Off-bead methods

Destructive methods, where the analytical sample is consumed by the analysis, and nondestructive methods will be presented and their qualitative or quantitative nature will be discussed. They will be divided into off-bead methods, where the resin-bound reaction product(s) are cleaved from the support with subsequent analysis of the cleavage solution, and on-bead methods, where single or multiple beads are analyzed directly. 

The cleavage of resin-bound materials and their full analytical characterization in solution are used as the most accurate way to monitor the outcome of a reaction carried out in the SP. The methods used are those of classical organic chemistry and will not be commented on further. The reaction products can be weighed and an accurate structure determination can be obtained. There are, however, some limitations to the usefulness of off-bead methods for reaction monitoring in SPS. 

The use of fast, reliable, sensitive on-bead methods circumvents the drawbacks to off-bead analysis outlined above. The modification of common analytical techniques has provided the SP chemist with valuable and often preferred alternatives to off-bead methods for SPS reaction monitoring. 

The cleavage and characterization of intermediates or final compounds, as for off-bead reaction monitoring (Section 1.3.2), are the most reliable methods to quantify the outcome of an SPS. The final target molecule on SP has to be cleaved into solution so that it can be characterized by classical off-bead methods. The synthetic intermediates obtained after each SPS step can also be characterized off-bead when the cleavage conditions do not affect their structure and when the amount of resin beads lost during the characterization process is negligible. 

The loading of resin 60 and the success of each step of its synthesis was determined by an off-bead analysis involving the removal of the reaction products from the resin through an oxidative hydrolysis of the sulfoximine group at the S—N bond with formation of the corresponding sulfones by a method we have described recently [42]. 

Larock.38 The method allows for variation in the aromatic ring component. An interesting feature of this work, probably influenced by the ease of cleavage of the Rink linker, is that all characterization and yield calculations were done off-bead. 

Direct structure determination methods, where positives are characterized directly via off-bead or on-bead identification of their chemical structure, will be described in detail in this section. Indirect methods that determine the structure of positives from the library architecture will be covered later they use either deconvolutive methods (Section 7.3), where the iterative synthesis of library pools with decreasing complexity via sequential determination of the best monomers leads to the identification of a positive structure, or encoding methods (Section 7.4), where, during the library synthesis, the structure of each component is coupled to a tag that can be read from a single bead after the library screening. 

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