Efficient catalysts and processes for scalable polymer synthesis

The goal of my graduate research is to develop new catalysts and processes for ring-opening polymerizations (ROP). ROP is one of the most powerful methods for generating polyesters and polycarbonates which are foundational materials to the modern-day society with diverse applications ranging from consumer products to therapeutic materials. In the course of my graduate work, I have invented new catalysts, developed new polymerization strategies and applied them to continuous-flow for automated high-throughput library synthesis, drastically accelerating the process of materials synthesis and discovery. While organocatalysts have streamlined the ROP workflow compared to metal-based catalysts, typical polymerizations can still take hours to days. I discovered a class of urea anions that are up to 106 times more active than the benchmark DBU/thiourea cocatalysts. By varying the electronic substituents, the activity of the urea anion can be tuned to range over almost 4 orders of magnitude, where more electron-rich anions led to faster reactions. With the appropriate catalysts, the controlled polymerization of a wide range of cyclic ester and carbonate monomers can reach high conversions within a few seconds. This family of catalyst is simple to prepare and use and has been widely adopted by many other members of the lab and initiated several new areas of research. To understand the relationship of the new class of urea anion catalysts with the classic base/H-bond donor cooperative system, I investigated the chemical space of bases and H-bond donors over a wide pKa range and uncovered several new series of cocatalyst pairs. Mechanistically, it was found that in the cooperative system, stronger bases lead to faster reactions, ultimately converging to the urea anion system. For a given base, the maximal activity is observed when the pKa of the urea and the base-H+ are similar, which is a result of the two competing mechanisms (anion vs cooperative). These trends and the critical role of pKa provide guidelines for the rational design of new catalysts. From these finding, I screened other chemical groups within the useful pKa range to expand the anion catalyst space, discovering that certain structural motifs, such as bis-indole and squaramide, when deprotonated lead to very controlled polymerizations, and that deprotonation is in fact a general approach to creating new classes of ROP catalysts. As a modern approach to batch processes, continuous-flow polymerization offers many advantages, such as rapid mass and heat transfer. The unique combination of the highly active urea anion catalysts and the rapid mixing of flow enables polymerizations that are too fast for batch processes, such as one with a reaction time of 6 ms (TOF = 24,000,000 h-1). A long-standing challenge in preparing well-defined block copolymers is when the monomers have widely different reactivities, such that the volume of the flow reactor segments for the individual blocks can differ by over 4 orders of magnitude, making the preparation of some polymers non-trivial. This problem was solved with a facile catalyst switch of urea anions via a simple proton transfer, where catalysts with the appropriate activities can be matched with each monomer. By coupling continuous-flow with automation, I built an automated system for the rapid preparation of homopolymer and diblock copolymer libraries (i.e. making 100 challenging diblock copolymers in 9 min) to demonstrate the high-throughput ability of the platform for accelerated material library synthesis and optimization. Continuous-flow also provides a scale-up solution for target hits, for which ~20 g of a model polymer can be produced in 40 s. For monomers that thermodynamically do not polymerize at room temperature, their polymerization can be driven by lowering the temperature. Such polymerizations are only possible with the high activity and functional group tolerance of the urea anions, which enabled the synthesis of a series of new polymers for applications such as self-immolative materials for drug delivery.

Keywords: Chemistry.
Advisor: Waymouth Robert M. 
Herschlag Daniel 
Wender Paul A.