Anatomy of the substituent effect in complex N-heterocycles

The substituent effect in heterocyclic compounds is a critical concept in chemistry, influencing the properties and reactivity of these molecules. In simple systems, like benzene derivatives, it is well-understood. However, in heterocycles with multiple substituents and fused rings-important nature's building blocks-the situation becomes complex and hard to comprehend. In this work, quantum-chemical calculations (at the DSD-PBEP86-D3BJ/def2-TZVPP level of theory), including substituent effect descriptors and the electron density of delocalized bonds decomposition scheme, were performed on derivatives of cytosine, isocytosine, guanine, isoguanine, thioguanine, hypoxanthine and 5-aza-7-deazaguanine in different tautomeric forms, allowing the determination and quantitative comparison of the strength of different interactions between substituents and heteroatomic fragments in each studied molecule. The comparisons allowed formulating several rules that help understand and predict the strength, and the resonance/inductive nature of the substituent effect in complex N-heterocyclic systems.