Single bead FTIR

Fmoc amino acid Single bead FTIR Fmoc cleavage Compound cleavage... 

In this experiment, cyclopentylacetic acid, 2-norbornaneacetic acid, and 1-adman-taneacetic acid reacted, respectively, with the alcohol resins (1) (Scheme 12.2) of three sizes. These resins have different diameter ranges, namely, 35-75, 160-200, and 500-560 pm. The relative conversion of the starting material to the product was determined by single bead FTIR method. Fig. 12.6 shows IR spectra taken at... 

Fig. 12.6 Single bead FTIR spectra of resins at various times during the reaction between (1) an d (5). Panel A is for reaction carried out on resins with a diameter of 35-75 pm, B is for resins with a diameter of 150-200 pm, and C for resins with a diameter of 500-550 pm.

The bromination reaction (Scheme 12.3) was also carried out on resins (1) of three different sizes (Fig. 12.5). Single bead FTIR study and the kinetics analysis were carried out as in the esterification reaction studies. Rate constants are hsted in Tab. 12.2. The relationship between the rate constants and the bead size is shown in Fig. 12.7b. 

To check the completion of the reaction in Scheme 12.6, the single bead FTIR measurement (Fig. 12.10) alone was not conclusive because there was no IR band from the starting resin (11) to monitor. Resin elemental analysis (Cl) of (11) could conclusively show if the reaction was complete. The accuracy and the reproducibility of the resin elemental analysis methods have been evaluated before [14]. 

Two acylation reactions as depicted in Schemes 12.7 and 12.8 had the same issue when monitored by single bead FTIR (Fig.s 12.11 and 12.12). The starting resins (13) and (15) did not have convenient signal to monitor by FTIR. A chloranil test [15] specific for the secondary amines was used to confirm the complete consumption of (13), therefore the reaction completion. An iron-chloride-pyridine test [16] was used to confirm the complete consumption of (15). In both color tests, a blue color would suggest the presence of the starting material. In both cases we observed the disappearance of the blue color that indicated the reaction completion. 

To check the completion of the reaction depicted in Scheme 12.9, single bead FTIR seemed quite conclusive because the IR band from the starting material (alcohol) has converted to the product carbonate band (Fig. 12.13). The hydroxyl stretch disappeared completely in the FTIR data. However, the possible presence of a trace amount of hydroxyl groups might not be evident in the IR spectrum. The fluorescent dye 9-anthroylnitrile reacted with resin-bound alcohol and it was very sensitive in detecting trace amount of hydroxyl groups [19]. It was used to detect the residual resin-bound alcohol and to confirm the reaction completion. 

The reductive amination reaction (Scheme 12.10) has two steps the formation of imine and the reduction of imine. The single bead FTIR results (Fig. 12.14) show the combined result of both steps. The aldehyde IR bands at 1682 and 2769 cm disappeared in the final product. However, this did not suggest that the... 

Fig. 12.8 Single bead FTIR spectra for resin-bound compounds (7) and (8).

Resins (19) ( 30 mg each) reacted with 5% TFA in DCM. Droplet of suspension was taken at various time intervals for single bead FTIR (Fig. 12.15) and kinetics analysis (Fig. 12.16). The data was also fitted to a first order reaction rate equation and rate constants were determined to be 4.8x10 (5% TFA). Cleavage of carbamides (18), (20), (21), ureas (22-25), amides (26-29), and sulfonamides (30-33) were studied in the same way. 

The reactivity of seven resin-bound thiophenol esters toward n.-butylamine (41) varied depending on their structures. The reaction of aromatic thiophenol esters (resins (34-36) took about 24 h to complete as indicated by the complete disappearance of carbonyl band in single bead FTIR spectra. On the other hand, the same reaction with alkyl thiophenol esters (resins 38-40) went to completion in less than 8 hours. The reaction with benzimidazolecarboxylic thiophenol ester (resin (37) was the fastest, finished in 3 h. 

Fig. 12.18 Single bead FTIR spectra (A) and HPLC/UV chromatograms (B) of resin (40) at various times during the n-butylamine cleavage reaction.

The rate of a chemical reaction depends on temperature. A rule of thumb for many organic reactions in solution is that a 10 °C change in temperature causes a two- to three-fold change in rate of reaction [25]. To study the temperature dependence of solid-phase reactions, the cleavage reaction of resin (35) with n-butyla-mine at 20, 40 and 60 °C were carried out. The cleavage time courses and pseudo-first-order rate fits at these three temperatures are shown in Fig. 12.20. The rate constants from single bead FTIR analysis are Hsted in Tab. 12.4. Compared with the reaction at 20 °C, the solid-phase cleavage reaction of resin 3b was two times faster at 40 °C and four times faster at 60 °C. 

Yan, B. Kumaravel, G. Progression of Organic Reactions on Resin Supports Monitored by Single Bead FTIR Microspectroscopy, Tetrahedron 1996, 52, 843. 

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,4 that is, a combination of Wang resin 1 with succinimidyl 6-(iV-(7-nitrobenz-2-oxa-l,3-diazo-4-yl)amino)hex-anoate 2 to produce compound 3. The IR spectra for this transformation are... 

Figure 7.1. IR spectra of the reaction product at various times during reaction 1 obtained by (a) the single-bead FTIR and (b) the beam condenser FTIR.

Figure 7.2. Time course of reaction 1 followed by integration of the IR band of the product at 1732 cm-1 from single bead FTIR experiments.

Figure 7.11. UV-Visible absorption of 9-anthroylnitrile in the supernatant (A) and single-bead FTIR spectra taken from the resin (B) before and after a 20-min reaction.

Yan, B., Yan, H. Combination of single bead FTIR and chemometrics in combinatorial chemistry Application of the multivariate calibration method in monitoring solid-phase organic synthesis J. Comb. Chem., 2001, 3, 78-84... 

B Yan, JB Fell, G Kumaravel. Progression of organic reactions on resin supports monitored by single bead FTIR microspectroscopy. J Org Chem 61 7467-7472, 1996. 

B Yan, H Gstach. An indazole synthesis on solid support monitored by single bead FTIR microspectroscopy. Tetrahedron Lett 37 8325-8328, 1996. 

De Miguel, Y., Shearer, A.R. and Alison, S. (2001) Infrared spectroscopy in solid-phase synthesis. Biotechnol. Bioeng. 71 119-129. Yan, B., Fell, J. B. and Kumaravel, G (1996) Progression of organic reactions on resin supports monitored by single bead FTIR microscopy. J. Org. Chem. 61 7467-7472. 

THE APPLICATION OF SINGLE-BEAD FTIR AND COLOR TEST FOR REACTION MONITORING AND BUILDING BLOCK VALIDATION IN COMBINATORIAL LIBRARY SYNTHESIS... 

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