The Alkylating Agents

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. 

The formation of isopropylbenzene when n-propyl chloride is employed as the alkylating agent is readily accounted for by the isomerisation of the alkyl carbonium (or alkylium) ion ... 

Quaternarj salts are obtained by alkylation of selenazole bases, the heterocyclic nitrogen atom playing the role of nucleophile with regard to the electrophilic carbon of the alkylating, agent. 

Next an alkyl halide (the alkylating agent) is added to the solution of sodium acetylide Acetylide ion acts as a nucleophile displacing halide from carbon and forming a new carbon-carbon bond Substitution occurs by an 8 2 mechanism... 

Alkyl halides by themselves are insufficiently electrophilic to react with benzene Aluminum chloride serves as a Lewis acid catalyst to enhance the electrophihcity of the alkylating agent With tertiary and secondary alkyl halides the addition of aluminum chlonde leads to the formation of carbocations which then attack the aromatic ring... 

We see that a secondary alkyl halide is needed as the alkylating agent The anion of diethyl malonate is a weaker base than ethoxide ion and reacts with secondary alkyl halides by substitution rather than elimination Thus the synthesis of 3 methylpentanoic acid begins with the alkylation of the anion of diethyl mal onate by 2 bromobutane... 

Even the tertiary amine competes with ammonia for the alkylating agent The product is a quaternary ammonium salt... 

All lation of Phenols. The approach used to synthesize commercially available alkylphenols is Friedel-Crafts alkylation. The specific procedure typically uses an alkene as the alkylating agent and an acid catalyst, generally a sulfonic acid. Alkene and catalyst interact to form a carbocation and counter ion (5) which interacts with phenol to form a 7T complex (6). This complex is held together by the overlap of the filled TT-orbital of the aromatic... 

Equation 4 can be classified as S, , ie, substitution nucleophilic bimolecular (221). The rate of the reaction is influenced by several parameters basicity of the amine, steric effects, reactivity of the alkylating agent, and solvent polarity. The reaction is often carried out in a polar solvent, eg, isopropanol, which may increase the rate of reaction and make handling of the product easier. 

Chemotherapeutic agents are grouped by cytotoxic mechanism. The alkylating agents, such as cyclophosphamide [50-18-0] and melphalan [148-82-3] interfere with normal cellular activity by alkylation deoxyribonucleic acid (DNA). Antimetabohtes, interfering with complex metaboHc pathways in the cell, include methotrexate [59-05-2] 5-fluorouracil [51-21-8] and cytosine arabinoside hydrochloride [69-74-9]. Antibiotics such as bleomycin [11056-06-7] and doxombicin [23214-92-8] h.a.ve been used, as have the plant alkaloids vincristine [57-22-7] and vinblastine [865-21-4]. 

V-Phenyl glycine [103-01 -5] the key intermediate for indigo, may be manufactured by alkylation of aniline with chloroacetic acid, but it is much more economical, even though three in situ stages are required, to use formaldehyde as the alkylating agent. 

Manufacture of alkylsulfones, important intermediates for metal-complex dyes and for reactive dyes, also depends on O-alkylation. An arylsulphinic acid in an aqueous alkaline medium is treated with an alkylating agent, eg, alkyl haUde or sulfate, by a procedure similar to that used for phenols. In the special case of P-hydroxyethylsulfones (precursors to vinylsulfone reactive dyes) the alkylating agent is ethylene oxide or ethylene chlorohydrin. 

All these kinetic results can be accommodated by a general mechanism that incorporates the following fundamental components (1) complexation of the alkylating agent and the Lewis acid (2) electrophilic attack on the aromatic substrate to form the a-complex and (3) deprotonation. In many systems, there m be an ionization of the complex to yield a discrete carbocation. This step accounts for the fact that rearrangement of the alkyl group is frequently observed during Friedel-Crafts alkylation. 

Alkylation Hazards arise from the alkylating agents, e.g. dimethyl sulphate (suspected human carcinogen), hydrogen fluoride (highly toxic irritant gas) Thermal alkylation processes require higher temperatures and pressures, with associated problems... 

Alkylation of enamines can take place on carbon or on nitrogen (see Section I). The theoretical considerations and reaction conditions which determine whether C or N alkylation takes place have already been studied extensively 26-32). These studies have shown that the facility with which alkylation takes place depends on the basicity of theenamine, on the ease of formation of a trigonal atom in the transition state, and on the nature of the enamine, the alkylating agent, and the solvent. 

The required xanthates 1 can be prepared from alcohols 5 by reaction with carbon disulfide in the presence of sodium hydroxide and subsequent alkylation of the intermediate sodium xanthate 6. Often methyl iodide is used as the alkylating agent ... 

The first step in alkylation is the generation of a carbocation (carbo-nium ion). When an olefin is the alkylating agent, a carbocation intermediate forms. 

Alkylation reactions are subject to the same constraints that affect all Sn2 reactions (Section 11.3). Thus, the leaving group X in the alkylating agent R—X can be chloride, bromide, iodide, or tosylate. The alkyl group R should be primary or methyl, and preferably should be allylic or benzylic. Secondary halides react poorly, and tertiary halides don t react at all because a competing E2 elimination of HX occurs instead. Vinylic and aryl halides are also unreactive because backside approach is sterically prevented. 

Alkylating agent, a reactive chemical that forms a covalent bond with chemical moieties on the biological target (usually a protein). For instance, p-haloalkylamines generate an aziridinium ion in aqueous base that inserts into -SH, -CHOH, or other chemical structures in peptides. Once inserted, the effects of the alkylating agent are irreversible. 

Other examples of esterification with trialkyloxonium salts have been reported.7,8 The present procedure offers the advantages that the reactive carboxylate ion is generated in sitv and that a low-boiling, nonaqueous solvent is employed, whereby the experimental procedure is considerably simplified. A related method has been reported which utilizes a hindered amine wdth dimethyl sulfate [Sulfuric acid, dimethyl csterj as the alkylating agent.9 The present procedure is carried out under somewhat milder conditions and avoids the use of highly toxic reagents. 

Notes, (a) The alkylating agent must be reactive, i.e. a methyl, ethyl, ally] or benzyl halide. 

Relative rates of alkylation of toluene and benzene using a mixture of nitro-sonium hexafluorophosphate, nitromethane (or acetonitrile) and aliphatic amine as the alkylations agent have been determined at 25 °C as follows360 1.5 (ethyl-amine), 2.5 (i-propylamine) and 3.5 (benzylamine) nothing more as yet is known about the kinetics of alkylation with these new alkylating reagents. 

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