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PubMed2002

Cadmium cyclam complexes: interconversion of cis and trans configurations and fixation of CO(2).

There is current interest in the antiviral activity of metal, especially zinc, cyclam (1,4,8,11-tetraazacyclotetradecane) complexes. Their biological activity appears to be dependent on recognition of membrane proteins (viral coreceptors) and therefore on their configurations. Here, we use Cd(II) as a probe for Zn(II) on account of its useful NMR properties. We have prepared and characterized Cd(II) complexes of cyclam, Cd(cyclam)(ClO(4))(2) (1), Cd(cyclam)Cl(2) (2), and [Cd(3)(cyclam)(3)(CO(3))](ClO(4))(4).3H(2)O (3), and have identified key markers for various configurations adopted by these complexes under a variety of solution conditions using 1D and 2D (1)H, (13)C, (15)N, and (111)Cd NMR spectroscopy, including Karplus-type analyses of (1)H, (1)H and (1)H, (111)Cd coupling constants. These complexes were stable at high pH (>8.2) but dissociated completely on lowering the pH to 5.3. Two major configurations of both 1 and 2 exist in aqueous solution: trans-I (R,S,R,S at nitrogen) and cis-V (R,R,R,R). (3)J((111)Cd, (1)H) coupling constants showed that the five-membered rings of the trans-I configuration adopt the eclipsed conformation, and the six-membered rings adopt chair conformations. The X-ray crystal structure of 3 shows that the cation adopts the unusual folded cis-I configuration in which all of the N-H bonds are oriented up (or down) in a novel tri-cadmium cluster. This complex contains triply bridged carbonate fixed from atmospheric CO(2). Each Cd(II) is bound by two cis oxygen atoms from CO(3)(2-) (Cd-O bond lengths 2.373 and 2.412 A) and four nitrogen atoms from cyclam (C-N bond lengths 2.270-2.323 A). The geometry can be described as trigonal bipyramidal with the two donor oxygen atoms occupying one of the apices of the in-plane triangle. In acetonitrile solution, complex 3 gives rise to only one configuration, trans-I, with eclipsed five-membered rings, and six-membered rings with chair conformations.

Cadmium↗
PubMed2004

Structural, spectroscopic, and computational study of an octahedral, non-heme [Fe-NO](6-8) Series: [Fe(NO)(cyclam-ac)]2+/+/0.

The reaction of low-spin [FeIICl(cyclam-ac)] with NO in CH3CN yields the octahedral, non-heme (nitrosyl)iron complex [Fe(NO)(cyclam-ac)](PF6) (2), S = 1/2, which can be one-electron oxidized with (tris(4-bromophenyl)ammoniumyl)hexachloroantimonate to the complex [Fe(NO)(cyclam-ac)](PF6)2 (1'), S = 0, or complex [Fe(NO)(cyclam-ac)]Cl(ClO4).H2O (1); (cyclam-ac)- represents the pentadentate monoanion of 1,4,8,11-tetraazacyclotetradecane-1-acetic acid. Similarly, in CH3CN solution 2 can be electrochemically or chemically reduced by one-electron to the neutral complex [Fe(NO)(cyclam-ac)]0 (3), S = 0. 1-3 represent members of the [FeNO]6-8 series, respectively. The electronic structure of these three species have been spectroscopically elucidated by EPR, UV-vis, Mössbauer, and IR spectroscopy. The crystal structures of 1 and 2 have been determined by X-ray crystallography. In addition, detailed density functional calculations have been performed for all three species taking into account the possibility that 3 is actually a protonated HNO or NOH species. For all complexes structures, energetics, IR parameters, and Mössbauer parameters as well as EPR parameters (g-values and hyperfine couplings) have been calculated using state-of-the art DFT methods which are compared to experiment. The results establish unequivocally that 3 is indeed the elusive [FeNO]8 species. Furthermore a detailed picture of the bonding in the low-spin non-heme iron nitrosyl series [FeNO]6, [FeNO]7, and [FeNO]8 has been developed. This allows a description of 1 as a low-spin ferrous complex containing an N-coordinated NO+, whereas 2 is a low-spin ferrous species with a NO* ligand and 3 is a low-spin ferrous complex with a coordinated NO-. On the basis of this description, all spectroscopic and geometric observables find a satisfactory interpretation.

Journal Article↗
PubMed2004

Cyclam-based dendrimers as ligands for lanthanide ions.

We have investigated the complexation of lanthanide ions (Nd3+, Eu3+, Gd3+, Tb3+, Dy3+) with three cyclam-based ligands (cyclam = 1,4,8,11-tetraazacyclotetradecane), namely 1,4,8,11-tetrakis(naphthylmethyl)cyclam (1), and two dendrimers consisting of a cyclam core appended with four dimethoxybenzene and eight naphthyl units (2) and twelve dimethoxybenzene and sixteen naphthyl units (3). In the free ligands the fluorescence of the naphthyl units is strongly quenched by exciplex formation with the cyclam nitrogens. Complexation with the metal ions prevents exciplex formation and revives the intense naphthyl fluorescence. Fluorescence and NMR titration experiments have revealed the formation of complexes with different metal/ligand stoichiometries in the case of 1, 2 and 3. Surprisingly, the large dendrimer 3 gives rise to a stable [M(3)3]3+ species. Energy transfer from the lowest singlet and triplet excited states of the peripheral naphthyl units to the lower lying excited states of Nd3+, Eu3+, Tb3+, Dy3+ coordinated to the cyclam core does not take place.

Journal Article↗
PubMed2001

[Ni(cyclam)(OCOR)2], a finite molecular complex: hydrogen-bonded supramolecular aggregation in one, two and three dimensions, and coordination polymers in one and two dimensions.

In the complexes [Ni(cyclam)(OCOR)2] (cyclam = 1,4,8,11-tetraazacyclotetradecane), where (RCOO)- is 2-naphthoate [bis-(2-naphthoato)-1,4,8,11-tetraazacyclotetradecanenickel(II), (I), monoclinic P2(1)/c, Z' = 0.5], 3,5-dinitrobenzoate [bis-(3,5-dinitrobenzoato)-1,4,8,11-tetraazacyclotetradecanenickel(II), (II), triclinic P1, Z' = 0.5], 4-nitrobenzoate [bis-(4-nitrobenzoato)-1,4,8,11-tetraazacyclotetradecanenickel(II), (III), monoclinic P2(1)/n, Z' = 0.5], 3-hydroxybenzoate [bis-(3-hydroxybenzoato)-1,4,8,11-tetraazacyclotetradecanenickel(II), (IV), monoclinic P2(1)/c, Z' = 0.5] and 4-aminobenzoate [bis-(4-aminobenzoato)-1,4,8,11-tetraazacyclotetradecanenickel(II), (V), monoclinic C2/c, Z' = 0.5], the Ni lies on a centre of inversion with monodentate carboxylato ligands occupying trans sites. Compound (I) consists of isolated molecules. In (II) and (III), N-H...O hydrogen bonds link the complexes into chains. Compounds (IV) and (III) form two- and three-dimensional structures generated entirely by hard hydrogen bonds. The 5-hydroxyisophthalate(2-) anion forms a hydrated complex, [Ni(cyclam)(5-hydroxyisophthalate)(H2O)]*4H2O [[aqua-(5-hydroxyisophthalato)-1,4,8,11-tetraazacyclotetradecanenickel(II)] tetrahydrate, (VI), monoclinic Cc, Z' = 1], in which the monodentate carboxylato ligand and a water molecule occupy trans sites at Ni: extensive hydrogen bonding links the molecular aggregates into a three-dimensional framework. The terephthalate(2-) anion forms a hydrated linear coordination polymer [catena-poly[terephthalato-1,4,8,11-tetraazacyclotetradecanenickel(II)] monohydrate, (VII), monoclinic C2/c, Z' = 0.5]. In 1,2,4,5-benzenecarboxylate tris[1,4,8,11-tetraazacyclotetradecanenickel(II)] diperchlorate hydrate (VIII), [Ni(cyclam)]3*[1,2,4,5-benzenetetracarboxylate(4-)]*[ClO4]2*[H2O]3, there are two distinct Ni sites: [Ni(cyclam)]2+ and centrosymmetric [C10H2O8]4- units form a two-dimensional coordination polymer, whose sheets are linked by centrosymmetric [Ni(cyclam)(H2O)2]2+ cations.

Journal Article↗
PubMed1977

Three cases of human bladder cancer following high dose cyclamate ingestion.

Vesical implantation and oral feeding studies in animals raised sufficient suspicion of the carcinogenic propensity of cyclamates to result in their withdrawal from sale throughout the world. The structural similarity to known carcinogens, an effect on human chromosomes in tissue culture and a high carcinogenic potential when combined with non-injurious co-carcinogens gave further support to this ban. On the other hand, numerous epidemiological studies failed to support any statistical relationship between cyclamate ingestion and vesical carcinoma in man. Three patients are described in whom vesical carcinoma developed after a prolonged period of ingestion of an unusually high amount of cyclamate sweetener. Moreover, the severity of the disease appeared to be proportional to the dose ingested. Although this is not a conclusive indictment of the role of cyclamates we believe that patients with bladder cancer should be questioned about intake of cyclamates either directly or in diet soft drinks.

Aged↗
PubMed2000

Determination of cyclamate in low-calorie foods by high-performance liquid chromatography with indirect visible photometry.

A rapid and simple method using reversed-phase high-performance liquid chromatography combined with indirect visible photometry at 433 nm was developed to determine cyclamate in some food samples. Cyclamate was not detected in these chosen samples as its use is banned in Hong Kong. Cyclamate can easily be detected in spiked samples using a mobile phase consisting of 30 mumol dm-3 Methyl Red and 0.02 mol dm-3 phosphate buffer (pH 7.0)-methanol in a volume ratio of 3:2. The column temperature was set at 23 degrees C. The detection limit was 0.14 mmol dm-3 and the relative standard deviation of the peak area response was 0.58% for a solution containing 5.0 mmol dm-3 of cyclamate (n = 8). This method was successfully applied to the analysis of eight spiked food samples and the cyclamate recoveries for these samples ranged from 93 to 99%.

Carcinogens↗
PubMed1986

Multistage transformation of cultured rat urothelium: the effects of N-methyl-N-nitrosourea, sodium saccharin, sodium cyclamate and 12-O-tetradecanoylphorbol-13-acetate.

Rat bladder epithelial cell transformation was found to involve at least three distinct phenotypic stages in vitro. The effects on this process of N-methyl-N-nitrosourea (MNU), sodium saccharin, sodium cyclamate and 12-O-tetradecanoylphorbol-13-acetate (TPA) alone or in combination were investigated. MNU was a potent inducer of proliferating preneoplastic epithelial foci. Sodium saccharin alone induced a transient hyperplastic response of the cultured urothelium but did not induce significantly more foci than in controls, though a late toxic effect of saccharin may have masked focus induction. In combination with a single dose of 250 micrograms/ml MNU, sodium saccharin did not increase focus incidence compared with MNU treatment alone but following a single treatment with 25 micrograms/ml MNU which alone induced no foci, saccharin induced a significant number of foci indicating a promoting effect under these conditions. Sodium cyclamate alone induced a marked and prolonged epithelial hyperplasia and a significant increase in focus incidence above controls and above MNU-treated cultures. Following a single treatment with 250 micrograms/ml MNU, cyclamate increased focus incidence still further. TPA, the potent skin tumour promoting agent, alone induced significantly more foci than in controls. Rapidly-proliferating cell lines were established from nine foci induced by treatment with MNU alone or MNU + saccharin. Four of these were tumorigenic. These results indicate that MNU is a potent inducer of preneoplastic foci in rat urothelial cultures. Sodium saccharin and sodium cyclamate can act as promoting agents in this in vitro system as in the in vivo induction of tumours and sodium cyclamate appears to be active as a complete inducer under these conditions.

Animals↗
PubMedDate not supplied

Spectrophotometric determination of cyclamate in foods: NMKL collaborative study.

A spectrophotometric method for the determination of cyclamate was collaboratively studied in 9 laboratories. Ethyl acetate is added to extract cyclamate from acidic aqueous solution into water, and the cyclamate is then quantitatively converted to N,N-dichlorocyclohexylamine by adding excess hypochlorite. N,N-Dichlorocyclohexylamine is determined by measuring its UV absorption at 314 nm. Six samples, 3 soft drinks with cyclamate levels of 0.36-0.47 g/kg and 3 jams with levels of 1.23-1.50 g/kg, were included in the study. Average recoveries of cyclamate were 99.7% in the soft drinks and 103.8% in the jams. Reproducibility coefficients of variation were 6.7% for the soft drinks and 4.4% for the jams.

Beverages↗
PubMed2004

Dendrimers as ligands: an investigation into the stability and kinetics of Zn2+ complexation by dendrimers with 1,4,8,11-tetraazacyclotetradecane (cyclam) cores.

We have investigated the complexation of Zn(2+) with 1,4,8,11-tetrakis(naphthylmethyl) cyclam (1; cyclam=1,4,8,11-tetraazacyclotetradecane) and with two dendrimers consisting of a cyclam core with four dimethoxybenzene and eight naphthyl appendages (2), and twelve dimethoxybenzene and sixteen naphthyl appendages (3). An important, common feature of model compound 1 and dendrimers 2 and 3 is that their potentially fluorescent naphthyl units are quenched by exciplex formation with the cyclam nitrogen atoms. Complexation with Zn(2+), however, prevents exciplex formation and results in the appearance of an intense naphthyl fluorescence signal that can be used for monitoring the complexation process. Luminescence titration, together with competition experiments and (1)H NMR titration, have shown that 1:1 and 1:2 (metal/ligand) complexes are formed in the cases of 2 and 3, whereas model compound 1 gives only a 1:1 complex. We have also investigated the 1:1 complexation kinetics by the stopped-flow technique. In the case of 1, a second-order process (k(1)=44x10(5) M(-1) s(-1)) is followed by two consecutive first-order steps (k(2)=0.53 s(-1) and k(3)=0.10 s(-1)). For 2, a slower second-order process (k(1)=4.9x10(5) M(-1) s(-1)) is followed by a slow first-order step (k(2)=0.40 s(-1)). In the case of 3, only a very slow second-order process was observed (k(1)=1.2x10(5) M(-1) s(-1)). The different metal-ion incorporation rates for model compound 1 and dendrimers 2 and 3 have been discussed in terms of conformational changes of the dendron subunits affecting the chelating properties of the cyclam core. This work reports the first kinetic study on metal-ion coordination by dendrimers with a well-defined coordination site.

Journal Article↗
PubMed2007

Configurations of nickel-cyclam antiviral complexes and protein recognition.

Nickel(II)-xylylbicyclam is a potent anti-HIV agent and binds strongly to the CXCR4 co-receptor. We have investigated configurational equilibria of Ni(II)-cyclam derivatives, since these are important for receptor recognition. Crystallographic studies show that both trans and cis configurations are readily formed: [Ni(cyclam)(OAc)(2)] x H(2)O adopts the trans-III configuration with axial monodentate acetates, as does [Ni(benzylcyclam)(NO(3))(2)] with axial nitrate ligands, whereas [Ni(benzylcyclam)(OAc)](OAc)2 x H(2)O has an unusual folded cis-V configuration with Ni(II) coordination to bidentate acetate. UV/Vis and NMR studies show that the octahedral trans-III configuration slowly converts to square-planar trans-I in aqueous solution. For Ni(II)-xylylbicyclam, a mixture of cis-V and trans-I configurations was detected in solution. X-ray diffraction studies showed that crystals of lysozyme soaked in Ni(II)-cyclam or Ni(II) (2)-xylylbicyclam contain two major binding sites, one involving Ni(II) coordination to Asp101 and hydrophobic interactions between the cyclam ring and Trp62 and Trp63, and the second hydrophobic interactions with Trp123. For Ni(II)-cyclam bound to Asp101, the cis-V configuration predominates.

Antiviral Agents↗
PubMed2001

Molecular and electronic structure of [Mn(V)N(cyclam-acetato)]PF6. A combined experimental and DFT study.

From the reaction of Li(cyclam-acetate), MnCl(2).4H(2)O, and KPF(6) in methanol brown microcrystals of [Mn(III)Cl(cyclam-acetato)]PF(6) (1) were obtained in the presence of air (cyclam-acetic acid = 1,4,8,11-tetraazacyclotetradecane-1-acetic acid). The reaction of 1 in aqueous NH(3) solution with NaOCl produced blue crystals of [Mn(V)N(cyclam-acetato)]PF(6) (2). Complexes 1 and 2 were characterized by single-crystal X-ray crystallography, IR and Raman, electronic absorption, and (1)H, (13)C, and (15)N NMR spectroscopies. Their magnetochemistry as well as their electrochemistry have been investigated. The complexes [MnN(cyclam-acetato)](+/2+) were studied by theoretical calculations at the DFT and semiempirical levels in order to obtain more insight into the ground and excited states of the Mn(V)(triple bond)N unit. Structural and spectroscopic parameters were successfully calculated and compared to experiment. A pictorial description of the bonding has been developed.

Journal Article↗
PubMed2004

Three-ring, branched cyclam derivatives and their interaction with nickel(II), copper(II), zinc(II) and cadmium(II).

The interaction of two symmetrically branched tris-cyclam derivatives based on 1,3,5-trimethylenebenzene and phloroglucinol cores with nickel(II), copper(II), zinc(II) and cadmium(II) is reported. All four metal ions yield solid complexes in which the metal : ligand ratio is 3 : 1. For both ligand types, spectrophotometric titrations confirm the formation of nickel(II) and copper(II) complexes of similar 3 : 1 stoichiometry in dimethyl sulfoxide. Visible spectral, electrochemical, magnetic moment, ESR and NMR studies have been performed to probe the nature of the respective complexes. Where appropriate, the results from the above metal-ion studies are compared with those from parallel investigations in which the corresponding (substituted) mono-cyclam analogues were employed as the ligands. A structural determination employing a poorly diffracting crystal of the trinuclear nickel(II) complex of the tris-cyclam ligand incorporating a 1,3,5-trimethylenebenzene core was successfully carried out with the aid of a synchrotron radiation source. A nickel ion occupies each cyclam ring in a square-planar coordination arrangement, with each cyclam ring adopting the stable trans-III configuration.

Journal Article↗
PubMed1989

Assessment of the genotoxicity of calcium cyclamate and cyclohexylamine.

Calcium cyclamate and its major metabolite cyclohexylamine have been subjected to numerous evaluations for genetic activity. With the exception of studies for chromosome damage, the results have been negative. Results from a wide range of in vitro and in vivo cytogenetic assays ranged from clearly negative to various degrees of clastogenicity. Interpretation of the cytogenetic studies has been complicated by the conflicting responses, although some of the positive effects seem to be the consequence of secondary effects produced by high ion levels and excessive toxicity. In the studies presented here calcium cyclamate and cyclohexylamine were tested for mutagenic activity using an in vitro mammalian cells assay for gene mutation and an in vitro unscheduled DNA synthesis assay in rat hepatocytes with the Drosophila sex-linked recessive lethal assay. Calcium cyclamate was not genetically active in any of the three assays when tested to the maximum possible concentrations. The compound was largely nontoxic but did show some evidence of cytotoxicity in rat hepatocytes at concentrations of 1 mg/ml and higher. Cyclohexylamine was also negative in the three assays, but was considerably more cytotoxic at the concentrations used. The results from the three studies conducted in this evaluation are in general agreement with the majority of published genetic toxicology data for these two chemicals and indicated that the calcium cyclamate and cyclohexylamine have no direct, intrinsic genotoxicity of the type measured by these assays.

Animals↗
PubMed1988

Effects of sodium cyclamate and sodium saccharin on focus induction in explant cultures of rat bladder.

The tumour-promoting activities of sodium cyclamate and sodium saccharin were investigated in an assay based on the induction of epithelial foci exhibiting enhanced growth potential in a rat bladder explant culture system. An initiating, non-focus-inducing dose was defined for the carcinogen N-methyl-N-nitrosourea (MNU) to make promotion studies possible. Saccharin induced epithelial foci when added to cultures pretreated with an initiating dose of MNU, and also increased the incidence of foci in cultures treated with transforming doses of MNU. Cyclamate was found to induce a high incidence of foci when added to cultures by itself. When MNU and cyclamate treatments were combined, an additive effect could be detected. These results indicate that both cyclamate and saccharin can contribute to epithelial transformation in this system.

Animals↗
PubMed1975

Evaluation of a new model to detect bladder carcinogens or co-carcinogens; results obtained with saccharin, cyclamate and cyclophosphamide.

A sensitive rat model has been designed to detect potential weak bladder carcinogens or co-carcinogens. The test compound is given to animals which have received a single initiating, but non-carcinogenic, dose of N-methyl-N-nitrosourea (MNU). The model has been used to investigate two compounds currently under suspicion as weak bladder carcinogens, namely sodium saccharin and sodium cyclamate, and one compound known to be cytotoxic but not carcinogenic for the bladder epithelium namely cyclophosphamide. For comparison, these three compounds were also tested as solitary carcinogens in animals not pre-treated with MNU. At the very high dose levels used, sodium saccharin and sodium cyclamate were weak solitary carcinogens producing 4/253 and 3/228 bladder tumours respectively, and the first of these tumours did not appear for more than 80 weeks. When tested in the MNU/rat model more than half the animals receiving either sodium saccharin or sodium cyclamate developed bladder tumours from 10 weeks onwards. By contrast, cyclophosphamide failed to produce any tumours when tested either as a solitary carcinogen or in the MNU/rat model. It must be emphasized that the doses of saccharin and cyclamate used were far higher than those consumed by man, including diabetics, and these results should not be directly extrapolated to man without careful consideration of many other factors including negative epidemiological findings. The theoretical basis of the model is discussed and also the relevance, in terms of environmental human exposure, of detecting compounds which have a synergistic effect with other known bladder carcinogens. It appears that this model can be used to detect a carcinogenic or co-carcinogenic potential in compounds which are organotropic for the bladder more rapidly and with fewer animals than if the compounds are tested as solitary carcinogens by more conventional methods. It is suggested that it could be used to detect those compounds which require further investigation.

Administration, Oral↗
PubMed1985

Metabolic adaptation of rat faecal microflora to cyclamate in vitro.

Previous studies have demonstrated that the rat faecal microflora maintained in vitro under conditions of continuous flow possesses bacteriological and metabolic characteristics similar to those of the native bacterial population of the caecum. Addition of sodium cyclamate (75 mM) to the culture concurrent with the progressive dilution of the growth medium promoted metabolism of cyclamate to cyclohexylamine (sulphamatase activity) within 4 wk. The maximum formation of cyclohexylamine was attained in about 8 wk and was equivalent to a 2-3% molar conversion of cyclamate to cyclohexylamine. The recovery of viable cells from the culture and the total microscopic count decreased during the adaptation period, although the relative proportions of the major bacterial types remained unchanged. Concurrent with the increase in sulphamatase activity, other enzyme functions (as assessed by the API-zym system) decreased markedly. The ability to hydrolyse cyclamate to cyclohexylamine developed independently of other bacterial biotransformation enzymes in vitro, and was not associated with any gross taxonomic changes. These studies demonstrate the suitability of continuous culture systems for investigating the metabolic activity of the rat gut flora.

Adaptation, Biological↗
PubMed2004

The metabolism of cyclamate to cyclohexylamine in humans during long-term administration.

A group of 14 subjects, who had been identified from 261 volunteers in a 1-week screen as being able to metabolize the sweetener cyclamate to cyclohexylamine (>0.2% of a daily dose), and 31 nonconverters (<0.2% metabolism) were given calcium cyclamate tablets (equivalent to 250 mg cyclamic acid, 3 times daily) for a period of 13 weeks. The metabolism of cyclamate to cyclohexylamine was determined using twice-weekly timed (3 h) urine collections during week 1-3 and 7-13. Urine specimens were collected on all other study days to investigate day-to-day fluctuations in cyclohexylamine excretion. Analyses of the twice weekly timed urine collections showed that subjects recruited as nonconverters essentially remained nonconverters. Of the converters, three showed consistently low metabolism, five showed erratic metabolism, five showed low metabolism initially, which increased during the latter part of the study, and one subject showed consistently high metabolism throughout the study. Analysis of the day-to-day urine specimens showed marked intrasubject variability. The plasma concentrations of cyclohexylamine measured on weeks 1-3 and 7-13 reflected the urine profiles. The highest individual long-term average steady-state excretion values based on the 3-h urine collections and daily samples were 21%, 23%, 25%, 29%, 34%, and 38%. The maximum % metabolism detected in the high converters occasionally reached the value of 60% reported in previous short-term studies, but this high activity was not maintained, and was followed by periods of lower metabolism. The results of this metabolism study support an acceptable daily intake (ADI) of 0-11 mg/kg body weight per day.

Adult↗
PubMed2004

Inside or outside a ligand cleft? Synthetic, structural, and kinetic inertness studies of zinc, cadmium, and mercury complexes of cross-bridged cyclam and cyclen.

Ethylene cross-bridging of the popular tetraazamacrocyclic ligand cyclam has led to metal complexes with enhanced kinetic inertness. The synthesis and spectral characterization of zinc(II), cadmium(II), and mercury(II) complexes of cross-bridged cyclam (L1) as well as cross-bridged cyclen (L2) are reported along with the details of our synthetic route to L2. X-ray structural studies revealed that all Zn(II) and Cd(II) cations are fully kappa(4)N-coordinated inside the respective ligand's molecular cleft with L1 providing the better fit for Zn(II). While Hg(II) is similarly coordinated to L2, it has been found to complex L1 outside the ligand cleft in a novel exo-kappa(2)N-mode. Solution NMR data of the kappa(4)N complexes are consistent with the presence of only a single cis-folded isomer in each case. Ligand (1)H and (13)C coupling to both (111,113)Cd and (199)Hg in their complexes can be clearly discerned. The relative kinetic inertness of representative cross-bridged complexes in acidic aqueous solution has been assessed and found to be in the following order: Zn(II) > Cd(II)[dbl greater-than] Hg(II). The data also reaffirm that cross-bridged cyclam ligand L1 forms a substantially more inert complex with zinc(II) than either the smaller cyclen analogue L2 or the unbridged 1,4,8,11-tetramethyl-cyclam L3.

Bridged-Ring Compounds↗