Skip to main content


Log in

Structure-toxicity relationships of nitroaromatic compounds

Full-length paper

  • Published:
Molecular Diversity Aims and scope Submit manuscript


The toxicity data of 28 nitroaromatic compounds (nitrobenzenes and, for comparison, benzene and toluene) related to a 50% lethal dose concentration for rats (LD50) were used to develop quantitative structure-activity relationships (QSARs).

A genetic algorithm and multiple regression analysis were applied to select the descriptors and to generate the correlation models. The obtained equations consist of one to three descriptors. A number of molecular descriptors was obtained from HF/6-31G(d) and DFT (B3LYP/6-311+G(d, p)) level calculations. The calculated molecular geometry and electronic properties were evaluated by comparison with the available experimental data (where applicable). All parameters obtained at the B3LYP/6-311+G(d, p) level and the topological descriptors derived from this geometry were found to be reliable, except for dipole moment, due to the large uncertainty of its estimation.

Satisfactory relationships were observed for the one-parameter structure-toxicity models between topological (X5Av, Ms) and quantum-chemical (ELUMO) descriptors. For better predictability two- and three-parameter QSAR analyses were performed. These analyses resulted in much better equations with correlation coefficient values r = 0.872−0.924. These models have been obtained with a set of topological, fragment and quantum-chemical descriptors (Ms, PCR, PCD, BELe1, C-026 and ELUMO).

The toxicity of nitroaromatic compounds appears to be governed by a number of factors, such as the number of nitrogroups, the electrotopological state, the presence of certain fragments and the electrophilicity/reactivity parameter (ELUMO). Nitrobenzenes exhibited electrophilic reactivity (as was shown by correlation of the toxicity with the energy of the lowest unoccupied orbital, ELUMO).

The toxicity LD50 parameter for rats has been utilized for the first time for QSAR analysis of nitrobenzenes. The predictive ability of the models is determined by a cross-validation “leave-one-out” method.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others



Highest Occupied Molecular Orbital


Lowest Unoccupied Molecular Orbital


Single-Occupied Molecular Orbital


density functional theory


Becke threeparameter hybrid functional combined with Lee–Yang–Parr correlation functional


Austin Model 1 semiempirical method


Genetic Algorithm


Multiple Linear Regression Analysis method




unrestricted Hartree-Fock




quantitative structure-activity relationships


ionization potential

LD50 :

lethal dose which causes the death of 50% (one half) of a group of test animals


  1. Hartter, D.R., The use and importance of nitroaromatic chemicals in the chemical industry, In Rickert, D.E. (Ed.), Toxicity of nitroaromatic compounds. Chemical Industry Institute of Toxicology Series, Chemisphere, Washington, D.C., 1985, pp. 1–14.

  2. Nitrobenzene. Initial report of the TSCA Interagency Testing Committee to the administrator. EPA 560-10-78/001. U.S. Environmental Protection Agency, Washington, D.C., 1978.

  3. Kriek, E., Aromatic amines and related compounds as carcinogenic hazards to man, In Emmelot, P. and Kriek, E. (Eds.), Environmental carcinogenesis, Elsevier, Amsterdam, 1979, pp. 143–164.

    Google Scholar 

  4. Won, W.D., di Salvo, L.H. and Ng. J., Toxicity and mutagenicity of 2,4,6-trinitrotoluene and its microbial metabolites, Appl. Environ. Microbiol., 31 (1976) 576–580.

    PubMed  CAS  Google Scholar 

  5. Slater, E.C., Mechanism of uncoupling of oxidative phosphorylation by nitrophenols, Comp Biochem Physiol., 4 (1962) 281–301.

    Article  PubMed  CAS  Google Scholar 

  6. Donlon, B.A., Razo-Flores, E., Field, J.A. and Lettinga, G., Toxicity of N-substituted aromatics to acetoclastic methanogenic activity in granular sludge, Appl. Environ. Microbiol., 61 (1995) 3889–3893.

    PubMed  CAS  Google Scholar 

  7. Soffers, A.E.M.F., Boersma, M.G., Vaes, W.H.J., Vervoort, J., Tyrakowska, B., Hermens, J.L.M. and Rietjens, I.M.C.M., Computer-modeling-based QSARs for analyzing experimental data on biotransformation and toxicity, Toxicology in Vitro, 15 (2001) 539–551.

    Article  PubMed  CAS  Google Scholar 

  8. Katritzky, A.R., Oliferenko, P., Oliferenko, A., Lomaka, A. and Karelson, M., Nitrobenzene toxicity: QSAR correlations and mechanistic interpretations, J. Phys. Org. Chem., 16 (2003) 811–817.

    Article  CAS  Google Scholar 

  9. Agrawal, W.K. and Khadikar, P.V., QSAR prediction of toxicity of nitrobenzenes, Bioorg. Med. Chem., 9 (2001) 3035–3040.

    Article  PubMed  CAS  Google Scholar 

  10. Cronin, M.T.D. and Schultz, T.W., Development of Quantitative Structure-Activity Relationships for the Toxicity of Aromatic Compounds to Tetrahymena pyriformis: Comparative Assessment of the Methodologies, Chem. Res. Toxicol., 14 (2001) 1284–1295.

    Article  PubMed  CAS  Google Scholar 

  11. Mekenyan, O., Roberts, D.W. and Karcher, W., MO-Parameters as Predictors of Skin Sensitization Potential of Halo- and Pseudohalobenzenes Acting as SNAr Electrophiles, Chem. Res. Toxicol., 10 (1997) 994–1000.

    Article  PubMed  CAS  Google Scholar 

  12. Cronin, M.T.D., Gregory, B.W. and Schultz, T.W., Quantitative structure-activity analyses of nitrobenzene toxicity to Tetrahumena pyriformis, Chem. Res. Toxicol., 11 (1998) 902–908.

    Article  PubMed  CAS  Google Scholar 

  13. Schmitt, H., Altenburger, R., Jastorff, B. and Schuurmann, G., Quantitative stucture-activity analysis of the algae toxicity of nitroaromatic compounds, Chem. Res. Toxicol., 13 (2000) 441–450.

    Article  PubMed  CAS  Google Scholar 

  14. Toxicological Profile For Nitrophenols: 2-Nitrophenol, 4-Nitrophenol, Agency for Toxic Substances and Disease Registry, U.S. Public Health Service, July 1992.

  15. Toxicological Profile for Dinitrocresols. U.S. Department of Health and Human Services, US Public Health Service, Agency for Toxic Substances and Disease Registry, August 1995.

  16. Toxicological Profile For Dinitrophenols. U.S. Department Of Health And Human Services, US Public Health Service, Agency for Toxic Substances and Disease Registry, August 1995.

  17. Toxicological Profile For 1,3-Dinitrobenzene and 1,3,5-Trinitrobenzene. U.S. Department Of Health And Human Services, US Public Health Service, Agency for Toxic Substances and Disease Registry, August 1995.

  18. Toxicological Profile For 2,4- and 2,6-Dinitrotoluene. U.S. Department Of Health And Human Services, US Public Health Service, Agency for Toxic Substances and Disease Registry, December 1998.

  19. Toxicological Profile For Nitrobenzene. Agency for Toxic Substances and Disease Registry, U.S. Public Health Service, December 1990.

  20. Becke, A.D., Density-Functional Thermochemistry .3. The Role of Exact Exchange, J. Chem. Phys., 98 (1993) 5648.

    Article  CAS  Google Scholar 

  21. Lee, C., Yang, W. and Parr, R.G., Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density, Phys. Rev. B, 37 (1988) 785.

    Article  CAS  Google Scholar 

  22. Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Zakrzewski, V.G., Montgomery, Jr., J.A.; Stratmann, R.E., Burant, J.C., Dapprich, S., Millam, J.M., Daniels, A.D., Kudin, K.N., Strain, M.C., Farkas, O., Tomasi, J., Barone, V., Cossi, M., Cammi, R., Mennucci, B., Pomelli, C., Adamo, C., Clifford, S., Ochterski, J., Petersson, G.A., Ayala, P.Y.; Cui, Q., Morokuma, K., Malick, D.K., Rabuck, A.D., Raghavachari, K., Foresman, J.B., Cioslowski, J., Ortiz, J.V., Baboul, A.G., Stefanov, B.B., Liu, G., Liashenko, A., Piskorz, P., Komaromi, I., Gomperts, R., Martin, R.L., Fox, D.J., Keith, T., Al-Laham, M.A., Peng, C.Y., Nanayakkara, A., Gonzalez, C., Challacombe, M., Gill, P.M.W., Johnson, B., Chen, W., Wong, M.W., Andres, J.L., Gonzalez, C., Head-Gordon, M., Replogle, E.S., and Pople, J.A., Gaussian 98, Revision A.11, Gaussian, Pittsburgh PA, 1998.

  23. Todeschini, R. and Consonni, V. DRAGON software for the Calculation of Molecular Descriptors, web version 3.0 for Windows, 2003.

  24. Todeschini, R. and Consonni, V. Handbook of Molecular Descriptors, Wiley-VCH, Weinheim and New York, 2000.

    Google Scholar 

  25. Davis, L. Handbook of Genetic Algorithms, Van Nostrand Reinhold, N.Y. (USA), 1991.

    Google Scholar 

  26. Devillers, J. Genetic Algorithms in Molecular Modeling, Academic Press, Ltd., London, 1996.

    Google Scholar 

  27. de Oliveira, D.B. and Gaudio, A.C., BuildQSAR: A new computer program for QSAR studies, Quant. Struct.-Act. Relat., 19 (2000) 599–601.

    Article  CAS  Google Scholar 

  28. Shishkov, I., Vilkov, L.V., Kovacs, A. and Hargittai. I., Molecular geometry of 2-nitrotoluene from gas phase electron diffraction and quantum chemical study, J. Mol. Structure, 445 (1998) 259–268.

    Article  CAS  Google Scholar 

  29. Sadova, N.I., Khaikin, L.S. and Vilkov, L.V., Certain questions of stereochemistry of nitrogen-compounds in the gaseous-phase, Russ. Chem. Rev., 61 (1992) 2129–2171.

    Article  CAS  Google Scholar 

  30. Chiş, V., Molecular and vibrational structure of 2,4-dinitrophenol: FT-IR, FT-Raman and quantum chemical calculations, Chem. Phys., 300 (2004) 1–3.

    Article  CAS  Google Scholar 

  31. Lampert, H., Mikenda, W. and Karpfen, A., Intramolecular hydrogen bonding in 2-hydroxybenzoyl compounds: Infrared spectra and quantum chemical calculations, J. Phys. Chem., 100 (1996) 7418–7424.

    Article  CAS  Google Scholar 

  32. Lide, D.R. (Ed.) CRC Handbook of Chemistry and Physics 74th Edition, CRC Press, Boca Raton, 2000.

    Google Scholar 

  33. Barve, J.V. and Pant, L.M., Structure of para-nitrotoluene, Acta Cryst., B27 (1971) 1158–1162.

    Google Scholar 

  34. Iwasaki, F. and Kawano, Y., Crystal and molecular-structure of ortho-nitrophenol, Acta Cryst., B34 (1978) 1286–1290.

    CAS  Google Scholar 

  35. Pandarese, F., Ungaretti, L. and Coda, A., Crystal-structure of a monoclinic phase of meta-nitrophenol, Acta Cryst., B31 (1975) 2671–2675.

    CAS  Google Scholar 

  36. Coppens, P. and Schmidt, G.M.J., The crystal structure of the a-modification of p-nitrophenol near 90 K, Acta Cryst., 18 (1965) 62–67.

    Article  CAS  Google Scholar 

  37. Mak, T.C.W. and Trotter, J., The crystal structure of p-chloronitrobenzene, Acta Cryst., 15 (1962) 1078–1080.

    Article  CAS  Google Scholar 

  38. Trotter, J. and Williston, C.S., Bond lengths and thermal vibrations in m-dinitrobenzene, Acta Cryst., 21 (1966) 285–288.

    Article  CAS  Google Scholar 

  39. Kagawa, T., Kawai, R. and Haisa, M., The crystal and molecular structure of 2,4-dinitrophenol, Acta Cryst., B32 (1976) 3171–3175.

    CAS  Google Scholar 

  40. Wilkins, A. and Small, R.W.H., Structure of 1-fluoro-2,4-dinitrobenzene, Acta Cryst., C47 (1991) 220–221.

    CAS  Google Scholar 

  41. Kovac, A. and Hargittai, I., Theoretical investigation of the additivity of structural substituent effects in benzene derivatives, Struct. Chem., 11 (2000) 193–201.

    Article  Google Scholar 

  42. Di Labio, G.A., Pratt, D.A. and Wright, J.S., Theoretical calculation of gas-phase ionization potentials for mono- and polysubstituted benzenes, Chem. Phys. Lett, 311 (1999) 215–220.

    Article  CAS  Google Scholar 

  43. Krygowski, T.M., Ejsmont, K., Stepien, B.T., Cyranski, M.K., Poater, J. and Sola, M. Relation between the substituent effect and aromaticity, J. Org. Chem., 69 (2004) 6634–6640.

    Article  PubMed  CAS  Google Scholar 

  44. Linstrom, P.J. and Mallard, W.G., (Eds.) NIST Chemistry WebBook, NIST Standard Reference Database Number 69, (, March 2003.

  45. Bentley, T.W. and Johnstone, R.A.W., Aspects of mass spectra of organic compounds .8. calculation of ionization potentials of disubstituted benzenes and their importance in hammett correlations in mass spectrometry, J. Chem. Soc. B, 2 (1971) 263–270.

    Article  Google Scholar 

  46. Hehre, W.J., Radom, L., Schleyer, P. and Pople, J.A. Ab initio Molecular Orbital Theory, Wiley, New York, 1986.

    Google Scholar 

  47. Prabhumirashi, L.S. and Kunte, S.S., Solvent effects on electronic absorption spectra of nitrochlorobenzenes, nitrophenols and nitroanilines –I. Studies in nonpolar solvents, Spectrochim Acta A, 42A (1986) 435–439.

    Article  CAS  Google Scholar 

  48. Desfrançois, C., Périquet, V., Lyapustina, S.A., Lippa, T.P., Robinson, D.W., Bowen, K.H., Nonaka, H. and Compton, R.N., Electron binding to valence and multipole states of molecules: Nitrobenzene, para- and meta-dinitrobenzenes, J. Chem. Phys., 111 (1999) 4569–4576.

    Article  Google Scholar 

  49. Hall, L.H., Mohney, B. and Kier, L.B., The electrotopological state - structure information at the atomic level for molecular graphs, J. Chem. Inf. Comp Sci., 31 (1991) 76–82.

    Article  CAS  Google Scholar 

  50. Huuskonen, J., Estimation of water solubility from atom-type electrotopological state indices, Env. Toxicol. Chem., 20 (2001) 491–497.

    Article  CAS  Google Scholar 

  51. Livingstone, D.J., Ford, M.G., Huuskonen, J.J. and Salt, D.W., Simultaneous prediction of aqueous solubility and octanol/water partition coefficient based on descriptors derived from molecular structure, J. Comp. Aided Mol. Design, 15 (2001) 741–752.

    Article  CAS  Google Scholar 

  52. Ghose, A.K. and Crippen, G.M., Atomic Physicochemical Parameters for Three-Dimensional Structure-Directed Quantitative Structure-Activity Relationships I. Partition Coefficients ans a Measure of Hydrophobicity, J. Comput. Chem., 7 (1986) 565–577.

    Article  CAS  Google Scholar 

  53. Hall, L.H., Mohney, B. and Kier, L.B., An Electrotopological-State: An Atom Index for QSAR, Quant. Struct. Act. Relat., 10 (1991) 43–51.

    Article  CAS  Google Scholar 

  54. Kubinyi, H., Folkers, G. and Martin, Y.C. (Eds.) 3D QSAR in Drug Design, Vol. 2: Ligand-Protein Interactions and Molecular Similarity, Kluwer/ESCOM, Dordrecht (The Netherlands), 1998, pp. 339–353.

  55. Devillers, J. and Balaban, A.T. (Eds.) Topological indices and related descriptors in QSAR and Drug Design, Gordon & Breach, Amsterdam, 2000.

    Google Scholar 

  56. Rietjens, I.C.M.M., Cnubben, N.H.P., Haandel, M., Tyrakowska, B., Soffers, A.E.M.F. and Vervoort, J., Different metabolic pathways of 2,5-difluoronitrobenzene and 2,5-difluoroaminobenzene compared to molecular orbital substrate characteristics, Chem. Biol. Interact., 94 (1995) 49–72.

    Article  PubMed  CAS  Google Scholar 

  57. Bearden, A.P. and Schultz, T.W., Comparison of Tetrahymena and Pimephales toxicity based on mechanism of action, SAR and QSAR in Environ. Res., 9 (1998) 127–53.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations


Corresponding author

Correspondence to Jerzy Leszczynski.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Isayev, O., Rasulev, B., Gorb, L. et al. Structure-toxicity relationships of nitroaromatic compounds. Mol Divers 10, 233–245 (2006).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: