Ind. Eng. Chem. Res. 2004, 43, 7907-7911
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CO2-Protected Amine Formation from Nitrile and Imine Hydrogenation in Gas-Expanded Liquids Xiaofeng Xie, Charles L. Liotta, and Charles A. Eckert* Schools of Chemical Engineering and Chemistry and Specialty Separations Center, Georgia Institute of Technology, 311 Ferst Drive NW, Atlanta, Georgia 30332-0100
Gas-expanded liquids are tunable media for reaction and separation. We report that gas-expanded liquids under CO2 pressure are unique media for amine formation and separation. In the heterogeneous hydrogenation of benzonitrile and phenylacetonitrile with NiCl2/NaBH4 in CO2expanded ethanol, the primary amines are protected by CO2 so that the yield of the primary amines is greatly increased and the production of the secondary amines is effectively suppressed. In the homogeneous hydrogenation of benzonitrile and phenylacetonitrile with RhH(P-i-Pr3)3 and benzophenone imine with Rh(1,5-C8H12){P(C6H5)3}2]PF6 in CO2-expanded tetrahydrofuran, the primary amines are separated in situ in the form of solid carbamic acids and/or ammonium carbamates with increased yield while the catalyst remains in the solution. These results demonstrate the potential for using modest pressures of CO2 to facilitate reactions as well as to separate products. Introduction Gas-eXpanded Liquids (GXLs) are generally organic solvents containing significant amounts of a gas, most often CO2. Such fluids offer advantages as reaction1-4 and separation5-7 media. Compared to regular solvents, GXLs afford increased solubility of gases, enhanced mass transfer, a measure of tunability of solvent strength, and the additional safety provided by a nonflammable solvent. Compared to supercritical or liquid CO2, GXLs afford higher solubility of homogeneous catalysts at significantly lower pressures. GXLs have a great potential to overcome many of the chemical, engineering, and environmental difficulties associated with the conventional heterogeneously or homogeneously catalyzed multiphase reactions between reactants in the gas phase and those in the liquid phase, such as hydrogenation with H2, oxidation with O2, and hydroformylation with CO. As many of these reactions are carried out under pressure anyway, the capital investment for the high-pressure equipment related to CO2 is less of an obstacle than in processes currently operated at ambient pressure. The properties of CO2-expanded liquids can be tuned with CO2 pressure and temperature,8 which has been used for separation, especially gas antisolvent precipitation (GAS).9 Compared to supercritical CO2 (scCO2), the dielectric constants of CO2-expanded liquids are much more tunable, which allows for a wider range of solubility variation for many substances, such as polymers10 and homogeneous catalysts.2 However, the tunability of CO2-expanded liquids has been much less exploited for reactions than that of scCO2 since only a few reactions have been tried in CO2-expanded liquids to date. The reactions in scCO2 are tuned mainly with pressure, temperature, and cosolvent, which will physically change the solution structure11 with scCO2 as an inert reaction medium that undergoes no chemical reaction. In a few cases, CO2 interacts with certain functional groups and can thus impact the chemical transformation. For example, methanol and ethylene glycol under
Figure 1. Formation of carbamic acid and ammonium carbamate between amines and CO2.
CO2 pressure are catalytic media for the acetal formation reaction of cyclohexanone with alkylcarbonic acids formed in situ as possible catalysts.12 Amines can react with CO2 to form carbamic acids and/or ammonium carbamates (Figure 1) with various structures,13,14 a method long used for CO2 separation from gases.15 The interaction between sufficiently basic amines and CO2 decreases the nucleophilicity of the nitrogen atom and makes it less reactive in CO2 solution.16,17 Another example is Dimcarb, which is the dimethylamine CO2 adduct used as a solvent. It is reasonable to expect these chemical interactions to happen in CO2-expanded liquids since the CO2 concentration is significant in many solvents under only a few tens of bars of CO2 pressure.18 Some carbamic acids and/or ammonium carbamates can be isolated in solid form when CO2 pressure is applied to liquid amines or amine solutions.19 If amines are produced from certain reactions, such as hydrogenation of nitriles and imines, and precipitate out in the form of carbamic acids and/or ammonium carbamates in CO2-expanded liquids, this separation scheme is similar to the in situ product separation for precipitation polymerization in scCO220 and CO2-expanded liquids.21 Nitrile hydrogenation is practiced industrially on a large scale to produce mono- and polyamines, which are important chemicals and intermediates. Heterogeneous catalysts, such as Raney nickel, are used in almost all the commercial processes; the art of homogeneous nitrile
10.1021/ie0498201 CCC: $27.50 © 2004 American Chemical Society Published on Web 10/21/2004
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Ind. Eng. Chem. Res., Vol. 43, No. 24, 2004
Table 1. Experiments in Literature That Were Repeated in CO2-Expanded Liquids in This Worka no.
substrate
solvent
catalyst
ref
1 2 3
benzonitrile, phenylacetonitrile benzonitrile, phenylacetonitrile benzophenone imine
MeOH THF THF
NiCl2/NaBH4 RhH(P-i-Pr3)3 Rh(1,5-C8H12){P(C6H5)3}2]PF6
28 33 38
a Experiment 1, heterogeneous nitrile hydrogenation; experiment 2, homogeneous nitrile hydrogenation; experiment 3, homogeneous imine hydrogenation.
hydrogenation catalysis is much less extensive, and reported catalysts almost always suffer from low rates or poor selectivity to primary amines.22 In organic synthesis, the nitrile group is ordinarily reduced using either catalytic hydrogenation or a strong hydride donor, such as lithium hydride, which is not especially selective. Sodium borohydride is generally not strong enough to bring about reduction. Various transition metal salts, such as cobalt(II) and nickel(II) salts, have been known to improve dramatically the reactivity of sodium borohydride.23 The catalytic hydrogenation of imines to amines has attracted considerable interest in recent years, especially for prochiral substrates given the growing importance of enantiomerically pure nitrogen-containing compounds in the pharmaceutical and agrochemical industries. Asymmetric hydrogenation of prochiral imines is mainly achieved with homogeneous catalysts.24 Compared with homogeneous hydrogenation of carboncarbon and carbon-oxygen double bonds, homogeneous hydrogenation of carbon-nitrogen double bonds is more difficult in terms of reaction conditions and is consequently less developed. In this work, we transferred several existing hydrogenation reactions of nitriles and imines in organic solvents (Table 1) into CO2-expanded liquids and compared the results with those in the original experiments. Experimental Section Chemicals. The chemicals used in these investigations were obtained and used without further purification except for carbon dioxide, nitrogen, and hydrogen gas, which went through gas purifiers from the cylinder to other parts of the experimental system. They include carbon dioxide (Matheson, SFC grade, 99.999%), nitrogen (Air Products, high purity grade), hydrogen gas (Air Products, ultrahigh purity), methanol (Aldrich, 99.93% HPLC grade, anhydrous), tetrahydrofuran (THF, Aldrich, 99.9+%, Biotech grade), sodium borohydride (NaBH4, Aldrich, 99.995%), phenylacetonitrile (Aldrich, 99+%), benzonitrile (Aldrich, 99.9%, HPLC grade), phenethylamine (Aldrich, 99+%), benzylamine (Aldrich, 99.5+%), acetic anhydride (Aldrich, 99+%), di-tert-butyl dicarbonate (Aldrich, 99+%), benzophenone imine (Aldrich, 97+%), (diphenylmethyl)amine (Aldrich, 97+%), nickel(II) chloride hexahydrate (Aldrich, 99.99%), triisopropylphosphine (Aldrich, 90%), dichloromethane (Aldrich, HPLC, 99.9%), ethanol (Aldrich, absolute, 99.8+%), diethyl ether (Aldrich, 99+%), benzene (Aldrich, 99+%), water (Aldrich, HPLC), triphenylphosphine (Aldrich, 99%), Chloro(1,5-cyclooctadiene)rhodium(I) dimer ([RhCl(1,5-C8H12)]2, Strem, 98%), potassium hexafluorophosphate (Aldrich, 99.9%), rhodium(III) chloride (Aldrich, 99.9%), and sodium mercury amalgam (Aldrich, 1% Na, 99.9%). (1,5-Cyclooctadiene)(triphenylphosphine)rhodium hexafluorophosphate (Rh(1,5-C8H12){P(C6H5)3}2]PF6) and (triisopropylphosphine)rhodium hydride (RhH(P-i-Pr3)3) were synthesized according to literature methods.25,26
Apparatus and Procedures. The temperatures in the reactors were measured to (0.1 °C with type J thermocouples (Omega), which were previously calibrated in a hot point cell (Omega) and connected to digital temperature indicators (HH-22, Omega). The pressures in the reactors were measured to (0.07 bar with pressure transducers (Druck Limited, DPI 260 readout PDCR-3040 transducer) which were previously calibrated against a hydraulic dead weight tester (Ruska). Heterogeneous Nitrile Hydrogenation under CO2 Pressure. Reactions were performed in a 125 mL 316 stainless steel high-pressure/high-temperature stirred autoclave with 1.75 in. internal depth and 2 in. internal diameter (Parr model 4560). The temperature was regulated to within 1 °C of the set point using a Parr (model 4832) controller. Agitation was maintained at 300 ( 5 rpm using a four-blade 85° pitched-blade impeller. A solution of NiCl2 (6H2O) (0.1783 g, 0.75 mmol) in ethanol (35 mL) was loaded into the reactor using gastight syringes under a nitrogen atmosphere. After the temperature was stable, a solution of NaBH4 (0.0568 g, 1.5 mmol in 5 mL of ethanol) was added to the stirred solution by syringe pump over 1.5-2 min. After 15 min, a solution of benzonitrile (0.775 g, 7.5 mmol) or phenylacetonitrile (0.8786 g, 7.5 mmol) and n-decane (0.1423 g, 1 mmol) in ethanol (10 mL) was added by syringe pump. After another 15 min, the reactor was opened and finely pulverized NaBH4 (0.5675 g, 15.0 mmol) was added to the solution. CO2 was then filled into the reactor to the specified pressure through a valve with a syringe pump (ISCO model 260 D). It took a few minutes for the temperature and pressure to stabilize. Periodically, the reactor was depressurized and samples (ca. 2 mL each) of the heterogeneous reaction mixture were taken. After samples were centrifuged, 1 mL aliquots of the supernatant were withdrawn and mixed with diluted HCl (2 mL of 1:9 concentrated HCl/EtOH). Each aliquot was shaken vigorously to decompose both NaBH4 and Ni2B and then centrifuged. The supernatant was analyzed by gas chromatography. A control experiment in which no solid NaBH4 was added to the mixture of PhCN and Ni2B showed that less than 1% reduction had occurred after 2 h. Heterogeneous Nitrile Hydrogenation without CO2 Pressure. The same reactor and conditions were used as described above, but no CO2 was added. Instead, di-tert-butyl dicarbonate (3.2750 g, 15 mmol), acetic anhydride (1.5314 g, 15 mmol), or nothing was added to the reactor with the final batch of NaBH4. Homogeneous Nitrile Hydrogenation. Under nitrogen atmosphere, a solution of the catalyst RhH(P-iPr3)3 (0.0059 g, 0.01 mmol), the nitrile (phenylacetonitrile) (0.1172 g, 1 mmol), n-decane (0.0142 g, 0.1 mmol) in THF (2 mL), and a stirring bar (1/16 in. × 1/8 in.) were put into a test tube (round bottom, 1 cm o.d. × 10 cm), which was then capped with a filter (0.2 µm) and placed in a 150 mL windowed pressure vessel (Jerguson Gauge,
Ind. Eng. Chem. Res., Vol. 43, No. 24, 2004 7909 Table 2. Primary Amine Yield Improvement by Protecting Agents (15 mmol) or CO2 (30 bar) in Phenylacetonitrile (7.5 mmol) Hydrogenation Reaction Catalyzed by Sodium Borohydride (16.5 mmol) with Nickel Chloride (0.75 mmol) in Ethanol at 30 °Ca
time/h
secondary amine yield/%
without protection without protection
1 20
87 (86) 99 (99)
acetic anhydride di-tert-butyl dicarbonate carbon dioxide (30 bar)
24 24 24
0.91 0.12 0.15
protecting agents
Figure 2. Formation of secondary and tertiary amines in nitrile hydrogenation.
model 19T40). The vessel was then mounted on an arm and placed on a stirring plate. With the stirrer on, the vessel was pressurized with only H2 or H2 and then CO2 to the desired pressures at room temperature (23-25 °C). Periodically, the vessel was turned upside down and the liquid phase was released into a sampling loop. Solid, if any, was retained by the filter. After depressurization, the test tube was rinsed with methanol to recover the solid, and the methanol solution was collected in a volumetric flask. The THF solution and methanol solution samples were analyzed by gas chromatography. Homogeneous Imine Hydrogenation. Treatment of a suspension of Rh(1,5-C8H12){P(C6H5)3}2]PF6 (0.001 g, 0.0011 mmol) in MeOH (2 mL) with 1 atm of H2 at room temperature (23-25 °C) for 2 h afforded a pale yellow solution of [Rh(H)2(PPh3)2(MeOH)2]PF6. Excess benzophenone imine (g, 0.11 mmol, Rh:imine ) 1:100) was added to the methanol solution under 1 atm of H2, and the solution was analyzed by gas chromatography at the end of the reaction. The same reactor and other procedures described above for homogeneous nitrile hydrogenation were used. Gas Chromatographic Analysis. The samples were analyzed by gas chromatography (GC, Hewlett-Packard model 6890) equipped with mass spectrometry (MS) and flame ionization detector (FID). The MS detector was used for identification, while the FID detector was used for quantification. External standards of known concentration of substrates and products and internal standard n-decane were used to calibrate the FID detector for quantification. Results and Discussion Heterogeneous Nitrile Hydrogenation. The addition of two hydrogen molecules to the carbon-nitrogen triple bond of nitriles proceeds stepwise to yield the primary amine product. However, the intermediate imine species (carbon-nitrogen double bond) is quite reactive to produce secondary and/or tertiary amines (Figure 2), which are undesired byproducts in most situations. In industry, the formation of higher amines is usually suppressed with a large amount of ammonia. In organic synthesis, a strong hydride donor, such as lithium aluminum hydride, leads to high primary amine yield but low chemoselectivity (cohydrogenation of other groups).22 If weaker but more selective reducers are used, the formation of higher amines can be significant sometimes.27 One way to increase primary amine yield is to trap the initially formed primary amine in situ, by acylation for example, so that the reduced nucleophilicity of the resultant amide would prevent further reaction with the intermediate imine.28
primary amine yield/%
