Catalytic Hydrogen Isotope Exchange Research Articles

Theoretical and experimental constraints on hydrogen isotope equilibrium in C1-C5 alkanes

Stable isotope ratios of C1–C5 alkanes, the major constituents of subsurface gaseous hydrocarbons, can provide valuable insights on their origins, transport, and fates. Equilibrium isotope effects are fundamental to interpreting stable isotope signatures, as recognition of them in natural materials indicates reversible processes and constrains the temperatures of equilibrated systems. Hydrogen isotope equilibrium of C1–C5 alkanes is of particular interest because evidence shows that alkyl H can undergo isotopic exchange with coexisting compounds under subsurface conditions. We present the results of a combined experimental and theoretical effort to determine equilibrium hydrogen isotope distributions in mixtures of these hydrocarbon compounds. We created two mixtures: one with C1, C2 and C3 (where C1 indicates methane, C2 ethane, etc., hereinafter called ‘C1–C3 mixture’) and another one with C2, C3, iC4, nC4, iC5 and nC5 (hereinafter called ‘C2–C5 mixture’); in both cases, the mixtures were created to start out of hydrogen isotope equilibrium. We tested the performance of several metal catalysts as aids to H isotopic exchange by exposing these mixtures to different metal catalysts at 100 or 200 °C and analyzing the compound-specific hydrogen isotope ratios of the product gases. The C1–C3 mixture exchanged hydrogen isotopes among the starting gas components rapidly in the presence of Ru/Al2O3 at 200 °C. The isotope ratios reach a steady-state (presumably equilibrium) after 72 h of heating (up to 120 h). The hydrogen isotopic ratios of alkanes in the C2–C5 mixture shifted significantly in the presence of Rh/Al2O3 at 100 °C and C3-C5 compounds approached steady state after 70 h, whereas C2 had not yet reached a steady state D/H ratio after 216 h of heating. We evaluated the reaction progress of isotope exchange for each compound as a function of time with a reaction-network model informed by constraints on chemical kinetics. The model indicates that C3, iC4, nC4, iC5 and nC5 in the C2-C5 mixture reached internal isotope equilibrium after 70 h, hence we used their values to calculate experimental equilibrium results. We also calculated equilibrium isotope fractionations with the Bigeleisen-Mayer theorem using vibrational frequencies computed from the density functional theory (B3LYP/aug-cc-pVTZ). We included torsional conformers and explicit H positions in the calculations. We found that the experimental results from both the 200 ˚C C1–C3 experiment and 100 ˚C C2–C5 experiment are consistent with theoretical equilibrium results within experimental uncertainty. Additionally, our reaction-network model for catalyzed hydrogen isotope exchange between alkanes succeeded in fitting our experimental results. This modeling framework can be adjusted to simulate exchange in natural settings for constraining temperature histories and sources of natural gases.

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.

Development of Sterically Hindered and Basic Sodium Amides for Catalytic Hydrogen Isotope Exchange

AbstractSodium amides are gaining momentum in synthetic chemistry, emerging not only as more sustainable alternatives to lithium amides but also as superior reagents in synthesis and catalysis. Despite recent advances in sodium organometallics, the information available about the constitution of these reagents is very limited. Advancing the understanding on structure/reactivity correlations in sodium amide chemistry, here, we report the synthesis and characterisation of four new sodium amides, with different sterically demanding substituents (adamantyl/trimethylsilyl and dicyclohexyl groups at the nitrogen atom) and different polyamine donors as well as investigate their ability to promote catalytic hydrogen isotope exchange using deuterated benzene as deuterium source. These studies have revealed that sodium dicyclohexylamide in combination with PMDETA (N,N,N’,N’’,N’’‐pentamethyldiethylentriamine) offers only slightly lower deuterium incorporation for non‐activated arenes than sodium 2,2,6,6‐tetramethylpiperidide, which is significantly more expensive and less available.

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.

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.

Significantly improved radiochemical yields in gaseous tritium reactions by iridium(i)-catalyzed hydrogen isotope exchange

Hydrogen isotope exchange reactions with iridium(i) catalyst [(COD)Ir(IMes)(PPh3)]X 2 with significantly increased (up to 7 fold) radiochemical yields (RCY) in tritium gas reactions are reported.

Catalytic Hydrogen Isotope Exchange Reactions in Late-Stage Functionalization

AbstractThe introduction of deuterium and tritium into molecules is of great importance in drug discovery. Many attempts have been made to develop late-stage hydrogen isotope exchange (HIE) reactions to avoid multistep syntheses using commercially available labeled precursors. In this review, we summarize recent progress in catalytic HIE reactions, with our main focus on their applications in the late-stage labeling of bioactive complex molecules and pharmaceuticals1 Introduction2 Non-Transition-Metal-Catalyzed Hydrogen Isotope Exchange2.1 Organocatalysis2.2 Photoredox Catalysis3 Transition-Metal-Catalyzed Hydrogen Isotope Exchang3.1 Palladium3.2 Ruthenium3.3 Iridium3.4 Other Metals4 Summary

Synthesis of [3 H] and [14 C]genipin.

[3 H]Genipin was synthesized in a single step by Ir(I) catalyzed hydrogen isotope exchange. Conditions for selective exchange of the sp2 CH bond ortho to the methyl ester functionality were developed through deuterium modeling studies through a catalyst screen. Optimized conditions so obtained were then utilized with tritium gas to generate [3 H]genipin at a specific activity of 18.5 Ci/mmol. Racemic [14 C]genipin was prepared in eight steps in overall 5.4% radiochemical yield from potassium [14 C]cyanide.

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

AbstractAn 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.

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.

Ruthenium(II)‐Catalyzed Hydrogen Isotope Exchange of Pharmaceutical Drugs by C−H Deuteration and C−H Tritiation

AbstractWell‐defined ruthenium(II) biscarboxylate complexes enabled selective ortho‐deuteration with weakly‐coordinating, synthetically useful carboxylic acid with outstanding levels of isotopic labeling. The robust nature of the catalytic system was reflected by a broad functional group tolerance in an operationally‐simple manner, allowing the isotope labeling of challenging pharmaceuticals and bioactive heterocyclic motifs. The synthetic power of our method was highlighted by the selective tritium‐labeling of repaglinide, an antidiabetic drug, providing access to defined tritium labeled therapeutics.

Synthesis, Structure, and Hydrogenolysis of Pyridine Dicarbene Iron Dialkyl Complexes.

Two methods for the synthesis of bis(imidazol-2-ylidene)pyridine iron dialkyl complexes, (CNC)Fe(CH2SiMe3)2, have been developed. The first route consists of addition of two equivalents of LiCH2SiMe3 to the iron dihalide complex, (CNC)FeBr2, while the second relies on addition of the free CNC ligand to readily-prepared (py)2Fe(CH2SiMe3)2 (py = pyridine). With aryl-substituted CNC ligands, octahedral complexes of the type ( Ar CNC)Fe(CH2SiMe3)2(N2) ( Ar CNC = bis(arylimidazol-2-ylidene)pyridine) were isolated, where the dinitrogen ligand occupies the site trans to the pyridine of the CNC-chelate. In contrast, the alkyl-substituted variant, (tBuACNC)Fe(CH2SiMe3)2 (tBuACNC = 2,6-(tBu-imidazol-2-ylidene)2pyridine) was isolated as the five-coordinate compound lacking dinitrogen. Exposure of the ( Ar CNC)Fe(CH2SiMe3)2(N2) derivatives to an H2 atmosphere resulted in formation of the corresponding iron hydride complexes ( Ar CNC)FeH4. These compounds catalyzed hydrogen isotope exchange between the deuterated benzene solvent and H2, generating isotopologues and isotopomers of ( Ar CNC)Fe(H n )(D4-n ) (n = 0-4). When (3,5-Me2 MesCNC)Fe(CH2SiMe3)2(N2) (3,5-Me2 MesCNC = 2,6-(2,4,6-Me3-C6H2-imidazol-2-ylidene)2-3,5-Me2-pyridine) was treated successively with H2 and then N2, the corresponding reduced dinitrogen complex (3,5-Me2 MesCNC)Fe(N2)2 was isolated. The same product was also obtained following addition of pinacolborane to (3,5-Me2 MesCNC)Fe(CH2SiMe3)2(N2).

Solid state catalytic hydrogen exchange for deuterium in cycloprolylglycine

The reaction of spillover hydrogen (SH) with cyclopropylglycine (cPG) in high-temperature solid-state catalytic hydrogen isotope exchange (HTCIE) has been studied experimentally and using density functional theory (DFT). NMR spectroscopy and mass spectrometry have shown a high regioselectivity and stereoselectivity for the reaction of spillover hydrogen with cPG fragments. The Gly fragment has been shown to be the most reactive in HTCIE, for which high stereoselectivity of substitution of hydrogen by deuterium has been demonstrated.

Solid-State Catalytic Isotope Exchange of Hydrogen for Deuterium in Cyclopropylglycine

The reaction of spillover hydrogen (SH) with cyclopropylglycine (cPG) in high-temperature solid-state catalytic hydrogen isotope exchange (HTCIE) has been studied experimentally and using density functional theory (DFT). NMR spectroscopy and mass spectrometry have shown a high regioselectivity and stereoselectivity for the reaction of spillover hydrogen with cPG fragments. The Gly fragment has been shown to be the most reactive in HTCIE, for which high stereoselectivity of substitution of hydrogen by deuterium has been demonstrated.

Synthesis of Iron Hydride Complexes Relevant to Hydrogen Isotope Exchange in Pharmaceuticals

Addition of H2 gas to the bis(arylimidazolin-2-ylidene)pyridine iron bis(dinitrogen) complex (H4-iPrCNC)Fe(N2)2 resulted in facile oxidative addition of the H–H bond to yield a mixture of (H4-iPrCNC)FeH4 and trans-(H4-iPrCNC)FeH2(N2), depending on the partial pressures of H2 and N2. Both iron hydride complexes were characterized by X-ray diffraction and proved relevant to the catalytic hydrogen isotope exchange of arene C(sp2)–H bonds. Activation of the benzene-d6 solvent at ambient temperature produced deuterated isotologues of both compounds that exhibit large isotopic perturbation of resonances in the hydride signals.

Inside Cover: The Synthesis of Highly Active Iridium(I) Complexes and their Application in Catalytic Hydrogen Isotope Exchange (Adv. Synth. Catal. 17/2014)

The inside cover picture, by Kerr and co-workers depicts a series of robust, yet highly active Ir(I) complexes bearing specifically encumbered N-heterocyclic carbene and phosphine ligands. These complexes are extremely effective in hydrogen isotope exchange processes (with D or T), with low catalyst loadings, good levels of selectivity, and broad directing group applicability. The labelling of several complex drug molecules further highlights the catalysts’ utility. Mechanistic insight into the operation of these catalysts has also been provided by a combination of NMR and theoretical DFT studies.

The Synthesis of Highly Active Iridium(I) Complexes and their Application in Catalytic Hydrogen Isotope Exchange

AbstractA series of robust iridium(I) complexes bearing a sterically encumbered N‐heterocyclic carbene ligand, alongside a phosphine ligand, has been synthesised and investigated in hydrogen isotope exchange processes. These complexes have allowed isotope incorporation over a range of substrates with the use of practically convenient deuterium and tritium gas. Moreover, these active catalysts are capable of isotope incorporation to particularly high levels, whilst employing low catalyst loadings and in short reaction times. In addition to this, these new catalyst species have shown flexible levels of chemoselectivity, which can be altered by simple manipulation of preparative approaches. Furthermore, a number of industrially‐relevant drug molecules has also been labelled, including the sulfonamide containing drug, Celecoxib. Alongside detailed NMR experiments, initial mechanistic investigations have also been performed, providing insight into both substrate binding energies, and, more importantly, relative energies of key steps in the mechanistic cycle as part of the overall exchange process.magnified image

ChemInform Abstract: Highly Active Iridium(I) Complexes for Catalytic Hydrogen Isotope Exchange.

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Highly active iridium(i) complexes for catalytic hydrogen isotope exchange

Practically convenient methods have been developed for the preparation of new iridium complexes, possessing bulky N-heterocyclic carbene and phosphine ligands; these routinely handled complexes are highly active catalysts within directed hydrogen isotope exchange processes.

Application of 1‐butyl‐3‐methylimidazolium hexafluorophosphate to Ir(I)‐catalyzed hydrogen isotope exchange labelling of substrates poorly soluble in dichloromethane

AbstractSubstrate solubility remains a major limitation in Ir(I)‐catalyzed isotopic hydrogen exchange labelling. In the search for an alternative to the solvent dichloromethane, which is critical to the success of the reaction, we examined a series of ionic liquids for their suitability. Commercially available 1‐butyl‐3‐methylimidazolium hexafluorophosphate (abbreviated to [BMI][PF6]) was found to support efficient deuterium and tritium exchange labelling of N‐(4‐methoxyphenyl)‐N‐methyl benzamide 1 under standard conditions. The solvent dissolves both polar hydroxyl and carboxylic acid substituted acetanilides, providing isotopomers in unprecedentedly high deuterium incorporation as compared to dichloromethane. We report the application of [BMI][PF6] and its potential for extending the scope of Ir(I)‐catalyzed H/T exchange to more polar compounds. Copyright © 2003 John Wiley & Sons, Ltd.