A Straightforward Method for the Generation of Hyperpolarized Orthohydrogen with a Partially Negative Line.

The hydrogen molecule, which exists in two spin isomers (ortho- and parahydrogen), is a highly studied system due to its fundamental properties and practical applications. Parahydrogen is used for Nuclear Magnetic Resonance signal enhancement, which is hyperpolarization of other molecules, including biorelevant ones. Hyperpolarization can be achieved by using Signal Amplification by Reversible Exchange (SABRE). SABRE can also convert parahydrogen into orthohydrogen, and surprisingly, in some cases, it has been discovered that orthohydrogen's resonance has the Partially Negative Line (PNL) pattern. Here, an approach for obtaining orthohydrogen with a PNL signal is presented for two catalysts: Ir-IMes, and Ir-IMesBn. The type of solvent in which SABRE is conducted is crucial for the observation of PNL. Specifically, a PNL signal can be easily generated in benzene using both catalysts, but it is more intense for Ir-IMesBn. In acetone, PNL is observed only for Ir-IMesBn. In methanol, no PNL is detected. The PNL effect is only detectable during the initial steps of pre-catalyst activation, and disappears as the activation process progresses. We have proposed a working hypothesis that explains our results. The presented data may facilitate the further investigation of PNL and its applications in material science and catalysis.

Deeper Insight into Photopolymerization: The Synergy of Time-Resolved Nonuniform Sampling and Diffusion NMR.

The comprehensive real-time in situ monitoring of chemical processes is a crucial requirement for the in-depth understanding of these processes. This monitoring facilitates an efficient design of chemicals and materials with the precise properties that are desired. This work presents the simultaneous utilization and synergy of two novel time-resolved NMR methods, i.e., time-resolved diffusion NMR and time-resolved nonuniform sampling. The first method allows the average diffusion coefficient of the products to be followed, while the second method enables the particular products to be monitored. Additionally, the average mass of the system is calculated with excellent resolution using both techniques. Employing both methods at the same time and comparing their results leads to the unequivocal validation of the assignment in the second method. Importantly, such validation is possible only via the simultaneous combination of both approaches. While the presented methodology was utilized for photopolymerization, it can also be employed for any other polymerization process, complexation, or, in general, chemical reactions in which the evolution of mass in time is of importance.

Cubosomal Lipid Formulation for Combination Cancer Treatment: Delivery of a Chemotherapeutic Agent and Complexed α-Particle Emitter 213Bi.

Here, we propose tailored lipid liquid-crystalline carriers (cubosomes), which incorporate an anticancer drug (doxorubicin) and complexed short-lived α-emitter (bismuth-213), as a strategy to obtain more effective action toward the cancer cells. Cubosomes were formulated with doxorubicin (DOX) and an amphiphilic ligand (DOTAGA-OA), which forms stable complexes with 213Bi radionuclide. The behavior of DOX incorporated into the carrier together with the chelating agent was investigated, and the drug liberation profile was determined. The experiments revealed that the presence of the DOTAGA-OA ligand affects the activity of DOX when they are incorporated into the same carrier. This unexpected influence was explained based on the results of release studies, which proved the contribution of electrostatics in molecular interactions between the positively charged DOX and negatively charged DOTAGA-OA in acidic and neutral solutions. A significant decrease in the viability of HeLa cancer cells was achieved using sequential cell exposure: first to the radiolabeled cubosomes containing 213Bi complex and next to DOX-doped cubosomes. Therefore, the sequential procedure for the delivery of both drugs encapsulated in cubosomes is suggested for further biological and in vivo studies.

Deactivation of catalysts in simultaneous reversible and irreversible parahydrogen NMR signal enhancement, and the role of co-ligands in the stabilization of the reversible method.

Signal Amplification by Reversible Exchange (SABRE) and hydrogeneable Parahydrogen Induced Polarization (hPHIP) can enhance weak NMR signals, and thus increase the range of NMR applications. Here, using an N-heterocyclic carbene Ir-based catalyst, simultaneous SABRE and hPHIP was achieved for the compound with an N-donor site and an acetylene triple bond. It was demonstrated that the interplay between SABRE and hPHIP can be manipulated. Specifically, it was found that the hPHIP effect could be almost completely suppressed, while stable SABRE was observed in subsequent consecutive experiments. The presented results have the potential to increase the numbers of parahydrogen hyperpolarizable molecules.

Photoreactivity of an Exemplary Anthracene Mixture Revealed by NMR Studies, including a Kinetic Approach.

Anthracenes are an important class of acenes. They are being utilized more and more often in chemistry and materials sciences, due to their unique rigid molecular structure and photoreactivity. In particular, photodimerization can be harnessed for the fabrication of novel photoresponsive materials. Photodimerization between the same anthracenes have been investigated and utilized in various fields, while reactions between varying anthracenes have barely been investigated. Here, Nuclear Magnetic Resonance (NMR) spectroscopy is employed for the investigation of the photodimerization of two exemplary anthracenes: anthracene (A) and 9-bromoanthracene (B), in the solutions with only A or B, and in the mixture of A and B. Estimated k values, derived from the presented kinetic model, showed that the dimerization of A was 10 times faster in comparison with B when compounds were investigated in separate samples, and 2 times faster when compounds were prepared in the mixture. Notably, the photoreaction in the mixture, apart from AA and BB, additionally yielded a large amount of the AB mixdimer. Another important advantage of investigating a mixture with different anthracenes is the ability to estimate the relative reactivity for all the reactions under the same experimental conditions. This results in a better understanding of the photodimerization processes. Thus, the rational photofabrication of mix-anthracene-based materials can be facilitated, which is of crucial importance in the field of polymer and material sciences.

NMR Crystallography Enhanced by Quantum Chemical Calculations and Liquid State NMR Spectroscopy for the Investigation of Se-NHC Adducts*.

N-heterocyclic carbene ligands (NHC) are widely utilized in catalysis and material science. They are characterized by their steric and electronic properties. Steric properties are usually quantified on the basis of their static structure, which can be determined by X-ray diffraction. The electronic properties are estimated in the liquid state; for example, via the 77 Se liquid state NMR of Se-NHC adducts. We demonstrate that 77 Se NMR crystallography can contribute to the characterization of the structural and electronic properties of NHC in solid and liquid states. Selected Se-NHC adducts are investigated via 77 Se solid state NMR and X-ray crystallography, supported by quantum chemical calculations. This investigation reveals a correlation between the molecular structure of adducts and NMR parameters, including not only isotropic chemical shifts but also the other chemical shift tensor components. Afterwards, the liquid state 77 Se NMR data is presented and interpreted in terms of the quantum chemistry modelling. The discrepancy between the structural and electronic properties, and in particular the π-accepting abilities of adducts in the solid and liquid states is discussed. Finally, the 13 C isotropic chemical shift from the liquid state NMR and the 13 C tensor components are also discussed, and compared with their 77 Se counterparts. 77 Se NMR crystallography can deliver valuable information about NHC ligands, and together with liquid state 77 Se NMR can provide an in-depth outlook on the properties of NHC ligands.

Triptycene Derivatives: From Their Synthesis to Their Unique Properties.

Since the first preparation of triptycene, great progress has been made with respect to its synthesis and the understanding of its properties. Interest in triptycene-based systems is intense; in recent years, advances in the synthetic methodology and properties of new triptycenes have been reported by researchers from various fields of science. Here, an account of these new developments is given and placed in reference to earlier pivotal works that underpin the field. First, we discuss new approaches to the synthesis of new triptycenes. Progress in the regioselective synthesis of sterically demanding systems is discussed. The application of triptycenes in catalysis is also presented. Next, progress in the understanding of the relations between triptycene structures and their properties is discussed. The unique properties of triptycenes in the liquid and solid states are elaborated. Unique interactions, which involve triptycene molecular scaffolds, are presented. Molecular interactions within a triptycene unit, as well as between triptycenes or triptycenes and other molecules, are also evaluated. In particular, the summary of the synthesis and useful features will be helpful to researchers who are using triptycenes as building blocks in the chemical and materials sciences.

Magnetic Resonance Signal Amplification by Reversible Exchange of Selective PyFALGEA Oligopeptide Ligands Towards Epidermal Growth Factor Receptors.

The biorelevant PyFALGEA oligopeptide ligand, which is selective towards the epidermal growth factor receptor (EGFR), has been successfully employed as a substrate in magnetic resonance signal amplification by reversible exchange (SABRE) experiments. It is demonstrated that PyFALGEA and the iridium catalyst IMes form a PyFALGEA:IMes molecular complex. The interaction between PyFALGEA:IMes and H2 results in a ternary SABRE complex. Selective 1D EXSY experiments reveal that this complex is labile, which is an essential condition for successful hyperpolarization by SABRE. Polarization transfer from parahydrogen to PyFALGEA is observed leading to significant enhancement of the 1 H NMR signals of PyFALGEA. Different iridium catalysts and peptides are inspected to discuss the influence of their molecular structures on the efficiency of hyperpolarization. It is observed that PyFALGEA oligopeptide hyperpolarization is more efficient when an iridium catalyst with a sterically less demanding NHC ligand system such as IMesBn is employed. Experiments with shorter analogues of PyFALGEA, that is, PyLGEA and PyEA, show that the bulky phenylalanine from the PyFALGEA oligopeptide causes steric hindrance in the SABRE complex, which hampers hyperpolarization with IMes. Finally, a single-scan 1 H NMR SABRE experiment of PyFALGEA with IMesBn revealed a unique pattern of NMR lines in the hydride region, which can be treated as a fingerprint of this important oligopeptide.

Lipidic Cubic-Phase Nanoparticles (Cubosomes) Loaded with Doxorubicin and Labeled with 177Lu as a Potential Tool for Combined Chemo and Internal Radiotherapy for Cancers.

Lipid liquid-crystalline nanoparticles (cubosomes) were used for the first time as a dual-modality drug delivery system for internal radiotherapy combined with chemotherapy. Monoolein (GMO)-based cubosomes were prepared by loading the anticancer drug, doxorubicin and a commonly used radionuclide, low-energy beta (ß-)-emitter, 177Lu. The radionuclide was complexed with a long chain derivative of DOTAGA (DOTAGA-OA). The DOTAGA headgroup of the chelator was exposed to the aqueous channels of the cubosomes, while, concerning OA, the hydrophobic tail was embedded in the nonpolar region of the lipid bilayer matrix, placing the radioactive dopant in a stable manner inside the cubosome. The cubosomes containing doxorubicin and the radionuclide complex increased the cytotoxicity measured by the viability of the treated HeLa cells compared with the effect of single-drug cubosomes containing either the DOX DOTAGA-OA or DOTAGA-OA-177Lu complex. Multifunctional lipidic nanoparticles encapsulating the chemotherapeutic agent together with appropriately complexed (ß-) radionuclide are proposed as a potential strategy for effective local therapy of various cancers.

Blue-Shift Hydrogen Bonds in Silyltriptycene Derivatives: Antibonding σ* Orbitals of the Si-C Bond as Effective Acceptors of Electron Density.

Triptycene derivatives are widely utilized in different fields of chemistry and materials sciences. Their physicochemical properties, often of pivotal importance for the rational design of triptycene-based functional materials, are influenced by noncovalent interactions between substituents mounted on the triptycene skeleton. Herein, a unique interaction between electron-rich substituents in the peri position and the silyl group located on the bridgehead sp3 -carbon is discussed on the example of 1,4-dichloro-9-(p-methoxyphenyl)-silyltriptycene (TRPCl) which exists in solution in the form of two rotamers differing by dispositions, syn or anti, of the Si-CPh (the CPh atom is from the p-methoxyphenyl group) bond against the peri-Cl atom. For the first time, substantial differences between the Si-CPh bonds in these two dispositions are identified, based on indirect experimental and direct theoretical evidence. For these two orientations, the experimental 1 J(Si,CPh ) values differ by as much as 10 percent. The differences are explained in terms of effective electron density transfer from the peri-Cl atom to the antibonding σ* orbitals of the Si-X bonds (X=H, CPh ) oriented anti to that atom. The electronic effects are revealed by an NBO analysis. Connections of these observations with the notion of blue-shifting hydrogen bonds are discussed.

Ion Channels Made from a Single Membrane-Spanning DNA Duplex.

Because of their hollow interior, transmembrane channels are capable of opening up pathways for ions across lipid membranes of living cells. Here, we demonstrate ion conduction induced by a single DNA duplex that lacks a hollow central channel. Decorated with six porpyrin-tags, our duplex is designed to span lipid membranes. Combining electrophysiology measurements with all-atom molecular dynamics simulations, we elucidate the microscopic conductance pathway. Ions flow at the DNA-lipid interface as the lipid head groups tilt toward the amphiphilic duplex forming a toroidal pore filled with water and ions. Ionic current traces produced by the DNA-lipid channel show well-defined insertion steps, closures, and gating similar to those observed for traditional protein channels or synthetic pores. Ionic conductances obtained through simulations and experiments are in excellent quantitative agreement. The conductance mechanism realized here with the smallest possible DNA-based ion channel offers a route to design a new class of synthetic ion channels with maximum simplicity.

A formal synthesis of ezetimibe via cycloaddition/rearrangement cascade reaction.

A formal synthesis of a powerful cholesterol inhibitor, ezetymibe 1, is described. The crucial step of the synthesis is based on Cu(I)-mediated Kinugasa cycloaddition/rearrangement cascade reaction between terminal acetylene derived from acetonide of L-glyceraldehyde and suitable C,N-diarylnitrone. The adduct with (3R,4S) configuration at the azetidinone ring, obtained with high stereoselectivity, was subsequently subjected to deprotection of the diol side chain followed by glycolic cleavage and base-induced isomerization at the C3 carbon atom to afford the (3S,4S) aldehyde, which has been already transformed into ezetimibe by the Schering-Plough group.

Direct, catalytic synthesis of carbapenams via cycloaddition/rearrangement cascade reaction: unexpected acetylenes' structure effect.

Reactions of acetylenes derived from glyceraldehyde and propargyl aldehyde show remarkable reactivity in Kinugasa cycloaddition/rearrangement cascade process catalyzed by Cu(I) ion. Reactions proceed by formation of a rigid dinuclear copper(I) complex in which each copper ion is coordinated to one or both oxygen atoms in the acetylene molecule and to both triple bonds. It has been demonstrated that one oxygen atom can be replaced by the phenyl ring, which is able to coordinate the copper ion by the aromatic sextet. Kinugasa reactions that proceed in a high yield can also be performed in the presence of a catalytic amount of the copper salt to provide products in an acceptable yield without a decrease of diastereoselectivity.

Structure-chiroptical properties relationship of carbapenams by experiment and theory.

The present work examines the relationship between the molecular structure and chiroptical properties of carbapenams through use of electronic circular dichroism spectroscopy (ECD). The applicability of the helicity rule that correlates the molecular structures of various ß-lactam analogues and their ECD spectra is examined against a set of differently substituted carbapenams. It is demonstrated that the studied compounds conform to the rule. The rule can be also applied to the carbapenams with an additional chromophoric unit interfering with the amide chromophore. For the representative carbapenams, the experimental curves are compared to the ECD spectra computed using time-dependent density functional theory (TDDFT) in order to validate the experimental data. The study reveals a high effectiveness of the ECD spectroscopy for the configurational assignment at the bridgehead carbon atom and demonstrates a strong dependence of the molecular conformation on substitution of the five-membered ring and side-chain flexibility of investigated carbapenams.

Asymmetric Kinugasa reaction of cyclic nitrones and nonracemic acetylenes.

Kinugasa reactions between chiral acetylenes and five-membered nitrones, achiral and bearing a stereogenic center in both enantiomeric forms, proceed in moderate to good yield with high diastereoselectivity affording mostly one dominant product. The first step of the reaction is controlled by the configuration of the nitrone, whereas the protonation of intermediate enolate in the second step depends mainly on the configuration of the bridgehead carbon atom formed in the first step. In the case of the mismatched pair, the configuration at the C-6 center of the carbapenam skeleton may also be affected by the configuration of the stereogenic center in the acetylene portion.

Diastereoselective synthesis of carbapenams via Kinugasa reaction.

A facile approach to carbapenams via Kinugasa reaction between terminal copper acetylides and nonracemic cyclic nitrones derived from malic and tartaric acid is reported. The stereochemical preferences observed in these reactions are explained. The reaction provides an entry to the carbapenams basic skeleton.