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By raising the temperature to 80°C for coupling and 90 °C for Fmoc-deprotection, we obtained β-peptide 1 in 89% purity using the multimode microwave reactor, similar to our best results with the monomode reactor (ref 2). The higher temperatures for synthesis in the multimode instrument were surprising, because earlier attempts to increase reaction temperature in the monomode instrument (60 °C set temperature for coupling) led to the formation of a side-product via premature Fmoc-deprotection and addition of a second monomer unit during the double-coupling of the N-terminal ACHC to form β-peptide 3. Although higher temperatures may be beneficial for the difficult reaction steps, we found through subsequent work that the polypropylene filter plates were not stable to these conditions. The discrepancy in optimized temperatures between the two different reactors may be explained by the following factors. In the monomode reactor, the combination of continuous cooling of the sample (Leadbeater, N. E.; Pillsbury, S. J.; Shanahan, E.; Williams, V. A. Tetrahedron 2005, 61, 3565), the experimental set up (ref 2), and the built-in IR temperature sensor, which measures the external temperature of the glass reaction vessel (ref 23), result in an observed temperature that is much lower than the internal temperature of the reaction mixture measured more accurately with the fiber-optic probe of the multimode instrument.
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Reaction vessels were 4.0-mL polypropylene solid-phase extraction tubes; turntable available from CEM.
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This is an average of 95% for each of the 10 reaction steps.
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