equation 7), and they have been especially useful for the introduction of alkyl groups at C-17 of the steroid nucleus. Thus the pregnenolones (10) and (11) can be converted into mixtures of rearrangement products (12) and (13), with the latter usually predominating in polar, protic solvents (Scheme... 

Any structural modification which tends to destroy coplanarity inhibits resonance. The introduction of alkyl groups ortho to a dialkyl-amino, an acyl, or a nitro group hinders the formation of a structure like XXXV, and as a result these substituted derivatives resemble their aliphatic analogs more closely. In addition to arguments based upon dipole moments,16 molecular refractivity,17 and ultraviolet absorption spectra,18 there is other chemical evidence which indicates the steric in-... 

In a large number of carbene and carbenoid addition reactions to alkenes the thermodynamically less favored syn-isomers are formed 63). The finding that in the above cyclopropanation reaction the anti-isomer is the only product strongly indicates that the intermediates are organonickel species rather than carbenes or carbenoids. Introduction of alkyl groups in the 3-position of the electron-deficient alkene hampers the codimerization and favors isomerization and/or cyclodimerization of the cyclopropenes. Thus, with methyl crotylate and 3,3-diphenylcyclopropene only 16% of the corresponding vinylcyclopropane derivative has been obtained. 2,2-Dimethyl acrylate does not react at all with 3,3-dimethylcyclopropene to afford frons-chrysanthemic add methyl ester. This is in accordance with chemical expectations 69) since in most cases the tendency of alkenes to coordinate to Ni(0) decreases in the order un-, mono-< di- < tri- < tetrasubstituted olefines. 

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