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Alkylation

February 16, 2024

Alkylation is a chemical reaction that entails transfer of an alkyl group. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). [1] 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. In oil refining contexts, alkylation refers to a particular alkylation of isobutane with olefins. For upgrading of petroleum, alkylation produces a premium blending stock for gasoline.[2] In medicine, alkylation of DNA is used in chemotherapy to damage the DNA of cancer cells. Alkylation is accomplished with the class of drugs called alkylating antineoplastic agents.

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

Nucleophilic alkylating agents edit

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 Kumada coupling employs 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 edit

C-alkylation edit

C-alkylation is a process for the formation of carbon-carbon bonds. The largest example of this takes place in the alkylation units of petrochemical plants, which convert low-molecular-weight alkenes into high octane gasoline components. Electron-rich species such as phenols are also commonly alkylated to produce a variety of products; examples include linear alkylbenzenes used in the production of surfactants like LAS, or butylated phenols like BHT, which are used as antioxidants. This can be achieved using either acid catalysts like Amberlyst, or Lewis acids like aluminium.[3] On a laboratory scale the Friedel–Crafts reaction uses alkyl halides, as these are often easier to handle than their corresponding alkenes, which tend to be gasses. The reaction is catalysed by aluminium trichloride. This approach is rarely used industrially as alkyl halides are more expensive than alkenes.

N-,P-, S- alkylation edit

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 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.

 
Menshutkin-reaction

Thiols are readily alkylated to give thioethers via the thiol-ene reaction.[4] 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.

O-alkylation edit

Alcohols alkylate to give ethers:

 

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.[5]

 
(with Na+ as a spectator ion)

More complex alkylation of a alcohols and phenols involve ethoxylation. Ethylene oxide is the alkylating group in this reaction.

Oxidative addition to metals edit

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 edit

 
Triethyloxonium tetrafluoroborate is one of the most electrophilic alkylating agents.[6]

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.

Methylation with diazomethane edit

Diazomethane is a popular methylating agent in the laboratory, but it is too hazardous (explosive gas with a high acute toxicity) to be employed on an industrial scale without special precautions.[7] Use of diazomethane has been significantly reduced by the introduction of the safer and equivalent reagent trimethylsilyldiazomethane.[8]

Hazards edit

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.

Catalysts edit

 
Friedel-Crafts alkylation of benzene is often catalyzed by aluminium trichloride.

Electrophilic alkylation uses 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:[9]

 

In biology edit

Main article: methylation

Alkylation in biology causes DNA damage. It is the transfer of alkyl groups to the nitrogenous 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 the Base Excision Repair (BER) pathway.[10]

 
The SN2-like methyl transfer reaction in DNA methylation. Only the SAM cofactor and cytosine base are shown for simplicity.

Commodity chemicals edit

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).[11]

 
Sodium dodecylbenzene, obtained by alkylation of benzene with dodecene, is a precursor to linear alkylbenzene sulfonate detergents.

Gasoline production edit

Main article: alkylation unit
 
Typical acid-catalyzed route to 2,4-dimethylpentane.

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.[12] Ionic liquids are used in place of the older generation of strong Bronsted acids.[13][14]

Dealkylation edit

Complementing alkylation reactions are the reverse, dealkylations. Prevalent are ether dealkylations.[15]

See also edit

References edit

  1. ^ March Jerry; (1985). Advanced Organic Chemistry reactions, mechanisms and structure (3rd ed.). New York: John Wiley & Sons, inc. ISBN 0-471-85472-7
  2. ^ Stefanidakis, G.; Gwyn, J.E. (1993). "Alkylation". In John J. McKetta (ed.). Chemical Processing Handbook. CRC Press. pp. 80–138. ISBN 0-8247-8701-3.
  3. ^ Ma, Qisheng; Chakraborty, Deb; Faglioni, Francesco; Muller, Rick P.; Goddard, William. A.; Harris, Thomas; Campbell, Curt; Tang, Yongchun (1 February 2006). "Alkylation of Phenol: A Mechanistic View". The Journal of Physical Chemistry A. 110 (6): 2246–2252. Bibcode:2006JPCA..110.2246M. doi:10.1021/jp0560213. PMID 16466262.
  4. ^ D. Landini; F. Rolla (1978). "Sulfide Synthesis In Preparation Of Dialkyl And Alkyl Aryl Sulfides: Neopentyl Phenyl Sulfide". Org. Synth. 58: 143. doi:10.15227/orgsyn.058.0143.
  5. ^ G. S. Hiers and F. D. Hager (1941). "Anisole". Organic Syntheses.; Collective Volume, vol. 1, p. 58
  6. ^ H. Perst; D. G. Seapy (2008). "Triethyloxonium Tetrafluoroborate". Encyclopedia of Reagents for Organic Synthesis. doi:10.1002/047084289X.rt223.pub2. ISBN 978-0471936237.
  7. ^ Proctor, Lee D.; Warr, Antony J. (November 2002). "Development of a continuous process for the industrial generation of diazomethane". Organic Process Research & Development. 6 (6): 884–892. doi:10.1021/op020049k.
  8. ^ Shioiri, Takayuki; Aoyama, Toyohiko; Snowden, Timothy (2001). "Trimethylsilyldiazomethane". Encyclopedia of Reagents for Organic Synthesis. e-EROS Encyclopedia of Reagents for Organic Synthesis. doi:10.1002/047084289X.rt298.pub2. ISBN 0471936235.
  9. ^ Misono, Makoto (2009). "Recent progress in the practical applications of heteropolyacid and perovskite catalysts: Catalytic technology for the sustainable society". Catalysis Today. 144 (3–4): 285–291. doi:10.1016/j.cattod.2008.10.054.
  10. ^ Bouziane, M.; Miao, F.; Ye, N.; Holmquist, G.; Chyzak, G.; O'Connor, T. R. (1998). "Repair of DNA alkylation damage". Acta Biochimica Polonica. 45 (1): 191–202. ISSN 0001-527X. PMID 9701511.
  11. ^ Bipin V. Vora; Joseph A. Kocal; Paul T. Barger; Robert J. Schmidt; James A. Johnson (2003). "Alkylation". Kirk‐Othmer Encyclopedia of Chemical Technology. doi:10.1002/0471238961.0112112508011313.a01.pub2. ISBN 0471238961.
  12. ^ Michael Röper, Eugen Gehrer, Thomas Narbeshuber, Wolfgang Siegel "Acylation and Alkylation" in Ullmann's Encyclopedia of Industrial Chemistry, Wiley-VCH, Weinheim, 2000. doi:10.1002/14356007.a01_185
  13. ^ Kore, Rajkumar; Scurto, Aaron M.; Shiflett, Mark B. (2020). "Review of Isobutane Alkylation Technology Using Ionic Liquid-Based Catalysts—Where Do We Stand?". Industrial & Engineering Chemistry Research. 59 (36): 15811–15838. doi:10.1021/acs.iecr.0c03418. S2CID 225512999.
  14. ^ "Oil & Gas Engineering | Ionic liquid alkylation technology receives award". 2 January 2018.
  15. ^ Weissman, Steven A.; Zewge, Daniel (2005). "Recent advances in ether dealkylation". Tetrahedron. 61 (33): 7833–7863. doi:10.1016/j.tet.2005.05.041.

External links edit

  • Macrogalleria page on polycarbonate production
  • Alkylating+agents at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

February 16, 2024
alkylation, chemical, reaction, that, entails, transfer, alkyl, group, alkyl, group, transferred, alkyl, carbocation, free, radical, carbanion, carbene, their, equivalents, alkylating, agents, reagents, effecting, alkylation, alkyl, groups, also, removed, proc. Alkylation is a chemical reaction that entails transfer of an alkyl group The alkyl group may be transferred as an alkyl carbocation a free radical a carbanion or a carbene or their equivalents 1 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 In oil refining contexts alkylation refers to a particular alkylation of isobutane with olefins For upgrading of petroleum alkylation produces a premium blending stock for gasoline 2 In medicine alkylation of DNA is used in chemotherapy to damage the DNA of cancer cells Alkylation is accomplished with the class of drugs called alkylating antineoplastic agents Typical route for alkylation of benzene with ethylene and ZSM 5 as a heterogeneous catalystContents 1 Nucleophilic alkylating agents 2 Alkylation by carbon electrophiles 2 1 C alkylation 2 2 N P S alkylation 2 3 O alkylation 2 4 Oxidative addition to metals 2 5 Electrophilic alkylating agents 2 6 Methylation with diazomethane 2 7 Hazards 2 8 Catalysts 3 In biology 4 Commodity chemicals 5 Gasoline production 6 Dealkylation 7 See also 8 References 9 External linksNucleophilic alkylating agents editNucleophilic 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 nbsp The Kumada coupling employs 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 editC alkylation edit C alkylation is a process for the formation of carbon carbon bonds The largest example of this takes place in the alkylation units of petrochemical plants which convert low molecular weight alkenes into high octane gasoline components Electron rich species such as phenols are also commonly alkylated to produce a variety of products examples include linear alkylbenzenes used in the production of surfactants like LAS or butylated phenols like BHT which are used as antioxidants This can be achieved using either acid catalysts like Amberlyst or Lewis acids like aluminium 3 On a laboratory scale the Friedel Crafts reaction uses alkyl halides as these are often easier to handle than their corresponding alkenes which tend to be gasses The reaction is catalysed by aluminium trichloride This approach is rarely used industrially as alkyl halides are more expensive than alkenes N P S alkylation edit 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 lt secondary amine lt 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 nbsp Menshutkin reactionThiols are readily alkylated to give thioethers via the thiol ene reaction 4 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 O alkylation edit Alcohols alkylate to give ethers R OH R X R O R displaystyle ce R OH R X gt R O R nbsp 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 5 Ph O Me 2 SO 4 Ph O Me Me SO 4 displaystyle ce Ph O Me2 SO4 gt Ph O Me Me SO4 nbsp with Na as a spectator ion More complex alkylation of a alcohols and phenols involve ethoxylation Ethylene oxide is the alkylating group in this reaction Oxidative addition to metals edit 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 edit nbsp Triethyloxonium tetrafluoroborate is one of the most electrophilic alkylating agents 6 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 Methylation with diazomethane edit Diazomethane is a popular methylating agent in the laboratory but it is too hazardous explosive gas with a high acute toxicity to be employed on an industrial scale without special precautions 7 Use of diazomethane has been significantly reduced by the introduction of the safer and equivalent reagent trimethylsilyldiazomethane 8 Hazards edit 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 Catalysts edit nbsp Friedel Crafts alkylation of benzene is often catalyzed by aluminium trichloride Electrophilic alkylation uses Lewis acids and Bronsted acids sometimes both Classically Lewis acids e g aluminium trichloride are employed when the alkyl halide are used Bronsted 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 9 C 2 H 4 CH 3 CO 2 H CH 3 CO 2 C 2 H 5 displaystyle ce C2H4 CH3CO2H gt CH3CO2C2H5 nbsp In biology editMain article methylation Alkylation in biology causes DNA damage It is the transfer of alkyl groups to the nitrogenous 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 the Base Excision Repair BER pathway 10 nbsp The SN2 like methyl transfer reaction in DNA methylation Only the SAM cofactor and cytosine base are shown for simplicity Commodity chemicals editSeveral 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 11 nbsp Sodium dodecylbenzene obtained by alkylation of benzene with dodecene is a precursor to linear alkylbenzene sulfonate detergents Gasoline production editMain article alkylation unit nbsp Typical acid catalyzed route to 2 4 dimethylpentane 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 Bronsted 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 12 Ionic liquids are used in place of the older generation of strong Bronsted acids 13 14 Dealkylation editComplementing alkylation reactions are the reverse dealkylations Prevalent are ether dealkylations 15 See also editHydrodealkylation Transalkylation Alkynylation Friedel Crafts reaction Category Alkylating agents Category Ethylating agents Category Methylating agentsReferences edit March Jerry 1985 Advanced Organic Chemistry reactions mechanisms and structure 3rd ed New York John Wiley amp Sons inc ISBN 0 471 85472 7 Stefanidakis G Gwyn J E 1993 Alkylation In John J McKetta ed Chemical Processing Handbook CRC Press pp 80 138 ISBN 0 8247 8701 3 Ma Qisheng Chakraborty Deb Faglioni Francesco Muller Rick P Goddard William A Harris Thomas Campbell Curt Tang Yongchun 1 February 2006 Alkylation of Phenol A Mechanistic View The Journal of Physical Chemistry A 110 6 2246 2252 Bibcode 2006JPCA 110 2246M doi 10 1021 jp0560213 PMID 16466262 D Landini F Rolla 1978 Sulfide Synthesis In Preparation Of Dialkyl And Alkyl Aryl Sulfides Neopentyl Phenyl Sulfide Org Synth 58 143 doi 10 15227 orgsyn 058 0143 G S Hiers and F D Hager 1941 Anisole Organic Syntheses Collective Volume vol 1 p 58 H Perst D G Seapy 2008 Triethyloxonium Tetrafluoroborate Encyclopedia of Reagents for Organic Synthesis doi 10 1002 047084289X rt223 pub2 ISBN 978 0471936237 Proctor Lee D Warr Antony J November 2002 Development of a continuous process for the industrial generation of diazomethane Organic Process Research amp Development 6 6 884 892 doi 10 1021 op020049k Shioiri Takayuki Aoyama Toyohiko Snowden Timothy 2001 Trimethylsilyldiazomethane Encyclopedia of Reagents for Organic Synthesis e EROS Encyclopedia of Reagents for Organic Synthesis doi 10 1002 047084289X rt298 pub2 ISBN 0471936235 Misono Makoto 2009 Recent progress in the practical applications of heteropolyacid and perovskite catalysts Catalytic technology for the sustainable society Catalysis Today 144 3 4 285 291 doi 10 1016 j cattod 2008 10 054 Bouziane M Miao F Ye N Holmquist G Chyzak G O Connor T R 1998 Repair of DNA alkylation damage Acta Biochimica Polonica 45 1 191 202 ISSN 0001 527X PMID 9701511 Bipin V Vora Joseph A Kocal Paul T Barger Robert J Schmidt James A Johnson 2003 Alkylation Kirk Othmer Encyclopedia of Chemical Technology doi 10 1002 0471238961 0112112508011313 a01 pub2 ISBN 0471238961 Michael Roper Eugen Gehrer Thomas Narbeshuber Wolfgang Siegel Acylation and Alkylation in Ullmann s Encyclopedia of Industrial Chemistry Wiley VCH Weinheim 2000 doi 10 1002 14356007 a01 185 Kore Rajkumar Scurto Aaron M Shiflett Mark B 2020 Review of Isobutane Alkylation Technology Using Ionic Liquid Based Catalysts Where Do We Stand Industrial amp Engineering Chemistry Research 59 36 15811 15838 doi 10 1021 acs iecr 0c03418 S2CID 225512999 Oil amp Gas Engineering Ionic liquid alkylation technology receives award 2 January 2018 Weissman Steven A Zewge Daniel 2005 Recent advances in ether dealkylation Tetrahedron 61 33 7833 7863 doi 10 1016 j tet 2005 05 041 External links editMacrogalleria page on polycarbonate production Alkylating agents at the U S National Library of Medicine Medical Subject Headings MeSH Retrieved from https en wikipedia org w index php title Alkylation amp oldid 1196831278, wikipedia, wiki, book, books, library,

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