Introduction Of Deuterium Research Articles

Novel deuterated cyclopentadienyl zirconium/hafnium precursors for atomic layer deposition of high-performance ZrO2/HfO2 thin films

The need to improve the electrical properties of ZrO2 and HfO2 thin films deposited by atomic layer deposition (ALD), which is widely used in the field of microelectronics, is growing. Attempts to improve precursor stability unavoidably lead to reduced reactivity and diminished utility. Therefore, we synthesized and developed two new ALD precursors by introducing deuterium, which simultaneously exhibit enhanced thermal stability and enhanced reactivity as a result of the introduction of deuterium. For the substitution of deuterium for hydrogen in the precursors responsible for the enhanced thermal stability, we experimentally and theoretically demonstrated that thermal stability and reactivity can be simultaneously enhanced by reducing the bonding dissociation energy of ligands that have not undergone deuterium substitution. This observation led to the development of ZrO2 and HfO2 ALD processes that result in no impurities within the thin films and minimal substrate damage even at a very high deposition temperature of 400 °C. In particular, the improvement in crystallinity through ultra-high-temperature ALD deposition resulted in excellent electrical properties in a metal–insulator–metal capacitor in which the film was incorporated; the capacitor demonstrated a dielectric constant of 37.9 and leakage current of 3.52 × 10−9 A cm−2, without the need for a subsequent annealing process.

Late-Stage C–H Deuteration of Organic Compounds via Ligand-Enabled Palladium-Catalyzed Hydrogen Isotope Exchange

AbstractOver the past years our lab has established a research program towards the late-stage introduction of deuterium into organic molecules using Pd-catalyzed reversible C–H activation as a means to affect hydrogen isotope exchange. Through catalyst design, including the introduction of novel ligand scaffolds, as well as the use of strategically chosen optimization and screening approaches, e.g., exploiting microscopic reversibility by first optimizing de-deuteration processes or using a multi-substrate screening approach, our studies have resulted in a number of synthetically useful labelling protocols and are described herein from a personal perspective.1 Introduction2 β-C(sp3)–H Deuteration of Free Carboxylic Acids3 Nondirected C–H Deuteration of Arenes4 Nondirected C–H Deuteration of Heteroarenes5 Conclusion

Electroreductive deuteroarylation of alkenes enabled by an organo-mediator.

Electroreduction mediated by organo-mediators has emerged as a concise and effective strategy, holding significant potential in the site-specific introduction of deuterium. In this study, we present an environmentally friendly electroreduction approach for anti-Markovnikov selective deuteroarylation of alkenes and aryl iodides with D2O as the deuterium source. The key to the protocol lies in the employment of a catalytic amount of 2,2'-bipyiridine as an efficient organo-mediator, which facilitates the generation of aryl radicals by assisting in the cleavage of the C-X (X = I or Br) bonds in aryl halides. Because its reduction potential matches that of aryl iodides, the organo-mediator can control the chemoselectivity of the reaction and avoid the side reactions of competitive substrate deuteration. These phenomena are theoretically supported by CV experiments and DFT calculations. Our protocol provides a series of mono-deuterated alkylarenes with excellent deuterium incorporation through two single-electron reductions (SER), without requiring metal catalysts, external reductants, and sacrificial anodes.

SYNTHESIS OF DEUTERIUM-LABELED SALICYLCARNOSINE

The effect of temperature on the effectiveness of the introduction of deuterium into a new biologically active compound salicylcarnosine (SC) has been studied. Deuterium gas and heavy water were used as a source of deuterium. The synthesis of labeled SC by the solid-phase method at 190°C leads to the production of [D]SC with a yield of 53%, and a deuterium content of about 4.8 atoms per molecule. During isotope exchange with deuterated water, it was shown that after pretreatment of the catalyst at room temperature with deuterium gas, isotope exchange between SC protons and deuterated water occurs more efficiently. [D]SC is formed with a yield of 46% and contains about 7.3 deuterium atoms per molecule. During the preparative synthesis of labeled SC according to this technique at 190°C, the yield of [D]SC was 60–70%, with a deuterium content of about 6.2 atoms per molecule. A new technique for activating the inclusion of deuterium in peptides opens up additional opportunities for obtaining highly labelled drugs.

Photoredox Catalytic Installation of an Alkyl/Aryl Side Chain and Deuterium into (S)-Methyleneoxazolidinone: Synthesis of Enantioenriched α-Deuterated α-Amino Acid Derivatives.

A photoredox catalytic asymmetric method has been established for the installation of both aliphatic and aromatic side chains and the introduction of deuterium into the chiral methyleneoxazolidinone simultaneously. Efficient coupling of readily available boronic acids with the chiral auxiliary delivers structurally diverse α-deuterated α-amino acid derivatives with a high level of diastereoselectivity and deuteration.

Bioorthogonal chemical imaging of solid lipid nanoparticles with minimal labeling by stimulated Raman scattering microscopy

AbstractSolid lipid nanoparticles (SLNs) are a state‐of‐the‐art lipid‐based pharmaceutical drug delivery system. Advantages of SLNs include high biocompatibility, low immunogenicity, superiority in drug encapsulation capacity, and improved colloidal stability. They became widely known in late 2020, as several COVID‐19 vaccines are built upon SLNs technology. Despite the increasing impact, the characterization methods of SLNs are currently very limited especially in biological environment, which hinders fundamental understanding of the delivery mechanism and contributes to relatively low success rate in clinical translations. Here, we present close‐to‐label‐free imaging of deuterated SLNs using the emerging stimulated Raman scattering (SRS) microscopy. The introduction of deuterium to lipid structure renders bioorthogonal chemical specificity. Notably, with this approach, we have achieved ultrahigh single‐particle sensitivity both in vitro and in vivo, even with particle counting ability. Our bioorthogonal chemical imaging modality by SRS microscopy can be generalized to visualize a wide spectrum of lipid‐based drug carriers with high spatiotemporal resolution, chemical specificity, and ultimate sensitivity. This work opens up ways to address critical questions in SLN drug delivery and could also facilitate innovations in lipid nanotechnology and clinical translations.Key points Direct imaging of lipid nanocarrier that is the basis of the COVID‐19 vaccines. Novel single‐particle imaging technique applied to nanomedicine. Frontier of nanomaterial, optical imaging, and molecular pharmacology.

SYNTHESIS OF DEUTERIUM-LABELED PYRROLYLCARNOSINE

The effect of temperature on the effectiveness of the introduction of deuterium into pyrrolylcarnosine (PC) has been studied. Deuterium gas and heavy water were used as a source of deuterium. Isotope exchange was carried out using solid-phase and liquid-phase methods. It was found that it is better to use isotope exchange with deuterated water to obtain preparative amounts of labeled pyrrolylcarnosine. When using the solid-phase method, the main label is in pyrrole. The inclusion of deuterium at a higher temperature occurs more evenly. In addition, the use of deuterated water made it possible to reduce the amount of unlabeled isotopomer to almost 0%, obtain a product with a yield of 70% and a content of more than 7 deuterium atoms. It is established that the content of deuterium in the substance can be increased by pretreating the reaction mixture with deuterium gas. This approach opens up additional opportunities for synthesis of labeled compounds.

Evaluation of efficacy and safety after replacement of methyl hydrogen with deuterium at methyl formate of Clopidogrel

Background and PurposeDespite being a first-line clinical drug, thienopyridines have many unsatisfactory aspects, including the low bioavailability of clopidogrel(CLP) and the high bleeding risk of prasugrel. We synthesized deuterium clopidogrel(D-CL, patented in China) to alleviate the deficiency of CLP in clinical, such as a slow onset, a greater influence of gene polymorphism, and a high frequency of drug-drug interaction. Experimental ApproachMolecular docking was used to analyze the affinity between D-CL and the P2Y12 receptor. The levels of active metabolites of D-CL were detected using HPLC/MS-MS and the activities of main metabolic enzymes were analyzed; Subsequently, platelet aggregation function, thrombus model were used to evaluate the pharmacodynamics of D-CL. Finally, the safety of D-CL were evaluated through examination of blood routine, PT, APTT, bleeding time, serological tests, liver pathological biopsy, liver cell apoptosis and detection of apoptosis-related proteins. Key ResultsThe introduction of deuterium made the binding of CLP to P2Y12 receptor more stable, improved the concentration of active metabolites, and substantially reduced the inhibition of major metabolic enzymes, including CYP2B6, CYP2C9, and CYP2C19, thereby, exerting better antiplatelet effects without increasing the risk of bleeding, along with a concomitant decrease in the apoptosis of hepatocytes.

Catalytic Hydrogen Isotope Exchange Reactions in Late-Stage Functionalization

AbstractThe introduction of deuterium and tritium into molecules is of great importance in drug discovery. Many attempts have been made to develop late-stage hydrogen isotope exchange (HIE) reactions to avoid multistep syntheses using commercially available labeled precursors. In this review, we summarize recent progress in catalytic HIE reactions, with our main focus on their applications in the late-stage labeling of bioactive complex molecules and pharmaceuticals1 Introduction2 Non-Transition-Metal-Catalyzed Hydrogen Isotope Exchange2.1 Organocatalysis2.2 Photoredox Catalysis3 Transition-Metal-Catalyzed Hydrogen Isotope Exchang3.1 Palladium3.2 Ruthenium3.3 Iridium3.4 Other Metals4 Summary

Effect of Processes Occurring in the Presence of Metal Catalysts on the Main Characteristics of the Hydrogen Isotope Labeled Organic Compounds Obtained

The main deuterium and tritium sources used for preparing hydrogen isotope labeled compounds are presented. The mechanisms of hydrogenation and isotope exchange in organic compounds in the presence of heterogeneous and homogeneous catalysts when using gaseous tritium (or deuterium) or tritium (or deuterium) water are considered. Examples of the participation of solvent protons in introduction of deuterium and tritium into organic compounds by dehalogenation are presented. The problem of selective hydrogenation and dehalogenation is briefly discussed. Particular attention is paid to isotope exchange with deuterium or tritium in the presence of homogeneous iridium catalysts.

Synthesis of Isotopically Modified Derivatives of Dopamine, Serotonin, and Doxorubicin with Boc-Pro and Boc-[2H]Pro

Boc-Pro-Dox, Boc-Pro-DOPA, Boc-Pro-Srt, and Pro-Dox, Pro-DOPA, Pro-Srt, as well as Boc-[2Н]Pro-Dox, Boc-[2Н]Pro-DOPA, Boc-[2Н]Pro-Srt, and [2Н]Pro-Dox, [2Н]Pro-DOPA, [2Н]Pro-Srt have been synthesized for the first time. Boc-[2Н]Pro is the most promising reagent for the preparation of deuterated compounds. The hydrogenation of Boc-ΔPro in ethyl acetate on palladium catalyst has allowed the introduction of deuterium by a factor of 1.6–1.65 larger than by the hydrogenation of unsaturated proline bound to serotonin and by a factor of three larger than by the hydrogenation of unsaturated proline bound to dopamine. Due to doxorubicin instability under conditions of unsaturated proline hydrogenation, its condensation with Boc-[2Н]Pro is the sole possibility to prepare Boc-[2Н]Pro-Dox. The content of isotopomers in the deuterated products has been determined by mass spectrometry.

Palladium-catalyzed site-selective hydrogen isotope exchange (HIE) reaction of arylsulfonamides using amino acid auxiliary

Hydrogen isotope exchange (HIE) is a versatile method for the introduction of deuterium to organic compounds. Herein, regioselective deuteration of sulfonamides is achieved by palladium-Catalyzed HIE reaction. By using amino acid as weakly coordination-directing auxiliary, a variety of sulfonamides are efficiently deuterated at the ortho-position. Placing competing directing groups on the aromatic ring does not affect the site-selectivity.

Transformations of the amorphous and crystalline modifications of fullerene C70 under high pressures and high temperatures

Phase transformations of the amorphous phase of fullerene C70 at high temperature (HT) (up to 1100 °C) and high pressure (HP) (2–8 GPa) have been investigated and compared with the previous studies on the crystalline phase of fullerene C70. The amorphous phase of fullerene C70 was obtained by ball-milling. The study was conducted using neutron diffraction, Raman spectroscopy and HRTEM. It was shown that under the influence of HT and HP, the amorphous-like phase of fullerene C70 retains an amorphous structure up to 500 °C and transforms аt temperatures 800–1100 °C into amorphous-like or nanocrystalline graphite. The interesting difference of the transformation of the amorphous and crystalline phases of C70 is the structure of formed amorphous-like graphite. These types of amorphous-like graphite differ in the type of neutron diffraction patterns and in the presence or absence of graphite nanoclusters. An explicit anisotropy of amorphous-like graphite is revealed, which is manifested in the dependence of the diffraction patterns on the direction of measurement of the diffraction pattern in the sample under study. The introduction of deuterium affects the structure and diffraction spectra of amorphous-like graphite formed at HTHP.

A Novel, Green Synthesis of Deuterium Labeled Compounds

While deuterium (D) is barely different from its most abundant isotope hydrogen (H), the additional neutron makes a significant difference in the properties of deuterated compounds. While metabolic enzymes easily transform drug molecules to metabolites that the body can excrete, the introduction of deuterium to drugs appears to strengthen the resistance of drugs toward metabolism. The higher the stability, the longer the drug can work, which may result in lower dosage, therefore less side effects. In fact, the carbon‐deuterium bond is known to be six‐ten times stronger than its C‐H counterpart. There are several known methods for the introduction of deuterium to organic compounds; most methods, however, do not conform to the recent expectations and standards of sustainable synthesis. In order to develop an environmentally benign deuteration method we have turned our attention to the Al‐H2O system that is commonly applied for hydrogenation reactions. Replacing the H2O with its deuterated version D2O this hydrogen generating system can be turned to an easy and safe source of deuterium. The application of either the commercially available Ni‐Al alloy or Al only in conjunction with common hydrogenation catalysts, such as Pd or Pt, for the H‐D exchange of compounds with reactive C‐H bonds can be easily performed, while yielding no harmful byproducts. The low reactivity of the aluminum metal can be significantly enhanced by the application of ultrasonic irradiation. The H‐D exchange reaction can be carried out under relatively mild conditions; in more difficult cases the application of microwave irradiation yields the final products in a 1 h reaction. The success of the method was demonstrated by applying a broad variety of compounds from essential amino acids to actual drug compounds. By generating stronger bonds, the drugs would be able to remain active for an extended period of time, allowing the use of lower amounts, thus significantly improve the safety of their use.

Nickel‐Catalyzed Deoxygenative Deuteration of Aryl Sulfamates

AbstractThe nickel‐catalyzed deoxygenative deuteration of aryl/heteroaryl sulfamates has been developed, and the effective incorporation of deuterium into a variety of aromatic compounds was achieved with sufficient catalytic efficiency and high deuteration degree. This process tolerated reducible functional moieties and heterocyclic structures. Additionally, a double introduction of deuterium also successfully gave a desired product with a high yield and deuterium content.magnified image

Deuterodechlorination of Aryl/Heteroaryl Chlorides Catalyzed by a Palladium/Unsymmetrical NHC System.

The catalytic deuterodechlorination of aryl/heteroaryl chlorides was developed with a palladium/unsymmetrical NHC system, and the precisely controlled introduction of deuterium into a variety of aryl/heteroaryl compounds was achieved with a high level of efficiency, selectivity, and deuteration degree. This method was also successfully applied to the transformation of bioactive agents even in a gram-scale synthesis. The crystal structure analysis of Pd-NHC complexes led to the observation of Pd-arene interaction.

Identification of (Z)-3:(E)-2-Hexenal Isomerases Essential to the Production of the Leaf Aldehyde in Plants

The green odor of plants is characterized by green leaf volatiles (GLVs) composed of C6 compounds. GLVs are biosynthesized from polyunsaturated fatty acids in thylakoid membranes by a series of enzymes. A representative member of GLVs (E)-2-hexenal, known as the leaf aldehyde, has been assumed to be produced by isomerization from (Z)-3-hexenal in the biosynthesis pathway; however, the enzyme has not yet been identified. In this study, we purified the (Z)-3:(E)-2-hexenal isomerase (HI) from paprika fruits and showed that various plant species have homologous HIs. Purified HI is a homotrimeric protein of 110 kDa composed of 35-kDa subunits and shows high activity at acidic and neutral pH values. Phylogenetic analysis showed that HIs belong to the cupin superfamily, and at least three catalytic amino acids (His, Lys, Tyr) are conserved in HIs of various plant species. Enzymatic isomerization of (Z)-3-hexenal in the presence of deuterium oxide resulted in the introduction of deuterium at the C4 position of (E)-2-hexenal, and a suicide substrate 3-hexyn-1-al inhibited HI irreversibly, suggesting that the catalytic mode of HI is a keto-enol tautomerism reaction mode mediated by a catalytic His residue. The gene expression of HIs in Solanaceae plants was enhanced in specific developmental stages and by wounding treatment. Transgenic tomato plants overexpressing paprika HI accumulated (E)-2-hexenal in contrast to wild-type tomato plants mainly accumulating (Z)-3-hexenal, suggesting that HI plays a key role in the production of (E)-2-hexenal in planta.

Deuterium-labeling Toward Robust Function of Organic Molecules: Enhanced Photo-stability of Partially Deuterated 1', 3', 3'-Trimethyl-6-nitrospiro[2H-1- benzopyran-2, 2'-indoline

Synthesis of a deuterium-labeled derivative of nitrospirobenzopyran (NSP), one of representative photochromic compounds, has been described. Four deuteriums were successfully introduced on 1-methyl and <TEX>${\alpha}$</TEX>-methyne relative to spiro-carbon in the title compound with more than 95atom%D purity. Main photodegraded products of NSP were two oxindoles in acetonitrile, and additional products were formed in poly(isobutyl-methacrylate) films possibly due to restricted molecular motion in polymer matrix. Quantitative HPLC analysis revealed that partial introduction of deuterium to NSP brought a noticeable isotope effect, recognizable enhancement in photo-resistivity of NSP, i.e.,8.3% in solutions and 29% in polymeric films.

Iridium-catalyzed H/D exchange: ligand complexes with improved efficiency and scope.

Hydrogen isotope exchange (HIE) is one of the most attractive tools for the introduction of deuterium or tritium to an organic compound. Herein, iridium complexes with N,P-ligands, highly active catalysts for asymmetric double bond reductions, have been tested for their HIE capabilities. Electron-rich ligands, containing dicyclohexylphosphines or phosphinites, have been identified as excellent ligands for efficient deuterium incorporation. Substrates with strong directing groups, that is, pyridines, ketones, and amides, as well as weak ligating units, such as, nitro, sulfones, and sulfonamides, could be labeled efficiently. With the addition of tris(pentafluorophenyl) borane to the reaction mixture, also highly deactivating nitrile substituents were well tolerated in the reaction. Based on the excellent results obtained with the chiral ThrePhox ligand, a structurally simpler, achiral ligand was developed. The iridium complex containing this ligand, proved to be a powerful catalyst for HIE reactions.

Introduction of deuterium and tritium into 2-methyl-5-(p-methoxyphenyl)benzoic acid N-methylamide and N-methyl-N-(2-methyl-4-methoxy-5-trifluoromethylphenyl)-N′-methylurea

2-Methyl-5-(p-methoxyphenyl)benzoic acid N-methylamide and N-methyl-N-(2-methyl-4-methoxy-5-trifluoromethylphenyl)-N′-methylurea, labeled with hydrogen isotopes, were prepared. The number of the incorporated deuterium atoms per molecule was 5.4 for 2-methyl-5-(p-methoxyphenyl)benzoic acid N-methylamide and 1.82 for N-(2-methyl-4-methoxy-5-trifluoromethylphenyl)-N′-methylurea. The molar radioactivities of the tritium-labeled forms of these compounds reached 90 and 30 Ci mmol−1, respectively.