Isomerization Mechanism in Hydrazone-Based Rotary Switches: Lateral Shift, Rotation, or Tautomerization?

Two intramolecularly hydrogen-bonded arylhydrazone (aryl = phenyl or naphthyl) molecular switches have been synthesized, and their full and reversible switching between the E and Z configurations have been demonstrated. These chemically controlled configurational rotary switches exist primarily as the E isomer at equilibrium and can be switched to the protonated Z configuration (Z-H^+) by the addition of trifluoroacetic acid. The protonation of the pyridine moiety in the switch induces a rotation around the hydrazone C═N double bond, leading to isomerization. Treating Z-H^+ with base (K_(2)CO_3) yields a mixture of E and “metastable” Z isomers. The latter thermally equilibrates to reinstate the initial isomer ratio. The rate of the Z → E isomerization process showed small changes as a function of solvent polarity, indicating that the isomerization might be going through the inversion mechanism (nonpolar transition state). However, the plot of the logarithm of the rate constant k vs the Dimroth parameter (E_T) gave a linear fit, demonstrating the involvement of a polar transition state (rotation mechanism). These two seemingly contradicting kinetic data were not enough to determine whether the isomerization mechanism goes through the rotation or inversion pathways. The highly negative entropy values obtained for both the forward (E → Z-H^+) and backward (Z → E) processes strongly suggest that the isomerization involves a polarized transition state that is highly organized (possibly involving a high degree of solvent organization), and hence it proceeds via a rotation mechanism as opposed to inversion. Computations of the Z ↔ E isomerization using density functional theory (DFT) at the M06/cc-pVTZ level and natural bond orbital (NBO) wave function analyses have shown that the favorable isomerization mechanism in these hydrogen-bonded systems is hydrazone–azo tautomerization followed by rotation around a C–N single bond, as opposed to the more common rotation mechanism around the C═N double bond

Sulphur-rich functionalized calix[4]arenes for selective complexation of Hg2+ over Cu2+, Zn2+ and Cd2+

[Abstract] The syntheses of two new ligands based on a calix[4]arene scaffold in the cone conformation functionalized on the phenolic positions 1 and 3 by diethylthiophosphonates (L1) or tetra(tri)thioethyleneglycol (L2) crowns are described. Together with ligand L3, the parent calix[4]arene substituted by a penta(tetra)thioethyleneglycol crown, the spectroscopic properties of the ligands were determined by means of UV-Vis absorption spectroscopy and steady-state and time-resolved fluorescence spectroscopy, showing that the ligands display modest but non-negligible intrinsic fluorescence properties (ϕfluo = 0.023; 0.026 and 0.029 for L1, L2 and L3 in CH2Cl2, respectively). The X-ray crystal structures of ligand L1, and of its synthetic precursor were determined and analyzed for their capacity to accommodate the incoming cationic species. The ligands were further investigated for their complexation properties of divalent cations such as Cu2+, Zn2+, Hg2+ and Cd2+ (under their nitrate salts) in 1:1 CH3CN/CH2Cl2 solutions (I = 0.01 M Et4NNO3, T = 25.0(2) °C), in which the additions of cations were monitored by absorption and steady-state fluorescence spectrophotometries. The stoichiometries of the corresponding complexes were assessed by ESI-MS, while insights into the structures of the complexes in solution were obtained with density functional theory (DFT) calculations. The influence of the sulphur and phenol coordinating moieties was addressed to show that the thiocrown compounds L2 and L3 displayed a marked affinity towards the soft mercuric cation (ΔlogK ≥ 2), with no particular size selectivity effect, whereas ligand L1 can accommodate both the thio and phenol units to coordinate with Cu(II). Altogether, these results point to the use of L3 as a selective fluoroionophore for detection of Hg2+

Highly relaxing gadolinium based MRI contrast agents responsive to Mg2+ sensing

[Abstract] A Gd complex based on a polyphosphonated pyridyl ligand shows a very high stability in aqueous solution (logKEuL = 25.7), a high relaxivity (8.5 mM−1 s−1 at 25 °C and 20 MHz) and a marked and selective relaxivity enhancement (37%) in the presence of Mg2+, opening interesting perspectives for the design of cation responsive contrast agents

Importance of outer-sphere and aggregation phenomena in the relaxation properties of phosphonated gadolinium complexes with potential applications as MRI contrast agents

[Abstract] A series composed of a tetra-, a tris- and a bisphosphonated ligand based on a pyridine scaffold (L4, L3 and L2, respectively) was studied within the frame of lanthanide (Ln) coordination. The stability constants of the complexes formed with lanthanide cations (Ln=La, Nd, Eu, Gd, Tb, Er and Lu) were determined by potentiometry in aqueous solutions (25.0 °C, 0.1 M NaClO4), showing that the tetraphosphonated complexes are among the most stable LnIII complexes reported in the literature. The complexation of L4 was further studied by different titration experiments using mass spectrometry and various spectroscopic techniques including UV/Vis absorption, and steady state and time-resolved luminescence (Ln=Eu and Tb). Titration experiments confirmed the formation of highly stable [LnL4] complexes. 31P NMR experiments of the LuL4 complex revealed an intramolecular interconversion process which was studied at different temperatures and was rationalized by DFT modelling. The relaxivity properties of the GdIII complexes were studied by recording their 1H NMRD profiles at various temperatures, by temperature dependent 17O NMR experiments (GdL4) and by pH dependent relaxivity measurements at 0.47 T (GdL3 and GdL2). In addition to the high relaxivity values observed for all complexes, the results showed an important second-sphere contribution to relaxivity and pH dependent variations associated with the formation of aggregates for GdL2 and GdL3. Finally, intravenous injection of GdL4 to a mouse was followed by dynamic MRI imaging at 1.5 T, which showed that the complex can be immediately found in the blood stream and rapidly eliminated through the liver and in large part through the kidneys.Torino. Compagnia di San Paolo; CSP-2012 NANOPROGL

Arylmethylamino steroids as antiparasitic agents

In search of antiparasitic agents, we here identify arylmethylamino steroids as potent compounds and characterize more than 60 derivatives. The lead compound 1o is fast acting and highly active against intraerythrocytic stages of chloroquine-sensitive and resistant Plasmodium falciparum parasites (IC50 1–5?nM) as well as against gametocytes. In P. berghei-infected mice, oral administration of 1o drastically reduces parasitaemia and cures the animals. Furthermore, 1o efficiently blocks parasite transmission from mice to mosquitoes. The steroid compounds show low cytotoxicity in mammalian cells and do not induce acute toxicity symptoms in mice. Moreover, 1o has a remarkable activity against the blood-feeding trematode parasite Schistosoma mansoni. The steroid and the hydroxyarylmethylamino moieties are essential for antimalarial activity supporting a chelate-based quinone methide mechanism involving metal or haem bioactivation. This study identifies chemical scaffolds that are rapidly internalized into blood-feeding parasites