Nmr oc Publications

As a result of calcium ion binding, the calcium-dependent regulatory protein calmodulin (CaM) undergoes a conformational change, enabling it to bind to and activate a variety of enzymes. However, the detoxification enzyme glutathione S-transferase (GST) is notably not among the enzymes activated by CaM. In this study, we demonstrate the feasibility of establishing, in vitro, an artificial regulatory link between CaM and GST using bifunctional chemical transducer (CT) molecules possessing binders for CaM and GST. We show that the CTs convert the constitutively active GST into a triggerable enzyme whose activity is unnaturally regulated by the CaM conformational state and consequently, by the level of calcium ions. The ability to reconfigure the regulatory function of CaM demonstrates a novel mode by which CTs could be employed to mediate artificial protein crosstalk, as well as a new means to achieve artificial control of enzyme activity by modulating the coordination of metal ions. Within this study, we also investigated the impact of covalent interaction between the CTs and the enzyme target. This investigation offers further insights into the mechanisms governing the function of CTs and the possibility of rendering them isoform specific.

Bond activation and catalysis using s-block metals are of great significance. Herein, a series of calcium pincer complexes with deprotonated side arms have been prepared using pyridine-based PNP and PNN ligands. The complexes were characterized by NMR and X-ray crystal diffraction. Utilizing the obtained calcium complexes, unprecedented N₂O activation by metal-ligand cooperation (MLC) involving dearomatization-aromatization of the pyridine ligand was achieved, generating aromatized calcium diazotate complexes as products. Additionally, the dearomatized calcium complexes were able to activate the N−H bond as well as reversibly activate H₂, offering an opportunity for the catalytic hydrogenation of various unsaturated molecules. DFT calculations were applied to analyze the electronic structures of the synthesized complexes and explore possible reaction mechanisms. This study is an important complement to the area of MLC and main-group metal chemistry.

Electrochemical CO₂ reduction reaction in aqueous electrolytes is a promising route to produce added-value chemicals and decrease carbon emissions. However, even in Gas-Diffusion Electrode devices, low aqueous CO₂ solubility limits catalysis rate and selectivity. Here, we demonstrate that when assembled over a heterogeneous electrocatalyst, a film of nitrile-modified Metal-Organic Framework (MOF) acts as a remarkable CO₂-solvation layer that increases its local concentration by ~27-fold compared to bulk electrolyte, reaching 0.82 M. When mounted on a Bi catalyst in a Gas Diffusion Electrode, the MOF drastically improves CO₂-to-HCOOH conversion, reaching above 90% selectivity and partial HCOOH currents of 166 mA/cm² (at −0.9 V vs RHE). The MOF also facilitates catalysis through stabilization of reaction intermediates, as identified by operando infrared spectroscopy and Density Functional Theory. Hence, the presented strategy provides new molecular means to enhance heterogeneous electrochemical CO₂ reduction reaction, leading it closer to the requirements for practical implementation.

The hexameric capsules of resorcin[4]arenes and pyrogallol[4]arenes are fascinating, catalytically active, and highly accessible structures having large cavities. Despite the apparent similarity between these two types of hexamers, the hexameric capsules of C11-resorcin[4]arenes (1) are much more efficient nanoreactors than the C11-pyrogallol[4]arene (2) capsules. In this study, we investigated the encapsulation of two bulky and structurally related isosteric guests namely adamantane-1-carboxylic acid (3) and 3,5,7-tri-fluoro adamantane-1-carboxylic acid (4) into these hexamers in a competitive (chloroform) and a non-competitive (benzene) solvent. Through the application of NMR spectroscopy, diffusion NMR, and 19F guest exchange saturation transfer (GEST) applied for the first time on such hexameric capsules, we show that the two apparently similar hexamers behave differently towards these two isosteric guests. We found that in C6D6 the hexamers of 1 preferentially encapsulate the non-fluorinated guest 3 over guest 4, while the hexamers of 2 preferentially encapsulate the fluorinated isosteric guest 4. For the hexameric capsule of 2 encapsulating guest 4, 19F-NMR shows that the disruption of the hexameric capsule by methanol is a more complex process than one would have anticipated revealing, for the first time, three populations of 4 having different exchange rates. The combination of 1H/19F diffusion and 19F-GEST NMR provides new insights into these important and catalytically active capsular systems demonstrating the advantages of using this combination of NMR methods to explore such supramolecular systems in solution.

Acridine-based PNP-type pincer ligands (AcrPNP) have previously been used for the construction of a small number of Ru(II), Mn(I), Rh(III) and Ir(III) complexes, with most attention being given to the catalytically-active ruthenium complexes. In the present work, we significantly expand the scope of known AcrPNP complexes by introducing a series of new Ir(I) and Ir(III) complexes. These were synthesized from two AcrPNP ligands differing in their P-substituents (ⁱPr vs Ph), in conjunction with various Ir(I)-olefin precursors, through different sequences of reactions that include intramolecular C[sbnd]H activations and additions of H₂ and NaBEt₃H. The new iridium complexes, with their observed structures and reactivities, reflect the unique properties of the acridine-based PNP ligands, i.e., their inherent structural flexibility and ability to support both metal-centered reactivity (C[sbnd]H and H[sbnd]H oxidative addition) and ligand-centered reactivity (hydride- and H₂-induced dearomatization).

The electrification of ammonia synthesis is a key target for its decentralization and lowering impact on atmospheric CO₂ concentrations. The lithium metal electrochemical reduction of nitrogen to ammonia using alcohols as proton/electron donors is an important advance, but requires rather negative potentials, and anhydrous conditions. Organometallic electrocatalysts using redox mediators have also been reported. Water as a proton and electron donor has not been demonstrated in these reactions. Here a N₂ to NH₃ electrocatalytic reduction using an inorganic molecular catalyst, a tri-iron substituted polyoxotungstate, {SiFe₃W₉}, is presented. The catalyst requires the presence of Li⁺ or Na⁺ cations as promoters through their binding to {SiFe₃W₉}. Experimental NMR, CV and UV-vis measurements, and MD simulations and DFT calculations show that the alkali metal cation enables the decrease of the redox potential of {SiFe₃W₉} allowing the activation of N₂. Controlled potential electrolysis with highly purified ¹⁴N₂ and ¹⁵N₂ ruled out formation of NH₃ from contaminants. Importantly, using Na⁺ cations and polyethylene glycol as solvent, the anodic oxidation of water can be used as a proton and electron donor for the formation of NH₃. In an undivided cell electrolyzer under 1 bar N₂, rates of NH₃ formation of 1.15 nmol sec^-1 cm^-2, faradaic efficiencies of ∼25%, 5.1 equiv of NH₃ per equivalent of {SiFe₃W₉} in 10 h, and a TOF of 64 s^-1 were obtained. The future development of suitable high surface area cathodes and well solubilized N₂ and the use of H₂O as the reducing agent are important keys to the future deployment of an electrocatalytic ammonia synthesis.

Metal-capped molecular hosts are unique in supramolecular chemistry, benefitting from the inner cavity's hydrophobic nature and the metal center's electrochemical properties. It is shown here that the paramagnetic properties of the metals in lanthanide-capped cyclodextrins (Ln-α-CDs and Ln-β-CDs) are a convenient NMR indicator for different populations of host-guest complexes in a given solution. The paramagnetic guest exchange saturation transfer (paraGEST) method was used to study the exchange dynamics in systems composed of Ln-α-CDs or Ln-β-CDs with fluorinated guests, revealing multiple co-existing populations of host-guest complexes exclusively in solutions containing Ln-β-CDs. The enhanced spectral resolution of paraGEST, achieved by a strong pseudo contact shift induction, revealed that different molecular guests can adopt multiple orientations within Ln-β-CDs' cavities and, in contrast, only a single orientation inside Ln-α-CDs. Thus, paraGEST, which can significantly improve NMR detectability and spectral resolution of host-guest systems that experience fast exchange dynamics, is a convenient tool for studying supramolecular systems of metal-capped molecular hosts.

Biomass-originated materials are the future's next-tier polymers. This work suggests improving mechanical and barrier properties of nature-sourced polymers using non-covalent supramolecular interactions. Polysaccharide chitosan is modified with amino acids via an esterification pathway using a systematic variation of hydrogen bond and aromatic domains (Degrees of substitution 1249%). These controlled modifications improve stability due to non-covalent interactions, resulting in biopolymers with tailored thermal (decomposition temperature 232275 °C), mechanical (Young's modulus 5402667 MPa), and surface properties (roughness 440 nm). Chitosan and natural amino acids that are already manufactured at scale are purposely selected. The facile synthesis, controlled properties, stimuli-responsive potential, and inexhaustible origin of the raw materials provide the presented findings with the potential to become the method for the formation of high-performance biodegradable alternatives to petroleum-based polymers that can be used in packaging, food, agriculture, and medicine.

Mechanisms of nucleation and growth of crystals are still attracting a great deal of interest, in particular with recent advances in experimental techniques aimed at studying such phenomena. Studies of kinetic isotope effects in various reactions have been useful for elucidating reaction mechanisms, and it is believed that the same may apply for crystal formation kinetics. In this work, we present a kinetic study of the formation of europium-doped terbium phosphate nanocrystals under acidic conditions, including a strong H/D isotope effect. The nanocrystal growth process could be quantitatively followed through monitoring of the europium luminescence intensity. Hence, such lanthanide-based nanocrystals may serve as unique model systems for studying crystal nucleation and growth mechanisms. By combining the luminescence and NMR kinetics data, we conclude that the observed delayed nucleation occurs due to initial formation of pre-nucleation clusters or polymers of the lanthanide and phosphate ions, which undergo a phase transformation to crystal nuclei and further grow by cluster attachment. A scaling behavior observed on comparison of the H₂O and D₂O-based pre-nucleation and nanocrystal growth kinetics led us to conclude that both pre-nucleation and nanocrystal growth processes are of similar chemical nature.

Molecular confinement effects can profoundly alter the physicochemical properties of the confined species. A plethora of organic molecules were encapsulated within the cavities of supramolecular hosts, and the impact of the cavity size and polarity was widely investigated. However, the extent to which the properties of the confined guests can be affected by the symmetry of the cage─which dictates the shape of the cavity─remains to be understood. Here we show that cage symmetry has a dramatic effect on the equilibrium between two isomers of the encapsulated spiropyran guests. Working with two Pd-based coordination cages featuring similarly sized but differently shaped hydrophobic cavities, we found a highly selective stabilization of the isomer whose shape matches that of the cavity of the cage. A Td-symmetric cage stabilized the spiropyrans colorless form and rendered them photochemically inert. In contrast, a D2h-symmetric cage favored the colored isomer, while maintaining reversible photoswitching between the two states of the encapsulated spiropyrans. We also show that the switching kinetics strongly depend on the substitution pattern on the spiropyran scaffold. This finding was used to fabricate a time-sensitive information storage medium with tunable lifetimes of the encoded messages

The development of catalysts for environmentally benign organic transformations is a very active area of research. Most of the catalysts reported so far are based on transition-metal complexes. In recent years, examples of catalysis by main-group metal compounds have been reported. Herein, we report a series of magnesium pincer complexes, which were characterized by NMR and X-ray single-crystal diffraction. Reversible activation of H2 via aromatization/dearomatization metal-ligand cooperation was studied. Utilizing the obtained complexes, the unprecedented homogeneous main-group metal catalyzed semihydrogenation of alkynes and hydrogenation of alkenes were demonstrated under base-free conditions, affording Z-alkenes and alkanes as products, respectively, with excellent yields and selectivities. Control experiments and DFT studies reveal the involvement of metal-ligand cooperation in the hydrogenation reactions. This study not only provides a new approach for the semihydrogenation of alkynes and hydrogenation of alkenes catalyzed by magnesium but also offers opportunities for the hydrogenation of other compounds catalyzed by main-group metal complexes.

The NMR-detectability of elements of organic ligands that stabilize colloidal inorganic nanocrystals (NCs) allow the study of their diffusion characteristics in solutions. Nevertheless, these measurements are sensitive to dynamic ligand exchange and often lead to overestimation of diffusion coefficients of dispersed colloids. Here, we present an approach for the quantitative assessment of the diffusion properties of colloidal NCs based on the NMR signals of the elements of their inorganic cores. Benefiting from the robust ¹⁹F-NMR signals of the fluorides in the core of colloidal CaF₂and SrF₂, we show the immunity of ¹⁹F-diffusion NMR to dynamic ligand exchange and, thus, the ability to quantify, with high accuracy, the colloidal diameters of different types of nanofluorides in situ. With the demonstrated ability to characterize the formation of protein corona at the surface of nanofluorides, we envision that this study can be extended to additional formulations and applications.

An MRI-responsive agent that spontaneously self-assembles to a large supramolecular structure under physiological conditions was designed. The obtained assembly provides an extended time window for in vivo studies, as demonstrated for a fluorine-19 probe constructed to sense Zn2+ with 19F-iCEST MRI, in the future.

High-throughput nanomole-scale synthesis allows for late-stage functionalization (LSF) of compounds in an efficient and economical manner. Here, we demonstrated that copper-catalyzed azidealkyne cycloaddition could be used for the LSF of covalent kinase inhibitors at the nanoscale, enabling the synthesis of hundreds of compounds that did not require purification for biological assay screening, thus reducing experimental time drastically. We generated crude libraries of inhibitors for the kinase MKK7, derived from two different parental precursors, and analyzed them via the high-throughput In-Cell Western assay. Select inhibitors were resynthesized, validated via conventional biological and biochemical methods such as western blots and liquid chromatographymass spectrometry (LC-MS) labeling, and successfully co-crystallized. Two of these compounds showed over 20-fold increased inhibitory activity compared to the parental compound. This study demonstrates that high-throughput LSF of covalent inhibitors at the nanomole-scale level can be an auspicious approach in improving the properties of lead chemical matter.

Catalytic semihydrogenation of internal alkynes using H2 is an attractive atom-economical route to various alkenes, and its stereocontrol has received widespread attention, both in homogeneous and heterogeneous catalyses. Herein, a novel strategy is introduced, whereby a poisoning catalytic thiol is employed as a reversible inhibitor of a ruthenium catalyst, resulting in a controllable H2-based semihydrogenation of internal alkynes. Both (E)- and (Z)-alkenes were obtained efficiently and highly selectively, under very mild conditions, using a single homogeneous acridine-based ruthenium pincer catalyst. Mechanistic studies indicate that the (Z)-alkene is the reaction intermediate leading to the (E)-alkene and that the addition of a catalytic amount of bidentate thiol impedes the Z/E isomerization step by forming stable ruthenium thiol­(ate) complexes, while still allowing the main hydrogenation reaction to proceed. Thus, the absence or presence of catalytic thiol controls the stereoselectivity of this alkyne semihydrogenation, affording either the (E)-isomer as the final product or halting the reaction at the (Z)-intermediate. The developed system, which is also applied to the controllable isomerization of a terminal alkene, demonstrates how metal catalysis with switchable selectivity can be achieved by reversible inhibition of the catalyst with a simple auxiliary additive.

The olefin metathesis reaction is among the most widely applicable catalytic reactions for carboncarbon double bond formation. Currently, Mo and Rucarbene catalysts are the most common choices for this reaction. It has been suggested that an iron-based catalyst would be a desirable economical and biocompatible substitute of the Ru catalysts; however, practical solutions in this regard are still lacking. Here, we report the discovery and mechanistic studies of three-coordinate iron(II) catalysts for ring-opening metathesis polymerization of olefins. Remarkably, their reactivity enabled the formation of polynorbornene with stereoregularity and high molecular weight (>107gmol1). The polymerization in the presence of styrene revealed cross metathesis reactivity with iron catalysts. Mechanistic studies suggest the possible role of metalligand cooperation in formation of the productive catalyst. This work opens the door to the development of iron complexes that can be economical and biocompatible catalysts for olefin metathesis reactions.

Lithium metal anodes offer a huge leap in the energy density of batteries, yet their implementation is limited by solid electrolyte interphase (SEI) formation and dendrite deposition. A key challenge in developing electrolytes leading to the SEI with beneficial properties is the lack of experimental approaches for directly probing the ionic permeability of the SEI. Here, we introduce lithium chemical exchange saturation transfer (Li-CEST) as an efficient nuclear magnetic resonance (NMR) approach for detecting the otherwise invisible process of Li exchange across the metal-SEI interface. In Li-CEST, the properties of the undetectable SEI are encoded in the NMR signal of the metal resonance through their exchange process. We benefit from the high surface area of lithium dendrites and are able, for the first time, to detect exchange across solid phases through CEST. Analytical Bloch-McConnell models allow us to compare the SEI permeability formed in different electrolytes, making the presented Li-CEST approach a powerful tool for designing electrolytes for metal-based batteries.

Imaging of gene-expression patterns in live animals is difficult to achieve with fluorescent proteins because tissues are opaque to visible light. Imaging of transgene expression with magnetic resonance imaging (MRI), which penetrates to deep tissues, has been limited by single reporter visualization capabilities. Moreover, the low-throughput capacity of MRI limits large-scale mutagenesis strategies to improve existing reporters. Here we develop an MRI system, called GeneREFORM, comprising orthogonal reporters for two-color imaging of transgene expression in deep tissues. Starting from two promiscuous deoxyribonucleoside kinases, we computationally designed highly active, orthogonal enzymes ('reporter genes') that specifically phosphorylate two MRI-detectable synthetic deoxyribonucleosides ('reporter probes'). Systemically administered reporter probes exclusively accumulate in cells expressing the designed reporter genes, and their distribution is displayed as pseudo-colored MRI maps based on dynamic proton exchange for noninvasive visualization of transgene expression. We envision that future extensions of GeneREFORM will pave the way to multiplexed deep-tissue mapping of gene expression in live animals.

We show that the optical properties of indigo carmine can be modulated by encapsulation within a coordination cage. Depending on the host/guest molar ratio, the cage can predominantly encapsulate either one or two dye molecules. The 1:1 complex is fluorescent, unique for an indigo dye in an aqueous solution. We have also found that binding two dye molecules stabilizes a previously unknown conformation of the cage.

NMR has been instrumental in studies of both the structure and dynamics of molecular systems for decades, so it is not surprising that NMR has played a pivotal role in the study of host-guest complexes and supramolecular systems. In this mini-review, selected examples will be used to demonstrate the added value of using (multiparametric) NMR for studying macrocycle-based host-guest and supramolecular systems. We will restrict the discussion to synthetic host systems having a cavity that can engulf their guests thus restricting them into confined spaces. So discussion of selected examples of cavitands, cages, capsules and their complexes, aggregates and polymers as well as organic cages and porous liquids and other porous materials will be used to demonstrate the insights that have been gathered from the extracted NMR parameters when studying such systems emphasizing the information obtained from somewhat less routine NMR methods such as diffusion NMR, diffusion ordered spectroscopy (DOSY) and chemical exchange saturation transfer (CEST) and their variants. These selected examples demonstrate the impact that the results and findings from these NMR studies have had on our understanding of such systems and on the developments in various research fields.

Colloidal inorganic nanofluorides have aroused great interest for various applications with their development greatly accelerated thanks to advanced synthetic approaches. Nevertheless, understanding their colloidal evolution and the factors that affect their dispersion could improve the ability to rationally design them. Here, using a multimodal in situ approach that combines DLS, NMR, and cryogenic-TEM, we elucidate the formation dynamics of nanofluorides in water through a transient aggregative phase. Specifically, we demonstrate that ligand-cation interactions mediate a transient aggregation of as-formed CaF2 nanocrystals (NCs) which governs the kinetics of the colloids' evolution. These observations shed light on key stages through which CaF2 NCs are dispersed in water, highlighting fundamental aspects of nanofluorides formation mechanisms. Our findings emphasize the roles of ligands in NCs' synthesis beyond their function as surfactants, including their ability to mediate colloidal evolution by complexing cationic precursors, and should be considered in the design of other types of NCs.

Fast ion-chelate dissociation rates and weak ion-chelate affinities are desired kinetic and thermodynamic features for imaging probes to allow reversible binding and to prevent deviation from basal ionic levels. Nevertheless, such properties often result in poor readouts upon ion binding, frequently result in low ion specificity, and do not allow the detection of a wide range of concentrations. Herein, we show the design, synthesis, characterization, and implementation of a Zn2+-probe developed for MRI that possesses reversible Zn2+-binding properties with a rapid dissociation rate (koff = 845 ± 35 s1) for the detection of a wide range of biologically relevant concentrations. Benefiting from the implementation of chemical exchange saturation transfer (CEST), which is here applied in the 19F-MRI framework in an approach termed ion CEST (iCEST), we demonstrate the ability to map labile Zn2+ with spectrally resolved specificity and with no interference from competitive cations. Relying on fast koff rates for enhanced signal amplification, the use of iCEST allowed the designed fluorinated chelate to experience weak Zn2+-binding affinity (Kd at the mM range), but without compromising high cationic specificity, which is demonstrated here for mapping the distribution of labile Zn2+ in the hippocampal tissue of a live mouse. This strategy for accelerating ion-chelate koff rates for the enhancement of MRI signal amplifications without affecting ion specificity could open new avenues for the design of additional probes for other metal ions beyond zinc.

Multicolor luminescent portrayal of complexed arrays is indispensable for many aspects of science and technology. Nevertheless, challenges such as inaccessible readouts from opaque objects, a limited visible-light spectrum and restricted spectral resolution call for alternative approaches for multicolor representation. Here, we present a strategy for spatial COlor Display by Exploiting Host-guest Dynamics (CODE-HD), comprising a paramagnetic cavitand library and various guests. First, a set of lanthanide-cradled α-cyclodextrins (Ln-CDs) is designed to induce pseudo-contact shifts in the ¹⁹F-NMR spectrum of Ln-CD-bound guest. Then, capitalizing on reversible host-guest binding dynamics and using magnetization-transfer ¹⁹F-MRI, pseudo-colored maps of complexed arrays are acquired and applied in molecular-steganography scenarios, showing CODE-HDs ability to generate versatile outputs for information encoding. By exploiting the widely shifted resonances induced by Ln-CDs, the guest versatility and supramolecular systems' reversibility, CODE-HD provides a switchable, polychromatic palette, as an advanced strategy for light-free, multicolor-mapping.

The weak thermal polarization of nuclear spins limits the sensitivity of MRI, even for MR-sensitive nuclei as fluorine-19. Therefore, despite being the source of inspiration for the development of background-free MRI for various applications, including for multiplexed imaging, the inability to map very low concentrations of targets using ¹⁹F-MRI raises the need to further enhance this platform's capabilities. Here, we employ the principles of CEST-MRI in ¹⁹F-MRI to obtain a 900-fold signal amplification of a biocompatible fluorinated agent, which can be presented in a \u201cmulticolor\u201d fashion. Capitalizing on the dynamic interactions in hostguest supramolecular assemblies in an approach termed GEST, we demonstrate that an inhalable fluorinated anesthetic can be used as a single ¹⁹F-probe for the concurrent detection of micromolar levels of two targets, with potential in vivo translatability. Further extending GEST with new designs could expand the applicability of ¹⁹F-MRI to the mapping of targets that have so-far remained non-detectable.

Glycolic acid is a useful and important α-hydroxy acid that has broad applications. Herein, the homogeneous ruthenium catalyzed reforming of aqueous ethylene glycol to generate glycolic acid as well as pure hydrogen gas, without concomitant CO₂ emission, is reported. This approach provides a clean and sustainable direction to glycolic acid and hydrogen, based on inexpensive, readily available, and renewable ethylene glycol using 0.5 mol % of catalyst. In-depth mechanistic experimental and computational studies highlight key aspects of the PNNH-ligand framework involved in this transformation.

We have recently reported the previously unknown synthesis of thioesters by coupling thiols and alcohols (or aldehydes) with liberation of H2, as well as the reverse hydrogenation of thioesters, catalyzed by a well-defined ruthenium acridine-9H based pincer complex. These reactions are highly selective and are not deactivated by the strongly coordinating thiols. Herein, the mechanism of this reversible transformation is investigated in detail by a combined experimental and computational (DFT) approach. We elucidate the likely pathway of the reactions, and demonstrate experimentally how hydrogen gas pressure governs selectivity toward hydrogenation or dehydrogenation. With respect to the dehydrogenative process, we discuss a competing mechanism for ester formation, which despite being thermodynamically preferable, it is kinetically inhibited due to the relatively high acidity of thiol compared to alcohol and, accordingly, the substantial difference in the relative stabilities of a ruthenium thiolate intermediate as opposed to a ruthenium alkoxide intermediate. Accordingly, various additional reaction pathways were considered and are discussed herein, including the dehydrogenative coupling of alcohol to ester and the Tischenko reaction coupling aldehyde to ester. This study should inform future green, (de)hydrogenative catalysis with thiols and other transformations catalyzed by related ruthenium pincer complexes.

The ability to mediate the kinetic properties and dissociation activation energies (E_a) of bound guests by controlling the characteristics of \u201csupramolecular lids\u201d in host-guest molecular systems is essential for both their design and performance. While the synthesis of such systems is well advanced, the experimental quantification of their kinetic parameters, particularly in systems experiencing fast association and dissociation dynamics, has been very difficult or impossible with the established methods at hand. Here, we demonstrate the utility of the NMR-based guest exchange saturation transfer (GEST) approach for quantifying the dissociation exchange rates (k_out) and activation energy (E_a,out) in host-guest systems featuring fast dissociation dynamics. Our assessment of the effect of different monovalent cations on the extractedE_a,outin cucurbit[7]uril:guest systems with very fastk_outhighlights their role as \u201csupramolecular lids\u201d in mediating a guest's dissociationE_a. We envision that GEST could be further extended to study kinetic parameters in other supramolecular systems characterized by fast kinetic properties and to design novel switchable host-guest assemblies.

Understanding inorganic nanocrystal (NC) growth dynamic pathways under their native fabrication environment remains a central goal of science, as it is crucial for rationalizing novel nanoformulations with desired architectures and functionalities. We here present an in-situ method for quantifying, in real time, NCs size evolution at sub-nm resolution, their concentration, and reactants consumption rate for studying NC growth mechanisms. Analyzing sequential high-resolution liquid-state ¹⁹F-NMR spectra obtained in-situ and validating by ex-situ cryoTEM, we explore the growth evolution of fluoride-based NCs (CaF₂ and SrF₂) in water, without disturbing the synthesis conditions. We find that the same nanomaterial (CaF₂) can grow by either a particle-coalescence or classical-growth mechanism, as regulated by the capping ligand, resulting in different crystallographic properties and functional features of the fabricated NC. The ability to reveal, in real time, mechanistic pathways at which NCs grow open unique opportunities for tunning the properties of functional materials.

Direct hydrogenation of thioesters with H2 provides a facile and waste-free method to access alcohols and thiols. However, no report of this reaction is documented, possibly because of the incompatibility of the generated thiol with typical hydrogenation catalysts. Here, we report an efficient and selective hydrogenation of thioesters. The reaction is catalyzed by an acridine-based ruthenium complex without additives. Various thioesters were fully hydrogenated to the corresponding alcohols and thiols with excellent tolerance for amide, ester, and carboxylic acid groups. Thiocarbamates and thioamides also undergo hydrogenation under similar conditions, substantially extending the application of hydrogenation of organosulfur compounds.

Ion diffusion affects the optoelectronic properties of halide-perovskites (HaPs). Until now, the fastest diffusion has been attributed to the movement of the halides, largely neglecting the contribution of protons, on the basis of computed density estimates. Here, the process of proton diffusion inside HaPs, following deuteriumhydrogen exchange and migration in MAPbI₃, MAPbBr₃, and FAPbBr₃ single crystals, is proven through D/H NMR quantification, Raman spectroscopy, and elastic recoil detection analysis, challenging the original assumption of halide-dominated diffusion. The results are confirmed by impedance spectroscopy, where MAPbBr₃- and CsPbBr₃-based solar cells respond at very different frequencies. Water plays a key role in allowing the migration of protons as deuteration is not detected in its absence. The water contribution is modeled to explain and forecast its effect as a function of its concentration in the perovskite structure. These findings are of great importance as they evidence how unexpected, water-dependent proton diffusion can be at the basis of the ≈7 orders of magnitude spread of diffusion (attributed to I⁻ and Br⁻) coefficient values, reported in the literature. The reported enhancement of the optoelectronic properties of HaP when exposed to small amounts of water may be related to the finding.

Thioesters play important roles in chemistry and biology, but their synthesis generally exhibits a poor atom economy and generates copious waste. We report here the dehydrogenative coupling of alcohols and thiols to yield thioesters and evolve H-2. This waste-free reaction is catalysed by an acridine-based ruthenium pincer complex in hexamethyldisiloxane as the optimal solvent without any additives. Various thioesters were formed in good-to-excellent yields using equivalent amounts of alcohols and thiols in excellent selectivity with hydrogen gas as the only by-product. A plausible mechanism, which involves an outer-sphere dehydrogenation process in which the thiol not only serves as a reactant, but also as an assisting ligand, is proposed based on mechanistic studies and the isolation of intermediates. This system provides a facile, efficient and waste-free synthesis of thioesters.

Paramagnetic relaxation enhancement (PRE) is the current strategy of choice for enhancing magnetic resonance imaging (MRI) contrast and for accelerating MRI acquisition schemes. Yet, debates regarding lanthanides biocompatibility and PRE-effect on MRI signal quantification have raised the need for alternative strategies for relaxation enhancement. Herein, we show an approach for shortening the spin-lattice relaxation time (T1) of fluoride-based nanocrystals (NCs) that are used for in-vivo 19F-MRI, by inducing crystal defects in their solid-crystal core. By utilizing a phosphate-based rather than a carboxylate-based capping ligand for the synthesis of CaF2 NCs, we were able to induce grain boundary defects in the NC lattice. The obtained defects led to a ten-fold shorter T1 of the NCs fluorides. Such paramagnetic-free relaxation enhancement of CaF2 NCs, gained without affecting neither their size nor their colloidal characteristics, improved 4-fold the obtained 19F-MRI signal-to-noise ratio, allowing their use, in-vivo, with enhanced hot-spot MRI sensitivity.

Host-guest solution chemistry with a wide range of organic hosts is an important and established research area, while the use of inorganic hosts is a more nascent area of research. In the recent past in a few cases, Keplerate type molybdenum oxide based porous, spherical clus-ters, shorthand notation {Mo132}, have been used as hosts for organic guests. Here we demonstrate the synthetically controlled encapsula-tion of first row transition metals (M = Mn, Fe, and Co) within a Keplerate cluster that was lined on the inner core with phosphate ani-ons, {Mo132PO4}. The resulting M2+x{Mo132PO4} host-guest complexes were characterized by 31P NMR and ENDOR spectroscopy that substantiated the encapsulation of the first-row transition metal guest. Magnetic susceptibility measurements showed that the encap-sulation of up to 10 equivalents showed little magnetic interaction between the encapsulated metals, indicating that each guest atom occupied a single site. Visualization of the capsules and differentiation of the Mo atoms of the capsule framework and the encapsulated transition metal was possible using spherical and chromatic double aberration-corrected electron microscopy combined with energy-filtered TEM (EFTEM) elemental maps. In addition, use of visible light induced XPS for chemically resolved electrical measurements (CREM) confirmed the successful encapsulation of M within {Mo132PO4} and furthermore showed photoinduced electron transfer from M to Mo. In the future such targeted electron transfer between host {Mo132} and a transition metal guest could be used as photo-initiated switches using inorganic compounds and for single site photocatalytic reactions in confined space.

A series of PNP zinc pincer complexes capable of bond activation via aromatization/dearomatization metal-ligand cooperation (MLC) were prepared and characterized. Reversible heterolytic N-H and H-H bond activation by MLC is shown, in which hemilability of the phosphorus linkers plays a key role. Utilizing this zinc pincer system, base-free catalytic hydrogenation of imines and ketones is demonstrated. A detailed mechanistic study supported by computation implicates the key role of MLC in facilitating effective catalysis. This approach offers a new strategy for (de)hydrogenation and other catalytic transformations mediated by zinc and other main group metals.

The widespread crisis of plastic pollution demands discovery of new and sustainable approaches to degrade robust plastics such as nylons. Using a green and sustainable approach based on hydrogenation, in the presence of a ruthenium pincer catalyst at 150 °C and 70 bar H2, we report here the first example of hydrogenative depolymerization of conventional, widely used nylons and polyamides, in general. Under the same catalytic conditions, we also demonstrate the hydrogenation of a polyurethane to produce diol, diamine, and methanol. Additionally, we demonstrate an example where monomers (and oligomers) obtained from the hydrogenation process can be dehydrogenated back to a poly(oligo)amide of approximately similar molecular weight, thus completing a closed loop cycle for recycling of polyamides. Based on the experimental and density functional theory studies, we propose a catalytic cycle for the process that is facilitated by metal-ligand cooperativity. Overall, this unprecedented transformation, albeit at the proof of concept level, offers a new approach toward a cleaner route to recycling nylons.

PROteolysis Targeting Chimeras (PROTACs) represent an exciting inhibitory modality with many advantages, including sub-stoichiometric degradation of targets. Their scope, though, is still limited to-date by the requirement for a sufficiently potent target binder. A solution that proved useful in tackling challenging targets is the use of electrophiles to allow irreversible binding to the target. However, such binding will negate the catalytic nature of PROTACs. Reversible covalent PROTACs potentially offer the best of both worlds. They possess the potency and selectivity associated with the formation of the covalent bond, while being able to dissociate and regenerate once the protein target is degraded. Using Brutons tyrosine kinase (BTK) as a clinically relevant model system, we show efficient covalent degradation by non-covalent, irreversible covalent and reversible covalent PROTACs, with 85% degradation. Our data suggests that part of the degradation by our irreversible covalent PROTACs is driven by reversible binding prior to covalent bond formation, while the reversible covalent PROTACs drive degradation primarily by covalent engagement. The PROTACs showed enhanced inhibition of B cell activation compared to Ibrutinib, and exhibit potent degradation of BTK in patients-derived primary chronic lymphocytic leukemia cells. The most potent reversible covalent PROTAC, RC-3, exhibited enhanced selectivity towards BTK compared to non-covalent and irreversible covalent PROTACs. These compounds may pave the way for the design of covalent PROTACs for a wide variety of challenging targets.

The eyes of many fish contain a reflecting layer of organic crystals partially surrounding the photoreceptors of the retina, which are commonly believed to be composed of guanine. Here we study an unusual fish eye from Stizostedion lucioperca that contains two layers of organic crystals. The crystals in the outer layer are thin plates, whereas the crystals in the inner tapetum layer are block-shaped. We show that the outer layer indeed contains guanine crystals. Analyses of solutions of crystals from the inner layer indicated that the block-shaped crystals are composed of xanthopterin. A model of the structure of the block-shaped crystals was produced using symmetry arguments based on electron diffraction data followed by dispersion-augmented DFT calculations. The resulting crystal structure of xanthopterin included, however, a problematic repulsive interaction between C=O and N of two adjacent molecules. Knowing that dissolved 7,8-dihydroxanthopterin can oxidize to xanthopterin, we replaced xanthopterin with 7,8-dihydroxanthopterin in the model. An excellent fit was obtained with the powder X-ray diffraction pattern of the biogenic crystals. We then analyzed the biogenic block-shaped crystals in their solid state, using MALDI-TOF and Raman spectroscopy. All three methods unequivocally prove that the block-shaped crystals in the eye of S. lucioperca are crystals of 7,8-dihydroxanthopterin. On the basis of the eye anatomy, we deduce that the guanine crystals form a reflective layer producing the silvery color present on part of the eye surface, whereas the block-shaped crystals backscatter light into the retina in order to increase the light sensitivity of the eye.

Arylazopyrazoles represent a new family of molecular photoswitches characterized by a near-quantitative conversion between two states and long thermal half-lives of the metastable state. Here, we investigated the behavior of a model arylazopyrazole in the presence of a self-assembled cage based on Pd-imidazole coordination. Owing to its high water solubility, the cage can solubilize the E isomer of arylazopyrazole, which, by itself, is not soluble in water. NMR spectroscopy and X-ray crystallography have independently demonstrated that each cage can encapsulate two molecules of E-arylazopyrazole. UV-induced switching to the Z isomer was accompanied by the release of one of the two guests from the cage and the formation of a 1:1 cage/Z-arylazopyrazole inclusion complex. DFT calculations suggest that this process involves a dramatic change in the conformation of the cage. Back-isomerization was induced with green light and resulted in the initial 1:2 cage/E-arylazopyrazole complex. This back-isomerization reaction also proceeded in the dark, with a rate significantly higher than in the absence of the cage.

Dynamic processes in host-guest systems, such as the exchange between bound and free guests, can endow such systems with unique properties and function. However, both the dynamic exchange and the relatively low concentration of a studied complex reduce the sensitivity and limit the efficiency of the currently available analytical tools to explore such processes. In this highlight, we present an NMR approach based on saturation transfer, termed GEST - Guest Exchange Saturation Transfer. This technique can be used to detect micromolar concentrations of complexes with the sensitivity of millimolar concentrations, thus offering the ability to amplify otherwise undetected signals in NMR spectra. In addition, by performing the GEST experiment and fitting the data using computational simulations, the exchange rate of free and bound guest and the fractional occupancy of the host can be extracted. We further present several examples of how GEST can be employed to extract important information from host-guest systems. This method can expand the NMR toolbox available to study dynamic host-guest systems in solution without any special expertise or dedicated hardware and can assist in developing more advanced host-guest systems that can be used for many applications, including in molecular and cellular MRI.

The accumulated knowledge regarding molecular architectures is based on established, reliable, and accessible analytical tools that provide robust structural and functional information on assemblies. However, both the dynamicity and low population of noncovalently interacting moieties within studied molecular systems limit the efficiency and accuracy of traditional methods. Herein, the use of a saturation transfer-based NMR approach to study the dynamic binding characteristics of an anion to a series of synthetic receptors derived from bambusuril macrocycles is demonstrated. The exchange rates of BF4- are mediated by the side chains on the receptor (100 s(-1)

The c-Jun NH2-terminal kinase (JNK) signaling pathway is central to the cell response to stress, inflammatory signals, and toxins. While selective inhibitors are known for JNKs and for various upstream MAP3Ks, no selective inhibitor is reported for MKK7one of two direct MAP2Ks that activate JNK. Here, using covalent virtual screening, we identify selective MKK7 covalent inhibitors. We optimized these compounds to low-micromolar inhibitors of JNK phosphorylation in cells. The crystal structure of a lead compound bound to MKK7 demonstrated that the binding mode was correctly predicted by docking. We asserted the selectivity of our inhibitors on a proteomic level and against a panel of 76 kinases, and validated an on-target effect using knockout cell lines. Lastly, we show that the inhibitors block activation of primary mouse B cells by lipopolysaccharide. These MKK7 tool compounds will enable better investigation of JNK signaling and may serve as starting points for therapeutics.

The electrochemical reduction of CO2 has been extensively investigated in recent years, with the expectation that a detailed mechanistic understanding could achieve the goal of finding a stable catalyst with high turnover frequencies and low reduction potentials. In the catalytic cycle of the carbon dioxide hydrogenase enzyme, it has been suggested that the reduced metal center reacts with CO2 to form a carboxylate intermediate that is stabilized by hydrogen bonding using a histidine moiety in the second coordination sphere. Using the well-known fac-Re(I)bipyridine(CO)(3)Cl complex as a starting point, the bipyridine ligand was modified in the second coordination sphere with a thiourea tether that is known to form hydrogen bonds with carbonyl moieties. The resulting Re(I) catalyst was an excellent electrocatalyst for the selective reduction of CO2 to CO, with a turnover frequency of 3040 s(-1). The binding of CO2 to the thiourea tether was observable by H-1 NMR, and NOE experiments showed that the hydrogen atoms of the thiourea group were labile. Further experiments indicated that the thiourea moiety is also a local proton source and addition of an external proton source actually inhibits catalysis. The absence of a kinetic isotope effect was explained through DFT calculations that showed that the proton invariably jumps to the nearest CO2 oxygen atom to form a metal-carboxylic acid without going through any minimum or transition state. EPR and NMR spectroscopies were used to identify the various reduced intermediates. Thus, the thiourea tether in the second coordination sphere can bind CO2, stabilize carboxylic acid reaction intermediates, and directly act as a local proton source, leading to a significantly more active catalyst.

The unique synthesis and reactivity of [( ^RPNP∗)NiH] complexes (1a,b), based on metal-ligand cooperation (MLC), are presented ( ^RPNP∗ = deprotonated PNP ligand, R = ⁱPr, ^tBu). Unexpectedly, the dearomatized complexes 1a,b were obtained by reduction of the dicationic complexes [( ^RPNP)Ni(MeCN)](BF ₄) ₂ with sodium amalgam or by reaction of the free ligand with Ni ⁰(COD) ₂. Complex 1b reacts with CO via MLC, to give a rare case of a distorted-octahedral PNP-based pincer complex, the Ni(0) complex 3b. Complexes 1a,b also react with CO ₂ via MLC to form a rare example of η ¹ binding of CO ₂ to nickel, complexes 4a,b. An unusual CO ₂ cleavage process by complex 4b, involving C-O and C-P cleavage and C-C bond formation, led to the Ni-CO complex 3b and to the new complex [(P ⁱPr ₂NC ₂O ₂)Ni(P(O) ⁱPr ₂)] (5b). All complexes have been fully characterized by NMR and X-ray crystallography.

Confining molecules to volumes only slightly larger than the molecules themselves can profoundly alter their properties. Molecular switches-entities that can be toggled between two or more forms upon exposure to an external stimulus-often require conformational freedom to isomerize. Therefore, placing these switches in confined spaces can render them non-operational. To preserve the switchability of these species under confinement, we work with a water-soluble coordination cage that is flexible enough to adapt its shape to the conformation of the encapsulated guest. We show that owing to its flexibility, the cage is not only capable of accommodating-and solubilizing in water-several light-responsive spiropyran-based molecular switches, but, more importantly, it also provides an environment suitable for the efficient, reversible photoisomerization of the bound guests. Our findings pave the way towards studying various molecular switching processes in confined environments.

Active control over the shape, composition, and crystalline habit of nanocrystals has long been a goal. Various methods have been shown to enable postsynthesis modification of nanoparticles, including the use of the Kirkendall effect, galvanic replacement, and cation or anion exchange, all taking advantage of enhanced solid-state diffusion on the nanoscale. In all these processes, however, alteration of the nanoparticles requires introduction of new precursor materials. Here we show that for cesium lead halide perovskite nanoparticles, a reversible structural and compositional change can be induced at room temperature solely by modification of the ligand shell composition in solution. The reversible transformation of cubic CsPbX3 nanocrystals to rhombohedral Cs4PbX6 nanocrystals is achieved by controlling the ratio of oleylamine to oleic acid capping molecules. High-resolution transmission electron microscopy investigation of Cs4PbX6 reveals the growth habit of the rhombohedral crystal structure is composed of a zero-dimensional layered network of isolated PbX6 octahedra separated by Cs cation planes. The reversible transformation between the two phases involves an exfoliation and recrystalliztion process. This scheme enables fabrication of high-purity monodispersed Cs4PbX6 nanoparticles with controlled sizes. Also, depending on the final size of the Cs4PbX6 nanoparticles as tuned by the reaction time, the back reaction yields CsPbX3 nanoplatelets with a controlled thickness. In addition, detailed surface analysis provides insight into the impact of the ligand composition on surface stabilization that, consecutively, acts as the driving force in phase and shape transformations in cesium lead halide perovskites.

High-order elementary reactions in homogeneous solutions involving more than two molecules are statistically improbable and very slow to proceed. They are not generally considered in classical transition-state or collision theories. Yet, rather selective, high-yield product formation is common in self-assembly processes that require many reaction steps. On the basis of recent observations of crystallization as well as reactions in dense phases, it is shown that self-assembly can occur by preorganization of reactants in a noncovalent supramolecular assembly, whereby directing forces can lead to an apparent one-step transformation of multiple reactants. A simple and general kinetic model for multiple reactant transformation in a dense phase that can account for many-bodied transformations was developed. Furthermore, the self-assembly of polyfluoroxometalate anion [H2F6NaW18O56](7-) from simple tungstate Na2WO2F4 was demonstrated by using 2D F-19-F-19 NOESY, 2D F-19-F-19 COSY NMR spectroscopy, a new 2D F-19{W-183} NMR technique, as well as ESI-MS and diffusion NMR spectroscopy, and the crucial involvement of a supramolecular assembly was found. The deterministic kinetic reaction model explains the reaction in a dense phase and supports the suggested self-assembly mechanism. Reactions in dense phases may be of general importance in understanding other self-assembly reactions.

Homogeneous catalytic hydrogenation of esters to alcohols is an industrially important, environmentally benign reaction. While precious metal-based catalysts for this reaction are now well known, only very few catalysts based on first-row metal complexes were reported. Here we present the hydrogenation of esters catalyzed by a complex of earth-abundant manganese. The reaction proceeds under mild conditions and insight into the mechanism is provided based on an NMR study and the synthesis of novel Mn complexes postulated as intermediates.

The ability to accurately determine and quantitatively evaluate kinetic phenomena associated with supramolecular assemblies, in real time, is key to a better understanding of their defined architectures and diverse functionalities. Therefore, analytical tools that can precisely assess a wide range of exchange rates within such systems are of considerable importance. This study demonstrates the ability to use an NMR approach based on saturation transfer for the determination of rates of guest exchange from molecular capsules. By using cavitands that assemble into distinct dimeric assemblies, we show that this approach, which we term guest exchange saturation transfer (GEST), allows the use of a conventional NMR setup to study and quantitatively assess a wide range of exchange rates, from 35 to more than 5000s(-1).

The first example of base-metal-catalysed synthesis of amides from the coupling of primary amines with either alcohols or esters is reported. The reactions are catalysed by a new manganese pincer complex and generate hydrogen gas as the sole byproduct, thus making the overall process atom-economical and sustainable.

The first example of a base metal (manganese) catalyzed acceptorless dehydrogenative coupling of methanol and amines to form formamides is reported herein. The novel pincer complex (iPr-PN^HP)Mn(H)(CO)₂ catalyzes the reaction under mild conditions in the absence of any additives, bases, or hydrogen acceptors. Mechanistic insight based on the observation of an intermediate and DFT calculations is also provided.

The characteristics of host-guest systems, such as molecular recognition, complexation, encapsulation, guest composition, and dynamic exchange, are manifested by changes in the chemical shifts (Δω) in the NMR spectrum. However, in cases where NMR signals cannot be detected, due to low concentrations, poor solubility, or relatively fast exchange, an alternative is needed. Here, we show that by using the magnetization transfer (MT) method, the undetectable NMR signals of host-guest assemblies can be amplified by two orders of magnitude. It is shown that the binding kinetics characteristics of a fluorinated guest and cucurbit[n]uril (CB[n]) hosts in aqueous solutions determine the NMR signal amplification of host-guest assemblies. In addition, by using the MT technique within the ¹⁹F-NMR framework, one can detect μM concentrations of the complex and study the effect of different solutes on the resulting host-guest system. The results expand the \u201cNMR toolbox\u201d available to explore a wider range of dynamic host-guest systems in which NMR signals cannot be detected.

The use of confined space to modulate chemical reactivity and to sequester organic compounds spans significant disciplines in chemistry and biology. Here, the inclusion and assembly of arenes into a water-soluble porous metal oxide nanocapsule [{(Mo^VI)Mo^V₅O₂₁(H₂O)₆}₁₂{Mo^V₂O₄(CH₃COO)}₃₀]⁴²⁻(Mo₁₃₂) is reported. The uptake of benzene, halobenzenes, alkylbenzenes, phenols, and other derivatives was studied by NMR, where it was possible to follow the encapsulation process from the outside of the capsule through its pores and then into the interior. The importance of size or shape of the arenes, and various intermolecular bond interactions contributed by the benzene substituent on the encapsulation process was studied, showing the importance of ππ stacking and CHπ interactions. Furthermore, by using NOESY, ROESY, and HOESY NMR techniques it was possible to understand the interaction of the encapsulated arenes and the acetate linkers or ligands that line the interior of the Mo₁₃₂capsule.