Solvent-free elimination

The use of sodium hydrogen carbonate under solvent-free conditions and microwave irradiation is best method for N-alkylating pyrazoles. The yields are good and the method is devoid of side reactions like quatemization, isomerization and hydrogen halide elimination. Solvent-free conditions are the only ones that allow the preparation of 1-substituted pyrazoles from secondary halides (Almena et al., 2009). 

Fig. 8. Pseudo-binary (solvent-free)jy-x phase diagrams for determining which component is to be the distillate where (—) is the 45° line, (a) No solvent (b) and (c) sufficient solvent to eliminate the pseudo-a2eotiope where the distillate is component 1 and component 2, respectively (51) and (d) experimental VLE data for cyclohexane—ben2ene where A, B, C, and D represent 0, 30, 50, and 90 mol % aniline, respectively (52).

It may even be possible to eliminate solids handling by processing in a solution. However, this may require an assessment of the hazards of a toxic or flammable solvent in a process compared to the hazards of the solvent-free process. 

Whilst total elimination of volatile organic solvents from all chemical manufacturing processes is a worthy goal, the pursuit of this goal must be subject to some caution. Alternative organic solvent-free processes may have poor heat and/or mass transfer and/or viscosity limitations, which could result in excessive energy use or the production of less pure... 

Solid-phase microextraction eliminates many of the drawbacks of other sample preparation techniques, such as headspace, purge and trap, LLE, SPE, or simultaneous distillation/extraction techniques, including excessive preparation time or extravagant use of high-purity organic solvents. SPME ranks amongst other solvent-free sample preparation methods, notably SBSE (Section 3.5.3) and PT (Section 4.2.2) which essentially operate at room temperature, and DHS (Section 4.2.2),... 

Frejd and co-workers utilized a different tactic for aniline cyclization by first employing a Heck-Jeffery protocol under solvent-free conditions to prepare o-amino dehydrophenylalanine derivatives from o-aminoaryl iodides with the former undergoing a spontaneous la cyclization-elimination sequence to afford 2-methoxycarbonyl indoles <06S1183>. Dimethyl(methylthio)sulfonium trifluoromethanesulfonate (DMTST) was used by the Okuma group to promote the cyclization of o-vinyl-A-p-toluenesulfonylanilide to N-tosylindole <06CL1122>. 

This approach may find application in peptide bond formation that would eliminate the use of irritating and corrosive chemicals such as trifluoroacetic acid and piperidine as has been demonstrated recently for the deprotection of N-boc groups (Scheme 6.7) a solvent-free deprotection of N-tert-butoxycarbonyl group occurs upon exposure to microwave irradiation in the presence of neutral alumina doped with aluminum chloride (Scheme 6.7) [41]. 

There are distinct advantages of these solvent-free procedures in instances where catalytic amounts of reagents or supported agents are used since they provide reduction or elimination of solvents, thus preventing pollution at source . Although not delineated completely, the reaction rate enhancements achieved in these methods may be ascribable to nonthermal effects. The rationalization of microwave effects and mechanistic considerations are discussed in detail elsewhere in this book [25, 193]. A dramatic increase in the number of publications [23c], patents [194—203], a growing interest from pharmaceutical industry, with special emphasis on combinatorial chemistry, and development of newer microwave systems bodes well for micro-wave-enhanced chemical syntheses. 

Although the initial reason for the development of solvent-free conditions for micro-wave irradiation was safety, it soon became apparent that use of these conditions had many other benefits - simplicity, efficiency, easy work-up, very often higher yields, and enhanced reaction rates. The absence of solvent is, furthermore, time- and moneysaving and often enables elimination of waste treatment. 

Ketene acetals and dithioacetals have been prepared in a solvent-free procedure by base catalyzed / -elimination under PTC conditions. The yields obtained by use of irradiation are much higher than those obtained by use of ultrasound or conventional heating under the same conditions [82] (Scheme 8.58). 

Eliminations belong to one of the most diverse reaction types [76] and numerous solvent-free pyrolyses (sometimes quantitative melt reactions) provided useful syntheses [58,81-87]. However, quantitative solid-state eliminations are rare (examples are found in the halogenations of 110,112, and 114 (Scheme 12)). If an elimination reaction cannot be performed purely thermally or photo-chemically, usually a catalyst or other auxiliary has to be added and it is then no longer waste-free. 

As indicated in Table 3, reducing the excess methanol to only a 3 fold molar excess (rendering a nearly solvent free process) far exceeded expectations and allowed significant reductions in the catalyst levels. Under these conditions, catalyst turnover numbers exceeding 10,000 mol MPA/mol Pd were achieved with a turnover frequency of >3400 mol MPA/mol Pd/h. The reaction mixtures obtained from this process formed two liquid phases and the product spontaneously separated from the amine and amine hydrochloride. As a consequence of eliminating large methanol excesses, the methyl pivaloylacetate concentration in the product was raised to 26 wt. % without additional reaction time being required. This represents an additional ca. 2.5 fold improvement in reactor productivity. No attempt was made to reduce the methanol further. 

Clearly, the most effective way to avoid problems with solvent contamination of the environment is to eliminate the use of the solvent entirely. Even though this clearly is not possible for most applications, there are some innovative solvent-free cleaning processes that deserve mention. 

The simplest solvent-free method involves irradiation of neat reactants in an open container. In the absence of reagents or supports, the scope for such processes appears to be limited to relatively straightforward condensations that can be conducted without added catalysts, or to intramolecular thermolytic processes such as rearrangement or elimination. 

T pe of reaction elimination Reaction condition solvent-free... 

Solvent-Free Elimination under Microwave Irradiation... 

The elimination of volatile organic solvents in organic syntheses is a most important goal in green chemistry. Solvent-free organic reactions make syntheses simpler, save energy, and prevent solvent wastes, hazards, and toxicity. 

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