Keto-enol/enolate equilibria in the N-acetylamino-p-methylacetophenone system. Effect of a beta-nitrogen substituent

The cis-enol of N-acetylamino-p-methylacetophenone was generated flash photolytically and its rates of ketonization in aqueous HClO(4) and NaOH solutions as well as in HCO(2)H, CH(3)CO(2)H, H(2)PO(4)(-), (CH(2)OH)(3)CNH(3)(+), and NH(4)(+) buffers were measured. Rates of enolization of N-acetylamino-p-methylacetophenone to the cis-enol were also measured by hydrogen exchange of its methylene protons, and combination of the enolization and ketonization data gave the keto-enol equilibrium constant pK(E) = 5.33, the acidity constant of the enol ionizing as an oxygen acid pQ(a)(E)= 9.12, and the acidity constant of the ketone ionizing as a carbon acid pQ(a)(K)= 14.45. Comparison of these results with corresponding values for p-methylacetophenone itself shows that the N-acetylamino substituent raises all three of these equilibrium constants: K(E) by 3 orders of magnitude, Q(a)(E) by 1 order of magnitude, and Q(a)(K)by 4 orders of magnitude. This substituent also retards the rate of H+ catalyzed enol ketonization by 4 orders of magnitude. The origins of these substituent effects are discussed.     

Generation of the enol of methyl mandelate by flash photolysis of methyl phenyldiazoacetate in aqueous solution and study of rates of ketonization of this enol in that medium

Flash photolysis of methyl phenyldiazoacetate in aqueous solution produced phenylcarbomethoxycarbene, whose hydration generated a short-lived transient species that was identified as the enol isomer of methyl mandelate. This assignment is supported by the shape of the rate profile for decay of the enol transient, through ketonization to its carbonyl isomer, as well as by solvent isotope effects and the form of acid-base catalysis of the ketonization reaction. Comparison of the present results with previously published information on the enol of mandelic acid shows some interesting and readily understandable similarities and differences.     

Comparison of oxygen and sulfur effects on keto-enol chemistry in benzolactone systems: benzo[b]-2,3-dihydrofuran-2-one and -2-thione and benzo[b]-2,3-dihydrothiophene-2-one and -2-thione

Carbon-acid ionization constants, Q(K)(a)(concentration quotient at ionic strength = 0.10 M), were determined by spectrophotometric titration in aqueous solution for benzo[b]-2,3-dihydrofuran-2-one (3, pQ(K)(a) = 11.87), benzo[b]-2,3-dihydrothiophene-2-one (2, pQ(K)(a) = 8.85), and benzo[b]-2,3-dihydrofuran-2-thione (1, pQ(K)(a) = 2.81). Rates of approach to keto-enol equilibrium were also measured for the latter two substrates in perchloric acid, sodium hydroxide, and buffer solutions, and the rate profiles constructed from these data gave the ionization constants of the enols ionizing as oxygen or sulfur acids pQ(E)(a) = 5.23 for 2 and pQ(E)(a) = 2.69 for 1. Combination of these acidity constants with the carbon-acid ionization constants according to the relationship Q(K)(a)/Q(E)(a) = K(E) then gave the keto-enol equilibrium constants pK(E) = 3.62 for 2 and pK(E) = 0.12 for 1. The fourth, all-sulfur, member of this series, benzo[b]-2,3-dihydrothiophene-2-thione (4), proved to exist solely as the enol in aqueous solution, and only the enol ionization constant pQ(E)(a) = 3.44 could be determined for this substance; the limits pK(E) < 1.3 and pQ(K)(a) < 2.1, however, could be set. The unusually high acidities and enol contents of these substances are discussed, as are also the relative values of the ketonization and enolization rate constants measured; in the latter cases, Marcus rate theory is used to determine intrinsic kinetic reactivities, free of thermodynamic effects.     

Keto-enol/enolate equilibria in the isochroman-4-one system. Effect of a beta-oxygen substituent.

The enol of 1-tetralone was generated flash photolytically, and rates of its ketonization were measured in aqueous HClO4 and NaOH solutions as well as in CH3CO2H, H2PO4(-), (CH2OH)3CNH3(+), and NH4(+) buffers. The enol of isochroman-4-one was also generated, by hydrolysis of its potassium salt and trimethylsilyl ether, and rates of its ketonization were measured in aqueous HClO4 and NaOH. Rates of enolization of the two ketones were measured as well. Combination of the enolization and ketonization data for isochroman-4-one gave the keto-enol equilibrium constant pK(E) = 5.26, the acidity constant of the enol ionizing as an oxygen acid p = 10.14, and the acidity constant of the ketone ionizing as a carbon acid p = 15.40. Comparison of these results with those for 1-tetralone shows that the beta-oxygen substituent in isochroman-4-one raises all three of these constants: K(E) by 2 orders of magnitude, by not quite 1 order of magnitude, and by nearly 3 orders of magnitude. The beta-oxygen substituent also retards the rate of hydronium-ion-catalyzed ketonization by more than 3 orders of magnitude. The origins of these substituent effects are discussed.     

Ketonization of the remarkably strongly acidic elongated enol generated by flash photolytic decarboxylation of p-benzoylphenylacetic acid in aqueous solution

Photodecarboxylation of p-benzoylphenylacetic acid in aqueous solution produces the elongated enol 5, whose strength as an oxygen acid (pQ(E/a)= 7.67) makes it more acidic than simple enol analogs by several orders of magnitude.     

The first example of isomeric solid amide and its enol

[Structure: see text] The first example of a crystalline amide and its tautomeric enol was obtained for the amide MeNHCSCH(CN)CONHMe (8) and its enol MeNHCSC(CN)=C(OH)NHMe (9). Their X-ray structures were determined, and their structural features resemble those of other related amides and enols. No other example of a similar pair was obtained. In solution, both 8 and 9 and a small percentage of the isomeric enol of thioamide MeNHCOC(CN)=C(SH)NHMe (10) were obtained in solvent-dependent compositions, which are rapidly established.     

Reactions of enols of amides with diazomethane

The reaction of 10 carboxamides activated by two beta-electron-withdrawing groups, which mostly exist completely or partially in their enol forms, with diazomethane was investigated. The main outcome is the diversity of reactions observed. With the most acidic enols 3-7, activated by at least one trifluoroethoxycarbonyl group or a cyano group, O-methylation or O,N-dimethylation takes place. With beta-dimethoxycarbonyl-activated systems 5 and 8, the C-methylation product of the amide form was one of the products. With a Meldrum's acid anilide enol 2, a cleavage took place leading to the C-alkylated imine having a CH(CO(2)Me)(2) group. Exchange of one 2,2,2-trifluoroethoxycarbonyl by a methoxycarbonyl in the C,N-dimethylation product of Me(2)CHNHC(OH)[double bond]C(CO(2)CH(2)CF(3))(2) 4 took place. The 2-anilido-1,3-cyclopentanedione 10 was methylated on a ring carbonyl while the enol of the 1,3-indanedione analogue 11 reacted with three diazomethane molecules and underwent a ring expansion and O-methylation to the 3-anilido-1,4-dimethoxynaphthalene. It is suggested that the reaction initiates by protonation of the diazomethane by the enol and an approximate qualitative relationship exists between the acidity of the enol and K(enol) and the regioselectivity of the reaction.     

Carbonylverbindungen als Kohlenstoffsäuren

Proton transfer to carbon bases (enols) and from carbon acids (ketones) determines the rate of ketonization and enolization reactions, respectively. Kinetic studies performed over the last two decades have provided absolute rate constants and reliable equilibrium constants for a broad range of prototropic reactions. Structure-reactivity and free energy relationships now form a reliable framework to predict the reactivity of the transient species involved in these fundamental reactions. Comparison of reaction rates in aqueous solution with rates achieved by enzymes reveals the striking efficiency of the latter.     

The photo-Nazarov cyclisation of 1-cyclohexenyl-phenyl-methanone revisited: II: Reaction between primary and secondary key intermediates

Trans-1-cyclohexenyl-phenyl-methanone (2) and enol 4, both key intermediates in the title reaction, react with each other in a Michael-type addition to form predominantly enol 10. This enol, kinetically stable but too reactive to be isolated, reveals its presence in the irradiated solutions by formation of the isomeric ketone 11 on acid catalysis, and by formation of the oxidation product 9 on exposure to atmospheric oxygen. In the absence of acid, formation of 10 competes significantly with the title reaction of cis-1-cyclohexenyl-phenyl-methanone (1). In a secondary photoreaction of 10, 1,6-hydrogen abstraction by the excited carbonyl group and cyclisation afford 13 and 14. Enols 4, 10, and 13, in striking contrast to enol ethers and to thermodynamically stable enols, are unstable towards atmospheric oxygen. Thus, 4 autoxidises to form five compounds (Ox-1 through Ox-5), 10 to form 9, and 13 to form 15.     

The keto-enol tautomerization of ethyl butylryl acetate studied by LC-NMR

The keto-enol tautomerism of ethyl butylryl acetate was studied in mixed solvents under a variety of experimental conditions. The direct measurement of ketonization of the enol tautomer was performed by using the hyphenated technique LC-NMR. The keto and enol tautomers can be separated by using HPLC and their interconversion is a slow process on the NMR timescale. The ketonization reaction was found to be acid catalyzed and the solvent isotope effect, kH2O/kD2O, in an acetonitrile/water mixture, is 5.4. The ketonization rate constants were also measured at different compositions of binary solvents, such as CH3CN/D2O, CD3OD/D2O, and CH3CN/CD3OD. The rate constant and water percentage were found to have an exponential relationship. The reaction rate as a function of solvent polarity will be discussed in this paper.     

Chemoselective reduction of aldehydes and ketones by potassium diisobutyl-t-butoxy aluminum hydride (PDBBA)

t-Butoxy derivatives of DIBALH [lithium diisobutyl-t-butoxyaluminum hydride (LDBBA), sodium diisobutyl-t-butoxyaluminum hydride (SDBBA), and potassium diisobutyl-t-butoxyaluminum hydride (PDBBA)] were examined as chemoselective reducing agents of carbonyl compounds. Among them, PDBBA was found to be the most efficient for the reduction of aldehydes and ketones to the corresponding alcohols in the presence of ester, amide, and nitrile substituents at ambient temperature. In addition, the optimal conditions gave higher chemoselectivity for aldehydes in the presence of ketones.     

Enols of amides. The effect of fluorine substituents in the ester groups of dicarboalkoxyanilidomethanes on the enol/amide and E-enol/Z-enol ratios. A multinuclei NMR study.

Condensation of phenyl isocyanate substituted by 4-MeO, 4-Me, 4-H, 4-Br, and 2,4-(MeO)(2) with esters CH(2)(CO(2)R)CO(2)R', R = CH(2)CF(3), R' = CH(3), CH(2)CF(3), CH(CF(3))(2), or R = CH(3), R' = CH(CF(3))(2) gave 17 "amides" ArNHCOCH(CO(2)R)CO(2)R' containing three, six, or nine fluorines in the ester groups. X-ray crystallography of six of them revealed that compounds with > or =6 fluorine atoms exist in the solid state as the enols of amides ArNHC(OH)=C(CO(2)R)CO(2)R' whereas the ester with R = R' = CH(3) was shown previously to have the amide structure. In the solid enols, the OH is cis and hydrogen bonded to the better electron-donating (i.e., with fewer fluorine atoms) ester group. X-ray diffraction could not be obtained for compounds with only three fluorine atoms, i.e., R = CH(2)CF(3), R' = CH(3) but the (13)C CP-MAS spectra indicate that they have the amide structure in the solid state, whereas esters with six and nine fluorine atoms display spectra assigned to the enols. The solid enols show unsymmetrical hydrogen bonds and the expected features of push-pull alkenes, e.g., long C(alpha)=C(beta) bonds. The structure in solution depends on the number of fluorine atoms and the solvent, but only slightly on the substituents. The symmetrical systems (R = R' = CH(2)CF(3)) show signals for the amide and the enol, but all systems with R not equal R' displayed signals for the amide and for two enols, presumably the E- and Z-isomers. The [Enol I]/[Enol II] ratio is 1.6-2.9 when R = CH(2)CF(3), R' = CH(3), CH(CF(3))(2) and 4.5-5.3 when R = CH(3), R' = CH(CF(3))(2). The most abundant enol display a lower field delta(OH) and a higher field delta(NH) and assigned the E-structure with a stronger O-H.O=C(OR) hydrogen bond than in the Z-isomer. delta(OH) and delta(NH) values are nearly the same for all systems with the same cis CO(2)R group. The [Enols]/[Amide] ratio in various solvents follows the order CCl(4) > CDCl(3) > CD(3)CN > DMSO-d(6). The enols always predominate in CCl(4) and the amide is the exclusive isomer in DMSO-d(6) and the major one in CD(3)CN. In CDCl(3) the major tautomer depends on the number of fluorines. For example, in CDCl(3,) for Ar = Ph, the % enol (K(Enol)) is 35% (0.54) for R = CH(2)CF(3,) R' = CH(3), 87% (6.7) for R = R' = CH(2)CF(3), 79% (3.8) for R = CH(3), R' = CH(CF(3))(2) and 100% (> or =50) for R = CH(2)CF(3), R' = CH(CF(3))(2). (17)O and (15)N NMR spectra measured for nine of the enols are consistent with the suggested assignments. The data indicate the importance of electron withdrawal at C(beta), of intramolecular hydrogen bonding, and of low polarity solvents in stabilizing the enols. The enols of amides should no longer be regarded as esoteric species.     

The 2-oxocyclohexanecarboxylic acid keto-enol system in aqueous solution

Flash photolysis of 2-diazocycloheptane-1,3-dione or 2,2-dimethyl-5,6,7,8-tetrahydrobenzo-4H-1,3-dioxin-4-one in aqueous solution produced 2-oxocyclohexylideneketene, which underwent hydration to the enol of 2-oxocyclohexanecarboxylic acid, and the enol then isomerized to the keto form of the acid. Isomerization of the enol to keto forms was also observed using solid enol, a substance heretofore commonly believed to be the keto acid. Rates of ketonization were measured in perchloric acid, sodium hydroxide, and buffer solutions, and a ketonization rate profile was constructed. Rates of enolization of the keto acid were also measured using bromine to scavenge the enol as it formed. Rates of enolization and ketonization were then combined to provide the keto-enol equilibrium constant pK(E) = 1.27. This and some of the other results obtained are different from the corresponding quantities for the 2-oxocyclopentanecarboxylic acid keto-enol system. These differences are discussed.     

Cyano-, nitro-, and alkoxycarbonyl-activated observable stable enols of carboxylic acid amides

A search for the enol structures of several amides YY'CHCONHPh with Y,Y' = electron-withdrawing groups (EWGs) was conducted. When Y = CN, Y' = CO(2)Me the solid structure is that of the enol (8b) MeO(2)CC(CN)=C(OH)NHPh, whereas in solution the NMR spectrum indicate the presence of both the amide MeO(2)CCH(CN)CONHPh (8a) and 8b. When Y = NO(2), Y' = CO(2)Et the main compound in CDCl(3) is the amide, but <10% of enol(s), presumably EtO(2)CC(NO(2))=C(OH)NHPh (9b), are also present. When Y = COEt, Y' = CO(2)Me or Y = COMe, Y' = CO(2)Et (10 and 11) enolization in solution and of 11 also in the solid state occurs at the carbonyl rather than at the ester site. With Y = Y' = CN a rapid exchange between the amide (NC)(2)CHCONHPh (12a) and a tautomer, presumably the enol, take place in several solvents on the NMR time scale. With YY' = barbituric acid moiety the species in DMSO-d(6) is an enol of an amide although which CONH group enolizes is unknown. B3LYP/6-31G calculations showed that the enol (NC)(2)C=C(OH)NH(2) (13b) is more stable by DeltaG of 0.4 kcal/mol than (NC)(2)CHCONH(2) (13a) due to a combination of stabilization of 13b and destabilization of 13a and both are much more stable than the hydroxyimine and ketene imine tautomers. The effect of Y,Y' and the solvent on the relative stabilization of enols of amides is discussed.     

Retro‐Corey‐Chaykovsky Epoxidation: Converting Geminal Disubstituted Epoxides to Ketones

Corey‐Chaykovsky epoxidation has been widely applied in the conversion of aldehydes and ketones to epoxides with sulfonium and sulfoxonium ylides. The reverse transformation is realized for conversion of geminal disubstituted epoxides to ketones in the presence of DABCO in refluxing mesitylene. The method is a weak basic transformation from epoxides to ketones with loss of a methylene group and can be applied as an alternative strategy of the acid‐catalyzed Meinwald rearrangement or oxidation for conversion of epoxides to carbonyl compounds.     

Chemistry of α-halometalcompounds : A general method for obtaining epoxides from aldehydes and ketones

A general oxirane synthesis from a geminal dibromide and a carbonyl compound was studied. The reaction proceeds through an α-bromolithium species, most conveniently generated by reacting a geminal dihalogenide (e.g. ethylidene, isopropylidene, benzylidene bromide and ethyl dibromoacetate) and butyllitium or lithium suspended in THF. Aliphatic, alicyclic and aromatic aldehydes and ketones give rise to the corresponding epoxides, in good yields.     

The 2-oxocyclobutanecarboxylic acid keto-enol system in aqueous solution: a remarkable acid-strengthening effect of the cyclobutane ring

Flash photolysis of 2-diazocyclopentane-1,3-dione in aqueous solution produced 2-oxocyclobutylideneketene, which underwent hydration to the enol of 2-oxocyclobutanecarboxylic acid; the enol then isomerized to the keto form of this acid. Rates of the ketene and enol reactions were measured in acid, base, and buffer solutions across the acidity range [H+] = 10(-1)-10(-13) M, and analysis of these data, together with rates of enolization of the keto form of 2-oxocyclobutanecarboxylic acid determined by bromine scavenging, gave keto-enol equilibrium constants as well as acidity constants of the keto and enol forms. The keto-enol equilibrum constants proved to be 2 orders of magnitude less than those reported previously for the next higher homolog, 2-oxocyclopentanecarboxylic acid, reflecting the difficulty of inserting a carbon-carbon double bond into a small, strained carbocyclic ring. The acidity constant of the enol group of 2-oxocyclobutanecarboxylate ion, on the other hand, is greater, by 4 orders of magnitude, than that of the corresponding enol in the cyclopentyl system. This remarkable increase in acidity with diminishing ring size is consistent with the enhanced s character of the orbitals used to make the exocyclic bonds of the smaller cyclobutane ring.     

Determination of conformation of halomethyl ketones from the temperature dependence of Geminal H,H coupling constants

The temperature dependence of the geminal H,H coupling constant in solutions of α-chloroacetophenone, α-bromoacetophenone, 1-bromo-3-chloro-1-phenylpropan-2-one and 1,3-dibromo-1-phenylpropan-2-one has been determined at temperatures between 230 and 404 K. The values indicate that in the chloromethyl ketones the conformer with halogen and oxygen eclipsed is favored over that with hydrogen and oxygen eclipsed, while in the bromomethyl ketones the two conformers are of more nearly equal energy. The use of geminal coupling constants to indicate conformational preferences in substituted ketones appears promising.     

Aspects of Electrochemical Behavior of Aldehydes and Ketones in Protic Media

Reduction of carbonyl group in aldehydes and ketones, as well as oxidation of numerous aldehydes is discussed, as well as those reductions of organic compounds where the C?O group activates cleavage of an adjacent C? X bond where X is a good leaving group like halogen, OH, NH₂ or SR or activates hydrogenation of an adjacent C?C group. Survey involves aliphatic and aromatic aldehydes, aryl alkyl and diaryl ketones, as well as α‐ketoacids, 1,2‐diketones and compounds where the carbonyl group is a part of a ring. The role of acid–base, hydration–dehydration and in some cases keto–enol equilibria on electrochemical behavior is pointed out, as well as the role of buffer kind and concentration and the nature of the cation of supporting electrolyte. Better understanding of these factors promises finding of best conditions for electroanalytical procedures.     

Further studies on the synthesis of α-fluoro carbonyl compounds [1]

The trimethylsilyl enol ethers of cycloalkanones and acid esters are converted in high yields (70–90%) to the corresponding α-fluoro carbonyl derivative using XeF₂ in CH₂Cl₂. Non-cyclic α-hydroxy ketones such as ethyl mandelate are efficiently transformed to the α-fluoro product by DAST and by Ishikawa's reagent. Nucleophilic displacement of halogen by fluoride failed in cyclic systems, giving instead, α,β-unsaturated ketones in DMF or CH₃CN (18-crown-6) and 1,2-diones in DMSO, with KF acting as a base. Attempts at DMSO oxidation of I(Br)F adducts failed to give the α-fluoro ketones, but resulted in dehydrohalogenation to the $\text{trans}$-vinyl fluorides.