Alkylation

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Typical route for alkylation of benzene with ethylene and ZSM-5 as a heterogeneous catalyst EthylbenzenePost2000route.svg
Typical route for alkylation of benzene with ethylene and ZSM-5 as a heterogeneous catalyst

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.

Contents

Nucleophilic alkylating agents

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). Katalysezyklus-Kumada-Kupplung.png
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

C-alkylation

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

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 Menschutkin.svg
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

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

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

Triethyloxonium tetrafluoroborate is one of the most electrophilic alkylating agents. Triethyloxonium tetrafluoroborate.png
Triethyloxonium tetrafluoroborate is one of the most electrophilic alkylating agents.

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

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

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

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

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

Commodity chemicals

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

Gasoline production

Typical acid-catalyzed route to 2,4-dimethylpentane. 2,4-Me2pentaneRoute.png
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

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

See also

Related Research Articles

<span class="mw-page-title-main">Carboxylic acid</span> Organic compound containing a –C(=O)OH group

In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group attached to an R-group. The general formula of a carboxylic acid is often written as R−COOH or R−CO2H, sometimes as R−C(O)OH with R referring to the alkyl, alkenyl, aryl, or other group. Carboxylic acids occur widely. Important examples include the amino acids and fatty acids. Deprotonation of a carboxylic acid gives a carboxylate anion.

<span class="mw-page-title-main">Ether</span> Organic compounds made of alkyl/aryl groups bound to oxygen (R–O–R)

In organic chemistry, ethers are a class of compounds that contain an ether group—an oxygen atom connected to two alkyl or aryl groups. They have the general formula R−O−R′, where R and R′ represent the alkyl or aryl groups. Ethers can again be classified into two varieties: if the alkyl or aryl groups are the same on both sides of the oxygen atom, then it is a simple or symmetrical ether, whereas if they are different, the ethers are called mixed or unsymmetrical ethers. A typical example of the first group is the solvent and anaesthetic diethyl ether, commonly referred to simply as "ether". Ethers are common in organic chemistry and even more prevalent in biochemistry, as they are common linkages in carbohydrates and lignin.

<span class="mw-page-title-main">Ester</span> Compound derived from an acid

In chemistry, an ester is a compound derived from an acid in which the hydrogen atom (H) of at least one acidic hydroxyl group of that acid is replaced by an organyl group. Analogues derived from oxygen replaced by other chalcogens belong to the ester category as well. According to some authors, organyl derivatives of acidic hydrogen of other acids are esters as well, but not according to the IUPAC.

<span class="mw-page-title-main">Phenols</span> Chemical compounds in which hydroxyl group is attached directly to an aromatic ring

In organic chemistry, phenols, sometimes called phenolics, are a class of chemical compounds consisting of one or more hydroxyl groups (−OH) bonded directly to an aromatic hydrocarbon group. The simplest is phenol, C
6
H
5
OH
. Phenolic compounds are classified as simple phenols or polyphenols based on the number of phenol units in the molecule.

<span class="mw-page-title-main">Haloalkane</span> Group of chemical compounds derived from alkanes containing one or more halogens

The haloalkanes are alkanes containing one or more halogen substituents. They are a subset of the general class of halocarbons, although the distinction is not often made. Haloalkanes are widely used commercially. They are used as flame retardants, fire extinguishants, refrigerants, propellants, solvents, and pharmaceuticals. Subsequent to the widespread use in commerce, many halocarbons have also been shown to be serious pollutants and toxins. For example, the chlorofluorocarbons have been shown to lead to ozone depletion. Methyl bromide is a controversial fumigant. Only haloalkanes that contain chlorine, bromine, and iodine are a threat to the ozone layer, but fluorinated volatile haloalkanes in theory may have activity as greenhouse gases. Methyl iodide, a naturally occurring substance, however, does not have ozone-depleting properties and the United States Environmental Protection Agency has designated the compound a non-ozone layer depleter. For more information, see Halomethane. Haloalkane or alkyl halides are the compounds which have the general formula "RX" where R is an alkyl or substituted alkyl group and X is a halogen.

<span class="mw-page-title-main">Epoxide</span> Organic compounds with a carbon-carbon-oxygen ring

In organic chemistry, an epoxide is a cyclic ether, where the ether forms a three-atom ring: two atoms of carbon and one atom of oxygen. This triangular structure has substantial ring strain, making epoxides highly reactive, more so than other ethers. They are produced on a large scale for many applications. In general, low molecular weight epoxides are colourless and nonpolar, and often volatile.

The Friedel–Crafts reactions are a set of reactions developed by Charles Friedel and James Crafts in 1877 to attach substituents to an aromatic ring. Friedel–Crafts reactions are of two main types: alkylation reactions and acylation reactions. Both proceed by electrophilic aromatic substitution.

In chemistry, an electrophile is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively charged, have an atom that carries a partial positive charge, or have an atom that does not have an octet of electrons.

<span class="mw-page-title-main">Williamson ether synthesis</span> Method for preparing ethers

The Williamson ether synthesis is an organic reaction, forming an ether from an organohalide and a deprotonated alcohol (alkoxide). This reaction was developed by Alexander Williamson in 1850. Typically it involves the reaction of an alkoxide ion with a primary alkyl halide via an SN2 reaction. This reaction is important in the history of organic chemistry because it helped prove the structure of ethers.

In retrosynthetic analysis, a synthon is a hypothetical unit within a target molecule that represents a potential starting reagent in the retroactive synthesis of that target molecule. The term was coined in 1967 by E. J. Corey. He noted in 1988 that the "word synthon has now come to be used to mean synthetic building block rather than retrosynthetic fragmentation structures". It was noted in 1998 that the phrase did not feature very prominently in Corey's 1981 book The Logic of Chemical Synthesis, as it was not included in the index. Because synthons are charged, when placed into a synthesis an uncharged form is found commercially instead of forming and using the potentially very unstable charged synthons.

α-Halo ketone

In organic chemistry, an α-halo ketone is a functional group consisting of a ketone group or more generally a carbonyl group with an α-halogen substituent. α-Halo ketones are alkylating agents. Prominent α-halo ketones include phenacyl bromide and chloroacetone.

<span class="mw-page-title-main">Tetrafluoroborate</span> Anion

Tetrafluoroborate is the anion BF
4
. This tetrahedral species is isoelectronic with tetrafluoroberyllate (BeF2−
4
), tetrafluoromethane (CF4), and tetrafluoroammonium (NF+
4
) and is valence isoelectronic with many stable and important species including the perchlorate anion, ClO
4
, which is used in similar ways in the laboratory. It arises by the reaction of fluoride salts with the Lewis acid BF3, treatment of tetrafluoroboric acid with base, or by treatment of boric acid with hydrofluoric acid.

<span class="mw-page-title-main">Stork enamine alkylation</span> Reaction sequence in organic chemistry

The Stork enamine alkylation involves the addition of an enamine to a Michael acceptor or another electrophilic alkylation reagent to give an alkylated iminium product, which is hydrolyzed by dilute aqueous acid to give the alkylated ketone or aldehyde. Since enamines are generally produced from ketones or aldehydes, this overall process constitutes a selective monoalkylation of a ketone or aldehyde, a process that may be difficult to achieve directly.

<span class="mw-page-title-main">Organocopper chemistry</span> Compound with carbon to copper bonds

Organocopper chemistry is the study of the physical properties, reactions, and synthesis of organocopper compounds, which are organometallic compounds containing a carbon to copper chemical bond. They are reagents in organic chemistry.

Amine alkylation (amino-dehalogenation) is a type of organic reaction between an alkyl halide and ammonia or an amine. The reaction is called nucleophilic aliphatic substitution, and the reaction product is a higher substituted amine. The method is widely used in the laboratory, but less so industrially, where alcohols are often preferred alkylating agents.

Electrophilic amination is a chemical process involving the formation of a carbon–nitrogen bond through the reaction of a nucleophilic carbanion with an electrophilic source of nitrogen.

Reactions of organocopper reagents involve species containing copper-carbon bonds acting as nucleophiles in the presence of organic electrophiles. Organocopper reagents are now commonly used in organic synthesis as mild, selective nucleophiles for substitution and conjugate addition reactions.

An insertion reaction is a chemical reaction where one chemical entity interposes itself into an existing bond of typically a second chemical entity e.g.:

The Ritter reaction is a chemical reaction that transforms a nitrile into an N-alkyl amide using various electrophilic alkylating reagents. The original reaction formed the alkylating agent using an alkene in the presence of a strong acid.

In organic chemistry, vinylation is the process of attaching a vinyl group to a substrate. Many organic compounds contain vinyl groups, so the process has attracted significant interest, especially since the reaction scope includes substituted vinyl groups. The reactions can be classified according to the source of the vinyl group.

References

  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.