Theoretical Study On The Nitroaromatics' QSAR And Toxic Mechanism

Nitroaromatics are widely used either as materials or as intermediates in explosives,dyestuffs, pesticides, and organic synthesis. They exist as industrial wastes and directpollutants in the environment, and are relatively soluble in water and detectable in rivers,ponds, and soil. Nitroaromatics are representative of electrophilic toxicants. Nitroaromaticcompounds have attracted considerable attention because of their varied toxic effects, suchas narcosis, mutagenicity, and carcinogenicity. Furthermore, some of them can be degradedinto more toxic molecules. Thus, it is necessary to study the toxicities of nitroaromatics.Quantitative structure-activity relationship (QSAR) is a mathematical modeldescribing the relationship between toxic potency and one or more descriptors of achemical. QSAR has been widely used for studying nitroaromatics' toxicity. However,there is a very serious problem, that is, how to obtain the molecular descriptors for QSAR.In earlier QSAR works, the descriptors were gotten by experiments or semi-empiricalmolecular orbital (MO) calculations. Both of the two means have limitations. The formerneeds more time, money, and manpower, while the latter uses the empirical orexperimental parameters to deal with the Schrodinger equation and omit some molecularintegral calculations, so its result is not accurate. As the development of computer andquantum chemical theory, first principle method density functional theory (DFT) has beenused to study nitroaromatics' structures and activities now, and it can get the compounds'molecular descriptors easily and accurately. But there is still no reference about the DFTapplication for QSAR study of nitroaromatics' toxicity.Another evidence obtained in studies on human and model laboratory animals havedemonstrated the formation of hemoglobin (Hb) adducts upon inhalation, ingestion, or skincontact with 2,4,6-trinitrotoluene (TNT), and there is a correlation between total TNTexposure level and its Hb adduct content. The Hb adducts of other nitroaromaties havebeen documented too. The mechanism of covalent binding of TNT or other nitroaromatiesto critical cellular proteins has been of interest. However there is still no dynamictheoretical calculation study on it.In this paper, the hybrid density functional scheme B3LYP is employed to give thesystemic theoretical studies on the QSAR of nitroaromatics and an explicit illustration onnitroaromaties' toxic mechanism have been done. The whole work consists of threechapters.1. QSAR models of nitroaromatics toxicity to fathead minnow are established based on different theoretical levels, which are compared with each other to select the best one.Semiempirical MO AM1 and PM3 methods, ab initio MO HF method with 6-31G^*,and DFT-B3LYP method with 6-311G^** were used to calculate the electronic andstructural properties of 28 nitroaromatics. QSARs were established based on theseproperties and the toxicity of nitroaromatics to the fathead minnow. The results show thatthe models established based on the first principle methods (HF and DFT-B3LYP) arebetter than those based on semiempirical methods (AM1 and PM3). HF model is a littlebetter than DFT-B3LYP model on correlation and significance. But the B3LYP model givesmore reasonable interpretation of nitroaromatics toxic mechanism. As far as this exampleis concerned, the B3LYP method is the best choice for nitroaromatics toxicity study.2. DFT-B3LYP method was used to study the QSAR of nitroaromatics toxicity. Thekey factors affecting their toxicity are found, the toxic mechanism of nitroaromatics isdiscussed based on the QSAR studies, and the toxic values of some nitroaromatics arepredicted by QSAR models. This work gives significant informations for nitroaromaticstoxic mechanism study and provides usable suggestions for detoxifying the river or soilpolluted by nitroaromatics.The DFT-B3LYP method, with the basis set 6-311G^**, was employed to optimize themolecular geometries and electronic structures of nitroaromatics such as mono- (multi-)nitrobenzene, mono- (multi-) nitrotoluene, nitroaniline, and halogenated nitrobenzenederivatives. The quantum chemical parameters were selected as molecular structuraldescriptors. According to the type and number of substituents, the acute toxicity of suchnitroaromatics to Tetrahymena pyriformis, golden orfe fish, and the algae (Scenedesmusobliguus) along with the structural descriptors, was used to establish the QSARs. The nitro,amido, and halogen substituents' influences on nitroaromatics toxicity were discussed. Theresults indicate that the toxicity of nitroaromatics increases with the increase of the numberof the nitro substituents. The toxic mechanisms of mono-nitrobenzene andmulti-nitrobenzene are different. Mono-nitrobenzenes belong to polar narcosis toxicants,whose toxicity is decided by both its hydrophobicity and electronic activity.Multi-nitroaromatics are reactive toxicants. The electrophilic or nucleophilic reactions willoccur between these chemicals and the proteins in vivo. The other substituents on benzenering have important influences on nitroaromatics toxicity too. The amidoes decrease thetoxicity of nitroaromtics while the halogen substituents increase it. In one word, the nitrogroup is the primary toxic group of nitroaromatics. Therefore, wrapping or reducing thenitro groups on benzene ring is an available approach to degrade the nitroaromatics toxicity. In addition, the stable and remarkable QSAR models established in the part can be used topredict the nitroaromatics toxicity.3. The theoretical calculations have been done on the reactions of the nitrosoaromaticswith the ethanethiol instead of protein that has the thiol (-SH) group. The nitrosoaromaticsare the nitrosoarene intrermediates of nitroaromatics yielded by 2-electron reduction ofnitro groups in vivo. The nitroaromatics studied here are TNT and its two metabolites2-amino-4,6-dinitrotoluene (2A) and 4-amino-2,6-dinitrotoluene (4A), nitrobenzene (NB),1,3-dinitrobenzene (13-DNB) and 1,4-dintrobenzene (14-DNB), three halogenatednitrobenzenes including 4-fluoronitrobenzene(4-FNB), 4-chloronitrobenzene (4-CNB), and4-bromonitrobenzene (4-BrNB). Reaction profiles between the nitrosoaromatics and theethanethiol have been studied. Stationary points including their transition states weresuccessfully located and characterized for the first time at the B3LYP/6-31G^* level withoutany restriction on the internal coordinates. Studies on the geometry, charge, and energy ofthe stationary points were carried out to illustrate the adduct process.All the nitrosoaromatics studied here could bind covalently with the ethanethiol. Theorder of the activation barrier height is TNT＜2A＜4A, 14-DNB＜13-DNB＜NB, 4-FNB≈4-CNB≈4-BrNB. This binding is found to be largely dependent upon the number ofnitro substituents. The type and position of the substituents on the benzene ring is relatedwith the compound's reactivity directly too. The more nitro groups the benzene ring has,the more the reactivity of nitroaromatics are. The compounds with nitro groups positionedortho to each other are more reactive than the isomers having the nitro groups in the metaorientation. The amido on the benzene ring will decrease the activity of nitroaromacties.These relative reactivity orders are consistent with their toxic value orders. These resultsindicate that the covalent binding of nitrosoaromatics with proteins, for example,hemoglobin, may be the key step of nitroaromatics toxic reaction in vivo.For 4-FNB, 4-CNB, and 4-BrNB, their near activation barrier heights indicate thedifference of halogen substituents on the same position of the benzene ring have littleinfluence on their reaction with ethanethiol. Further analysis suggests that the halogens onthe benzene ring may be replaced by nuloephilic compounds such as DNA in vivo, whichmay be another toxic action of halogenated nitroaromatics.In summary, the first principle DFT-B3LYP method has been employed in this thesisto study the QSAR of nitroaromatics toxicity and their toxic mechanism for the first time.The stable QSAR models of nitroaromtics toxicity to different species have beenestablished, which provide the primary structural factors affecting the compounds' toxicity and can be used to predict some unknown congeneric compounds' toxicity. The dynamictheoretical calculations have been done on nitroaromatics toxic mechanism for the firsttime. A simple model of nitroaromatics' reaction with proteins and the concrete toxicprocedure has been suggested. The transition states and activation energy of the keyelementary reaction have been successfully located here. The substituent effects and sterichindrance in the toxic reaction were discussed. The above theoretical study onnitroaromatics QSAR and toxic mechanism presents new example and results, providesabundant original data and correlating rules to the cross research and the developmentbetween theoretical chemistry, material chemistry and environment chemistry.