An alkali-free synthesis strategy for high-yield unsymmetrical indocyanine dyes

Abstract

Unsymmetrical indocyanine dyes have extremely important applications in the field of biological detection. To address the key challenges of low yield and purity during the synthesis of these compounds, a new method via a two-step process is proposed for the synthesis of a series of the unsymmetrical indocyanine dyes. In the first step, an indole with a quaternary ammonium structure is reacted with a condensing agent in acetic anhydride to synthesize the hemicyanine intermediate. In the second step, an indole with an enamine structure is reacted with the hemicyanine intermediate to synthesize the unsymmetrical indocyanine dye with no additional base catalyst. This effectively inhibits the reverse reaction of the hemicyanine intermediates to indole with a quaternary ammonium structure in basic conditions, thereby suppressing the formation of indocyanine byproducts that are difficult to separate. As a result, the yields of the unsymmetrical indocyanine dyes have been greatly improved. The higher nucleophilicity of indole containing an enamine structure than indole with a quaternary ammonium structure has been reasonable explained by DFT calculations of Frontier Molecular Orbitals and electrostatic surface potentials. This study provided a new strategy for synthesizing high-yield unsymmetrical indocyanine dyes.