Bridging synthetic chemistry and computational methods: studying the stability and reactivity of metal-binding macrocycles

Freire, David Marcial

Item

Bridging synthetic chemistry and computational methods: studying the stability and reactivity of metal-binding macrocycles

Freire, David Marcial

Date

2024-12-13

Abstract

The stability constant (log KML = log β) of metal complexes is a critical thermodynamic parameter, providing valuable insights into the stability and formation dynamics of these complexes. Traditionally, stability constants have been central in analytical chemistry, aiding in metal ion speciation and selectivity. However, they are equally crucial in fields such as catalysis, therapeutic development, and energy applications, where understanding the stability of metal complexes informs their robustness and applicability. Beyond thermodynamic stability, the log β value also influences the reactivity of inorganic complexes; commonly, highly stable complexes tend to have diminished reactivity, whereas less stable complexes may lack the necessary ligand-mediated control over metal reactivity due to their tendency to dissociate. In this context, macrocyclic ligands are often employed to achieve highly stable metal complexes, as they leverage the chelate effect of multidentate binding alongside an optimal ion-size match. Such stability makes macrocycles particularly useful for applications in drug delivery, therapeutic imaging, and catalysis. Yet, balancing stability with reactivity remains a significant challenge. High-throughput organic synthesis offers a potential solution by generating ligand libraries, though this approach can be resource-intensive and often produces compounds unsuitable for specific applications. As a result, other approaches are necessary. This dissertation investigates the role of the log β parameter in guiding the speciation and reactivity of transition metals complexed with 12-membered pyridinophane macrocycles. Initially, we examine Mn(II) complexes, illustrating how the stability constant influenced both the reactivity of high-valent manganese ions, and the synthetic approaches used. Subsequently, we developed a computational workflow to refine the predictive accuracy of stability constants, beginning with closed-shell Zn(II) complexes and extending to open-shell Cu(II) complexes. This work advances the understanding of stability-reactivity relationships in metal complexes, offering computational insights that enhance ligand design and complexation strategies in diverse applications.