Ring-chain Tautomeric Equilibria Research Articles

Pattern-free generation and quantummechanical scoring of ring-chain tautomers.

In contrast to the computational generation of conventional tautomers, the analogous operation that would produce ring-chain tautomers is rarely available in cheminformatics codes. This is partly due to the perceived unimportance of ring-chain tautomerism and partly because specialized algorithms are required to realize the non-local proton transfers that occur during ring-chain rearrangement. Nevertheless, for some types of organic compounds, including sugars, warfarin analogs, fluorescein dyes and some drug-like compounds, ring-chain tautomerism cannot be ignored. In this work, a novel ring-chain tautomer generation algorithm is presented. It differs from previously proposed solutions in that it does not rely on hard-coded patterns of proton migrations and bond rearrangements, and should therefore be more general and maintainable. We deploy this algorithm as part of a workflow which provides an automated solution for tautomer generation and scoring. The workflow identifies protonatable and deprotonatable sites in the molecule using a previously described approach based on rapid micro-pKa prediction. These data are used to distribute the active protons among the protonatable sites exhaustively, at which point alternate resonance structures are considered to obtain pairs of atoms with opposite formal charge. These pairs are connected with a single bond and a 3D undistorted geometry is generated. The scoring of the generated tautomers is performed with a subsequent density functional theory calculation employing an implicit solvent model. We demonstrate the performance of our workflow on several types of organic molecules known to exist in ring-chain tautomeric equilibria in solution. In particular, we show that some ring-chain tautomers not found using previously published algorithms are successfully located by ours.

Experimental Study of Tautomeric Equilibria of 2-Cyanobenzoic Acids in Gas, Solution and Solid Phase

2-cyanobenzoic acids are very important compounds in several sciences, and it is because of this that studying their tautomeric equilibria is of great interest. Ring-chain tautomeric equilibria of 2-, 3- and 4- cyanobenzoic, 3-benzyl-2-cyanobenzoic and 1-cyano-2-naphthoic acids were studied in gas phase by means of mass spectrometry (MS). Furthermore, evidences of ring-chain tautomerism of 2-cyanobenzoic acid were found in solution using 1H and 13C nuclear magnetic resonance and in solid phase by infrared spectroscopy.

Solvent‐Catalyzed Ring–Chain–Ring Tautomerization in Axially Chiral Compounds

The mechanism of ring-chain-ring tautomerization and the prominent effect of the solvent environment have been computationally investigated in an effort to explain the enantiomeric interconversion observed in 2-oxazolidinone derivatives, heterocyclic analogues of biphenyl atropisomers, which were isolated as single stable enantiomers and have the potential to be used as axially chiral catalysts. This study has shed light on the identity of the intermediate species involved in the ring-chain-ring tautomerization process as well as the catalytic effect of polar protic solvents. These mechanistic details will prove very useful in predicting and understanding ring-chain tautomeric equilibria in similar heterocyclic systems and will further enable experimentalists to devise appropriate experimental conditions in which axially chiral catalysts remain stable as single enantiomers.

Condensation of 2-alkoxypropenals with N,N- and N,O-1,2-binucleophiles. A route to 2-(1′-alkoxyvinyl)imidazo-lidines and -oxazolidines

Condensation of 2-ethoxypropenal with diaminoethylene in different solvents (CHCl3, MeCN, H2O, DMSO) at room temperature gives an equilibrium mixture (1:1–1.5) of tautomeric 2-(1′-ethoxyvinyl)-1,3-imidazolidine and 2-aminoethylimine of 2-ethoxypropenal as well as 1,2-bis(2′-ethoxypropenyl-ideneamino)ethylene. The latter is readily prepared in quantitative yield using a twofold excess of the aldehyde. 1H NMR was used to demonstrate the effect of heating on the dynamics of the ring-chain tautomeric equilibrium. Reaction of the 2-alkoxypropenals with N-methyl- and N,N′-diphenyl-1,2-diaminoethylenes and with N-phenylaminoethanol gives only the corresponding substituted imidazolidines in 43–95% yield.

Ring–chain tautomerism and protolytic equilibria of 3-hydroxy-3-phosphonoisobenzofuranone studied by 1H, 13C and 31P NMR-controlled titrations

Treatment of 3-chloro-3-(dimethylphosphono)isobenzofuranone (3) with NaI in acetonitrile caused its monodemethylation to sodium 3-chloro-3-(methylphosphonato)isobenzofuranone (4). Compound 4 hydrolyzed in aqueous solution slowly to 3-hydroxy-3-(methylphosphono)isobenzofuranone (5). Upon refluxing in water, 4 demethylated simultaneously with the hydrolysis of the chloride, to afford 3-hydroxy-3-phosphonoisobenzofuranone (6). NMR spectra of the 3-hydroxyphosphonoisobenzofuranone derivatives 5 and 6 were found to be pH dependent. Raising the pH of the aqueous solutions to 10 by adding Na2CO3 caused changes in their 13C and 31P spectra, indicating opening of the isobenzofuranone ring and the formation of ortho-phosphonatoformylbenzoate anions (7) and (8). Acidification of solutions of 7 and 8 yielded 5 and 6, via ortho-phosphonoformylbenzoic acids (9) and (10), respectively, as putative intermediates. The facile formation of the cyclic tautomers 3, 4, 5 and 6, is interpreted in terms of the strong electron withdrawing effect of the phosphonyl group. High-resolution 1D and 2D NMR spectra observing nuclei 1H, 13C and 31P established the molecular structures. Macroscopic dissociation constants were determined for a triprotic acid of type H3L. Using sensor nuclei 1H, 13C and 31P in advanced techniques of NMR controlled titrations confirmed concerted protolytic and ring–chain tautomeric equilibria. Probabilities of different sequences of protonation are discussed.

Substituent effects on the gas‐phase ring‐chain tautomerism of 3,4,5,6‐tetrahydro‐2H‐1,3‐oxazines

The electron ionization mass spectra of five series of seven 2-aryl,4-R-substituted (R = Me, Et, i-Pr, t-Bu or Ph) 3,4,5,6-tetrahydro-2H-1,3-oxazines were recorded at 14 and 70 eV in order to study the ring-chain tautomeric equilibria in the gas phase. Certain fragment ions were associated with the ring or with the open-chain forms of the compounds. As in chloroform solution, the electron-withdrawing effect of the aryl substituent (p-NO(2), m-Br, p-Cl, H, p-Me, p-OMe and p-NMe(2)) shifts the equilibrium towards the ring form. The correlation of ring-chain equilibria (log K = [ring]/[chain]) with the Hammett sigma+ constants of the aryl substituents was in general good or satisfactory although in some cases the p-NMe(2) did not fit these correlations.

Reaction of aroyl- and hetaroyltrifluoroacetones with acylhydrazines: Regioselectivity and tautomerism of the condensation products

Acylhydrazines react with 1,3-diketones of the general formula CF3COCH2COR (where R is an aryl or hetaryl group) at both carbonyl groups. The reaction at the trifluoroacetyl group is favored by donor substituents in the aromatic ring of the 1,3-diketone or by the 2-furyl and, especially, 2-thienyl group as a hetaryl substituent, as well as by elevated temperature. The condensation products at the carbonyl group contiguous to the aryl or hetaryl ring have the structure of 5-hydroxy-4,5-dihydropyrazoles and do not undergo tautomeric transformations in solution. The condensation products at the trifluoroacetyl group have either 5-hydroxy-4,5-dihydropyrazole or hydrazone structure and give rise to ring-chain tautomeric equilibrium in solution. Electron-withdrawing substituents in the aromatic ring of the 1,3-dicarbonyl fragment and CDCl3 as solvent favor formation of the cyclic tautomer. The state of the tautomeric equilibrium is weakly sensitive to structural variations in the hydrazine component.

Reaction of 2‐Alkoxypropenals with 2‐Aminoethanethiol and Ring‐Chain Tautomerism of the Resulting 2‐(1‐Alkoxyvinyl)‐1,3‐thiazolidines.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Reaction of 2-Alkoxypropenals with 2-Aminoethanethiol and Ring-Chain Tautomerism of the Resulting 2-(1-Alkoxyvinyl)-1,3-thiazolidines

2-Alkoxypropenals react with 2-aminoethanethiol to give tautomeric mixtures of the corresponding 2-(1-alkoxyvinyl)-1,3-thiazolidines and 2-(2-alkoxy-2-propenylideneamino)ethanethiols in quantitative yield. The state of the ring-chain tautomeric equilibrium depends on the polarity and acidity of the medium and initial reactant ratio, and it does not change on raising the temperature and is only slightly affected by microwave irradiation.

2-(1′-alkoxyvinyl) thiazolidines: synthesis and study of ring-chain tautomerism

2-Alkoxypropenals react with 2-aminoethanethiol to yield mixtures of tautomeric 2-(1-alkoxyvinyl)thiazolidines and imino thiols. The ring-chain tautomeric equilibria, studied by 1H NMR spectroscopy, were strongly dependent on the solvent polarity, ratio of reagents, and pH of the medium.

Ring-Chain Tautomerism of 1,2,3,4-Tetrahydroquinazolines. The Products of Reaction of 1,3-Dicarbonyl Compounds with 2-Aminomethylaniline

The reaction of 2-aminomethylaniline with 1,3-dicarbonyl compounds gives a series of 1,2,3,4-tetrahydroquinazoline derivatives. A ring-chain tautomeric equilibrium of the type enamine-1,2,3,4-tetrahydroquinazoline is observed in solutions of these compounds and its position depends of the structure of the starting dicarbonyl component and the solvent polarity.

Synthesis and stereochemistry of indano[1,2‐d][1,3]oxazines and thiazines, new ring systems

AbstractA set of structurally varied indano[1,2‐d][1,3]oxazines and thiazines, which are new ring systems, were prepared by ring‐closure reactions of amino alcohols 4–6. The reactions of cis‐ and trans‐1‐amino‐ and cis‐ 1‐benzylamino‐2‐hydroxymethylindane (4–6) with 1 equivalent of an aromatic aldehyde in methanol at room temperature resulted in three‐component equilibria (15a‐g), or a Schiff base (16), or a ring‐closure product alone (17a‐c), respectively, depending on the substitution or configuration of the starting amino alcohol. The ring‐chain tautomeric equilibria can be described by an equation of Hammett type.

Ring[bond]chain tautomerism of 2-Aryl-substituted cis- and trans-decahydroquinazolines.

In CDCl(3) at 300 K, 2-aryl-substituted cis- and trans-3-isopropyldecahydroquinazolines and trans-3-phenyldecahydroquinazolines proved to be three-component (r(1)[bond]o[bond]r(2)) ring[bond]chain tautomeric mixtures, whereas only ring-closed tautomers could be detected for the 3-methyl-substituted analogues. The proportions of the ring-chain tautomeric forms at equilibrium were strongly influenced by the N-substitutents and the cis-trans ring junction and could be described by the equation log K(X) = rho sigma(+) + log K(X=H). These are the first examples among 2-aryl-1,3-N,N-heterocycles of a three-component ring-chain tautomeric equilibrium characterized by a Hammett-type equation. The stabilities of the ring-closed forms of cis- and trans-2-aryldecahydroquinazolines and the corresponding 3,1-benzoxazines were found to increase in the following sequence of the heteroatom at position 3: NPh < N-i-Pr < O < NMe.

Ab initio and Density Functional Calculations on the Ring-Chain Tautomerism of γ-Oxocarboxylic Acids

The results of ab initio (HF, MP2) and density functional (B3LYP) calculations on a series of γ-oxocarboxylic acids [(Z)-3-acetyl or benzoylacrylic and 2-acetyl or benzoylbenzoic acids] A and their cyclic tautomers B are presented. For the open-chain tautomers, different rotamers were considered. Bulk solvent effects were considered by using the polarised continuum model (PCM) and were found to be essential for a proper description of the ring-chain tautomeric equilibrium. Acetyl derivatives generally prefer the cyclic form, whereas for benzoyl derivatives the preference depends on the nature of the link. Introduction of substituents (methyl, phenyl) at C2 and/or C3 for acrylic acid derivatives substantially shifts the equilibrium towards the cyclic form B.

Reactions of carbonyl compounds in basic solutions. Part 33.1 Effect of 2-trichloro- and tribromoacetyl substituents on the alkaline hydrolysis of methyl benzoate, as well as the hydrolysis of the corresponding benzoate anions and ionisation/ring–chain tautomerism of the corresponding acids

Rate coefficients have been measured for the alkaline hydrolysis of methyl 2-trichloro- and tribromoacetylbenzoate, as well as the alkaline hydrolysis of the corresponding 2-trichloro- and tribromobenzoate anions, in 30% (v/v) dioxane–water at several temperatures. The relative rates of hydrolysis and activation parameters demonstrate relatively rapid hydrolysis via neighbouring group participation by the acyl-carbonyl group in the ester hydrolysis and slower hydrolysis via intramolecular fission of the adducts in the benzoate anion hydrolysis. The pKa values of the corresponding benzoic acids have been measured in water and their ring–chain tautomeric equilibrium constants determined.

Rate constants and activation parameters for ring–chain tautomerism in 5-, 6- and 7-ring-1,3-dinitrogen heterocycles

Free energies, enthalpies and entropies of activation have been measured for the ring–chain tautomeric equilibria existing in imidazolidine, hexahydro-pyrimidine and -diazepine ring systems under acid- catalysed conditions in a solvent consisting of 4∶1 DMSO–D2O using computer analysis of NMR signal bandshape.

Synthesis and properties of unique mesoionic 1,3-thiazolium-4-olates

N-bridged 1,3-thiazolium-4-olates were synthesized by reaction of 3-substituted 3-aminothioacrylanilides with bromoacetic acid ethyl ester in refluxing xylene. Their structural aspects were investigated by means of mass, NMR, and absorption spectroscopy. They display an unusual ring-chain tautomeric equilibrium, which is governed by the nature of the solvents and thepH value.

Mass spectrometric behaviour of simple oxazolidines under electron impact and chemical ionization

AbstractThe 70 eV electron impact mass spectra of 33 differently substituted oxazolidines were studied to determine the effect of substituents and the existence of the ring—chain tautomeric equilibrium on the decomposition of the molecular ions. Most of the fragmentations can be rationalized to start as the cleavage initiated by the radical site at nitrogen. Isomeric compounds showed different spectra and were easily differentiated. The position of the ring—chain equilibrium could be located only roughly. The chemical ionization mass spectra of the compounds were also recorded, with ammonia, isobutane, acetone or methane as reagent gas. Methane was the only reagent gas that promoted extensive fragmentation of the protonated molecules. However, no information about the position of ring‐chain tautomerism was obtained under these conditions. Analogously to other related five‐membered heterocycles, the oxazolidines reacted under acetone chemical ionization conditions to afford [M + CH3CO]+ adduct ions. These adducts were stable, however, and unlike those of 1,3‐dioxolanes and 1,3‐oxathiolanes, they did not decompose and form stable oxonium ions.

Ring-chain tautomerism and three- to four-component equilibria in fused-ring tetrahydro-1,3-oxazines

The condensation of cis - (1) and trans -2-hydroxymethyl-4-cyclo-hexenyl-1-amine (2) and 2,3- diexo - (3) and 2,3- diendo -3-hydroxymethylbicyclo[2.2.1]heptylamine (4) with 8 different aromatic aldehydes led to ring-chain tautomeric equilibria between epimeric tetrahydro-1,3-oxazines and open-chain Schiff bases, in all cases the equilibrium mixtures consisted of two epimeric ring forms although the 2-axial epimers of the cyclohexene-fused derivatives had only a minor contribution to the ring-chain tautomeric equilibria. For the norbornane-fused derivatives the ring-chain tautomeric equilibria were taken equal to the ratio of the sum of the ring forms and the amount of the E-isomer of the open form in which case the simple equation, log K X = 0.76σ + + log K X=H derived recently for ring-chain tautomerism in 1,3-oxazines prevailea again for each system studied.

The apparent p Ka of the oxidation product of spermine or spermidine: A p Ka masked by a ring-chain tautomeric equilibrium

The previously reported acid titration curve (S. Brandänge, L.-H. Eriksson, and B. Rodriguez, Acta Chem. Scand., 1984, B38, 526) for the aminal oxidation product of the title compounds in D 2O is computer simulated based on a model consisting of a ring-chain tautomeric equilibrium ( K T) for the monodeuteronated bicyclic aminal followed by a second deuteronation of the resultant monocyclic primary amine ( K a1 ) to give a dication. The fractional amount of dicationic acid product is given by the term [D +] ([D +] + K app ) where K app, the apparent dissociation constant, equals 5.47 × 10 −6, the product of K T and K a1 .