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Solid-Phase Organic Synthesis. Edited by Kevin Burgess Copyright © 2000 John Wiley & Sons, Inc. ISBNs: 0-471-31825-6 (Hardback); 0-471-22824-9 (Electronic)
VIBRATIONAL SPECTROSCOPY FOR OPTIMIZATION OF SOLID-PHASE ORGANIC SYNTHESES
Novartis Pharmaceuticals Corporation
This chapter describes how Fourier transform infrared (FTIR) spectroscopy can be used to monitor solid-phase organic reactions directly on solid supports. Examples encompassing a range of reaction conditions are discussed to demonstrate the value of this method for optimization of solid-phase organic syntheses.
220 VIBRATIONAL SPECTROSCOPY
7.1.1. Optimization of Solid-Phase Organic Synthesis
Solid-phase organic syntheses' typically use large excesses of reagents to drive reactions to completion so that, ideally, products liberated from resins should not require purification. Optimization of conditions is a critical part of solid-phase syntheses. Transfer of organic reactions in solution to a solid matrix is not a trivial undertaking, and lack of analytical methods accentuates this problem. Libraries prepared without adequate refinement of conditions tend to be of poor quality. For libraries so large that all the constituents cannot be fully characterized, well-optimized reaction conditions are absolutely essential. Techniques like “split and pool,”2 for instance, can only be applied successfully after thorough optimization.
7.1.2. Monitoring Solid-Phase Organic Synthesis by FTIR Spectroscopy
Organic reactions selected to synthesize a combinatorial library should be reproducible and well behaved; hence the resin-bound products are rarely unknowns. Consequently, the major analytical task in solid-phase organic synthesis is to confirm the presence of the desired products rather than a full structural elucidation. For several reasons, FTIR spectroscopy is particularly suited for this task. First, functional group interconversions are easily monitored by IR spectroscopy. The functional group monitored need not be directly involved in the reaction; the building blocks used in reaction optimization can be selected to contain an IR detectable group at a remote site. Second, direct observation of compounds on a solid phase is generally quicker and more convenient than methods based on cleavage and then analysis of intermediates. Third, some synthetic intermediates are unstable to the necessary cleavage conditions. Conversely, on-support analytical methods indicate the success of the reaction prior to the cleavage step; this is the most relevant information. Finally, FTIR spectroscopy is a sensitive technique that requires only small amounts of sample. Moreover, it can be performed without destruction of even the small amount of material that is required.
7.1.3. Typical Characteristics of Solid Supports
Typical solid supports used in organic syntheses are resin beads formed from cross-linked polystyrene (PS; 40-150 Llm diameter), polystyrene-
7.2. SPECTROSCOPIC METHODS APPLICABLE TO DIFFERENT SAMPLE SIZES 221
polyethyleneglycol (PS-PEG) polymer grafts, or surface-functionalized polypropylenes such as in the multipin method (see Chapter 6).
Low cross-linked polystyrene resins (1% divinylbenzene) is probably the most popular solid support. These resins swell to 2-6 times their original volume depending on the solvent used. Swollen resin, after removal of solvent and without excessive drying, remains in a rubbery state and can be easily flattened for FTIR study in the transmission mode. The support-bound compound should be washed free of reagent and solvent.
7.2. SPECTROSCOPIC METHODS APPLICABLE TO DIFFERENT SAMPLE SIZES
Ten milligrams of resin contains approximately 50,000-70,000 beads (~50 |im diameter). Sample sizes used in analyses via vibrational spectroscopy range from single beads to 10-mg aliquots.
7.2.1. Single-Bead Analyses
FTIR Microspectroscopy.3 A microscope accessory coupled to a liquid-nitrogen-cooled mercury-cadmium-telluride (MCT) detector can be used to obtain an IR spectrum. This is possible in both the transmission and reflectance modes. Several beads are spread on an IR-transparent window (NaCl, KBr, diamond) and possibly flattened via a hand-press or a compression cell. The IR beam is focused on a single bead using the view mode of the microscope. The blank area surrounding the bead is isolated using an adjustable aperture, and a spectrum is recorded using 32 scans (<1 min). A nearby blank area of the same size on the IR transparent window is recorded as the background.
Single-Bead FT Raman Spectroscopy.4 Microscope accessories are also available that facilitate collection of FT Raman spectra on single-bead samples. Fourier transform FT Raman spectroscopy is a technique based on inelastic light scattering, in which scattered photons exchange energy with the sample. Most commonly, the scattered photon loses energy to a vibrational mode of the sample molecule, leading to a downward frequency shift. This Raman shift is equal in energy to the light absorbed by the same