Research

Overview

Our group applies mechanistic principles to develop new concepts in catalysis.  Our goal is to advance new conceptual strategies for catalytic reactions to provide novel solutions to problems ranging from materials design, energy conversion, selective oxidation reactions, to drug delivery. Areas of focus include the development of organic or organometallic catalysts for the synthesis of macromolecules with novel chemical, physical or biological properties, selective catalytic (including electrocatalytic) redox reactions, and the application of new in-situ techniques for interrogating catalytic reactions.

 

Organocatalytic Polymerization Reactions

Urea and thiourea anions for fast and selective ring-opening polymerizations

Our group has pioneered the design and application of organic catalysts for polymer chemistry. In collaboration with Dr. James Hedrick of IBM, we have developed a platform of organic catalysts that exhibit activities that rival the most active metal-based catalysts and, by virtue of their novel mechanisms of enchainment, provide access to polymer architectures that are difficult to access by conventional approaches.  Significant achievements include organocatalytic strategies for the synthesis of polyesters, polycarbonates, polysiloxanes, and polyacrylates, the chemical recycling of commodity polyesters, the use of metal-free polymers to template inorganic nanostructures for microelectronics applications, and the generation of new families biocompatible polymers for biomedical applications. The development of new families of organic polymerization catalysts have stimulated worldwide interest in this strategy for the generation of new families of biodegradable materials.

references

Lin, B.; Waymouth, R. M. “Urea Anions: Simple, Fast, and Selective Catalysts for Ring-Opening Polymerizations” J. Am. Chem. Soc., 2017, 139(4), 1645–1652, doi: 10.1021/jacs.6b11864.

Zhang, X.; Jones, G. O.; Hedrick, J.L.; Waymouth, R. M. “Fast and Selective Ring-Opening Polymerization by Alkoxides and Thioureas ” Nature Chem. 2016, 8, 1047-1053. doi: 10.1038/nchem.2574.

Kiesewetter, M. K.; Shin, E. J.; Hedrick, J. L.; Waymouth. R. M. “Organocatalysis: Opportunities and Challenges for Polymer Synthesis” Macromolecules, 2010, 43, 2093-2107. doi: 10.1021/ma9025948 DOI: http://dx.doi.org/10.1021/ma9025948

Kamber, N. E.; Jeong, W.; Waymouth, R. M.; Pratt, R. C.; Lohmeijer, B. G. G.; Hedrick, J. L. “Organocatalytic Ring-Opening Polymerization” Chem. Rev. 2007, 107, 5813-5840.  DOI: http://dx.doi.org/10.1021/cr068415b

 

Functional Biodegradable Polymers for Biomedical Applications

Functionalized polymer for mRNA delivery (CART: Charge-Altering Releasable Transporters)

We have exploited the high functional tolerance of organic catalysts to generate several families of biodegradable functional polyesters and polycarbonates for biomedical applications.  In collaboration with the Wender group, we have generated a family of functionalized polymers that mimic the function of cell-penetrating peptides for the delivery of drugs and probes and nucleic acids into cells, as well as injectable hydrogels and self-assembled nanoparticles for drug delivery.  We have discovered a general, safe, and remarkably effective concept for RNA delivery based on a new class of synthetic cationic materials, Charge-Altering Releasable Transporters (CARTs). These new materials operate by an unprecedented mechanism for the delivery and transcription of proteins in both cell culture and live animals.  The CARTs behave as “physical property chameleons” changing from polycations that complex and protect RNA, to neutral species that release RNA upon cell entry.

references

McKinlay, C. J.; Vargas, J. R.; Blake, T. R.; Hardy, J. W.; Kanada, M.; Contag, C. H.; Wender, P. A.; Waymouth, R. M. “Charge-altering Releasable Transporters (CARTs) for the delivery and release of messenger RNA in living animals” Proc. Nat. Acad. Sci., Proc. Natl. Acad. Sci., 2017, 114, E448-E456, online publication 01/09/17, doi: 10.1073/pnas.1614193114.

McKinlay, C. J., Waymouth, R. M.; Wender, P.A. “Cell-Penetrating, Guanidinium-Rich Oligophosphoesters: Effective and Versatile Molecular Transporters for Drug and Probe Delivery”, J. Am. Chem. Soc., 2016, 138, 3510-3517.

Geihe, E. I.; Cooley, C. B.; Simon, J. R.; Kiesewetter, M. K.; Edward, J. A.; Hickerson, R. P., Wender, P. A. “Designed guanidinium-rich amphipathic oligocarbonate molecular transporters complex, deliver and release siRNA in cells” Proc. Nat. Acad. Sci. 2012, 109, 13171-13176.

Cooley, C. B.; Trantow, B. M.; Nederberg, F.; Kiesewetter, M. K.; Hedrick, J. L.; Waymouth, R. M.; Wender, P. A. “Oligocarbonate Molecular Transporters: Oligomerization-Based Syntheses and Cell-Penetrating Studies” J. Am. Chem. Soc. 2009, 131, 16401-16403.

 

Selective Catalytic Oxidation of Complex Polyols

The cationic Pd complex is a versatile catalyst forthe selective aerobic oxidation of primary and secondary alcohols, vicinal diols, and polyols.

Our group discovered a new palladium catalyst that exhibits a remarkable selectivity for the aerobic oxidation of unprotected diols and complex polyols to hydroxyketones. The chemoselective oxidation of glycerol affords a selective catalytic strategy for the synthesis of dihydroxyacetone; oxidative lactonization of a-w diols affords new lactone monomers, and more complex polyols such as unprotected glycosides are oxidized selectively to the 3-ketoses.

references

Chung, K., Waymouth, R.M. “Selective Catalytic Oxidation of Unprotected Carbohydrates” ACS Catalysis, 2016, 6, 4653-4659.

Blake, T.; Waymouth, R. M. ” Organocatalytic Ring Opening Polymerization of Morpholinones:  New Strategies to Functionalized Polyesters ” J. Am. Chem. Soc., 2014, 136, 9252-9255.

Chung, K.; Banik, S. M.; De Crisci, A. G.; Pearson, D. M.; Blake, T.; Olsson, J. V.; Ingram, A. J.; Zare, R. N.; Waymouth, R. M. “Chemoselective Pd-catalyzed Oxidation of Polyols: Synthetic Scope and Mechanistic Studies” J. Am. Chem. Soc., 2013, 135, 7593-7602.  doi: 10.1021/ja4008694

Painter, R. M.; Pearson, D. M.; Waymouth, R. M. “Selective Catalytic Oxidation of Glycerol to Dihydroxyacetone” Angew. Chem., Int. Ed. 2010, 49, 9456-9459

 

High Resolution in-situ Mass Spectrometry: A New Window into Homogeneous Catalysis

Ions observed during hydrogen peroxide disproportionation

In collaboration with Prof. Richard Zare, we are utilizing and developing new methods in ambient mass spectrometry to interrogate the mechanism of catalytic reactions.  These powerful new methods, when combined with kinetic and mechanistic studies, provide new insights on the speciation of catalytic intermediates.

references

Davis, D.C.; Walker, K. L.; Hu, C.; Zare, R. N.; Waymouth, R. M.; Dai, M. “Catalytic Spirolactonization of Hydroxycyclopropanols: Total Synthesis of Levantenolides”  J. Am. Chem. Soc., 2016, 138, 10693-10699.  doi:10.1020/jac.6b06573.

Ingram, A. J.; Walker, K. L.; Zare, R. N.; Waymouth, R. M. “Catalytic Role of Multinuclear Palladium-Oxygen Intermediates in Aerobic Oxidation Followed by Hydrogen Peroxide Disproportionation” J. Am. Chem. Soc. 2015, 137, 13632-13646, doi: 10.1021/jacs.5b08719.

Ingram, A. J.; Solis-Ibarra, D.; Zare, R. N.; Waymouth, R. M., “Trinuclear Pd3O2 Intermediate in Aerobic Oxidation Catalysis” Angew. Chem., Int. Ed., 2014, 53, 5648-5652. dx.doi.org/10.1002/anie.201400134

Chung, K.; Banik, S. M.; De Crisci, A. G.; Pearson, D. M.; Blake, T.; Olsson, J. V.; Ingram, A. J.; Zare, R. N.; Waymouth, R. M. “Chemoselective Pd-catalyzed Oxidation of Polyols: Synthetic Scope and Mechanistic Studies” J. Am. Chem. Soc., 2013, 135, 7593-7602.  doi: 10.1021/ja4008694

Perry, R. H.; Chingin, K.; Brownell, K. R.; Waymouth, R. M.; Cahill, T. J.; Zare, R. N. “Transient Ru-Methyl Formate Intermediates Generated in Noyori Transfer Hydrogenation Catalysis” Proc. Nat. Acad. Sci. 2012, 109(7), 2246-2250. doi:10.1073/pnas.1118934109

 

Electrocatalysis for Energy-Efficient Fuel Conversion

General scheme for electrocatalytic alcohol oxidation with a ruthenium catalyst

The energy-efficient conversion of chemical fuels into useful forms of energy is arguably the most important chemistry to the future of humankind. Electrocatalysis provides an energy-efficient strategy for the removal of high free energy electrons stored in chemical fuels, or the storage of electrical energy as liquid fuels.  Our goal is to develop electrocatalytic strategies to utilize alcohols as viable energy storage carriers for electrochemical energy conversion.  We are investigating highly active transfer-hydrogenation catalysts as potential electrocatalysts, as these systems should provide energy-efficient pathways for reversible electro-hydrogenation or -dehydrogenation reactions.  Metal hydrides are key intermediates in transfer hydrogenation reactions, but the electrochemical generation of metal hydrides or electrochemical oxidation of metal hydrides are energetically inefficient as they typically require multiple stepwise electron and proton transfers.  We are investigating the electrocatalytic behavior of transfer hydrogenation catalysts as well as investigating new strategies for the electrochemical generation and oxidation of metal hydrides.

references

Waldie, K.M.; Flajslik, K.R.; McLoughlin, E.; Chidsey, C.E.D.; Waymouth, R. M. “Electrocatalytic Alcohol Oxidation with Ruthenium Transfer Hydrogenation Catalysts” J. Am. Chem. Soc., 2017, 139(2), 738-748,  doi: 10.1021/jacs.6b09705.

Ramakrishnan, S.; Waldie, K.M.; Warnke, I.; De Crisci, A. G.; Batista, V.S.; Waymouth, R. M.; Chidsey, C. E. D. ” Experimental and Theoretical Study of CO2 Insertion into Ruthenium Hydride Complexes” Inorg. Chem. 2016, 55, 1623-1632, doi: 10.1021/acs.inorgchem.5b02556.

Buonaiuto, M.; De Crisci, A. G.; Jaramillo, T. F.; Waymouth, R. M. “Electrooxidation of Alcohols with Electrode-Supported Transfer Hydrogenation Catalysts”  ACS Catal. 2015, 5, 7343-7349, doi:10.1021/acscatal.5b01830.

Brownell, K. R.; McCrory, C. C. M.; Chidsey, C. E. D.; Perry, R. H.; Zare, R. N.; Waymouth. R. M. “Electrooxidation of Alcohols Catalyzed by Amino Alcohol Ligated Ruthenium Complexes, J. Am. Chem. Soc., 2013, 135, 14299-14305. dx.doi.org/10.1021/ja4055564.

 

Zwitterionic Ring-Opening Polymerization: Cyclic Macromolecules

The +/- charges keep both ends of the polymer chain in close proximity to counter entropy.

We have pioneered the development of a new synthetic method to generate large macrocyclic macromolecules. The Zwitterionic Ring-Opening Polymerization (ZROP) strategy entails the use of potent nucleophiles to mediate the ring-opening polymerization of strained cyclic monomers;  the resulting zwitterionic growing chains can cyclize to generate large cyclic macromolecules.  This new polymerization strategy provides access to large quantities of cyclic polymers, which are of considerable theoretical interest as the properties of cyclic macromolecules (including cyclic DNA) differ considerably from linear chains in ways that still remain poorly understood.

references

Chang, Y. A.; Rudenko, A. E.; Waymouth, R. M. “Zwitterionic Ring-Opening Polymerization of N-substituted 8-membered Cyclic Carbonates to Generate Cyclic Poly(carbonate)s” ACS Macro. Lett. , 2016, 5, 1162-1166. doi:  10.1021/acsmacrolett.6b00591.

Chang, Y.; Waymouth, R. M. “Ion-pairing Effects in the Zwitterionic Ring-Opening Polymerization of Valerolactone”  Polym. Chem., 2015, 6, 5212-5218. doi: 10.1039/c5py00662g.

Brown, H. A.; Waymouth, R. M. “Zwitterionic Ring-Opening Polymerization for the Synthesis of High Molecular Weight Cyclic Polymers” Acc. Chem. Res. 2013, 46, 2585-2596.

Culkin, D. A.; Jeong, W. H.; Csihony, S.; Gomez, E. D.; Balsara, N. R.; Hedrick, J. L.; Waymouth, R. M. “Zwitterionic polymerization of lactide to cyclic poly(lactide) by using N-heterocyclic carbene organocatalysts” Angew. Chem., Int. Ed. 2007, 46, 2627-2630.

 

Dynamic Covalent Materials with Novel Properties

Self-assembly and reversible crosslinking of dithiolane-containing polymers

We have exploited the versatile behavior of 1,2-dithiolanes to generate dynamic covalent materials whose emergent properties derive from cooperative self-assembly and the reversible cascade polymerization of 1,2-dithiolanes. Hydrogels derived from ambiphilic dithiolane-containing block copolymers exhibit dynamic properties that are responsive to pH, temperature, and a thiol-capping reagent such as maleimide. The versatile chemistry of 1,2-dithiolanes leads to dynamic and responsive materials where the rates and equilibria of thiol-disulfide exchange of 1,2-dithiolanes can be modulated to control the bulk material properties.

references

Zhang, X., Waymouth, R. M. “1,2 Dithiolane Derived Dynamic, Covalent Materials: Cooperative Self-assembly and Reversible Crosslinking”  J. Am. Chem. Soc.2017139(10), 3822-3833. doi: 10.1021/jacs.7b00039.

Barcan, G. A.; Zhang, X.; Waymouth, R. M. “Covalent Adaptable Networks derived from Dithiolanes: Deformable Hydrogels.” J. Am. Chem. Soc. 2015, 137, 5650-5653. doi: 10.1021/jacs.5b02161.

 

Sustainable Materials for the 21st Century

We are developing both chemical and microbial strategies for generating sustainable materials for the 21st century, where materials are designed not only for function and performance, but incorporate into their structural design means for recovery and reuse.  In collaboration with Jim Hedrick of IBM and Craig Criddle of Stanford, we have developed chemical and microbial catalytic chemical recycling strategies for plastics, and new strategies for generating plastics from non-traditional resources, including waste streams.

references

Myung, J.; Flanagan, J.C.A.; Waymouth, R. M.; Criddle, C.S. “Methane- or Methanol-Oxidation Dependent Synthesis of Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) by Obligate Type II Methanotrophs” Process Biochem.  2016, 51, 561-567. dx.doi.org/10.1016/j.procbio.2016.02.005.

Flanagan, J.C.A.; Myung, J.; Waymouth, R. M.; Criddle, C. S. “Poly(hydroxyalkanoate) recycling: a combined chemical-biological approach utilizing methane and methanotrophic bacteria” Chemistry Select20161, 2327-2331.  doi: 10.1002/slct.201600592.

Myung, J.; Strong, N.I.; Galega, W.M.; Sundstrom, E.R.; Flanagan, J. C. A.; Woo, S-G.; Waymouth, R. M.; Criddle, C. S. “Disassembly and reassembly of polyhydroxyalkanoates: Recycling through abiotic depolymerization and biotic repolymerization” Bioresource Technol. 2014, 167-174.  dx.doi.org/10.1016/j.biortech.2014.07.105.

Fukushima, K.; Coulembier, O.; Lecuyer, J. M.; Al-Megren, H. A.; Mohammad, A.; Alsewailem, F. D.; McNeil, M. A.; Dubois, P.; Waymouth, R. M.; Horn, H. W.; Rice, J. E.; Hedrick, J. L. “Closing the Loop on Recycling: Organocatalytic Depolymerization of Poly(ethyleneterephthalate)”  J. Polym. Sci. Part A: Polym. Chem., 2011 49, 1273-1281.  doi:10.2002/pola.24551.

 

Funding

We are grateful for the generous support of several funding agencies:

The National Science Foundation under Grant Nos. CHE-1565947, CHE-1607092, DMR-1407658; the Department of Energy under Grant No. DOE DESC0005430; the Office of Naval Research under Grant No. N0014-14-1-0551; and the Stanford Woods Institute for the Environment.

Any opinions, findings, conclusions, or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation, the Department of Energy, or the Office of Naval Research.