On-bead analysis

For on-bead analysis vibrational spectroscopy (IR-spectroscopy) can be employed attenuated total reflection is a method allowing fast and nondestructive on-bead analysis of small samples (single bead analysis) without significant sample preparation. Solid phase NMR is the method of choice if complex structural analysis is intended on the support. Spatially resolved analysis on the resin is possible with microscopic techniques. 

Recently, EVOTEC has developed a system for the homogeneous analysis of bead-surface interactions. This system will enable compound screening to take place without the need to remove compounds from the surface of the bead. The system also enables direct recovery of single beads for further analysis. By enabling the rapid, on-bead analysis of thousands of beads, the EVOTEC system eliminates a critical bottleneck, namely the need for deconvolution of solid-phase diversity. 

FT-Infrared Spectroscopy and IR-Microscopy On-Bead Analysis of Solid-Phase Synthesis... 

The following spectroscopic methods can be also applied for on-bead analysis however, they are not suitable for routine high-throughput analysis but more for special research projects. 

Parallel to the synthesis of library compounds on solid supports, the direct analysis (i.e. on-bead ) is an attractive concept. Leaving aside the methods of on-bead-infrared-spec-troscopy [41] using attenuated total reflection (ATR) and gel-phase NMR-techniques [42, 43], we wish to consider the use of on-bead analysis in mass spectrometry. The requirements of the ionization process restrict on-bead analysis to the MALD1 technique. However, also for MALDI-analysis, in so-called direct monitoring studies [44-46], the compounds are cleaved from the bead before the actual ionization. True on-bead analysis under MALDI conditions is only possible with photolytically cleavable linkers, and this technique has been dealt with in several publications [28,29] in which the compounds are both cleaved and ionized simultaneously within the MALDI source with a single laser shot. The wavelength of the MALDI-laser must however correspond with the wavelength required to cleave the compounds from the resin. Therefore, on-bead analysis represents a method for special analytical problems which is limited to MALDI. 

Nevertheless, the primary tool used in solution-phase synthesis for structural elucidation is NMR spectroscopy. There has been some interest in developing NMR methods for analyzing resin-bound compounds and monitoring the progress of chemical reactions on solid-phase by on-bead analysis (without cleavage of the product from the resin). Many improvements have been achieved in NMR for SPS, but hmitations remain. On the one hand, the limited mobility of polymers, as well as the poor mobility of attached compounds, leads to broad bands with low spectral resolution. On the other hand, the broad signals due to the polymer matrix can mask or overlay with bands from the desired product. The main advantage of this technique is its nondestructive nature, as the sample can be easUy recovered. The next section will focus on the most powerful technique developed to monitor and characterize polymer-supported compounds gel-phase HR-MAS NMR spectroscopy. 

There are three different types of infrared spectrometer available dispersive, interferometric, and laser based. The present situation is that FTTR dominates the market. The reasons for this are that the combination of price, performance, and versatility offered by FTIR is unmatched by any competing technology. This trend is likely to continue for at least the next five years and probably the next decade. FTIR is a mature technology and most chemical laboratories have, at least, a simple bench-top unit as a piece of routine analytical equipment. There will be an increasing use of black-box analyzers where the sample is inserted and an answer is produced. The fact that the box is actually an FTIR spectrometer will be largely irrelevant to the user it will be a tool in the same way that a balance or a pFI meter is. This is already happening dedicated instruments for used oil analysis, semiconductor analysis, and on-bead analysis in combinatorial chemistry are commercially available. 

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