Abstract

The Abraham solvation parameter model is a

frequently applied, theoretically well founded linear
solvation energy relationships model. It correlates a
solubility property, such as gas liquid chromatographic
(GLC) retention, with several additive terms which
represent specific solubility interactions.
In this contribution, a theoretical investigation has
been carried out to find the quantum chemical bases of the
Abraham solvation parameters for GLC stationary phases.
23 molecular (non-polymeric and non-ionic) stationary
phases have been considered. 86 structure driven
descriptors have been derived applying PM6 semiempirical
calculations combined with conductor-like screening model
(COSMO). Comprehensive search for an optimal model
has been carried out, based on best subset selection
(BSS). A unified quantitative structure-property relationship
model is presented for all five Abraham parameters.
Principal component analysis (PCA) and cluster analysis
(CA) have been done, demonstrating that the calculated
parameters can be utilized for classification of stationary
phases.

The Abraham solvation

parameter model for GLC

lg SP c1 r1R2 s1 2H a1 2H b1 2H l1 lg L16
Where
R2 is an excess molar refraction;

2H

is the dipolarity/polarizability (derived

from GLC measurements);
and
refer to the hydrogen-bond
2H
2H
propensity of a solute surrounded by solvent
molecules;
L16 is the gas-hexadecane partition
coefficient at 25 C.
The subscripts 1 and 2 denote solvent and solute
properties, respectively.
The coefficients c1, r1, s1, a1, b1, l1 are determined from
least-squares fitting of the model.

Semiempirical calculations
Starting geometries of stationary phase molecules
(Table 1.) were generated in the molecular graphics program
ACD/ChemSketch [1], and pre-optimized with molecular
mechanics (the force-field based [2,3] 3-dimensional optimizer of
ChemSketch). Where available, experimental or pre-calculated
structures available via the PubChem [4] database were utilized
as well. From the structure files, systematic names were
generated with the mol2nam application (part of the Lexichem
suite [5]), and graphical depictions were made with the mol2ps
utility (from the Ogham suite [6]).
Full geometry optimization was carried out for isolated
(gas-phase) molecules by the PM6 semiempirical QC method [7],
as implemented in MOPAC2009 [8]. The convergence criterion
was typically a gradient norm of 0.1 kcal/mol . The convergence
of geometries to local minima, rather than saddle points, was
checked by harmonic vibrational frequency calculations
From the converged MOPAC output the following quantities were
extracted: coordinates and Mulliken charges of each atoms;
distances and bond orders of each atom pairs; dipole moment;
isotropic average polarizability; energies of the highest occupied
and lowest unoccupied molecular orbitals (HOMO and LUMO);
largest positive charge on any H atom, and largest negative
charge on any atom. Various derived quantities describing the
surface distribution of charges were also calculated. The list of
descriptors considered is given in Table 2.

Model building and variable

selection

Large-scale BSS search was carried out, with a bruteforce method implemented in our own software [10], for locating
optimal models. All possible combinations from the list of 86
prospective descriptors were submitted to multi linear regression
(MLR) fitting with five independent variables (3.5107 possibilities per
dependent variable).
At the first stage most raw models had some fitted
coefficients with large estimated standard errors, compared to their
absolute values were pruned, to leave only terms that are highly
significant. In a stepwise manner, the parameter with the highest
relative error was deleted, if that exceeded the limit set at 50%.
To simplify a physical picture emerging from the
interpretation, models that had ratio descriptors containing both the
surface and volume as denominators were discarded (except for
Mwt/Vol and Alpha/Vol, which ratios are physically justifiable
quantities on their own).
The final decision for selecting a best model is based on
combining a number of criteria. To begin with, models were only
allowed if their R2 for all five individual fits were within chosen limits
from the best of each group: 10% for s1, a1, l1 and r1, and 20% for
c1. Further, combined limits were set for the root-mean-square
(RMS) average R2 of the three equations for s1, a1 and l1, and four
equations for r1, s1, a1 and l1 (both within 2%). The overall R2 of all
five equations was required to be within 5% from the best such
value, as well. From among the models remaining on this filtered list
of alternatives, the one with the lowest RMS of the inter-descriptor
multiple correlation coefficients was finally selected. Notably, this
same choice also had the minimal value for the maximums of the
multiple correlation coefficients, as well as the lowest RMS average
relative error of MLR coefficients.

The model
c1 = - 0.75Alpha/Vol - 0.52MSig2 - 0.59MHBacc3/CSA
r1 = 0.57Alpha/Vol - 0.46MSig2+ 0.74MHBacc3/CSA
- 0.78MaxPosH/CSA
s1 = 0.54Alpha/Vol + 0.87MSig2+ 0.46 MHBacc3/CSA
- 0.52HOMO/CSA
a1 = 0.31MSig2 + 0.81 MHBacc3/CSA - 0.14 HOMO/CSA
l1 = - 0.38Alpha/Vol - 0.91MSig2 - 0.40 MHBacc3/CSA

+0.33HOMO/CSA
Overall R2=0.920. Full statistics are shown for in Table 3 A cumulative
histogram for residuals from all five fits, shown in Fig. 1., indicates no
deviation from the normal distribution of errors.

Physico-chemical background of the

selected independent variables
Alpha/Vol is the volume-specific polarizability; the inclusion of the
denominator can be rationalized, considering that for similar molecules
with different sizes the polarizabilities would scale similarly to the
volumes. MSig2, the second moment of the COSMOments-type sigmapotential, has already been identified as a measure of the overall
electrostatic polarity of molecules [11]. The COSMOments-type
hydrogen bond acceptor moment, MHBacc3, is a quantitative measure
of the acceptor capacity [11]. The role of HOMO as surrogate for
covalent Lewis basicity (molecular orbital basicity) has been reported
early on [12-14]. The largest positive charge on any H atom, MaxPosH,
is an often used theoretical LSER descriptor for electrostatic acidity
[12-14].

References
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