A Water Molecule Triggers Guest Exchange at a Mono-Zinc Centre Confined in a Biomimetic Calixarene Pocket: a Model for Understanding Ligand Stability in Zn Proteins.

In this study, the ligand exchange mechanism at a biomimetic ZnII centre, embedded in a pocket mimicking the possible constrains induced by a proteic structure, is explored. The residence time of different guest ligands (dimethylformamide, acetonitrile and ethanol) inside the cavity of a calix[6]arene-based tris(imidazole) tetrahedral zinc complex was probed using 1D EXchange SpectroscopY NMR experiments. A strong dependence of residence time on water content was observed with no exchange occurring under anhydrous conditions, even in the presence of a large excess of guest ligand. These results advocate for an associative exchange mechanism involving the transient exo-coordination of a water molecule, giving rise to 5-coordinate ZnII intermediates, and inversion of the pyramid at the ZnII centre. Theoretical modelling by DFT confirmed that the associative mechanism is at stake. These results are particularly relevant in the context of the understanding of kinetic stability/lability in Zn proteins and highlight the key role that a single water molecule can play in catalysing ligand exchange and controlling the lability of ZnII in proteins.

A Water Molecule Triggers Guest Exchange at a Mono-Zinc Centre Confined in a Biomimetic Calixarene Pocket: A Model for Understanding Ligand Stability in Zn Proteins.

Invited for the cover of this issue are Kristin Bartik, Olivia Reinaud and co-workers at the Université libre de Bruxelles and Université Paris Descartes. The image depicts a Zn protein and highlights the role that a single water molecule can play in catalysing ligand exchange. Read the full text of the article at 10.1002/chem.202102184.

Closing a Calix[6]arene-Based Funnel Zn2+ Complex at Its Large Rim Entrance: Consequences on Metal Ion Affinity and Host-Guest Properties.

A molecular capsule based on a calix[6]arene core closed at the small rim by a three-point coordinated metal ion and at the large rim by a three-point covalent capping is described. It is derived from a trisimidazole funnel complex capped by a trenamide unit that prevents in/out exchange of guest molecules through the large rim. A detailed comparative study with three different calixarenes provides a unique opportunity for (i) comparing the binding ability of two different coordination sites in well three-dimensional (3D)-structured macrocyclic receptors and (ii) evaluating the impact of a covalent closing of one rim of a funnel receptor while the other rim is closed by weaker coordination bonds. Indeed, this study allowed for highlighting various interesting new features. It is first shown that the trenamide site can bind a metal ion such as Zn2+ by itself. This involves a 1:1 coordination of the metal ion to the three carbonyl groups of the amide functions, which undergo trans-to-cis isomerization and are partially embedded in the calix core. When the trisimidazole core is present, the Zn2+ ion preferentially binds at the small rim, thus closing the cavity. Guest ligand exchange must then occur through a decoordination/recoordination process of the metal ion. The modification and rigidification of the calixarene conformation induced by the large rim capping strengthen the metal ion coordination at the small rim. This also leads to a selective metallo-receptor that readily binds EtNH2 under conditions where PrNH2 is not recognized at all. The increased rigidity of the receptor, however, weakens the host-guest interactions, precluding important induced-fit behaviors that are at work in the parent, large rim opened, funnel complex.

Tuning the Fluorescence Through Reorientation of the Axle in Calix[6]arene-Based Pseudorotaxanes.

This work describes a calix[6]arene-based wheel that binds, in non-polar media, a stilbazolium salt to yield a mixture of pseudorotaxane orientational isomers. The isomer's abundance ratio evolves with time and can be reversibly tuned by adjusting the temperature. The spectroscopic properties, and notably the emission spectrum, of the bound guest depend on its orientation inside the non-palindromic wheel, suggesting such a system as a switch with spectroscopic readout.

Synthesis and Binding Properties of a Tren-Capped Hexahomotrioxacalix[3]arene.

The straightforward synthesis of a new hexahomotrioxacalix[3]arene-based ligand capped by a tren subunit was developed and the binding properties of the corresponding zinc complex were explored by NMR spectroscopy. Similarly to the closely related calix[6]tren-based systems, the homooxacalixarene core ensures the mononuclearity of the zinc complex and the metal center displays a labile coordination site for exogenous guests. However, very different host-guest properties were observed: i) in CDCl3 , the zinc complex strongly binds a water molecule and is reluctant to recognize other neutral guests, ii) in CD3 CN, the exo-coordination of anions prevails. Thus, in strong contrast to the calix[6]tren-based systems, the coordination of neutral guests that thread through the small rim and fill the polyaromatic cavity was not observed. This unique behaviour is likely due to the fact that the 18-membered ethereal macrocycle is too small to let a molecule threading through it. This work illustrates the key role played by the second coordination sphere in the binding properties of metal complexes.

Selective EPR Detection of Primary Amines in Water with a Calix[6]azacryptand-Based Copper(II) Funnel Complex.

A water-soluble calix[6]arene-based azacryptand was synthesized. The corresponding tren [tris(2-aminoethyl)amine] cap grafted at the small rim coordinates strongly a copper(II) ion over a wide range of pH. The host-guest properties of the complex were explored by EPR spectroscopy. Due to second coordination sphere effects and the hydrophobic effect ascribed to the calixarene cavity, this funnel complex selectively binds neutral molecules (alcohols, nitriles, amines) versus anions in water near physiological pH. Among the coordinating guests, hydrophobic primary amines are preferentially recognized thanks to the combined effect of the better metal-ligand interaction and hydrogen bonding to the oxygen atoms present at the small rim. Hence, this Cu(II) calix[6]arene-based funnel complex behaves as a sensitive and selective EPR probe for primary amines, including biologically important molecules such as tyramine and tryptamine, in water, over a large pH window.

Photo-CIDNP Reveals Different Protonation Sites Depending on the Primary Step of the Photoinduced Electron-/Proton-Transfer Process with Ru(II) Polyazaaromatic Complexes.

The excited-state quenching of [Ru(TAP)2(HAT)]2+ (TAP = 1,4,5,8-tetraazaphenanthrene, HAT= 1,4,5,8,9,12-hexaazatriphenylene) by hydroquinone (H2Q), N-acetyl-tyrosine (N-Ac-Tyr) or guanosine-5'-monophosphate (GMP) was investigated at various pH values. The quenching occurs via electron/proton transfer, as evidenced by transient absorption spectroscopy and confirmed by 1H photochemically induced dynamic nuclear polarization (photo-CIDNP). Reductive quenching also occurs in strongly acidic solution despite a much shorter lifetime of the protonated excited-state complex. Photo-CIDNP revealed a different mechanism at low pH, involving protonation before electron transfer and yielding a distinct protonated monoreduced complex. The experimental photo-CIDNP patterns are consistent with density functional theory calculations. This work highlights the power of 1H photo-CIDNP for characterizing, at the atomic level, transient species involved in electron-transfer processes.

NMR Study of the Reductive Decomposition of [BMIm][NTf2 ] at Gold Electrodes and Indirect Electrochemical Conversion of CO2.

Potential controlled electrolyses of [BMIm][NTf2 ] ionic liquid were performed at a gold cathode under nitrogen atmosphere. The structures of the major conversion products of the BMIm+ cation were elucidated on the basis of 1D and 2D nuclear magnetic resonance (NMR) analyses and gas chromatography (GC) analysis of the volatile compounds. Recombination of the imidazol-2-yl radicals, generated at the electrode by single electron transfer, leads to neutral diastereomeric dimers in equal proportions, with a faradaic efficiency of 80 %, while disproportionation of these radicals and/or reaction with hydrogen atoms adsorbed at the electrode generates a neutral monomer with 20 % faradaic efficiency. Both pathways also yield the N-heterocyclic carbene imidazolin-2-ylidene, which is involved in fast proton exchange with the parent BMIm+ cation. The reductive decomposition products of the BMIm+ cation are no longer detected if the pre-electrolysed sample is reacted with CO2 , which undergoes an indirect reduction and generates the carboxylate adduct.

pH Dependence of Photoinduced Electron Transfer with [Ru(TAP)3]2.

The quenching of the excited state of [Ru(TAP)3]2+ (TAP = 1,4,5,8-tetraazaphenanthrene) by guanosine-5'-monophosphate (GMP), N-acetyltyrosine (N-Ac-Tyr), and hydroquinone (H2Q) has been studied in aqueous solution over a wide range of pH values including, for the first time, strongly acidic media. This quenching by electron transfer was examined by steady-state 1H photochemically induced dynamic nuclear polarization (photo-CIDNP) as well as by more conventional techniques, among which are pulsed laser-induced transient absorption and emission experiments. A deeper knowledge of the photochemical behavior of [Ru(TAP)3]2+ has been gained thanks to the combined use of these two approaches, photo-CIDNP and electronic spectroscopies, highlighting their complementarity. In contrast to what was believed, it is found that the protonated excited state of [Ru(TAP)3]2+ may give rise to an electron transfer with N-Ac-Tyr and H2Q. Such a photoinduced electron transfer does not occur with protonated GMP, however. 1H photo-CIDNP experiments are expected to be particularly promising for characterization of the reductive quenching of excited-state ruthenium(II) polypyridyl complexes comprising several nonequivalent protonation sites.

Kinetic and Thermodynamic Stabilization of Metal Complexes by Introverted Coordination in a Calix[6]azacryptand.

The Huisgen thermal reaction between an organic azide and an acetylene was employed for the selective monofunctionalization of a X6 -azacryptand ligand bearing a tren coordinating unit [X6 stands for calix[6]arene and tren for tris(2-aminoethyl)amine]. Supramolecular assistance, originating from the formation of a host-guest inclusion complex between the reactants, greatly accelerates the reaction while self-inhibition affords a remarkable selectivity. The new ligand possesses a single amino-leg appended at the large rim of the calixarene core and the corresponding Zn(2+) complex was characterized both in solution and in the solid state. The coordination of Zn(2+) not only involves the tren cap but also the introverted amino-leg, which locks the metal ion in the cavity. Compared with the parent ligand deprived of the amino-leg, the affinity of the new monofunctionalized X6 tren ligand 6 for Zn(2+) is found to have a 10-fold increase in DMSO, which is a very competitive solvent, and with an enhancement of at least three orders of magnitude in CDCl3 /CD3 OD (1:1, v/v). In strong contrast with the fast binding kinetics, decoordination of Zn(2+) as well as transmetallation appeared to be very slow processes. The monofunctionalized X6 tren ligand 6 fully protects the metal ion from the external medium thanks to the combination of a cavity and a closed coordination sphere, leading to greater thermodynamic and kinetic stabilities.

Triflate-functionalized calix[6]arenes as versatile building-blocks: application to the synthesis of an inherently chiral Zn(ii) complex.

Cavity-based metal complexes can find many applications notably in the fields of catalysis and biomimicry. In this context, it was shown that metal complexes of calix[6]arenes bearing three aza-coordinating arms at the small rim provide excellent structural models of the poly-imidazole sites found in the active site of many metallo-enzymes. All these N-donor ligands were synthesized from the 1,3,5-tris-methoxy-p-tBu-calix[6]arene platform, which presents some limitations in terms of functionalization. Therefore, there is a need for the development of new calix[6]arene-based building-blocks selectively protected at the small rim. Herein we describe the regioselective one step synthesis of two calix[6]arenes decorated with triflate groups, i.e. X6H4Tf2 and X6H3Tf3, from the parent calix[6]arene X6H6. It is shown that the triflate groups can either act as protecting or deactivating groups, allowing the elaboration of sophisticated calixarene-based systems selectively functionalized at the large and/or at the small rim. In addition, X6H3Tf3 is functionalized on the A, B, and D rings and thus gives access to inherently chiral compounds, as demonstrated by the synthesis of a rare example of inherently chiral cavity-based metal complex.

Selective recognition of neutral guests in an aqueous medium by a biomimetic calix[6]cryptamide receptor.

The design of artificial receptors that can efficiently work in water is a challenging research area. A possible biomimetic approach for the elaboration of such receptors consists of associating a hydrophobic cavity with a polar polyfunctional binding site. On this basis, a hydrophilic calix[6]cryptamide decorated with oligo(ethylene glycol) units (i.e. 8) was synthesized through an efficient [1 + 1] macrocyclization reaction as the key-step. The complexation of neutral molecules was evaluated by NMR spectroscopy through competition experiments either in apolar or aqueous media. In both media, host 8 can bind neutral species that display H-bonding acceptor and donor groups such as amides or ureas. Interestingly, the most polar and acidic molecule is the best guest in chloroform and the worst one in an aqueous medium, highlighting the importance of the environment. As shown by NMR and X-ray diffraction data, the mode of recognition involves a complementary DAAAD-ADDDA quintuple H-bonding array between the binding partners as well as multiple CH-π interactions. A comparison of this calix[6]arene-based host-guest system with the binding site of biotin-binding proteins shows strong similarities. Besides, the acid-base control of the binding properties of receptor 8 in aqueous media is highly reminiscent of allosteric processes encountered in natural systems.

Insights into the structure-activity relationships of chiral 1,2-diaminophenylalkane platinum(II) anticancer derivatives.

The structure-activity relationships of chiral 1,2-diaminophenylalkane platinum(II) anticancer derivatives are studied, including interactions with telomeric- and genomic-like DNA sequences, the pKa of their diaqua species, structural properties obtained from DFT calculations and resonant X-ray emission spectroscopy. The binding modes of the compounds to telomeric sequences were elucidated, showing no major differences with conventional cis-platinum(II) complexes like cisplatin, supporting that the cis-square planar geometry governs the binding of small Pt(II) complexes to G4 structures. Double-stranded DNA platination kinetics and acid-base constants of the diaqua species of the compounds were measured and compared, highlighting a strong steric dependence of the DNA-binding kinetics, but independent to stereoisomerism. Structural features of the compounds are discussed on the basis of dispersion-corrected DFT, showing that the most active series presents conformers for which the platinum atom is well devoid of steric hindrance. If reactivity indices derived from conceptual DFT do not show evidences for different reactivity between the compounds, RXES experiments provide new insight into the availability of platinum orbitals for binding to nucleophiles.

Tailored functionalization of polyphenol-based molecular platforms.

General and efficient methods for selective modification of macrocyclic oligomers are rare, mostly because restricting a reaction to a defined number of identical functional groups is difficult to achieve. This work describes a unique, general, and rational methodology for the iteroselective functionalization of polyphenolic platforms by N-tert-butylaminocarbonyl (Bac) groups. The methodology consists of reacting the oligomeric platform with t-BuNCO and an inorganic base in an apolar solvent. This very simple one-step procedure has been applied to various calix[4, 5, 6, and 8]arenes, and in all cases, calixarenes with a single leftover phenolic moiety were isolated in high yields (>90%). Interestingly, this so-called "all-but-one" methodology gives a straightforward access to calixarenes displaying inherent chirality. It is also shown that the Bac group can be used as a protective group. Thus, the all-but-one methodology has been used for the efficient monofunctionalization of a key precursor platform, illustrating its huge potential for the tailored synthesis of sophisticated macrocyclic oligomers.

Supramolecular assistance for the selective monofunctionalization of a calix[6]arene tris-carboxylic acid-based receptor.

The selective functionalization of macrocyclic receptors remains extremely challenging because it generally requires the transformation of one and only one functional group among several identical groups. Recently, some of us described that the host-guest properties of a calix[6]arene-based Zn complex could be exploited for its selective monofunctionalization. Herein, we report on the extension of this synthetic strategy to a calix[6]arene-based receptor displaying a different recognition pattern with its guest. More precisely, a calix[6]arene tris-carboxylic acid-based receptor bearing three azido groups at the large rim was selectively monofunctionalized through an intramolecular thermal Huisgen reaction with a hexynNH3(+) ion accommodated into the cavity. This work shows that the monofunctionalization methodology can also be performed efficiently with host-guest systems involving ionic/H-bonding interactions, and it is thus not limited only to the use of metal-ligand interactions. In other words, this supramolecular methodology can be used as a general tool for the selective functionalization of molecular receptors.

17O NMR study of diamagnetic and paramagnetic lanthanide(III)-DOTA complexes in aqueous solution.

The complexes between the polyaminocarboxylate DOTA ligand and the whole series of stable lanthanide(III) metal ions, except Gd(3+), were studied in aqueous solution by (17)O NMR. For all of the paramagnetic systems, the (17)O NMR signals of both the nonchelating (O1) and chelating (O2) oxygen atoms could be detected, and for some of them, the signals of both the SAP and TSAP (TSAP') conformational isomers were also observed. Line width data analysis reveals that signal broadening is not dominated by paramagnetic relaxation enhancement, as it was believed to be. The data indicate that quadrupole relaxation and, for some complexes, chemical exchange between the SAP and TSAP isomers are the major contributions to the (17)O NMR line width at 25 °C. Besides, the Fermi contact and pseudocontact contributions to the observed lanthanide-induced shifts could be extracted. The (17)O hyperfine coupling constants determined for O2 in the SAP and TSAP isomers are similar to each other and to the values reported for several Gd(III) complexes comprising fast-exchanging ligands. Interestingly, the results suggest that (17)O NMR should prove to be useful for the study of highly paramagnetic Gd(III) complexes of nonlabile ligands.

An induced-fit process through mechanical pivoting of aromatic walls in host-guest chemistry of calix[6]arene aza-cryptands.

The per-ipso-nitration of a TMPA-capped calix[6]arene has been achieved. The substitution of the six bulky tBu substituents for nitro groups has a strong impact on the behavior of the ligand during guest recognition. The complexation of the aza cap (by H(+) or Cu(+)) associated with the encapsulation of a guest triggers an induced-fit process leading to the loss of the cone conformation of the host in favor of alternate conformations. Such a "pivoting" response of one or two walls of the calixarene core induces a large mechanical motion of the corresponding aromatic units. This stands in strong contrast with the "breathing" phenomena previously identified with other calix[6]arene-based complexes that expand or shrink the size of their cone as a function of the guest. Because of the covalently attached rigid TMPA cap, three arene units of this new calixarene host have a restricted mobility, which forces it to respond in a different manner to a supramolecular stress.

Acid-base-controlled stereoselective metalation of overhanging carboxylic acid porphyrins: consequences for the formation of heterobimetallic complexes.

Overhanging carboxylic acid porphyrins have revealed promising ditopic ligands offering a new entry in the field of supramolecular coordination chemistry of porphyrinoids. Notably, the adjunction of a so-called hanging-atop (HAT) Pb(II) cation to regular Pb(II) porphyrin complexes allowed a stereoselective incorporation of the N-core bound cation, and an allosterically controlled Newton's cradle-like motion of the two Pb(II) ions also emerged from such bimetallic complexes. In this contribution, we have extended this work to other ligands and metal ions, aiming at understanding the parameters that control the HAT Pb(II) coordination. The nature of the N-core bound metal ion (Zn(II), Cd(II)), the influence of the deprotonation state of the overhanging COOH group and the presence of a neutral ligand on the opposite side (exogenous or intramolecular), have been examined through (1)H NMR spectroscopic experiments with the help of radiocrystallographic structures and DFT calculations. Single and bis-strap ligands have been considered. They all incorporate a COOH group hung over the N-core on one side. For the bis-strap ligands, either an ester or an amide group has been introduced on the other side. In the presence of a base, the mononuclear Zn(II) or Cd(II) complexes incorporate the carbonyl of the overhanging carboxylate as apical ligand, decreasing its availability for the binding of a HAT Pb(II). An allosteric effector (e.g., 4-dimethylaminopyridine (DMAP), in the case of a single-strap ligand) or an intramolecular ligand (e.g., an amide group), strong enough to compete with the carbonyl of the hung COO(-), is required to switch the N-core bound cation to the opposite side with concomitant release of the COO(-), thereby allowing HAT Pb(II) complexation. In the absence of a base, Zn(II) or Cd(II) binds preferentially the carbonyl of the intramolecular ester or amide groups in apical position rather than that of the COOH. This better preorganization, with the overhanging COOH fully available, is responsible for a stronger binding of the HAT Pb(II). Thus, either allosteric or acid-base control is achieved through stereoselective metalation of Zn(II) or Cd(II). In the latter case, according to the deprotonation state of the COOH group, the best electron-donating ligand is located on one or the other side of the porphyrin (COO(-)>CONHR>COOR>COOH): the lower affinity of COOH for Zn(II) and Cd(II), the higher for a HAT Pb(II). These insights provide new opportunities for the elaboration of innovative bimetallic molecular switches.

Full assignment of the 1H NMR spectrum of heteroleptic polyazaaromatic Ru(II) complexes based on long-range interligand NOEs.

Chemical equivalence in symmetrical polyazaaromatic ligands is not necessarily retained in the corresponding heteroleptic ruthenium(II) complexes, and the assignment of the (1)H NMR spectrum of these octahedral metallic compounds is therefore not straightforward. This work shows that full assignment can be achieved on the basis of long-range interligand NOE measurements.

Unprecedented copper(I) bifluoride complexes: synthesis, characterization and reactivity.

To be or not to bifluoride: Two synthetic pathways to unprecedented N-heterocyclic carbene copper(I) bifluoride complexes have been developed. Catalytic tests demonstrated that copper(I) bifluorides are very efficient catalysts, which do not require any additional activating agent. The first Cu-catalyzed diastereoselective allylation of (R)-N-tert-butanesulfinyl aldimines was also established. The method enables efficient, simple and general synthesis of enantiomerically enriched homoallylic amines at room temperature in high yields.