I. C–H Functionalization

The conversion of carbon-hydrogen (C–H) bonds into new functional groups represents a powerful strategy for the construction of organic molecules. The C–H functionalization field has transformed the way that chemists approach the synthesis of natural products and bioactive molecules, enabling fast and efficient derivatization. However, despite tremendous recent progress, selective C–H functionalization can still only be achieved in the context of a limited set of organic substrates and types of C–H sites. Our group is focused on the development of new transition metal-catalyzed C–H functionalization methods to enable the selective C–H functionalization of a variety of different substrates, ranging from simple, commodity chemicals such as benzene and methane to complex natural products and pharmaceuticals. Our work in this area includes:

Key references:

  1. Mbofana, C. T.; Chong, E.; Lawniczak, J.; Sanford, M. S. "Iron-Catalyzed Oxyfunctionalization of Aliphatic Amines at Remote Benzylic C–H Sites," Org. Lett. 201618, 4258-4261.
  2. Cook, A. K.; Schimler, S. D.; Matzger, A. J.; Sanford, M. S. "Catalyst-Controlled Selectivity in the C–H Borylation of Methane and Ethane,” Science 2016,351, 1421-1424.
  3. Topczewski, J. T.; Cabrera, P. J.; Saper, N. I.; Sanford, M. S. "Palladium-Catalysed Transannular C–H Functionalization of Alicyclic Amines,”Nature 2016531, 220-224.
  4. Lee, M.; Sanford, M. S. "Platinum-Catalyzed, Terminal-Selective C(sp3)–H Oxidation of Aliphatic Amines,” J. Am. Chem. Soc. 2015137, 12796-12799.

II. Organometallics

A second research area in the Sanford laboratory focuses on the design, synthesis, and reactivity studies of high valent group ten organometallic complexes (e.g., Pd(IV), Ni(III), Ni(IV) complexes). In particular, our research probes the accessibility of these complexes and their ability to mediate challenging bond-forming reactions. These species have been implicated as reactive intermediates in a variety of catalytic transformations including C–H bond functionalization, alkene difunctionalization, and cross-coupling reactions. However, their transient nature has hindered definitive characterization of their roles in catalysis. Our group rationally designs and synthesizes model complexes of these catalytic intermediates in order to directly interrogate their reactivity towards catalytically-relevant bond-forming reactions. Ultimately, a fundamental understanding of these organometallic reactions informs the optimization of known catalytic transformations and drives the development of novel catalytic reactions. Our interests in this field include:

Key references:

  1. Bour, J. R.; Camasso, N. M.; Sanford, M. S. "Oxidation of NiII to NiIV with Aryl Electrophiles Enables Ni-Mediated Aryl–CF3 Coupling,” J. Am. Chem. Soc. 2015137, 8034-8037.
  2. Camasso, N. M.; Sanford, M. S. "Design, Synthesis, and Carbon-Heteroatom Coupling Reactions of Organometallic Nickel(IV) Complexes,” Science2015347, 1218-1220.
  3. Pérez-Temprano, M. H.; Racowski, J. M.; Kampf, J. W.; Sanford, M. S. "Competition Between sp3-C–N vs sp3-C–F Reductive Elimination from PdIV Complexes,” J. Am. Chem. Soc. 2014136, 4097-4100.
  4. Maleckis, A.; Kampf, J. W.; Sanford, M. S. "A Detailed Study of Acetate-Assisted C–H Activation at Palladium(IV) Centers,” J. Am. Chem. Soc. 2013135, 6618-6625.

III. Fluorination

Fluorine-containing molecules are important in the agrochemical, pharmaceutical, and medical imaging sectors, as carbon-fluorine bonds are present in >25% of agrochemicals and pharmaceuticals and >90% of positron emission tomography imaging agents. Despite the prevalence of fluorinated organic molecules, there are still very limited synthetic methods for the selective formation of carbon-fluorine bonds. Challenges in this area include: (1) the requirement for forcing conditions due to the low solubility of alkali metal fluorides in organic solvents; (2) the dearth of metal catalysts for selective C–F coupling reactions; (3) the limited substrate scope of existing C–F coupling reactions; and (4) the slow rate of most fluorination methods, which is problematic for time-sensitive applications like radiofluorination. Our research in this area is focused on addressing these challenges through the development of novel selective, mild, and inexpensive fluorination processes. We also pursue applications of these new methods to the radiofluorination of biologically relevant molecules in collaboration with Prof. Peter Scott (UM Department of Radiology) and to the fluorination of agrochemicals, in collaboration with Dr. Douglas Bland (Dow Chemical Company).

Key references:

  1. Makaravage, K. J.; Brooks, A. F.; Mossine, A. V.; Sanford, M. S.; Scott, P. J. H. "Copper-Mediated Radiofluorination of Arylstannanes with [18F]KF,” Org. Lett. 2016, ASAP.
  2. Schimler, S. D.; Ryan, S. J.; Bland, D. C.; Anderson, J. E.; Sanford, M. S. "Anhydrous Tetramethylammonium Fluoride for Room-Temperature SNAr Fluorination,” J. Org. Chem. 201580, 12137-12145.
  3. Mossine, A. V.; Brooks, A. F.; Makaravage, K. J.; Miller, J. M.; Ichiishi, N.; Sanford, M. S.; Scott, P. J. H. "Synthesis of [18F]Arenes via the Copper-Mediated [18F]Fluorination of Boronic Acids,” Org. Lett. 201517, 5780-5783.
  4. Allen, L. J.; Lee, S. H.; Cheng, Y.; Hanley, P. S.; Muhuhi, J. M.; Kane, E.; Powers, S. L.; Anderson, J. E.; Bell, B. M.; Roth, G. A.; Sanford, M. S.; Bland, D. C. " Developing Efficient Nucleophilic Fluorination Methods and Application to Substituted Picolinate Esters,” Org. Process Res. Dev. 201418, 1045-1054.

IV. Flow Batteries

Efforts to incorporate renewable energy sources such as wind and solar power into the electrical grid have increased the need for reliable and inexpensive energy storage systems. Redox flow batteries offer great promise to meet the demands of grid-scale storage. Flow batteries operating in non-aqueous media are particularly attractive (yet underdeveloped) targets, as they leverage the high cell potentials available in organic solvents such as acetonitrile. These batteries consist of dissolved solutions of redox active organic molecules or transition metal complexes. As such, the design, optimization, and testing of new battery materials is achieved through a combination of synthetic and physical organic chemistry along with electrochemical testing. Our group is focused on addressing several key challenges in the field, including: (i) the development of highly soluble organic and inorganic molecules that undergo reversible redox processes; (ii) the design of redox activate molecules capable of multiple electron transfers to enhance battery capacity; and (iii) the identification of molecules that are stable and persistent in their oxidized or reduced states to increase battery lifetimes. Our research in this area includes:

Key references:

  1. Sevov, C.S.; Brooner, R. E. M.; Chenard, E.; Assary, R. S.; Moore, J. S.; Rodríguez-Lopez, J.; Sanford, M. S. “Evolutionary Design of Low Molecular Weight Organic Anolyte Materials for Applications in Nonaqueous Redox Flow Batteries,” J. Am. Chem. Soc. 2015, 137, 14465-14472.
  2. Cabrera, P. J.; Yang, X.; Suttil, J. A.; Hawthorne, K. L.; Brooner, R. E. M.; Sanford, M. S.; Thompson, L. T. “Complexes Containing Redox Noninnocent Ligands for Symmetric, Multielectron Transfer Nonaqueous Redox Flow Batteries,” J. Phys. Chem. C 2015, 119, 15882-15889.