Hydrogen Isotope Exchange Reactions Research Articles

Deuteration and Tritiation of Pharmaceuticals by Non-Directed Palladium-Catalyzed C-H Activation in Heavy and Super-Heavy Water.

Deuterated and tritiated analogs of drugs are valuable compounds for pharmaceutical and medicinal chemistry. In this work, we present a novel hydrogen isotope exchange reaction of drugs using non-directed homogeneous Pd-catalysis. Aromatic C-H activation is achieved by a commercially available pyridine ligand. Using the most convenient and cheapest deuterium source, D2O, as the only solvent 39 pharmaceuticals were labelled with clean reaction profiles and high deuterium uptakes. Additionally, we describe the first application of non-directed homogeneous Pd-catalysis for H/T exchange on three different pharmaceuticals by using T2O as isotopic source, demonstrating the applicability to the synthesis of radiotracers.

Deuteration and Tritiation of Pharmaceuticals by Non‐Directed Palladium‐Catalyzed C−H Activation in Heavy and Super‐Heavy Water

AbstractDeuterated and tritiated analogs of drugs are valuable compounds for pharmaceutical and medicinal chemistry. In this work, we present a novel hydrogen isotope exchange reaction of drugs using non‐directed homogeneous Pd‐catalysis. Aromatic C−H activation is achieved by a commercially available pyridine ligand. Using the most convenient and cheapest deuterium source, D2O, as the only solvent 39 pharmaceuticals were labelled with clean reaction profiles and high deuterium uptakes. Additionally, we describe the first application of non‐directed homogeneous Pd‐catalysis for H/T exchange on three different pharmaceuticals by using T2O as isotopic source, demonstrating the applicability to the synthesis of radiotracers.

Recent progress in transition metal complexes featuring silylene as ligands.

Silylenes, divalent silicon(II) compounds, once considered highly reactive and transient species, are now widely employed as stable synthons in main-group and coordination chemistry for myriad applications. The synthesis of stable silylenes represents a major breakthrough, which led to extensive exploration of silylenes in stabilizing low-valent main-group elements and as versatile ligands in coordination chemistry and catalysis. In recent years, the exploration of transition metal complexes stabilized with silylene ligands has captivated significant research attention. This is due to their robust σ-donor characteristics and capacity to stabilize transition metals in low valent states. It has also been demonstrated that the transition metal complexes of silylenes are effective catalysts for hydroboration, hydrosilylation, hydrogenation, hydrogen isotope exchange reactions, and small molecule activation chemistry. This review article focuses on the recent progress in the synthesis and catalytic application of transition metal complexes of silylenes.

Pegylated Phosphine Ligands in Iridium(I) Catalyzed Hydrogen Isotope Exchange Reactions in Aqueous Buffers.

The synthesis of a water-soluble, phosphine-pegylated iridium(I) catalyst and its application in hydrogen isotope exchange (HIE) reactions in buffer is reported. The longer polyethylene glycol side chains on the phosphine increased the water solubility independently from the pH. HIE reactions of polar substrates in protic solvents were studied. DFT calculations gave further insights into the catalytic processes. The scope and limitation of the pegylated catalyst was studied in HIE reactions of several complex compounds in borax buffer at pH 9 and the best conditions were applied in a tritium experiment with the drug telmisartan.

Direct Multi-Deuterium Labelling of Pirtobrutinib.

Herein, we demonstrate an efficient method for multi-deuterium labelling of pirtobrutinib-a Bruton's tyrosine kinase inhibitor recently approved by the FDA-using a straightforward hydrogen isotope exchange (HIE) reaction. A remarkably high level of deuterium incorporation was achieved using an excess of a Kerr-type iridium catalyst. The key factor in the significant deuterium labelling was the decision to employ a deuterium uniformly labelled solvent, chlorobenzene-d5, at an elevated temperature. Virtually, no d0-d3 species were detected, with only traces of d4-d5 isotopomers (< 5%) observable in the mass spectrum of pirtobrutinib-d8, fulfilling requirements for stable isotope-labelled internal standard. The labelled compound-mainly consisting of isotopomers d6-d9 at 82.4% of the total abundance-was isolated in a high yield (73%) and purity (99%). Noteworthy, fluorine group acting as a directing group was observed for the first time. Significant incorporation of deuterium in ortho-positions, exceeding 87%, was observed. Interestingly, chlorinated solvent used in the HIE reactions was non-specifically deuterated yielding up to 0.42 deuterium per chlorobenzene molecule even at an exceptionally low iridium catalyst loading of 4.17 × 10-2 mol%.

Recent Advances in Deuteration Reactions†

Comprehensive SummaryThe deuteration of organic compounds has attracted more attentions in recent years for the potential applications in new drug discovery and synthetic chemistry. For this purpose, many efficient deuterium labeling methodologies have been developed, including hydrogen isotope exchange (HIE), reductive deuteration, and dehalogenative deuteration that allow for the synthesis of selectively deuterated compounds. In the last few years, great breakthroughs in selective isotope labeling have been achieved and the interest in new methodologies for the deuteration of organic molecules is rising. In this review, we summarized the recent developments in the selective deuteration of organic molecules since 2021. Several types of key processes in deuterium incorporation reactions, including H/D exchange, reductive deuteration and dehalogenative deuteration, are introduced and discussed. Key ScientistsIn the 2000s, Derdau and Atzrodt's group have made great contributions to the directing group assisted noble‐metal catalyzed hydrogen isotope exchange of arenes and applications of labeled compounds. During the same period, Sajiki and co‐workers completed a series of deuteration reactions by heterogeneous platinum‐group metal catalysts. Since 2015, Gregory Pieters and co‐workers have developed ruthenium catalysts for selective hydrogen isotope exchange. In 2016, Chirik's group achieved hydrogen isotope exchange in the presence of a homogeneous iron complex. David MacMillan and coworkers have made breakthroughs in photocatalyzed HIE reactions for α‐amino C(sp3)–H bonds. From 2020, a series of nanoelectrodes were designed for selective dehalogenative deuterations and reductive deuteration of unactivated unsaturated bonds by Zhang's group. Recently, Beller's group developed several efficient strategies for isotopic labeling using heterogeneous earth‐abundant catalysts. Our review summarized the latest and important developments since 2021.

B(C6F5)3-Catalyzed Intramolecular Hydroalkoxylation Deuteration Reactions of Unactivated Alkynyl Alcohols.

Using D2O as a deuterium source, a method for the deuteration of intra- and extra-cyclic methylene has been developed for cyclic ethers with moderate yield and excellent deuterium incorporation. This transformation features superb functional group tolerance in a wide range of alkynols. Notably, the critical factor to achieve high deuterium incorporation is determined by the hydrogen isotope exchange reaction of an unstable oxonium ion. This novel methodology provides an efficient and concise synthetic route to a number of valuable deuterated cyclic ethers that are often difficult to prepare with other methods.

In situ Generated Iridium Nanoparticles as Hydride Donors in Photoredox‐Catalyzed Hydrogen Isotope Exchange Reactions with Deuterium and Tritium Gas

AbstractWe have studied the photoredox‐catalyzed hydrogen isotope exchange (HIE) reaction with deuterium or tritium gas as isotope sources and in situ formed transition metal nanoparticles as hydrogen atom transfer pre‐catalysts. By this means we have found synergistic reactivities applying two different HIE mechanisms, namely photoredox‐catalyzed and CH‐functionalization HIE leading to the synthesis of highly deuterated complex molecules. Finally, we adopted these findings successfully to tritium chemistry.

In situ Generated Iridium Nanoparticles as Hydride Donors in Photoredox-Catalyzed Hydrogen Isotope Exchange Reactions with Deuterium and Tritium Gas.

We have studied the photoredox-catalyzed hydrogen isotope exchange (HIE) reaction with deuterium or tritium gas as isotope sources and in situ formed transition metal nanoparticles as hydrogen atom transfer pre-catalysts. By this means we have found synergistic reactivities applying two different HIE mechanisms, namely photoredox-catalyzed and CH-functionalization HIE leading to the synthesis of highly deuterated complex molecules. Finally, we adopted these findings successfully to tritium chemistry.

Ru supported on MnBCD derived from Mn MOF for thermo- and electro-catalytic synthesis of ethylene-d4 glycol.

Deuterium-labeled polyols were one of the most extensive applications in biochemistry and biophysics. However, the deuteriation reaction still exhibit low deuteriation rate and indistinct reaction mechanism. In this paper, Ru supported on MnBDC (derived from Mn-MOF) nano-catalyst, with agglomerated sheet-type structure, which ensure that possibility of achieving both thermo- and electro-catalytic hydrogen isotope exchange (HIE) reaction. Furthermore, XPS characterization affirmed that the specific structural changes in the electron density of Ru outer layers were modulated through the impregnation and reduction processes. According to the change of outer electronic structure, hydrogen spillover and electron-rich flow promote the reaction of catalyst in thermo- and electro-catalytic systems respectively. And, the results indicate that high deuterium rates of 97% can be obtained, which the catalytic technology has enormous potential for the synthesis of a broad variety of deuterium-labeled compounds.

Experimental determinations of carbon and hydrogen isotope fractionations and methane clumped isotope compositions associated with ethane pyrolysis from 550 to 600 °C

Methane clumped isotope compositions signify the relative natural abundances of rare, doubly substituted isotopic species of methane (13CH3D and 12CH2D2) and have emerged as a new isotopic tool to trace the sources, sinks, and lifecycles of methane in the environment. Such measurements can identify equilibration (or re-equilibration) temperatures if found to be in isotopic equilibrium or non-equilibrium processes (e.g., kinetically controlled reactions or mixing) if not in isotopic equilibrium. Naturally occurring thermogenic methane—formed by the thermally activated breakdown of larger organic molecules—has been found to have clumped isotope compositions consistent with equilibrium at reasonable gas formation temperatures in some settings and non-equilibrium processes occurring during either formation, migration, storage, or extraction in others. To explore the potential controls on the isotopic composition of thermogenic methane, we conducted isothermal time-series ethane pyrolysis experiments at 550 and 600 °C to measure methane and ethane 13C/12C and D/H fractionations and methane clumped isotope compositions (resolved 13CH3D and 12CH2D2). We explore the effects of modifying the initial clumped isotope composition of ethane and the addition of water vapor to pyrolysis experiments. We observe that ethane and methane 13C/12C are controlled by kinetic isotope effects and Rayleigh distillation processes. In contrast, ethane and methane D/H and methane clumped isotope compositions appear to be controlled by a combination of these processes and hydrogen isotope exchange. The hydrogen isotope exchange processes lead to isotopic equilibrium as reaction completion is approached for both D/H (ethane/methane) and methane clumped isotope compositions. We develop a chemical model based on a mass balance approach that accounts for inheritance vs. hydrogen-abstraction formation pathways for singly and doubly substituted isotopologues of ethane and methane that is compared to the experimental data. The model allows the determination of carbon and hydrogen kinetic isotope effects associated with ethane cracking and hydrogen abstraction reactions that, where applicable, we compare to prior theoretical constraints. From the comparison of the model to the experimental data, we infer that the kinetically controlled ethane and methane bulk isotope compositions and methane clumped isotope compositions are controlled by kinetic isotope effects (both primary and secondary) associated with both CC bond and CH bond cleavage reactions. Specifically, the methane clumped isotope compositions likely result from a combination of clumped isotope effects associated with ethane breakdown and/or assembly of methane isotopologues (expressed in terms of γ-factor parameters ≠ 1) and combinatorial effects that arise probabilistically. We discuss our experimental results in the context of recent pyrolysis experiments and observations of naturally occurring thermogenic methane. We consider a proposal consistent with observations from nature that the hydrogen isotope exchange reactions that promote equilibration of methane isotopic molecules at or near formation temperature may be facilitated by free radicals generated by pyrolysis reactions. In this framework, isotope exchange effectively ceases when pyrolysis effectively ceases locking in compositions that can be consistent with peak formation temperatures.

Isotopic Fractionation as a Mechanistic Probe in Light-Driven C-H Bond Exchange Reactions.

Here, we report a diagnostic framework for elucidating the mechanisms of photoredox-based hydrogen isotope exchange (HIE) reactions based on hydrogen/deuterium (H/D) fractionation. Traditional thermal HIE methods generally proceed by reversible bond cleavage and bond reformation steps that share a common transition state. However, bond cleavage and bond reformation in light-driven HIE reactions can proceed via multiple, non-degenerate sets of elementary steps, complicating both mechanistic analysis and attendant optimization efforts. Building on classical treatments of equilibrium isotope effects, the fractionation method presented here extracts information regarding the nature of the key bond-forming and bond-breaking steps by comparing the extent of deuterium incorporation into an exchangeable C-H bond in the substrate relative to the H/D isotopic ratio of a solvent reservoir. We show that the extent of fractionation is sensitive to the mechanism of the exchange process and provides a means to distinguish between degenerate and non-degenerate mechanisms for isotopic exchange. In model systems, the mechanisms implied by the fractionation method align with those predicted by thermochemical considerations. We then employed the method to study HIE reactions whose mechanisms are ambiguous on thermodynamic grounds.

Hydrogen Isotope Exchange by Homogeneous Iridium Catalysis in Aqueous Buffers with Deuterium or Tritium gas.

We have studied the highly selective homogeneous iridium-catalyzed hydrogen isotope exchange (HIE) with deuterium or tritium gas as an isotope source in water and buffers. With an improved water-soluble Kerr-type catalyst, we have achieved first insights to apply HIE reactions in aqueous media with different pH media. DFT calculations gave consistent insights in the calculated energies of transition states and coordination complexes, further explaining the observed reactivity and guidance on the scope and limitations for HIE reactions in water. Finally, we adopted these findings successfully to tritium chemistry.

Hydrogen Isotope Exchange by Homogeneous Iridium Catalysis in Aqueous Buffers with Deuterium or Tritium Gas

AbstractWe have studied the highly selective homogeneous iridium‐catalyzed hydrogen isotope exchange (HIE) with deuterium or tritium gas as an isotope source in water and buffers. With an improved water‐soluble Kerr‐type catalyst, we have achieved the first insight into applying HIE reactions in aqueous media with varying pH. Density functional theory (DFT) calculations gave consistent insights in the calculated energies of transition states and coordination complexes, further explaining the observed reactivity and guidance on the scope and limitations for HIE reactions in water. Finally, we successfully adapted these findings to tritium chemistry.

Quantitative analysis of hydrogen isotope gas mixtures by low resolution quadrupole mass spectrometer

Quadrupole mass spectrometry (QMS) has an important application in the field of rapid on-line analysis of hydrogen isotopes. However, due to the interference of isotope fractionation effect and mass overlap peaks, accurate quantitative analysis of hydrogen isotopes by quadrupole mass spectrometry has always been a challenging problem. For the calibration of a low-resolution quadrupole mass spectrometry, standard samples of hydrogen isotopes gas mixtures with different HD contents were prepared by platinum catalyst that accelerated hydrogen isotope exchange reaction. The results show that the fraction of ionized fragments of various hydrogen isotopes in the mixture is stable and less affected by the coexistence of other isotopes. Taking the main fragment peak as the calibration basis, considering the isotope fractionation effect and mass overlap peak interference, the calibration curve between hydrogen isotope abundance and mass spectral signal was obtained by systematic correction method, and the linear correlation coefficient is 0.9991. The average relative errors between the correction values and the standard values of isotope abundance measured are 1.87% (hydrogen content) and 3.43% (deuterium content), respectively. The method developed in this work can be used for rapid on-line quantitative analysis of hydrogen isotope gas mixtures.

Alkali-metal bases in catalytic hydrogen isotope exchange processes.

The preparation of compounds labelled with deuterium or tritium has become an essential tool in a range of research fields. Hydrogen isotope exchange (HIE) offers direct access to said compounds, introducing these isotopes in a late stage. Even though the field has rapidly advanced with the use of transition metal catalysis, alkali-metal bases, used as catalysts or under stoichiometric conditions, have also emerged as a viable alternative. In this minireview we describe the latest advances in the use of alkali-metal bases in HIE processes, showcasing their synthetic potential as well as current challenges in the field. It is divided in different sections based on the isotope source used, emphasizing their benefits, disadvantages and limitations. The influence on the choice of alkali-metal in these processes as well as their possible mechanistic pathways are also discussed.

Electrochemical hydrogen isotope exchange of amines controlled by alternating current frequency.

Here, we report an electrochemical protocol for hydrogen isotope exchange (HIE) at α-C(sp3)-H amine sites. Tetrahydroisoquinoline and pyrrolidine are selected as two model substrates because of their different proton transfer (PT) and hydrogen atom transfer (HAT) kinetics at the α-C(sp3)-H amine sites, which are utilized to control the HIE reaction outcome at different applied alternating current (AC) frequencies. We found the highest deuterium incorporation for tetrahydroisoquinolines at 0 Hz (i.e., under direct current (DC) electrolysis conditions) and pyrrolidines at 0.5 Hz. Analysis of the product distribution and D isotope incorporation at different frequencies reveals that the HIE of tetrahydroisoquinolines is limited by its slow HAT, whereas the HIE of pyrrolidines is limited by the overoxidation of its α-amino radical intermediates. The AC-frequency-dependent HIE of amines can be potentially used to achieve selective labeling of α-amine sites in one drug molecule, which will significantly impact the pharmaceutical industry.

N-Heterocyclic Carbene-Based Iridium and Ruthenium/Iridium Nanoparticles for the Hydrogen Isotope Exchange Reaction through C–H Bond Activations

Suppressing aromatic ring reduction in noble-metal-catalyzed H/D exchange reactions remains a challenge. This drawback may be overcome by finding a synergetic effect in bimetallic nanoparticles (NPs). Herein, we report the synthesis of bimetallic lipo- and water-soluble Ru/Ir NPs. They were characterized by state-of-the-art techniques such as transmission electron microscopy (TEM), high-resolution TEM, attenuated total reflection Fourier transform infrared, powder X-ray diffraction, and solid-state nuclear magnetic resonance. These NPs were found to disperse in both organic and aqueous media because of the stabilization and coordination of adequate N-heterocyclic carbene (NHC) ligands to the NP surface. They were tested in the deuteration of 2-phenylpyridine, 2-methyl-naphthylamine, 5,6,7,8-tetrahydro-naphthtylamine, and l-lysine using D2 as the isotopic source. Bimetallic NPs showed an unusual selectivity toward the H/D exchange of 2-phenylpyridine, deuterating not only the expected C–H positions close to the N atom but also remote positions on the heterocycle. Additionally, reduction of the aromatic rings, which is a common undesired side reaction catalyzed by Ru NPs, was not observed. These outcomes, rationalized by a synergetic effect of both metals, are enhanced when NHC ligands are on the surface in comparison to model catalysts stabilized by polyvinylpyrrolidone. With regard to non-aromatic substrates, CH2-α and CH2-ε positions with respect to the amino acid group of l-lysine were fully deuterated, while moderate deuteration of the γ position was observed as the iridium content was increased in the bimetallic system.

Cationic Iridium(I) NHC‐Phosphinidene Complexes and Their Application in Hydrogen Isotope Exchange Reactions

AbstractThe reaction of the dimeric iridium complex [Ir(cod)Cl]2 (cod=1,5‐cyclooctadiene) with the N‐heterocyclic carbene‐phosphinidene adduct (IDipp)PH (1, IDipp=1,3‐bis(2,6‐diisopropylphenyl)imidazolin‐2‐ylidene) afforded the neutral bimetallic iridium(I) complex [μ‐{(IDipp)PH}{Ir(cod)Cl}2] (2), and further addition of IDipp(PH) (1) yielded the corresponding monometallic iridium(I) complex [{(IDipp)PH}Ir(cod)Cl] (3). Dechlorination of these complexes with sodium tetrakis[3,5‐bis(trifluoromethyl)phenyl]borate (NaBArF4) yielded their cationic derivatives [{μ‐(IDipp)PH}{Ir(cod)}2{μ‐Cl}][BArF4] (4) and [{(IDipp)PH}Ir(cod)(PPh3)][BArF4] (5). All complexes were structurally characterized and showed the expected square‐planar coordination geometry and significant polarization of the P−C bond of the NHC‐phosphinidene adduct upon metal coordination. The complexes 4 and 5 were tested for their applicability in catalytic H/D exchange reactions, and both complexes showed high activity for a broad range of aromatic substrates, ranging from ketones, amides, esters, nitro compounds and heterocycles.

Recent Developments for the Deuterium and Tritium Labeling of Organic Molecules

Organic compounds labeled with hydrogen isotopes play a crucial role in numerous areas, from materials science to medicinal chemistry. Indeed, while the replacement of hydrogen by deuterium gives rise to improved absorption, distribution, metabolism, and excretion (ADME) properties in drugs and enables the preparation of internal standards for analytical mass spectrometry, the use of tritium-labeled compounds is a key technique all along drug discovery and development in the pharmaceutical industry. For these reasons, the interest in new methodologies for the isotopic enrichment of organic molecules and the extent of their applications are equally rising. In this regard, this Review intends to comprehensively discuss the new developments in this area over the last years (2017-2021). Notably, besides the fundamental hydrogen isotope exchange (HIE) reactions and the use of isotopically labeled analogues of common organic reagents, a plethora of reductive and dehalogenative deuteration techniques and other transformations with isotope incorporation are emerging and are now part of the labeling toolkit.