Unusual Para-Substituent Effects on the Intramolecular Hydrogen Bond in Hydrazone-Based Switches: Insights from Chemical Landscape Analysis and DFT Calculations

Abstract

Тhe adequacy of chemical property predictions strongly depends on the structure representation, including the proper treatment of the tautomeric and isomeric forms. A combination of an in-house developed open-source tool for automatic generation of tautomers, Ambit-Tautomer, based on H-atom shift rules and standard quantum chemical (DFT) calculations is used for a detailed investigation of the possible geometric isomers, conformers and tautomers of unsubstituted and para-substituted phenylhydrazones, systems with experimentally observed unusual para-substituent effects on the intramolecular hydrogen bond (IMHB) for E-isomers of the compounds. The computational results show that the energetically preferred E-isomers are characterized by stronger IMHBs than the corresponding Z-isomers. The HN–N=C–C=N molecular fragment in the E-configurations is less sensitive to the substitution effect than the HN–N=C–C=O fragment in the isomers with Z-configuration. A probable reason for this decreased sensitivity of E-isomers to phenyl ring substitution is the more efficient conjugation and charge distribution in the HN–N=C–C=N fragment.

Tuning the pH of Activation of Fluorinated Hydrazone-Based Switches─A Pathway to Versatile 19F Magnetic Resonance Imaging Contrast Agents

“…Earlier work by the Aprahamian group indicated that the substitution of the aniline aromatic ring of a hydrazone switch affects the strength of the N–H···N hydrogen bond. , Essentially, its strength was lowered with the electron-donating effect of the substituent, leading to the decreased p K a of hydrazones. However, the extent to which the pH range of isomerization can be shifted by substitution of either a pyridine ring or an aniline ring was unclear.…”