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Developing methods to cross-bridge pentaazamacrocycles

Developing methods to cross-bridge pentaazamacrocycles. Timothy J. Hubin , Allen G. Oliver, Jeanette A. Krause, Timothy J . Prior Prior. Ethylene Cross-Bridged Tetraazamacrocycles. Bencini , Ciampolini , Mecheloni , et. al. 1994, Supramol . Chem. Weisman 1990, JACS.

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Developing methods to cross-bridge pentaazamacrocycles

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  1. Developing methods to cross-bridge pentaazamacrocycles Timothy J. Hubin, Allen G. Oliver, Jeanette A. Krause, Timothy J. Prior Prior

  2. Ethylene Cross-Bridged Tetraazamacrocycles • Bencini, Ciampolini, Mecheloni, et. al. 1994, Supramol. Chem. • Weisman 1990, JACS

  3. Topologically constrained like a cryptate • Short cross-bridge rigidifies the macrocycle • Tunable: ring size and Me group can be modified • Simple, high yielding organic synthesis • Leaves octahedral metal ions coordinatively unsaturated • Neutral ligand giving charged complexes • Resistant to oxidation The “Busch Catalyst”: A Remarkably Diverse Oxidation Catalyst • Ethylene Cross-Bridged Cyclams are successful tight-binding ligands • Mn(Bcyclam)Cl2 identified as active oxidation catalyst • AlkeneEpoxidation • Hydrogen Atom Abstraction US Patents: 6,218,351 B1; 6,387,862 B2; 6,606,015 B2; 6,906,189; 7,125,832 Hubin, et al., JACS, 2000, 2512. Hubin, et al., Inorg. Chem., 2001, 435. Hubin, et al., Inorg, Chim. Acta, 2003, 76.

  4. Kinetics of Decomplexation • Ethylene cross-bridged tetraazamacrocycles are proton sponges • Formation constants (Thermodynamic Stability) by potentiometric titrations difficult because ligand never loses last proton in water • Kinetic Stability of copper complexes often studied by observing UV-Vis peak in strongly acidic conditions and calculating Pseudo 1st Order Rate Constant and/or Half-Life for Decomplexation Cu(Me2EBC)2+ in 5M HCl at 90 oC

  5. Kinetics of Decomplexation

  6. The Sophistication of Cross-Bridged Tetraazamacrocyles • N-Functionalized • C-Functionalized • Bis- and Tris • Bio-Conjugated

  7. Why Ethylene Cross-Bridged Pentaazamacrocycles? • Additional macrocyclic Nitrogen donor might make complexes more stable • Cross-bridged 1,4,7,10,13-pentaazacyclopentadecane chemistry has not been explored • We should make the complexes to compare them to the tetraaza versions • Analogues of Bridged Pentaazamacrocycles Transition Metal Complexes 1) Hancock, J. Chem. Soc. Chem. Commun. 1987, 1129. • Side-bridged ligand structure published, but not synthetic details • No details of complexes 2) Guilard, Perkin 1, 1998, 639. Caravan, Mol. Pharm. 2014, 617. • Pycup pyridine cross-bridged cyclam • Copper complex crystallized Caravan

  8. 3) Jones/Hubin, Inorg. Chem. 2015, 54, 2221. Shircliff/Hubin, Inorg. Chem. Comm. 2105, 59,71. • Pyridine pendant armed cross- and side-bridged cyclams • Pentadendate, but not bridged pentaazamacrocycle • Pendant arm actually speeds up dissociation of Metal Ion 4) Fortier, McAuleyInorg. Chem. 1989, 28, 655. “In aqueous solution, both the [NiII(L1)(H2O)]2+ and [CuII(L1)]2+ complexes are exceptionally acid-stable. Both complexes may be recrystallized from hot 1 M HClO4, and their respective UV-Vis spectra are identical in both H2O and in 4 M HClO4. Furthermore, the latter spectra show no decomposition after 14 days at room temperature.”

  9. Making Cross-Bridged Pentaazamacrocycles • Synthetic Strategy 1: Apply Weisman’s Glyoxal Template to 15aneN5 • Requires 15aneN5 The following improvements on the literature route (Sherry, Synthetic Communications, 1999, 2817.): 1. Convenience: several manipulations reported to require Schlenk (under N2) techniques were performed in air 2. Drying time: we were able to skip a vacuum drying step that took a total of 2-3 days, and proceed in the presence of the remaining water with little effect on yield. 3. Extraction time: we were able to replace a continuous (Soxhlet) extraction of 5 day with an extraction of the wet product through the frit with hot acetonitrile (~30 min) with little effect on yield. 4. Our improved procedure has been adopted by ARK Pharm (an independent chemical supplier). They failed to prepare the compound following literature procedures multiple times over 6 months. Upon adoption of our procedure, they produced 10g in 3 weeks.

  10. Metal Complexes of Un-Bridged 15aneN5 Only a handful of transition metal complexes have been synthesized and fully characterized with 15aneN5—12 crystal structures in CSD with Mn2+, Fe2+, Ni2+, Cu2+, Zn2+. Metal complexes of Cr3+, Mn2+, Fe3+, Co3+, Ni2+, Cu2+, Zn2+, and Ru2+ were synthesized and fully characterized, including the crystal structures shown here. [CuII(15aneN5)]2+ [ZnII(15aneN5)]2+ [MnII(15aneN5)(H2O)]2+ [CrIII(15aneN5)Cl]2+ [NiII(15aneN5)(OAc)]+ [RuII(15aneN5-Diimine)Cl]+ [FeIII(15aneN5-imine)(OAc)2]+ [CoIII(15aneN5)Cl]2+ [CoIII(15aneN5)(CoCl4)]+ [CoIII(15aneN5)Cl]Cl2· H2O

  11. The Glyoxal Condensate with 15aneN5 (Tetracycle) LH+ = 238 C H N Calc 56.90 10.07 25.92 Found 57.17 10.05 26.05

  12. The Alkylated Tetracycle C H N Calc 31.54 6.18 12.26 Found 31.86 6.01 11.74

  13. Reduction to the Me3-CB-15aneN5 LH+ = 283

  14. Transition Metal Complexes of Me3-CB-15aneN5

  15. Indications of a rich, complicated organic chemistry

  16. Synthetic Strategy 2: Winchell (Concat, Inc.), 1996, US Pat. 5,874,573 TACN MW = 241.38 MW = 549.75 C H N Calc55.717.2312.49 Found 56.076.9011.95 Advantages of this method: Greatly shortens the syntheses from glyoxal route Greatly improve the yields Improves purity Produces a flexible cross-bridged “parent” C H N Calc41.52 7.8118.55 Found41.738.1817.98 *We synthesized by glyoxal route using benzylation/debenzylation

  17. Transition Metal Complexes of H3-CB-15aneN5 CuLCl+ CuL+

  18. Kinetic Stability of [Cu(H3-CB-15aneN5)]2+

  19. Synthetic Strategies for Different Ring Sizes • Glyoxal Strategies • TACN Strategy

  20. Past Contributors to this project: Anthony Shircliff Abbagale Bond Current research group: Elisabeth Allbritton Faith Okorocha Megan Whorton Phillip Nguyen David Tresp Angelica Manning James Nimsey Makynna Koper Tanner Tadlock Taleigh Davis Funding ACS-PRF NSF OK-LSAMP OCAST NIH OK-INBRE Dreyfus Foundation SWOSU Dept. of Chemistry COLLABORATORS Jeanette Krause (U. Cincinnati) Allen Oliver (Notre Dame) Tim Prior (U. of Hull) Steve Archibald (U. of Hull) Ben Burke (U. of Hull) Kayla Green (TCU) Ashish Ranjan (Ok. St. U.) Guochuan Yin (HuazhongU.) Dominique Schols (K.U. Leuven) Faruk Khan (U. of Charleston) Babu Tekwani (Southern Research) Doug Linder (SWOSU)

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