Resolving Bromonitromethane Sourcing by Synthesis: Preparation at Decagram Scale

Abstract

The accessibility of bromonitromethane has declined in recent years, limiting its viability as a reagent for chemical synthesis. Reinvestigation and optimization of a variety of preparations, and the development of safe operating principles, are described. The reproducible protocol described here leverages the effectiveness of hydroxide for nitromethane bromination, while respecting its incompatibility with the product it forms. This careful balance is achieved at scales up to 56 grams, resulting in a reproducible procedure that provides straightforward, sustainable, and affordable access to this critical reagent.

Graphical Abstract

INTRODUCTION:

Bromonitromethane is a versatile reagent used in the preparation of nitroheterocycles,¹ nitrocyclopropanes,² α-functionalized terminal nitroalkanes,³ and to a limited extent, 1,3-dipolar cycloaddition products.⁴ Advances in the synthesis of enantiopure amines, amides, and peptides have relied increasingly on the reagent,^5,6 which was commercially available at reasonable cost for many years. More recently, our work leveraging bromonitromethane as a reagent⁷ was stymied by the need to contract with a supplier for amounts both smaller and more expensive (ranging USD $0.48 to >$6/mmol) than previously available. Nitromethane, however, remains readily available and stable in cost (less than USD $0.01/mmol). In this context, we turned to literature procedures describing the preparation of bromonitromethane from nitromethane. After some investment of time and effort, attempts to reproduce the most promising preparation were successful on a 13 to 56 -gram scale (Scheme 1). We detail here the key factors for reproducible production of bromonitromethane at laboratory scale. We also take the opportunity to highlight some safe operating procedures associated with the preparation and purification of reagents in this class. This robust, renewable, and inexpensive bromonitromethane preparation should alleviate any future supply obstacles, thereby stimulating further use of bromonitromethane in organic synthesis.

Scheme 1.

General outline of the optimized bromonitromethane synthesis from nitromethane.

A selection of bromonitromethane syntheses have been published, each varying significantly in the protocols described.^{8,9,10,11,12,13} Key differences include temperature (−15 °C to 35 °C), the addition rate of reagents, and the inclusion of sodium bromide in a substoichiometric amount. While all protocols report a yield between 60–90%, in our hands, we were unable to reproduce any single procedure consistently as described. A critical metric for success is the pre-distillation ratio of bromonitromethane to dibromonitromethane (and unconverted nitromethane); we sought high ratios that might eliminate the need for distillation for most applications. Procedures conducted in the −10 to −15 °C range led to freezing of the reaction mixture. This phase change prevented proper stirring, resulting in significant increases in dibrominated product. When operating at a higher temperature range, variable results were typical.

RESULTS AND DISCUSSION:

Most notable among the literature procedures replicated is a 1950’s patent¹² in which extensive experimental detail is described. However, this procedure offers a wide acceptable temperature range (0 to 35 °C), as well as a bromine addition time of up to 2 minutes. Our attempts to replicate this procedure provided inconsistent results, particularly with varying ratios of mono-brominated to dibrominated product, despite careful control of addition rate and internal temperature (Table 1, entries 1–3). Inconsistency was further amplified when attempting to scale these bromination reactions (Table 1, entries 4–7). These collective experiences led us to refine the most promising method into a robust, operationally detailed procedure. This includes modifications and clarifications to the hydroxide/elemental bromine approach additions.

Table 1.

Optimization of bromonitromethane preparation at decagram scale.^a

entry	scale (g)b	NaBr	BrCH2NO2:Br2CHNO2	yield (%)c (isolated)
1	13	–	1.5:1	–
2	13	–	20:1	–
3	14	–	1.5:1	–
4	14	–	10.5 ± 0.7 : 1 (2)	66d
5	28	–	11.5 ± 4.3 : 1 (5)	66d
6e	28	–	30:1	78
7	56	–	2.75 ± 0.5 : 1 (4)	–
8	13	60 mol %	21.5 ± 2.1 : 1 (2)	–
9	28	60 mol %	21:1	–
10e	56	60 mol %	27:1	79
11f	28	60 mol %	4.5:1	–
12f	28	60 mol %	7:1	–
13g	28	60 mol %	22:1	–
14g	28	60 mol %	20:1	–

^aConditions: Entries 1–8: 0 °C using traditional stirring, with bro-mine added as a single addition; concentration was 740 mM; for any reaction leading to product ratios lower than 5:1, the material was discarded. Crude percent recoveries were >80% by mass for all reactions. Ratios in entries 4–5 and 7–8 are shown as mean ± stand-ard deviation. Parentheses indicate the number of experiments av-eraged for each entry.

^bTheoretical yield (in grams) of bromonitro-methane.

^cReported yield is a distilled yield unless stated otherwise (Caution!¹⁶).

^dThe crude reaction mixtures from entries 4 and 5 were combined and distilled together, leading to a 66% yield of bromonitromethane (15:1).

^eThe reaction used mechanical stirring apparatus (see Supporting Information Figure S1).

^fEntries 11–12: dropwise addition of bromine.

^gEntries 13–14: single addition of bromine.

We focused on the use of aqueous sodium hydroxide-based formation of the nitromethane nitronate, and bromination using elemental bromine and sodium bromide. These studies focused not only on the specific formation of bromonitromethane, but also on the minimization of dibromonitromethane formation. The latter is formed presumably by competitive bromonitromethane deprotonation and bromination. The presumption is that this might occur if the exposure of bromonitromethane to the basic conditions is significant, and competitive with its own formation.

We found that the presence of sodium bromide increased the reproducibility of the results (Table 1, entry 8). Few examples have employed sodium bromide as a substoichiometric additive. However, when exploring other bromination protocols in the literature, we encountered several reports detailing the use of an alkali metal tribromide to provide instantaneous and selective bromination. Furthermore, it has been demonstrated that the use of liquid Br₂ in the presence of aqueous KBr produces potassium tribromide in situ,¹⁴ and overall provides better brominating efficiency and selectivity.¹⁵ We hypothesized that this may translate well to our bromination protocol, and therefore carefully tested the use of sodium bromide. Indeed, the addition of sodium bromide provided more consistent reaction outcomes with increasing scale (Table 1, entries 8–10). Presumably, Br₂ and NaBr in aqueous conditions are forming sodium tribromide in situ, perhaps attenuating the bromonium electrophilicity to better match the nucleophilicity of the nitronate.

Another key feature is the bromine addition rate. We found that a rapid single addition of bromine was essential to high selectivity for the mono-brominated product. When the bromine was added dropwise, selectivity suffered greatly (Table 1, c.f. entries 11–12 vs. 13–14). These results further support our hypothesis that the slow generation of bromonitromethane under basic conditions leads to the competitive dibrominated product. Therefore, a rapid addition favors selective bromonitromethane formation.

The internal reaction temperature was also evaluated (Table 2). Although the literature procedure states the reaction temperature can range from 0 °C to 35 °C,¹² we found that lower temperatures consistently provide better selectivity for the mono-brominated product. When the reaction was conducted at 25 °C, the ratio of mono-brominated to dibrominated product decreased substantially (Table 2, entry 1). The temperature was systematically decreased to determine the ideal temperature range for high selectivity. As illustrated in Table 2, we found that temperatures starting below −5 °C are consistent, reproducible, and provide heightened selectivity for mono-brominated product in comparison to higher temperatures. These results hold true over multiple reaction scales (13-gram, 20-gram, 28-gram). Temperatures below −5 °C did not show any significant improvement, and instead were often detrimental to selectivity. It should be noted that on larger scales (above 28 grams) below −6 °C, the reaction mixture begins to freeze, resulting in poor stirring, and presumably slower incorporation of bromine throughout the mixture (Table 2, entries 11 and 12). This slower incorporation of bromine is likely similar to a dropwise addition approach, both resulting in significantly larger amounts of dibromonitromethane. This can be mitigated, however, with the use of a mechanical stirrer. If access to a mechanical stirrer is not feasible, several experiments can be conducted at 28 grams or less and pooled together for a larger scale distillation. Entries 12–13 in Table 2 demonstrate that high selectivity can be achieved at these lower temperatures so long as proper mixing is promoted. Ultimately, the temperature study demonstrated that as long as the reaction is started at −5 °C and does not spike higher than 20 °C, high selectivity for mono-brominated product is observed. This temperature spike (see max. temp, Table 2) occurs following the addition of bromine. It is important to note that all temperatures reported are measured internally to ensure consistency.

Table 2.

Correlation of temperature control to reproducibility and high selectivity for bromonitromethane.^a

entry	scale (g)b	initial T (°C)c	maximum T (°C)d	BrCH2NO2:Br2CHNO2
1	13	25	43	3:1
2	28	0	14	20.5:1
3	28	0	12	15:1
4	13	−5	19	20:1
5	28	−5	5	16.5:1
6	28	−6	10	20:1
7	28	−7	13	22:1
8	28	−8	3	20.5:1
9	13	−10	−5	41:1
10	13	−10	−7	41:1
11	13	−10	−7	23:1
12e	20	−15	−10	20:1
13e	20	−15	−10	24:1

^aConditions: Traditional (magnetic) stirring unless noted otherwise, with bromine added as a single addition. Concentration was 740 mM. For any reaction lower than a 5:1 ratio, the material was discarded. Crude percent recoveries were >80% (mass) for all reactions.

^bScale refers to the theoretical yield of bromonitromethane.

^cInitial temperature is the reaction temperature measured prior to bromine addition but after nitromethane addition (measured internally).

^dMaximum temperature is the maximum temperature measured either during or after bromine addition (measured internally).

^eMechanical stirring used.

Following this sequence of optimization, we assessed the scalability of the final procedure (Table 3). For scales up to 28 grams, we found using the optimized conditions provides ratios greater than 20:1 (Table 3, entries 1–5). As the scale increased, it became substantially more important to ensure efficient mixing (Table 3, entries 4–5 versus 6–7). Below −5 °C, the solution can become slushy in consistency, but a mechanical stirrer ensures that fast addition of the elemental bromine is coupled with rapid mixing. In general, a mechanical stirrer is recommended at scales larger than 28 grams to achieve high selectivity (Table 3, entries 8–9). High yields, generally >70% (post distillation) were readily and reproducibly attained, (Table 3, entries 1, 3, 5, and 7–9). Percent recoveries of the crude mass were also consistently high (80–90%), allowing material to be pooled together for a larger scale distillation.¹⁶

Table 3.

Scaling of optimized procedure from 10 to 56 grams.^a

entry	scale (g)b	BrCH2NO2:Br2CHNO2	recovery (%)c	yield (%)c
1	13	35.4 ± 9.8 : 1 (3)	90.7 ± 1.5	77d
2	13	21.5 ± 2.1 : 1 (2)	–	–
3	26	40:1	83	77d
4	28	20.8 ± 1.0 : 1 (3)	–	–
5	28	32:1	80	73
6e	28	15:1	–	–
7e	28	16.5:1	84	81
8f	56	18:1	88	68
9f	56	27:1	81	79

^aConditions: Temperature established at −5 °C with traditional (magnetic) stirring for entries 1–7, mechanical stirring for entries 8–9. Bromine was added as a single addition; concentration was 740 mM. Ratios in entries 1–2 and 4 are shown as mean ± standard deviation. Parentheses indicate the number of experiments averaged for each entry.

^bScale refers to the theoretical yield of bromonitromethane.

^cRecovery is the % mass recovery of pre-distilled BrCH₂NO₂, and % yield is determined using distilled BrCH₂NO₂ (Caution!¹⁶).

^dThe crude reaction mixtures from entries 1 and 3 were combined and distilled together, leading to a 77% yield of bromonitromethane (35:1).

^eSolution froze due to insufficient stirring (magnetic).

^fMechanical stirring used.

Typical selectivity for the 28-gram scale reaction is greater than 20:1 favoring the mono-brominated product. Ultimately, we found that with the optimized procedures, the ratio of mono-brominated product was high enough that a purification via distillation was not necessary. However, if desired, the crude material can be further purified by vacuum distillation at 42 °C (5–18 Torr).¹⁶ Despite the large boiling point difference, enrichment of bromonitromethane was not easily achieved by fractional distillation in our experience.

The apparent contradiction that effective bromonitromethane formation uses a hydroxide base, and our discovery that bromonitromethane decomposes rapidly with hydroxide bases under phase transfer catalysis conditions,¹⁷ left us nonplussed. Consideration, if not resolution of this paradox was important to define safe operating procedures associated with bromonitromethane synthesis. Within the three dozen preparations executed for this study, at scales ranging from 66.8 mmol (10 g) to 374 mmol scale (56 g), only one showed evidence of a comparable decomposition. In that experiment (187 mmol scale), a viscous orange liquid was noted in the workup, after extraction. As we noted previously,17 when bromonitromethane is exposed to solid hydroxide base, an exothermic reaction occurs alongside deposition of an orange oil on the hydroxide solid. The success of the preparation detailed here may be due in part to the limited exposure of nascent bromonitromethane to hydroxide base. Furthermore, care during the workup/neutralization may be more important than usual.

We note an additional experience that may increase practice within the safe operating limits.^18,19 In order to examine the behavior of α-bromonitronate in other reactions, the potassium salt of 1-bromo-1-nitropropane (2 mmol) was prepared in aqueous potassium hydroxide at ice-bath temperature, then cooled to −78 °C for lyophilization (Scheme 2, eq 1). Once dry, the solid was scraped and crushed into a free-flowing powder without incident in a glass flask. The solid was transferred to a screw-cap vial and moved to a drawer for temporary storage. Within minutes, and seemingly unprovoked, the vial shattered due to decomposition forces. This singular experience reaffirms that the isolation of desolvated nitronate salts should be avoided. This experience is reminiscent of reports that the dry sodium salt of nitromethane can react explosively with chlorine gas,^20,21 and the 1,1,4,4-tetranitrobutane dinitronate (potassium) salt “occasionally exploded even while still wet”.^22,23 A more rigorous analysis of a terminal nitroalkane’s process safety has been published,²⁴ highlighting the generally wide safe operating parameters that align with our collective experience.²⁵ Similarly, the nitration of the nitromethane sodium nitronate is reported to proceed without event in warm (50 °C) water.²⁶ We have also repeated the formation of methazonic acid from the nitronate of nitromethane without event.²⁷

Scheme 2.

Safety considerations for the preparation and use of bromonitroalkanes.

Overall, after careful exploration of temperature, addition rates, and additives, an optimal procedure for the synthesis of bromonitromethane has been developed that is consistently reproducible over a range of scales. Furthermore, this procedure yields material of high purity, such that further purification by distillation is optional for most applications.¹⁶ We detail a simple experimental setup that can be replicated in any lab setting using commonly available lab supplies. The resulting procedure provides straightforward and sustainable access to this important reagent at an affordable cost.