WO2006045886A1

WO2006045886A1 - Continuous process for obtaining a product comprising at least one hydrogen isotope

Info

Publication number: WO2006045886A1
Application number: PCT/FI2005/000462
Authority: WO
Inventors: Kari Hartonen; Boris Kerler; Marja-Liisa Riekkola
Original assignee: Kari Hartonen; Boris Kerler; Marja-Liisa Riekkola
Priority date: 2004-10-27
Filing date: 2005-10-27
Publication date: 2006-05-04
Also published as: FI20041388A0

Abstract

A method provides obtaining a product substrate comprising at least one hydrogen isotope, the isotope comprising at least one neutron. The method comprises feeding a compound of the at least one isotope and a substrate to at least one pressurised flow reactor. The method further comprises passing the compound and the substrate through the flow reactor for providing the substrate with the at least one isotope. The method further comprises collecting the product substrate, the flow reactor allowing simultaneous feeding and collecting of material. A flow reactor and a flow reactor system are configured to execute the method.

Description

Continuous process for obtaining a product comprising at least one hydrogen isotope.

Field of the invention

The present invention relates to methods and systems for obtaining substrates comprising at least one hydrogen isotope, the isotope comprising at least one neutron. In particular, but not exclusively, the present invention relates to exchanging at least one hydrogen radical of a substrate containing hydrogen to at least one hydrogen isotope comprising at least one neutron. For example, the present invention relates to hydrogen to deuterium (H/D) or hydrogen to tritium (H/T) replacement reactions on aromatic hydrocarbons and other organic and inorganic substrates containing hydrogen. Furthermore, the present invention relates to hydrolysing a substrate to contain at least one hydrogen isotope comprising at least one neutron.

Background of the invention

To produce materials in a way that is more benign to human health and the environment, 'green chemistry' searches for reduction or elimination of hazardous substances in chemical industry [e.g. i]. Replacement of harmful solvents or reactants is an aspect of this approach due to their wide-range usage in different chemical processes.

Near-critical (p > pc, T < Tc) or supercritical fluids (p > pc, T > Tc), like CO₂ (ScCO₂; Pc = 73.8 bar, T₀ = 31.1 ⁰C) or water (p_c = 221 bar, T₀ = 374.2 ⁰C), have been investigated as environmentally benign alternative to conventional organic solvents for a broad range of chemical reactions and extractions [e.g. ii, iii, iv, v, vi]. However, the applicability of pure ScCO₂ has often been limited by its non-changeable low dielectric constant ε and polarity [ii]. In contrast, reactions in near-critical or supercritical water profit from the pressure- or temperature-tunability of decisive solvent properties without changing the medium. For example, dielectric constant and pK_w value significantly vary for ambient and near-critical or supercritical conditions, (e.g. p/C_w(1 bar, 25 ⁰C) ~ 14, pKw(240 bar, 250 ⁰C) ~ 11 , pK_w(240 bar, 450 ⁰C) - 22) [vii], affecting both polarity as well as acid/base-catalytic properties [v]. Besides, near-critical and supercritical water provides a high solubility for many non-polar compounds and gases. This enhances mass transfer limited reactions. Potential of near-critical and supercritical water has been reported in detail by several groups for hydrolyses [e..g. v], hydrations [e.g. viii], dehydrations [e.g. ix], and partial oxidations [e.g. x].

In contrast, only rare literature focuses on the application of near-critical and supercritical D₂O (p_c = 214 bar, Tc = 372°C) as both cheap deuterium source as well as environmentally benign solvent for the production of deuterium labelled aromatic hydrocarbons in analytical chemistry (i.e., as standard or reference materials) [xi]. Conventional synthetic methods widely used [xii, xiii] are either based on Lewis-acid catalysed reactions (i.e., addition of a concentrated acid to a mixture of substrate and ²H source in so-called high temperature dilute acid procedure; HTDA) or homogeneous/heterogeneous noble metal catalysis (i.e., carried out with deuterium gas and an organic substrate solution) [xiv].

To overcome disadvantages of these conventional processes (e.g. need for acid-resistant reactors, harmful solvents), the base catalysed exchange of (even weakly) acidic hydrogen in near-critical or supercritical D₂O has been investigated in batch mode by several groups [xv, xvi, xvii, xviii, xix, xx].

Yao and Evilia [xv] studied the NaOD or KOD assisted deuteration of various aromatic hydrocarbons of different acidity (T = 340 - 500 ⁰C, t = 10 - 150 min), suggesting an acid-base reaction:

RH + OD^" ===^ FT + HOD (1)

The equilibrium constant for the reaction is given by KJK_N, where K_a is the acid dissociation constant of the weak acid (i.e., hydrocarbon RH) and K_N the self-ionisation constant of D₂O. By that, the ease of H/D exchange followed the acid strength of the CH bonds involved and the basicity of the solvent applied, respectively. However, even weakly acidic 2-methylpentane was successfully deuterated in a 0.16 M KOD/D₂O solution over 150 min at 380 ⁰C {d_z: 20 %).

Junk and Catallo [xvii] reported on the batch-wise deuterium exchange of arenes and heteroarenes in pressurized hot D₂O (p = 236 - 367 bar, T = 380 - 430 ⁰C, t = 1 - 24 h, addition of sodium deuteroxide solution). Aromatic substrates bearing methyl groups, e.g. 1,3,5-trimethylbenzene or 1,2- dimethylnaphthalene, were successfully perdeuterated (cfi₂: 96 - 97%) in contrast to the conventional HTDA approach, which favoured the exchange of only aromatic hydrogens. However, due to harsh conditions required, several compounds (e.g. 1 ,2-dichlorobenzene) decomposed by pyrolysis and were found not suitable for deuteration in batch reactors.

In our own preliminary studies [xviii], we tested different autoclave set-ups for the ²H-labelling of model compounds in near-critical D₂O with the aim of synthesizing GC-MS standards for our ongoing environmental research. Using in-house made Hastelloy batch reactors, maximum deuteration purities of 34% and 62% were observed for 2-methylnaphtalene-cf₇ (p = 295 bar, T = 400 ⁰C, t = 2 h) and eugenol-c/i, respectively (p = 85 bar, T = 300 ⁰C, t = 2 h). Addition of Na₂CO₃, forming NaOD in D2O solution, was found to be an effective basic catalyst for H/D exchange on 2-methylnaphtalene. By that, both deuteration level and isotopic purity were significantly enhanced at identical reaction conditions (2-methylnaphthalene-c/io = 51 %).

Nakahara et al. in US 5,733,984 [xix] described a batch process for the preparation of a deuterated compound using heavy water. The process was carried out in a batch pressure vessel in a temperature from 200° to 371⁰C and a pressure of from 5 to 21.7 MPa in a presence of sodium hydroxide.

Junk and Catallo in US 5,830,763 [xx] disclosed a batch process for preparing deuterium tagged compounds. Supercritical deuterium oxide was used a reaction medium in batch reactors.

Wegener in EP 02 276 675 A2 [xxi] disclosed a process for preparation of deuterated acrylic acid or methacrylic acid by direct exchange of hydrogen by deuterium from D₂O in the presence of a catalyst based on palladium, nickel and copper in a high temperature. The process of Wegener was carried out in a heated glass-tube at low pressure conditions.

Even if the known batch reactors may provide acceptable hydrogen to deuterium exchange ratio, batch reactions may require considerably long residence times for the reaction to take place. This may create problems. Requirements for batch reactors may be hard, as supercritical water is known to be a strongly corrosive agent, in particular in combination with halogenated compounds and acid catalysts. Furthermore, a number of substrates may be labile, such as readily polymerisable, at high temperatures. Long reaction times may result in, for example, unacceptably high polymerisation rate. Summary of the invention

The present invention provides a continuous set-up for obtaining a product substrate comprising at least one hydrogen isotope, the isotope comprising at least one neutron.

In accordance with an aspect of the invention, there is provided a method for obtaining a product substrate comprising at least one hydrogen isotope, the isotope comprising at least one neutron. The method comprises feeding a compound of the at least one isotope and a substrate to at least one pressurised flow reactor. The method further comprises passing the compound and the substrate through the flow reactor for providing the substrate with the at least one isotope. The method further comprises collecting the product substrate, the flow reactor allowing simultaneous feeding and collecting of material.

In accordance with another aspect of the invention, there is provided a flow reactor for obtaining a product substrate comprising at least one hydrogen isotope, the isotope comprising at least one neutron. The flow reactor comprises an inlet for feeding a compound of the at least one isotope and a substrate. Furthermore, the flow reactor comprises a pump for passing the compound and the substrate through the flow reactor at an elevated pressure for providing the substrate with the at least one isotope. Furthermore, the flow reactor comprises an outlet for collecting the product substrate, the inlet and the outlet allowing simultaneous feeding and collecting of material.

In accordance with another aspect of the invention, there is provided a flow reactor system comprising at least one such flow reactor.

In an embodiment, the substrate may be a substrate comprising hydrogen. The compound and the substrate may be passed through the flow reactor for exchanging at least one hydrogen radical of the substrate to the at least one hydrogen isotope.

In an embodiment, the compound may be an oxide of the at least one isotope. The compound and the substrate may be passed through the flow reactor for hydrolysing the substrate to contain the at least one hydrogen isotope.

In an embodiment, the substrate and the compound may be mixed before feeding to the flow reactor. In an embodiment, the substrate and the compound may be fed in at least one pressurised flow reactor with a hollow elongated shell having one of a circular, oval or rectangular cross section. In an embodiment, heating may take place from at least one of outside and inside the flow reactor.

In an embodiment, the substrate and the compound may be fed in at least one pressurised flow reactor, each reactor with at least two hollow elongated shells having one of a circular, oval and rectangular cross section, the shells being placed inside each other. In an embodiment, heating may take place from at least one of outside of the outermost of the at least two shells, inside of the innermost of the at least two shells and between at least two of the at least two shells.

In an embodiment, the compound may have at least one of a deuterated compound, a tritiated compound and a mixture of a deuterated compound and a tritiated compound. The compound may be at least one of deuterium oxide (D₂O), tritium oxide (T2O), tritium deuterium oxide (TDO), tritium hydrogen oxide (THO), deuterium hydrogen oxide (DHO), deuterated methanol and tritiated methanol.

In an embodiment, a mixture of the substrate and the compound may be passed through the flow reactor with a residence time of less than one hour. Preferably, the residence time may be less than 10 minutes.

In an embodiment, the pressure may be controlled in at least one of the inlet and the outlet of the flow reactor.

In an embodiment, the substrate and the compound may be passed through the flow reactor at a temperature of at least 100 ⁰C and at a pressure of at least 1 MPa. Preferably, the temperature may be in the range of from 100 to 500 ⁰C and the pressure in the range of from 1 to 50 MPa. In an embodiment, the substrate and the compound may be passed through the flow reactor at a near-critical temperature and pressure of the compound. In another embodiment, the substrate and the compound may be passed through the flow reactor at a supercritical temperature and pressure of the compound.

In an embodiment, the substrate may be at least one of a hydrogen containing organic compound, a hydrogen containing inorganic compound, an aromatic hydrocarbon, an aliphatic organic compound, an alkane, an alkene, a cyclic organic compound, an alcohol, a ketone, an ether, a heterocyclic compound, an amine, a carbohydrate, an amino acid, a carboxyiic acid, a hydrogen containing inorganic compound, a polyaromatic compound, a thiol, a sulfide, an organosilicon compound, an organometal, a halogenated organic compound, a phenol, a difunctional compound, a peptide and an ester.

In an embodiment, the substrate may be dissolved in the compound before the step of feeding.

In an embodiment, the substrate and the compound may be preheated before the step of feeding.

In an embodiment, the substrate may be collected by at least one of vacuum evaporation, isolating from an outlet mixture, cooling followed by phase separation and depressurisation followed by phase separation.

In an embodiment, at least a part of an outlet mixture may be circulated back to the step of feeding.

Various other aspects and embodiments of the invention shall become clear from the following description and figures.

Brief description of figures

The invention will now be described in further detail, by way of example only, with reference to the following examples and accompanying drawings, in which:

Figure 1 shows an example of a system in which embodiments of the invention may be implemented;

Figure 2 shows a further example of a system in which embodiments of the invention may be implemented;

Figure 3 shows a further example of a system in which embodiments of the invention may be implemented;

Figure 4 shows a further example of a system in which embodiments of the invention may be implemented;

Figure 5 shows chemical formulas of exemplifying substrates, which may be used in embodiments of the invention; Figure 6 shows results of deuteration of eugenol;

Figure 7 shows further results of deuteration of eugenol of Figure 6;

Figure 8 shows results of deuteration of 4-hydroxyacetophenone;

Figure 9 shows further results of deuteration of 4-hydroxyacetophenone of Figure 8;

Figure 10 shows further results of deuteration of 4-hydroxyacetophenone of figures 8 and 9.

Detailed description of the invention

Embodiments of the present invention provide a continuous set-up for obtaining a product substrate comprising at least one hydrogen isotope, the isotope comprising at least one neutron.

Embodiments of the present invention provide a continuous set-up for exchanging a hydrogen radical of a substrate containing hydrogen to a hydrogen isotope comprising at least one neutron at high temperature and pressure. Exchanging may comprise hydrogen to deuterium (H/D) or hydrogen to tritium (HfT) replacement reactions.

Further embodiments of the invention provide a continuous set-up for hydrolysing a substrate to contain at least one hydrogen isotope comprising at least one neutron. Hydrolysis may comprise an addition of an OD group or an OT group to the substrate.

A deuterated or tritiated compound or a mixture thereof is used as a source of the hydrogen isotope. Examples of such compounds may comprise, but are not limited to, deuterium oxide (D2O), tritium oxide (T₂O), tritium deuterium oxide (TDO), tritium hydrogen oxide (THO), deuterium hydrogen oxide (DHO) or deuterated or tritiated methanol and so on. The substrate containing hydrogen may comprise, but is not limited to, a hydrogen containing organic compound, a hydrogen containing inorganic compound, an aromatic hydrocarbon, an aliphatic organic compound, an alkane, an alkene, a cyclic organic compound, an alcohol, a ketone, an ether, a heterocyclic compound, an amine, a carbohydrate, an amino acid, a carboxylic acid, a hydrogen containing inorganic compound, a polyaromatic compound, a thiol, a sulfide, an organosilicon compound, an organometal, a halogenated organic compound, a phenol, a difunctional compound, a peptide and an ester. In an embodiment, the substrate is an aromatic hydrocarbon.

An objective of embodiments of the invention may comprise using an environmentally benign solvent and isotope source, such as deuterium oxide

(D₂O) or tritium oxide (T₂O) or the like. Another objective may comprise continuously and, by that, more competitively synthesizing labelled compounds. Another objective may comprise exploiting short contact times for a reduced thermal decomposition of labile substrates. Furthermore, safety concerns may be reduced or minimized, as the system hold-up may be lower compared to conventional batch processes. A further objective may comprise avoiding a need for using a catalyst in the reaction.

In the following, embodiments of the invention shall be described and tested for various aromatic model substrates. Results are contrasted to the results obtained for batch-wise deuteration with near-critical D2O. Labelling positions shall be identified by various analytical methods, such as GC-MS, ¹H-NMR, and GC-FTIR.

Figure 1 shows an exemplifying system in which embodiments of the invention may be implemented. The Figure 1 system comprises a pressurised flow reactor 10, having an inlet 11 and an outlet 12. The inlet and the outlet of the flow reactor allow simultaneous feeding and collecting of material. In other words, the flow reactor is configured to function in a continuous manner, or, is a continuous flow reactor. The reactor may be heated using heating means 13, such as an oven.

It shall be appreciated that Figure 1 is only an example showing one possible system in which embodiments of the invention may be implemented. Various variations and combinations may be possible. Some variations shall become clear from the following description.

In embodiments of the invention, the substrate is provided with at least one hydrogen isotope comprising at least one neutron, i.e. a deuterium and/or a tritium.

In an embodiment, at least one hydrogen radical of a substrate containing hydrogen, such as an aromatic hydrocarbon, is exchanged to at least one hydrogen isotope comprising at least one neutron, i.e. to a deuterium and/or a tritium. The substrate and a compound of the isotope, such as an oxide of the isotope, such as an oxide of deuterium or an oxide of tritium, depending on the desired reaction, is fed to the inlet 11 of at least one flow reactor 10.

In another embodiment, a substrate is hydrolysed to contain at least one hydrogen isotope. In other words, an OD or OT group may be introduced or added to the substrate by means of a hydrolysis reaction.

The substrate and the compound may be mixed before or in the inlet of the reactor. The mixture may be filtered, if needed, in a filtering unit 21 before entering the reactor. For feeding, an appropriate pump 22 or the like may be used. The pump may be selected based on the desired pressure and a desired flow rate. Examples may comprise, but are not limited to, a HPLC (high pressure liquid chromatography) pump.

The substrate and the compound, or a mixture thereof, are passed through the pressurised flow reactor 10, preferably at a temperature of at least 100 ⁰C and a pressure of at least 1 Mpa, for providing the substrate with at least one hydrogen isotope comprising at least one neutron. As mentioned above, the reaction may comprise exchanging at least one hydrogen radical of the substrate into the isotope or hydrolysing of the substrate to contain an oxide of the isotope. A product substrate comprising the isotope is collected in the outlet 12 of the at least one flow reactor.

The flow reactor may be of any appropriate material designed for the temperature and pressure used. The temperature and the pressure depend on the substrate and the compound of the isotope. Advantageous materials may comprise, but are not limited to, stainless steel, titanium, Hastelloy (nickel based alloys, such as Ni-Mo, Ni-Si, Ni-Cr-Mo, Ni-Cr-Fe-Mo-Cu) and lnconel (NiCrFe alloys).

The flow reactor may comprise a hollow elongated shell having a circular, oval or rectangular cross section, or another appropriate shape of cross section. In a further embodiment, the flow reactor may also comprise at least two hollow elongated shells having one of a circular, oval and rectangular cross section, which are placed inside each other. In an embodiment, the flow reactor may comprise a fixed-bed reactor. A mixture passing through the flow reactor may be heated from outside or inside the flow reactor. In case of at least two shells, the mixture may be heated from outside of the outermost of the at least two shells, inside of the innermost of the at least two shells or between at least two of the at least two shells.

In an embodiment, a pressurised flow reactor is a part of a reactor system. The reactor system may comprise various mixing, heating, substrate collection and recycling units and other desired units. Flow reactor systems comprising such units are described in this specification. However, it shall be appreciated that a reactor system may comprise further additional units as desired or needed, depending on the implementation.

In an embodiment, at least two such flow reactors are functioning together in a reactor system. For example, two or more tubular reactors may be connected in parallel. Tubular reactors may comprise various tube diameters. An example may comprise capillary tubes. The system may comprise, for example, several hundreds or even thousands of capillary reactors, thereby permitting dimensioning the process as desired. Such a reactor system may be heated from outside of the tubular reactors, preferably such that there is heating around each tubular reactor ensuring homogenous heating of the mixture inside of each tube.

In an embodiment, the tube or capillary tube may be shaped appropriately, for example, in a form of a spiral. This may, for example, extend the tube length in a given space.

Another example may comprise a tube having a larger diameter, which allows a heating means to be placed inside the tube. Heating means inside the reactor may allow further mixing of the mixture during the step of passing through the reactor, while ensuring homogenous heating of the mixture.

In another embodiment, at least two hollow rectangular reactors, each reactor having two wide and two narrow longitudinal sides, are placed next to each other such that a wide longitudinal side of one reactor is facing a wide longitudinal side of another reactor. Such a reactor system may be heated from outside such that heating means is placed in the space between the wide longitudinal sides of the reactors.

The flow rate and thus a residence time for passing the mixture through the flow reactor may depend on the substrate and the desired reaction. Furthermore, the residence time may depend on the dimensioning (diameter and length) of the reactor. Furthermore, the residence time may depend on the pressure and/or the temperature used in the reactor. Preferably, the residence time is less than one hour (1 h), more preferably less than ten minutes (10 min) and most preferably less than four minutes (4 min). Some exemplifying residence times and other conditions are mentioned in the experimental examples. However, exemplifying conditions mentioned in the experimental examples are given only for illustrating, not limiting, embodiments of the invention.

Referring back to Figure 1 , the pressure of the flow reactor 10 and the flow rate may be controlled by means of an appropriate pressure restrictor 14 in the inlet 11 and the outlet 12 of the flow reactor. Examples of pressure restrictors may comprise, but are not limited to, a valve, such as a needle valve, or to a capillary type restrictor.

The pressure and the temperature in the flow reactor may vary depending on the substrate and the dimensioning of the reactor. The pressure may be, for example, in the range of from 1 to 50 MPa. The temperature may be, for example, in the range of from 100 to 500 ⁰C. An example of advantageous temperature and pressure may comprise near-critical or supercritical conditions of the compound of the isotope. For example, for the deuterium oxide advantageous temperature and pressure may be near the pressure of 21.4 MPa and the temperature of 372 ⁰C. The conditions in the flow reactor may be followed and measured by means of appropriate measuring devices, such as a pressure indicator 15 and a thermometer 16.

The substrate may be any substrate to be labelled by a hydrogen isotope. Examples may comprise any substrate comprising hydrogen. Further examples may comprise any hydrolysable substrate. Examples may comprise organic substrates, such as aromatic hydrocarbons, e.g. eugenol, 9- fluorenone, 4-hydroxyacetophenone, xanthone and other compounds having similar structure and characteristics. Further examples may comprise, but are not limited to, aliphatic hydrocarbons, inorganic hydrogen containing compounds, heterocyclic organic compounds and carbohydrates.

The flow reactor 10 or the flow reactor system may further comprise a premixing unit 20 for dissolving the substrate in the oxide of the isotope before feeding to the reactor 10 or to the reactor system. The premixing unit may function at room temperature or at elevated temperature and pressure. Furthermore, the mixture may be preheated before feeding to the reactor or the reactor system. Heating the mixture before feeding may further reduce the residence time and/or improve the reaction rate.

In an embodiment, the premixing unit may comprise a heated low-pressure stainless-steel reservoir 23 as shown in Figure 2. Solubility of the substrate in the oxide of the isotope may be improved in this way.

In an embodiment, the reaction may further be enhanced using an additional acid, base, metal or metal salt catalyst. If used, such an additional component may be dissolved in the mixture before feeding to the reactor. In an embodiment, a catalyst may be supported inside the reactor, for example inside of a fixed-bed reactor. A catalyst may have an effect on the residence time, as well.

The resulting substrate comprising at least one hydrogen isotope, namely deuterium or tritium, radical may be collected in the outlet or after the outlet of the reactor by means of an appropriate collection method or means, such as a vacuum evaporation device 30. Other appropriate collection methods may comprise, but are not limited to, cooling and/or depressurising the outlet liquid flow, followed by phase separation.

In an embodiment, an effluent stream may be recycled by means of a recycling unit as a recycled effluent stream 40 from the outlet 14 of the reactor 10 to the inlet of the reactor or to the premixing unit 20, as shown in Figure 3. The substrate may be isolated from the outlet flow and the remaining effluent steam may be recycled. In a further embodiment, the effluent stream may be extracted by an appropriate solvent 42, such as an organic solvent, as shown in Figure 4. In an embodiment, the extracted stream may be used to determine an exchange yield, for example, by means of an on-line or off-line liquid-liquid extraction.

Experimental examples

1. Deuteration reaction

Substrates for testing embodiments of the invention were first selected using batch reactions. H/D exchange batch reactions were performed on different aromatic hydrocarbons (e.g. eugenol, 9-fluorenone, 4-hydroxyacetophenone, xanthone) in parallel batch runs using several in-house made high-pressure Hastelloy C-22 autoclaves (p_max = 400 bar, T_max = 500 ⁰C, V = 3 mL). Substrate and, where applicable, base (i.e., Na₂CO₃) or metal catalyst (i.e., Pd/C) were charged into the batch reactor (molar ratio substrate : catalyst = 1 : 0.5) at room temperature. Subsequently, the amount of D2O, needed for the desired pressure at reaction temperature (approximation by NIST/ASME Steam Properties Database), was added (m = 0.5 - 3 g, molar ratio D2O : substrate = 1550 : 1). The closed autoclaves were placed in an oven (Fractovap GC; Carlo Erba) and heated up to the chosen near-critical temperature and pressure. After completion of reaction time (t = 2 h), the reactors were quenched by cooling in a water bath (15 min) and the deuterated substrate was thrice liquid-liquid extracted from the aqueous solution with 3 mL methylene chloride each. Remaining deuterium oxide was removed from the organic phase by addition of 1 g Na2SO4 and the solution was diluted with methylene chloride (molar ratio = 1 : 5) before analyzing by GC-MS. A more detailed description of the experimental procedure has been reported earlier in Kalpala et al. [xviii].

Continuous deuteration experiments according to an embodiment of the invention were conducted in a capillary flow reactor (p_maχ = 400 bar, T_max = 500 ⁰C, V = 0.9 mL) online coupled with liquid-liquid extraction, as shown schematically in Figure 4. A test substrate (i.e., eugenol, 4- hydroxyacetophenone) was dissolved under vigorous stirring in degassed D₂O at room temperature (c_max = 0.04 mg/mL and 0.5 mg/mL, i.e., molar ratio of D₂O : substrate = 215000 : 1 and 15000 : 1 , respectively). By a HPLC pump (PU-980; Jasco), the premixed aqueous solution was continuously fed through an oven-heated Hastelloy capillary reactor (L = 2 m, dj = 0.75 mm; Vici Valco) at near-critical conditions and a flow rate of 0.15 - 0.85 mL/min. By that, a short residence time in the hot reactor zone was ensured (τ_max = 6 min). Operating the pump in constant volumetric flow rate mode, the system pressure was adjusted by a pressure control valve (Tescom) at the reactor outlet. After depressurising, the outlet flow was cooled down at air to room temperature. The deuterated substrate was continuously liquid-liquid extracted from the aqueous flow with methylene chloride, the methylene chloride having a volumetric flow rate of two times the volumetric flow rate of the aqueous flow (PU-1580; Jasco). The setup was purged with substrate mixture for 30 min at reaction conditions (e.g. temperature, pressure, flow-rates), before samples of typically 2.5 mL D₂O and 5 mL methylene chloride extract, respectively, were withdrawn every 15 min for 2 h. The organic phase was separated in a funnel and dried by a mixture of 1 mg Na₂SO₄. 50 μl of a methylene chloride solution of 4,4'-dibromooctafiuorobiphenyl (c = 0.155 mg/mL) were added as internal standard for GC-MS analysis. Residence time τ is defined as

τ = (Vreactor/fRT) ' (Preactor/PRτ) (2)

where Vic_tor is the volume of the capillary reactor, fpj the volumetric flow rate of the HPLC-pump at 25 °C, p_reactor and PRT the density of the aqueous phase at reaction conditions and room temperature, respectively. Both of the latter were approximated by the NIST/ASME Steam Properties Database for water.

Deuterium oxide (deuteration purity: 99.9%) was supplied by Euriso-top. Eugenol (purity: 99%) was acquired from Sigma, 9-fluorenone (purity: > 99%), xanthone (purity: > 97%), Na₂SO₄ (pro analysis grade), 4- hydroxyacetophenone (pro analysis grade), and 10% Pd/C from Fluka. Na₂COs (pro analysis grade) was delivered from Merck, 4,4'- dibromooctafluorobiphenyl (purity: 99%) from Aldrich, and methylene chloride (purity: 99.5%) from Mallinckrodt Baker.

2. Analysis

An Agilent Technologies 6890N gas chromatograph with on-column injection (Agilent Technologies 7683 auto sampler) connected to an Agilent Technologies 5973 mass spectrometer was used for identification and quantification of isotopic composition of fresh and labelled substrates (HP-5 analytical column, 15 m x 0.18 mm x 0.18 μm; Agilent diphenyltetramethyldisilazane deactivated retention gap, 4 m x 0.53 mm). The GC runs were performed at 100 kPa with Helium as carrier gas (purity 99.996%; AGA). The oven temperature was programmed from 8O⁰C (4 min hold) to 28O⁰C (10 min hold) with a heating rate of 20 °C/min. The GC-MS transfer line was thermostated at 300⁰C. The MS was operated in scan mode with El (70 eV) ionisation with a temperature of ion source and quadrupole analyser of 25O⁰C and 12O⁰C, respectively. Isotopic purities of deuterated substrates were calculated from the respective mass fraction m/z and the total ion chromatogram. Absolute concentrations of the substrate were derived by calibration curves using 4,4'-dibromooctafluorobiphenyl as internal standard, which were validated for each experiment. ¹H-NMR chemical shifts were recorded by a Bruker DRX 500 spectrometer (5 mm, BBI with z-gradient) to identify H/D exchange positions. For that, methylene chloride was replaced by deuterated chloroform (deuteration purity: 99.8%, 0.03% tetramethylsilane; euriso-top) as solvent for either the fresh substrate or as extraction medium after batch and continuous runs. ¹H-NMR assignments were verified by COSY experiments, comparison with the online SDBS Database of the National Institute of Advanced Industrial Science and Technology of Japan [xxii] and approximations of the chemical shifts by a group contribution method [xxiii].

For additional information on deuterated sites, GC-FTIR analysis was performed on fresh and batch-wise deuterated 4-hydroxyacetophenone solutions using methylene chloride as solvent and extraction medium. FTlR spectra were obtained by a Bio-Rad FTS-45 FTIR spectrometer connected to a Hewlett-Packard 5890 Series Il gas chromatograph (SE-54 silica capillary column, 30 m x 0.32 mm x 0.25 μm) with splitless injection. Helium (purity 99.996%) was used as carrier gas with a flow-rate of 33 cm/s. The GC oven temperature was programmed from 40⁰C (1 min hold) to 25O⁰C (10 min hold) with a heating rate of 10°C/min.

Possible leaching of Cr or Ni from the Hastelloy capillary reactor into D2O was determined by the metal concentration in the outlet solution derived from atomic absorption spectroscopy (3030 Atomic Absorption Spectrophotometer; Perkin Elmer) at a wavelength of 357.9 nm and 232 nm, respectively.

3. Results on batch screening studies

Prior to deuteration in the continuous flow set-up, various aromatic substrates (i.e., eugenol, 9-fluorenone, 4-hydroxyacetophenone, xanthone; Figure 5 (a),

(b), (c), (d), respectively, wherein nomenclature of hydrogen atoms is highlighted in bold) and reaction conditions (i.e., temperature, reaction time, addition of catalyst) were screened for H/D exchange with D₂O at 300 bar in parallel batch runs (Table 1). Deuteration at 250 ⁰C without addition of catalyst led to highest isotopic purity on eugenol (d-r. 59%) and 4-hydroxyacetophenone

(c⁽ ₅: 90%). 9-Fluorenone (do: 89%) and xanthone (d₀: 87%) virtually remained unaffected by D₂O, despite almost identical acid dissociation constants (pK_w =

9.5 - 9.8 [xxiv] compared to pK_w = 10.23 - 10.82, predicted for eugenol and 4- hydroxyacetophenone [xxv]). Elevated temperatures of 350 ⁰C (eugenol) or 450 ⁰C (9-fluorenone and xanthone), respectively, led to an enhanced deuteration level of the substrates (e.g. cfe: 43% for eugenol; ό-i. 31 % for fluorenone; d₃: 29% for xanthone). These findings were explained by an increased acid dissociation constant K_a of the hydrocarbon (according eq. 1) as well as more rapid reaction kinetics at higher temperature [xv]. Additionally, the dramatic decrease in the self-ion ization constant K_w of D2O beyond its critical temperature (T > 372 ⁰C) caused the same effect [xxvi]. However, a pronounced rise in temperature finally led to decomposition of thermally instable compounds (e.g. eugenol and 4-hydroxyacetophenone at T = 450 ⁰C). As observed in our previous studies [xviii], addition of Na₂CO₃ markedly improved the H/D exchange level compared to non-catalysed runs (e.g. xanthone run X4 at 250 ⁰C, d₃: 36%). In solution with D₂O, Na₂CO₃ formed NaOD, which enhanced solvent basicity and concurrently shifted the acid-base equilibrium towards higher deuteration according eq. 1 [xv]. In contrast, a Pd/C catalyst favoured the perdeuteration of substrates (e.g. 9-fluorenone at 250 ⁰C, d₈: 92%). Complete H/D exchange on Pd-based catalysts has also been reported for the deuteration of 1-methylimidazole in near-critical D₂O before [xxvii].

The H/D exchange on eugenol and 4-hydroxyacetophenone was chosen as model process for the detailed investigation under continuous flow conditions, since remarkable isotopic purities were obtained without addition of catalysts (e.g. eugenol Gf₁: 59%; 4-hydroxyacetophenone d₅: 90%).

4. Results on continuous deuteration according to embodiments of the invention

Table 2 summarizes the results for the non-catalysed continuous deuteration of eugenol and 4-hydroxyacetophenone in near-critical D₂O at different temperature and residence time. Influence of metal leaching (e.g. Cr, Ni) from the Hastelloy capillary reactor on the deuteration results was excluded by rinsing the system with H₂O at characteristic process conditions for several hours. AAS analysis of the effluent stream revealed only negligible Ni and Cr concentrations of 3.2 mg/L and < 0.2 mg/L, respectively.

Studying the deuteration of eugenol (p = 300 bar), H/D exchange rates were clearly favoured with increasing temperature due to higher acid dissociation constant of the substrate and faster reaction kinetics (e.g. at 250 ⁰C, d₀ = 46%; at 350 ⁰C, c/₃ = 51%). In contrast, the self-ionisation constant of D₂O should not have a significant impact on the deuteration results, since the pKW value change only slightly over the temperature range studied [vii]. Doubling the residence time at isothermal conditions enhanced both number of exchanged sites and purity of most dominant isotope (e.g. 2 min, d₂: 48%; 4 min, cfe: 51%). Recovery of labelled eugenol after liquid-liquid extraction with methylene chloride was ca. 50%. These yields were almost comparable to those of reported for literature batch runs (recovery 42 - 85% [xvii]), even without further optimisation of extraction conditions (e.g. effluent flow - solvent flow ratio, choice of extraction medium, temperature). Figure 6 compares isotopic composition of the fresh eugenol stock solution with those after deuteration in batch and continuous mode at optimized temperature and reaction/residence time. In Figure 6, the blank D column denotes fresh stock solution, dark grey column D denotes deuteration of eugenol in batch in a molar ratio of D₂O : eugenol = 1550 : 1 , T = 250 ⁰C, t = 2 h, and light grey column D denotes deuteration of eugenol in continuous mode according to an embodiment of the invention in a molar ratio of D₂O : eugenol = 215000 : 1 , T = 300 ⁰C, τ = 2 min, using pressurized hot D₂O (p = 300 bar). Note that each dn₊i also includes signal arising from ¹³C in d_n. A higher d-i-fraction (M+1) than that expected due to ¹³C (ca. 11 %) was detected for fresh eugenol, which might be caused by ion-molecule reactions in the MS ion source due to relatively high substrate concentration [xxviii]. Continuous flow experiments accomplished identical purity of the major eugenol isotope (d-i: 61%, T = 300 ⁰C, τ = 2 min) as batch runs before (di: 59 %, T = 250 ⁰C, t = 2 h), while reducing the reaction time by almost two orders of magnitude and shifting the isotopic spectrum to slightly lower deuteration levels (Fig. 6). Major mass fragments of m/z 164 (molecular peak), m/z 149 (loss of methyl group), m/z 91 (benzyl/tropylium ion) of fresh eugenol and m/z 165 (molecular peak), m/z 150, ml z 92 for eugenol-di suggested a H/D exchange at the aromatic ring. ¹H- NMR analysis of reactor inlet and outlet solution clearly identified the deuteration of the H-9 hydrogen atom (Fig. 5 (a)) by disappearance of its corresponding chemical shift at δ = 6.85 ppm, as illustrated in Figure 7. In Figure 7, ¹H chemical shifts are shown for (a) eugenol (fresh stock solution) and (b) eugenol-di (continuous deuteration, molar ratio of D₂O : eugenol = 215000 : 1 , p = 300 bar, T = 300 ⁰C, τ = 2 min): δ = 3.3 ppm (d, 2H; H-1), 3.9 (s, 3H; H-2), 5.05 (m, 1 H; H-3), 5.1 (m, 1 H; H-4), 5.5 (s, 1 H; H-5), 5.9 (m, 1 H; H-6), 6.67 (m, 1H; H-7), 6.69 (m, 1H; H-8), 6.85 (m, 1H; H-9). Nomenclature of hydrogens is according to Figure 5. To selectively tailor the deuteration level of eugenol, the effluent flow was recycled as reactor feed for several times in an additional test series (T = 300 ⁰C, t = 2 min; Table 3). For each cycle, the number of labelled sites increased, however, accompanied by diminished isotopic purity (e.g. 1^st cycle, c/i: 61 %; 4^th cycle, cfe: 45%). Nevertheless, further optimisation of recycling conditions is expected to provide tunability of isotopic purity and exchange level.

When screening reaction conditions for the continuous deuteration of 4- hydroxyacetophenone (p = 300 bar; Table 2), identical trends were noticed as before on eugenol. As a result of acid dissociation constant and reaction kinetics, isotope spectra shifted to higher levels with increasing temperature

(e.g. at 250 ⁰C, d₂: 35%; at 350 ⁰C, cfe: 74%). A less pronounced influence was found for extension of residence time at reaction temperature below 350 ⁰C (e.g. 1 min, d₄: 39; 2 min, cfe: 62%). Extraction recovery of typically 65% was slightly higher than for deuteration of eugenol and again competitive to those of batch runs from literature [xvii].

Figure 8 shows deuteration of 4-hydroxyacetophenone. In Figure 8, the blank D column denotes fresh stock solution, the dark grey column D denotes deuteration of 4-hydroxyacetophenone in batch in a molar ratio of D₂O : 4- hydroxyacetophenone = 1550 : 1 , T = 350 ⁰C, t = 2 h, and the light grey column D denotes deuteration of 4-hydroxyacetophenone in a continuous mode in a molar ratio of D₂O : 4-hydroxyacetophenone = 15000 : 1 , T = 350 ⁰C, τ = 2 min) using pressurized hot D₂O (p = 300 bar). Note that each c/_n+i also includes signal arising from ¹³C in d_n. At optimum conditions (Fig. 8), continuous deuteration of 4-hydroxyacetophenone accomplished almost as high H/D exchange (αf₅: 82%, T = 350 ⁰C, τ = 2 min) as in comparable batch runs (cfe: 91 %, T = 350 ⁰C, t = 2 h). The short contact time was again expected to decisively reduce the decomposition probability during the continuous run. GC-MS analysis revealed main mass fragments of m/z 136 (molecular peak), m/z 121 (loss of methyl group), and m/z 93 (additional loss of CO) for 4- hydroxyacetophenone and m/z 141 , m/z 123, and m/z 95 for its 5-fold deuterated isotope, respectively. These observations indicated a H/D exchange at the methyl group and the aromatic ring.

¹H-NMR analysis provided a more detailed insight into the exact exchange positions of 4-hydroxyacetophenone, as illustrated in Figure 9. In Figure 9, ¹H chemical shifts are shown for (a) 4-hydroxyacetophenone (fresh stock solution) and (b) 4-hydroxyacetophenone-d₅ (continuous deuteration, molar ratio of D₂O : 4-hydroxyacetophenone = 15000 : 1 , p = 300 bar, T = 350 ⁰C, τ = 2 min): δ = 2.6 ppm (s, 3H; H-1), 6.9 (d, 1H; H-2), 7.9 (d, 1 H; H-3). Nomenclature of hydrogens is according to Figure 5. By disappearance of corresponding chemical shifts, H/D exchange was distinctly assigned to the methyl group (δ = 2.6 ppm; H-1) and both the hydrogens at m-position of the aromatic ring (δ = 6.9 ppm; H-2), whereas the hydroxy group was expected to remain unaffected by D₂O.

Fig. X shows a comparison of FTIR spectra of fresh and deuterated A- hydroxyacetophenone. IR bands of H/D exchanged groups generally shifted to lower wave numbers due to doubled mass. For experimentally obtained samples, this effect was clearly observed for the fully deuterated methyl group (4-hydroxyacetophenone: v(CHs) = 1361 cm^"1, 4-hydroxyacetophenone-cf₅: V(CD₃) = 1372 cm^"1). Bands of the twice labelled aromatic ring showed shifts about the same size in corresponding wave numbers (e.g. A- hydroxyacetophenone: v(aromatic ring) = 1283 cm^"1, 4-hydroxyacetophenone- d₅: v(aromatic ring) = 1271 cm^"1). Identical wavenumbers of the OH group of fresh and deuterated samples (v(OH) = 3150 - 3153 cm^"1) clearly validated the assumption of a non-exchanged hydroxy group proposed by ¹H-NMR before. Due to the acid-base reaction mechanism (eq. 1), the position of H/D exchange is generally determined by the acidity of the CH bonds involved. Methyl groups are most likely deuterated [xv], while aromatic hydrogens are favourably exchanged at positions nearest to electron-withdrawing groups, e.g. hydroxy group for 4-hydroxyacetophenone [xxix].

To proof the method applicability for a continuous production of deuterated compounds, long-time experiments of 10 h were performed for the H/D exchange on 4-hydroxyacetophenone without liquid-liquid extraction of the aqueous phase (p = 300 bar, T = 350 ⁰C, τ = 2 min). The deuterated product was separated from D₂O by evaporization in a vacuum rotary evaporizer after reaction. The complete recovery of 4-hydroxyacetophenone, that had been initially fed, excluded the loss of any compound during the reaction (e.g. by decomposition) and indicated a promising potential of the method developed as long-term continuous deuteration process for thermally sensitive substrates.

Although the invention has been described in the context of particular embodiments, various modifications are possible without departing from the scope and spirit of the invention as defined by the appended claims. It should be appreciated that whilst experimental examples illustrating the present invention have mainly been described in relation to deuterium oxide and aromatic hydrocarbons, embodiments of the present invention may be applicable to other types of deuterium or tritium containing compounds and to other types of organic or inorganic substrates containing hydrogen.

Claims

1. A method for obtaining a product substrate comprising at least one hydrogen isotope, the isotope comprising at least one neutron, the method comprising: feeding a compound of the at least one isotope and a substrate to at least one pressurised flow reactor; passing the compound and the substrate through the flow reactor for providing the substrate with the at least one isotope; and collecting the product substrate, the flow reactor allowing simultaneous feeding and collecting of material.

2. A method according to claim 1, wherein the step of feeding comprises feeding a substrate comprising hydrogen.

3. A method according to claim 2, wherein the step of passing comprises passing the compound and the substrate through the flow reactor for exchanging at least one hydrogen radical of the substrate to the at least one hydrogen isotope.

4. A method according to claim 1 , wherein the step of feeding comprises feeding an oxide of the at least one isotope.

5. A method according to claim 4, wherein the step of passing comprises passing the compound and the substrate through the flow reactor for hydrolysing the substrate to contain the at least one hydrogen isotope.

6. A method according to any of claims 1-5, wherein the step of feeding comprises mixing the substrate and the compound before feeding to the flow reactor.

7. A method according to any of claims 1-6, wherein the step of feeding comprises feeding the substrate and the compound in at least one pressurised flow reactor with a hollow elongated shell having one of a circular, oval or rectangular cross section.

8. A method according to claim 7, wherein the step of passing comprises heating from at least one of outside and inside the flow reactor.

9. A method according to any of claims 1-6, wherein the step of feeding comprises feeding the substrate and the compound in at least one pressurised flow reactor, each reactor with at least two hollow elongated shells having one of a circular, oval and rectangular cross section, the shells being placed inside each other.

10. A method according to claim 9, wherein the step of passing comprises heating from at least one of outside of the outermost of the at least two shells, inside of the innermost of the at least two shells and between at least two of the at least two shells.

11. A method according to any of claims 1-10, wherein the step of feeding comprises feeding at least one of a deuterated compound, a tritiated compound and a mixture of a deuterated compound and a tritiated compound.

12. A method according to claim 11 , wherein the step of feeding comprises feeding at least one of deuterium oxide (D₂O), tritium oxide (T₂O), tritium deuterium oxide (TDO), tritium hydrogen oxide (THO), deuterium hydrogen oxide (DHO), deuterated methanol and tritiated methanol.

13. A method according to any of claims 1-12, wherein the step of passing comprises passing a mixture of the substrate and the compound through the flow reactor with a residence time of less than one hour.

14. A method according to claim 13, wherein the step of passing comprises passing a mixture of the substrate and the compound through the flow reactor with a residence time of less than 10 minutes.

15. A method according to any of claims 1-14, wherein the step of passing comprises controlling the pressure in at least one of the inlet and the outlet of the flow reactor.

16. A method according to any of claims 1-15, wherein the step of passing comprises passing the substrate and the compound through the flow reactor at a temperature of at least 100 ⁰C and at a pressure of at least 1 MPa.

17. A method according to claim 16, wherein the step of passing comprises passing the substrate and the compound through the flow reactor at a temperature in the range of from 100 to 500 ⁰C and at a pressure in the range of from 1 to 50 MPa.

18. A method according to claim 17, wherein the step of passing comprises passing the substrate and the compound through the flow reactor at a near-critical temperature and pressure of the compound.

19. A method according to claim 17, wherein the step of passing comprises passing the substrate and the compound through the flow reactor at a supercritical temperature and pressure of the compound.

20. A method according to any of claims 1-19, wherein the step of feeding comprises feeding as the substrate at least one of a hydrogen containing organic compound, a hydrogen containing inorganic compound, an aromatic hydrocarbon, an aliphatic organic compound, an alkane, an alkene, a cyclic organic compound, an alcohol, a ketone, an ether, a heterocyclic compound, an amine, a carbohydrate, an amino acid, a carboxylic acid, a hydrogen containing inorganic compound, a polyaromatic compound, a thiol, a sulfide, an organosilicon compound, an organometal, a halogenated organic compound, a phenol, a difunctional compound, a peptide and an ester.

21. A method according to claim 20, wherein the step of feeding comprises feeding as the substrate an aromatic hydrocarbon.

22. A method according to any of claims 1-21, further comprising dissolving the substrate in the compound before the step of feeding.

23. A method according to any of claims 1-22, further comprising preheating the substrate and the compound before the step of feeding.

24. A method according to any of claims 1-23, wherein the step of collecting comprises collecting the substrate by at least one of vacuum evaporation, isolating from an outlet mixture, cooling followed by phase separation and depressurisation followed by phase separation.

25. A method according to any of claims 1-24, further comprising circulating at least a part of an outlet mixture back to the step of feeding.

26. A flow reactor for obtaining a product substrate comprising at least one hydrogen isotope, the isotope comprising at least one neutron, the flow reactor comprising: an inlet for feeding a compound of the at least one isotope and a substrate; a pump for passing the compound and the substrate through the flow reactor at an elevated pressure for providing the substrate with the at least one isotope; and an outlet for collecting the product substrate , the inlet and the outlet allowing simultaneous feeding and collecting of material.

27. A flow reactor according to claim 26, comprising a hollow elongated shell having one of a circular, oval and rectangular cross section.

28. A flow reactor according to claim 27, comprising a heater for heating from at least one of outside and inside the flow reactor.

29. A flow reactor according to claim 26, comprising at least two hollow elongated shells having one of a circular, oval and rectangular cross section, the shells being placed inside each other.

30. A flow reactor according to claim 29, comprising a heater for heating from at least one of outside of the outermost of the at least two shells, inside of the innermost of the at least two shells and between at least two of the at least two shells.

31. A flow reactor for obtaining a product substrate comprising at least one hydrogen isotope, the isotope comprising at least one neutron, the flow reactor configured to: feed a compound of the at least one isotope and a substrate to the flow reactor; pass the compound through the flow reactor at an elevated pressure for providing the substrate with the at least one isotope; and collect the product substrate , the flow reactor allowing simultaneous feeding and collecting of material.

32. A flow reactor for obtaining a product substrate comprising at least one hydrogen isotope, the isotope comprising at least one neutron, the flow reactor comprising: feeding means for feeding and a compound of the at least one isotope and a substrate to the flow reactor; passing means for passing the compound and the substrate through the flow reactor at an elevated pressure for providing the substrate with the at least one isotope; and collecting means for collecting the product substrate , the flow reactor allowing simultaneous feeding and collection of material.

33. A flow reactor system for obtaining a product substrate comprising at least one hydrogen isotope, the isotope comprising at least one neutron, the flow reactor system comprising at least one flow reactor according to any of claims 26-32.

34. A flow reactor system according to claim 33, further comprising a mixer for mixing the substrate and the compound before feeding to the at least one flow reactor.

35. A flow reactor system according to claim 33 or 34, further comprising a pressure restrictor for controlling the pressure in the inlet of the at least one flow reactor.

36. A flow reactor system according to any of claims 33-35, further comprising a pressure restrictor for controlling the pressure in the outlet of the at least one flow reactor.

37. A flow reactor system according to any of claims 33-36, further comprising a premixing unit for dissolving the substrate in the compound before the inlet.

38. A flow reactor system according to any of claims 33-37, further comprising a heater for preheating the substrate and the compound before the inlet.

39. A flow reactor system according to any of claims 33-38, further comprising a vacuum evaporator for collecting the substrate.

40. A flow reactor system according to any of claims 33-38, further comprising an isolating unit for isolating the substrate from an outlet mixture.

41. A flow reactor system according to any of claims 33-38, further comprising a cooling unit for cooling the substrate and a phase separation unit for phase separation of the substrate.

42. A flow reactor system according to any of claims 33-38, further comprising a depressurising unit for depressurising the substrate and a phase separation unit for phase separation of the substrate.

43. A flow reactor system according to any of claims 33-42, further comprising a recycler for circulating at least a part of an outlet mixture back to the step of feeding.