The use of N,N′-diisopropylcarbamimidate (1) to prepare a tert-butyl ester of a carboxylic acid was required for the synthesis of a key pharmaceutical intermediate. Commercial sources were not adequate to supply this reagent in the quantity and quality required for our campaigns. While developing a process to prepare this compound, we discovered that an aerobic coppercatalyzed reaction between tert-butyl alcohol and N,N′-diisopropylcarbodiimide (DIC) afforded superior reaction rates and conversion compared with the reported conditions under inert atmospheres. Screening and mechanistic studies concluded that Cu I Cl is oxidized in situ by O 2 in the atmosphere to a generate a more active Cu II (OH)Cl species. Screening studies designed to uncover key catalyst attributes concluded that both chloride and DIC act as ligands on the metal center. The consumption of O 2 over the course of the reaction resulted in the low-level production of impurities (notably N,N′-diisopropylurea, which is the stoichiometric byproduct in the ensuing reaction that utilizes 1), but sufficient reaction rates and conversion of DIC were not attainable in the absence of O 2 . The production of 1 was safely executed using commercially available atmospheres of 4−5% O 2 /95− 96% N 2 while still meeting our high-quality product needs. The benefit of aerobic copper catalysis was found to also be useful with less hindered alcohols to form the analogous isoureas.

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The conditional binding constants for a bis-guanidinium-like receptor and a series of dicarboxylate ligands have been determined in two buffer/solvent systems, namely 25 mM ammonium acetate/1% acetic acid in acetonitrile/methanol (7:3 v:v) and 30 mM N-methyl morpholine/15 mM methanesulfonic acid in acetonitrile/methanol (9:1 v:v). The latter buffer has not been applied before in capillary electrophoresis. The binding constants in both solvent systems decrease as the dicarboxylate length increases. The binding constants are larger in the less competitive N-methyl morpholine buffer. The dicarboxylates associate only weakly with a dicationic analog of the receptor, p-xylyl trimethylammonium, which is not a hydrogen bond donor.

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