2,4,6-Trinitrotoluene () is a class C carcinogen as rated by the Environmental Protection Agency. One of the toxicity mechanisms of is the covalent binding of its metabolites to critical proteins. However, knowledge about their molecular reaction mechanisms is scarce. Herein, we have provided density functional theory (DFT) simulation evidences for the reaction mechanisms of the nitroso metabolite of with the sulfhydryl group of model thiols for the first time. The results show that the solvent-mediated proton-transfer mechanism plays a significant role in the entire process. For the formation of semimercaptal, the mechanism is slightly different from the previous one where the thiolate anion attacks the nitroso group. The rearrangement of semimercaptal needs to be triggered by an acid or hydrated ion (HO), which is consistent with the previous assumption. The other pathway, the conversion of semimercaptal to hydroxylamine, has to overcome a higher barrier, although it does not need the participation of an acid or a hydrated ion. In addition, the details on transition states, intermediates and free energy surfaces for three reactions are given, which make up for the lack of experimental knowledge. These conclusions can help to deeply understand the toxic effects of and other nitroaromatic explosives.