Phase-transfer catalysis excels in a variety of reactions between inorganic nucleophiles and organic substrates. PTC offers several special advantages for azide reactions especially since PTC can usually reduce excess reactants and work at lower temperature and time. Since azide is obviously extremely hazardous, safety risk can be reduced to at least some extent by using less excess azide, working at lower the temperature and performing the reaction at shorter the reaction time.
However, one must still be extremely careful when using azide under PTC conditions! For example, it is usually best to avoid using quaternary ammonium salts that contain a methyl group or ethyl group as one or more of the alkyl chains on the quat since azide can attack those lower alkyl groups on the quat to form methyl azide or ethyl azide which are very explosive.
That is why PTC-azide reactions are often published using tetrabutylammonium as the PTC quat cation since the formation of butyl azide from attack of tetrabutylammonium is slower than attack on a quat such as methyl tributyl ammonium or triethyl benzyl ammonium. In addition, it is thought that if butyl azide is formed, it is less sensitive to explosion than methyl azide or ethyl azide (we have not verified this)
The reaction shown in the diagram uses 500 kg of sodium azide! The inventors report performing this reaction first on more prudent smaller scales (26 g sodium azide) before reporting the larger scale. The inventors reported performing the reaction on the 500 kg azide scale twice, once using toluene and once using xylene as the solvent, and they achieved very similar results in yield and product purity (Examples 3 and 4 in the patent).
We are surprised to read that the inventors performed the reaction at very long reaction times. We assume that very substantial safety testing was performed before attempting the large scale azide reactions, especially at such long reaction times.
In any case, never perform reactions with sodium azide on any scale before first performing a thorough hazardous operations analysis involving qualified highly training safety and industrial hygiene professionals!
