Reactions Applied to Solution Phase Combinatorial Chemistry

3 Reactions Applied to Solution-Phase Combinatorial Chemistry 

As has been mentioned above, there are principally no constraints in terms of reaction conditions in solution-phase combinatorial chemistry. However, the necessity to obtain sufficiently pure products may limit the types of reactions that are suitable for this purpose. These limitations may decrease with the advent of automated purification techniques, particularly those based on chromatography coupled with analytical tools such as mass spectrometry. 

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The use of supported reagents has always been recognized as a powerful tool in classical organic chemistry for a large number of applications, and excellent reviews covered this topic in the past [103-105]. Recently, this technique has been applied to solution-phase combinatorial chemistry, where it looks really promising in terms of simpler work-up procedures, elimination of excess reagents, and isolation of pure reaction products. 

Nevertheless, the achievable purity will remain an important criterion for whether or not a reaction is suitable for solution-phase combinatorial synthesis. The extent to which this criterion can be fulfilled depends on the uniformity of the reaction and on the efficiency with which the products can be purified. Therefore, this chapter will focus on reactions that have been more or less successfully applied to solution-phase combinatorial chemistry (including parallel synthesis), and particularly on the purification techniques that have been used. 

Examples where such reactions have been applied to solution-phase combinatorial chemistry are listed in Table 3.7. 

It has already been mentioned that the scope of reactions that lend themselves to solution-phase combinatorial chemistry is dependent on the possibility of purifying the products. A number of techniques have been used for this purpose, though their significance often depends on the size of the library and on how easily they can be automated. This applies particularly to most chromatographic methods. One of these that can be easily run in parallel fashion is flash chromatography, and this has therefore also been applied in library synthesis (e.g. [47, 111]) even of mixtures (e.g. [6]). Also simply shaking with sorbents (e.g., alumina/silica gel [115]) may be sufficient to purify the products Extraction procedures have been followed widely in solution-phase combinatorial chemistry, and these and some other techniques will now be reviewed briefly. 

An important tool for the fast characterization of intermediates and products in solution-phase synthesis are vibrational spectroscopic techniques such as Fourier transform infrared (FTIR) or Raman spectroscopy. These concepts have also been successfully applied to solid-phase organic chemistry. A single bead often suffices to acquire vibrational spectra that allow for qualitative and quantitative analysis of reaction products,3 reaction kinetics,4 or for decoding combinatorial libraries.5... 

Although the solid-phase technique was first developed for the synthesis of peptide chains and has seen considerable use for this prupose, it has also been used to synthesize chains of polysaccharides and polynucleotides in the latter case, solid-phase synthesis has almost completely replaced synthesis in solution. The technique has been applied less often to reactions in which only two molecules are brought together (nonrepetitive syntheses), but many examples have been reported. Combinatorial chemistry had its beginning with the Merrifield synthesis, particularly when applied to peptide synthesis, and continues as an important part of modem organic chemistry. ... 

Combinatorial synthesis is only feasible if the same reaction conditions can be applied to a broad spectrum of reactants, even if they are structurally diverse and may therefore differ to a larger extent in their reactivity. Moreover, irrespective of whether combinatorial chemistry is done on solid support or in solution, it is desirable to have reactions come to completion with respect to at least one of the components. With solid-phase synthesis this can mostly be achieved by using a large excess of those reactants that are added in solution. Applying such a procedure to solution synthesis is often limited by difficulties encountered in removing the surplus reagent(s). 

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