A new class of cross-bridged cyclam-based macrocycles featuring phosphonate pendant groups has been developed. 1,4,8,11-tetraazacyclotetradecane-1,8-di(methanephosphonic acid) (CB-TE2P, 1) and 1,4,8,11-tetraazacyclotetradecane-1-(methanephosphonic acid)-8-(methanecarboxylic acid) (CB-TE1A1P, 2) have been synthesized and have been shown to readily form neutral copper (II) complexes at room temperature as the corresponding dianions. Both complexes showed high kinetic inertness to demetallation and crystal structures confirmed complete encapsulation of copper (II) ion within each macrocycle’s cleft-like structure. Unprecedented for cross-bridged cyclam derivatives, both CB-TE2P (1) and CB-TE1A1P (2) can be radiolabeled with 64Cu at room temperature in less than 1 hour with specific activities >1mCi/μg. The in vivo behavior of both 64Cu-CB-TE2P and 64Cu-CB-TE1A1P were investigated through biodistribution studies using healthy, male, Lewis rats. Both new compounds showed rapid clearance with similar or lower accumulation in non-target organs/tissues when compared to other copper chelators including CB-TE2A, NOTA and Diamsar.

A cross-bridged cyclam ligand bearing two N-carboxymethyl pendant arms (1) has been found to form a copper(II) complex that exhibits significantly improved biological behavior in recent research towards (64)Cu-based radiopharmaceuticals. Both the kinetic inertness and resistance to reduction of Cu-1 are believed to be relevant to its enhanced performance. To explore the influence of pendant arm length on these properties, new cross-bridged cyclam and cyclen ligands with longer N-carboxyethyl pendant arms, 2 and 4, and their respective copper(II) complexes have been synthesized. Both mono- as well as di-O-protonated forms of Cu-2 have also been isolated and structurally characterized. The spectral and structural properties of Cu-2 and Cu-4, their kinetic inertness in 5 M HCl, and electrochemical behavior have been obtained and compared to those of their N-carboxymethyl-armed homologs, Cu-1 and Cu-3. Only the cyclam-based Cu-1 and Cu-2 showed unusually high kinetic inertness towards acid decomplexation. While both of these complexes also exhibited quasi-reversible Cu(II)/Cu(I) reductions, Cu-2 is easier to reduce by a substantial margin of +400 mV, bringing it within the realm of physiological reductants. Similarly, of the cyclen-based complexes, Cu-4 is also easier to reduce than Cu-3 though both reductions are irreversible. Biodistribution studies of (64)Cu-labeled 2 and 4 were performed in Sprague Dawley rats. Despite comparable acid inertness to their shorter-armed congeners, both longer-armed ligand complexes have poorer bio-clearance properties. This inferior in vivo behavior may be a consequence of their higher reduction potentials.

Dinuclear [(TPyA)MII(CA2-)MII(TPyA)]2+ [TPyA=tris(2-pyridylmethyl)amine; CA2-=chloranilate dianion; M=Co (1(2+)), Fe (2(2+))] complexes have been prepared by the reaction of M(BF4)(2).6H2O, TPyA, H2CA, and triethylamine in MeOH solution. Their reduced forms [(TPyA)MII(CA*3-)MII(TPyA)]+ [M=Co(1+), Fe (2+)] have been synthesized by using cobaltocene, and oxidized forms of 1, [(TPyA)CoIII(CAn)CoIII(TPyA)]z+ [z=3, n=3- (1(3+)); z=4, n=2- (1(4+))], have been obtained by using FcBF4 and ThianBF4 (Fc=ferrocenium; Thian=thianthrinium), respectively. The dinuclear compound bridged chloranilates (CA2- or CA*3-) were isolated and characterized by X-ray crystallography, electrochemistry, magnetism, and EPR spectroscopy. Unlike the other redox products, valence ambiguous 13+ forms via a complex redox-induced valence electron rearrangement whereby the one-electron oxidation of the [CoIICA2-CoII]2+ core forms [CoIIICA*3-CoIII]3+, not the expected simple 1-e- transfer mixed-valent [CoIICA2-CoIII]3+ core. The M ions in 1 and 2 have a distorted octahedral geometry by coordination with four nitrogens of a TPyA, two oxygens of a chloranilate. Due to the interdimer offset face-to-face pi-pi and/or herringbone interactions, all complexes show extended 1-D and/or 2-D supramolecular structures. The existence of CA*3- in 1(3+) is confirmed from both solid-state magnetic and solution EPR data. Co-based 1n+ exhibit antiferromagnetic interactions [1(2+): g=2.24, J/kB=-0.65 K (-0.45 cm-1); 1+: g=2.36, J/kB=-75 K (52 cm-1)], while Fe-based 2n+ exhibit ferromagnetic interactions [2(2+): g=2.08, J/kB=1.0 K (0.70 cm-1); 2+: g=2.03, J/kB=28 K (19 cm-1)] [H=-2JS1.S2 for 12+ and 2(2+); H=-2J(S1.S2+S2.S3) for 1+ and 2+]. Thus, due to direct spin exchange CA*3- is a much strong spin coupling linkage than the superexchange spin-coupling pathway provided by CA2-.

N-heterocyclic carbenes (NHCs) [1] and their complexes [2] are excellent catalysts for a broad array of organic transformations, where the NHC ligands impart useful electronic and steric properties to metal centers. [3] In these systems, with commonly used ancilliary NHC ligands that are substituted at nitrogen atom(s) by alkyl, aryl, or other groups, [2,3] all catalytic transformations take place at the metal center, which is stabilized and/or activated by the NHC ligand. However, transformations that may possibly involve both the metal center and at one ring nitrogen of the NHC ligand are much less common, [4, 5c,e-g] and are limited to protic NHC complexes [4][5][6] or their conjugated bases. Thus, the NÀH function of a protic NHC complex (A or D; Scheme 1) could behave as Brønsted acid, whereas the basic nitrogen atom in the imidazol-2-yl complex (B or C) may behave as a Brønsted base. Moreover, reactivity of A with a base could lead to B, a transient species with both a vacant metal coordination site and a basic nitrogen atom, which could bind (C) and activate a substrate (C to D). These reactivity patterns might also be compatible with protic NHC complexes derived from other NHC ligands.Herein, we report a versatile organometallic system in which the combined reactivity of the imidazol-2-ylidene or imidazol-2-yl fragments and the metal center lead to ligand exchange processes that involve A and B, hydrogen activation (B!C!D), and ultimately, catalytic behavior (D + ketone! E!B + alcohol). Key differences between results herein from previous work [4] include: 1) greatly enhanced rates of reaction (for example, ligand exchange within minutes instead of days); 2) the ability to tune ligand exchange rates over several orders of magnitude; and perhaps most importantly 3) catalytic behavior, which was not at all apparent before. Moreover, we show that 15 N chemical shift information on natural-abundance samples gives valuable information on the environment of the imidazol-2-yl or imidazolylidene ligand.Reaction of 1 [4] with [CpRuCl(cod)] (Cp = cyclopentadienyl, cod = 1,5-cyclooctadiene) in THF at 100 8C led to phosphorus coordination and complete tautomerization of the imidazole to carbene 2, which shows a low-field 1 H NMR signal (d = 10.28 ppm, NH) and a doublet in the 13 C{ 1 H} NMR (d = 184.1 ppm, 2 J CP = 22.5 Hz, C2) that are consistent with structure 2 (Scheme 2). Scheme 1. Imidazol-2-yl and imidazol-2-ylidene fragment systems. The square indicates a vacant site.Scheme 2. Synthesis and reactivity of imidazol-2-yl and imidazol-2-ylidene complexes (in [D 8 ]THF at room temperature unless otherwise specified). Yields are of isolated products unless otherwise specified. LDA = lithium diisopropylamide.[*] Dr.

Copper-64, a positron emitter suitable for positron emission tomography (PET), demonstrates improved in vivo clearance when chelated by the cross-bridged tetraazamacrocycle CB-TE2A compared to TETA. Good in vivo clearance was also observed for 64Cu-CB-TE2A conjugated to a peptide, which converts one coordinating carboxylate pendant arm to an amide. To better understand the in vivo stability of peptide- conjugated CB-TE2A, cross-bridged monoamides were synthesized. Crystal structures of natCu(II)-CB-TEAMA and natCu(II)-CB-PhTEAMA revealed hexadentate, distorted octahedral coordination geometry. In vivo biodistribution showed clearance of all 64Cu-radiolabeled cross-bridged monoamides from liver and bone marrow such that uptake at 24 h was <10% of uptake at 30 min. In contrast, >60% of 30 min uptake from 64Cu-TETA was retained in these tissues at 24 h. Clearance of 64Cu-cross-bridged monoamides from nontarget organs suggests good in vivo stability, thus supporting the use of CB-TE2A as a bifunctional chelator without modifications to the macrocycle backbone.

The hydrogermolysis reaction of PhGeH3 serves in the synthesis of discrete branched oligogermanes. Treatment of PhGeH3 with 3 equiv of the α-germyl nitriles R3GeCH2CN (R3 = Ph3 or Bu2CH2CH2OEt), which are generated in situ from the corresponding amides R3GeNMe2 and CH3CN, furnishes the tetragermanes PhGe(GePh3)3 and PhGe(GeBu2CH2CH2OEt)3 in excellent yield. The crystal structure of PhGe(GePh3)3 was determined. This compound is the first branched oligogermane to be structurally characterized. Reaction of the tetragermane PhGe(GeBu2CH2CH2OEt)3 with Bu i 2AlH generated the intermediate hydride PhGe(GeBu2H)3. Subsequent treatment of PhGe(GeBu2H)3 with the synthons R2Ge(NMe2)CH2CH2OEt (R = Bu, Et, Ph) in CH3CN solution furnished the heptagermanes PhGe(GeBu2GeR2CH2CH2OEt)3 (R = Bu, Et, Ph). The latter process also proceeds through the in situ formation of the α-germyl nitriles R2Ge(CH2CN)CH2CH2OEt.

A phosphonate pendant-armed cross-bridged cyclam chelator has been synthesized, complexed to Cu(ii), radiolabeled with (64)Cu under mild conditions, and its biodistribution studied.

A series of Pt-based heterobimetallic lantern complexes of the form [PtM(SAc)4(OH2)] (M = Co, 1; Ni, 2; Zn, 3) were prepared using a facile, single-step procedure. These hydrated species were reacted with 3-nitropyridine (3-NO2py) to prepare three additional lantern complexes, [PtM(SAc)4(3-NO2py)] (M = Co, 4; Ni, 5; Zn, 6), or alternatively dried in vacuo to the dehydrated species [PtM(SAc)4] (M = Co, 7; Ni, 8; Zn, 9). The Co- and Ni-containing species exhibit Pt-M bonding in solution and the solid state. In the structurally characterized compounds 1-6, the lantern units form dimers in the solid state via a short Pt···Pt metallophilic interaction. Antiferromagnetic coupling between 3d metal ions in the solid state through noncovalent metallophilic interactions was observed for all the paramagnetic lantern complexes prepared, with J-coupling values of -12.7 cm(-1) (1), -50.8 cm(-1) (2), -6.0 cm(-1) (4), and -12.6 cm(-1) (5). The Zn complexes 3 and 6 also form solid-state dimers, indicating that the formation of short Pt···Pt interactions in these complexes is not predicated on the presence of a paramagnetic 3d metal ion. These contacts and the resultant antiferromagnetic coupling are also not unique to heterobimetallic lantern complexes with axially coordinated H2O or the previously reported thiobenzoate supporting ligand.