ABSTRACT
We report here the improved synthesis of the tripodal picolinate chelator Tpaa, with an overall yield of 41% over five steps, in comparison to the previously reported 6% yield. Tpaa was investigated for its coordination chemistry with Ga(III) and radiolabeling properties with gallium-68 (68Ga). The obtained crystal structure for [Ga(Tpaa)] shows that the three picolinate arms coordinate to the Ga(III) ion, fully occupying the octahedral coordination geometry. This is supported by 1H NMR which shows that the three arms are symmetrical when coordinated to Ga(III). Assessment of the thermodynamic stability through potentiometry gives log KGa-Tpaa = 21.32, with a single species being produced across the range of pH 3.5-7.5. Tpaa achieved >99% radiochemical conversion with 68Ga under mild conditions ([Tpaa] = 6.6 µM, pH 7.4, 37 °C) with a molar activity of 3.1 GBq µmol-1. The resulting complex, [68Ga][Ga(Tpaa)], showed improved stability over the previously reported [68Ga][Ga(Dpaa)(H2O)] in a serum challenge, with 32% of [68Ga][Ga(Tpaa)] remaining intact after 30 min of incubation with fetal bovine serum.
ABSTRACT
Twenty novel Mn, Fe, and Cu complexes of ethylene cross-bridged tetraazamacrocycles with potentially copolymerizable allyl and benzyl pendant arms were synthesized and characterized. Multiple X-ray crystal structures demonstrate the cis-folded pseudo-octahedral geometry forced by the rigidifying ethylene cross-bridge and show that two cis coordination cites are available for interaction with substrate and oxidant. The Cu complexes were used to determine kinetic stability under harsh acidic and high-temperature conditions, which revealed that the cyclam-based ligands provide superior stabilization with half-lives of many minutes or even hours in 5 M HCl at 50-90 °C. Cyclic voltammetry studies of the Fe and Mn complexes reveal reversible redox processes indicating stabilization of Fe2+/Fe3+ and Mn2+/Mn3+/Mn4+ oxidation states, indicating the likelihood of catalytic oxidation for these complexes. Finally, dye-bleaching experiments with methylene blue, methyl orange, and rhodamine B demonstrate efficient catalytic decolorization and allow selection of the most successful monomeric catalysts for copolymerization to produce future heterogeneous water purification materials.
ABSTRACT
Tetraazamacrocycles, cyclic molecules with four nitrogen atoms, have long been known to produce highly stable transition metal complexes. Cross-bridging such molecules with two-carbon chains has been shown to enhance the stability of these complexes even further. This provides enough stability to use the resulting compounds in applications as diverse and demanding as aqueous, green oxidation catalysis all the way to drug molecules injected into humans. Although the stability of these compounds is believed to result from the increased rigidity and topological complexity imparted by the cross-bridge, there is insufficient experimental data to exclude other causes. In this study, standard organic and inorganic synthetic methods were used to produce unbridged dibenzyl tetraazamacrocycle complexes of Co, Ni, Cu, and Zn that are analogues of known cross-bridged tetraazamacrocycles and their transition metal complexes to allow direct comparison of molecules that are identical except for the cross-bridge. The syntheses of the known tetraazamacrocycles and the new transition metal complexes were successful with high yields and purity. Initial chemical characterization of the complexes was conducted by UV-Visible spectroscopy, while cyclic voltammetry showed more marked differences in electronic properties from bridged versions. Direct comparison studies of the unbridged and bridged compounds' kinetic stabilities, as demonstrated by decomposition using high acid concentration and elevated temperature, showed that the cyclen-based complex stability did not benefit from cross-bridging. This is likely due to poor complementarity with the Cu2+ ion while cyclam-based complexes benefited greatly. We conclude that ligand-metal complementarity must be maintained in order for the topological and rigidity constraints imparted by the cross-bridge to contribute significantly to complex robustness.
Subject(s)
Coordination Complexes , Cyclams , Transition Elements , Humans , Coordination Complexes/chemistry , Molecular Structure , X-Rays , Transition Elements/chemistry , Ethylenes/chemistry , Crystallography, X-RayABSTRACT
The chelator Bn2DT3A was used to produce a novel 68Ga complex for positron emission tomography (PET). Unusually, this system is stabilized by a coordinated hydroxide in aqueous solutions above pH 5, which confers sufficient stability for it to be used for PET. Bn2DT3A complexes Ga3+ in a hexadentate manner, forming a mer-mer complex with log K([Ga(Bn2DT3A)]) = 18.25. Above pH 5, the hydroxide ion coordinates the Ga3+ ion following dissociation of a coordinated amine. Bn2DT3A radiolabeling displayed a pH-dependent speciation, with [68Ga][Ga(Bn2DT3A)(OH)]- being formed above pH 5 and efficiently radiolabeled at pH 7.4. Surprisingly, [68Ga][Ga(Bn2DT3A)(OH)]- was found to show an increased stability in vitro (for over 2 h in fetal bovine serum) compared to [68Ga][Ga(Bn2DT3A)]. The biodistribution of [68Ga][Ga(Bn2DT3A)(OH)]- in healthy rats showed rapid clearance and excretion via the kidneys, with no uptake seen in the lungs or bones.
Subject(s)
Chelating Agents , Gallium Radioisotopes , Animals , Rats , Gallium Radioisotopes/chemistry , Chelating Agents/chemistry , Tissue Distribution , Positron-Emission Tomography/methods , Hydroxides , Radiopharmaceuticals/chemistryABSTRACT
Growth of the library of tetraaza macrocyclic pyridinophane ligands is a result of the potential to treat neurodegenerative diseases by binding unregulated redox active metal-ions, scavenging radicals, and reducing oxidative stress. As part of this work, the copper complex of OH PyN 3 Cu (3,6,9,15-tetraazabicyclo[9.3.1]penta-deca-1(15),11,13-trien-13-ol) was previously identified as a discrete molecule in the solid state when isolated at lower pH values. However, here we report that OH PyN 3 Cu forms a helical structure upon crystallization around pH 6.5. Several properties of the ligand and complex were evaluated to understand the driving forces that led to the concatenation and formation of this solid-state helix. DFT studies along with a comparison of keto/enol tautomerization stability and bond lengths were used to determine the keto-character of the C=O within each subunit. This pH dependent keto-enol tautomerization is responsible for the solid state intermolecular C=O···Cu bonds observed in this metallohelix (Cu1 H ) when produced around pH 6.5. Perchlorate templating that occurs through hydrogen bonding between perchlorate counter ions and each Cu1 H unit is the primary driving factor for the twist that leads to the helix structure. Cu1 H does not exhibit the typical factors that stabilize the formation of helices, such as intra-strand hydrogen bonding or π-stacking. The helix structure further highlights the diversity of inorganic metallohelices and demonstrates the importance of tautomerization and pH that occurs with the pyridinophane ligand used in this study. To our knowledge and although these phenomenon have been observed individually, this is the first example of a pH dependent keto-enol tautomerization in an azamacrocycle being the driving force for the formation of a metallohelix solid state structure and is a particularly unique observation for pyridinophane complexes.
ABSTRACT
Ethylene cross-bridged tetraazamacrocycles are known to produce kinetically stable transition metal complexes that can act as robust oxidation catalysts under harsh aqueous conditions. We have synthesized ligand analogs with single acetate pendant arms that act as pentadentate ligands to Mn, Fe, Co, Ni, Cu, and Zn. These complexes have been synthesized and characterized, including the structural characterization of four Co and Cu complexes. Cyclic voltammetry demonstrates that multiple oxidation states are stabilized by these rigid, bicyclic ligands. Yet, redox potentials of the metal complexes are modified compared to the "parent" ligands due to the pendant acetate arm. Similarly, gains in kinetic stability under harsh acidic conditions, compared to parent complexes without the pendant acetate arm, were demonstrated by a half-life seven times longer for the cyclam copper complex. Due to the reversible, high oxidation states available for the Mn and Fe complexes, the Mn and Fe complexes were examined as catalysts for the bleaching of three commonly used pollutant model dyes (methylene blue, methyl orange, and Rhodamine B) in water with hydrogen peroxide as oxidant. The efficient bleaching of these dyes was observed.
Subject(s)
Coordination Complexes , Cyclams , Transition Elements , Coordination Complexes/chemistry , Crystallography, X-Ray , Ethylenes/chemistry , Ligands , Oxidation-ReductionABSTRACT
Manganese-based contrast agents (MnCAs) have emerged as suitable alternatives to gadolinium-based contrast agents (GdCAs). However, due to their kinetic lability and laborious synthetic procedures, only a few MnCAs have found clinical MRI application. In this work, we have employed a highly innovative single-pot template synthetic strategy to develop a MnCA, MnLMe , and studied the most important physicochemical properties inâ vitro. MnLMe displays optimized r1 relaxivities at both medium (20 and 64â MHz) and high magnetic fields (300 and 400â MHz) and an enhanced r1b =21.1â mM-1 s-1 (20â MHz, 298â K, pHâ 7.4) upon binding to BSA (Ka =4.2×103 â M-1 ). Inâ vivo studies show that MnLMe is cleared intact into the bladder through renal excretion and has a prolonged blood half-life compared to the commercial GdCA Magnevist. MnLMe shows great promise as a novel MRI contrast agent.
ABSTRACT
Dinuclear metallodrugs offer much potential in the development of novel anticancer chemotherapeutics as a result of the distinct interactions possible with bio-macromolecular targets and the unique biological activity that can result. Herein, we describe the development of isostructural homo-dinuclear OsII -OsII and hetero-dinuclear OsII -RuII organometallic complexes formed from linking the arene ligands of [M(η6 -arene)(C2 O4 )(PTA)] units (M=Os/Ru; PTA=1,3,5-triaza-7-phosphaadamantane). Using these complexes together with the known RuII -RuII analogue, a chromatin-modifying agent, we probed the impact of varying the metal ions on the structure, reactivity and biological activity of these complexes. The complexes were structurally characterised by X-ray diffraction experiments, their stability and reactivity were examined by using 1 H and 31 Pâ NMR spectroscopy, and their biological activity was assessed, alongside that of mononuclear analogues, through MTT assays and cell-cycle analysis (HT-29 cell line). The results revealed high antiproliferative activity in each case, with cell-cycle profiles of the dinuclear complexes found to be similar to that for untreated cells, and similar but distinct profiles for the mononuclear complexes. These results indicate these complexes impact on cell viability predominantly through a non-DNA-damaging mechanism of action. The new OsII -OsII and OsII -RuII complexes reported here are further examples of a family of compounds operating via mechanisms of action atypical of the majority of metallodrugs, and which have potential as tools in chromatin research.
Subject(s)
Antineoplastic Agents , Organometallic Compounds , Osmium , Ruthenium , Antineoplastic Agents/pharmacology , Cell Line, Tumor , HEK293 Cells , HT29 Cells , Humans , Ligands , Magnetic Resonance Spectroscopy , Organometallic Compounds/pharmacology , X-Ray DiffractionABSTRACT
Co-crystallisation is widely explored as a route to improve the physical properties of pharmaceutical active ingredients, but little is known about the fundamental mechanisms of the process. Herein, we apply a hyphenated differential scanning calorimetry-X-ray diffraction technique to mimic the commercial hot melt extrusion process, and explore the heat-induced synthesis of a series of new co-crystals containing isonicotinamide. These comprise a 1:1 co-crystal with 4-hydroxybenzoic acid, 2:1 and 1:2 systems with 4-hydroxyphenylacetic acid and a 1:1 crystal with 3,4-dihydroxyphenylactic acid. The formation of co-crystals during heating is complex mechanistically. In addition to co-crystallisation, conversions between polymorphs of the co-former starting materials and co-crystal products are also observed. A subsequent study exploring the use of inkjet printing and milling to generate co-crystals revealed that the synthetic approach has a major effect on the co-crystal species and polymorphs produced.
ABSTRACT
Reaction of [ReOCl3(PPh3)2] or [ReO2I(PPh3)2] with 2,2'-diphenylglycine (dpgH2) in refluxing ethanol afforded the air-stable complex [ReO(dpgH)(dpg)(PPh3)] (1). Treatment of [ReO(OEt)I2(PPh3)2] with 1,2,3-triaza-7-phosphaadamantane (PTA) afforded the complex [ReO(OEt)I2(PTA)2] (2). Reaction of [ReOI2(PTA)3] with dpgH2 led to the isolation of the complex [Re(NCPh2)I2(PTA)3]·0.5EtOH (3·0.5EtOH). A similar reaction but using [ReOX2(PTA)3] (X = Cl, Br) resulted in the analogous halide complexes [Re(NCPh2)Cl2(PTA)3]·2EtOH (4·2EtOH) and [Re(NCPh2)(PTA)3Br2]·1.6EtOH (5·1.6EtOH). Using benzilic acid (2,2'-diphenylglycolic acid, benzH) with 2 afforded the complex [ReO(benz)2(PTA)][PTAH]·EtOH (6·EtOH). The potential for the formation of complexes using radioisotopes with relatively short half-lives suitable for nuclear medicine applications by developing conditions for [Re(NCPh2)(dpg)I(PTA)3] (7)[ReO4]- in a 4 h time scale was investigated. A procedure for the technetium analog of complex [Re(NCPh2)I2(PTA)3] (3) from 99mTc[TcO4]- was then investigated. The molecular structures of 1-7 are reported; complexes 3-7 have been studied using in vitro cell assays (HeLa, HCT116, HT-29, and HEK 293) and were found to have IC50 values in the range of 29-1858 µM.
Subject(s)
Coordination Complexes/chemistry , Coordination Complexes/toxicity , Cell Line, Tumor , Coordination Complexes/chemical synthesis , HEK293 Cells , Humans , Molecular Structure , Organotechnetium Compounds/chemical synthesis , Organotechnetium Compounds/chemistry , Phosphines/chemical synthesis , Phosphines/chemistry , Phosphines/toxicity , Rhenium/chemistry , Solubility , Water/chemistryABSTRACT
Metallation of biomacromolecular species forms the basis for the anticancer activity of many metallodrugs. A major limitation of these compounds is that their reactivity is indiscriminate and can, in principle, occur in healthy tissue as well as cancerous tissue, potentially leading to side effects in vivo. Here we present pH-dependent intramolecular coordination of an arene-tethered sulfonamide functionality in organometallic ruthenium(II) ethylenediamine complexes as a route to controlling the coordination environment about the central metal atom. Through variation of the sulfonamide R group and the length of the tether linking it to the arene ligand the acidity of the sulfonamide NH group, and hence the pH-region over which regulation of metal coordination occurs, can be modulated. Intramolecular sulfonamide ligation controlled the reactivity of complex 4 within the physiologically relevant pH-region, rendering it more reactive towards 5'-GMP in mildly acidic pH-conditions typical of tumour tissue compared to the mildly alkaline pH-conditions typical of healthy tissue. However, the activation of 4 by ring-opening of the chelate was found to be a slow process relative to the timescale of typical cell culture assays and members of this series of complexes were found not to be cytotoxic towards the HT-29 cell line. These complexes provide the basis for the development of analogues of increased potency where intramolecular sulfonamide ligation regulates reactivity and therefore cytotoxicity in a pH-dependent, and potentially, tissue-dependent manner.
Subject(s)
Antineoplastic Agents/chemistry , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Diamines/chemistry , Organometallic Compounds/pharmacology , Ruthenium/chemistry , Sulfonamides/chemistry , Antineoplastic Agents/pharmacology , Cell Survival/drug effects , Chelating Agents/chemistry , Coordination Complexes/chemical synthesis , Coordination Complexes/toxicity , Crystallography, X-Ray , Diamines/pharmacology , Ethylenediamines/chemistry , Ethylenediamines/pharmacology , Guanosine Monophosphate/metabolism , HT29 Cells , Humans , Hydrogen-Ion Concentration , Kinetics , Ligands , Models, Molecular , Organometallic Compounds/chemistry , Ruthenium/pharmacology , Sulfonamides/pharmacologyABSTRACT
A total of 44 bis-aryl-monocyclic polyamines, monoaryl-monocyclic polyamines and their transition metal complexes were prepared, chemically characterized, and screened in vitro against the Leishmania donovani promastigotes, axenic amastigotes and intracellular amastigotes in THP1 cells. The IC50 and/or IC90 values showed that 10 compounds were similarly active at about 2-fold less potent than known drug pentamidine against promastigotes. The most potent compound had an IC50 of 2.82 µM (compared to 2.93 µM for pentamidine). Nine compounds were 1.1-13.6-fold more potent than pentamidine against axenic amastigotes, the most potent one being about 2-fold less potent than amphotericin B. Fourteen compounds were about 2-10 fold more potent than pentamidine, the most potent one is about 2-fold less potent than amphotericin B against intracellular amastigotes in THP1 cells. The 2 most promising compounds (FeL7Cl2 and MnL7Cl2), with strong activity against both promastigotes and amastigotes and no observable toxicity against the THP1 cells are the Fe2+- and Mn2+- complexes of a dibenzyl cyclen derivative. Only 2 of the 44 compounds showed observable cytotoxicity against THP1 cells. Tetraazamacrocyclic monocyclic polyamines represent a new class of antileishmanial lead structures that warrant follow up studies.
ABSTRACT
The authors wish to make the following correction to their paper [...].
ABSTRACT
Macrocyclic ligands have been explored extensively as scaffolds for transition metal catalysts for oxygen and hydrogen atom transfer reactions. C-C reactions facilitated using earth abundant metals bound to macrocyclic ligands have not been well-understood but could be a green alternative to replacing the current expensive and toxic precious metal systems most commonly used for these processes. Therefore, the yields from direct Suzuki-Miyaura C-C coupling of phenylboronic acid and pyrrole to produce 2-phenylpyrrole facilitated by eight high-spin iron complexes ([Fe3+L1(Cl)2]+, [Fe3+L4(Cl)2]+, [Fe2+L5(Cl)]+, [Fe2+L6(Cl)2], [Fe3+L7(Cl)2]+, [Fe3+L8(Cl)2]+, [Fe2+L9(Cl)]+, and [Fe2+L10(Cl)]+) were compared to identify the effect of structural and electronic properties on catalytic efficiency. Specifically, catalyst complexes were compared to evaluate the effect of five properties on catalyst reaction yields: (1) the coordination requirements of the catalyst, (2) redox half-potential of each complex, (3) topological constraint/rigidity, (4) N atom modification(s) increasing oxidative stability of the complex, and (5) geometric parameters. The need for two labile cis-coordination sites was confirmed based on a 42% decrease in catalytic reaction yield observed when complexes containing pentadentate ligands were used in place of complexes with tetradentate ligands. A strong correlation between iron(III/II) redox potential and catalytic reaction yields was also observed, with [Fe2+L6(Cl)2] providing the highest yield (81%, -405 mV). A Lorentzian fitting of redox potential versus yields predicts that these catalysts can undergo more fine-tuning to further increase yields. Interestingly, the remaining properties explored did not show a direct, strong relationship to catalytic reaction yields. Altogether, these results show that modifications to the ligand scaffold using fundamental concepts of inorganic coordination chemistry can be used to control the catalytic activity of macrocyclic iron complexes by controlling redox chemistry of the iron center. Furthermore, the data provide direction for the design of improved catalysts for this reaction and strategies to understand the impact of a ligand scaffold on catalytic activity of other reactions.
ABSTRACT
Steel slag is a major by-product of the steel industry and a potential resource of technology critical elements. For this study, a basic oxygen furnace (BOF) steel slag was tested for bacterial leaching and recovery of aluminium (Al), chromium (Cr), and vanadium (V). Mixed acidophilic bacteria were adapted to the steel slag up to 5% (w/v). In the batch tests, Al, Cr, and V were bioleached significantly more from steel slag than in control treatments. No statistical difference was observed arising from the duration of the leaching (3 vs 6â¯d) in the batch tests. Al and Cr concentrations in the leachate were higher for the smaller particle size of the steel slag (<75⯵m), but no difference was observed for V. In the column tests, no statistical difference was found for pH, Al, Cr and V between the live culture (one-step bioleaching) and the supernatant (two-step bioleaching). The results show that the culture supernatant can be effectively used in an upscaled industrial application for metal recovery. If bioleaching is used in the 170-250 million tonnes of steel slag produced per year globally, significant recoveries of metals (100% of Al, 84% of Cr and 8% of V) can be achieved, depending on the slag composition. The removal and recovery percentages of metals from the leachate with Amberlite®IRA-400 are relatively modest (<67% and <5%, respectively), due to the high concentration of competing ions (SO42-, PO43-) in the culture medium. Other ion exchange resins can be better suited for the leachate or methods such as selective precipitation could improve the performance of the resin. Further research is needed to minimise interference and maximise metal recovery.
Subject(s)
Aluminum/isolation & purification , Chromium/isolation & purification , Steel , Vanadium/isolation & purification , Industrial Waste , RecyclingABSTRACT
The host-guest interaction of a series of cyclohexyl-appended guests with cucurbit[8]uril (Q[8]) was studied by ¹H NMR spectroscopy, isothermal titration calorimetry (ITC), and X-ray crystallography. The X-ray structure revealed that two cycloalkane moieties can be simultaneously encapsulated in the hydrophobic cavity of the Q[8] host to form a ternary complex for the first time.
Subject(s)
Bridged-Ring Compounds/chemistry , Cyclohexylamines/chemistry , Imidazoles/chemistry , Calorimetry , Crystallography, X-Ray , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Structure , ThermodynamicsABSTRACT
Two new tricyclic ß-aminoacrylate derivatives (2e and 3e) have been found to be inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) with Ki 0.037 and 0.15µM respectively. 1H and 13C NMR spectroscopic data show that these compounds undergo ready cis-trans isomerisation at room temperature in polar solvents. In silico docking studies indicate that for both molecules there is neither conformation nor double bond configuration which bind preferentially to PfDHODH. This flexibility is favourable for inhibitors of this channel that require extensive positioning to reach their binding site.
Subject(s)
Acrylates/pharmacology , Oxidoreductases Acting on CH-CH Group Donors/antagonists & inhibitors , Plasmodium falciparum/enzymology , Acrylates/chemical synthesis , Acrylates/chemistry , Dihydroorotate Dehydrogenase , Dose-Response Relationship, Drug , Molecular Docking Simulation , Molecular Structure , Oxidoreductases Acting on CH-CH Group Donors/genetics , Oxidoreductases Acting on CH-CH Group Donors/metabolism , Structure-Activity RelationshipABSTRACT
Heating a mixture of Nd(NO3)3·6H2O, KCl, Q[10] and Q[5] in HCl for 10 min affords the inclusion complex {NdQ[5]K@Q[10](H2O)4}·4NO3·20H2O. The structure of the inclusion complex has been investigated by single crystal X-ray diffraction and by X-ray Photoelectron spectroscopy (XPS).
Subject(s)
Amantadine/analogs & derivatives , Amantadine/chemistry , Coordination Complexes/chemistry , Neodymium/chemistry , Amantadine/chemical synthesis , Crystallography, X-Ray/methods , Molecular Structure , Photoelectron Spectroscopy/methods , X-Ray Diffraction/methodsABSTRACT
We report a powerful new technique: hyphenating synchrotron X-ray powder diffraction (XRD) with differential scanning calorimetry (DSC). This is achieved with a simple modification to a standard laboratory DSC instrument, in contrast to previous reports which have involved extensive and complex modifications to a DSC to mount it in the synchrotron beam. The high-energy X-rays of the synchrotron permit the recording of powder diffraction patterns in as little as 2 s, meaning that thermally induced phase changes can be accurately quantified and additional insight on the nature of phase transitions obtained. Such detailed knowledge cannot be gained from existing laboratory XRD instruments, since much longer collection times are required. We demonstrate the power of our approach with two model systems, glutaric acid and sulfathiazole, both of which show enantiotropic polymorphism. The phase transformations between the low and high temperature polymorphs are revealed to be direct solid-solid processes, and sequential refinement against the diffraction patterns obtained permits phase fractions at each temperature to be calculated and unit cell parameters to be accurately quantified as a function of temperature. The combination of XRD and DSC has further allowed us to identify mixtures of phases which appeared phase-pure by DSC.
Subject(s)
Calorimetry, Differential Scanning/methods , Glutarates/chemistry , Powder Diffraction/methods , Sulfathiazoles/chemistry , X-Ray Diffraction/methods , Phase Transition , Stereoisomerism , Sulfathiazole , TemperatureABSTRACT
Glyoxal-bridged bisaminal tetraazamacrocyclic derivatives of 1,4,7,10-tetraazacyclododecane (cyclen) and 1,4,8,11-tetraazacyclotetradecane (cyclam) can be N-functionalized to incorporate coordinating groups or for conjugation to biomolecules. Herein, we present an improved N-functionalization methodology using mechanochemistry which reduces reaction times in comparison with conventional synthetic routes. A range of six alkyl halides were reacted with cyclen and cyclam bisaminal derivatives in various ratios to form mono- and bis-functionalized quaternary ammonium salts. Cross-bridged cyclam, a key intermediate for CB-TE2A, a commonly used chelator in positron emission tomography medical imaging with (64)Cu, has been synthesized using nonconventional synthetic methodologies (grinding and microwave heating) with intermediates characterized by 2D NMR and single crystal XRD. The overall synthesis time of CB-TE2A from cyclam could be shortened to 5 days from the 35 days required for the conventional synthesis.