Tethering surface tension to organic synthesis: a quest for chemoselectivity

Abstract

The development of chemoselective processes is of utmost importance for the future of synthetic organic chemistry and has been described as ‘one of the greatest obstacles to complex molecule synthesis.’ This dissertation was written with this main objective in mind, which was pursued from two perspectives.
Development of surface-tension driven droplet devices towards parallel and chemoselective synthesis of substituted 2H-chromen-2-ones was at first investigated on a sub-millimolar scale (Chapters 1-3). Multi-droplet sorting devices were manufactured and key parameters such as droplet composition, substrate temperature and orientation were optimised. Test reactions in aqueous propylene glycol (PG) were conducted in batch conditions, affording 3,6-disubstituted coumarins references via Knoevenagel condensation of 5-substituted salicyladehydes with activated methylene compounds and acid-promoted intramolecular cyclisation. Reactivity transposition onto droplets was thoroughly investigated, leading to a three-pair reagent (3x3) chemical sorter. Product quantification method by 1H-NMR spectroscopy was successfully implemented in micro-liter sized droplets, proving how chemoselectivity can be achieved following such unconventional, synthetic methodology.
The second project studied chemoselective formation of 2-alkenyl tertiary anilines and 1,1,2-trimethylindolinium hexafluorophosphates via charged aza-Claisen rearrangement and thermal cyclisation of quaternary N-allylated ammonium salts (Chapter 4-6). In the latter case, early attempts of the reaction were unsuccessful due to decomposition catalysed by the bromide anion, but a switch to a non-nucleophilic anion (PF6-) allowed the ring closure to occur. Compound library synthesis was carried out to assess the synthetic methodology robustness. Key strengths and limitations were identified and ammonium substrate regiochemical effects were examined and discussed. Finally, interesting research avenues were suggested to broaden substrate scope studies and, most importantly, to link structural connectivity analysis of ammonium salts with modulation of their surface properties.