Deuterium Substitution Research Articles

Designing chemical systems for precision deuteration of medicinal building blocks.

Methods are lacking that can prepare deuterium-enriched building blocks, in the full range of deuterium substitution patterns at the isotopic purity levels demanded by pharmaceutical use. To that end, this work explores the regio- and stereoselective deuteration of tetrahydropyridine (THP), which is an attractive target for study due to the wide prevalence of piperidines in drugs. A series of d0-d8 tetrahydropyridine isotopomers were synthesized by the stepwise treatment of a tungsten-complexed pyridinium salt with H-/D- and H+/D+. The resulting decomplexed THP isotopomers and isotopologues were analyzed via molecular rotational resonance (MRR) spectroscopy, a highly sensitive technique that distinguishes isotopomers and isotopologues by their unique moments of inertia. In order to demonstrate the medicinal relevance of this approach, eight unique deuterated isotopologues of erythro-methylphenidate were also prepared.

SAL0114: a novel deuterated dextromethorphan-bupropion combination with improved antidepressant efficacy and safety profile.

Esketamine, the first Food and Drug Administration-approved fast-acting antidepressant, has limited use because of its addictive properties. Although the combination of dextromethorphan and bupropion partially addresses the limitations of esketamine, concerns remain regarding neurologic side effects related to dextromethorphan metabolites, and seizure risks associated with high-dose bupropion. SAL0114, a novel formulation combining deuterated dextromethorphan (in which hydrogen atoms are replaced with deuterium) with bupropion, seeks to enhance dextromethorphan stability through deuteration of its metabolic sites. This approach is expected to increase antidepressant efficacy, reduce metabolite-induced safety issues, and allow for lower bupropion dosages. Radioligand competition binding assays were used to evaluate the impact of deuterium substitution on the in vitro activity of dextromethorphan and its metabolite, dextrorphan. In vitro hepatic microsomal stability and in vivo mouse pharmacokinetic assays were performed to assess the effects of deuteration on dextromethorphan stability. Two mouse models of behavioral despair were used to determine the antidepressant and synergistic effects of deuterated dextromethorphan and bupropion. Additionally, a reserpine-induced hypothermia rat model and an ammonia-induced cough mouse model were used to assess the in vivo effects from a pathological perspective. Deuterated dextromethorphan maintained the same in vitro activity as dextromethorphan while exhibiting twice the metabolic stability both in vitro and in vivo. Combination with bupropion further improved its in vivo stability, increasing the exposure by 2.4 times. The combination demonstrated efficacy and synergistic effects in all tested animal models, showing superior efficacy compared with the dextromethorphan-bupropion combination. Deuteration improved dextromethorphan metabolic stability without altering its in vitro activity. Bupropion enhanced this stability and synergistically boosted the antidepressant effect by increasing deuterated dextromethorphan exposure in vivo. This enhanced metabolic stability suggests a reduction in dextromethorphan metabolites associated with clinical neurological side effects. Consequently, SAL0114 is hypothesized to offer improved efficacy and safety compared with the non-deuterated combination, potentially allowing for lower bupropion dosages. Further clinical studies are required to confirm these preclinical findings.

Novel deuterated cyclopentadienyl zirconium/hafnium precursors for atomic layer deposition of high-performance ZrO2/HfO2 thin films

The need to improve the electrical properties of ZrO2 and HfO2 thin films deposited by atomic layer deposition (ALD), which is widely used in the field of microelectronics, is growing. Attempts to improve precursor stability unavoidably lead to reduced reactivity and diminished utility. Therefore, we synthesized and developed two new ALD precursors by introducing deuterium, which simultaneously exhibit enhanced thermal stability and enhanced reactivity as a result of the introduction of deuterium. For the substitution of deuterium for hydrogen in the precursors responsible for the enhanced thermal stability, we experimentally and theoretically demonstrated that thermal stability and reactivity can be simultaneously enhanced by reducing the bonding dissociation energy of ligands that have not undergone deuterium substitution. This observation led to the development of ZrO2 and HfO2 ALD processes that result in no impurities within the thin films and minimal substrate damage even at a very high deposition temperature of 400 °C. In particular, the improvement in crystallinity through ultra-high-temperature ALD deposition resulted in excellent electrical properties in a metal–insulator–metal capacitor in which the film was incorporated; the capacitor demonstrated a dielectric constant of 37.9 and leakage current of 3.52 × 10−9 A cm−2, without the need for a subsequent annealing process.

Hydrogen-donating capacity of hydrothermal system in catalytic and non-catalytic desulfurization of sulfur compound of unconventional crudes and residues: Deuterium tracing study

This research tries to figure out the role of water as a green and environmental hydrogen-donor solvent for catalytic and non-catalytic hydrothermal desulfurization (HT-DS) of dibenzyl sulfide (DBS) as a sulfur model compound of unconventional crudes and petroleum residues using deuterium tracing techniques. In addition, the ordinary water (H2O) was replaced by heavy water (D2O) to ease the evaluation of the donating capacity of water as a hydrogen donor during HT-DS process of selected sulfur model compound. The hydrothermal conversion (HTC) of dibenzyl sulfide and donating performance of heavy water were deeply investigated through comprehensive analysis of the initial and converted obtained products encompassing gas, liquid, and solid phase (if obtained), using different techniques GC, GC–MS, FTIR, high resolution deuterium (2H) NMR, and isotope analysis. The results of the non-catalytic and catalytic HTC of DBS show high conversion degree of 75.79 and 97.34 %, respectively, resulting in the formation of desulfurized compounds consisting of bibenzyl and stilbene. Additionally, the results of the deuterium tracing study proved the role of water as a green and environmental hydrogen-donor solvent during HT-DS of DBS, verified by considerable deuterium substitution (H/D exchanges) in both liquid (converted) and gases products. The results of the GC–MS as a tracing technique showed by molecular weight data the formation of the individual deuterium containing products in liquid and gas phases for both catalytic and non-catalytic HT-DS. Simultaneously, both experimental and DFT results showed that the application of nickel (II) stearate as an oil-soluble catalyst promoted both HTC of DBS. The important finding about the role of water in catalytic and non-catalytic HT-DS of DBS not only enriches the theoretical basis in this area, but also provides a strong support for the combined use of water and catalysts for improving conversion and desulfurization performance, thereby offering insights into the optimization of hydrothermal processes for unconventional sources of energy.

Enhancing the Properties of Natural Products and Other Drugs: Deuterium: A Novel Approach

Deuterium substitution is a new approach used to enhance the metabolic profile of a drug. The carbon-deuterium bond seems to be stronger than a usual carbon-hydrogen bond. It leads to improved biological half-life and prolonged action of the drug. The deuterated drugs also show improved pharmacokinetics of the drug and reduce the dosing frequency. This paves the way for drugs from natural sources with good therapeutic effects but poor pharmacokinetic profiles, which can be deuterated for improved properties. Though this seems to be an alternate pathway, the isotope exchange with hydrogen has to be studied well for toxicity and the safety profile of the drug should be evaluated. The present review provides an outline of the deuterium approach in natural products and other drugs which are opted for deuterium to improve the metabolic profile.

Cumulative lifetime enhancement effect of deuteration in blue organic light‐emitting diodes

AbstractThis research investigates the impact of deuteration on the operational lifetime of blue organic light‐emitting diodes (OLEDs). Our study focuses on the kinetic isotope effect (KIE) and how it enhances device lifetime. Specifically, we examine the effects of deuteration on OLEDs with emitters based on common polycyclic aromatic hydrocarbons by deuterating anthracene‐based host materials. Our findings show that the deuterated analogues with incremental deuterium substitutions exhibit similar electroluminescence (EL) performances but progressively prolonged device lifetimes as a function of deuteration, indicating a cumulative enhancement effect. We observed a twofold increase in device lifetime with partial deuterium substitutions, while highly deuterated hosts realized up to a fourfold improvement. Furthermore, we found that device degradation is initiated from the interface of the hole transport layer (HTL) and emitting layer (ETL), and deuteration can mitigate the degraded reactions in the devices, thereby improving operational stability. These results provide insight into how deuteration can increase the operational lifetime of OLEDs, which has important implications for developing more efficient and durable OLED materials.

Synthesis of Deuterated Enaminones with High Isotopic Fidelity.

The unexpected oxidation of nitrogenous heterocycles by aldehyde oxidase (AO) may be addressed by the substitution of deuterium for hydrogen adjacent to the heterocycle nitrogen atom. Enaminones are versatile intermediates in the synthesis of nitrogenous heterocycles. We report that heretofore inaccessible monodeuterated enaminones of the general structure RC(=O)CH=CDNMe2 may be synthesized from methyl ketones and DCO2Me with high isotopic fidelity and efficient utilization of deuterium.

Dynamic Behavior of Heavy Water Inside and Outside of Poly (N-Isopropylacrylamide) (PNIPAM) Microgel Using Broadband Dielectric Spectroscopy

One pot free radical precipitation polymerization was used to synthesize an aqueous suspension of non-ionic poly ( <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">N</i> -isopropylacrylamide) [PNIPAM] microgel particles. For dielectric measurements in the frequency range of 100 MHz to 50 GHz and temperature range of 288 K to 323 K, 10 wt. % of freeze-dried PNIPAM microgels dispersed in heavy water were used. The relaxation process was seen at around 15 GHz, which corresponds to the entire rotational motion of the heavy water, both within and outside the microgel. Furthermore, in the high frequency relaxation spectrum, heavy water outside the microgel (h1-process with a relaxation time of h1, τ <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">h1</sub> , fixed as that of pure heavy water) and confined heavy water within the microgel (h2-process with a relaxation time of h2, τ <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">h2</sub> ) were evaluated in view of the two-water model’s assumption and contribution. Under volume phase transition temperature (VPTT), τ <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">h2</sub> is about 4 to 5 times larger than τ <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">h1</sub> , and it does not change much even though the temperature is raised. However, τ <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">h2</sub> rapidly increases above VPTT from 7 to 14, which reveals that the dynamics of heavy water are severely constrained inside the shrunken state of the PNIPAM microgel. The obtained results are compared to the dynamics of pure water in PNIPAM microgels aqueous suspension to better understand the effect of deuterium substitution for hydrogen on the dynamics of heavy water inside and outside of PNIPAM microgels.

Influence of a Single Deuterium Substitution for Protium on the Frequency Generation of Different-Size Bubbles in IFNA17.

The influence of a single 2H/1H replacement on the frequency generation of different-size bubbles in the human interferon alpha-17 gene (IFNA17) under various energies was studied by a developed algorithm and mathematical modeling without simplifications or averaging. This new approach showed the efficacy of researching DNA bubbles and open states both when all hydrogen bonds in nitrogenous base pairs are protium and after an 2H-substitution. After a single deuterium substitution under specific energies, it was demonstrated that the non-coding region of IFNA17 had a more significant regulatory role in bubble generation in the whole gene than the promoter had. It was revealed that a single deuterium substitution for protium has an influence on the frequency generation of DNA bubbles, which also depends on their size and is always higher for the smaller bubbles under the largest number of the studied energies. Wherein, compared to the natural condition under the same critical value of energy, the bigger raises of the bubble frequency occurrence (maximums) were found for 11-30 base pair (bp) bubbles (higher by 319%), 2-4 bp bubbles (higher by 300%), and 31 bp and over ones (higher by 220%); whereas the most significant reductions of the indicators (minimums) were observed for 11-30 bp bubbles (lower by 43%) and bubbles size over 30 bp (lower by 82%). In this study, we also analyzed the impact of several circumstances on the AT/GC ratio in the formation of DNA bubbles, both under natural conditions and after a single hydrogen isotope exchange. Moreover, based on the obtained data, substantial positive and inverse correlations were revealed between the AT/GC ratio and some factors (energy values, size of DNA bubbles). So, this modeling and variant of the modified algorithm, adapted for researching DNA bubbles, can be useful to study the regulation of replication and transcription in the genes under different isotopic substitutions in the nucleobases.

First detection of deuterated methylidyne (CD) in the interstellar medium

While the abundance of elemental deuterium is relatively low (D/H ~ a few ×10−5), orders of magnitude higher D/H abundance ratios have been found for many interstellar molecules, enhanced by deuterium fractionation. In cold molecular clouds (T &lt; 20 K), deuterium fractionation is driven by the H2D+ ion, whereas at higher temperatures (T ≥ 20–30 K) gas-phase deuteration is controlled by reactions with CH2D+ and C2HD+. While the role of H2D+ in driving cold interstellar deuterium chemistry is well understood, thanks to observational constraints from direct measurements of H2D+, deuteration stemming from CH2D+ is far less understood as a result of the absence of direct observational constraints of its key ions. Therefore, making use of chemical surrogates is imperative in order to explore deuterium chemistry at intermediate temperatures. Formed at an early stage of ion-molecule chemistry directly from the dissociative recombination of CH3+ (CH2D+), CH (CD) is an ideal tracer for investigating deuterium substitution initiated by reactions with CH2D+. This paper reports the first detection of CD in the interstellar medium (ISM), carried out using the APEX 12 m telescope toward the widely studied low-mass protostellar system IRAS 16293–2422. Observed in absorption towards the envelope of the central protostar, the D/H ratio derived from the column densities of CD and CH is found to be 0.016 ± 0.003. This is an order of magnitude lower than the values found for other small molecules like C2H and H2CO observed in emission but whose formation, which is similar to that of CH, is also initiated via pathways involving warm deuterium chemistry. Gas-phase chemical models reproducing the CD/CH abundance ratio suggest that it reflects ‘warm deuterium chemistry’ (which ensues in moderately warm conditions of the ISM) and illustrates the potential use of the CD/CH ratio in constraining the gas temperatures of the envelope gas clouds it probes.

Effect of position of deuterium atoms on gas chromatographic isotope effects

Deuterium substitution provides various benefits in drug molecules, including improvement in pharmacokinetic properties, reduction of toxicity, reduction of epimerization, etc. Also, it has been shown that the position of deuterium substitution affects the properties of drug molecules. Therefore, it is important to study low molecular weight deuterated isotopologues which constitute the deuterated pool and are building blocks of larger deuterated molecules. The effect of the position and number of deuterium atoms on the retention of 23 deuterated isotopologues on two gas chromatography stationary phases of different polarities was evaluated. It was observed that the ratio of calculated chromatographic isotope effects resulting from a deuterium atom connected to an sp2 vs. an sp3 hybridized carbon was more on the polar IL-111i stationary phase compared to the nonpolar PDMS-5, for each group of isotopologues. Also, a compound with a deuterium atom connected to an sp2 hybridized carbon always had greater retention than the analogous compound where deuterium was connected to an sp3 hybridized carbon. The van't Hoff plots for all analytes showed that the effect of entropy was almost negligible in the separation of deuterated vs. protiated isotopologues, thus these separations were mainly enthalpy driven.

Assignment of the absolute configuration of molecules that are chiral by virtue of deuterium substitution using chiral tag molecular rotational resonance spectroscopy.

Chiral tag molecular rotational resonance (MRR) spectroscopy is used to assign the absolute configuration of molecules that are chiral by virtue of deuterium substitution. Interest in the improved performance of deuterated active pharmaceutical ingredients has led to the development of precision deuteration reactions. These reactions often generate enantioisotopomer reaction products that pose challenges for chiral analysis. Chiral tag rotational spectroscopy uses noncovalent derivatization of the enantioisotopomer to create the diastereomers of the 1:1 molecular complexes of the analyte and a small, chiral molecule. Assignment of the absolute configuration requires high-confidence determinations of the structures of these weakly bound complexes. A general search method, CREST, is used to identify candidate geometries. Subsequent geometry optimization using dispersion corrected density functional theory gives equilibrium geometries with sufficient accuracy to identify the isomers of the chiral tag complexes produced in the pulsed jet expansion used to introduce the sample into the MRR spectrometer. Rotational constant scaling based on the fact that the diastereomers have the same equilibrium geometry gives accurate predictions allowing identification of the homochiral and heterochiral tag complexes and, therefore, assignment of absolute configuration. The method is successfully applied to three oxygenated substrates from enantioselective Cu-catalyzed alkene transfer hydrodeuteration reaction chemistry.

4.1: Cumulative Lifetime Enhancement Effect of Deuteration in Blue OLEDs

The cumulative effects of deuteration on the device lifetime of blue OLEDs with emitters based on common polycyclic aromatic hydrocarbons were studied using two anthracene‐based host materials. Their deuterated analogues with incremental deuterium substitutions exhibited similar EL efficiencies but progressively prolonged device lifetimes as a function of deuteration.

Quantum dynamics calculations on isotope effects of hydrogen transfer isomerization in formic acid dimer

We present a quantum dynamics study on the isotope effects of hydrogen transfer isomerization in the formic acid dimer, and this is achieved by multidimensional dynamics calculations with an efficient quantum mechanical theoretical scheme developed by our group, on a full-dimensional neural network ab initio potential energy surface. The ground-state and fundamental tunneling splittings for four deuterium isotopologues of formic acid dimer are considered, and the calculated results are in very good general agreement with the available experimental measurements. Strong isotope effects are revealed, the mode-specific fundamental excitation effects on the tunneling rate are evidently influenced by the deuterium substitution of H atom with the substitution on the OH bond being more effective than on the CH bond. Our studies are helpful for acquiring a better understanding of isotope effects in the double-hydrogen transfer processes.

Impact of the R and Mg on the structural, hydrogenation and magnetic properties of R3-Mg Co9 (R = Pr, Nd, Tb and Y) compounds

R2MgCo9 (R = Pr, Nd, Tb and Y) compounds have been synthesized by a powder sintering method and the corresponding hydrides have been prepared by a solid gas method. Their crystal structures and magnetic properties have been systematically studied. X-ray diffraction analysis showed that all R2MgCo9 compounds belong to the PuNi3-type structure. The elements Tb, Y, Nd, Pr yield a lowering of the equilibrium pressure which correlates well with the increase in cell volume. The R2MgCo9H(D)x (R = Pr, Nd, Tb and Y; (9.4 ≤ x ≤ 12)) hydrides (deuterides) preserve the PuNi3-type structure with hydrogenation-induced volume expansion ranging from 14.7 to 19.6%. The substitution of deuterium for hydrogen in R2MgCo9–(H,D)2 (R = Tb and Y) prevents fast desorption at room temperature and ambient pressure. As for the magnetic properties, all the studied intermetallic compounds show ferromagnetic or ferrimagnetic behavior, and in some cases a temperature dependent spin reorientation. Hydrogen insertion reduces the magnetization and decreases the magnetic ordering temperature (TC), whereas Mg for R substitution increases TC.

Experimental and Theoretical Evidence for Relativistic Catalytic Activity in C-H Activation of N-Phenylbenzamide Using a Cationic Iridium Complex.

This study elucidates that relativistic effect plays a key role in catalytic C-H activation using a cationic Ir complex. Experiments show that the cationic Ir(I)-diphosphine catalyst can be used for the deuterium substitution of N-phenylbenzamide, whereas a cationic Rh(I)-diphosphine catalyst is scarcely effective. Density functional theory calculations, including the relativistic effect, demonstrate a large difference in the reaction energy diagrams for the C-H activation of N-phenylbenzamide between the cationic Ir and Rh catalysts. In particular, the relatively low reaction barrier and considerably stabilized product obtained for the Ir catalysts are rationalized by strong Ir-C and Ir-H interactions, which originate from the relativistic self-consistent d-orbital expansion of Ir.

Selective deuteration of bupropion slows epimerization and reduces metabolism

Strategically replacing hydrogen with deuterium at sites of metabolism in small molecule drugs can significantly alter clearance and potentially enhance clinical safety. Bupropion is an antidepressant and smoking cessation medication with the potential to cause seizures. We hypothesized that incorporating deuterium at specific sites in bupropion may greatly reduce epimerization, potentially slow metabolism, and reduce the formation of toxic metabolites, namely hydroxybupropion which has been associated with bupropion’s toxicity. Four deuterated analogues were synthesized incorporating deuterium at sites of metabolism and epimerization with the aim of altering the metabolic profile of bupropion. Spectroscopic binding and metabolism studies with bupropion and R-or S-d4 and R-or S-d10 analogs were performed with recombinant CYP2B6, human liver microsomes, and human hepatocytes. Results demonstrate that deuterated bupropion analogues exhibited 20–25% decrease in racemization and displayed a significant decrease in the formation of CYP2B6-mediated R,R - or S,S-hydroxybupropion with recombinant protein and human liver microsomes. In primary human hepatocytes, metabolism of deuterated analogs to R,R - and S,S-hydroxybupropion and threo- and erythro-hydrobupropion was significantly less than R/S-d0 bupropion. Selective deuterium substitution at metabolic soft spots in bupropion has the potential to provide a drug with a simplified pharmacokinetic profile, reduced toxicity and improved tolerability in patients.

Interaction between Heavy Water and Single-Strand DNA: A SERS Study.

The structure and function of biological macromolecules change due to intermolecular deuterium bond formation or deuterium substitution with environmental D2O. In this study, surface-enhanced Raman spectroscopy (SERS) was used to detect interaction sites between D2O and ssDNA and their action mechanisms. SERS peaks of ssDNA changed with increasing D2O proportions, and the site of action mainly involved A and G bases, whose number strengthened the interaction between sequences and D2O and hence the SERS peak intensities. Fixing the number of A and G bases prevented changes in their positions from significantly altering the map. We also identified the interaction between ssDNA sequences that easily formed a G-quadruplex structure and D2O. The amplitude of the SERS peak intensity change reflected the ssDNA structural stability and number of active sites. These findings are highly significant for exploring genetic exchanges and mutations and could be used to determine the stability and structural changes of biological macromolecules.

Photo-Induced Reactions between Glyoxal and Hydroxylamine in Cryogenic Matrices.

In this paper, the photochemistry of glyoxal–hydroxylamine (Gly–HA) complexes is studied using FTIR matrix isolation spectroscopy and ab initio calculations. The irradiation of the Gly–HA complexes with the filtered output of a mercury lamp (λ > 370 nm) leads to their photoconversion to hydroxyketene–hydroxylamine complexes and the formation of hydroxy(hydroxyamino)acetaldehyde with a hemiaminal structure. The first product is the result of a double hydrogen exchange reaction between the aldehyde group of Gly and the amino or hydroxyl group of HA. The second product is formed as a result of the addition of the nitrogen atom of HA to the carbon atom of one aldehyde group of Gly, followed by the migration of the hydrogen atom from the amino group of hydroxylamine to the oxygen atom of the carbonyl group of glyoxal. The identification of the products is confirmed by deuterium substitution and by MP2 calculations of the structures and vibrational spectra of the identified species.

Enantioselective Synthesis of Enantioisotopomers with Quantitative Chiral Analysis by Chiral Tag Rotational Spectroscopy.

Fundamental to the synthesis of enantioenriched chiral molecules is the ability to assign absolute configuration at each stereogenic center, and to determine the enantiomeric excess for each compound. While determination of enantiomeric excess and absolute configuration is often considered routine in many facets of asymmetric synthesis, the same determinations for enantioisotopomers remains a formidable challenge. Here, we report the first highly enantioselective metal‐catalyzed synthesis of enantioisotopomers that are chiral by virtue of deuterium substitution along with the first general spectroscopic technique for assignment of the absolute configuration and quantitative determination of the enantiomeric excess of isotopically chiral molecules. Chiral tag rotational spectroscopy uses noncovalent chiral derivatization, which eliminates the possibility of racemization during derivatization, to perform the chiral analysis without the need of reference samples of the enantioisotopomer.