Combinatorial chemistry structure elucidation

Mass spectrometry is an indispensable analytical tool in chemistry, biochemistry, pharmacy, and medicine. No student, researcher or practitioner in these disciplines can really get along without a substantial knowledge of mass spectrometry. Mass spectrometry is employed to analyze combinatorial libraries [1,2] sequence biomolecules, [3] and help explore single cells [4,5] or other planets. [6] Structure elucidation of unknowns, environmental and forensic analytics, quality control of drugs, flavors and polymers they all rely to a great extent on mass spectrometry. [7-11]... 

An illustration of CP-MAS is given in Fig. 7.9. The sharp lines that are obtained permit CP-MAS to be used for structure elucidation of organic and inorganic compounds, in much the same way as liquid state spectra are used. As we see in Chapter 10, two-dimensional NMR methods are applicable to solids and form part of the analytical capability of CP-MAS and CRAMPS. One important application is in combinatorial chemistry, where molecules are synthesized on resin beads. It is feasible to obtain good H and 13C spectra from a single bead. 

Most commonly, a commercial library, containing a subset of compounds that matches a desired set of properties (if known), is screened in an initial study. Once hits are obtained and verified, a small library of compounds is synthesized to produce a set of compounds in the same chemical-stmctural space as the original hit stmcture. This process allows for hits with higher potency and elucidates information of the structure-activity relationship within the system of interest. Such synthetic libraries of chemically diverse compounds have been made possible through combinatorial chemistry (52-56) and diversity-oriented synthesis (52). 

Robust automation for structural determinations in combinatorial chemistry [13]. Two-dimensional mass spectrometry [14] could be regarded as the poor cousin of 2D NMR insofar as it has seen little application to real-world problems. This could be a technique that is ripe for exploiting structural elucidation in complex mixtures. 

Detection schemes will also continue to evolve. While NMR is covered in another chapter in this volume, advances in NMR used as an LC detector have also been reported (25-28) that may eventually increase the utility of this tool for combinatorial chemistry. Used in both stopped flow and on line modes, LC/NMR can be extremely useful for structure elucidation provided the proper mobile phases or solvent suppression techniques are used (27). 

In conclusion, parallel synthesis and more generally, combinatorial chemistry, seems to be an attractive approach in aroma research to help identifying new odorants with interesting sensory properties. It allows rapid synthesis of a large number of components in a reasonable time. The reference compoimds can be very usefril for structure elucidation of unknown odorants. 

High-throughput preparative HPLC coupled to electrospray ionization mass spectrometry (Chapter 17), which disposes upon a signal for collecting detected compounds of the defined molecular mass, is one of the highly promising new developments in this area. Such systems can be incorporated for synthesis purposes into the periphery of automated multicomponent systems, thus making a valuable contribution to the rationalization and quality enhancement of combinatorial synthesis processes. The combination of automated synthesis, purification and on-line instrumental identification (NMR, IR, MS) will become feasible in the near future, and as a matter of routine operation. Analytic methods of structure elucidation will then also be able to be combined with automated combinatorial chemistry. 

X-Y Xiao, MP Nova. Radiofrequency encoding and additional techniques for the structure elucidation of synthetic combinatorial libraries. In SR Wilson, AW Czamik, eds. Combinatorial Chemistry Synthesis and Application. New York Wiley, 1997, pp. 135-152. 

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