Tuning Antiaromaticity Through <i>Meso</i> ‐Substituent Orientation in Core‐Modified Isophlorins

Abstract Antiaromaticity is an essential principle in organic chemistry that significantly influences the properties of cyclic π‐conjugated systems. This study systematically investigated the effects of meso ‐substituents on the antiaromaticity of dithiadioxaisophlorins (S 2 O 2 Iphs), which are stable isophlorin derivatives with strong antiaromatic characteristics. We synthesized two new S 2 O 2 Iphs derivatives with 3,5‐bis(trifluoromethyl)phenyl and 5‐cyanothien‐2‐yl substituents along with a previously reported pentafluorophenyl‐substituted analog. Notably, a derivative with sterically demanding 2,6‐dichlorophenyl substituents could not be isolated despite being detected by mass spectrometry, highlighting the delicate balance between electronic stabilization, and steric effects. Through comprehensive analysis using ¹H NMR spectroscopy, UV/vis absorption spectroscopy, and multiple computational approaches (NICS, GIMIC, HOMA/HOMAc, and AV1245/AV min ), we demonstrate that the steric bulkiness of meso ‐substituents predominantly determines their tilt angle relative to the isophlorin macrocycle, critically influencing antiaromaticity. Bulkier substituents maintain larger tilt angles, preserving stronger antiaromaticity, while less bulky groups allow greater π‐conjugation with the macrocycle, thereby reducing antiaromaticity. These findings provide valuable guidance for the design of functional antiaromatic materials with tunable electronic properties.