Identifying the Transients and Transformation Products in Hydroxyl Radical-Methimazole Reactions Using DFT and UPLC-Q-TOF MS/MS Approaches.

Oxidative reactions of the hydroxyl radical (·OH) with methimazole (MMI), an antithyroid drug, are crucial for understanding its fate in oxidizing environments. By synergistically integrating density functional theory and ultraperformance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF MS/MS) techniques, we elucidated the transients and transformation products (TPs) arising from the ·OH-MMI reactions. We probed two hydrogen-atom abstraction (HA) reactions, three radical adduct formation reactions, and single electron transfer (SET) at the M06-2X/6-311++G(d,p)/SMD(water) level. All proposed reaction channels, except for HA from the methyl group and SET, were found to be barrier-free. SET is the dominant oxidation pathway, accounting for 44% of oxidations, as determined by branching ratio analysis. The selenium analogue, MSeI, exhibited minor reactivity differences compared to MMI, yet its overall patterns resembled those of ·OH-MMI reactions. TPs were generated experimentally by reacting MMI with ·OH produced by UV-photolysis of H2O2. Eight TPs were identified from an approximately 24% degradation of MMI using UPLC-Q-TOF MS/MS analysis, and an additional two TPs were identified from the approximately 52% degraded MMI sample. The exact identities of all of the TPs were established through their corresponding fragmentation patterns. This study elucidates the drug's susceptibility to free radical species under physiologically relevant conditions.

Insights into the Mechanism of Hydroxyl Radical Mediated Oxidations of 2-Aminopurine: A Computational and Sonochemical Product Analysis Study.

Mechanistic details of hydroxyl radical (•OH) mediated oxidations of 2-aminopurine (2AP) in the aqueous phase have been established in this study via a combination of DFT calculations (at the M05-2X/6-311+G(d,p) level with SMD solvation) and sonochemical end product analyses by the LC-Q-TOF-MS/MS method. Rate constants and branching ratios for single electron transfer (SET), two H-abstractions (HA), and seven radical adduct formation (RAF) reactions of •OH with 2AP were evaluated using transition state theory (TST). The RAF at the C8-position of 2AP is noted as the dominant process, which constitutes almost 46.1% of overall reaction routes. The SET mechanism accounts for the second major pathway (39.6%) followed by RAF at the C6-position (14.3%). Formations of 14 transformation products (TPs, i.e., the nonradical end products) in the sonochemical reactions of •OH with 2AP have been identified by means of the LC-Q-TOF-MS/MS technique. Among the 14 TPs (designated as TP1 to TP14), the lowest and highest mass to charge ratio (m/z) were respectively observed at 129 and 269 in ESI-MS positive ionization mode. The identities of all TPs have been proposed on the basis of elemental composition of [M + H]+ ions and their respective MS-MS fragmentation pattern. Four TPs (including guanine) are considered as obtained directly from primary transients by radical elimination, radical-radical combination/disproportionation reactions. The remaining 10 TPs are postulated as a result of successive self- and/or cross-reactions of primary transients/four first generation TPs with reagents such as •OH, O2, and solvent H2O molecules.

Contrasting reactions of hydrated electron and formate radical with 2-thio analogues of cytosine and uracil.

2-Thiocytosine (TC) and 2-thiouracil (TU) were subjected to hydrated electron (eaq-), formate radical (CO2˙-) and 2-hydroxypropan-2-yl radical ((CH3)2˙COH) reactions in aqueous medium. Transients were characterized by absorption spectroscopy and the experimental findings were rationalized by DFT calculations at LC-ωPBE and M06-2X levels using a 6-311+G(d,p) basis set and SMD solvation. In eaq- reactions, a ring N-atom protonated radical of TC and an exocyclic O-atom protonated radical of TU were observed via addition of eaq- and subsequent protonation by solvent molecules. However, two competing but simultaneous mechanisms are operative in CO2˙- reactions with TC and TU. The first one corresponds to formations of N(O)-atom protonated radicals (similar to eaq- reactions); the second mechanism led to 2 center-3 electron, sulfur-sulfur bonded neutral dimer radicals, TCdim˙ and TUdim˙. DFT calculations demonstrated that H-abstraction by CO2˙- from TC(TU) results in S-centered radical which upon combination with TC(TU) provide the dimer radical. In some cases, DFT energy profiles were further validated by CBS-QB3//M06-2X calculations. This is the first time report for a contradictory behavior in the mechanisms of eaq- and CO2˙- reactions with any pyrimidines or their thio analogues.

Coumarin-Chalcone Hybrids as Peroxyl Radical Scavengers: Kinetics and Mechanisms.

The primary antioxidant activity of coumarin-chalcone hybrids has been investigated using the density functional and the conventional transition state theories. Their peroxyl radical scavenging ability was studied in solvents of different polarity and taking into account different reaction mechanisms. It was found that the activity of the hybrids increases with the polarity of the environment and the number of phenolic sites. In addition, their peroxyl radical scavenging activity is larger than those of the corresponding nonhybrid coumarin and chalcone molecules. This finding is in line with previous experimental evidence. All the investigated molecules were found to react faster than Trolox with (•)OOH, regardless of the polarity of the environment. The role of deprotonation on the overall activity of the studied compounds was assessed. The rate constants and branching ratios for the reactions of all the studied compounds with (•)OOH are reported for the first time.

Canolol: a promising chemical agent against oxidative stress.

The OOH radical scavenging activity of canolol (CNL) has been studied in aqueous and lipid solutions, using the density functional theory. CNL is predicted to react about 3.6 times faster in aqueous solution than in lipid media. The overall rate coefficients are predicted to be 2.5 × 10(6) and 6.8 × 10(5) M(-1) s(-1), respectively. The OOH radical scavenger activity of canolol is predicted to be similar to that of carotenes, higher than that of allicin, and much higher than that of melatonin. Branching ratios for the different channels of reaction are reported for the first time. It was found that the reactivity of canolol toward OOH radicals takes place almost exclusively by H atom transfer from the phenolic moiety in canolol, regardless of the polarity of the environment. Taking into account that the reactivity of peroxyl radicals is significantly lower than that of other reactive oxygen species, canolol is proposed to be a very good antioxidant.

OH radical gas phase reactions with aliphatic ethers: a variational transition state theory study.

A theoretical study of the mechanism and kinetics of the OH radical reactions with aliphatic ethers is presented. Several methods were evaluated using the 6-311++G(d,p) basis set, with dimethyl ether as a test molecule. On the basis of the dimethyl ether results, the M05-2X functional was selected for the rest of the calculations. All the possible H abstraction paths have been modeled, and the importance of differentiating among H atoms bonded to the same C atom, according to their orientation with respect to the O atom in the ether, is analyzed. The rate coefficients are calculated using interpolated variational transition-state theory by mapping (IVTST-M), within the IVTST-M-4/4 scheme, in conjunction with small-curvature tunneling (SCT) corrections. The discussion is focused on the 280-400 K temperature range, but additional information is provided for an extended range (280-2000 K). Our analysis suggests a stepwise mechanism involving the formation of H bonded complexes in the entrance and exit channels. The vicinity of the O atom was found to increase the relative site reactivity. In fact, it was found to influence reactivity to a larger extent than the nature of the carbon site (primary, secondary, or tertiary). The overall agreement between the calculated and the available experimental data is very good and supports the reliability of the rate coefficients and the branching ratios proposed here for the first time. It also supports the performance of the M05-2X functional and the IVTST-M-4/4 scheme for kinetic calculations.