Multifaceted computational profiling of thymol and geraniol against the human proteome for bio-repellent alternatives: Toxicity predictions, degradation analysis, and quantum mechanical approaches.

With growing interest in natural compounds as alternative mosquito repellents, assessing the toxicity and structure of potential repellent naturals like thymol (monoterpene phenol) and geraniol (monoterpene alcohol) is vital for understanding their stability and human impact. This study aimed to determine the structural, toxicity, and binding profiles of thymol and geraniol using computational predictions, xTB metadynamics, quantum mechanics, and principal component analysis. Toxicity studies using Protox-II, T.E.S.T, and SwissADME indicated that thymol and geraniol belong to toxicity class 4 and 5, respectively, with low toxicity predictions in other endpoints. Overall pharmacokinetic profile was generated via pkCSM. Off-target predictions via SwissTarget Predictions, LigTMap, Pharmapper, and SuperPred showed that these molecules can bind to 614 human proteins. The degradation of thymol and geraniol were performed using xTB metadynamics and the outcomes showed that the degradants for both compounds were stable and had lower toxicity profile. Nine tautomers were generated via quantum mechanics for thymol and four for geraniol, with RMSD ranging from 3.8 to 6.3 Å for thymol and 3.6 to 4 Å for geraniol after superimpositions. DFT studies found that HOMO-LUMO values and electronegativity parameters of thymol and geraniol did not differ significantly from their isomers. Binding affinity studies against 614 proteins, analysed via PCA and violin plots, highlighted the probable range of binding. These multifaceted in-silico findings corroborate the stability and potential utility of thymol and geraniol as safer alternatives in repellent applications.

Spectral and HPLC Analyses of Synthesized Butin and Butein.

Butin and butein are significant bioactive flavanones derived from plants, existing as tautomers of each other. However, their physicochemical attributes, such as their spectral profiles under varying experimental conditions in aqueous solutions and established chromatographic methods for distinguishing between them, remain undetermined. In this study, we determined the basic properties of butin and butein using conventional spectroscopic, reversed-phase, and chiral HPLC analyses. The spectra of the synthesized butin and butein were analyzed using a UV-Vis spectrophotometer in several solvents with different polarities as well as in aqueous solutions at various pH values. Furthermore, the behavior of the measured spectra was reproduced by calculations to reveal the effects of the solvent and pH on the spectra of butin and butein in organic and aqueous solutions. Subsequently, we assessed the structural stability of butin and butein using reversed-phase HPLC, which revealed that butein is unstable compared with butin in a general culture medium. The synthesized butin was effectively separated into R- and S-isomers with positive and negative Cotton effects, respectively, via HPLC using a chiral column. These findings will aid in uncovering the individual properties of both butin and butein that may have been concealed by their tautomerism and enable the synthesis of S-butin, which is typically challenging and time-consuming to isolate.

Synthesis, Theoretical Study, and Anticonvulsant Evaluation of N-Arylenaminones.

N-Arylenaminones are highly versatile compounds which can be synthesized in relatively simple ways. In this work we explored the synthesis of the four monosubstituted N-(4-R-phenyl)enaminones 3 a (R=NO2), 3 b (R=F), 3 c (R=H), and 3 d (R=OMe) with the goal of determining the influence of the substituents' electronic effects on tautomer stability and biological activity. These compounds were analyzed by means of Density Functional Theory calculations (DFT), to evaluate the relative stability of the possible tautomers. We found that the enaminone structure is the most stable with respect to the ketoimine and iminoenol forms. In addition, all four compounds display anticonvulsant activity, with 3 d being the one that mostly increased latency and mostly decreased the number of convulsions with respect to the control group. The suggested mechanism of action involves blockage of the voltage-dependent Na+ channels, considering that these molecules meet the structural characteristics needed to block the receptor, as is the case of the positive control molecules phenytoin (PHT) and valproic acid (VPA).

The intramolecular SN2 reaction tautomeric ent-Kauranoids isolated from the aerial parts of Isodon amethystoides.

As our ongoing searching for the bioactive natural terpenoids, nine ent-kauranoids (1-9), including three previously undescribed ones (1, 2, and 9), were isolated from the aerial parts of Isodon amethystoides. Their structures were elucidated on the basis of spectroscopic data analysis, including NMR, MS, and ECD. Compounds 1 and 2 were a pair of tautomeric compounds, which was confirmed by the HPLC analysis and low temperature NMR testing. The underlying mechanism of the tautomer was proposed as an intramolecular SN2 reaction, which was explained by quantum chemical calculation. The HOMO-LUMO gap and the free energy revealed the spontaneous of the tautomeric of the 1 and 2. Additionally, the similar phenomena were also found in the two groups of known compounds 3 and 4 and 6 and 7, respectively. Apart from the tautomer, compounds 3 and 4 can be hydrolyzed into 5 through ester hydrolysis in CDCl3, while compounds 6, 7 can be hydrolyzed into 8 through ester hydrolysis. These phenomena were also confirmed through HPLC analysis and low temperature nuclear magnetic resonance tests and the mechanism was studied using quantum chemical calculation.

Regioselective Iridium-Catalyzed C8-H Borylation of 4-Quinolones via Transient O-Borylated Quinolines.

The quinolone-quinoline tautomerization is harnessed to effect the regioselective C8-borylation of biologically important 4-quinolones by using [Ir(OMe)(cod)]2 as the catalyst precursor, the silica-supported monodentate phosphine Si-SMAP as the ligand, and B2 pin2 as the boron source. Initially, O-borylation of the quinoline tautomer takes place. Critically, the newly formed 4-(pinBO)-quinolines then undergo N-directed selective Ir-catalyzed borylation at C8. Hydrolysis of the OBpin moiety on workup returns the system to the quinolone tautomer. The C8-borylated quinolines were converted to their corresponding potassium trifluoroborate (BF3 K) salts and to their C8-chlorinated quinolone derivatives. The two-step C-H borylation-chlorination reaction sequence resulted in various C8-Cl quinolones in good yields. Conversion to C8-OH-, C8-NH2 -, and C8-Ar-substituted quinolones was also feasible by using this methodology.

Clarifying the structures of imidines: using crystallographic characterization to identify tautomers and localized systems of π-bonding.

Nitrogen heterocycles are a class of organic compounds with extremely versatile functionality. Imidines, HN[C(NH)R]2, are a rare class of heterocycles related to imides, HN[C(O)R]2, in which the O atoms of the carbonyl groups are replaced by N-H groups. The useful synthesis of the imidine compounds succinimidine and glutarimidine, as well as their partially hydrolyzed imino-imide congeners, was first described in the mid-1950s, though structural characterization is presented for the first time in this article. In the solid state, these structures are different from the proposed imidine form: succinimidine crystallizes as an imino-amine, 2-imino-3,4-dihydro-2H-pyrrol-5-amine, C4H7N2 (1), glutarimidine as 6-imino-3,4,5,6-tetrahydropyridin-2-amine methanol monosolvate, C5H9N3·CH3OH (2), and the corresponding hydrolyzed imino-imide compounds as amino-amides 5-amino-3,4-dihydro-2H-pyrrol-2-one, C4H6N2O (3), and 6-amino-4,5-dihydropyridin-2(3H)-one, C5H8N2O (4). Imidine 1 was also determined as the hydrochloride salt solvate 5-amino-3,4-dihydro-2H-pyrrol-2-iminium chloride-2-imino-3,4-dihydro-2H-pyrrol-5-amine-water (1/1/1), C4H8N3+·Cl-·C4H7N3·H2O (1·HCl). As such, 1 and 2 show alternating short and long C-N bonds across the molecule, revealing distinct imino (C=NH) and amine (C-NH2) groups throughout the C-N backbone. These structures provide definitive evidence for the predominant imino-amine tautomer in the solid state, which serves to enrich the previously proposed imidine-focused structures that have appeared in organic chemistry textbooks since the discovery of this class of compounds in 1883.

Theoretical modelling of structure, vibrational and UV-vis absorbance spectra of rubrofusarin molecule.

The structure of the rubrofusarin molecule (CAS: 3567-00-8, IUPAC name 5,6-dihydroxy-8-methoxy-2-methyl-4H-benzo[g]chromen-4-one, molecular formula C15H12O5) and its possible rotational conformers and tautomer were investigated within DFT approach. It was noted that for a stable molecules the group symmetry is close to Cs. The smallest potential barrier for rotational conformers is associated with the methoxy group rotation. The rotation of hydroxyl groups leads to a stable states that are substantially higher in energy than the ground state. Modeling and interpretation of vibrational spectra for the case of the ground state molecule in the gas phase and methanol solution was carried out, the influence of the solvent is discussed. The modelling of electronic singlet transition within the TD-DFT approach and the interpretation of obtained UV-vis absorbance spectra were carried out. A relatively small shift in the two most active absorption bands wavelength takes place for methoxy group rotation conformer. At the same time the redshift of the HOMO-LUMO transition takes place for this conformer. Much larger long wavelength shift of the absorption bands was noted for the tautomer.

A method for in vitro data and structure curation to optimize for QSAR modelling of minimum absolute potency levels and a comparative use case.

Large screening programs such as the US Tox21 are releasing experimental in vitro results for many endpoints of relevance for human health. In (Q)SAR modelling, it is essential to clearly define the endpoint (OECD QSAR Validation Principle 1) and extract the most robust data points according to the definition. We have developed a comprehensive data curation procedure to interpret in vitro experimental data sets for (Q)SAR development, with modules for selecting actives according to quality of curve fittings, magnitude of activity and 'absolute' potency cut-offs, requiring non-cytotoxicity at activity concentration; extracting only very robust inactives; selecting only substances tested in high purity; and accounting for assay signal interference. A structure curation procedure with uniform representation of tautomeric classes of substances is also developed. The detailed method and a use case of modelling Tox21 data for an estrogen receptor α agonism assay with and without use of the method is presented.

Characterization of tautomeric forms of anti-cancer drug gemcitabine and their interconversion upon mechano-chemical treatment, using ATR-FTIR spectroscopy and complementary methods.

Gemcitabine is a widely used anti-cancer drug of pyrimidine structure, which can exist as a free base molecular form in crystals. Tautomers are structural isomers of molecules, which interconvert via proton transfer. Mechano-chemistry studies reactions of solids under mechanical impact. We investigated gemcitabine free base for the presence of specific molecular tautomers, using ATR-FTIR spectroscopic analysis, powder XRD, optical microscopy and HPLC. The amino-keto tautomer has the characteristic infrared (IR) peak of the amino group at 3390 cm-1. For the first time, the imino-keto tautomer of gemcitabine free base was detected. The imino-keto tautomer has the characteristic IR peak of the =N-H group, and its peak due to the CO group in pyrimidine ring is shifted vs. that of the amino-keto tautomer. This serves as the unique spectroscopic "fingerprints" of these tautomers. The ATR-FTIR spectroscopic analysis shows that gemcitabine free base can be enriched with the amino-keto or the imino-keto tautomer. Further, we studied the transformation of gemcitabine free base in crystals between its tautomers under conditions of liquid-assisted grinding (LAG). The imino-keto tautomer undergoes tautomerization to the amino-keto tautomer, while the amino-keto tautomer remains stable. No destruction of molecules of gemcitabine free base, when present as either tautomer, occurs during LAG as was verified by the HPLC-UV analysis. LAG is a new, straightforward, facile and fast method to interconvert tautomers in crystals, and ATR-FTIR spectroscopy is a method of choice to study tautomerization reactions of pharmaceuticals. The presented approach is promising for analysis of crystals of drugs containing one or more than one tautomer, and the knowledge-driven design of composite materials, which contain specific tautomeric molecular forms of pyrimidines, purines and other biologically active heterocyclic compounds.

Tautomerization and Isomerization in Quantitative NMR: A Case Study with 4-Deoxynivalenol (DON).

The regulated mycotoxin 4-deoxynivalenol (DON) has a heterocyclic structure that is readily amenable to tautomerization and conformational isomerization in solution. An analysis of DON in solution by NMR revealed the presence of hemiacetal tautomer(s) and putative conformational isomers, which maintain the intact enone functional group. The extent and type of tautomerization/isomerization vary according to the NMR solvent used and produce different signal patterns in the NMR spectra. Thus, the same proton produces multiple signals depending on which isomer/tautomer it belongs to. To maintain the accuracy of quantitative NMR (qNMR) measurements, it was essential to conclusively identify all signals belonging to the same proton to avoid underestimating its integral value. A strategy to overcome the complications of DON tautomerization and isomerization in solution during qNMR is reported. Of all proton atoms on the DON carbo-skeleton, H-10 produced clearly defined signals centered at 6.6 ppm for suspected conformational isomers and at 5.5 ppm for hemiacetal tautomers. To determine the purity of DON by quantitative proton NMR, the collective integrals of all isomeric and tautomeric signals belonging to H-10 provided the most accurate value. The purity of DON obtained with this protocol is highly accurate and suitable for the value assignment of certified reference materials (CRMs).

Synthesis of 4,4-Disubstituted 3,4-Dihydropyrimidin-2(1H)-ones and -thiones, the Corresponding Products of Biginelli Reaction Using Ketone, and Their Antiproliferative Effect on HL-60 Cells.

An efficient synthetic method for novel 4,4-disubstituted 3,4-dihydropyrimidin-2(1H)-ones 5 and -thiones 6 was developed. The cyclocondensation reaction of O-methylisourea hemisulfate salt 11 with 8 gives a tautomeric mixture of dihydropyrimidines 12 and 13 following acidic hydrolysis of the cyclized products to produce 5 in high yields. Thionation reaction of 5 at the 2-position smoothly proceeds to give 2-thioxo derivatives 6. These compounds 5 and 6, corresponding to the products of a Biginelli-type reaction using urea or thiourea, a ketone and a 1,3-dicarbonyl compound, have long been inaccessible and hitherto unavailable for medicinal chemistry. These methods are invaluable for the synthesis of 5 and 6, which have been inaccessible by conventional methods. Therefore, the synthetic methods established in this study will expand the molecular diversity of their related derivatives. These compounds were also assessed for their antiproliferative effect on a human promyelocytic leukemia cell line, HL-60. Treatment of 10 µM 6b and 6d showed high inhibitory activity similarly to 1 µM all-trans retinoic acid (ATRA), indicating that the 2-thioxo group and length of two alkyl substituents at the 4-position are strongly related to activity.

Crystal structure and Hirshfeld surface analysis of 6,6'-((1E,1'E)-{[1,4-phenyl-enebis(methyl-ene)]bis(aza-nylyl-idene)}bis-(methane-ylyl-idene))bis-(2-meth-oxy-phenol).

The Schiff base compound, C24H24N2O4, was synthesized by the inter-action of 2-hy-droxy-3-meth-oxy benzaldehyde and 1,4-benzene dimethanamine in ethanol, and crystallizes in the monoclinic space group P21/n with Z' = 0.5. The mol-ecule is not planar, the 1,4-di-ethyl-benzene and the phenol rings are twisted with respect to each other, making a dihedral angle of 74.27 (5)°. The mol-ecular structure is stabilized by an O-H⋯N hydrogen bond, forming an S(6) ring motif. In the crystal, mol-ecules are linked by C-H⋯O hydrogen bonds, resulting in the formation of sheets parallel to the bc plane. A Hirshfeld surface analysis was undertaken to investigate the various inter-molecular contacts controlling the supra-molecular topology, suggesting the H⋯O (18%) contacts to be the most significant inter-actions, whereas the H⋯H (50.5%) and C⋯H (24.3%) inter-actions are less significant.

Crystal structure and Hirshfeld surface analysis of (Z)-2-{[(2,4-di-methyl-phen-yl)imino]-meth-yl}-4-methyl-phenol.

The title compound, C16H17NO, is a Schiff base that exists in the enol-imine tautomeric form and adopts a Z configuration. The mol-ecule is non-planar, with the twisted rings making a dihedral angle of 39.92 (4)°. The intra-molecular O-H⋯N hydrogen bond forms an S(6) ring motif. In the crystal, mol-ecules are linked by C-H⋯π inter-actions and very weak π-π stacking inter-actions also help to consolidate the crystal packing. A Hirshfeld surface analysis was performed to investigate the contributions of different inter-molecular contacts within the supra-molecular structure. The major contributions are from H⋯H (65%), C⋯H (19.2%) and O⋯H (6.6%) inter-actions.

Atomistic mechanisms of the tautomerization of the G·C base pairs through the proton transfer: quantum-chemical survey.

This study is devoted to the investigation of the G·C*tO2(WC)↔G*NH3·C*t(WC), G·C*O2(WC)↔G*NH3·C*(WC) and G*·C*O2(WC)↔G*NH3·C(wWC)↓ tautomerization reactions occurring through the proton transfer, obtained at the MP2/6-311++G(2df,pd)//B3LYP/6-311++G(d,p) level of theory in gas phase under normal conditions ('WC' means base pair in Watson-Crick configuration, T=298.15 K). These reactions lead to the formation of the G*NH3·C*t(WC), G*NH3·C*(WC) and G*NH3·C(wWC)↓ base pairs by the participation of the G*NH3 base with NH3 group. Gibbs free energies of activation for these reactions are 6.43, 11.00 and 1.63 kcal·mol-1, respectively. All of these tautomerization reactions are dipole active. Finally, we believe that these non-dissociative processes, which are tightly connected with the tautomeric transformations of the G·C base pairs, play an outstanding role in supporting of the spatial structure of the DNA and RNA molecules with various functional purposes.

Stabilization of an elusive tautomer by metal coordination.

The solid-state isolation of the different tautomers of a chemical compound can be a challenging problem. In many cases, tautomers with an energy very close to the most stable one cannot be isolated (elusive tautomers). In this article, with reference to the 4-methyl-7-(pyrazin-2-yl)-2H-[1,2,4]triazolo[3,2-c][1,2,4]triazole ligand, for which the elusive 3H-tautomer has an energy only 1.4 kcal mol-1 greater than the most stable 2H form, we show that metal complexation is a successful and reliable way for stabilizing the elusive tautomer. We have prepared two complexes of the neutral ligand with CuBr2 and ZnBr2, namely, aquabromidobis[4-methyl-7-(pyrazin-2-yl)-3H-[1,2,4]triazolo[3,2-c][1,2,4]triazole]copper(II) bromide trihydrate, [CuBr(C8H7N7)2(H2O)]Br·3H2O, and dibromido[4-methyl-7-(pyrazin-2-yl)-2H-[1,2,4]triazolo[3,2-c][1,2,4]triazole][4-methyl-7-(pyrazin-2-yl)-3H-[1,2,4]triazolo[3,2-c][1,2,4]triazole]zinc(II) monohydrate, [ZnBr2(C8H7N7)2]·H2O. The X-ray analysis shows that, in both cases, the elusive 3H-tautomer is present. The results of the crystallographic analysis of the two complexes reflect the different coordination preferences of CuII and ZnII. The copper(II) complex is homotautomeric as it only contains the elusive 3H-tautomer of the ligand. The complex can be described as octahedral with tetragonal distortion. Two 3H-triazolotriazole ligands are bis-chelated in the equatorial plane, while a water molecule and a bromide ion in elongated axial positions complete the coordination environment. The zinc(II) complex, on the other hand, is heterotautomeric and contains two bromide ions and two monodentate ligand molecules, one in the 2H-tautomeric form and the other in the 3H-tautomeric form, both coordinated to the metal in tetrahedral geometry. The observation of mixed-tautomer complexes is unprecedented for neutral ligands. The analysis of the X-ray molecular structures of the two complexes allows the deduction of possible rules for a rational design of mixed-tautomer complexes.

Simple and efficient preparation of high-purity trehalulose from the waste syrup of isomaltulose production using solid-phase extraction followed by hydrophilic interaction chromatography.

A simple and efficient method was developed for the preparation of high-purity trehalulose from the waste syrup of isomaltulose production. The waste syrup was pre-treated with C18 solid-phase extraction, where 98% decolorization and 97% reducing sugar recovery were obtained, followed by hydrophilic interaction liquid chromatography separation on a cysteine-bonded zwitterionic column. Under optimized conditions, trehalulose was separated from isomaltulose isomer and prepared on a semi-preparative scale with >99% purity. The structure of the prepared trehalulose was subsequently confirmed by nuclear magnetic resonance, and three tautomers of trehalulose (α-D-glucosylpyranosyl-1,1-ß-D-fructopyranose, α-D-glucosylpyranosyl-1,1-ß-D-fructofuranose, and α-D-glucosylpyranosyl-1,1-α-D-fructofuranose) were detected and completely characterized by 13 C NMR spectroscopy for the first time in this study. The tautomerization of α-D and ß-D type transition was observed by hydrophilic interaction liquid chromatography on an AdvanceBio Glycan Mapping column, with smaller particle size (2.7 µm). Furthermore, the prepared trehalulose was applied as a standard for trehalulose quantification during the sucrose conversion by Klebsiella sp. LX3. The combination of solid-phase extraction and hydrophilic interaction liquid chromatography offers a new avenue for the preparation of sugar isomers from complex natural or fermentation products.

Characterization and demonstration of drug compound ring-chain tautomer formation and its impacts on quality control.

Unknown chromatographic peaks, potential impurities, were observed in a series of related compounds. This led to the identification and characterization of tautomeric equilibria. Structural elucidation was required to understand the potential impurity profile, thus impacting method development for quality control. In this work, characterization of the chemical structures, AZ13581258 and AZD5718, and equilibria of the tautomeric forms was performed using a range of advanced analytical techniques such as preparative chromatography, nuclear magnetic resonance (NMR), chromatographic detection by mass spectrometry (MS), MSMS, and ultraviolet spectroscopy (UV). Predictions using density functional theory (DFT) further explains and confirms the tautomer equilibria through predictions of reaction barrier energies, UV-spectra and NMR data. These investigations led to fully understand the impurity profile and to the development of a quality control method for AZD5718 drug substance and drug product. In conclusion, ring-chain tautomeric structures are predominately formed under acidic conditions, and the additional peaks observed in LC during organic impurity determination were found to originate from ring-chain closed tautomers in equilibria with the parent open form compound. Hence, the closed and open tautomer forms should all be considered as the same compound.

[Development of Efficient Synthetic Method for Tautomeric Dihydropyrimidines and Analysis of Their Functionality].

I here present the results of our studies on the synthesis and functional analysis of tautomeric dihydropyrimidines (DPs) and related compounds in two sections. In the first section, we describe our experimental and theoretical studies on the thermodynamics and properties of 2-substituted 1,4- and 1,6-dihydropyrimidine-5-carboxylates by 1H NMR measurements and density functional theory (DFT) calculations, respectively. The concentration ratios of tautomers a/b of DPs 1, 2, and 3 were determined under various conditions to determine the effects of temperature, solvent, and concentration on thermodynamics data. The obtained free energy differences (ΔG), enthalpy differences (ΔH), and entropy differences (ΔS) are discussed in terms of the molecular structures, dipole moments (DM), and electrostatic potential maps obtained by DFT calculations to clarify the nature of DPs 4-8. In the second section, an efficient synthetic method developed for 6-unsubstituted 3,4-dihydropyrimidin-2(1H)-thiones 9 and 2-ones 10 is described. The novelties of the synthesis protocol are as follows: 1) the use of Lewis acid-mediated reaction, 2) good to high yields, and 3) its broad scope of applicability to aldehydes and ureas. Hitherto unavailable 6-unsubstituted 2-amino DP 11 and 2-aryl DP 12 were obtained from 9 by a substitution reaction with the amine and the Liebeskind-Srogl reaction, respectively. The compounds 9, 10, and related 6-methyl derivatives 19-21 were assessed for their antiproliferative effect on the human promyelocytic leukemia cell line HL-60. 4,4-Dipropyl derivative 20 showed relatively strong activity with an IC50 value of 341 nM.

Pattern-free generation and quantum mechanical 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.