Hydrogen Isotope Exchange Catalyzed by Ru Nanocatalysts: Labelling of Complex Molecules Containing N-Heterocycles and Reaction Mechanism Insights

Ruthenium nanocatalysis can provide effective deuteration and tritiation of oxazole, imidazole, triazole and carbazole substructures in complex molecules using D₂ or T₂ gas as isotopic sources. Depending on the substructure considered, this approach does not only represent a significant step forward in practice, with notably higher isotope uptakes, a broader substrate scope and a higher solvent applicability compared to existing procedures, but also the unique way to label important heterocycles using hydrogen isotope exchange. In terms of applications, the high incorporation of deuterium atoms, allows the synthesis of internal standards for LC-MS quantification. Moreover, the efficacy of the catalyst permits, even under subatmospheric pressure of T₂ gas, the preparation of complex radiolabeled drugs owning high molar activities. From a fundamental point of view, a detailed DFT-based mechanistic study identifying undisclosed key intermediates, allowed a deeper understanding of C−H (and N−H) activation processes occurring at the surface of metallic nanoclusters.     

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.     

Photoredox-Mediated Hydrogen Isotope Exchange Reactions of Amino-Acids,Peptides, and Peptide-Derived Drugs

Hydrogen isotopically labelled compounds are essential diagnostic tools in drug research and development, as they provide vital information about the biological metabolism of drug candidates and their metabolites. Herein we report a photoredox-initiated hydrogen atom transfer (HAT) protocol which efficiently and selectively introduces deuterium or tritium at C(sp³)−H bonds, utilizing heavy water (D₂O or T₂O) as the hydrogen isotope source, and a guanidine base. This protocol has been successfully applied to the incorporation of deuterium in several amino acids (lysine, glycine and proline) and small peptides. Finally, the method has been applied to tritium, because tritium-labelled peptides are essential for application in biological experiments, such as ligand-binding assays, or absorption, distribution, metabolism, and excretion (ADME) studies.     

Large Isotope Effects in Organometallic Chemistry

The kinetic isotope effect (KIE) is key to understanding reaction mechanisms in many areas of chemistry and chemical biology, including organometallic chemistry. This ratio of rate constants, k_H/k_D, typically falls between 1–7. However, KIEs up to 105 have been reported, and can even be so large that reactivity with deuterium is unobserved. We collect here examples of large KIEs across organometallic chemistry, in catalytic and stoichiometric reactions, along with their mechanistic interpretations. Large KIEs occur in proton transfer reactions such as protonation of organometallic complexes and clusters, protonolysis of metal–carbon bonds, and dihydrogen reactivity. C−H activation reactions with large KIEs occur with late and early transition metals, photogenerated intermediates, and abstraction by metal-oxo complexes. We categorize the mechanistic interpretations of large KIEs into the following three types: (a) proton tunneling, (b) compound effects from multiple steps, and (c) semi-classical effects on a single step. This comprehensive collection of large KIEs in organometallics provides context for future mechanistic interpretation.     

Mild,Selective Ru-Catalyzed Deuteration Using D2O as a Deuterium Source

A method for the selective deuteration of polyfunctional organic molecules using catalytic amounts of [RuCl₂(PPh₃)₃] and D₂O as a deuterium source is presented. Through variation of additives like CuI, KOH, and various amounts of zinc powder, orthogonal chemoselectivities in the deuteration process are observed. Mechanistic investigation indicates the presence of different, defined Ru-complexes under the given specific conditions.     

Ruthenium-Catalyzed Deuteration of Aromatic Carbonyl Compounds with a Catalytic Transient Directing Group

A novel ruthenium-catalyzed C−H activation methodology for hydrogen isotope exchange of aromatic carbonyl compounds is presented. In the presence of catalytic amounts of specific amine additives, a transient directing group is formed in situ, which directs selective deuteration. A high degree of deuteration is achieved for α-carbonyl and aromatic ortho-positions. In addition, appropriate choice of conditions allows for exclusive labeling of the α-carbonyl position while a procedure for the preparation of merely ortho-deuterated compounds is also reported. This methodology proceeds with good functional group tolerance and can be also applied for deuteration of pharmaceutical drugs. Mechanistic studies reveal a kinetic isotope effect of 2.2, showing that the C−H activation is likely the rate-determining step of the catalytic cycle. Using deuterium oxide as a cheap and convenient source of deuterium, the methodology presents a cost-efficient alternative to state-of-the-art iridium-catalyzed procedures.     

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.     

Hydrogen-Deuterium Isotope Exchange of Methane via Non-redox Palladium Catalysis

Under mild conditions, Pd(II) catalysts coordinated to tridentate NHC-amidate-ether ligand successfully activated the carbon-hydrogen bond to facilitate the hydrogen/deuterium isotope exchange on methane. The structural features and catalytic behavior suggested an intriguing non-redox catalytic system derived from the amidate nitrogen. As the amidate nitrogen acts as an internal base, the metal center was able to maintain the oxidation state throughout the reaction. Accordingly, the catalytic system demonstrated its reactivity and stability during the H/D exchange on methane resulting in a high degree of deuterium conversions (44 %) and turnover number (346) under low temperature conditions.     

C−H Functionalization—Prediction of Selectivity in Iridium(I)‐Catalyzed Hydrogen Isotope Exchange Competition Reactions

An assessment of the C?H activation catalyst [(COD)Ir(IMes)(PPh₃)]PF₆ (COD=1,5‐cyclooctadiene, IMes=1,3‐bis(2,4,6‐trimethylphenyl)imidazol‐2‐ylidene) in the deuteration of phenyl rings containing different functional directing groups is divulged. Competition experiments have revealed a clear order of the directing groups in the hydrogen isotope exchange (HIE) with an iridium (I) catalyst. Through DFT calculations the iridium–substrate coordination complex has been identified to be the main trigger for reactivity and selectivity in the competition situation with two or more directing groups. We postulate that the competition concept found in this HIE reaction can be used to explain regioselectivities in other transition‐metal‐catalyzed functionalization reactions of complex drug‐type molecules as long as a C?H activation mechanism is involved.     

锆吸氘和氚的动力学同位素效应

应用反应速率分析方法,在高真空金属系统上测定了锆在恒容体系和450～630 ℃范围内吸收氘和氚的p-t曲线。由p-t曲线可知,在同一温度下,锆吸氚的速率低于锆吸氘的速率;而随着温度的升高,由于解吸逆反应的影响,锆吸氚(氘)的反应速率降低。根据p-t曲线计算了吸气反应在不同温度的速率常数,得到锆吸氘和氚的表观活化能分别为(-25.9±0.7)和(-16.8±0.8)kJ·mol^-1。从活化能数据可以看出     

NHC‐Stabilized Iridium Nanoparticles as Catalysts in Hydrogen Isotope Exchange Reactions of Anilines

The preparation of N‐heterocyclic carbene‐stabilized iridium nanoparticles and their application in hydrogen isotope exchange reactions is reported. These air‐stable and easy‐to‐handle iridium nanoparticles showed a unique catalytic activity, allowing selective and efficient hydrogen isotope incorporation on anilines using D₂ or T₂ as isotopic source. The usefulness of this transformation has been demonstrated by the deuterium and tritium labeling of diverse complex pharmaceuticals.     

Iridium(I)‐Catalyzed Regioselective CH Activation and Hydrogen‐Isotope Exchange of Non‐aromatic Unsaturated Functionality

Isotopic labelling is a key technology of increasing importance for the investigation of new C?H activation and functionalization techniques, as well as in the construction of labelled molecules for use within both organic synthesis and drug discovery. Herein, we report for the first time selective iridium‐catalyzed C?H activation and hydrogen‐isotope exchange at the β‐position of unsaturated organic compounds. The use of our highly active [Ir(cod)(IMes)(PPh₃)][PF₆] (cod=1,5‐cyclooctadiene) catalyst, under mild reaction conditions, allows the regioselective β‐activation and labelling of a range of α,β‐unsaturated compounds with differing steric and electronic properties. This new process delivers high levels of isotope incorporation over short reaction times by using low levels of catalyst loading.     

Small Molecule Activation with Intramolecular “Inverse” Frustrated Lewis Pairs

The intramolecular “inverse” frustrated Lewis pairs (FLPs) of general formula 1-BR₂-2-[(Me₂N)₂C=N]-C₆H₄ ( 3 – 6 ) [BR₂=BMes₂ ( 3 ), BC₁₂H₈, ( 4 ), BBN ( 5 ), BBNO ( 6 )] were synthesized and structurally characterized by multinuclear NMR spectroscopy and X-ray analysis. These novel types of pre-organized FLPs, featuring strongly basic guanidino units rigidly linked to weakly Lewis acidic boryl moieties via an ortho-phenylene linker, are capable of activating H−H, C−H, N−H, O−H, Si−H, B−H and C=O bonds. 4 and 5 deprotonated terminal alkynes and acetylene to form the zwitterionic borates 1-(RC≡C-BR₂)-2-[(Me₂N)₂C=NH]-C₆H₄ (R=Ph, H) and reacted with ammonia, BnNH₂ and pyrrolidine, to generate the FLP adducts 1-(R₂HN→BR₂)-2-[(Me₂N)₂C=NH]-C₆H₄, where the N-H functionality is activated by intramolecular H-bond interactions. In addition, 5 was found to rapidly add across the double bond of H₂CO, PhCHO and PhNCO to form cyclic zwitterionic guanidinium borates in excellent yields. Likewise, 5 is capable of cleaving H₂, HBPin and PhSiH₃ to form various amino boranes. Collectively, the results demonstrate that these new types of intramolecular FLPs featuring weakly Lewis acidic boryl and strongly basic guanidino moieties are as potent as conventional intramolecular FLPs with strongly Lewis acidic units in activating small molecules.     

C−H Functionalisation for Hydrogen Isotope Exchange

The various applications of hydrogen isotopes (deuterium, D, and tritium, T) in the physical and life sciences demand a range of methods for their installation in an array of molecular architectures. In this Review, we describe recent advances in synthetic C?H functionalisation for hydrogen isotope exchange.     

Palladium-Catalyzed Selective meta-C−H Deuteration of Arenes: Reaction Design and Applications

Deuterium-labeled compounds find wide applications in kinetic studies, and within the pharmaceutical industry. An easily removable pyrimidine-based auxiliary has been employed for the meta-C−H deuteration of arenes. The scope of this Pd-catalyzed deuteration using commercially available [D₁]- and [D₄]-acetic acid has been demonstrated by its application in phenylacetic acid and phenylmethanesulfonate derivatives. A detailed mechanistic study led us to explore the reversibility of the non-rate determining C−H activation step. The present study of meta-deuterium incorporation illustrates the template morphology in terms of selectivity. The applicability of this method has been demonstrated by the selective deuterium incorporation into various pharmaceuticals.     

Labelling Studies to Determine Product Formation from Reactions of CO and Hydrogen Catalysed by Ru Clusters and Rh Complexes

Reaction of CO with hydrogen in the presence of [Ru₃(CO)₁₂], KI and N-methylpyrrolidone produces small amounts of methanol under mild conditions. Using D₂ the methanol is CD₃OD confirming that it is a product of CO hydrogenation. In the presence of added H₂O, CH _x D_1-y OH/D (y=0–3) are produced. Carrying out the same reaction in the presence of MeI water and RhCl₃·xH₂O (x=3–4) produces ethanoic acid in a slow reaction which continues for at least 64 h. The effects of different reaction parameters are discussed and labelling using ¹³CH₃I shows that some of the ethanoic acid originates from sources other than MeI whilst labelling with D₂, CD₃I, and/or D₂O suggest that some originates from CO and H₂. Electrospray mass spectrometry and high pressure infra-red spectroscopic studies show that the main species present in catalytic solutions are [HRu₃(CO)₁₁]⁻, [HRu₄(CO)₁₃]⁻ and [Ru(CO)₃I₃]⁻ for methanol carbonylation, [Ru(CO)₃I₃]⁻ and [RhI₂(CO)₂]⁻ for ethanoic acid production. A reaction carried out in the absence of [Ru₃(CO)₁₂] gave similar results to a reaction in which it was added, suggesting that the entire process may be catalysed by rhodium complexes alone. Electronic Supplementary Material  Supplementary material for this article is available at and is accessible for authorized users.

Catalytic C−C/C−H Bond Activation Relay for Synthesis of Fluorescent Naphthoquinolizinium Salts

Herein, we report the design and synthesis of a series of novel cationic nitrogen-embedded polyaromatic hydrocarbons with a planar geometry. The synthetic pathway is based on catalytic C−C/C−H bond activation relay that enabled preparation of regioselectively 5,6,10,11-tetrasubstituted naphtho[2,1,8-ija]quinolizinium salts bearing various types of substituents. Single-crystal X-ray analyses of selected compounds confirmed planarity of the quinolizinium core. Most of the prepared compounds exhibited strong fluorescence (Φ_s up to >99 %) ranging from 420–600 nm depending on the substitution pattern. According to DFT calculations LUMO is always distributed over the quinolizinium framework regardless of the attached substituents, whereas delocalization of HOMO is related to the substitution pattern. Electrochemical measurements show irreversible reduction of all compounds, which is supported by the calculated location of LUMO orbitals.     

Nanopolyaniline Coupled with an Anticorrosive Graphene as a 3D Film Electrocatalyst for Efficient Oxidation of Toluene Methyl C−H Bonds and Hydrogen Production at Low Voltage

A graphene-wrapped polyaniline nanoparticles film embedded in carbon cloth (CC/PANI/G) was fabricated and used as a 3D anodic electrocatalyst for oxidation of toluene methyl C−H groups. The methyl C−H bonds can be oxidized effectively at the CC/PANI/G anode with 99.9 % toluene conversion at a low applied voltage of only 1.0 V, which implies low energy input. Importantly, 86.6 % of toluene methyl C−H groups were converted to benzoyl groups (C=O), and hydrogen was produced efficiently at the cathode. The electrocatalytic efficiency at the CC/PANI/G anode was higher at lower voltage (1.0 V) than at higher voltage (1.5 V), and more hydrogen was produced at the corresponding cathode. The synergistic effect between the dynamic redox chemistry of nanoPANI and the excellent conductivity and anticorrosive action of graphene determined the high electrocatalytic efficiency of the oxidation of toluene methyl C−H groups at the CC/PANI/G anode. Owing to the chemical bonding between graphene and PANI, the anticorrosive CC/PANI/G anodic electrocatalyst was durable and effective for oxidation of toluene methyl C−H groups in acidic environment. This approach provides advanced electrode materials for transforming stable chemical bonds (C−H) into useful functional groups (C=O), which will be beneficial for the synthesis of organic intermediates with coupled hydrogen production.