Incompatibilities between N-Bromosuccinimide and Solvents

Safety/Environmental Report pubs.acs.org/OPRD

Incompatibilities between N‑Bromosuccinimide and Solvents Sumio Shimizu,* Yoshiaki Imamura, and Tatsuo Ueki Chemical Development Center, CMC Development Laboratories, Shionogi & Co., Ltd., 1-3, Kuise Terajima 2-Chome, Amagasaki, Hyogo 660-0813, Japan (ARSST), which employs a glass cell and Teflon-coated thermocouple, and is free of contact with metal materials. Here we report the safety evaluations between NBS and solvents which involve measurements of the reaction heat by ARSST7 and reaction calorimeter (RC1e),8 and mechanistic considerations of the incompatibilities between NBS with amides.

ABSTRACT: Incompatibilities between N-bromosuccinimide (NBS) and solvents were examined by measuring the heat of reaction by an advanced reactive system screening tool (ARSST) and a reaction calorimeter (RC1e). The ARSST experiments showed that amides, THF, and toluene solutions require consideration of incompatibilities with NBS. Isothermal analyses by RC1e revealed accurate heats of incompatibilities and the autocatalytic behaviors of the incompatibilities. Experiments in the presence of a radical initiator or inhibitor demonstrated that the incompatibility is caused by the radical mechanism and the incompatibility is increased by the presence of radical initiators. Further experiments made clear that DBDMH, an alternative brominating reagent, showed behavior similar to that of NBS.

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RESULTS AND DISCUSSION The stabilities of mixtures of NBS and solvents were probed with ARSST experiments using the following procedure. A 5-g sample of 10 wt % NBS in solvent was loaded into the ARSST 10-mL glass test cell with a Teflon-coated thermocouple, which was sealed in a 350-mL vessel and pressurized to 250−420 psi nitrogen to prevent solvent evaporation. The samples were heated from 30 to 150−200 °C at 2−3 °C/min under a polynominal control condition by stirring with a Teflon-coated magnetic stirring bar. In the four amide solvents of DMF, DMA, NMP and N,Ndimethylpropionamide, exothermic events were observed at onset temperatures of about 110, 60, 45 and 68 °C, respectively (Figure 1). In DMF, the peak rate of temperature rise (dT/dt)

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INTRODUCTION N-Bromosuccinimide (NBS) is widely used for radical and electrophilic brominations of organic compounds.1 In particular, NBS in DMF has been used for mild selective bromination of electron-rich aromatic hydrocarbons, heterocycles, phenols and anilines.2 Although NBS is easier and safer to handle than bromine and few incidents have been reported, reactions involving NBS are exothermic, and extra precautions must be taken when used on a large scale.3 Recently, an unanticipated exothermic reaction of NBS with DMF was reported.3c Both Shinohara and Kunito reported that the dramatic onset temperature of heat generation decreases in differential scanning calorimetry (DSC) of the DMF solution of NBS compared with the crystals.3c,4 Shilcrat reported that NBS is incompatible with DMA and must not be premixed with it, because an exothermic reaction easily occurs at ambient temperature.5 Previously, we had studied, by means of DSC thermal analysis, the incompatibility between NBS and solvents to select a solvent for bromination of a heterocyclic compound. This led to dichloromethane being selected as a solvent. Recently, a scanning electron microscope study revealed that gold-plated surfaces of commercially supplied DSC crucibles contain pinholes which cause samples to easily come into contact with the underlying copper or nickel.6 Thus, consideration of the crucible surface is important when carrying out process safety testing on a laboratory scale where the relative amount of surface exposed will be much greater than in process vessels. These considerations led us to reevaluate the incompatibilities between NBS and solvents. Because the crucible material can have an influence on the DSC analysis of NBS,4 we used an advanced reactive system screening tool © XXXX American Chemical Society

Figure 1. Temperature and pressure profiles of 10 wt % NBS in amides were determined using ARSST.

reached 105 °C/min. (Figure 2). The stabilities of NBS in these amide solvents were ranked as follows: DMF > N,Ndimethylpropionamide > DMA > NMP. The presence of the α proton of the carbonyl group is suspected as the cause of the destabilization although the stability of NBS varies with the kind of amide. No clear reason could be demonstrated. Received: June 26, 2013

A

dx.doi.org/10.1021/op400360k | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Safety/Environmental Report

observed at the relatively low onset temperature of about 69 °C (Table 1 entry 9). This is consistent with the previously reported incompatibility between NBS and THF, where the presence of peroxides in the THF used was suggested as a possible cause of this behaviour.3b It is important that there was no secondary heat generation up to the maximum temperature in these ARSST experiments (Table 1 entries 1−5, 8 and 9), because if the precise reaction heat and adiabatic rise in temperature can be measured and estimated, the incompatibilities between NBS and solvents can be judged more accurately. This led us to conduct reaction calorimeter analysis using RC1e. Namely, to 10 wt % NBS concentration was added dropwise with stirring 30 wt % NBS solution (50 g) into the RC1e reactor in which the solvent (100 g) was stirred at an assay temperature. The obtained 10 wt % NBS solution was monitored to measure the reaction heat until the end of heat generation. Alternatively, into the RC1e reactor in which a solvent (90 g) was being stirred at the assay temperature, NBS crystals (10 g) were added as a batch. Fortunately, the heat of solution of NBS was negligible. The obtained 10 wt % NBS solution was monitored with stirring at the temperature to measure the reaction heat. In DMF at 80 °C, during addition of 30 wt % NBS in DMF solution, close to 14% of the total heat was generated, and then 10 wt % NBS in DMF produced heat simultaneously with the end of the addition. The total heat output was 129 kJ/mol of NBS, corresponding to a predicted adiabatic temperature rise of 33 °C (Figure 4). In DMA at 40 °C, generation of the reaction

Figure 2. Temperature and pressure rates profile of 10 wt % NBS in DMF.

By contrast, a small event was observed at an onset temperature of about 130 °C in ethyl acetate, but was not observed in acetonitrile or dichloromethane (Figure 3).

Figure 3. Temperature and pressure profile of 10 wt % NBS in EtOAc, MeCN and CH2Cl2.

Acetonitrile, dichloromethane and ethyl acetate can be recommended as solvents of NBS from the ARSST experiments, because the exothermic heat of NBS with these solvents is negligible. The estimated onset temperature and adiabatic temperature rise are summarized in Table 1. In toluene, the events were observed at an onset temperature of 108 °C (Table 1 entry 8). The reaction of NBS with toluene caused the generation of benzyl bromide through a radical pathway, as demonstrated by 1H NMR analysis. In THF, the event was

Figure 4. Reaction heat profile of NBS in DMF at 80 °C.

heat started at the beginning of addition of 30 wt % NBS in DMA solution and continued for 120 min after NBS addition. The total heat output was 100 kJ/mol of NBS, corresponding to a predicted adiabatic temperature rise of 28 °C (Figure 5). In N,N-dimethylpropionamide at 40 °C, the reaction heat was almost evenly divided, the total heat output was 113 kJ/mol of NBS, corresponding to a predicted adiabatic temperature rise of 31 °C (Figure 6). These reaction heat profiles of RC1e appear to contradict the ARSST onset results. In order to clarify this difference, we examined the isothermal analysis of NBS in DMF by RC1e at 55, 60 and 65 °C, respectively. These results are summarized in Figure 7 and Table 2 (entries 4−6). The total heat values at these temperatures were nearly equal, and the heat induction times were completely temperature-dependent. Isothermal analysis revealed an autocatalytic behavior of the reaction of NBS in DMF. Since the maximum heat rates were not

Table 1. Thermal safety evaluation of 10 wt % NBS in solvents by ARSST

a

entry

solvents

onset (°C)a

ΔTad (°C)b

1 2 3 4 5 6 7 8 9

DMF DMA NMP N,N-dimethylpropionamide AcOEt MeCN CH2Cl2 Toluene THF

108 60 45 68 130 >200 >150 108 69

20 22 10 22 4 − − 20 28

Onset: Estimated onset temperature. temperature rise.

b

ΔTad: Estimated adiabatic B




temperature-dependent, the time to the maximum rate under adiabatic conditions could not be estimated by a zeroth-order approximation.9 However, as a function of the reciprocal of the absolute temperature, when the heat induction times were displayed by the natural logarithm, a straight line was obtained. The straight line can be used to estimate the induction time under isothermal conditions (at 43 °C, estimated induction time = 24 h). The contradiction between RC1e and ARSST onset results may have been due to the autocatalytic behaviors not being detected by the screening mode of ARSST which has a quick screening rate of 2−3 °C/min. The reaction heat values and the adiabatic temperature rises by RC1e are summarized in Table 2. Among these solvents (entries 1−8), 10 wt % NBS in DMF generates 129 kJ(s)/mol as the maximum total heat, and the corresponding adiabatic temperature rise has a maximum value of merely 33 °C. Clearly, these data show that, in manufacturing processes which use 10 wt % NBS solutions, the probability of an explosion incident is low. However, there are some processes which use high concentrations of DMF solutions of NBS for high throughput.10 We therefore decided to examine the influence of the NBS concentration by ARSST analysis. An exothermic event of 30 wt % NBS in DMF was observed at the same onset temperature as 10 wt % NBS (Figure 8). The estimated

Figure 5. Reaction heat profile of NBS in DMA at 40 °C.

Figure 6. Reaction heat profile of NBS in N,N-dimethylpropionamide at 40 °C.

Figure 8. Temperature and pressure profile of 30 wt % and 10 wt % NBS in DMF from ARSST findings.

adiabatic temperature rise by ARSST was about 100 °C, approximately the same as the calculated adiabatic temperature rise (33 × 3) by the RC1e experiment. Thus, from the safety viewpoint, when using a high concentration solution of NBS,10 strict temperature control is necessary to prevent a pressure rise.

Figure 7. Reaction heat profile of NBS in DMF at 55, 60 and 65 °C.

Table 2. Thermal safety evaluation of 10 wt % NBS in solvents by RC1e

a

entry

solvents

temp (°C)

ΔTad (K)a

reaction heat (kJ/mol)

induction time (min)

maximum heat rate (W/kg)

1 2 3 4b 5b 6b 7b 8b

DMF DMA N,N-dimethylpropionamide DMF DMF DMF DMA toluene

80 40 40 65 60 55 60 80

33 28 31 31 32 33 29 31

129 100 113 113 109 113 97 104

− − − 59 108 239 0 27

− − − 81 109 59 73 39

ΔTad: Adiabatic temperature rise. bNBS crystals added as a batch. C




N-Methyl-N-succinimidomethylacetoamide (2a) is known as a radical reaction product of NBS with DMA (Scheme 1).11 We Scheme 1. Radical reaction of NBS with amides in CCl4

synthesized 2a as an authentic compound by a method in the literature.11 We obtained N-methyl-N-succinimidomethylformamide (2b) as the coupling product of DMF by the same reaction procedure. Generation of these compounds 2a and 2b in the thermal reaction of NBS in amides was demonstrated by GC−MS and LC−MS analysis. The effects of the radical initiator and inhibitor on the thermal reaction of NBS were also examined. Azobisisobutyronitrile (AIBN) is commonly used as a radical initiator in radical brominations by NBS.12 For the inhibitor, we chose picric acid, an electron-deficient phenol.13 By addition of 1 mol % (versus NBS) of AIBN or picric acid, a definite effect was observed in toluene (Figure 9). The exothermic event was

Figure 10. Temperature and pressure profile of 10 wt % NBS in DMF in the presence of 10 mol % AIBN or picric acid from ARSST findings.

and high bromine content.14 We conducted a safety evaluation of DBDMH and amides by ARSST (Figure 11) and RC1e; the

Figure 11. Temperature and pressure profile of 10 wt % DBDMH in DMF and DMA by ARSST.

Figure 9. Temperature and pressure profile of 10 wt % NBS in toluene in the presence of 1 mol % AIBN or picric acid from ARSST findings.

Table 3. Thermal safety evaluation of 10 wt % DBDMH in solvents by ARSST

observed with an onset temperature of about 96 °C, and decreased by about 12 °C in the presence of the radical initiator. By contrast, in the presence of 1 mol % of picric acid, the exothermic event was observed with an onset temperature of about 126 °C, higher by about 18 °C in the presence of the radical inhibitor. However, in DMF and THF the 1 mol % addition did not have a definite impact on the heat profiles. On the other hand, addition of 10 mol % of AIBN in DMF led to the exothermic event being observed with an onset temperature of about 85 °C, which decreased by about 25 °C in the presence of the radical initiator (Figure 10). By contrast, in the presence of 10 mol % of picric acid, there was no exothermic event (Figure 10). These results show that the exothermic event due to the thermal reaction of NBS involves a radical chain reaction, the progression of which is influenced by the kind of solvent. Since the reaction onset temperature decreases by mixing impurities such as a radical initiator, the quality of the solvent to be used needs to be confirmed in advance. 1,3-Dibromo-5,5-dimethylhydantoin (DBDMH) is regularly substituted for NBS in industrial applications due to its low cost

entry

solvents

onset (°C)

ΔTad (K)

1 2

DMF DMA

99 88

26 29

Table 4. Thermal safety evaluation of 10 wt % DBDMH in solvents by RC1e entry solvents 1 2

DMF DMA

temp (°C)

ΔTad (K)

reaction heat (kJ/mol)

induction time (min)

maximum heat rate (W/kg)

60 60

49 44

265 240

260 63

78 117

results are summarized in Tables 3 and 4. Like NBS, DBDMH is more stable in DMF than DMA (Figure 11 and Table 3). Because DBDMH has two bromine atoms in the molecule, the reaction heat values of DBDMH are more than twice those of NBS, and the corresponding adiabatic temperature rises are 1.5 times that of NBS (Table 4). In the RC1e isothermal experiments, at 60 °C in DMF and DMA, the reaction heat was generated at 260 and 63 min after addition of the DBDMH D




(7) http://www.fauske.com/chemical-industrial/adiabaticcalorimetry-relief-system-design. (8) http://us.mt.com/us/en/home/products/L1_ AutochemProducts/Level_2_ALR_Calorimeters_RC1_LabMax/ Calorimeters-RC1-MultiMax.html. (9) (a) Stoessel, F.; Fierz, H.; Lerena, P.; Kille, G. Org. Process Res. Dev. 1997, 1, 428. (b) Stoessel, F. Thermal Safety of Chemical Processes: Risk Assessment and Process Design; Wiley-VCH: Weinheim, 2008. (10) (a) Pelleter, J.; Renaud, F. Org. Process Res. Dev. 2009, 13, 698. (b) Daniewski, A. R.; Lie, W.; Okabe, M. Org. Process Res. Dev. 2004, 8, 411. (11) Caristi, C.; Cimino, G.; Ferlazzo, A.; Gattuso, M.; Parisi, M. Tetrahedron Lett. 1983, 24, 2685. (12) (a) Rowlands, G. J. Tetrahedron 2010, 66, 1593. (b) Smiley, R. A. Kirk-Othmer Encyclopedia of Chemical Technology, 3rd ed.; Wiley & Sons, Ltd.: New York, 1981; pp 888−909. (13) Johnson, H. W., Jr.; Bublitz, D. E. J. Am. Chem. Soc. 1957, 80, 3150. (14) (a) Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.; Wiley & Sons, Ltd.: New York, 2001; pp 1556−1558. (b) Thieu, T.; Sclafani, J. A.; Levy, D. V.; McLean, A.; Breslin, H. J.; Ott, G. R.; Bakale, R. P.; Dorsey, B. D. Org. Lett. 2011, 13, 4204. (c) Rayala, R.; Wnuk, S. F. Tetrahedron Lett. 2012, 53, 3333. (d) Azarifar, D.; Ghasemnejad-Bosra, H. Synthesis 2006, 1123.

crystals, respectively. Thus, DBDMH also shows the behavior of autocatalytic heat generation in amides, and strict temperature control is necessary to prevent an incident, as with NBS.

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CONCLUSION Acetonitrile, dichloromethane and ethyl acetate do not show significant incompatibility with NBS and can be recommended as solvents for use with this reagent. However, amides, THF and toluene do show significant incompatibility with NBS with autocatalytic behavior. The use of solutions of NBS in such solvents should be avoided, particularly at high concentration or elevated temperature and with preparation ahead of time. Ideally, a procedure should be adopted whereby NBS is allowed to react with the target substrate, either by addition as a solid or as a solution in an inert solvent. Since incompatibilities between NBS and solvents are caused by the radical cascade and the risk of incompatibilities is increased by mixing in impurities such as a radical initiator, consideration of the solvent quality is needed. DBDMH showed the same behavior as NBS, and therefore the same considerations of incompatibility would be needed.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Mr. Y. Takeuchi, Mr. M. Nishiwaki, Dr. S. Takechi, and Dr. K. Nishi of the Chemical Development Center, CMC Development Laboratories, Shionogi & Co., Ltd., for their encouragements and support in reporting this work. We also thank two anonymous reviewers for their relevant suggestions.

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REFERENCES

(1) (a) Djerassi, C. Chem. Rev. 1948, 43, 271. (b) Synthetic Reagents; Pizey, J. S., Ed.; Wiley & Sons, Ltd.: New York, 1974; Vol. 2, p 1. (c) Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.; Wiley & Sons, Ltd.: New York, 2001; pp 768−773. (2) (a) Hitchell, R. H.; Lai, Y.-H.; Williams, R. V. J. Org. Chem. 1979, 44, 4733. (b) Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.; Wiley & Sons, Ltd.: New York, 2001; pp 773−774. (3) (a) Bretherick’s Handbook of Reactive Chemical Hazards, 7th ed.; Urben, P. G., Ed.; Elsevier: Amsterdam, 2007; p 556. (b) Mauragis, M. A.; Veley, M. F.; Lipton, M. F. Org. Process Res. Dev. 1997, 1, 39. (c) Kunito, Y. Presented at the Summer Symposium of The Japan Society for Process Chemistry, Funabori, Tokyo, July 2010. He reported that the onset temperature of DSC analysis of the NBS crystal was 175 °C, whereas that of the NBS solution in DMF (NBS/ DMF = 1/1) dropped down to 63 °C. (4) Shinohara, H. Presented at The Second Workshop of the Chemical Process Safety Assessment Study Group (existing Process Safety Study Group) of Environment & Safety Committee of The Japan Pharmaceutical Manufacturers Association, Nihonbashi, Tokyo, November, 2007. (5) Shilcrat, S. Presented at The 25th International Conference and Exhibition of Organic Process Research and Development, San Francisco, CA, United States, March 2012. (6) (a) Akiyoshi, M.; Sasakibara, T.; Okada, K.; Usuba, S.; Matsunaga, T. ; Okuda, A. Presented at The 44th National Conference of Japan Society for Safety Engineering, Yonezawa, Yamagata, Japan, December 2011. (b) Japanese Industrial Standard: Measurement Method of Exothermic Decomposition Energy for Explosive Estimation, JIS K 4834; Japanese Standards Association: Tokyo, 2013; 18 (in Japanese). E


Incompatibilities between N-Bromosuccinimide and Solvents

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