Hydrophobic Pockets of HPMC Enable Extremely Short Reaction Times in Water

Abstract

Although greener and faster access to fine chemicals and APIs is highly desirable, there are currently no synthetic methodologies which undergo reaction completions within a few seconds to minutes in water under benchtop laboratory conditions. Here, we report a methodology that allows the instantaneous formation of ligated ultrasmall Pd nanoparticles in the hydrophobic pockets of benign cellulose derivative (HPMC) for chemical reactions to proceed very fast in water under mild reaction conditions. Unprecedented short reaction times were exemplified for the Buchwald–Hartwig aminations. In addition, very short reaction times of less than a minute were also demonstrated for the amide couplings, which is the most utilized reaction type in the pharmaceutical industry.

Water as the reaction medium in organic chemistry: from our worst enemy to our best friend

“…The addition of HPMC to water (0.1–2 wt%) leads to remarkable rate enhancements, with reaction times on the order of minutes, and in some cases, even seconds. 73 The homogeneity of the reaction mixture was also greatly improved, which is important for scale up processes. The mechanism is unclear but the presence of small hydrophobic pockets within a polymer matrix might favor the reaction, via the hydrophobic effect ( Fig.…”

Organic synthesis in Aqueous Multiphase Systems — Challenges and opportunities ahead of us

“…More recently, water chemistry enabled by polymers has led to several remarkable advances [9,10,56,57] with researchers at Abbvie, led by Braje, who, in partnering with Handa, demonstrated spectacular rate enhancements during reactions performed in water. The key additive is the readily available and biodegradable polymer HPMC.…”

“…We were later followed by several other chemical and pharmaceutical organizations, evidenced by the formation of working groups within the ACS Green Chemistry Pharmaceutical Roundtable, and interest also grew in parallel within the academic field, thus leading to rapid development and successes in a plethora of transformations. Remarkable alternative approaches relying this time on hydrophobic effects generated by suitable polymers also appeared as viable options [9,10]. We have witnessed the impact of surfactant-based compartmentalization reaction mixtures (media) to enable more selective and productive transformations compared with conventional organic solvents because of the mild conditions associated with the (supra)molecular arrangement of the excipients, that is, their aggregate formation and microscopic phase separation.…”

Teflon Magnetic Stirring Capsules (TMSC) as a Practical and Reusable Delivery System for Sensitive Reagents and Catalysts

“…Although numerous technical solutions exist for handling such chemicals, these can be expensive or may require a certain degree of expertise and, consequently, slow down the pace of discovery [1–3] . Driven by the needs to provide practical and operationally simple solutions to the practitioners of organic synthesis, the delivery of sensitive reagents or catalysts to a chemical reaction has gained important momentum in recent years [4–12] . In this context, the hydrophobic paraffin wax capsules developed by Buchwald and coworkers represent a turning point [13,14] .…”