Favorskii Reaction
The rearrangement of cyclopropanones, often obtained as intermediates from the base-catalyzed reaction of α-halo ketones, leading to carboxylic acids and derivatives.
Mechanism of the Favorskii Reaction
Esters are obtained if alkoxide bases are used:
A direct conversion from α-halo ketones is possible:
Ring-contraction:
Finkelstein Reaction
Treatment of a primary alkyl halide or pseudohalide with an alkali metal halide (e.g. KF, KI) leads to replacement of the halogen via an SN2 Reaction.
Mechanism of the Finkelstein Reaction
The equilibrium position of the reaction depends on the nucleophilicity of the anion, whether a good leaving group is present, and whether one anion is better stabilized than the other in a given solvent (see Nucleophilic Substitution). For example, reactions with KF will thus lead cleanly to fluoroalkanes, because fluoride is such a poor leaving group due to the stability of the C-F bond.
In general, the reaction is run with an excess of the metal halide. The use of metal salts that have a high lattice energy require the addition of a crown ether (compare the reaction times for KF and CsF in the example above).
The equilibrium position of the reaction also depends on the solubility of the metal salt in the solvent used. Thus, the substitution of bromo- and chloroalkanes with KI in acetone leads cleanly to the desired iodoalkane products, since KCl and KBr are insoluble in acetone and are consequently removed from the equilibrium:
Fischer Esterification
Fischer-Speier Esterification
The Lewis or Brønstedt acid-catalyzed esterification of carboxylic acids with alcohols to give esters is a typical reaction in which the products and reactants are in equilibrium.
The equilibrium may be influenced by either removing one product from the reaction mixture (for example, removal of the water by azeotropic distillation or absorption by molecular sieves) or by employing an excess of one reactant.
Mechanism of the Fischer Esterification
Addition of a proton (e.g.: p-TsOH, H2SO4) or a Lewis acid leads to a more reactive electrophile. Nucleophilic attack of the alcohol gives a tetrahedral intermediate in which there are two equivalent hydroxyl groups. One of these hydroxyl groups is eliminated after a proton shift (tautomerism) to give water and the ester.
Alternative reactions employ coupling reagents such as DCC (Steglich Esterification), preformed esters (transesterification), carboxylic acid chlorides or anhydrides (see overview). These reactions avoid the production of water. Another pathway for the production of esters is the formation of a carboxylate anion, which then reacts as a nucleophile with an electrophile (similar reactions can be found here). Esters may also be produced by oxidations, namely by the Baeyer-Villiger oxidation and oxidative esterifications.
Fischer Indole Synthesis
The conversion of aryl hydrazones to indoles; requires elevated temperatures and the addition of Brønsted or Lewis acids. Some interesting enhancements have been published recently; for example a milder conversion when N-trifluoroacetyl enehydrazines are used as substrates. (abstract).
Mechanism of the Fischer Indole Synthesis
Fleming-Tamao Oxidation
Tamao-Kumada Oxidation
Fleming (-Tamao) Oxidation
(Fleming-) Tamao (-Kumada) Oxidation
Parallel procedures for the oxidation of silyl groups to hydroxy groups were developed by Fleming and Tamao. The conversion of a dimethylphenylsilyl group, which involves a specific reaction mechanism, was pioneered by Fleming.
Mechanism of the Fleming-Tamao Oxidation
Silyl groups, which are non-polar electropositive groups without lone pairs, tolerate many chemical reactions that would not be possible in presence of hydroxy groups. The Fleming-Tamao Oxidation permits silyl groups to be used as "masked hydroxy groups", which has found broad application in total syntheses. In addition, enantioselective hydrosilylation of alkenes followed by Fleming-Tamao oxidation allows the preparation of chiral alcohols.The first step of the Fleming Oxidation is the removal of the phenyl group in which the very stable phenylsilane group is converted into a more reactive halosilane after electrophilic aromatic substitution:
The removal may be done as separate step followed by the addition of the oxidation reagents or in one of the more convenient one-pot procedures (for an overview: I. Fleming, R. Henning, D. C. Parker, H. E. Plaut, P. E. J. Sanderson, J. Chem. Soc. Perkin Trans. 1, 1995, 317-337. DOI). The phenyl group can also be activated through bromination using excess bromine or a bromide source leading to phenyl bromide as by-product.
The displacement of the halide by peracetic acid leads to an intermediate that rearranges to give a silanol. Protic work-up gives the desired alcohol:
The Tamao Oxidation uses the more reactive fluoro- or chlorosilanes (RSiMenX(2-n)), in which the silicon is a stronger Lewis acid and shows more metallic character than the substrates used in the Fleming oxidation. Further activation by a fluoride ion then leads to a pentavalent intermediate which is able to bind hydrogen peroxide. The transition state is also stabilized through hydrogen bonding between fluorine and hydrogen:
For a computational study see: M. M. Mader, P.-O. Norrby, J. Am. Chem. Soc. 2001, 123, 1970-1976. DOI
Strained siletanes may also be used in the Tamao Oxidation instead of halosilanes; these intermediates offer a comparable Lewis acidity because coordination of the fluoride ion releases angle strain.
Lewis acidity enhanced by strain release
Friedel-Crafts Acylation
This electrophilic aromatic substitution allows the synthesis of monoacylated products from the reaction between arenes and acyl chlorides or anhydrides. The products are deactivated, and do not undergo a second substitution. Normally, a stoichiometric amount of the Lewis acid catalyst is required, because both the substrate and the product form complexes.
The Friedel-Crafts Alkylation may give polyalkylated products, so the Friedel-Crafts Acylation is a valuable alternative. The acylated products may easily be converted to the corresponding alkanes via Clemmensen Reduction or Wolff-Kishner Reduction.
Mechanism of the Friedel-Crafts Acylation
Friedel-Crafts Acylation
This electrophilic aromatic substitution allows the synthesis of monoacylated products from the reaction between arenes and acyl chlorides or anhydrides. The products are deactivated, and do not undergo a second substitution. Normally, a stoichiometric amount of the Lewis acid catalyst is required, because both the substrate and the product form complexes.
The Friedel-Crafts Alkylation may give polyalkylated products, so the Friedel-Crafts Acylation is a valuable alternative. The acylated products may easily be converted to the corresponding alkanes via Clemmensen Reduction or Wolff-Kishner Reduction.
Mechanism of the Friedel-Crafts Acylation
Friedel-Crafts Alkylation
This Lewis acid-catalyzed electrophilic aromatic substitution allows the synthesis of alkylated products via the reaction of arenes with alkyl halides or alkenes. Since alkyl substituents activate the arene substrate, polyalkylation may occur. A valuable, two-step alternative is Friedel-Crafts Acylation followed by a carbonyl reduction.
Mechanism of the Friedel-Crafts Alkylation
Using alkenes :
Fries Rearrangement
The Fries Rearrangement enables the preparation of acyl phenols.
Mechanism of the Fries Rearrangement
T he reaction is catalyzed by Brønsted or Lewis acids such as HF, AlCl3, BF3, TiCl4 or SnCl4 . The acids are used in excess of the stoichiometric amount, especially the Lewis acids, since they form complexes with both the starting materials and products.
The complex can dissociate to form an acylium ion. Depending on the solvent, an ion pair can form, and the ionic species can react with each other within the solvent cage. However, reaction with a more distant molecule is also possible:
After hydrolysis, the product is liberated.
The reaction is ortho,para-selective so that, for example, the site of acylation can be regulated by the choice of temperature. Only sterically unhindered arenes are suitable substrates, since substituents will interfere with this reaction.
The requirement for equimolar quantities of the catalyst, the corrosive and toxic conditions (HF), and the violent reaction of the catalyst with water have prompted the development of newer protocols. Zeolites have proven to be unsuitable, since they are deactivated, but strong acids, such as sulfonic acids, provide a reasonable alternative.
An additional option for inducing a Fries Rearrangement is photochemical excitation, but this method is only feasible in the laboratory:
Fukuyama Coupling
The palladium-catalyzed coupling of organozinc compounds with thioesters to form ketones. This reaction
t olerates a variety of functional groups due to the low reactivity of the organozinc reagents.
Mechanism of the Fukuyama Coupling
Oxidative addition of the thioester is followed by transmetalation from the zinc compound. Reductive elimination leads to the coupled product.
Fukuyama Reduction
The conversion of carboxylic acids to aldehydes is normally conducted in two steps by reduction of the acids or their derivatives to the corresponding alcohols followed by mild oxidation.
The Fukuyama Reduction allows the convenient and selective reduction of thioesters, which are easily prepared from the corresponding carboxylic acids, for example by the Steglich Esterification.
Mechanism of the Fukuyama Reduction
Compared to other direct reductions of carboxylic acids or carboxylic acid derivates such as using DIBAL-H or Rosenmund conditions, the Fukuyama Reduction is a mild alternative, offering outstanding functional group tolerance (see recent literature).
An initial oxidative addition of Pd(0) to the C(sp2)-S bond is followed by transmetallation of the resultant acylpalladium species with Et3SiH. Reductive elimination from the acylpalladium hydride leads to the desired aldehyde.
On the basis of this mechanism, it was surmised that substitution of Et3SiH by an appropriate organometallic reagent would provide access to ketones. Extensive screening of various transition metal catalysts and organometallic reagents have revealed suitable conditions, which are currently used in the Fukuyama-Coupling.
For a review see: T. Fukuyma, H. Tokuyama, Aldrichimica Acta 2004, 37, 87.
Friedlaender Synthesis
The starting materials for this quinoline synthesis are o-aminoaryl aldehydes or ketones and a ketone possessing an α-methylene group. After an initial amino-ketone condensation, the intermediate undergoes base- or acid-catalyzed cyclocondensation to produce a quinoline derivative.
Mechanism of the Friedlaender Synthesis
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