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In their Comment (DOI: 10.1021/jacs.2c02965) on two related publications by our groups (J. Am. Chem. Soc.2021, 143, 20884–20890; DOI: 10.1021/jacs.1c09455) and another (J. Am. Chem. Soc.2022, 144, 1380–1388; DOI: 10.1021/jacs.1c11754), Huang and Granick discuss the diffusion NMR measurements of molecules during a copper-catalyzed azide–alkyne cycloaddition (CuAAC) “click” reaction. Here we respond to these comments and maintain that no diffusion enhancement was observed for any species during the reaction. We show that the relaxation agent does not interfere with the CuAAC reaction kinetics nor the diffusion of the molecules involved. Similarly, the gradient pulse length and diffusion time do not affect the diffusion coefficients. Peak overlap was completely removed in our study with the use of hydrazine as the reducing agent. The steady-state assumption does not hold for these diffusion measurements that take several minutes, which is the reason monotonic gradient orders are not suitable. Finally, we discuss the other reactions where similar changes in diffusion have been claimed. Our conclusions are fully supported by the results represented in our original JACS Article and the corresponding Supporting Information.
