Real-time monitoring of solid-phase reactions

Yan B, Kumaravel HA, Wu A, Petter RC, Jewell C, Wareing J, Infrared spectrum of a single resin bead for real time monitoring of solid phase reactions, J. Org. Chem., 60 5736-5738, 1995. 

Micro-IR spectra were used for real-time monitoring of solid phase reactions (12,15,16) and, utilizing deuterium isotope containing protecting groups, for quantitative infrared analysis of solid phase, resin-bound chemical reactions (13). 

The use of deuterated reactants permits the real-time monitoring of solid-phase reactions via IR-microscopy. A few resin beads were trapped in a flow-through cell which can be charged with solvents and reagents using an HPLC pump. These beads were analyzed during the amidation of amino methyl polystyrene resin with deuterated benzoic acid, demonstrating that the reaction was complete after 12.7 min [36,37]. 

Yanl995 Yan, B., Kumaravel, G., Anjaria, H., Wu, A., Petter, R.C., Jewell, C.F., Jr. and Wareing, J.R., Infrared Spectrum of a Single Resin Bead for Real-Time Monitoring of Solid-Phase Reactions, J. Org. Chem., 60 (1995) 5736-5738. 

The monitoring of solid-phase synthesis in a real time quantitative manner has always been a goal since invention of the process. Many qualitative color tests exist, principal amongst these being the ninhydrin-based Kaiser test.f 1 The Kaiser test is less sensitive when the N-terminal is a secondary amine and for this reason many other tests have been applied.t °l Although a quantitative Kaiser test has been proposed,t l it has never achieved prominence as a routinely applicable method and the results are not usually available in time to influence progress of the reaction. 

S. Manabe and Y. Ito, On-resin real-time reaction monitoring of solid-phase oligosaccharide synthesis, J. Am. Chem. Soc., 124 (2002) 12638-12639. 

FT-IR microspectroscopy is a new nondestructive, fast and rehable technique for solid-phase reaction monitoring. It is the most powerful of the currently available IR methods as it usually requires only a single bead for analysis, thus it is referred to as single bead FT-IR [166]. (See also Chapter 12 for further details). The high sensitivity of the FT-IR microscope is achieved thanks to the use of an expensive liquid nitrogen-cooled mercury cadmium telluride (MCT) detector. Despite the high cost of the instrument, this technique should become more widely used in the future as it represents the most convenient real-time reaction monitoring tool in SPOS [166, 167]. 

These precedent syntheses have shown that is possible to circumvent one of the main drawbacks usually attributed to the solid-phase mode, which is the lack of control of the reactions taking place on the support. Thus, the / situ monitoring of all reactions in real time, using FT-IR (KBr pellets), x gel-phase NMR and C MAS-NMR, made possible a Ml and an accurate control of the progress in these syntheses <04QSAR6l>. 

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