Solid-phase peptide synthesis (SPPS) and solid-phase organic synthesis (SPOS) are key enabling tools in organic chemistry. The common denominator in both is the solid-phase, typically a polymer bead. The most widely used, cost effective bead is cross-linked polystyrene (PS). For chemistry using PS beads the solvent has to solvate (swell) the resin to allow reaction to proceed; this typically results in the use of very ‘ungreen’ solvents to achieve swelling such as dimethylformamide (DMF) and dichloromethane (DCM). Dimethylformamide (DMF) is reprotoxic, resulting in its classification as a substance of highest concern under the EU REACH regulations. Chlorinated solvents such as dichloromethane are also known to be highly toxic.
There is extensive interest (both within industry and academia) in the development of replacements for conventional solvents which have low toxicity and are sustainably sourced. Our aim is to build on our empirical data bank in the area of polymer compatibility with sustainable solvents but, more importantly, to develop an understanding of the underlying chemical principles involved in this process.
This project will be a synergistic amalgamation of organic chemistry (SPPS) and modelling studies. For example, one area of this project is understanding the swelling of resins in alcoholic solvents and to investigate this further. The project will involve the use of SPPS to prepare threonine containing peptides attached to both polystyrene and PEG resins and to study how the presence of free OH groups in the resin-peptide system influences swelling in alcoholic solvents. Once the empirical data is generated, HSPiP (Hansen Solubility Parameters in Practice) software will be used to model the resin-solvents interactions in terms of the relative importance of each Hansen solubility parameter and to develop resin swelling guidelines based on the Hansen solubility parameters. Further work will be guided by these results with the ultimate aim of allowing us to predict the solvent changes required during a synthetic protocol (either SPPS or SPOS).
This project is extremely timely with the impetus to replace solvents that will be banned or severely restricted in the near future. The applicants bring complementary expertise together to develop a ground-breaking approach chemistry on the solid-phase. The methodology we propose is novel and there is, to our knowledge, no precedent to our approach. This project could significantly ‘fast forward’ the adoption of sustainable solvents in the chemical industry with subsequent benefit to human health, the environment, the UK economy and business. It will also provide an exemplar of the adoption of circular economy principles within synthetic solid-phase chemistry.
This project is expected to be of significant commercial interest, especially by the pharmaceuticals sector. Solvents are critical to the chemistry carried out in this sector (both in solution and on the solid-phase). The next subset of solvents to be banned will be the polar aprotic amides so any work showing that biodegradable and non-toxic replacements (e.g. cyclic carbonates) can be used in place of traditional polar aprotic solvents will be of significant interest and ultimately the ability to design a solid-phase synthesis with not only the reagents but optimal sustainable solvent(s) for each step of the synthesis.
The project is multi-disciplinary and will provide excellent lab-based training since it involves a wide range of techniques. In addition, the student will participate in the chemistry department’s postgraduate training. They will take a selection of suitable training courses, which, depending on their background will complement lab-based training. The student will be provided with a number of opportunities to network and present their work as a poster or oral presentation both within and external to the University. The student will be encouraged to attend two major international conferences during their PhD. The project will also give the student opportunities to interact/collaborate with interested industry
All Chemistry research students have access to our innovative Doctoral Training in Chemistry (iDTC): cohort-based training to support the development of scientific, transferable and employability skills: https://www.york.ac.uk/chemistry/postgraduate/idtc/
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. This PhD project is available to study full-time or part-time (50%).
This PhD will formally start on 1 October 2020. Induction activities will start on 28 September.