Explosion Hazards of Sodium Hydride in Dimethyl Sulfoxide, N,N

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Explosion Hazards of Sodium Hydride in Dimethyl Sulfoxide, N,N‑Dimethylformamide, and N,N‑Dimethylacetamide Qiang Yang,*,† Min Sheng,‡ James J. Henkelis,† Siyu Tu,† Eric Wiensch,† Honglu Zhang,† Yiqun Zhang,§ Craig Tucker,‡ and David E. Ejeh‡ †

Product Design & Process R&D, Corteva Agriscience, 9330 Zionsville Road, Indianapolis, Indiana 46268, United States Reactive Chemicals, Corteva Agriscience, Midland, Michigan 48667, United States § Analytical Sciences, The Dow Chemical Company, Midland, Michigan 48667, United States Downloaded via 94.231.219.180 on August 10, 2019 at 13:26:58 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

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ABSTRACT: The hazards associated with the thermal decomposition of chemically incompatible sodium hydride solvent matrices are known, with reports from the 1960s detailing the inherent instability of NaH/dimethyl sulfoxide, NaH/N,Ndimethylformamide, and NaH/N,N-dimethylacetamide mixtures. However, these hazards remain underappreciated and undercommunicated, likely as a consequence of the widespread use of these NaH/solvent matrices in synthetic chemistry. We report herein detailed investigations into the thermal stability of these mixtures and studies of the formation of gaseous products from their thermal decomposition. We expect this contribution to promote awareness of these hazards within the wider scientific community, encourage scientists to identify and pursue safer alternatives, and most importantly, help to prevent incidents associated with these reactive mixtures. KEYWORDS: sodium hydride (NaH), dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), thermal instability, explosion

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maintained at 70 °C for 1 h and then cooled, during which time they observed a sharp temperature spike followed by an explosion that was accompanied by a noxious gas. Immediately after the disclosure of this incident, an analogous explosion from a NaH/DMSO mixture was reported,8 albeit at a lower temperature (50 °C) and concentration (0.17:1 NaH/DMSO on a molar basis) compared with the conditions employed in the earlier incident.6 The thermal decomposition of a NaH/DMF mixture was first observed in the early 1960s, first by Powers et al., who noted energetic decomposition during a NaH-mediated cleavage of a formyl group,9 and Brimacombe et al. during the alkylation of a carbohydrate using NaH as the base.10 Nasipuri et al. later reported the aromatization of various cyclohexenones using NaH in DMF, in which the authors acknowledged the decomposition of DMF in the presence of NaH but still carried out their reactions at 100 °C.11 The researchers proposed that the active base in these reactions was sodium dimethylamine, resulting from the reaction of DMF with NaH. The hazards associated with the thermal instability of NaH/ DMF pose an even greater risk as the reaction scale increases. Reports of large-scale incidents associated with the thermal instability of NaH/DMF were noted in the early 1980s. In the first reported example, conducted on a pilot-plant scale at SmithKline Beckman, a condensation reaction employing NaH in DMF experienced uncontrolled self-heating on 2500 L scale that resulted in the failure of a reactor’s rupture disk.12

INTRODUCTION The use of NaH as a strong base is commonplace in synthetic organic chemistry.1 Generally speaking, NaH is easy to handle and store and often offers predictable reactivity and high atom efficiency. As a result, it has been used to facilitate a wide range of chemical transformations.2 The most commonly used solvents for reactions that use NaH are dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), and N,N-dimethylacetamide (DMAc) because of their complementary physical properties and their ability to solubilize both organic and inorganic compounds. The hazards associated with the thermal instability of NaH/ DMSO, NaH/DMF, and NaH/DMAc mixtures have been a growing concern within the chemistry community.3 In addition to the desirable physical properties of DMSO to solubilize both organic and inorganic compounds, dimsyl ion (also known as sodium dimsylate or methyl sulfinyl carbanion), prepared via the reaction of NaH with DMSO under nitrogen at 70−75 °C, has found wide applications in a variety of chemical transformations since the seminal publication by Corey and Chaykovsky in the early 1960s.4 The thermal instability of dimsyl ion was first highlighted by Corey and Chaykovsky in 19654b and further studied by many research groups.5 The first reported explosion resulting from a NaH/ DMSO mixture was in 1966,6 when scientists at the Cancer Chemotherapy Research Department of Mount Zion Hospital and Medical Center (Palo Alto, CA) were scaling up a methylation reaction that employed NaH in DMSO, following a method reported by Russell and Weiner.7 The scientists noted incomplete conversion when the reaction was carried out using a NaH/DMSO molar ratio of 0.19:1 and thus increased the ratio to 0.24:1. The reaction mixture was © XXXX American Chemical Society

Special Issue: Corteva Agriscience Received: June 18, 2019

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DOI: 10.1021/acs.oprd.9b00276 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Article

Through a series of calorimetric studies, the research team observed that mixtures of NaH with either DMF or DMAc would begin to self-heat at temperatures as low as 26 °C and that the temperature would rapidly increase to 80 °C, at which point the cooling capacity of the pilot-plant reactor would be exceeded. They further commented that the onset temperature of decomposition was between 40 and 50 °C with carefully dried DMF; however, the detailed thermal stability data resulting from the study were not reported. A second account was reported by Burdick and Jackson Laboratories in the same year, stating that uncontrolled heating of a NaH/DMF reaction mixture began at 40 °C and that the reaction temperature quickly rose to more than 100 °C in less than 10 min.13 Although full cooling was applied to the reaction vessel, the temperature could not be controlled, and the majority of the DMF solvent evaporated before the reaction subsided. They commented that the reaction had been conducted many times without an incident, which highlights the unpredictable nature of this chemistry. While they suspected the reactor’s material of construction (stainless steel) to be the likely cause of the decomposition, this hypothesis was proven invalid by later studies and data presented in this contribution. The safety concerns regarding the thermal instability of NaH mixtures were reiterated in two editorials by the previous Organic Process Research & Development Editor-in-Chief, Trevor Laird,14 who commented that multiple runaway reactions with NaH/DMF mixtures had occurred before the first report was published in 1982. These editorials drew muchneeded attention to NaH-containing reactive mixtures and highlighted the importance of scientific communication to raise awareness of these hazards and alert others to such dangers. Despite the numerous reports intended to caution scientists, the hazards associated with NaH/DMSO, NaH/DMF, and NaH/DMAc reactive mixtures remain underappreciated and inadequately discussed, overshadowed by the sheer number of publications that utilize these hazardous conditions, further diminishing their impact upon the chemistry community. As shown in Figures 1−3, the number of publications reporting the use of these hazardous conditions each year remains consistently high. Between 2014 and 2018, Organic Letters published 38−62 examples/year (Figure 1), whereas The Journal of Organic Chemistry (Figure 2) and the Journal of Medicinal Chemistry (Figure 3) published 28−46 and 67−94 examples/year, respectively. It should be noted that most of the papers published in Organic Process Research & Development employing NaH/ DMSO, NaH/DMF, and NaH/DMAc only reported these hazardous conditions in their original discovery-phase routes (Figure 4). In most instances, the authors acknowledged the inherent safety hazards associated with these reactive mixtures and designed their processes away from these mixtures in the final routes. For example, Dahl et al.15 employed sodium dimsylate as the base in their process for the synthesis of (S)-2({3-[(S)-5-chloro-1-(4-chlorophenyl)indan-1-yl]propyl}methylamino)propionic acid. The researchers performed a detailed reaction calorimetry evaluation, which indicated that the sodium dimsylate decomposed at temperatures as low as ∼50 °C with an adiabatic temperature rise (ΔTad) of 500 °C in pure DMSO. In contrast, when the DMSO solution of sodium dimsylate was diluted with THF, the lowest observed decomposition temperature was ∼100 °C with a ΔTad of 230 °C. On the basis of these results, the researchers

Figure 1. Numbers of publications using NaH/DMSO, NaH/DMF, and NaH/DMAc in Organic Letters in 2014−2018.

Figure 2. Numbers of publications using NaH/DMSO, NaH/DMF, and NaH/DMAc in The Journal of Organic Chemistry in 2014−2018.

Figure 3. Numbers of publications using NaH/DMSO, NaH/DMF, and NaH/DMAc in the Journal of Medicinal Chemistry in 2014−2018.

developed a safer process in which the reaction was performed using 4 equiv of DMSO (relative to NaH) in 7 volumes of THF (relative to DMSO) and successfully scaled up this process to 4.1 kg of 60 wt % NaH in mineral oil. Nonetheless, there are examples where these hazardous mixtures were employed in the final reaction conditions, one of which includes a large-scale production that operated using 880 mol B



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RESULTS AND DISCUSSION

An exothermic reaction is typically maintained at the optimal temperature by applying external cooling until reaction completion and then cooled for workup and isolation of the product. However, in cases of insufficient cooling or cooling failure, unreacted components will further react to release energy, leading to a higher reaction temperature. In a worstcase scenario (e.g., all reactants are accumulated and the reaction continues under adiabatic conditions), the reaction temperature would reach the maximum temperature of a synthesis reaction (MTSR), which is equal to the desired reaction temperature plus ΔTad.17 In cases when the MTSR exceeds the onset temperature of reaction mixture decomposition, a secondary reaction would be initiated, potentially leading to runaway scenarios. It is thus crucial to evaluate reaction calorimetry and thermal stability hazards of chemical reactions and to design control strategies accordingly in order to ensure that thermal decomposition of the reaction mixture is not triggered. Measurements of the heat of the desired reaction and ΔTad are generally performed using an instrument such as an RC1 reaction calorimeter, a micro reaction calorimeter (μRC), or an EasyMax HF Cal heat flow calorimeter. The thermal stability of reaction mixtures is generally characterized with a differential scanning calorimetry (DSC), a thermal screening unit (Tsu), an accelerating rate calorimetry (ARC), and/or a vent-sizing package (VSP). 1. Thermal Stability Evaluation of NaH/DMSO. ARC analysis of 4.55 g of a mixture of 9.7% NaH, 6.4% mineral oil, and 83.9% DMSO18 recorded two small exothermic events followed by a significant exothermic event with an onset temperature of 56.8 °C (Figure 5 and Table 1). This exotherm caused the rupture of an ARC cell designed with an average burst pressure of 14 500 psi (Figure 6, left). The force generated from this explosion was strong enough to displace the reactor housing, which sat on top of the ARC reactor (Figure 6, right). The full heat and pressure information on these exothermic events could not be recorded because of this rupture. A mixture of 10.3% NaH, 6.9% mineral oil, and 82.8% DMSO was then studied by DSC to better understand the total heat output that could result from an exothermic event strong enough to rupture an ARC cell. As shown in Figure 7, DSC analysis recorded an endothermic event (14 to 39 °C), a minor exothermic event (39 to 120 °C), and two consecutive major exothermic events (120 to 285 °C). The first major

Figure 4. Numbers of publications using NaH/DMSO, NaH/DMF, and NaH/DMAc in Organic Process Research & Development in 1997− 2018.

of NaH (35.2 kg of 60 wt % NaH in mineral oil).16 In these cases the authors restated that alternative reaction conditions were not appropriate and that all of the reactions were conducted within safe operating ranges and in a reactor made of compatible materials of construction.8 It is worth noting that calorimetry studies have proven that these hazards are independent of the reactor material of construction (stainless steel). Furthermore, critical reaction parameters, such as residual water, reaction temperature, and relative concentration of NaH, might help mitigate some of the hazards associated with their use, but they do not completely address the dangers of spontaneous thermal decomposition. This literature survey shows that reactions with these matrices continue to appear in publications, indicating their relatively common use and suggesting that the safety hazards associated with the thermal instability of NaH/DMSO, NaH/ DMF, and NaH/DMAc mixtures remain underappreciated. In this contribution, we communicate the results of detailed thermal stability evaluations of these hazardous combinations in order to promote awareness of these hazards within the chemistry community and encourage scientists to employ safer reaction conditions, with the ultimate goal of preventing incidents relating to these hazards.

Figure 5. ARC heat rate and pressure vs temperature profiles of a NaH/DMSO mixture. C



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Table 1. ARC Analysis of a NaH/DMSO Mixture sample description total sample mass (g) Cp of sample (J g−1 °C−1) ARC cell mass (g) set end temperature (°C) phi onset temperature (°C) peak temperature (°C) end temperature (°C) max self-heating rate (°C/min) total heat (J/g)

9.7% NaH + 6.4% mineral oil + 83.9% DMSO 4.5471 1.923 21.9702 350 2.06 56.8 − − − ruptured

Figure 8. ARC temperature and pressure vs time profiles of a NaH/ DMSO mixture.

overlaid in red (air blank) and black (sample of interest), are compared in Figure 9. The gases detected in the sample

Figure 6. Pictures of (left) a ruptured Hastelloy C ARC cell and (right) the displaced ARC reactor housing resulting from the cell explosion.

Figure 9. Headspace GC/MS analysis of the gaseous products from the thermal decomposition of a NaH/DMSO mixture.

referenced against the NIST chemical library supported the presence of ethylene and dimethyl sulfide as the decomposition products,20 along with DMSO.21 Undoubtedly, the generation of large volumes of gases poses a significant safety concern and contributed to the explosion during the dominant exothermic event. 2. Thermal Stability Evaluation of NaH/DMF. The thermal stability of NaH/DMF mixtures was evaluated by ARC analysis. As shown in Figure 10, a significant exothermic decomposition with an onset temperature of 76.1 °C was detected with a mixture of 9.5% NaH, 6.3% mineral oil, and 84.2% DMF. This decomposition produced an exotherm of −528.4 J/g with a maximum self-heating rate of 7.23 °C/min. Increasing the weight ratio of NaH to 24.6% (in 16.4% mineral oil and 59% DMF) significantly lowered the decomposition onset temperature to 39.8 °C and increased the peak selfheating rate to 634.7 °C/min, affording a total exotherm of greater than −601.8 J/g (Table 2). Both tests had substantial cool-down pressures, confirming that the decomposition of DMF resulted in the formation of significant amounts of gaseous products. Identification of the gaseous products resulting from the thermal decomposition of NaH/DMF was performed using evolved gas analysis (EGA) Micro-GC analysis. In a control experiment with NaH in mineral oil, only the residual water in the EGA Micro-GC system, transfer lines, and sample cup was detected at 199.7 634.7 >−601.8

temperature reached ∼165 °C and ended at ∼360 °C, indicating that the formation of H2 was caused by the thermal decomposition of NaH rather than hydrolysis by residual water (Figure 11).

Figure 12. Gaseous products (EGA Micro-GC) from the thermal decomposition of NaH/DMF.

3. Thermal Stability Evaluation of NaH/DMAc. Similar to the thermal decomposition of NaH/DMF, ARC analysis of a mixture of 9% NaH, 6% mineral oil, and 85% DMAc evidenced a decomposition onset temperature of 56.4 °C with a peak self-heating rate of 5.78 °C/min and a total heat release of −422.6 J/g. Increasing the content of NaH to 16.2% significantly lowered the decomposition onset temperature to 30.1 °C and substantially increased the maximum self-heating rate to 479.1 °C/min with a total heat output of −528.2 J/g (Figure 13 and Table 3). Again, both experiments resulted in significantly high cool-down pressures, confirming the formation of noncondensable gaseous products from the thermal decomposition. These results confirm that the thermal decomposition of the NaH/DMAc combination could also result in runway scenarios. EGA Micro-GC analysis of the NaH/DMAc reaction mixture showed that the release of H2 occurred at a lower temperature (300 °C.22 The formation of these gaseous products suggests that a more complicated, potentially radical decomposition mechanism occurs during the thermal decomposition of NaH/DMF. E



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Figure 13. ARC heat rate and pressure vs temperature profiles of NaH/DMAc mixtures.

Table 3. ARC Analysis of NaH/DMAc Mixtures sample description total sample mass (g) Cp of sample (J g−1 °C−1) ARC cell mass (g) set end temperature (°C) phi onset temperature (°C) peak temperature (°C) end temperature (°C) max self-heating rate (°C/min) total heat (J/g)

9% NaH + 6% mineral oil + 85% DMAc 4.2240 1.975 22.0010 350 2.11 56.4 123.0 157.8 5.78 −422.6

16.2% NaH + 10.8% mineral oil + 73.1% DMAc 5.3631 1.943 14.7578 200 1.60 30.1 122.7 200 479.1 −528.2

explosion during the ARC analysis that was forceful enough to displace the ARC housing. We expect this report to promote awareness of these hazards in the chemistry community, encouraging scientists to employ safer alternative conditions (e.g., alternative bases, NaH with stable solvents, etc.)23 and avoid incidents related to these hazards.

the majority of H2 generation occurring in the temperature range of 104−305 °C. Other noncondensable gaseous products, such as CH4, ethane, ethylene or acetylene, and CO, were also observed in this temperature range as well as above 300 °C (Figure 14).22

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EXPERIMENTAL SECTION General. All reagents were commercially available and used as purchased without further purification. Procedure for ARC Analysis. An accelerating rate calorimeter manufactured by Thermal Hazard Technology was used in this study. A preweighted NaH/mineral oil sample was loaded into a Hastelloy C ARC cell. The ARC sphere was connected to the calorimeter lid and purged with N2. The ARC test was started and put in EXO mode, and then the reaction solvent was manually injected with a syringe. The ARC experiment was performed in heat−wait−search (HWS) mode. A heat step of 5 °C, waiting time of 30 min, and detection threshold of 0.02 °C/min were utilized for each sample. Procedure for DSC Analysis. A Q2500 differential scanning calorimeter from TA Instruments was used for the constant-heating-rate tests (at 10 °C/min) in this study. A 3.2515 mg sample (a mixture of 10.3% NaH, 6.9% mineral oil, and 82.8% DMSO) was sealed within a gold-plated highpressure crucible with N2 in the headspace. The sealed crucible had a total internal volume of ∼20 μL and was able to withstand pressures of up to 3000 psi at 400 °C, preventing the release of any reaction materials, products, or byproducts. The DSC analysis of pure DMSO was performed following the same method in a sealed glass capillary tube under N2.24

Figure 14. Gaseous products (EGA Micro-GC) from the thermal decomposition of NaH/DMAc.

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CONCLUSIONS The inherent thermal instability hazards of NaH/DMSO, NaH/DMF, and NaH/DMAc mixtures have been welldocumented in the literature over the past few decades, yet the dangers remain underappreciated and poorly communicated, as evidenced by their continued appearance in hundreds of publications. The data outlined in this contribution confirm that these reactive mixtures undergo exothermic decomposition at relatively low temperatures, occurring concurrently with the generation of noncondensable gases. The dangers associated with NaH/DMSO mixtures were evidenced by an F



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Procedure for EGA Micro-GC Analysis. A Varian model CP-490 Micro-GC system was used for EGA of the NaH/ solvent mixtures using a Frontier Py2020iD pyrolysis unit (Figure 15). Approximately 2 mg of NaH (60% dispersion in

Channel 2: 10 m MS5A module with backflush, SN 61162, PN 494001360. Channel 3: 10 m PPQ module with backflush, SN 61222, PN 494001430. Channel 4: 6 m 19CB module, SN 61607, PN 492004810. Dell Latitude Laptop PC with Agilent EZChrom Elite software, version 3.2.2 SP2. Method Settings. Sample time: 40 s. Sample line temperature: 100 °C. Stabilizing time: 5 s. Continuous flow: disabled. Number of flush cycles: 1. Peak simulation: disabled. The channel settings are shown in Table 4. Procedure for Headspace GC/MS Analysis. The sample was preheated at 40 °C for 1 h in a headspace vial and analyzed along with an empty headspace vial, which served as the blank. An Agilent 5975C inert XL GC/MSD system with triple-axis detector was used. The instrument was equipped with both direct liquid, SPME, and headspace capabilities. A Supelco QPLOT capillary column with dimensions of 30 m × 0.32 mm (cat. no. 24242) was used for the analysis. The agitation temperature of the sample compartment was set at 40 °C. The NIST chemical library was used for the identification of gaseous products.

Figure 15. Flow diagram of the EGA Micro-GC system.

mineral oil) was added with 15 μL of solvent (DMF or DMAc). The sample was analyzed by EGA Micro-GC using helium as the purge gas through the pyrolysis oven. The ramp rate of the pyrolysis oven was 5 °C/min, and the samples were heated from 40 to 400 °C. The Micro-GC system was used to analyze the gases evolved after the sample was inserted into the pyrolysis oven and the programmed heating cycle was started. An aliquot of the pyrolysis effluent was injected into the Micro GC system every 150 s. The helium flow rate was approximately 13 mL/min. A Molsieve 5A (MS5A) module with argon as the carrier gas was used to separate H2. An MS5A module with helium as the carrier gas was used to separate CO and CH4. A PoraPLOT Q (PPQ) module with helium as the carrier gas was used to separate CO2, CH4, water, ethane, and ethylene/acetylene. A 19CB module with helium as the carrier gas was used to separate DMF and DMAc. Quantitation was performed using a microthermal conductivity detector (TCD). H2, N2, CO, CO2, CH4, ethane, propane, and butane responses were calibrated against certified gas standard mixtures (Matheson Tri-Gas). H2O responses were identified and estimated on the basis of literature references.25 Varian CP-490 Quad-Channel Micro-GC Specifications. Serial no. (SN): GC0912B639. Channel 1: 20 m MS5A module with backflush, SN 61685, part no. (PN) 494001370.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Qiang Yang: 0000-0003-3762-5015 Siyu Tu: 0000-0002-6126-5729 Author Contributions

The manuscript was written through contributions of all authors. All of the authors approved the final version of the manuscript. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank Dr. Gregory T. Whiteker for his constructive suggestions during the preparation of this manuscript.

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REFERENCES

(1) Hansley, V. L.; Carlisle, P. J. The Production of Sodium Hydride and Some of its Reactions. Chem. Eng. News 1945, 23 (15), 1332− 1380.

Table 4. Micro-GC Channel Settings

module carrier gas column temp. (°C) injection temp. (°C) injection time (ms) backflush time (s) detector TCD temp. limit check sensitivity pressure mode initial pressure (psi) sampling frequency (Hz) run time (s) acquisition delay (s)

channel 1

channel 2

channel 3

channel 4

20 m MS5A argon 146 100 50 10 on on auto static 30 100 150 0

10 m MS5A helium 90 100 50 10 on on auto static 30 100 150 0

10 m PPQ helium 73 100 50 20 on on auto static 16 100 150 0

6 m 19CB helium 80 100 50 NA on on auto static 18 100 150 0

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Explosion Hazards of Sodium Hydride in Dimethyl Sulfoxide, N,N

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