- Email: [email protected]
Gas phase oxidation of ethane to acetic acid using high-throughput screening in a massively parallel microfluidic reactor system
Applied Catalysis A: General 254 (2003) 67–76
Gas phase oxidation of ethane to acetic acid using high-throughput screening in a massively parallel microfluidic reactor system Sam Bergh a , Shenheng Guan a , Alfred Hagemeyer a,∗ , Claus Lugmair a , Howard Turner a , Anthony F. Volpe Jr. a , W. Henry Weinberg a , Graham Mott b b
a Symyx Technologies Inc., 3100 Central Expressway, Santa Clara, CA 95051, USA Celanese Ltd., Corpus Christi Technical Center, 1901 Clarkwood Road, Corpus Christi, TX 78409/78469, USA
Received 30 September 2002; accepted 18 December 2002
Abstract High-throughput primary synthesis and screening methods have been applied to the heterogeneously-catalyzed gas phase oxidation of ethane to acetic acid using mixed metal oxide catalysts. The discovery libraries consisted of 16 × 16 arrays of 256 catalysts on 3 × 3 quartz wafers. Catalysts were prepared using automated liquid-dispensing techniques and screened in parallel for catalytic activity in a Symyx Technologies 256-channel microfluidic reactor. Product detection was performed using parallel colorimetric techniques on products adsorbed on silica-coated glass TLC plates. This workflow allows the screening of more than 3000 samples per day. Promising leads were confirmed in focus libraries and are being optimized in secondary screening. MoV was identified as the most active binary of redox metals and was subsequently doped with main group, rare earth, and transition metals to form ternaries. Prior art MoVX (X = Nb, Ni, Sb) catalysts were successfully reproduced and it was shown that Pd doping significantly increases the catalytic activity of these systems. Three novel MoVY ternary systems were discovered. © 2003 Elsevier Science B.V. All rights reserved. Keywords: Acetic acid; Selective oxidation; High-throughput screening; Combinatorial chemistry; Microreactors
1. Introduction Acetic acid is produced commercially by methanol carbonylation, aceteldehyde oxidation, and the uncatalyzed oxidative cleavage of C4–C8 hydrocarbons [1]. The direct gas phase oxidation of ethylene has recently been announced by Showa Denko and is based on a supported palladium catalyst [2]. Ethane oxidation is an attractive alternative route to acetic acid that has become increasingly attractive due to the availability ∗ Corresponding author. Tel.: +1-408-764-2059; fax: +1-408-748-0175. E-mail address: [email protected] (A. Hagemeyer). URL: http://www.symyx.com.
of low cost ethane feedstock from natural gas sources and is being pursued by several groups. H3 C–CH3 + 1.5O2 → CH3 –COOH + H2 O Union carbide pioneered this work using MoVNb systems for the coupled production of varying amounts of ethylene and acetic acid depending on the severity of reaction conditions [3]. Preparation, structural characterization, and catalytic properties of MoVNb oxide catalysts for this reaction have recently been reinvestigated [4]. Various other mixed metal oxide catalysts have been reported including VTi, MoV, MoW, as has the noble metal doping of these oxidic systems with Pd, Re, Ir, Ag, and Au [5–10]. MoVNbPd appears to
0926-860X/$ – see front matter © 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S0926-860X(03)00264-3
68
S. Bergh et al. / Applied Catalysis A: General 254 (2003) 67–76
be among the best performing catalyst systems and it has been proposed that Pd accelerates the oxidation of the ethylene intermediate in the consecutive reaction sequence [11]. The operation of a fixed bed and fluidized bed reactor has recently been simulated and the oxidation kinetics over MoVNbPd modeled [12]. It was concluded that ethane activation is the rate determining step for oxidizing ethane, and that the formation of the Pd Wacker center by water adsorption is rate determining for converting ethylene to acetic acid. A comprehensive characterization of the MoVNbPd catalyst has also been carried out [13]. While a consecutive reaction scheme dominates at low temperatures with ethylene as an intermediate leading to acetic acid, ethylene and acetic acid are mainly formed in parallel at high temperatures. Hydrothermally synthesized MoVAlTi and MoV-AlGaFeBiSbTe mixed oxide catalysts were also found to be active for selective ethane oxidation [14]. Heteropoly compounds have also been studied for the selective oxidation of light alkanes including ethane [15]. Site isolation of the active V centers was found to be crucial in the ethane oxidation to acetic acid over VPMoO/TiO2 [16] and a kinetic model for Mo-doped VPO has been presented [17]. Possible technical implementations of the process (e.g. in fluidized beds or reactor cascades) have also been disclosed [18]. Integrated processes for the manufacture of ethyl acetate and vinyl acetate by reaction of ethylene and acetic acid intermediates have been proposed as well [19]. A catalyst system composed of Pd-impregnated MoVNbSb composite oxides has been developed for the related oxidation of ethylene to acetic acid [20] and efficient Ni catalysts have been discovered for the related oxidative ethane dehydrogenation reaction [21]. A review of catalysts and their preparation, liquid and gas phase oxidation of ethane, and reaction mechanisms has recently been published [22]. The direct oxidation of ethane to acetic acid has not yet been commercialized, primarily because the existing catalyst systems suffer from relatively low activity and/or insufficient selectivity to acetic acid. Thus, there remains a need for the discovery and optimization of novel catalyst systems to make this reaction commercially viable. In this paper we describe the use of high-throughput combinatorial synthesis and screening techniques for the exploration of large composition spaces to quickly
identify active and selective catalyst lead compounds for this reaction. The general screening strategy implemented at Symyx is based on two hierarchical screens. The primary screen is characterized by very high throughput in continuous flow 256-channel parallel microreactors. Acetic acid was detected in parallel using pH-based colorimetric techniques on products adsorbed on silica coated glass TLC plates. Identified hits were scaled up and further optimized in the secondary screen. In this paper we focus on primary screening of mixed metal oxide ternaries; results on quaternaries will be presented in forthcoming publications. 2. Experimental procedures 2.1. Catalyst preparation Wafer-formatted catalyst libraries were designed and synthesized using Symyx Proprietary Library Studio® and Impressionist® Software [23]. Commercial 3 in. × 3 in. quartz wafers were bead blasted through steel masks with ␣-Al2 O3 powder to produce 16 × 16 arrays of wells which were then pre-coated with an ␣-alumina primer layer by slurry dispensation and dried. The metal precursor solutions were dispensed onto the wafers using automated liquid handling robots (Fig. 1) and the catalysts were prepared by subsequent drying and calcination steps. Aqueous metal nitrates (alkali, earth alkali, rare earth, Group IIIB, IB, IIB metals, Zr, Cr, Mn, Fe, Co, Ni, Al, Ga, In, Pb, Bi, Ru, Rh, Pd, and Pt), oxalates (Ti, V, Nb, Ta, Mo, Sn, and Ge), ammonium salts (vanadate, tungstate, and Sb oxalate) and acids (boric, perrhenic, telluric, selenic, and phosphoric) and in some cases chlorides (Hf, Sn, Ir, and Pt) were used as the standard metal precursors. Concentrations of stock solutions were 1 M for Mo and V oxalate, 0.5 M for all other metals, and 0.01–1 wt.% for noble metals. Incompatible stock solutions were dispensed sequentially. Bulk (unsupported except for the ␣-alumina primer layer) as well as supported mixed metal oxides were synthesized. Carriers used were silica, alumina, titania, and zirconia which were slurry dispensed onto the wafer prior to metal deposition. Initially the wafer was impregnated two to three times with the same library design (from the same microtiter plate) to
S. Bergh et al. / Applied Catalysis A: General 254 (2003) 67–76
69
Fig. 1. (a) Synthesis station with liquid handling robot, rack of stock solutions, microtitre plate, and catalyst wafers; (b) quartz wafer with 16 × 16 catalyst matrix; (c) liquid dispensing into carrier pre-coated wafer wells (2 ml dispense volume/well; ∼0.5 mg catalyst loading/well).
increase the catalyst loading in the wells (to about 1 mg; 2 ml dispense volume per well per dispense step) to achieve higher acetic acid productivity and thus higher detection signal intensity. A typical post synthesis treatment involved a drying step at 120 ◦ C and calcination in air at 350–400 ◦ C for 4 h. 2.2. Catalyst screening 2.2.1. High-throughput reactor system High-throughput screening experiments of combinatorial libraries were performed using a parallel microreactor based on a microfluidic flow distribution device, 256-element catalyst array, and colorimetric detection methodology allowing parallel reaction and parallel detection (Figs. 2 and 3). This reactor is Symyx, second generation primary screening tool and offers significant technological advances over its predecessor, the scanning mass spectrometer [24], which is a rapid serial screening tool. The microflu-
idic parallel screening reactor provides identical gas flows [25] to the 16 × 16 array of microreactors by employing a fluidic device constructed using microfabrication technologies [26]. The microreactors are formed by contacting the catalyst wafer and gas distribution wafer together. A single reaction stream provided by conventional flow controllers and vaporizers is divided into 256 streams with a binary splitting pattern (bifurcation) on a two-dimensional area. Each individual stream is allowed to contact a 2 mm diameter× ∼0.2 mm deep well containing approximately 1 mg of catalyst. The accuracy of the flow division is ensured by the precision of the microfabricated channel structures and the bifurcation strategy for the division. Since a very low flow rate contacting the catalyst is possible, the concentration of each reactant component and products in the individual reactors is spatially distributed within the reactor volume due to the relatively large effect of diffusion compared to the velocity of the reaction flow stream. Variation in
70
S. Bergh et al. / Applied Catalysis A: General 254 (2003) 67–76
Fig. 2. Schematic representation of microfluidic parallel screening reactor system showing components and photograph of actual reaction station (US and Foreign Patents Pending).
contact time is kept small by the microfabricted upstream flow restricting distribution manifold that was designed to have a flow restriction greater than twenty times that of all downstream flow restrictions, which
Fig. 3. Drawing of a single reactor channel (top) and photograph of gas distribution wafer (bottom left) and sample image (bottom right) from the microfluidic parallel screening reactor. (US and Foreign Patents Pending).
in this geometry are also small. The accuracy of flow splitting using precision microfabricated channels in a large area silicon chip was measured offline using a flow meter and the channel-to-channel flow difference between channels was below 1%. All 256 reaction streams then flow through a temperature gradient before making contact with an absorbent plate or array where the products of interest are trapped either by absorption, chemical reaction, and/or condensation. The system is carefully designed so that a uniform reaction temperature and product trapping temperature are achieved in each of the reaction channels. Reaction exotherms are negligible due to the effective heat and mass transfer on the small scale as well as the relatively low conversions and corresponding high selectivities to acetic acid. After sufficient amounts of products have accumulated, the absorbent array is removed from the reactor and typically subjected to a spray of dye solution to develop certain optical properties of the array. These properties include absorption of certain colors, fluorescence, or bleach of absorption or fluorescence caused by selective reaction of the dye with products. The developed absorbent array is then imaged by a high resolution
S. Bergh et al. / Applied Catalysis A: General 254 (2003) 67–76
71
Fig. 4. (a) The absorption spectra of the acid (red) and base (yellow) form of the Methyl Red dye and (b) the integrated intensity vs. acid amount on TLC plate calibration curve.
CCD camera. As a first approximation, the integrated intensity of the CCD image is proportional to the amount of products. Since all 256 reactions, product trapping and development, and imaging are done as single processes, throughput is greatly increased and variations among reaction channels is minimized. The relative variation in yield was periodically checked by running a library of identical catalysts and was less than about 15%, including variations due to catalyst synthesis, reactor residence time, reaction temperature non-uniformities, adsorbent thickness variation, dye spray inhomogeneity, and data integration and processing. This range of data scatter does not inhibit our ability to discriminate between catalysts. The integral detection scheme (signal accumulation over TLC exposure time) and the amplification of performance differences when monitoring initial kinetics (maximum kinetic rates) also help in ranking the catalysts. For instance, signal intensities for the MoVX ternaries were found to vary by more than an order of magnitude among the various X dopants screened. A model feed (3 sccm of C2 , 2 sccm of O2 ) was used for the high density discovery wafers whereas the more active focus wafers were screened with a more realistic feed (2.5 sccm of C2 , 2 sccm of O2 , 8 sccm of N2 ). Contact time was about 2 s and reaction temperature was 375 ◦ C. 2.2.2. Parallel product analysis A detection method for acetic acid was developed and consists of product condensation on a silica TLC plate in an array of spots, followed by pH detection of trapped acetic acid with Methyl Red indicator (Fig. 4)
[27]. There is no significant diffusion of the products on the TLC plate within the time frame of the experiment. Thus there is minimal channel-to-channel cross-talk on the TLC plate.1 The exposed TLC plate is removed from the MEMS reactor and a water/methanol solution of Methyl Red and KOH is evenly sprayed onto it. The base form of Methyl Red is yellow and in the presence of acetic acid it is red. The KOH ensures that the dye is in its base form when sprayed and it neutralizes the acidic sites on the silica TLC material as well as some of the acetic acid. The sensitivity of the detection system can be adjusted by varying the amount of KOH in the dye solution. For the amount of acetic acid produced in each reactor the dye solution was optimized to contain 0.0007 M Methyl Red and 0.02 M KOH in a solution of 10% water in methanol. The color change from white to red was recorded in an automated imaging station equipped with a backlight for the TLC plate, an optical filter, and the CCD camera. The absorption spectra of the acid and base form of the dye are shown in Fig. 4a. The appearance of the base form of the dye was measured using a 550 nm band pass filter. To calibrate the detection system, acetic acid standards (known amounts of acetic acid in water) were spotted onto a TLC plate and sprayed with the dye solution. A photograph of the TLC plate was taken with the data 1 Cross-talk is occasionally observed in cases where highly active catalysts surround a completely inactive or blank well (see the blank diagonal in Fig. 8). Although this can result in false positives, it rarely affects the conclusions of screening since gradients are being examined in the majority of experiments. False positives are also screened out in focused primary screening and secondary screening.
72
S. Bergh et al. / Applied Catalysis A: General 254 (2003) 67–76
in units of absorbance and the intensity of each color spot was integrated. The calibration curve showed a linear response of intensity versus the amount of acetic acid present over about one order of magnitude (Fig. 4b). Interference by CO2 was negligible because of its much lower sticking coefficient to the (untreated) TLC plate (compared to the condensable acetic acid) and its much weaker acidity (approximate pH range for Methyl Red is 4.8–6.0, approximate pH value of 0.01 N acetic acid is 3.4). Catalyst library wafers and TLC plates were routinely rotated by 90◦ during the screening experiment to distinguish real spots (do rotate) from experimental artifacts such as scratches on TLC plate (do not rotate). Typically, a 15 min exposure time was used to develop a TLC plate and each wafer was screened for 1 h (at four different reaction conditions). In order to better differentiate small performance differences between similar catalysts and to increase the detection sensitivity, in some cases the KOH concentration of the Methyl Red indicator solution was increased (to accumulate more acetic acid before the color change). Another approach was to design a C4-symmetric li-
brary and rotate the wafer and/or TLC plate by 90◦ with the TLC signals accumulated to average over experimental fluctuations (at the expense of throughput, 64 versus 256 samples per library). The combined exhaust gas of all 256 channels downstream of the TLC compartment was occasionally checked by mass spectrometry and products other than C2 (cracking fragment of C2 H6 ; parent of C2 H4 overlap with CO), CO2 , and acetic acid were not observed.
3. Results Approximately forty catalyst libraries consisting of binary, ternary, and quaternary compositions were screened in the microfluidic parallel screening reactor over a 2-week period. About half of these were synthesized and the rest were from our catalyst archive. The overall screening protocol/strategy is summarized in Fig. 5. Primary screening was initially targeted to identify the best binary combinations of redox metals selected from V, Mo, Cr, Mn, Fe, Co, Ni, Cu, Ag,
Fig. 5. Screening protocol showing library studio library designs (top) and post reaction images of TLC detection wafers (bottom). Note that the white TLC plates appear black and the red spots appear white in the photo. Compositional details are given in Figs. 6–9: (a) binaries of redox active metals; (b) extension of binaries into ternaries by adding dopants; (c) focus ternaries of best hits; (d) noble metal doping of MoVNb ternary.
S. Bergh et al. / Applied Catalysis A: General 254 (2003) 67–76
Re, Sn, Sb, Ti, and Bi. The best hits and synergistic combinations of redox metal binaries were then extended to ternaries by adding single dopants selected from the main group metals, transition metals, and rare earth metals. Focused ternaries for the best hits were screened next in order to determine the most active compositional regions. Finally, the most active focus ternaries were doped evenly with noble metals over the ternary gradients. The effect of noble metal content was studied by synthesizing identical daughter wafers of the particular mixed oxide ternary followed by impregnation with solutions of different noble metal concentrations. Thirty redox binaries containing 8-point gradients were synthesized on each wafer along with 16 blanks to define the 0-point reference. A sample experiment is depicted in Fig. 6. For this wafer, the most active binaries were shown to be MoV, CrV, and MnV, with MoV being by far the most active. MnCr, CeCr, VTi, and MoTi displayed a low level of activity. It should be noted that an initial discovery screening protocol based on ternaries (e.g. three redox metals or two redox metals + 1 dispersant) produced more hits than the binary systems (results not shown).
73
Next, 18 non-symmetrical discovery ternaries consisting of 15 and 9 points were synthesized on each wafer leaving one row and one column blank. Fig. 7 shows an example of the library design for MoVX ternaries. The image shows that Nb, Ni, Sb, and Ce doping results in higher acetic acid productivity [8]. Other dopants that cannot be disclosed at this time, M1, M2, and M3, are also active. Eight focus ternaries of 28 points each can be accommodated on a single wafer with the two diagonals left blank. Fig. 8 shows a sample wafer for MoVX focus ternaries. The image indicates that Nb, M1, M2, and M3 produce the highest acetic acid yields. The MoVNb result is consistent with the literature [3,4]. Pd doping further significantly enhances the performance of the MoVNb ternary (Fig. 9) and this has also been previously reported [11]. Several other metal dopants also produced hits.
4. Discussion Patented catalyst examples for ethane to acetic acid were successfully confirmed in Symyx parallel
Fig. 6. Library design for 30 redox binaries (8-point gradients) and post-reaction TLC image (375 ◦ C reaction temperature, 15 min TLC exposure time, 100 ul/ MT plate well). MoV is by far the most active redox binary, other active binaries are CrV, MnV, MnCr, CeV, CoCr, CoV, VTi, and MoTi.
74
S. Bergh et al. / Applied Catalysis A: General 254 (2003) 67–76
Fig. 7. Library design for 18 MoVX ternaries (15 and 9-point ternaries) and post-reaction TLC image (375 ◦ C reaction temperature, 15 min TLC exposure time, 100 ul/well). Nb, Ni, Sb, Ce, M1, M2, and M3 dopants enhance activity of MoV binary.
Fig. 8. Library design for eight MoVX focus ternaries (28-point focus ternaries) and post-reaction TLC image (375 ◦ C reaction temperature, 15 min TLC exposure time, 100 ul/well). X = Nb, M1, M2, M3 are the most active ternaries.
S. Bergh et al. / Applied Catalysis A: General 254 (2003) 67–76
75
Fig. 9. Symmetric bis-ternary library design for MoVX focus ternary (lower left MoVNb ternary doped with flat Pd layer) and post-reaction TLC image (325 ◦ C reaction temperature, 15 min TLC exposure time, 100 ul/well). Pd doping enhances catalytic activity.
microreactor using wafer formatted libraries thus demonstrating the relevance of the primary screen for this oxidation. The performance ranking of redox binaries was found to be MoV CrV, MnV, CoV, VTi, MoTi, CoCr, MnCr. For MoV, the Mo-rich composition gives a higher yield. The ranking of MoVX ternaries is MoV-Nb, MoV-M3, MoV-M2, MoV-M1 > MoV-Ni, MoV-Sb, MoV-Ce > MoV-Fe. Three new dopants (M1, M2, M3) were discovered that at least equal the MoVNb system under the MEMS reactor testing conditions. Pd doping of MoVNb greatly enhances the acetic acid yield in full agreement with published data. Pd doping allowed lowering of the reaction temperature for screening in MEMS by about 50 K. It is observed that performance differences between catalysts are exaggerated in this primary screen thus facilitating catalyst discrimination. Differences in product formation rates are much more pronounced if initial differential kinetics at low conversion is monitored (as in MEMS) rather than integral productivities at high conversions. The acetic acid yield in MEMS was estimated by relative comparison to the known acetic acid standards spotted on each TLC detection plate at about 1%. By using a high-throughput microfluidic
parallel screening reactor in conjunction with Symyx high-throughput synthesis and catalyst archive, it was possible to screen more than 10,000 catalysts in a 2-week period.
References [1] K. Weissermel, H.J. Arpe, Industrial Organic Chemistry, Wiley, Weinheim, 1994; H. Koyama, Shokubai 38 (8) (1996) 626–633. [2] K. Sano, H. Uchida, S. Wakabayashi, Catal. Surv. Jpn. 3 (1) (1999) 55–60. [3] E.M. Thorsteinson, T.P. Wilson, F.G. Young, P.H. Kasai, J. Catal. 52 (1978) 116–132. [4] K. Ruth, R. Burch, R. Kieffer, J. Catal. 175 (1) (1998) 27–39; K. Ruth, R. Kieffer, R. Burch, J. Catal. 175 (1) (1998) 16–26; R. Burch, R. Kieffer, K. Ruth, Top. Catal. 3 (3–4) (1996) 355–364. [5] WO 98/23371 to Consortium fuer Elektrochemische Industrie. [6] EP 627401, US 5750777 to Rhone Poulenc. [7] JP 11290684 to Daicel. [8] EP 1043064, EP 492813, EP 480594, US 6333444, US 5260250, WO 00/14047, WO 99/51339 to BP. [9] US 6160162, US 6156928, US 6114278, US 6087297, US 6060421, US 6030920, US 6013597, US 5907056, WO 01/083103, WO 00/038833, WO 00/029105, WO 99/13980 to Sabic.
76
S. Bergh et al. / Applied Catalysis A: General 254 (2003) 67–76
[10] WO 01/090039, WO 99/20592, WO 98/47851, WO 98/47850, WO 98/05619, WO 97/44299, US 6399816, US 6274765, US 6194610, US 6034270 to Celanese. [11] US 6060421, US 6030920, WO 00/029105 to Sabic US 6399816, US 6274765, US 6034270, WO 01/090039, WO 98/05619, WO 97/44299 to Celanese. [12] D. Linke, D. Wolf, M. Baerns, S. Zeyss, U. Dingerdissen, L. Mleczko, Chem. Eng. Sci. 57 (1) (2002) 39–51; D. Linke, D. Wolf, M. Baerns, S. Zeyss, U. Dingerdissen, J. Catal. 205 (1) (2002) 32–43; D. Linke, D. Wolf, M. Baerns, U. Dingerdissen, S. Zeyss, Natural Gas Conversion VI, Stud. Surf. Sci. Catal. 136 (2001) 477–482. [13] D. Linke, D. Wolf, M. Baerns, O. Timpe, R. Schloegl, S. Zeyss, U. Dingerdissen, J. Catal. 205 (1) (2002) 16–31. [14] N.F. Chen, K. Oshihara, W. Ueda, Catal. Today 64 (1–2) (2001) 121–128; K. Oshihara, Y. Nakamura, M. Sakuma, W. Ueda, Catal. Today 71 (1–2) (2001) 153–159; W. Ueda, K. Oshihara, Appl. Catal. A 200 (1–2) (2000) 135– 143; W. Ueda, N.F. Chen, K. Oshihara, Kinet. Catal. 40 (3) (1999) 401–404; N.F. Chen, W. Ueda, K. Oshihara, Chem. Commun. (6) (1999) 517–518. [15] J.S. Min, N. Mizuno, Catal. Today 71 (1–2) (2001) 89–96; J.S. Min, N. Mizuno, Catal. Today 66 (1) (2001) 47–52; W. Li, W. Ueda, in: Proceedings of the Third World Congress on Oxidation Catalysis, 1997, Stud. Surf. Sci. Catal., vol. 110, pp. 433–442, JP 2001334149 to Showa Denko.
[16] J.C. Volta, Top. Catal. 15 (2–4) (2001) 121–129; M. Roy, H. Ponceblanc, J.C. Volta, Top. Catal. 11–12 (1–4) (2000) 101–109; M. Roy, M. Gubelmann-Bonneau, H. Ponceblanc, J.C. Volta, Catal. Lett. 42 (1) (1996) 93–97; L. Tessier, E. Bordes, M. Gubelmann-Bonneau, Catal. Today 24 (3) (1995) 335–340; EP 719756 to Rhone Poulenc; EP 683153 to Rhone Poulenc. [17] A.H. Fakeeha, Y.M. Fahmy, M.A. Mustafa, S.M. Saeed, J. Chem. Technol. Biotechnol. 75 (12) (2000) 1160– 1168. [18] US 5300684, EP 0546677 to The Standard Oil Company WO 02/030861 to Union Carbide WO 00/014047, EP 1202017, EP 1163954 to BP WO 02/038526, WO 98/47851 to Celanese. [19] EP 1201631, EP 1201630, WO 98/05620 to BP WO 01/090043, WO 01/090042 to Celanese WO 01/021570, WO 00/069802, US 6258992, US 6143921 to Sabic. [20] JP 11043314, JP 10017523 to Mitsubishi. [21] US 2002055664, US 6417422, Liu, Symyx. [22] X. Ge, J. Shen, Shiyou Yu Tianranqi Huagong 29 (6) (2000) 273–275, 283; M. Baerns, O.V. Buyevskaya, Erdoel Erdgas Kohle 116 (1) (2000) 25–30; M. Baerns, O.V. Buyevskaya, Catal. Today 45 (1–4) (1998) 13–22. [23] EP 1080435, Additional Patents Pending. [24] US Patent No. 5,959,297, Weinberg et al., Symyx. [25] US Patent No. 6,149,882, Guan et al., Symyx. [26] PCT Application WO 00/51720, Bergh et al., Symyx. [27] PCT Application WO 00/14529, Desrosiers et al., Symyx.
Gas phase oxidation of ethane to acetic acid using high-throughput screening in a massively parallel microfluidic reactor system Sam Bergh a , Shenheng Guan a , Alfred Hagemeyer a,∗ , Claus Lugmair a , Howard Turner a , Anthony F. Volpe Jr. a , W. Henry Weinberg a , Graham Mott b b
a Symyx Technologies Inc., 3100 Central Expressway, Santa Clara, CA 95051, USA Celanese Ltd., Corpus Christi Technical Center, 1901 Clarkwood Road, Corpus Christi, TX 78409/78469, USA
Received 30 September 2002; accepted 18 December 2002
Abstract High-throughput primary synthesis and screening methods have been applied to the heterogeneously-catalyzed gas phase oxidation of ethane to acetic acid using mixed metal oxide catalysts. The discovery libraries consisted of 16 × 16 arrays of 256 catalysts on 3 × 3 quartz wafers. Catalysts were prepared using automated liquid-dispensing techniques and screened in parallel for catalytic activity in a Symyx Technologies 256-channel microfluidic reactor. Product detection was performed using parallel colorimetric techniques on products adsorbed on silica-coated glass TLC plates. This workflow allows the screening of more than 3000 samples per day. Promising leads were confirmed in focus libraries and are being optimized in secondary screening. MoV was identified as the most active binary of redox metals and was subsequently doped with main group, rare earth, and transition metals to form ternaries. Prior art MoVX (X = Nb, Ni, Sb) catalysts were successfully reproduced and it was shown that Pd doping significantly increases the catalytic activity of these systems. Three novel MoVY ternary systems were discovered. © 2003 Elsevier Science B.V. All rights reserved. Keywords: Acetic acid; Selective oxidation; High-throughput screening; Combinatorial chemistry; Microreactors
1. Introduction Acetic acid is produced commercially by methanol carbonylation, aceteldehyde oxidation, and the uncatalyzed oxidative cleavage of C4–C8 hydrocarbons [1]. The direct gas phase oxidation of ethylene has recently been announced by Showa Denko and is based on a supported palladium catalyst [2]. Ethane oxidation is an attractive alternative route to acetic acid that has become increasingly attractive due to the availability ∗ Corresponding author. Tel.: +1-408-764-2059; fax: +1-408-748-0175. E-mail address: [email protected] (A. Hagemeyer). URL: http://www.symyx.com.
of low cost ethane feedstock from natural gas sources and is being pursued by several groups. H3 C–CH3 + 1.5O2 → CH3 –COOH + H2 O Union carbide pioneered this work using MoVNb systems for the coupled production of varying amounts of ethylene and acetic acid depending on the severity of reaction conditions [3]. Preparation, structural characterization, and catalytic properties of MoVNb oxide catalysts for this reaction have recently been reinvestigated [4]. Various other mixed metal oxide catalysts have been reported including VTi, MoV, MoW, as has the noble metal doping of these oxidic systems with Pd, Re, Ir, Ag, and Au [5–10]. MoVNbPd appears to
0926-860X/$ – see front matter © 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S0926-860X(03)00264-3
68
S. Bergh et al. / Applied Catalysis A: General 254 (2003) 67–76
be among the best performing catalyst systems and it has been proposed that Pd accelerates the oxidation of the ethylene intermediate in the consecutive reaction sequence [11]. The operation of a fixed bed and fluidized bed reactor has recently been simulated and the oxidation kinetics over MoVNbPd modeled [12]. It was concluded that ethane activation is the rate determining step for oxidizing ethane, and that the formation of the Pd Wacker center by water adsorption is rate determining for converting ethylene to acetic acid. A comprehensive characterization of the MoVNbPd catalyst has also been carried out [13]. While a consecutive reaction scheme dominates at low temperatures with ethylene as an intermediate leading to acetic acid, ethylene and acetic acid are mainly formed in parallel at high temperatures. Hydrothermally synthesized MoVAlTi and MoV-AlGaFeBiSbTe mixed oxide catalysts were also found to be active for selective ethane oxidation [14]. Heteropoly compounds have also been studied for the selective oxidation of light alkanes including ethane [15]. Site isolation of the active V centers was found to be crucial in the ethane oxidation to acetic acid over VPMoO/TiO2 [16] and a kinetic model for Mo-doped VPO has been presented [17]. Possible technical implementations of the process (e.g. in fluidized beds or reactor cascades) have also been disclosed [18]. Integrated processes for the manufacture of ethyl acetate and vinyl acetate by reaction of ethylene and acetic acid intermediates have been proposed as well [19]. A catalyst system composed of Pd-impregnated MoVNbSb composite oxides has been developed for the related oxidation of ethylene to acetic acid [20] and efficient Ni catalysts have been discovered for the related oxidative ethane dehydrogenation reaction [21]. A review of catalysts and their preparation, liquid and gas phase oxidation of ethane, and reaction mechanisms has recently been published [22]. The direct oxidation of ethane to acetic acid has not yet been commercialized, primarily because the existing catalyst systems suffer from relatively low activity and/or insufficient selectivity to acetic acid. Thus, there remains a need for the discovery and optimization of novel catalyst systems to make this reaction commercially viable. In this paper we describe the use of high-throughput combinatorial synthesis and screening techniques for the exploration of large composition spaces to quickly
identify active and selective catalyst lead compounds for this reaction. The general screening strategy implemented at Symyx is based on two hierarchical screens. The primary screen is characterized by very high throughput in continuous flow 256-channel parallel microreactors. Acetic acid was detected in parallel using pH-based colorimetric techniques on products adsorbed on silica coated glass TLC plates. Identified hits were scaled up and further optimized in the secondary screen. In this paper we focus on primary screening of mixed metal oxide ternaries; results on quaternaries will be presented in forthcoming publications. 2. Experimental procedures 2.1. Catalyst preparation Wafer-formatted catalyst libraries were designed and synthesized using Symyx Proprietary Library Studio® and Impressionist® Software [23]. Commercial 3 in. × 3 in. quartz wafers were bead blasted through steel masks with ␣-Al2 O3 powder to produce 16 × 16 arrays of wells which were then pre-coated with an ␣-alumina primer layer by slurry dispensation and dried. The metal precursor solutions were dispensed onto the wafers using automated liquid handling robots (Fig. 1) and the catalysts were prepared by subsequent drying and calcination steps. Aqueous metal nitrates (alkali, earth alkali, rare earth, Group IIIB, IB, IIB metals, Zr, Cr, Mn, Fe, Co, Ni, Al, Ga, In, Pb, Bi, Ru, Rh, Pd, and Pt), oxalates (Ti, V, Nb, Ta, Mo, Sn, and Ge), ammonium salts (vanadate, tungstate, and Sb oxalate) and acids (boric, perrhenic, telluric, selenic, and phosphoric) and in some cases chlorides (Hf, Sn, Ir, and Pt) were used as the standard metal precursors. Concentrations of stock solutions were 1 M for Mo and V oxalate, 0.5 M for all other metals, and 0.01–1 wt.% for noble metals. Incompatible stock solutions were dispensed sequentially. Bulk (unsupported except for the ␣-alumina primer layer) as well as supported mixed metal oxides were synthesized. Carriers used were silica, alumina, titania, and zirconia which were slurry dispensed onto the wafer prior to metal deposition. Initially the wafer was impregnated two to three times with the same library design (from the same microtiter plate) to
S. Bergh et al. / Applied Catalysis A: General 254 (2003) 67–76
69
Fig. 1. (a) Synthesis station with liquid handling robot, rack of stock solutions, microtitre plate, and catalyst wafers; (b) quartz wafer with 16 × 16 catalyst matrix; (c) liquid dispensing into carrier pre-coated wafer wells (2 ml dispense volume/well; ∼0.5 mg catalyst loading/well).
increase the catalyst loading in the wells (to about 1 mg; 2 ml dispense volume per well per dispense step) to achieve higher acetic acid productivity and thus higher detection signal intensity. A typical post synthesis treatment involved a drying step at 120 ◦ C and calcination in air at 350–400 ◦ C for 4 h. 2.2. Catalyst screening 2.2.1. High-throughput reactor system High-throughput screening experiments of combinatorial libraries were performed using a parallel microreactor based on a microfluidic flow distribution device, 256-element catalyst array, and colorimetric detection methodology allowing parallel reaction and parallel detection (Figs. 2 and 3). This reactor is Symyx, second generation primary screening tool and offers significant technological advances over its predecessor, the scanning mass spectrometer [24], which is a rapid serial screening tool. The microflu-
idic parallel screening reactor provides identical gas flows [25] to the 16 × 16 array of microreactors by employing a fluidic device constructed using microfabrication technologies [26]. The microreactors are formed by contacting the catalyst wafer and gas distribution wafer together. A single reaction stream provided by conventional flow controllers and vaporizers is divided into 256 streams with a binary splitting pattern (bifurcation) on a two-dimensional area. Each individual stream is allowed to contact a 2 mm diameter× ∼0.2 mm deep well containing approximately 1 mg of catalyst. The accuracy of the flow division is ensured by the precision of the microfabricated channel structures and the bifurcation strategy for the division. Since a very low flow rate contacting the catalyst is possible, the concentration of each reactant component and products in the individual reactors is spatially distributed within the reactor volume due to the relatively large effect of diffusion compared to the velocity of the reaction flow stream. Variation in
70
S. Bergh et al. / Applied Catalysis A: General 254 (2003) 67–76
Fig. 2. Schematic representation of microfluidic parallel screening reactor system showing components and photograph of actual reaction station (US and Foreign Patents Pending).
contact time is kept small by the microfabricted upstream flow restricting distribution manifold that was designed to have a flow restriction greater than twenty times that of all downstream flow restrictions, which
Fig. 3. Drawing of a single reactor channel (top) and photograph of gas distribution wafer (bottom left) and sample image (bottom right) from the microfluidic parallel screening reactor. (US and Foreign Patents Pending).
in this geometry are also small. The accuracy of flow splitting using precision microfabricated channels in a large area silicon chip was measured offline using a flow meter and the channel-to-channel flow difference between channels was below 1%. All 256 reaction streams then flow through a temperature gradient before making contact with an absorbent plate or array where the products of interest are trapped either by absorption, chemical reaction, and/or condensation. The system is carefully designed so that a uniform reaction temperature and product trapping temperature are achieved in each of the reaction channels. Reaction exotherms are negligible due to the effective heat and mass transfer on the small scale as well as the relatively low conversions and corresponding high selectivities to acetic acid. After sufficient amounts of products have accumulated, the absorbent array is removed from the reactor and typically subjected to a spray of dye solution to develop certain optical properties of the array. These properties include absorption of certain colors, fluorescence, or bleach of absorption or fluorescence caused by selective reaction of the dye with products. The developed absorbent array is then imaged by a high resolution
S. Bergh et al. / Applied Catalysis A: General 254 (2003) 67–76
71
Fig. 4. (a) The absorption spectra of the acid (red) and base (yellow) form of the Methyl Red dye and (b) the integrated intensity vs. acid amount on TLC plate calibration curve.
CCD camera. As a first approximation, the integrated intensity of the CCD image is proportional to the amount of products. Since all 256 reactions, product trapping and development, and imaging are done as single processes, throughput is greatly increased and variations among reaction channels is minimized. The relative variation in yield was periodically checked by running a library of identical catalysts and was less than about 15%, including variations due to catalyst synthesis, reactor residence time, reaction temperature non-uniformities, adsorbent thickness variation, dye spray inhomogeneity, and data integration and processing. This range of data scatter does not inhibit our ability to discriminate between catalysts. The integral detection scheme (signal accumulation over TLC exposure time) and the amplification of performance differences when monitoring initial kinetics (maximum kinetic rates) also help in ranking the catalysts. For instance, signal intensities for the MoVX ternaries were found to vary by more than an order of magnitude among the various X dopants screened. A model feed (3 sccm of C2 , 2 sccm of O2 ) was used for the high density discovery wafers whereas the more active focus wafers were screened with a more realistic feed (2.5 sccm of C2 , 2 sccm of O2 , 8 sccm of N2 ). Contact time was about 2 s and reaction temperature was 375 ◦ C. 2.2.2. Parallel product analysis A detection method for acetic acid was developed and consists of product condensation on a silica TLC plate in an array of spots, followed by pH detection of trapped acetic acid with Methyl Red indicator (Fig. 4)
[27]. There is no significant diffusion of the products on the TLC plate within the time frame of the experiment. Thus there is minimal channel-to-channel cross-talk on the TLC plate.1 The exposed TLC plate is removed from the MEMS reactor and a water/methanol solution of Methyl Red and KOH is evenly sprayed onto it. The base form of Methyl Red is yellow and in the presence of acetic acid it is red. The KOH ensures that the dye is in its base form when sprayed and it neutralizes the acidic sites on the silica TLC material as well as some of the acetic acid. The sensitivity of the detection system can be adjusted by varying the amount of KOH in the dye solution. For the amount of acetic acid produced in each reactor the dye solution was optimized to contain 0.0007 M Methyl Red and 0.02 M KOH in a solution of 10% water in methanol. The color change from white to red was recorded in an automated imaging station equipped with a backlight for the TLC plate, an optical filter, and the CCD camera. The absorption spectra of the acid and base form of the dye are shown in Fig. 4a. The appearance of the base form of the dye was measured using a 550 nm band pass filter. To calibrate the detection system, acetic acid standards (known amounts of acetic acid in water) were spotted onto a TLC plate and sprayed with the dye solution. A photograph of the TLC plate was taken with the data 1 Cross-talk is occasionally observed in cases where highly active catalysts surround a completely inactive or blank well (see the blank diagonal in Fig. 8). Although this can result in false positives, it rarely affects the conclusions of screening since gradients are being examined in the majority of experiments. False positives are also screened out in focused primary screening and secondary screening.
72
S. Bergh et al. / Applied Catalysis A: General 254 (2003) 67–76
in units of absorbance and the intensity of each color spot was integrated. The calibration curve showed a linear response of intensity versus the amount of acetic acid present over about one order of magnitude (Fig. 4b). Interference by CO2 was negligible because of its much lower sticking coefficient to the (untreated) TLC plate (compared to the condensable acetic acid) and its much weaker acidity (approximate pH range for Methyl Red is 4.8–6.0, approximate pH value of 0.01 N acetic acid is 3.4). Catalyst library wafers and TLC plates were routinely rotated by 90◦ during the screening experiment to distinguish real spots (do rotate) from experimental artifacts such as scratches on TLC plate (do not rotate). Typically, a 15 min exposure time was used to develop a TLC plate and each wafer was screened for 1 h (at four different reaction conditions). In order to better differentiate small performance differences between similar catalysts and to increase the detection sensitivity, in some cases the KOH concentration of the Methyl Red indicator solution was increased (to accumulate more acetic acid before the color change). Another approach was to design a C4-symmetric li-
brary and rotate the wafer and/or TLC plate by 90◦ with the TLC signals accumulated to average over experimental fluctuations (at the expense of throughput, 64 versus 256 samples per library). The combined exhaust gas of all 256 channels downstream of the TLC compartment was occasionally checked by mass spectrometry and products other than C2 (cracking fragment of C2 H6 ; parent of C2 H4 overlap with CO), CO2 , and acetic acid were not observed.
3. Results Approximately forty catalyst libraries consisting of binary, ternary, and quaternary compositions were screened in the microfluidic parallel screening reactor over a 2-week period. About half of these were synthesized and the rest were from our catalyst archive. The overall screening protocol/strategy is summarized in Fig. 5. Primary screening was initially targeted to identify the best binary combinations of redox metals selected from V, Mo, Cr, Mn, Fe, Co, Ni, Cu, Ag,
Fig. 5. Screening protocol showing library studio library designs (top) and post reaction images of TLC detection wafers (bottom). Note that the white TLC plates appear black and the red spots appear white in the photo. Compositional details are given in Figs. 6–9: (a) binaries of redox active metals; (b) extension of binaries into ternaries by adding dopants; (c) focus ternaries of best hits; (d) noble metal doping of MoVNb ternary.
S. Bergh et al. / Applied Catalysis A: General 254 (2003) 67–76
Re, Sn, Sb, Ti, and Bi. The best hits and synergistic combinations of redox metal binaries were then extended to ternaries by adding single dopants selected from the main group metals, transition metals, and rare earth metals. Focused ternaries for the best hits were screened next in order to determine the most active compositional regions. Finally, the most active focus ternaries were doped evenly with noble metals over the ternary gradients. The effect of noble metal content was studied by synthesizing identical daughter wafers of the particular mixed oxide ternary followed by impregnation with solutions of different noble metal concentrations. Thirty redox binaries containing 8-point gradients were synthesized on each wafer along with 16 blanks to define the 0-point reference. A sample experiment is depicted in Fig. 6. For this wafer, the most active binaries were shown to be MoV, CrV, and MnV, with MoV being by far the most active. MnCr, CeCr, VTi, and MoTi displayed a low level of activity. It should be noted that an initial discovery screening protocol based on ternaries (e.g. three redox metals or two redox metals + 1 dispersant) produced more hits than the binary systems (results not shown).
73
Next, 18 non-symmetrical discovery ternaries consisting of 15 and 9 points were synthesized on each wafer leaving one row and one column blank. Fig. 7 shows an example of the library design for MoVX ternaries. The image shows that Nb, Ni, Sb, and Ce doping results in higher acetic acid productivity [8]. Other dopants that cannot be disclosed at this time, M1, M2, and M3, are also active. Eight focus ternaries of 28 points each can be accommodated on a single wafer with the two diagonals left blank. Fig. 8 shows a sample wafer for MoVX focus ternaries. The image indicates that Nb, M1, M2, and M3 produce the highest acetic acid yields. The MoVNb result is consistent with the literature [3,4]. Pd doping further significantly enhances the performance of the MoVNb ternary (Fig. 9) and this has also been previously reported [11]. Several other metal dopants also produced hits.
4. Discussion Patented catalyst examples for ethane to acetic acid were successfully confirmed in Symyx parallel
Fig. 6. Library design for 30 redox binaries (8-point gradients) and post-reaction TLC image (375 ◦ C reaction temperature, 15 min TLC exposure time, 100 ul/ MT plate well). MoV is by far the most active redox binary, other active binaries are CrV, MnV, MnCr, CeV, CoCr, CoV, VTi, and MoTi.
74
S. Bergh et al. / Applied Catalysis A: General 254 (2003) 67–76
Fig. 7. Library design for 18 MoVX ternaries (15 and 9-point ternaries) and post-reaction TLC image (375 ◦ C reaction temperature, 15 min TLC exposure time, 100 ul/well). Nb, Ni, Sb, Ce, M1, M2, and M3 dopants enhance activity of MoV binary.
Fig. 8. Library design for eight MoVX focus ternaries (28-point focus ternaries) and post-reaction TLC image (375 ◦ C reaction temperature, 15 min TLC exposure time, 100 ul/well). X = Nb, M1, M2, M3 are the most active ternaries.
S. Bergh et al. / Applied Catalysis A: General 254 (2003) 67–76
75
Fig. 9. Symmetric bis-ternary library design for MoVX focus ternary (lower left MoVNb ternary doped with flat Pd layer) and post-reaction TLC image (325 ◦ C reaction temperature, 15 min TLC exposure time, 100 ul/well). Pd doping enhances catalytic activity.
microreactor using wafer formatted libraries thus demonstrating the relevance of the primary screen for this oxidation. The performance ranking of redox binaries was found to be MoV CrV, MnV, CoV, VTi, MoTi, CoCr, MnCr. For MoV, the Mo-rich composition gives a higher yield. The ranking of MoVX ternaries is MoV-Nb, MoV-M3, MoV-M2, MoV-M1 > MoV-Ni, MoV-Sb, MoV-Ce > MoV-Fe. Three new dopants (M1, M2, M3) were discovered that at least equal the MoVNb system under the MEMS reactor testing conditions. Pd doping of MoVNb greatly enhances the acetic acid yield in full agreement with published data. Pd doping allowed lowering of the reaction temperature for screening in MEMS by about 50 K. It is observed that performance differences between catalysts are exaggerated in this primary screen thus facilitating catalyst discrimination. Differences in product formation rates are much more pronounced if initial differential kinetics at low conversion is monitored (as in MEMS) rather than integral productivities at high conversions. The acetic acid yield in MEMS was estimated by relative comparison to the known acetic acid standards spotted on each TLC detection plate at about 1%. By using a high-throughput microfluidic
parallel screening reactor in conjunction with Symyx high-throughput synthesis and catalyst archive, it was possible to screen more than 10,000 catalysts in a 2-week period.
References [1] K. Weissermel, H.J. Arpe, Industrial Organic Chemistry, Wiley, Weinheim, 1994; H. Koyama, Shokubai 38 (8) (1996) 626–633. [2] K. Sano, H. Uchida, S. Wakabayashi, Catal. Surv. Jpn. 3 (1) (1999) 55–60. [3] E.M. Thorsteinson, T.P. Wilson, F.G. Young, P.H. Kasai, J. Catal. 52 (1978) 116–132. [4] K. Ruth, R. Burch, R. Kieffer, J. Catal. 175 (1) (1998) 27–39; K. Ruth, R. Kieffer, R. Burch, J. Catal. 175 (1) (1998) 16–26; R. Burch, R. Kieffer, K. Ruth, Top. Catal. 3 (3–4) (1996) 355–364. [5] WO 98/23371 to Consortium fuer Elektrochemische Industrie. [6] EP 627401, US 5750777 to Rhone Poulenc. [7] JP 11290684 to Daicel. [8] EP 1043064, EP 492813, EP 480594, US 6333444, US 5260250, WO 00/14047, WO 99/51339 to BP. [9] US 6160162, US 6156928, US 6114278, US 6087297, US 6060421, US 6030920, US 6013597, US 5907056, WO 01/083103, WO 00/038833, WO 00/029105, WO 99/13980 to Sabic.
76
S. Bergh et al. / Applied Catalysis A: General 254 (2003) 67–76
[10] WO 01/090039, WO 99/20592, WO 98/47851, WO 98/47850, WO 98/05619, WO 97/44299, US 6399816, US 6274765, US 6194610, US 6034270 to Celanese. [11] US 6060421, US 6030920, WO 00/029105 to Sabic US 6399816, US 6274765, US 6034270, WO 01/090039, WO 98/05619, WO 97/44299 to Celanese. [12] D. Linke, D. Wolf, M. Baerns, S. Zeyss, U. Dingerdissen, L. Mleczko, Chem. Eng. Sci. 57 (1) (2002) 39–51; D. Linke, D. Wolf, M. Baerns, S. Zeyss, U. Dingerdissen, J. Catal. 205 (1) (2002) 32–43; D. Linke, D. Wolf, M. Baerns, U. Dingerdissen, S. Zeyss, Natural Gas Conversion VI, Stud. Surf. Sci. Catal. 136 (2001) 477–482. [13] D. Linke, D. Wolf, M. Baerns, O. Timpe, R. Schloegl, S. Zeyss, U. Dingerdissen, J. Catal. 205 (1) (2002) 16–31. [14] N.F. Chen, K. Oshihara, W. Ueda, Catal. Today 64 (1–2) (2001) 121–128; K. Oshihara, Y. Nakamura, M. Sakuma, W. Ueda, Catal. Today 71 (1–2) (2001) 153–159; W. Ueda, K. Oshihara, Appl. Catal. A 200 (1–2) (2000) 135– 143; W. Ueda, N.F. Chen, K. Oshihara, Kinet. Catal. 40 (3) (1999) 401–404; N.F. Chen, W. Ueda, K. Oshihara, Chem. Commun. (6) (1999) 517–518. [15] J.S. Min, N. Mizuno, Catal. Today 71 (1–2) (2001) 89–96; J.S. Min, N. Mizuno, Catal. Today 66 (1) (2001) 47–52; W. Li, W. Ueda, in: Proceedings of the Third World Congress on Oxidation Catalysis, 1997, Stud. Surf. Sci. Catal., vol. 110, pp. 433–442, JP 2001334149 to Showa Denko.
[16] J.C. Volta, Top. Catal. 15 (2–4) (2001) 121–129; M. Roy, H. Ponceblanc, J.C. Volta, Top. Catal. 11–12 (1–4) (2000) 101–109; M. Roy, M. Gubelmann-Bonneau, H. Ponceblanc, J.C. Volta, Catal. Lett. 42 (1) (1996) 93–97; L. Tessier, E. Bordes, M. Gubelmann-Bonneau, Catal. Today 24 (3) (1995) 335–340; EP 719756 to Rhone Poulenc; EP 683153 to Rhone Poulenc. [17] A.H. Fakeeha, Y.M. Fahmy, M.A. Mustafa, S.M. Saeed, J. Chem. Technol. Biotechnol. 75 (12) (2000) 1160– 1168. [18] US 5300684, EP 0546677 to The Standard Oil Company WO 02/030861 to Union Carbide WO 00/014047, EP 1202017, EP 1163954 to BP WO 02/038526, WO 98/47851 to Celanese. [19] EP 1201631, EP 1201630, WO 98/05620 to BP WO 01/090043, WO 01/090042 to Celanese WO 01/021570, WO 00/069802, US 6258992, US 6143921 to Sabic. [20] JP 11043314, JP 10017523 to Mitsubishi. [21] US 2002055664, US 6417422, Liu, Symyx. [22] X. Ge, J. Shen, Shiyou Yu Tianranqi Huagong 29 (6) (2000) 273–275, 283; M. Baerns, O.V. Buyevskaya, Erdoel Erdgas Kohle 116 (1) (2000) 25–30; M. Baerns, O.V. Buyevskaya, Catal. Today 45 (1–4) (1998) 13–22. [23] EP 1080435, Additional Patents Pending. [24] US Patent No. 5,959,297, Weinberg et al., Symyx. [25] US Patent No. 6,149,882, Guan et al., Symyx. [26] PCT Application WO 00/51720, Bergh et al., Symyx. [27] PCT Application WO 00/14529, Desrosiers et al., Symyx.