Macrocyclization Reactions at High Concentration (≥0.2M): The Role of Catalysis

The synthesis of macrocycles is fundamental to obtain useful quantities of this unique family of organic compounds. However, most current syntheses still require highly diluted conditions (generally < 0.1M), which makes the synthesis extremely inefficient in the reactor volume. Here we review, quantify, and analyze the few synthetic methods for macrocycles reported so far where the reaction solution is at ≥ 0.2 M concentration. Parametrization of the results with the Emac (efficiency macrocyclization) index unveils that catalytic methods are much more efficient than non-catalyzed methods. Beyond this conclusion, the present study also shows clear evidence that high-concentration macrocyclization reactions are not only possible but necessary, and suggests the use of catalytic reactions, including solid catalysts and in-flow reactions, to develop macrocyclization reactions under high concentration conditions.