Discovery of new reaction modes in organic synthesis triggered by HFIP

The impact of solvents on chemical reactions holds a paramount role in shaping reaction outcomes and processes. Solvents assume multifaceted roles: they serve as a medium for reactant dissolution, influence reactant interaction and mobility, and exert control over reaction rates, selectivity, and even mechanisms. The solvation environment created by the selected solvent stabilizes intermediates and transition states, leading to shifts in reaction pathways and product distributions. Polarity of solvents significantly affects ionic and polar reactions, whereas nonpolar solvents’ hydrophobic interactions can control reaction conformations. Furthermore, the choice of solvent directly influences catalyst solubility, stability, and activity, thereby impacting overall reaction efficiency and selectivity. However, despite these crucial roles, the significance of solvents is often overlooked.

In recent years, the landscape of organic synthesis has been transformed by the emergence of innovative organic solvents, with perfluorinated variants especially 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) leading the charge. These solvents have ushered in remarkable breakthroughs in reaction discovery and synthetic methodologies. The transition of HFIP from an infrequently employed solvent to a prominent choice across various domains of organic synthesis is underpinned by its unique attributes. This shift is primarily driven by empirical observations that consistently demonstrate the superior performance of reactions conducted in HFIP compared to alternative solvents. Consequently, HFIP has garnered increased attention as a solvent of choice. The ongoing exploration of the reactivity interplay between HFIP and organic or organometallic species not only promises to deepen our understanding of reaction mechanisms but also serves as a wellspring of inspiration for the design and development of transformative synthetic pathways.

Within this Doctoral Thesis, our primary objective will be centered around the conception and implementation of novel synthetic protocols, all facilitated by the inclusion of HFIP. The central goal of our endeavor is to broaden the spectrum of functions that this perfluorinated alcohol can undertake in the domains of both metal-free and TM-catalysis. Through a systematic exploration of HFIP’s potential, we aim to forge innovative pathways in the realm of catalytic methodologies.

Chapter II, entitled ´HFIP-assisted selective intramolecular synthesis of heterocycles enabled by single electron transfer´ provides a new heterocycles formation protocol involving aliphatic sp3 C–H functionalization. We reveal that by simply combining bench-stable PhI(OTFA)₂ and HFIP we can switch from the well-established HLF mechanism to a new and versatile reaction pathway that enables the selective functionalization of aliphatic C–H bonds. We exploit the facile formation of radical cations via single electron transfer (SET), in the presence or absence of light, to synthesize pyrrolidines and piperidines, including drug-type molecules, along with O-heterocycles. Experimental and computational mechanistic studies support two possible mechanistic pathways depending on the electron density of the substrate, where the HFIP plays a multifunctional role.

Chapter III, entitled ´HFIP-enabled spin catalysis´ discloses a “non-excited” singlet-triplet intersystem crossing (ISC) via secondary-coordination sphere interactions with HFIP. Despite this perfluorinated solvent has exhibited unique behavior promoting organic and organometallic transformations, its participation in ISC events had not been contemplated. Employing experimental and computational approaches, we investigated this intriguing phenomenon, ultimately harnessing it to develop a versatile site-selective cobalt-catalyzed Mizoroki-Heck protocol, that includes the activation of inexpensive and readily available aryl chlorides, and late-stage functionalization (LSF) strategies.

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