Scale-up of microwave-assisted organic synthesis

In 1986 it was first reported that organic reactions could be conducted by heating in sealed containers in domestic microwave ovens1,2. Rate enhancements of up to three orders of magnitude were disclosed3. However, temperature and pressure measurement were technically difficult to achieve and in some instances the vessels deformed or exploded1-3. 

From these publications, workers interested in exploring the microwave technique perceived it to be simultaneously beneficial through increased rates, yet hazardous in the presence of flammable organic solvents. Subsequently, a vast body of work was carried out with domestic microwave ovens, but under solvent-free conditions and without recourse to sample mixing or temperature measurement. This continued across a broadening front on the laboratory scale. These and other developments in microwave chemistry have been reviewed extensively in journals, book chapters4-20 and in a recent monograph21. 

With conventional heating, energy transfer occurs mainly through conduction and convection. With microwaves, the primary mechanism is dielectric loss4,52. The dielectric loss factor (loss factor, s ) and the dielectric constant ( ) of a material are two determinants of the efficiency of heat transfer to the sample. Their quotient ( / ) is the dissipation factor (tan 8), high values of which indicate ready susceptibility to microwave energy. 

Differences in sample size and composition can also affect heating rates. In the latter case, this particularly applies when ionic conduction becomes possible through the addition or formation of salts. For compounds of low-molecular weight, the dielectric loss contributed by dipole rotation decreases with rising temperature, but that due to ionic conduction increases. Therefore, as an ionic sample is microwave irradiated, the heating results predominantly from dielectric loss by dipole rotation initially, but the contribution from ionic conduction becomes more significant with temperature rise. 

Several workers have claimed that under the influence of microwaves, some reactions proceed faster than under conventional conditions at the same temperature because of various non-thermal microwave effects 48,53-56. Other investigators have rejected the theory of specific activation at a controlled temperature in homogeneous media57-62. A study by Stadler el al,63 on the rate enhancements observed in solid-phase reactions revealed that the significant rate enhancements were a result of direct, rapid in-core heating of the solvent by microwave energy and not a specific non-thermal microwave effect . The existence or otherwise of non-thermal microwave effects continues to be a source of great debate and if proven would have serious potential consequences for scale-up, particularly if such effects were unpredictable. 

---

Komatsu K (2005) The Mechanochemical Solid-State Reaction of Fullerenes. 254 185-206 Kremsner JM, Stadler A, Kappe CO (2006) The Scale-Up of Microwave-Assisted Organic Synthesis. 266 233-278... 

Kniep R, Simon P (2007) Fluorapatite-Gelatine-Nanocomposites Self-Organized Morphogenesis, Real Structure and Relations to Natural Hard Materials. 270 73-125 Koenig BW (2007) Residual Dipolar Couplings Report on the Active Conformation of Rhodopsin-Bound Protein Fragments. 272 187-216 Komatsu K (2005) The Mechanochemical Solid-State Reaction of Fullerenes. 254 185-206 Kremsner JM, Stadler A, Kappe CO (2006) The Scale-Up of Microwave-Assisted Organic Synthesis. 266 233-278... 

---