Synthesis and Application of Robust Spiro [Fluorene­9] CAAC Ruthenium Alkylidene Complexes for the "One-Pot" Conversion of Allyl Acetate to Butane-1,4-diol.

A series of a novel CAAC ligands featuring a spiro-fluorene group have been synthesized and complexed with ruthenium alkylidenes, yielding the corresponding Hoveyda-type derivatives as a new family of olefin metathesis catalysts. The novel complexes have been characterized by XRD, HRMS and NMR measurements. The synthetized complexes were tested in catalysis and showed good activity in olefin metathesis, as demonstrated on diethyl diallylmalonate and allyl acetate substrates. The unique backbone in the ligand system with the large, yet inflexible condensed system renders interesting properties to the catalyst, exemplified by the good catalytic performance and improved Z­selectivity. In addition, the complex can also serve as a hydrogenation catalyst in a consecutive (one-pot) reaction. The latter reaction can convert allyl acetate to butane­1,4­diol, a valuable chemical intermediate for biodegradable polybutylene succinate (PBS).

Synthesis of Chroman-2,4-diones via Ring-Opening/Ring-Closing Reaction Involving Palladium-Catalyzed Intramolecular Aryloxycarbonylation.

Palladium-catalyzed aminocarbonylation of 3-iodochromone was studied in the presence of primary and secondary amines using atmospheric pressure of carbon monoxide as a carbonyl source. This procedure successfully provided a library of chromone-3-carboxamides and 3-substituted chroman-2,4-diones in 40 to 92% isolated yields. The reaction proceeded via highly chemoselective aminocarbonylation (up to 100%) in the presence of secondary amines by using monodentate or bidentate phosphine ligands. The tendency of 3-iodochromone substrate to undergo ANRORC rearrangement with N-nucleophiles was crucial to shift the reaction toward an unprecedented chemoselective carbonylative transformation, where a late-stage carbonyl insertion is favored concomitantly to the last ring-closure step. The proposed aza-Michael addition/ring-opening/intramolecular aryloxycarbonylation sequence showed compatibility, uniquely, to primary amines when XantPhos was used as a ligand. The solid-state structures of chromone-3-carboxamide (2a) and chroman-2,4-dione (3s) were undoubtedly established by single-crystal XRD analysis. A catalytic cycle was proposed to rationalize the formation of the two types of carbonylated compounds.

Competing Domino Knoevenagel-Cyclization Sequences with N-Arylcinnamylamines.

Domino Knoevenagel-cyclization reactions of N-arylcinnamylamines were carried out with active methylene reagents, which took place with five competing cyclization mechanisms: intramolecular hetero Diels-Alder reaction, stepwise polar [2 + 2] cycloaddition, styryl or aza-Diels-Alder reactions followed by rearomatization, and [1,5]-hydride shift-6-endo cyclization. In the stepwise aza-Diels-Alder reaction, the N-vinylpyridinium moiety acted as an azadiene, producing a condensed heterocycle with tetrahydroquinolizinium and tetrahydroquiniline subunits. Antiproliferative activity with low micromolar IC50 values was identified for some of the novel scaffolds.

Triaza-tricyclanos - synthesis of a new class of tricyclic nucleoside analogues by stereoselective cascade cyclocondensation.

Herein, we report a stereoselective synthesis of a novel type of conformationally constrained nucleoside analogue in which the sugar part is replaced by a new symmetrical tricycle consisting of a morpholine ring condensed with two imidazolidines. 1,5-Dialdehydes obtained from trityl- and dimethoxytrityl-protected uridine, ribothymidine, inosine, cytidine, adenosine and guanosine by metaperiodate oxidation were reacted with N1,N3-dibenzyl-1,2,3-triaminopropane; the latter reactant was produced using a new method that avoids explosive intermediates. Reactions of dialdehydes with propane-triamine via cascade tricyclization resulted in the corresponding triaza-tricyclic derivatives bearing three new stereogenic centers in high yields. Out of the eight possible diastereoisomers, one stereoisomer was formed in each case due to the chiral control of the starting nucleoside-dialdehydes and the steric constraint of the condensed ring system. The absolute configuration of the new stereotriad was determined by X-ray diffraction and NMR experiments. A mechanistic study performed under reductive conditions to trap the presumed bicyclic intermediate showed that the triamine reactant first attacks the 2'-aldehyde group, followed by a rapid bicyclization to form the imidazolidino-morpholine unit.

Half-Sandwich Type Platinum-Group Metal Complexes of C-Glucosaminyl Azines: Synthesis and Antineoplastic and Antimicrobial Activities.

While platinum-based compounds such as cisplatin form the backbone of chemotherapy, the use of these compounds is limited by resistance and toxicity, driving the development of novel complexes with cytostatic properties. In this study, we synthesized a set of half-sandwich complexes of platinum-group metal ions (Ru(II), Os(II), Ir(III) and Rh(III)) with an N,N-bidentate ligand comprising a C-glucosaminyl group and a heterocycle, such as pyridine, pyridazine, pyrimidine, pyrazine or quinoline. The sugar-containing ligands themselves are unknown compounds and were obtained by nucleophilic additions of lithiated heterocycles to O-perbenzylated 2-nitro-glucal. Reduction of the adducts and, where necessary, subsequent protecting group manipulations furnished the above C-glucosaminyl heterocycles in their O-perbenzylated, O-perbenzoylated and O-unprotected forms. The derived complexes were tested on A2780 ovarian cancer cells. Pyridine, pyrazine and pyridazine-containing complexes proved to be cytostatic and cytotoxic on A2780 cells, while pyrimidine and quinoline derivatives were inactive. The best complexes contained pyridine as the heterocycle. The metal ion with polyhapto arene/arenyl moiety also impacted on the biological activity of the complexes. Ruthenium complexes with p-cymene and iridium complexes with Cp* had the best performance in ovarian cancer cells, followed by osmium complexes with p-cymene and rhodium complexes with Cp*. Finally, the chemical nature of the protective groups on the hydroxyl groups of the carbohydrate moiety were also key determinants of bioactivity; in particular, O-benzyl groups were superior to O-benzoyl groups. The IC50 values of the complexes were in the low micromolar range, and, importantly, the complexes were less active against primary, untransformed human dermal fibroblasts; however, the anticipated therapeutic window is narrow. The bioactive complexes exerted cytostasis on a set of carcinomas such as cell models of glioblastoma, as well as breast and pancreatic cancers. Furthermore, the same complexes exhibited bacteriostatic properties against multiresistant Gram-positive Staphylococcus aureus and Enterococcus clinical isolates in the low micromolar range.

Copper(II) Complexes of Pyridine-2,6-dicarboxamide Ligands with High SOD Activity.

Copper(II) complexes of pyridine-based ligands functionalized with alanine (PydiAla) and tyrosine (PydiTyr) moieties have been synthesized as novel superoxide dismutase mimics. The complexes were characterized by pH-potentiometric, spectroscopic (UV-vis, circular dichroism, mass spectrometry, electron paramagnetic resonance spectroscopy), computational (DFT), and X-ray diffraction methods. Both ligands form high stability copper(II) complexes via the (Npy,N-,N-) donor set supported by the binding of the carboxylate pendant arms. Although the coordination mode is the same for the two systems, the tyrosine containing counterpart exhibits increased copper(II) binding affinity, which is most likely due to the presence of the aromatic moiety of the side chains. Both copper(II) complexes are capable of binding N-methylimidazole, and the formation of the corresponding ternary species was observed at physiological pH. The binary and ternary copper(II) complexes exhibit high SOD activity. The PydiTyr complex exhibits about 1 order of magnitude higher activity than the PydiAla complex. This is probably due to the presence of the phenolic OH group in the former species, which promotes the binding of the superoxide anion radical to the metal center. The results serve as a basis for designing highly efficient copper(II) mimics for medical and practical applications.

Reactive Oxygen Species Production Is Responsible for Antineoplastic Activity of Osmium, Ruthenium, Iridium and Rhodium Half-Sandwich Type Complexes with Bidentate Glycosyl Heterocyclic Ligands in Various Cancer Cell Models.

Platinum complexes are used in chemotherapy, primarily as antineoplastic agents. In this study, we assessed the cytotoxic and cytostatic properties of a set of osmium(II), ruthenium(II), iridium(III) and rhodium(III) half-sandwich-type complexes with bidentate monosaccharide ligands. We identified 5 compounds with moderate to negligible acute cytotoxicity but with potent long-term cytostatic activity. These structure-activity relationship studies revealed that: (1) osmium(II) p-cymene complexes were active in all models, while rhodium(III) and iridium(III) Cp* complexes proved largely inactive; (2) the biological effect was influenced by the nature of the central azole ring of the ligands-1,2,3-triazole was the most effective, followed by 1,3,4-oxadiazole, while the isomeric 1,2,4-oxadiazole abolished the cytostatic activity; (3) we found a correlation between the hydrophobic character of the complexes and their cytostatic activity: compounds with O-benzoyl protective groups on the carbohydrate moiety were active, compared to O-deprotected ones. The best compound, an osmium(II) complex, had an IC50 value of 0.70 µM. Furthermore, the steepness of the inhibitory curve of the active complexes suggested cooperative binding; cooperative molecules were better inhibitors than non-cooperative ones. The cytostatic activity of the active complexes was abolished by a lipid-soluble antioxidant, vitamin E, suggesting that oxidative stress plays a major role in the biological activity of the complexes. The complexes were active on ovarian cancer, pancreatic adenocarcinoma, osteosarcoma and Hodgkin's lymphoma cells, but were inactive on primary, non-transformed human fibroblasts, indicating their applicability as potential anticancer agents.

Catalytic Decomposition of Long-Chain Olefins to Propylene via Isomerization-Metathesis Using Latent Bicyclic (Alkyl)(Amino)Carbene-Ruthenium Olefin Metathesis Catalysts.

One of the most exciting scientific challenges today is the catalytic degradation of non-biodegradable polymers into value-added chemical feedstocks. The mild pyrolysis of polyolefins, including high-density polyethylene (HDPE), results in pyrolysis oils containing long-chain olefins as major products. In this paper, novel bicyclic (alkyl)(amino)carbene ruthenium (BICAAC-Ru) temperature-activated latent olefin metathesis catalysts, which can be used for catalytic decomposition of long-chain olefins to propylene are reported. These thermally stable catalysts show significantly higher selectivity to propylene at a reaction temperature of 75 °C compared to second generation Hoveyda-Grubbs or CAAC-Ru catalysts under ethenolysis conditions. The conversion of long-chain olefins (e.g., 1-octadecene or methyl oleate) to propylene via isomerization-metathesis is performed by using a (RuHCl)(CO)(PPh3 )3 isomerization co-catalyst. The reactions can be carried out at a BICAAC-Ru catalyst loading as low as 1 ppm at elevated reaction temperature (75 °C). The observed turnover number and turnover frequency are as high as 55 000 and 10 000 molpropylene molcatalyst -1 h-1 , respectively.

Synthesis of Hydrofluoroolefin-Based Iodonium Reagent via Dyotropic Rearrangement and Its Utilization in Fluoroalkylation.

[1,2]-shift of atoms in alkyl fragments belongs to the class of dyotropic rearrangements. Various atoms, including halogens can be involved in the migration, however participation of iodine is unprecedented. Herein, we report our experimental and DFT studies on the oxidation triggered dyotropic rearrangement of iodo and chloro functions via butterfly-type transition state to demonstrate the migrating ability of λ3 -iodane centre. With the exploitation of dyotropic rearrangement we designed and synthesized a novel fluoroalkyl iodonium reagent from industrial feedstock gas HFO-1234yf. We demonstrated that the hypervalent reagent serves as an excellent fluoroalkylation agent for various amines and nitrogen heterocycles.

Highly Selective Synthesis of 6-Glyoxylamidoquinoline Derivatives via Palladium-Catalyzed Aminocarbonylation.

The aminocarbonylation of 6-iodoquinoline has been investigated in the presence of large series of amine nucleophiles, providing an efficient synthetic route for producing various quinoline-6-carboxamide and quinoline-6-glyoxylamide derivatives. It was shown, after detailed optimization study, that the formation of amides and ketoamides is strongly influenced by the reaction conditions. Performing the reactions at 40 bar of carbon monoxide pressure in the presence of Pd(OAc)2/2 PPh3, the corresponding 2-ketocarboxamides were formed as major products (up to 63%). When the monodentate triphenylphosphine was replaced by the bidentate XantPhos, the quinoline-6-carboxamide derivatives were synthesized almost exclusively under atmospheric conditions (up to 98%). The isolation and characterization of the new carbonylated products of various structures were also accomplished. Furthermore, the structure of three new mono- and double-carbonylated compounds were unambiguously established by using a single-crystal XRD study.

Donor Atom Preference of Organoruthenium and Organorhodium Cations on the Interaction with Novel Ambidentate (N,N) and (O,O) Chelating Ligands in Aqueous Solution.

Two novel, pyridinone-based chelating ligands containing separated (O,O) and (Namino,Nhet) chelating sets (Namino = secondary amine; Nhet = pyrrole N for H(L3) (1-(3-(((1H-pyrrole-2-yl)methyl)-amino)propyl)-3-hydroxy-2-methylpyridin-4(1H)-one) or pyridine N for H(L5) (3-hydroxy-2-methyl-1-(3-((pyridin-2-ylmethyl)amino)propyl)pyridin-4(1H)-one)) were synthesized via reduction of the appropriate imines. Their proton dissociation processes were explored, and the molecular structures of two synthons were assessed by X-ray crystallography. These ambidentate chelating ligands are intended to develop Co(III)/PGM (PGM = platinum group metal) heterobimetallic multitargeted complexes with anticancer potential. To explore their metal ion binding ability, the interaction with Pd(II), [(η6-p-cym)Ru]2+ and [(η5-Cp*)Rh]2+ (p-cym = 1-methyl-4-isopropylbenzene, Cp* = pentamethyl-cyclopentadienyl anion) cations was studied in aqueous solution with the combined use of pH-potentiometry, NMR and HR ESI-MS. In general, organorhodium was found to form more labile complexes over ruthenium, while complexation of the (N,N) chelating set was slower than the processes of the pyridinone unit with (O,O) coordination. Formation of the organoruthenium complexes starts at lower pH (higher thermodynamic stabilities of the corresponding complexes) than for [(η5-Cp*)Rh]2+ but, due to the higher affinity of [η6-p-cym)Ru]2+ towards hydrolysis, the complexed ligands are capable of competing with hydroxide ion in a lesser extent than for the rhodium systems. As a result, under biologically relevant conditions, the rhodium binding effectivity of the ligands becomes comparable or even slightly higher than their effectivity towards ruthenium. Our results indicate that H(L3) is a less efficient (N,N) chelator for these metal ions than H(L5). Similarly, due to the relative effectivity of the (O,O) and (N,N) chelates at a 1:1 metal-ion-to-ligand ratio, H(L5) coordinates in a (N,N) manner to both cations in the whole pH range studied while, for H(L3), the complexation starts with (O,O) coordination. At a 2:1 metal-ion-to-ligand ratio, H(L3) cannot hinder the intensive hydrolysis of the second metal ion, although a small amount of 2:1 complex with [(η5-Cp*)Rh]2+ can also be detected.

Syntheses and Study of a Pyrroline Nitroxide Condensed Phospholene Oxide and a Pyrroline Nitroxide Attached Diphenylphosphine.

The reaction of a diene nitroxide precursor with dichlorophenylphosphine in a McCormac procedure afforded 1,1,3,3-tetramethyl-5-phenyl-1,2,3,4,5,6-hexahydrophospholo[3,4-c]pyrrole-5-oxide-2-oxyl. Lithiation of the protected 3-iodo-pyrroline nitroxide followed by treatment with chlorodiphenylphosphine after deprotection afforded (1-oxyl-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-3-yl)diphenylphosphine oxide, and after reduction, (1-oxyl-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-3-yl)diphenylphosphine was realized, which was also supported by X-ray single crystal diffraction measurements. This pyrroline diphenylphosphine derivative was converted to hexadecylphosphonium salt, which is an analogue of antineoplastic agent, MITO-CP.

Stereoselective Thioconjugation by Photoinduced Thiol-ene Coupling Reactions of Hexo- and Pentopyranosyl d- and l-Glycals at Low-Temperature-Reactivity and Stereoselectivity Study.

A comprehensive optimization and mechanistic study on the photoinduced hydrothiolation of different d- and l- hexo- and pentoglycals with various thiols was performed, at the temperature range of RT to -120 °C. Addition of thiols onto 2-substituted hexoglycals proceeded with complete 1,2-cis-α-stereoselectivity in all cases. Hydrothiolation of 2-substituted pentoglycals resulted in mixtures of 1,2-cis-α- and -ß-thioglycosides of varying ratio depending on the configuration of the reactants. Hydrothiolation of unsubstituted glycals at -80 °C proceeded with excellent yields and, except for galactal, provided the axially C2-S-linked isomers with high selectivity. Cooling was always beneficial to the efficacy, increased the yields and in most cases significantly raised the stereoselectivity. The suggested mechanism explains the different conformational preferences of the intermediate carbon-centered radicals, which is a crucial factor in the stereoselectivity of the reactions.

Tetravalent Metal Ion Guests in Polyoxopalladate Chemistry: Synthesis and Anticancer Activity of [MO8Pd12(PO4)8]12- (M = SnIV, PbIV).

The first two examples of polyoxopalladates(II) (POPs) containing tetravalent metal ion guests, [MO8Pd12(PO4)8]12- (M = SnIV, PbIV), have been prepared and structurally characterized in the solid state, solution, and gas phase. The interactions of the metal ion guests and the palladium-oxo shell were studied by theoretical calculations. The POPs were shown to possess anticancer activity by causing oxidative stress inducing caspase activation and consecutive apoptosis of leukemic cells.

Design and application of diimine-based copper(i) complexes in photoredox catalysis.

Structurally different bis(imino)copper(i) complexes were prepared in a highly modular manner and utilized as copper-based photocatalysts in the ATRA reactions of styrenes and alkyl halides. The new photocatalysts showed good catalytic activity and ensured efficient chemical transformations.

Tricyclanos: conformationally constrained nucleoside analogues with a new heterotricycle obtained from a d-ribofuranose unit.

A novel type of nucleoside analogue in which the sugar part is replaced by a new tricycle, 3,7,10-trioxa-11-azatricyclo[5.3.1.05,11]undecane has been prepared by substrate-controlled asymmetric synthesis. 1,5-Dialdehydes obtained from properly protected or unprotected uridine, ribothymidine, cytidine, inosine, adenosine and guanosine by metaperiodate oxidation reacted readily with tris(hydroxymethyl)aminomethane to provide the corresponding tricyclic derivatives with three new stereogenic centers. Through a double cyclisation cascade process the tricyclic compounds were obtained in good to high yields, with very high diastereoselectivity. Formation of one stereoisomer, out of the eight possible, was observed in all cases. The absolute configuration of the new stereotriad-containing tricyclic systems was aided by conventional NMR experiments followed by chemical shift calculations using an X-ray crystal structure as reference that was in good agreement with H-H distances obtained from a new ROESY NMR method. The synthesis was compatible with silyl, trityl and dimethoxytrityl protecting groups. A new reagent mixture containing ZnCl2, Et3SiH and hexafluoroisopropanol was developed for detritylation of the acid-sensitive tricyclano nucleosides.

Development and Characterisation of Modified Release Hard Gelatin Capsules, Based on In Situ Lipid Matrix Formation.

A new technology was developed to form extended release hard gelatin capsules, based on the lipid matrix formation of Gelucire 50/13 and cetostearyl alcohol. Matrices were formed in situ by filling pulverised lipids, ethylcellulose and active ingredients such as diclofenac sodium, acetaminophen and metronidazol into capsules and heating at 63°C for 11 min. Effects of heating were investigated also on the brittleness of capsule shells. Inhibition of the evaporation of water reduced capsule damage. Dissolution tests and texture analysis were performed to discover the release and mechanical profiles of the matrices. Tests were repeated after 1 month storage and results were compared. Gelucire 50/13 alone prolonged drug release but cetostearyl alcohol slowed drug liberation even further. Drug release from all compositions was found to follow first-order kinetic. Significant softening of the matrices was detected during storage in composition containing only Gelucire 50/13, ethylcellulose and diclofenac sodium. Thermal analysis and IR tests were also performed to discover physicochemical interactions between active pharmaceutical ingredients and excipients. Thermal analysis confirmed a notable interaction between diclofenac sodium and Gelucire 50/13 which could be the cause of the observed softening. In conclusion, modified release hard gelatin capsules were developed by a simple and fast monolithic lipid matrix formation method.

Complexation of Ln(3+) Ions with Cyclam Dipicolinates: A Small Bridge that Makes Huge Differences in Structure, Equilibrium, and Kinetic Properties.

The coordination properties toward the lanthanide ions of two macrocyclic ligands based on a cyclam platform containing picolinate pendant arms have been investigated. The synthesis of the ligands was achieved by using the well-known bis-aminal chemistry. One of the cyclam derivatives (cb-tedpa(2-)) is reinforced with a cross-bridge unit, which results in exceptionally inert [Ln(cb-tedpa)](+) complexes. The X-ray structures of the [La(cb-tedpa)Cl], [Gd(cb-tedpa)](+), and [Lu(Me2tedpa)](+) complexes indicate octadentate binding of the ligands to the metal ions. The analysis of the Yb(3+)-induced shifts in [Yb(Me2tedpa)](+) indicates that this complex presents a solution structure very similar to that observed in the solid state for the Lu(3+) analogue. The X-ray structures of [La(H2Me2tedpa)2](3+) and [Yb(H2Me2tedpa)2](3+) complexes confirm the exocyclic coordination of the metal ions, which gives rise to coordination polymers with the metal coordination environment being fulfilled by oxygen atoms of the picolinate groups and water molecules. The X-ray structure of [Gd(Hcb-tedpa)2](+) also indicates exocyclic coordination that in this case results in a discrete structure with an eight-coordinated metal ion. The nonreinforced complexes [Ln(Me2tedpa)](+) were prepared and isolated as chloride salts in nonaqueous media. However, these complexes were found to undergo dissociation in aqueous solution, except in the case of the complexes with the smallest Ln(3+) ions (Ln(3+) = Yb(3+) and Lu(3+)). A DFT investigation shows that the increased stability of the [Ln(Me2tedpa)](+) complexes in solution across the lanthanide series is the result of an increased binding energy of the ligand due to the increased charge density of the Ln(3+) ion.

[Tl(III)(dota)](-): An Extraordinarily Robust Macrocyclic Complex.

The X-ray structure of {C(NH2)3}[Tl(dota)]·H2O shows that the Tl(3+) ion is deeply buried in the macrocyclic cavity of the dota(4-) ligand (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate) with average Tl-N and Tl-O distances of 2.464 and 2.365 Å, respectively. The metal ion is directly coordinated to the eight donor atoms of the ligand, which results in a twisted square antiprismatic (TSAP') coordination around Tl(3+). A multinuclear (1)H, (13)C, and (205)Tl NMR study combined with DFT calculations confirmed the TSAP' structure of the complex in aqueous solution, which exists as the Λ(λλλλ)/Δ(δδδδ) enantiomeric pair. (205)Tl NMR spectroscopy allowed the protonation constant associated with the protonation of the complex according to [Tl(dota)](-) + H(+) ⇆ [Tl(Hdota)] to be determined, which turned out to be pK(H)Tl(dota) = 1.4 ± 0.1. [Tl(dota)](-) does not react with Br(-), even when using an excess of the anion, but it forms a weak mixed complex with cyanide, [Tl(dota)](-) + CN(-) ⇆ [Tl(dota)(CN)](2-), with an equilibrium constant of Kmix = 6.0 ± 0.8. The dissociation of the [Tl(dota)](-) complex was determined by UV-vis spectrophotometry under acidic conditions using a large excess of Br(-), and it was found to follow proton-assisted kinetics and to take place very slowly (∼10 days), even in 1 M HClO4, with the estimated half-life of the process being in the 10(9) h range at neutral pH. The solution dynamics of [Tl(dota)](-) were investigated using (13)C NMR spectroscopy and DFT calculations. The (13)C NMR spectra recorded at low temperature (272 K) point to C4 symmetry of the complex in solution, which averages to C4v as the temperature increases. This dynamic behavior was attributed to the Λ(λλλλ) ↔ Δ(δδδδ) enantiomerization process, which involves both the inversion of the macrocyclic unit and the rotation of the pendant arms. According to our calculations, the arm-rotation process limits the Λ(λλλλ) ↔ Δ(δδδδ) interconversion.

Lower denticity leading to higher stability: structural and solution studies of Ln(III)-OBETA complexes.

The heptadentate ligand OBETA (2,2'-oxybis(ethylamine)-N,N,N',N'-tetraacetic acid) was reported to form complexes with Ln(3+) ions more stable than those formed by the octadentate and more popular congener EGTA (ethylene glycol O,O'-bis(ethylamine)-N,N,N',N'-tetraacetic acid). The structural features leading to this puzzling coordination paradox were investigated by X-ray diffraction, solution state NMR, molecular modeling, and relaxometric studies. The stability constant of Gd(OBETA) (log KGdL = 19.37, 0.1 M KCl) is 2 orders of magnitude higher than that of the higher denticity analogue Gd(EGTA) (log KGdL = 17.66, 0.1 M KCl). The half-lives (t1/2) for the dissociation reactions of Gd(OBETA) and Gd(EGTA) ([Cu(2+)]tot = 0.2 mM, [Cit(3-)]tot = 0.5 mM, [PO4(3-)]tot = 1.0 mM, and [CO3(2-)]tot = 25 mM at pH = 7.4 and 25 °C in 0.1 M KCl solution) are 6.8 and 0.63 h, respectively, reflecting the much higher inertness of Gd(OBETA) near physiological conditions. NMR studies and DFT calculations using the B3LYP functional and a large-core ECP indicate that the [Gd(OBETA)(H2O)2](-) complex most likely exists in solution as the Δ(λλ)(δδδδ)A/Λ(δδ)(λλλλ)A enantiomeric pair, with an activation free energy for the enantiomerization process of ∼40 kJ·mol(-1). The metal ion is nine-coordinate by seven donor atoms of the ligand and two inner-sphere water molecules. The X-ray crystal structure of [C(NH2)3]3[Lu(OBETA)(CO3)]·2H2O is in agreement with the predictions of DFT calculations, the two coordinated water molecules being replaced by a bidentate carbonate anion. The (1)H NMRD and (17)O NMR study revealed that the two inner-sphere water molecules in Gd(OBETA) are endowed with a relatively fast water exchange rate (kex(298) = 13 × 10(6) s(-1)). The higher thermodynamic stability and inertness of Ln(OBETA) complexes, peaking in the center of the 4f series, combined with the presence of two coordinated water molecules suggests that Gd(OBETA) is a promising paramagnetic probe for MRI applications.