The mandelamide keto-enol system in aqueous solution. Generation of the enol by hydration of phenylcarbamoylcarbene

Flash photolysis of diazophenylacetamide in aqueous solution produced phenylcarbamoylcarbene, whose hydration generated a transient species that was identified as the enol isomer of mandelamide. This assignment is based on product identification and the shape of the rate profile for decay of the enol transient, through ketonization to its carbonyl isomer, as well as by the form of acid-base catalysis of and solvent isotope effects on the decay reaction. Rates of enolization of mandelamide were also determined, by monitoring hydrogen exchange at its benzylic position, and these, in combination with the ketonization rate measurements, gave the keto-enol equilibrium constant pK(E) = 15.88, the acidity constant of the enol ionizing as an oxygen acid, pQ(E)(a)= 8.40, and the acidity constant of the amide ionizing as a carbon acid pQ(K)(a)= 24.29. (These acidity constants are concentration quotients applicable at ionic strength = 0.10 M.) These results show the enol content and carbon acid strength of mandelamide, like those of mandelic acid and methyl mandelate, to be orders of magnitude less than those of simple aldehydes and ketones; this difference can be attributed to resonance stabilization of the keto isomers of mandelic acid and its ester and amide derivatives, through electron delocalization into their carbonyl groups from the oxygen and nitrogen substituents adjacent to these groups. The enol of mandelamide, on the other hand, again like the enols of mandelic acid and methyl mandelate, is a substantially stronger acid than the enols of simple aldehydes and ketones. This difference can be attributed to the electronegative nature of the oxygen and nitrogen substituents geminal to the enol hydroxyl group in the enols of mandelic acid and its derivatives; in support of this, the acidity constants of these enols correlate well with field substituent constants of these geminal groups.     

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.     

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.     

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.     

Effect of ring size on the tautomerization and ionization reaction of cyclic 2-nitroalkanones: an experimental and theoretical study

The keto-enol tautomerism of some cyclic 2-nitroalkanones was studied in cyclohexane. Keto-enol equilibrium constants, K(T), at 25 °C were obtained from (1)H NMR spectra. The relative enol content for the investigated ketones as a function of ring size decreases in the order 6 > 7 > 11 > 12 > 15. This trend apparently is different from that observed in water. Density functional theory (DFT) calculations have been performed to rationalize the effects of ring size and of the solvent on tautomerism. The acidity constants, K(a)(KH), for the different keto tautomers were measured spectrophotometrically at 25 °C in buffered aqueous solutions. No simple correlations between K(a)(KH) and ring size was observed, and this is in agreement with a DFT analysis performed on the same compounds.     

Spectroscopic evidence of keto-enol tautomerism in deliquesced malonic acid particles

Scanning transmission X-ray microscopy combined with near-edge X-ray absorption fine structure spectroscopy (STXM/NEXAFS) and optical microscopy coupled with Fourier transform infrared spectroscopy (micro-FTIR) have been applied to observe hygroscopic growth and chemical changes in malonic acid particles deposited on substrates. The extent of the hygroscopic growth of particles has been quantified in terms of the corresponding water-to-solute ratios (WSR) based on STXM/NEXAFS and micro-FTIR data sets. WSR values derived separately from two applied methods displayed a remarkable agreement with previous data reported in the literature. Comparison of NEXAFS and FTIR spectra acquired at different relative humidity (RH) shows efficient keto-enol tautomerization of malonic acid, with the enol form dominating at higher RH. The keto-enol equilibrium constants were calculated using relevant peak intensities in the carbon and oxygen K-edge NEXAFS spectra as a function of RH. We report strong dependence of the equilibrium constant on RH, with measured values of 0.18 ± 0.03, 1.11 ± 0.14, and 2.33 ± 0.37 corresponding to 2, 50, and 90% RH, respectively. Enols are important intermediates in aldol condensation reactions pertaining to formation and atmospheric aging of secondary organic aerosol (SOA). The present knowledge assumes that constituents of atmospheric deliquesced particles undergo aqueous chemistry with kinetic and equilibrium constants analogous to reactions in bulk solutions, which would estimate absolute dominance of the keto form of carboxylic acids. For instance, the keto-enol equilibrium constant of malonic acid in diluted aqueous solution is <10(-4). Our results suggest that in deliquesced micrometer-size particles, carboxylic acids may exist in predominantly enol forms that need to be explicitly considered in atmospheric aerosol chemistry.     

Ionization and tautomerization of 2-nitrocyclohexanone in aqueous solution

The keto-enol tautomerism of 2-nitrocyclohexanone (2-NCH) was studied in aqueous solution under different experimental conditions. Ketonization rate constants were measured spectrophotometrically at 25 degrees C at an ionic strength of 0.4 mol dm-3 (NaCl) in diluted hydrochloric acid, in diluted sodium hydroxide, and in several buffers by using NaHSO3 as the scavenger of the keto form. A value of pK(a)(EH) = 4.78 for the enol form was obtained from the rate-pH profile of the reaction. A value of pK(a)(KH) = 5.97 for the keto form was directly obtained from the UV-vis spectra of 2-NCH recorded at different pHs. The equilibrium constant for the keto-enol tautomerism, pK(T) = -log([enol]/[ketone]) = 1.19, was obtained by combining the two pKa values (pK(T) = pK(a)(KH) - pK(a)(EH)). A comparison of these results with the corresponding values (Keefe, J. R.; Kresge, A. J. In The Chemistry of Enols; Rappoport, Z., Ed.; Wiley & Sons: New York, 1990; pp 399-480) for cyclohexanone shows the dramatic effects of an alpha-nitro substituent on the keto-enol acidities and the tautomerization constant of alicyclic ketones. Rates and equilibria were discussed in the light of the Br?nsted equation, the principle of nonperfect synchronization, and the Marcus theory. It turns out that, on passing from nitroalkanes to nitroketones, the resonance contribution to pKa and deprotonation rate decreases, being overwhelmed by steric and inductive effects.     

7─羟基喹啉与甲醇、乙醇形成1：2桥式氢键化合物的AM1法研究

利用半经验ＡＭ１方法计算了基态与第一激发态７－羟基喹啉的两种异构体及其与甲醇等溶济分子形成１：２桥式氢键化合物的结构与稳定性。在基态，烯醇式结构比酮式结构稳定；而在第一激发态酮式比烯醇式稳定。１：２桥式氢键的形成使得酮式能量降低比烯醇式多。烯醇式１：２桥式氢键化合物呈交叉式结构，酮式１：２桥式氢键化合物呈折叠式结构，激发态的形成对氢键结构影响不大。在７－羟基喹啉羟基（或羰基）的邻位和间位引入取代基后，对喹啉环和桥式氢键结构的影响均不明显。     

7─羟基喹啉与甲醇、乙醇形成1：2桥式氢键化合物的AM1法研究

利用半经验ＡＭ１方法计算了基态与第一激发态７－羟基喹啉的两种异构体及其与甲醇等溶济分子形成１：２桥式氢键化合物的结构与稳定性。在基态，烯醇式结构比酮式结构稳定；而在第一激发态酮式比烯醇式稳定。１：２桥式氢键的形成使得酮式能量降低比烯醇式多。烯醇式１：２桥式氢键化合物呈交叉式结构，酮式１：２桥式氢键化合物呈折叠式结构，激发态的形成对氢键结构影响不大。在７－羟基喹啉羟基（或羰基）的邻位和间位引入取代基后，对喹啉环和桥式氢键结构的影响均不明显。     

Gas-phase study of molecular switches based on tautomeric proton transfer

The keto-enol tautomeric equilibrium in two newly developed molecular switches was studied by using various mass spectral techniques. In these two compounds, namely 4-(phenyldiazenyl)-2-(piperidin-1- ylmethyl)naphthalen-1-ol and 2-[(1,4,7,10-tetraoxa-13-azacyclopentadecan-13-yl)methyl]-4- (phenyldiazenyl)naphthalen-1-ol, the switching on/off states are achieved by a controlled shift of the tautomeric equilibrium. In the first compound, electron impact-mass spectrometry confirms that the unprotonated dye exists as an enol tautomer, while the electrospray ionization tandem mass spectrometry (ESI-MS/MS) experiment proves the clear shift to the keto tautomeric form under switching with acid addition. In the second compound, the addition of the alkali metal ions causes transition of the tautomeric equilibrium from the pure enol to the pure keto form. The ESI-MS study demonstrated better sensitivity towards lithium ions.     

Mechanistic aspects of alloxan diabetogenic activity: a key role of keto-enol inversion of dialuric acid on ionization

The inversion of the keto-enol stability order of dialuric acid on ionization was calculated and verified experimentally. The radical cations in both forms were characterized. The spectrum of the keto form was observed upon direct ionization of dialuric acid under matrix conditions, whereas the enol form was formed upon a sequential electron-proton-proton attachment to alloxan under acidic aqueous condition. Facilitation of the one-electron oxidation of dialuric acid upon its enolization can result in a more effective formation of superoxide radical anion in the process of its auto-oxidation. This process is discussed in reference to the alloxan diabetogenic action. Both neutral keto and enol forms are energetically close, and under favorable conditions, the auto-oxidation of dialuric acid could involve participation of the enol form.     

Base-pairing, tautomerism, and mismatch discrimination of 7-halogenated 7-deaza-2'-deoxyisoguanosine: oligonucleotide duplexes with parallel and antiparallel chain orientation

Oligonucleotides containing 2'-deoxyisoguanosine (1, iG(d)), 7-deaza-2'-deoxyisoguanosine (2, c(7)iG(d)), and its 7-halogenated derivatives 3 and 4 were synthesized on solid phase using the phosphoramidite building blocks 5-7. The hybridization properties of oligonucleotides were studied on duplexes with parallel and antiparallel chain orientation. It was found that the 7-halogenated nucleoside analogues 3 and 4 enhance the duplex stability significantly in both parallel (ps) and antiparallel (aps) DNA. Moreover, the halogenated nucleosides shift the tautomeric keto-enol equilibrium strongly toward the keto form, with K(TAUT) [keto]/[enol] approximately 10(4) coming close to that of 2'-deoxyguanosine (10(4)-10(5)), while the nonhalogenated 7-deaza-2'-deoxyisoguanosine 2 shows a K(TAUT) of around 2000 and the enol concentration of 1 is 10% in aqueous solution. Consequently, nucleosides 3 and 4 show a much better mismatch discrimination against dT than compound 1 or 2 in antiparallel as well as in parallel DNA. 3 and 4 are expected to increase the selectivity of base incorporation opposite to isoC(d) in the form of triphosphates or in the polymerase-catalyzed reaction in comparison to 1 or 2.     

NMR-spektroskopische Untersuchung der Keto-Enol-Tautomerie von 2-Halogenoacetoacetarylamiden

Based on the differing chemical shifts of the methyl group of the keto versus the methyl group of the enol form or of the chemical shifts of the OH-group of the enol form versus the CHX-group of the keto form of the 2-halogeno-acetoacetarylamides, it is possible to study the keto-enol equilibrium. We have pointed out, that this equilibrium depends on the kind of substituent at the amido group.     

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.     

Synthesis,Spectroscopic Studies and Keto-Enol Tautomerism of Novel 1,3,4-Thiadiazole Derivative Containing 3-Mercaptobutan-2-one and Quinazolin-4-one Moieties

In this study, a novel 1,3,4-thiadiazole derivative containing 3-mercaptobutan-2-one and quinazolin-4-one moieties (Compound 3) is synthesized by the coupling of 2-amino-1,3,4-thiadiazole-5-(3-mercaptobutan-2-one) (Compound 1) with 2-Phenyl-4H-3,1-benzoxazin-4-one (Compound 2) in one molecule moiety. Compound 3 is found to exist as two types of intra-molecular hydrogen bonding with keto-enol tautomerism characters, which is further confirmed using FTIR, ¹H-NMR, ¹³C-NMR, mass spectrometer, and UV-Visible spectra. The ¹H-NMR and UV-Visible spectra of Compound 3 are investigated in different solvents such as methanol, chloroform, and DMSO. Compound 3 exhibits keto-enol tautomeric forms in solvents with different percentage ratios depending on the solvent polarity. The ¹H-NMR and UV-Visible spectral results show that Compound 3 favors the keto over the enol form in polar aprotic solvents such as DMSO and the enol over the keto form in non-polar solvents such as chloroform. The ¹³C-NMR spectrum gives two singles at δ 204.5 ppm, due to ketonic carbon, and δ 155.5 ppm, due to enolic carbon, confirming the keto-enol tautomerism of Compound 3. Furthermore, the molecular ion at m/z 43 and m/z 407 in the mass spectrum of Compound 3 and fragmentation mechanisms proposed reveal the existence of the keto and enol forms, respectively.     

Single molecule solvation and its effects on tautomeric equilibria in a self-assembled capsule

A self-assembled cylindrical capsule provides a nanoscale environment that affects keto-enol equilibria. The equilibrium constants for encapsulated beta-ketoesters show values that differ by an order of magnitude from that of the free tautomers in solution. For complexes with a single, large encapsulated guest, the inner surfaces of the capsule and the seam of the hydrogen bonds influence the equilibrium between the encapsulated keto and enol forms. For complexes of smaller beta-ketoesters, the coencapsulated solvent influences the equilibria. The solvent reduces the space available and affects the positioning of the ester in the capsule.     

Enolization of acetone in superheated water detected via radical formation

Muoniated free radicals have been detected in muon-irradiated aqueous solutions of acetone at high temperatures and pressures. At temperatures below 250 degrees C, the radical product is consistent with muonium addition to the keto form of acetone. However, at higher temperatures, a different radical was detected, which is attributed to muonium addition to the enol form. Muon hyperfine coupling constants have been determined for both radicals over a wide range of temperatures, significantly extending the range of conditions under which these radicals and the keto-enol equilibrium have been studied.     

Lancifodilactone G: insights about an unusually stable enol

From quantum mechanics calculations we confirm that the naturally occurring enol lancifodilactone G is stable over the keto form (by 2.6 kcal/mol in water), the only known stable aliphatic enol (devoid of conjugated or bulky aromatics and lacking a 1,3-diketone structural motif known to stabilize enols). We determine architectural elements responsible for the enol stabilization and find a mechanism for keto-enol conversion in solution. In addition, we correct previously reported computational results that were performed on the misinterpreted structure demonstrating that the enol form of this natural product is more stable than previously thought.     

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.     

Effect of pH on concentration of species present in aqueous solutions of carbonyl compounds affected by hydration-dehydration and keto-enol equilibria

Equations have been derived for hydration-dehydration and keto-enol equilibria of carbonyl compounds, showing the changes, with pH, of individual species present in aqueous solutions. An Egtran computer program has been constructed, so that the pH-variation of individual species for widely varying values of equilibrium constants can be evaluated. The treatment enables isolation of individual equilibrium constants from experimental data and identification of the system involved. The ratios of hydrated and non-hydrated, as well as of keto and enol forms, are pH-independent.