Safe use of Nitromethane for Aldol Reactions in Flow

Using a simple flow reactor, the safe use of nitromethane at elevated reaction temperatures was demonstrated in a nitro aldol reaction of different aldehydes. The reaction products were isolated in good yields after a short reaction time. Introduction Nitromethane has been shown to have extensive energetic properties and been used as a fuel and explosive for many years [1]. Its explosive properties were first reported in 1958 in a rail tanker accident [2], although it was not considered to be a dangerous compound at the time. Although insensitive by itself, upon mixture with oxidants, amines or microbeads detonation can be triggered readily [3]. This obviously poses a risk when nitromethane is being used in chemical synthesis. It has been shown that the presence of as little as 3% of an amine can cause detonation within a confined space. Therefore, nitromethane as a highly energetic compound is utilised in organic synthesis in many ways such as conjugate addition reactions under a limited set of reaction conditions [4]. Scale-up of these reactions remains a challenge particularly at high nitromethane concentrations. Carbon-carbon bond formation is at the core of organic synthesis and has been widely studied for decades. The Henry reaction, or the nitro-aldol reaction, between nitroalkanes and carbonyl compounds to produce nitro alcohols was discovered in 1895. The reaction has been used in many important syntheses to date. Classically the nitroaldol reaction is promoted by the presence of a base in an organic solvent, and conducted at room temperature. The most common bases and solvents used for this reaction are metal hydroxides, carbonates, bicarbonates and alkoxides in water or ethanol. Many reviews have been written within the area of the nitroaldol reaction under batch conditions [5, 6]