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The bicyclic hexaamine "cage" ligand Me(8)tricosaneN(6) (1,5,5,9,13,13,20,20-octamethyl-3,7,11,15,18,22-hexaazabicyclo[7.7.7]tricosane) is capable of encapsulating octahedral metal ions, yet its expanded cavity allows the complexed metal to adopt a variety of geometries comprising either hexadentate or pentadentate coordination of the ligand. When complexed to Cu(II) the lability of the metal results in a dynamic equilibrium in solution between hexadentate- and pentadentate-coordinated complexes of Me(8)tricosaneN(6). Both [Cu(Me(8)tricosaneN(6))](ClO(4))(2) (6-coordinate) and [Cu(Me(8)tricosaneN(6))](S(2)O(6)) (5-coordinate) have been characterized structurally. In weak acid (pH 1) a singly protonated complex [Cu(HMe(8)tricosaneN(6))](3+) has been isolated that finds the ligand binding as a pentadentate with the uncoordinated amine being protonated. vis-NIR and electron paramagnetic resonance (EPR) spectroscopy show that the predominant solution structure of [Cu(Me(8)tricosaneN(6))](2+) at neutral pH comprises a five-coordinate, square pyramidal complex. Cyclic voltammetry of the square pyramidal [Cu(Me(8)tricosaneN(6))](2+) complex reveals a reversible Cu(II/I) couple. All of these structural, spectroscopic, and electrochemical features contrast with the smaller cavity and well studied "sarcophagine" (sar, 3,6,10,13,16,19-hexaazabicyclo[6.6.6]eicosane) Cu(II) complexes which are invariably hexadentate coordinated in neutral solution and cannot stabilize a Cu(I) form.

Single crystal X-ray studies are recorded for five copper(II) complexes of macrobicyclic ligands. In both [Cu(sar)][ZnCl4] (295, 170 K) determinations (‘sar’ = 3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane) and [Cu(NH3)2sar]Cl4·6H2O (295 K), the ligand encapsulates the copper atom by coordinating through all six nitrogen atoms, though distortions of the primary coordination sphere from an octahedral array are both marked and quite different in the two cases. [Cu(sar)]2+ undergoes a relatively facile detachment of one ligand strand in acid solution, giving a species with a different bound-N configuration to that of the reactant and which may be crystallised in various forms. In the solid of composition Cu(ClO4)2·2HClO4·½HCl·H2O·sar (295 K) the complex present is binuclear ‘[(sarH)CuClCu(sarH2)](ClO4)6·2H2O’, with the linear CuClCu array comprising the apical bonds of a pair of square-pyramidal ClCuN4 components. In mononuclear [Cu(sarH2)(ONO2)](NO3)3·3H2O (295 K) two of the ligand strings coordinate in a quasi-square-planar array, with an approach of an anionic oxygen atom to one of the remaining opposed axial coordination sites. In the crystalline complex formed between copper(II) triflate (Cu(tfs)2; ‘tfs’ = F3CSO $$ _{3}^{ - } $$ ) and the expanded macrobicycle Me5tricosaneN6 (Me5tricosaneN6 ≡ fac-1,5,9,13,20-pentamethyl-3,7,11,15,18,22-hexaazabicyclo[7.7.7]tricosane), the ligand, despite the lack of any protonation, is found (295, 150 K) to be bound in a quinquedentate form, with one triflate-O occupying the sixth coordination site about the metal, in the mononuclear complex [Cu(Me5tricosaneN6)(O-tfs)](tfs). This contrasts with the perchlorate counterpart wherein all nitrogen atoms are coordinated within an encapsulating cage. Structural studies of Cu(II) complexes of macrobicyclic hexamines characterise the ready displacement of some of the N-donor atoms from the coordination sphere of the metal.

The advancement of positron emission tomography (PET) depends on the development of new radiotracers that will complement 18 F-FDG. Copper-64 ( 64 Cu) is a promising PET radionuclide, particularly for antibody-targeted imaging, but the high in vivo lability of conventional chelates has limited its clinical application. The objective of this work was to evaluate the novel chelating agent SarAr (1- N -(4-aminobenzyl)-3, 6,10,13,16,19-hexaazabicyclo[6.6.6] eicosane-1,8-diamine) for use in developing a new class of tumor-specific 64 Cu radiopharmaceuticals for imaging neuroblastoma and melanoma. The anti-GD2 monoclonal antibody (mAb) 14.G2a, and its chimeric derivative, ch14.18, target disialogangliosides that are overexpressed on neuroblastoma and melanoma. Both mAbs were conjugated to SarAr using carbodiimide coupling. Radiolabeling with 64 Cu resulted in >95% of the 64 Cu being chelated by the immunoconjugate. Specific activities of at least 10 μCi/μg (1 Ci = 37 GBq) were routinely achieved, and no additional purification was required after 64 Cu labeling. Solid-phase radioimmunoassays and intact cell-binding assays confirmed retention of bioactivity. Biodistribution studies in athymic nude mice bearing s.c. neuroblastoma (IMR-6, NMB-7) and melanoma (M21) xenografts showed that 15–20% of the injected dose per gram accumulated in the tumor at 24 hours after injection, and only 5–10% of the injected dose accumulated in the liver, a lower value than typically seen with other chelators. Uptake by a GD2-negative tumor xenograft was significantly lower (64 Cu-SarAr-mAb system described here is potentially applicable to 64 Cu-PET imaging with a broad range of antibody or peptide-based imaging agents.

The racemic C3 hexadentate cage complex, [Pt(Me5-tricosatrieneN6)]Cl4 (1,5,9,13,20-pentamethyl-3,7,11,15,18,22-hexaazabicyclo[7.7.7]tricosa-3,14,18-triene)platinum(IV) tetrachloride), was synthesised stereospecifically and regiospecifically from a reaction of the bis-triamine template [Pt(tame)2]Cl4 (bis[1,1,1-tris(aminomethyl)ethane]platinum(IV) tetrachloride) with formaldehyde and then propanal, in acetonitrile under basic conditions. Largely, one racemic diastereoisomer was obtained in a surprisingly high yield (∼ 50%), even though the molecule has seven chiral centres. The origins of the stereoselective synthesis are addressed. The crystal structure of [Pt(Me5-tricosatrieneN6)](ZnCl4)1.5Cl·2H2O showed that all three imines were attached to one tame fragment with a chiral amine site (ΛSSS, ΔRRR) and a chiral methine carbon site (ΛRRR, ΔSSS) on each ligand strand. The PtN64+ moiety had a slightly distorted octahedral configuration with the two types of Pt–N bonds related to the imine and the amine donors, 2.050(7) and 2.072(6) A, respectively. Treatment with sodium borohydride (15 s, 20 °C) at pH ∼ 12.5 reduced the imine groups, but not the Pt(IV) ion, producing a C3 saturated ligand complex [Pt(Me5-tricosaneN6)]Cl4 ((1,5,9,13,20-pentamethyl-3,7,11,15,18,22-hexaazabicyclo[7.7.7]tricosane)platinum(IV)tetrachloride). X-ray crystallographic analysis showed that the average Pt–N bond distance in the cation increased upon imine reduction to 2.10 (av) A. The cyclic voltammograms of the two cage complexes displayed irreversible two-electron reduction waves in aqueous media and a ∼ 0.3 V shift to more positive potentials compared to that of the smaller cavity sar (3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane) analogue. After reduction, net dissociation of one strand of the cage was also evident, to give unstable square planar Pt(II) macrocyclic products.

The protonation and metal complex formation of the branched pentaamine ligand 2,2,6,6-tetrakis(aminomethyl)-4-azaheptane (ditame, L) with CoII, CoIII, NII, CuII, ZnII, and CDII have been studied. The crystal structures of [Ni(ditame)(EtOH)] Br2, [CO2(ditame)2(O2)Cl4 ·4H2O, and [Co2-(ditame)2(O2)]Cl2 [ZnCl4][ZnCl3(H2O)]·H2O were determined by X-ray diffraction analyses. The metal complexes showed octahedral coordination geometries with exclusive formation of six-membered chelate rings, the four primary amino groups being in equatorial positions and the secondary amino group (Nsec) apical. This geometry enforces a relatively short M-Nsec bond. Complex formation in aqueous solution was evaluated by potentiometric titration. The ditame ligand forms a surprisingly stable NiII complex with logKNiL = 17.8 (25 °C, 0.1 M KNO3), and formation of protonated species [Ni(Hnditame)](n+2)+ (n = 1, 2) is not significant. Different behavior is evident for ZnII and CdII, with which protonated species are extensively formed, while the stability of [ML]2+ is relatively low. Complex formation between ditame and CuII in the range 3 < pH < 7 resulted in the formation of [Cu(H2ditame)]4+. In slightly alkaline solution, the dinuclear [Cu2(ditame)2]4+ appears to be formed. The structural assignment of this dimer is based on its UV/Vis and EPR characteristics, with the EPR data indicating a CuII···CuII separation of about 5.9 Å. The redox behavior of the Ni and Co complexes was investigated by cyclic voltammetry. The mononuclear species showed quasi-reversible electron transfer for the NiII/III and ColII/III couples. For the dinuclear peroxo/superoxo-bridged CoII/III complexes, quasi-reversible electron transfer corresponding to oxidation/reduction of the O22-/O2- bridge was observed. (© Wiley-VCH Verlag GmbH and Co. KGaA, 69451 Weinheim, Germany, 2003).

Sodium dithionite was found to reduce a range of α-iminoacidato ligands, chelated to cobalt(III), to the related α-aminoacidato species. For the bis(1,2-ethanediamine) system, the distribution of the products showed a small stereoselectivity towards the ΛR,ΔS diastereoisomers. The most significant selectivity was exhibited in the preparation of the valinato complex, via reduction of the related imine, [(en)2Co(Vim)]2+, where ΛR,ΔS/ΛS,ΔR = 4.2. Smaller selectivities (≈1.5) were observed in reductions using borohydride reagents. Reduction of the α-imino acid by sodium dithionite is optimised under acidic conditions (pH 3.5–5.5) in a dinitrogen atmosphere, whilst the corresponding reduction by sodium borohydride is optimised under mildly alkaline conditions (pH 9–10). Reduction conditions are therefore available to suit molecules with either acid or base sensitive functional groups. A mechanism for the reduction of the chelated imino acids by dithionite is proposed.

Rac.-p-(tris(2-aminoethyl)amine-2-(nitromethyl)ornithine)cobalt(III) trichloride (2d) was obtained by a simple three-step procedure from ornithine using cobalt template chemistry. p-(Tris(2-aminoethyl)amine-ornithine)cobalt(III) trichloride (2a) was obtained from tris(2-aminoethyl)amine (tren) and (S)-ornithine in the presence of cobalt(II), which was oxidised to cobalt(III) during the reaction. Complex 2a was selectively oxidised with thionyl chloride–dimethyl formamide to p-(tris(2-aminoethyl)amine-dehydro-ornithine)cobalt(III) trichloride 2b. Complex 2c, in which reaction of thionyl chloride–dimethyl formamide has also occurred at the δ-amine of ornithine, was obtained at longer reaction times. Complex 2b reacted with nitromethane anion to give rac.-p-(tris(2-aminoethyl)amino-2-(nitromethyl)ornithine)cobalt(III) trichloride (2d). The amino acid rac.-2-(nitromethyl)ornithine (1b) was released by reducing complex 2d with aqueous ammonium sulfide. Complex 2d was expected to release 2-(nitromethyl)ornithine (1b) in hypoxic cells, where the amino acid could act as an inhibitor of ornithine decarboxylase. Preliminary data indicated that complex 2d was weakly cytotoxic in one cell type studied.

A new hexaazamacrobicyclic cage ligand, 1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]eicosane-1,8-diamine (SarAr) has been designed for conjugation to proteins. SarAr was synthesised and characterised by microanalyses, 1H NMR and electrospray mass spectrometry. The complexation of selected transition metal ions (Cu(II), Ni(II) and Co(II) at 10−6 M) by SarAr was complete within 30 min over pH 6 to 8. The [64Cu(SarAr)]2+ complex was investigated with a view to applications in radioimaging. The [64Cu(sar)]2+ complex was found to be stable in human plasma for at least 174 h and biodistribution studies in mice, showed that the [64Cu(SarAr)]2+complex was rapidly excreted through the renal system unlike the free 64Cu2+. Overall, the simple synthesis, ready complexation behaviour of SarAr, the kinetic inertness of the [Cu(SarAr)]2+ complex to dissociation of 64Cu and its facile elimination from mice make it an attractive prospect for use in nuclear medicine.

The Hg2+aq- and HgCl+aq-assisted aquations of [PtCl4]2- (1), [PtCl3(H2O)]- (2), cis-[PtCl2(H2O)2] (3), trans-[PtCl2(H2O)2] (4), [PtCl(H2O)3]+ (5), [PtCl3Me2SO]- (6), trans-[PtCl2(H2O)Me2SO] (7), cis-[PtCl(H2O)2Me2SO]+ (8), trans-[PtCl(H2O)2M32SO]+ (9), trans-[PtCl2(NH3)2] (10), and cis-[PtCl2(NH3)2] (11) have been studied at 25.0 degrees C in a 1.00 M HClO4 medium buffered with chloride, using stopped-flow and conventional spectrophotometry. Saturation kinetics and instantaneous, large UV/vis spectral changes on mixing solutions of platinum complex and mercury are ascribed to formation of transient adducts between Hg2+ and several of the platinum complexes. Depending on the limiting rate constants, these adducts are observed for a few milliseconds to a few minutes. Thermodynamic and kinetics data together with the UV/vis spectral changes and DFT calculations indicate that their structures are characterized by axial coordination of Hg to Pt with remarkably short metal-metal bonds. Stability constants for the Hg2+ adducts with complexes 1-6, 10, and 11 are (2.1 +/- 0.4) x 10(4), (8 +/- 1) x 10(2), 94 +/- 6, 13 +/- 2, 5 +/- 2, 60 +/- 6, 387 +/- 2, and 190 +/- 3 M-1, respectively, whereas adduct formation with the sulfoxide complexes 7-9 is too weak to be observed. For analogous platinum(II) complexes, the stabilities of the Pt-Hg adducts increase in the order sulfoxide << aqua < ammine complex, reflecting a sensitivity to the pi-acid strength of the Pt ligands. Rate constants for chloride transfer from HgCl+ and HgCl2 to complexes 1-11 have been determined. Second-order rate constants for activation by Hg2+ are practically the same as those for activation by HgCl+ for each of the platinum complexes studied, yet resolved contributions for Hg2+ and HgCl+ reveal that the latter does not form dinuclear adducts of any significant stability. The overall experimental evidence is consistent with a mechanism in which the accumulated Pt(II)-Hg2+ adducts are not reactive intermediates along the reaction coordinate. The aquation process occurs via weaker Pt-Cl-Hg or Pt-Cl-HgCl bridged complexes.

Ascorbate (Asc) reductions of the oral anticancer platinum(IV) prodrugs cis,trans,cis-[PtCl2(OAc)2(cha)(NH3)] (JM216) and cis,trans,cis-[PtCl2(OCOC3H7)2(cha)(NH3)] (JM221) and of the isomers of JM216, viz.trans,cis,cis-[PtCl2(OAc)2(cha)(NH3)] (JM394) and trans,trans,trans-[PtCl2(OAc)2(cha)(NH3)] (JM576) (OAc = acetate, cha = cyclohexylamine) have been investigated in a 1.0 M aqueous perchlorate medium using stopped-flow and conventional UV/VIS spectrophotometry as a function of temperature and pH. JM216 and 221 are reduced to cis-[PtCl2(cha)(NH3)] (JM118) and JM394 and 576 to cis- and trans-[Pt(OAc)2(cha)(NH3)], respectively. The redox reactions follow the second-order rate law: −d[Pt(IV)]/dt = k [Pt(IV)] [Asc]tot where k is a pH dependent second-order overall rate constant and [Asc]tot = [Asc2−] + [HAsc−] + [H2Asc]. Reduction of JM216 and JM221 is slow (overall rate constants k298 = 5.08 ± 10−2 and 3.25 × 10−2 mol−1 dm3 s−1 at pH 7.12, respectively) and is suggested to take place via an outer-sphere mechanism. Reductions of JM394 and JM576 are more than three orders of magnitude faster (k298 = 230 ± 6 mol−1 dm3 s−1 at pH 7.0 for JM394). They are suggested to take place by a mechanism involving a reductive attack on one of the mutually trans chloride ligands by Asc2− and less efficiently by HAsc− leading to the formation of a chloride-bridged activated complex. The second-order rate constants for reduction of JM394 by HAsc− and Asc2− at 25 °C are 0.548 ± 0.004 and (4.46 ± 0.01) × 106 mol−1 dm3 s−1, respectively. The rate constants for reduction of JM216 and JM221 by Asc2− at 25 °C are calculated to be 672 ± 15 and 428 ± 10 mol−1 dm3 s−1, respectively and reduction by HAsc− was not observed under these conditions. Thus, Asc2− is up to 7 orders of magnitude more efficient as a reductant than HAsc−. H2Asc is virtually inactive. The activation parameters ΔH‡ and ΔS‡ for reduction of JM216, JM221, JM394, and JM576 by Asc2− are 52 ± 1, 46 ± 1, 56.2 ± 0.5, and 63 ± 2 kJ mol−1 and −97 ± 4, −120 ± 4, −24 ± 2, and −8 ± 5 J K−1 mol−1, respectively. An isokinetic relationship gives further support to the mechanistic assignments.

The crystal structures of (1,5,9,13,20-pentamethyl-3,7,11,15,18,22-hexaazabicyclo[7.7.7]tricosane-κ6 N,N′,N′′,N′′′,N′′′′,N′′′′′)nickel(II) diperchlorate–x(water) (x = 0.530), [Ni(C22H48N6)](ClO4)2.0.530H2O, and (1,5,9,13,20-pentamethyl-3,7,11,15,18,22-hexaazabicyclo[7.7.7]tricosane-κ6 N,N′,N′′,N′′′,N′′′′,N′′′′′)zinc(II) diperchlorate–x(water) (x = 0.608), [Zn(C22H48N6)](ClO4)2.0.608H2O, are isomorphic and each is described as an intergrowth of four substructures, consistent with different modulations of an idealized parent structure of space group C2/c. Two substructures correspond to alternative orientations of a C1¯ structure for which x = 0 in the general formula [M(C22H48N6)](ClO4)2.xH2O, and two substructures correspond to alternative origins of a P21/n structure for which x = 1. Twinning also occurs. An analysis of the pseudosymmetry, a description of the refinement and a description of the refined structures are presented. The MN6 coordination geometry is essentially octahedral, in contrast to the trigonal-prismatic geometry observed for the CdII and HgII complexes of the same ligand.

The syntheses of a cobalt(III) complex, 2, containing N-(2-pyridylmethyl)urea and of six complexes, 3, containing phenyl-substituted N-2-pyridylmethyl-N'-(X)phenylureas (where X = 4-H, 4-CH(3), 4-Br, 3-Cl, 4-CF(3), and 4-NO(2)), have been accomplished by reaction of [(en)(2)Co(OSO(2)CF(3))(2)](CF(3)SO(3)) with the urea ligands in tetramethylene sulfone. The complexes have been characterized by UV-vis, FTIR, (1)H NMR, and (13)C NMR spectra along with elemental analysis. Also, X-ray crystallographic analysis of 2 confirms that the urea ligand chelates as a bidentate through the pyridyl nitrogen atom and the endo deprotonated, urea nitrogen atom to form a stable five-membered ring. Crystals of the perchlorate salt of 2 were monoclinic, space group P2(1)/c with a = 9.743(1) Å, b = 13.924(3) Å, c = 15.006(4) Å, beta = 97.07(1) degrees, and Z = 4. Reflection data (3454) with I = 3sigma(I) were refined to conventional R factors of 0.037 and 0.051. In acidic solution (0.05-1.00 M HCl at 55 degrees C), the phenyl-substituted complexes undergo hydrolysis to form the bis(ethylenediamine)(2-picolylamine-N,N')cobalt(III) ion, 4, aniline, and CO(2). The hydrolysis kinetics of the phenyl-substituted complexes were studied by UV-vis spectroscopy (I = 1.00 M HCl/LiCl). At 55 degrees C the observed rate constants fit the rate law k(obsd) = kK[H(+)]/(1 + K[H(+)]). It is proposed that the protonated urea eliminates aniline to give a coordinated isocyanate intermediate that hydrolyzes rapidly to the pyridyl methylamine complex and CO(2) via the carbamate complex. Since all of the studies of this kind to date appear to involve the NCO intermediate, it raises the prospect that urease also functions by a similar path and that urease should be tested with NCO(-) as a substrate.

Reaction of K2PtCl6 with the tripodal ligand tame [1,1,1-tris(aminomethyl)ethane] in dimethylformamide catalysed by K2PtCl4 afforded the octahedral bis(tridentate ligand) [Pt(tame)2]4+ ion. The cyclic voltammogram of [Pt(tame)2]4+ in aqueous media showed an irreversible reduction of the six-co-ordinate platinum(IV) species to PtII and bulk electrochemical reduction of the [PtIV(tame)2]4+ ion quantitatively produced a square planar platinum(II) complex [Pt(tame)2]2+. Crystallographic analysis of the protonated complex [PtII(Htame)2][ZnCl4]2·2H2O, showed two dissociated nitrogen atoms on opposite sides of the PtN42+ co-ordination plane which has typical PtII–N bond lengths (2.042(6) A). The routes to the formation of the [PtIV(tame)2]4+ ion and its reduced product are addressed.

Two new, trigonally symmetrical, triamide tripodal ligands and their complexes with the cobalt(III) ion, [1,1,1-tris(4-amino-1-oxo-2-azabutyl)ethanato]cobalt(III)trihydrate 1 and [1,1,1-tris(4-amino-4-methyl-3-oxo-2-azapentyl)ethanato]cobalt(III)–water–ethanol (1/8/0.5) 2 have been prepared. The hexadentate structures of the neutral, trigonal, triamido complexes have been established by an X-ray study of 1 and 13C NMR spectrometry of both molecules. The chemical, spectroscopic and electrochemical properties of the complexes have been investigated as well as those of the monoamido tripodal complex [1,9-diamino-5-(4-amino-2-azabutyl)-5-ethoxycarbonyl-4-oxo-3,7-diazanonanato]cobalt(III) chloride.

A facile synthesis of the tetrapodal pentaamine ligand 2,2′-dimethyl-2,2′-iminodimethylenebis(1,3-propanediamine), ditame, has been achieved and some unusual effects of its topology and preference for square pyramidal co-ordination in cobalt(III) complexes explored. Potential influences of the ditame structure on substitution chemistry in [Co(ditame)X]n+ systems are defined by crystal structure analyses for [Co(ditame)Cl][ZnCl4] and [Co(ditame)(NH3)]Cl[ZnCl4]. Proton exchange, nitrogen inversion and chloride anation reactivity, and substitution stereochemistry studies have been carried out on the [Co(ditame)Cl]2+ and [Co(ditame)(OD2)]3+ complexes by using 13C NMR spectroscopy. The base hydrolysis rate constant for [Co(ditame)Cl]2+ (68 dm3 mol–1 s–1 at 25 °C, I 1.0 mol dm–3) is 250 fold greater than that for the analogous [Co(NH3)5Cl]2+ ion. This difference is attributed to an enhanced trans influence and a bond-coupled co-operative mechanism that facilitate the Cl– dissociation in the conjugate base of [Co(ditame)Cl]2+. The bond-coupled mechanism also aids dissociative processes for the relatively fast aquation and anation chemistry of [Co(ditame)Cl]2+ and [Co(ditame)(OH2)]3+. Two results for the reactivity of the [Co(ditame)X]n+ (X = Cl– or H2O) ions are attributed to restricted rearrangement of the square pyramidal Co(ditame) fragment in the course of Xn – 3 substitutions. One is the very small amount of [Co(ditame)(N3)]2+ (1.1 ± 0.3%) formed in competition with [Co(ditame)(OH)]2+ during base hydrolysis in aqueous 1 mol dm–3 NaN3, which indicates an unusually short lifetime for the proposed intermediate. Also, there were no species detected that arise from partial dissociation of the amine, neither in the base hydrolysis nor in the aquation and anation experiments, even at temperatures >50 °C and in the presence of strong acids. There are important consequences for substitution chemistry in other [M(pentaamine)X]n+ systems where rearrangement of the MN5(amine) fragment is restricted. The quantitatively simple substitution processes also make these reagents valuable as protective groups in synthetic applications such as peptide cleavage and synthesis.

Treatment of the two CoIII-hexaamine complexes [Co(taci)2]3+ and [Co(tmca)2]3+ (taci = 1,3,5-triamino-1,3,5-trideoxy-cis-inositol, tmca = all-cis-2,4,6-trimethoxycyclohexane-1,3,5-triamine) in CH3CN with NEt3 and excess paraformaldehyde gave the corresponding hexamethylideneimino (hmi) derivatives [Co(taci)2-hmi]3+ and [Co(tmca)2-hmi]3+ in excellent yield. Both hexaimines were stable in acidic aqueous solution and were isolated as solid compounds. They were characterized by elemental analyses, 13C NMR, 1H NMR, IR, and visible spectroscopy, mass spectrometry, and single-crystal X-ray analyses. [Co(taci)2-hmi]Cl3·6H2O crystallizes in the monoclinic space group C2/m, C18Cl3CoH42N6O12, Z = 2, a = 13.046(2) A, b = 9.802(2) A, c = 12.332(2) A, β = 118.42(1)°. [Co(tmca)2-hmi](HSO4)3 crystallizes in the monoclinic space group C2/c, C24CoH45N6O18 S3, Z = 4, a = 14.087(3) A, b =15.890(3) A, c = 15.502(3) A, β = 95.27(3)°. Subsequent treatment of [Co(taci)2-hmi]3+ with nitromethane and base resulted in the formation...

The ability of available molecular mechanics programs to calculate structures and relative energies of metal complexes is examined via a comparative study of five different force fields: Molmec, Momec91(H), Momec91(C), Xnviron, and Spartan. The method used for assessing the validity of the force fields showed that four of the force fields were able to reproduce successfully the structures of various Co(III) hexaamine cations determined by X-ray analysis, even when these structures were considerably distorted. In certain cases, the calculated relative steric energies were not reliable. Small variations in force fields parameters sometimes led to large changes in the calculated steric energies, and in some instances, in the order of steric strain for different isomers. The most notable changes occurred when metal-dependent parameters were altered.

The H+- and Cl--assisted dissociation kinetics and the stabilities of the complexes [Hg(sar)](2+) and [Hg((NH2)(2)-sar)](2+) (sar = 3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane and (NH2)(2)-sar = 1,8-diamino-sar) were determined. The Hg2+ dissociation rates depend on both the proton and the chloride ion concentrations. H+ competes with the metal ion for dissociated amine groups, and Cl- competes with the amine for vacant coordination sites. The rate laws are complicated. For the [Hg(sar)](2+) system (0.1 less than or equal to [H+] less than or equal to 1.0 M, 0.01 less than or equal to [Cl-] less than or equal to 1.0 M, I = 2.0 M (NaO3SCF3), 25.0 degrees C) the observed rate law is upsilon(-Hg2+) = (a + b[Cl-])[H+][Hg(sar)(2+)]/(1 + c[Cl-]), with a = 35(3) M-1 s(-1), b = 2.9(4) x 10(3) M-2 s(-1), and c = 33(5) M-1. For the [Hg((NH3)(2)-sar)](4+) system (0.001 less than or equal to [H+] less than or equal to 1.0 M, 0.01 less than or equal to [Cl-] less than or equal to 1.0 M, I = 1.0 M (LiClO4), 25.0 degrees C) the observed rate law is upsilon(-Hg2+) = (a + b[H+] + c[H+](2))[Cl-][Hg((NH3)(2)-sar)(4+)])/((1 + d[Cl-])(1 + e[H+])), with a = 0.056(6) M-1 s(-1), b = 8(3) M-2 s(-1), c = 5(3) M-3 s(-1), d = 1.3(4) M-1, and e = 1.1(5) x 10(2) M-1. Intimate mechanisms for the dissociation reactions are proposed. Using iodide ion or sar ligand as competing ligands and the reported values for the stabilities of HeI3- and HgI42- the stability constants at 25.0 degrees C were determined for [Hg(sar)](2+) (10(28.1(1)) M-1), [Hg(sar)I](+) (10(29.1(1)) M-2), [Hg((NH2)(2)-sar)I](+) (10(28.5(1)) M-2), and [Hg(cyclam)I](+) (10(30.8(1)) M-2) (cyclam = 1,4,8,11-tetraazacyclotetradecane) with [OH-] = 0.1 M, I = 0.5 M (NaClO4) and for [Hg((NH2)(2)-sar)](2+) (10(26.4(3)) M-1) with [OD-] = 0.1 M, I = 0.1 M (NaOD).

[Fe(tmca)2]3+ and [Co(tmca)2]3+ (tmca = all-cis-2,4,6-trimethoxycyclohexane-1,3,5-triamine) were prepared and characterized by elemental analyses, NMR, and FAB+ mass spectrometry and by spectroscopic methods (UV−vis). Magnetic susceptibility measurements established a low-spin d5 electron configuration for the FeIII hexaamine complex. In aqueous solution, cyclic voltammetry revealed a quasi reversible one electron reduction for both complexes with MIII/MII redox potentials of +0.16 and −0.30 V (vs SHE), respectively. The two compounds [M(tmca)2]Cl3·5H2O·EtOH (C20H58Cl3MN6O12, M = Fe, Co) are isostructural. They both crystallize in the triclinic space group P1, Z = 2. Fe complex: a = 10.338(3) A, b = 13.062(4) A, c = 14.042(4) A, α = 80.20(2)°, β = 72.07(2)°, γ = 69.11(2)°. Co complex: a = 10.307(3) A, b = 13.066(2) A, c = 14.029(2) A, α = 80.14(1)°, β = 72.18(2)°, γ = 69.55(2)°. The ligand tmca is compared with the unsubstituted 1,3,5-triamino-1,3,5-trideoxy-cis-inositol (taci) and the N-methylated 1,3...

The template syntheses of various CoIII-hexaazaicosane-type cage complexes with aromatic substituents are described. The parent template, [Co(sen)]3+ ion {sen = 4,4′,4″-ethylidynetris(3-azabutan-1-amine)}, paraformaldehyde, a methyl aryl ketone and a base were reacted in acetonitrile to give aroyl substituents attached to the fully saturated sarcophagine cage (1-aroyl-8-methyl-3,6,10,13,16,19-hexaazabicyclo[6.6.6]-icosane cobalt(III) ion) and aryl substituents attached to an analogous imine-type cage (2-aryl-8-methyl-3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosa-2-ene cobalt(III) ion). Phenyl, napthyl, phenanthryl, anthracenyl and anthraquinonyl substituents have been bound to the cage simply by this route to give molecules that can act as intercalators in DNA or as photosensitizers attached to reversible redox-active metal centres and can couple an organic two-electron reagent with an inorganic one-electron reagent. An X-ray crystallographic analysis of a phenanthroyl cage complex has also been carried out. These substances and their progeny should be useful as biological probes and fluorescent indicators and for energy capture and conversion.

When hepatocytes are incubated with the chelator diamsar, two pools can be identified, which we have termed extractable and nonextractable. On entering the hepatocyte, 67Cu first associates with the extractable pool and, after approximately 2 h, moves to the nonextractable pool. Both pools demonstrate saturation and are filled as a function of Cu concentration and incubation time. Using the Michaelis-Menten equation, we have estimated the size of the pools after incubation with 67Cu for 30 min and 4 h. During this period the extractable pool decreases in size from 200 +/- 27 to 116 +/- 5 pmol/microgram DNA, whereas the nonextractable pool increases from 28 +/- 9 to 77 +/- 11 pmol/microgram DNA. Movement of Cu from the nonextractable pool to the extractable pool is slow and incomplete. Using [3H]diamsar, we demonstrate that uptake of the chelator is not rate limiting and probably does not occur by pinocytosis. Incubation with diamsar does not affect the activity of superoxide dismutase or cytochrome-c oxidase, although it does prevent the incorporation of 67Cu into ceruloplasmin. Incubation with zinc, which induces metallothionein, results in an increase in 67Cu associated with the nonextractable pool, suggesting that 67Cu-metallothionein constitutes at least part of the nonextractable pool.

This paper describes aspects of the synthesis of cage complexes in relation to their prospects for use in biology. The means of attaching peptides, cholestane, paraffin tails and aromatic residues are outlined. Also, the properties of some of these molecules, especially a new class of detergents, a new polymer able to capture metal ions, the selectivity of the cages for metal ions and the DNA intercalating properties of aromatic residues attached to the cages are discussed.

A study of high- and low-spin cobalt(II) derivatives having hexadentate encapsulated ligands known as ‘sar’ is reported (sar = 3,6,10,13,16,19-hexaazabicyclo(6.6.6)icosane). The chemically prepared derivatives have well defined EPR spectra at 4 K especially in the g = 9 region, and were clearly high-spin Co(II). However, when the Co II centres were prepared by radiation-induced electron addition to the Co(III) complex at 77 K, a low-spin species was initially formed with g values in the free-spin region. These were converted into the normal high-spin form on annealing to ∼ 115 K.

A new template synthetic route to hexa-aza macropentacyclic cobalt(III) complexes is described together with the X-ray crystal structure of a new conformationally rigid cobalt cage complex.

Complexation of the penta-, hexa- and hepta-N-methylated derivatives of the macrobicyclic hexaamine sar (3,6,10,13,16,19-hexaaza-bicyclo[6.6.6]icosane) with nickel(II) and copper(II) is reported. Unlike their analogous hexadentate-coordinated [M(sar)](2+) complexes, the Cu(II) and Ni(II) complexes of N-Me(5)sar, N-Me(6)sar and N-Me(7)sar(+) show the ligands coordinating only as tetradentates, both in the solid state and in solution. The X-ray crystallographic analyses of [Ni(N-Me(5)sar)](ClO4)(2), orthorhombic, space group P2(1)2(1)2(1), a 9.915(2), b 10.694(2), c 25.549(6) Angstrom, Z = 4; {[Ni(HN-Me(6)sar)](ClO4)(3).2H(2)O}(3), triclinic, space group P $($) over bar$$ 1, a 14.160(2), b 17.739(4), c 21.617(5) Angstrom, alpha 75.20(2), beta 89.72(2), gamma 68.31(1)degrees, Z = 2; [Ni(N-Me(7)sar)](ClO4)(3), orthorhombic, space group P2(1)2(1)2(1), a 10.752(2), b 13.410(2), c 21.643(3) Angstrom, Z = 4; [Cu(N-Me(5)sar)](ClO4)(2), orthorhombic, space group P2(1)2(1)2(1), a 10.005(1), b 10.524(1), c 25.731(2) Angstrom, Z = 4 and [Cu(N-Me(7)sar)](ClO4)(3).0.5H(2)O, orthorhombic, space group P2(1)2(1)2(1), a 11.337(2), b 12.802(2), c 22.170(2) Angstrom, Z = 4, are reported. The Ni(II). complexes exhibit marked solvent, temperature and pH-dependent electronic spectra as a result of high-spin/low-spin equilibria. Molecular mechanics calculations indicate that hexadentate coordination of N-Me(6)sar to metal ions such as Cu(II) and Ni(II) will be unfavorable as a result of severe steric strain.

A range of structurally different cage complexes are shown to be incorporated in high concentrations in thin (ca.0.5–5 μm) Nafion® films covering graphite electrodes. The incorporated cage complexes show well-defined cyclic and square-wave voltammograms with reduction potential shifts which reflect the biphasic hydrophilic and hydrophobic composition of Nafion®. The large partition ratios relative to aqueous electrolyte solution also have interesting analytical perspectives. Finite film-thickness effects are reflected in deviations from linear Randles-Sevcik plots at small scan rates. The concentration dependence of the apparent diffusion coefficients obtained from the linear part of the Randles-Sevik plots points to mobility of the cage complexes rather than electron hopping as the dominating charge transport mechanism. Both diffusion and migration appear important. Nafion® + cage compound electrodes in contact with buffer solutions containing cytochrome c or plastocyanin have so far not shown voltammetric signal changes compared with the signal from the Nafion® + cage compound electrodes in protein-free buffer. However, the question of cage compound-protein electron exchange is unresolved at present. Glucose oxidase is denatured at the interface with subsequent transport and adsorption of the flavin group in the Nafion® film region.

The cage complexes [Co{(NMe(2))(2)sar}](3+) and [Co{(NMe(2),Me)sar}](3+) (sar = sarcophagine = 3,6,10,13,16,19 hexaazabicyclo[6.6.6]icosane; (NMe(2))(2)sar 1,8-bis(dimethylamino)sarcophagine; (NMe(2),Me)sar 1-(dimethylamino)-8-methylsarcophagine) are obtained by methylation of amino substituents on the parent cage complexes using formaldehyde and formic acid. Further methylation with methyl iodide in dimethyl sulfoxide, or with dimethyl sulfate in N,N-dimethylformamide, converts the dimethylamino substituents to trimethylammonium substituents and essentially inverts the circular dichroism (CD) spectrum in comparison to that of the protonated parent cage complex, [Co{(NH3)(2)sar}](5+). A combination of NMR and electronic spectroscopic measurements indicates that the inversion of the CD spectra is due to conformational inversions in the 1,2-ethanediamine rings from mainly a lel conformation in [Co{(NH3)(3)sar}](5+) to an obs conformation in [Co{(NMe(3))(2)sar}](5+), (without inversion at any of the seven stereogenic centers; Co plus six coordinated amines). This ob(3) conformation was identified in the solid state by an X-ray crystallographic analysis of [Co{(NMe(3))(2)sar}](NO3)(5).3H(2)O: monoclinic, P2(1)/n, a 14.382(4) Angstrom, b = 14.604(3) Angstrom, c 16.998(6) Angstrom, beta = 100.28(3)degrees, Z= 4. The electron self-exchange rate constant of the [Co((NMe(3))2sar)](5+/4+) redox couple (+0.05 V vs NHE, 0.011(1) M(-1) s(-1) at 25 degrees C, I = 0.2 M (NaCl)) is a factor of 2 smaller than that of the [Co((NH3)2sar)](5+/4+) couple under the same conditions and is the slowest electron-transfer rate so far measured for a hexaamine cage complex of this type. However, it is still much faster than those of the parent [Co(en)(3)](3+/2+) and [Co(NH3)(6)](3+/2+) couples. This paper also provides hard evidence for the conformations of other Co(III) cage complexes in solution as well as the solid state.

The encapsulation of transition metal ions by hexa-amine ligands of the sarcophagine type permits their electronic and spectroscopic properties to be studied in a magnetically dilute and kinetically inert environment. In particular, the saturated nature of the amine yields a cryptand of the innocent kind so that the ligand field absorption of the metal containing cages is not obscured by intense charge transfer bands. This paper presents the results of magnetic, vis-UV spectroscopic and NMR measurements on a series of hexa-aza Werner complexes of encapsulated divalent iron performed over a range of temperature. The data reveal that both low-spin and high-spin isomers of the iron(II) cages coexist in solution. The temperature dependence of the physical parameters is characteristic of a spin equilibrium between molecular states of 1A1g and 5T2g origin.

The three monodentate pentaamminecobalt(III) linkage isomers of glycinamide have been synthetized and characterized by visible and 1 H and 13 C NMR spectroscopy and microanalysis. A nitrile-bonded ammonioacatonitrile complex was synthesized, it reacts in liquid ammonia to produce the amidine-bonded aminoacatamidine complex while in aqueous base it hydrolyzes to the amido-N-bonded glyanamida ion. Both [(NH 3 ) 5 CoNHCOCH 2 NH 2 ] 2+ and [(NH 3 ) 5 CoNHC(OH)CH 2 NH 3 ] 2+ have been isolatad

Electron transfer kinetics for the reduction of spinach plastocyanin and horse cytochrome c by several cobalt-cage complexes have been determined. The reduction of plastocyanin by [Co((N(CH 3 ) 3 ) 2 -sar)] 4+ shows saturation kinetics with K Co(II) = (1.5±0.2)×10 3 M -1 , and κ' et =4.0±0.2 s -1 . This reaction is stereoselective (κ Δ /κ Δ = 1.7) and the stereoselectivity is independent of ionic strength.

The redox potentials, E 1/2 , for the reversible cobalt (III/II) redox couples of complexes of substituted macrobicyclic ligands derived from 3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane show a substantial variation with the type of substituent. The variation was subjected to a Hammett type treatment yielding a series of inductive or polar substituent constants σ E that correlate with the organic substituent constants obtained by a variety of other methods

Various (α-amino acidato) cobalt (III) complexes have been treated with SOCl 2 in DMF. Provided the amino acid side chain does not contain functionalities that react with SOCl 2 , the complex undergoes a facile oxidation to give the related α-imino acidato complex. A mechanism is proposed for these reactions

Low-spin hexadentate cobalt(II) and cobalt(III) complexes of the hexathioether cage (1,8-dimethyl-3,6,10,13,16,19-hexathiabicyclo[6.6.6]icosarie) have been synthesised, their redox and spectral properties have been investigated, and the encapsulation of the cobalt(II) ion has been established by an X-ray crystal structure determination, which shows the metal ion to be coordinated to six thioether sulphur atoms at distances ranging from 2.265(3) to 2.354(2)A.

Conversion of chelated homoserine to 2-amino-4-bromobutyrate and treatment with aqueous base leads directly to chelated 1-aminocyclopropane-1-carboxylate.

The cobalt(III) complex of the large hexathioether cage (1,9-dimethyl-3,7,11,15,18,22-hexathiabicyclo[7.7.7]tricosane) shows substantially different redox and spectral properties relative to the smaller homologous [6.6.6]icosane.

A new strategy has been developed to attach N-methylpyridine and its derivatives simply and directly to the CoIII sarcophagine cage frame (sar = 3,6,10,13,16,19-hexaazsbicyclo[6.6.6]icosane).

This paper describes aspects of the synthesis of cage complexes in relation to their prospects for use in biology. The means of attaching peptides, cholestane, paraffin tails and aromatic residues are outlined. Also, the properties of some of these molecules, especially a new class of detergents, a new polymer able to capture metal ions, the selectivity of the cages for metal ions and the DNA intercalating properties of aromatic residues attached to the cages are discussed.

The reaction of [NH4]2[OsBr6] with neat 1,2-ethanediamine (en) yields cis-[Os(en-H)2(en)]Br2, which is recrystallized as cis-[Os(en-H)2(en)]I·Br in 40–50% yield. [Os(en)3]Br3·2H2O is obtained from the filtrate in ∼ 40% yield by the addition of EtOH, to give a recovery of ∼ 90% of osmium 1,2-ethanediamine complexes. This cis[Os(en-H)2(en)]2+ complex protonates to form [Os(en-H)(en)2]3+ and both OsIV complexes have been characterized by 1H and 13C NMR, IR and UV-Vis spectroscopies. Since the NH exchange rate for the doubly deprotonated OsIV complex is slow at the amido sites their cis relationship is maintained. The OsIV complexes are reduced readily to [Os(en)3]3+ by a variety of reductants. A reversible OsIII/II couple is observed at −0.52 V versus NHE in 0.1 M NaCF3SO3. All of these complexes are oxidized in air to form [Os(en)2(diim)]2+ (diim=ethanediimine) and [Os(en)(diim)2]2+ as the eventual product. The latter were characterized by 1H and 13C NMR, UV-Vis and IR spectroscopy. The mechanism of the dehydrogenation reaction is discussed in detail, in relation to related Fe and Ru amine chemistry.

The electrochemical reduction of [Cu II (sar)] 2+ ion 1 in aqueous solution is essentially irreversible and leads to extrusion of Cu from the cage, leaving the organic framework intact. This extrusion process also appeared to be very rapid on the cyclic voltammetry time scales available (up to 200 V/s). We were prompted, therefore, to look at the reduction process by pulse radiolysis over a shorter time scale (ns→10 ms) using the hydrated electron in order to probe for the events which lead to extrusion of the metal ion in such a facile way

Chelate complexes derived from 2-imino carboxylato ligands contain both electrophilic and nucleophilic sites for reaction. To explore both the utility and control of these properties, reactions of the simple pyruvate imine complex [(NH 3 ) 4 Co(NH=C(CH 3 )CO 2 )] 2+ with a variety of polyfunctional molecules have been examined. Diethyl oxaloacetate reacts to provide a substituted pyridine, showing that the previously observed reaction of the complex with biacetyl to give a pyrroline can be varied to provide to other heterocycles

The oxidation of bis(1,2-ethanediamine)(sarcosinato)cobalt(III) ion with SOCl2 in dimethylformamide gave the N-methylthiooxamato complex as the final product. The results, along with others, implicate the acid chloride chelate, a sulfine, and the methyl thiooxamato chelate as intermediates en route. The thiooxamato sulfur atom retains a nucleophilic capability and adds readily to cyclohexene in the thionyl chloride-dmf reaction medium to give an unusual imido hydroxycyclohexane thioester complex. Various results, including those in this paper, indicate that the chelated acid chloride readily loses an alpha-carbon proton and the resulting carbanion captures SOCl+. Elimination of HCl yields the sulfine and further addition of SOCl+, eliminations, and rearrangement yield chelated thiooxamate, which reacts even further under the pseudo-Vilsmeier conditions to the N-methyloxamato chelate complex.

Chelated 4-hydroxypyrrolidine-2-carboxylic acid bound to the cobalt(III) ion reacts with thionyl chloride in dimethylformamide to give the chelated 4-hydroxy- and 4-chloro-2-pyrroline-2-carboxylato complexes via an established route for oxidising chelated amino acids to imino acids. Thionyl chloride also partly chlorinates the hydroxyamino acid to give the chloro derivative. Both the substituted pyrrolinecarboxylato complexes undergo rapid base catalysed eliminations to give the chelate [Co(en)2(L4)]Cl·2H2O (H2L4= pyrrole-2-carboxylic acid, en = ethane-1,2-diamine). The product is identical with that prepared from the pyrrole-2-carboxylate ion and [Co(en)2(OH)(OH2)]2+. The reactivity of the pyrrole carboxylate chelate towards electrophiles is very different from that of the free ligand.