On the Determination of the Reaction Rate Constant and Selectivity in Gas and Liquid-Phase Organic Reactions: Temperature and Solvent Effects Aikaterini Diamanti A thesis submitted for the Doctor of Philosophy degree of Imperial College London and the Diploma of Imperial College. Centre for Process Systems Engineering Department of Chemical Engineering Imperial College London London SW7 2AZ United Kingdom 9th December 2016 Declaration of Originality I, Aikaterini Diamanti, certify that this thesis, and the research to which it refers, are the product of my own work, and that any ideas or quotations from the work of other people, published or otherwise, are fully acknowledged in accordance with the standard referencing practices of the discipline. Copyright The copyright of this thesis rests with the author and is made available under a Creative Commons Attribution Non-Commercial No Derivatives licence. Researchers are free to copy, distribute or transmit the thesis on the condition that they attribute it, that they do not use it for commercial purposes and that they do not alter, transform or build upon it. For any reuse or distribution, researchers must make clear to others the licence terms of this work. 2 Abstract Chemical reactions occur abundantly in nature and the rates at which they proceed are critically influenced by factors such as the temperature and the solvent medium in which they take place. These two factors do not only affect the rate of the reaction but may also have a significant impact on other metrics, such as the selectivity and the catalytic activity, as well as on the overall performance of a process application. Faced with such a broad scope of considerations, the identification of an optimum reaction environment remains a challenge. This thesis provides an in-depth investigation of gas and liquid-phase reactions in the context of predicting selected reaction metrics under different thermodynamic and media conditions. In particular, the effect of temperature on the rate constant of a gas-phase reaction and the effects of solvent media on the rate constant and selectivity of a liquid-phase reaction are considered. A gas-phase hydrogen abstraction reaction between ethane and the hydroxyl radical is stud- ied in a broad range of temperatures. A thorough computational investigation is performed of the temperature dependence of the reaction rate constant, assessing several ab initio and density functional theory methods with various basis sets. A novel hybrid strategy is proposed for the de- velopment of correlative kinetic models that incorporate information from quantum-mechanical calculations and experiments into classical Arrhenius expressions. The hybrid models derived bring new insight into the value and contribution of the data obtained via quantum-mechanical calculations and via measurements. The benefits of such models in the context of accuracy, statistical significance, applicability and practical importance on the study of reactions with scarce experimental data, are highlighted. A regioselective Williamson reaction between sodium β-naphthoxide and benzyl bromide is selected for the investigation of solvent effects on the reaction rate constant and product selectivity. The solvent medium has a key impact on the selectivity of the reaction for alkylation at two possible sites (an oxygen or a carbon atom) resulting in O- and C-alkylated products. For this reaction, a systematic study is performed combining detailed kinetic experiments and density functional theory calculations to determine the reaction rate constants in a set of solvents. The challenges in conducting reliable experiments using NMR spectroscopy are highlighted, and the performance of the various computational methods is scrutinized. Good agreement is obtained between computational predictions and experimental data for the reaction rate constants as well as for the ranking of solvents in terms of the product selectivity ratios for a number of the theoretical methods considered. These promising results pave the way for future computer-aided molecular design tools for the identification of solvents for improved reaction performance. Acknowledgements The completion of my PhD would not have been possible without the support of many people. First of all, I am deeply grateful to my supervisors Claire Adjiman and Amparo Galindo for all their help during these years. I thank them for their invaluable advice, invariable good disposition, inspiring enthusiasm, and kind motivational comments. This work was supported financially by Syngenta and I would like to gratefully acknowledge the attention received from their team. Especially, I would like to thank Patrick M. Piccione and Anita M. Rea for our constructive meetings, and for giving me the opportunity to complete part of my research work in Syngenta's International Research Centre at Jealott's Hill. I feel privileged to be a member of the MSE group and I would like to thank everyone in the group for the happy moments we had together and especially Christianna, Sadia, Eirini, Isaac, Suela, Eliana. I would like to thank my friends Eva, Maria and Sara for being happy with me the good days and cheering me up the difficult days. Also, I would like to thank my friends Maria and Spyros for reminding me how it is having friends close to you and for bringing a little flavour of Greece in my daily life in London. Nothing would have been possible without the love, continuous support and encouragement of my parents and my brother, who, despite being far away, have always been by my side. Finally, the truth is I would not have the strength to complete this PhD without the love and support of my other half Alon. Thank you for believing in me wholeheartedly, inspiring me with your example and making every day of my life more beautiful! 4 Στoυ& γoν´ις µoυ, Bασ´ιλιo και Γαλατια´ , και τoν αδλφo´ µoυ, Aθανασιo´ . Contents Abstract 3 List of Figures 9 List of Tables 18 1 Introduction 32 1.1 Temperature and solvent effects on chemical reactions............... 32 1.2 Predicting temperature and solvent effects on reaction rates............ 34 1.3 Objectives of the thesis................................ 35 1.4 Outline of the thesis.................................. 36 2 Determination of reaction kinetics: temperature and solvent effects 37 2.1 Basic kinetic concepts................................. 37 2.2 Conventional transition state theory......................... 39 2.3 Determination of reaction kinetics.......................... 41 2.3.1 Experimental techniques............................ 41 2.3.2 Computational methods............................ 43 2.4 Modelling solvent effects................................ 45 2.4.1 Solvation models................................ 46 2.4.2 Predictive capabilities of continuum solvation models............ 51 2.5 Modelling temperature effects............................. 53 2.5.1 First order temperature dependence..................... 54 2.5.2 Second order temperature dependence.................... 55 2.5.3 Other approaches................................ 57 2.6 Summary........................................ 58 6 3 Predicting temperature effects on gas-phase reaction kinetics 60 3.1 Introduction....................................... 60 3.2 Computational methodology.............................. 63 3.2.1 Quantum-mechanical calculations....................... 63 3.2.2 Rate-constant calculations........................... 64 3.3 Computational investigation of the reaction kinetics................ 66 3.3.1 Activation energy barrier........................... 66 3.3.2 Reaction rate constant at 298 K....................... 70 3.3.3 Geometry and frequency calculations..................... 72 3.3.4 Rate constants at different temperatures................... 73 3.4 Hybrid correlative models............................... 79 3.4.1 Methodology.................................. 80 3.4.2 Arrhenius-type hybrid models......................... 83 3.4.3 Results..................................... 86 3.5 Summary........................................ 92 4 Kinetic investigation of a Williamson reaction in acetonitrile 94 4.1 Theoretical background for kinetic predictions in the liquid phase......... 95 4.1.1 Liquid-phase reaction rate constant by CTST................ 95 4.1.2 The SMD solvation model........................... 97 4.1.3 Liquid-phase reaction rate constant and selectivity ratio by CTST and the SMD solvation model............................. 100 4.2 The Williamson reaction of sodium β-naphthoxide and benzyl bromide...... 101 4.3 Experimental methodology.............................. 107 4.3.1 Monitoring technique............................. 107 4.3.2 Proton-exchange experiment......................... 108 4.3.3 Methodology for kinetic experiments..................... 111 4.4 Experimental results.................................. 115 4.4.1 Kinetic experiments at 298, 313 and 323 K................. 115 4.4.2 Thermodynamic analysis based on experimental data........... 125 4.5 Computational methodology.............................. 129 4.6 Computational results................................. 131 4.6.1 Structure search for stable conformations of sodium β-naphthoxide.... 131 7 4.6.2 Transition-state structures for the O- and C-alkylation........... 133 4.6.3 Selectivity and reaction kinetics at 298 K.................. 139 4.6.4 Thermodynamic analysis based on QM-calculated data.......... 147 4.7 Summary........................................ 152 5 Kinetic investigation of a Williamson reaction