Classical heating

A disadvantage of the two-state methods is that modelling of a real potential energy surface (PES) by a TLS cannot always been done. Moreover, this truncated treatment does not cover the high-temperature regime since the truncation scheme does not hold at T> coq. With the assumption that transition is incoherent, similar approximations can be worked out immediately from the nonlocal effective action, as shown in Sethna [1981] and Chakraborty et al. [1988] for T = 0, and in Gillan [1987] for the classical heat bath. 

Scheme 19). The reaction times were brought down from hours (5-7 h) to seconds (40-80 s) with improved yields compared to classical heating [29]. 

In their search for new hgands with a very high binding affinity for the nicotinic acetylchohne receptor (nAChR), potentially useful in positron emission tomography (PET) when radiolabeled with [ F], Horti et al. described the synthesis of BOC-protected 5-(azetidin-2-ylmethoxy)-2-chloro-6 -fluoro-3,3 -bipyridine via a sequential classical heating and microwave irradiation of (2-fluoro-5-pyridinyl)(trimethyl)stannane with f-butyl 2- [(6-chloro-5-... 

Soluble polymers have also been used as support. These exploit the combined advantage of homogeneous with those of soHd-phase chemistry [36]. PEG linked 5-bromothiophene-2-carboxyUc acid was cross-coupled with several arylboronic acids under microwave irradiation (constant power of 75 W) using water as the solvent (Scheme 17). Interestingly, microwave irradiation gave less ester cleavage than classical heating (70 °C). The polymeric support remained stable under both conditions. 

N-Arylpiperazin-2-ones, N-arylpiperazin-2,5-diones and N-aryl-3,4-dihydro-quinolin-2(lff)-ones have been synthesized via a microwave-enhanced Goldberg reaction [105]. N-arylation reactions with 4-benzylpiperazin-2-one and 4-benzylpiperazin-2,5-dione performed in the microwave (reflux conditions) were tremendously accelerated in comparison with the same transformations performed under classical heating at reflux (Schemes 103 and 104). The phenylation of 3,4-dihydroquinolin-2(lH)-one under microwave irradiation was also faster but less pronounced. 

Microwave irradiation at solvent-free conditions induces pyrazoyl 2-azadienes to undergo Diels-Alder reactions with nitroalkenes, within 5-10 min good yields of pyrazolo[ 3,4-b pyridine s are obtained (see Eq. 8.25).39 Without irradiation the reaction produces only traces of products on classical heating. 

The same concept of volumetric in situ heating by microwaves was also exploited by Larhed and coworkers in the context of scaling-up a biochemical process such as the polymerase chain reaction (PCR) [25], In PCR technology, strict control of temperature in the heating cycles is essential in order not to deactivate the enzymes involved. With classical heating of a milliliter-scale sample, the time required for heat transfer through the wall of the reaction tube and to obtain an even temperature in the whole sample is still substantial. In practice, the slow distribution of heat... 

Operating with chemicals and pressurized containers always carries a certain risk, but the safety features and the precise reaction control of the commercially available microwave reactors protect the users from accidents, perhaps more so than with any classical heating source. The use of domestic microwave ovens in conjunction with flammable organic solvents is hazardous and must be strictly avoided as these instruments are not designed to withstand the resulting conditions when performing chemical transformations. 

In addition to cydocondensation reactions of the Paal-Knorr type, cycloaddition processes play a prominent role in the construction of pyrrole rings. Thus, 1,3-dipo-lar cycloadditions of azomethine ylides with alkene dipolarophiles are very important in the preparation of pyrroles. The group of de la Hoz has studied the micro-wave-induced thermal isomerization of imines, derived from a-aminoesters, to azomethine ylides (Scheme 6.185) [346]. In the presence of equimolar amounts of /i-nitrostyrenes, three isomeric pyrrolidines (nitroproline esters) were obtained under solvent-free conditions in 81-86% yield within 10-15 min at 110-120 °C through a [3+2] cycloaddition process. Interestingly, using classical heating in an oil bath (toluene reflux, 24 h), only two of the three isomers were observed. 

In a related study, Turnbull and coworkers described the attachment of carbohydrates to amino-derivatized glass slides. They found a significant rate enhancement when performing this step under microwave irradiation as compared to classical heating [47]. This method should be an efficient aid for the construction of functional carbohydrate array systems. 

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). 

This energy dissipation in the core of materials results in a much more uniform temperature than classical heating. Classical thermal phenomena (conduction, convection, radiation, etc.) only play a secondary role in the a posteriori equilibration of temperature. 

A decrease in the activation energy AG is certainly a major effect. Because of the contribution of enthalpy and entropy to the value of AG (= AH -TAS ), it might be predicted that the magnitude of the -TAS term would increase in a microwave-induced reaction, because organization is greater than with classical heating, as a consequence of dipolar polarization. 

This is essentially true, as is evidenced by the rates of esterification in alcoholic media of propan-l-ol with ethanoic acid [27] or of propan-2-ol with mesitoic acid [28], The absence of a specific microwave effect became apparent from several experiments carefully conducted in alcohols or in DMF under similar conditions but with microwave or classical heating [7]. 

It is apparent there is a definite advantage to operating under solvent-free conditions. The specific microwave effect is here of low magnitude, but evident, because after 3 min the yield increases from 64 to 98%. Prolongation of the reaction time with classical heating led to an equivalent result. The microwave effect is rather limited here, because of a near-synchronous mechanism. 

To illustrate these trends, we now present some typical illustrative examples. These have been selected because strict comparisons of microwave and classical heating activation were made under similar conditions (time, temperature, pressure, etc.. ..) for the same reaction medium and using, preferably, a monomode system equipped with stirring. They mostly involve reactions performed under solvent-free conditions or, occasionally, in a nonpolar solvent, because these conditions are also favorable for observation of microwave effects. 

A nonthermal microwave effect was not observed when identical temperature gradients were produced by classical heating and microwave irradiation and if the reaction temperature was strictly controlled. 

The rate enhancement for the esterification of benzoic acid with methanol was close to 100, when compared with the classical heating under reflux. On the other hand, the rate enhancement for the esterification with n-pentanol, using the same power level (560 W) was only 1.3. The approximate reaction temperature was almost the same for the two alcohols (134 °C and 137 °C respectively). It should be noted, however, that the rate enhancement for the esterification in pentanol increased to 6 times when a higher power level (630 W) was used, the reaction temperature being higher (162 °C). 

Sun et al. [34] reported that the rate of hydrolysis of the biomolecule ATP under MW irradiation was 25 times faster than under classical heating at similar temperatures. However, the same research group [35] later observed that, with more accurate temperature control, the hydrolysis rates were in fact almost identical. 

We have investigated a number of reactions in polar solvents, most of which had been previously reported to occur more rapidly under microwave heating than classical heating in open vessels, to see if there are any significant MW rate enhancements, which could suggest to the involvement of a specific MW effect [19, 20]. 

We have found it convenient to compare MW and conventional reactions using reflux conditions, since the temperatures are constant at the boiling point of the solvent. To eliminate the problem of the time required to reach the reflux temperature, reaction mixtures without one of the reactants or catalyst are heated to reflux and then the other reactant or catalyst quickly added. The reflux times required to give similar yields for a reaction, taken only partially to completion by MW and classical heating, are then compared. Small rate enhancements might still be expected merely because of superheating by up to 40 °C by the MW [39, 40, 46], and localized heating... 

Since there appeared to be strong evidence for a nonthermal effect in this type of reaction, we repeated the reaction of o-phenylenediamine 34 (Scheme 4.13, Rj = R2 = H) with ethyl acetoacetate 35 (R = CH3) [19], which was one of the reactions reported by Soufiaoui [53] to give the diazepine only on MW heating. However, when the same reaction mixtures were heated forlO min with the same temperature profile, almost identical yields of the diazepines were obtained by MW and classical heating. Later, this was also found to be the case in the reaction of 34 with ethyl benzoylacetate 35 (R = Ph). 

A number of other reactions in homogeneous media have been shown to occur at the same rate under MW heating and classical heating at the same temperature. 

A recent study by Goncalo et al. [58] adds support to the hypothesis that observed rate increases of MW heated reactions compared with classical heating are due only to thermal effects. They studied the intramolecular cyclization of 2-hydroxyphenyla-... 

Scheme 4.21 Reactions occurring at the same rate under the action of microwave and classical heating.

In summary, observations of increased rates of MW-assisted homogeneous reactions, compared with classically heated reactions at the same apparent temperature, may be explained by one or more of the following problems or effects ... 

Linders et al. [73] studied the Diels-Alder reaction of 6-demethoxy-/J-dihydrothe-baine with an excess of methyl vinyl ketone (used both as reactant and solvent), which gives a mixture of two isomeric adducts. When the reaction was performed using classical heating extensive polymerization occurred, whereas much less poly-... 

Because this change in selectivity is difficult to explain by a classical heating effect, Langa et al. [9] consider that it is one of the most convincing examples of a possible specific microwave effect. 

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