Katalytische fosforylatie van alcoholen voor de synthese van fosfaatesters

Alongside key elements like hydrogen, carbon, oxygen and nitrogen, phosphorus is vital in nature through phosphate ester (PE) structures, found in DNA and ATP. Nature's use of phosphorylations to form P(O)-O bonds inspires the development of phosphorus-based APIs like pronucleotides and prodrugs to combat diseases. While APIs support life, PE based pesticides target harmful organisms to protect crops and ensure food security. PEs are also used industrially, such as in flame retardants and surfactants. In this way, the application of phosphate esters are widespread into our lives, rendering them an important synthetic target with ongoing advances in their production. Chapter 1 outlines various synthetic pathways towards phosphate esters, placing this PhD work within the broader field of alcohol phosphorylation. The transformation of phosphate rock into white phosphorus (P₄), though energy-intensive, remains key for producing P-precursors. Current methods rely mainly on nucleophilic substitution of P₄-derived phosphoryl chlorides, but newer phosphorylating reagents aim to offer more selective and sustainable alternatives. H-phosphonates, as P(III) reagents, enable mild Atherton-Todd-type reactions, although oxidative conditions can limit their use. This has led to growing interest in P(V) reagents like phosphoanhydrides, dialkyl phosphates or leaving group activated phosphates, which show high reactivity under suitable conditions. Despite progress, there's a strong demand for milder, more atom-efficient phosphorylation strategies and the application of heterogeneous catalysis. In Chapter 2, the use of isopropenyl phosphate was studied as phosphorylating reagent of alcohols enabling an atom efficient method that produces acetone as the only by-product. The reaction proceeds at room temperature using catalytic potassium tert‑butoxide avoiding commonly applied equimolar base amounts. A catalytic cycle is sustained by the enolate anion regenerating the nucleophile, achieving full conversion of the enolphosphate. This reaction mechanism was further elucidated by composing experimental kinetic plots through in operando 31P NMR spectroscopy with high resolution. Furthermore, with an extensive alcohol reaction scope including a nucleotide, the reaction potential for the selective phosphorylation of primary alcohols was illustrated. Subsequently, the atom efficiency of alcohol phosphorylations could be improved further in Chapter 3 by the direct esterification of phosphoric acid with water as the only by-product, catalyzed by Brønsted acids. With H3PO4 produced directly from phosphate rocks, P4 is circumvented completely in the synthetic pathway towards PEs. Initially, a Dean-Stark set-up using NBP:o‑xylene was optimized to move the equilibrium towards the product side. To address separation issues with homogeneous acids and PEs, heterogeneous niobium oxides were experimentally evaluated as catalyst with decent alcohol conversions observed. To increase the alcohol conversion, the niobium oxide catalyst was pretreated with phosphoric acid to increase its acidity resulting in high mono-ester yields. The increased acidity and H3PO4 adsorption were characterized by Hammett titrations and 31P solid state NMR respectively, whereas the selectivity was further studied by kinetic experiments to determine relative reactivities. Finally, the reaction potential was shown with a scope of high boiling alcohols, including the synthesis of an oleyl phosphate surfactant. Chapter 4 explored creatine phosphate as a P4-independent phosphorylating agent to selectively produce phosphate mono-esters under mild reaction conditions, inspired by its biochemical functionality. By applying Brønsted acidic catalysis, the P-N bond could be activated allowing creatine to act as leaving group in a room temperature nucleophilic substitution. Although strong homogeneous Brønsted acids were effective with excess alcohol, heterogeneous aluminum-rich zeolites were evaluated as well. A clear correlation of the zeolites Si/Al ratio and the creatine phosphate conversion were observed, with a faujasite and Si/Al=5.2 performing best. By conducting recycling experiments, intermittent calcination was shown to be essential to prevent acid site neutralization by adsorbed creatine. With an extensive alcohol scope, a high functional group tolerance was observed. In conclusion, in this PhD manuscript, innovative phosphorylating agents were studied as well as the application of heterogeneous catalysis for the synthesis of phosphate esters to increase the overall sustainability of these reactions.