Enol Tautomeric Form Research Articles

Carbonic Anhydrase Inhibitors. Comparison of Chlorthalidone and Indapamide X-ray Crystal Structures in Adducts with Isozyme II: When Three Water Molecules and the Keto−Enol Tautomerism Make the Difference

Thiazide diuretics inhibit all mammalian isoforms of carbonic anhydrase (CA, EC 4.2.1.1) with a different profile as compared to classical inhibitors. Acting as moderate-weak inhibitors of CA II and CA I, chlorthalidone and indapamide considerably inhibit other isozymes among the 16 CAs present in vertebrates. These compounds show a different behavior against CAs I and II, with chlorthalidone being 18.3 times more potent against CA II and 150 times more potent against CA I, as compared to indapamide. In the X-ray crystal structures of the CA II-chlorthalidone adduct three active site water molecules interacting with the inhibitor scaffold were observed that lack in the corresponding indapamide adduct. Chlorthalidone bound within the active site is in an enolic tautomeric form, with the OH moiety participating in two strong hydrogen bonds with Asn67 and a water molecule. This binding mode may be exploited for designing better CA II inhibitors.

Carbonic anhydrase inhibitors. Comparison of chlorthalidone, indapamide, trichloromethiazide, and furosemide X-ray crystal structures in adducts with isozyme II, when several water molecules make the difference

Thiazide and high ceiling diuretics were recently shown to inhibit all mammalian isoforms of carbonic anhydrase (CA, EC 4.2.1.1) with a very different profile as compared to classical inhibitors, such as acetazolamide, methazolamide, and ethoxzolamide. Some of these structurally related compounds have a very different behavior against the widespread isozyme CA II, with chlorthalidone, trichloromethiazide, and furosemide being efficient inhibitors against CA II ( K Is of 65–138 nM), whereas indapamide is a much weaker one ( K I of 2520 nM). Furthermore, some of these diuretics are quite efficient (low nanomolar) inhibitors of other isoforms, for example, chlorthalidone against hCA VB, VII, IX, and XIII; indapamide against CA VII, IX, XII, and XIII, trichloromethiazide against CA VII and IX, and furosemide against CA I and XIV. Examining the four X-ray crystal structures of their CA II adducts, we observed several (2–3) active site water molecules interacting with the chlorthalidone, trichloromethiazide, and furosemide scaffolds which may be responsible for this important difference of activity. Indeed, indapamide bound to CA II has no interactions with active site water molecules. Chlorthalidone bound within the CA II active site is in an enolic (lactimic) tautomeric form, with the enolic OH also participating in two strong hydrogen bonds with Asn67 and a water molecule. The newly evidenced binding modes of these diuretics may be exploited for designing better CA II inhibitors as well as compounds with selectivity/affinity for various isoforms with medicinal chemistry applications.

Crystal Structure of Garciniaphenone and Evidences on the Relationship between Keto–Enol Tautomerism and Configuration

AbstractGarciniaphenone (=rel‐(1R,5R,7R)‐3‐benzoyl‐4‐hydroxy‐8,8‐dimethyl‐1,7‐bis(3‐methylbut‐2‐en‐1‐yl)bicyclo[3.3.1]non‐3‐ene‐2,9‐dione; 1), a novel natural product, was isolated from a hexane extract of Garcinia brasiliensis fruits. The crystal structure of 1 as well as the selected geometrical and configurational features were compared with those of known related polyprenylated benzophenones. Garciniaphenone is the first representative of polyprenylated benzophenones without a prenyl substituent at C(5). Notably, the absence of a 5‐prenyl substituent has an impact on the molecular geometry. The tautomeric form of 1 in the solid state was readily established by a residual‐electronic‐density map generated by means of a difference Fourier analysis, and there is an entirely delocalized six‐membered chelate ring encompassing the keto–enol moiety. The configuration at C(7) was used to rationalize the nature of the keto–enol tautomeric form within 1. The intermolecular array in the network is maintained by nonclassical intermolecular H‐bonds.

Substituent effects on keto–enol tautomerization of β-diketones from X-ray structural data and DFT calculations

Single crystal X-ray structure determinations of six crystals 1–6 of β-diketones, the related DFT calculations as well as a systematic investigation, on the CSD (Cambridge Structural Database) files, of all acyclic β-diketones having at least one α-hydrogen, in both β-diketo and β-keto–enol tautomeric forms, are reported. In spite of the stabilization energy gained by the formation of strong intramolecular O–H⋯O resonace assisted hydrogen bonds (RAHB) a certain number of non-enolized structures were retrieved. The structural data show that the steric and electronic properties of the substituents play a definite role in tuning the hydrogen bond strength and determining the enolic site but the driving force able to shift from the more common β-keto–enol tautomer to the β-diketo one can be only the steric hindrance of bulky groups. In this context the substituents in position 2 play a crucial role in establishing the tautomeric form. In fact, while the 2-unsubstituted β-diketones (or 2-substitued by a group linked by a sp2carbon) assume almost exclusively the β-keto–enol form with some exceptions for very bulky substituents, β-diketones carrying 2-alkyl substituents, in general, display the β-diketo tautomeric form. The only exceptions are the 2-alkyl curcumin derivatives where the planar β-keto–enol group is stabilized by extended π-conjugation within the whole molecule and by the absence of short contacts between the alkyl R2groups and R1 or R3 substituents. DFT calculations on the six compounds, 1–6, show that in the four more overcrowded structures, 3–6, the trans-β-diketo tautomer is more stable than the Z-β-keto–enol isomer unlike what happens for 1 and 2 where the Z-β-keto–enol isomer is the most stable by a few kcal mol−1. Thereby, the occurrence of the trans-β-diketo tautomer for all compounds, in the crystal, can be interpreted in terms of the existence of a large activation energy in the mechanism to attain the Z-β-keto–enol isomer containing an intramolecular O–H⋯O hydrogen bond.

2-(3,4-Dimethoxyphenyl)-3-hydroxybut-2-enenitrile

The title compound, C12H13NO3, adopts its enol tautomeric form and crystallizes with two mol­ecules in the asymmetric unit, with similar conformations. In the crystal structure, mol­ecules inter­act via O—H⋯N hydrogen bonds, leading to infinite chains.

A molecular corner:fac-tricarbonylchloridobis[3-(4-pyridyl)pentane-2,4-dione-κN]rhenium(I) chloroform solvate

The title compound, [ReCl(C10H11NO2)2(CO)3]·CHCl3, has Re—N distances of 2.202 (8) and 2.237 (7) A, an N—Re—N angle of 84.1 (3)° and 2-hydr­oxy-4-oxopent-2-en-3-yl (acacH) units which are uncoordinated. The acacH units are in the enol tautomeric form, with delocalized single and double bonds.

Influence of Modification pH and Temperature on the Interaction of Methylacetoacetate with (S)-Glutamic Acid-Modified Ni{111}

The adsorption of (S)-glutamic acid onto Ni{111} from solution was investigated with reflection absorption infrared spectroscopy as functions of modification temperature and pH. Modification at 300 K results in the formation of approximately one monolayer of adsorbate. The extent of protonation of the adsorbate decreases with increasing pH. Modification at 350 K produces a thicker adsorbate layer, which is assigned to nickel glutamate (low pH) and a mixture of nickel and sodium glutamate (high pH). Adsorption of methylacetoacetate onto the chirally modified surfaces occurs predominantly in the diketone tautomeric form when adsorbed glutamic acid exists in the protonated form. By contrast, methylacetoacetate exists primarily in the enol tautomeric form when glutamate (i.e., anionic) species are present. The implications of our findings for understanding the mechanism of Ni-catalyzed β-ketoester hydrogenation are discussed.

Redetermination of curcumin: (1E,4Z,6E)-5-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,4,6-trien-3-one

The uncertainty associated with the position of one H atom in curcumin, C21H20O6, has been resolved by establishing the enol tautomeric form supported by an intra­molecular O—H⋯O hydrogen bond.

Tautomeric Equilibria and Pi Electron Delocalization for Some MonohydroxyarenesQuantum Chemical Studies

Keto-enol tautomeric interconversions and variations of the pi-electron distribution were studied for 11 isolated monohydroxyarenes at the DFT(B3LYP)/6-311++G(2df,2p) level. For two monohydroxyarenes (phenol and 9-anthrol), the PCM model of solvation (water) was also applied to the DFT geometries. The geometry-based HOMA index was applied to estimate pi-electron delocalization in the keto and enol tautomeric forms. Thermodynamic parameters of tautomeric interconversions (DeltaET, DeltaGT, TDeltaST, pKT) were calculated to estimate relative stabilities of individual tautomers and their percentage contents in the tautomeric mixtures. In almost all cases, the aromatic enol forms are strongly favored. An exception is 9-anthrol, which prefers its keto form. The resonance stabilization of this form comes from the central ring. Generally, aromaticity is the main factor that influences tautomeric equilibria in monohydroxyarenes. Hydration effect is considerably smaller and it does not change the tautomeric preference.

Synthesis and spectroscopic studies of mixed-ligand and polymeric dinuclear transition metal complexes with bis-acylhydrazone tetradentate ligands and 1,10-phenanthroline

Two types of dinuclear copper(II) and nickel(II) complexes with two tetradentate N 2O 2 donor ligands 1,4-bis(1-anthranoylhydrazonoethyl)benzene (L 1), 1,4-bis(1-salicyloylhydrazonoethyl)benzene (L 2) and N, N′-bidentate heterocyclic base [1,10-phenonthroline (phen)] have been synthesized and characterized by elemental analysis, infrared spectra, UV–vis electronic absorption spectra and magnetic susceptibility measurements. The reaction of metal(II) acetates with the solution containing ligand and 1,10-phenonthroline in methanol gives mixed-ligand dinuclear metal(II) complexes with general formula [M 2L(phen) 2]Cl 2 (L = L 1 or L 2), whereas, the ligands react with metal(II) acetates to form polymeric dinuclear complexes with general formula [(M 2L 2) n ] (L = L 1 or L 2). In the complexes, the ligands act as dianionic tetradentate and coordination takes place in the enol tautomeric form with the enolic oxygen and azomethine nitrogen atoms while the phenolic hydroxyl and amino groups of aroylhydrazone moiety do not participate in coordination. The effect of varying pH and solvent on the absorption behavior of both ligands and complexes has been investigated.

TAUTOMERISM OF 4-HYDROXY-4(1H)QUINOLON

The tautomerism of 4-Hydroxy-4(1H) quinolon I was studied using infrared spectroscopy, 1 H, 13 C NMR spectroscopy and X-ray crystallography. The keto-form of I is favored in the crystal form and at room temperature in polar solutions like water and dimethylsulfoxide. Introduction. Quinolons produced by different bacteria inhibit the respiratory (1) as well as photosynthetic electron transport chains (2). They were used as lead compounds for finding new strong inhibitors. One of the most important physical and chemical properties of this class of heteroaromatic compounds is their involvement in a prototropic tautomerism (Figure 1). In order to understand the biological activity of I we investigated its crystal structure and studied the tautomerism in water and DMSO solution by 1 H and 13 C NMR spectroscopy. To further investigate the tautomerism of compound I in solution we synthesized the O-methylated derivate II, which mimics the enol-tautomeric form (Figure 1). Single crystals of I for X-ray analysis were obtained from dichloromethane. The crystal structure exists as a dimer. The monomers are connected by an intermolecular hydrogen bond (O...HN distance of 1.795 A) between the imino hydrogen and the carbonyl group (Figure 2 and Figure 3). The carbon oxygen bonds length of 1.246 A for C1A-O1A and 1.262 A for C1-O1 are in the range of the C=O length. Also the C3N4 and C5N4 bonds of 1.352 A and 1.383 A indicate a nitrogen carbon single bond. This results show that the keto tautomer is favored in the crystal structure.

Investigating the Mechanism of Chiral Surface Reactions: The Interaction of Methylacetoacetate with (S)-Glutamic Acid Modified Ni{111}

The enantioselective hydrogenation of beta ketoesters over Ni-based catalysts is a rare example of a heterogeneously catalyzed chiral reaction. The key step in catalyst preparation is the adsorption from solution of chiral molecules (modifiers). One particularly interesting modifier is (S)-glutamic acid because the dominant enantiomeric product in the catalytic reaction depends upon the modification temperature. We report a reflection absorption infrared spectroscopy (RAIRS) study of the adsorption of methylacetoacetate (the simplest beta ketoester) onto (S)-glutamic acid modified Ni{111} surfaces as functions of the modifier coverage and modification temperature. We show that the sticking probability of methylacetoacetate is close to 0 on saturated (S)-glutamic acid covered surfaces. At lower modifier coverage, methylacetoacetate adsorption can occur. Adsorption of methylacetoacetate onto a Ni{111} surface modified by (S)-glutamic acid at 300 K results in the diketo tautomeric form, with evidence being observed for a 1:1 interaction between zwitterionic (S)-glutamate and methylacetoacetate. In contrast, adsorption of methylacetoacetate onto a Ni{111} surface modified by (S)-glutamic acid at 350 K occurs exclusively in the enol tautomeric form. The implications for the heterogeneous catalytic reaction are discussed.

Inhibitors designed for the active site of dihydroorotase

Four new compounds have been synthesized as potential inhibitors of dihydroorotase from Escherichia coli. NMR spectroscopy was used to show that 4,6-dioxo-piperidine-2( S)-carboxylic acid ( 3), exists in solution as a mixture of the hydrate ( 7), enol ( 8), and enolate ( 9) tautomeric forms. This compound was found to be a competitive inhibitor versus dihydroorotate and thio-dihydroorotate at pH values of 7–9. The K i of 76 μM was lowest at pH 7.0 where the ketone and hydrate forms of the inhibitor 3 predominate in solution. Compound 3 was reduced to the two diastereomeric 4-hydroxy derivatives ( 4 and 5) and then dehydrated to yield the alkene derivative, 1,2,3,6-tetrahydro-6-oxopyridine-2( S)-carboxylic acid ( 6). Compounds 4– 6 were competitive inhibitors versus thio-dihydroorotate at pH 8.0 with K i values of 3.0, 1.6, and 2.3 mM. Dihydroorotase was unable to dehydrate the 4-hydroxy derivative 4 or 5 to the alkene 6 or catalyze the reverse reaction.

Synthesis and spectroscopic studies of copper(II) and nickel(II) complexes containing hydrazonic ligands and heterocyclic coligand

Two types of copper(II) and nickel(II) complexes derived from benzophenone anthranoylhydrazone (L 1), 2-acetonaftanone anthranoylhydrazone (L 2), 4-phenylacetonaftonone anthranoylhydrazone (L 3), benzophenone salicyoylhydrazone (L 4), 2-acetonaftanon salicyoylhydrazone (L 5), 4-phenylacetonaftanon salicyoylhydrazone (L 6) and bidentate heterocyclic base [1,10-phenanthroline (phen)] with general stoichiometry [ML 2] and [ML(phen)]Cl have been synthesized and characterized by elemental analysis, infrared spectra, UV–vis electronic absorption spectra and magnetic susceptibility measurements. The effect of varying pH and solvent on the absorption behavior of both ligands and complexes have been investigated. According to the IR spectra, the ligands act as monobasic bidentate and coordination takes place in the enol tautomeric form.

Calculation and Analysis of the IR Spectra of Cytosine in Various Phase States

Plane vibrations and intensities of the IR spectra of the ketone and enol forms of cytosine and deuterocytosine in various phase states are calculated and analyzed. It is shown that in a crystalline state and an aqueous solution cytosine forms a hydrogen bond of two types: C2=O8...HN1 and C2=O8...HN10, with a stronger intermolecular interaction in both phases being implemented by the hydrogen bonds between the O8 and N1 atoms. A satisfactory interpretation of the spectrum of the isolated molecules of cytosine, with the simultaneously existing ketone and enol tautomeric forms, is possible in the presence of the structural isomers of the enol form that differ in the position of multiple bonds.

NMR, FT-IR, ESI MS studies and PM5 semiempirical calculations of lasalocid ethylene glycol ester complexes with Li + and Na + cations

In the present work we studied the ability of new lasalocid ester with ethylene glycol (Las4) to form complexes with Li + and Na + cations using ESI mass spectrometry, 1H, 13C NMR and FT-IR spectroscopic methods. The ESI-MS spectra indicate that Las4 forms stable 1:1 complexes with both cations, independent of the stoichiometry in which they were added to the ester. Even different cone voltage values did not influence this stoichiometry. However, increasing cone voltages, lead to degradation of the complexes and formation of various fragmentary cation complexes, still in a 1:1 stoichiometry. In acetonitrile solution, the NMR and FT-IR spectra of the 1:1 complexes of Las4 with Na + and Li +, indicate the existence of both, the keto and enol tautomeric forms. The PM5 semiempirical calculations are in agreement with the spectroscopic data. They allow the calculation of the interatomic distances between the cations and the coordinating oxygen atoms as well as visualisation of the structures of the Las4–Li + and Las4–Na + complexes. The structures indicate the existence of two structural and functional different parts of the ester complex. One part includes the salicylic group, which is stabilised by two intramolecular hydrogen bonds and does not contribute to the complexation process. The second part contains five oxygen atoms, strongly interacting with the cations.

Thioacetylacetone: structural and vibrational assignments.

Thioacetylacetone and its variously deuterated isotopomers have been investigated using electronic and vibrational spectroscopy combined with quantum chemical calculations. Thioacetylacetone is known for its photochromic properties, but the structures of the initial and final forms have been the subject of a long debate. Analysis of the IR spectra recorded in low-temperature argon and xenon matrices, room-temperature solutions, and in the gas phase has allowed us to establish the nature of the photochromic species and of its precursor. Similar to the case of another beta-thioxoketone, monothiodibenzoylmethane, the photo-product has been assigned to the nonchelated SH exo-rotamer of the (Z)-enethiol tautomeric form, whereas the dominant ground-state species corresponds to the chelated (Z)-enol tautomeric form. Detailed vibrational assignments have been proposed for both forms based on quantum chemical calculations and polarization experiments. In the case of the chelated (Z)-enol species prevailing in the ground state, a second-order perturbative anharmonic analysis at the B3LYP/cc-pVTZ level indicated strong anharmonic effects associated with the intramolecular hydrogen bond, leading to a shift of more than 600 cm-1 of the wavenumber of the OH-stretching vibration. A small fraction of the SH endo-rotameric chelated (Z)-enethiol form was also detected under unperturbed conditions. The (Z)-enethiol form can be converted into the (Z)-enol form by irradiation at 290 nm.

Preparation of long‐chain β‐enaminones and β‐diketones from long‐chain 3,5‐disubstituted isoxazole compounds

AbstractA series of long‐chain compounds containing the β‐enaminone functionality were prepared in yields ranging from 71 to 88% from their corresponding long‐chain 3,5‐disubstituted isoxazole precursors utilizing a Raney nickel‐catalyzed reductive ring‐opening procedure. These newly prepared multifunctional compounds were subsequently hydrolyzed under mild acidic conditions (pH 4–5) to give their corresponding long‐chain β‐diketones in yields ranging from 79 to 98%. Both the β‐enaminone and β‐diketone functionalized compounds were characterized by NMR, IR spectroscopy, GC‐MS, and m.p. The mass spectra for these two classes of compounds, derived by utilizing electron impact ionization, gave distinctive McLafferty rearrangement fragmentation ions that clearly established the newly introduced functionality to reside at the C‐2 and C‐4 positions of the lipid’s alkyl chain. 1H NMR spectra of the pure β‐diketone compounds were complex owing to the keto enol tautomerism displayed by the β‐diketone moiety. In solution the β‐diketone compounds were shown to exist mainly in the enolic tautomeric form. Long‐chain β‐diketone compounds are known to be relatively common constituents of some plant waxes, and the overall procedure starting from soybean methyl esters provides a complementary approach to prepare these types of compounds.

Theoretical and experimental investigations on the chemical reactions of positively charged phenyl radicals with cytosine and 1-methylcytosine.

The chemical behavior of positively charged phenyl radicals toward cytosine, 1-methylcytosine, and some pyrimidine analogues in the gas phase was investigated both theoretically by performing molecular orbital calculations and experimentally by using FT/ICR mass spectrometry. The phenyl radicals react with cytosine and 1-methylcytosine predominately by hydrogen abstraction and addition. For cytosine, the preferred site for hydrogen abstraction appears to be the amino group, and addition occurs preferentially at the N3 and N1 positions of the keto and enol tautomeric forms, respectively. For 1-methylcytosine, the methyl group is the thermodynamically favored site for hydrogen abstraction and N3 for addition. Possible structures and formation mechanisms are suggested for two unknown product ions formed upon the reaction of cytosine with the 3-dehydro-N-phenylpyridinium radical cation.

Взаємодія з карбоксилат-іоном у безводному ДМСО зсуває прототропну кето-енольну рівновагу в нуклеозидах урацилу і тиміну в бік енольної таутомерної форми: дані спектроскопії 1Н ЯМР

Взаємодія з карбоксилат-іоном у безводному ДМСО зсуває прототропну кето-енольну рівновагу в нуклеозидах урацилу і тиміну в бік енольної таутомерної форми: дані спектроскопії 1Н ЯМР