Friedel Crafts Alkylation

11 Key excerpts on "Friedel Crafts Alkylation"

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  Applied Organic Chemistry

  Reaction Mechanisms and Experimental Procedures in Medicinal Chemistry

  • Surya K. De(Author)
  • 2020(Publication Date)
  • Wiley-VCH

    (Publisher)

  [ 1, 2 ]. The Friedel–Crafts alkylation is still one of the widely studied and most utilized reactions in organic synthesis even after more than 143 years of its discovery. This reaction has the great versatility in scope and applicability to continue its crucial role in the synthesis of more and more complex molecules [3-67]. After more than a century, the asymmetric version on this reaction has been developed [ 34,35,38,40–42,45,46,51,52,55 ]. Several catalysts such as carbon monoxide [ 9 ], Sc(OTf) 3 [ 12, 17 ], Cu(OTf) 2 [ 13, 15 ], Zn(II)‐complex [ 21 ], In(III)‐salts [ 22 ], lanthanide triflates [ 23, 25 ], gold‐catalyst [ 24 ], FeCl 3 [ 26 ], and biocatalyst [ 53 ] have been employed on this reaction. Friedel–Crafts acylation Friedel–Crafts alkylation Mechanism For the Friedel–Crafts acylation, the electrophile is an acylium ion that is formed by a reaction between an acid chloride and an aluminum chloride as shown in the mechanism below. Step 1 : The initial step is the coordination between acyl chloride and AlCl 3 (complexation). Step 2 : The Lewis acid (AlCl 3) abstracts the chloride from acyl chloride to form an electrophilic acylium and a tetrachloride aluminum anion. Step 3 : An aromatic electrophilic substitution reaction results in a cationic intermediate with the loss of aromaticity. Step 4 : Deprotonation with aluminum anion ensures the

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  Asymmetric Functionalization of C-H Bonds

  • Shu-Li You(Author)
  • 2015(Publication Date)
  • Royal Society of Chemistry

    (Publisher)

  214 CHAPTER 6 Asymmetric Friedel–Crafts Alkylation Reactions QIANG KANG a AND SHU-LI YOU* b a Key Laboratory of Coal to Ethylene Glycol and Its Related Technology, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, 155 Yangqiao Road West, Fuzhou 350002, China; b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China *E-mail: [email protected] 6.1 Introduction Friedel–Crafts alkylation is one of the most frequently used and widely stud-ied reactions in organic chemistry. Since the initial discovery by Charles Friedel and James Mason Crafts in 1877, 1 a large number of applications have emerged for the construction of substituted aromatic compounds. Friedel–Crafts alkylation processes involve the replacement of C e H bond of an aromatic ring by an electrophilic partner in the presence of a Lewis acid or Brønsted acid catalyst. Particularly, catalytic asymmetric Friedel–Crafts alkylation is a very attractive, direct, and atom-economic approach for the synthesis of optically active aromatic compounds. However, it took more than 100 years from the discovery of this reaction until the first catalytic asymmet-ric Friedel–Crafts (AFC) alkylation of naphthol and ethyl pyruvate was real-ized by Erker in 1990. 2 Nowadays, owing to continued efforts in developing RSC Catalysis Series No. 25 Asymmetric Functionalization of C e H Bonds Edited by Shu-Li You © The Royal Society of Chemistry 2015 Published by the Royal Society of Chemistry, www.rsc.org 215 Asymmetric Friedel–Crafts Alkylation Reactions more efficient catalytic systems and understanding the mechanistic aspects, catalytic asymmetric Friedel–Crafts alkylations have been greatly improved, with the synthesis of optically active compounds with excellent enantioselec-tivity (>90% ee).

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  Organic Chemistry

  • David R. Klein(Author)
  • 2021(Publication Date)
  • Wiley

    (Publisher)

  AlCl 3 Cl Cl 18.7 A Friedel–Crafts alkylation is an electrophilic aromatic sub- stitution in which the electrophile (E + ) is a carbocation. In previous chapters, we have seen other methods of forming carbocations, such as protonation of an alkene using a strong acid. A carbo- cation formed in this way can also be attacked by a benzene ring, resulting in alkylation of the aromatic ring. With this in mind, draw a mechanism for the following transformation: (68%) H 2 SO 4 18.6 Friedel–Crafts Acylation 841 MECHANISM 18.7 FRIEDEL–CRAFTS ACYLATION H In the first step, the aromatic ring functions as a nucleophile, forming an intermediate sigma complex In the second step, the sigma complex is deprotonated, restoring aromaticity AlCl 3 Cl Nucleophilic attack Proton transfer Sigma complex H C O R H C O R H C O R C R O R C O AlCl 3 Cl C O R AlCl 4 Cl C O R AlCl 3 R C O R C O + + + + + + + - - - Acylium ions are resonance stabilized, as shown here: Resonance stabilized C O R C O R + + The second resonance structure is more significant, because all atoms exhibit a full octet. As such, this resonance structure contributes more character (and stability) to the overall resonance hybrid. The stabilization associated with full octets would be lost if an acylium ion were to undergo a carbo- cation rearrangement. Therefore, acylium ions do not rearrange. Acylium ions are excellent electrophiles and can be attacked by benzene in an electrophilic aro- matic substitution reaction (Mechanism 18.7). The acylium ion is attacked by the benzene ring to produce an intermediate sigma complex, which is then deprotonated to restore aromaticity. The product of a Friedel–Crafts acylation is an aryl ketone, which can be reduced using a Clemmensen reduction. R R O HCl, heat Zn(Hg) In the presence of HCl and amalgamated zinc (zinc that has been treated so that its surface is an alloy, or mixture, of zinc and mercury), the carbonyl group is completely reduced and replaced with two hydrogen atoms.

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  Macroscale and Microscale Organic Experiments

  • Kenneth Williamson, Katherine Masters(Authors)
  • 2016(Publication Date)
  • Cengage Learning EMEA

    (Publisher)

  409 The Friedel–Crafts 1 alkylation of aromatic rings most often uses an alkyl halide and a strong Lewis acid catalyst. Some of the catalysts that can be used, in order of decreasing activity, are the halides of aluminum, antimony, iron, titanium, tin, bis-muth, and zinc. Although useful, the reaction has several limitations. The aromatic ring must be unsubstituted or bear activating groups; because the product—an alkylated aromatic molecule—is more reactive than the starting material, multiple substitution usually occurs. Furthermore, primary halides will rearrange under the reaction conditions. Friedel–Crafts Alkylation of Benzene and Dimethoxybenzene; Host-Guest Chemistry CHAPTER 29 PRE-LAB EXERCISE: Prepare a flow sheet for the alkylation of benzene and the alkylation of dimethoxybenzene, indicating how the catalysts and unreacted starting materials are removed from the reaction mixture. CH 2 CH 2 CH 3 _ 6 C: 60% +35 C: 40% Reaction Temperature 40% 60% C H 3 C CH 3 H AlCl 3 CH 3 CH 2 CH 2 Cl In this experiment, a tertiary halide and the most powerful Friedel–Crafts cata-lyst, AlCl 3 , are allowed to react with benzene. (If you prefer not to work with ben-zene, you can carry out alkylations of dimethoxybenzene or m -xylene.) The initially formed t -butylbenzene is a liquid, whereas the product, 1,4-di-t -butylbenzene, which has a symmetrical structure, is a beautiful crystalline solid. The alkylation reaction probably proceeds through the carbocation under the conditions of the experiments in this chapter. 1 Charles Friedel and James Crafts (who later became the president of MIT) discovered this reaction in 1879. Copyright 2017 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience.

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  Experimental Organic Chemistry

  A Miniscale & Microscale Approach

  • John Gilbert, Stephen Martin(Authors)
  • 2015(Publication Date)
  • Cengage Learning EMEA

    (Publisher)

  Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it. Chapter 15 ■ Electrophilic Aromatic Substitution 511 15.3 F R I E D E L -C R A F T S A C Y L A T I O N O F A N I S O L E As described in Section 15.2 and in the Historical Highlight Discovery of the Friedel-Crafts Reaction, which is available online, Friedel and Crafts discovered that alkyl groups could be introduced onto an aromatic ring by reaction of arenes with alkyl halides in the presence of aluminum chloride, AlCl 3 , and other Lewis acids (Eq. 15.1, E 1 5 alkyl). The role of aluminum chloride, a strong Lewis acid, in this reaction is to convert the alkyl halide into a reactive electrophilic intermediate, in the form of a car-bocation or a highly polarized carbon-halogen bond (Eq. 15.8). The electrophile then undergoes attack by an arene, which functions as a Lewis base, resulting in aromatic substitution (Eqs. 15.8 and 15.9). The overall transformation is an example of an S E 2 reaction, as noted in Section 15.1. They also investigated the reaction of arenes with acid chlorides, 7 , in the pres-ence of Lewis acids and discovered that this produced aryl ketones, 9 , as shown in Equation 15.12. The first step in this process is reaction of the Lewis acid with the acid chloride to form an acylonium ion , 8 , which serves as the electrophile. Subsequently 8 adds to the arene, introducing an acyl group on the ring to provide an aryl ketone, 9 . In honor of its inventors, the reaction is named the Friedel-Crafts acylation . The resonance structures shown for 8 in Equation 15.12 symbolize the distribution of the positive charge in acylonium ions.

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  Zinc Catalysis

  Applications in Organic Synthesis

  • Stephan Enthaler, Xiao-Feng Wu, Stephan Enthaler, Xiao-Feng Wu(Authors)
  • 2015(Publication Date)
  • Wiley-VCH

    (Publisher)

  4 Zinc-Catalyzed Friedel–Crafts Reactions

  Yonghai Hui, Lili Lin, Xiaohua Liu and Xiaoming Feng

  4.1 Introduction

  Since its discovery in 1877 by Friedel and Crafts[1], the substitution of aromatic or aliphatic substrates with various alkylating agents in the presence of Lewis acid is called the Friedel–Crafts alkylation [2]. A closely related reaction is the introduction of a keto group into an aromatic or aliphatic substrate by using an acyl halide or anhydride in the presence of a Lewis acid catalyst, called the Friedel–Crafts acylation (Scheme 4.1 ). Benzenes, indoles, pyrroles, and furans have been usually used as the nucleophilic substrates in Friedel–Crafts reactions (Figure 4.1 ). After over 130 years of development, Friedel–Crafts reactions have become one of the most important carbon–carbon bond-forming reactions in organic and medical synthesis.

  Scheme 4.1

  Friedel–Crafts reactions.

  Figure 4.1

  Representative Friedel–Crafts nucleophilic substrates.

  Zinc is the twenty-fourth most abundant element in the earth's crust. Catalysts based on zinc as a central metal take a key place in Friedel–Crafts reactions and considerable progress has been made in recent years. In the following text, the main achievements in this field of Friedel–Crafts reactions are summarized. Various Friedel–Crafts reactions catalyzed by zinc salts or their complexes are covered.

  4.2 Friedel–Crafts Acylation

  Readily available zinc oxide is low cost, noncorrosive, and nonhygroscopic. As a solid-phase catalyst, it can catalyze the Friedel–Crafts acylation of electron-rich aromatic compounds with acyl chlorides under solvent-free conditions at room temperature, affording the corresponding ketones in 50–98% yields (Scheme 4.2 a) [3]. The products and the catalyst can be easily separated through filtering, and no chromatographic separation is needed to get the most spectra-pure products. The catalyst, zinc oxide, can be easily recovered by simple washing with dichloromethane and efficiently reused for at least three further cycles without loss of efficiency. Mechanistically, it seems that ZnCl2 is the true catalyst generated in situ

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  Organic Chemistry as a Second Language

  Second Semester Topics

  • David R. Klein(Author)
  • 2019(Publication Date)
  • Wiley

    (Publisher)

  4.3 FRIEDEL–CRAFTS ALKYLATION AND ACYLATION 73 So, instead we will have to use a Friedel–Crafts acylation followed by a Clemmensen reduction: AlCl 3 , O Cl 2) Zn(Hg), HCl, heat 1) For each of the following problems, show what reagents you would use to accomplish the transformation. In some situations, you will want to use a Friedel–Crafts alkylation, while in other situations, you will want to use a Friedel–Crafts acylation. 4.10 4.11 4.12 4.13 4.14 4.15 Predict the products of the following reaction. Cl AlCl 3 (Hint: There should be a mixture of multiple products in this case. Be sure to consider all of the possible rearrangements that can take place. If you are rusty on carbocation rearrangements, then you should go back and review them now.) 74 CHAPTER 4 ELECTROPHILIC AROMATIC SUBSTITUTION 4.16 On a separate piece of paper, draw a mechanism of formation for each one of the three products from the previous problem. 4.17 On a separate piece of paper, draw a mechanism for the following transformation. Make sure to show the mechanism of formation of the acylium ion that reacts with the ring: AlCl 3 , O O Cl Friedel–Crafts reactions have a few limitations. You should take a moment to read about them in your textbook. The two most important limitations are as follows: 1. When performing a Friedel–Crafts alkylation, it is often difficult to install just one alkyl group. Each alkyl group makes the ring more reactive toward a subsequent attack on the same ring. 2. When performing a Friedel–Crafts acylation, it is generally not possible to install more than one acyl group. The presence of one acyl group makes the ring less reactive toward a second acylation. We need to understand WHY an alkyl group makes the ring more reactive, and WHY an acyl group makes the ring less reactive. We will explain this in greater detail during the upcoming sections. But first, we have one more electrophile to discuss.

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  Chemical Reaction Technology

  • Dmitry Yu. Murzin(Author)
  • 2015(Publication Date)
  • De Gruyter

    (Publisher)

  Chapter 12

  Alkylation

  Alkylation is defined as the introduction of alkyl groups into organic molecules and is applied in synthesis or alkylaromatics, alkylation of isoparaffins, or transformations of epoxides.

  Alkylation reactions can be classified based on the type of the formed bond: alkylation by substituting hydrogen located at a carbon atom (C-alkylation) with an alkyl group, substituting oxygen or sulfur (O- and S-alkylation), or nitrogen (N-alkylation). Alkyl groups can also have substituents, such as hydroxyl or carboxy groups. In the current chapter, C-, N- and O- alkylation as well as β-oxyalkylation will be described.

  Alkylation can be done using unsaturated compounds such as olefins and acetylene; chloro-containing compounds with active Cl, which can be replaced; aldehydes or ketones, for example, in N-alkylation; epoxides when alkylation proceeds with a carbon-oxygen bond rupture.

  Olefins are mainly used for C-alkylation, while they are typically not used for N-alkylation and not effective for O- and S-alkylation. Alkylation activity of olefins depends on their ability to form stable carbocations; thus, chain increase and branching is favorable for reactivity improvement.

  12.1 Alkylation of aromatics

  For alkylation of aromatics with olefins, either AlCl3 or other acid catalysts (HF, sulfuric acid, supported phosphoric acid, zeolites) can be used. Either liquid- or gas-phase alkylations are applied over a broad range of temperature and pressure as discussed in detail below.

  Side reactions include formation of polyalkylaromatics, as well as generation of coke, cracking, and polymerization of olefins. The reaction network is given in Fig. 12.1 .

  The traditional process for the production of EB was developed around 1930. The catalyst used was AlCl3 -HCl, and all operations were carried out in agitated reactors, under moderate conditions: 130–170°C (depending on the transalkylation arrangement) and ca. 0.7 MPa. Transalkylation can be done either in the same reactor, or alternatively, after separation, the polyethylaromatics are transalkylated with benzene. A substantial amount of ethylbenzene is still produced by this technology utilizing AlCl3

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  Catalytic Asymmetric Reactions of Conjugated Nitroalkenes

  • Irishi N.N. Namboothiri, Meeta Bhati, Madhu Ganesh, Basavaprabhu Hosamani, Thekke V. Baiju, Shimi Manchery, Kalisankar Bera(Authors)
  • 2020(Publication Date)
  • CRC Press

    (Publisher)

  5 Catalytic Asymmetric Friedel–Crafts Reactions of Nitroalkenes

  5.1 Introduction

  Catalytic asymmetric Michael additions of various carbonyl compounds to nitroalkenes have been described in the previous chapters. However, nitroalkenes also participate in other reactions such as Friedel–Crafts reaction, which in the present context is a conjugate addition of aryl groups to nitroalkenes, which are covered in this chapter. The asymmetric Friedel–Crafts alkylation of indoles, pyrroles and electron-rich benzenoid aromatic compounds with nitroalkenes affords the corresponding enantioenriched indoles, pyrroles, etc. The indole and pyrrole rings can be subjected to further diastereoselective reduction to afford optically active derivatives, which are precursors to pharmaceuticals and natural products. A wide variety of metal-ligand complexes, such as Lewis acids and organocatalysts such as thioureas, squaramides and phosphoric acids as Brønsted acids have been employed as catalysts in Friedel–Crafts reactions.

  5.2 Friedel–Crafts Reaction

  The asymmetric Friedel–Crafts alkylation of indoles with nitroalkenes has gained substantial importance owing to the synthetic utility and versatility of chiral indole scaffolds in the frameworks of diverse biologically active indole alkaloids. Over the last two decades, substantial contributions have been made for this reaction by the development of several efficient catalytic systems. For instance, bifunctional hydrogen-bond donor organocatalysts and metal-based catalysts provided dual activation of the nitro group and the indole NH moiety. In 2008, the Jørgensen group reviewed asymmetric Friedel–Crafts alkylation catalyzed by copper.1 Later, Dalpozzo and co-workers published two review articles in 20102 and 20153 and highlighted the asymmetric functionalization of indoles, where few of the asymmetric Friedel–Crafts reactions of indole with nitroalkenes were discussed.4–18

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  Principles of Organic Synthesis

  • Richard O.C. Norman(Author)
  • 2017(Publication Date)
  • Routledge

    (Publisher)

  Studies of the mechanism indicate that the electrophilic entity is the hydroxymethyl cation. This reacts to give an alcoholic product that, in the presence of hydrogen chloride, is converted into the chloromethyl product:

  Chloromethylation, unlike Friedel–Crafts reactions, is successful even with quite strongly deactivated nuclei such as that of nitrobenzene, although m-dinitrobenzene and pyridine are inert.

  Two complications can occur in chloromethylation. First, the chloromethyl product can alkylate another molecule of the aromatic compound in the presence of the acid catalyst, e.g. This secondary reaction is of particular significance when the aromatic compound is strongly activated and for this reason chloromethylation is not a suitable procedure for phenols and anilines.

  Second, the chloromethyl group is activating, although less so than methyl because the chlorine substituent in the methyl group reduces the +I effect of that group. It is usually difficult to avoid the occurrence of some further chloromethylation, although this is not nearly so important a problem as it is in Friedel-Crafts alkylation.

  The reaction conditions may be varied widely. Anhydrous hydrogen chloride may be replaced by the concentrated aqueous acid; formaldehyde may be introduced as paraformaldehyde or methylal (CH2 (OCH3 )2 ); and zinc chloride may be replaced by sulfuric acid or phosphoric acid or omitted altogether in the chloromethylation of very reactive aromatic compounds such as thiophen. In a typical example, a mixture of naphthalene, paraformaldehyde, glacial acetic acid, 85% phosphoric acid, and concentrated hydrochloric acid, heated at 80°C for 6 hours, gives a 75% yield of 1-chloromethylnaphthalene.

  The principal value of chloromethylation lies in the ease of displacement of the benzylic chloride by nucleophiles. Conversion into the corresponding alcohols, ArCH2 OH, ethers, ArCH2 OR, nitriles, ArCH2 CN, and amines, ArCH2 NR2

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  Catalytic Asymmetric Friedel-Crafts Alkylations

  • Marco Bandini, Achille Umani-Ronchi, Marco Bandini, Achille Umani-Ronchi(Authors)
  • 2009(Publication Date)
  • Wiley-VCH

    (Publisher)

  However, if we consider, in general, the synthesis of an alkyl halide versus an alcohol, then the picture is less clear, since the alcohol may well be derived from the chloride via hydrolysis, in which case a direct FC reaction with the halide will generally be better, given similar efficiencies of the steps. A knowledge of the synthesis of the starting materials is therefore necessary before a sensible result can be obtained. In order to do this, a more complex metric is required. The ultimate metric is provided by a life cycle analysis, which looks at all the inputs (energy and chemicals) and outputs (waste) associated with a product throughout its life cycle. This includes contributions from all reagents, solvents and catalysts (and their precursors), transportation of raw materials (and their precursors), intermedi- ates and products, and the fate of the product at the end of its useful life. This makes a full life cycle analysis very complex to carry out, and few have been done rigorously. However, the approach is extremely valuable as an indication of the factors that should be considered, even where all the data is not available. A diagram of a partial life cycle assessment is shown in Figure 8.2 for a catalyst in a FC reaction. Figure 8.1 Atom economy in FC reactions of benzene as a function of alkylating agent. Figure 8.2 Partial, simplified life cycle assessment for a catalyst, indicating the main inputs and outputs which need to be quantified. E ¼ energy, C ¼ chemicals, W ¼ waste. 8.2 Green Chemistry and the Friedel–Crafts Reaction j 273 For the whole process, a similar set of diagrams would be needed for all the components. This is clearly a major undertaking for which key data may not be available. Simplified versions have therefore been developed, which allow a partial answer to be derived [15]. One of the main foci of green chemistry over the last 20 years or so has been the development of new, less polluting catalysts for chemical processes [16].

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