Publication: Direct decarboxylation of fluorinated carboxylates enabled by iron photocatalysis
Authors
Fernández García, Sara
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Escuela Internacional de Doctorado
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Juliá Hernández, Francisco
Publisher
Universidad de Murcia
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DOI
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info:eu-repo/semantics/doctoralThesis
Description
Abstract
Los ácidos carboxílicos fluorados constituyen materias primas abundantes, económicas y con una excelente eficiencia atómica, lo que los convierte en candidatos ideales como precursores de radicales en síntesis orgánica. Son compuestos estables, fáciles de manejar y capaces de generar radicales centrados en carbono mediante procesos de descarboxilación, liberando CO2 como único subproducto. Sin embargo, a pesar de estas ventajas, su utilización directa como agentes fluoroalquilantes en química radicalaria ha sido históricamente limitada. Esta dificultad se debe a sus elevados potenciales de oxidación (Eox> 2.0 V vs SCE), que los sitúan fuera del alcance de las estrategias convencionales de activación basadas en transferencia electrónica de esfera externa, como la fotocatálisis redox. Como consecuencia, los métodos existentes requieren condiciones fuertemente oxidantes, lo que compromete la selectividad, la tolerancia a grupos funcionales y su aplicabilidad en la funcionalización de moléculas complejas, especialmente relevantes en el ámbito farmacéutico.Esta tesis aborda este desafío mediante una estrategia alternativa de activación basada en un mecanismo de esfera interna, empleando catalizadores de hierro abundantes y accesibles. En este enfoque, los carboxilatos fluorados se coordinan a especies fotoactivas de Fe(III), formando complejos que, tras la absorción de luz visible, experimentan una excitación de tipo LMCT (ligand-to-metal charge transfer). Este proceso induce la ruptura homolítica del enlace Fe-O y genera un radical carboxilato que, de forma inmediata, libera CO2 para dar lugar al correspondiente radical fluoroalquilo. De este modo, la generación del radical deja de depender de las propiedades redox del sustrato y pasa a estar gobernada por su coordinación al metal, lo que permite superar las limitaciones de las estrategias convencionales y operar bajo condiciones suaves.En el Capítulo 2 se valida este concepto mediante el desarrollo de un sistema fotocatalítico Fe-LMCT capaz de promover la descarboxilación directa de trifluoroacetato de sodio, generando radicales CF3. Estos radicales se emplean en la trifluorometilación directa de enlaces C(sp2)-H en una amplia variedad de (hetero)arenos, incluyendo sustratos ricos en electrones y sensibles a la oxidación, lo que pone de manifiesto que la reactividad está controlada por la coordinación al hierro y no por las propiedades redox del sustrato.En el Capítulo 3, esta plataforma se integra con procesos electroquímicos, dando lugar a un sistema fotoelectrocatalítico en el que la oxidación anódica sustituye al oxidante estequiométrico. Esto permite la regeneración continua del catalizador bajo control electroquímico, mejorando la sostenibilidad del proceso y permitiendo la funcionalización eficiente de sustratos especialmente sensibles. Los estudios mecanísticos revelan la coexistencia de distintas especies de hierro con funciones complementarias dentro del ciclo catalítico.El Capítulo 4 amplía el alcance de esta estrategia a halodifluoroacetatos, permitiendo la generación de radicales CF2X (X = Cl, Br) bajo condiciones suaves. Estos radicales reaccionan de forma selectiva con (hetero)arenos, mostrando una elevada tolerancia a grupos funcionales y compatibilidad con moléculas complejas. Además, los grupos introducidos pueden transformarse posteriormente en fluoruro de acilo, estableciendo una conexión directa entre la funcionalización radicalaria y la diversificación sintética.Finalmente, en el Capítulo 5 se extiende la metodología a la activación directa del ácido difluoroacético, permitiendo la generación de radicales CF2H sin necesidad de condiciones drásticas ni reactivos preactivados. Este proceso proporciona una vía práctica para la difluorometilación de una amplia variedad de sustratos, independientemente de su naturaleza electrónica, y confirma la versatilidad del enfoque desarrollado.En conjunto, esta tesis establece la catálisis Fe-LMCT como una plataforma general y versátil para la activación directa de ácidos carboxílicos fluorados, ofreciendo una alternativa sostenible y eficaz a las metodologías tradicionales y abriendo nuevas posibilidades para la funcionalización de moléculas complejas.
Fluorinated carboxylic acids are abundant and inexpensive chemical feedstocks that offer strong potential as radical precursors. They are stable and easy to handle and can potentially undergo oxidative decarboxylation to generate carbon-centered radicals, producing CO2 as the sole byproduct. Yet, their direct use as reactive radical fluoroalkylating reagents has remained largely underexplored due to their high oxidation potentials (Eox > 2.0 V vs. SCE), that place them beyond the reach of conventional redox-based outer-sphere activation strategies, such as photoredox catalysis. As a result, current approaches rely on harsh reaction conditions, compromising selectivity, functional-group tolerance, and sustainability. Current decarboxylation protocols typically require highly oxidizing conditions, which are incompatible with their application to the fluoroalkylation of complex molecules, which are key targets in pharmaceutical synthesis and drug discovery. This thesis addresses this problem through an innovative activation strategy based on am orthogonal inner-sphere electron-transfer pathway using Earth-abundant and readily available iron catalysts. In this approach, fluorinated carboxylates coordinate to photoactive Fe(III) species, resulting in Fe(III) carboxylate complexes. Intriguingly, visible-light absorption induces homolytic Fe-O bond cleavage, generating carboxylate radical species that rapidly release CO2 to form the corresponding fluoroalkyl radicals, primed for further functionalization. This process proceeds via population of dissociative ligand-to-metal charge transfer (LMCT) excited states, highlighting an emerging reactivity paradigm in organic synthesis. By shifting radical generation from a redox-controlled to a coordination-driven process, this strategy overcomes intrinsic redox limitations and enables the direct use of fluorinated carboxylic acids as fluoroalkylating reagents under mild conditions, an approach we have leveraged to develop novel (hetero)arene functionalization reactions.In Chapter 2, an Fe-LMCT photocatalytic system enables the direct decarboxylation of sodium trifluoroacetate, generating CF3 radicals. These radicals undergo direct C(sp2)-H trifluoromethylation across a broad range of (hetero)arenes, including electron-rich and oxidation-sensitive substrates, demonstrating that reactivity is governed by metal coordination rather than substrate redox properties. The inner-sphere electron transfer pathway was supported by experimental evidence, including radical trap experiments and UV-Vis absorption studies.In Chapter 3, this platform is translated into a photoelectrocatalytic regime, where anodic oxidation replaces the stoichiometric oxidant, enabling continuous regeneration of the active Fe(III) species under electrochemical control while preserving LMCT-driven CF3 radical generation. This dual activation enables the efficient functionalization of electron-rich and oxidation-sensitive substrates that are typically incompatible with conventional approaches. Mechanistic studies reveal the coexistence of multiple iron species with complementary roles in radical formation and catalyst turnover, highlighting the complexity and flexibility of the catalytic system.The scope of this concept is expanded in Chapter 4 to halodifluoroacetates, enabling the direct generation of electrophilic CF2X (X = Cl, Br) radicals under mild conditions. These species engage in selective C(sp2)-H halodifluoromethylation of electron-rich (hetero)arenes, showing broad functional-group tolerance and compatibility with structurally complex molecules, highlighting its potential for late-stage functionalization. Notably, the installed CF2X groups can be further transformed into valuable functional groups such as acyl fluorides, establishing a direct link between radical C-H functionalization and downstream diversification for the rapid generation of families of fluorinated derivatives.In Chapter 5, the Fe-LMCT platform is further extended to the direct activation of difluoroacetic acid, enabling the generation of CF2H radicals under mild conditions without the need for preactivation or strongly oxidative reagents. This transformation provides a practical and direct entry to difluoromethylation from simple feedstocks and displays broad applicability across a wide range of aromatic and heteroaromatic substrates. Despite the ambiphilic nature of the · CF2H radical, controlled radical aromatic substitution is achieved
Fluorinated carboxylic acids are abundant and inexpensive chemical feedstocks that offer strong potential as radical precursors. They are stable and easy to handle and can potentially undergo oxidative decarboxylation to generate carbon-centered radicals, producing CO2 as the sole byproduct. Yet, their direct use as reactive radical fluoroalkylating reagents has remained largely underexplored due to their high oxidation potentials (Eox > 2.0 V vs. SCE), that place them beyond the reach of conventional redox-based outer-sphere activation strategies, such as photoredox catalysis. As a result, current approaches rely on harsh reaction conditions, compromising selectivity, functional-group tolerance, and sustainability. Current decarboxylation protocols typically require highly oxidizing conditions, which are incompatible with their application to the fluoroalkylation of complex molecules, which are key targets in pharmaceutical synthesis and drug discovery. This thesis addresses this problem through an innovative activation strategy based on am orthogonal inner-sphere electron-transfer pathway using Earth-abundant and readily available iron catalysts. In this approach, fluorinated carboxylates coordinate to photoactive Fe(III) species, resulting in Fe(III) carboxylate complexes. Intriguingly, visible-light absorption induces homolytic Fe-O bond cleavage, generating carboxylate radical species that rapidly release CO2 to form the corresponding fluoroalkyl radicals, primed for further functionalization. This process proceeds via population of dissociative ligand-to-metal charge transfer (LMCT) excited states, highlighting an emerging reactivity paradigm in organic synthesis. By shifting radical generation from a redox-controlled to a coordination-driven process, this strategy overcomes intrinsic redox limitations and enables the direct use of fluorinated carboxylic acids as fluoroalkylating reagents under mild conditions, an approach we have leveraged to develop novel (hetero)arene functionalization reactions.In Chapter 2, an Fe-LMCT photocatalytic system enables the direct decarboxylation of sodium trifluoroacetate, generating CF3 radicals. These radicals undergo direct C(sp2)-H trifluoromethylation across a broad range of (hetero)arenes, including electron-rich and oxidation-sensitive substrates, demonstrating that reactivity is governed by metal coordination rather than substrate redox properties. The inner-sphere electron transfer pathway was supported by experimental evidence, including radical trap experiments and UV-Vis absorption studies.In Chapter 3, this platform is translated into a photoelectrocatalytic regime, where anodic oxidation replaces the stoichiometric oxidant, enabling continuous regeneration of the active Fe(III) species under electrochemical control while preserving LMCT-driven CF3 radical generation. This dual activation enables the efficient functionalization of electron-rich and oxidation-sensitive substrates that are typically incompatible with conventional approaches. Mechanistic studies reveal the coexistence of multiple iron species with complementary roles in radical formation and catalyst turnover, highlighting the complexity and flexibility of the catalytic system.The scope of this concept is expanded in Chapter 4 to halodifluoroacetates, enabling the direct generation of electrophilic CF2X (X = Cl, Br) radicals under mild conditions. These species engage in selective C(sp2)-H halodifluoromethylation of electron-rich (hetero)arenes, showing broad functional-group tolerance and compatibility with structurally complex molecules, highlighting its potential for late-stage functionalization. Notably, the installed CF2X groups can be further transformed into valuable functional groups such as acyl fluorides, establishing a direct link between radical C-H functionalization and downstream diversification for the rapid generation of families of fluorinated derivatives.In Chapter 5, the Fe-LMCT platform is further extended to the direct activation of difluoroacetic acid, enabling the generation of CF2H radicals under mild conditions without the need for preactivation or strongly oxidative reagents. This transformation provides a practical and direct entry to difluoromethylation from simple feedstocks and displays broad applicability across a wide range of aromatic and heteroaromatic substrates. Despite the ambiphilic nature of the · CF2H radical, controlled radical aromatic substitution is achieved
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30-may-2027
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