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Micro-Reaction Technology (MRT) for the Safe Industrial Application of Diazoalkane-Chemistry: New Chances for Process Intensification

Michael Struempel, Bernd Ondruschka, and Annegret Stark. Institute for Technical Chemistry and Environmental Chemistry, Friedrich-Schiller University Jena, Lessingstr. 12, Jena, 07743, Germany

Many very reactive organic compounds are known to be theoretically applicable to the selective derivatization of fine chemicals or pharmaceutical products under mild conditions. However, since most processes in these areas are operated semi-continuously or even with standard laboratory batch equipment, the use of highly toxic, reactive, and therefore often explosive reagents is in most cases not possible from an occupational health and safety point of view.

In general, the key points for the intensification of a process include a) the increase of the concentrations of educts in a (if possible, single) solvent system throughout all process steps, b) minimizing the use of excess chemicals, solvents and auxiliaries to improve the atom efficiency, and c) to work under energy efficient conditions (temperature, pressure) to enhance yield, selectivity and conversion while maintaining short residence times. Regarding the Green Chemistry aspect as part of Process Intensification, other advantages of MRT are that an inherently operational safe process can be achieved at an early R&D stage, thus reducing both investment costs and time-to-market.

The industrial relevance of diazomethane, for example, is severely limited by its hazardous properties (explosiveness, toxicity, carcinogenicity), although it offers a vast chemistry as mild methylating agent, 1,3-dipolar compound and carbene source. Thus, a technology allowing for its save and sustainable use would open new pathways to these technically interesting compounds for the fine chemical and pharmaceutical sector.

This contribution shows that MRT offers a safe way to deliver diazomethane on demand, including the in situ conversion to the desired product to avoid handling and storage of diazomethane solutions. Diazomethane is generated from the precursor Diazald and directly converted with benzoic acid to yield benzoic acid methyl ester, as a model reaction, [1] thus a continuous two-stage micro-reaction process was developed and optimized by varying important parameters in conjunction with comparative batch experiments.

A critical point of this method remaining is the high amount of p-toluenesulfonic acid as side-product of the generation of diazomethane from Diazald® (low atom economy). In our ongoing project, a recycling strategy of this acid to the precursor Diazald® is developed. Due to several steps which involve highly reactive compounds (alkyl amines, chlorinating agents, sodium nitrite), the envisaged complete synthesis is also favorably carried out using MRT.

Acknowledgement: M.S. gratefully thanks the German Federal Environmental Foundation (DBU) for a scholarship.

[1] M. Struempel, B. Ondruschka, R. Daute, A. Stark; Green Chemistry, 2008; DOI: 10.1039/b710554a