Microwave irradiation mechanism

Since the revised Biginelli mechanism was reported in 1997, numerous papers have appeared addressing improvements and variations of this reaction. The improvements include Lewis acid catalysis, protic acid catalysis, non-catalytic conditions, and heterogeneous catalysis. In addition, microwave irradiation (MWI) has been exploited to increase the reaction rates and yields. 

In a less straightforward way, D-glucose (393) underwent a Maillard-type reaction with an excess of glycine (394) under microwave irradiation to afford 5-hydroxy-l,3-dimethyl-2(l/f)-quinoxahnone (395) as a major product, Repetition with labeled reactants suggested that the product contained six carbon atoms from the sugar and four from the amino acid on this evidence, a detailed mechanism has been postulated. 

The overall mechanism of how energy is imparted to a substance under microwave irradiation is complex, consisting of several different aspects. 

Langa et al. [26, 59, 60], while conducting the cycloaddition of N-methylazo-methine ylide with C70 fullerene, proposed a rather similar approach. Theoretical calculations predict an asynchronous mechanism, suggesting that this phenomenon can be explained by considering that, under kinetic control, microwave irradiation will favor the more polar path corresponding to the hardest transition state . 

This reaction is well known but, unfortunately, using classical procedures is only possible under very harsh conditions (temperature 240 °C, sealed containers, long reaction times) and gives modest yields [70] (30%). Its difficulty constitutes a good challenge to check the effectiveness of microwave irradiation, because the mechanism involves a dipolar transition state [71] (Eq. (18) and Tab. 3.8) and this should also favor the involvement of a microwave effect. 

The methylation of secondary amines works better than for primary amines because there is no competition between the formation of mono- or dimethylated products. The best results for the microwave-enhanced conditions were obtained when the molar ratios of substrate/formaldehyde/formic acid were 1 1 1, so that the amount of radioactive waste produced is minimal. The reaction can be carried out in neat form if the substrate is reasonably miscible with formic acid/aldehyde or in DM SO solution if not. Again the reaction is rapid - it is complete within 2 min at 120 W microwave irradiation compared to longer than 4 h under reflux. The reaction mechanism and source of label is ascertained by alternatively labeling the formaldehyde and formic acid with deuterium. The results indicate that formaldehyde contri-... 

Partially hydrogenated quinoline cores are also present in some important bioactive compounds. For example, the 4-aza-analogs of Podophyllotoxin, a plant lignan that inhibits microtubule assembly, revealed to be more potent and less toxic anticancer agents. In 2006, Ji s group reported a green multicomponent approach to a new series of these derivatives, consisting of the reaction of either tetronic acid or 1,3-indanedione with various aldehydes and substituted anilines in water under microwave irradiation conditions (Scheme 26) [107]. For this efficient and eco-friendly transformation, the authors proposed a mechanism quite similar to the one that was postulated for the synthesis of tetrahydroquinolines in the precedent section. 

An example of the use of DMF as CO source in the Pd-catalyzed aminocarbonylation with microwave irradiation is shown in Scheme 28. Thus, n-bromotoluene was reacted with benzylamine (4 equiv.) in the presence of Pd-dppf catalyst, imidazole, KOBu, and DMF (17equiv.) with microwave irradiation for 20min to give amide 196 in 94% yield (Scheme 28). A proposed mechanism (Scheme 28) has a close similarity to that of the aminocarbonylation of aryl bromide with formamide (see Scheme 22). However, in this process, a large excess (4 equiv.) of benzylamine was used to suppress a possible reaction involving dimethylamine generated in situ from DMF under reaction conditions. 

In this chapter, the recent advances in amidocarbonylations, cyclohydrocarbonylations, aminocarbonylations, cascade carbonylative cyclizations, carbonylative ring-expansion reactions, thiocarbonylations, and related reactions are reviewed and the scope and mechanisms of these reactions are discussed. It is clear that these carbonylation reactions play important roles in synthetic organic chemistry as well as organometallic chemistry. Some of the reactions have already been used in industrial processes and many others have high potential to become commercial processes in the future. The use of microwave irradiation and substitutes of carbon monoxide has made carbonylation processes suitable for combinatorial chemistry and laboratory syntheses without using carbon monoxide gas. The use of non-conventional reaction media such as SCCO2 and ionic liquids makes product separation and catalyst recovery/reuse easier. Thus, these processes can be operated in an environmentally friendly manner. Judging from the innovative developments in various carbonylations in the last decade, it is easy to anticipate that newer and creative advances will be made in the next decade in carbonylation reactions and processes. 

Hydro acylation of alkenes was achieved in the presence of Wilkinson s catalyst and microwave irradiation under solvent-free conditions. As an example, benzaldehyde was reacted with dec- 1-ene to give 1-phenylundecan- 1-one in 83%yield within 30 min. Both domestic microwave ovens and single-mode reactors have been used for this reaction. The presence of an amine such as 2-amino-3-picoline or aniline and a carboxylic acid is crucial for the success of the reaction, showing that the formation of an imine plays an important role as an intermediate in the mechanism of this reaction29. 

According to the first group of theories, in spite of the fact that the course of chemical processes under microwave conditions is considerably shorter than under conventional conditions, the kinetics and mechanism of the reactions are still the same. The reduction of the reaction time is the result of sudden and, sometimes, uncontrollable temperature growth of the reaction mixture under microwave irradiation, which in turn leads to the increase of reaction rates following common kinetic laws. 

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