Microwave independence

In the Bom-Oppenheimer picture the nuclei move on a potential energy surface (PES) which is a solution to the electronic Schrodinger equation. The PES is independent of the nuclear masses (i.e. it is the same for isotopic molecules), this is not the case when working in the adiabatic approximation since the diagonal correction (and mass polarization) depends on the nuclear masses. Solution of (3.16) for the nuclear wave function leads to energy levels for molecular vibrations (Section 13.1) and rotations, which in turn are the fundamentals for many forms of spectroscopy, such as IR, Raman, microwave etc. 

The fact that microwave conductivity measurements can be performed in a contact-free manner allows us to use them for quality control during the production of photoactive powders or thin layers, or for electrochemical process technology. After the buildup of sufficient knowledge, microwave conductivity measurements themselves, independent of classic electrochemical information, may be used to obtain electrochemical information in cases where conventional techniques are not convenient or accessible. 

Independently, Antane reported that arylisonipecotic acids were obtained from aryl bromides in a two-step process involving microwave-assisted palladium-catalyzed amination with ethyl isonipecotate followed by ester hydrolysis with KOH (Scheme 91) [96]. Interestingly, toluene, which is the standard solvent for Buchwald-Hartwig aminations under conventional heating, was used as the sole reaction medium, although it is a very weak... 

Independently, Caddick et al. reported microwave-assisted amination of aryl chlorides using a palladium-N-heterocyclic carbene complex as the catalyst (Scheme 99) [lOlj. Initial experiments in a domestic microwave oven (reflux conditions) revealed that the solvent is crucial for the reaction. The Pd source also proved very important, since Pd(OAc)2 at high power in DMF gave extensive catalyst decomposition and using it at medium and low power gave no reaction at all. Pd(dba)2/imidazohum salt (1 mol% catalyst loading) in DME with the addition of some DMF was found to be suitable. Oil bath experiments indicated that only thermal effects are governing the amination reactions. 

Another example of a microwave-assisted 1,3-dipolar cycloaddition using azomethine ylides and a dipolarophile was the intramolecular reaction reported for the synthesis of hexahydrochromeno[4,3-fo]pyrrolidine 105 [70]. It was the first example of a solvent-free microwave-assisted intramoleciflar 1,3-dipolar cycloaddition of azomethine ylides, obtained from aromatic aldehyde 102 and IM-substituted glycinate 103 (Scheme 36). The dipole was generated in situ (independently from the presence of a base like TEA) and reacted directly with the dipolarophile present within the same molecifle. The intramolecu-... 

The apphed pretreatment techniques were digestion with a combination of acids in the pressurized or atmospheric mode, programmed dry ashing, microwave digestion and irradiation with thermal neutrons. The analytical methods of final determination, at least four different for each element, covered all modern plasma techniques, various AAS modes, voltammetry, instrumental and radiochemical neutron activation analysis and isotope dilution MS. Each participating laboratory was requested to make a minimum of five independent rephcate determinations of each element on at least two different bottles on different days. Moreover, a series of different steps was undertaken in order to ensure that no substantial systematic errors were left undetected. 

In microwave spectroscopy, the situation is characterized by the fact that the number of independent pieces of observable data is often restricted to three rotational constants, while the number of degrees of freedom—3N-6 or 3N-5, where N is the number of atoms—can be significantly larger. The number of independent experimental rotational constants can be effectively increased by recording the spectra of isotopically substituted species, but that is not always possible. Thus, structural studies by microwave spectroscopy are often seriously underdetermined and extraneous information is useful in aiding the spectroscopic assignment. 

FIGURE 2.2 Resolution may increase with increasing frequency. A two-line EPR absorption spectrum is given at three different microwave frequencies. The line splitting (and also the line position) is caused by an interaction that is linear in the frequency the linewidth is independent of the frequency. This is a theoretical limit of maximal resolution enhancement by frequency increase. In practical cases the enhancement is usually less in some cases there is no enhancement at all. 

Another experiment to recognize interaction is based on its independence of the microwave frequency. If we increase the frequency, then the Zeeman interaction will gain relative importance, and the shape of the spectra should simplify. Experimentally, this may turn out to be a difficult approach due to the rapidly... 

In this chapter, microwave scale-up to volumes > 100 mL in sealed vessels is discussed. An important issue for the process chemist is the potential for direct seal-ability of microwave reactions, allowing rapid translation of previously optimized small-scale conditions to a larger scale. Several authors have reported independently on the feasibility of directly scaling reaction conditions from small-scale singlemode (typically 0.5-5 mL) to larger scale multimode batch microwave reactors (20-500 mL) without reoptimization of the reaction conditions [24, 87, 92-94],... 

Independent investigations by Maes and coworkers have involved the use of commercially available and air-stable 2-(dicydohexylphosphanyl)biphenyl (ligand B) as a ligand system for the successful and rapid coupling of (hetero)aryl chlorides with amines under microwave Buchwald-Hartwig conditions (0.5-2 mol% palladium catalyst) [129, 130]. Both methods provide very high yields of products within an irradiation time of 10 min. 

Scheme 6.186) [347]. The condensation of O-allylic and O-propargylic salicylalde-hydes with a-amino esters was carried out either in the absence of a solvent or - if both components were solids - in a minimal volume of xylene. All reactions performed under microwave conditions rapidly proceeded to completion within a few minutes and typically provided higher yields compared to the corresponding thermal protocols. In the case of intramolecular alkene cycloadditions, mixtures of hexa-hydrochromeno[4,3-b]pyrrole diastereoisomers were obtained, whereas transformations involving alkyne tethers provided chromeno[4,3-b]pyrroles directly after in situ oxidation with elemental sulfur (Scheme 6.186). Independent work by Pospisil and Potacek involved very similar transformations under strictly solvent-free conditions [348]. 

A closely related protocol for the synthesis of imidazoles was independently investigated by Sparks and Combs (Scheme 6.199) [362]. Here, the authors employed readily available unsymmetrical keto-oximes as building blocks, initially leading to N-hydroxyimidazoles. Diaryl keto-oximes were condensed with various aldehydes (1.1 equivalents) in the presence of 4 equivalents of ammonium acetate under microwave conditions at 160 °C. In this way, the N-hydroxyimidazoles were formed... 

Grieco and coworkers have independently described the same type of Pictet-Spengler cyclization reactions involving tryptophan methyl ester and aldehydes, but using methanol as solvent and hydrochloric acid as a catalyst (microwave irradiation, 50 °C, 20-50 min) [416], Moderate to good product yields were obtained. 

Although the ability of microwaves (MW) to heat water and other polar materials has been known for half a century or more, it was not until 1986 that two groups of researchers independently reported the application of MW heating to organic synthesis. Gedye et al. [1] found that several organic reactions in polar solvents could be performed rapidly and conveniently in closed Teflon vessels in a domestic MW oven. These reactions included the hydrolysis of amides and esters to carboxylic acids, esterification of carboxylic acids with alcohols, oxidation of alkyl benzenes to aromatic carboxylic acids and the conversion of alkyl halides to ethers. 

Durable changes of the catalytic properties of supported platinum induced by microwave irradiation have been also recorded [29]. A drastic reduction of the time of activation (from 9 h to 10 min) was observed in the activation of NaY zeolite catalyst by microwave dehydration in comparison with conventional thermal activation [30]. The very efficient activation and regeneration of zeolites by microwave heating can be explained by the direct desorption of water molecules from zeolite by the electromagnetic field this process is independent of the temperature of the solid [31]. Interaction between the adsorbed molecules and the microwave field does not result simply in heating of the system. Desorption is much faster than in the conventional thermal process, because transport of water molecules from the inside of the zeolite pores is much faster than the usual diffusion process. 

In various experiments, it was shown that the use of microwave technology leads to a significant decrease in the reaction time and in some cases also to less by-product and a higher yield. This technology allowed us to optimize the reaction with focus on work-up and purification, independent of reaction temperature and boiling point of the solvent. In most cases the reaction conditions, applied on 15 ml scale in the Emrys Optimizer, were transferred without further optimization to the microwave reactors tested and led to comparable results. Additional optimization in a few cases was limited to small adjustments in reaction temperature or reaction time. A number of scale-up experiments were conducted using a Synthos 3000 reactor and we showed that a scale-up to 100 g is feasible. 

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