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Explosion Hazards of Sodium Hydride in Dimethyl Sulfoxide, N,N-Dimethylformamide, and N,N-Dimethylacetamide
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  • Qiang Yang*
    Qiang Yang
    Product Design & Process R&D, Corteva Agriscience, 9330 Zionsville Road, Indianapolis, Indiana 46268, United States
    *E-mail: [email protected]
    More by Qiang Yang
    Orcidhttp://orcid.org/0000-0003-3762-5015
  • Min Sheng
    Min Sheng
    Reactive Chemicals, Corteva Agriscience, Midland, Michigan 48667, United States
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  • James J. Henkelis
    James J. Henkelis
    Product Design & Process R&D, Corteva Agriscience, 9330 Zionsville Road, Indianapolis, Indiana 46268, United States
    More by James J. Henkelis
  • Siyu Tu
    Siyu Tu
    Product Design & Process R&D, Corteva Agriscience, 9330 Zionsville Road, Indianapolis, Indiana 46268, United States
    More by Siyu Tu
    Orcidhttp://orcid.org/0000-0002-6126-5729
  • Eric Wiensch
    Eric Wiensch
    Product Design & Process R&D, Corteva Agriscience, 9330 Zionsville Road, Indianapolis, Indiana 46268, United States
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  • Honglu Zhang
    Honglu Zhang
    Product Design & Process R&D, Corteva Agriscience, 9330 Zionsville Road, Indianapolis, Indiana 46268, United States
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  • Yiqun Zhang
    Yiqun Zhang
    Analytical Sciences, The Dow Chemical Company, Midland, Michigan 48667, United States
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  • Craig Tucker
    Craig Tucker
    Reactive Chemicals, Corteva Agriscience, Midland, Michigan 48667, United States
    More by Craig Tucker
  • David E. Ejeh
    David E. Ejeh
    Reactive Chemicals, Corteva Agriscience, Midland, Michigan 48667, United States
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Organic Process Research & Development

Cite this: Org. Process Res. Dev. 2019, 23, 10, 2210–2217
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https://doi.org/10.1021/acs.oprd.9b00276
Published August 10, 2019

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Abstract

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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,N-dimethylformamide, 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.

Copyright © 2019 American Chemical Society

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SPECIAL ISSUE

This article is part of the Corteva Agriscience special issue.

Introduction

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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 1965 (4b) 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 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) 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 much-needed 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.

Figure 1

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

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Figure 2

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

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Figure 3

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

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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 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 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.

Figure 4

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

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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.

Results and Discussion

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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 worst-case 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% DMSO (18) 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.

Figure 5

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

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Figure 6

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

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Table 1. ARC Analysis of a NaH/DMSO Mixture
sample description9.7% NaH + 6.4% mineral oil + 83.9% DMSO
total sample mass (g)4.5471
Cp of sample (J g–1 °C–1)1.923
ARC cell mass (g)21.9702
set end temperature (°C)350
phi2.06
onset temperature (°C)56.8
peak temperature (°C)–
end temperature (°C)–
max self-heating rate (°C/min)–
total heat (J/g)ruptured
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 exothermic event had a peak temperature of 146 °C and a total heat of −413.5 J/g, while the second major exothermic event had a peak at 255 °C and a total heat of −810.2 J/g. With the combined heat of these two events (−1123.7 J/g), this mixture was considered to be explosive according to the Yoshida correlation. (19) As a direct comparison, pure DMSO decomposes at around 278 °C with a heat output of −911.59 J/g by DSC analysis.

Figure 7

Figure 7. DSC analysis of a NaH/DMSO mixture.

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While the first of the two small exothermic events recorded by ARC (21.3 to 26.4 °C, EXO1 in Figure 8) was attributed to the heat of mixing, the second one (36.9 to 43.5 °C, EXO2 in Figure 8), with a total heat of only −93.2 J/g, was most likely caused by the reaction between NaH and DMSO. Surprisingly, this minor exotherm generated a significant amount of noncondensable gases that raised the cell pressure from 129 to 1289 psi between the end of the first exothermic event (109 min) and the start of the major exothermic event (635 min, EXO3 in Figure 8).

Figure 8

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

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Analysis of the gaseous products from EXO2 was performed using headspace GC/MS. The total ion chromatograms (TIC), overlaid in red (air blank) and black (sample of interest), are compared in Figure 9. The gases detected in the sample 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.

Figure 9

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

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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 self-heating 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.

Figure 10

Figure 10. ARC heat rate and pressure vs temperature profiles of NaH/DMF mixtures.

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Table 2. ARC Analysis of NaH/DMF Mixtures
sample description9.5% NaH + 6.3% mineral oil + 84.2% DMF24.6% NaH + 16.4% mineral oil + 59% DMF
total sample mass (g)4.12343.3896
Cp of sample (J g–1 °C–1)2.0101.930
ARC cell mass (g)21.892614.8079
set end temperature (°C)350200
phi2.111.95
onset temperature (°C)76.139.8
peak temperature (°C)133.8126.2
end temperature (°C)200.7>199.7
max self-heating rate (°C/min)7.23634.7
total heat output (J/g)–528.4>−601.8
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 <100 °C. Release of H2 gas was detected when the 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 11

Figure 11. Thermogram of NaH in mineral oil by EGA Micro-GC.

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The profiles of the gaseous products resulting from the thermal decomposition of the NaH/DMF mixture are shown in Figure 12. Water was detected when the temperature was below 140 °C and was likely the result of residual water in the EGA Micro-GC system, transfer lines, and sample cup. Two separate peaks were detected for H2, the first at 140–270 °C and the second at 270–360 °C. In addition to H2, carbon monoxide (CO), methane (CH4), and ethylene or acetylene were also observed within the same temperature range as the first H2 peak. A trace amount of carbon dioxide (CO2) was also found at >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.

Figure 12

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

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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.

Figure 13

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

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Table 3. ARC Analysis of NaH/DMAc Mixtures
sample description9% NaH + 6% mineral oil + 85% DMAc16.2% NaH + 10.8% mineral oil + 73.1% DMAc
total sample mass (g)4.22405.3631
Cp of sample (J g–1 °C–1)1.9751.943
ARC cell mass (g)22.001014.7578
set end temperature (°C)350200
phi2.111.60
onset temperature (°C)56.430.1
peak temperature (°C)123.0122.7
end temperature (°C)157.8200
max self-heating rate (°C/min)5.78479.1
total heat (J/g)–422.6–528.2
EGA Micro-GC analysis of the NaH/DMAc reaction mixture showed that the release of H2 occurred at a lower temperature (<110 °C) than with the NaH/DMF sample, with 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)

Figure 14

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

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Conclusions

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The inherent thermal instability hazards of NaH/DMSO, NaH/DMF, and NaH/DMAc mixtures have been well-documented 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 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.

Experimental Section

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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 high-pressure 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)

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 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.

Figure 15

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

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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. 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.
Table 4. Micro-GC Channel Settings
 channel 1channel 2channel 3channel 4
module20 m MS5A10 m MS5A10 m PPQ6 m 19CB
carrier gasargonheliumheliumhelium
column temp. (°C)146907380
injection temp. (°C)100100100100
injection time (ms)50505050
backflush time (s)101020NA
detectoronononon
TCD temp. limit checkonononon
sensitivityautoautoautoauto
pressure modestaticstaticstaticstatic
initial pressure (psi)30301618
sampling frequency (Hz)100100100100
run time (s)150150150150
acquisition delay (s)0000

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 Q-PLOT 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.

Author Information

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  • Corresponding Author
  • Authors
    • Min Sheng - Reactive Chemicals, Corteva Agriscience, Midland, Michigan 48667, United States
    • James J. Henkelis - Product Design & Process R&D, Corteva Agriscience, 9330 Zionsville Road, Indianapolis, Indiana 46268, United States
    • Siyu Tu - Product Design & Process R&D, Corteva Agriscience, 9330 Zionsville Road, Indianapolis, Indiana 46268, United States;  Orcidhttp://orcid.org/0000-0002-6126-5729
    • Eric Wiensch - Product Design & Process R&D, Corteva Agriscience, 9330 Zionsville Road, Indianapolis, Indiana 46268, United States
    • Honglu Zhang - Product Design & Process R&D, Corteva Agriscience, 9330 Zionsville Road, Indianapolis, Indiana 46268, United States
    • Yiqun Zhang - Analytical Sciences, The Dow Chemical Company, Midland, Michigan 48667, United States
    • Craig Tucker - Reactive Chemicals, Corteva Agriscience, Midland, Michigan 48667, United States
    • David E. Ejeh - Reactive Chemicals, Corteva Agriscience, Midland, Michigan 48667, United States
  • 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.

Acknowledgments

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

References

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This article references 25 other publications.

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    (b) Bretherick, L. Sodium hydride: Dimethylformamide. In Bretherick’s Handbook of Reactive Chemical Hazards, 3rd ed.; Butterworths: London, 1985; p 1133.
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    (a) Corey, E. J.; Chaykovsky, M. Methylsulfinylcarbanion. J. Am. Chem. Soc. 1962, 84, 866– 867,  DOI: 10.1021/ja00864a039
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    Methylsulfinyl carbanion
    Corey, E. J.; Chaykovsky, Michael
    Journal of the American Chemical Society (1962), 84 (), 866-7CODEN: JACSAT; ISSN:0002-7863.
    Reaction of powd. NaH with dry Me2SO (500-600 ml./mole NaH) at 65-70° under N with stirring gave Na+(Me2SO)- (I). Sep. reactions of I with equimolar amts. of Ph2CO and BzH yielded Ph2C(OH)CH2SOMe, m. 148.0-8.5°, and a mixt. of diastereomers of PhCH(OH)CH2SOMe, m. 78-123°, resp. I is strongly basic and reacts rapidly with Ph3CH to yield Ph3C- and Me2SO. Interaction of I with EtPh3PBr at room temp. gave Ph3P:CHMe. PhCl reacts with an excess of I (6.7 equivs.) to yield PhCH2SOMe; with less of I (2.5 equivs.), Ph2CHSOMe is also formed.
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    (b) Corey, E. J.; Chaykovsky, M. Methylsulfinyl Carbanion (CH3-SO-CH2–). Formation and Applications to Organic Synthesis. J. Am. Chem. Soc. 1965, 87, 1345– 1353,  DOI: 10.1021/ja01084a033
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    4b
    Methylsulfinyl carbanion. Formation and application to organic synthesis
    Corey, E. J.; Chaykovsky, Michael
    Journal of the American Chemical Society (1965), 87 (6), 1345-53CODEN: JACSAT; ISSN:0002-7863.
    A detailed account is given of the generation of the conjugate base of Me2SO (MeSOCH2-). The chem. properties and utility of this reagent are illustrated by a number of synthetic applications. For example, a new synthetic route to ketones is described.
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  5. 5
    (a) Price, G. G.; Whiting, M. C. The sodium derivative of dimethyl sulfoxide, Dimsylsodium. Chem. Ind. (London) 1963, 775– 776
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    5a
    The sodium derivative of dimethyl sulfoxide, Dimsylsodium
    Price, G. G.; Whiting, M. C.
    Chemistry & Industry (London, United Kingdom) (1963), (), 775-6CODEN: CHINAG; ISSN:0009-3068.
    The Corey-Chayokowski MeS(O)CH2Na reagent (I) (CA 57, 650h) can be used for titration of very weak acids, examn. of electronic spectra of many anions above 3500 A., hydrolysis of esters, and prepn. of various derivs. I is equiv. to an alk. soln. of H- = 30 or more and can be used in concns. up to 2M for titrations under anaerobic conditions with Ph3CH or Ph2CH2 as indicator. More complex reactions than simple deprotonation occurs with AcOEt, PhCH2CO2Et, PhCH2CN, and glycerol; the esters react with 2 equivs. of I, the nitrile gives, in fairly concd. solns., too intense a color to permit titration, and glycerol reacts with 1.5 equivs. of I to give a bimol. anion with three O...H-O groups. Spectra detns. are made on Me2SO solns. of the compds. under anaerobic conditions. Measurements are made within one min. after prepn. of the soln., the max. does not increase in intensity with time, but deterioration occurs slowly. MeCOPh and PhC ≡ CH are carboxylated by titration as above followed by addn. of the soln. to solid CO2, acidification, isolation of the acids, and recrystn. BzOEt is completely hydrolyzed within two min. at 20° after injection into a suspension of NaOH.
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    (b) Sjoberg, K. Stable solutions of methylsulfinyl carbanion. Tetrahedron Lett. 1966, 7, 6383– 6384,  DOI: 10.1016/S0040-4039(00)70182-1
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    (c) Lyness, W. I.; O’Connor, D. E.; Berry, J. S. Sulfinyl carbanions for preparing surface-active detergents. U.S. Patent 3,288,860, Nov 29, 1966.
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  6. 6
    French, F. A. Sodium Hydride–DMSO Mixture Explodes. Chem. Eng. News 1966, 44 (15), 48
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    6
    Sodium hydride-dimethyl sulfoxide (DMSO) mixture explodes
    French, Frederic A.
    Chemical & Engineering News (1966), 44 (15), 48CODEN: CENEAR; ISSN:0009-2347.
    Me sulfinyl carbanion was prepd. successfully in small quantities by C-methylating heteroaromatics. Later 4.5 moles NaH was added in 5 portions to 18.4 moles DMSO at 70° and stirred. As soln. was complete the temp. rose sharply and an explosion occurred.
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  7. 7
    Russell, G. A.; Weiner, S. A. Methylation of Aromatic Hydrocarbons by Dimethyl Sulfoxide in the Presence of Base. J. Org. Chem. 1966, 31, 248,  DOI: 10.1021/jo01339a056
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    Methylation of aromatic hydrocarbons by dimethyl sulfoxide in the presence of base
    Russell, Glen A.; Weiner, Steven A.
    Journal of Organic Chemistry (1966), 31 (1), 248-51CODEN: JOCEAH; ISSN:0022-3263.
    The methylsulfinyl carbanion (MeSOCH2-) is a unique methylating agent of the ylide type. Quinoline, isoquinoline, anthracene, phenanthrene, acridine, phenanthridine, and benzoxazole are converted to methyl derivs. by reaction with the methylsulfinyl carbanion in Me2SO at 70°.
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    Olson, G. L. Lab explosions. Chem. Eng. News 1966, 44 (24), 7
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    Laboratory explosions
    Olson, Gary L.
    Chemical & Engineering News (1966), 44 (24), 7CODEN: CENEAR; ISSN:0009-2347.
    cf. CA 65, 2116g. In prepg. Me sulfinyl carbanion a similar explosion was observed at a lower temp. (50°) and ∼0.5 of the concn. (3.27 moles NaH and 19.5 moles Me2SO as previously mentioned.
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  9. 9
    Powers, J. C.; Seidner, R.; Parsons, T. G. The cleavage of formyl groups by sodium hydride. Tetrahedron Lett. 1965, 6, 1713– 1716,  DOI: 10.1016/S0040-4039(00)90114-X
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    Brimacombe, J. S.; Jones, B. D.; Stacey, M.; Willard, J. J. Alkylation of carbohydrates using sodium hydride. Carbohydr. Res. 1966, 2, 167,  DOI: 10.1016/S0008-6215(00)81480-9
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    Alkylation of carbohydrates by using sodium hydride
    Brimacombe, J. S.; Jones, B. D.; Stacey, M.; Willar, J. J.
    Carbohydrate Research (1966), 2 (2), 167-9CODEN: CRBRAT; ISSN:0008-6215.
    Treatment of carbohydrate derivs. with NaH in HCONMe2 or N-methyl-2-pyrrolidinone, followed by an alkyl halide (usually the bromide) at 0-25° gave the corresponding ethers in high yield. The procedure was used for methylation, butylation, octylation, allylation, and benzylation of Me 4,6-O-benzylidene-α-D-glucopyranoside (I), and for the 1-step methylation and allylation of sucrose. The 2,3-dipropargyl ether of I was prepd. by using tetrahydrofuran as solvent. Treatment of the diallyl ether of I with tert-BuOK in Me2SO gave the corresponding bis(1-propenyl) ether.
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    Nasipuri, D.; Bhattacharyya, A.; Hazra, B. G. Novel Aromatisation Reaction of Cyclohexenone Derivatives with Sodium Hydride. J. Chem. Soc. D 1971, 13, 660,  DOI: 10.1039/c29710000660
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    Buckley, J.; Webb, R. L.; Laird, T.; Ward, R. J. Report on thermal reaction. Chem. Eng. News 1982, 60 (28), 5
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    Report on thermal reaction
    Buckley, J.; Webb, R. Lee; Laird, T.; Ward, R. J.
    Chemical & Engineering News (1982), 60 (28), 5CODEN: CENEAR; ISSN:0009-2347.
    A thermal runaway reaction is reported which occurred while working with NaH in dimethylformamide (DMF) [68-12-2]. A reactor charged with DMF and NaH was heated and held at 50° without cooling. The mixt. self-heated to 75° and although cooling water was applied, the temp. continued to rise and the contents vented through a burst rupture disk on the vessel. In subsequent studies, the mixt. was obsd. to self-heat as low as 25°. Similar behavior was obsd. for NaH in dimethylacetamide (DMAC) [127-19-5]. Residues remaining after the reactions contained NaO2CH (with DMF) and Na acetate (with DMAC).
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    DeWall, G. Sodium hydride and DMF. Chem. Eng. News 1982, 60 (37), 5
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    Sodium hydride and DMF
    DeWall, Gordon
    Chemical & Engineering News (1982), 60 (37), 5, 43CODEN: CENEAR; ISSN:0009-2347.
    A thermal runaway reaction involving NaH and DMF [68-12-2] is reported. The mixt. was being stirred and slowly warmed when an exothermic reaction started to occur at 40°. Although fuel jacket cooling water was applied, the temp. rose to >100° in <10 min. The runaway reaction occurred in a stainless steel reactor. Reactions in a glass-lined reactor occurred without adverse reactions.
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    (a) Laird, T. Org. Process Res. Dev. 2002, 6, 876,  DOI: 10.1021/op025601k
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    Special feature section: safety of chemical processes
    Laird, Trevor
    Organic Process Research & Development (2002), 6 (6), 876CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
    There is no expanded citation for this reference.
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    (b) Laird, T. Org. Process Res. Dev. 2005, 9, 951,  DOI: 10.1021/op050197l
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    Safety Feature
    Laird, Trevor
    Organic Process Research & Development (2005), 9 (6), 951CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
    There is no expanded citation for this reference.
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    Dahl, A. C.; Mealy, M. J.; Nielsen, M. A.; Lyngsø, L. O.; Suteu, C. Route Scouting and Process Development of Lu AA26778. Org. Process Res. Dev. 2008, 12, 429,  DOI: 10.1021/op7002584
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    Route Scouting and Process Development of Lu AA26778
    Dahl, Allan C.; Mealy, Michael J.; Nielsen, Martin A.; Lyngso, Lars O.; Suteu, Cristina
    Organic Process Research & Development (2008), 12 (3), 429-441CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
    Route scouting and process development for the synthesis of (S)-2-({3-[(S)-5-chloro-1-(4-chlorophenyl)indan-1-yl]propyl}methylamino)propionic acid, Lu AA26778, are described. The strategy is based on a short synthesis and simulated moving bed (SMB) resoln. of a key chiral intermediate for the introduction of one of the two stereocenters. The second stereocenter is introduced via a com. available alanine ester, optionally bearing a N-Me group. The main concern during scale-up of the synthesis was the safety of a step incorporating sodium dimsylate (the sodium salt of DMSO): this problem was solved using THF as a safety blanket in the large-scale process.
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  16. 16
    Ishii, Y.; Fujimoto, R.; Mikami, M.; Murakami, S.; Miki, Y.; Furukawa, Y. Practical syntheses of Chiral α-Amino Acids and Chiral Half-Esters by Kinetic Resolution of Urethane-Protected α-Amino Acid N-Carboxyanhydrides and Desymmetrization of Cyclic meso-Anhydrides with New Modified Cinchona Alkaloid Catalysts. Org. Process Res. Dev. 2007, 11, 609,  DOI: 10.1021/op700023h
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    16
    Practical Syntheses of Chiral α-Amino Acids and Chiral Half-Esters by Kinetic Resolution of Urethane-Protected α-Amino Acid N-Carboxyanhydrides and Desymmetrization of Cyclic meso-Anhydrides with New Modified Cinchona Alkaloid Catalysts
    Ishii, Yutaka; Fujimoto, Ryosuke; Mikami, Masafumi; Murakami, Satoshi; Miki, Yasushi; Furukawa, Yoshiro
    Organic Process Research & Development (2007), 11 (3), 609-615CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
    The large-scale applications of the kinetic resoln. of urethane-protected α-amino acid N-carboxyanhydrides (NCAs) and the desymmetrization of cyclic meso-anhydrides using modified cinchona alkaloids are described. These asym. reactions are effective organocatalytic methods for the synthesis of chiral α-amino acids and chiral half-esters on an industrial scale, because the organocatalyst recovery and product purifn. can be carried out by a simple extractive procedure obviating a chromatog. purifn. step. The modified cinchona alkaloid catalysts (DHQD)2AQN and (DHQ)2AQN, as reported by Deng et al., are not readily available and therefore not suitable for industrial-scale synthesis. Various O-alkylated quinidine and quinine derivs. were prepd. and screened as catalysts for the kinetic resoln. of phenylalanine NCA with alc. The readily prepd. O-propargylquinidine (OPQD) and O-propargylquinine (OPQ) were discovered to be highly enantioselective and practical catalysts. These new catalysts were applied to the synthesis of (S)-Boc-propargylglycine (I) and cyclopentanedicarboxylate deriv. II, on an industrial scale, by the kinetic resoln. of propargylglycine N-carboxyanhydride III and the desymmetrization of cyclic meso-anhydride IV, resp.
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    Stoessel, F. Thermal Safety of Chemical Processes: Risk Assessment and Process Design; Wiley-VCH: Weinheim, Germany, 2008.
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  18. 18

    This combination is a result of using 60% NaH in mineral oil for the evaluations.

    There is no corresponding record for this reference.
  19. 19
    Yoshida, T.; Yoshizawa, F.; Itoh, M.; Matsunaga, T.; Watanabe, M.; Tamura, M. Prediction of Fire and Explosion Hazards of Reactive Chemicals (I). Estimation of Explosive Properties of Self-Reactive Chemicals from SC-DSC Data. Kogyo Kayaku 1987, 48, 311– 316
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    Prediction of fire and explosion hazards of reactive chemicals. I. Estimation of explosive properties of self-reactive chemicals from SC-DSC data
    Yoshida, Tadao; Yoshizawa, Fujiroku; Itoh, Mamoru; Matsunaga, Takehiro; Watanabe, Masatoshi; Tamura, Masamitsu
    Kogyo Kayaku (1987), 48 (5), 311-16CODEN: KOKYBR; ISSN:0368-6450.
    A procedure is sought for prediction of the fire and explosion hazards of various reactive chem. from fundamental thermal characteristics. The heat of decompn. QDSC as measured by DSC with a sealed cell and the extrapolated onset temp. TDSC (ASTM E-537) were the characteristics. The BAM 50/60 Fe tube test data for detonation propagation of high explosives, the Mk III ballistic mortar test data for deflagration propagation of reactive chems., and data from the Mk III ballistic mortar test with detonator or small card gap for shock sensitivity were used as criteria of a hazardous property. Scattered diagrams; the degrees of propagation or sensitivity on the log QDSD-log(TDSC-25) plane show a clear nonpropagative or insensitive region, resp. Two judgement equations, viz. explosion propagation = log QDSC - 0.38log (TDSC - 25) - 1.67, and shock sensitivity = log QDSC - 0.72log (TDSC - 25) -0.98, were obtained from the border lines on these diagrams. The hazardous property of a new reactive chem. can be estd. by interpolating the QDSC and TDSC obtainable by conventional DSC. Some errors caused by measurement of DSC are discussed.
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  20. 20
    Brandes, B. T.; Smith, D. K. Calorimetric study of the exothermic decomposition of dimethyl sulfoxide. Process Saf. Prog. 2016, 35, 374– 391,  DOI: 10.1002/prs.11802
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    20
    Calorimetric study of the exothermic decomposition of dimethyl sulfoxide
    Brandes, B. Todd; Smith, Daniel K.
    Process Safety Progress (2016), 35 (4), 374-391CODEN: PSAPE2; ISSN:1066-8527. (John Wiley & Sons, Inc.)
    DMSO (DMSO) is a widely used solvent often employed for a variety of org. syntheses. It is stable at room temp. can dissolve many types of org. materials, and is miscible in water. However, upon heating in a closed system under conditions typically achievable in a com. chem. plant, DMSO undergoes significantly exothermic and hazardous decompn. which could realistically lead to a pressure vessel explosion unless adequate protection layers were installed, possibly including a pressure relief system. This study provides calorimetry data from several app. and methods to characterize the decompn. to aid in assessing hazards and designing protection systems. 2016 American Institute of Chem. Engineers Process Saf Prog 35: 374-391, 2016.
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  21. 21

    This method was not designed for the detection of hydrogen gas. It would have coeluted with the carrier gas helium if it was present as part of the decomposition products.

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  22. 22

    The presence of dimethylamine (Me2NH) in the decomposition products has been reported previously. (12) Detection of Me2NH was not attempted during this analysis.

    There is no corresponding record for this reference.
  23. 23
    (a) Prashad, M.; Har, D.; Hu, B.; Kim, H.-Y.; Girgis, M. J.; Chaudhary, A.; Repič, O.; Blacklock, T. J.; Marterer, W. Process Development of a Large-Scale Synthesis of TKA731: A Tachykinin Receptor Antagonist. Org. Process Res. Dev. 2004, 8, 330– 340,  DOI: 10.1021/op0341824
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    23a
    Process Development of a Large-Scale Synthesis of TKA731: A Tachykinin Receptor Antagonist
    Prashad, Mahavir; Har, Denis; Hu, Bin; Kim, Hong-Yong; Girgis, Michael J.; Chaudhary, Apurva; Repic, Oljan; Blacklock, Thomas J.; Marterer, Wolfgang
    Organic Process Research & Development (2004), 8 (3), 330-340CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
    An efficient and chromatog.-free large-scale synthesis of tachykinin receptor antagonist TKA731 (I) is described. The key step is the coupling reaction between dipeptide II and 2-chloro-4(3H)-quinazolinone III. The overall yield of I from Boc-L-3-(2-naphthyl)alanine in six linear steps (total of eight steps) is 63%. This new convergent approach avoided the use of Me iodide and the formation of methanethiol byproduct in the last step involving the construction of the quinazolinone ring in the original discovery synthesis. A novel, water-assisted N-methylation of IV with di-Me sulfate in the presence of sodium hydride in THF was also developed that eliminated the use of Me iodide, silver oxide, and KCN. Deprotection of the Boc group in the N-methylated deriv. of IV with sulfuric acid circumvented the formation of diketopiperazine and tetrapeptide obsd. with HCl and trifluoroacetic acid, resp.
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    (b) McCabe Dunn, J. M.; Duran-Capece, A.; Meehan, B.; Ulis, J.; Iwama, T.; Gloor, G.; Wong, G.; Bekos, E. The Safe Use of Sodium Hydride on Scale: The Process Development of a Chloropyrimidine Displacement. Org. Process Res. Dev. 2011, 15, 1442,  DOI: 10.1021/op200114t
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    23b
    The Safe Use of Sodium Hydride on Scale: The Process Development of a Chloropyrimidine Displacement
    McCabe Dunn, Jamie M.; Duran-Capece, Alicia; Meehan, Brendan; Ulis, James; Iwama, Tetsuo; Gloor, Guy; Wong, George; Bekos, Evan
    Organic Process Research & Development (2011), 15 (6), 1442-1446CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
    Sodium hydride was found to be the best base for a displacement reaction on a chloropyrimidine. Due to the insoly. of sodium hydride in all solvents and high reactivity with atm. moisture, solns. dealing with the assocd. safety concerns on kilogram scale are described. The use of sodium hydride in premeasured dissolvable bag packaging (SecuBags), online process anal. technol. (PAT) to monitor the hydrogen off-gas, and the development of anal. methods to monitor residual polymer and potential degrdn. products allowed for a successful scale-up and on-time delivery of a quality product.
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    (c) Yang, Q.; Li, X.; Lorsbach, B. A.; Muhuhi, J. M.; Roth, G. A.; Gray, K.; Podhorez, D. E. Development of a Scalable Process for the Insecticidal Candidate Tyclopyrazoflor. Part 2. Fit-for-Purpose Optimization of the Route to Tyclopyrazoflor Featuring [3 + 2] Cyclization of 3-Hydrazinopyridine·2HCl and Methyl Acrylate. Org. Process Res. Dev. 2019,  DOI: 10.1021/acs.oprd.9b00128
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  24. 24
    (a) Tou, J. C.; Whiting, L. F. A cradle-glass ampoule sample container for differential scanning calorimetric analysis. Thermochim. Acta 1980, 42, 21,  DOI: 10.1016/0040-6031(80)87111-5
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    A cradle-glass ampoule sample container for differential scanning calorimetric analysis
    Tou, James C.; Whiting, Larry F.
    Thermochimica Acta (1980), 42 (1), 21-34CODEN: THACAS; ISSN:0040-6031.
    A sample container system was developed, which consists of a sealed microampul as the pressure vessel and the cradle designed to optimize the heat-detection efficiency, reproducibility, baseline stability, and thermal responses. The efficiency and thermal responses of the container system were detd. and compared to those of others. The interpretation of the heat measurements by differential scanning calorimetry is also discussed.
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    (b) Yang, Q.; Canturk, B.; Gray, K.; McCusker, E.; Sheng, M.; Li, F. Evaluation of Potential Safety Hazards Associated with the Suzuki–Miyaura Cross-Coupling of Aryl Bromides with Vinylboron Species. Org. Process Res. Dev. 2018, 22, 351– 359,  DOI: 10.1021/acs.oprd.8b00001
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    Evaluation of Potential Safety Hazards Associated with the Suzuki-Miyaura Cross-Coupling of Aryl Bromides with Vinylboron Species
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    Organic Process Research & Development (2018), 22 (3), 351-359CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
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Cite this: Org. Process Res. Dev. 2019, 23, 10, 2210–2217
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https://doi.org/10.1021/acs.oprd.9b00276
Published August 10, 2019

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  • Abstract

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    Figure 1

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

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    Figure 2

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

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    Figure 3

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

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    Figure 4

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

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    Figure 5

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

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    Figure 6

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

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    Figure 7

    Figure 7. DSC analysis of a NaH/DMSO mixture.

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    Figure 8

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

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    Figure 9

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

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    Figure 10

    Figure 10. ARC heat rate and pressure vs temperature profiles of NaH/DMF mixtures.

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    Figure 11

    Figure 11. Thermogram of NaH in mineral oil by EGA Micro-GC.

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    Figure 12

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

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    Figure 13

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

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    Figure 14

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

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    Figure 15

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

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  • References

    This article references 25 other publications.

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      The Corey-Chayokowski MeS(O)CH2Na reagent (I) (CA 57, 650h) can be used for titration of very weak acids, examn. of electronic spectra of many anions above 3500 A., hydrolysis of esters, and prepn. of various derivs. I is equiv. to an alk. soln. of H- = 30 or more and can be used in concns. up to 2M for titrations under anaerobic conditions with Ph3CH or Ph2CH2 as indicator. More complex reactions than simple deprotonation occurs with AcOEt, PhCH2CO2Et, PhCH2CN, and glycerol; the esters react with 2 equivs. of I, the nitrile gives, in fairly concd. solns., too intense a color to permit titration, and glycerol reacts with 1.5 equivs. of I to give a bimol. anion with three O...H-O groups. Spectra detns. are made on Me2SO solns. of the compds. under anaerobic conditions. Measurements are made within one min. after prepn. of the soln., the max. does not increase in intensity with time, but deterioration occurs slowly. MeCOPh and PhC ≡ CH are carboxylated by titration as above followed by addn. of the soln. to solid CO2, acidification, isolation of the acids, and recrystn. BzOEt is completely hydrolyzed within two min. at 20° after injection into a suspension of NaOH.
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      Treatment of carbohydrate derivs. with NaH in HCONMe2 or N-methyl-2-pyrrolidinone, followed by an alkyl halide (usually the bromide) at 0-25° gave the corresponding ethers in high yield. The procedure was used for methylation, butylation, octylation, allylation, and benzylation of Me 4,6-O-benzylidene-α-D-glucopyranoside (I), and for the 1-step methylation and allylation of sucrose. The 2,3-dipropargyl ether of I was prepd. by using tetrahydrofuran as solvent. Treatment of the diallyl ether of I with tert-BuOK in Me2SO gave the corresponding bis(1-propenyl) ether.
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    11. 11
      Nasipuri, D.; Bhattacharyya, A.; Hazra, B. G. Novel Aromatisation Reaction of Cyclohexenone Derivatives with Sodium Hydride. J. Chem. Soc. D 1971, 13, 660,  DOI: 10.1039/c29710000660
      There is no corresponding record for this reference.
    12. 12
      Buckley, J.; Webb, R. L.; Laird, T.; Ward, R. J. Report on thermal reaction. Chem. Eng. News 1982, 60 (28), 5
      12
      Report on thermal reaction
      Buckley, J.; Webb, R. Lee; Laird, T.; Ward, R. J.
      Chemical & Engineering News (1982), 60 (28), 5CODEN: CENEAR; ISSN:0009-2347.
      A thermal runaway reaction is reported which occurred while working with NaH in dimethylformamide (DMF) [68-12-2]. A reactor charged with DMF and NaH was heated and held at 50° without cooling. The mixt. self-heated to 75° and although cooling water was applied, the temp. continued to rise and the contents vented through a burst rupture disk on the vessel. In subsequent studies, the mixt. was obsd. to self-heat as low as 25°. Similar behavior was obsd. for NaH in dimethylacetamide (DMAC) [127-19-5]. Residues remaining after the reactions contained NaO2CH (with DMF) and Na acetate (with DMAC).
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    13. 13
      DeWall, G. Sodium hydride and DMF. Chem. Eng. News 1982, 60 (37), 5
      13
      Sodium hydride and DMF
      DeWall, Gordon
      Chemical & Engineering News (1982), 60 (37), 5, 43CODEN: CENEAR; ISSN:0009-2347.
      A thermal runaway reaction involving NaH and DMF [68-12-2] is reported. The mixt. was being stirred and slowly warmed when an exothermic reaction started to occur at 40°. Although fuel jacket cooling water was applied, the temp. rose to >100° in <10 min. The runaway reaction occurred in a stainless steel reactor. Reactions in a glass-lined reactor occurred without adverse reactions.
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    14. 14
      (a) Laird, T. Org. Process Res. Dev. 2002, 6, 876,  DOI: 10.1021/op025601k
      14a
      Special feature section: safety of chemical processes
      Laird, Trevor
      Organic Process Research & Development (2002), 6 (6), 876CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
      There is no expanded citation for this reference.
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      (b) Laird, T. Org. Process Res. Dev. 2005, 9, 951,  DOI: 10.1021/op050197l
      14b
      Safety Feature
      Laird, Trevor
      Organic Process Research & Development (2005), 9 (6), 951CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
      There is no expanded citation for this reference.
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    15. 15
      Dahl, A. C.; Mealy, M. J.; Nielsen, M. A.; Lyngsø, L. O.; Suteu, C. Route Scouting and Process Development of Lu AA26778. Org. Process Res. Dev. 2008, 12, 429,  DOI: 10.1021/op7002584
      15
      Route Scouting and Process Development of Lu AA26778
      Dahl, Allan C.; Mealy, Michael J.; Nielsen, Martin A.; Lyngso, Lars O.; Suteu, Cristina
      Organic Process Research & Development (2008), 12 (3), 429-441CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
      Route scouting and process development for the synthesis of (S)-2-({3-[(S)-5-chloro-1-(4-chlorophenyl)indan-1-yl]propyl}methylamino)propionic acid, Lu AA26778, are described. The strategy is based on a short synthesis and simulated moving bed (SMB) resoln. of a key chiral intermediate for the introduction of one of the two stereocenters. The second stereocenter is introduced via a com. available alanine ester, optionally bearing a N-Me group. The main concern during scale-up of the synthesis was the safety of a step incorporating sodium dimsylate (the sodium salt of DMSO): this problem was solved using THF as a safety blanket in the large-scale process.
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    16. 16
      Ishii, Y.; Fujimoto, R.; Mikami, M.; Murakami, S.; Miki, Y.; Furukawa, Y. Practical syntheses of Chiral α-Amino Acids and Chiral Half-Esters by Kinetic Resolution of Urethane-Protected α-Amino Acid N-Carboxyanhydrides and Desymmetrization of Cyclic meso-Anhydrides with New Modified Cinchona Alkaloid Catalysts. Org. Process Res. Dev. 2007, 11, 609,  DOI: 10.1021/op700023h
      16
      Practical Syntheses of Chiral α-Amino Acids and Chiral Half-Esters by Kinetic Resolution of Urethane-Protected α-Amino Acid N-Carboxyanhydrides and Desymmetrization of Cyclic meso-Anhydrides with New Modified Cinchona Alkaloid Catalysts
      Ishii, Yutaka; Fujimoto, Ryosuke; Mikami, Masafumi; Murakami, Satoshi; Miki, Yasushi; Furukawa, Yoshiro
      Organic Process Research & Development (2007), 11 (3), 609-615CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
      The large-scale applications of the kinetic resoln. of urethane-protected α-amino acid N-carboxyanhydrides (NCAs) and the desymmetrization of cyclic meso-anhydrides using modified cinchona alkaloids are described. These asym. reactions are effective organocatalytic methods for the synthesis of chiral α-amino acids and chiral half-esters on an industrial scale, because the organocatalyst recovery and product purifn. can be carried out by a simple extractive procedure obviating a chromatog. purifn. step. The modified cinchona alkaloid catalysts (DHQD)2AQN and (DHQ)2AQN, as reported by Deng et al., are not readily available and therefore not suitable for industrial-scale synthesis. Various O-alkylated quinidine and quinine derivs. were prepd. and screened as catalysts for the kinetic resoln. of phenylalanine NCA with alc. The readily prepd. O-propargylquinidine (OPQD) and O-propargylquinine (OPQ) were discovered to be highly enantioselective and practical catalysts. These new catalysts were applied to the synthesis of (S)-Boc-propargylglycine (I) and cyclopentanedicarboxylate deriv. II, on an industrial scale, by the kinetic resoln. of propargylglycine N-carboxyanhydride III and the desymmetrization of cyclic meso-anhydride IV, resp.
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    17. 17
      Stoessel, F. Thermal Safety of Chemical Processes: Risk Assessment and Process Design; Wiley-VCH: Weinheim, Germany, 2008.
      There is no corresponding record for this reference.
    18. 18

      This combination is a result of using 60% NaH in mineral oil for the evaluations.

      There is no corresponding record for this reference.
    19. 19
      Yoshida, T.; Yoshizawa, F.; Itoh, M.; Matsunaga, T.; Watanabe, M.; Tamura, M. Prediction of Fire and Explosion Hazards of Reactive Chemicals (I). Estimation of Explosive Properties of Self-Reactive Chemicals from SC-DSC Data. Kogyo Kayaku 1987, 48, 311– 316
      19
      Prediction of fire and explosion hazards of reactive chemicals. I. Estimation of explosive properties of self-reactive chemicals from SC-DSC data
      Yoshida, Tadao; Yoshizawa, Fujiroku; Itoh, Mamoru; Matsunaga, Takehiro; Watanabe, Masatoshi; Tamura, Masamitsu
      Kogyo Kayaku (1987), 48 (5), 311-16CODEN: KOKYBR; ISSN:0368-6450.
      A procedure is sought for prediction of the fire and explosion hazards of various reactive chem. from fundamental thermal characteristics. The heat of decompn. QDSC as measured by DSC with a sealed cell and the extrapolated onset temp. TDSC (ASTM E-537) were the characteristics. The BAM 50/60 Fe tube test data for detonation propagation of high explosives, the Mk III ballistic mortar test data for deflagration propagation of reactive chems., and data from the Mk III ballistic mortar test with detonator or small card gap for shock sensitivity were used as criteria of a hazardous property. Scattered diagrams; the degrees of propagation or sensitivity on the log QDSD-log(TDSC-25) plane show a clear nonpropagative or insensitive region, resp. Two judgement equations, viz. explosion propagation = log QDSC - 0.38log (TDSC - 25) - 1.67, and shock sensitivity = log QDSC - 0.72log (TDSC - 25) -0.98, were obtained from the border lines on these diagrams. The hazardous property of a new reactive chem. can be estd. by interpolating the QDSC and TDSC obtainable by conventional DSC. Some errors caused by measurement of DSC are discussed.
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    20. 20
      Brandes, B. T.; Smith, D. K. Calorimetric study of the exothermic decomposition of dimethyl sulfoxide. Process Saf. Prog. 2016, 35, 374– 391,  DOI: 10.1002/prs.11802
      20
      Calorimetric study of the exothermic decomposition of dimethyl sulfoxide
      Brandes, B. Todd; Smith, Daniel K.
      Process Safety Progress (2016), 35 (4), 374-391CODEN: PSAPE2; ISSN:1066-8527. (John Wiley & Sons, Inc.)
      DMSO (DMSO) is a widely used solvent often employed for a variety of org. syntheses. It is stable at room temp. can dissolve many types of org. materials, and is miscible in water. However, upon heating in a closed system under conditions typically achievable in a com. chem. plant, DMSO undergoes significantly exothermic and hazardous decompn. which could realistically lead to a pressure vessel explosion unless adequate protection layers were installed, possibly including a pressure relief system. This study provides calorimetry data from several app. and methods to characterize the decompn. to aid in assessing hazards and designing protection systems. 2016 American Institute of Chem. Engineers Process Saf Prog 35: 374-391, 2016.
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    21. 21

      This method was not designed for the detection of hydrogen gas. It would have coeluted with the carrier gas helium if it was present as part of the decomposition products.

      There is no corresponding record for this reference.
    22. 22

      The presence of dimethylamine (Me2NH) in the decomposition products has been reported previously. (12) Detection of Me2NH was not attempted during this analysis.

      There is no corresponding record for this reference.
    23. 23
      (a) Prashad, M.; Har, D.; Hu, B.; Kim, H.-Y.; Girgis, M. J.; Chaudhary, A.; Repič, O.; Blacklock, T. J.; Marterer, W. Process Development of a Large-Scale Synthesis of TKA731: A Tachykinin Receptor Antagonist. Org. Process Res. Dev. 2004, 8, 330– 340,  DOI: 10.1021/op0341824
      23a
      Process Development of a Large-Scale Synthesis of TKA731: A Tachykinin Receptor Antagonist
      Prashad, Mahavir; Har, Denis; Hu, Bin; Kim, Hong-Yong; Girgis, Michael J.; Chaudhary, Apurva; Repic, Oljan; Blacklock, Thomas J.; Marterer, Wolfgang
      Organic Process Research & Development (2004), 8 (3), 330-340CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
      An efficient and chromatog.-free large-scale synthesis of tachykinin receptor antagonist TKA731 (I) is described. The key step is the coupling reaction between dipeptide II and 2-chloro-4(3H)-quinazolinone III. The overall yield of I from Boc-L-3-(2-naphthyl)alanine in six linear steps (total of eight steps) is 63%. This new convergent approach avoided the use of Me iodide and the formation of methanethiol byproduct in the last step involving the construction of the quinazolinone ring in the original discovery synthesis. A novel, water-assisted N-methylation of IV with di-Me sulfate in the presence of sodium hydride in THF was also developed that eliminated the use of Me iodide, silver oxide, and KCN. Deprotection of the Boc group in the N-methylated deriv. of IV with sulfuric acid circumvented the formation of diketopiperazine and tetrapeptide obsd. with HCl and trifluoroacetic acid, resp.
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      (b) McCabe Dunn, J. M.; Duran-Capece, A.; Meehan, B.; Ulis, J.; Iwama, T.; Gloor, G.; Wong, G.; Bekos, E. The Safe Use of Sodium Hydride on Scale: The Process Development of a Chloropyrimidine Displacement. Org. Process Res. Dev. 2011, 15, 1442,  DOI: 10.1021/op200114t
      23b
      The Safe Use of Sodium Hydride on Scale: The Process Development of a Chloropyrimidine Displacement
      McCabe Dunn, Jamie M.; Duran-Capece, Alicia; Meehan, Brendan; Ulis, James; Iwama, Tetsuo; Gloor, Guy; Wong, George; Bekos, Evan
      Organic Process Research & Development (2011), 15 (6), 1442-1446CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
      Sodium hydride was found to be the best base for a displacement reaction on a chloropyrimidine. Due to the insoly. of sodium hydride in all solvents and high reactivity with atm. moisture, solns. dealing with the assocd. safety concerns on kilogram scale are described. The use of sodium hydride in premeasured dissolvable bag packaging (SecuBags), online process anal. technol. (PAT) to monitor the hydrogen off-gas, and the development of anal. methods to monitor residual polymer and potential degrdn. products allowed for a successful scale-up and on-time delivery of a quality product.
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      (c) Yang, Q.; Li, X.; Lorsbach, B. A.; Muhuhi, J. M.; Roth, G. A.; Gray, K.; Podhorez, D. E. Development of a Scalable Process for the Insecticidal Candidate Tyclopyrazoflor. Part 2. Fit-for-Purpose Optimization of the Route to Tyclopyrazoflor Featuring [3 + 2] Cyclization of 3-Hydrazinopyridine·2HCl and Methyl Acrylate. Org. Process Res. Dev. 2019,  DOI: 10.1021/acs.oprd.9b00128
      There is no corresponding record for this reference.
    24. 24
      (a) Tou, J. C.; Whiting, L. F. A cradle-glass ampoule sample container for differential scanning calorimetric analysis. Thermochim. Acta 1980, 42, 21,  DOI: 10.1016/0040-6031(80)87111-5
      24a
      A cradle-glass ampoule sample container for differential scanning calorimetric analysis
      Tou, James C.; Whiting, Larry F.
      Thermochimica Acta (1980), 42 (1), 21-34CODEN: THACAS; ISSN:0040-6031.
      A sample container system was developed, which consists of a sealed microampul as the pressure vessel and the cradle designed to optimize the heat-detection efficiency, reproducibility, baseline stability, and thermal responses. The efficiency and thermal responses of the container system were detd. and compared to those of others. The interpretation of the heat measurements by differential scanning calorimetry is also discussed.
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      (b) Yang, Q.; Canturk, B.; Gray, K.; McCusker, E.; Sheng, M.; Li, F. Evaluation of Potential Safety Hazards Associated with the Suzuki–Miyaura Cross-Coupling of Aryl Bromides with Vinylboron Species. Org. Process Res. Dev. 2018, 22, 351– 359,  DOI: 10.1021/acs.oprd.8b00001
      24b
      Evaluation of Potential Safety Hazards Associated with the Suzuki-Miyaura Cross-Coupling of Aryl Bromides with Vinylboron Species
      Yang, Qiang; Canturk, Belgin; Gray, Kaitlyn; McCusker, Elizabeth; Sheng, Min; Li, Fangzheng
      Organic Process Research & Development (2018), 22 (3), 351-359CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
      The potential safety hazards assocd. with the Suzuki-Miyaura cross-coupling of aryl bromides with vinylboron species were evaluated. In the Suzuki-Miyaura cross-coupling of 1-bromo-3-(trifluoromethyl)benzene with potassium vinyltrifluoroborate in the presence of potassium carbonate (K2CO3) in 9:1 DMSO (DMSO)/water at 80°C, the thermal profile revealed a significant exotherm upon the addn. of catalytic 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride [Pd(dppf)Cl2]. Further investigations indicated that the exotherm was consistently higher and the reactions were faster in the studied aq. systems compared to anhyd. conditions. Although under anhyd. conditions the exotherms were comparable among the studied cases, the rate of the exotherm was highly dependent on the choice of aryl electrophile, solvent, base, catalyst, as well as vinylboron species. In many of the studied cases the max. temp. of a synthesis reaction (MTSR) was considerably higher than the b.p. of the solvent and/or the onset temp. of the DMSO decompn., indicating that in the absence of active cooling the system could quickly exceed the b.p. of the solvent or trigger the decompn. of the reaction mixt. to result in a runaway reaction.
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      (c) Yang, Q.; Cabrera, P. J.; Li, X.; Sheng, M.; Wang, N. X. Safety Evaluation of the Copper-Mediated Cross-Coupling of 2-Bromopyridines with Ethyl Bromodifluoroacetate. Org. Process Res. Dev. 2018, 22, 1441– 1447,  DOI: 10.1021/acs.oprd.8b00261
      24c
      Safety Evaluation of the Copper-Mediated Cross-Coupling of 2-Bromopyridines with Ethyl Bromodifluoroacetate
      Yang, Qiang; Cabrera, Pablo J.; Li, Xiaoyong; Sheng, Min; Wang, Nick X.
      Organic Process Research & Development (2018), 22 (10), 1441-1447CODEN: OPRDFK; ISSN:1083-6160. (American Chemical Society)
      Potential safety hazards assocd. with Cu-mediated cross-coupling of 2-bromopyridines with Et bromodifluoroacetate were evaluated. An accelerating rate calorimetry thermal stability evaluation of the post-reaction mixt. of 50.6 mmol 2-bromopyridine with 1.3 equiv. Et bromodifluoroacetate in the presence of 2.1 equiv. Cu in 40 mL DMSO indicated a significant decompn. event with a 115.5° onset temp., which was significantly lower than that of neat DMSO. The reaction mixt. in N,N-dimethylformamide did not display any exothermic decompn. up to 400° using differential scanning calorimetry. Reaction calorimetry evaluation of this reaction in DMSO showed a heat output (ΔH) of -13.5 kJ and an adiabatic temp. rise (ΔTad) of 129.5°, resulting in a max. temp. of a synthesis reaction (MTSR) of 189.5°. The predicted heat of reaction using d. functional theory with BLYP functional agreed well with exptl. data. Scope studies with a multiple substituted 2-bromopyridines showed similar ΔH and ΔTad magnitudes vs. 2-bromopyridine when reacted at the same concn. In all studied cases, MTSR was significantly higher than the onset temp. of reaction mixt. decompn., indicating that in the absence of active cooling, the system could quickly trigger decompn. of the reaction mixt. and result in a runaway reaction.
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      (d) Yang, Q.; Sane, N.; Klosowski, D.; Lee, M.; Rosenthal, T.; Wang, N. X.; Wiensch, E. Mizoroki–Heck Cross-Coupling of Bromobenzenes with Styrenes: Another Example of Pd-Catalyzed Cross-Coupling with Potential Safety Hazards. Org. Process Res. Dev. 2019,  DOI: 10.1021/acs.oprd.9b00126
      There is no corresponding record for this reference.
      (e) Sheng, M.; Valco, D.; Tucker, C.; Cayo, E. Practical Use of Differential Scanning Calorimetry for Thermal Stability Hazard Evaluation. Org. Process Res. Dev. 2019,  DOI: 10.1021/acs.oprd.9b00266
      There is no corresponding record for this reference.
    25. 25
      Dietz, W. A. Response factors for gas chromatographic analyses. J. Chromatogr. Sci. 1967, 5, 68– 71,  DOI: 10.1093/chromsci/5.2.68
      25
      Response factors for gas chromatographic analyses
      Dietz, Walter A.
      Journal of Gas Chromatography (1967), 5 (2), 68-71CODEN: JGCRAY; ISSN:0096-2686.
      Correction factors and relative sensitivity values for quant. results in gas chromatography are given for H flame detectors and thermal cond. detectors.
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