STUDIES ON SOLUBILITY AND SOLUBILITY RELATED PROCESSES A Thesis presented to the University of London in partial fulfilment of the requirements for the degree of Doctor of Philosophy in the Faculty of Science By Gary Stephen Whiting Sir Christopher Ingold Laboratory Chemistry Department University College London March 1991 ProQuest Number: 10610889 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest ProQuest 10610889 Published by ProQuest LLC(2017). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code Microform Edition © ProQuest LLC. ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 4 8 1 0 6 - 1346 ABSTRACT A general description is given of solubility and solubility related processes, including the solubility of gases and vapours in liquids, and the partition of solutes between two condensed phases. Particular attention is devoted to gas-liquid chromatography (GLC) and reverse-phase high performance liquid chromatography (RP-HPLC). Theories of solubility are surveyed, including Hildebrand's theory, the scaled particle theory, and theories based on linear regression analysis. The latter requires a knowledge of characteristic parameters of solutes (solvation parameters), and solvents (solvatochromic parameters), and the determination of these is discussed. It is shown that the method of multiple linear regression analysis is very useful in the study of solution and solubility related processes, and the aim of the work in the thesis is to set out characteristic solute parameters, and apply them to a wide range of processes. Methods are given for the determination of solute solvation parameters based on experimental procedure. A collection of parameters (R 2 - an excess molar refraction, x *2 - dipolarity, an2 - hydrogen bond acidity, B H 2 - hydrogen bond basicity, log L 16 - Ostwald solubility coefficient on n-hexadecane, Vx - size parameter) is assembled for a wide range of solutes. The construction of a solute parameter database, and its associated programs is also discussed. A thermodynamically consistent set of explanatory variables, all related to Gibbs energy are determined. New scales of multifunctional solvation parameters reflecting real solubility situations are developed ( E x H2, Ea H 2 and EB1^). These, and the older parameters, above, are applied to various processes using equations 1 and 2 (where SP is the dependant solute variable); log SP (gas ^ condensed phase) — C r. R2 + s . S A + a.EoFi + bX&x + /.log U6 [1] log SP (within condensed phase) — C + r .R 2 “I" £ .E ‘J^*2 + fl.EoF2 “I" Z7.E£P2 + 771. V X [2] Equations 1 and 2 are shown to be extremely useful for the prediction of physicochemical and biochemical data, and for the interpolation of factors influencing solubility and solubility related processes. I CONTENTS Abstract I SECTION 1 1.1 An Introduction to Chromatography 1 1.11 Gas Chromatography 2 1.12 An Assessment of the Gas Chromatographic Method 4 1.2 Partition 6 1.21 Partition Coefficients From Headspace Analysis 8 1.22 Partition Coefficients From GLC 10 1.3 The Theoretical Basis of Chromatography 14 1.31 Considerations for GLC Efficay and Optimisation 20 1.4 A Comparison of Headspace Analysis and Dynamic GLC 25 1.5 High Performance Liquid Chromatography 26 1.51 Reversed-Phase HPLC 29 SECTION 2 2.1 Theories of Solubility 31 2.11 The Hildebrand Solubility Parameter 31 2.12 The Scaled Particle Theory and Linear Solvation Energy Relationship 32 2.13 Linear Free Energy Relationships 35 2.14 Quantitative Structure Activity Relationships 36 2.2 Prediction of Vapour-Liquid Equilibria byGroup Contribution Methods 37 2.3 Multiple Linear Regression Analysis with LSER andQSAR 41 2.31 Application of MLRA in This Work 43 SECTION 3 3.1 Solvatochromic Parameters for Solvents 48 3.2 Solvatochromic Parameters for Solutes 52 3.21 The Solute Cavity Size/Dispersion Parameter 56 3.22 The Importance of Hydrogen Bonding Parameters 60 n SECTION 4 4.1 Charcterisation of Stationary Phase Solvent Properties 61 4.2 Surface Acoustic Wave Chemical Sensors 69 4.21 Introduction to Piezoelectric Sorption Detectors and SAW devices 69 4.22 Selection of Suitable SAW Coating Materials 75 4.23 SAW Devices Used in Sensor Arrays 77 SECTION 5 5.1 Aims of the Present Work 81 SECTION 6 6 .1 Determination and Calculation of New Solvation Parameters 87 6 .11 Analysis of the Laffort Data 87 6 .12 Analysis of the McReynolds Data 101 6.13 Calculation of Effective Hydrogen Bond Basicity,EBH 2 , from HPLC Data 116 6.14 Parameter Back-Calculation from GLC Data 125 6.20 The Log L 16 Parameter 149 6.30 The Construction of a New Solute Parameter Database 164 SECTION 7 7.0 Application of Solvation Equations 173 7.10 Characterisation of Some ^-Substituted Amides as Solvents and Comparison With Some GLC Stationary Phases 173 7.20 Application to QSAR Construction for Upper Respiratory Tract Irritation by Airborne Chemicals in Mice 184 7.30 Application to Transfer of Solutes from Hexadecane to Water 193 7.40 Application to the Characterisation of Solvents and Solvent/Water Partition Coefficients 203 7.50 Characterisation of Candidate SAW Phases 224 7.60 Application to Characterisation of GLC Phases Studied by Poole 241 m SECTION 8 8.10 Summary Discussion, Conclusions and Future Work 252 8.11 Future Work 255 SECTION 9 9.10 Experimental 257 9.11 Dynamic GLC Experimental 257 9.12 Static Headspace Experimental 279 SECTION 10 10.1 Appendix 1 281 10.11 The Params Database and the Fortran 77 Programs Used 281 10.12 The MhaBasel and MhaBase2 Database and SmartH 4GL Programs 282 Appendix 2 - Published work - bound in at end of thesis. 10.2 References 286 Errata Throughout the text, read physicochemical for phvsiochemical IV ACKNOWLEDGEMENTS My sincere thanks to Mike Abraham for his help over the last three years of this project. His enthusiasm and intimate knowledge of the subject ensured that I learnt a great deal and enabled the research to proceed without too many problems. I am extremely grateful for his encouragement, particularly on the computing side of the work, and for kindly providing suitable equipment on which to carry it out. I was greatly helped in the early stages of the project by 'Rodge' Andrew McGill, whose work I followed on from. My thanks to him for patiently explaining the rudiments, and imparting his knowledge of the practical side of chromatography to me. Thanks are also due to Jenik Nazari-Dehnari and Johnathan W. Steed for carrying out some of the chromatographic measurements used in the characterisation of candidate surface acoustic wave phases. Thanks to David Walsh for some headspace measurements used in the characterisation of solvents, and the contribution he has undoubtedly made to the lab since joining two years ago. All the best to him with the rest of his research. Good luck also to Harpreet Chadha, who is continuing work along similar lines. In addition, I would like to thank all those who helped me in the early days during my time at the Chemistry Department at the University of Surrey, especially Vic Zettel, Priscilla Grellier, Gabriel Buist, and Professor Jones for his support. My thanks to the many who have helped me at University College London and made my time there so enjoyable. I am grateful to the US Army Research Development and Standardization Group for support of this work under Contract DAJA 45-87-C-0004. V 1.10 An Introduction to Chromatography The technique of chromatography constitutes the majority of the experimentation carried out in this work, so a generalised introduction and detailed discussion of the theoretical basis of it is therefore appropriate. Chromatography is derived from Greek, "khroma" meaning colour, and "grafein" meaning written. The technique as such and the word ’'chromatography" was first used in 1906 by Tswett 1 to detail the separation he carried out when percolating coloured plant pigments through a column of calcium carbonate (the stationary phase), with a mobile phase of petroleum. The process can be defined then as a physical method of separation, in which the components to be separated are distributed between two phases, the stationary phase and the mobile phase, the latter being either a gas or a liquid. Tswett’s work 1 was liquid-solid chromatography (LSC). There are three other basic forms of chromatography, classified according to the nature of the stationary and mobile phase. Liquid liquid chromatography was first used by Martin and Synge 2 in 1941, and here both phases are liquid. Also in 1941 gas solid chromatography (GSC) was introduced by Hesse et al3, and by Tiselius 4 and Claesson 5 in 1943 and 1946 respectively. The work presented here is mostly concerned with gas liquid chromatography (GLC), introduced in 1952 by James and Martin6, and to a lesser extent, high performance liquid chromatography (HPLC). This is a variant on liquid chromatography, the emergence of which is usually considered to have started with the publication by Huber and Hulsman 7 in 1967, although Giddings 8 had already shown the potential advantage in terms of column efficiencies and speed of analysis of liquid chromatography over gas chromatography, (GC). 1 Many physical properties can be determined from GC work, and Figure 1 shows a general classification of these. They are of three basic types. Firstly, equilibrium properties such as parameters for distribution of a volatile solid between gas and fixed phase can be obtained by measuring the retention time.