Organic Process Research & Development 1997, 1, 339−349
Kinetic and Calorimetric Considerations in the Scale-Up of the Catalytic Reduction of a Substituted Nitrobenzene M. J. Girgis, K. Kiss, C. A. Ziltener, M. Prashad, D. Har, R. S. Yoskowitz, B. Basso, O. Repic, T. J. Blacklock, and R. N. Landau* NoVartis Pharmaceuticals Corporation, 59 Route 10, East HanoVer, New Jersey 07936
Abstract: A reaction calorimetric investigation was conducted to assess proposed scale-up conditions (30 psig, 10 °C, initial reactant concentration ) 0.69 M, catalyst concentration of 6.66 × 10-3 g/g of reactant) for the batchwise reduction of a substituted nitrobenzene to give the corresponding aniline in the presence of H2, Pd/C catalyst, and ethyl acetate solvent. Heat evolution rates under these conditions were judged to be too large for safe plant operation. Alternative processing conditions were investigated, accounting for heat removal, pressure limitations, and gas-liquid mass transfer rates in the plant equipment as well as differences in reactivity between plant- and laboratoryprepared reactants. The recommended conditions (30 psig, 20 °C, and catalyst concentration of 7.53 × 10-3 g/g of reactant) were employed in the pilot plant, which resulted in conversion rates almost identical to those in the laboratory reactor, demonstrating the value of reaction calorimetry for scaling up a highly exothermic reaction without byproduct formation. Major improvements over the originally proposed process included operation at 20 °C to take advantage of the greater cooling capacity and decreasing the batch holding time by more than 35% with the additional constraints imposed by mass transfer. Additional experiments using nitrobenzene reactant demonstrated that water produced by the reaction promotes catalyst activity; in reactions where no water was initially present, a maximum was observed in the reaction rate, whereas a monotonically decreasing rate was observed for a 0.44 M initial water concentration.
conditions that could lead to a safer and more economical process. We discuss here a reaction calorimetric study performed to address these goals. Process conditions based on this work were selected for the scale-up. Comparison of the pilot plant run data with the calorimeter results indicates that the latter accurately predicted plant performance, demonstrating its great utility as a predictive tool for successfully scaling up this highly exothermic reaction.
Introduction A key step in the manufacture of a pharmaceutical intermediate comprises the batchwise reduction of the nitro group on a substituted nitrobenzene to give the corresponding aniline in the presence of H2, Pd/C catalyst, and ethyl acetate solvent:
where
Experimental Section Calorimeter Principles. Reaction experiments were performed using a Mettler Toledo RC1 reaction calorimeter, comprising a 1-L jacketed glass vessel and a drafting agitator. The calorimeter operating principles are derived from an energy balance on the contents of the vessel, which can be expressed as follows:
The heat accumulation rate in the vessel includes accumulation by both the reaction mixture and the immersed reactor inserts (i.e., stirrer, temperature sensor, calibration probe; see below). Mathematically, the energy balance can be expressed as follows: dTr dt
(1)
Qrxn - UA(Tr - Tj) + (mrCpr + miCpi)
Qrxn ) heat evolution rate by chemical reaction, W U ) overall heat transfer coefficient between vessel contents and jacket fluid, W/(m2‚K) A ) wetted area of reaction vessel, m2 Tr, Tj ) temperatures of vessel contents and jacket, respectively, K or °C mr, Cpr ) mass (kg) and specific heat (J/(kg‚K)) of reaction
Previous experiments showed that, at 10 °C and 30 psig H2 pressure, the reaction is rapid and highly exothermic. Our goals in the present investigation were to (1) quantify the kinetics and the heat evolved at 10 °C and 30 psig, and thus assess safety aspects for an upcoming scale-up in a pilot plant; (2) assess the impact of gas-to-liquid mass transfer to obtain similar conversion rates and selectivities in the pilot plant reactor and laboratory; and (3) evaluate other process
mixture, respectively mi, Cpi ) mass (kg) and specific heat (J/(kg‚K)) of immersed reactor inserts, respectively
The quantity UA is determined by applying a known amount of power Qc (i.e., heat per unit time) using a calibrated heater (calibration probe) immersed in the reaction mixture before the reaction begins (i.e., when Qrxn is 0 and the temperature
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Table 1. Feed and catalyst sources and experimental conditions run no.
feed source
catalyst source
temp, °C
pressure, psig
stirring speed, rpm
reactant concn, M
catalyst/reactant ratio, 103 g/g
reactor fill, La
19603 19604 19605 19606 19607 19609 19610 19614 19615 19616
lab lab lab lab lab lab lab pilot plant pilot plant pilot plant
Aldrich, water added Aldrich, water added Aldrich, Lot No. 10324DN Aldrich, Lot No. 10324DN Aldrich, Lot No. 10324DN Aldrich, Lot No. 10324DN Aldrich, Lot No. 10324DN Aldrich, Lot No. 10324DN Aldrich, Lot No. 10324DN Aldrich, Lot No. 10324DN
10 10 20 20 20 20 20 20 20 20
30 30 10 30 40 30 45 30 30 30
1000 1000 1000 1000 1000 500 500 500 500 500
0.696 0.692 0.706 0.706 0.706 0.706 0.706 0.706 0.714 0.736
6.66 6.66 3.32 3.36 3.45 3.25 3.34 5.01 7.53 7.14
0.586 0.581 0.392 0.392 0.393 0.393 0.392 0.393 0.396 0.399
a
Based on estimated density of 0.908 and 0.896 g/cm3 at 10 and 20 °C, respectively for reactor contents.1
of the reactor contents in constant). The energy balance then reads Qc ) UA(Tr - Tj)
(2)
and since Qc is known and Tr and Tj are measured, UA can be determined. Because the heat transfer coefficient changes with composition, an additional calibration is performed after completion of the reaction; interpolated values can thus be used during the reaction to account for heat transfer coefficient variation with composition. The heat capacity of the reaction mixture is determined by performing a linear temperature ramp before reaction begins. The heat capacity is determined from the energy balance: dTr UA(Tr - Tj) + miCpi dt Cpr ) dTr mr dt
(3)
with the heat capacity of the inserts presumed to be known. Variation of heat capacity with composition is estimated by performing an additional ramp after reaction is complete and interpolating between the two values. The heat evolution rate (HER) due to chemical reaction is thus determined by measurement of jacket and internal temperatures using eq 1. Procedure. A weighed amount of Pd/C catalyst was transferred manually to the vessel. The substituted nitrobenzene, dissolved in ethyl acetate solvent, was subsequently added, followed by the additional solvent necessary to give the desired concentration. Reaction conditions are summarized in Table 1. The concentrations were calculated by assuming that the reaction mixture density is equal to that of ethyl acetate solvent, which was calculated using the method of Hankinson et al.1 After charging to the RC1 vessel, air was purged from the system by alternately applying house vacuum (70 Torr) and 5 psig of N2 three times. A temperature ramp (typically 5 °C) to the desired reaction temperature was performed over a 10-min period to measure the heat capacity of the vessel contents, following which the calibrated heater was turned (1) Reid, R. C.; Prausnitz, J. M.; Poling, B. E. The Properties of Gases and Liquids, 4th ed.; McGraw-Hill: New York, 1987. 340
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Table 2. GC conditions oven temp program injector temp detector temp carrier gas column head pressure injection vol. split ratio
60 °C for 0 min, 25 °C/min to 90 °C, 15 °C/min to 200 °C, hold for 2 min 250 °C 300 °C He 25 psig 1 mL 50/1
on to determine the quantity UA. N2 was subsequently purged from the system and H2 introduced into the head space by applying vacuum and H2 pressure three times, with the stirrer turned off. The reaction was initiated by turning on the stirrer with the reactor at the desired H2 pressure. At the end of the reaction, additional determinations of UA and the heat capacity of the reaction mixture were performed, as described above. Ethyl acetate (99.9% purity) was obtained from Burdick and Jackson. Laboratory-synthesized batches of the substituted nitrobenzene were used in most experiments; the last three runs were performed with material made in the pilot plant (Table 1). All experimental materials were used as received. Water was added to the Pd/C catalyst in the first few runs to obtain a 50% wet form. In subsequent runs, the pilot plant catalyst was employed; this catalyst was composed of a prewetted form (50% wet) and supplied by Aldrich (Table 1). In all cases, the Pd content of the catalyst was 10 wt % on a dry basis. Several 2-mL samples taken from the reactor at various reaction times were analyzed using a Hewlett-Packard 6890 GC equipped with a capillary column (30-m × 0.25-mm i.d., HP-5MS 5% phenyl methyl siloxane phase, 0.25-mm film thickness) and a flame ionization detector. GC conditions are summarized in Table 2. The internal standard method of analysis was employed, with n-decane used as internal standard. Results and Discussion 1. Evaluation of Initially Proposed Conditions. Experiments were first performed to evaluate the initially proposed conditions of 10 °C, 30 psig, initial reactant concentration of 0.69 M, and catalyst/reactant ratio of 6.66 × 10-3 (runs 19603 and 19604, Table 1). A high stirring
Figure 1. Reproducibility and self-consistency of replicate RC1 runs (19603 and 19604, Table 1) performed at 30 psig, 20 °C, and a catalyst/reactant ratio of 6.66 × 10-3 g/g: (A) heat evolution rate, (B) reactant conversion, and (C) H2 uptake (run 19604) as functions of time.
speed (1000 rpm) was selected to obtain high gas-liquid mass transfer rates. Results from replicate runs reproduced well, as evidenced by nearly coinciding heat evolution rate (HER) curves and GC-determined reactant conversions (Figure 1A,B). The self-consistency of the data was demonstrated by the nearly identical times (ca. 1.4 h) required to attain zero heat evolution and complete conversion for each run. Data selfconsistently is also shown in Figure 1C, which indicates that the pressure in the H2 supply cylinder to the RC1 vessel decreased and attained a constant value at a time coinciding with the attainment of zero HER and complete reactant conversion. The extent of reaction could thus be monitored in three different ways. Figure 1A also shows that the HER curve, which is proportional to the reaction rate, increased from a nonzero initial value, attained a maximum, and then decreased to zero at long reaction times. This profile, which was reproduced
in subsequent experiments, is clearly more complex than the monotonically decreasing heat evolution curve expected for a reaction forming one product and obeying simple (e.g., first-order) kinetics. We address the shape of the heat evolution curve later. The initially proposed conditions gave a reasonable reaction time (ca. 1.4 h). Furthermore, the substituted aniline product was formed in almost 100% yield, with the yield of substituted toluidine byproduct being 95% (Figures 2, 10, and 12). The activating effect of water (Figure 11) is thus implicated as the primary cause of the apparent autocatalytic behavior observed. Conclusions Reaction calorimetry experiments were performed to evaluate proposed conditions for scale-up of the catalytic reduction of a substituted nitrobenzene. Heat evolution rates under the proposed conditions were estimated to be beyond the safe operating limits of the pilot plant reactor. A comprehensive evaluation of alternative conditions was performed taking into consideration plant heat removal and pressure constraints, plant reactor gas-liquid mass transfer, and reactivity differences between plant- and laboratoryprepared reactants. The evaluation led to the selection of reaction conditions for the pilot plant campaign (30 psig, 20
°C, and catalyst concentration of 7.53 × 10-3 g of catalyst/g of reactant) incorporating safety improvements and batch holding time savings. Very good agreement between conversion data from the pilot plant and laboratory reactor was obtained, demonstrating the capability of reaction calorimetry in successfully scaling up a highly exothermic reaction without byproduct formation. Major improvements over the initially proposed process include (a) increasing the safety margin by operation at 20 °C and thus taking advantage of the greater cooling capacity and (b) decreasing the batch holding time by more than 35%. The maximum in the observed HER profile was attributed to the activating effect of water on the Pd/C catalyst by comparing HER profiles from experiments with and without water in the feed. This insight also demonstrates the potential of reaction calorimetry for elucidating catalyst promotional effects. Acknowledgment We thank J. Streemke and S. Khan for valuable comments and insightful discussions pertaining to the determination of plant heat transfer coefficients. Received for review March 24, 1997.X OP970015Q X
Abstract published in AdVance ACS Abstracts, June 15, 1997.
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