Alkylation Reactions

Alkylation is a chemical process by which an alkyl group is attached to an organic substrate molecule via addition or substitution. An alkyl group is an alkane molecule that is missing a hydrogen atom. For example, methyl groups are the simplest alkyls and result from the removal of a hydrogen atom from methane. Alkyl groups substitute or add to molecules, such as carbocations, carboanions, radicals or carbenes. Alkyl groups may bond to a number of atoms including carbon, nitrogen and oxygen atoms in substrate molecules. Alkylating agents are typically olefin, alcohols, sulfates halides and various nitrogen containing compounds that promote alkylation by enabling alkyl groups to selectively bond to molecules. Often, alkylation requires a catalyst. Common alkylating catalysts are acids, such as HF or H₂SO₄. In certain processes, zeolites or Lewis acids are used as alkylation catalysts.

Alkylation is the process of adding alkyl groups to a substrate molecule and has importance in a variety of applications:

• In organic chemistry, alkylation reactions are common. One of the frequently employed alkylation reactions is the Friedel-Crafts. In this reaction, the presence of a Lewis acid catalyst such as AlCl₃, an alkyl halide, and an aryl compound form a substituted aromatic ring structure.
  
• In the manufacturing of gasoline, alkylation is used to produce high octane product by converting isoparaffins and low-molecular-weight alkenes into alkylate.
  
• In medical applications, a class of cancer treatment is alkylating antineoplastic agents, in which DNA is methylated, causing damage to the cancerous cells and inhibiting growth.  

In the petroleum industry, alkylation units are large chemical reaction vessels and associated technology. The alkylation process produces alkylate from propylene, butylene, and isobutane (i.e. alkylating olefins to form longer branched-chain hydrocarbons). The alkylate is a mixture of high-octane hydrocarbons that is blended into gasoline to improve performance and drivability. The gaseous feedstock for the reaction comes from the oil refining process (i.e. the gases are recycled). In an alkylation unit, the reactant gases are pressurized, liquefied and mixed with an acid catalyst, which is either HF or H₂SO₄. In a different alkylating process, solid zeolite is used as the catalyst. The purpose of the catalyst is to achieve alkylation at both lower temperature and pressures, and depending on which catalyst is used, the ratio of the reactants is adjusted. The products of the reaction are sent to a separating vessel where the liquid acid catalyst settles to the bottom, is drawn off, and recycled back to the alkylating reactor. After being treated with caustic to neutralize the remaining acid, the hydrocarbon top layer is passed to a fractionator to separate the different product components that include propane, butane and alkylate. 

Operating conditions of the alkylating unit, including temperature, pressure, agitation and butane/olefin ratio are critical. In addition, the type of olefin present in the feedstock (propylene, butene, i-butylene, pentene) affects the octane quality of the alkylate product (RON/MON). 

Alkylation reactions may be either nucleophilic or electrophilic, and occur by addition or substitution. Alkylation will readily form carbon bonds between nitrogen, phosphorus, oxygen and sulfur atoms in organic compounds.

Some examples:

• Alkylation of an aldehyde or ketone to form C-C bonds (Grignard Reaction)
• Coupling reaction of an alkylhalide and an organometallic to form a C-C bond (Wurtz reaction)
• Alkylation of aromatic rings via alkyl halide (Friedel-Crafts alkylation reaction)
• Alkylation of alkyl halides (Suzuki cross-coupling reaction)
• Acids form esters via reaction with diazo compounds 
• Alcohols form ethers with diazo compounds or alkyl halides
• Ethers are formed by the reaction of an alkoxide with an alkyl halide
• Alkylation of nitrogen heterocycles with alkyl halide
• Alkylation of primary amines to form quaternary ammonium cation
• Alkylation of thiols to thioethers
• Alkylation of phosphines to phosphonium salts
• Aminoalkylation of ketone to form the beta-aminoketone (Mannich base)
• Alkylation of phthalimide with alkyl halides to form primary amines (Gabriel synthesis)

The petroleum industry relies on alkylation reactions as starting points for modern consumer products. One of the products of crude oil refining is benzene, which is prepared by “cracking”. At high temperatures, oil is vaporized to obtain raw pyrolysis gas, from which benzene is extracted and separated from other compounds. Benzene is converted to cumene via alkylation with propylene, and to ethylbenzene by alkylation with ethylene. Cumene and ethylbenzene are the starting chemicals to produce a wide range of commercial polymers, coatings, adhesives, resins, etc.

Alkylation is an important reaction for the production of fuels from petroleum. The alkylation process produces alkylate from propylene, butylene and isobutane (i.e. alkylating olefins to form longer branched-chain hydrocarbons). The gaseous feedstock for the alkylating reaction comes from the oil refining process (i.e. the gases are recycled). Alkylate itself is a mixture of high-octane hydrocarbons that is a blended into gasoline to improve performance and drivability. 

DNA contains four primary bases. Methyl alkylation of adenine and guanine at the nitrogen atom, and guanine at the oxygen atom, can readily occur with alkylating chemicals, such as methyl-nitrosamine and dimethylsulfate. If these errors are not corrected by DNA repair processes, cellular mutation may follow. In medicine, alkylation of DNA is used to an advantage in the treatment of cancer. Alkylating chemicals affect DNA replication and therefore can cause cells to die. This effect is especially pronounced in rapidly dividing cells, as found in cancer.

There are a number of alkylating chemicals used in chemotherapy, including nitrogen mustards, nitrosoureas, alkyl sulfonates, triazines and ethylenimines. Alkylating chemotherapies have been used for years and can be effective for many types of cancers. However, because all cells are affected, side effects can be severe. The aim in using these older alkylating neoplastic agents is to carefully titrate the dosage to ensure that the cancerous cells are most highly affected, while minimizing damage to non-cancerous cells.  

In this on-demand webinar, Kevin Stone discusses how Merck & Co., Inc. leverages process fingerprinting tools in the development of an alkylation reaction. The final chemical transformation in the synthesis of doravirine (an NNRTI drug intended for the treatment of HIV) is an alkylation reaction with key process variables and interactions that had historically produced high sensitivities in reaction performance. Now, high-throughput experimentation and data-intensive PAT tools characterize and optimize this reaction for improved performance. Large data sets are produced to:

• Measure reaction kinetics
• Build models
• Define ideal operating parameters to reduce impurity generation and process variability

Alkylations in organic chemistry comprise of many reaction classes, mechanisms and reaction conditions, requiring reactor control parameters and analysis capability to be equally versatile. Reaction yield and selectivity is a function of the substrate, alkylating reagent and reaction variables. This combination of requirements make the need for in-situ analysis and precise control of variables an important objective in optimizing alkylation reactions.

A thorough understanding of the kinetics, thermodynamics and effect of reaction variables on alkylations is necessary for reaction development, scale-up, safety and to achieve final product specifications:

• Chemical reactors and reaction calorimeters have important roles in ensuring that reaction energetics are well understood and the effect of variables on reaction performance are adequately modelled. 
• In-situ FTIR and Raman spectrometers are useful for tracking and monitoring key reaction species, providing both kinetics and mechanistic information.
• When offline analysis of reaction samples is required, EasySampler allows for fully automated in-situ sample removal.

These three in-situ technologies used in conjunction with automated reactors provide the chemist with a thorough understanding of how reaction conditions and variables relate to overall reaction performance. 

Epifanov, M., Foth, P. J., Gu, F., Barrillon, C., Kanani, S. S., Higman, C. S., Hein, J. E., & Sammis, G. M. (2018). One-Pot 1,1-Dihydrofluoroalkylation of Amines Using Sulfuryl Fluoride. Journal of the American Chemical Society, 140(48), 16464–16468.

The authors report a novel method for dihydrofluoralkylation of a broad range of primary and secondary amines, as well as certain longer, linear dihydrofluoroalcohols such as pentafluoropropanol and heptafluorobutanol. To accomplish this they use a common commodity chemical, sulfuryl fluoride (SO₂F₂) and bubble the gas through a solution containing the amine, 1,1-dihydrofluoroalcohol, and diisopropylethylamine. This one-pot reaction resulted in 40-80% yields of the 1,1-dihydrofluoroalkylated amines and is shown to be preferable with respect to other fluoroalkylating agents.  

ReactIR was used to track the reaction of trifluoroethylsulfate with morpholine to form the fluoroethylated amine product. This was the first time the fluorosulfate was used as an amine alkylating agent. Also, the authors used ReactIR to further understand the kinetics involved in the reaction of SO₂F₂ with morpholine to form a fluorosulfamide. ReactIR showed that the reaction of SO₂F₂ by trifluoroethanol is faster than fluoroalkylation of morpholine, and this enables the in-situ accumulation of trifluoroethyl fluorosulfate.

Tang, E., Zhao, Y., Li, W., Wang, W., Zhang, M., & Dai, X. (2016). Catalytic Selenium-Promoted Intermolecular Friedel–Crafts Alkylation with Simple Alkenes. Org. Lett., 18(5), 912-915.

Using N-phenylselenophthalimide (NPSP) to provide selenium, and trimethylsilyl trifluoromethanesulfonate (TMSOTf) as a catalyst, the authors report the development of a novel fluorine-carbon alkylation method. The C-C bond-forming synthesis has high regioselectivity and diastereoselectivity. The reaction yields 1,1-diarylsubstituted alkenes having chiral hydrocarbons with an aryl moiety at the stereogenic carbon atom, when a chiral selenium reagent is used.

ReactIR technology was used to help support a proposed mechanism for the reaction. The in-situ IR experiments showed the presence of a band 1067 cm^-1 that was assigned to the byproduct phthalimide, and a band 1033 cm^-1 that was assigned to the O-Si of a silyl enol ether intermediate. The proposed mechanism suggests that TMSOTf activates NPSP to form an episelenonium ion intermediate from alkenes.

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