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.     

Intramolecular hydrogen bonding of novel o-hydroxythioacetophenones and related compounds evaluated by deuterium isotope effects on 13C chemical shifts

A new class of compounds, the 2-hydroxythioacetophenones, and related compounds have recently been synthesized. The hydrogen-bond system has been characterized by NMR chemical shifts and deuterium isotope effects on these as well as by DFT calculations. Use of solid-state (13)C NMR has enabled measurements of the intrinsic deuterium isotope effects of the most abundant tautomer of beta-thioxoketones. The compounds show very interesting long-range deuterium isotope effects on the thiocarbonyl carbon. The intramolecular hydrogen bonds of o-hydroxythioacetophenones are found to be slightly stronger than those of the corresponding acetophenones. The reactivity and stability of the compounds can be related to hydrogen bonding and to the presence of electron donating substituents.     

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.     

Deuterium isotope effects on 13C NMR chemical shifts of some α-(2-hydroxyaryl)-N-phenylnitrones (Schiff base N-oxides)

The deuterium isotope effect on the ¹³C NMR chemical shifts of some α-2-hydroxyaryl-N-phenylnitrones (Schiff base N-oxides) was studied. The existence of an intramolecular hydrogen bond with the proton localized on the phenolic oxygen atom was evidenced. Exceptionally large isotope effects ΔC-2(D) and ΔC-α(D) suggest that the substitution of the proton of the OH group by deuterium leads to a weakening of the hydrogen bond and some conformational changes in the molecule. This conclusion was drawn on the basis of a comparison of the deuterium isotope effects of Schiff base N-oxides and parent Schiff bases. Copyright © 2001 John Wiley & Sons, Ltd.     

Secondary isotope effects in liquid chromatography behaviour of 2H and 3H labelled solutes and solvents

The separation of solutes that differ only in the extent of isotopic substitution of their hydrogen atoms, using either mixtures of isotopically non-modified or perdeuterated solvents as mobile phases, is described. The occurrence of a secondary isotope effect is demonstrated in reversed-phase liquid chromatography, which is independent of the nature of the stationary phase (different octadecyl-bonded silicas, an embedded alkylamide-bonded silica, as well as one polymeric stationary phase were tested), and the water content and the nature of organic modifier of the mobile phase. The separation of 24 structurally different isotopologue pairs (apolar compounds and polar compounds with exchangeable or non-exchangeable hydrogen atoms) is examined using reversed-phase liquid chromatography. It is found that the greater the number of isotopically substituted hydrogen atoms in a given organic solute, the better is the separation of a particular isotopologue pair. The single secondary isotope effect is shown to be dependent on the number of isotopic substitutions. The greater the number of these substitutions, the smaller is the single isotope effect. The single secondary isotope effect is higher for aromatic hydrocarbons than for aliphatic hydrocarbons. A secondary isotope effect is also observed in chiral chromatography and normal-phase liquid chromatography, as well as on changing the nature of the substituting isotope, i.e.: tritium instead of deuterium. Thus, we have demonstrated that the total secondary isotopic effect for hydrogen/tritium is higher than for hydrogen/deuterium. This isotope effect involves only the consequences of changes in interactions due to nuclear motions. Overall this study confirms the predominance of hydrophobic effects in retention processes in reversed-phase liquid chromatography. In reversed-phase liquid chromatography, a secondary isotope effect related to mobile phase composition is also observed. The behaviour of deuterium oxide and water in mobile phases of the same composition (%, w/w) is compared. Independent of the nature of the organic modifier (methanol, acetonitrile or ethanol), the effect of replacing H2O with 2H2O in the mobile phase, is an increase in the retention factors and an improvement in the chromatographic resolution of isotopologue pairs. This increase in the resolution is not accompanied by a change in the chromatographic selectivity. The measurement of liquid-liquid extraction coefficients proves that the effect is mainly due to the modification of the phase ratio. In general the effect of 2H-labelled solvents (2H2O and C2H3CN) as mobile phase components, compared to their isotopically non-modified isomers, can be rationalized on the basis of their lower polarisabilities. Overall the use of perdeuterated rather than isotopically non-modified solvents as mobile phase components leads to the most efficient separation systems.     

Geometric H/D isotope effects and cooperativity of the hydrogen bonds in porphycene.

We investigate the primary, secondary, and vicinal hydrogen/deuterium (H/D) isotope effects on the geometry of the two intramolecular hydrogen bonds in porphycene. Multidimensional potential energy surfaces describing the anharmonic motion in the vicinity of the trans isomer are calculated for the different symmetric (HH/DD) and asymmetric (HD) isotopomers. From the solution of the nuclear Schr?dinger equation the ground-state wavefunction is obtained, which is further used to determine the quantum corrections to the classical equilibrium geometries of the hydrogen bonds and thus the geometric isotope effects. In particular, it is found that the hydrogen bonds are cooperative, that is, both expand simultaneously even in the case of an asymmetric isotopic substitution. The theoretical predictions compare favorably with NMR chemical-shift data.     

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.     

On the models for deuterium long-range isotope effects in13C NMR spectroscopy

The long-range deuterium isotope effects on¹³C nuclear shielding are physically not yet completely understood. Two existing models for explaining these effects, vibrational and substituent, are compared here. The vibrational model is based on the Born-Oppenheimer approximation, but it can explain only one-bond deuterium effects. To the contrary, the substituent model may explain many long-range isotope effects, but it is controversial due to the assumption of some distinct electronic properties of isotopes. We explain how long-range deuterium isotope effects may be rationalized by the subtle electronic changes induced by isotope substitution, which does not violate the Born-Oppenheimer approximation.     

Hydrogen Isotope Exchange by Homogeneous Iridium Catalysis in Aqueous Buffers with Deuterium or Tritium Gas

We have studied the highly selective homogeneous iridium-catalyzed hydrogen isotope exchange (HIE) with deuterium or tritium gas as an isotope source in water and buffers. With an improved water-soluble Kerr-type catalyst, we have achieved the first insight into applying HIE reactions in aqueous media with varying pH. Density functional theory (DFT) calculations gave consistent insights in the calculated energies of transition states and coordination complexes, further explaining the observed reactivity and guidance on the scope and limitations for HIE reactions in water. Finally, we successfully adapted these findings to tritium chemistry.     

NMR parameters and geometries of OHN and ODN hydrogen bonds of pyridine-acid complexes

In this paper, equations are proposed which relate various NMR parameters of OHN hydrogen-bonded pyridine-acid complexes to their bond valences which are in turn correlated with their hydrogen-bond geometries. As the valence bond model is strictly valid only for weak hydrogen bonds appropriate empirical correction factors are proposed which take into account anharmonic zero-point energy vibrations. The correction factors are different for OHN and ODN hydrogen bonds and depend on whether a double or a single well potential is realized in the strong hydrogen-bond regime. One correction factor was determined from the known experimental structure of a very strong OHN hydrogen bond between pentachlorophenol and 4-methylpyridine, determined by the neutron diffraction method. The remaining correction factors which allow one also to describe H/D isotope effects on the NMR parameters and geometries of OHN hydrogen bond were determined by analysing the NMR parameters of the series of protonated and deuterated pyridine- and collidine-acid complexes. The method may be used in the future to establish hydrogen-bond geometries in biologically relevant functional OHN hydrogen bonds.     

Factor analysis of deuterium isotope effects on 13C NMR chemical shifts in Schiff bases

We have analyzed deuterium isotope effects on (13)C chemical shifts in a series of o-hydroxy Schiff bases by applying factor analysis. Two orthogonal factors were obtained that explain about 80 and 10 % of the variance of the data. The numerical values of these factors can be related to 1H NMR chemical shifts of the proton involved in the intramolecular bonds delta(XH) (X = O or N). Such a relation allows one to identify clusters of compounds with different tautomeric forms of hydrogen bonding. Application of a similar approach to solution 13C NMR chemical shifts produces three important factors, which have a different structure to factors describing isotope effects. This illustrates well the different nature of chemical shifts and isotope effects. The three factors explain about 54, 15, and 13 % of variance. They can be rationalized and are strongly related to the electronic properties and location of substituents.     

In situ Generated Iridium Nanoparticles as Hydride Donors in Photoredox-Catalyzed Hydrogen Isotope Exchange Reactions with Deuterium and Tritium Gas

We have studied the photoredox-catalyzed hydrogen isotope exchange (HIE) reaction with deuterium or tritium gas as isotope sources and in situ formed transition metal nanoparticles as hydrogen atom transfer pre-catalysts. By this means we have found synergistic reactivities applying two different HIE mechanisms, namely photoredox-catalyzed and CH-functionalization HIE leading to the synthesis of highly deuterated complex molecules. Finally, we adopted these findings successfully to tritium chemistry.     

Isomeric Effect on H/D Exchange of Resveratrol Studied by NMR Spectroscopy

Resveratrol (3,5,4′‐trihydroxylstilbene), a phytoalexin in response to injury or fungal attack, is found in grapes and other food products. It has been well documented that the compound has beneficial effects as hypolipidemic, anticancer, antiviral, neuroprotective, antiaging, and anti‐inflammatory natural active principle. It was observed that both trans‐ and cis‐resveratrols undergo hydrogen‐deuterium (H/D) exchange at H‐2,6 and H‐4 positions of the A‐ring. The exchange rates were determined by ¹H NMR spectroscopy. The results reveal that the exchange rates are configuration and pH dependent. Derivative of 2‐O‐β‐D‐glucoside can significantly speed up the H/D exchange reactions for both isomers. The trans‐resveratrol experiences faster H/D exchanging than the cis‐resveratrol. Such isomeric effect is possibly due to the factor that the trans‐resveratrol is in favor of forming larger/super conjugative system and has less spatial interference. Theoretical calculation shows that electronegativity at these positions is in the order of H‐2,6>H‐4, which is in consistent with the exchange rates observed by NMR. The results may be of help in understanding the properties of resveratrol, and in analysis of resveratrol in natural products or body fluids using mass spectroscopy that occasionally requires stable deuterium isotope labeling.     

Ab initio EOM-CCSD spin-spin coupling constants for hydrogen-bonded formamide complexes: bridging complexes with NH3, (NH3)2, H2O, (H2O)2, FH, and (FH)2

EOM-CCSD spin-spin coupling constants across hydrogen bonds have been computed for complexes in which NH3, H2O, and FH molecules and their hydrogen-bonded dimers form bridging complexes in the amide region of formamide. The formamide one-bond N-H coupling constant [(1)J(N-H)] across N-H...X hydrogen bonds increases in absolute value upon complexation. The signs of the one-bond coupling constants (1h)J(H-X) indicate that these complexes are stabilized by traditional hydrogen bonds. The two-bond coupling constants for hydrogen bonds with N-H as the donor [(2h)J(N-X)] and the carbonyl oxygen as the acceptor [(2h)J(X-O)] increase in absolute value in the formamide/dimer relative to the corresponding formamide/monomer complex as the hydrogen bonds acquire increased proton-shared character. The largest changes in coupling constants are found for complexes of formamide with FH and (FH)2, suggesting that bridging FH monomers and dimers in particular could be useful NMR spectroscopic probes of amide hydrogen bonding.     

1H NMR isotope shifts arising from the substitution of 12C by 13C: application to polycyclic aromatic hydrocarbon anions

Isotope shifts are a well-established tool for structural analysis by NMR. The substitution of a protium with a deuterium is the most widely studied of these effects. However, such studies call for specific deuteration that requires complex synthetic techniques owing to the low natural abundance of deuterium. ¹³C occurs at a higher natural abundance and couples strongly with its attached proton. We have developed and refined a method to reliably observe these much smaller shifts without needing to resort to chemical synthesis. We show that carbon induced isotope shifts reflect structural features. Copyright © 2001 John Wiley & Sons, Ltd.     

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.     

Kinetic isotope effect evidence for a concerted hydrogen transfer mechanism in transfer hydrogenations catalyzed by [p-(Me2CH)C6H4Me]Ru- (NHCHPhCHPhNSO2C6H4-p-CH3)

The isotope effects in the reaction of [p-(Me2CH)C6H4Me]Ru(NHCHPhCHPhNSO2C6H4-p-CH3) (1) with isopropyl alcohol were 1.79 for transfer of hydrogen from OH to N and 2.86 for transfer from CH to Ru. The isotope effect for transfer of deuterium from doubly labeled material (kCHOH/kCDOD = 4.88) was within experimental error of the product of the two individual isotope effects. These isotope effects provide convincing evidence for a mechanism involving concurrent transfer of hydrogen from oxygen to nitrogen and from carbon to ruthenium.     

Hydrogen bonds in ionic liquids revisited: (35/37)Cl NMR studies of deuterium isotope effects in 1-n-butyl-3-methylimidazolium chloride

Detailed knowledge of the structure, dynamics, and interionic interactions of ionic liquids (ILs) is critical to understand their physicochemical properties. In this letter, we show that deuterium isotope effects on the chloride ion 35/37Cl NMR signal represent a useful tool in the study of interionic hydrogen bonds in imidazolium chloride ILs. Sizable Delta35/37Cl(H,D) values obtained for the model system 1-n-butyl-3-methylimidazolium chloride ([C4mim]Cl) upon deuteriation of the imidazolium C-2 and C-2,4,5 positions, of nearly 1 and 2 ppm, respectively, show that the approach can readily identify and differentiate Cl...H hydrogen bonds between the anion and cation. Our study is one of a few examples in which hydrogen-bonding in ILs has been investigated using deuterium isotope effects and, to our knowledge, the only one employing 35/37Cl NMR to detect these interactions. The methodology described could be easily extended to the study of other systems bearing NMR-active nuclei.     

Tautomerism of sterically hindered schiff bases. Deuterium isotope effects on 13C chemical shifts

A series of sterically hindered o-hydroxy Schiff bases derived from o-hydroxyaceto- and benzophenones with very short intramolecular hydrogen bonds were described qualitative and quantitatively by deuterium isotope effects on (13)C chemical shift, (n)DeltaC(XD), (n)DeltaF(XD), (1)J(N,H) coupling constants, deltaNCH(3) chemical shifts and UV spectra. All the investigated compounds are found to be tautomeric. The tautomeric character is described by the signs of the deuterium isotope effects on the (13)C chemical shifts. For the 3-nitro-5-chloro derivatives at low temperature, the equilibrium is shifted almost fully toward the proton transferred form in CD(2)Cl(2). Intrinsic deuterium isotope effects on chemical shifts of these compounds as well as (1)J(N,H) coupling constants suggest that a zwitterionic resonance form is dominant for the proton transferred form. Structures, (1)H, (19)F, and (13)C chemical shifts, and deuterium isotope effects on (13)C chemical shifts are calculated by ab initio methods. The potential energy functions and the total deuterium isotope effects are calculated, and they are shown to correspond well with the experimental findings.     

H/D Isotope Substitution Effect on the Structural and Thermodynamic Parameters of Intermolecular Interaction in Methanol at 278-318 K

The effect of H/D isotope substitution in methanol molecules on the geometrical parameters of the latter and the energetics of particle interactions is discussed in terms of scale particle theory and a model using internal pressure as a measure of nonspecific interactions in liquids. Deuteration leads to reduced space occupied by a molecule in the structural matrix of methanol. It is established that isotopic substitution differentiates the distribution of specific and van der Waals interactions. The former are strengthened and the latter weakened when protium is substituted by deuterium in a group forming hydrogen bonds, and the case is opposite when deuterium is replaced in the methyl radical of methanol.