Friedel Crafts Acylation

12 Key excerpts on "Friedel Crafts Acylation"

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  Hydrocarbon Chemistry

  • George A. Olah, Arpad Molnar, G. K. Surya Prakash(Authors)
  • 2017(Publication Date)
  • Wiley

    (Publisher)

  8 Acylation

  The acylation of aromatic hydrocarbons was first described by Friedel and Crafts in 1877.1 Since then the reaction has been widely and thoroughly studied. It is one of the most important reactions in synthetic organic chemistry and a widely applied method to prepare aromatic ketones. It is also of considerable practical significance in the chemical industry2 since the products are intermediates in the manufacture of fine chemicals and other intermediates. Related topics, which include the Hueben–Hoesch reaction and aldehyde synthesis (formylation of aromatics), and the acylation of aliphatic compounds, in contrast, are less important, and consequently, will be treated accordingly. The acylation of aromatic2 – 10 and aliphatic compounds10–13 and the related processes10,14–18 are covered in reviews, and discussions of acylations can be found in other review papers about the use of homogeneous and heterogeneous electrophilic catalysts.19,20

  8.1 Acylation of Aromatics

  8.1.1 General Characteristics

  Friedel–Crafts acylation is an electrophilic aromatic substitution to afford ketones by replacing one of the hydrogens of an aromatic ring. Carboxylic acid derivatives, characteristically acid halides and anhydrides, serve as acylating agents, and Lewis acid metal halides are the characteristic catalysts required to induce the transformation. Esters, in general, are not satisfactory reagents since they give both alkyl- and acyl-substituted products.

  In Friedel–Crafts acylation of aromatics with acid chlorides and Lewis acid metal halides, the reactive electrophile is considered to be formed in the interaction of the reagent and the catalyst. First the highly polarized donor–acceptor complex 1 is formed, which can further give other complexes and ion pairs.21 The various possible intermediates are depicted in Scheme 8.1 . Spectroscopic and kinetic data show the presence of these species in the reaction mixture. The scheme includes acyl cation 2, which is usually regarded as the reacting species in aromatic Friedel–Crafts acylations and forms the σ complex upon interacting with the aromatic compound.6,22,23

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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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  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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  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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  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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  Comprehensive Organic Chemistry Experiments for the Laboratory Classroom

  • Carlos A M Afonso, Nuno R Candeias, Dulce Pereira Simão, Alexandre F Trindade, Jaime A S Coelho, Bin Tan, Robert Franzén, Carlos A M Afonso, Nuno R Candeias, Dulce Pereira Simão, Alexandre F Trindade, Jaime A S Coelho, Bin Tan, Robert Franzén(Authors)
  • 2020(Publication Date)
  • Royal Society of Chemistry

    (Publisher)

  This mechanism has two steps: attack by an electrophile on the aromatic ring to give a cationic nonaromatic intermediate known as an arenium ion followed by loss of a proton from the cation to restore the aromaticity. A Friedel–Crafts alkylation is an example of electrophilic aromatic substitution 1 – 4 where the electrophile is a carbocation, which usually is produced by reaction with an alkyl halide in the presence of a Lewis acid (catalyst), with aluminum chloride the most common catalyst. 5 A tertiary alcohol can be used instead of an alkyl halide, in the presence of a strong acid (sulfuric acid). 6 In this experiment the electrophile is a stable tertiary butyl cation generated by treating a tertiary alcohol (t -butyl alcohol) with sulfuric acid. The Friedel–Crafts alkylations only occur if the aromatic ring is either unsubstituted or has activating substituents. Another limitation of this reaction is the formation of side products through polyaklylation, since the product is more reactive than the starting material, which leads to lower yields. 1 – 4 In this experiment, the starting material is an aromatic ring activated by two methoxy groups, which will react with the tertiary butyl cation to result in the dialkylated aromatic ether 1,4-di- t -butyl-2,5-dimethoxybenzene. Additional Safety The use of a fume hood is not mandatory. However, fuming sulfuric acid is highly corrosive and reacts violently with water and it must be handled inside the hood. Wear appropriate protective eyeglasses and gloves to prevent skin exposure

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  Stereoselective Organocatalysis

  Bond Formation Methodologies and Activation Modes

  • Ramon Rios Torres(Author)
  • 2013(Publication Date)
  • Wiley

    (Publisher)

  Chapter 9 Other Reactions for C–C Bond Formation

  9.1 Friedel–Crafts Alkylation Reactions

  9.1.1 Introduction

  The asymmetric Friedel–Crafts alkylation (FCA) is one of the most powerful organic transformations to synthesize optically active aromatic compounds bearing chiral benzylic carbon centers. Since the first example of organocatalytic FCA reaction reported in 2001, continuous interest in this area has resulted in the development of many effective transformations and publications. It's worthy to note that a few important reviews and books have appeared in the literature [1]. This chapter aims to review the progress in the last decade and is organized on the base of different alkylation reagents employed.

  9.1.2 Reactions with Alkenes

  9.1.2.1 α, β-Unsaturated Aldehydes

  In 2001, Macmillan and co-workers reported the first example of the FCA reaction with α,β-unsaturated aldehydes as electrophiles catalyzed by the trifluoroacetic acid salt of (L )-phenylalanine-derived chiral imidazolidione 1 . Based on the LUMO-lowering activation strategy by reversible formation of iminium salts with the catalyst, good yields and enantioselectivities were observed when the reaction of pyrroles with α,β-unsaturated aldehydes took place in the presence of 20 mol% catalyst (Eq. (a), Scheme 9.1 ) [2]. The scope of this reaction was successfully expanded to indoles and aniline derivatives (Eqs. (b) and (c), Scheme 9.1 ) [3]. Subsequently, Xiao and co-workers [4] demonstrated an intramolecular reaction of indoles with α,β-unsaturated aldehydes for the construction of polycyclic indoles catalyzed by 2 and 3,5-dinitrobenzoic acid (Scheme 9.2 ). They further introduced (E )-dialkyl-3-oxoprop-1-enylphosphonates to the FCA reaction and indole alkylations furnished in good enantioselectivities using 20 mol% of 2

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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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  Advances in Friedel-Crafts Acylation Reactions

  Catalytic and Green Processes

  • Giovanni Sartori, Raimondo Maggi(Authors)
  • 2009(Publication Date)
  • CRC Press

    (Publisher)

  155 5 chapter Direct phenol acylation The Fries rearrangement The direct acylation of phenols represents an ex‑ tremely complex reaction. Phenol is a typical ambi‑ dental system and reacts with acylating reagents in the presence of convenient homogeneous or hetero‑ geneous catalysts to give esters by O‑acylation as well as ketones by C‑acylation of the aromatic ring. Furthermore, phenyl esters can undergo the Fries rearrangement, complicating the entire process. The O‑acylation process is much more rapid than the C‑acylation one and, in general, the ortho ‑hydroxyaryl ketones are prevalent with respect to para‑isomers. 1 This is probably due to the ortho‑directing effect of the OH group, which can stabilize by hydrogen bond the transition state leading to the ortho attack (Scheme 5.1) in a way resembling thecomplex‑induced proximity effect (CIPE). 2 The production of aromatic hydroxyketones can also be performed by the Fries rearrangement; in this case, the mode of para‑acylation is probably different from that of ortho‑acylation. Indeed, the ortho‑isomer is a primary product, whereas the para‑isomer seems to be a secondary product. Of course, other methods for OH R + HX O O H R O H O H R X O X R = alkyl, aryl X = Cl, OCOR, OH Scheme 5.1 156 Advances in Friedel–Crafts acylation reactions the formation of ortho ‑hydroxyaryl ketones can result from the acylation of phenols with phenyl esters, which are better acylating agents than carboxylic acids. Results from the literature suggest that direct phenol acylation and the Fries rearrangement are frequently competitive processes and difficult to characterize by the mechanistic point of view. Consequently, in Section 5.1, we include the synthetic process where the phenol substrate, the acylating agent, and the catalyst are mixed together in the starting reaction mixture aside from the specific reaction mechanism, whereas in Section 5.2 we include reactions involv‑ ing phenyl esters.

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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)

  Scheme 5.9 ).28 In the postulated mechanism, indole 6a is added to the activated nitroalkene 1 which is also the enantioselectivity-determining step to form the aci -nitro complex. This aci -nitro complex 8 reacts with nitroalkene 1 , eliminates the aci -nitro ligand and rearranges to the Friedel–Crafts adduct 7a with the regeneration of catalyst C1 .

  SCHEME 5.9 Asymmetric Friedel–Crafts alkylation of indoles with nitroalkenes catalyzed by Rh-aqua complex catalyst system.

  Zhang reported enantioselective Friedel–Crafts reaction of indoles 9 with nitroalkenes 1 catalyzed by an air-stable, well-defined Cu/Eu/Cu heterotrimetallic complex L8a , which is based on a salen-type ligand L8 .29 The corresponding products 10 were obtained in excellent yields and enantioselectivities (Scheme 5.10 ). The possible mechanism involves a unique cooperative triple activation of the substrate, wherein one of the square planar Cu(II) centers initially bind to the indole and then the central unsaturated Eu(III) site coordinate to the nitroalkene 1 , which further interacts with another Cu(II) center by the nucleophilic oxygen atom and allows the substrate to undergo alkylation.

  SCHEME 5.10 Asymmetric Friedel–Crafts alkylation of indoles with nitroalkenes catalyzed by trinuclear Cu/Eu/Cu complex.

  The enantioselective Friedel–Crafts fluoroalkylation of indoles 4 by employing chiral phosphoric acid C3 has been described by Lin and Xiao (Scheme 5.11 ).30 Chiral phosphoric acid C3 assists the reaction as a bifunctional catalyst and activates the nucleophile as well as the electrophile by hydrogen bonding. It was found that the absence of a hydrogen atom on the nitrogen atom or the presence of a methyl group at the 2-position of indole 4

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  Best Synthetic Methods: Acetylenes, Allenes and Cumulenes

  • Lambert Brandsma(Author)
  • 2003(Publication Date)
  • Academic Press

    (Publisher)

  6 Carboxylation, Acylation and Related Reactions 6.1 INTRODUCTION Acetylenic derivatives in which the triple bond is conjugated with a C ¼ O group are versatile intermediates in organic synthesis, especially in cycloaddition reactions [1]. A number of these systems have been prepared by transformation of other functional groups. Acetylenic aldehydes, R 1 C CCH ¼ O, for example, can be obtained by acid hydrolysis of acetylenic acetals, R 1 C CCH(OR 2 ) 2 , which, in their turn, are accessible from acetylenic Grignard reagents, R 1 C CMgBr, and trialkoxymethanes, HC(OR 2 ) 3 . Acetylenic ketones, R 1 C CCOR 2 , are formed by oxidation of the alcohols, R 1 C CCH(OH)R 2 , with chromic acid [2]. In most cases, however, the C ¼ O function can be intro-duced in a direct manner and this chapter gives several excellent procedures. These generally use an organic solvent. Tetrahydrofuran and diethyl ether are the most favoured ones, the former often being preferred for reasons of solu-bility. While the use of strongly polar solvents such as DMSO and HMPT, does not offer special advantages – the acylation and carboxylation reactions proceed at a convenient rate in THF or Et 2 O – it could give rise to difficulties in the purification of the desired compounds. Liquid ammonia is generally unsuitable due to the ammonia-sensitivity of the functionalisation reagent or of the product. For most derivatisations of acetylides Li þ is preferred to Na þ , K þ or XMg þ as a counter ion, mainly because of a better solubility of the acetylide. The general experience is that lithium compounds react more satis-factorily than do the Grignard derivatives. For data on carboxylations, acylations and related reactions of acetyle-nic $ allenic carbanionic species and on their regiochemistry the reader is referred to the reviews [3–8]. A number of reactions with heterocumulenes is summarised in Table 6.1. 135

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