tert-Butyl nitrite, also known as   tbuono, has the molecular formula C?H?NO?. Its molecular structure is derived from nitrous acid, with the hydroxyl group replaced by a tert-butyl group. It decomposes easily when exposed to heat or light and is a commonly used diazotizing and nitrosating agent. In organic synthesis, it is used to prepare diazo compounds, oximes, and azo derivatives; it can also serve as a free-radical initiator and an intermediate in the synthesis of pharmaceuticals and pesticides.

Low-Level Quantification of tert-Butyl Nitrite in a Pharmaceutical Intermediate

tert-Butyl nitrite (TBN) is a highly valuable reagent for various transformations in organic chemistry. Since TBN is inexpensive, acid- and metal-free, and easy to procure commercially, it is a reagent of choice for many organic reactions such as nitrosation, oximation, diazotization, nitration, oxidation, etc. for the synthesis of several biologically essential scaffolds, mostly targeting nitrogen insertion. tert-Butyl nitrite is a liquid at room temperature (RT) with a boiling point of 61–63 °C with good solubility. The fast and versatile reactivity of TBN is governed by the cleavage pattern of the O–N single bond. Through heterolytic cleavage, TBN releases nitrous and nitric acid, which facilitate nitrosation and diazotization reactions. Alternatively, the nitration and oxidation reactions of TBN are effected by the ?NO and t-BuO? radicals generated by homolytic cleavage. As a result of its chemical versatility, TBN is often part of the synthesis strategy for the generation of many biologically important molecules and active pharmaceutical ingredients (APIs). While tert-butyl nitrite is a chemical reagent with numerous applications, it is also identified as a potential genotoxic impurity (pGTI) by many toxicological databases, such as ToxAlert, MolTox, etc., due to its reactivity in biological systems. According to a report by Bursi et al. and Cronin et al., the nitrite functional group likely induces reactivity by increasing the electrophilicity of the carbon atom directly connected to it and by serving as a leaving group following protonation of the nitrogen atom. Toxic and fatal effects due to inhalation of alkyl nitrites as recreational drugs have also been reported.[1]

Synthetic chemists explore various reagents for different chemical transformations during the synthesis of APIs; however, despite their value, some reagents could end up on the list of potential structural alerts. As a part of the control strategy, the analytical team has to accordingly develop and validate appropriate methods for determining the trace levels of these reagents. Because of its chemical versatility, tert-Butyl nitrite is one such reagent that has become part of the synthesis strategy of many biologically important compounds and APIs. Owing to its known reactivity (toxicity) in biological systems, trace-level determination of TBN in one of the pharmaceutical intermediates under development at Bristol Myers Squibb became imperative, and hence, a quantitative method using conventional HS/GC–FID technology was developed and validated. A systematic solvent screening study was performed to select the diluent to ensure good solubility of the analyte and sample matrix. The challenge related to tert-Butyl nitrite stability in the sample diluent (DMSO) was addressed by adding a base (imidazole) to the diluent. Validation experiments demonstrated that the specificity, sensitivity, precision, linear correlation, and accuracy for TBN were well within the acceptance criteria. The inherent benefit of this method is that it enables detection and quantification of trace levels of intact tert-Butyl nitrite without any derivatization and thus has the potential to be a viable alternative for existing derivatization or degradation methods of TBN determination. This method could readily be used for low-level quantification of TBN present in different organic reactions with adequate reliability and sensitivity. This report is novel in its approach of using a stabilization strategy to prevent the degradation of TBN to TBA and determine tert-Butyl nitrite “as is” in a sample matrix.

Continuous Flow Synthesis of tert-Butyl Nitrite and Its Applications as Nitrating Agent

Alkyl nitrites have been used in the field of pharmaceuticals as medicines and in organic chemistry as reagents and catalysts. Among many alkyl nitrites, tert-butyl nitrite (TBN) has been widely explored in organic chemistry. It is used in many organic reactions such as nitration, alkyne to nitrile, diazotization, nitrosation, and oxidation. However, the synthesis of tert-butyl nitrite requires the utmost process safety measures. It is prepared by reacting tert-butanol with nitrous acid (HNO2). Nitrous acid is unstable and decomposes rapidly. Thus, it is generated in situ by reacting sodium nitrite (NaNO2) with hydrochloric acid (HCl). This reaction is extremely exothermic, which requires the slow addition of reagents. Longer residence time of alkyl nitrite in reaction medium increases the risk of nitrite decomposition, which leads to lower yield. Strict control over addition rate and stoichiometry is needed to avoid the release of highly toxic nitrogen oxides. The current reports for the preparation of tert-butyl nitrite through this route are based on batch or semi batch type processes, which have several limitations associated with safety and scalability. Considering these challenges, there is a need to develop a highly scalable flow process. In flow, reagents are pumped, and product is removed continuously providing very little time for product to decompose. Short residence times are highly desirable to prevent decomposition of unstable nitrites. In flow, gaseous reagents can be fed continuously, providing good liquid and gas contact for the reactions. This is important to allow effective air and liquid contact to provide required oxygen in the reaction of alkene with tert-butyl nitrite. Overall, continuous flow synthesis (CFS) provides benefit in three areas mainly, reducing the plant footprint, increasing the selectivity and improving the process safety.[2]

The flow process provided 95% yield in a very short residence time of 1 min corresponding to a space time yield of 13 g/h/mL. In addition, we used tert-butyl nitrite for metal-free stereoselective nitration of alkenes. The reported process had a higher batch cycle time of 12 to 24 h, limiting its application for commercial production. We developed a continuous-flow nitration process using a fixed bed column reactor. In the process, we provided the continuous air purging to ensure adequate supply of oxygen in the reaction. This has helped us to reduce the reaction time from 12 h in batch to 3 min in flow. The optimized nitration process conditions were applied on a series of styrene and acrylate derivatives. The methodology has potential for industrial-scale production of tert-butyl nitrite and its use as a nitrating agent.

References

[1]Patel, N., Chokkalingam, T., Das, S., Saha, S., Jayaraman, K., & Bhutani, H. (2021). Low-Level Quantification of tert-Butyl Nitrite in a Pharmaceutical Intermediate. Organic Process Research & Development, 25(11), 2415–2424. https://doi.org/10.1021/acs.oprd.1c00158

[2]Mittal, A. K., Prakash, G., Pathak, P., Dutta, B., Ahalyan, N., Maiti, S., & Maiti, D. (2023). Continuous Flow Synthesis of tert-Butyl Nitrite and Its Applications as Nitrating Agent. Organic Process Research & Development, 28(5), 1510–1514. https://doi.org/10.1021/acs.oprd.3c00143