Determination of Determination of solvation solvation parametersparametersusing using MarvinSketchMarvinSketch

Paul Laffort*, Pierre Héricourt

CNRS, Centre Européen des Sciences du Goût, 21000 Dijon, France

*http://paul.laffort.free.fr

CENTRE NATIONALDE LA RECHERCHESCIENTIFIQUE

Conceptual definition of solvation parameters(previously called “solubility factors” by P. Laffort and co-authors)

B: solvents

A:

solu

tes

SP:

experimental matrix of a solubility property;

e.g. retention indices in GLC

if: SP = A*B,

then A and B are respectively matrices of solute and solvent solvation parameters

Experimental definition of solvation parameters1

The first tool needed is a solid database SP of a solubility property.

• In 1972-1987, together with Andrew Dravnieks, we used unpublished retention indices in GLC, by W.O. McReynolds, from Celanese Chem.Co., Bishop, Texas: A matrix of 75 solutes x 25 stationary phases (i.e. solvents).

• In 2005 we used a very accurate matrix of 133 solutes x 10 stationary phases, by Erwin Kováts and co-authors, from five papers (1990-1995)

Experimental definition of solvation parameters2

The 2nd tool needed is a suitable statistical analysis: the MMA algorithm

INPUT OUTPUT

solvent parameters

predicted retention indices

op

timiz

ed

solu

te p

ara

me

ters

experimental retention indices

solu

te p

ara

m.

unde

r ch

eck

ing

A

R

B

A*B

A

MMA

Standard error of R

Pearson correlation coefficients of A

Pearson correlation coefficients of A

First application of the MMA algorithm:the number of terms

0

2

4

6

8

10

12

14

0 1 2 3 4 5 6 7 8 9 10

Number of terms

Sta

nd

ard

err

or

Nature of the five solute solubility parameters

There is an agreement between the authors presently involved in solvation parameters, to consider that five solute parameters and five solvent parameters are needed and sufficient to take into account the solubility phenomena.

The five solute parameters are:

• DISPER: dispersion related to the molar volume

• ORIENT: orientation or polarity

• POLARIZ: polarizability/induction independent of the

• ACID: acidity (proton donor) molar volume

• BASIC: basicity (proton acceptor)

The nature of the solvent parameters is not yet completely identified

Experimental definition of solvation parameters3

The 3rd tool needed is an INPUT set values of the solute parameters, from theoretical or empirical considerations, as close as possible of the output values obtained using together the MMA algorithm and an accurate GLC set of experimental retention indices (here, by Kováts and co-authors).

Among all published values, we only tested those concerning five solute parameters, including our own previous studies (in 1976 and 1982). In addition to the already mentioned good correlation between INPUT and OUPUT values, two additional criteria have been considered:

1. A good independence of the solute parameters (poor mutual correlation)

2. An OUTPUT set of solvent parameters without negative values, difficult to understand in physico-chemical terms.

A good independence of the INPUT solute parameters

Among the five published data sets tested, the set by Michael Abraham (1993) presents the best mutual independence of the solute parameters, after an internal rearrangement of the original values via two simple equations.

DISPER ORIENT POLARIZ ACID DISPER ORIENT POLARIZ ACID

Abraham, 1993 N = 314 Modified according to Laffort et al., 2005 ORIENT H

2 0.45 2 0.06

POLARIZ R2 0.52 0.61 R2 0.24 -0.02

ACID H2 0.14 0.32 0.15 H

2 0.08 0.27 0.15

BASIC H2 . 0.06 0.31 -0.14 0.14 H

2 . 0.06 0.24 -0.14 0.14

log L16 H2 R2

H2 2 2 R2

H2

Original data set Slightly modified data set

A first set of updated solute solvation parameters

The rearranged data of Michael Abraham (1993):

• provide, as we will saw now, a good INPUT matrix using the MMA algorithm and the experimental retention indices of Kováts and co-authors, for 133 compounds;

• also provide a first set of updated solute solvation parameters for 314 compounds.

Experimental definition of solvation parameters: 1 + 2 + 3

The Abraham (1993) rearranged data appear as an INPUT data set reasonably good. The version according to Laffort et al. (2005) has been chosen as the best INPUT, generating updated solute parameters for 133 compounds.

INPUT / OUTPUT correlations Number in Number of OUTPUT A neg. values MODELS DISPER ORIENT POLARIZ ACID BASIC of 5.0r in matrix B random numbers 0.04 0.10 0.00 0.12 0.07 3 zero Abraham (original) log L16 2

H R2 H2 H

2 (param. 4 & 5)

1.00 0.99 0.91 0.98 0.98 2 15 Abraham (modified) 2 2 R2 H

2 H2

(param. 4)

0.99 0.97 0.91 0.98 0.98 zero 6 Laffort et al., 2005 fnVb 2 R96 H

2 H2

0.98 0.97 0.92 0.98 0.98 zero zero

Getting optimized values for more solutes

Three ways are now available to get other solute solvation para-meters:

1. A 100% experimental procedure using GLC with five columns (open tubular, if possible, rather than filled), containing two apolar phases of different molecular weight, a strongly fluorinated, a classical polyether and an alcoholic (e.g. diglycerol), after “learning” the set for 133 compounds.

2. A rewriting of the numerous data published by Michael Abraham and co-authors (Colin Poole, Alan Katritzky, Andreas Klamt, William Acree Jr. and many others), using the two already mentioned equations of internal rearrangement plus a third unpublished equation when these authors use Vx (the molar volume) in place of L16 (partition coefficient air-hexadecane).

3. A simplified molecular topology (SMT) which principally takes into account, for each atom of a molecule, its nature, the nature of its bonds and in some cases the nature of its first neighbors. The SMT algorithm is based on the MarvinSketch program and other Java functionalities of ChemAxon Ltd. The learning is based on a pool of the two subsets of solubility parameters already mentioned ( 314 + 133), having a total of 369 defined compounds.

Principle and examples of the SMT

Structural elements

Bonds Topological features Subcategories

Carbon ≤ 4 C0, C1, C11, C111, C1111, C2, C12, C112,

C22, C3, C13

Oxygen ≤ 2 O0, O11

Oxygen ≤ 2 O1 linked to C1, C11, C111, C1111, C112

Oxygen ≤ 2 O2 linked to C12, C112, others

The index of polarizability/induction 1: the model

Features Coefficients Partial F ratios

Constant 0.300C1 -0.150 515C111 0.150 182C1111 0.318 140C12 0.055 182C112 0.222 607N111 0.250 35F1 -0.237 561Br1 0.152 73I1 0.482 262S tot 0.267 127O2 x C112 -0.158 72

POLARIZABILITY

The index of polarizability/induction 2: the validation

-1.5

-0.5

0.5

1.5

2.5

-1.5 -0.5 0.5 1.5 2.5

experimental

top

olo

gic

al

POLARIZABILITY

r = 0.96

F = 369

Conclusion and perspectives

1. A 100% experimental procedure using GLC with five columns is certainly one of the ways to be pursued.

2. A Simplified Molecular Topology (SMT) based on the MarvinSketch program and other Java functionalities of ChemAxon Ltd., deserves also to be pursued, and perhaps to be refined with the help of more values from experimental origin.

3. By the moment, the theoretical approaches are not so precise than the

empirical ones, but that could be change in a near future.

_____________

More details can be seen in:

Laffort, P. et al., 2005, J.Chromatogr. A, 1100, 90-107Laffort, P., Héricourt, P., 2006, J. Chem. Inf. Model., 46, 1723-1734