Determining Abraham solute and system parameters for neutral organic compounds using quantum chemical methods
Date
2016
Authors
Journal Title
Journal ISSN
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Publisher
University of Delaware
Abstract
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.