Complexation studies of the dinucleating ligand H₃L (H₃L=2-{[bis(pyridin-2-ylmethyl)amino]methyl}-6-{[bis(6-pivaloylamidopyridin-2-ylmethyl)amino]methyl}-4-methylphenol), with metal-binding sites A and B, which both provide four donors to a metal ion; a tertiary amine; two pyridines (substituted with amide hydrogen-bond donors in site B), and a bridging phenolate, with Zn^II, Cu^II, and Ga^III are reported. The titration of H₃L with the three metal ions in solution was monitored by NMR spectroscopy or EPR and UV/Vis/near-IR spectroscopy, as well as by ESI-MS to analyze the selectivity of the two metal-ion sites A and B of this model ligand for metallophosphatases; the spectroscopic assignments are supported by X-ray crystallography results. The first Zn^II ion coordinates to site A with unsubstituted pyridine donors and, upon addition of a second equivalent of Zn^II, this coordinates to the sterically less accessible site B. From a similar titration with Ga^III, it emerges that only a mononuclear complex is obtained, with the Ga^III center coordinated to site A. When one equivalent of Ga^III is reacted with the mononuclear Zn^II complex, Zn^II is forced by Ga^III to exchange the site; this results in a dinuclear complex with Ga^III in site A and Zn^II in site B. With Cu^II, two isomers are observed: one with and the other without a bridging phenolate; these differ significantly in their spectroscopic and magnetic properties.

The efficient transformation of the hexadentate bispidinol 1 into carbamate derivatives yields functional bispidines enabling convenient functionalization for targeted imaging. The BODIPY-substituted bispidine 3 combines a coordination site for metal ions, such as radioactive ⁶⁴Cu^II, with a fluorescent unit. Product 3 was thoroughly characterized by standard analytical methods, single crystal X-ray diffraction, radiolabeling, and photophysical analysis. The luminescence of ligand 3 was found to be strongly dependent on metal ion coordination: Cu^II quenches the BODIPY fluorescence, whereas Ni^II and Zn^II ions do not affect it. It follows that, in imaging applications with the positron emitter ⁶⁴Cu^II, residues of its origin from enriched ⁶⁴Ni and the decay products ⁶⁴Ni^II and ⁶⁴Zn^II, efficiently restore the fluorescence of the ligand. This allows for monitoring of the emitted radiation as well as the fluorescence signal. The stability of the ⁶⁴Cu^II3 complex is investigated by transmetalation experiments with Zn^II and Ni^II, using fluorescence and radioactivity detection, and the results confirm the high stability of ⁶⁴Cu^II3. In addition, metal complexes of ligand 3 with the lanthanide ions Tb^III, Eu^III, and Nd^III are shown to exhibit emission of the BODIPY ligand and the lanthanide ion, thus enabling dual emission detection.

Two synthetic derivatives of the naturally occurring cyclic pseudooctapeptides patellamide A–F and ascidiacyclamide, that is, H₄pat², H₄pat³, as well as their Cu^II complexes are described. These cyclic peptide derivatives differ from the naturally occurring macrocycles by the variation of the incorporated heterocyclic donor groups and the configuration of the amino acids connecting the heterocycles. The exchange of the oxazoline and thiazole groups by dimethylimidazoles or methyloxazoles leads to more rigid macrocycles, and the changes in the configuration of the side chains leads to significant differences in the folding of the cyclic peptides. These variations allow a detailed study of the various possible structural changes on the chemistry of the Cu^II complexes formed. The coordination of Cu^II with these macrocyclic species was monitored by high-resolution electrospray mass spectrometry (ESI-MS), spectrophotometric (UV/Vis) and circular dichroic (CD) titrations, and electron paramagnetic resonance (EPR) spectroscopy. Density functional theory (DFT) calculations and molecular mechanics (MM) simulations have been used to model the structures of the Cu^II complexes and provide a detailed understanding of their geometric preferences and conformational flexibility. This is related to the Cu^II coordination chemistry and the reactivity of the dinuclear Cu^II complexes towards CO₂ fixation. The variation observed between the natural and various synthetic peptide systems enables conclusions about structure–reactivity correlations, and our results also provide information on why nature might have chosen oxazolines and thiazoles as incorporated heterocycles.

The synthesis and characterization of a novel dinucleating ligand L (L=4,11-dimethyl-1,8-bis{2-[N-(di-2-pyridylmethyl)amino]ethyl}cyclam) and its μ-oxo-bridged diferric complex [(H₂L){Fe^III₂(O)}(Cl)₄]²⁺ are reported. This diiron(III) complex is the first example of a truly functional purple acid phosphatase (PAP) mimic as it accelerates the hydrolysis of the activated phosphomonoester 2,4-dinitrophenyl phosphate (DNPP). The spectroscopic and kinetic data indicate that only substrates that are monodentately bound to one of the two ferric ions can be attacked by a suitable nucleophile. This is, most probably, a terminal iron(III)-bound hydroxide. DFT calculations support this assumption and also highlight the importance of secondary interactions, exerted by the protonated cyclam platform, for the positioning and activation of the iron(III)-bound substrate. Similar effects are postulated in the native enzyme but addressed in PAP mimics for the first time.

The iron–bispidine-catalyzed oxidation and dioxygenation (catechol dioxygenase activity) [i.e., the oxidation of 3,5-di-tert-butylcatecholate (dbc^2–) by [Fe^II(L)X₂]ⁿ⁺ (L = 3,7-dimethyl-9-oxo-2,4-bis(2-pyridyl)-3,7-diazabicyclo[3.3.1]nonane-1,5-dicarboxylate methyl ester)] and air (O₂) was studied experimentally and supported by the analysis of the X-ray crystal structure of [Fe(L·MeOH)(tcc)][B(Ph)₄] with the deactivated tetrachlorocatecholate tcc^2– and a DFT-based analysis. The [Fe^II(L)X₂]ⁿ⁺/O₂/dbc^2– system catalyzes the intradiol cleavage of dbc^2– but with a relatively low activity (5 % yield); most of the substrate is oxidized in a two-electron oxidation to the benzoquinone (dbq) product (48 % yield). The crystallographic and DFT-based theoretical analyses indicate that this is due to the high oxidation potential of the Fe^III oxidant (fast and efficient electron transfer), that is, the oxidation to the benzoquinone side product is faster, and due to the bonding mode of the catecholate substrate to the Fe^III oxidant, with little spin density transferred to the catecholate substrate.

High-valent bispidine iron-oxo complexes are among the most efficient nonheme iron oxidation catalysts. Here, we report the synthesis and structural analysis of two derivatives of the known pentadentate bispidine ligand L¹ {L¹ = 2,4-pyridyl-7-(pyridine-2-ylmethyl)-3,7-diazabicyclo[3.3.1]nonane}: L² and L³ {L² = 2,4-pyridyl-7-[1-(pyridine-2-yl)ethyl]-3,7-diazabicyclo[3.3.1]nonane; L³ = 2,4-pyridyl-7-[phenyl(pyridine-2-yl)methyl]-3,7-diazabicyclo[3.3.1]nonane}, and of their Fe^II complexes. The yield of the catalytic epoxidation of cyclooctene and styrene with iodosylbenzene as oxidant increases from the L¹- to the L²- to the L³-based catalyst (e.g., the yield of styrene oxide, with MeCN as solvent, under anaerobic conditions, is 40 %, 90 %, 96 %, respectively), and this is correlated to the Fe^III/II reduction potentials {[Fe(L¹)(NCMe)]ⁿ⁺ (1.01 V), [Fe(L²)(NCMe)]ⁿ⁺ (1.13 V), and [Fe(L³)(NCMe)]ⁿ⁺ (1.19 V), in MeCN, vs. SCE}. Although this correlation is not unexpected, the interpretation is not entirely trivial, and this is discussed in detail. The rigidity of the bispidine ligands and their preference for relatively large metal ions (low oxidation states, high spin multiplicities) is believed to be responsible for the efficiency of the bispidine-based catalyst systems, and the present results show possible approaches to further improve the performance of these catalysts.

When the dichloroiron(II) complex of the tetradentate bispidine ligand L=3,7-dimethyl-9-oxo-2,4-bis(2-pyridyl)-3,7-diazabicyclo[3.3.1]nonane-1,5-dicarboxylate methyl ester is oxidized with H₂O₂, tBuOOH, or iodosylbenzene, the high-valent FeO complex efficiently oxidizes and halogenates cyclohexane. Kinetic D isotope effects and the preference for the abstraction of tertiary over secondary carbon-bound hydrogen atoms (quantified in the halogenation of adamantane) indicate that CH activation is the rate-determining step. The efficiencies (yields in stoichiometric and turnover numbers in catalytic reactions), product ratios (alcohol vs. bromo- vs. chloroalkane), and kinetic isotope effects depend on the oxidant. These results suggest different pathways with different oxidants, and these may include iron(IV)– and iron(V)–oxo complexes as well as oxygen-based radicals.

The distorted trigonal-bipyramidal Cu^II complex [Cu(L¹)(NCCH₃)]²⁺ of the novel tetradentate bispidine-derived ligand L¹ with four tertiary amine donors (L¹=1,5-diphenyl-3-methyl-7-(1,4,6-trimethyl-1,4-diazacycloheptane-6-yl)diazabicyclo[3.3.1]nonane-9-one) is a very efficient catalyst for the aziridination of olefins in the presence of a nitrene source. In agreement with the experimental data (in situ spectroscopy, product distribution, and its dependence on the geometry of the substrate and of the nitrene source), a theoretical analysis based on DFT calculations indicates that the active catalyst has the Cu center in its +II oxidation state, that electron transfer is not involved, and that the conversion of the olefin to an aziridine is a stepwise process involving a radical intermediate. The striking change of efficiency and reaction mechanism between classical copper–bispidine complexes and the novel L¹-based catalyst is primarily attributed to the structural variation, enforced by the ligand architecture.

The copper(II) coordination chemistry of westiellamide (H₃L^wa), as well as of three synthetic analogues with an [18]azacrown-6 macrocyclic structure but with three imidazole (H₃L¹), oxazole (H₃L²), and thiazole (H₃L³) rings instead of oxazoline, is reported. As in the larger patellamide rings, the N_heterocycle-N_peptide-N_heterocycle binding site is highly preorganized for copper(II) coordination. In contrast to earlier reports, the macrocyclic peptides have been found to form stable mono- and dinuclear copper(II) complexes. The coordination of copper(II) has been monitored by high-resolution electrospray mass spectrometry (ESI-MS), spectrophotometric and polarimetric titrations, and EPR and IR spectroscopies, and the structural assignments have been supported by time-dependent studies (UV/Vis/NIR, ESI-MS, and EPR) of the complexation reaction of copper(II) with H₃L¹. Density functional theory (DFT) calculations have been used to model the structures of the copper(II) complexes on the basis of their spectroscopic data. The copper(II) ion has a distorted square-pyramidal geometry with one or two coordinated solvent molecules (CH₃OH) in the mononuclear copper(II) cyclic peptide complexes, but the coordination sphere in [Cu(H₂L^wa)(OHCH₃)]⁺ differs from those in the synthetic analogues, [Cu(H₂L)(OHCH₃)₂]⁺ (L=L¹, L², L³). Dinuclear copper(II) complexes ([Cu^II₂(HL)(μ-X)]⁺; X=OCH₃, OH; L=L¹, L², L³, L^wa) are observed in the mass spectra. While a dipole–dipole coupled EPR spectrum is observed for the dinuclear copper(II) complex of H₃L³, the corresponding complexes with H₃L (L=L¹, L², L^wa) are EPR-silent. This may be explained in terms of strong antiferromagnetic coupling (H₃L¹) and/or a low concentration of the dicopper(II) complexes (H₃L^wa, H₃L²), in agreement with the mass spectrometric observations.

Experimental and DFT-based computational results on the aziridination mechanism and the catalytic activity of (bispidine)copper(I) and -copper(II) complexes are reported and discussed (bispidine=tetra- or pentadentate 3,7-diazabicyclo[3.1.1]nonane derivative with two or three aromatic N donors in addition to the two tertiary amines). There is a correlation between the redox potential of the copper(II/I) couple and the activity of the catalyst. The most active catalyst studied, which has the most positive redox potential among all (bispidine)copper(II) complexes, performs 180 turnovers in 30 min. A detailed hybrid density functional theory (DFT) study provides insight into the structure, spin state, and stability of reactive intermediates and transition states, the oxidation state of the copper center, and the denticity of the nitrene source. Among the possible pathways for the formation of the aziridine product, the stepwise formation of the two NC bonds is shown to be preferred, which also follows from experimental results. Although the triplet state of the catalytically active copper nitrene is lowest in energy, the two possible spin states of the radical intermediate are practically degenerate, and there is a spin crossover at this stage because the triplet energy barrier to the singlet product is exceedingly high.

Mechanistic pathways for the aromatic hydroxylation by [Cu^II(L¹)(TMAO)(O)]⁻ (L¹=hippuric acid, TMAO=trimethylamine N-oxide), derived from the ON bond homolysis of its [Cu^II(L¹)(TMAO)₂] precursor, were explored by using hybrid density functional theory (B3LYP) and highly correlated ab initio methods (QCISD and CCSD). Published experimental studies suggest that the catalytic reaction is triggered by a terminal copper–oxo species, and a detailed study of electronic structures, bonding, and energetics of the corresponding electromers is presented. Two pathways, a stepwise and a concerted reaction, were considered for the hydroxylation process. The results reveal a clear preference for the concerted pathway, in which the terminal oxygen atom directly attacks the carbon atom of the benzene ring, leading to the ortho-selectively hydroxylated product. Solvent effects were probed by using the PCM and CPCM solvation models, and the PCM model was found to perform better in the present case. Excellent agreement between the experimental and computational results was found, in particular also for changes in reactivity with derivatives of L¹.