Determining Abraham solute and system parameters for neutral organic compounds using quantum chemical methods

Di Toro, Dominic M.The polyparameter linear free energy relationships (pp-LFERs) that employ Abraham solute and system parameters have been widely used to predict environmentally significant properties that can aid in evaluating the fate, transport, and risks of chemicals to the environment. At present, more than 400 pp-LFERs are available. However, the availability of Abraham solute and system parameters can limits their application. This doctoral dissertation presents a new method to determine the Abraham solute and system parameters so that predictions can be made using the pp-LFER method for a variety of environmentally significant properties. In Chapter 2, an experimentally-based method is used to estimate the Abraham solute parameters using measured solvent-water partition coefficients in a set of chemically diverse systems. The compounds investigated include hexahydro-1,3,5- trinitro-1,3,5-triazacyclohexane (RDX), octahydro-1,3,5,7-tetranitro-1,3,5,7- tetraazacyclooctane (HMX), hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX), hexahydro-1,3,5-trinitroso-1,3,5-triazine (TNX), hexahydro-1,3-dinitroso-5- nitro- 1,3,5-triazine (DNX), 2,4,6-trinitrotoluene (TNT), 1,3,5-trinitrobenzene (TNB), and 4- nitroanisole (4NAN). They are munition constituents (MCs) and munition-like compounds, which have raised environmental and health concerns due to their nitrocontaining functionalities and abundance in the environment. The solvents considered in the solvent-water systems are hexane, dichloromethane, trichloromethane, octanol, and toluene. The only available solvent-water partition coefficients in the literature are octanol-water partition coefficients for some of the investigated compounds and they are in good agreement with the experimental measurements. ☐ Solvent-water partition coefficients predicted using the experimentally derived Abraham solute parameters have significantly smaller root mean square error (RMSE = 0.38) than predictions using ABSOLV estimated solute parameters (RMSE = 3.56) for the investigated compounds. Additionally, the predictions for various physicochemical properties using the experimentally derived solute parameters agree with available literature reported values with prediction errors within 0.79 log units except for water solubility of RDX and HMX with errors of 1.48 and 2.16 log units respectively. Predictions using ABSOLV estimated solute parameters have larger prediction errors of up to 7.68 log units. This large discrepancy is most likely due to missing –R2N-NO2 and –R2N-NO2 functional groups in the ABSOLV fragment database. ☐ In Chapter 3, a quantum chemical method is developed to compute Abraham solute parameters E, S, A, B, and V based on molecular structure only without relying on experimental measurements. The Abraham parameters for 1828 solutes are included. The method uses solvent-water partition coefficients for sixty-five solventwater systems computed using the quantum mechanical COSMO-SAC model, and molecular polarizability computed using the density functional/basis set M062X/augcc- pVDZ. The use of molecular polarizability to compute molar refraction and E is critical and allows reliable estimation of the remaining solute parameters S, A, and B from a multiple linear regression using the sixty-five solvent-water partition coefficients. These Quantum Chemically determined Abraham Parameters are referred to as QCAP. ☐ To improve the compatibility of QCAP parameters with existing system parameters, the experimentally-based Abraham solute parameters that are available in the literature are used to establish linear prediction equations for each of the solute parameters using the five QCAP parameters as the independent variables. The resulting Abraham parameters are referred as QCEAP. ☐ QCAP and QCEAP are validated by comparing predicted and experimental partition coefficients for various systems, as well as to predictions made using ABSOLV predicted Abraham parameters and direct quantum chemical computations using COSMO-SAC. Predictions are made for partition coefficients for 25 solventwater systems, 22 solvent-air systems, and the water-air system. QCEAP generally has the smallest RMSEs followed by QCAP, ABSOLV, and COSMO-SAC. Overall, the QCEAP solute parameters appear to be the best choice currently available for estimating Abraham parameters using quantum chemical estimation methods for use with existing system parameters. ☐ Chapter 4 extends the methodology presented in Chapter 3. The performance of QCAP and ABSOLV solute parameters are compared by examining the predictions of pp-LFERs that are developed using experimentally determined partition coefficients for various solvent-water and solvent-air systems. The system parameters estimated using experimental partition coefficients and QCAP solute parameters (termed QCAPSP) reproduce experimental partition coefficients in various solvent-water systems with the RMSEs ranging from 0.278 to 0.639, and the system parameters estimated using experimental partition coefficients and ABSOLV estimated solute parameters (termed ABSOLV-SP) reproduce experimental solvent-water partition coefficients with RMSEs from 0.329 to 0.632. The comparison of predictions of solvent-water partition coefficients for munition constituents and munition-like compounds indicates that QCAP-based predictions reproduce the experimental values with much smaller errors than do the ABSOLV-based predictions. ☐ For solvent-air systems, the predictions of QCAP-SP have slightly larger errors than ABSOLV-SP but both methods have RMSEs ranging from 0.199 to 0.441. For water-air partition coefficients, predictions using ABSOLV-SP improve marginally with recalibrated system parameters. However, recalibrating the system parameters significantly improves QCAP and eliminates the prediction bias. The predictions using QCAP-SP have the smallest RMSE = 0.633. ☐ In summary, the methods presented in this dissertation can be employed to predict the Abraham parameters based only on the molecular structure of the compound of interest. Using these parameters, key physico-chemical properties of a compound can be estimated and used to evaluate the environmentally related properties of the compound. This has important environmental significance, especially for compounds in their early stages of development, or for regulatory evaluation, when only the compound’s molecular structure is available.University of Delaware, Department of Civil and Environmental EngineeringPh.D