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[Abstract] We present a quantitative analysis of the thermodynamic stabilities of Mn(II) complexes, defined by the equilibrium constants (log KMnL values) and the values of pMn obtained as −log[Mn]free for total metal and ligand concentrations of 1 and 10 μM, respectively. We used structural descriptors to analyze the contributions to complex stability of different structural motifs in a quantitative way. The experimental log KMnL and pMn values can be predicted to a good accuracy by adding the contributions of the different motifs present in the ligand structure. This allowed for the identification of features that provide larger contributions to complex stability, which will be very helpful for the design of efficient chelators for Mn(II) complexation. This issue is particularly important to develop Mn(II) complexes for medical applications, for instance, as magnetic resonance imaging (MRI) contrast agents. The analysis performed here also indicates that coordination number eight is more common for Mn(II) than is generally assumed, with the highest log KMnL values generally observed for hepta- and octadentate ligands. The X-ray crystal structure of [Mn2(DOTA)(H2O)2], in which eight-coordinate [Mn(DOTA)]2– units are bridged by six-coordinate exocyclic Mn(II) ions, is also reported. C.P.-I. and D.E.-G. (PID2019-104626GB-I00) and A.R.-R. (Grant PID2019-108352RJ-I00) thank Ministerio de Ciencia e Innovación and Xunta de Galicia (Grant ED431B 2020/52) for generous financial support. R.U.-V. thanks the Xunta de Galicia (Grant ED481A-2018/314) for funding her Ph.D. contract. L.V is indebted to CACTI (Universidade de Vigo) for X-Ray measurements. P.C. acknowledges funding from the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK121789) Xunta de Galicia; ED431B 2020/52 Xunta de Galicia; ED481A-2018/314 Estados Unidos de América. National Institute of Diabetes and Digestive and Kidney Diseases; R01DK121789

Investigating the relaxation of water 1H nuclei induced by paramagnetic Mn(II) complexes is important to understand the mechanisms that control the efficiency of contrast agents used in diagnostic magnetic resonance imaging (MRI). Herein, a series of potentially hexadentate triazacyclononane (TACN) derivatives containing different pendant arms were designed to explore the relaxation of the electron spin in the corresponding Mn(II) complexes by using a combination of 1H NMR relaxometry and theoretical calculations. These ligands include 1,4,7-triazacyclononane-1,4,7-triacetic acid (H3NOTA) and three derivatives in which an acetate group is replaced by sulfonamide (H3NO2ASAm), amide (H2NO2AM), or pyridyl (H2NO2APy) pendants. The analogue of H3NOTA containing three propionate pendant arms (H3NOTPrA) was also investigated. The X-ray structure of the derivative containing two acetate groups and a sulfonamide pendant arm [Mn(NO2ASAm)]− evidenced six-coordination of the ligand to the metal ion, with the coordination polyhedron being close to a trigonal prism. The relaxivities of all complexes at 20 MHz and 25 °C (1.1–1.3 mM–1 s–1) are typical of systems that lack water molecules coordinated to the metal ion. The nuclear magnetic relaxation profiles evidence significant differences in the relaxivities of the complexes at low fields (, The nature of the donor atoms and particularly the coordination polyhedron affect dramatically the zero field splitting in six-coordinate Mn(II) complexes, which has a strong impact in the relaxivities measured at low magnetic fields.

Rigid derivatives of the acyclic ligand PDTA4− (H4PDTA = propylenediamine-N,N,N′,N′-tetraacetic acid) were prepared by functionalization of a 1,3-diaminocyclobutyl spacer. The new ligands contain either four acetate groups attached to the central scaffold (H4L1) or incorporate pyridyl (H2L2) or propylamide (H2L3) units replacing two of the carboxylate groups. The ligand protonation constants and the stability constants of their Mn2+ complexes were determined using potentiometric and spectrophotometric titrations. The stability of the [Mn(L1)]2− complex was found to be significantly higher than that of the flexible [Mn(PDTA)]2− derivative (log KMnL = 10.78 and 10.01, respectively). A detailed study of the 1H Nuclear Magnetic Relaxation Dispersion (NMRD) profiles and 17O NMR measurements evidence that the [Mn(L1)]2− and [Mn(L2)] complexes display a hydration equilibrium in solution involving a seven-coordinate species with an inner-sphere water molecule and a six-coordinate species that lacks a coordinated water molecule. As a result the 1H relaxivities of these complexes are somewhat lower than that of [Mn(EDTA)]2− and related systems. The introduction of propylamide groups in [Mn(L3)] shifts the hydration equilibrium to the seven-coordinate species, which results in a 1H relaxivity (r1p = 3.7 mM−1 s−1 at 22 MHz and 25 °C) exceeding that of [Mn(EDTA)]2− (r1p = 3.3 mM−1 s−1 at 22 MHz and 25 °C). The parameters that control the relaxivities in this family of complexes were determined by simultaneous fitting of the experimental 1H NMRD and 17O NMR data (transverse relaxation rates and chemical shifts), with the aid of computational studies performed at the DFT and CASSCF/NEVPT2 levels. These studies provide detailed insight of the parameters that control the efficiency of these relaxation agents at the molecular level.

We present two ligands containing a N-ethyl-4-(trifluoromethyl)benzenesulfonamide group attached to either a 6,6'-(azanediylbis(methylene))dipicolinic acid unit (H3DPASAm) or a 2,2'-(1,4,7-triazonane-1,4-diyl)diacetic acid macrocyclic platform (H3NO2ASAm). These ligands were designed to provide a pH-dependent relaxivity response upon complexation with Mn2+ in aqueous solution. The protonation constants of the ligands and the stability constants of the Mn2+ complexes were determined using potentiometric titrations complemented by spectrophotometric experiments. The deprotonations of the sulfonamide groups of the ligands are characterized by protonation constants of log KiH = 10.36 and 10.59 for DPASAm3- and HNO2ASAm2-, respectively. These values decrease dramatically to log KiH = 6.43 and 5.42 in the presence of Mn2+, because of the coordination of the negatively charged sulfonamide groups to the metal ion. The higher log KiH value in [Mn(DPASAm)]- is related to the formation of a seven-coordinate complex, while the metal ion in [Mn(NO2ASAm)]- is six-coordinated. The X-ray crystal structure of Na[Mn(DPASAm)(H2O)]·2H2O confirms the formation of a seven-coordinate complex, where the coordination environment is fulfilled by the donor atoms of the two picolinate groups, the amine N atom, the N atom of the sulfonamide group, and a coordinated water molecule. The lower conditional stability of the [Mn(NO2ASAm)]- complex and the lower protonation constant of the sulfonamide group results in complex dissociation at relatively high pH (

[Abstract] Several bifunctional chelators have been synthesized in the last years for the development of new 64Cu-based PET agents for in vivo imaging. When designing a metal-based PET probe, it is important to achieve high stability and kinetic inertness once the radioisotope is coordinated. Different competitive assays are commonly used to evaluate the possible dissociation mechanisms that may induce Cu(II) release in the body. Among them, acid-assisted dissociation tests or transchelation challenges employing EDTA or SOD are frequently used to evaluate both solution thermodynamics and the kinetic behavior of potential metal-based systems. Despite of this, the Cu(II)/Cu(I) bioreduction pathway that could be promoted by the presence of bioreductants still remains little explored. To fill this gap we present here a detailed spectroscopic study of the kinetic behavior of different macrocyclic Cu(II) complexes. The complexes investigated include the cross-bridge cyclam derivative [Cu(CB-TE1A)]+, whose structure was determined using single-crystal X-ray diffraction. The acid-assisted dissociation mechanism was investigated using HClO4 and HCl to analyse the effect of the counterion on the rate constants. The complexes were selected so that the effects of complex charge and coordination polyhedron could be assessed. Cyclic voltammetry experiments were conducted to investigate whether the reduction to Cu(I) falls within the window of common bioreducing agents. The most striking behavior concerns the [Cu(NO2Th)]2+ complex, a 1,4,7-triazacyclononane derivative containing two methylthiazolyl pendant arms. This complex is extremely inert with respect to dissociation following the acid-catalyzed mechanism, but dissociates rather quickly in the presence of a bioreductant like ascorbic acid. The authors thank Ministerio de Ciencia e Innovación (PID2019-104626GB-I00) and Xunta de Galicia (ED431B 2020/52) for generous financial support. R.U.-V. thanks Xunta de Galicia (Grant ED481A-2018/314) for funding her PhD contract. V. P. and R. T. acknowledge the Ministère de l'Enseignement Supérieur et de la Recherche and the Centre National de la Recherche Scientifique. L.V. thanks CACTI (Universidade de Vigo) for X-ray measurements Xunta de Galicia; ED431B 2020/52 Xunta de Galicia; ED481A-2018/314

Rigid derivatives of the acyclic ligand PDTA4- (H

We present two ligands containing a

[Abstract] We report two macrocyclic ligands based on a 1,7-diaza-12-crown-4 platform functionalized with acetate (𝑡O2DO2A²⁻) or piperidineacetamide (𝑡O2DO2AMᴾⁱᵖ) pendant arms and a detailed characterization of the correspondingMn(II) complexes. The X-ray structure of [Mn(𝑡O2DO2A)(H₂O)]∙.2H₂O shows that the metal ion is coordinated by six donor atoms of the macrocyclic ligand and one water molecule, to result in seven-coordination. The Cu(II) analogue presents a distorted octahedral coordination environment. The protonation constants of the ligands and the stability constants of the complexes formed with Mn(II) and other biologically relevant metal ions (Mg(II), Ca(II), Cu(II) and Zn(II)) were determined using potentiometric titrations (∕ = 0.15 M NaCl, T = 25 ºC). The conditional stabilities of Mn(II) complexes at pH 7.4 are comparable to those reported for the cyclen-based 𝑡DO2A²⁻ ligand. The dissociation of the Mn(II) chelates were investigated by evaluating the rate constants of metal exchange reactions with Cu(II) under acidic conditions (∕ = 0.15MNaCl, T = 25 ºC). Dissociation of the [Mn(𝑡O2DO2A)(H₂O)] complex occurs through both proton- and metal-assisted pathways, while the [Mn(𝑡O2DO2AMᴾⁱᵖ)(H₂O)] analogue dissociates through spontaneous and proton-assisted mechanisms. The Mn(II) complex of 𝑡O2DO2A²⁻ is remarkably inert with respect to its dissociation, while the amide analogue is significantly more labile. The presence of a water molecule coordinated to Mn(II) imparts relatively high relaxivities to the complexes. The parameters determining this key property were investigated using ¹⁷O NMR (Nuclear Magnetic Resonance) transverse relaxation rates and ¹H nuclear magnetic relaxation dispersion (NMRD) profiles. This research was funded by Hungarian National Research, Development and Innovation Office, Projects NKFIH K-120224 and 134694); Ministerio de Economía y Competitividad (CTQ2016-76756-P) and Xunta de Galicia (ED431B 2020/52) Hungarian Scientific Research; NKFIH K-120224 Hungarian Scientific Research; NKFIH K-134694 Xunta de Galicia; ED431B 2020/52

[Abstract] We report a pentadentate ligand containing a 2,2′-azanediyldiacetic acid moiety functionalized with a picolinate group at the nitrogen atom (H3paada), as well as a lipophylic derivative functionalized with a dodecyloxy group at position 4 of the pyridyl ring (H3C12Opaada). The protonation constants of the paada3− ligand and the stability constant of the Mn(II) complex were determined using a combination of potentiometric and spectrophotometric titrations (25 °C, 0.15 M NaCl). A detailed relaxometric characterisation was accomplished by recording 1H Nuclear Magnetic Relaxation Dispersion (NMRD) profiles and 17O chemical shifts and relaxation rates. These studies provide detailed information on the microscopic parameters that control their efficiency as relaxation agents in vitro. For the sake of completeness and to facilitate comparison, we also characterised the related [Mn(nta)]− complex (nta = nitrilotriacetate). Both the [Mn(paada)]− and [Mn(nta)]− complexes turned out to contain two inner-sphere water molecules in aqueous solution. The exchange rate of these coordinated water molecules was slower in [Mn(paada)]− (k298ex = 90 × 107 s−1) than in [Mn(nta)]− (k298ex = 280 × 107 s−1). The complexes were also characterised using both DFT (TPSSh/def2–TZVP) and ab initio CAS(5,5) calculations. The lipophylic [Mn(C12Opaada)]− complex forms micelles in solution characterised by a critical micellar concentration (cmc) of 0.31 ± 0.01 mM. This complex also forms a rather strong adduct with Bovine Serum Albumin (BSA) with an association constant of 5.5 × 104 M−1 at 25 °C. The enthalpy and entropy changes obtained for the formation of the adduct indicate that the binding event is driven by hydrophobic interactions. Authors R. P.-P., I. B., E. I., C. P.-I. and D. E.-G. thank Ministerio de Economía y Competitividad (CTQ2016-76756-P) and Xunta de Galicia (ED431B 2017/59 and ED431D 2017/01) for generous financial support and Centro de Supercomputación of Galicia (CESGA) for providing the computer facilities. R. P.-P. thanks Ministerio de Economía y Competitividad for a PhD FPI grant (BES-2014-068399) and a fellowship for a short term stay in Alessandria (EEBB-I-18-13075). R. U.-V. thanks Xunta de Galicia for a PhD grant (ED481A-2018/314). M.B. and F.C. are grateful to Università del Piemonte Orientale for financial support (Ricerca locale 2016). This work was carried out within the framework of the COST CA15209 Action “European Network on NMR Relaxometry” Xunta de Galicia; ED431B 2017/59 Xunta de Galicia; ED431D 2017/01 Xunta de Galicia; ED481A-2018/314

Triazines and their degradation products are transported to the aquatic environment, and once there, the probability to reach the marine environment is very high. In this paper, solid phase extraction (SPE) and extraction by matrix solid phase dispersion (MSPD) to analyse nine triazines (ametryn, atrazine, cyanazine, prometryn, propazine, simazine, simetryn, terbuthylazine and terbutryn) and eight degradation products (desethylatrazine, desethyldesisopropylatrazine, desethyl-2-hydroxyatrazine, desethylterbuthylazine, desisopropylatrazine, desisopropyl-2-hydroxyatrazine, 2-hydroxyatrazine and 2-hidroxyterbuthylazine) in seawater and marine sediments samples were used. The analysis was carried out using liquid chromatography with tandem mass spectrometry (LC-ESI-MS/MS). The methods were optimized and validated to achieve a selective and sensitive determination of the analytes from different sample, regardless of its complexity. Under the optimum conditions, the proposed methods provided adequate limits of quantification (0.05–0.45 μg L−1 and 0.23–4.26 μg kg−1 in seawater and marine sediments, respectively). Intra- and inter-day relative standard deviation were below 1.41% for all compounds. Recoveries were evaluated, and acceptable values that ranged from 87.5–99.4 and 60.9–99.7% for the seawater and sediment samples, respectively, were obtained. The proposed methods were applied to the analysis of the target compounds in seawater samples and marine sediments from a coastal area of Galicia (NW of Spain).