Tautomers and Aromaticity

Molecules in real solvents can exist in one or more tautomeric forms. The use of different tautomers in calculations can lead to significant variation in the estimated log P values (Pig. 15.1). Accurate prediction of the dominant tautomer requires ah initio calculahons. Due to speed limitations such calculations are not feasible for virtual screening and prediction of large compound collections. Moreover, the interpretation of the results can also be difficult, for example, the lacton-lactim (Pig. 15. IB) is the stable form of maleic hydrazide in the gas phase but the difference between this and the dilacton form (Pig. 15.1C and D) disappears in solution 

Other difficulties arise from the incorrect treatment of aromaticity, e.g. the tautomeric form C can be also represented as an aromatic compound. However, ALOGPS, for example, does not consider this ring as an aromatic one. Inconsistently defined aromaticity lowers the prediction performance (Fig. 15.ID). The use of SDF files, which do not explicitly define aromaticity solves this problem. All these factors are not limiting when the data are prepared with the same coding scheme and consistency. However, these issues are very important for method application and benchmarking. 

SLIPPER calculations, A. Saravanaraj (University of Georgia, USA) for SPARC calculations, M. Totrov (MolSoft, USA) for GBLOGP calculations, G. Vistoli (University of Milan) for VEGA calculations, and J. Votano (CliemSilico, USA) for CSlogP calculations. 

1 Sangster, J. Octanol-water partition coefficients of simple organic compounds./. Phys. Chem. Ref. Data 1989, 18.1111-1229. 

3 Duffy, E. M., Jorgensen, W. L. Prediction of properties from simulations free energies of solvation in hexadecane, octanol, and water. /. Am. Chem. Soc. 2000, 122, 2878-2888. 

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Chemical descriptors are in most of the cases obtained with equations that are not known. Even if the references to certain general equations are given, in practice, it is difficult to replicate the results obtained with chemical descriptors. As we have discussed, chemical descriptors based on tridimensional structures are subject to manual optimization, and this may change the descriptor values. But even in the case of other simpler descriptors, we found that using software from two different commercial sources, the results may be different. Even the use of two different versions of the same software may provide different results for the same descriptor. Even descriptors, which seem simple, such as number of double bonds, or of aromatic rings, are critical because they depend on how tautomers and aromaticity are considered in the different software, or are sensitive to the structure format that is used. 

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