Constrained Ligand Topology and Excellent Kinetic Stability
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ChemComm An ethylene cross-bridged pentaazamacrocycle and its Cu2+ complex: constrained ligand topology and excellent kinetic stability Journal: ChemComm Manuscript ID CC-COM-02-2020-000919.R1 Article Type: Communication Page 1 of 5 Please doChemComm not adjust margins COMMUNICATION An ethylene cross-bridged pentaazamacrocycle and its Cu2+ complex: constrained ligand topology and excellent kinetic stability Received 00th January 20xx, Anthony D. Shircliff,a Benjamin P. Burke, b Dustin J. Davilla,a Gwendolyn E. Burgess,a Faith A. Accepted 00th January 20xx Okorocha,a Alina Shrestha,a Elisabeth M. A. Allbritton,a Phillip T. Nguyen,a Rachael L. Lamar,a a a a a a DOI: 10.1039/x0xx00000x Donald G. Jones, Michael-Joseph Gorbet, Michael B. Allen, John I. Eze, Andrea T. Fernandez, Daniel Ramirez,a Stephen J. Archibald,b Timothy J. Prior,c Jeanette A. Krause,d Allen G. Oliver,e and Timothy J. Hubina* Rigid and topologically constrained ethylene cross-bridged tetraaazamacrocycles have been increasingly utilised for thirty N N N N years as they form remarkably stable transition metal complexes N N N N for catalysis, biomedical imaging, and inorganic drug molecule 1 2 applications. Extending these benefits to pentaazamacrocycles has can be overcome to release the metal ion, as exemplified by been achieved and a first transition metal complex prepared and the cyanide removal of Ni2+ in the classical synthesis of the free structurally characterized. cyclam.2 Additional complex stability must utilise factors beyond Coordination chemists can maximise binding affinity in their complementarity, such as ligand/complex rigidity and metal-ligand complexes by first optimising the first-order increasing ligand topological complexity. These factors can be complementarity factors (Fig. 1) that match ligand and metal grouped into a constraint category1 that unlike ion properties: size, geometric preference, and electronic complementarity factors do not, or at least as of yet have not, 1 2+ 2 properties. Ni(cyclam) exemplifies these factors as the ionic been ultimately exploited. Ethylene cross-bridged 2+ radius of Ni fits nearly perfectly into the cyclam cavity; the tetraazamacrocycles3, 4 represent a successful effort at pushing 8 2+ square planar preference of d Ni coincides with the those boundaries forward, as the short ethylene cross-bridge rigidifies the macrocycle, particularly upon metal ion binding, as well as giving the ligand the topological properties of the classical cryptands (Fig. 2). Numerous studies5, 6 have demonstrated that the first-row transition metal complexes of these ethylene cross-bridged tetraazamacrocycles are among the most kinetically stable towards harsh acidic/basic arrangement of the cyclam’s nitrogen donors; and the conditions of known synthetic transition metal complexes. Yet, Fig. 1. Graphical representation of the factors that can be their tetradentate nature ensures labile coordination sites that optimized to produce increasing metal-ligand kinetic stability. allow reactivity and/or binding ability that has made these 7-21 22-30 Fig. 2. Ethylene cross-bridged cyclam (1) and cyclen (2). complexes favoured for catalytic, biomedical imaging, 31-35 borderline hard/soft characteristics of the metal and ligand and inorganic drug compound applications. lead to favourable bonding. Yet the stability of this complex The ethylene cross-bridged tetraazamacrocycles introduced in the 1990’s have become increasingly popular choices for applications requiring harsh aqueous conditions (365 references identified by SciFinder for an ethylene cross- a. Department of Chemistry and Physics, Southwestern Oklahoma State University, bridged cyclam substructure (1); 684 references identified by 100 Campus Drive, Weatherford, OK, 73096, United States. b. Positron Emission Tomography Research Centre, Department of Biomedical SciFinder for an ethylene cross-bridged cyclen substructure Sciences University of Hull Cottingham Road Hull, HU6 7RX, United Kingdom. (2)). We have added a new class of similarly topologically c. Department of Chemistry, University of Hull, Cottingham Road, Hull HU6 7RX, United Kingdom. constrained azamacrocycle, the ethylene cross-bridged d. Department of Chemistry, University of Cincinnati, 301 Clifton Ct., Cincinnati, OH pentaazamacrocycle, to the toolbox for chemists in need of 45221-0172, United States. e. Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, United States. † Footnotes relating to the title and/or authors should appear here. Electronic Supplementary Information (ESI) available: [details of any supplementary information available should be included here]. See DOI: 10.1039/x0xx00000x Please do not adjust margins Please doChemComm not adjust margins Page 2 of 5 COMMUNICATION Journal Name N N Fig. 5. Structural isomers possible for glyoxal condensation H N N N N with 15aneN5. N N N N NH HN 3 4 N N N N NH N NH N Fig. 3. Me3-CB-15aneN5 (3) and H3-CB-15aneN5 (4). 5 5' constructing stable transition metal complexes to survive Fig. 6. X-ray crystal structure of a byproduct 6’, a methylation under harsh conditions. It is our belief that the ethylene cross- isomer of 6 demonstrating the connectivity of glyoxal bridged pentaazamacrocycles, as exemplified by the novel condensate 5. Selected protons H11 and H12 shown. synthesis and initial structural characterization of (3), as well pentaazamacrocycles, similar to 1 and 2, might be possible. as structural and stability characterization of a first transition Although less efficient than for tetraazamacrocycles due to metal complex presented here (Cu(3)2+), will have a similarly complications from the fifth amine, this route was indeed impactful future. successful (Fig. 4). Further, benzylation of 5 has allowed the As pioneering practitioners of cross-bridged independent synthesis, upon debenzylation of the benzylated tetraazamacrocyclic chemistry, we have seen their increased use and sophistication, which has led us to consider additional opportunities to influence the field. It occurred to us that analogous ethylene cross-bridged pentaazamacrocycles - with an additional nitrogen donor, one open coordination site, and potentially similar stability properties - may provide a analogue of 3, to yield 4 by our new glyoxal route. Production foundation for the development of a new generation of cross- of this tris secondary amine will allow the addition of a variety bridged azamacrocycle coordination chemistry (Fig. 3). of pendant arms to allow the same kind of spread of this ligand Whereas cross-bridge cyclen (2) may be thought of as two into other areas of chemistry. This work will be published fused TACN’s, Me3-CB-15aneN5 (3) is a TACN fused with a later. cyclen. Simple methylation of the unbridged nitrogen atoms The synthesis of 3 may be best thought of as a “one-pot” was our target, as the all-tertiary nitrogen ligands 1 and 2 are approach. Multiple isomers of 5, 6, and 3 are likely present more stable than cross-bridged tetraazamacrocycles with after each step. Yet, it appears either the multiple isomers secondary amines18, 21 that are vulnerable to oxidation which converge to 3, or those that don’t can be removed upon provides a pathway for complex decomposition.36 We also did extraction of 3 into a nonpolar organic solvent, while any not want additional donor-containing pendant arms as we quaternized amine products remain in the aqueous layer. targeted an open coordination site for potential binding of Although the full set of isomers at each step have not been substrate or oxidants for catalysis. fully characterized, the un-optimized “one-pot” approach Initial literature searching found no match for target 3. yields 3 in high purity. However, the tris secondary amine analogue, H3-CB-15aneN5 15aneN5 was synthesized by a modified literature (4) and various tris oxygen-donor pendant armed derivatives method.44 Two potential structural isomers were envisioned designed for biological imaging, have appeared in the patent for literature.37-42 Due to the complexity and lack of details in the the initial condensation of glyoxal with 15aneN5 (Fig. 5.). patent multistep synthetic routes and familiarity with the short Based on the analogous tetraazamacrocyclic chemistry where and efficient glyoxal condensation route to ethylene cross- 6-membered rings are favoured, it was hypothesised that 5 bridged tetraazamacrocycles,3, 21, 43 we hypothesized that a (internal rings: 6,5,6,8), would be thermodynamically favoured over 5’ (internal rings: 5,6,5,9). Although only one major MS+ N N H peak at m/z = 238 (LH+) was observed, the 1H and 13C NMR NH HN a N N b spectra (see ESI) gave evidence of more than a single isomer NH HN NH N being present. For example, sixteen 13C signals were 15aneN5 5 reproducibly observed even though the compound has only 2 I- twelve carbon atoms. It is hypothesised that both 5 and 5’ are N N present (this would help explain four different 13C resonances N N c N N between 78-86 ppm) and that additional cis/trans isomers N N N N (with respect to the two methyne protons of the two-carbon 6 3 bridge) may also exist in the mixture. However, the synthetic similar glyoxal condensation route to ethylene cross-bridged route in Fig. 4 might reasonably be expected to succeed even Fig. 4. Synthetic route to Me -CB-15aneN5 (3): a) 1 eq 40% aq 3 with such a mixture of isomers, so no purification was glyoxal, MeOH, 16h, RT, 85% yield; b) i. 10 eq MeI, MeCN, 5d, attempted prior to continued reaction. RT; ii. Evaporate to solid, wash with DCM, not isolated— Many attempts were made to structurally characterize 5 contains isomers; c) i. 20 eq NaBH , 95% EtOH, 5d, RT, N ; ii. 4 2 without success. However, a byproduct of the methylation 6M HCl, evaporate, 30% aq KOH, CHCl extraction, 32% yield. 3 step (discussed below) to prepare 6 fortuitously crystallized Full experimental details and characterization data in ESI. and demonstrated the predicted glyoxal condensate 2 | J. Name., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 20xx Please do not adjust margins Page 3 of 5 Please doChemComm not adjust margins Journal Name COMMUNICATION connectivity (Fig.