Ligand controlled orthogonal selectivity between distal positions of fully unbiased aliphatic amines

02 June 2023, Version 1


Aliphatic C(sp3)‒H bonds are inherently difficult to activate owing to their inertness and chemical indistinguishability. This challenge has been overcome mostly by directing group approach however the regioselectivity in distal aliphatic positions has mostly been substrate dependent, with substrate biasness being a pre-requisite for distal C(sp3)‒H activation; a direct consequence of the Thorpe-Ingold effect. Extending the methodology to fully unbiased straight chain aliphatic substrates, in which all the available positions are sterically and statistically equally probable for functionalization and in which the Thorpe-Ingold effect loses its significance, has been a long-standing problem. To this aim, we developed a ligand enabled orthogonal selectivity between the proximal γ and distal δ positions of such fully unbiased straight chain aliphatic amines in a regioselective fashion. These straight chain alkyl amines, though both δ and γ positions are equally probable for functionalization, can be orthogonally functionalized between these two positions just by changing the ligand, all other reaction parameters remaining constant; signifying the immense importance of ligand in controlling the selectivity between the aforementioned positions of such inert aliphatic C(sp3)‒H bonds. Experimental as well as DFT studies have been carried out to generalize the nature of ligand that would be promoting the orthogonal selectivity between these positons, with electron-rich pyridone ligands favoring selective distal δ functionalization while electron-deficient pyridone ligands tuning the selectivity favorably towards the γ position. This regioselective orthogonal selectivity tuned from γ to δ positions have also been mechanistically established through control reactions, kinetic studies and theoretical calculations.


Supplementary materials

Ligand controlled orthogonal selectivity between distal positions of fully unbiased aliphatic amines
The supporting information file contains the necessary reaction procedures and all related data file of the manuscript.


Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.