The Question of Solvents Alternative Reaction Media

Sustainable development and Green Chemistry have now become a strategic industrial and societal focus [24—27], the former is our ultimate goal and the latter is a means to achieve it. 

Another important issue in green chemistry is the use of organic solvents. The use of many traditional organic solvents, such as chlorinated hydrocarbons, has been severely curtailed. Indeed, so many of the solvents that are favored by organic chemists have been blackhsted that the whole question of solvent use requires rethinking and has become a primary focus, especially in the manufacture of pharmaceuticals [29, 30]. In our original studies of E factors of various processes. 

85% of die total mass of chemicals involved in pharmaceutical manufacture comprises solvents. Consequently, pharmaceutical companies are focusing their effort on minimizing solvent use and in replacement of many traditional organic solvents, such as chlorinated and aromatic hydrocarbons, by more environmentally friendly alternatives. 

These issues surrounding a wide range of volatile and nonvolatile, polar aprotic solvents have shmulated the fine chemicals and pharmaceutical industries to seek 

There is a definite need, therefore, for systems that combine the advantages of high activity and selectivity of homogeneous catalysts with the facile recovery and recycling characteristic of their heterogeneous counterparts. This can be achieved by employing a different type of heterogeneous system, namely liquid-liquid biphasic catalysis, whereby the catalyst is dissolved in one liquid phase and the reactants and product(s) are in a second liquid phase. The catalyst is recovered and recycled by simple phase separation. Preferably, the catalyst solution remains in the reactor and is reused with a fresh batch of reactants without further treatment or, ideally, it is adapted to continuous operation. 

The best solvent is no solvent and if a solvent (diluent) is needed then water is preferred [100]. Water is non-toxic, non-inflammable, abundantly available and inexpensive. Moreover, owing to its highly polar character one can expect novel reactivities and selectivities for organometallic catalysis in water. Furthermore, this provides an opportunity to overcome a serious shortcoming of homogeneous catalysts, namely the cumbersome recovery and recycling of the catalyst. Thus, performing the reaction in an aqueous biphasic system, whereby the 

An example of a large scale application of this concept is the Ruhrchemie/ Rhone Poulenc process for the hydroformylation of propylene to n-butanal, which employs a water-soluble rhodium(I) complex of trisulfonated triphenyl-phosphine (tppts) as the catalyst [103]. The same complex also functions as the catalyst in the Rhone Poulenc process for the manufacture of the vitamin A intermediate, geranylacetone, via reaction of myrcene with methyl acetoacetate in an aqueous biphasic system (Fig. 1.35) [104]. 

Similarly, Pd/tppts was used by Hoechst [105] as the catalyst in the synthesis of phenylacetic acid by biphasic carbonylation of benzyl chloride (Fig. 1.36) as an alternative to the classical synthesis via reaction with sodium cyanide. Although the new process still produces one equivalent of sodium chloride, this is substantially less salt generation than in the original process. Moreover, sodium cyanide is about seven times more expensive per kg than carbon monoxide. 

The salt production can be circumvented by performing the selective Pd/ tppts-catalysed carbonylation of benzyl alcohol in an acidic aqueous biphasic system (Fig. 1.36) [106]. This methodology was also applied to the synthesis of ibuprofen (see earlier) by biphasic carbonylation of l-(4-isobutylphenyl)ethanol [107] and to the biphasic hydrocarboxylation of olefins [108]. 

As mentioned earlier (Section 1.5) another example of novel catalysis in an aqueous medium is the use of lanthanide triflates as water-tolerant Lewis acid catalysts for a variety of organic transformations in water [39]. 

---

Many of the traditional solvents that are favoured by organic chemists have been blacklisted by international regulations, for instance chlorinated hydrocarbon solvents have been severely curtailed. Thus, the question of the solvent requires a major rethink in terms of green chemistry issues this need is driving the search for alternative reaction media. Such media are the basis of many of the cleaner chemical technologies that have reached commercial development. Typical non-conventional reaction media are supercritical carbon dioxide (31.1 °C, 73 atm)22 and supercritical water (374 °C, 218 atm), water under PjT standard conditions, " room-temperature ionic liquids,up to and including solvent-free conditions. ... 

Sipping a cup of decaffeinated coffee the reader may wonder on the somewhat unusual classification of solvents as alternative alternatives to what And why would we need alternative media for doing chemistry or for any other purpose These may be the first questions for those who are just starting to discover the existing new developments on using solvents other than volatile and often toxic organics for synthesis and especially for catalytic reactions. Yes, indeed,... [1. ... 

There has been a review commentary of substitutions in non-polar media addressing the question, are weak interactions responsible for kinetic catalytic behaviour in 5 NAr reactions A kinetic study of the reactions of picryl fluoride with alcohols in carbon tetrachloride shows that the order in alcohol is greater than unity. This is interpreted as evidence for specific interaction between the substrate and alcohol prior to rate-limiting reaction with a further alcohol molecule. Self-association of amine molecules to form dimers which act as the effective nucleophile is an alternative explanation for the high kinetic orders observed in non-polar solvents. Results for the reaction of l-chloro-2,4-dinitrobenzene with aromatic amines in toluene - " and in benzene-hexane mixtures have been interpreted on this basis. Rate constants have been measured for reactions of l-halo-2,4-dinitrobenzenes with primary and secondary amines in a variety of aprotic binary solvent systems and correlations have been attempted with solvatochromic data, including t(30) values. ... 

---