Safe Generation and Synthetic Utilization of Hydrazoic Acid in a Continuous Flow Reactor

Abstract

Hydrazoic acid (HN 3 ) was used in a safe and reliable way for the synthesis of 5-substitued-1H-tetrazoles and for the preparation of N-(2-azidoethyl)acylamides in a continuous flow format. Hydrazoic acid was generated in situ either from an aqueous feed of sodium azide upon mixing with acetic acid, or from neat trimethylsilyl azide upon mixing with methanol. For both processes, subsequent reaction of the in situ generated hydrazoic acid with either organic nitriles (tetrazole formation) or 2-oxazolines (ring opening to b-azido-carboxamides) was performed in a coil reactor in an elevated temperature/pressure regime. Despite the explosive properties of HN 3 , the reactions could be performed safely at very high temperatures to yield the desired products in short reaction times and in excellent product yields. The scalability of both protocols was demonstrated for selected examples. Employing a commercially available benchtop flow reactor, productivities of 18.9 g/h of 5-phenyltetrazole and 23.0 g/h of N-(1-azido-2-methylpropan-2-yl)acetamide were achieved.

In Situ Generation of Diimide from Hydrazine and Oxygen: Continuous‐Flow Transfer Hydrogenation of Olefins

“…The continuous‐flow setup (Figure 1) consists of a pump (P), a mass‐flow controller (MFC), a glass static mixer (GSM) to generate segments of the liquid phase and O 2 , a residence time unit (RT) made of perfluoroalkoxy copolymer (PFA), a heat exchanger (HE), and a static (BPR1) as well as an adjustable back pressure regulator (BPR2) 14. Preliminary experiments using ethanol as the solvent revealed that at a backpressure of 20 bar, a liquid flow rate of 0.4 mL min −1 , and a gaseous stream of 2 mL min −1 are necessary to maintain both a suitable segment pattern and a proper residence time (10 min).…”

In Situ Generated Iron Oxide Nanocrystals as Efficient and Selective Catalysts for the Reduction of Nitroarenes using a Continuous Flow Method

“…Removal of the agglomerated Fe 3 O 4 particles with a magnet ( Figure S1) recovered approximately 95 % of the total Fe from the sample, according to ICP-MS measurements. stainless-steel coil preheated to 150 8C (Uniqsis FlowSyn reactor, Figure S7), [21] the crude reaction mixture collected at the output line after a residence time of approximately 1.8 min revealed full conversion to aniline (GC-MS). However, a significant disadvantage is the exothermicity of the hydrazine-based reduction, limiting the possibility for a safe scaleup in batch format (see Figure S6).…”

“…When an approximately 1m solution of nitrobenzene in methanol, containing 0.25 mol % Fe(acac) 3 precursor and hydrazine hydrate (20 % molar excess) was pumped at 4.0 mL min À1 through a 20 mL (1.0 mm i.d.) stainless-steel coil preheated to 150 8C (Uniqsis FlowSyn reactor, Figure S7), [21] the crude reaction mixture collected at the output line after a residence time of approximately 1.8 min revealed full conversion to aniline (GC-MS). Notably, in the absence of the Fe(acac) 3 precursor, an extremely poor conversion (2-3 %) was achieved, ruling out any catalytic activity of the stainless steel coil itself.…”

Managing Hazardous Reactions and Compounds in Process Chemistry

“…The cycloaddition of an azide to a nitrile provides a useful entry to tetrazoles (Scheme 27) when performed in flow (101,102). The reaction can be performed at high temperatures in the flow system in a much safer manner than in batch-mode (103).…”