Diketo Form Research Articles

Single‐crystal X‐ray analysis of the diketo form of asymmetric curcuminoids and coupled with NMR insights into its β‐Keto‐enol tautomerization at ambient temperature

AbstractIn this study, we present a detailed analysis of the structural forms of asymmetric curcuminoids through single‐crystal X‐ray diffraction and nuclear magnetic resonance (NMR) spectroscopy. Curcuminoids substituted with electron‐withdrawing groups (Cl and Br) predominantly adopt the β‐keto‐enol form, whereas those with an OMe group exhibit both diketo and β‐keto‐enol forms. Variable‐temperature X‐ray diffraction studies confirm that the structural state of curcuminoids is influenced by temperature. Our findings also reveal that the β‐keto‐enol form is favored in acidic and neutral conditions, while the diketo form is more prevalent in basic environments. The theoretical Density Functional Theory (DFT) calculations further elucidate the energy differences between the diketo and β‐keto‐enol forms, emphasizing the significance of electronic effects and temperature on tautomeric distributions. These insights enhance our understanding of the structural dynamics of curcuminoids, with implications for their biological activity and pharmacological applications.

An NMR study on the keto-enol tautomerism of 1,3-dicarbonyl drug precursors.

The effective implementation of drug precursor legislation has driven the innovation and design of new alternative substances. The application of 1,3-dicarbonyl precursors as alternative precursors for the synthesis of 1-phenyl-2-propanone (P2P) and 3,4-methylenedioxyphenyl-2-propanone (MDP2P) has created new challenges to legal control. Their 1,3-dicarbonyl structure allows the precursors to exist as an equilibrium mixture of the tautomeric diketo and keto-enolic forms during the nuclear magnetic resonance (NMR) analysis. In this study, the keto-enol tautomerism of four 1,3-dicarbonyl drug pre-precursors, α-phenylacetoacetamide (APAA), methyl α-phenylacetoacetate (MAPA), ethyl α-phenylacetoacetate (EAPA), and methyl 2-(benzo[d][1,3]dioxol-5-yl)-3-oxobutanoate (MAMDPA) were investigated through NMR. One-dimensional (1D) and 2D NMR were combined to assign signals for the diketo and keto-enolic tautomers. Results showed that the keto-enol tautomerism was solvent-dependent but was also influenced by the substituent present in the molecule. Further, the analysis results indicated that majority of substances existed mainly in the diketo form. The enol-keto equilibrium constant (Keq) was stable in dimethyl sulfoxide-d6 and chloroform-d, while unstable for some compounds in acetone-d6 and deuterated methanol. The presence of impurities in the seized sample may disrupt the equilibrium between keto-enol tautomers in 1,3-dicarbonyl precursors. After the optimization of several key quantitative parameters, a quantitative NMR method for the quantification of 1,3-dicarbonyl drug precursors were also developed to facilitate their quantitative analysis. This is the first study to investigate the keto-enol tautomerism and quantification of 1,3-dicarbonyl drug precursors by NMR, providing a new approach for structure analysis and quantification of new precursor analogues.

Crystal structure, tautomerism and photostability of 2-(2-pyridyl)-phenalene-1,3-dione

Tautomerism of cyclic β-diketones has been of scientific interest for decades due to the practical applications it can render, from sensors to photostable materials. In this work the tautomerism of 2-(2-pyridyl)-phenalene-1,3-dione (PPD) was studied in solid state, in solution, and in gas phase through a combination of experimental and theoretical methods. Single-crystal X-ray diffraction analysis of PPD revealed its existence in diketo form in the solid state with protonated pyridyl nitrogen that is stabilized by the intramolecular hydrogen bond of N-H···O type. A very large Stokes shift was observed in the emission spectra in DMSO (ca. 177 nm) and in ethanol (ca. 160 nm), indicating on possible excited-state intramolecular proton transfer (ESIPT) process. DFT calculations in ground state (gas phase and water medium) and in the excited singlet state (B3LYP-6311++G(d,p)) agree very well with the experimental data and suggest reverse order of the possible OH and NH tautomers in the ground and the excited singlet state, namely the diketo NH tautomer is the most stable one in the ground state whereas in the excited singlet state the enol OH form is more stable. The photostability of PPD was estimated by irradiation experiments that were performed in comparison with 2-acetylindan-1,3-dione (2AID), which is a compound with proven high photostability in ethanol and fast ESIPT. The data showed that unlike 2AID, the 2-(2-pyridyl)-phenalene-1,3-dione exhibits lower photostability in ethanol. These results could suggest that either the ESIPT process is not the only transformation that takes place in the excited state of PPD, or it is not as fast as the one of 2AID.

Theoretical studies on the photo protective mechanism of curcuminoids

In this work, the deactivation pathways of curcuminoids after photoexcitation was studied by employing density functional theory to explore their UVA radiation screening capacity. A comprehensive computational characterization of the excited-state processes of curcumin, demethoxycurcumin, and bis-demethoxycurcumin was done. The molecules exist in diketo and enol forms which are in equilibrium and interconvertible through keto-enol tautomerism. The enolic forms of each of the studied molecules have eight geometric cis–trans isomers as a result of torsion rotation about three different carbon–carbon double bonds across the aliphatic chain. For each geometric isomer, sixteen possible rotamers are found to exist due to rotation about five different carbon–carbon single bond rotations, also across the skeleton of the aliphatic chain. Upon photoexcitation, the studied molecules follow three main pathways of radiationless decay: (a) rotamerism and interconversion between rotamers of comparable energies which are in equilibrium, (b) interconversion between the cis–trans geometrical isomers where an efficient vibrational relaxation path is formed at ∼90° during torsion rotation about carbon–carbon double bond, and (c) excited state intramolecular proton transfer in a single O–H stretching vibration through a cyclic intramolecular hydrogen bonded ring formed at the centre of the molecule giving back the original structure. The absorption and emission spectra of the molecules were also simulated where the theoretically obtained absorption and emission maxima are close to the reported experimental values.

Petrosamine Revisited. Experimental and Computational Investigation of Solvatochromism, Tautomerism and Free Energy Landscapes of a Pyridoacridinium Quaternary Salt.

Petrosamine (1)-a colored pyridoacridine alkaloid from the Belizean sponge, Petrosia sp., that is also a potent inhibitor of acetylcholine esterase (AChE)-was investigated by spectroscopic and computational methods. Analysis of the petrosamine-free energy landscapes, pKa and tautomerism, revealed an accurate electronic depiction of the molecular structure of 1 as the di-keto form, with a net charge of q = +1, rather than a dication (q = +2) under ambient conditions of isolation-purification. The pronounced solvatochromism (UV-vis) reported for 1, and related analogs were investigated in detail and is best explained by charge delocalization and stabilization of the ground state (HOMO) of 1 rather than an equilibrium of competing tautomers. Refinement of the molecular structure 1 by QM methods complements published computational docking studies to define the contact points in the enzyme active site that may improve the design of new AChE inhibitors based on the pyridoacridine alkaloid molecular skeleton.

On the photobehaviour of curcumin in biocompatible hosts: The role of H-abstraction in the photodegradation and photosensitization.

Curcumin (CUR) is a naturally occurring pigment extensively studied due to its therapeutic activity and delivered by suitable nanocarriers to overcome poor solubility in aqueous media. The significant absorption of CUR in the visible blue region has prompted its use as a potential phototherapeutic agent in treating infectious and cancer diseases, although the mechanism underlying the phototoxic effects is still not fully understood. This contribution investigates the photobehaviour of CUR within polymeric micelles, microemulsions, and zein nanoparticles, chosen as biocompatible nanocarriers, and human serum albumin as a representative biomolecule. Spectroscopic studies indicate that in all host systems, the enolic tautomeric form of CUR is converted in a significant amount of the diketo form because of the perturbation of the intramolecular hydrogen bond. This leads to intermolecular H-abstraction from the host components by the lowest excited triplet state of CUR with the formation of the corresponding ketyl radical, detected by nanosecond laser flash photolysis. This radical is oxidized by molecular oxygen, likely generating peroxyl and hydroperoxyl radical species, unless in Zein, reasonably due to the poor availability of oxygen in the closely packed structure of this nanocarrier. In contrast, no detectable formation of singlet oxygen was revealed in all the systems. Overall these results highlight the key role of the H-abstraction process over singlet oxygen sensitization as a primary photochemical pathway strictly dictated by the specific features of the microenvironment, providing new insights into the photoreactivity of CUR in biocompatible hosts that can also be useful for a better understanding of its phototoxicity mechanism.

3,3'-(Phenyl-methyl-ene)bis-(1-ethyl-3,4-di-hydro-1H-2,1-benzo-thia-zine-2,2,4-trione): single-crystal X-ray diffraction study, quantum-chemical calculations and Hirshfeld surface analysis.

The title compound, C27H26N2O6S2, possesses potential anti-microbial, analgesic, and anti-inflammatory activity. This compound has three tautomeric forms, which relative energies were estimated with quantum-chemical calculations. All these tautomers (dienol form 7A, keto-enol form 7B, and diketo form 7C) were optimized by the M06-2X/cc-pVTZ method in a vacuum, using the PCM model with chloro-form and DMSO as solvent. The diketo form of the title compound proved to be the most energetically favourable as compared to the keto-enol or dienol forms. The diketo form can exist as three possible stereoisomers with the same configuration of one stereogenic center and different configurations of the stereogenic centers at two other atoms: ( R , R , R ), (S , R , S ) and ( R , R , S ). The ( R , R , S ) stereoisomer was found in the crystal phase. It was revealed that the thia-zine rings of equivalent benzo-thia-zine fragments have different conformations, (a sofa or a half-chair). The two bicyclic fragments connected through the phenyl-methyl-ene group are oriented almost orthogonal to each other, subtending a dihedral angle of 82.16(7)°.

A wearable colorimetric sweat pH sensor-based smart textile for health state diagnosis.

Sweat pH is an important indicator for diagnosing disease states, such as cystic fibrosis. However, conventional pH sensors are composed of large brittle mechanical parts and need additional instruments to read signals. These pH sensors have limitations for practical wearable applications. In this study, we propose wearable colorimetric sweat pH sensors based on curcumin and thermoplastic-polyurethane (C-TPU) electrospun-fibers to diagnose disease states by sweat pH monitoring. This sensor aids in pH monitoring by changing color in response to chemical structure variation from enol to di-keto form via H-atom separation. Its chemical structure variation changes the visible color due to light absorbance and reflectance changes. Furthermore, it can rapidly and sensitively detect sweat pH due to its superior permeability and wettability. By O2 plasma activation and thermal pressing, this colorimetric pH sensor can be easily attached to various fabric substrates such as swaddling and patient clothing via surface modification and mechanical interlocking of C-TPU. Furthermore, the diagnosable clothing is durable and reusable enough to neutral washing conditions due to the reversible pH colorimetric sensing performance by restoring the enol form of curcumin. This study contributes to the development of smart diagnostic clothing for cystic fibrosis patients who require continuous sweat pH monitoring.

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.

Click synthesis of novel dendronized curcumin and analogs. Strengthening of physicochemical properties toward biological applications.

Curcumin and its analogs, chalcones, and C5-monocarbonyl are molecules of great therapeutic potential, but their poor stability and hydrophobicity have hampered their extensive use in clinical trials. Therefore, significant efforts have been made in materials science to improve their physicochemical properties. In this study, we propose dendronization as a synthetic strategy to strengthen some physicochemical properties such as solubility and stability of curcumin and analogs, taking advantage of the click chemistry (CuAAC) to attach second-generation polyester dendrons to the unsaturated cores. The dendronization, with the subsequent formation of aromatic triazole groups as linkers, not only modified the solubility and stability of the molecular systems but also favored the diketo tautomeric form of curcumin, as demonstrated spectroscopically. This result is significant since the diketo tautomer, which preserves the antioxidant properties of curcumin, is the most biologically active form. The hydrophobic/hydrophilic balance, achieved after dendronization, allowed the solubilization of the chromophoric molecules in buffered solutions at relevant pH values (7.4 and 6.4). Furthermore, the stability of all molecules was also upgraded since UV-vis absorption spectra did not exhibit modified profiles after 7 days at physiologic pH. From photochemical stability experiments irradiating at 415 nm, the dendritic derivatives containing triazole linkers were more susceptible to being degraded. All derivatives exhibited emission properties according to the length of each conjugate fragment. Fluorescence experiments evidenced the role of dendrons in preventing emission quenching by aggregation and exhibited differentiated emission behavior depending on the linker type (triazole or ester) between the chromophoric core and the polyester dendrons.

Curcumin analogues for possible cancer treatment A QSAR and partial ordering study

The possible effect of curcumin as a potential natural cancer treatment drug has been intensively discussed. In the present study the probabilities of a series of curcumin analogues to possess potential as antineoplastic, prostate cancer treatment and anticarcinogenic agents has been studied theoretically applying a selection of quantitative structure-activity relation and absorption, distribution, metabolism, and excretion (ADME) approaches. From spectroscopic studies it is evident that these compounds can be found in both enol and diketo forms, the former in general the more predominant in non-polar solvents, whereas in polar solvents, like water an increasing amount of the diketo form can be noted. Hence, the probabilities for both the enols and diketo forms to possess the above-mentioned effects were studied. In most cases the enol form shows the highest probabilities for being effective although the differences are not significant. Thus, it is suggested to look at the sum of effects of the keto and the enol forms in relation to the possible therapeutic effects of the compounds here studied.

CH⋯O H-bond mediated tautomerization of 2-methyl-1,3-cyclohexanedione: A combined IR spectroscopic and theoretical study

Molecular association and its impact on the keto-enol tautomerization of 2-methyl-1,3-cyclohexanedione (MCHD) have been investigated in low temperature argon matrix and thin solid film. The system exists exclusively in diketo tautomeric form in argon matrix. The CH⋯O H-bonded homodimers of the diketo tautomer are produced by annealing the matrix at 28 K. No trace of the keto-enol tautomer is observed in matrix isolated homodimers in the temperature range of 8–28 K. However, tautomeric conversion initiates in a thin film of pure diketo tautomer when the temperature of the film is raised to ~170 K. Transition state calculations on the monomeric and dimeric MCHD demonstrate that CH⋯O H-bond formations between diketo tautomers play a vital role in lowering the tautomerization barrier. However, the extent of CH⋯O H-bonded dimer formation in matrix isolation, as well as extent of tautomerization in the neat sample are found to be smaller than that for the previously reported 1,3-cyclohexanedione (CHD) under similar experimental conditions (J. Phys. Chem. A 2012, 116, 3836–3845). Electronic structure calculations suggest that formation of the CH⋯O H-bonded dimer is less feasible in presence of the bulky 2-methyl groups of MCHD, as compared to CHD. Additionally, the transition state geometry of the dimeric keto-enol product of MCHD, as compared to the same for CHD, is more strained and offers a weaker CH---O H-bond that contributes to lesser tautomeric conversion in the former.

A Contribution to the Solid State Forms of Bis(demethoxy)curcumin: Co-Crystal Screening and Characterization.

Bis(demethoxy)curcumin (BDMC) is one of the main active components found in turmeric. Major drawbacks for its usage are its low aqueous solubility, and the challenging separation from other curcuminoids present in turmeric. Co-crystallization can be applied to alter the physicochemical properties of BDMC in a desired manner. A co-crystal screening of BDMC with four hydroxybenzenes was carried out using four different methods of co-crystal production: crystallization from solution by slow solvent evaporation (SSE), and rapid solvent removal (RSR), liquid-assisted grinding (LAG), and crystallization from the melt phase. Two co-crystal phases of BDMC were obtained with pyrogallol (PYR), and hydroxyquinol (HYQ). PYR-BDMC co-crystals can be obtained only from the melt, while HYQ-BDMC co-crystals could also be produced by LAG. Both co-crystals possess an equimolar composition and reveal an incongruent melting behavior. Infrared spectroscopy demonstrated the presence of BDMC in the diketo form in the PYR co-crystals, while it is in a more stable keto-enol form in the HYQ co-crystals. Solubility measurements in ethanol and an ethanol-water mixture revealed an increase of solubility in the latter, but a slightly negative effect on ethanol solubility. These results are useful for a prospective development of crystallization-based separation processes of chemical similar substances through co-crystallization.

Lithium aluminum hydride reduction of 1-phenylbutane-1,3-dione, and acetylation of the products: NMR and GC-MS analysis

Reduction of ?-diketones with lithium aluminum hydride (LiAlH4, LAH) can lead to different products, depending on the tautomeric equilibrium: the reduction of diketo forms gives the corresponding diols and the reduction of ketoenol forms yields elimination products, saturated and unsaturated ketones and alcohols. Here, we report on the results of LAH reduction of 1-phenylbutane-1,3-dione. The products of reduction were further acetylated and separated by dry flash chromatography. The obtained products, phenylbut(en)ols, phenylbut(en)ones and phenylbut(en)yl acetates, were characterized by spectral (1H and 13C NMR, MS) and retention index (RI) data. It can be concluded that LAH preferentially reduces the carbonyl group more distant from the phenyl group of 1-phenylbutane-1,3-dione. The structure-retention index relationships between isomers were discussed. Proton splitting patterns were resolved by proton NMR simulations.

Curcumin in silver nanoparticles aqueous solution: Kinetics of keto-enol tautomerism and effects on AgNPs

The tautomerism of curcumin (CUR) in aqueous solution was investigated in the presence of silver nanoparticles (AgNPs) in the temperature range 294−314 K. The kinetic data indicate that the conversion of the keto-enol into the diketo form is associated to higher rate constants in comparison to those obtained in pure water. Moreover, nonlinear Arrhenius behavior was observed in the investigated temperature range. The effects of CUR on the AgNPs were determined by zeta potential and dynamic light scattering measurements and supported by spectroscopic analysis suggesting that interactions with metal surface occur preserving nanoparticles from self-aggregation in the investigated conditions. The results reported herein contribute to enhance the kinetics of CUR tautomerism in aqueous media.

Unravelling the Keto-Enol Tautomer Dependent Photochemistry and Degradation Pathways of the Protonated UVA Filter Avobenzone.

Avobenzone (AB) is a widely used UVA filter known to undergo irreversible photodegradation. Here, we investigate the detailed pathways by which AB photodegrades by applying UV laser-interfaced mass spectrometry to protonated AB ions. Gas-phase infrared multiple-photon dissociation (IRMPD) spectra obtained with the free electron laser for infrared experiments, FELIX, (600–1800 cm–1) are also presented to confirm the geometric structures. The UV gas-phase absorption spectrum (2.5–5 eV) of protonated AB contains bands that correspond to selective excitation of either the enol or diketo forms, allowing us to probe the resulting, tautomer-dependent photochemistry. Numerous photofragments (i.e., photodegradants) are directly identified for the first time, with m/z 135 and 161 dominating, and m/z 146 and 177 also appearing prominently. Analysis of the production spectra of these photofragments reveals that that strong enol to keto photoisomerism is occurring, and that protonation significantly disrupts the stability of the enol (UVA active) tautomer. Close comparison of fragment ion yields with the TD-DFT-calculated absorption spectra give detailed information on the location and identity of the dissociative excited state surfaces, and thus provide new insight into the photodegradation pathways of avobenzone, and photoisomerization of the wider class of β-diketone containing molecules.

Mechanism and kinetic investigations of 5-fluorouracil tautomeric conversions in the gas phase: DFT and CBS-QB3 methods using multichannel Rice–Ramsperger–Kassel–Marcus steady-state approximation theory

In this work, chemical computations were carried out to study of tautomeric conversion of 5-fluorouracil (A → products) at CBS-QB3, M06-2x, and B3LYP levels of theory. These 11 tautomers connected to each other via 10 transition state molecules and four pathways. In addition, the stationary points (including stable structures and transition states), in which playing a significant role on ground potential energy surfaces of isomerization processes, were found. Multichannel RRKM steady-state approximation calculations have been performed to calculate the rate constants at 1 atm pressure and over a range of temperature from 268.15 to 310.15 K to cover the in vivo and atmospheric conditions. The stability ranking of tautomers obtained and demonstrated that di-keto form of 5-fluorouracil is the most stable tautomer. The energy barriers for tautomeric conversions were calculated. The information reported in this study may help with the identification of drug in vivo and in the laboratory.

Condensation of ninhydrin with phenols: Regioselective formation of diverse organic scaffolds and crystal structure studies

In the present work, a range of phenolic compounds have been reacted with ninhydrin in acid medium to afford different indanone-based molecules via regioselective C–C bond formation. Ninhydrin reacts with 2,7-Dihydroxynaphthalene and 4-cyanophenol in AcOH producing ortho selective adduct 3a and 3b respectively; however, unlike 3a remaining as cyclic hemiketal structure, 3b exists as ring-opened diketo form. On the other hand, ortho-substituted phenols like o-cresol, guaiacol, o-chloro/iodophenol condense with ninhydrin to accomplish para selective diarylated adducts 5a-d, whereas 3-methoxy phenol provides corresponding monoarylated adduct 5e as the major product. Different hydroxy benzoic acids deliver versatile scaffolds like diarylated indanone, indenofuran, benzofuran or spirolactone 7a-e depending upon the substitution pattern and acidity of the reaction medium. All the compounds are characterized by 1H and 13C NMR spectra. In the solid state, scissors-shaped molecule 5a has been found to form inclusion complex with disordered o-cresol molecule and function as building unit of supramolecular network. In the crystal structure of spirolactone 7d, anti-parallel motif of dipolar···dipolar (CO(δ−)···C(δ+) = O) interaction results ladder-like arrangement.

Argentophilic Interactions in Two AgI Complexes of 3-(2-(Pyridin-4-yl)ethyl)pentane-2,4-dione, a Promising Ditopic Ligand

Reactions of 3-(2-(pyridin-4-yl)ethyl)pentane-2,4-dione (HacacPyen) with AgPF6 and AgBF4 afforded cationic silver complexes [Ag(HacacPyen)2]+ with essentially linear coordination of the Ag I cation by two pyridine N atoms. Rather unexpectedly, the HacacPyen ligands in the PF6- salt 1 adopt the diketo form, in contrast to the uncoordinated HacacPyen molecule, whereas the corresponding BF4- salt 2 and the majority of 3-substituted acetylacetones crystallizes as the enol tautomer. In both compounds 1 and 2, complex cations aggregate via short Ag...Ag interactions to pairs. These contacts amount to 3 . 21 Å in 1 and 3 . 26 Å or 3 . 31 Å in 2. As they are unsupported by any additional bridging ligands and correspond to the closest interionic interactions between neighbouring complex cations, they may be addressed as argentophilic interactions. The PF6- anions in 1 and the BF4- counter ions in 2 are involved in long and presumably electrostatic Ag...F contacts of ca. 2 . 9 Å. Additional coordination between Ag I and keto O atoms of symmetry-equivalent ligands occurs in 1 and leads to an extended two-periodic supramolecular structure.

A computational study of gas-phase acidity and basicity of azulene-based uracil analogue

In this paper, we suggest a computational scheme for the theoretical estimation of gas-phase acidity and basicity of azulene-based uracil analogue. The proton affinities (PAs) of the two oxygen and of the two nitrogen atoms and the deprotonation energies (DPEs) of the two NH and of the two OH bonds of azulene-based uracil analogue isomers are calculated by density functional theory (DFT) using the 6-31+G(d,p) basis set and by high ab initio MO theory (CBS-QB3) method. The PAs of the oxygen and nitrogen atoms of 13 tautomers range from 197.9 to 230.4 kcal/mol and the DPEs of the OH and NH groups from 300 to 342.3 kcal/mol. The proton affinities of di-keto form AZU1 followed the order O9 (N1 site), O9 (N3 site), O11 (N3 site), and O11 (H13 site).