Friedel-Crafts Alkylation

The Friedel-Crafts alkylation synthesizes alkylated products, such as alkylbenzenes, via the reaction of alkyl halides or alkenes with aromatic hydrocarbons. The reaction removes a hydrogen atom on the aromatic ring and replaces it with an electrophile. Thus, it occurs via electrophilic aromatic substitution and is catalyzed using strong Lewis acids, such as AlCl₃ or FeCl₃. Depending on the number of substituents on the alkyl halide (i.e., primary, secondary, or tertiary alkyl halide), the positively charged alkyl species interacts with the aromatic ring as a simple carbocation or as a carbocation complex of the Lewis acid.

The mechanism of the Friedel-Crafts alkylation occurs in several steps. Initially, the alkyl halide and Lewis acid react to form the carbocation. The carbocation then attacks the aromatic ring breaking one of the ring double bonds, resulting in the formation of a non-aromatic intermediate. Deprotonation of this intermediate then occurs, the ring regains aromaticity and the removed proton forms an acid that restores the Lewis acid catalyst.

Friedel-Crafts reactions are among the most important in organic chemistry for C-H activation and forming C-C bonds. By adding an alkyl group to an arene molecule, Friedel-Crafts style alkylations form the basis for the production of a diverse set of industrial products. The chemistry takes common chemical feedstock, such as benzene, and converts it into a wide array of intermediate and final products. One of the classic industrial Friedel-Crafts alkylations is the acid-catalyzed reaction of benzene and ethylene to produce ethylbenzene. The scale of ethylbenzene production is enormous, measured in millions of tons yearly. It is the precursor molecule of styrene, which in turn is used in the formation of polystyrene polymers. Cumene, xylene, and toluene all can be produced via Friedel-Craft type reactions. As an example, p-xylene is a precursor molecule to form terephthalic acid and dimethyl terephthalate monomers used in the production of polyethylene terephthalate (PET). Additionally, Friedel-Crafts alkylations have important roles in the development of fine chemicals and natural products. 

The fundamental difference between Friedel-Crafts alkylation and Friedel-Crafts acylation is that the former reaction alkylates an aromatic hydrocarbon, whereas the latter acylates the arene. Furthermore, Friedel-Crafts acylation helps to overcome some of the fundamental limitations of the Friedel-Crafts alkylation synthesis. These limitations include that only certain alkylbenzene compounds can be made due to rearrangement of the carbocation and the tendency for overalkylation of the molecule leading to undesirable by-products.

In Friedel-Crafts acylation, the acyl group [-C(O)R] forms an acylium ion in the presence of AlCl₃. The acylium ion attacks the benzene ring, forming a complexed intermediate in which the ring loses its aromaticity. Next, the AlCL₄ ion removes a proton from the ring restoring the ring aromaticity as well as regenerating the AlCl₃ catalyst. The resulting product is the ring with an attached ketone moiety. No rearrangements take place due to the resonance stabilization of the acylium ion, and deactivation stops electrophilic attack eliminating further ring substitutions.

The classic Friedel-Crafts alkylation reaction is a catalyzed electrophilic substitution reaction that arises from a carbocation attack on the double bond of an arene molecule. The catalyst for this reaction is typically a chloride, such as AlCl₃, which acts as a condensing agent. This approach to alkylation has led to the development of diverse hydrocarbon molecules. In addition to alkylation of arene molecules, the Friedel-Crafts reaction has been extended to include a range of compounds resulting from the alkylation or acylation of aliphatic hydrocarbons containing double bonds. Thus, the Friedel-Crafts alkylation reaction has proven value to the synthesis of a broad range of important polymers via polymerization of unsaturated hydrocarbons.

The diversity of Friedel-Crafts type alkylations (and acylations) has been driven by the development of a broad range of different catalysts that support the various applications. These generally include Lewis acids (AlCl₃, FeCL₃) or protic Brønsted acids (HF, H₂SO_4, etc.), as well as solid lattice structures, such as acidic cation exchange resins, anhydrous acid-exchanged zeolites and carbon based materials, such as graphene.

There are a wide range of substrates, reagents, catalysts and reaction conditions that are used in Friedel-Crafts alkylations. Given the scope and diversity of this reaction class, a thorough understanding of the kinetics, thermodynamics and effect of reaction variables is required for optimized reaction development, scale-up, safety and to meet product quality and yield objectives.

Automated chemical reactors and reaction calorimeters have important roles in ensuring that reaction energetics are well understood and that the effect of variables on reaction performance are adequately modelled. 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 and reproducible in-situ sample removal.

These technologies provide a thorough understanding of how reaction conditions and variables are related to overall reaction performance. 

E Tang, Yinjiao Zhao, Wen Li, Weilin Wang, Meng Zhang, and Xin Dai, “Catalytic Selenium-Promoted Intermolecular Friedel−Crafts Alkylation with Simple Alkenes”, Org. Lett. 2016, 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. 

Corey M. Parada, Bin Yang, C. Garrett Campbell, Robson F. Storey, “Synthesis, characterization, and photopolymerization of (meth)acrylate-functional polyisobutylene macromers produced by cleavage/alkylation of butyl rubber”, J Polym Sci. 2020; 1–16. 

Using a previously described acid-catalyzed cleavage/alkylation method, researchers synthesized a library of linear polyisobutylene (PIB) macromers containing multiple phenoxypropyl (meth)acrylate functionalities. Via UV-curing, the macromers were polymerized and their properties were compared to analogous polymers produced from photopolymerization of a PIB triacrylate macromer made by a living polymerization using a trifunctional initiator. By using ReactIR to track the loss of the acrylate peak (1615–1638 cm⁻¹), the authors investigated the effect of photoinitiator concentration on the curing rate of the PIB (meth)acrylates. They also used ReactIR measurements to differentiate the curing kinetics of the living PIB triacrylate control and the various multi-functional macromers prepared via the cleavage/alkylation process.

• Beutner, G.L., Albrecht, J., Fan, J., Fanfair, D. et al. (2017). Preparation of the HIV Attachment Inhibitor BMS-663068. Part 3. Mechanistic Studies Enable a Scale-Independent Friedel−Crafts Acylation, Org. Process Res. Dev., 21, 8, 1174–1185. https://doi.org/10.1021/acs.oprd.7b00138
• Bream, R.N., Hulcoop, D.G., Gooding, S.J., Watson, S.A & Blore, C. (2012).  Development of a Selective Friedel−Crafts Alkylation Surrogate: Safe Operating Conditions through Mechanistic Understanding.  Org. Process Res. Dev. 16, 12, 2043–2050. https://doi.org/10.1021/op300257z
• Csihony, S., Mehdi, H. & Horváth, I.T. (2001). In situ infrared spectroscopic studies of the Friedel–Crafts acetylation of benzene in ionic liquids using AlCl3 and FeCl3. Green Chemistry, 3, 307–309.
• Gigante, L., Lunghi, A., Martinelli, S. & Cardillo, P. (2003). Calorimetric Approach and Simulation for Scale-Up of a Friedel-Crafts Reaction.  Org. Process Res. Dev. 7, 1079−1082 10.1021/op030043a
• Heravi, M.M, Zadsirjan, V., Heydari, M., Masoumi, B.,(2019). Organocatalyzed Asymmetric Friedel‐Crafts Reactions: An Update, The Chemical Record, 19, 11, 2236-2340.
• Majia, B. (2019). Stereoselective Haliranium-, Thiiranium- and Seleniranium Ion-Triggered Friedel-Crafts-Type Alkylations to Polyene Cyclizations. Advanced Synthesis & Catalysis, 361,15, 3453-3489. https://doi.org/10.1002/adsc.201900028.
• Nayak, Y.N., Nayak, S., Nadaf, Y.F. Shetty, N.S., Gaonkar, S.L., (2020). Zeolite Catalyzed Friedel-Crafts Reactions: A Review, Letters in Organic Chemistry, 17, 7, 491-506. http://dx.doi.org/10.2174
• Rueping, M., Nachtsheim, B. “A Review of New Developments in the Friedel–Crafts Alkylation – From Green Chemistry to Asymmetric Catalysis”, Beilstein Journal of Organic Chemistry, 2010, 6, 6. 
• Tang, E., Zhao, Y., Li, W., Wang, W., Zhang, M., & Dai, X. (2016). Catalytic Selenium-Promoted Intermolecular Friedel-Crafts Alkylation with Simple Alkenes. ChemInform, 47(30), 912–915. https://doi.org/10.1002/chin.201630228