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. 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
Alkene Epoxidation
Hydrogen Atom Abstraction
US Patents: 6,218,351 B1; 6,387,862 B2; 6,606,015 B2; 6,906,189; 7,125,832
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
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
Half-lives of selected copper(II) complexes in 5 M HCl
Complex
50 oC
90 oC
reference
Ligand Structure
Cu(H2EBC)
-----
11.8 min
Weisman, EJIC
2005, 4829.
Cu(Me2EBC)
7.3 d
79 min
Hubin, Inorg. Chem., 2015, 2221.
Cu(PyMeEBC)
14.7 min
< 2 min
Cu(TETA)
3.2 hour
4.5 min
2005, 4829
Cu(CB-TE2A)
154 hour

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, Caravan, Mol. Pharm. 2014, 617.
Pycup pyridine cross-bridged cyclam
Copper complex crystallized Caravan

8. 4) Fortier, McAuley Inorg. Chem. 1989, 28, 655.
3) Jones/Hubin, Inorg. Chem. 2015, 54, 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, McAuley Inorg. 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+
[CrIII(15aneN5)Cl]2+
[MnII(15aneN5)(H2O)]2+
[NiII(15aneN5)(OAc)]+
[RuII(15aneN5-Diimine)Cl]+
[FeIII(15aneN5-imine)(OAc)2]+
[CoIII(15aneN5)Cl]2+
[CoIII(15aneN5)Cl]Cl2 · H2O
[CoIII(15aneN5)(CoCl4)]+

11. The Glyoxal Condensate with 15aneN5 (Tetracycle)
LH+ = 238
C H N
Calc
Found

12. The Alkylated Tetracycle
C H N
Calc
Found

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

14. Transition Metal Complexes of Me3-CB-15aneN5H N
Calculated
[Cu(C15H33N5)](C2H3O2)0.6(PF6)1.4
PUBLISHABLE
33.24
5.99
11.96
Found GB08
33.03
6.00
11.83
[Ni(C15H33N5)](PF6)2
VERY CLOSE
28.50
5.26
11.08
Found AF08A
29.17
5.19
11.25
[Ru(C15H33N5)Cl](PF6) NH4PF6
24.21
5.07
11.48
Found MG08A
24.10
5.09
11.11
[Cr(C15H33N5)Cl](PF6)2
27.26
5.03
10.60
Found DJ08B
27.47
5.40
11.0 7
[Co(C15H33N5)](PF6)2
CLOSE
28.49
Found DR08B
28.56
5.13
10.39

15. Indications of a rich, complicated organic chemistry

16. Synthetic Strategy 2: Winchell (Concat, Inc.), 1996, US Pat. 5,874,573
TACN
MW =
MW =
C H N
Calc
Found
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
Calc
Found
*We synthesized by glyoxal route
using benzylation/debenzylation

17. Transition Metal Complexes of H3-CB-15aneN5
Calculated
[Fe(C12H27N5)(C2H3O2)2](PF6) . 2CH3OH
CLOSE
27.06
5.39
9.86
Found AS09
27.38
4.95
9.19
[Mn(C12H27N5)(C2H3O2)](PF6) . 1.2NH4PF6
PUBLISHABLE WITH C
24.16
5.04
12.48
Found DT09C
23.84
5.17
12.21
[Ni(C12H27N5)(C2H3O2)](PF6) . 0.4(NH4PF6)
PUBLISHABLE
29.54
5.59
13.29
Found EA09
29.63
5.50
12.97
[V(C12H27N5)Cl](PF6) NH4PF6
CLOSE WITH GC09B
23.58
5.01
13.40
Found GC09B
23.50
5.78
13.36 C H N
Calculated
[Cu(C12H27N5)](C2H3O2)0.4(PF6)1.6
PUBLISHABLE WITH KS09
27.43
5.07
12.50
Found KS09
27.72
4.97
12.10
[Co(C12H27N5)](C2H3O2)(PF6) . 0.5NH4PF6
CLOSE WITH MF09A
28.70
5.51
13.15
Found MF09A
28.88
5.40
12.21
[Zn(C12H27N5)(C2H3O2)1.1](PF6)0.9
CLOSE
33.96
6.08
13.95
Found SC09A
34.53
6.16
12.97
[Cr(C12H27N5)Cl](PF6)2
CLOSE WITH 2APOW
23.29
4.40
11.32
Found TT09-2APOW
24.65
5.35
11.90
CuLCl+
CuL+

18. Kinetic Stability of [Cu(H3-CB-15aneN5)]2+
Half-lives of selected copper(II) complexes in 5 M HCl
Complex
50 oC
90 oC
reference
Ligand Structure
Cu(H2EBC)
-----
11.8 min
Weisman, EJIC
2005, 4829.
Cu(Me2EBC)
7.3 d
79 min
Jones, Inorg. Chem. 2015, 2221
Cu(CB-TE2A)
154 hour
2005, 4829
Cu(15aneN5)2+
< 2 min
This work
[Cu(H3-CB-15aneN5)]2+
160 d
84 d

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

20. SWOSU Dept. of Chemistry
Funding
ACS-PRF NSF OK-LSAMP
OCAST NIH OK-INBRE
Dreyfus Foundation
SWOSU Dept. of Chemistry
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
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 (Huazhong U.)
Dominique Schols (K.U. Leuven)
Faruk Khan (U. of Charleston)
Babu Tekwani (Southern Research)
Doug Linder (SWOSU)