Aromatic ketone-Lewis acid complex

The initial step of the mechanism is the coordination of the first equivalent of the Lewis acid to the carbonyl group of the acylating agent. Next, the second equivalent of Lewis acid ionizes the initial complex to form a second donor-acceptor complex which can dissociate to an acylium ion in ionizing solvents. The typical SsAr reaction gives rise to an aromatic ketone-Lewis acid complex that has to be hydrolyzed to the desired aromatic ketone. 

Depending on the specific reaction conditions, complex 4 as well as acylium ion 5 have been identified as intermediates with a sterically demanding substituent R, and in polar solvents the acylium ion species 5 is formed preferentially. The electrophilic agent 5 reacts with the aromatic substrate, e.g. benzene 1, to give an intermediate cr-complex—the cyclohexadienyl cation 6. By loss of a proton from intermediate 6 the aromatic system is restored, and an arylketone is formed that is coordinated with the carbonyl oxygen to the Lewis acid. Since a Lewis-acid molecule that is coordinated to a product molecule is no longer available to catalyze the acylation reaction, the catalyst has to be employed in equimolar quantity. The product-Lewis acid complex 7 has to be cleaved by a hydrolytic workup in order to isolate the pure aryl ketone 3. 

A unique method to generate the pyridine ring employed a transition metal-mediated 6-endo-dig cyclization of A-propargylamine derivative 120. The reaction proceeds in 5-12 h with yields of 22-74%. Gold (HI) salts are required to catalyze the reaction, but copper salts are sufficient with reactive ketones. A proposed reaction mechanism involves activation of the alkyne by transition metal complexation. This lowers the activation energy for the enamine addition to the alkyne that generates 121. The transition metal also behaves as a Lewis acid and facilitates formation of 120 from 118 and 119. Subsequent aromatization of 121 affords pyridine 122. 

Si. rra(pentafluorophenyl)boron was found to be an efficient, air-stable, and water-tolerant Lewis-acid catalyst for the allylation reaction of allylsilanes with aldehydes.167 Sc(OTf)3-catalyzed allylations of hydrates of a-keto aldehydes, glyoxylates and activated aromatic aldehydes with allyltrimethylsilane in H2O-CH3CN were examined. a-Keto and a-ester homoallylic alcohols and aromatic homoallylic alcohols were obtained in good to excellent yields.168 Allylation reactions of carbonyl compounds such as aldehydes and reactive ketones using allyltrimethoxysilane in aqueous media proceeded smoothly in the presence of 5 mol% of a CdF2-terpyridine complex (Eq. 8.71).169... 

A considerable difference between Friedel-Crafts alkylation and acylation is the amount of the Lewis acid necessary to induce the reaction. Friedel-Crafts alkylation requires the use of only catalytic amounts of the catalyst. Lewis acids, however, form complexes with the aromatic ketones, the products in Friedel-Crafts acylations, and the catalyst is thus continuously removed from the system as the reaction proceeds. To achieve complete conversion, therefore, it is necessary to use an equimolar amount of Lewis acid catalyst when the acylating agent is an acyl halide. Optimum yields can be obtained using a 1.1 molar excess of the catalyst. With... 

The above reactions in this section have been examples of addition alone or addition followed by elimination. Ligand reactions involving nucleophilic substitution are also known and these are of the dealkylation type. Lewis acids such as aluminum chloride or tin(IV) chloride have been used for many years in the selective demethylation of aromatic methyl ethers, where chelation is involved (Scheme 27). Similar cleavage of thioethers, specially using mercury(II) salts, is commonly used to remove thioacetal functions masking ketones (equation 27).104 In some cases, reactions of metal ions with thioether ligands result in isolation of complexes of the dealkylated organic moiety (equations 28 and 29).105-107... 

Aldehydes and ketones react with aromatic compounds in the presence of Bransted or Lewis acids. The actual electrophile is the carboxonium ion formed in an equilibrium reaction by protonation or complexation, respectively. The primary product is a substituted benzyl alcohol, which, however, is not stable and easily forms a benzyl cation. The latter continues to react further, either via an SN1 or an El reaction. Thereby, the following overall functionalizations are realized Ar—H —> Ar—C-Nu or Ar—H — Ar—C=C. 

Against this background it is important that—quite fitting in this still new millennium— the first catalytic Friedel-Crafts acylations of (still relatively electron-rich) aromatic compounds were reported (Figure 5.35). Trifluoromethane sulfonates ( triflates ) of rare-earth metals, e. g., scandium(III)triflate, accomplish Friedel-Crafts acylations with amounts of as little as 1 mole percent. Something similar is true of the tris(trifluoromethanesulfonyl)-methides ( triflides ) of rare-earth metals. Unlike conventional Lewis acids, the cited rare-earth metal salts can form 1 1 complexes with the ketone produced, but these are so unstable that the Lewis acid can re-enter the reaction. Whether this works analogously for the third catalytic system of Figure 5.35 is unclear. 

When R-C O+ is used as the electrophile a ketone is produced If an aldehyde were wanted, H-C=0+ would have to be used but it cannot be made from HCOC1 because that is unstable. Instead, it can be generated by passing carbon monoxide and hydrogen chloride through a mixture of the aromatic hydrocarbon, a Lewis acid, and a co-catalyst, usually copper (I) chloride. Copper (I) chloride is known to form a complex with carbon monoxide and this probably speeds up the proto-nation step. 

It is well known that Friedel-Crafts acylation of aromatic compounds requires more than one equivalent of a Lewis acid relative to the substrate to bring the reaction to the completion, because the ketone produced deactivates the Lewis acid by complexation. Despite this, only 1 mol % TiCl(OTf)3 and 10 mol % TfOH in di-chloromethane or acetonitrile proved sufficient for the acylation shown in Eq. (175) this is, therefore, a catalytic Friedel-Crafts reaction [434]. The high regioselectivity obtained is also useful. 

The concept of in situ protection of the less hindered or more Lewis basic of two ketones to enable selective reduction of the usually less reactive groups has been successfully developed. The sterically hindered Lewis acid MAD (78) derived from BHT and trimethyl aluminum was used to coordinate preferentially to the less hindered ketone and DIBAL-H reduced the more hindered ketone that remained un-complexed. An approximate order of comparative reactivity for various classes of ketones has been established. The selectivity was improved by using the more hindered Lewis acid MAB (79) and/or di-bromoalane as the reducing agent. The discrimination between aromatic ketones is good but less successful between two dialkyl ketones. The chemoselectivity was demonstrated in the reduction of diketone (80) to keto alcohol (81) in 87% yield and excellent selectivity (equation 20). 

Carbonyl groups form complexes or intermediates with Lewis acids like AICI3, BF3, and SnCl4. For example, in the Friedel-Crafts acylation reaction in nonpolar solvents, an aluminum chloride complex of an acid chloride is often the acylating agent. Because of the basicity of ketones, the products of the acylation reaction are also complexes. For more detail on electrophilic aromatic substitution, see Section 7. 

Phenol-ketone novolacs 1487, 1488 Phenol-nitrile complexes 377 Phenol radical cations 1101 fragmentation of 289-291 Phenols—see also Biphenols, Bis-phenols, Hydroxybenzenes, Polyphenols acidities of, gas-phase 310-312 acylation of 629-632, 933, 934 Lewis acid catalyzed 631 montmoriUonite-catalyzed 632 pyridine-catalyzed 631 adsorption of 944 alkylation of 606-629, 941 Brdnsted acid catalyzed 612 Lewis acid catalyzed 607-611 solid acid catalyzed 612-621 stereoselective 621-626 under supercritical conditions 621 as antioxidants 139-143, 840-901 ort/io-substituted 845 thermochemistry of 139, 140, 179 autoxidation of 1118, 1119 bromination of 649-651 jr-cation interaction of 322 chlorination of 649 comparison with isoelectronic methyl, amino and fluoro aromatic derivatives 226... 

But-3-enyltrimethylsilanes undergo cyclodesilylation to give cyclopropanes 7 on reaction with acid chlorides activated by a Lewis acid. Titanium(IV) chloride was found to be the most effective activator of the Lewis acids studied. No reaction was observed for boron trifluoride-diethyl ether complex, zinc(II) chloride and iron(III) chloride. A variety of aliphatic, aromatic and alkenoyl chlorides were successfully utilized affording the corresponding cyclo-propylmethyl ketones in fairly good yields. It has been verified that the j8-chloro ketones 9 are secondary reaction products derived from the cyclopropyl ketones 7. The formation of these chloro ketones can be avoided by performing the reaction at low temperature. 

Another well known example of successful application of Beta zeolite is the substitution of AICI3 for Friedel-Crafts acylation. This reaction is an important industrial process, used for the preparation of various pharmaceuticals, agrochemicals and other chemical products, since it allows us to form a new carbon-carbon bond onto an aromatic ring. Friedel-Crafts acylations generally require more than one equivalent of for example, AICI3 or BF3. This is due to the strong complexation of the Lewis acid by the ketone product. 

The alkylation of aromatic compounds using alkyl halides and a Lewis acid only requires a small amount of catalyst. Because Lewis acids form complexes with carbonyl compounds, the Lewis acids are effectively removed from the reagent system to the extent that product is formed. Although an equilibrium exists between the product complex and free Lewis acid, there is an apparent inhibition of formation of the acylating species. The net effect is that the amount of the ketone that is formed is normally proportional to the molar quantity of catalyst added. In reactions using acyl halides, completion occurs when slightly more than 1 mol of catalyst is used. When using a carboxylic anhydride, an excess over 2 mol of catalyst will usually be required because the other product, a carboxylic acid, will also complex with the Lewis acid. 

The conventional method for preparation of these aromatic ketones involves reaction of the aromatic hydrocarbon with a carboxylic acid derivative in the presence of a Lewis acid (AICI3, FeClj, BF3, ZnCl2, TiCy or Brpnsted acids (poly-phosphoric acid, FIF). The major drawback of the Friedel-Crafts reaction is the need to use a stoichiometric quantity of Lewis acid relative to the ketone formed. This stoichiometric quantity is required because the ketone (product of the reaction) forms a stable stoichiometric complex with the Lewis acid. The decomposition of this complex is generally performed with water, leading to total destruction and loss of the Lewis acid. 

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