Hydrogen Isotope Exchange Research Articles

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.

Multideuteration of Nitroaromatics by Silver-Catalyzed Hydrogen-Isotope Exchange.

Silver-catalyzed deuteration of nitroaromatics has been achieved using D2O as the deuterium source. Distinct from the well-established directing group-guided hydrogen-isotope exchange, this protocol showed an interesting deuteration pattern, where considerable deuterium accumulation was observed around the aromatic rings. Controlling experiments suggested that the deuteration was initiated by a silver-promoted C-H activation. Therefore, a tentative two-stage deuteration mechanism involving aryl-silver species was proposed to explain the deuteration on meta- and para-positions.

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.

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.

Reproducible measurements of the δ2H composition of non-exchangeable hydrogen in complex organic materials using the UniPrep2 online static vapour equilibration and sample drying system

Non-exchangeable hydrogen-isotope (δ2Hn) measurements of complex organic samples are used in forensics to determine sample authenticity, traceability, and provenance. However, δ2Hn assays of organics are usually complicated by uncontrolled “exchangeable hydrogen” and residual moisture contamination; hence, δ2Hn assays are persistently incomparable amongst laboratories. We introduce a revised technical solution (UniPrep2) to control hydrogen-isotope exchange and for robust online sample drying and vapour equilibration. The UniPrep2 device is coupled to a high-temperature thermochemical elemental analyser and continuous-flow isotope-ratio mass spectrometer. This technical solution empowers isotope analysts to:•Conduct reproducible controlled vapour equilibrations of complex organic samples and standards to determine the δ2Hn values by controlling hydrogen-isotope exchange.•Conduct online vacuum-oven evacuation with extensive helium drying without exposure to air to reabsorb or exchange hydrogen with ambient water vapour.The protocol describes the operation of the UniPrep2 device and the step-by-step procedures needed to obtain accurate and precise δ2Hn values for a wide range of organic sample types. Two analytical approaches are described in detail; the Dual-Vapour Equilibration (DVE) approach, intended for determining δ2Hn for a complex organic environmental sample where matrix equivalent H isotope reference materials are not available, and the Comparative Equilibration (CE) approach, which is intended for routine high-throughput analyses of complex organic samples where at least two matrix-equivalent organic isotope reference materials with consensus δ2Hn values are being used. These standard operating procedures are envisioned to be a sound basis for advancing hydrogen-isotope analysis for different organic environmental matrices and studies.

Deuterium to protium isotope exchange in W-D co-deposited films below 200°C

Hydrogen isotope exchange as a method for removal of heavy hydrogen isotopes from tungsten co-deposits in fusion devices was investigated by exposing fresh W-D co-deposited films in protium atmosphere. The temperature was in the range from room temperature to 473 K (200°C), the protium pressure was 1 atm, the time of exposure was 18 hours. It was shown that the efficiency of exchange increases with temperature, and at least 99% of deuterium was removed at 473 K from 250 nm thick films. Vacuum annealing was much less efficient at all experimental conditions. Similar to polycrystalline materials, multiple occupation of traps by hydrogen isotopes is suggested to be a key mechanism of D to H exchange in the co-deposits.

Hydrogen isotope plasma-driven permeation through RAFM steel: isotope exchange and helium irradiation effect

Hydrogen isotope exchange in China low activation martensitic (CLAM) steel was investigated by plasma-driven permeation (PDP) measurements in the temperature range of ∼670–920 K. It was found that as H was introduced into D plasma, the permeation flux of HD increased while that of D2 decreased. The total D permeation flux, however, remained almost unchanged. Such a result allowed the analysis of isotope replacement and showed that the reduction of D2 is balanced by the rise of HD. In addition, the formation of HD was found to be closely related to the H and D content in plasma. Hydrogen isotopic effects on H and D plasma dissociation/ionization rate and on incident flux were evaluated by measuring plasma parameters including electron temperature and electron density using a triple Langmuir probe. The correlation between isotope effects on ionization rate in the plasma and isotope effects in the permeation flux was discussed. He plasma pre-irradiation and seeding during D PDP were also conducted to investigate the He effects on D diffusion. The total D permeation flux was found to be reduced by He seeding. Data analysis of Langmuir probe showed that ionization rate of D plasma was influenced by He seeding. Besides, under simultaneous D + He irradiation, He atoms were preferentially trapped at the defects resulting in a shallower D concentration gradient that described the observed decrease in D permeation rate. He plasma pre-irradiation was found to reduce D permeation flux with a much slower breakthrough to reach steady-state. The amount of D trapped at He-induced defects was derived quantitatively from the transient permeation curves. It is believed that He bubbles formed at the near surface act as trapping sites of D atoms, leading to a less effective diffusion coefficient and an enhanced retention in the material.

Benzylic deuteration of alkylnitroaromatics via amine-base catalysed exchange with deuterium oxide.

This paper describes the deuterium-labelling of alkylnitroaromatics by base-catalysed exchange with deuterium oxide. As the alkyl protons alpha to the aromatic ring are the most acidic sites in the molecule, regioselective hydrogen isotope exchange at this benzylic location leads to a regiospecifically deuterated product. The exchange labelling takes place in good yields and with high atom% abundance in the presence of an appropriate nitrogen base. Alkylated 2,4-dinitrobenzenes deuterate at room temperature under catalysis by triethylamine, whilst alkylated 2-nitro- or 4-nitrobenzenes and related mono-nitroaromatics require higher temperatures and catalysis by 1,5-diazobicyclo[4.3.0]non-5-ene (DBN). The labelling reactions require an inert gas atmosphere, but otherwise are simple and high yielding with no obvious byproducts. Those compounds in which the benzylic protons are in an ortho-orientation with respect to the nitro group label somewhat more slowly than the analogues where there is a para relationship. In addition, higher alkyl homologues undergo benzylic deuteration at slower rates than methyl.

Cesium Amide-Catalyzed Selective Deuteration of Benzylic C-H Bonds with D2 and Application for Tritiation of Pharmaceuticals.

Hydrogen isotope exchange (HIE) represents one of the most attractive labeling methods to synthesize deuterium- and tritium-labeled compounds. Catalytic HIE methods that enable site-selective C-H bond activation and exchange labeling with gaseous isotopes D2 and T2 are of vital importance, in particular for high-specific-activity tritiation of pharmaceuticals. As part of our interest in exploring s-block metals for catalytic transformations, we found CsN(SiMe3 )2 to be an efficient catalyst for selective HIE of benzylic C-H bonds with D2 gas. The reaction proceeds through a kinetic deprotonative equilibrium that establishes an exchange pathway between C-H bonds and D2 gas. By virtue of multiple C-H bonds activation and high activity (isotope enrichment up to 99 %), the simple cesium amide catalyst provided a very powerful and practically convenient labeling protocol for synthesis of highly deuterated compounds and high-specific-activity tritiation of pharmaceuticals.

An Update on Phosphine‐Imidazolin‐2‐Imine Iridium(I) Catalysts for Hydrogen Isotope Exchange

AbstractThe reaction of the bidentate P,N ligand [2‐(1,3,4,5‐tetramethylimidazolin‐2‐imino)phenyl]di‐tert‐butylphosphine (1) with [Ir(COD)Cl]2 (COD=1,5‐cyclooctadiene) followed by addition of sodium tetrakis[3,5‐bis(trifluoromethyl)phenyl]borate, NaBArF24, or lithium tetrakis(nonafluoro‐tert‐butoxy)aluminate, Li[Al{OC(CF3)3}4], afforded the complexes [(1)Ir(COD)][BArF24] (2 a) and [(1)Ir(COD)][Al{OC(CF3)3}4] (2 b). Exposure of 2 b to one atmosphere of dihydrogen gas afforded the diiridium tetrahydride [(1)2Ir2H4][Al{OC(CF3)3}4]2 (3 b). The molecular structures of 2 a, 2 b, and 3 b were determined by single‐crystal X‐ray diffraction analyses. In the latter complex, the positions of the hydrogen atoms in the Ir2H4 core could be refined freely, which had previously proved impossible for the corresponding complex 3 a containing the BArF24 anion. Since 2 a is an established catalyst for ortho‐directed hydrogen isotope exchange (HIE), the performance of 2 a and 2 b in deuterium labelling reactions was compared for various substrates, including phenylacetic acid derivates and nitrogen‐containing aromatic compounds.magnified image

Perdeuteration of Arenes via Hydrogen Isotope Exchange Catalyzed by the Superbasic Sodium Amide Donor Species NaTMP·PMDETA.

Hydrogen isotope exchange (HIE) has become one of the most studied methods to prepare deuterated molecules, with the primary focus recently on metal-catalyzed C-H activation with transition metals. Here we report the use of a simple sodium amide, NaTMP (TMP = 2,2,6,6-tetramethylpiperidide), combined with tridentate Lewis donor PMDETA (N,N,N',N″,N″-pentamethyldiethylenetriamine), which is able to catalytically promote the HIE of a series nonactivated arenes under mild reaction conditions using C6D6 as the deuterium source. Establishing the potential of NaTMP for the deuteration of aromatic molecules, several nonactivated substrates such as naphthalene, diphenylacetylene, and stilbene could be deuterated under mild reaction conditions without the need of transition metals. Combining NMR studies with the isolation of key organometallic intermediates, we demonstrate that the ability of NaTMP/PMEDTA to partially metalate C6D6, with concomitant generation of TMP(D), is key to enable the catalytic deuteration.

Palladium-Catalyzed Ligand-Free ortho-Deuteration of Aromatic Carboxylic Acids with D2O

AbstractA ligand-free, palladium-catalyzed ortho-deuteration of aromatic carboxylic acids was developed using D2O as the deuterium source. Compared to their meta-substituted analogues, an unusually lower reactivity in para- and ortho-substituted benzoic acids toward hydrogen isotope exchange was observed. Further investigation revealed that the reaction temperature is a critical parameter for the reactivity, and the modified conditions can afford deuterated products with good to excellent deuterium incorporation.

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.

One-Pot Sequential Hydrogen Isotope Exchange/Reductive Deuteration for the Preparation of α,β-Deuterated Alcohols using Deuterium Oxide.

An efficient one-pot sequential hydrogen isotope exchange (HIE)/reductive deuteration approach was developed for the preparation of α,β-deuterated alcohols using ketones as the precursors. The HIE step can also be used for the synthesis of α-deuterated ketones. This method has been applied in the synthesis of four deuterated drug and MS internal standards.

Distinct chemical and stable isotope compositions of smectite formed during steaming of Clearwater Formation oil-sands from Cold Lake, Alberta

Chemical reactions between oil-sands and injected steam or steam condensate during cyclic steam stimulation (CSS), commonly used to mobilize heavy oil and bitumen, result in decomposition of pre-existing minerals and formation of new phases including clay minerals. These changes can reduce reservoir permeability and limit hydrocarbon recovery. In this study, the chemical and stable isotope compositions of berthierine and smectitic clay minerals contained in pre- and post-steam Clearwater Formation oil-sands from Cold Lake, Alberta were analyzed to investigate how these phases were affected by CSS. Berthierine abundance in the injection-zone decreased after steaming whereas the abundance of smectitic clay minerals increased. Pre- and post-steam berthierine exhibited the same range of chemical compositions, while those of pre- and post-steam smectitic clay minerals commonly differed. Some post-steam smectitic clay minerals from the steam injection-zone, in particular, contain significantly more Fe and Si but less Al than pre-steam samples. It is proposed that that berthierine contributed to the formation of new smectitic clay minerals during CCS through partial inheritance of the berthierine 1:1 structure. This inheritance model approximates the unique chemical compositions of the post-steam smectitic clay minerals. The model also helps to explain the incomplete oxygen and hydrogen isotope exchange between injection fluids and smectitic clay minerals formed during CSS.

Species variation in the hydrogen isotope composition of leaf cellulose is mostly driven by isotopic variation in leaf sucrose.

Experimental approaches to isolate drivers of variation in the carbon-bound hydrogen isotope composition (δ2 H) of plant cellulose are rare and current models are limited in their application. This is in part due to a lack in understanding of how 2 H-fractionations in carbohydrates differ between species. We analysed, for the first time, the δ2 H of leaf sucrose along with the δ2 H and δ18 O of leaf cellulose and leaf and xylem water across seven herbaceous species and a starchless mutant of tobacco. The δ2 H of sucrose explained 66% of the δ2 H variation in cellulose (R2 = 0.66), which was associated with species differences in the 2 H enrichment of sucrose above leaf water ( : -126% to -192‰) rather than by variation in leaf water δ2 H itself. was positively related to dark respiration (R2 = 0.27), and isotopic exchange of hydrogen in sugars was positively related to the turnover time of carbohydrates (R2 = 0.38), but only when was fixed to the literature accepted value of ‰. No relation was found between isotopic exchange of hydrogen and oxygen, suggesting large differences in the processes shaping post-photosynthetic fractionation between elements. Our results strongly advocate that for robust applications of the leaf cellulose hydrogen isotope model, parameterization utilizing δ2 H of sugars is needed.

C(sp2)-H Activation with Bis(silylene)pyridine Cobalt(III) Complexes: Catalytic Hydrogen Isotope Exchange of Sterically-Hindered C-H Bonds.

The bis(silylene)pyridine cobalt(III) dihydride boryl, trans-[ ptol SiNSi]Co(H)2BPin (ptolSiNSi = 2,6-[EtNSi(NtBu)2CAr]2 C5H3N, where Ar = C6H5CH3, and Pin =pinacolato) has been used as a precatalyst for the hydrogen isotope exchange (HIE) of arenes and heteroarenes using benzene-d 6 as the deuterium source. Use of D2 as the source of the isotope produced modest levels of deuterium incorporation and stoichiometric studies established modification of the pincer ligand through irreversible addition of H2 across the silylene leading to catalyst deactivation. High levels of deuterium incorporation were observed with benzene-d 6 as the isotope source and enabled low (0.5 - 5 mol%) loadings of the cobalt precursor. The resulting high activity for C-H activation enabled deuterium incorporation at sterically encumbered sites previously inaccessible with first-row metal HIE catalysts. The cobalt-catalyzed method was also compatible with aryl halides, demonstrating a kinetic preference for chemoselective C(sp2)-H activation over C(sp2)-X (X = Cl, Br) bonds. Monitoring the catalytic reaction by NMR spectroscopy established cobalt(III) resting states at both low and high conversions of substrate and the overall performance was inhibited by the addition of HBPin. Studies on precatalyst activation with cis-[ ptol SiNSi]Co(Bf)2H and cis-[ ptol SiNSi]Co(H)2Bf (where Bf = 2-benzofuranyl), support the intermediacy of bis(hydride)aryl cobalt intermediates as opposed to bis(aryl)hydride cobalt complexes in the catalytic HIE method. Mechanistic insights resulted in an improved protocol using [ ptol SiNSi]Co(H)3 NaBHEt3 as the precatalyst, ultimately translating onto higher levels of isotopic incorporation.

Superacid‐Mediated Late‐Stage Aromatic Polydeuteration of Pharmaceuticals

The field of medicinal chemistry is currently witnessing a deuterium rush owing to the remarkable properties of this element as bioisoster of hydrogen atom. Aromatic hydrogen isotope exchange (HIE) is one of the most studied strategies nowadays as it promises to access deuterium-modified drugs directly from their non-labeled parents. While most of the recent studies focus on metal-catalyzed C-H activation strategy, the use of superacidic conditions has been largely overlooked. This study shows that the use of TfOD as reaction medium allows the late-stage polydeuteration of a broad library of pharmaceuticals bearing a wide array of functional groups, complementing existing procedures.

Liquid‐Phase Catalytic Exchange of Hydrogen Isotopes over Ion Sputtering Platinum on Superhydrophobic Coatings

AbstractLiquid‐phase catalytic exchange (LPCE) of hydrogen isotopes has extensive application in upgrading of recycled water and wastewater treatment. This low‐temperature catalytic exchange requires hydrophobic catalysts for keeping high exchange efficiency and catalytic stability. To eliminate diffusional influences in conventional porous catalysts, we designed a flat catalyst coating with fully exposed platinum (Pt) active sites by two steps. The hydrophobic coating was firstly established by superhydrophobic silica nanospheres (SSNs) and then Pt nanoparticles were dispersed on the surface of coating by ion sputtering. By adjusting the time of ion sputtering, the catalytic exchange efficiency of optimized catalyst coating (50‐Pt/SSNs/PDMS) improved up to 86% at 60 °C and maintained stability for at least 5 h, behaving high catalytic exchange efficiency and good stability. Besides, the turnover frequency of the 50‐Pt/SSNs/PDMS was 1.7 times than that of “PDMS+Pt/SSNs” prepared by “glue+power” method. The “step by step” strategy can effectively improve the utilization of Pt and provide a new idea for the preparation of Pt‐based hydrophobic catalysts.

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.