The Physico-Chemical Properties of Supramolecular Systems Involving Pharmaceuticals and Anions

THE PHYSICO-CHEMICAL PROPERTIES OF SUPRAMOLECULAR SYSTEMS INVOLVING PHARMACEUTICALS AND ANIONS By Maan Abdulrazzaq Suwiad Al-Nuaim A Thesis is Submitted for the Degree of Doctor of Philosophy Thermochemistry Laboratory Department of Chemistry Faculty of Engineering and Physical Sciences University of Surrey, United Kingdom January, 2016 © Maan Abdulrazzq Suwaid Al-Nuaim Abstract Abstract Currently, the discharge of pollutants to the environment is considered one of the biggest problems challenging chemists and environmental scientists. These pollutants come from different sources and might be carcinogenic, toxic or radioactive compounds which can cause serious health hazards to humans, animals and plants. Intensive thermodynamic studies by Danil de Namor and co-workers in the Thermochemistry Laboratory indicated that functionalisation of calix[4]pyrroles, cyclodextrines and calix[n]arenes ( n=4,6 ) leads to the production of selective macrocyclic receptors for the removal of anions, toxic heavy metals and other pollutants from water. The objective of this thesis is to design, synthesise and characterise macrocyclic receptors with suitable functional groups for the selective removal of drugs and anions from water. The drugs selected for this study are diclofenac, sodium diclofenac, clofibric acid, carbamazepine, aspirin and ibuprofen. This selection is based on the fact that these drugs are extensively used and as a result these contaminate sewage, surface and ground water. Supramolecular chemistry is one of the most important areas of chemistry which offers many advantages due to the efficient, fast and economical way for removing pollutants from water. In this thesis a large number of macrocycles based on calix[4]arene, calix[4]pyrrole resorc[4]arene and pyrogalol[4]arene have been synthesised and characterised by 1H NMR and microanalysis. From these receptors those based on cyclodextrin and calix[4]arene derivatives have been selected for sodium diclofenac while for drugs containing carboxylic acids in their structure, a partially substituted calix[4]arene amine was selected for further investigations involving these drugs. These interactions were assessed in solution by several techniques such as 1H NMR titration, UV-Visible, conductivity, isothermal titration calorimetry. In the solid state, thermogravimetry and differential scanning calorimetry were explored. The extraction of these pharmaceuticals by some of these macrocycles under different conditions is reported. The importance of fundamental studies in searching for applications is demonstrated where the selectivity of the calix[4]arene amine for these drugs is shown in the extraction process. Modified silica with amino functional groups is explored for extracting aspirin from water. Preliminary research on the efficiency of pyrogallol[4]arene and resorcine[4]arene to work as molecular containers for selected drugs were tested by 1H NMR Two novel calix[4]pyrroles were investigated for complexation with halides and phosphates showing their selectivity for phosphates relative to halides. Final conclusions are given as well as suggestions for further work particularly with the new oligomeric material which has been characterised by various techniques which are FTIR, XRD, SEM, BET analysis iii Acknowledgement Acknowledgements I am greatly indebted to my supervisor Professor Angela F. Danil de Namor for her supervision, guidance, dedication and patience in the writing of the present thesis and for her kind husband Dr. Melhem Namor for his encouragement. I would like to thank my co-supervisor Prof. J. Varcoe for his help and support, Prof. B. Howlin for his help in the chemical modelling and interesting interpretations. I would also like to thank Prof. I. Cunningham for his great advice given by me during the research period. I wish to thank all academic staff in the Chemistry Department at the University of Surrey for their help and encouragement. Also, I wish to say special thank you to all my colleagues in the Thermochemistry Laboratory, Oliver, Abdel, Weam, Adnan, Adhwa, Nawal and Rachida for their help and for sharing their scientific knowledge. Also, I would like to thank the technical staff in the Chemistry Department at the University of Surrey, Judith, V. Dokova, Dave, Graham, Dan, Deryck, Nikki and Qinmin. Also, I should to thank my colleagues in the College of Pharmacy in Basra University/ Iraq. I would like to thank the Ministry of Higher Education & Scientific Research in Iraq for the financial support for this research through the College of Pharmacy in the University of Basra. Finally, I have to say thank you for all the members of the Iraqi Cultural Attachee in London specially Prof. Mousa Al-Mousawi and Dr. Fadwaa Al-Saffar for their help and support Dedication Dedication To My Father& Mother with love Table of Contents Table of Contents……………………………………………………………...Page 1. Chapter I Introduction………………………………………………………………………1 1.1 Supramolecular Chemistry…………………. ……………………………………...................2 1.2 Pharmaceuticals, phosphate and halides in the environment…………………………………...3 1.2.1 Occurrence of pharmaceuticals in the aquatic environment………………………………3 1.2.2 Phosphate and halides in aquatic environment………………………………….………..5 1.3 Classification of macrocyclic receptors…………………………..…………………...……….6 1.3.1 Naturally occuring macrocycles……………...……………………..................................6 1.3.2 Synthetic macrocyclic receptors (crown ethers, cryptands, spherands and pillarenes)…..8 1.4 Calix[4]arenes………………………………………..…………………………………........15 1.4.1 Properties and conformations of calix[4]arene………………..…………………...........17 1.4.2 Lower Rim functionalisation of Calix[4]arenes……………………………………........20 1.4.3 Upper rim functionallisation of calix[4]arene…………………………………………...25 1.4.4 Applications of Calixarenes and derivatives…………………………………………….29 1.5 Calix[4]pyrrole…………………………………………………………..…………......…….30 1.5.1 Calix[4]pyrrole conformations……………………..……………..……………….........31 1.5.2 Functionalisation of calix[4]pyrrole…………………………………………………….32 1.5.2.1 Functionalisation of C-rim (β-position)….……………….………………………..32 1.5.2.2 Functionalisation of N-rim………………………………………….……………..34 1.5.2.3 Functionalisation of meso position……………………………….………………..34 1.5.3 Application of calix[4]pyrrole………...…………………………….……………..........39 Table of Contents 1.6 Resorcin[4]arene……………………………………………………….…………………….40 1.7 Pyrogallol[4]arene…………………………………………..………….……………..……...45 1.8 The use of silica based compounds for extraction purposes......................................................48 1.8.1 Click chemistry………………………………………………………………………….51 1.9 BET theory…………………………………………………………………………………...53 1.10 Aims of the thesis………………………………………………………...………………….53 2. Chapter two: Experimental Part…………………………………………………………….60 2.1 List of abbreviation…………………………………………………………………………...61 2.2 Chemicals…………………………………………………………………………………….63 2.2.1 Solvents used in this work……………………………………………………………….63 2.2.2 Deuterated solvents used for the 1H NMR…………………………………………........64 2.2.3 Pharmaceuticals……………………………………………………………………........64 2.2.4 Analytical reagents……………………………………………………………...............65 2.2.5 Purification of solvents………………………………………….....................................66 2.2.6 Instruments used………………………………………………………………………...67 2.3 Solubility measurements……………………………………………………………………..68 2.3.1 Solubility of selected pharmaceuticals in different organic solvents at 298.15 K………..68 2.3.2 Calibration curve for the determination of the solubility of pharmaceuticals………........69 2.3.3 Solubility of selected pharmaceuticals…………………………………………………..69 2.4 Determination of partition coefficients of selected drugs in water-1-octanol solvent system...69 2.5 Synthesis of receptors………………………………………………………………………...70 Table of Contents 2.5.1 Synthesis and characterization of heptakis-(6-chloro-6-deoxy)--cyclodextrin…...........70 2.5.2 Synthesis of heptakis-(2, 3, 6-tri-O-benzoyl)--cyclodextrin…………………………...71 2.5.3 Synthesis of 5, 11, 17, 23-tert-butyl-25, 26, 27, 28-(oxy-ethylethanoate)calix[4]arene....71 2.5.4 Synthesis of 5, 11, 17, 23-tetra-p-tert-butyl-25, 27-bis(2-cyanomethoxy)-26, 28- dihydrocalix[4]arene CA-(CN)2 ……………….……………………………………………..73 2.5.5 Synthesis of 5, 11, 17, 23-tetra-p-tert-butyl-25, 27-bis(2-cyanomethoxy)-26, 28- dihydrocalix[4]arene CA-(NH2)2………………………………………………......................73 2.5.6 Synthesis of 25, 26, 27, 28-tetrahydroxycalix[4]arene………………………………….74 2.5.7 Synthesis and characterisation of 5- tert-butyl-3-azidomethyl-2-hydroxybenzaldehyde.75 2.5.8 Synthesis and characterisation of 5-tert-butyl-2-hydroxybenzaldehyde………………...75 2.5.9 Synthesis and characterisation of 5-tert-butyl-3-chloromethyl-2-hydroxybenzaldehyde.76 2.5.10 Synthesis of 5-tert-butyl-3-azidomethyl-2-hydroxybenzaldehyde……………….........76 2.5.11 Synthesis and characterisation of 25, 27-dihydroxy-26, 28-dioxypropargyl-tert- butylcalix[4]arene………………………………………………………….............................76 2.5.12 Synthesis and Characterization of azido calix[4]arene ………………………………...77 2.5.13 Preparation of 2-azidoacetamide……………………………………............................78 2.5.14 Synthesis of 25, 26, 27, 28-(diethylamino) ethoxy calix[4]arene……………................79 2.5.15 Synthesis of meso-tetramethyl-tetrakis-(4-hydroxyphenyl ethyl)calix[4]pyrrole……..80 2.5.16 Synthesis of meso-tetramethyl-tetrakis-(4-ethylacetatophenoxyethyl)calix[4]pyrrole TTECP…………………………………………………………………………………..........81 2.5.17 Polymerisation of meso-tetramethyl-tetrakis-[2-(4- hydroxyphenyl)ethyl] calix Table of Contents [4]pyrrole

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