Article pubs.acs.org/OPRD
Isoclast Active Manufacture: In Situ Spectroscopic Investigation of the Unstable Products of Cyanamide and Sodium Hypochlorite Reactions Xiaoyun Chen,*,† Chad Meece,‡ Mike Gonzalez,*,§ Hsu Chiang,∥ Xiaohua Qiu,† Yiyong He,† Mark A. Rickard,† and Daniel Friedhoff∥ †
Analytical Sciences, The Dow Chemical Company, 1897 Building, Midland, Michigan 48667 Kelly Services, Troy, Michigan 48083 § Global Agricultural Production Support, Dow AgroSciences LLC, The Dow Chemical Company, 1710 Building, Midland, Michigan 48667 ∥ Engineering and Process Sciences, The Dow Chemical Company, 1776 Building, Midland, Michigan 48667 ‡
S Supporting Information *
ABSTRACT: Isoclast Active is a new insecticide manufactured by Dow AgroSciences LLC. In an effort to lower the cost of manufacture of Isoclast Active, we have studied the reaction which produces N-cyano sulfilimine, which is the precursor to Isoclast Active. The reaction involves the oxidative coupling of cyanamide with the sulfide intermediate using sodium hypochlorite. In this study, we demonstrated that a transient intermediate species is produced by the reaction between bleach and cyanamide. On the basis of in situ Raman, IR, and NMR spectroscopic evidence we propose that the intermediate is the anionic form of N-chlorocyanamide: ClN−−CN. The degradation of this intermediate species was found to be highly sensitive to its environment and leads to a complicated mixture of products. This work also demonstrates that in situ Raman and IR spectroscopy are powerful and invaluable tools for monitoring reactions/processes involving unstable reaction intermediates for kinetic modeling and process R&D.
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INTRODUCTION Isoclast Active (3, Figure 1) is an insecticide that has recently been commercialized by Dow AgroSciences and has received regulatory approval in the USA.1 The last two steps for manufacturing Isoclast Active involves the bleach facilitated oxidative coupling of cyanamide with pyridine sulfide (1) to the sulfilimine (2), which in turn is oxidized to Isoclast Active. During our investigations directed at optimizing the yield of the sulfilimine reaction we found that premixing the bleach and cyanamide before addition of the sulfide 1 could give improved yields, but that the yield was sensitive to several factors, in particular time and temperature. We utilized in situ spectroscopy to better understand the reaction(s) which were occurring. As outlined below, we have collected compelling evidence that the N-chlorocyanamide anion is a key intermediate. The coupling of cyanamide with sulfides to form Ncyanosulfilimines described in the literature can generically be classified into two categories: (1) activation of cyanamide and (2) activation of the sulfide.2 Generic examples for each, in which electrophilic chlorine is used as the activating agent, are depicted in Figure 2. This brief literature summary is limited to activation of cyanamide with electrophilic chlorine since the evidence we have collected indicates our sulfilimine reaction proceeds via that mechanism. In 1981 Swern and co-workers3 proposed that the reaction of cyanamide with tert-butyl hypochlorite at 0 °C is cyanonitrene: “N− CN”. The nitrene is reported to be susceptible to dimerization to dicyanodiazene and reaction with nucleophiles. In 1982 Swern conducted 1H and 13C NMR and ESR experiments to monitor the reactions and “characterize” the products and intermediates.4 Kemp and co-workers5 proposed a mechanism involving a cyanonitrene in the formation of N-cyano sulfilimines prepared from sulfides and cyanamide using iodobenzene diacetate. In our studies disclosed in this article, Raman, infrared, and NMR spectroscopy were combined to demonstrate that the [N−ClCN]Na+ is the relevant intermediate species produced by the cyanamide and bleach reaction which reacts further with compound 1 to form sulfilimine 2.
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EXPERIMENTAL SECTION Materials and Reagents. Commercially purchased ∼12− 13 wt % bleach (sodium hypochlorite), ∼50 wt % cyanamide, and reagent grade acetonitrile was used in these studies. The pyridine sulfide 1 was obtained from the current Isoclast Active manufacturing facility. Special Issue: Process Analytical Technologies (PAT) 14 Received: October 14, 2013 Published: December 5, 2013 139
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Figure 1. The last two chemical steps for the Isoclast Active manufacturing process.
Figure 2. Two proposed pathways for cyanamide and sulfide coupling.
pVTZ basis set9 in acetonitrile. Solvent effects were calculated with the integral equation formalism variant of the polarizable continuum model (IEFPCM).10 Vibrational frequencies were corrected with a 0.968 scaling factor.11
Reactor Setup. Reactions were carried out either in a Mettler Toledo EasyMax reactor apparatus (for in situ IR experiments) or a Mettler Toledo RC1 reactor apparatus (for in situ Raman experiments). Accurate temperature control down to −20 °C could be achieved with both reactors. The addition sequence (cyanamide added to bleach, or bleach added to cyanamide) was not observed to have significant influence in the products formed. When the water−acetonitrile mixed solvent was used, the high ionic strength of bleach caused phase separation. The tips of the IR and Raman immersion probes were immersed at half depth of the solution during in situ experiments, and 900 rpm agitation rate was used to ensure good mixing. Raman Spectroscopy. A RXN1 Raman spectrometer (Kaiser Optical System Inc.) equipped with a 785 nm Invictus laser (400 mW) and a MR probe with a short-focus immersion optic was used to collect Raman spectra at a back-scattering geometry. The short-focus immersion optic was chosen because it maximized the Raman signal from a turbid system with multiple phases (usually two liquid phases, but sometimes with an additional solid phase in low-temperatures experiments). Each spectrum was collected with 5 s exposure time averaging three accumulations and with the cosmic-removal algorithm on, which resulted in a total collection time of 30 (5 × 3 × 2) seconds per spectrum. Spectra were continuously collected at roughly 32.6-s intervals, with 2.6 s being the overhead time. Spectra were collected between 160 and 3250 cm−1. IR Spectroscopy. A Mettler Toledo ReactIR 45m equipped with a silver halide fiber-optical diamond ATR probe was used to collect FTIR spectra at 1 min per spectrum rate between 700 and 2800 cm−1 at 4 cm−1 resolution. NMR. Reaction solution was prepared in the EasyMax reactor and transferred to a precooled NMR tube and immediately analyzed. For the water−acetonitrile mixed solvent system, only the acetonitrile-rich top phase was analyzed. A Varian Inova 400 MHz NMR spectrometer equipped with a 10 mm probe was used for both 1H and 13C analysis. Ab Initio Calculations. Optimized geometries and vibrational frequencies were calculated with the Gaussian 09 software package6 using the B3LYP method7,8 and aug-cc-
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RESULTS AND DISCUSSION Aqueous-Only Experiments. We first observed the presence of the intermediate species generated in the reaction between cyanamide and bleach using in situ IR experiment as shown in Figure 3. Artifacts between 1900 and 2400 cm−1 in
Figure 3. In situ IR spectra of (a) water, (b) after cyanamide addition, (c) after sodium hypochlorite addition, and (d) after addition of Reagent A.
the initial water spectrum (curve a in Figure 3) are caused by the diamond absorption bands of the diamond ATR element. Cyanamide solution (0.15 mol, 50 w.t.%) was added to 40 mL H2O, and this gave rise to the broad cyanamide CN stretch bands centered at 2250 cm−1 (curve b in Figure 3). Sodium hypochlorite solution (0.12 mol, 13 wt %) was then slowly added, and the reaction temperature was held at −5 °C. The cyanamide CN stretch band disappeared, and a new sharp band at 2090 cm−1 appeared (curve c in Figure 3). The intensity of the 2090 cm−1 slowly decreased over time, and its 140
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and all cyanamide was added, respectively. Several new bands were observed in spectra (b) and (c) at 234, 546, in addition to the 2095 cm−1 CN band (the peak center position may change ±5 cm−1, depending on its environment), while the hypochlorite band diminished. The CN stretch is consistent with the IR results and the anionic species ClN−CN in the ab initio calculations (Table 1).
disappearance accelerated upon the addition of compound 1 (0.1 mol) (curve d in Figure 3), demonstrating the existence of an intermediate species. There were many other subtle features associated with the generation and subsequent consumption of the intermediate species, but they were overwhelmed by the strong IR bands from water. To overcome the strong water interference, in situ Raman spectra were collected from a similar reaction. Representative spectra from this reaction are shown in Figure 4. The baseline-
Table 1. Comparison of calculated and experimental CN frequencies in various species CN stretch frequency (cm−1) species
structure
calcd
exp (Raman)
1 4 5 6 7
H3C−CN H2N−CN HN−−CN ClNH−CN ClN−−CN
2274 2251 2056 2236 2053
2253 2220 and 2260 2105 unknown 2095
The calculations clearly show that there is a substantial decrease (∼190 cm−1) in the frequency of the CN stretch from the neutral species to the anion. There is a corresponding increase (∼65 cm−1) in the C−N stretch frequency (see Supporting Information [SI]). These frequency shifts are consistent with a longer CN bond and a shorter C−N bond upon deprotonation due to resonance stabilization of the anion. In addition to the CN stretch, the other calculated bands of ClN−−CN are consistent with the observed Raman bands. These features continued to grow as more cyanamide was added, and reached their maximum shortly before the addition of cyanamide was completed, as cyanamide was in slight excess. Several new bands also appeared before the cyanamide addition was completed such as a sharp band at 1518 cm−1, and a series of bands between 1190 and 1330 cm−1. These bands are believed to be from degradation products of ClN−−CN, but the exact origin is not completely understood. The reaction was then held at −10 °C, and a fast degradation was observed. Spectra (d) and (e) were collected 22 and 130 min after the cyanamide addition was completed. The ClN−−CN band at 2095 cm−1 continued to decrease while new CN bands at 2150 and 2250 cm−1 gained intensity. The shape of these features continued to change from spectra (c) to (e), indicating that multiple species with varying concentrations were present. The pH of the system remained below 10 throughout the cyanamide addition, which is well above the pK a of cyanamide,13 thus precluding the possibility that the 2095 cm−1 band arises from HN−−CN. Another experiment was carried out (results not shown) by converting cyanamide first to HN−−CN by adding NaOH, and then to ClN−−CN by adding bleach solution. A Raman feature about 2105 cm−1 was found, corresponding to HN−−CN, and it shifted to 2095 cm−1 upon bleach addition, further supporting the assignments in Table 1. To further elucidate the molecular structure of the unstable intermediate species, a 13C NMR experiment was carried out to monitor the evolution of NMR spectra of an aqueous mixture (2.5 mmol sodium hypochlorite, 2.5 mmol of cyanamide in 2.5 g of water) at −15 °C, and the results are shown in Figure 6. There is only one dominant peak at 135 ppm at the beginning. Nitrile carbon is usually around 120 ppm. It is expected that its anion should be further downfield, which is consistent with the proposed structure of ClN−−CN. As the reaction progresses, a group of peaks around 120 ppm becomes evident, and
Figure 4. Representative in situ Raman spectra from a reaction. (a) Sodium hypochlorite solution, (b) half addition of cyanamide, (c) complete addition of cyanamide, (d)/(e) 22/130 min after (c). The shaded areas represent the bands used for reaction monitoring (refer to Figure 5).
corrected integrated peak area profiles for several relevant bands (represented by the shaded area in Figure 4) are plotted as a function of time in Figure 5. In this reaction, 0.55 mol
Figure 5. Reaction profiles based on three bands (refer to Figure 4). Vertical dashed lines denote the time points for the corresponding spectra in Figure 4
bleach in 330 g water was first cooled to −20 °C, and a spectrum (Figure 4a) was collected. The 710 cm−1 band originates from the Cl−O stretch of ClO−,12 while the rest of the sharp bands are from the sapphire window of the Raman probe, which generally remained unchanged throughout the reaction. A 50% aqueous solution containing 0.70 mol cyanamide was then fed at a constant rate over 30 min. Spectra (b) and (c) in Figure 4 were collected after about half 141
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Figure 7. In situ Raman spectra from Reaction 2 at −20 °C: (a) bleach solution, (b) after cyanamide addition, (c) immediately before addition of pyridine sulfide 1, and (d) 1.6 h afterwards.
Figure 6. 13C NMR spectra of the water phase: (a) 2 min, (b) 16 min, (c) 60 min, and (d) 180 min into the reaction.
towards the end, a group of peaks around 165 ppm also starts to emerge. The chemical shift of 120 ppm is consistent with that of HO−NH−CN or similar structures, and the chemical shift around 165 ppm is consistent with either the cyclic degradation product or the urea-like degradation product (simulated NMR results based on ACD 13C NMR software prediction package). The time-dependent integrated peak area evolution can be found in the SI. 1H NMR was not carried out due to the rapid proton exchange. Water/Acetonitrile Mixture Experiments. Bleach solution (71 mmol, 43.5 g 12%) was mixed with cyanamide solution (84 mmol, 7.0 g 50%) and 43.5 g deuterated acetonitrile at −10 °C for 30 s and then allowed to phase separate. 1H and 13C NMR experiments were alternately carried out for the acetonitrile phase, and the spectra can be found in the SI. The same 135 ppm peak as found in the aqueous-only system was observed, but it was found to decrease at a slower rate, indicating potential environmental influences on the ClN−−CN degradation kinetics. More interestingly, no proton signal was found in the 1H NMR at the same abundance as the 135 ppm peak in 13C NMR experiments (cyanamide was used as an internal standard to establish the equivalence in the 1 H and 13C NMR spectra, as it appears in both). This further supports the intermediate structure being ClN−−CN. Raman spectroscopy offers the advantage to simultaneously analyze a time-weighted average of both the aqueous and acetonitrile phases with adequate mixing. The acetonitrile solvent also provided strong Raman bands that could be used for normalization such as the bands at 2250 and 920 cm−1. Two similar reactions were carried at −20 °C (Figure 7 and Figure 8) and −10 °C (Figure 9 and Figure 10) with Raman monitoring. In both experiments, 0.44 mol of cyanamide was first added to 0.39 mol of bleach solution. The 2095 cm−1 band from ClN−−CN reached its maximum immediately after complete cyanamide addition, regardless of the reaction temperature (spectra (b) in Figure 7 and Figure 9), indicating that the cyanamide and sodium hypochlorite reaction is instantaneous within the temporal resolution of this study (32.6 s per spectrum). At −20 °C, the degradation of ClN−− CN is detectable but slow, while its degradation was significantly faster at −10 °C (compare Figure 8 to Figure 10). For the −20 °C reaction, 0.19 mol of compound 1 was fed into the reaction mixture at a constant rate over 10 min. The reaction between ClN−−CN and compound 1 was relatively
Figure 8. Concentration profiles of ClN−−CN, compound 1, and sulfilimine for Reaction 1 at −20 °C. Vertical dashed lines refer to the time points for spectra (a−d) shown in Figure 7
Figure 9. In situ Raman spectra from Reaction 2 at −10 °C: (a) bleach solution, (b) after cyanamide addition, (c) and (d) before and after addition of pyridine sulfide 1.
slow, and a substantial amount of compound 1 accumulation was observed. The quantitation of ClN−−CN, compound 1, and sulfilimine was done using a classical least-squares approach,14 and the details are provided in the SI. The concentration decay of compound 1 and ClN−−CN (in 142
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Thus, we continue to use in situ spectroscopy in conjunction with calorimetry to assess such parameters as stoichiometry, temperature, residence time, and various reactor configurations.
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ASSOCIATED CONTENT
S Supporting Information *
Details on ab initio calculations, on classical least-squares for quantitative spectral analysis, and on NMR results. This material is available free of charge via the Internet at http:// pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Authors
*
[email protected] *
[email protected]. Notes
Figure 10. Concentration profiles of ClN−−CN, compound 1, and sulfilimine for Reaction 2 at −10 °C. Vertical dashed lines refer to the time points for spectra (a−d) shown in Figure 9
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors gratefully acknowledge the inspiring discussions with Dr. Dan Hickman and Dr. Joseph Bonadies, Jr.
excess) and the formation of sulfilimine product followed a typical second-order reaction kinetics during the postaddition reaction as shown in Figure 8. In contrast, for the −10 °C reaction, a significant amount of ClN−−CN degradation product was observed. Fourteen moles of compound 1 was fed into the reaction mixture at a constant rate over 30 min. The reaction between ClN−−CN and compound 1 was rapid enough that no accumulation of compound 1 was detected. It should be noted that the reaction kinetics observed between ClN−−CN and compound 1, faster at −10 °C than at −20 °C, may not only be due to the reaction temperature, but may also result from the different phase-separation behavior or pH variation at the two different temperatures.
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REFERENCES
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CONCLUSIONS In this paper we described how in situ spectroscopy and ab initio calculations were employed to understand the reaction between cyanamide and bleach. This reaction appears to result in the formation of an intermediate consistent with the anion of N-chlorocyanamide. While other investigators have also provided evidence for and proposed the existence of Nchlorocyanamide using other reagents, to our knowledge this is the first report in which evidence is provided for hypochlorite and cyanamide being used to form it. The unstable nature of this intermediate makes it difficult to isolate or study using other ex situ techniques and precludes more rigorous characterization and structural assignment using techniques such as mass spectrometry or elemental analysis. Our studies clearly show that when the intermediate is treated with sulfide 1 that the intermediate rapidly disappears and the sulfilimine 2 is formed. In addition, no new peaks are observed in the Raman spectrum during the reaction of 1 + intermediate to 2, which indicates that the lifetime (or concentration) of any intermediate that is formed is very short-lived under the conditions studied. The studies further demonstrated that in situ Raman and IR are powerful tools to obtain reaction kinetics for process R&D. With these recent learnings in hand, Dow AgroSciences has an ongoing proprietary R&D program devoted to studying how best to scale up this chemistry. What started out as chemistry investigation has now become an engineering project to develop an economical, safe, and robust commercial process. 143
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(13) Cameron, W., Cyanamides. In Kirk-Othmer Encyclopedia of Chemical Technology; John Wiley & Sons, Inc.: New York, 2000. (14) Beebe, K. R.; Seasholtz, M. B.; Pell, R. J., Chemometrics: A Practical Guide. Wiley-Interscience: New York, 1998.
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