5+1-Heterocyclization as preparative approach for carboxy-containing triazolo[1,5-c]quinazolines with anti-inflammatory activity.

Present article is devoted to the purposeful search of novel anti-inflammatory agents among carboxyl-containing partially hydrogenated [1,2,4]triazolo[1,5-с]quinazolines and products of their tandem cyclization. It has been shown that target compound's could be obtained via interaction between [2-(3-R-1H-1,2,4-triazol-5-yl)phenyl]amines and oxo-containing carboxylic acids and their esters of various structure. The structures of synthesized compounds were verified by appropriate methods, the features of NMR-spectra patterns were discussed as well. The low predicted toxicity of obtained compounds has been estimated using in silico methods. In vivo study on the model of acute aseptic inflammation (carrageenan test) have been revealed that synthesized compounds expose anti-inflammatory activity in the range of 0.94-52.66%. 4-(2-(Ethoxycarbonyl)-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolin-5-yl)benzoic acid has been identified as most active compound. Additionally, the effects of some (2-R-5,6-dihydro[1,2,4]triazolo[1,5-c]quinazolin-5-yl)benzoic acids (compounds 3) on the levels of key inflammatory markers have been estimated. It has been shown that studied compounds decrease the level of neutrophils, COX-2, nitrotyrosine, IL-1b, C-reactive protein and increase level of eNOS. 4-(2-(Ethoxycarbonyl)-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolin-5-yl)benzoic acid (3.2) has been identified as compound with most expressed anti-inflammatory activity and significant effect on the levels of marker of inflammatory processes. Molecular docking study towards СОХ-1 and СОХ-2 has been conducted to substantiate possible mechanism of obtained compounds anti-inflammatory activity. It has been found that fixation of 4-(2-(ethoxycarbonyl)-5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolin-5-yl)benzoic acid (3.2) molecule in active site of enzyme is outstandingly similar to the reference ligands. The essential value of carboxylic group for presence of anti-inflammatory activity has been estimated as result of SAR-analysis. It has been found that studied class of compounds is perspective for further structural modification aimed to the creation of novel anti-inflammatory agents.

Ligand-Mediated Regioselective Rhodium-Catalyzed Benzotriazole-Allene Coupling: Mechanistic Exploration and Quantum Chemical Analysis.

The ligand-controlled rhodium-catalyzed regioselective coupling of 1,2,3-benzotriazoles and allenes was investigated by DFT calculations. Because allylation can occur at either the N1 or N2 position of the 1,2,3-benzotriazole, the complete Gibbs free energy profiles for both pathways were computed. A kinetic preference emerged for the experimentally observed N1 allylation with the JoSPOphos ligand, whereas N2 allylation was favored with DPEphos. Analysis of the regiodetermining oxidative addition step by using the activation strain model in conjunction with a matching energy decomposition analysis has revealed that the unprecedented N2 reaction regioselectivity is dictated by the strength of the electrostatic interactions between the 1,2,3-benzotriazole and the rhodium catalyst. The nature of the electrostatic interaction was rationalized by analysis of the electrostatic potential maps and Hirshfeld charges: a stabilizing electrostatic interaction was found between the key atoms involved in the oxidative addition for the N2 pathway, analogous interactions are weaker in the N1 case.

A density functional theory investigation of degradation of Nitroguanidine in the photoactivated triplet state.

It is well known that nitroguanidine (NQ) undergoes photodegradation when exposed to UV-radiation. However, the mechanism of NQ photolysis is not fully understood. Earlier investigations have shown that nitrocompounds undergo to their triplet state population through crossing of electronic singlet and triplet excited state potential energy surfaces due to the nitrogroup rotation and nonplanarity under electronic excitation. Therefore, it is expected that under electronic excitation, the presence of nitrogroup in NQ would also lead to the population of electronic lowest energy triplet state. To shed a light on the degradation of NQ in alkaline solution under electronic excitation, we performed a detailed investigation of a possible degradation mechanism at the IEFPCM/B3LYP/6-311++G(d,p) level in the electronic lowest energy triplet state. We found that degradation ability of NQ in the electronic triplet state would be significantly larger than in the electronic ground singlet state. It was revealed that the photodecomposition of nitroguanidine might occur through several pathways involving N-N and C-N bond ruptures, nitrite elimination, and hydroxide ion attachment. Nitrogen of nitrogroup would be released in the form of nitrite and nitrogen (I) oxide. Computationally predicted intermediates and products of nitroguanidine photolysis such as nitrite, hydroxyguanidine, cyanamide, and urea correspond to experimentally observed species.

Role of Singlet Oxygen in the Degradation of Selected Insensitive Munitions Compounds: A Comprehensive, Quantum Chemical Investigation.

DNAN (2,4-dinitroanisole), NTO (3-nitro-1,2,4-triazol-5-one), and NQ (nitroguanidine) are important energetic materials used in military applications. They may find their way to the environment during manufacturing, transportation, storage, training, and disposal. A detailed investigation of possible mechanisms for reactions of the nitrocompounds with singlet oxygen, one of the potential methods for their degradation, was performed by computational study using the PCM(Pauling)/M06-2X/6-311++G(d,p) approach. Obtained results suggest that reactivity of the investigated munitions compounds toward singlet oxygen follows the order: DNAN > NTO(anion) > NQ ≫ NTO. DNAN is involved in [4 + 2]-addition with oxygen, and further formation of diepoxide or epoxyketone through diradical intermediates have been predicted. The NTO may undergo intramolecular rearrangement with formation of peroxide compound or nitrite radical elimination, and NQ may be transformed into urea.

QSPR modeling of optical rotation of amino acids using specific quantum chemical descriptors.

Many chemical phenomena occur in solution. Different solvents can change the optical activity of chiral molecules. The optical rotation angles of solutes of 75 amino acids in dimethylformamide, water and methanol were analyzed using the quantitative structure-activity relationships approach. For an accurate description of chirality, we used specific quantum chemical descriptors, which reflect the properties of a chiral center, and continuous symmetry measures. The set of specific quantum chemical descriptors for atoms located near the chiral center, such as Mulliken charges, the sum of Mulliken charges on an atom (with the hydrogen charges summed up with the adjacent non-hydrogen atoms), and nuclear magnetic resoncance tensors was applied. To represent solvent effects, we used mixture-like structural simplex descriptors and quantum chemical descriptors obtained for structures optimized for specified solvent using PBE1PBE/6-31G** level of theory with the polarizable continuum model. Multiple linear regression, M5P, and locally weighted learning techniques were used to achieve accurate predictions. The specific quantum chemical descriptors proposed here demonstrated high specificity in the majority of the developed models and established direct quantitative structure-property relationships.

Origin of Substituent Effect on Tautomeric Behavior of 1,2,4-Triazole Derivatives: Combined Spectroscopic and Theoretical Study.

The reaction of 2-aryl-[1,2,4]triazolo[1,5-c]quinazolines with nucleophilic reagents (hydrazine hydrate, sodium hydroxide, sodium methoxide, hydrochloric acid) under acidic conditions leads to formation of compounds that tend to tautomerize. The products of the transformation are distinguished by the position (ortho-, meta-, para-) of the OCH3 group in the aryl moiety. To assign their structures we used the combined approach: experiment and theoretical modeling. The procedure included calculation of the relative stability for possible tautomers, simulation of UV/vis spectra for the most stable forms, and comparison of the resulting curves with the experimental spectral data taking into account the Boltzmann weighting. Through computations, we showed that the orientation of OCH3 substituent remarkably impacts on the tautomeric behavior of triazoles. In the case of ortho-OCH3 it is controlled by formation of the intramolecular hydrogen bond while for meta- and para- derivatives the degree of conjugation plays the decisive role. In order to balance the accuracy and cost of calculations we evaluated the performance of selected DFT methods and 6-31G*, 6-311++G**, and STO##-3Gel basis sets. The last one is a physically justified basis set previously constructed in our group, and its combination with PBE1PBE approach is shown to be the best choice for UV/vis simulations in the frame of the current research.

A Counterion-Directed Approach to the Diels-Alder Paradigm: Cascade Synthesis of Tricyclic Fused Cyclopropanes.

An approach to the intramolecular Diels-Alder reaction has led to a cascade synthesis of complex carbocycles composed of three fused rings and up to five stereocenters with complete stereocontrol. Computational analysis reveals that the reaction proceeds by a Michael/Michael/cyclopropanation/epimerization cascade in which size and coordination of the counterion is key.

In Silico Alkaline Hydrolysis of Octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine: Density Functional Theory Investigation.

HMX (octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine), an energetic material used in military applications, may be released to the environment during manufacturing, transportation, storage, training, and disposal. A detailed investigation of a possible mechanism of alkaline hydrolysis, as one of the most promising methods for HMX remediation, was performed by computational study at PCM(Pauling)/M06-2X/6-311++G(d,p) level. Obtained results suggest that HMX hydrolysis at pH 10 represents a highly exothermic multistep process involving initial deprotonation and nitrite elimination, hydroxide attachment accompanied by cycle cleavage, and further decomposition of cycle-opened intermediate to the products caused by a series of C-N bond ruptures, hydroxide attachments, and proton transfers. Computationally predicted products of HMX hydrolysis such as nitrite, 4-nitro-2,4-diazabutanal, formaldehyde, nitrous oxide, formate, and ammonia correspond to experimentally observed species. Based on computed reaction pathways for HMX decomposition by alkaline hydrolysis, the kinetics of the entire process was modeled. Very low efficiency of this reaction at pH 10 was observed. Computations predict significant increases (orders of magnitude) of the hydrolysis rate for hydrolysis reactions undertaken at pH 11, 12, and 13.

Alkaline hydrolysis of hexahydro-1,3,5-trinitro-1,3,5-triazine: M06-2X investigation.

Alkaline hydrolysis mechanism of possible environmental contaminant RDX (hexahydro-1,3,5-trinitro-1,3,5-triazine) was investigated computationally at the PCM(Pauling)/M06-2X/6-311++G(d,p) level of theory. Results obtained show that the initial deprotonation of RDX by hydroxide leads to nitrite elimination and formation of a denitrated cyclohexene intermediate. Further nucleophilic attack by hydroxide onto cyclic CN double bond results in ring opening. It was shown that the presence of hydroxide is crucial for this stage of the reaction. The dominant decomposition pathway leading to a ring-opened intermediate was found to be formation of 4-nitro-2,4-diazabutanal. Hydrolytic transformation of its byproduct (methylene nitramine) leads to end products such as formaldehyde and nitrous oxide. Computational results are in a good agreement with experimental data on hydrolysis of RDX, suggesting that 4-nitro-2,4-diazabutanal, nitrite, formaldehyde, and nitrous oxide are main products for early stages of RDX decomposition under alkaline conditions.

Comprehensive investigations of kinetics of alkaline hydrolysis of TNT (2,4,6-trinitrotoluene), DNT (2,4-dinitrotoluene), and DNAN (2,4-dinitroanisole).

Combined experimental and computational techniques were used to analyze multistep chemical reactions in the alkaline hydrolysis of three nitroaromatic compounds: 2,4,6-trinitrotoluene (TNT), 2,4-dinitrotoluene (DNT), and 2,4-dinitroanisole (DNAN). The study reveals common features and differences in the kinetic behavior of these compounds. The analysis of the predicted pathways includes modeling of the reactions, along with simulation of UV-vis spectra, experimental monitoring of reactions using LC/MS techniques, development of the kinetic model by designing and solving the system of differential equations, and obtaining computationally predicted kinetics for decay and accumulation of reactants and products. Obtained results suggest that DNT and DNAN are more resistant to alkaline hydrolysis than TNT. The direct substitution of a nitro group by a hydroxide represents the most favorable pathway for all considered compounds. The formation of Meisenheimer complexes leads to the kinetic first-step intermediates in the hydrolysis of TNT. Janovsky complexes can also be formed during hydrolysis of TNT and DNT but in small quantities. Methyl group abstraction is one of the suggested pathways of DNAN transformation during alkaline hydrolysis.

Hydrazinolysis of 3-R-[1,2,4]triazino[2,3-c]quinazolin-2-ones. Synthetic and theoretical aspects.

It has been shown that heating of 3-R-[1,2,4]triazino[2,3-c]quinazolin-2-ones with 5-fold excess of hydrazine hydrate in propanol-2 gave the corresponding 3-(2-aminophenyl)-6-R-1,2,4-triazin-5-ones with high yields. The mechanism of the reaction has been proposed based on the results of theoretical investigation at B3LYP and MP2 levels of theory. According to calculations, an attack of the hydrazine molecule on the C6═N7 double bond leads to ring-opening with N5-C6 bond cleavage. The process continues by addition of the second nucleophile molecule and elimination of the formazan fragment through a series of transformations that yield the target product.

Catalytic enantioselective synthesis of indanes by a cation-directed 5-endo-trig cyclization.

5-Endo-trig cyclizations are generally considered to be kinetically unfavourable, as described by Baldwin's rules. Consequently, observation of this mode of reaction under kinetic control is rare. This is usually ascribed to challenges in achieving appropriate approach trajectories for orbital overlap in the transition state. Here, we describe a highly enantio- and diastereoselective route to complex indanes bearing all-carbon quaternary stereogenic centres via a 5-endo-trig cyclization catalysed by a chiral ammonium salt. Through computation, the preference for the formally disfavoured 5-endo-trig Michael reaction over the formally favoured 5-exo-trig Dieckmann reaction is shown to result from thermodynamic contributions to the innate selectivity of the nucleophilic group, which outweigh the importance of the approach trajectory as embodied by Baldwin's rules. Our experimental and theoretical findings demonstrate that geometric and stereoelectronic constraints may not be decisive in the observed outcome of irreversible ring-closing reactions.

DFT M06-2X investigation of alkaline hydrolysis of nitroaromatic compounds.

The nitroaromatic compounds 2,4,6-trinitrotoluene (TNT), 2,4-dinitrotoluene (DNT) and 2,4-dinitroanisole (DNAN) are potential environmental contaminants and their transformations under a variety of environmental conditions are consequently of great interest. One possible method to safely degrade these nitrocompounds is alkaline hydrolysis. A mechanism of the initial stages of this reaction was investigated computationally. Simulations of UV-VIS and NMR spectra for this mechanism were also produced. The results obtained were compared to available experimental data on the alkaline hydrolysis of TNT and suggest that the formation of Meisenheimer complexes and an anion of TNT are potential first-step intermediates in the reaction path. As the reaction proceeds, computational results indicate that polynegative complexes dominate the degradation pathway, followed by cycles of carbon chain opening and breaking. A second possible pathway was identified that leads to polymeric products through Janovsky complex formation. Results from this study indicate that the order of increasing resistance to alkaline hydrolysis is TNT, DNT and DNAN.

Ethanolysis of N-substituted norbornane epoxyimides: discovery of diverse pathways depending on substituent's character.

Combined experimental and theoretical studies have been carried out to investigate the transformations of the epoxyimides of norbornane into heterocyclic compounds. We established that interaction of the aryl-substituted epoxyimides of norbornane with sodium ethoxide results in the formation of new heterocyclic compounds in preparatively useful yields and with complete regioselectivity. The reactions of epoxyimides, containing aryl electron-donor substituents, result in the formation of endo-9-carbamoyl-exo-2-hydroxy-5-oxo-4-oxatricyclo[4.2.1.0(3,7)]nonanes, while in the case of the absence of an aryl electron-donor group or the presence of aryl electron-withdrawing group in the epoxyimide, exo-2-hydroxy-5-oxo-4-azatricyclo[4.2.1.0(3,7)]nonan-endo-9-carboxylic acids were obtained as products of the ethanolysis reaction. Unexpectedly, the ethanolysis of alkyl-substituted epoxyimides leads to dihydroxyimide formation as the major product. In order to understand the vital role of the imide substituent, a systematic theoretical DFT study at the PCM/B3LYP/6-31+G(d) level was carried out. We found that substituents at the nitrogen atom of epoxyimides exerted remarkable effects on the regioselectivity in the ethanolysis reaction, based on the solvent effects and intramolecular electronic interactions. Particularly, the preference for the formation of dihydroxyimides over heterocyclic systems for alkyl derivatives might be explained by kinetic stability of the formed acetal intermediate over the competitive epoxyamido acid intermediate. The above results provide a convenient and efficient method for predicting the structures of heterocyclic systems formed under basic ethanol conditions depending on the substituent on the nitrogen atom of the norbornane epoxyimides.

Comprehensive DFT and MP2 level investigations of reaction of 2,3-dihydro-1,5-benzodiazepine-2-thiones with hydrazine.

Density functional theory approach was used for the 4-phenyl-2,3-dihydro-1,5-benzodiazepine-2-thione compound to determine the mechanism of hydrazinolysis of 4-substituted 2,3-dihydro-1,5-benzodiazepine-2-thiones. Single-point calculations at the MP2/6-311+G(d,p)//B3LYP/6-311+G(d,p) level were performed for the more accurate energy prediction. The solvent effect was taken into account by carrying out single-point calculations using the PCM methodology. The obtained results show that in the investigating mechanism the first step consists of the hydrazine molecule addition to the thiocarbonyl bond of the 4-phenyl-2,3-dihydro-1,5-benzodiazepine-2-thione following removal of H(2)S. Further addition of another hydrazine molecule to the azomethyne bond and cyclization with pyrazole ring formation occur, and then the diazepine ring-opening and the removal of hydrazine molecule proceed. Finally, imine-enamine tautomerization leads to 5-N-(2-aminophenyl-1-amino)-3-phenylpyrazole as a main product that is in agreement with the experimental observation. The cyclization step is a rate-determining step of this reaction.

Theoretical study of mechanism of 2,3-dihydro-1,5-benzodiazepin-2-ones hydrazinolysis.

Density functional theory approach was used for the 4-methyl-2,3-dihydro-1,5-benzodiazepin-2-one compound to determine the mechanism of hydrazinolysis of 4-substituted 2,3-dihydro-1,5-benzodiazepin-2-ones. Single point computations at the MP2/6-311+G(d,p)//B3LYP/6-31G(d) level were performed for the more precise energy prediction. The solvent effect was taken into account by carrying out single point calculations using the PCM methodology. The obtained results show that in the investigating mechanism the first step consists of the hydrazine molecule addition to the azomethine bond of the 4-methyl-2,3-dihydro-1,5-benzodiazepin-2-one. Further cyclization occurs with pyrazole ring formation, and then the diazepine ring opening is revealed. Finally, removal of o-phenylendiamine leads to 3-methylpyrazolone-5 as a main product that is in agreement with the experimental observation. The final step is a rate-determining step of this reaction.

Computational study of the aminolysis of anhydrides: effect of the catalysis to the reaction of succinic anhydride with methylamine in gas phase and nonpolar solution.

Different possible pathways of the aminolysis reaction of succinic anhydride were investigated by applying high level electronic structure theory, examining the general base catalysis by amine and the general acid catalysis by acetic acid, and studying the effect of solvent. The density functional theory at the B3LYP/6-31G(d) and B3LYP/6-311++G(d,p) levels was employed to investigate the reaction pathways for the aminolysis reaction between succinic anhydride and methylamine. The single point ab initio calculations were based on the second-order Møller-Plesset perturbation theory (MP2) with 6-31G(d) and 6-311++G(d,p) basis sets and CCSD(T)/6-31G(d) level calculations for geometries optimized at the B3LYP/6-311++G(d,p) level of theory. A detailed analysis of the atomic movements during the process of concerted aminolysis was further obtained by intrinsic reaction coordinate calculations. Solvent effects were assessed by the polarized continuum model method. The results show that the concerted mechanism of noncatalyzed aminolysis has distinctly lower activation energy compared with the addition/elimination stepwise mechanism. In the case of the process catalyzed by a second methylamine molecule, asynchronous proton transfer takes place, while the transition vectors of the acid-catalyzed transition states correspond to the simultaneous motion of protons. The most favorable pathway of the reaction was found through the bifunctional acid catalyzed stepwise mechanism that involves formation of eight-membered rings in the transition state structures. The difference between the activation barriers for the two mechanisms averages 2 kcal/mol at various levels of theory.