Alkylation

Alkylationis achemical reactionthat entails transfer of analkylgroup. The alkyl group may be transferred as an alkylcarbocation,afree radical,acarbanion,or acarbene(or their equivalents).Alkylating agentsarereagentsfor effecting alkylation. Alkyl groups can also be removed in a process known asdealkylation.Alkylating agents are often classified according to theirnucleophilicorelectrophiliccharacter. In oil refining contexts,alkylationrefers to a particular alkylation ofisobutanewitholefins.For upgrading ofpetroleum,alkylation produces a premium blending stock for gasoline.In medicine, alkylation ofDNAis used inchemotherapyto damage the DNA of cancer cells. Alkylation is accomplished with the class of drugs calledalkylating antineoplastic agents.

Typical route for alkylation of benzene with ethylene andZSM-5as a heterogeneous catalyst

Nucleophilic alkylating agents

Nucleophilic alkylating agentsdeliver the equivalent of analkylanion(carbanion). The formal "alkyl anion" attacks anelectrophile,forming a newcovalent bondbetween the alkyl group and the electrophile. The counterion, which is a cation such as lithium, can be removed and washed away in thework-up.Examples include the use oforganometallic compoundssuch asGrignard (organomagnesium),organolithium,organocopper,andorganosodiumreagents. These compounds typically can add to an electron-deficient carbon atom such as at acarbonyl group.Nucleophilic alkylating agents can displacehalidesubstituents on a carbon atom through theSN2mechanism. With acatalyst,they also alkylate alkyl andarylhalides, as exemplified bySuzuki couplings.

TheKumada couplingemploys both a nucleophilic alkylation step subsequent to the oxidative addition of the aryl halide (L =Ligand,Ar =Aryl).

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.

Alkylation by carbon electrophiles

C-alkylation

C-alkylation is a process for the formation of carbon-carbon bonds. The largest example of this takes place in thealkylation unitsof petrochemical plants, which convert low-molecular-weightalkenesinto high octanegasolinecomponents. Electron-rich species such asphenolsare also commonly alkylated to produce a variety of products; examples includelinear alkylbenzenesused in the production ofsurfactantslikeLAS,or butylated phenols likeBHT,which are used asantioxidants.This can be achieved using either acid catalysts likeAmberlyst,orLewis acidslike aluminium.On a laboratory scale theFriedel–Crafts reactionusesalkyl halides,as these are often easier to handle than their corresponding alkenes, which tend to be gasses. The reaction is catalysed byaluminium trichloride.This approach is rarely used industrially as alkyl halides are more expensive than alkenes.

N-,P-, S- alkylation

N-, P-, and S-alkylation are important processes for the formation of carbon-nitrogen, carbon-phosphorus, and carbon-sulfur 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 ongreen chemistrymethods involving alkylation of amines with alcohols, the byproduct being water.Hydroaminationis another green method for N-alkylation.

In theMenshutkin reaction,atertiary amineis converted into aquaternary ammonium saltby reaction with analkyl halide.Similar reactions occur when tertiary phosphines are treated with alkyl halides, the products being phosphonium salts.

Menshutkin-reaction

Thiolsare readily alkylated to givethioethersvia thethiol-ene reaction.The reaction is typically conducted in the presence of a base or using the conjugate base of the thiol. Thioethers undergo alkylation to givesulfonium ions.

O-alkylation

Alcoholsalkylate to giveethers:

${\ce {R-OH + R'-X -> R-O-R'}}$

When the alkylating agent is an alkyl halide, the conversion is called theWilliamson 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.

${\ce {Ph-O- + Me2-SO4 -> Ph-O-Me + Me-SO4-}}$

(withNa⁺as aspectator ion)

More complex alkylation of a alcohols and phenols involveethoxylation.Ethylene oxideis the alkylating group in this reaction.

Oxidative addition to metals

In the process calledoxidative addition,low-valent metals often react with alkylating agents to give metal alkyls. This reaction is one step in theCativa processfor the synthesis ofacetic acidfrommethyl iodide.Manycross coupling reactionsproceed via oxidative addition as well.

Electrophilic alkylating agents

Triethyloxonium tetrafluoroborateis one of the most electrophilic alkylating agents.

Electrophilic alkylating agents deliver the equivalent of an alkylcation.Alkyl halides are typical alkylating agents.Trimethyloxonium tetrafluoroborateandtriethyloxonium tetrafluoroborateare particularly strong electrophiles due to their overt positive charge and an inert leaving group (dimethyl or diethyl ether).Dimethyl sulfateis intermediate in electrophilicity.

Methylation with diazomethane

Diazomethaneis a popularmethylating agentin the laboratory, but it is too hazardous (explosive gas with a high acute 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 reagenttrimethylsilyldiazomethane.

Hazards

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 ofalkylating antineoplastic agents.Somechemical weaponssuch asmustard 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.

Catalysts

Friedel-Crafts alkylationof benzene is often catalyzed by aluminium trichloride.

Electrophilic alkylation usesLewis acidsandBrønsted 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 acidis used to manufactureethyl acetateby the alkylation ofacetic acidbyethylene:

${\ce {C2H4 + CH3CO2H -> CH3CO2C2H5}}$

In biology

Main article:methylation

Alkylation in biology causesDNA damage.It is the transfer of alkyl groups to thenitrogenous bases.It is caused by alkylating agents such as EMS (Ethyl Methyl Sulphonate). Bifunctional alkyl groups which have two alkyl groups in them cause cross linking in DNA. Alkylation damaged ring nitrogen bases are repaired via theBase Excision Repair(BER) pathway.

The S_N2-like methyl transfer reaction inDNA methylation.Only theSAM cofactorand cytosine base are shown for simplicity.

Commodity chemicals

Several commodity chemicals are produced by alkylation. Included are several fundamental benzene-based feedstocks such asethylbenzene(precursor tostyrene),cumene(precursor tophenolandacetone),linear alkylbenzene sulfonates(for detergents).

Sodium dodecylbenzene, obtained by alkylation of benzene with dodecene, is a precursor tolinear alkylbenzene sulfonatedetergents.

Gasoline production

Main article:alkylation unit

Typical acid-catalyzed route to2,4-dimethylpentane.

In a conventionaloil refinery,isobutaneis alkylated with low-molecular-weightalkenes(primarily a mixture ofpropeneandbutene) in the presence of a Brønsted acid catalyst, which can includesolid acids(zeolites). The catalyst protonates the alkenes (propene, butene) to producecarbocations,which alkylate isobutane. The product, called "alkylate", is composed of a mixture of high-octane,branched-chainparaffinichydrocarbons(mostlyisoheptaneandisooctane). Alkylate is a premiumgasolineblending stock because it has exceptional antiknock properties and is clean burning. Alkylate is also a key component ofavgas.By combiningfluid catalytic cracking,polymerization, and alkylation, refineries can obtain a gasoline yield of 70 percent. The widespread use ofsulfuric acidandhydrofluoric acidin refineries poses significant environmental risks.Ionic liquidsare used in place of the older generation of strong Bronsted acids.

Dealkylation

Complementing alkylation reactions are the reverse, dealkylations. Prevalent aredemethylations,which are prevalent in biology, organic synthesis, and other areas, especially formethyl ethersandmethyl amines.

See also

• Hydrodealkylation
• Transalkylation
• Alkynylation
• Friedel–Crafts reaction
• Category:Alkylating agents
  • Category:Ethylating agents
  • Category:Methylating agents

External links

• Macrogalleria page on polycarbonate production
• Alkylating+agentsat the U.S. National Library of MedicineMedical Subject Headings(MeSH)