Hydrogen Isotope Exchange Reactions Research Articles

A quantitative empirical directing group scale for selectivity in iridium-catalysed hydrogen isotope exchange reactions

Competition hydrogen isotope exchange (HIE) experiments are used to construct quantitative directing group scales for two catalysts; these can be used to predict the outcomes of HIE reactions of substrates with multiple directing groups.

Synthesis of Pd−Rh Bimetallic Nanoparticles with Different Morphologies in Reverse Micelles and Characterization of Their Catalytic Properties

Synthesis of bimetallic nanoparticles (NPs) of the transition metals Rh and Pd in H2O/AOT/isooctane (where AOT is dioctyl sodium sulfosuccinate) reverse-micelle solutions (RMSs) in the presence of molecular oxygen and quercetin, a flavonoid, is described. The methods for NP synthesis used here enable us to prepare alloyed-type Rh−Pd NPs and core/shell Pd/Rh and Rh/Pd NPs with the metal molar ratio of 1 : 1. With both Rh3+ and Pd2+ ions present in an RMS simultaneously, palladium ions are reduced first, and the formed Pd NPs have an inhibitive effect on reduction of rhodium ions. The stability of a mixture of Rh and Pd NPs in RMSs is investigated, and the mixture of NPs with a mean diameter of ~2.7 nm is found to be stable for at least 25 days. Pd and Rh NP-based catalysts are prepared by absorption of the synthesized NPs on γ-Al2O3, and their catalytic activity is tested in the monomolecular hydrogen isotope exchange reaction. A synergetic effect, manifested as an enhanced catalytic activity, is observed for the catalyst prepared by adsorption of the mixture of Rh and Pd NPs on γ-Al2O3.

Highlights of C (sp2 )-H hydrogen isotope exchange reactions.

The highlights of C (sp2 )-H hydrogen isotope exchange (HIE) methods developed over the past 10 years are summarized in this review. Major developments include improved Ir(I) catalysts with greater functional group and solvent compatibility and the development of novel base metal catalysts for HIE. In addition, a number of novel Ru-based catalysts have been developed with promising activity. In the area of Pt- and Pd-catalysed exchange, in addition to new advances on heterogeneous Pt- and Pd-catalysed HIE by Sajiki and Shevchenko, a number of groups have reported on homogenous catalysts of Pt and Pd that show an interesting activity and selectivity.

Highlights of aliphatic C(sp3 )-H hydrogen isotope exchange reactions.

This review summarizes the highlights of aliphatic C (sp3 )-H carbon hydrogen isotope exchange (HIE) methods developed in the last 10 years. In particular, new highly selective and reactive protocols in the areas of nanoparticle and metal-catalyzed homogeneous catalysis are reported.

Comparison of Iridium(I) Catalysts in Temperature Mediated Hydrogen Isotope Exchange Reactions.

The reactivity and selectivity of iridium(I) catalysed hydrogen isotope exchange (HIE) reactions can be varied by using wide range of reaction temperatures. Herein, we have done a detailed comparison study with common iridium(I) catalysts (1–6) which will help us to understand and optimize the approaches of either high selectivity or maximum deuterium incorporation. We have demonstrated that the temperature window for these studied iridium(I) catalysts is surprisingly very broad. This principle was further proven in some HIE reactions on complex drug molecules.

Directed Iridium-Catalyzed Hydrogen Isotope Exchange Reactions of Phenylacetic Acid Esters and Amides.

For the first time, a catalytic protocol for a highly selective hydrogen isotope exchange (HIE) of phenylacetic acid esters and amides under very mild reaction conditions is reported. Using a homogeneous iridium catalyst supported by a bidentate phosphine-imidazolin-2-imine P,N ligand, the HIE reaction on a series of phenylacetic acid derivatives proceeds with high yields, high selectivity, and with deuterium incorporation up to 99 %. The method is fully adaptable to the specific requirements of tritium chemistry, and its effectiveness was demonstrated by direct tritium labeling of the fungicide benalaxyl and the drug camylofine. Further insights into the mechanism of the HIE reaction with catalyst 1 have been provided utilizing DFT calculations, NMR studies, and X-ray diffraction analysis.

Reaction Monitoring Using SABRE-Hyperpolarized Benchtop (1 T) NMR Spectroscopy.

The conversion of [IrCl(COD)(IMes)] (COD = cis,cis-1,5-cyclooctadiene, IMes = 1,3-bis(2,4,6-trimethyl-phenyl)imidazole-2-ylidene) in the presence of an excess of para-hydrogen (p-H2) and a substrate (4-aminopyridine (4-AP) or 4-methylpyridine (4-MP)) into [Ir(H)2(IMes)(substrate)3]Cl is monitored by 1H NMR spectroscopy using a benchtop (1 T) spectrometer in conjunction with the p-H2-based hyperpolarization technique signal amplification by reversible exchange (SABRE). A series of single-shot 1H NMR measurements are used to monitor the chemical changes that take place in solution through the lifetime of the hyperpolarized response. Non-hyperpolarized high-field 1H NMR control measurements were also undertaken to confirm that the observed time-dependent changes relate directly to the underlying chemical evolution. The formation of [Ir(H)2(IMes)(substrate)3]Cl is further linked to the hydrogen isotope exchange (HIE) reaction, which leads to the incorporation of deuterium into the ortho positions of 4-AP, where the source of deuterium is the solvent, methanol-d4. Comparable reaction monitoring results are achieved at both high-field (9.4 T) and low-field (1 T). It is notable that the low sensitivity of the benchtop (1 T) NMR enables the use of protio solvents, which when used here allows the effects of catalyst formation and substrate deuteration to be separated. Collectively, these methods illustrate how low-cost low-field NMR measurements provide unique insight into a complex catalytic process through a combination of hyperpolarization and relaxation data.

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.

Tools for work-up and prepurification of tritium-labeled small molecules.

This practitioner protocol describes the use and application of different types of solid-phase extractions and metal scavengers for small-scale reactions, particularly in the context of purifying tritiated molecules from heavily contaminated reaction mixtures. Polymer-bound strong cation exchangers are especially suitable for separating basic compounds from neutral or acidic molecules and have been widely applied in the work-up of iridium-based hydrogen isotope exchange reactions. Polymer-bound strong anion exchangers can help to separate acidic compounds from their neutral or basic counterparts or to easily convert a trifluoroacetate or formate salt to its free base after HPLC purification. Metal scavengers have been used for the work-up of metal-catalyzed coupling reactions and hydrogen isotope exchange reactions, facilitating subsequent chromatographic purifications.

Highly Selective Directed Iridium-Catalyzed Hydrogen Isotope Exchange Reactions of Aliphatic Amides.

For the first time, we describe highly selective homogeneous iridium‐catalyzed hydrogen isotope exchange (HIE) of unactivated C(sp3) centers in aliphatic amides. When using the commercially available Kerr catalyst, the HIE with a series of common antibody–drug conjugate (ADC) linker side chains proceeds with high yields, high regioselectivity, and with deuterium incorporation up to 99 %. The method is fully translatable to the specific requirements of tritium chemistry and its effectiveness was demonstrated by direct tritium labelling of a maytansinoid. The scope of the method can be extended to simple amino acids, with high HIE activity observed for glycine and alanine. In di‐ and tripeptides, a very interesting protecting‐group‐dependent tunable selectivity was observed. DFT calculations gave insight into the energies of the transition states, thereby explaining the observed selectivity and the influence of the amino acid protecting groups.

Highly Selective Directed Iridium‐Catalyzed Hydrogen Isotope Exchange Reactions of Aliphatic Amides

AbstractFor the first time, we describe highly selective homogeneous iridium‐catalyzed hydrogen isotope exchange (HIE) of unactivated C(sp3) centers in aliphatic amides. When using the commercially available Kerr catalyst, the HIE with a series of common antibody–drug conjugate (ADC) linker side chains proceeds with high yields, high regioselectivity, and with deuterium incorporation up to 99 %. The method is fully translatable to the specific requirements of tritium chemistry and its effectiveness was demonstrated by direct tritium labelling of a maytansinoid. The scope of the method can be extended to simple amino acids, with high HIE activity observed for glycine and alanine. In di‐ and tripeptides, a very interesting protecting‐group‐dependent tunable selectivity was observed. DFT calculations gave insight into the energies of the transition states, thereby explaining the observed selectivity and the influence of the amino acid protecting groups.

Evaluation of a P,N-Ligated Iridium(I) Catalyst in Hydrogen Isotope Exchange Reactions of Aryl and Heteroaryl Compounds

Evaluation of a P,N-Ligated Iridium(I) Catalyst in Hydrogen Isotope Exchange Reactions of Aryl and Heteroaryl Compounds

Hydrogen's isotopic exchange reaction in the C‐methyl sides in the medicinal agent xymedon: NMR spectroscopy and ab initio calculations

AbstractThe kinetics of intramolecular and intermolecular exchange processes in xymedon (1‐(2‐hydroxyethyl)‐4,6‐dimethyl‐1,2‐dihydropyrimidin‐2‐one, a regeneratory, wound‐healing drug) and its analogue were investigated in the solution. Hydrogen's mobility was detected in the C‐methyl sides of these compounds. This mobility was monitored via NMR in the hydrogen/deuterium exchange reaction in water. Two models were proposed as explanations for this hydrogen‐deuterium exchange. According to the main model, the key intermediates of these reactions are low‐energy tautomers of xymedon in which the N3 is protonated following which one proton leaves either 6‐Me or 4‐Me and thus its hybridization is changed. This hydrogen‐to‐deuterium exchange reaction is much faster under acidic conditions although it also occurs in alkaline conditions.Methylation via MeOTs or MeI leads to products with a quaternized ring N3 atom in which a hydrogen‐to‐deuterium exchange reaction also takes place, although the rates of the 6‐Me and 4‐Me hydrogens exchange are reversed.According to density functional theory calculations, the presence of methyl groups at the C4/C6 positions and of the C═O fragment is crucial to remarkably lower the energies of these “rare” tautomers. The exact position of the C═O in heterocycle is also very important in the tautomers' relative stability.

Mechanistic investigation of the formation of H2 from HCOOH with a dinuclear Ru model complex for formate hydrogen lyase

We report the mechanistic investigation of catalytic H2 evolution from formic acid in water using a formate-bridged dinuclear Ru complex as a formate hydrogen lyase model. The mechanistic study is based on isotope-labeling experiments involving hydrogen isotope exchange reaction.

Burgess iridium(I)-catalyst for selective hydrogen isotope exchange.

We have evaluated the commercially available Burgess catalyst in hydrogen isotope exchange reactions with several substrates bearing different directing group functionalities and have obtained moderate to high (50%-97%D) deuterium incorporations. The broad applicability in hydrogen isotope exchange reactions makes the Burgess catalyst a possible alternative compared to other commercially available iridium(I)-catalysts.

Hydrogen‐Isotope Exchange (HIE) Reactions of Secondary and Tertiary Sulfonamides and Sulfonylureas with Iridium(I) Catalysts

For the first time we report the optimized hydrogen‐isotope exchange (HIE) conditions for the selective aromatic deuteriation of various sulfonylureas and tertiary sulfonamides, as well as for a broad range of secondary sulfonamides. Based on a comprehensive screening of readily available Ir catalysts, the Kerr‐type NHC catalyst 5 proved to be most efficient in the HIE reaction of secondary sulfonamides and sulfonylureas. However, for tertiary sulfonamides, the commercially available Burgess catalyst 6, not yet utilized in HIE reactions, resulted in a much higher incorporation of deuterium. Finally, we tested the new HIE protocol for the labelling of a series of sulfa drugs and adapted the conditions to allow for selective tritium labelling.

Synthesis and selective 2 H-, 13 C-, and 15 N-labeling of the Tau protein binder THK-523.

A new synthetic route to the Tau binder, THK-523, is disclosed herein, which can easily be adapted to 13 C- and D-isotope labeling. The synthesis proceeds via two key reactions, namely, a Pd-catalyzed carbonylative Sonogashira coupling and a reductive ring-closing step with hydrogen or deuterium gas. By carrying out these reactions in a 2-chamber reactor we reported previously, ex situ-generated carbon monoxide and hydrogen/deuterium can be applied in stoichiometric quantities, thereby facilitating isotope labeling of this Tau-binding compound. Iridium-catalyzed hydrogen isotope exchange (HIE) reactions were performed on THK-523 and its 13 C-labeled analog providing access to 4 additional analogues labeled with deuterium as well. Finally, by applying a Buchwald-Hartwig coupling, we were able to prepare a 15 N-THK-523 variant with the isotope label in the quinoline ring system.

Density Functional Theory Calculations of H/D Isotope Effects on Polymer Electrolyte Membrane Fuel Cell Operations

Abstract To elucidate hydrogen isotope effects observed between fuel and exhaust hydrogen gases during polymer electrolyte membrane fuel cell operations, H-to-D reduced partition function ratios (RPFRs) for the hydrogen species in the Pt catalyst phase of the anode and the electrolyte membrane phase of the fuel cell were evaluated by density functional theory calculations on model species of the two phases. The evaluation yielded 3.2365 as the value of the equilibrium constant of the hydrogen isotope exchange reaction between the two phases at 39 °C, which was close to the experimentally estimated value of 3.46–3.99 at the same temperature. It was indicated that H+ ions on the Pt catalyst surface of the anode and H species in the electrolyte membrane phase were isotopically in equilibrium with one another during fuel cell operations.

Investigation of Hydrogen Isotope Exchange Reaction Rate in Mixed Gas (H2 and D2) at Pressure up to 200 MPa Using Raman Spectroscopy

Currently the problem of theoretical calculation and experimental determination of the isotopic exchange rate in mixes of hydrogen isotopes is open. There are a few experimental data on exchange rate constants that are rather discrepant. Of interest are experimental data on isotopic exchange rate in a gaseous mix of hydrogen isotopes at high pressures (thousands atmospheres). Raman spectroscopy is a relevant method for obtaining objective data on isotopic exchange rate in a gaseous mix of hydrogen isotopes, since it allows one to determine a gaseous mix composition without sampling in a real time. The paper describes equipment which allows registration of Raman spectra for gases under pressure up to 400 MPa and experimental data determining the constants of isotopic exchange rate in a protium-deuterium mix at pressures up to 200 MPa.

Investigation of Hydrogen Isotope Exchange Reaction Rate in Mixed Gas (H2 and D2) at Pressure up to 200 MPa Using Raman Spectroscopy

Investigation of Hydrogen Isotope Exchange Reaction Rate in Mixed Gas (H2 and D2) at Pressure up to 200 MPa Using Raman Spectroscopy