Enol Tautomer Research Articles

The Interplay of Hydration and Hydrolysis upon the Keto–Enol Tautomerism of β-Diketones

The Interplay of Hydration and Hydrolysis upon the Keto–Enol Tautomerism of β-Diketones

Synthesis of Hemiindigo Derivatives via a Gold‐Catalyzed Intramolecular Cyclization Strategy

AbstractWe described a gold‐catalyzed synthesis of Z‐hemiindigo frameworks from ortho‐propynol phenyl azides via the β‐hydroxy‐α‐imino gold carbene intermediates. The intermediates are trapped by water or acetone and then subsequently undergo enol tautomerization and dehydration, or release of acetone. The reaction has the advantage of being able to be carried out under mild conditions and in a gram‐scale. Importantly, this method enables a simple and efficient synthesis of the special hemiindigo derivatives for the development of environmentally sensitive photoswitches in biological systems.

Impact of Cations and Implicit Solvent on the Sensitivity of the Enol Tautomers of 3-Nitro-1,2,4-Triazole-5-One: A DFT Study

The explosive sensitivity of the supramolecular interaction between cations (Mn+ = Li+, Na+, K+, Be2+, Ca2+ and Mg2+) with enol tautomers (c0 and c1) of 3-nitro-1,2,4-triazole-5-one (NTO) complexes has been investigated using Density Functional Theory (DFT). The effect of water as the solvent was included via the CPCM approach. At the gas phase, the presence of the metal cations, especially Be2+, significantly increased the bond dissociation energy (BDE) of C-NO2 of the enol tautomers. However, in the presence of the solvent, the BDE was lower than in the gas phase, even in the supramolecular complex of Be2+ - c0 and Be2+ - c1.

Divergent Metabolic Fates of Aromatic Amino Acid-Derived Isomers: Insights from Ex Vivo Metabolomics and HDX-HRMS/MS-Based Resolution of Tautomers.

Tautomers are one of the many types of isomers, and differences in tautomeric structures confer altered chemical and biological properties. Using ultrahigh-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) ex vivo metabolomics, we investigate, in whole blood, the divergent metabolism of enol and keto forms of indole-3-pyruvate (IPyA), a tautomeric product of aromatic amino acid metabolism. Two new compounds resulting from IPyA metabolism were discovered, 3-(1H-indol-3-yl)-2,3-dioxopropanoic acid or "indole-3-oxopyruvic acid" and glutathionyl-indole pyruvate (GSHIPyA), which were characterized via ultraviolet photodissociation (UVPD) and higher-energy collisional dissociation (HCD). Computational calculations support the hypothesis that GSHIPyA forms specifically through the enol form of IPyA. GSHIPyA is also hypothesized to be tautomeric, and a hydrogen-deuterium exchange-high-resolution tandem mass spectrometry (HDX-HRMS/MS) approach is developed to prove the presence of an enol and keto tautomer. HDX of GSHIPyA labels the keto form with an additional deuterium, relative to the enol form. HRMS/MS of the labeled isomers is employed to leverage the relationship of resolving power scaling inversely with the square root of m/z, for Orbitrap mass analyzers. HRMS/MS yields a smaller-molecular-weight deuterated tautomeric product ion, reducing the analyte ion m/z and thus lowering the resolving power necessary to separate the deuterated keto tautomer product ion from the [13]C product ion.

Synthesis of 5-(4-Formylphenyl)barbituric Acid to Access Enolizable Chromophoric Barbituric Acids

AbstractBarbituric acids mono-substituted at the 5-position show keto–enol tautomerism. In the keto form, conjugation to an aryl substituent is interrupted due to the sp³-hybridized carbon atom at the 5-position of barbituric acid. The enol form generates a conjugated π-system to the aryl substituent and acts as an electron-donating group. If the aryl substituent is electron-deficient, a push-pull system is generated that shows typical UV/Vis absorption. These types of compounds are difficult to access synthetically due to their intrinsic convertibility. The synthesis of barbituric acids with a 4-formylphenyl functionality at the 5-position is reported. This compound, 5-(4-formylphenyl)barbituric acid, could be used to introduce extended π-systems with electron-withdrawing groups in great variety by simple condensation reactions. We demonstrate this by a Horner–Wadsworth–Emmons reaction that forms the enolizable dye (E)-5-(4-(4-nitrostyryl)phenyl)barbituric acid.

Stationary External Electric Field-Mimicking the Solvent Effect on the Ground-State Tautomerism and Excited-State Proton Transfer in 8-(Benzo[d]thiazol-2-yl)quinolin-7-ol.

The effect of the external electric field on the ground-state tautomerism in 8-(benzo[d]thiazol-2-yl)quinolin-7-ol has been studied by using density functional theory. The compound exists as an enol tautomer (off state) and under the influence of the external electric field a long-range intramolecular proton transfer can occur, placing the tautomeric proton at the quinolyl nitrogen atom (on state). This is a result of the much higher dipole moment of the end keto tautomer and indicates that the external electric field can be used to mimic the implicit solvent effect in tautomeric systems. In the excited state, the further stabilization of the most polar on state leads to a situation when the excited-state intramolecular proton transfer becomes impossible, limiting the intramolecular rotation to the conical intersection region.

Primordial aqueous alteration recorded in water-soluble organic molecules from the carbonaceous asteroid (162173) Ryugu

We report primordial aqueous alteration signatures in water-soluble organic molecules from the carbonaceous asteroid (162173) Ryugu by the Hayabusa2 spacecraft of JAXA. Newly identified low-molecular-weight hydroxy acids (HO-R-COOH) and dicarboxylic acids (HOOC-R-COOH), such as glycolic acid, lactic acid, glyceric acid, oxalic acid, and succinic acid, are predominant in samples from the two touchdown locations at Ryugu. The quantitative and qualitative profiles for the hydrophilic molecules between the two sampling locations shows similar trends within the order of ppb (parts per billion) to ppm (parts per million). A wide variety of structural isomers, including α- and β-hydroxy acids, are observed among the hydrophilic molecules. We also identify pyruvic acid and dihydroxy and tricarboxylic acids, which are biochemically important intermediates relevant to molecular evolution, such as the primordial TCA (tricarboxylic acid) cycle. Here, we find evidence that the asteroid Ryugu samples underwent substantial aqueous alteration, as revealed by the presence of malonic acid during keto–enol tautomerism in the dicarboxylic acid profile. The comprehensive data suggest the presence of a series for water-soluble organic molecules in the regolith of Ryugu and evidence of signatures in coevolutionary aqueous alteration between water and organics in this carbonaceous asteroid.

Cu‐Catalyzed Reaction of Trifluoromethylated β‐Keto Diazos and Nitriles Proceeding via H2O Addition to Nitrile Ylides

AbstractA Cu‐catalyzed multi‐component reaction of trifluoromethylated β‐amino ketones and nitriles using tert‐butyl nitrite as a diazotization reagent has been developed. Under the optimized conditions, N‐trifluoroalkyl amides were obtained with yields up to 87%. Control experiments and computational studies reveal that the reaction proceeds through the generation of diazo, in situ formation of nitrile ylide, water addition and final enol tautomerism. This approach features mild reaction conditions, wide substrate tolerance, and scale‐up applicability, which provides an efficient and practical strategy for amide synthesis.

Calculating Thermodynamic Stabilities of Keto–Enol Tautomers of Aldehydes, Ketones, Esters, and Amides

Calculating Thermodynamic Stabilities of Keto–Enol Tautomers of Aldehydes, Ketones, Esters, and Amides

Decoding the commutable first hyperpolarisability of keto–enol tautomer using DFT and AI-based soft computing method

ABSTRACT Non-linear optical (NLO) parameter of a series of donor–acceptor substituted N-salicylidene-4-benzenesulfonylaniline (SBSA) derivatives with a contrast of first hyperpolarisability has been investigated using density functional-based theory. The derivative of SBSA with both the donor and acceptor substitution (NMe2-SBSA-NO2) exhibits the highest first hyperpolarisability ( ∼ 3 × 103 a.u in gas phase) value. Frequency and solvent polarity responsive behaviours of first hyperpolarisability are utilised to demonstrate the variation of NLO as switchable electrical parameter. Each of the studied compounds displays very high NLO response at frequency corresponding to the absorption maxima of their electronic state. Likewise, the increase of solvent polarity induces a substantial increase of first hyperpolarisability. The computation of NLO responsive first hyperpolarisability by varying the frequency and solvent dielectric constant within a wide domain is very tedious and time-consuming. To overcome the lacuna, we implemented machine learning tools such as artificial neural networks (ANNs), fuzzy logic (FL) and adaptive neuro-fuzzy inference system (ANFIS) to predict the computation data of the NMe2-SBSA-NO2 and moderately good results were obtained using ANFIS as soft computing tool.

Spectral, crystal structure of novel Pyran-2-one Zwitterion Schiff derivative: Thermal, Physicochemical, DFT/HSA-interactions, enol↔imine tautomerization and anticancer activity

A novel Schiff base (SB) derivative, (E)-3-(1-((2,6-diisopropylphenyl)-imino)-ethyl)-4‑hydroxy-6-methyl-2H-pyran-2-one, was synthesized in a high yield through the direct condensation of 2,6-diisopropylaniline with 3-acetyl-4‑hydroxy-6-methyl-2H-pyran-2-one in ethanol under reflux conditions. The synthesized ligand was identified using different elemental analysis (CHN-EA) and spectroscopic techniques (2D-nuclear magnetic resonance (1H- & 13C- NMR), Fourier transform infrared (FT-IR) and mass (MS) spectroscopies), and their structural analysis was performed by single crystal X-ray diffraction (XRD). In addition, the thermogravimetric behavior of the ligand was evaluated using thermogravimetric analysis (TGA) and differential thermal analysis (DTA). The DFT calculations on the gaseous state and in chloroform as solvent using B3LYP-D3/6–311++G(2d,p) and the HSA calculations were performed to examine the stability of the tautomeric forms of the ligand and to understand its Zwitterionic behaviors. The results showed that the ligand exhibits a zwitterionic form stabilized by an intramolecular single proton transfer process between the enol and imine tautomerism. The enol↔imine tautomerization was determined by XRD and computed by DFT/HSA calculations, which proved the stabilization of the [N+−−H⋯O−−] zwitterionic form via S6 intra-H-bond. In addition, the Colorimetric [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that the ligand exhibits high activity against cancer cells, specifically HeLa cells, at low concentrations.

5-chloro-3-(2-(2,4-dinitrophenyl) hydrazono)indolin-2-one: synthesis, characterization, biochemical and computational screening against SARS-CoV-2

Chemical prototypes with broad-spectrum antiviral activity are important toward developing new therapies that can act on both existing and emerging viruses. Binding of the SARS-CoV-2 spike protein to the host angiotensin-converting enzyme 2 (ACE2) receptor is required for cellular entry of SARS-CoV-2. Toward identifying new chemical leads that can disrupt this interaction, including in the presence of SARS-CoV-2 adaptive mutations found in variants like omicron that can circumvent vaccine, immune, and therapeutic antibody responses, we synthesized 5-chloro-3-(2-(2,4-dinitrophenyl)hydrazono)indolin-2-one (H2L) from the condensation reaction of 5-chloroisatin and 2,4-dinitrophenylhydrazine in good yield. H2L was characterised by elemental and spectral (IR, electronic, Mass) analyses. The NMR spectrum of H2L indicated a keto–enol tautomerism, with the keto form being more abundant in solution. H2L was found to selectively interfere with binding of the SARS-CoV-2 spike receptor-binding domain (RBD) to the host angiotensin-converting enzyme 2 receptor with a 50% inhibitory concentration (IC50) of 0.26 μM, compared to an unrelated PD-1/PD-L1 ligand–receptor-binding pair with an IC50 of 2.06 μM in vitro (Selectivity index = 7.9). Molecular docking studies revealed that the synthesized ligand preferentially binds within the ACE2 receptor-binding site in a region distinct from where spike mutations in SARS-CoV-2 variants occur. Consistent with these models, H2L was able to disrupt ACE2 interactions with the RBDs from beta, delta, lambda, and omicron variants with similar activities. These studies indicate that H2L-derived compounds are potential inhibitors of multiple SARS-CoV-2 variants, including those capable of circumventing vaccine and immune responses.

Ground-State Tautomerism and Excited-State Proton Transfer in 7-Hydroxy-4-methyl-8-((phenylimino)methyl)-2H-chromen-2-one as a Potential Proton Crane

The tautomerism in the title compound as a potential long-range proton transfer (PT) switch has been studied by using the DFT and TD-DFT approaches. The data show that in aprotic solvents, the enol tautomer dominates, while the increase in the content of the keto tautomer (short-range PT) rises as a function of polarity of the solvent. In ethanol, due to specific solute–solvent stabilization through intermolecular hydrogen bonding, a substantial amount of the keto forms exists in solution. The irradiation leads to two competitive processes in the excited state, namely ESIPT and trans/cis isomerization around the azomethine bond as in other structurally similar Schiff bases. The studied compound is not suitable for bistable tautomeric switching, where long-range PT occurs, due to the difficult enolization of the coumarin carbonyl group.

Omadacycline dihydrate, C29H40N4O7·2H2O, from X-ray powder diffraction data.

The crystal structure of the title compound {systematic name: (4S,4aS,5aR,12aR)-4,7-bis-(di-methyl-amino)-9-[(2,2-di-methyl-propyl-amino)-meth-yl]-1,10,11,12a-tetra-hydroxy-3,12-dioxo-4a,5,5a,6-tetra-hydro-4H-tetra-cene-2-carb-oxamide dihydrate, C29H40N4O7·2H2O} has been solved and refined using synchrotron X-ray powder diffraction data: it crystallizes in space group R3 with a = 24.34430 (7), c = 14.55212 (4) Å, V = 7468.81 (2) Å3 and Z = 9. Most of the hydrogen bonds are intra-molecular, but two classical N-H⋯O inter-molecular hydrogen bonds (along with probable weak C-H⋯O and C-H⋯N hydrogen bonds) link the mol-ecules into a three-dimensional framework. The framework contains voids, which contain disordered water mol-ecules. Keto-enol tautomerism is apparently important in this mol-ecule, and the exact mol-ecular structure is ambiguous.

Structural flexibility of favipiravir and its structural analogues in solutions: experimental and computational insight.

Combined UV-vis and quantum chemical studies of the structural flexibility and tautomerism of 6-R-3-hydroxy-2-pyrazine carboxamides in solutions revealed that their keto-enol transformations are accompanied by the deprotonation of enol tautomers and the formation of the corresponding anionic species. Both the solvent and the 6-R substituent strongly influence the relative abundance of the above forms in solutions. Anions are not formed in 1,2-dichloroethane (DCE), but the probability of deprotonation in neutral water and N,N-dimethylformamide (DMF) increases in the order R = H < F < NO2. Only enol tautomers of all solutes are found in DCE. DMF stabilizes keto forms only moderately and assists much strongly in the deprotonation of all three compounds. Water tends to stabilize both keto tautomers and deprotonated anions: the keto form dominates in the case of R = H (antiviral drug T-1105), the anions are found exclusively for R = NO2, and the aqueous solution of another antiviral drug, favipiravir (R = F), contains both the keto tautomer and the anionic form. The results of quantum chemical free energy calculations are in agreement with the experimental observations.

Formation of methylglyoxal (CH3C(O)CHO) in interstellar analog ices - a key intermediate in cellular metabolism.

Ketoaldehydes are key intermediates in biochemical processes including carbohydrate, lipid, and amino acid metabolism. Despite their crucial role in the interstellar synthesis of essential biomolecules necessary for the Origins of Life, their formation mechanisms have largely remained elusive. Here, we report the first bottom-up formation of methylglyoxal (CH3C(O)CHO)-the simplest ketoaldehyde-through the barrierless recombination of the formyl (HĊO) radical with the acetyl (CH3ĊO) radical in low-temperature interstellar ice analogs upon exposure to energetic irradiation as proxies of galactic cosmic rays. Utilizing vacuum ultraviolet photoionization reflectron time-of-flight mass spectrometry and isotopic substitution studies, methylglyoxal and its enol tautomer 2-hydroxypropenone (CH3C(OH)CO) were identified in the gas phase during the temperature-programmed desorption of irradiated carbon monoxide-acetaldehyde (CO-CH3CHO) ices, suggesting their potential as promising candidates for future astronomical searches. Once synthesized in cold molecular clouds, methylglyoxal can serve as a key precursor to sugars, sugar acids, and amino acids. Furthermore, this work provides the first experimental evidence for tautomerization of a ketoaldehyde in interstellar ice analogs, advancing our fundamental knowledge of how ketoaldehydes and their enol tautomers can be synthesized in deep space.

Favipiravir vs. Deferiprone: Tautomeric, photophysical, in vitro biological studies, and binding interactions with SARS-Cov-2-MPro/ACE2

Coronavirus disease 2019 (COVID-19) still remains the most disastrous infection continuously affecting millions of people worldwide. Herein, we performed a comparative study between the anti-influenza drug favipiravir (FAV) and the anti-thalassemia drug deferiprone (DFP) in order to examine their potential as basic scaffolds for the generation of most effective and structurally novel antivirals. To conduct the initial molecular modelling and virtual screening steps, our recently proposed single crystal X-ray diffraction (SCXRD)/HYdrogen DEssolvation (HYDE) technology platform has been used. This platform allows molecular design, interactive prioritization and virtual evaluation of newly designed molecules, simultaneously affecting two COVID-related targets, including angiotensin-converting enzyme 2 (ACE2) as a host-cellular receptor (host-based approach) and the main protease (Mpro) enzyme of the spike glycoprotein of SARS-Cov-2 (virus-based approach). Based on the molecular docking results, DFP has shown higher binding affinity (Ki HYDE values) over FAV towards both biological targets. The tautomeric, physicochemical, and biological properties of FAV and DFP have been studied both experimentally and theoretically using molecular spectroscopy (UV–VIS absorption), parallel artificial membrane permeability assay, and cell biology (PAMPA and MTT assay), as well as DFT quantum chemical calculations. According to the obtained results, the enol tautomers of both compounds are considerably more stable in different organic solvents. However, the keto tautomer of FAV was estimated to be most preferable under physiological conditions, which is in good agreement with the molecular docking studies. The isolated crystal structure of DFP is in an excellent agreement with the computation in respect of the most stable tautomer. Combined single X-ray/molecular modeling studies including HYDE analyses provided not only insights into the protein–ligand interactions within the binding site of SARS-Cov-2-ACE2 and SARS-Cov-2-Mpro, but also a valuable information regarding the most stable enol tautomeric form of DFP that contributes to its estimated higher potency against these targets.

The role of pH-induced tautomerism of polyvinylpyrrolidone on the size, stability, and antioxidant and antibacterial activities of silver nanoparticles synthesized using microwave radiation.

Tautomerism alters the structure and properties of materials, which can be exploited to control their chemical and biological activities. The role of pH-induced tautomerism of polyvinylpyrrolidone (PVP) was determined by measuring the size, stability, and antioxidant and antibacterial properties of microwave synthesized-silver nanoparticles (AgNPs). TEM and XRD analyses confirmed the formation of face-centered cubic silver nanoparticles. PVP stabilized the AgNPs by interaction with the carbonyl or hydroxyl groups depending on the tautomerization under different pH conditions. At pH 4, PVP was stable in the keto tautomer, stabilizing Ag through electron donation of oxygen atoms in the carbonyl group, producing smaller AgNPs with a higher zeta potential. At pH 7 and 9, the enol tautomer PVP stabilized the AgNPs via oxygen atoms in the hydroxyl group, forming large nanoparticles. The keto form of PVP improved the stability and antioxidant and antibacterial properties of AgNPs compared with the enol form. This study also excluded the antioxidant contribution of PVP via hydrogen donation to free radicals. A facile method for controlling the size of AgNPs by adapting the pH-induced tautomerism of PVP that affects their stability and antioxidant and antibacterial activities is thus reported.

Rate-Enhancing Role of Water in H-BEA and Sn-BEA for Keto–Enol Tautomerization of Acetone: A DFT Study

Rate-Enhancing Role of Water in H-BEA and Sn-BEA for Keto–Enol Tautomerization of Acetone: A DFT Study

Investigation on the stability of the Enol Tautomer of Favipiravir and its derivatives by DFT, QTAIM, NBO, NLO and 1H-NMR

Relative stability energies of enol and keto forms of Favipiravir drug (6-fluoro-3-hydroxy-2-pyrazine carboxamide) and its twelve derivatives were theoretically envisaged using the B3LYP/6-311 + G(3df,2p)//B3LYP/6-311 + G(d,p) level of theory. Influence of the nature of the substituted groups on the geometric structures, IMHB, vibrational frequencies, dipole moments, and global reactivity descriptors was systematically studied. The enol form was found to be more stable than the keto form, regardless of the nature of the substituted group, by an average of 12.5 and 5.4 kcal/mol in the gas phase and in the aqueous solution, respectively. The role of the IMHB strength in the stability of the enol form compared with the keto form was investigated in terms of QTAIM and NBO analysis and 1H NMR chemical shifts. The NLO properties at CAM-B3LYP with 6-311 + G(d,p) basis set of the two forms and their derivatives were also used to explain the relative stability.