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Novel approaches to reducing resource use and waste generation in nucleophilic substitution reactions through low waste synthetic routes and reaction energy profile modelling
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Date
2024
Authors
Ryan, David.
Journal Title
Journal ISSN
Volume Title
Publisher
University College Cork
Published Version
Abstract
This thesis is split into two parts based on two different areas of research.
Part I
Part I relates to research conducted on the development of a sustainable protocol for the bromination of alcohols. It is divided into five chapters (including a dedicated chapter for the literature references across the entirety of Part I). Chapter 1 provides an introduction to the background of the project as well as a review of existing research conducted in this area.
Chapter 2 provides details on the research carried out in this project on the sustainable synthesis of alkyl bromides by diphenyl H-phosphonate-mediated deoxygenative bromination of alcohols. The Conclusions and Future Work section relating to this area of research constitutes
Chapter 3. Chapter 4 outlines the experimental work for Part I. All of the literature references for Part I are collected together to form Chapter 5. There also exists a dedicated Appendix containing images of all of the NMR spectra reported in Chapter 3, as well as Excel spreadsheets dedicated to the calculation of green metrics (CHEM21 worksheet) (details on how to access this are given in Section III below). The synthesis of complex value-added chemicals frequently employs reactive species such as alkyl halides. As the focus on implementation of green chemistry principles in industrial and academic chemical applications grows, the use of such species may be minimised but never truly eliminated. Conventional means for synthesising alkyl halides are highly problematic in that they are associated with vast amounts of waste generation and resource use. In 2007, and again in 2018, the American Chemical Society Green Chemistry Institute Pharmaceutical Roundtable designated the activation of alcohols toward nucleophilic substitution as one of their ten key research areas. The focus of the project described in Part I of this thesis was on development of a methodology addressing this challenge, focusing specifically on generation of alkyl bromides from alcohols using bromide ion as the nucleophile. The methodology reported herein, while valuable in its own right, was designed to be a ‘stepping-stone’ on the way to a general methodology for the nucleophilic substitution of alcohols i.e., the scope of nucleophiles may be readily expanded beyond the bromide ion. The methodology described in Part I constitutes the open-air, relatively low-temperature, one-pot activation and substitution of alcohols using benign materials of minimal environmental impact. It results in high yields and near complete stereoinversion (where applicable with enantiopure chiral alcohols). The methodology developed was applied to 34 alcohols containing a wide range of functional groups, in addition to several biologically active and pharmaceutically relevant substrates. A thorough analysis of the green metrics associated with the methodology is also presented, demonstrating an improvement on the state-of-the-art from a green chemistry perspective.
Finally, exciting new research avenues are described which have the potential to further elevate the ‘greenness’ of this approach, in addition to the development of asymmetric variants or a general nucleophilic substitution platform.
Part II
Part II relates to research conducted on the development of a model for the prediction of Gibbs energies of activation and the generation of Gibbs energy profiles. It is divided into five chapters (including a dedicated chapter for the literature references across the entirety of Part I). Chapter 6 involves an introduction to the novel concept behind the model presented herein, as well as a review of existing research conducted in this area. Chapter 7 provides details on the research carried out in this project on modelling of the Gibbs energy profiles of SN2 reactions of nitrite anion as a representative nucleophile. The Conclusions and Future Work
section relating to this area of research constitutes Chapter 8. Chapter 9 outlines the experimental work for Part II. Chapter 10 then contains the literature references for the entirety of Part II. There also exists an Appendix containing images of all NMR spectra reported (and not shown) in Chapter 9, as well as Excel spreadsheets containing intrinsic reaction coordinate data and Gibbs energy profile models for the reactions studied (details on how to access this are given in Section III below). A desire to understand and predict the factors that control the rates of chemical reactions has been at the heart of the field of Physical Organic Chemistry since its inception. Indeed, such factors determine the real-world behaviour of chemical species and so are of great importance. Since reaction parameters such as duration, temperature, concentration as well as factors such as selectivity and impurity generation all rely on the rates of chemical reactions, the ability to predict reaction rates would be a powerful addition to the organic chemist’s toolkit. In this project, a novel means of predicting Gibbs energies of activation (and by extension reaction rates) for reactions in solution is described. The approach described here avoids many of the issues associated with even the best modern computational approaches for determination of Gibbs energies of transition states (and hence Gibbs energies of activation) and also circumvents obstacles associated with theoretical treatments such as Marcus theory to predict the Gibbs energies of activation for 18 reactions with a high degree of accuracy. This was accomplished through a combination of robust computational data (values of ΔrG°, and
Intrinsic Reaction Coordinate calculations performed at a high level of theory) and experimental measurements as a point of reference. Substantial kinetic measurements were undertaken in order to establish experimental values for the Gibbs energies of activation. These were used to validate the predictions of the model developed. The use of Intrinsic Reaction Coordinates also allowed for the generation of Gibbs energy profile diagrams which are likely to closely replicate the true Gibbs energy profiles for the reactions in question marking the first time that this has been achieved. A total of 22 Gibbs energy profile diagrams were generated. Access to these has enabled the measurement of reaction coordinate lengths and an in-depth analysis of the corresponding Gibbs energy profiles, enabling the comparison of a range of Gibbs energy profiles and their features. The ability to predict Gibbs energies of activation and understand the topologies of Gibbs energy profiles could have far reaching consequences for reaction planning and design. A further outcome may be the significant reduction in resource use and waste generation through the elimination of wasteful trial-and-error base approaches that are commonplace in modern approaches for process optimisation and synthesis planning.
Description
Keywords
Green chemistry , Sustainable , Synthestis , Halogenation , Resource use , Waste , Energy profile , Modelling , Nitrite
Citation
Ryan, D. 2024. Novel approaches to reducing resource use and waste generation in nucleophilic substitution reactions through low waste synthetic routes and reaction energy profile modelling. PhD Thesis, University College Cork.