Keto Tautomer Research Articles

Blue-Emitting 2-(2'-Hydroxyphenyl)benzazole Fluorophores by Modulation of Excited-State Intramolecular Proton Transfer: Spectroscopic Studies and Theoretical Calculations.

This article describes the synthesis, spectroscopic studies, and theoretical calculations of nine original fluorophores based on the 2-(2'-hydroxyphenyl)benzazole (HBX) scaffold, functionalized at the 4-position of the phenol ring by ethynyl-extended aniline moieties. HBX dyes are well-known to display an excited-state intramolecular proton transfer (ESIPT) process, owing to a strong six-membered hydrogen bond in their structure that allows for an enol/keto tautomerism after photoexcitation. Appropriate electronic substitution can perturb the ESIPT process, leading to dual fluorescence, both excited tautomers emitting at specific wavelengths. In the examples described herein, it is demonstrated that the proton transfer can be finely frustrated by a modification of the constitutive heteroring, leading to a single emission band from the excited enol or keto tautomer or a dual emission with relative intensities highly dependent on the environment. Moreover, the nature of the functionalization of the N-alkylated aniline moiety also has a significant importance on the relative excited-state stabilities of the two tautomers in solution. To shed more light on these features, quantum chemical calculations by the density functional theory are used to determine the excited-state energies and rationalize the experimental spectroscopic data.

Modifying the proton transfer of 3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazole by water, confinement and confined water

The effect of water, confinement and confined water on the proton transfer of 3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazole (bis-HPTA) was investigated. Water alters the proton transfer process. At higher pH, an anion is formed in water and it undergoes intermolecular proton transfer and forms a keto tautomer. Confinement of molecule in β-cyclodextrin affects the intramolecular proton transfer. It also prevents the intermolecular proton transfer of the anionic form. In reverse micelle, the molecule resides in the interfacial region and interacts with bound water. The intermolecular hydrogen bond of the surfactants opens the intramolecular hydrogen bond in the weaker β-ring of bis-HPTA. It led to single tautomer emission from bis-HPTA. An increase in water amount enhances the relative amount of trans-enol, but predominantly tautomer emission is observed.

Surface-Induced Keto-Enol Tautomerization of DNA Base Molecules and Consequent [4 + 2]-like Cycloaddition on Si(111)7×7.

Adsorption and film growth of deoxyribonucleic acid (DNA) base molecules (cytosine, guanine, thymine, and adenine) on Si(111)7×7 have been studied by combining X-ray photoelectron spectroscopy (XPS) with ab initio calculations based on the density functional theory (DFT). Multiple tautomeric forms and keto-enol tautomerization are revealed by the O 1s, N 1s, and C 1s XPS spectra of the O-containing DNA bases: cytosine, guanine, and thymine. While the carbonyl group-containing keto tautomer is more stable in a thick film and in powder, the hydroxyl group-containing enol tautomer is found at the interface. The keto-enol tautomerization, as induced by the reactive Si(111)7×7 surface, leads to the formation of a conjugated aromatic six-membered ring with a delocalized π electron system and to the consequent [4 + 2]-like cycloaddition between the enol tautomer and the 7×7 surface. The DFT calculation suggests that the enol tautomer exhibits a kinetic advantage over the keto one for the [4 + 2]-like cycloaddition. Among the several plausible pathways for the cycloaddition provided by the enol tautomer, the experimentally determined one involves a ring N and ring C atom (a polar pair), rather than two ring C atoms (a nonpolar pair), to better match the polar Si adatom-restatom pair of the 7×7 surface. Furthermore, the reacted ring C atom does not have any attached terminal functional group (e.g., -NH2 and -OH). Further deposition leads to continuous film growth in the keto tautomeric form for cytosine and guanine. For the only O-free DNA base molecule, adenine, dative bonding N → Si, rather than the [4 + 2]-like cycloaddition, is observed on the 7×7 surface. Of the four DNA base molecules, adenine is also the only one with its aromaticity maintained when adsorbed on the Si(111)7×7 surface. A reactive surface like the 7×7 surface could therefore provide a new control to trigger tautomerization that is often associated with genetic mutation.

Deuterated solvent effects in the kinetics and thermodynamics of keto-enol tautomerization of ETFAA

Ethyl 4,4,4-trifluoroacetoacetate (ETFAA) is a β-ketoester that is used as a starting material in the synthesis of a variety of biologically active compounds. The reactivity of this compound is solvent dependent, and here we investigate the kinetics and thermodynamics of keto-enol tautomerization of ETFAA through benchtop 19F NMR in both non-deuterated and deuterated solvents. We determined that tautomerization dynamics in protic and aprotic solvents displayed differences in reaction rates and in the proportion of the keto and enol tautomers present. Moreover, our results demonstrated a positive correlation in aprotic solvents between solvent polarity and the proportion of keto tautomer present. We further employed density functional theory (DFT) calculations to probe the specific chemical interactions responsible for these observed trends. From the DFT calculations it was found that the major source of stability of the enol tautomer compared to the keto tautomer was its intramolecular hydrogen bond. Knowing the equilibrium of the keto-enol tautomerization of ETFAA is vital for synthesis of biologically active compounds derived from ETFAA, and maintaining a computational perspective can be useful in determining the advantages and disadvantages of various computational methods used in modeling keto-enol tautomerization.

Quantum mechanics/molecular mechanics studies on the mechanistic photophysics of sunscreen oxybenzone in methanol solution.

Herein, we have employed the QM(CASPT2//CASSCF)/MM method to explore the photophysical and photochemical mechanism of oxybenzone (OB) in methanol solution. Based on the optimized minima, conical intersections and crossing points, and minimum-energy reaction paths related to excited-state intramolecular proton transfer (ESIPT) and excited-state decay paths in the 1ππ*, 1nπ*, 3ππ*, 3nπ*, and S0 states, we have identified several feasible excited-state relaxation pathways for the initially populated S2(1ππ*) state to decay to the initial enol isomer' S0 state. The major one is the singlet-mediated and stretch-torsion coupled ESIPT pathway, in which the system first undergoes an essentially barrierless 1ππ* ESIPT process to generate the 1ππ* keto species, and finally realizes its ground state recovery through the subsequent carbonyl stretch-torsion facilitating S1 → S0 internal conversion (IC) and the reverse ground-state intramolecular proton transfer (GSIPT) process. The minor ones are related to intersystem crossing (ISC) processes. At the S2(1ππ*) minimum, an S2(1ππ*)/S1(1nπ*)/T2(3nπ*) three-state intersection region helps the S2 system branch into the T1 state through a S2 → S1 → T1 or S2 → T2 → T1 process. Once it has reached the T1 state, the system may relax to the S0 state via direct ISC or via subsequent nearly barrierless 3ππ* ESIPT to yield the T1 keto tautomer and ISC. The resultant S0 keto species significantly undergoes reverse GSIPT and only a small fraction yields the trans-keto form that relaxes back more slowly. However, due to small spin-orbit couplings at T1/S0 crossing points, the ISC to S0 state occurs very slowly. The present work rationalizes not only the ultrafast excited-state decay dynamics of OB but also its phosphorescence emission at low temperature.

A low-polarity small organic molecule with a stable keto form for photocatalytic H2 evolution.

Five small organic molecules (SOMs) with different degrees of enol to keto tautomerism were synthesized for photocatalytic H2 evolution. The SOM possessing the highest activity features a stable keto form that greatly facilitates the flowing of the excited electrons toward the carbonyl O site where the reduction reaction occurs.

Two Tautomers of Thiobarbituric Acid in One Crystal: The Experimental Charge Density Perspective.

High-quality crystals of a certain polymorphic form of thiobarbituric acid containing both keto and enol tautomers in the asymmetric unit were obtained. High-resolution X-ray diffraction data up to sinθ/λ = 1.0 Å−1 were collected and subsequently successfully used for the refining of the multipolar model of electron density distribution. The use of a crystal containing both ketone and enol forms allowed a direct comparison of the topological analysis results and a closer look at the differences between these two forms. The similarities and differences between the deformation densities, electrostatic potentials, Laplacian maps and bond characteristics of the tautomers were analysed. Additionally, the spectrum of the intermolecular interactions was identified and studied from classical, relatively strong N-H···O and O-H···O hydrogen bonds through weaker N-H···S hydrogen bonds to weak interactions (for instance, C-H···O, C-H···S and N···O). The results of these studies point toward the importance of including both the geometrical features and the details of the electron density distribution in the analysis of such weak interactions.

Dynamic Kinetic Sensitization of β-Dicarbonyl Compounds-Access to Medium-Sized Rings by De Mayo-Type Ring Expansion.

Herein, we present a photocatalyzed two-carbon ring expansion of β-dicarbonyl compounds with unactivated olefins that provides facile access to medium-sized rings. Selective sensitization of the substoichiometric enol tautomer enables reactivity of substrates incompatible with the classical De Mayo reaction conditions. Key to success is the identification of the metal-based sensitizer fac-[Ir(CF3 -pmb)3 ], which can be excited using common near-visible LEDs, and possesses a high triplet excited state energy of 73.3 kcal mol-1 . This exactly falls in the range between the triplet energies of the enol and keto tautomer, thereby enabling a dynamic kinetic sensitization. Demonstrating the applicability of fac-[Ir(CF3 -pmb)3 ] as a photocatalyst in organic synthesis for the first time, we describe a two-step photocycloaddition-ring-opening cascade with β-ketoesters, -diketones, and -ketoamides. The mechanism has been corroborated by time-resolved spectroscopy, as well as further experimental and computational studies.

Fluorescent Organic Lewis-Pair Nanoparticles: Excited-State Intramolecular Proton Transfer Molecule 2-(2'-Hydroxyphenyl)benzothiazole Undergoes GSIPT Reactions To Be a Solid-State Nanoemitter.

The excited-state intramolecular proton transfer (ESIPT) reaction, one of the fundamental photochemical processes, is known to occur in 2-(2'-hydroxyphenyl)benzothiazole (HBT), showing an enol-to-keto phototautomerization. In this article, Lewis-pair adduct formation is demonstrated between HBT (Lewis base) and diphenylborinic anhydride (DPBA; Lewis acid), in which the proton transfer occurs in the ground state to form the keto tautomer of HBT. The HBT/DPBA Lewis-pair adduct exhibits strong pale-blue fluorescence at 480 nm in dichloroethane. Additionally, organic Lewis-pair nanoparticles of HBT/DPBA are successfully synthesized on the basis of a reprecipitation protocol in which HBT in conjunction with DPBA dissolved in acetone was rapidly injected into water under ultrasonication. DPBA here also acts as a stabilizing or protecting agent to form spherical nanoparticles with well dispersion. The nanoparticles also exhibit strong keto-type emission centered at 490 nm, changing the emission color to bluish-green. Quantum chemical calculations find the sole formation of the keto tautomer of HBT counterpart in the Lewis pair. Importantly, the present synthesis methodology based on Lewis acid-base chemistry does not require complicated operations to organically synthesize solid-state emitters and thus will play a key role in simply controlling the emission behavior for the new type of organic nanoparticles.

Keto-enol tautomerism, spectral (infrared, Raman and NMR) studies and Normal coordinate analysis of 4-Methyl-2-hydroxyquinoline using quantum mechanical calculations

The Raman (3500−100 cm−1) and mid-infrared (4000−400 cm−1) spectra of 4-Methyl-2-hydroxyquinoline (MHQ) have been recorded. Owing to the keto-enol tautomerism and rotation of methyl group around C4–C13 single bond, six structures (S1–S6) were hypothetically proposed. Full geometry optimization and frequency calculations were performed for keto (quinolone) and enol (hydroxyquinoline) structures using the DFT methods including B3LYP, ωB97XD and mPW1PW91 with basis sets up to 6–311+G(2d,p). In addition, 1H/13C NMR chemical shifts (δ, ppm) were estimated utilizing GIAO approach and IEF-PCM solvation model. The computational outcomes favor keto tautomer, 4-Methylquinolin-2-one (MQO) while the methyl group is staggered to C4–C5 bond (S5). However, other structures were excluded owing to high energy differences besides having an imaginary wavenumber for the transition state structures S2, S4 and S6. These results agree with the observed/calculated vibrational spectral data along with 1H/13C NMR chemical shifts. Aided by the calculated wavenumbers and normal coordinate analysis, complete assignments for the observed infrared/Raman bands to their corresponding vibration modes were quantitatively reported herein for keto- MQO. Employing B3LYP/6–311+(2d,p) structural parameters, the thermo kinetic parameter F-number (5.3936707 cm−1) is estimated along with V3 barrier (1067±48/1219±62 cm−1, 3.05±0.14/3.48±0.18 kcal/mol) using the calculated/observed methyl torsion at 217/233 cm−1.

Using Desmotropes, Cocrystals, and Salts to Manipulate Reactivity in Mechanochemical Organic Reactions.

Performing reactions in the solid state offers the largely unexplored possibility of influencing reactivity by manipulating the solid form of the starting reactants. In this work, we explore the use of various solid forms of barbituric acid and its effect on reaction paths and kinetics in a Knoevenagel condensation reaction with vanillin. Modifications of barbituric acid included the use of its desmotrope, a cocrystal, and a salt as the starting reactant. Comparing these reactions with the reaction starting from the commercial keto tautomer of barbituric acid, we find that the reaction kinetics could be accelerated or decelerated, together with a change in the reaction mechanism. Exploring solid forms of reactants can be used as general methodology for manipulating mechanochemical reactivity, further highlighting the benefits of conducting reactions in the solid state, because many of the modifications of solids become unavailable upon dissolution.

Stable Catechol Keto Tautomers in Cytotoxic Heterodimeric Cyclic Diarylheptanoids from the Seagrass Zostera marina.

Two diarylheptanoid heterodimers, zosterabisphenones A (1) and B (2), were isolated from the seagrass Zostera marina. They feature unprecedented catechol keto tautomers, stable because of steric constraints. Their structure elucidation was based on extensive low-temperature NMR studies and ECD and MS data, with the essential aid of DFT prediction of NMR and ECD spectra. Zosterabisphenone B (2) was selectively cytotoxic against the adenocarcinoma colon cancer cell line HCT116 with IC50 3.6 ± 1.1 μM at 48 h.

Ultrafast nonadiabatic excited-state intramolecular proton transfer in 3-hydroxychromone: A surface hopping approach.

We employ the ab initio molecular dynamics within the surface hopping method to explore the excited-state intramolecular proton transfer taking place on the coupled "bright" S1 (ππ*) and "dark" S2 (nπ*) states of 3-hydroxychromone. The nonadiabatic population transfer between these states via an accessible conical intersection would open up multiple proton transfer pathways. Our findings reveal the keto tautomer formation via S1 on a timescale similar to the O-H in-plane vibrational period (<100fs). Structural analysis indicates that a few parameters of the five-membered proton transfer geometry that constitute the donor (hydroxyl) and acceptor (carbonyl) groups would be adequate to drive the enol to keto transformation. We also investigate the role of O-H in-plane and out-of-plane vibrational motions in the excited-state dynamics of 3-hydroxychromone.

7-OH quinoline Schiff bases: are they the long awaited tautomeric bistable switches?

Two novel, 7-hydroxyquinoline based, Schiff bases have been synthesized and their spectral properties have been investigated by combined use of optical and NMR spectroscopy and theoretical DFT calculations. The results indicate that 8-((phenylimino)methyl)quinolin-7-ol exists as a mixture of enol and two keto tautomers in solution, while 8-(((pentarfluorophenyl)imino)methyl)quinolin-7-ol is presented as a single enol form. Upon irradiation, in both compounds, through excited state intramolecular proton transfer mechanism, a rotation around the Cquin-CH bond occurs, indicating that they are suitable to be used as bistable switches. The back relaxation is faster comparing to the theoretical expectations, due to the additional flexibility around the azomethine bond. As a result of forming complexes with the acidic counter ion, no intramolecular rotation happens upon protonation with trifluoroacetic acid.

Simulation and computational study of graphene oxide nano-carriers, absorption, and release of the anticancer drug of camptothecin.

The structure of nano-graphene oxide has attracted special attention in drug release due to its special properties such as hydrophilicity, special surface, biocompatibility, and the possibility of high loading of hydrophilic and hydrophobic drugs. In this study, after simulating and optimizing the structure of nano-graphene and then nano-graphene oxide (NGO), it was used to load the anti-cancer drug of camptothecin (CA) in an aqueous medium, and the optimal conditions for achieving maximum loading efficiency of the drug were investigated. Due to the structure of the drug, there are two forms, one form of lactone ring and the other carboxylate. If the lactone ring form is predominant, the effectiveness of the drug is increased. This depends on pH of the environment. The calculated thermodynamic and structural results show that the solubility of the drug about nano-graphene and its lactone ring state is maintained by using nano-graphene oxide. To increase the effectiveness of the drug, the lactone ring form must be maintained in the drug structure. The use of folic acid as an intermediate in the aqueous medium preserves the lactone form in the drug structure and increases its effectiveness. The results show that the presence of the ring in the drug structure and its binding to the mediator of folic acid to nano-graphene oxide is a stabilizing factor of keto tautomer. The calculation of vibrational frequencies shows that the presence of folic acid intermediate reduces the vibrational frequency of the hydroxyl group (OH) so that its absorption energy (Ead) is equal to the lowest value 65.24 a.u.

Quantum-chemical study on the relative stability of sildenafil tautomers

The tautomeric equilibrium of sildenafil molecule was theoretically studied using B3LYP and M06-2X density functional theory (DFT) methods in connection with aug-cc-pVDZ correlation consistent basis set. Calculations were performed for gas phase and water solution conditions modelled by polarizable continuum model (PCM). Three tautomeric forms are possible. Two keto forms: A — where the tautomeric proton in more distant from carbonyl group and B — where it is closer, and one enol form denoted, C. Both DFT methods qualitatively give similar tautomer stability order: B > A > C. The B tautomer is dominant in gas phase and water environment, whereas the C tautomer is too high in energy to be present in the tautomeric mixture. Regarding the A tautomer, it is not present in the gas phase but is present in small amounts in water solution. According to B3LYP/aug-cc-pVDZ, the relative Gibbs-free energies for A and C relative to B are 10.05 kcal/mol and 11.91 kcal/mol for gas phase and 5.49 kcal/mol and 12.49 kcal/mol for water solution. According to M06-2X/aug-cc-pVDZ, the relative Gibbs-free energies for A and C are 9.12 kcal/mol and 10.60 kcal/mol for gas phase and 4.27 kcal/mol and 10.23 kcal/mol for water solution. Therefore, for in vivo conditions, we expect that the B tautomer is dominant, and there may exist small amounts of the A tautomer. The C enol tautomer is not present at all. This picture is very different from the parent tautomeric system: 4-hydroxypyrimidine/4-pyrimidinone where the C enol tautomer is less stable than keto B only by about 1 kcal/mol in the gas phase and the A keto tautomer is the least stable and not present in the tautomeric mixture. In order to understand these differences, we performed additional calculations for a series of parent molecules starting from 4-hydroxypyrimidine/4-pyrimidinone, going through two in-between model molecules and ending at Sildenafil molecule. We found that the most important reasons of C form destabilization are dearomatization of the 6-membered ring caused by the fusion with pyrazole ring, lack of strong intramolecular hydrogen bond in C form of sildenafil and presence of destabilizing steric interaction of oxygen and nitrogen atoms of two 6-memberd rings in this tautomer.

Effects of Intermolecular Hydrogen Bonding and Solvation on Enol-Keto Tautomerism and Photophysics of Azomethine-BODIPY Dyads.

Boron-dipyrromethene derivatives (BODIPYs) are a category of molecules with excellent photophysical properties and can be applied to various fields. This work investigates the fluorescent properties of two azomethine-BODIPY dyads in different solvents based on the time-dependent density functional theory (TD-DFT) method. The potential energy curves (PECs) show that the polar protic solvent and the enhanced π-conjugation effect can lower the proton-transfer (PT) barriers, causing the main configuration of NA-BODIPY in methanol to be the keto form, while the main configuration of NA-BODIPY in toluene and SA-BODIPY in methanol and toluene is the enol form. The keto forms of the two compounds possess the twisted intramolecular charge transfer (TICT) decay pathway in the excited state identified by the optimized twisted configurations and the appropriate barriers of the TICT process, whereas the twisted configurations of the enol forms are nonexistent. TICT successfully competes with excited-state proton transfer (ESIPT) of the keto form, which leads to the fluorescence quenching of NA-BODIPY in methanol. This work provides new ideas for the influence of enol-keto tautomerism and the competitiveness of TICT and ESIPT on the photophysical properties of BODIPYs and is expected to provide guidance for the design of new BODIPY functional molecules.

One molecule to light it all: The era of dual-state emission

One molecule to light it all: The era of dual-state emission

2‐Hydroxy‐5‐nitropyridine and 5‐nitro‐2‐pyridone: Tautomerism, infrared, Raman, and NMR spectral interpretations, normal coordinate analysis, and DFT calculations

AbstractRaman (3700–50 cm−1) and infrared (IR) (4000–230 cm−1) spectra of 2‐hydroxy‐5‐nitropyridine (HNP; C5H4N2O3) have been recorded in the solid phase in addition to 1H, 13C, and 15N nuclear magnetic resonance (NMR) spectra of the sample in dimethyl sulfoxide‐d6 (DMSO‐d6). Initially, keto and enol tautomeric forms were proposed owing to proton transfer from the hydroxyl group to pyridine nitrogen atom. Quantum mechanical calculations based on density functional theory (DFT; B3LYP, ωB97XD, and mPW1PW91) were carried out using 6‐31G(d) and 6‐311++G(d,p) basis sets favoring keto‐NPO, 5‐nitro‐2‐pyridone, tautomer by ~0.857–1.345 kcal/mol with minor enol‐HNP in the gas phase. Moreover, 1H, 13C, and 15N NMR chemical shifts were predicted using gauge‐invariant atomic orbital‐DFT calculation at 6‐311++G(d,p) basis set using integral equation formalism of the polarization continuum solvation model including solvent effects. The calculated chemical shifts and spin–spin coupling constants (JHH) for keto tautomer better resemble those experimentally observed rather than the enol form. The observed IR/Raman bands were assigned quantitatively to their normal modes based on the calculated vibrational frequencies, force constants in internal coordinates, normal coordinate analysis, and potential energy distributions. Finally, the nitro and hydroxyl barriers to internal rotations were predicted via a relaxed potential energy surface scan using B3LYP/6‐311++G(d,p) calculations. The results are reported herein and compared with similar molecules whenever appropriate.

1′-hydroxy-2′-acetonaphthone: A simple fluorescence turn-on signaling probe with high selectivity and sensitivity for Al3+ in pure water

Adverse effects of Aluminium ion (Al3+) on human health and the environment, when present above the acceptable concentration, have stimulated much attention to its detection. Many probes are being developed to detect Al3+, most of them suffer from protracted synthesis, less aqueous solubility, and limited selectivity and sensitivity. We report a highly selective and sensitive, fluorescence turn-on sensor for Al3+ detection in pure water by employing the simple, inexpensive commercial probe, 1′-hydroxy-2′-acetonaphthone (HAN). This probe displays remarkably high ~ 120 folds fluorescence enhancement upon complexing with Al3+, the highest reported so far in an aqueous solution for Al3+ sensing. The detection limit obtained was as low as 42 nM. The huge fluorescence enhancement towards Al3+ is attributed to the chelation enhanced fluorescence (CHEF) effect and consequent impediment on the excited-state tautomeric interconversion process between keto (K*) and twisted keto (KR*) tautomers of HAN associated to its ESIPT process. This Al3+ induced inhibition in the interconversion process between K* and KR* tautomers eventually lead to the complete tautomeric arrest of KR* form of the dye complexed with Al3+, a phenomenon not reported to date for the HAN dye in any system. Notably, the present system also illustrates an efficient response towards Al3+ in tap water, suggesting the practical applicability of the current sensor system in real biological and environmental samples.