A Convenient and “Greener” Synthesis of Methyl Nitroacetate

Communication pubs.acs.org/OPRD

A Convenient and “Greener” Synthesis of Methyl Nitroacetate Eric C. Johnson,† Pablo E. Guzmán,*,† Leah A. Wingard,† Jesse J. Sabatini,*,† and Rose A. Pesce-Rodriguez‡ †

Energetics Technology Branch, ‡Energetic Materials Science Branch, U.S. Army Research Laboratory, Aberdeen Proving Ground, Maryland 21005, United States S Supporting Information *

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ABSTRACT: A new procedure for the synthesis and isolation of methyl nitroacetate is described. The previously published method required drying the explosive dipotassium salt of nitroacetic acid in a vacuum desiccator, followed by grinding this material into a fine powder with a mortar and pestle prior to esterification. To obtain the desired product, benzene was employed as the extraction solvent, sodium sulfate was used as the drying agent, and two distillations were required. The new procedure eliminates drying and grinding of the explosive dipotassium salt, employs ethyl acetate or dichloromethane as the extraction solvent, eliminates the need for a drying agent, and requires a single distillation to furnish the end product in high yield and purity.

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INTRODUCTION The presence of the unbranched nitroacetic ester moiety in organic synthesis has found wide application, as evidenced by the historical review written by Shipchandler.1 More recently, nitroacetic esters have been used in palladium-catalyzed crosscoupling reactions with aryl halides to generate 2-aryl-2nitroacetates.2 Most recently, Machetti and co-workers have found that nitroacetic esters react with alkenes and alkynes in the presence of DABCOand in the notable absence of a dehydrating agentto produce isoxazolines and isoxazoles.3 One such nitroacetic ester that can be used for the aforementioned applications is the commercially available methyl nitroacetate. Though a relatively expensive material to buy,4 methyl nitroacetate can be prepared in a two-step process from inexpensive materials, as summarized in Scheme 1.5 The Scheme 1. Original Synthesis of Methyl Nitroacetate

treatment of nitromethane with potassium hydroxide at a high temperature results in the formation of the dipotassium nitronate salt (1, see Figure S1 in the Supporting Information for the proposed mechanism). The conversion of 1 to methyl nitroacetate (2) is realized upon exposure of 1 to sulfuric acid in methanol at low temperature.6 This article not subject to U.S. Copyright. Published XXXX by the American Chemical Society

RESULTS AND DISCUSSION

Although the synthesis of methyl nitroacetate appears trivial, the current route suffers from several issues. When 1 is synthesized, reports call for the material to be dried in a vacuum desiccator overnight and then ground into a fine powder with a mortar and pestle (Figure 1). However, 1 is a potentially shock sensitive and explosive material, as has been pointed out by an explosion of the dry powder.7 Thus, keeping 1 wet and using it in the next step without isolation would provide a significant increase in safety protocols when handling the material. Second, when purifying 2, benzene is used as the solvent of choice for extraction. Benzene, however, is a toxic solvent and has negative health effects.8 Third, two distillations are required to obtain 2 in high purity. One distillation is needed to remove benzene, and a second distillation under reduced pressure is needed to isolate the pure product. Thus, despite appearing to be a simple synthesis, synthesizing methyl nitroacetate has historically been a labor-intensive process plagued by safety and toxicity issues. In light of these issues, an alternative process was investigated to make the synthesis of methyl nitroacetate in a more safety conscious, environmentally responsible, and timely manner. While the general synthesis in Scheme 1 did not change, the process of isolating pure methyl nitroacetate was altered significantly to afford 2 in a safer and “greener” process. The new process is displayed in Figure 2. In this process, 1 was isolated by filtration and washed with methanol per the original procedure. The material was not dried on the filter, however, and was transferred wet to a round-bottom flask, where it was used immediately in the esterification step. Once the esterification reaction was complete, the reaction mixture was filtered, the solid was discarded, and the mother liquor was concentrated by rotary evaporation as per the original procedure. Instead of adding benzene, water was added to the resulting oil, and the crude material was neutralized with a saturated aqueous solution of NaHCO3. Failure to neutralize the crude esterification product prior to distillation resulted in an unstable protonated species, which under elevated temperature, can result in a detonation. After neutralization, 2 was isolated by a simple extraction with ethyl acetate or dichloromethane.9 Following rotary evaporation of the solvent, vacuum distillation of the dark amber liquid afforded 2 in high purity as a clear, colorless liquid. The overall yield for the new procedure was 38%. Although this Received: March 12, 2017

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DOI: 10.1021/acs.oprd.7b00093 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Communication

Figure 1. Original synthesis process of methyl nitroacetate.

Figure 2. New synthesis process of methyl nitroacetate.

blast shield and that proper protective equipment, including a face shield, be worn at all times during the operation. To a three-necked 3 L round-bottom flask, equipped with a mechanical stirrer, was added H2O (112 mL) and KOH (224 g, 4.00 mol, 4.00 equiv). Nitromethane (54 mL, 1.00 mol, 1.00 equiv) was added over 0.5 h. During the addition, the internal temperature of the reaction reached 70 °C. After 5 min, a yellow tinge was visible, and then the reaction turned reddishbrown. Once the addition was complete, the mechanical stirring was stopped, and the reaction was heated for 1 h (oil bath temperature = 160 °C, internal temperature = 135 °C). The reaction was then allowed to cool to room temperature, and the crude salt was collected by Büchner filtration. The salt was rinsed with MeOH until the salt was colorless. The salt, still wetted with MeOH in the Büchner funnel, was immediately transferred to a three-necked 3 L round-bottom flask, and MeOH (465 mL) was added with overhead stirring. The suspension was cooled to −15 °C. Once cooled, concentrated H2SO4 (116 g, 1.16 mol) was added dropwise with vigorous stirring, over 1 h via a pressure-equalizing dropping funnel. The reaction was maintained at −15 °C for the duration of the addition. The reaction was then allowed to stir and was gradually warmed to room temperature overnight. The resulting precipitate was removed by filtration with a glass frit, and the filtrate was concentrated under reduced pressure to remove as much MeOH as possible. The material was then transferred to an Erlenmeyer flask, 200 mL of H2O was added, and a saturated aqueous solution of NaHCO3 was carefully added, with stirring, until neutrality was achieved. The solution was transferred to a separatory funnel and was extracted with

yield is lower than the ca. 52% overall yield reported previously,5 the new environmentally conscious and improved safety process makes the sacrifice in yield acceptable. DSC analysis showed that 2 had a reasonable thermal stability, with a thermal onset temperature of 251 °C, and a peak exothermic decomposition temperature of 272 °C.

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CONCLUSION In summary, a synthesis for methyl nitroacetate has been developed, with an emphasis on minimizing explosion hazards, improving the “green” aspects of the synthesis, and improving the general process in an effort to make the material in a more efficient manner. Given the many potential synthetic uses of methyl nitroacetate, this new procedure can be used to provide this organic building block in a safer manner.

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EXPERIMENTAL SECTION Chemicals and solvents were used as received from SigmaAldrich. 1H and 13C NMR spectra were recorded using a Bruker 400 and 100 MHz instrument, respectively. The chemical shifts quoted in ppm in the text refer to typical standard tetramethylsilane (1H, 13C) in CDCl3 as the solvent. Infrared spectra were measured with a Bruker Alpha-P FTIR instrument. Decomposition temperatures were measured at a heating rate of 5 °C/min using a TA Instruments Q10 DSC instrument. Methyl Nitroacetate (2). Warning: Although no incidents occurred, the intermediates generated, as well as the end product, are energetic and should be handled as if they are explosive materials. It is essential that all reactions be conducted behind a B

DOI: 10.1021/acs.oprd.7b00093 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Communication

ethyl acetate or dichloromethane (4 × 250 mL). The combined organic extracts were washed with brine and water. The material was concentrated under reduced pressure to yield an amber colored liquid. Distillation under reduced pressure yielded 22.67 g (38%) of the desired product as a clear colorless liquid, bp 65 °C (3.9 Torr). 1H NMR (400 MHz; CDCl3) δ 5.18 (s, 2H), 3.87 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.5, 76.2, 53.6; IR (neat): 3041, 2967, 1751, 1557; Tdec = 251 °C (onset), 272 °C (peak).

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.7b00093. 1 H, 13C NMR, IR, and DSC data (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. Phone: 410-278-0235. *E-mail: [email protected]. Phone: 410-278-8608. ORCID

Jesse J. Sabatini: 0000-0001-7903-8973 Author Contributions

P.E.G. and E.C.J. contributed equally to this work. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors are indebted to the U.S. Army for financial support in carrying out this work. ABBREVIATIONS KOH = potassium hydroxide; MeOH = methanol; H2SO4 = sulfuric acid; DCM = methylene chloride; NaHCO3 = sodium bicarbonate; NaOH = sodium hydroxide

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REFERENCES

(1) Shipchandler, M. T. Synthesis 1979, 9, 666−686. (2) Metz, A. E.; Kozlowski, M. C. J. Org. Chem. 2013, 78, 717−722. (3) Cecchi, L.; De Sarlo, F.; Machetti, F. Eur. J. Org. Chem. 2006, 2006, 4852−4860. (4) Alfa Aesar currently offers methyl nitroacetate at a price of $22.20 per gram. (5) Zen, S.; Koyama, M.; Koto, S.; Ando, M.; Büchi, G. Org. Synth. 1976, 55, 776. (6) NaOH was not as effective as KOH involving the dimerization of nitromethane, thus resulting in significantly reduced yields. (7) Lyttle, D. A. Chem. Eng. News 1949, 27, 1473. (8) Snyder, R.; Witz, G.; Goldstein, B. D. Environ. Health Perspect. 1993, 100, 293−306. (9) Ethyl acetate is a suitable extraction solvent. It was observed that ethyl acetate carries over small amounts of impurities, presumably from the esterification reaction, compared to dichloromethane. The impurities were observed to be less generally than 1%.

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DOI: 10.1021/acs.oprd.7b00093 Org. Process Res. Dev. XXXX, XXX, XXX−XXX