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Online ESI-MS Analysis of Reactions under High Pressure Roberto A. Paz-Schmidt,† Werner Bonrath,‡ and Dietmar A. Plattner*,† Institute of Organic Chemistry and Biochemistry, University of Freiburg, Albertstrasse 21, D-79104, Freiburg im Breisgau, Germany, and DSM Nutritional Products Limited, P.O. Box 2676, CH-4002 Basel, Switzerland A new approach for real-time mass spectrometric analysis and identification of intermediates in confined, pressurized vessels is presented. The high-pressure reaction media is depressurized, mixed with a solvent, and fed directly to the atmospheric pressure electrospray ionization source of a tandem mass spectrometer. The method was applied to track product evolution for the dehydration of hydroxenin monoacetate, a commercially, important vitamin A precursor, and for the hydrogenation of 5-norbornene-2-carbonitrile with Pd/CaCO3 as catalyst. Faster access but comparable results as by conventional offline methods were obtained in every case. The specific properties of compressed gases below the critical point or in supercritical state have found numerous applications in organic synthesis.1 Under pressure, gases like CO2 approach densities and solvating strengths of liquids, while diffusion and viscosity remain in the range typical for gases. A particular advantage in industrial applications lies in the simplified workup and reduced waste.1 The focus of our work is the application of such fluids as media for heterogeneous as well as homogeneous catalysis. With many of the reactive species involved in catalytic cycles being ionic, mass spectrometry (MS) comes into play as a tool for monitoring reactions and analyzing their outcome.2,3 Mass spectrometers and particularly electrospray ionization mass spectrometers (ESI-MS) have been already successfully coupled to several reactor types mostly in connection with analytical applications.4-6 These direct couplings open the door to online monitoring: the transport of reaction medium into the analyzing instrument in real time for immediate analysis. A simple reactor can be made with a mixing tee and two streams of reactants. The outlet of the tee is fed into the mass spectrometer.7 A more complicated setup, like the one presented here, uses a normal batch reactor where a small portion of the reaction medium * To whom correspondence should be addressed. Fax: ++49 761-203-8714. Phone: ++49 761-203-6013. E-mail:
[email protected]. † University of Freiburg. ‡ DSM Nutritional Products Ltd. (1) van Eldik, R., Hubbard, C. D., Eds. Chemistry Under Extreme and NonClassical Conditions; John Wiley & Sons: New York, 1997. (2) Plattner, D. A. Int. J. Mass Spectrom. 2001, 207, 125–144. (3) Plattner, D. A. Top. Curr. Chem. 2003, 225, 153–203. (4) Metzger, J. O. Int. J. Mass Spectrom. 2005, 246, 84–104. (5) Sam, J. W.; Tang, X. J.; Magliozzo, R. S.; Peisach, J. J. Am. Chem. Soc. 1995, 117, 1012–1018. (6) Wang, H.; Metzger, J. O. Organometallics 2008, 27, 2761–2766. (7) Meyer, S.; Metzger, J. O. Anal. Bioanal. Chem. 2003, 377, 1108–1114. 10.1021/ac802754q CCC: $40.75 2009 American Chemical Society Published on Web 03/30/2009
is fed into the instrument through a fishing tube. Faster access to results, real-time kinetics, easier sample handling, and the possibility to modify the conditions of the reaction during operation are just some of the advantages of such a method. On the other hand not all kinds of samples can be fed directly into an instrument, some may need special treatment, like complexing, esterification, or silylation, to decrease boiling points, separation from masking compounds, etc. Some of those methods can be performed in real time. It must also be considered that the availability of the instrument during the reaction is reduced because no other samples can be run in between. Recently, the account of a gas chromatograph connected to an ESI-MS has surfaced; the authors used a similar approach, but the outlet of the column feeds directly the stream that exits the ESI capillary to enter the heated capillary in the ion source.8 Here we report the successful coupling between a highpressure reactor equipped with a 20 kHz sonotrode capable of producing cavitation under certain conditions and an ESI-MS.9 It is well-documented in the literature that ultrasound irradiation produces cavitation in dense fluids, when they are below the critical point, and thus induces formation of radical species.10 ESI has been chosen as ionization method because it is an effective and gentle method to transfer ions from solution to the gas phase and thus is very often used in conjunction with a mass detector to identify ionic intermediates.11 EXPERIMENTAL SECTION Chemicals used were of reagent grade and used without further purification. The mass spectrometer used was a Finnigan MAT TSQ 7000 triple quadrupole tandem mass spectrometer. The reactor is built of stainless steel and consists of two parts, the upper part is where the sonotrode assembly is fastened and the container is the lower half. Total inner volume is 40 mL. Several inlets and outlets allow easy filling and sampling as well as pressure and temperature monitoring via pressure sensors and thermocouples. A specially trimmed (max 150 bar) overpressure valve is also fitted. Handling of pressurized equipment was done in sheltered areas by trained personnel. Under the condition described here two phases exist inside the reactor: a lower and (8) Brenner, N.; Haapala, M.; Vuorensola, K.; Kostiainen, R. Anal. Chem. 2008, 80, 8334–8339. (9) First presented at the 10th meeting of the European Sonochemistry Society, Hamburg, Germany, June, 4-8, 2006. (10) Kuijpers, M. W. A.; van Eck, D.; Kemmere, M. F.; Keurentjes, J. T. F. Science 2002, 298, 1969–1971. (11) Fenn, J. B. Angew. Chem., Int Ed. 2003, 42, 3871–3894.
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Figure 1. (a) Reactor and mass spectrometer assembly: 1, highpressure valve; 2, high-pressure split valve; 3, reactor assembly with fishing tube and sonotrode; 4, syringe for electrospray solvent; 5, ultrasonic piezoelectric transducer with horn; 6, mass spectrometer ion source; 7, fishing tube; 8, sample path and direction.(b) Reactor and mass spectrometer assembly.
denser and an upper and less dense phase. The fishing tube can be accommodated to sample from either of the two. Ultrasound irradiation was provided by a horn-type sonotrode operated at 19704 Hz. The link between the fishing tube in the reactor and the electrospray tip was made out of a polyetheretherketone (PEEK) capillary, high-pressure-resistant split valves, and a tee (Figure 1, parts a and b). The tee is used to mix the reaction media with the electrospray solvent in order to provide a
homogeneous fluid suitable for the electrospray process to occur. To sample and acquire a spectrum, valve 2 is opened for approximately 1 min, see Figure 1b, and the spectrum is recorded. When valve 2 is open the sample moves through the capillary tube pushed by the inner reactor’s pressure, mixes with the electrospray solvent, and then continues inside the mass spectrometer. The tube is then purged with the same kind of solvent used for electrospray. The analytes that leave the reactor dissolve in the electrospray solvent, methanol or watersmethanol in these cases, to enter the electrospray process where they are transported to the gas phase and finally arrive at the mass detector. The mass spectrometer used is built around two mass analyzers separated by a collision chamber. A schematic can be seen in Figure 2. This instrument had been successfully used to identify ionic intermediates in solution-phase as well as in gas-phase reactions.2,3 Ultrasonically Mediated Reaction. To fully utilize the described setup the ultrasonically assisted dehydration of hydroxenin monoacetate (HMA) in CCl4/alcohol mixtures was employed12 (see Scheme 1). HMA is one of the last intermediates in a commercial process of producing vitamin A acetate by acidic dehydration followed by extraction. The reaction is based on the sonolysis of a CCl4/alcohol mixture, whereas HCl is produced in small quantities. HMA then reacts with HCl yielding a carbocation after loss of water. Vitamin A acetate is then produced after isomerization of this carbocation and loss of a proton. Ethers are formed as a byproduct when the carbocation reacts with the alcohol, which is the favored pathway at temperatures around and above 20 °C.12 In our experiments only the ethers where produced due to the high temperature. Identification of neutral molecules was achieved by taking advantage of Na+ ions, already present in the solvents, to complex the carbonyl moiety of both reagents as well as products, thus producing detectable ionic species. This is one of those cases where a post-treatment of the sample is needed, though a trivial one, which can be performed in real time without introducing any delay in the sample analysis thus broadening the scope of the method. Mass spectrometric
Figure 2. Finnigan MAT TSQ7000 mass spectrometer: 1, ion source; 2, parent mass analyzer (quadrupole); 3, vacuum manifold; 4, collision cell (octopole); 5, daughter mass analyzer (quadrupole); 6, detector; 7 recorder.
Scheme 1. Reaction of HMA with CCl4/Alcohol under Ultrasound Irradiation
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Figure 3. Evolution of reaction product (ether) and HMA vs time (MS area %): ( HMA, 9 ether.
Figure 6. Evolution of reaction product norbornane vs time: ( NOR, 9 norbornane.
Scheme 2. Hydrogenation of NOR
analysis of blank samples, i.e., without application of ultrasound, containing HMA and ethanol or methanol, shows only sodiumcoordinated HMA in monomeric and dimeric forms as well as some oxidation products produced during electrospray. The reaction was performed at several pressures and frequencies to find the best conditions. In every run the reactor was filled with the alcohol, methanol, or ethanol, (10 mL), CCl4 (10 mL), and HMA (0.14 mmol), pressurized with CO2 to 20 bar (after 5 min sonication at 23 °C), and the mixture exposed to
ultrasound irradiation (19704 Hz) in pulsed mode during the whole course of the reaction. Sampling was performed at regular intervals (1 h), and the sample was analyzed by ESIMS using methanol as electrospray solvent. As a control experiment, the reaction without ultrasound was also performed leading to the detection of just unreacted starting material. Figure 3 summarizes some of the results obtained with this method, Figure 4 shows a typical spectrum obtained when the reaction is carried out with ethanol in the mixture, and Figure 5 shows the spectrum of a methanolic solution of HMA. Around 20% yield (MS area%) was obtained after 6 h. Carbocationic intermediates were not detected with the present approach; they are probably short-lived and thus escape the method’s time frame. The time it takes to detect a change in the reaction media in the mass spectrometer console was determined to be around 15 s. For that purpose a monocharged rhodium norbornadiene complex that was held in a reservoir connected to the reactor was released inside the reactor by opening a valve. The interval from the release to the time when the signal becomes visible in the screen was thus determined. Hydrogenation. The hydrogenation of 5-norbornene-2-carbonitrile (NOR) was achieved using the hydrogen-transfer method with 1,4-cyclohexadiene as donor and Pd on CaCO3 as catalyst, see Scheme 2.13,14 In the reactor described previously, NOR (5.35 mmol), 1,4-cyclohexadiene (5.35 mmol), internal standard solution (0.5 mL), and Pd on CaCO3 (21.6 mg, 5% Pd, 0.2 mmol %) were pressurized with CO2 (30 bar at 23 °C), heated up to 110 °C (pressure raises to 50 bar), and reacted for 2 h. Online monitoring with ESI-MS was used to track the course of the reaction. Ag+ ions were used to complex the otherwise neutral species, provided by a silver nitrate solution (5 mM) in 1:1 MeOH/ H2O used as electrospray solvent. A fishing tube that only samples low-density mixture was used, keeping the rest of the setup similar to the previous case. An internal standard (tetrabutylammonium iodide) that does not compete for silver ions was used (1 mM in ethanol). After 2 h the yield was approximately 30% (Figure 6).
(12) Aquino, F.; Bonrath, W.; Paz Schmidt, R. A.; Schiefer, G. Ultrason. Sonochem. 2005, 12, 107–114.
(13) Johnstone, R. A. W.; Wilby, A. H. Chem. Rev. 1985, 85, 129–170. (14) Wehage, H.; Heesing, A. Chem. Ber. 1994, 124, 2629–2631.
Figure 4. Mass spectrum of products (in ethanol) after 6 h: A+ is [HMA + Na]+, B+ is an oxidized form of HMA [HMA + O + Na]+, and C+ is the ethyl ester [HMA + OEt + Na]+.
Figure 5. Mass spectrum of HMA in methanol: A+ is [HMA + Na]+ and B+ is an oxidized form of HMA [HMA + O + Na]+.
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due to its unique characteristics: real-time sampling of reaction medium and analysis with rapid visualization and low delays between sampling and display of the spectra. Reactive intermediates, short-lived species, if they fall in the measuring time frame, and byproduct can be easily monitored. The detection of neutral molecules using an ESI-MS presents challenges in itself, because complexing agents may mask useful information or introduce artifacts. The presented cases demonstrates the broad scope of the method which also allows for semiquantitative analysis.
Figure 7. Mass spectrum of the silver complexes of the reaction product of hydrogenation of NOR together with unreacted starting material: A+ is [NOR + 107Ag]+, B+ contains both [NOR + 109Ag]+ and [product + 107Ag]+, and C+ contains only [product + 109Ag]+.
SUPPORTING INFORMATION AVAILABLE Description of an ultrasound-irradiated supercritical media reactor with continuous online monitoring. This material is available free of charge via the Internet at http://pubs.acs.org.
Figure 7 shows the mass spectrum of silver complexes of product together with unreacted starting material. CONCLUSIONS The approach described opens new analytical possibilities in the field of catalytic reactions under medium to high pressure
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Received for review December 29, 2008. Accepted February 27, 2009. AC802754Q
