Enol Tautomer Research Articles

Ketone–enol tautomerism, polymorphism, mechanofluorochromism and solid-state acidochromism of isoquinolinone–arylidenehydrazine derivatives

Four isoquinolinone–arylidenehydrazine derivatives with keto–enol tautomerism exhibit amazing multifunctional properties.

The keto-enol tautomerization of ethyl acetoacetate in choline ionic liquids: the role of cation and anion in switching the tautomeric equilibrium.

In this work, density functional theory (DFT) calculations were carried out to study the role of the explicit treatment of four different choline-based ionic liquids (CS, CP, NS, and NP) by utilizing two different cations and anions in the tautomeric equilibrium of ethyl acetoacetate (EAA). The involvement of the acidic N-H proton from the cationic part of NS and NP ionic liquid offers the possibility to have two more additional transition states for the tautomeric equilibrium of EAA. The computed results demonstrated that a high activation free energy barrier (ΔG = 49.4 kcal mol-1) is associated with the direct enol to keto (E → K) interconversion via a 4-membered ring transition state. Upon explicit involvement of the cationic part of ionic liquids in the tautomeric equilibrium via a 6-membered ring transition state (CAT), ΔG is substantially reduced to 21.88 kcal mol-1. Further, ΔG is drastically reduced to 10.57 kcal mol-1 upon the involvement of the anionic part of the ionic liquid explicitly via an 8-membered ring transition state (AAT). The W-shaped TS in the CAT pathway causes steric hindrance and increases the energy penalty, while the sickle-shaped TS in AAT facilitates easy proton transfer without the influence of the steric factor. In addition, the RDG scatter graphs predict large negative values of ρ*, which indicate that the hydrogen bonding network in AAT is stronger, enhancing the delocalization of the electron density. The QTAIM analysis substantiated the role of intermolecular hydrogen bonding interactions between the ionic liquid and EAA and within the anion-cation pair in stabilizing the keto group of EAA. Besides, the involvement of the acidic N-H proton in the transition state is the key factor in influencing the energetics of the keto-enol tautomerization reaction. The present study illustrates molecular-level insights into the role of individual ions of ionic liquids and also provides adequate ideas for designing novel ionic liquid-based catalysts for industrially relevant chemical reactions.

Cochineal quinone carbon dot synthesis via a keto–enol tautomerism strategy and their intermolecular photo-induced cross-redox interactions with tetracycline

Specific molecular recognition of tetracycline by carminic acid-formed carbon dots taking advantage of the common quinone molecular structural unit.

Structural insights into the bypass of the major deaminated purines by translesion synthesis DNA polymerase.

The exocyclic amines of nucleobases can undergo deamination by various DNA damaging agents such as reactive oxygen species, nitric oxide, and water. The deamination of guanine and adenine generates the promutagenic xanthine and hypoxanthine, respectively. The exocyclic amines of bases in DNA are hydrogen bond donors, while the carbonyl moiety generated by the base deamination acts as hydrogen bond acceptors, which can alter base pairing properties of the purines. Xanthine is known to base pair with both cytosine and thymine, while hypoxanthine predominantly pairs with cytosine to promote A to G mutations. Despite the known promutagenicity of the major deaminated purines, structures of DNA polymerase bypassing these lesions have not been reported. To gain insights into the deaminated-induced mutagenesis, we solved crystal structures of human DNA polymerase η (polη) catalyzing across xanthine and hypoxanthine. In the catalytic site of polη, the deaminated guanine (i.e., xanthine) forms three Watson-Crick-like hydrogen bonds with an incoming dCTP, indicating the O2-enol tautomer of xanthine involves in the base pairing. The formation of the enol tautomer appears to be promoted by the minor groove contact by Gln38 of polη. When hypoxanthine is at the templating position, the deaminated adenine uses its O6-keto tautomer to form two Watson-Crick hydrogen bonds with an incoming dCTP, providing the structural basis for the high promutagenicity of hypoxanthine.

Cytotoxic activities of synthesized curcumin and 3,4-Difluorinated curcumin against HepG2, LU-1 and KB cancer cell lines

Introduction: Natural curcuminoids isolated from turmeric (Curcuma longa L.) have been limited in number and the amount of substrates evaluated in semi-synthetic processes and biological tests. Currently, potent anticancer activities of curcuminoids have garnered increased attention such that a greater number of synthetic procedures of curcumin analogues have been developed for further biological evaluations. The fluorine substituent of fluorinated compounds is important for biological responses. However, natural products bearing fluorine have rarely been found. In the study herein, we employed an aldol condensation between 4-hydroxy-3-methoxybenzaldehyde/3,4- difluorobenzaldehyde and pentane-2,4-dione to synthesize the desired curcumin (Cur) and 3,4- difluorinated curcumin (3,4-DFCur). Their half-maximal inhibitory concentration (IC50) values against HepG2, LU-1 and KB cancer cell lines were then assessed.
 Methods: Pentane-2,4-dione was converted to enol form by using B2O3 before carrying out C-C coupling reactions with benzaldehyde analogues under basic conditions. The water scavenger was added to the reaction to capture the produced water. The reaction mixture was stirred at 70 ◦C. The reaction progress was monitored by thin layer chromatography (TLC). Crude products were purified by flash column chromatography (CC; SiO2, eluent: HEX/EA = 9/1!7/3). The chemical structures of the desired products were elucidated by 1H, 13C-NMR, HSQC and MS spectra. The anticancer activities of Cur and 3,4- DFCur against HepG2, LU-1 and KB cancer cell lines were determined using MTT method.
 Results: Under reasonable reaction conditions, the yields for the coupling reactions were 53 and 72% for Cur and 3,4-DFCur, respectively. The stable enol tautomer of 1,3-diketone and the trans-configuration in a seven-carbon chain of product skeletons were assigned by 1H-NMR spectra. All synthesized products showed anticancer activities, with Cur exhibiting higher inhibitory activities when compared with 3,4-DFCur. Cur and 3,4-DFCur are Michael Acceptors; their cytotoxic activities could be attributed to the inhibition of glutathione S-transferase, a detoxification enzyme, by forming glutathionyl adducts. The decreased inhibitory capacities of 3,4-DFCur were due to the effect of fluorine which results in the unfavorable formation of reactive radicals and an increase in lipophilicity.
 Conclusions: Curcumin and 3,4-difluorinated curcumin were completely synthesized in 53% and 72% yields. The synthetic procedure is applicable for synthesizing curcumin derivatives bearing various substituents on the aromatic rings, i.e., not limited to methoxy (-OCH3) and hydroxy (- OH) groups. Unexpectedly, the presence of fluorines in 3,4-DFCur led to lower cytotoxic activities against cancer cell lines. Our results provide greater insight on the structure-activity relationship of curcumin analogues against cancer cell lines.

New pyrazole‐4‐carbothioamide‐based metal complexes: Synthesis, spectral characterization, computational, antimicrobial, and antitumor investigations

A series of 5‐hydroxy‐4‐(N‐substituted carbothioamide) pyrazole derivatives (HL1–HL5) and their iron(III), nickel(II), and copper(II) complexes have been synthesized. Structural elucidations of the isolated ligands and their complexes are basically accomplished by FT‐IR, 1H NMR, 13C NMR, UV–Vis, ESR, MS, and thermogravimetric analysis (TGA). The analytical data propose the stoichiometries 1:3 (M:L) for Fe(III) and 2:3 for both Ni(II) and Cu(II) complexes. The spectral data substantiate the bidentate coordination mode for all ligands towards metal ions via S and O atoms of CS of the carbothioamide group at pyrazole‐C4 and OH group at C(5) where deprotonation occurs from the enolic tautomer on chelation. Likewise, bidentate pattern of a bridged acetate group is confirmed in the case of Ni(II) and Cu(II) complexes. The magnetic moment values validate high spin octahedral geometry for Fe(III) complexes whereas the diamagnetic feature of Ni(II) complexes is in conformity with the square planar symmetry of low spin state. ESR spectra of all Cu(II) complexes support their existence in distorted square planar geometry with a considerable electron exchange between two copper ion centers of dinuclear type. TGA and DTG analysis of six complexes display their considerable thermal stability. Besides, the in vitro biological screening effects of some selected compounds are tested against various human pathogen microorganisms. Among the ligands, HL5 exhibits the greatest antibacterial activity against two Gram‐positive species (Bacillus subtilis and Staphylococcus aureus) and one Gram‐negative (Proteus vulgaris) in comparison with gentamicin drug. Furthermore, IC50 values of [Cu2(L5)3(OAc)] complex reveal its significant anticancer activity against the three tumor cell lines HCT‐116, MCF‐7, and HepG‐2 compared with imatinib and cisplatin as positive controls. Finally, the optimized structures of all ligands and their molecular electrostatic potential surfaces are established by utilizing density functional theory (DFT).

A new insight of lignin pyrolysis mechanism based on functional group evolutions of solid char

To elucidate the mechanism of biomass lignin pyrolysis, the functional group evolution in lignin chars derived at 200–600 °C was investigated using two-dimensional perturbation correlation infrared spectroscopy, associated with the properties of the volatile products. Results from 2D-PCIS pointed that the change in the alcohol groups C–OH occurs earlier than that in the carbonyl groups CO before 250 °C, corresponding to the reaction of keto–enol tautomerization: C–OH → CO, and the cleavage of bonds and remodeling reactions of the side chains of the benzene rings are synchronous. Besides, the formation of simple substituted benzene structures was earlier than complex substituted benzene structures. Decarbonylation, dehydrogenation and dealkylation were intensified during polycondensation of benzene rings. These findings are significant for achieving an in-depth understanding of lignin pyrolysis.

Stability Studies of New Caged bis-deoxy-coelenterazine Derivatives and Their Potential Use as Cellular pH Probes.

The synthesis of new bis-deoxy-coelenterazine (1) derivatives bearing ester protective groups (acetate, propionate and butyrate esters) was accomplished. Moreover, their hydrolytic stability at room temperature was evaluated in dimethylsulfoxide (DMSO) as solvent, using the nuclear magnetic resonance (NMR) spectra of the key products at different time intervals. The results showed an increasing hydrolysis rate according to longest aliphatic chain, with a half-life of 24days of the more stable acetate derivative (4a). Furthermore, the analysis of the experimental data revealed the greater stability of the enol tautomer in this aprotic polar solvent. This result was confirmed by theoretical calculations using the density functional theory (DFT) approach, which gave us the opportunity to propose a detailed decomposition mechanism. Additionally, the derivatives obtained were tested by bioluminescence luciferase assays to evaluate their potential use as extracellular pH-sensitive reporter substrates of luciferase. The biological data support the idea that further structural modifications of these molecules may open promising perspectives in this field of research.

Theoretical investigation of solvent effect on the keto–enol tautomerization of pentane-2,4-dione and a comparison between experimental data and theoretical calculations

The equilibrium constants of stable keto and enol forms of pentane-2,4-dione (known as acetylacetone) are estimated, using the second-order Møller−Plesset (MP2), density functional theory (B3LYP and M06-2X), composite methods (G4, G3, G3B3, CBS-QB3, and G3MP2B3), double-hybrid density functional theory (B2PLYP), and long-range corrected (LC) hybrid functional (ωB97X-D). These methods are integrated with the PCM, CPCM, and SMD models to elucidate the effect of solvent on thermodynamic parameters. The reported measured enol contents in the solutions and gas phase are utilized to benchmark the predictions of different quantum mechanical methods for the keto–enol equilibrium in acetylacetone. In this study, we calculated the enol content in 16 acetylacetone solutions and in the gas phase. Among the applied methods, the MP2 level and the B3LYP level underestimate and overestimate, respectively, the enol content of acetylacetone in the gas phase and solutions. The G3B3 and G3MP2B3 levels give reasonable agreement with the measured data. The best results obtained by calculations at the B2PLYP/6-31+G(2d,p) and CBS-QB3 levels, with mean absolute errors (MAE) relative to experiments of 2.30 and 5.45 and root mean square deviation (RMSD) errors of 0.78 and 1.66, respectively. According to our calculations, one enol and two keto forms (Ket1 and Ket2) coexist in polar solutions. The effect of solvent was more pronounced on the structure and stability of the Ket2 tautomer than others. The strength of the intramolecular hydrogen bond in the enol form of acetylacetone is almost independent of the solvent polarity.

The Keto-Enol Tautomerism of Biliverdin in Bacteriophytochrome: Could it Explain the Bathochromic Shift in the Pfr Form?†.

Phytochromes are ubiquitous photoreceptors found in plants, eukaryotic algae, bacteria and fungi. Particularly, when bacteriophytochrome is irradiated with light, a Z-to-E (photo)isomerization takes place in the biliverdin chromophore as part of the Pr-to-Pfr conversion. This photoisomerization is concomitant with a bathochromic shift in the Q-band. Based on experimental evidence, we studied a possible keto-enol tautomerization of BV, as an alternative reaction channel after its photoisomerization. In this contribution, the noncatalyzed and water-assisted reaction pathways for the lactam-lactim interconversion through consecutive keto-enol tautomerization of a model BV species were studied deeply. It was found that in the absence of water molecules, the proton transfer reaction is unable to take place at normal conditions, due to large activation energies, and the endothermic formation of lactim derivatives prevents its occurrence. However, when a water molecule assists the process by catalyzing the proton transfer reaction, the activation free energy lowers considerably. The drastic lowering in the activation energy for the keto-enol tautomerism is due to the stabilization of the water moiety through hydrogen bonds along the reaction coordinate. The absorption spectra were computed for all tautomers. It was found that the UV-visible absorption bands are in reasonable agreement with the experimental data. Our results suggest that although the keto-enol equilibrium is likely favoring the lactam tautomer, the equilibrium could eventually be shifted in favor of the lactim, as it has been reported to occur in the dark reversion mechanism of bathy phytochromes.

Quantum-Chemical Modeling of Interaction between the Most Stable Methylamine-Pyridoxal-5'-Phosphate Tautomers and Water: Structure and Properties of Monohydrates and Dihydrates

Quantum chemical caculations of the most stable conformers of methylamine-pyridoxal-5-phosphate Schiff base three tautomeric (enol, keto, and zwitterionic) structures and their monohydrates and dihydrates have been carried out at the B3LYP/6-31+G**, M062X/6-31+G**, and BVP86/TZVP levels of theory. The optimized structures, harmonic force fields, and vibrational frequencies of tautomers have been obtained. The influence of macrohydration on the conformational composition of tautomers have been studied using the polarized continuum model. Vertical ionization potentials of the most stable monohydrates and dihydrates of methylamine-pyridoxal-5'-phosphate tautomers have been calculated. The influence of macrohydration and microhydration on the structure, spectra, and vertical ionization energies of the monohydrates and dihydrates of methylamine-pyridoxal-5-phosphate tautomers have been discussed.

Oligo(ethylene glycol) (OEG) functionalized 2-(2′-Hydroxy benzofuranyl) benzoxazole (HBBO) derivatives: Synthesis, photophysical properties and biomolecules binding studies

Two molecular fluorophores based on a 2-(2′-Hydroxybenzofuranyl) benzoxazole (HBBO) scaffold and presenting an Excited-State Intramolecular Proton Transfer (ESIPT) process are reported herein. These dyes incorporate strongly electrodonating aromatic amino groups on the benzofuranyl side, enabling the appearance of a dual fluorescence emission corresponding to the radiative decay of the excited enol (E*) and keto (K*) tautomers at high and low energy respectively. It was previously demonstrated that dual E*/K* emission could originate from a beneficial decrease of phenolic acidity upon absorption of light leading to a thermodynamic stabilization of the first excited-state. The innovation within these dyes lies in the double functionalization of the aniline moiety with 2-(2-methoxyethoxy)ethyl units which allowed a better solubilization in protic solvents, as compared to their butyl analogs while keeping strong electrodonating capacity. Their intrinsic amphiphilic character leads to a good vectorization in a wide range of solvents from toluene to PBS buffer. The investigation of the photophysical properties of these dyes in solution showed a clear dual emission in apolar solvents with the E* band gradually red-shifting along with the dipole moment of the solvent. Dual emission is also observed in the solid-state when these dyes are doped as 1% wt in PMMA or PS films. Finally, the interactions of one dye with calf-thymus (ct)-DNA and Bovine Serum Albumin (BSA) have been explored and reveal pronounced modifications of the UV–Vis profile of the dye. Additionally, a gradual hypsofluorochromic shift and narrowing of the K* band along with the appearance of the E* fluorescence band upon addition of ct-DNA or BSA is also observed, presumably evidencing an intercalation mode of binding.

8-(Pyridin-2-yl)quinolin-7-ol as a Platform for Conjugated Proton Cranes: A DFT Structural Design

Theoretical design of conjugated proton cranes, based on 7-hydroxyquinoline as a tautomeric sub-unit, has been attempted by using ground and excited state density functional theory (DFT) calculations in various environments. The proton crane action request existence of a single enol tautomer in ground state, which under excitation goes to the excited keto tautomer through a series of consecutive excited-state intramolecular proton transfer (ESIPT) steps with the participation of the crane sub-unit. A series of substituted pyridines was used as crane sub-units and the corresponding donor-acceptor interactions were evaluated. The results suggest that the introduction of strong electron donor substituents in the pyridine ring creates optimal conditions for 8-(pyridin-2-yl)quinolin-7-ols to act as proton cranes.

Computation of electrical responsive properties and global reactivity descriptors along the proton transfer co-ordinate of donor–acceptor substituted pyrazole derivatives

Ground and excited-state proton transfer and electrical responsive properties along the proton transfer co-ordinate of four donor–acceptor substituted pyrazole derivatives have been investigated using the density function-based range separated hybrid GGA functional ωB97XD with 6-311G(d) basis. Both intrinsic reaction coordinate (IRC) and distinguished co-ordinate (variation of O–H distance of the enol tautomer) have been chosen as a proton transfer co-ordinate of the titled compounds for comparison. Our study reveals that the various electrical responsive parameters like average polarizability (α av), first hyperpolarizability (β av) and global reactivity descriptors e.g., chemical hardness (η), electrophilicity index (ω) along the proton transfer co-ordinate are in conformity with the respective optimum principles. Maximum value of β av is found in the case of nitro substituted pyrazole derivative. Variation of β av along the proton transfer co-ordinate for all compounds have been correlated with the variation of Δµf 0/(S 1-S 0)3 using two-level approximation and electronic special extent (<R 2>) along the proton transfer coordinate.

Some Curcumin Isomers and Their Enol Tautomers - A DFT Treatment

Curcumin is a well known natural product having some health benefits. In the present study, within the constraints of density functional theory (at the level of B3LYP/6-31G(d,p)), some configurational isomers of curcumin and their keto-enol tautomers have been investigated. Some quantum chemical, QSAR and spectral data of them have been obtained and discussed.

Regioselective Synthesis of 6-Chlorofulvene and 6-Aminofulvene via Keto–Enol Tautomerism

Keto–enol tautomerism is a special example of structural isomerism. In this experiment, 6-chlorofulvene is predominantly yielded during the chlorination reaction of 6′-hydroxyfulvene with POCl3 in ...

Observing 3-hydroxyanthranilate-3,4-dioxygenase in action through a crystalline lens

The synthesis of quinolinic acid from tryptophan is a critical step in the de novo biosynthesis of nicotinamide adenine dinucleotide (NAD+) in mammals. Herein, the nonheme iron-based 3-hydroxyanthranilate-3,4-dioxygenase responsible for quinolinic acid production was studied by performing time-resolved in crystallo reactions monitored by UV-vis microspectroscopy, electron paramagnetic resonance (EPR) spectroscopy, and X-ray crystallography. Seven catalytic intermediates were kinetically and structurally resolved in the crystalline state, and each accompanies protein conformational changes at the active site. Among them, a monooxygenated, seven-membered lactone intermediate as a monodentate ligand of the iron center at 1.59-Å resolution was captured, which presumably corresponds to a substrate-based radical species observed by EPR using a slurry of small-sized single crystals. Other structural snapshots determined at around 2.0-Å resolution include monodentate and subsequently bidentate coordinated substrate, superoxo, alkylperoxo, and two metal-bound enol tautomers of the unstable dioxygenase product. These results reveal a detailed stepwise O-atom transfer dioxygenase mechanism along with potential isomerization activity that fine-tunes product profiling and affects the production of quinolinic acid at a junction of the metabolic pathway.

Temperature-Dependent Formation of Acetophenone Oligomers Accompanied by Keto–Enol Tautomerism: Real Space Distribution

We present a mechanistic study addressing formation, adsorption configuration, and stability of acetophenone oligomers on a catalytically active Pt(111) surface by a combination of scanning tunneli...

Environmental Effects on Guanine-Thymine Mispair Tautomerization Explored with Quantum Mechanical/Molecular Mechanical Free Energy Simulations.

DNA bases can adopt energetically unfavorable tautomeric forms that enable the formation of Watson-Crick-like (WC-like) mispairs, which have been proposed to give rise to spontaneous mutations in DNA and misincorporation errors in DNA replication and translation. Previous NMR and computational studies have indicated that the population of WC-like guanine-thymine (G-T) mispairs depends on the environment, such as the local nucleic acid sequence and solvation. To investigate these environmental effects, herein G-T mispair tautomerization processes are studied computationally in aqueous solution, in A-form and B-form DNA duplexes, and within the active site of a DNA polymerase λ variant. The wobble G-T (wG-T), WC-like G-T*, and WC-like G*-T forms are considered, where * indicates the enol tautomer of the base. The minimum free energy paths for the tautomerization from the wG-T to the WC-like G-T* and from the WC-like G-T* to the WC-like G*-T are computed with mixed quantum mechanical/molecular mechanical (QM/MM) free energy simulations. The reaction free energies and free energy barriers are found to be significantly influenced by the environment. The wG-T→G-T* tautomerization is predicted to be endoergic in aqueous solution and the DNA duplexes but slightly exoergic in the polymerase, with Arg517 and Asn513 providing electrostatic stabilization of G-T*. The G-T*→G*-T tautomerization is also predicted to be slightly more thermodynamically favorable in the polymerase relative to these DNA duplexes. These simulations are consistent with an experimentally driven kinetic misincorporation model suggesting that G-T mispair tautomerization occurs in the ajar polymerase conformation or concertedly with the transition from the ajar to the closed polymerase conformation. Furthermore, the order of the associated two proton transfer reactions is predicted to be different in the polymerase than in aqueous solution and the DNA duplexes. These studies highlight the impact of the environment on the thermodynamics, kinetics, and fundamental mechanisms of G-T mispair tautomerization, which plays a role in a wide range of biochemically important processes.

In Situ FTIR Spectroscopic Monitoring of the Formation of the Arene Diazonium Salts and its Applications to the Heck-Matsuda Reaction.

This study depicts the use of a fiber-optic coupled Fourier transform infrared spectroscopy-attenuated total reflection (FTIR-ATR) probe for the in-depth study of arene diazonium salt formation and their utilization in the Heck–Matsuda reaction. The combination of these chemical reactions and in situ IR spectroscopy enabled us to recognize the optimum parameters for arene diazonium salt formation and to track the concentrations of reactants, products and intermediates under actual reaction conditions without time consuming HPLC analysis and the necessity of collecting the sample amid the reaction. Overall advantages of the proposed methodology include precise reaction times as well as identification of keto enol tautomerization in allylic alcohols supporting the ‘path a’ elimination mechanism in the Heck–Matsuda reaction.