Proximity vs. strain in intramolecular ring-closing reactions

Abstract

The DFT and ab initio calculation results for ring-closing reactions of eight different ω-bromoalkanecarboxylate anions (1–8) reveal that the activation energy (ΔG ^‡) for the intramolecular cyclization process is strongly correlated with both (i) the experimental intramolecular cyclization rate (log k _intra) and (ii) the distance between the two reactive centres, whereas the slope values of the change in enthalpy (ΔH) vs. the attack angle (α) and the distance between the two reacting centres (r) were found to correlate strongly with the experimental strain energy of the cycle being formed (E _{s Exp}). These results assist in designing pro-prodrug systems that can be utilized to improve the overall biopharmaceutical profile of current medications in order to enhance their effectiveness and ease their utility.

Keywords:

• ab initio
• electronic structure
• quantum chemistry
• computational chemistry

Acknowledgements

The Karaman Co. and the German–Palestinian–Israeli funding agency are thanked for supporting our computational facilities. Special thanks are also given to Donia Karaman, Rowan Karaman and Nardene Karaman for technical assistance.

Notes

Note

Supplementary material can be viewed online.