Supramolecular catalysis: halogen bonding and regulation strategies applied to hydroboration and c-h functionalization reactions
- Autores: Lucas Carreras Vinent
- Directores de la Tesis: Antón Vidal i Ferran (dir. tes.)
- Lectura: En la Universitat Rovira i Virgili ( España ) en 2019
- Idioma: español
- Tribunal Calificador de la Tesis: Angela Marinetti (presid.), Anna Maria Costa Arnau (secret.), Lluisa Pérez García (voc.)
- Programa de doctorado: Programa de Doctorado en Ciencia y Tecnología Química por la Universidad Rovira i Virgili
- Materias:
- Enlaces
- Tesis en acceso abierto en: TDX
- Resumen
The present doctoral thesis encompasses the design and synthesis of new supramolecular catalysts based on halogen bonding interactions and the design and preparation of supramolecular catalytic systems based on regulation strategies. These approaches have been applied to transformations of interest such as hydroboration of terminal alkynes, leading to vinylboronates, and also to selective para-Csp2–H functionalization of phenol-like compounds that could be used for the preparation of molecules with pharmaceutical, biological or agrochemical interest.
Research efforts were initially directed to the preparation of halogen-bonded supramolecular catalysts (Chapter I). Preliminary models revealed that 2-pyridyldiphenylphosphine, containing the halogen-bond-acceptor motif, and 2-iodo-3,4,5,6-tetrafluorophenyldiphenylphosphine, incorporating the halogen-bond-donor moiety, respectively, were adequate for the formation of halogen-bonded rhodium(I) complexes. The preparation of the supramolecular complex, labeled as XBphos-Rh throughout this thesis, was successfully achieved starting from the above-mentioned ligands. The corresponding complex was fully characterized in solution and in the solid state, with the halogen bond interaction being observed in the solid-state. Further exploration of the architecture of the halogen-bonded complexes pointed to the fact that non-perfluorinated halogen-bond-donors were also compatible with the approach, as subsequently proven both experimentally and computationally. XBphos-Rh has been applied to the catalytic hydroboration of terminal alkynes, providing enhanced ratios of the branched vinylboronates, and exhibiting a higher catalytic activity for aryl terminal alkynes, when compared with reported mono- and bidentate phosphorus-rhodium catalysts.
Aiming to broaden the applicability of the previous approach, the influence of halogen-bonded bisphosphine ligands was subsequently studied on other rhodium(I) precursors (Chapter II). It was observed that rhodium(I) bisnorbornadiene tetrafluoroborate, [Rh(nbd)2]BF4, a common precursor in hydrogenation, rendered the corresponding cis heterocomplex incorporating 2-pyridyldiphenylphosphine and 2-iodo-3,4,5,6-tetrafluorophenyldiphenylphosphine as ligands in high yields (90% yield) and in a selective manner (the formation of homocomplexes was not observed). The influence of halogen bonding in this selective process was further supported by diffusion ordered spectroscopy (DOSY). In addition, complexation of the above-mentioned ligands with [Rh(acac)(CO)2], a widely used rhodium(I) precursor in hydroformylations, rendered the corresponding monodentate acetylacetonate carbonylrhodium(I) complexes. Useful stereoelectronic parameters of the ligands used in our studies, such as the Tolman electronic parameter and the percent buried volume of the ligands were determined. [Rh(acac)(cod)], a precursor used as catalyst for asymmetric hydrogenations, isomerization, or hydroformylation reactions among other transformations, displayed a different reactivity when used in combination with the above-mentioned ligands, leading to the selective formation of cyclometallated rhodium(III) complexes by oxidative addition of the metal center to the C–I bond. Experimental and DFT computational data pointed that this reactivity at the metal center was mediated by halogen bonding interactions. To the date, this is the first reported halogen-bond-mediated oxidative addition process to a metal center. The formation of Rh(III) rhodacycles, compounds with therapeutic potential, could be extended to other rhodium precursors.
Research efforts have also been directed towards the development of new gold(I) supramolecularly regulated catalysts. The modular design was based on a phosphite incorporating a 3,3',5,5'-tetra-tert-butyl-(1,1'-biphenyl) motif and a mono-functionalized tetraethyleneglycol fragment, with a steric effector appended at the end of the tetraethyleneglycol chain. The underlying principle is a supramolecularly regulated catalytic system, whose steric congestion around the metal center can be tuned by the choice of an external regulation agent (RA). After successfully preparing an array of ligands, binding between the ligand and alkali metal salts was studied, proving that the ion-dipole interactions between the salt and the polyether chain are thermodynamically favorable in standard organic solvents. With the ligands in hand, cationic gold catalysts were prepared and assayed in the selective para-functionalization of phenols. It was observed that bulkier steric effectors were detrimental for the activity of the catalyst. Therefore, further studies were performed with catalysts derived from the ligand with a methyl group as steric effector. Gold complexes derived from this ligand showed enhanced activities and selectivities when using large alkali metal salts such as cesium tetrafluoroborate. The effectiveness of the approach was tested by screening an array of electronically diverse phenols and naphthols. Enhancements of the catalytic activity upon using a suitable regulation agent (up to a 20% increase in yield) were observed in all cases. The utility of the approach was demonstrated by extending the use of the supramolecularly regulated catalysts to challenging substrates, such as tropolone, which displayed a unique reactivity, and by preparing an advanced synthetic intermediate of the world’s largest selling drug for the hormonal therapy of breast cancer (i.e., Tamoxifen). DFT calculations were performed in order to gain insight into the regulation mechanism. It was computationally demonstrated that complexes incorporating large alkali metal salts lead to a more energetically favorable pathway for the para-Csp2–H insertion reaction.
