Adamantyl-ureas with pyrazoles substituted by fluoroalkanes as soluble epoxide hydrolase inhibitors.

A series of soluble epoxide hydrolase (sEH) inhibitors containing halogenated pyrazoles was developed. Inhibition potency of the obtained compounds ranges from 0.8 to 27.5 nM. 1-Adamantyl-3-[(4,5-dichloro-1-methyl-1Н-pyrazol-3-yl)methyl]urea (3f, IC50 = 0.8 nM) and 1-[(Adamantan-1-yl)methyl]-3-[(4,5-dichloro-1-methyl-1Н-pyrazol-3-yl)methyl]urea (4f, IC50 = 1.2 nM) were found to be the most potent sEH inhibitors within the described series.

Thermochemistry, Tautomerism, and Thermal Stability of 5,7-Dinitrobenzotriazoles.

Nitro derivatives of benzotriazoles are safe energetic materials with remarkable thermal stability. In the present study, we report on the kinetics and mechanism of thermal decomposition for 5,7-dinitrobenzotriazole (DBT) and 4-amino-5,7-dinitrobenzotriazole (ADBT). The pressure differential scanning calorimetry was employed to study the decomposition kinetics of DBT experimentally because the measurements under atmospheric pressure are disturbed by competing evaporation. The thermolysis of DBT in the melt is described by a kinetic scheme with two global reactions. The first stage is a strong autocatalytic process that includes the first-order reaction (Ea1I = 173.9 ± 0.9 kJ mol-1, log(A1I/s-1) = 12.82 ± 0.09) and the catalytic reaction of the second order with Ea2I = 136.5 ± 0.8 kJ mol-1, log(A2I/s-1) = 11.04 ± 0.07. The experimental study was complemented by predictive quantum chemical calculations (DLPNO-CCSD(T)). The calculations reveal that the 1H tautomer is the most energetically preferable form for both DBT and ADBT. Theory suggests the same decomposition mechanisms for DBT and ADBT, with the most favorable channels being nitro-nitrite isomerization and C-NO2 bond cleavage. The former channel has lower activation barriers (267 and 276 kJ mol-1 for DBT and ADBT, respectively) and dominates at lower temperatures. At the same time, due to the higher preexponential factor, the radical bond cleavage, with reaction enthalpies of 298 and 320 kJ mol-1, dominates in the experimental temperature range for both DBT and ADBT. In line with the theoretical predictions of C-NO2 bond energies, ADBT is more thermally stable than DBT. We also determined a reliable and mutually consistent set of thermochemical values for DBT and ADBT by combining the theoretically calculated (W1-F12 multilevel procedure) gas-phase enthalpies of formation and experimentally measured sublimation enthalpies.

Thermal stability of emerging N6-type energetic materials: kinetic modeling of simultaneous thermal analysis data to explain sensitivity trends.

A number of new high-performing energetic materials possess explosophoric functionalities, high nitrogen content, and fused heterocyclic blocks. Two representatives of these materials have been synthesized recently, namely, 1,2,9,10-tetranitrodipyrazolo[1,5-d:5',1'-f][1,2,3,4]-tetrazine (1) and 2,9-dinitrobis([1,2,4]triazolo)[1,5-d:5',1'-f][1,2,3,4]tetrazine (2). The thermal stability of these energetic materials bearing the N-N-N = N-N-N fragment and three closely related compounds has been investigated for the first time. The thermal decomposition process of analyzed compounds was complicated by the appearance of the liquid phase, sublimation of the material, and autocatalysis by reaction products. In contrast to the traditional approach to the kinetic modeling based on data from either TGA or DSC, we use both signals' data measured at the same time and perform the joint kinetic analysis using the model-fitting technique to obtain the pertinent kinetic description of the process. Of the analyzed materials, 1 and 2 show the lowest thermal stability in melt with a characteristic rate constant of 2.6 × 10-3 s-1 at 250 °C. The kinetic parameters and calculated detonation performance data were used in the model to describe the mechanical sensitivity. The model output and the experimental friction sensitivity data show a respectable agreement, but more data are required to draw firm conclusions. In general, the provided thermal stability and kinetic data can be used for thermal response and storage modeling of these new N6-type energetic materials. The developed thermokinetic approach, joint model-fitting of several thermal analysis signals, can be applied to other complex thermally induced processes to increase the value and credibility of the kinetic findings.

Autocatalytic decomposition of energetic materials: interplay of theory and thermal analysis in the study of 5-amino-3,4-dinitropyrazole thermolysis.

A reliable kinetic description of the thermal stability of energetic materials (EM) is very important for safety and storage-related problems. Among other pertinent issues, autocatalysis very often complicates the decomposition kinetics of EM. In the present study, the kinetics and decomposition mechanism of a promising energetic compound, 5-amino-3,4-dinitro-1H-pyrazole (5-ADP) were studied using a set of complementary experimental (e.g., differential scanning calorimetry in the solid state, melt, and solution along with advanced thermokinetic models, accelerating rate calorimetry, and evolved gas analysis) and theoretical techniques (CCSD(T)-F12 and DLPNO-CCSD(T) predictive quantum chemical calculations). The experimental study revealed that the strong acceleration of the decomposition rate of 5-ADP is caused by two factors: the progressive liquefaction of the sample directly observed using in situ optical microscopy, and the autocatalysis by reaction products. For the first time, the processing of the non-isothermal data was performed with a formal Manelis-Dubovitsky kinetic model that accounts for both factors. With the aid of quantum chemical calculations, we have rationalized the autocatalysis present in the formal kinetic models at the molecular level. Theory revealed an unusual primary decomposition channel of 5-ADP, viz., the two subsequent sigmatropic H-shifts in the pyrazole ring followed by the C-NO2 bond scission yielding a pyrazolyl and nitrogen dioxide radicals as simple primary products. Moreover, we found the secondary reactions of the latter radical with the 5-ADP to be kinetically unimportant. On the contrary, the substituted pyrazolyl radical turned out to undergo a facile addition to 5-ADP, followed by a fast exothermic elimination of another ˙NO2 species. We believe the latter process to contribute remarkably to the observed autocatalytic behavior of 5-ADP. Most importantly, the calculations provide detailed mechanistic evidence complementing the thermoanalytical experiment and formal kinetic models.

Apparent autocatalysis due to liquefaction: thermal decomposition of ammonium 3,4,5-trinitropyrazolate.

Thermal decomposition of solids is often accompanied by autocatalysis, one of the possible causes of which is the formation of a liquid phase. The kinetic model considering the liquefaction of solid reactants under isothermal conditions was proposed by Bawn in the 1950s. The present study reports the application of the Bawn model to the thermolysis of 3,4,5-trinitropyrazole ammonium salt (ATNP) under nonisothermal conditions. The thermal decomposition of ATNP is comprised of low-temperature and high-temperature stages. The low-temperature stage exhibits two distinct exothermic peaks in differential scanning calorimetry (DSC), fitted by two consecutive autocatalytic reactions with a model-fitting kinetic analysis. The liquefaction of the solid reactant during the first reaction is directly observed, giving mechanistic evidence for the Bawn model. We have expressed the Bawn model by a combination of two extended Prout-Tompkins (ePT) equations with the activation energy for the leading liquid-state reaction of Ea = 140.6 ± 0.3 kJ mol-1. The release of ammonia is detected from the beginning, suggesting that the thermal dissociation of ATNP to 3,4,5-trinitropyrazole is an initiation reaction of the thermal decomposition. We proposed ATNP liquefication, leading to the apparent autocatalytic behavior of the first global decomposition reaction, is caused by the eutectic formation between ATNP and 3,4,5-trinitropyrazole, as it was confirmed by DSC analysis of the artificial mixture. The presented approach of the combination of ePT formalism with a Bawn model is generally applicable to a broader range of thermal processes accompanied by liquid phase formation and apparent acceleration.

Nitration of Azasydnones and Azasydnonimines: A Method for the Functionalization of Aryl Derivatives.

The first example of functionalization of mesoionic 3-R-1,2,3,4-oxatriazol-5-ones and 3-substituted-1,2,3,4-oxatriazol-5-imines (azasydnones and azasydnonimines, respectively) by the electrophilic reaction without destruction of the oxatriazole ring is reported. Nitration of a range of aryl derivatives bearing various electron donating and withdrawing substituents at the ortho-, meta- and para-positions using HNO3 /H2 SO4 mixtures has been assessed in order to develop an approach for the synthesis of corresponding nitroaryl derivatives. Whereas nitration occurs meta to the azasydnone ring, the regioselectivity of the electrophilic substitution can be affected by the nature of the substituent attached to the aryl ring, and a variety of polyfunctionalized derivatives can be readily accessed by using this methodology, which may have applications in the target-oriented synthesis. The reactivity, synthesis, and structure of the mesoionic 3-substituted-1,2,3,4-oxatriazole derivatives described here provide interesting new information on this known but poorly understood heterocycle.

Pyrazole-Tetrazole Hybrid with Trinitromethyl, Fluorodinitromethyl, or (Difluoroamino)dinitromethyl Groups: High-Performance Energetic Materials.

High-nitrogen-content compounds have attracted great scientific interest and technological importance because of their unique energy content, and they find diverse applications in many fields of science and technology. Understanding of structure-property relationship trends and how to modify them is of paramount importance for their further improvement. Herein, the installation of oxygen-rich modules, C(NO2 )3 , C(NO2 )2 F, or C(NO2 )2 NF2 , into an endothermic framework, that is, the combination of a nitropyrazole unit and tetrazole ring, is used as a way to design novel energetic compounds. Density, oxygen balance, and enthalpy of formation are enhanced by the presence of these oxygen-containing units. The structures of all compounds were confirmed by XRD. For crystal packing analysis, it is proposed to use new criterion, ΔOED , that can serve as a measure of the tightness of molecular packing upon crystal formation. Overall, the materials show promising detonation and propulsion parameters.

Nucleophilic dearomatization of 4-aza-6-nitrobenzofuroxan by CH acids in the synthesis of pharmacology-oriented compounds.

4-Aza-6-nitrobenzofuroxan (ANBF) reacts with 1,3-dicarbonyl compounds and other CH acids to give carbon-bonded 1,4-adducts - 1,4-dihydropyridines fused with furoxan ring. In the case of most acidic ß-diketones, which exist mainly in the enol form in polar solvents, the reactions proceed in the absence of any added base emphasizing the highly electrophilic character of ANBF. The resulting compounds combine in one molecule NO-donor furoxan ring along with a pharmacologically important 1,4-dihydropyridine fragment and therefore can be considered as prospective platforms for the design of pharmacology-oriented heterocyclic systems.

Novel Highly Energetic Pyrazoles: N-Trinitromethyl-Substituted Nitropyrazoles.

A new family of energetic compounds, nitropyrazoles bearing a trinitromethyl moiety at the nitrogen atom of the heterocycle, was designed. The desirable high-energy dense oxidizers 3,4-dinitro- and 3,5-dinitro-1-(trinitromethyl)pyrazoles were synthesized in good yields by destructive nitration of the corresponding 1-acetonylpyrazoles. All of the prepared compounds were fully characterized by multinuclear NMR and IR spectroscopy, as well as by elemental analysis. Single-crystal X-ray diffraction studies show remarkably high density. Impact sensitivity tests and thermal stability measurements were also performed. All of the pyrazoles possess positive calculated heats of formation and exhibit promising energetic performance that is the range of 1,3,5-trinitroperhydro-1,3,5-triazine and pentaerythritol tetranitrate. The new pyrazoles exhibit positive oxygen balance and are promising candidates for new environmentally benign energetic materials.

A direct approach to a 6-hetarylamino[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine library.

The synthesis of 6-hetarylamino[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazines is reported. The functionalized secondary amines were constructed via a K2CO3-mediated SNAr reaction of weakly basic hetarylamines with 3-(3,5-dimethylpyrazol-1-yl)[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazines, which allowed displacement 3,5-dimethylpyrazolyl leaving group. Significantly, the reaction exhibited a broad substrate scope and proceeded in good yields.

Liquid-phase synthesis of combinatorial libraries based on 7-trifluoromethyl-substituted pyrazolo[1,5-a]pyrimidine scaffold.

The parallel solution-phase synthesis of more than 2200 7-trifluoromethyl-substituted pyrazolo[1,5-a]pyrimidine and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine carboxamides on a 50-100-mg scale has been accomplished. Key reactions include assembly of the pyrazolo[1,5-a]pyrimidine ring by condensation of 5-aminopyrazole derivatives with the corresponding trifluoromethyl-beta-diketones. The libraries from libraries were then obtained in good yields and purities using solution-phase acylation and reduction methodologies. Simple manual techniques for parallel reactions using special CombiSyn synthesizers were coupled with easy purification procedures (crystallization from the reaction mixtures) to give high-purity final products. The scope and limitations of the developed approach are discussed.

Effects of C-nitropyrazoles and C-nitroazoles on ocular blood flow and retinal function recovery after ischemic insult.

AIM: Effects of C-nitropyrazoles and C-nitroazoles on ocular blood flow and retinal function recovery after ischemia have been studied. METHODS: The compounds were tested on ocular blood flow of ocular hypertensive (40 mmHg) rabbit eyes with colored microsphere technique. They were also tested on the retinal function recovery after ischemia of rat eyes with electroretinography. RESULTS: All compounds (DC-1 through DC-17) showed significant increase in retinal function recovery after ischemia in the range of 26 % to 120 % (P<0.05). Among five compounds (DC-1 through DC-5) studied, four compounds (DC-2 through DC-5) increased the blood flow in choroid, iris, and ciliary body, but not in retina. DC-1 did not show significant increase of blood flow in any of these ocular tissues. CONCLUSION: C-Nitropyrazoles can facilitate significant retinal function recovery after ischemic insult through the increase of ocular blood flow. Since rabbit's retina is scarce in vasculature, it did not show significant change in blood flow by C-nitropyrazoles as expected. Among all 17 compounds, DC-5 seems to be the most potent compound.