Phosphonium coupling solvent effect

Figure 2.2 Modern solid phase peptide synthesis. Process begins with a-N terminal Fmoc deprotection of resin bound C-terminal amino acid residue with piperidine (mechanism illustrated). Peptide link formation follows (typical solvent Al-methylpyrrolidone [NMP]) by carboxyl group activation with dicyclohexylcarbodiimide (DCC) (mechanism illustrated) in presence of hydroxybenzotriazole (HOBt). HOBt probably replaces DCC as an activated leaving group helping to reduce a-racemization during peptide link formation. Other effective coupling agents used in place of DCC/HOBt are HBTU 2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate Py-BOP benzotriazole-l-yl-oxy-tns-pyrrolidino-phosphonium hexafluorophosphate. The Process of a-N deprotection, and peptide link formation, continues for as many times as required (n-times), prior to global deprotection and resin removal.

The Lewis basicity or HB A ability of solvents is described by the Kamlet-Taft parameter, measured by means of the couples of solvatochromic probes 4-nitrophenol compared to 4-nitroanisole or 4-nitroaniline compared to 4-nitro-N, N-diethyaniline, the second probe of the couple serving to eliminate the effects of the solvent polarity and polarizability on its first probe. The resulting values of from the compilation of Jessop et al. [410], supplemented with data from Spange etal. [416] are shown inTable 6.16. An alternative measure of this property that has been applied by Schade et al. [413] to RTILs is Catalan s SB parameter, using the solvatochromic probe N.N-dimethyl-4-aminobenzodifuranone, and the resulting values are shown in Table 6.16. The SB values are linear with the values SB = 0.126 +1.056/. The basicity decreases in a series of RTILs with a common anion phosphonium > ammonium > pyrrolidinium > pyridinium > imidazolium, but more moderately than the acidity increases in the opposite direction shown above as shown by Spange et al. [416]. 

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