Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effecting alkylation. Alkyl groups can also be removed in a process known as dealkylation. Alkylating agents are often classified according to their nucleophilic or electrophilic character.
Nucleophilic alkylating agents deliver the equivalent of an alkyl anion (carbanion). The formal "alkyl anion" attacks an electrophile, forming a new covalent bond between the alkyl group and the electrophile. The counterion, which is a cation such as lithium, can be removed and washed away in the work-up. Examples include the use of organometallic compounds such as Grignard (organomagnesium), organolithium, organocopper, and organosodium reagents. These compounds typically can add to an electron-deficient carbon atom such as at a carbonyl group. Nucleophilic alkylating agents can displace halide substituents on a carbon atom through the SN2 mechanism. With a catalyst, they also alkylate alkyl and aryl halides, as exemplified by Suzuki couplings.
The SN2 mechanism is not available for aryl substituents, where the trajectory to attack the carbon atom would be inside the ring. Thus only reactions catalyzed by organometallic catalysts are possible.
C-alkylation is a process for the formation of carbon-carbon bonds. For alkylation at carbon, the electrophilicity of alkyl halides is enhanced by the presence of a Lewis acid such as aluminium trichloride. Lewis acids are particularly suited for C-alkylation. C-alkylation can also be effected by alkenes in the presence of acids.
N- and P-alkylation are important processes for the formation of carbon-nitrogen and carbon-phosphorus bonds.
Amines are readily alkylated. The rate of alkylation follows the order tertiary amine < secondary amine < primary amine. Typical alkylating agents are alkyl halides. Industry often relies on green chemistry methods involving alkylation of amines with alcohols, the byproduct being water. Hydroamination is another green method for N-alkylation.
In the Menshutkin reaction, a tertiary amine is converted into a quaternary ammonium salt by reaction with an alkyl halide. Similar reactions occur when tertiary phosphines are treated with alkyl halides, the products being phosphonium salts.
Thiols are readily alkylated to give thioethers. The reaction is typically conducted in the presence of a base or using the conjugate base of the thiol. Thioethers undergo alkylation to give sulfonium ions.
When the alkylating agent is an alkyl halide, the conversion is called the Williamson ether synthesis. Alcohols are also good alkylating agents in the presence of suitable acid catalysts. For example, most methyl amines are prepared by alkylation of ammonia with methanol. The alkylation of phenols is particularly straightforward since it is subject to fewer competing reactions.
In the process called oxidative addition, low-valent metals often react with alkylating agents to give metal alkyls. This reaction is one step in the Cativa process for the synthesis of acetic acid from methyl iodide. Many cross coupling reactions proceed via oxidative addition as well.
Electrophilic alkylating agents deliver the equivalent of an alkyl cation. Alkyl halides are typical alkylating agents. Trimethyloxonium tetrafluoroborate and triethyloxonium tetrafluoroborate are particularly strong electrophiles due to their overt positive charge and an inert leaving group (dimethyl or diethyl ether). Dimethyl sulfate is intermediate in electrophilicity.
Diazomethane is a popular methylating agent in the laboratory, but it is too hazardous (explosive gas with a high accute toxicity) to be employed on an industrial scale without special precautions. Use of diazomethane has been significantly reduced by the introduction of the safer and equivalent reagent trimethylsilyldiazomethane.
Electrophilic, soluble alkylating agents are often toxic and carcinogenic, due to their tendency to alkylate DNA. This mechanism of toxicity is relevant to the function of anti-cancer drugs in the form of alkylating antineoplastic agents. Some chemical weapons such as mustard gas (sulfide of dichloroethyl) function as alkylating agents. Alkylated DNA either does not coil or uncoil properly, or cannot be processed by information-decoding enzymes.
Electrophilic alkylations use Lewis acids and Brønsted acids, sometimes both. Classically, Lewis acids, e.g., aluminium trichloride, are employed when the alkyl halide are used. Brønsted acids are used when alkylating with olefins. Typical catalysts are zeolites, i.e. solid acid catalysts, and sulfuric acid. Silicotungstic acid is used to manufacture ethyl acetate by the alkylation of acetic acid by ethylene:
Several commodity chemicals are produced by alkylation. Included are several fundamental benzene-based feedstocks such as ethylbenzene (precursor to styrene), cumene (precursor to phenol and acetone), linear alkylbenzene sulfonates (for detergents).
In a conventional oil refinery, isobutane is alkylated with low-molecular-weight alkenes (primarily a mixture of propene and butene) in the presence of a Brønsted acid catalyst, which can include solid acids (zeolites). The catalyst protonates the alkenes (propene, butene) to produce carbocations, which alkylate isobutane. The product, called "alkylate", is composed of a mixture of high-octane, branched-chain paraffinic hydrocarbons (mostly isoheptane and isooctane). Alkylate is a premium gasoline blending stock because it has exceptional antiknock properties and is clean burning. Alkylate is also a key component of avgas. By combining fluid catalytic cracking, polymerization, and alkylation, refineries can obtain a gasoline yield of 70 percent. The widespread use of sulfuric acid and hydrofluoric acid in refineries poses significant environmental risks. Ionic liquids are used in place of the older generation of strong Bronsted acids.