Solvent-free methods

Applications under solvent-free conditions have been the subject of the greatest activity and have been reviewed extensively7,10 16 17. Besides apparent potential benefits in minimising solvent usage, reactions can be conducted conveniently and rapidly, without temperature measurement in domestic microwave ovens. A dedicated commercial reactor for applications at atmospheric pressure has also been used7. 

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. 

Loupy et al. have argued that if the mixture of neat starting materials is heterogeneous (comprising a solid and a liquid) reaction could occur by dissolution of the solid in the liquid or by adsorption of the liquid onto the solid and in either case a diluting solvent would slow the reaction7. 

Solid-liquid solvent-free phase-transfer catalysis (PTC) is specific for anionic reactions including base-catalysed isomerisation7. Usually, a catalyst (typically a tetraalky-lammonium salt or a cationic complexing agent) is added to an equimolar mixture of an electrophile and a nucleophile, one of which serves as both a reactant and the 

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Two years later, the same research group published an alternative to the solvent-free method, since this method cannot be applied to the synthesis of insoluble thiophene oligomers such as sexithiophene [43]. Obviously, their insolubility prevents separation of the AI2O3 solid support. The effectiveness of PdCl2(dppf)/KF in solution phase was tested in the synthesis of soluble quinquethiophene from diiodoterthiophene and 2-thi-... 

Particular advantages of solvent-free methods are enhancement of reactivity, because of the increased concentration, and specific selectivity, because of the restricted mobility. 

The use of solvent-free methods is particularly interesting because environmentally benign syntheses can be easily designed ... 

Likewise, this process [12] may also be carried out either as a solvent-free (baking) method or in the presence of solvents. Although initially performed as a solvent-free technique, it is the solvent version that currently dominates the field of copper phthalocyanine production from phthalic anhydride and urea. It should be mentioned, however, that this trend has been reversed in the very recent past and that solvent-free methods are gaining interest, especially for ecological reasons. 

Although beyond the scope of this book, a vast amount of work has been directed to supporting homogeneous catalysts on solid supports including silica, alumina and zeolites, and functionalized dendrimers and polymers [19]. These give rise to so-called solid-liquid biphasic catalysis and in cases where the substrate and product are both liquids or gases then co-solvents are not always required. In many ways solvent-free synthesis represents the ideal method but currently solvent-free methods can only be applied to a limited number of reactions [20],... 

Dyeing. Supercritical fluid can be used to provide a water and solvent-free method of textile dyeing. Fluoro-modified dyestuffs have been developed in order to provide improved light-fastness etc. and are readily available. It might be interesting to research die supercritical fluid solubility of these products.23-27... 

Danks reported a microwave-assisted variant of the classical Paal-Knoor pyrrole synthesis (Scheme 3.3)5. This solvent-free method provided a considerable rate advantage (reactions complete within 2 min compared to over 12 h in conventional thermal heating) over classical procedures and even non-nucleophilic amines were condensed smoothly in the absence of Lewis acid promoters. Purification consisted of a simple silica gel filtration. The use of an early-dedicated laboratory instrument in this work is also noteworthy however, information of how the reaction temperature was controlled is not provided. 

A clean, solvent-free method has been developed for the bis-hydroxylation of alkenes by the use of Nafion-based acidic catalysts and 30% H202.655 Nafion NR50 and SAC-13 exhibited high activity in the oxidation of isomeric C alkenes, cyclohexene [Eq. (5.228)], 1,4-cyclohexadiene, and allylic alcohols in the temperature... 

A chloride-free catalyst, Fe(BF4)2-6H20, was used for the reaction of P-oxo ester 24a with MVK (41a) in the ionic liquid [bmim][NTf2] [89]. Product 42a was obtained in about the same yield (95%) as for the solvent-free protocol with Fe(C104)3-9H20 (99% yield) (Scheme 8.27). Both protocols with ionic liquids are, however, operationally less simple than the solvent-free methods reported before, because of the use significant amounts of Et20 for workup and purification of the products. 

Aliphatic aldehydes typically provide only moderate yields in the Biginelli reaction unless special reaction conditions are employed, such as Lewis-acid catalysts or solvent-free methods, or the aldehydes are used in protected form [96]. The C4-unsubstituted DHPM can be prepared in a similar manner employing suitable formaldehyde synthons [96]. Of particular interest are reactions where the aldehyde component is derived from a carbohydrate. In such transformations, DHPMs having a sugar-like moiety in position 4 (C-nucleoside analogues) are obtained (see Section 4.7) [97-106]. Also of interest is the use of masked amino acids as building blocks [107, 108]. In a few cases, bisaldehydes have been used as synthons in Biginelli reactions [89, 109, 110]. 

By a similar but solvent-free method Plaquevent et al. produced the Michael adduct 30 from 2-pentyl-2-cyclopentenone in 91% yield and with 90% ee, by use of the quinine-derived catalyst 31 (Scheme 4.10) [16], When the quinidine-derived ammonium salt 32 was employed, 80% of the enantiomeric product ent-30 was ob-... 

Negrao, M.R. and M.F. Alpendurada. 1998. Solvent-free method for the determination of polynuclear aromatic hydrocarbons in waste water by solid-phase microextraction-high-performance liquid chromatography with photodiode-array detection. J. Chromatogr. A 823 211-218. 

As mentioned above, liquid fluoride salts like EtaN nHF (n = 3-5) and Et4NF-4HF have proved to be highly useful as the electrolytic media and fluoride ion source for selective anodic fluorination. However, this solvent-free method has an atom economy problem because of the use of an excessive amount of liquid salts in place of a solvent. 

Andryushkova O.V., Kirichenko O.A., Ushakov V.A., Poluboyarov V.A. Solvent-free method of the synthesis of substituted barium hexa-alummates, Chem. Sustainable Development 1994 2 451-54. 

Solvent free methods have been used extensively in supramolecular chemistry, coordination chemistry and the formation of transition metal clusters and polymers. Reactions range from very simple ligand substitution reactions for salts of labile metal ions to more complex procedures, some of which are outlined below. 

Figure 2.4 Some ID-coordination polymers formed using solvent free methods Zn(ii)-DABCO (left) and Ag(i)- r(2w -l,4-diaminocyclohexane (right).

Solvent free methods have also impacted on the preparation of other alternative reaction media. Namely, a range of ionic liquids (ILs) was prepared (including imidazolium, pyridinium and phosphonium salts) through halidetrapping anion metathesis reactions (Figure 2.17). The alkyl halide by-product was easily removed by vacuum or distillation and the products were obtained quantitatively in high purity. In addition to being solvent free, this route is more atom economic than the usual route to room temperature ionic liquids (RTILs) as it does not use silver(i), alkali metal or ammonium salts which are normally used in an anion metathesis reaction. 

Organic synthesis without solvents is already a mature field despite this, many chemists still assume that solvents are a necessity for most chemical processes. Therefore, the mindset of chemists needs to change and they must be willing to take up the opportunity that a solvent free method presents. Already, many multi-tonne industrial reactions are performed solvent free, particularly gas phase reactions such as ethylene polymerization. Although solid-solid reactions are yet to be performed on such a large scale, they have been performed on the kilogram scale. Also, solvent free approaches have recently been introduced into the multi-step synthesis of a potential antituberculosis drug,... 

Another advantage of using no solvent (or less solvent), is that reaction times are often shorter, especially when a ball mill or microwave reactor is used. It is likely that solvent free methods will become more widespread as the number of microwave reactors and ball mills in research laboratories increases. For the green chemist, it is also worth noting that significant efforts need to be made in greening the work up of many of the reactions presented here and elsewhere. In most cases, any VOC solvent readily available is used, when a less hazardous or bio-sourced VOC would be a better option. 

Microwave irradiation of a mixture of an acid anhydride, an amine adsorbed on silica gel, and TaCl5/Si02 is a solvent-free method for the synthesis of A-alkyl and A-aryl-imides [47]. Ni(II) promotes the conversion of an acrylamide to ethyl acrylate via a Diels-Alder adduct with (2-pyridyl)anthracene [48], Aromatic carboxylic acids [49] and mandelic acid [50] are efficiently esterified with Fc2(S04)3 XH2O as catalyst. Co(II) perchlorate in MeOH catalyzes the methanolysis of acetyl imidazole and acetyl pyrazole [51]. Hiyama et al. used FeCb as a catalyst for the acylation of a silylated cyanohydrin. The resulting ester was then cyclized to 4-amino-2(5H)-furanones (Sch. 5) [52]. 

The comparison mentioned under 2. will result in knowledge on which method can reliably be used under which conditions. As other methods might be simpler (in terms of man-hours and equipment needed to perform the measurement) compared to the Guideline or produce online results on-site, we have named them shortcut methods . Examples of these methods are a) the solid phase adsorption (SPA) method developed by KTH (7], b) a number of solvent-free tar collection systems used by BTG, BEF, IGT [8-10] and c) the FID online tar analysing method under development at the University of Stuttgart (11,12]. Currently it is unknown under which conditions these methods give reliable results, for example it is unknown whether the SPA method can be used for updraft gasifier tars and at which conditions the solvent-free methods fail to collect ail tars, for instance as a result of aerosol formation. 

This is a solvent-free method of obtaining crystals, which can be used for a material that has a significant vapor pressure at a temperature below its melting or decomposition point. There are... 

Rousset and co-workers [199] prepared Au/Zr02 catalysts simply via the oxidation of a Zro.sAuo.s single-phase alloy in air at 293K. Authors think that this solvent-free method, which requires neither costly post-S3mthetic heat treatments nor the costly set-ups involved in the physical routes of preparation, is a good and alternative route in terms of cost and environment and could be suitable method for the preparation of active gold catalysts on a large scale [199]. 

For reasons of economy and pollution, solvent-free methods are of great interest in order to modernize classical procedures making them more clean, safe and easy to perform. Reactions on solid mineral supports, reactions without any solvent/support or catalyst, and solid-liquid phase transfer catalysis can be thus employed with noticeable increases in reactivity and selectivity. A comprehensive review of these techniques is presented here. These methodologies can moreover be improved to take advantage of microwave activation as a beneficial alternative to conventional heating under safe and efficient conditions with large enhancements in yields and savings in time. 

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