Late-Stage Deuteration and Tritiation through Bioinspired Cooperative Hydrogenolysis

Organic Chemistry Chemistry Medicinal Chemistry Catalysis
hydrogenolysis deuteration tritiation bioinspired homogeneous catalysis

Academic Background

Hydrogenolysis, a fundamental chemical reaction that breaks chemical bonds through the addition of molecular hydrogen, is widely used in the upgrading of biomass, petroleum, and other feedstocks into high-value chemicals and fuels. Additionally, hydrogenolysis plays a crucial role in the pharmaceutical and fine chemical industries for synthesizing complex molecular structures. However, traditional hydrogenolysis typically relies on heterogeneous catalysis under high temperature and pressure, which has limited selectivity. In recent years, homogeneous catalysis has emerged as a promising alternative, offering higher selectivity under milder conditions. Despite this, homogeneous hydrogenolysis of carbon-halogen (C-X) bonds, particularly tritiation and deuteration, remains an unresolved challenge. Tritiation is especially important in drug development as it provides critical insights into the pharmacokinetics of drugs and their metabolites. However, existing tritiation methods are primarily limited to aromatic systems or positions adjacent to heteroatoms, with extremely limited development for the more abundant and accessible alkyl chlorides.

Therefore, this study aims to develop a bioinspired cooperative catalytic strategy, leveraging the synergistic interplay of carbon-halogen bond activation and hydrogenation, to achieve selective hydrogenolysis of unactivated organohalides. This approach not only enables efficient deuteration and tritiation but also allows precise site-selectivity in drug molecules.

Source of the Paper

This paper was co-authored by Beibei Zhang, Zhenyang Zhang, Yang Wang, and Da Zhao, affiliated with the School of Chemical Sciences, University of Chinese Academy of Sciences and the Binzhou Institute of Technology. The paper was published in April 2025 in the journal Nature Synthesis, titled Late-stage deuteration and tritiation through bioinspired cooperative hydrogenolysis.

Research Process

1. Research Design and Catalyst Development

The research team drew inspiration from biological systems, particularly the synergistic action of hydrogenases and reductive dehalogenases. Hydrogenases are responsible for splitting molecular hydrogen into protons and electrons, while the electrons are subsequently transferred to reductive dehalogenases, facilitating the removal of halogen atoms from organohalides. Based on this mechanism, the team designed a homogeneous catalytic system combining vitamin B12 (cobalamin) catalysis and hydrogen-splitting catalysis.

2. Catalyst Optimization and Photoinduced Reactions

The team discovered that vitamin B12 catalysts could generate highly reactive Co(I) species through a photoinduced ligand-to-metal charge transfer (LMCT) process. This species could undergo SN2 reactions with alkyl halides to form Co(III)-alkyl complexes, which subsequently release alkyl radicals upon photolysis. Meanwhile, hydrogen-splitting catalysts (e.g., Wilkinson’s catalyst) undergo oxidative addition with tritium gas to form metal ditritides, serving as the source of tritium. Due to the weaker metal-hydrogen bonds compared to C-H bonds, the two catalytic cycles rapidly converge through tritium atom transfer (TAT) to generate tritiated products.

3. Reaction Validation and Substrate Expansion

The team validated the effectiveness of this catalytic system through a series of experiments. First, they used UV-Vis spectroscopy to study the photoinduced LMCT process, confirming the generation of Co(I) species. Subsequently, they demonstrated the catalytic performance of the system through deuteration reactions, achieving a 99% yield of deuterated methane. Furthermore, the team expanded the substrate scope, verifying the system’s applicability to various alkyl halides, including primary, secondary, and tertiary halides, as well as substrates containing amides, aromatic heterocycles, boronic esters, thioethers, and other functional groups.

4. Implementation of Tritiation Reactions

Building on the success of deuteration, the team further applied the system to tritiation reactions. On a micromolar scale, using subatmospheric pressure of tritium gas, they successfully achieved tritiation of various drug molecules, obtaining products with high isotopic purity. Compared to traditional heterogeneous catalysis, this method significantly reduced isotopic scrambling and improved the molar activity of tritiated products.

Key Results

  1. Generation of Co(I) Species and Catalytic Cycle: Through the photoinduced LMCT process, the team successfully generated highly reactive Co(I) species and confirmed their critical role in carbon-halogen bond activation.
  2. Efficiency of Deuteration Reactions: The team achieved efficient deuteration of various alkyl halides, with high yields and isotopic purity of deuterated products.
  3. Implementation of Tritiation Reactions: On a micromolar scale, the team successfully tritiated various drug molecules, obtaining products with high isotopic purity.
  4. Substrate Expansion and Functional Group Compatibility: The system demonstrated excellent compatibility with various alkyl halides, including those containing amides, aromatic heterocycles, boronic esters, thioethers, and other functional groups.

Conclusions and Significance

This study successfully developed a homogeneous hydrogenolysis platform through a bioinspired cooperative catalytic strategy, enabling efficient deuteration and tritiation. This method not only addresses the long-standing challenge of homogeneous hydrogenolysis of carbon-halogen bonds but also provides a new pathway for isotope labeling of drug molecules. Additionally, the study introduces a novel catalyst activation mode, enriching the toolbox of vitamin B12 catalysis and offering new insights into the conversion of organohalides into high-value products.

Research Highlights

  1. Bioinspired Cooperative Catalytic Strategy: By mimicking the synergistic action of hydrogenases and reductive dehalogenases in biological systems, the team developed an efficient homogeneous hydrogenolysis platform.
  2. Efficient Deuteration and Tritiation Reactions: The system enables efficient deuteration and tritiation under mild conditions, yielding products with high isotopic purity.
  3. Broad Substrate Compatibility: The system exhibits excellent compatibility with various alkyl halides, including those with complex functional groups.
  4. Novel Catalyst Activation Mode: The generation of Co(I) species through photoinduced LMCT introduces a new catalyst activation mode, providing new directions for the advancement of vitamin B12 catalysis.

Additional Valuable Information

Through detailed mechanistic studies and experimental validation, the team further elucidated the kinetics and thermodynamics of the catalytic process, providing a theoretical foundation for the optimization and application of the system. Additionally, the team explored the potential applications of this system in drug development, particularly in isotope labeling and pharmacokinetic studies.

This study not only offers a new solution for homogeneous hydrogenolysis of carbon-halogen bonds but also makes significant contributions to isotope labeling of drug molecules and the advancement of catalytic chemistry.