Keywords

Deuterated products have received attention not only as useful tools for the investigation of drug metabolisms [1, 2] or reaction mechanisms [3, 4] as tracers or surrogate compounds, but also as functional materials such as fully deuterated polymers as components of optical fibers for high-speed telecommunication, which are virtually free of any optical absorption based on the C–H stretching vibration [5]. Multi-deuterated alkanes are anticipated as internal markers to prevent the distribution of illegal (illicit) light diesel oil [6] and deuterated medicines are expected to become new drugs having a longer duration of action based on the isotopic effect (resistant to the drug metabolism) [7]. Since the atomic nucleus of D can be fused with a tritium (T or 3H) nucleus into a helium (He) and a neutron together with the emission of a massive amount of energy (fusion energy) [8], it is expected as one of the most useful new sources of energy that avoids CO2 generation.

As summarized above, D is widely used in a variety of scientific fields as a representative nuclide of a stable isotope. The precedent preparation methods of D-labeled compounds can be classified into three types: (1) total synthetic methods starting from small deuterated raw materials; (2) reduction of reducible functionalities using deuterated reducing agents; and (3) post-synthetic direct deuteration (H–D exchange reaction). It is patently obvious that the catalytic reduction using D2 gas (deuterogenation) as a part of (2) and the catalytic H–D exchange reaction of non-deuterated compounds as (3) are preferable and practical methodologies associated with less waste. By the way, what kind of deuterium source is desired to achieve the H–D exchange reactions? The cheapest and most productive one is D2O. Natural water contains ca. 0.015% (150 ppm) of the D atom [9], which exists in the form of HDO by a disproportionation equilibrium. The D-abundance ratio that is highly enriched by the dual temperature isotope exchange process utilizing the difference in the chemical equilibrium constant between HDS and HDO in a temperature-dependent manner [H2S obtains a deuterium atom from HDO at a higher temperature (ca. 125 °C) and H2O obtains a deuterium from HDS at a lower temperature (ca. 25 °C); Girdler-Sulfide (GS) method] [10, 11]. Although nearly pure D2O has been industrially manufactured using the GS method, D2 gas is still produced by electrolysis of the incrassate (nearly pure) D2O using an enormous amount of electric energy. Since D2 gas, D2O and some deuterated compounds are designated as international controlled materials and subject to rigid control regarding import and export under security trade control, the development of efficient, mild, easily handled and catalytic preparation methods of regulated and combustible D2 gas would have to be developed in the respective countries, or even, each manufacturing site including laboratories in order to avoid the export, import and transportation problems.

In this review, we would like to describe the efficient platinum metal on carbon-catalyzed post-synthetic direct H–D exchange reactions using D2O as the deuterium source under a H2 atmosphere and a simple replacement method of sealed H2 gas by D2 gas via the Pd/C-catalyzed H2–D2 exchange reaction between H2 and D2O developed by us.

1 Heterogeneous Platinum Metal Catalyzed Post-synthetic Deuterium Labeling Method Using D2O as the Deuterium Source in the Presence of Hydrogen Gas

We have discovered that the H-atoms on the benzylic position of the substrate were time-dependently and site-selectively replaced with an equal number of D-atoms derived from D2O under mild and Pd/C-catalyzed hydrogenation conditions (Fig. 1) [12–14].

Fig. 1
figure 1

H–D exchange reaction at the benzylic positions

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The catalyst activity for the H–D exchange reaction under Pd/C–H2–D2O conditions was dramatically enhanced by the application of heat which facilitated the H–D exchange reaction at not only the benzylic sites, but also the inactive C–H bonds of alkyl-substituted aromatic compounds and heterocyclic nuclei [15–20]. Pt/C is an appropriate catalyst for the deuteration of aromatic nuclei, and the H–D exchange reaction smoothly proceeded under milder conditions [21, 22]. Furthermore, the mixed use of Pd/C and Pt/C or a bimetallic Pd–Pt on carbon was also found to be more efficient for the H–D exchange reaction in comparison to the independent use of Pd/C or Pt/C [23–25]. Furthermore, simple alkanes, which are inactive substrates by most definitions, could also be efficiently deuterated under the Rh/C-catalyzed heating conditions in a sealed tube (Fig. 2) [26].

Fig. 2
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Catalyst activity for the H–D exchange reaction

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The use of Ru/C enabled the regiospecific and efficient D incorporation at the α-position of alcohols at rt −80 °C and the results were applied as a regio- and stereoselective multi-deuteration method of sugar derivatives (Fig. 3) [27, 28].

Fig. 3
figure 3

Regiospecific deuterium incorporation at the α-positions of alcohols

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H2 gas is essential as an activating agent of the zero valent platinum group metal on carbon. Moreover, these H–D exchange methodologies are available to apply to the H–T (tritium, 3H) exchange reaction using highly diluted tritiated water (THO) indicating a low level of radioactivity, and the multi-tritium incorporated products indicates a higher specific radioactivity in comparison to the HTO based on the suppression of the reverse reaction due to the isotope effect of T (Fig. 4) [29].

Fig. 4
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H–T exchange reaction in highly diluted tritiated water

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These deuterium and tritium labeling methods using the platinum group metal on carbon–D2O–H2 combination can be achieved under simple and mild conditions in comparison to conventional methods, and a wide variety of labeled compounds are obtained in good to quantitative yields and deuterium efficiencies [30–32].

2 Replacement of Hydrogen Gas by Deuterium Gas via Pd/C-Catalyzed H2–D2 Exchange Reaction Between H2 and D2O

As for the preparation methods of D2 gas on a laboratory scale, the reaction of metals, such as sodium [33], iron [34], and magnesium [35] with D2O, have been reported in the literature, although a large quantity of metal sludge is produced and drastic reaction conditions (several hundred degrees Celsius) are required. While numerous catalytic H2–D2 exchange reactions between H2 and D2O have also been reported in the literature [36–44], such methods could not produce highly pure D2 gas and also required a high pressure, the use of a special catalyst, and/or strongly basic or acidic reaction conditions.

We have developed an efficient and quantitative in situ transmutation reaction of H2 gas into D2 gas utilizing the heterogeneous platinum group metal-catalyzed H2–D2 exchange reaction derived from D2O as the deuterium source that occurs at rt [30–32, 45, 46]. H2 gas sealed in the reaction flask is totally converted into nearly pure D2 gas (Fig. 5), which can be used for the one-pot reductive deuteration (deuterogenation) of a wide variety of substrates possessing reducible functionalities within the molecule. Since Rh/C indicates the highest activity and Pd/C, Ir/C and Pt/C are also effective as catalysts, the H2–D2 exchange study was effected by the selection of Pd/C as the catalyst from the aspect of cost and ready availability.

Fig. 5
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Quantitative transmutation of H2 gas into D2 gas at room temperature

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The H2–D2 exchange efficiency after 24 h of stirring of 7.4 mg of 10% Pd/C in D2O (3.0 mL, 166 mmol) in a hydrogen filled sealed flask with an effective internal volume of 160 mL (6.5 mmol/H2 at 25 °C; that is to say commercially designated as a 100 mL eggplant flask) at rt was determined by the incorporation ratio of the deuterium into dihydrocinnamic acid (2-d n ) by the 10% Pd/C-catalyzed hydrogenation and/or deuterogenation of cinnamic acid (1) at rt for 6 h in the H2–D2 exchanged sealed flask (Table 1). The deurterogenation of 1 efficiently proceeded by a 24 h pre-stirring (H2–D2 exchange reaction), and nearly 50% deuterium efficiencies (theoretical value) were observed on both the C1 and C2 methylenes (2- d n , Entry 1). On the other hand, little deuteration was observed without the 24 h pre-stirring (Entry 2). The deuterium efficiency was reduced with an inclease in volume of H2 using a larger flask (Entries 3 and 4). The D2 purity is significantly affected by the use a ratio of H2 and D2O based upon the H2–D2 exchange efficiency under the same time frame and reaction temperature.

Table 1 H2–D2 exchange efficiency under various conditionsa
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The replacement efficiency of H2 by D2 decreased with the deterioration in the deuterium content of D2O (Entries 5–8). The significant decrease in the deuterium efficiency of the deuterogenated product was observed and 50% D2O (HDO) led to virtually no incorporation of deuterium (Entry 7). Since the deterioration in purity of the D2O caused a significant drop in the H2–D2 exchange efficiency, an excess amount of D2O (3 mL, 166 mmol vs. 160 mL, 6.5 mmol of H2) should be required to circumvent the drastic degradation of the D2O purity.

The Pd/C-catalyzed H2–D2 exchange reaction is very likely proceeding via the illustrated reaction pathway shown in Fig. 6. The oxidative addition of the O–D bond of D2O to the H2-activated Pd metal on charcoal (I) produced the Pd(II) complex (II). Subsequently, the H–D exchange on a Pd(II) complex (III) and reductive elimination to give a HD-activated Pd metal on charcoal (IV). Further oxidative addition of excess D2O to IV, H–D exchange, reductive elimination and discharge of D2 gas could turn over the catalyst cycle.

Fig. 6
figure 6

Plausible reaction mechanism

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The reaction progress is clearly controlled by the isotopic effect between H and D. The oxidative addition of HDO to H2 or HD-activated Pd metal on charcoal (I or IV) should preferably occur at the O–H bonds (VIII or X) compared to the O–D bond (IX or XII) and virtually no reaction was observed as a result of the H–H exchange on VIII or X. Therefore, the formation of the complex (II or V) derived from D2O and I or IV should be necessary to generate HD or D2. The oxidative addition of the HD–activated Pd metal (IV) to D2O gave the complex (V), which would undergo the intramolecular H–D exchange, leading to the D2 generation via complex VI. Namely, increasing the H2O content in D2O with the ratio of 50% or more would result in no reaction due to the complexation with HDO or H2O and Pd metal (I or/and IV) followed by the intramolecular H–H exchange based on the isotopic effect (see also Table 1, Entries 7 and 8). Therefore, the use of a reasonably excess molar number of D2O compared with the use of H2 to avoid the unfavorable H–H exchange process should be required for the efficient generation of pure D2 gas.

The generated deuterium gas in a sealed flask is easily applicable for the one-pot deuterogenation of various substrates possessing a wide variety of reducible functionalities within the molecule, and the desired deuterium-incorporated products are obtained in excellent to quantitative deuterium efficiencies as shown in Table 2. The heterogeneous catalyst can be recovered by simple filtration, and the acidic deuterium atoms on the carboxylic acid, alcohol and amine functionalities were replaced by hydrogen atoms during the aqueous workup.

Table 2 Deuterium efficiency of deuteration using in-situ generated D2 gasa,b ,
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The chemoselective one-pot deuterogenation was also possible by the addition of a catalyst poison [47–53]. For example, the chemoselective one-pot deuterogenation of an olefin in the presence of an aromatic ketone or benzyl ester within the molecule proceeded with excellent deuterium efficiencies by the addition of a very low loading (0.01 equiv) of diphenylsulfide (Ph2S) as a catalyst poison (Table 2, 14- d 2 and 16- d 2 ), while the deuterogenation of the aromatic ketone or benzyl ester cannot be avoided without the addition of Ph2S (Table 2, 13- d 4 and 15- d 2 ) [45, 46]. Furthermore, a quite mild and fruitful deuterogenation of an aromatic nucleus is also possible. A partially (nearly 50%) deuterated cyclohexane derivative (17- d 6 ) can be easily obtained by the use of 10% Rh/C as a catalyst under gentle heating conditions (50 °C) [54–57].

It is noteworthy that almost pure and dried (waterless) D2 gas can be collected in a rubber balloon or gas collection bag via a drying tube from a pressure-resistant reaction vessel with an internal volume of 170 mL after the H2–D2 exchange reaction at rt although the increased use of 10% Pd/C (30–40 mg) and D2O (6–10 mL) under medium H2 pressure (3–4 atm) was required. The collected waterless D2 gas can be applied to the anhydrous deuterogenation and deuteration reactions, while the one-pot and in situ method is not applicable to water-sensitive substrates and reactions.

In summary, the H–D and H2–D2 exchange reactions introduced in this manuscript are readily and independently available at each laboratory and manufacturing site when necessary. Interestingly, these results strongly indicate that the H–H exchange reaction between the H2 gas, substrates and protic solvents, such as H2O, MeOH, etc. without the influence of the isotopic effect must frequently and continuously occur under the hydrogenation conditions, while the reaction seems to apparently undergo no reaction. This review should be helpful for the various international research groups who need the presented methodologies to prepare D labeled compounds and D2 gas. Since the methodologies in this review have already been put to practical use by Wako Pure Chemical Industries, Ltd. (deuterium labeled reagents and contract manufacturing service), it is possible to use such a service according to your needs.