Enol Tautomer Research Articles

An environmentally benign way to synthesize 2-thiocyano-1,3-dicarbonyl compounds with high antifungal activity: a key role of solvent.

The introduction of thiocyano groups into organic molecules is important for the preparation of many active ingredients and synthetic intermediates. A commonly used and attractive strategy is the nucleophilic substitution of halogens with the SCN anion or oxidative thiocyanation using an excess amount of external oxidants. A sustainable alternative to stoichiometric reagents is electrochemistry based on anodic oxidation of the SCN anion and other intermediates. Electrochemical thiocyanation of various organic compounds, carried out in the usual non-acidic organic solvents, is well known. Here, we present an electrochemical thiocyanation of 1,3-dicarbonyl compounds in which high efficiency was only achieved using AcOH as the solvent. Electrolysis proceeds in an undivided cell under constant current conditions without any additional halogen-containing electrolytes. Ammonium thiocyanate was used as the source of the SCN group and the electrolyte. Electrochemical thiocyanation of 1,3-dicarbonyl compounds begins with the generation of (SCN)2 from the thiocyanate anion, followed by the addition of thiocyanogen to the double bond of the enol tautomer of 1,3-dicarbonyl compounds, which finally gives the products. A variety of thiocyanated 1,3-dicarbonyl compounds bearing different functional groups were obtained in 37-82% yields and were shown to exhibit high antifungal activity.

New prebiotic molecules in the interstellar medium from the reaction between vinyl alcohol and CN radicals: unsupervised reaction mechanism discovery, accurate electronic structure calculations and kinetic simulations.

Vinyl alcohol (VyA) and cyanide (CN) radicals are relatively abundant in the interstellar medium (ISM). VyA is the enolic tautomer of acetaldehyde and has two low-lying conformers, characterized by the syn or anti placement of hydroxyl hydrogen with respect to the double bond. In this paper, we present a gas-phase model of the barrierless reactions of both VyA's conformers with CN employing accurate quantum chemical computations in the framework of a master equation approach based on the transition state theory. Our results indicate that both VyA conformers feature a similar reactivity with CN, starting with a barrierless addition to the double bond and followed by different isomerization, dissociation, and/or hydrogen elimination steps. The rate constants computed for temperatures up to 600 K show that several reaction channels are open even under the harsh conditions of the ISM, with the favoured one providing the first feasible formation route of a prebiotic molecule not yet detected in the ISM, namely cyanoacetaldehyde. This finding suggests looking for cyanoacetaldehyde in regions where both VyA and CN have already been detected, like, e.g., Sagittarius B2N or G+0.693-0.027.

Synthesis of interstellar propen-2-ol (CH3C(OH)CH2) - the simplest enol tautomer of a ketone.

Enols - tautomers of ketones or aldehydes - are anticipated to be ubiquitous in the interstellar medium and play a key role in the formation of complex organic molecules in deep space, but their fundamental formation mechanisms have remained largely elusive as of now. Here we present a combined experimental and computational study demonstrating the first preparation of propen-2-ol (CH3C(OH)CH2) and its isomer methyl vinyl ether (CH3OCHCH2) in low-temperature acetone (CH3COCH3) ices upon exposure to energetic electrons. Propen-2-ol is the simplest enol tautomer of a ketone. Exploiting tunable vacuum ultraviolet photoionization in conjunction with reflectron time-of-flight mass spectrometry, propen-2-ol and methyl vinyl ether were monitored in the gas phase upon sublimation during the temperature-programmed desorption process suggesting that both isomers are promising candidates for future astronomical searches such as via the James Webb Space Telescope. Electronic structure calculations reveal that the barrier of keto-enol tautomerization can be reduced by more than a factor of two (162 kJ mol-1) through the involvement of solvating water molecules under realistic conditions on interstellar grains. The implicit solvent effects, i.e., the influences of the solvent dipole field on the barrier height are found to be minimal and do not exceed 10 kJ mol-1. Our findings signify a crucial step toward a better understanding of the enolization of ketones in the interstellar medium thus constraining the molecular structures and complexity of molecules that form in extraterrestrial ices - ketones - through non-equilibrium chemistry.

Phenothiazine-based donor–acceptor covalent–organic frameworks with keto–enol irreversible tautomerism as a promising third-order nonlinear optics material

Keto–enol tautomerization endowed TFP-TZ with more D–A interaction strengths and an electron-withdrawing CO group in the keto form facilitated charge transfer.

Favipiravir-Tautomeric and Complexation Properties in Solution.

The tautomeric properties of favipiravir were investigated experimentally for the first time by using molecular spectroscopy (UV-Vis absorption, fluorescence and NMR), as well as DFT quantum-chemical calculations. According to the obtained results, the enol tautomer is substantially more stable in most of the organic solvents. In the presence of water, a keto form appears to be favored due to the specific solute-solvent interactions. Upon the addition of alkaline-earth-metal ions, deprotonation and complexation occurred simultaneously, giving the formation of 2 : 1 ligand : metal complexes. According to the theoretical simulations, the metal ion is captured between the carbonyl groups as a result of the size-fit effect.

Rearranged Lindenane Sesquiterpenoid Trimers from Chloranthus fortunei: Target Discovery and Biomimetic Conversion.

Seven lindenane-type sesquiterpenoid trimers, including four new ones (1-4) and three known analogues (5-7), were isolated from Chloranthus fortunei guided by high-performance liquid chromatography with photodiode array detection with characteristic absorption at 210 and 350 nm. Their structures, including absolute configurations, were achieved by high-resolution mass spectrometry, nuclear magnetic resonance, electronic circular dichroism, and quantum chemical calculations. Compound 1 was the first example of two lindenane units connected by a C-15-C-15' bond. The 5/7/5-fused ring system in 2 was presumably formed biogenetically by key keto-enol tautomerism and Cope rearrangement from 5. The 5/3/6 carbon skeleton in 3-5 and epi-cyclopropane in 3 and 6 might have originated from trishizukaol A (7) with a normal 3/5/6-fused ring system through vinylcyclopropane rearrangement. The biomimetic conversion from 7 to 3-6 was successfully achieved by adding a 365 nm ultraviolet lamp and a free radical initiator, and 2 was also spontaneously converted to 5 in methanol and CDCl3, which proved the correctness of the structural identification and the speculation described above. Compounds 1-7 exhibited anti-inflammatory activity with IC50 values in the range of 2.90-22.80 μmol/L.

A Mechanistic Study on the Formation of Acetone (CH3COCH3), Propanal (CH3CH2CHO), Propylene Oxide (c-CH3CHOCH2) along with Their Propenol Enols (CH3CHCHOH/CH3C(OH)CH2) in Interstellar Analog Ices

Carbonyl-bearing complex organic molecules (COMs) in the interstellar medium (ISM) are of significant importance due to their role as potential precursors to biomolecules. Simple aldehydes and ketones like acetaldehyde, acetone, and propanal have been recognized as fundamental molecular building blocks and tracers of chemical processes involved in the formation of distinct COMs in molecular clouds and star-forming regions. Although previous laboratory simulation experiments and modeling established the potential formation pathways of interstellar acetaldehyde and propanal, the underlying formation routes to the simplest ketone—acetone—in the ISM are still elusive. Herein, we performed a systematic study to unravel the synthesis of acetone, its propanal and propylene oxide isomers, as well as the propenol tautomers in interstellar analog ices composed of methane and acetaldehyde along with isotopic-substitution studies to trace the reaction pathways of the reactive intermediates. Chemical processes in the ices were triggered at 5.0 K upon exposure to proxies of Galactic cosmic rays in the form of energetic electrons. The products were detected isomer-selectively via vacuum ultraviolet (VUV) photoionization reflectron time-of-flight mass spectrometry. In our experiments, the branching ratio of acetone (CH3COCH3):propylene oxide (c-CH3CHOCH2):propanal (CH3CH2CHO) was determined to be (4.82 ± 0.05):(2.86 ± 0.13):1. The radical–radical recombination reaction leading to acetone emerged as the dominant channel. The propenols appeared only at a higher radiation dose via keto–enol tautomerization. The current study provides mechanistic information on the fundamental nonequilibrium pathways that may be responsible for the formation of acetone and its (enol) isomers inside the interstellar icy grains.

Long-Range Proton Transfer in 7-Hydroxy-Quinoline-Based Azomethine Dyes: A Hidden Reason for the Low Efficiency

In the tautomeric Schiff bases, derived from 7-hydroxyquinoline, two competitive channels are possible upon excitation of the enol tautomer, namely proton transfer (PT) through intramolecular hydrogen bonding to the corresponding keto form and trans-cis isomerization around the azomethine double bond. The former leads to switching, based on twist-assisted excited state intramolecular PT, where the long-range proton transfer can occur as a targeted process. The latter, determined by the flexibility of the crane part, reduces the efficiency of the main targeted process. In previously studied molecular switches based on the 7-hydroxyquinoline skeleton, only the intramolecular PT photo-process undergoing from the excited enol form towards the keto tautomer, which is in most cases barrierless, has been discussed. Therefore, in the current study, the ground state PT properties and isomerization of (E)-8-((phenylimino)methyl)quinolin-7-ol and (E)-8-(((pentafluorophenyl)imino)methyl)quinolin-7-ol are investigated in depth using the MP2 methodology, while the excited state energy profiles are calculated with the ADC(2) method. The obtained results are discussed in light of the existing experimental data.

Chelidamic acid tautomers in copper(II) compounds. One-pot synthesis, crystal structure, spectroscopic and DFT studies

Two copper(II) chelidamate compounds with 2,2'-bipyridine were obtained as crystals [Cu(Hcda)(bpy)(H2O)]∙2H2O (1) and [Cu(H2cda)(bpy)(H2O)](H2cda) (2) (H3L = H3cda = chel = chelidamic acid, bpy = 2,2′-bipyridine) through one-pot synthesis. In 1, the tridentate Hcda2− ligand, an enol tautomer of the 4-hydroxypyridine type, and a bpy molecule coordinate the Cu(II). In 2, the same tautomer of the tridentate H2cda− ligand (with one deprotonated carboxylic acid), along with bpy, forms a cationic [Cu(H2cda)(bpy)(H2O)]+ complex. It is charge-balanced by an H2chel− anion, featuring the rare keto tautomer of the 4-pyridone type. The alternately protonated and deprotonated carboxylic groups of both tautomers are involved in hydrogen bonds leading to 1D chains. The adjacent chains are connected to form 2D chain by hydrogen bonds between two different tautomers of chel. As confirmed by the DFT calculations, the crystal structures of 1 and 2 are mainly stabilised by hydrogen bonds and electrostatic interactions, the latter being especially noticeable in the [Cu(H2cda)(bpy)(H2O)]+ cationic complex (2). Additionally, π⋯π stack is formed between aromatic ring fragments. The presence of each particular tautomer in the crystal structures of 1 and 2 can be explained by the relative energies of the respective structural moieties in the aqueous environment, combined with coordination and intermolecular interaction preferences.

CHARACTERIZATION STUDIES ON A TETRAHYDROCURCUMIN-ZINC COMPLEX

Objective: Preparation and characterization studies on tetrahydrocurcumin complexed with zinc, with particular reference to the location of zinc in the complex. Methods: Structural characteristics of tetrahydrocurcumin and its complex with zinc were compared using elemental analysis, mass spectrometry (MS), proton, and carbon-13 nuclear magnetic resonance spectroscopy (NMR), ultraviolet-visible (UV) absorption spectroscopy, and Fourier transform infrared (FTIR) spectroscopy. Results: MS data indicates a Zn molecule holds two THCur components together. NMR data provide evidence that the zinc ion is associated with the 1,3-diketone part of the linker region of the associated THCur. FTIR data is consistent with zinc interaction with the enol tautomer of the 1,3-diketone at the center of the linker region of THCur. UV data indicate that a zinc-dependent shift in absorbance maximum is consistent with changes in the structure of THCur resulting from complexation with zinc. Together, this data indicates the complexation of zinc with tetrahydrocurcumin is consistent with zinc linking two molecules of tetrahydrocurcumin together by binding to the enol forms of the 1,3-diketone moieties located in the linker regions between the aromatic rings. Conclusion: The spectral properties of the tetrahydrocurcumin-zinc complex are consistent with a structure in which zinc is encased in two tetrahydrocurcumin moieties. Additional studies are needed to determine if this structure results in altered bioavailability, antioxidant activity and other properties important for pharmaceutical development.

AIEE active sensors for fluorescence enhancement based detection of Ni2+ in living cells: Mechanofluorochromic and photochromic properties with reversible sensing of acid and base

Stimuli responsive sensors QI 1 and QI 2 were rationally developed which exhibited diverse features of mutable mechanofluorochromism, reversible photochromism, solvatochromism, aggregation induced emission enhancement (AIEE), and metal ion sensing. After observing the exceptional structural property relationship, sensors were applied for reversible colorimetric and fluorometric determination of Ni2+ with low detection limits of 12 and 17 nM, respectively. Fluorescence emission enhancement based Ni2+ sensing was induced by chelation enhanced fluorescence (CHEF) mechanism. CHEF is triggered by the inhibition of excited state intramolecular proton transfer (ESIPT) and –C=N isomerization. The proposed Ni2+ sensing mechanism was investigated through 1H NMR, FT-IR titration, theoretical studies, and Jobs plots. Further, the developed sensors successfully demonstrated the selective acid-base induced absorption/emission switching through reversible ring-opening/closing and keto–enol tautomerization, evidenced by 1H NMR titration experiments. Additionally, the sensitivity of the sensor QI 1 towards Ni2+ was effectively mimicked in live MCF-7 cells and industrial effluents. Furthermore, monitoring of Ni2+ ions was also accessed through inexpensive and portable sensors’ coated fluorescent films. Finally, an INHIBIT logic gate was fabricated imputing Ni2+ and EDTA as input signals to electronically scrutinize the targeted Ni2+.

β-C-Glycosylation with 2-Oxindole Acceptors via Palladium-Catalyzed Decarboxylative Reactions.

This report describes a highly efficient β-selective C-glycosylation of bicyclic galactals with 2-oxindoles through a palladium-catalyzed decarboxylative pathway. A variety of substrates representing both glycosyl donors and acceptors could be transformed in greater than 90% yields under mild reaction conditions. The decarboxylation intermediate of galactal could serve as an efficient base to deprotonate the enol tautomer of 2-oxindole and enhance its nucleophilicity. The β-selective nucleophilic addition at the anomeric center originates from the steric hindrance imposed by the palladium and bulky ligand.

Sterically Hindered 2‐(2’‐Hydroxyphenyl)benzoxazole (HBO) Emitters: Synthesis, Spectroscopic Studies, and Theoretical Calculations

AbstractWe describe various synthetic pathways to introduce sterically hindered substituents (mesityl, 2,4,6‐triisopropylphenyl, anthracene) to the proton donor side of excited‐state intramolecular proton transfer (ESIPT)‐capable 2‐(2’‐hydroxyphenyl) benzoxazole (HBO) fluorophores. Two original synthetic approaches were investigated in order to synthesize seven HBO derivatives. Optimization studies concluded that electron rich and bulky phosphine ligands are required to ensure completion of the Suzuki‐Miyaura cross‐coupling reaction involving a bulky aromatic boronic acid. The photophysical properties of all dyes revealed a strong influence of the nature of the solvent on the optical properties, as protic solvents tend to stabilize enol tautomers and induce dual emission. Our studies confirmed that, unlike the majority of organic dyes, ESIPT fluorophores do not undergo π‐stacking in the solid‐state. The nature of the excited‐states was explored by ab initio calculations.

Synthesis, characterization and antimicrobial study of novel substituted Curcumin Derivatives

Chemically, curcumin is a diaryl heptanoid, belonging to the group of curcuminoids, which are natural phenols responsible for turmeric's yellow color. It is a Keto–enol tautomer, existing in enolic form in organic solvents and in keto form in water. The one pot three component of hydrazide substituted benzaldehyde was used for the synthesis of curcumin derivatives. In this work the synthesis of curcumin derivatives was done using an environmental friendly procedure via Mg-Al-CO3 hydrotalcites which have been used as efficient catalysts. These catalysts are inexpensive and non-toxic powders. Data of Spectra and other analytical technique supported identification of compound curcumin derivatives. The present work offers many merits such as the reaction conditions were extremely simple, there was operational simplicity, reaction time was short, easy to work up and purification was also easy for the products via simple means of re-crystallization. The antibacterial activity of three compounds B2, B4 and D3 was found to be near to the significant with standard compounds amoxicillin.

Synthesis, characterization, non-linear optical and DNA binding properties of a Schiff base ligand and its Cu(II) and Zn(II) complexes

In this work, a new Schiff base ligand (HL) derived from p-isopropylaniline and 2,3,4-trihydroxybenzaldeyhde and its Cu(II) and Zn(II) complexes [ML2] were synthesized. The structures of the synthesized compounds were characterized by elemental analysis, FT-IR, 1H/13C NMR (for ligand and Zn(II) complex) spectroscopies. The crystal structure of the ligand was determined by single crystal XRD study. The XRD data showed that the ligand favours the keto-amine tautomeric form in the crystalline state. The ligand molecules are linked by OH····O hydrogen bonds forming hydrogen bonded chains. The compounds were screed for their DNA binding properties using UV–Vis spectroscopic measurements. The ligand and its Cu(II) and Zn(II) complexes showed considerable binding affinities to DNA with comparable binding constants to the ethidium bromide. Furthermore, ethidium bromide replacement properties of the compounds were investigated by photoluminescence studies. The type of interactions, binding modes and binding energies of the compounds with fish-sperm DNA were investigated by Docking studies. Moreover, computational studies were performed to examine the enol and keto tautomerism of the ligand HL using B3LYP/6–31G(d) level. Nonlinear optic properties of the compounds were investigated by computational studies.

Curcumin-Based β-Diketo Ligands for Ga3+: Thermodynamic Investigation of Potential Metal-Based Drugs

Curcumin is known for its therapeutic properties; among these, antioxidant, anti-inflammatory and anti-cancer ones stand out. Besides, curcumin metal complexes have shown widespread application in medicine and can be exploited as lead structures for developing metal-based drugs. Unfortunately, curcumin is poorly bioavailable, mainly due to its instability in physiological conditions; this weakness is tightly connected to the presence of the β-diketo moiety undergoing tautomeric equilibrium. Stability and metal-chelating ability can be tuned by modulating the electronic effects and steric hindrance close to the β-diketo moiety; in addition, formation of a metal complex shifts the tautomeric equilibrium towards the β-keto–enol form and increases stability in biological media. Among the metals used in clinical therapy, gallium nitrate has shown to have significant antitumor activity against non-Hodgkin lymphoma and bladder cancer, thus indicating that gallium-based drugs have potential for further development as antineoplastic agents with improved therapeutic activity. Curcuminoids have demonstrated high affinity for gallium(III), allowing the formation of stable positively charged M:L 1:2 β-diketonate complexes that benefit from the therapeutic activity of both the metal and the ligand. Seven new curcumin derivatives were synthesized and completely characterized. The new derivatives retain the solvent-dependent keto–enol tautomerism, with the prevalence of the diketo form in aqueous solution. Enhanced stability in simulated physiological conditions was observed in comparison to the lead compound curcumin. The presence of Ga3+ anticipates the dissociation of the enolic proton, allowing chelate complex formation, and simultaneously it shifts the tautomeric equilibrium towards the keto–enol form. A complete 1H/13C NMR and UV–Vis study was performed to define the metal-to-ligand stoichiometry ratio and the overall stability constants. In addition, we demonstrated that some of the derivatives have increased antiproliferative activity on colon cancer cells compared to curcumin and antioxidant properties. On the whole, the synthesized curcumin-based molecules may act as new gallium(III) chelators with improved stability with respect to curcumin and could open interesting perspectives for the development of novel therapeutic agents for cancer.

Salen: Insight into the Crystal Structure, Hirshfeld Surface Analysis, Optical Properties, DFT, and Molecular Docking Studies

We report on a known Schiff base dye salen. The crystal structure of salen is in the enol–enol tautomer. Molecules are packed into a 3D supramolecular framework through C–H···π interactions. The absorption spectrum of salen in CH2Cl2 exhibits three bands in the UV region, while the spectrum in MeOH contains an additional band at 403 nm and a shoulder at 280 nm, corresponding to the cis-keto tautomer. The emission spectrum of salen in MeOH exhibits a band at 435 and 457 nm upon irradiation at 280 and 400 nm, respectively, arising from the enol–cis-keto* and/or cis-keto–cis-keto* tautomers. The solution of salen in CH2Cl2 showed dual emission with the bands at 349 and 462 nm upon irradiation at 290 nm with the low-energy emission band arising from the enol–cis-keto* and/or cis-keto–cis-keto* tautomers, while the high-energy band corresponds to the enol–enol* tautomer. The emission spectrum of salen in CH2Cl2 exhibits a single band at 464 nm upon irradiation at 380 nm, arising from the different conformers of the enol–cis-keto* and/or cis-keto–cis-keto* tautomers. The DFT calculations revealed that the enol–enol tautomer is the most favorable, followed by the enol–cis-keto tautomer. The global chemical reactivity descriptors were estimated from the HOMO and LUMO. The DFT calculations were also applied to probe salen as a potential corrosion inhibitor for some important metals used in implants. The enol–cis-keto and enol–trans-keto tautomers exhibit the best electron charge transfer from the molecule to the surface of all the studied metals, of which the most efficient electron charge transfer was established for Ni, Au, and Co. Molecular docking was applied to study interaction of tautomers of salen with a series of the SARS-CoV-2 proteins, of which the best binding affinity was found toward nsp14 (N7-MTase).

Cyclocondensation versus Cyclocondensation Plus Dehydroxylation During the Reaction of Flavones and Hydrazine

AbstractConcomitant selective dehydroxylation during the transformation of flavones into pyrazoles with hydrazine is determined by the A‐ring substitution pattern and propensity to keto enol tautomerization. The obtained pyrazoles show varied tyrosinase inhibition properties, including one nanomolar inhibitor.

Isomerization of 6-O-substituted glucose and fructose under neutral pH conditions and subsequent β-elimination reactions

Isomaltose (6-O-α-d-glucopyranosyl-d-glucose) and isomaltulose (palatinose; 6-O-β-d-glucopyranosyl-d-fructose) were heated to 90 °C in 100 mM sodium phosphate buffer (pH 7.5). Aldose–ketose isomerization between isomaltose, isomaltulose, and epi-isomaltulose was observed in the early stage of the reaction, alongside the release of a small amount of glucose. The total concentration of these disaccharides gradually decreased as the heating time increased. However, this decrease did not correlate with the amount of glucose or fructose released, suggesting that the releases of these monosaccharides were not caused by the hydrolysis of glycosidic linkages. A slight decrease in the pH of the reaction solution was attributed to the formation of two organic acids, 6-O-β-d-glucopyranosyl-3-deoxy-d-arabino-hexonic acid (1) and 6-O-β-d-glucopyranosyl-3-deoxy-d-ribo-hexonic acid (2). These compounds were formed from the β-elimination of the hydroxyl group at the C-3 of fructose, leaving a substituted glucose residue at the C-6 position, followed by keto–enol tautomerization and benzilic acid rearrangement. Although approximately 30% of 1 and 2 were degraded after 360 min of heating at 90 °C in 100 mM sodium phosphate, a little release of glucose was observed, indicating no hydrolysis of the glucoside bond at C-6. Besides 1 and 2, time-dependent changes in the NMR spectra of the reaction mixture in water indicated the formation of formic acid and the presence of species possibly resulting from the β-elimination of the hydroxyl group from 3- and 4-ulose. The glucose released by heating isomaltose and isomaltulose may be generated via tautomerizations of keto-enols between the C-4 and C-5 positions and cleavage of 6-O-glycosidic linkage via β-elimination.

ESIPT pathways and optical properties of 7-Hydroxy-1-Indanones

We explore the proton transfer pathways associated with the energetically close-lying S1 and S2 states of 7-Hydroxy-2,3-dihydro-1H-inden-1-one (DHI), 1-hydroxy-9H-fluoren-9-one (HF9), and 1-hydroxy-11H-benzo[b]fluoren-11-one (HF11). A systematic analysis of spatial energetics, conical intersections, and quantum wavepacket simulations suggests that the proton transfer can happen via both S1 and S2 states in DHI, whereas HF9 and HF11 display the proton transfer via S1 alone. Computed electronic absorption spectra of enol tautomers and emission spectra of both enol and keto tautomers agree well with the available experimental findings. Finally, we discuss the possible white light emission by assessing the emission features of these molecular systems that appear in a broad range of the visible spectrum.