Microwave non-thermal effects

Since the early days of microwave synthesis, the observed rate accelerations and sometimes altered product distributions compared to oil-bath experiments have led to speculation on the existence of so-called specific or non-thermal microwave effects. Historically, such effects were claimed when the outcome of a synthesis per-... 

Scheme 2.4 Involvement of non-thermal microwave effects in Diels—Alder cycloaddition reactions.

The same Suzuki couplings could also be performed under microwave-heated open-vessel reflux conditions (110 °C, 10 min) on a ten-fold larger scale, giving nearly identical yields to the closed-vessel runs [33, 35], Importantly, nearly the same yields were obtained when the Suzuki reactions were carried out in a pre-heated oil bath (150 °C) instead of using microwave heating, clearly indicating the absence of any specific or non-thermal microwave effects [34],... 

Most importantly, microwave processing frequently leads to dramatically reduced reaction times, higher yields, and cleaner reaction profiles. In many cases, the observed rate enhancements may be simply a consequence of the high reaction temperatures that can rapidly be obtained using this non-classical heating method, or may result from the involvement of so-called specific or non-thermal microwave effects (see Section 2.5). 

In general, the reasons for rate-enhancements in microwave-assisted transformations in comparison to conventional heating are not always fully understood. Some authors have postulated a specific non-thermal microwave effect for those effects that could not be rationalised as a simple consequence of superheated solvents and higher reaction temperatures. Stadler and Kappe therefore carried out a kinetic comparison of the thermal coupling of benzoic acid to chloro-Wang resin at 80° C, with the microwave-assisted coupling at the identical temperature of 80°C and otherwise identical reaction parameters. However, the reaction rates for the two runs were quite similar and the small observed differences could not be attributed to non-thermal effects. In order to confirm this hypothesis, the authors also carried out coupling experiments with... 

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. 

Although some of the speculation about non-thermal microwave effects appears to emanate from a misconception that microwave radiation can excite rotational transitions, the frequencies at which these occur are much higher than 2.45 GHz. For example, the first absorption lines of OCS, CO, HF and MeF occur at 12.2, 115, 1230 and 51 GHz, respectively. Internal bond rotations (torsional vibrations) also require higher frequencies, in the order of 100-400 cm-1 or 3000-12 000 GHz, for excitation61,62. 

The second group of theories supposes that during microwave irradiation of the reaction mixture there is a specific effect of microwave activation that causes an increase of the reaction rates for which the bulk temperature of the reaction mixture is an inadequate to explain. Such an effect has been accepted to be called the non - thermal microwave effect or the specific microwave effect. Recent critical reviews concerned with both group of theories have been published by Loupy et al. [16], Nuchter et al. [17], and de la Hoz et al. [18], respectively. 

Recently, it has been postulated that the increase of the polarity of the reaction system (i.e., either development or increase of dipole moment) from the ground state (GS) towards the transition state (TS) can result in an acceleration of the reaction due to a stronger interaction of microwaves with the reagents during the course of the reaction. Thus, non-thermal microwave effect can be expected for the reaction with polar mechanisms when the stabilization of the transition state (TS) is more effective than that of the ground state (GS), which results in an enhancement of the reactivity as a result of the decrease in activation energy (Fig. 2.3) [36]. 

Hoz, A.D.L., A. Dfaz-Ortiz and A. Moreno, Microwaves in Organic Synthesis. Thermal and Non-Thermal Microwave Effects, Chemical Society Reviews, 34, 164-178 (2005). 

Microwave-assisted reactions have become well established in contemporary synthetic methodology. Non thermal microwave effects, though, have been shown not to be a factor in the observed rate enhancement with the ring-closing metathesis reaction to form the azepine derivative 2 (88% coversion 20 minutes, 100 °C) from the acyclic diene 1 precursor with the ruthenium catalyst 3 <03JOC9136>. 

Loupy et al. have reported a specific non-thermal microwave effect in the synthesis of 4-atyl substituted 5-alkoxycarbonyl-6-methyl-3,4-dihydropyridones (81-91% under the action of microwaves compared with 17-28% with conventional heating) [188]. 

A. de la Hoz, A. Diaz-Ortiz and A. Moreno, Microwaves in organic synthesis Thermal and non-thermal microwave effects, Chem Soc Rev 34 164-178 2005. 

The action of microwave irradiation on chemical reactions is still under debate, and some research groups have mentioned the existence of so-called non-thermal microwave effects, i.e. inadequate to the observed reaction temperatures sudden acceleration of reaction rates [ 18]. Regardless of the type of activation (thermal) or kind of microwave effects (non-thermal), microwave energy has its own advantages which are stiU waiting to be understood fully and applied to chemical processes. 

In conclusion, Kappe s group demonstrated the absence of any differences between conventional and microwave heating in proline-catalyzed Mannich and aldol reactions as well as no evidence for specific or non-thermal microwave effects. In all cases, in contrast to the previous literature reports, the results obtained with microwave irradiation could be reproduced by conventional heating at the same reaction temperature and time in an oil bath. The differences observed in previous publications could be a result of incorrect temperature measurements [36]. After Kappe s [35] publication several articles appeared in the literature concerning the application of microwaves in asymmetric organocatalysis, mostly in aldol and Michael type reactions operating via enamine as well as iminium catalysis. 

In conclusion, microwave irradiation can be a useful tool for accelerating asymmetric organocatalytic reactions, especially with a higher-temperature tolerance. However, for several reactions presented in this section similar or almost identical results in terms of yield and enantioselectivity were obtained with conventional heating at the same temperature. There are also examples where under microwave conditions an increase in yield and/or enantioselectivity were observed. Unfortunately, because of relatively Uttle exploration of this area, it is still hard to speak about specific or non-thermal microwave effects. Therefore, in-depth mechanistic studies are required. 

---