Synthesis and Kinetics of Highly Energetic Intermediates by

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Ind. Eng. Chem. Res. 2010, 49, 4132–4139

Synthesis and Kinetics of Highly Energetic Intermediates by Micromixers: Direct Multistep Synthesis of Sodium Nitrotetrazolate Nikolay Zaborenko, Edward R. Murphy,† Jason G. Kralj,‡ and Klavs F. Jensen* Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts AVenue, Cambridge, Massachusetts 02139

A modular silicon micromixer is designed and fabricated for high-flow rapid mixing at a wide range of reaction conditions. The mixer operates by splitting two inlet flows into a large number of channels, interdigitating them, and constricting the laminated flow to create submicrometer diffusion lengths. Mixing is quantified using the Villermaux-Dushman method, with UV-vis detection of the photoactive species, and compared against a commercial micromixer. Micromixers and tubing are then used to perform a quantitative kinetic study of the direct two-step synthesis of sodium nitrotetrazolate (NaNT) by a Sandmeyer type reaction via a reactive diazonium intermediate. Orders of reactions and temperature dependence of both steps, as well as pH and ionic strength dependence of the second step, are evaluated. Successful production of 4.4 g/h of NaNT in solution is ultimately achieved in a compact footprint using the kinetic data, verifying the potential for scaling to typical production amounts. Introduction The ability to perform on-demand synthesis of hazardous intermediates is one of the more promising uses of microreactors, along with the opportunity to gain mechanistic understanding and rate parameters for scale-up to production levels.1,2 With reduced thermal mass and rapid mixing, conditions within a microreactor can be more tightly controlled than those in a traditional apparatus.3 Furthermore, the use of a microreactor limits the quantity of reactive intermediates to only that required for immediate processing, thus simplifying containment in the event of a reactor failure. The enhanced heat and mass transfer within microreactors has also been shown to reduce reagent consumption, accelerate reaction optimization, and grant access to reaction conditions that would be impractical to pursue by standard laboratory techniques.4,5 Reactions involving diazonium intermediates, such as the synthesis of azo dyes, have been of great interest in the microreactor community for some time as an example of multistep synthesis with microscale safety advantages. Reactive intermediates such as tetrazolediazonium are extensively used in many chemical industries, including medicine,6,7 biology,8,9 and explosives.10,11 However, the processes are often not well understood or optimized due to the difficulty in obtaining reaction kinetics and in scaling up from laboratory to pilot to production levels. The difficulties are presented by the instability of the reactive intermediates, making typical kinetic studies both difficult and potentially highly dangerous, requiring numerous precautions. These reactions have been performed safely using monolithic micro- and nanoreactors.12,13 Additionally, combinatorial synthesis of azo dyes in immiscible liquid slugs has also been demonstrated.14 To further advance the study of chemical synthesis via diazonium intermediates, we developed a system of modular * To whom correspondence should be addressed. E-mail: [email protected]. † Currently at DuPont Central Research and Development, Chemical Science and Engineering, Experimental Station, E304/C216, P.O. Box 80304, Wilmington, DE, 19880. ‡ Currently at National Institute of Standards and Technology, Biochemical Sciences, Experimental Station, 100 Bureau Drive, MS 8313, Gaithersburg, MD, 20899.

Scheme 1. Two-Step Formation of Sodium Nitrotetrazolate 3 (NaNT) from 5-Aminotetrazole 1 (AT) 1 via 5-Diazonium-1Htetrazole 2 (DHT) Intermediatea

a The acid-base equilibrium between DHT 2 and the nonreactive 5-hydroxydiazonium-1H-tetrazole (HDHT) 4 is also shown.

mixers with adjustable reaction residence volumes. Such a system is highly flexible, allowing rapid mixing while permitting isolation of intermediate species and varying the individual reaction times for each reaction step. Specifically, the system enabled us to explore the reactions involved by separately analyzing the initial diazotization step, as well as characterizing the effects of reaction conditions such as temperature and pH on conversion and selectivity. Moreover, the micromixer devices accommodated higher flow rates than typically possible in fixed volume microreactors, thus enabling the use of larger volumes and increased production. We selected the product sodium nitrotetrazolate 3 (NaNT) as a demonstration of a safe and efficient method of both performing kinetic studies and synthesizing a potentially highly explosive compound.15 NaNT 3 is directly synthesized when 5-aminotetrazole 1 (AT) reacts with nitrous acid to produce the 5-diazonium-1H-tetrazole 2 (DHT) intermediate, which further reacts with the nitrite ion via a modified Sandmeyer reaction (Scheme 1).

10.1021/ie100263p  2010 American Chemical Society Published on Web 03/29/2010

Ind. Eng. Chem. Res., Vol. 49, No. 9, 2010

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Figure 1. Interdigitated silicon micromixer. (a) Three-dimensional rendering and (d) photograph. (b) Close-up of corner of distribution channels showing the two flow streams being split into 50 and 51 interdigitated channels. (c) End of the interdigitated channel section forming 101 lamiae that are subsequently compressed in the converging channel.

In industrial processes, batch vessels are typically employed for the synthesis, and the direct synthesis scheme is avoided due to the hazards associated with it. Both DHT 2 and NaNT 3 are highly unstable in their crystalline form and, to an extent, in increased concentrations (6-7% for DHT 2).16,17 N2 gas released in the second reaction step (see Scheme 1) tend to create froth in a stirred batch vessel. This froth can accumulate on batch sidewalls and become concentrated or even form dry solids leading to potentially explosive conditions. Therefore, commercial production of NaNT 3 has typically applied alternative syntheses such as the use of copper(II) sulfate (CuSO4) that stabilizes DHT 2 and complexes with NaNT 3. However, this approach has the disadvantages of requiring elevated temperatures (70 °C) and addition of base to release NaNT 3 in its nonstabilized form for further reaction, causing some degradation of NaNT 3, reducing reaction yields, and forming solid copper oxide (CuO) precipitation.18–20 Furthermore, both reaction steps are highly pH sensitive, as are the intermediate and the product. DHT 2 degrades with time at low pH (such as the range at which it must be synthesized).16,18 In addition, at high pH, DHT 2 takes the form of nonreactive 5-hydroxydiazonium1H-tetrazole (HDHT) 4 (Scheme 1). Thus, NaNT 3 must be synthesized at a mildly acidic range, requiring introduction of a buffer and/or base, which must be carefully controlled, as NaNT also degrades at high pH and elevated temperatures. Because the reaction is exothermal, local temperature and concentration gradients can cause product loss, leading to mixing being a crucial parameter during both production (to maximize yield) and kinetic study (to ensure accurate study of actual reaction). With these considerations, a continuous flow system incorporating micromixers is presented, allowing for both rapid mixing and precise time control of composition with very little effort. The rest of this paper is laid out as follows. We begin by describing the design, production, and characterization of the micromixer devices. Next, the experimental design and setup

of the two-step NaNT 3 synthesis and kinetics study are described, followed by the results of and discussion of NaNT 3 synthesis kinetics. The conclusion provides a summary of our findings. Micromixer Production and Characterization It is desirable to utilize very similar systems for both kinetic study and optimized scaled-up process development to avoid problems with system transition and information transfer. Thus, the system has to use an low-volume, efficient micromixer, permitting fast kinetic analysis, and with a reasonably low pressure drop, allowing pumping at high flow rates for maximal production. In addition, the mixer design has to be sufficiently simple and cheap to manufacture. An interdigitated laminar mixer design with flow focusing was selected for rapid mixing with a relatively low pressure drop.21,22 A 4.1-µL micromixer (Figure 1) was designed to mix two liquid streams by separating each stream into 50 and 51 50-µm-wide channels, respectively, interdigitating them, and focusing them into a 500-µm channel, where the bulk of the mixing occurs. Mixing is expected to occur in under 10 ms for a diffusivity of 10-9 m2 s-1, representative for ions in aqueous solution.22,23 The pressure drop was calculated based on Hagen-Poiseuille relation and equivalent diameters24,25 to be 0.57 bar/Qµ, where Q is the total flow through the device in milliliters per minute and µ is the viscosity of said flow, in centipoise. The micromixers were fabricated using standard silicon fabrication methods, with wet (KOH) and dry (DRIE) etching for the bottom (microchannels) and top (focuser and manifolds) sides, respectively. Anodic bonding to Pyrex was used for capping. The devices were compression-packaged into Hastelloy fluidic interfaces with Teflon O-rings, providing good chemical compatibility. Mixing was evaluated with the well-known VillermauxDushman micromixing method,26–29 based on parallel competing

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Scheme 2. Competing Parallel Reactions of the Villermaux-Dushman Method

reactions of iodide/iodate and acid/base neutralization (Scheme 2), adapted for continuous flow applications.30–34 The mixing performance is inversely related to the amount to triiodide detected. Using the concentrations given by Panic´ et al.,34 aqueous solutions were prepared of sulfuric acid and of buffered KI/KIO3 and flowed through the micromixer directly into a UV detector. Under the chosen experimental conditions, the length and volume of the outlet tubing does not influence the measurement of triiodide because all of the acid is completely consumed prior to reaching the outlet. Detailed descriptions of this experimental setup, as well as of mixer design and microfabrication, are available as Supporting Information. Figure 2 depicts the mixing performance of the micromixer measured by the absorbance of triiodide at 286 nm, compared with that of a commercially available glass micromixer (mgt mikroglas, technik AG, Mainz, Germany) of 31 lamina (15 and 16 each for two flows) 50 µm wide and 150 µm deep, as obtained by Panic´ et al.;34 no error bars were available for these data. As expected given a smaller diffusion distance, our micromixer outperforms the commercial one, although both have very good mixing at all evaluated flow rates. With increasing flow rate, the mixing performance improves because the liquid moves into the narrow channel (with small diffusion distances) more rapidly, thus reducing the residence time available for the triiodide-forming reaction to occur before mixing is fully complete. NaNT 3 Setup Kinetic Evaluation of DHT 2 Formation. The kinetics of the first step of direct NaNT 3 synthesis, the production of DHT 2, were evaluated by mixing a stream of 5-AT 1 (0.025-0.05 M) in 1.5 M sulfuric acid with a stream of excess NaNO2 (0.025-0.05 M) in a micromixer and evaluating the quenched effluent. As the reaction can only proceed under acidic conditions, 4 M NaOH was used to quench the reaction, with the

Figure 2. Micromixer performance. Open squares correspond to the silicon micromixer (error bars are shown within the squares); filled triangles correspond to a commercial glass micromixer from mgt mikroglas, technik AG, Mainz, Germany, as reported by Panic´ et al.34 No error bars were available for the glass micromixer.

reaction and quench streams mixing in a second micromixer to ensure very rapid quenching. Reagents were used as received and prepared in deionized water filtered through a Millipore Academic Milli-Q water purifier. 5-Aminotetrazole 1 was purchased from Lancaster Synthesis, Inc., in Pelham, NH. Analytical reagent-grade sulfuric acid and sodium hydroxide were supplied by Mallinckrodt Chemicals (Phillipsburg, NJ). Sodium nitrite (97%) was purchased from Alfa Aesar in Ward Hill, MA. The solutions were degassed by ultrasonication prior to experiments. The reagents were delivered to the micromixers a single multihead Harvard Apparatus PHD 2200 syringe pump, delivering equal flow rates of each of the three solutions to the mixers via 0.04 in. i.d. tubing. After mixing the 5-AT 1 and NaNO2 streams in the first micromixer, the reaction stream entered a 17.5 cm length of 0.020 in. i.d. Teflon tubing, providing 39.5 µL of reaction volume (including 4.1 µL of the micromixer volume). The total flow rate was varied from 240 to 2000 µL/ min, providing residence times of 9.9 to 1.2 s, respectively. The reaction zone tubing connected to the second micromixer, where the reaction stream mixed with the NaOH quench stream (at a volumetric flow ratio 2:1) and exited through an additional 5-cm piece of 0.04 in. i.d. tubing. Reaction temperature control was achieved by completely submerging both compressed microreactors and the reaction zone tubing into an ethylene-glycol-filled heater/chiller recirculating bath (Neslab Endocal). To evaluate temperature dependence, the reaction was performed at four temperatures between 5 and 28 °C, inclusive, with 1.2 s residence time. Other experiments were performed at room temperature, measured to be 21 ( 1 °C. Reaction samples were collected into two-dram glass vials, with at least three samples collected per set of experimental conditions. At least five residence times were allowed to pass between attaining new experimental conditions and sample collection. Collected samples were diluted by a factor of 10 with mobile phase, loaded into a Waters 717+ Autosampler, and analyzed using a Waters Nova-pak C18 column (3.9 × 150 mm). The mobile phase was 0.1 M monobasic phosphate aqueous buffer, pumped isocratically at 1 mL/min by a Waters 1525 binary pump. The eluent was monitored on a Waters 2996 Photodiode Array Detector. Elution of all compounds was complete after 5 min. Because of the instability of DHT 2, the reaction conversion was measured indirectly by measuring the concentration of HDHT 4, which is in equilibrium with the diazonium salt. The excess sodium hydroxide in the quench ensured a quantitative conversion to HDHT 4, and, as a result, no NaNT 3 production was observed in this portion of the study. Peak absorbance of NO2- was observed at 209.7 ( 0.5 nm, of 5-AT 1, at 217.9 ( 0.5 nm, and of HDHT 4 at 261.5 ( 0.5 nm. Kinetic Evaluation of NaNT 3 Formation. The kinetics of the second step of direct NaNT 3 synthesis were evaluated by mixing the unquenched product stream of the DHT 2 production setup with a buffer solution in a micromixer and evaluating the quenched effluent. As the reaction can only proceed in a pH range from mildly acidic to very mildly basic, 4 M NaOH was used to quench the reaction. Because this reaction step is significantly slower than the first step, mixing through a T-mixer was sufficiently rapid for the quench. Reagents were used as above. In addition to the reagents used for DHT 2 synthesis, sodium acetate (Mallinckrodt Chemicals, Phillipsburg, NJ) and sodium phosphate (99%, EM Science, Gardena, CA) were used for the buffer solutions. DHT 2 was


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Figure 3. Reaction setup for the direct NaNT 3 synthesis kinetic study.

produced by combining 0.05-0.10 M 5-AT 1 in 1.5 M sulfuric acid with 0.20-0.35 M sodium nitrite at equal flow rates. Solutions were degassed by ultrasonication. A buffered base solution required for a pH of 5, comprising NaOH and sodium acetate was used for studies of reaction order and temperature dependence. The composition of the solution of buffered base varied based on the desired pH range of the reaction, assuming total conversion of 5-AT 1 to DHT 2 prior to mixing with the buffer. The calculation of pH range was bounded at 0% and 100% conversions of DHT 2 to NaNT 3, considering evolution of 2 mol H+/mol NaNT 3. The values of pKa of nitrous acid, sulfuric acid (second deprotonation), acetic acid, and phosphoric acid (all three deprotonations) were obtained from standard handbooks. The pKa of 5-nitrotetrazole, the protonated form of NaNT 3, is -0.82.35 The pKa of DHT 2 was approximated by titration of a product solution of DHT 2 of known composition and was found to be approximately 8. However, the calculations of pH were very insensitive to the pKa of DHT 2, given the low concentrations used and the nearly neutral nature of DHT 2. Calculations were performed to determine buffer composition for each desired set of experimental conditions and the desired pH at the start of the reaction, allowing pH to decrease by 0.15 at full conversion of DHT 2 to NaNT 3. For pH at and below 6, syringe concentrations of sodium acetate and NaOH from 0.6 to 2.4 M and from 0 to 3 M, respectively, were used. The buffered base solution was flowed at an equal flow rate as each of the other syringes. For pH of and above 6, syringe concentrations of sodium phosphate and NaOH from 0.044 to 1.2 M and from 1.5 to 1.8 M, respectively, were used. The buffered base solution was flowed at twice the flow rate of any of the other syringes, as the solubility of sodium phosphate was too low to use a more concentrated buffer. The setup schematic for the NaNT 3 kinetic study is shown in Figure 3. A single multihead Harvard Apparatus PHD 2200 syringe pump was used with all four syringes, delivering equal flow rates of each solution. For experiments with sodium phosphate buffer, a second pump was used for the buffer, at twice the flow rate. After mixing the 5-AT 1 and NaNO2 streams in the first micromixer, the reaction stream entered a 29.6 cm length of 0.040 in. i.d. Teflon tubing, providing 244 µL of reaction volume (including 4.1 µL of the micromixer volume). This provided complete conversion of 5-AT 1 (verified by HPLC) at the evaluated flow rates, which were varied from 100 to 300 µL/min of each component during reaction order

evaluation, providing a residence time of 74 to 25 s, respectively, in the DHT 2 formation zone. As the second step of the reaction evolves nitrogen gas (Scheme 1), a vacuum degasser was used to ensure that no gas bubbles evolved during the experiments, allowing for accurate residence time measurement. The vacuum degasser consisted of a machined aluminum vacuum chamber with gas-permeable Teflon AF tubing coiled within, connected to a vacuum pump (1/2 HP, Leland Faraday M291 A) via a rubber vacuum hose. No gas bubbles were seen entering or forming in the reaction zone tubing during experiments. However, if the pump was turned off and the reaction flows were allowed to proceed normally, evolution of gas slugs was seen within the Teflon AF tubing.36 The Teflon AF tubing (0.036 in. i.d., 48 cm, 361 µL) was used as the primary residence volume for the conversion of DHT 2 to NaNT 3, with a total residence volume (including mixer and connecting tubing) of 380 µL. This provided residence times of 25-76 s at the aforementioned flow rates. Upchurch NanoTight PEEK tubing sleeves were inserted into the degasser ports, and the gas-permeable tubing was threaded into them to a sufficient distance as to be held in place at the port by an Upchurch NanoTight headless fitting and ferrule (F-333N). The second end of each sleeve was attached by another such fitting to an Upchurch VacuTight union (P-845-01), which, via a VacuTight short fitting and ferrule (P-844) and a short piece of 0.040 in. i.d. Teflon tubing, were attached to the micromixer chuck on one end and to an Upchurch PEEK tee union (P-712) on the other end. At the tee union, the reaction stream mixed with the NaOH quench stream and exited through an additional 10 cm piece of 0.04 in. i.d. tubing. The reversible fittings at the mixer chuck and tee union allowed the mixer to be disconnected from the residence zone and the residence zone from the quench. This permitted disconnecting zone 1 or the quench to measure the pH of the reacting solution before and after the reaction with either EM Science colorpHast indicator strips or BakerpHIX pH papers. HPLC analysis was performed as above. Peak absorbance of NaNT 3 occurred at 256.7 ( 0.5 nm. Reaction temperature control was performed as in the first step study. The reaction temperature dependence was evaluated at four temperatures between 6 and 29 °C, inclusive, with three flow rates evaluated at each temperature. Other experiments were performed at room temperature. To measure temperature within the chamber during temperature dependence experiments, a digital thermometer (Omega HH-21A, with a K-type wire

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Figure 4. DHT 2 reaction order determination through consumption of nitride () initial concentrations of nitride and 5-AT of 0.0125 M each; 4 initial concentration of nitride of 0.0125 M and 5-AT of 0.025 M; × initial concentrations of nitride and 5-AT of 0.025 M each; - - - initial rate slope of the first two data series, and · · · initial rate slope of the third series).

thermocouple) was threaded into the chamber through a slit in the vacuum tubing, which was sealed with duct tape. Scale-up to NaNT 3 Production. The scale-up of direct NaNT 3 synthesis was performed using identical reagents and evaluation methods as for the kinetics evaluation. Samples were diluted by a factor of 100 for analysis. Reaction concentrations and conditions were selected using the knowledge of kinetics to attempt to maximize production of NaNT 3, mixing 1.6 M sodium nitrite with 0.4 M 5-AT 1 in 1.8 M sulfuric acid (more acidic to compensate for the increased nitrite concentration). In the second mixer, this was mixed with sodium acetate buffer (to a pH range of 5-4) and finally quenched with 4 M NaOH: the latter two flowed at 0.9 times the volumetric rates of the former two reagents. The setup from the kinetic study of NaNT 3 was modified as follows. Plastic single-use 60 mL Becton-Dickinson (BD) syringes were used to deliver the reagents. Two syringe pumps (identical to those in previous sections) were used: one for the two reagent streams and the other for the base and quench streams. The nitration step was performed in a 28 cm long piece of 1/4 in. o.d., 0.188 in. i.d. Teflon tube (5 mL residence volume), connected via a stainless steel Swagelok reducing union (SS-400-6-1) to 1/16 in. o.d., 0.04 in. i.d. Teflon tubing. Degassing was not performed because the large amounts of gas generated made it highly impractical. Thus, the residence time was not well-known due to the generated gas, creating a highly nonlinear dependence of residence time with reagent flow rate. During temperature evaluation experiments, the thermocouple was submerged into the ethylene glycol bath along with the reaction tubing to confirm temperature at the outer surface of the tubing. No 5-AT 1 was observed in any of the experiments, indicating full conversion of 5-AT 1 to DHT 2 in all cases. Results and Discussion Kinetic Evaluation of DHT 2 Formation. The order of the reaction of DHT 2 formation from 5-AT 1 and HONO was determined by analyzing the results of varying reagent concentrations (Figure 4). The increase of UV absorbance of HDHT 4 linearly correlated to the decrease of absorbance of nitrite, and the measured changes in concentration of 5-AT 1 corresponded nearly identically to the measured changes in concentration of NO2-. Combined with the observation of no other peaks in the UV analysis, the result indicates that only the desired reaction occurred in these studies.

Figure 5. Arrhenius correlation between temperature and DHT 2 production rate constant.

The initial rate of reaction was approximated by measuring the change in nitrite concentration from its starting value to that at 1.2 s into the reaction. For the baseline experiment with initial concentrations of 0.0125 M each of 5-AT 1 and of NO2- (total ion, assumed to be nearly completely in the form of HONO), the initial rate was measured to be 3.82 × 10-3 mol/(L s). When the initial concentration of 5-AT 1 was doubled to 0.025 M, keeping the nitrite concentration the same, the initial rate was measured to be 3.82 × 10-3 mol/(L s), or unchanged from the baseline case, and the conversion with time followed an identical trend to the baseline experiment. When the initial concentration of nitrite was also doubled (both 5-AT 1 and nitrite initially at 0.025 M), the initial rate increased to 1.75 × 10-2 mol/(L s), slightly over 4 times that of the baseline experiment, and the conversion with time followed a trend that indicated a secondorder reaction when compared to the baseline case. Combined, these results indicate that, at the evaluated conditions, the reaction is zero-order with respect to 5-AT 1 and second-order with respect to HONO, or following the rate law of eq 1. rDHT ) k1[HONO]2

(1)

Regarding the kinetics of diazotization for the identical reaction using arylamine in place of 5-AT 1, at acidities between 0.1 and 6.5 M [H+], the rate has been reported as the following equation:37 rDiaz ) k1[ArNH2][HONO]h0 + k2[ArNH+ 3 ][HONO]h0 (2) where h0 is the Hammet acidity function, which at this pH range is nearly equal to [H+]. However, for the same reaction at low acidities (pH > 2), the observed rate with arylamine is equivalent to eq 1.38 This change in rate expression is caused by the ratelimiting step of the mechanism becoming the formation of N2O3 from HONO, which is believed to be the actual reactive species.39 In the case of 5-AT 1 as the reagent, it is possible that, because tetrazole is more reactive than benzene due to the electron-donating effects of the alpha nitrogen, the formation of N2O3 is the rate-limiting step even at larger acidities. Therefore, our finding of the reaction being second-order in HONO is reasonable. Figure 5 shows the temperature dependence of DHT 2 formation as a plot of ln k1 vs 1/T. The Arrhenius parameters were determined to be k1 ) e(17.8(0.9)-(36.1(2.1kJ/mol/

k1,298K ) 26 1/(M s)

(RT))

(3)


Figure 6. NaNT 3 reaction order determination through formation of NaNT 3 () initial concentration of nitride of 0.05 M and 5-AT of 0.0167 M; 4 initial concentration of nitride of 0.05 M and 5-AT of 0.033 M; × initial concentration of nitride of 0.10 M and 5-AT of 0.033 M).

The observed rate constant data showed good agreement with the expected second-order kinetics. In addition, these data are within the range of typical values for secondary amines at similar conditions.40 However, the slight upward curvature of the data indicates that a multistep mechanism could also be present. Kinetic Evaluation of NaNT 3 Formation. The order of the reaction of NaNT 3 formation from DHT 2 and NO2- was determined by analyzing the results of varying reagent concentrations (Figure 6). The decrease of UV absorbance of HDHT 4 linearly correlated to the increase of absorbance of NaNT 3, and the measured changes in concentration of nitrite corresponded nearly identically to initial concentration of 5-AT 1 plus the measured concentration of NaNT 3. No 5-AT 1 was seen in the HPLC traces. Combined with no other peaks being observed in the UV analysis, this indicates that all of 5-AT 1 was initially reacted to DHT 2 and that only the desired reactions were occurring in these studies. The initial rate of reaction was approximated by measuring the NaNT 3 concentration at 25 s into the reaction. For the baseline experiment with initial concentrations of 0.0167 M of 5-AT 1 and 0.05 M of NaNO2 (after full conversion to DHT 2, resulting in 0.0167 M of DHT 2 and 0.0333 M of NaNO2, a 1:2 ratio), the initial rate was measured to be 1.60 × 10-5 mol/ (L s). When the initial concentration of 5-AT 1 was doubled to 0.0333 M, keeping the nitrite concentration the same (1:1 ratio of DHT 2 to nitrite), the initial rate was measured to be 3.20 × 10-5 mol/(L s) or twice that of the baseline case. When the initial concentration of nitrite was doubled, keeping 5-AT the same as in the baseline case (1:4 ratio of DHT 2 to nitrite), the initial rate was measured to be 3.40 × 10-5 mol/(L s) or slightly over twice that of the baseline case. Combined, these results indicate that, at the evaluated conditions, the reaction is first-order with respect to DHT 2 and with respect to HONO, i.e., rNaNT ) k2[DHT+][NO2-]

(4)

Equation 4 is written in terms of the nitrite ion because, this being a substitution reaction, only the dissociated nitrite ion participates in the reaction. To convert this rate to a more easily applied one using total nitrite and diazonium ion concentrations (in all forms), their acid-base dissociation equilibria were used to decouple the total concentrations from a function of pH (see the Supporting Information for full derivation). As the pKa of DHT 2 (pKDHT) is not well-known, this was treated as a parameter to be fitted.

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Figure 7. NaNT 3 generation rate vs pH and ionic strength. Filled symbols represent experimental results, and open symbols represent model calculations at corresponding pH and I () buffering with sodium acetate; 4 buffering with sodium phosphate). Data labels indicate the ionic strength at the initial conditions of each experiment.

In addition to pH, ion interactions and ionic shielding can play a significant role because this reaction occurs between two ions. The simplest approach to modeling ionic strength effects is by the Debye-Hu¨ckel limiting law, using activity coefficients of the reagents, which we applied to obtain a working model of the ionic strength dependency.41 This law is only accurate for binary-ion, highly dilute solutions; however, more involved models, such as the Meissner corresponding states model42 and Chen local composition model,43 require knowledge of certain parameters for each ion, many of which were not found in the literature. Using the Debye-Hu¨ckel model, the dependency function of pH and ionic strength could be decoupled from the concentrations and the Arrhenius dependence, as follows f(I, pH) )

√I

10pKDHT-pKHONO-4A √

(1 + 10pH-pKHONO-2A I)(1 + 10pKDHT-pH)

(5)

where I is the ionic strength of the solution and A is a constant that depends on the solvent, which is inversely proportional to T3/2 (Stephan-Boltzmann dependence). The full derivation is given in the Supporting Information. Thus, the overall reaction rate can be described by eq 6. rNaNT ) 10pKDHT-pKHONO-4A pH-pKHONO-2A√I

(1 + 10

√I pKDHT-pH

)(1 + 10

Are-Ea/RT[DHT]T[NaNO2]T )

(6) where Ar is the Arrhenius pre-exponential factor, T is the temperature of the solution, and [DHT]T and [NaNO2]T are the total concentrations of DHT 2 (including HDHT 4) and nitrite (including nitrous acid). To determine A (at room temperature) and KDHT, the pH of the reaction solution was varied by using different buffered base solutions in the reaction step. Ionic strength was calculated for each of the reaction mixtures. Additionally, several reactions were run at identical conditions but varying the ionic strength through addition of NaCl to the buffered base solution. The results are presented in Figure 7. Moreover, for each data point, the predicted reaction rate was calculated based on eq 6, treating the Arrhenius term group as a single constant. These predicted k values are shown in Figure 7 alongside the corresponding experimental points. Performing a parameter fitting, the following values were obtained:

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pKa,DHT+ ) 7.57 ( 0.07

ART ) 0.711 ( 0.026 kg1/2 /mol1/2

Using the determined values, there is reasonably good agreement between experimental and calculated reaction rate constant values at pH above 4. Below 4, the trend is maintained, but the calculated and experimental values divergesmost likely as the Debye-Hu¨ckel model becomes poorer at the more extreme conditions of pH. The value of the Ka of DHT 2 is in good agreement with the crudely evaluated value by titration. The value for A is lower than the experimentally obtained value for water of 1.172 kg1/2/mol1/2;44 but that value represents an ideal, highly dilute solution with small ionic species. The temperature dependence of NaNT 3 formation comes both from the Arrhenius parameters and the effect of temperature on the activity coefficients (and thus, the dissociation) of the reactive species. Temperature also affects the pH, but in the examined range, this effect was deemed negligible. To account for the effect of temperature on A, the following equation was considered: ln k2 ) ln(f(I, pH)) + ln Ar -

Ea 1 RT

(7)

Because the dependence of f(I, pH) on temperature is known, A was recalculated for each examined temperature, and the first term of eq 7 was subtracted from the left-hand side to yield a linear plot (Figure 8). The Arrhenius rate parameters for NaNT 3 formation were determined to be kArrhen ) e(11.3(0.9)-(25.5(2.1kJ/mol/

(RT))

(8)

The observed reaction rate constant at room temperature, using a buffer solution designed to maintain pH between 5 and 4.9 using the baseline experiment concentrations was 1.9 × 10-2 mol/(L s). It is interesting that the activation energy of the second step is lower than that of the first step of the direct synthesis, while the reaction rate is actually lower. However, the lower reaction rate reflects that the second step is a reaction of two ions in a solution of high ionic strength. Scale-up to NaNT 3 Production. For scaled-up direct synthesis of NaNT 3, a set of conditions was chosen based on information gleaned from the kinetic studies. For the nitration of DHT 2, the concentrations of 5-AT 1 and nitrite were increased significantly over those used in the kinetic studies. NaNO2 was used at a concentration 4 times that of 5-AT 1 to take advantage of the diazotization being second-order in nitrite. Additionally, 5-AT 1 is a more costly reagent than NaNO2 and is more desirable to be used as the limiting reagent. Sodium acetate was selected for the buffered base solution because it is more likely to be used industrially, as it can be used at higher concentration, leading to higher concentration of products. For total liquid flow rates through the second-step residence tubing of between 580 and 2900 µL/min, there is no significant change in yield of NaNT 3 (nonisolated) when an inline quench was used. Thus, the reaction was completed quickly, in under 2 min, and additional time does not increase, and may even decrease (possibly due to degradation), the amount of product. Higher flow rates were not explored due to the pressure limitation of the plastic syringes. The method was successful in safely and efficiently producing NaNT 3 in large yields and at sufficiently high production rates. Using two syringe pumps and a small benchtop setup, we were able to successfully produce (in solution) 2.8 g/h of NaNT 3 with the best yield of 84%, and to maximally produce 4.4 g/h of NaNT 3 at a yield of 66% from 5-AT 1. Faster production

Figure 8. Arrhenius correlation between temperature and NaNT 3 production rate constant.

can be easily achieved given proper equipment, such as highpressure HPLC-type piston pumps, easily allowing for typical production rates (∼50 g/h) without greatly increasing the footprint. The reaction was performed at temperatures from 5 to 35 °C with different buffer solutions. Using the optimal buffer, at a total reaction flow rate of 2900 µL/min, no significant differences were seen between the yields, which may be due to the residence times being affected by changing gas density. With a different buffer solution to create a slightly basic medium, the yield of NaNT 3 was lower, even with longer residence times, but no HDDT 4 or 5-AT 1 was seen in the traces. At increased concentrations, and especially at higher temperatures, NaNT 3 and HDHT 4 can degrade in basic solutions, the latter of which would reduce the available reactive DHT 3, a conclusion that is supported by the lack of HDHT 4 in the traces. Because this reaction is exothermic, performing it in batch with slow addition of base to the acidic nitrite/DHT 2 solution would result in local pH and temperature gradients, which could cause similar degradation of nitrite and of DHT 2, resulting in poorer yields. Thus, there are clear advantages to performing this reaction continuously with rapid inline mixing. Conclusion Direct synthesis of an energetic compound, NaNT 3, via a highly energetic intermediate, DHT 2, was achieved using rapid mixing in modular silicon-based laminar micromixers. Kinetics of the two steps of the reaction were successfully obtained, including the orders of the reaction and Arrhenius dependence of the first step (diazotization of 5-AT 1), and the orders of the reaction, dependence on pH, ionic strength (as a function of temperature), and Arrhenius dependence of the second step (nitration of DHT 2). The knowledge gained in the kinetic study was applied to design a scaled-up system to demonstrate production of NaNT 3. At room temperature, with a small footprint of two syringe pumps and a small area for two microreactors and tubing, production of 4.4 g/h of NaNT 3 in solution was performed in a safe manner. Minimizing concentration and temperature gradients and applying continuous flow enabled safe, room-temperature, continuous synthesis of NaNT 3, greatly simplifying and accelerating the process by an order of magnitude compared to the traditional batch method. This demonstration further confirmed the advantages of continuous flow production of NaNT 3 for both safety and efficacy. Acknowledgment We thank Pacific Scientific for funding, Michael Williams for discussions of chemistry and the industrial process, and the


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ReceiVed for reView February 2, 2010 ReVised manuscript receiVed March 14, 2010 Accepted March 16, 2010 IE100263P

Synthesis and Kinetics of Highly Energetic Intermediates by

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