Mechanistic investigation and optimization of aerobic palladium catalysts and base-triggered degrading poly(aminoester)s

Selective oxidations constitute an important class of reactions for the synthesis of fine and commodity chemicals, and it is ideal when O2 from the air can be utilized as the terminal oxidant from cost and environmental impact points of view. Palladium(II) neocuproine acetate triflate dimer (where neocuproine = 2,9-dimethyl-1,10-phenanthroline) has previously been shown to catalyze the selective alcohol oxidation of complex polyol substrates using air as the oxidant, but the turnover numbers (TONs) under aerobic conditions were low. A number of strategies to improve aerobic TON were developed based on a mechanistic understanding of catalyst deactivation pathways. Our data support a radical mechanism in which initial H-atom abstraction from the benzylic positions of the neocuproine ligand leads to catalyst death. In line with this theory, ligand modifications designed to retard H-atom abstractions and the use of H-atom donors as additives increase TON significantly. The aerobic oxidations were also hampered by Pd black formation, which we found could be mitigated by the addition of stoichiometric quantities of styrene. Further studies suggested a novel mechanism for styrene's role in this system that involves a rare example of O2 insertion into a Pd--alkyl bond. Together these strategies enabled the selective aerobic oxidation of polyols on the preparative scale using 0.25-1.5 mol% Pd, a significant improvement over previous work. Future directions would include generalizing the O2 insertion reaction to other Pd systems. A separate project was motivated by the growing interest in self-degrading polymers as a distinct class of stimuli-responsive materials that can release cargoes on-demand, such as for drug delivery applications. It was previously shown that a particular cationic poly(α-aminoester), designated the α-N polymer, promotes highly efficient mRNA delivery into a variety of cell lines. We propose that it is able to do so because of its rapid (within minutes at pH 7.0) and unique degradation characteristics upon exposure to base, which include the relatively selective production of a small molecule diketopiperazine (DKP) via alternating cyclization reactions. We investigated this degradation mechanism in depth and concluded that the source of selectivity is an ester-activating effect arising from an N-hydroxyethyl group in a reaction intermediate. A number of structurally related cationic poly(aminoester)s were synthesized that also degrade with sharp pH-dependence when treated with base. Three of them (the α-Gly, α-Me, and β-N polymers) in particular were studied in detail. Stochastic kinetics simulations and experimental model system studies proved to be highly valuable for elucidating their degradation mechanisms. Relatively small changes to the original α-N structure were shown to have large effects on the rates and rate laws of polymer degradation, and these properties can be further tuned by making copolymers of varying composition. With adjustable rates of degradation, these biodegradable polymers have potential applications in many fields.

Keywords: Chemistry.
Advisor: Waymouth Robert M. 
Trost Barry M. 
Wender Paul A.