Cyclam Ligand Research Articles

Lanthanide(III) complexes with a reinforced cyclam ligand show unprecedented kinetic inertness.

Lanthanide(III) complexes of a cross-bridged cyclam derivative containing two picolinate pendant arms are kinetically inert in very harsh conditions such as 2 M HCl, with no dissociation being observed for at least 5 months. Importantly, the [Ln(dota)](-) complexes, which are recognized to be extremely inert, dissociate under these conditions with lifetimes in the range ca. 1 min to 12 h depending upon the Ln(3+) ion. X-ray diffraction studies reveal octadentate binding of the ligand to the metal ion in the [Eu(cb-tedpa)](+) complex, while (1)H and (13)C NMR experiments in D2O point to the presence of a single diastereoisomer in solution with a very rigid structure. The structure of the complexes in the solid state is retained in solution, as demonstrated by the analysis of the Yb(3+)-induced paramagnetic shifts.

Spectroscopic characterization and reactivity studies of a mononuclear nonheme Mn(III)-hydroperoxo complex.

We report the first example of a mononuclear nonheme manganese(III)–hydroperoxo complex derived from protonation of an isolated manganese(III)–peroxo complex bearing an N-tetramethylated cyclam (TMC) ligand, [MnIII(TMC)(OOH)]2+. The MnIII-hydroperoxo intermediate is characterized with various spectroscopic methods as well as with density functional theory (DFT) calculations, showing the binding of a hydroperoxide ligand in an end-on fashion. The MnIII–hydroperoxo species is a competent oxidant in oxygen atom transfer (OAT) reactions, such as the oxidation of sulfides. The electrophilic character of the MnIII–hydroperoxo complex is demonstrated unambiguously in the sulfoxidation of para-substituted thioanisoles.

Highly Reactive Nonheme Iron(III) Iodosylarene Complexes in Alkane Hydroxylation and Sulfoxidation Reactions

AbstractHigh‐spin iron(III) iodosylarene complexes bearing an N‐methylated cyclam ligand are synthesized and characterized using various spectroscopic methods. The nonheme high‐spin iron(III) iodosylarene intermediates are highly reactive oxidants capable of activating strong CH bonds of alkanes; the reactivity of the iron(III) iodosylarene intermediates is much greater than that of the corresponding iron(IV) oxo complex. The electrophilic character of the iron(III) iodosylarene complexes is demonstrated in sulfoxidation reactions.

Highly reactive nonheme iron(III) iodosylarene complexes in alkane hydroxylation and sulfoxidation reactions.

High-spin iron(III) iodosylarene complexes bearing an N-methylated cyclam ligand are synthesized and characterized using various spectroscopic methods. The nonheme high-spin iron(III) iodosylarene intermediates are highly reactive oxidants capable of activating strong C-H bonds of alkanes; the reactivity of the iron(III) iodosylarene intermediates is much greater than that of the corresponding iron(IV) oxo complex. The electrophilic character of the iron(III) iodosylarene complexes is demonstrated in sulfoxidation reactions.

Synthesis and antimalarial activity of metal complexes of cross-bridged tetraazamacrocyclic ligands

Using transition metals such as manganese(II), iron(II), cobalt(II), nickel(II), copper(II), and zinc(II), several new metal complexes of cross-bridged tetraazamacrocyclic chelators namely, cyclen- and cyclam-analogs with benzyl groups, were synthesized and screened for in vitro antimalarial activity against chloroquine-resistant (W2) and chloroquine-sensitive (D6) strains of Plasmodium falciparum. The metal-free chelators tested showed little or no antimalarial activity. All the metal complexes of the dibenzyl cross-bridged cyclam ligand exhibited potent antimalarial activity. The Mn2+ complex of this ligand was the most potent with IC50s of 0.127 and 0.157μM against the chloroquine-sensitive (D6) and chloroquine-resistant (W2) P. falciparum strains, respectively. In general, the dibenzyl hydrophobic ligands showed better anti-malarial activity compared to the activity of monobenzyl ligands, potentially because of their higher lipophilicity and thus better cell penetration ability. The higher antimalarial activity displayed by the manganese complex for the cyclam ligand in comparison to that of the cyclen, correlates with the larger pocket of cyclam compared to that of cyclen which produces a more stable complex with the Mn2+. Few of the Cu2+ and Fe2+ complexes also showed improvement in activity but Ni2+, Co2+ and Zn2+ complexes did not show any improvement in activity upon the metal-free ligands for anti-malarial development.

Mechanistic Insights into the C–H Bond Activation of Hydrocarbons by Chromium(IV) Oxo and Chromium(III) Superoxo Complexes

The mechanism of the C-H bond activation of hydrocarbons by a nonheme chromium(IV) oxo complex bearing an N-methylated tetraazamacrocyclic cyclam (TMC) ligand, [Cr(IV)(O)(TMC)(Cl)](+) (2), has been investigated experimentally and theoretically. In experimental studies, reaction rates of 2 with substrates having weak C-H bonds were found to depend on the concentration and bond dissociation energies of the substrates. A large kinetic isotope effect value of 60 was determined in the oxidation of dihydroanthracene (DHA) and deuterated DHA by 2. These results led us to propose that the C-H bond activation reaction occurs via a H-atom abstraction mechanism, in which H-atom abstraction of substrates by 2 is the rate-determining step. In addition, formation of a chromium(III) hydroxo complex, [Cr(III)(OH)(TMC)(Cl)](+) (3), was observed as a decomposed product of 2 in the C-H bond activation reaction. The Cr(III)OH product was characterized unambiguously with various spectroscopic methods and X-ray crystallography. Density functional theory (DFT) calculations support the experimental observations that the C-H bond activation by 2 does not occur via the conventional H-atom-abstraction/oxygen-rebound mechanism and that 3 is the product formed in this C-H bond activation reaction. DFT calculations also propose that 2 may have some Cr(III)O(•-) character. The oxidizing power of 2 was then compared with that of a chromium(III) superoxo complex bearing the identical TMC ligand, [Cr(III)(O2)(TMC)(Cl)](+) (1), in the C-H bond activation reaction. By performing reactions of 1 and 2 with substrates under identical conditions, we were able to demonstrate that the reactivity of 2 is slightly greater than that of 1. DFT calculations again support this experimental observation, showing that the rate-limiting barrier for the reaction with 2 is slightly lower than that of 1.

Syntheses and solid state structures of cyclam-based copper and zinc compounds

Copper(II) and zinc(II) complexes of general formula [{H2(4−BtuPhCH2)2Cyclam}Cu]SO4, 1, [{H2(PhCH2)2Cyclam}Cu]X, (X = SO4, 2; X = (CH3COO)2, 3), [{H2(PhCH2)2Cyclam}Zn]SO4, 5, and [{H2(PhCH2)2Cyclam)}ZnCl]Cl, 6, were prepared by reaction of H2Bn2Cyclam (Bn = PhCH2 or 4−BtuPhCH2) with one equiv. of the appropriate Cu(II) or Zn(II) salt.The preparation of Cu(II) complexes of general formula [{H2(MeOCH2)2Cyclam}Cu]X (X = SO4, 7, (CH3COO)2, 8, and CuCl4, 9) displaying a modified cyclam ligand with two N-CH2OMe pending arms was achieved by nucleophilic attack of methanol to the bridging methylene groups of 1,4,8,11-tetraazatricyclo[9.3.1.14,8]hexadecane in a Cu2+ mediated process.

Synthesis, characterization, and reactivity of cobalt(III)-oxygen complexes bearing a macrocyclic N-tetramethylated cyclam ligand.

Mononuclear metal-dioxygen species are key intermediates that are frequently observed in the catalytic cycles of dioxygen activation by metalloenzymes and their biomimetic compounds. In this work, a side-on cobalt(III)-peroxo complex bearing a macrocyclic N-tetramethylated cyclam (TMC) ligand, [Co(III) (15-TMC)(O2 )](+) , was synthesized and characterized with various spectroscopic methods. Upon protonation, this cobalt(III)-peroxo complex was cleanly converted into an end-on cobalt(III)-hydroperoxo complex, [Co(III) (15-TMC)(OOH)](2+) . The cobalt(III)-hydroperoxo complex was further converted to [Co(III) (15-TMC-CH2 -O)](2+) by hydroxylation of a methyl group of the 15-TMC ligand. Kinetic studies and (18) O-labeling experiments proposed that the aliphatic hydroxylation occurred via a Co(IV) -oxo (or Co(III) -oxyl) species, which was formed by OO bond homolysis of the cobalt(III)-hydroperoxo complex. In conclusion, we have shown the synthesis, structural and spectroscopic characterization, and reactivities of mononuclear cobalt complexes with peroxo, hydroperoxo, and oxo ligands.

Oxidation of hydrogen peroxide by [NiIII(cyclam)]3 + in aqueous acidic media

The kinetics of oxidation of H2O2 by [NiIII(cyclam)]3 + , [NiIIIL1], was studied in aqueous acidic media at 25°C and I = 0.5 M (NaClO4). The [NiIIIL1] to [NiIIL1] reduction was found to be fast in the presence of Cu(II) ion than the oxidation of the cyclam ligand by \(^{\boldsymbol{\cdot}}\)OH. The rate constant showed an inverse acid dependence on H + ion at the pH range 1–1.5. The presence of sulphate retards the reaction. Macrocylic ligand oxidation was followed spectrophotometrically by examining the oxidation of nickel(II) complexes of macrocyclic ligands such as 1,8-bis(2-hydroxyethyl)-1,3,6,8,10,13-hexaazacyclotetradecane (L2), ms-5,7,7,12,14,14-hexamethyl-1,4,8,11-tetraazacyclotetradecane (L3), rac-Me6[14]-4,11-dieneN4 (L4) by reaction with hydrogen peroxide. The rate constant for the cross reaction is discussed in terms of Marcus relationship. The kinetic study of oxidation of H2O2 by [Ni(cyclam)]3 + (cyclam = 1,4,8,11- tetraazacycloteradecane) was catalysed by Cu(II) ions in aqueous acidic medium and a suitable mechanism was proposed. The effect of sulphate was studied.

Cross-Bridged Cyclen or Cyclam Co(III) Complexes Containing Cytotoxic Ligands as Hypoxia-Activated Prodrugs

A series of cobalt(III) complexes of the potent DNA minor groove alkylator (1-(chloromethyl)-5-hydroxy-1H-pyrrolo[3,2-f]quinolin-3(2H)-yl)(5,6,7-trimethoxy-1H-indol-2-yl)methanone (3; seco-CPyI-TMI), with cyclam or cyclen auxiliary ligands (L3 and L5) containing a cross-bridging ethylene (CH2CH2) group or the N,N'-dimethyl derivatives of these (L4 and L6), was prepared. Two 8-quinolinato (2) model complexes of these, [Co(L3)(2)](ClO4)2 and [Co(L6)(2)](ClO4)2, and the aquated derivative [Co(L6)(H2O)2](OTf)3 were characterized by X-ray crystallography. Electrochemistry of the 8-quinolinato model complexes showed that the Co(III)/(II) reduction potential was lowered relative to the unsubstituted cyclen ligand. Evaluation of the cytotoxicity of the racemic seco-CPyI cobalt complexes in vitro showed considerable attenuation of their cytotoxicity relative to the free alkylator and marked hypoxic selectivity, especially [Co(L3)(3)](2+) (9), which was 81-212-fold more potent under hypoxia than 20% oxygen in a panel of 10 human tumor cell lines. However, 9 did not elicit significant killing of hypoxic cells in HT29 tumor xenografts, suggesting possible pharmacological limitations in vivo.

A Mononuclear Non-Heme High-Spin Iron(III)–Hydroperoxo Complex as an Active Oxidant in Sulfoxidation Reactions

We report the first direct experimental evidence showing that a high-spin iron(III)-hydroperoxo complex bearing an N-methylated cyclam ligand can oxidize thioanisoles. DFT calculations showed that the reaction pathway involves heterolytic O-O bond cleavage and that the choice of the heterolytic pathway versus the homolytic pathway is dependent on the spin state and the number of electrons in the d(xz) orbital of the Fe(III)-OOH species.

Lewis-Acid-Promoted Stoichiometric and Catalytic Oxidations by Manganese Complexes Having Cross-Bridged Cyclam Ligand: A Comprehensive Study

Redox-inactive metal ions have been recognized to be able to participate in redox metal-ion-mediated biological and chemical oxidative events; however, their roles are still elusive. This work presents how the redox-inactive metal ions affect the oxidative reactivity of a well-investigated manganese(II) with its corresponding manganese(IV) complexes having cross-bridged cyclam ligand. In dry acetone, the presence of these metal ions can greatly accelerate stoichiometric oxidations of triphenylphosphine and sulfides by the manganese(IV) complexes through electron transfer or catalytic sulfoxidations by the corresponding manganese(II) complexes with PhIO. Significantly, the rate enhancements are highly Lewis-acid strength dependent on added metal ions. These metal ions like Al(3+) can also promote the thermodynamic driving force of the Mn(IV)-OH moiety to facilitate its hydrogen abstraction from ethylbenzene having a BDE(CH) value of 85 kcal/mol, while it is experimentally limited to 80 kcal/mol for Mn(IV)-OH alone. Adding Al(3+) may also improve the manganese(II)-catalyzed olefin epoxidation with PhIO. However, compared with those in electron transfer, improvements in hydrogen abstraction and electron transfer are minor. The existence of the interaction between Lewis acid and the manganese(IV) species was evidenced by the blue shift of the characteristic absorbance of the manganese(IV) species from 554 to 537 nm and by converting its EPR signal at g = 2.01 into a hyperfine 6-line signal upon adding Al(3+) (I = 5/2). Cyclic voltammograms of the manganese(IV) complexes reveal that adding Lewis acid would substantially shift its potential to the positive direction, thus enhancing its oxidizing capability.

Reactivity comparison of high-valent iron(iv)-oxo complexes bearing N-tetramethylated cyclam ligands with different ring size

The ring size effect of macrocyclic TMC ligands in nonheme iron(IV)-oxo complexes has been examined in hydrogen atom transfer (HAT) and oxygen atom transfer (OAT) reactions; an iron(IV)-oxo complex bearing a smaller TMC ligand is more reactive in both HAT and OAT reactions, resulting from its high Fe(IV/III) redox potential.

Chromium(IV)–Peroxo Complex Formation and Its Nitric Oxide Dioxygenase Reactivity

The O(2) and NO reactivity of a Cr(II) complex bearing a 12-membered tetraazamacrocyclic N-tetramethylated cyclam (TMC) ligand, [Cr(II)(12-TMC)(Cl)](+) (1), and the NO reactivity of its peroxo derivative, [Cr(IV)(12-TMC)(O(2))(Cl)](+) (2), are described. By contrast to the previously reported Cr(III)-superoxo complex, [Cr(III)(14-TMC)(O(2))(Cl)](+), the Cr(IV)-peroxo complex 2 is formed in the reaction of 1 and O(2). Full spectroscopic and X-ray analysis revealed that 2 possesses side-on η(2)-peroxo ligation. The quantitative reaction of 2 with NO affords a reduction in Cr oxidation state, producing a Cr(III)-nitrato complex, [Cr(III)(12-TMC)(NO(3))(Cl)](+) (3). The latter is suggested to form via a Cr(III)-peroxynitrite intermediate. [Cr(II)(12-TMC)(NO)(Cl)](+) (4), a Cr(II)-nitrosyl complex derived from 1 and NO, could also be synthesized; however, it does not react with O(2).

A novel nickel (II) complex based on a cyclam-cored generation-one dendrimeric salicylaldimine ligand and its application as a catalyst precursor in norbornene polymerization: Comparative study with some other first generation DAB-polypropyleneimine metallodendrimers

A new cyclam based first generation metallodendrimer with nickel centres on the periphery as well as at the core was synthesized by reacting a novel tetrakis(salicylaldimine) cyclam ligand with nickel acetate. The trinuclear complex was evaluated as a catalyst precursor in the vinyl polymerization of norbornene using methylaluminoxane as co-catalyst. The activity of this cyclam-based complex was compared with that of first generation DAB-PPI-salicylaldimine and DAB-PPI-pyridine-imine complexes (DAB=diaminobutane, PPI=polypropyleneimine). The cyclam based complex was found to have superior activity than both the DAB-PPI analogues as well as analogous mononuclear complexes.

Mononuclear Metal–O2 Complexes Bearing Macrocyclic N-Tetramethylated Cyclam Ligands

Metalloenzymes activate dioxygen to carry out a variety of biological reactions, including the biotransformation of naturally occurring molecules, oxidative metabolism of xenobiotics, and oxidative phosphorylation. The dioxygen activation at the catalytic sites of the enzymes occurs through several steps, such as the binding of O(2) at a reduced metal center, the generation of metal-superoxo and -peroxo species, and the O-O bond cleavage of metal-hydroperoxo complexes to form high-valent metal-oxo oxidants. Because these mononuclear metal-dioxygen (M-O(2)) adducts are implicated as key intermediates in dioxygen activation reactions catalyzed by metalloenzymes, studies of the structural and spectroscopic properties and reactivities of synthetic biomimetic analogues of these species have aided our understanding of their biological chemistry. One particularly versatile class of biomimetic coordination complexes for studying dioxygen activation by metal complexes is M-O(2) complexes bearing the macrocyclic N-tetramethylated cyclam (TMC) ligand. This Account describes the synthesis, structural and spectroscopic characterization, and reactivity studies of M-O(2) complexes bearing tetraazamacrocyclic n-TMC ligands, where M ═ Cr, Mn, Fe, Co, and Ni and n = 12, 13, and 14, based on recent results from our laboratory. We have used various spectroscopic techniques, including resonance Raman and X-ray absorption spectroscopy, and density functional theory (DFT) calculations to characterize several novel metal-O(2) complexes. Notably, X-ray crystal structures had shown that these complexes are end-on metal-superoxo and side-on metal-peroxo species. The metal ions and the ring size of the macrocyclic TMC ligands control the geometric and electronic structures of the metal-O(2) complexes, resulting in the end-on metal-superoxo versus side-on metal-peroxo structures. Reactivity studies performed with the isolated metal-superoxo complexes reveal that they can conduct electrophilic reactions such as oxygen atom transfer and C-H bond activation of organic substrates. The metal-peroxo complexes are active oxidants in nucleophilic reactions, such as aldehyde deformylation. We also demonstrate a complete intermolecular O(2)-transfer from metal(III)-peroxo complexes to a Mn(II) complex. The results presented in this Account show the significance of metal ions and supporting ligands in tuning the geometric and electronic structures and reactivities of the metal-O(2) intermediates that are relevant in biology and in biomimetic reactions.

Investigation of metal cyclam complexes as potential catalysts for the production of dimethyl carbonate

While Zn cyclam complexes are known to readily react with CO2 and methanol to provide carbonato complexes, we were interested in trying to extend this chemistry into a possible catalytic cycle for the production of dimethyl carbonate. This route would require a cleavage of the Zn-carbonato complex with methanol. Towards this goal we modified the cyclam ligands by attaching various Lewis basic donors as pendant groups on the cyclam that could potentially act as hemilabile arms. The crystal structures of 1-(2-pyridylmethyl)-1,4,8,11-tetraazacyclotetradecane 2, 1-(3-pyridylmethyl)-1,4,8,11-tetraazacyclotetradecane 3, and 1-propionitrile-1,4,8,11-tetraazacyclotetradecane 4 are presented. Ligand 2 was reacted with M[ClO4]2 (M=Zn, Cd) and the resulting complexes were structurally and spectroscopically characterized. Despite the modifications, again these complexes did not perform as catalysts for the formation of dimethyl carbonate. Ligand 4 was found to react with methanol in the presence of Zn[ClO4]2·6H2O to convert the nitrile group into a methyl propionimidate, forming the methyl propionimidate (1,4,8,11-tetraazacyclotetradecane) zinc perchlorate. It is likely that the donor arms used bind too strongly to Zn or Cd to allow complexation of CO2 or methanol.

Synthesis and structural characterization of novel cyclam-based zirconium complexes and their use in the controlled ROP of rac-lactide: access to cyclam-functionalized polylactide materials

Novel Bn(2)Cyclam-based zirconium complexes of the type (Bn(2)Cyclam)Zr(X)(X') (3, X = X' = OPh; 4, X = X' = SPh; 5, X = Cl, X' = O(i)Pr) were synthesized in good yields via metathesis routes involving the reaction of the dichloro precursor (Bn(2)Cyclam)Zr(Cl)(2) and the appropriate lithium salts. The molecular structures of compounds 3, 4 and 5, as determined by X-ray crystallographic studies, all confirmed the effective chelation of the Bn(2)Cyclam ligand in a κ(4)-N(2)N(2)' fashion, with the hexa-coordinated Zr center adopting a trigonal prismatic geometry. Complexes 3-5 as well as the diisopropoxide derivative (Bn(2)Cyclam)Zr(O(i)Pr)(2) (2) were all found to initiate the ring-opening polymerization (ROP) of rac-lactide in a controlled manner, as deduced from SEC data and linear correlations between molecular weight numbers (M(n)) and monomer conversion as the ROP proceeds. While initiator 2 polymerizes rac-lactide to afford, as expected, an O(i)Pr-ester-end PLA, the ROP of rac-lactide by species 3 or 4 affords an unusual cyclam-end group PLA, as deduced from MALDI-TOF data. The bonding and the electronic structures of the dialkoxides 2 and 3 were assessed by DFT and their possible influence on the polymerization mechanism is discussed.

Synthesis, Crystal Structure and Spectroscopic Properties of (Acetylacetonato)(1,4,8,11‐tetraazacyclotetradecane)chromium(III) Diperchlorate

AbstractThe complex [Cr(cyclam)(acac)](ClO4)2·0.5H2O (cyclam = 1,4,8,11‐tetraazacyclotetradecane; acac = acetylacetonate) was prepared and structurally characterized by single‐crystal X‐ray diffraction at 100 K. The chromium atom is in a slightly distorted octahedral environment with four nitrogen atoms of the macrocyclic ligand and two O‐bonded acac molecules in cis position. The cyclam ligand adopts the folded cis‐V configuration with six‐ and five‐membered chelate rings in chair and gauche conformation, respectively. The average Cr–N(cyclam) and Cr–O(acac) bonds are 2.080(4) and 1.941(3) Å, respectively. The IR and visible spectral properties are also described.

Di-μ-oxido-bis[(1,4,8,11-tetraazacyclotetradecane-κ4N,N′,N′′,N′′′)dimanganese(III,IV)] bis(tetraphenylborate) chloride acetonitrile disolvate

The title compound, [Mn2O2(C10H24N4)2](C24H20B)2Cl·2CH3CN, is a mixed-valent MnIII/MnIV oxide-bridged mangan­ese dimer with one chloride and two tetra­phenyl­borate counter-anions. There are two non-coordinated mol­ecules of acetonitrile in the formula unit. A center of inversion is present between the two metal atoms, and, consequently, there is no distinction between MnIII and MnIV metal centers. In the Mn2O2 core, the Mn—O distances are 1.817 (3) and 1.821 (3) Å. The cyclam ligand is in the cis configuration. The chloride counter-anion resides on a center of symmetry, whereas the tetra­phenyl­borate counter-anion is in a general position. The cyclam ligand is hydrogen bonded to the acetonitrile as well as to the chloride anion. One of the phenyl rings of the anion and the acetonitrile solvent molecule are each disordered over two sets of sites.