Optimization in Solid-Phase Organic Syntheses

Organic reactions carried out on polymer support have generally been assumed to be slower than the corresponding homogeneous solution reactions. The experimental data to test this speculation have not been obtained until recently when single-bead FTIR is used in the study of reaction 

One approach to following reaction kinetics on a solid phase is as follows. A trace amount of resin beads is taken out of a reaction vessel, rinsed briefly with solvent, and subjected to single-bead FTIR analysis or analysis by FTIR with a beam condenser. As an example, the kinetics of the reaction shown in reaction 1 was studied, that is, a combination of Wang resin 1 with succinimidyl 6-(A-(7-nitrobenz-2-oxa-l,3-diazo-4-yl)amino)hex-anoate 2 to produce compound 3. The IR spectra for this transformation are 

Optimal reaction conditions and reaction rates in solid-phase syntheses vary greatly among solid supports. This is due to the chemical/physical environ- 

Several reactions (3, 5, 11-14, and 16) were carried out on these resins under identical conditions to compare reaction rates on polystyrene and polystyrene-PEG resins. The results are collected in Table 7.1. These data show that reactions on polystyrene-PEG resin are not always faster than on polystyrene resins. For example, reaction 16 is much slower on polystyrene-PEG resin than on polystyrene resin. 

Perhaps, unsurprisingly, the effects of polymer matrix on the reaction rate are probably at least as complex as solvent effects in solution-phase reactions, and broad generalizations about the characteristics of any given support in a series of different reactions are inappropriate. Reaction rates on supports depend on solvent swelling, selective adsorption, hydrogen bonding, hydrophobicity, and polarity. No single polymer support is best for all reactions. 

OPTIMIZATION IN SOLID-PHASE ORGANIC SYNTHESES 7.3.1. Reaction Kinetics 

---

OPTIMIZATION IN SOLID-PHASE ORGANIC SYNTHESES 233 TABLE 1. Comparison of Reaction Rates on PS- and TG-Based Resins... 

Analyses of sample sizes of approximately 100 beads are convenient at the reaction optimization stage in solid-phase organic syntheses. As in singlebead analyses, reactions in progress can be followed continually using microscale analysis methods. Several readily available spectroscopic accessories that facilitate such analyses are described below. 

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. 

---