Stereoselective cycloaddition of biologically active thioindoline with the smallest nanocage in gas phase versus solution via density functional theory

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Abstract
A fine speculation of enantioselectivity prior to the expensive experimental endeavors is truly one of the ultimate goals of the computational organic chemists. In this survey, we have predicted stereo specificity for hetero Diels–Alder (DA) cycloaddition of (E)‐3‐benzylidene‐indoline‐2‐thione (I) with C20 to give (Ia) as drug delivery in the gas phase and in solution, at density functional theory (DFT)–self‐consistent reaction field (SCRF). The enthalpy difference between liquid (l) and gas (g) phases (∆Hl‐g), as well as activation energy (Eexo≠, Eendo≠) of Ia cycloadduct, appears proportional to the dielectric constant of solvent (ε). In contrast to the above trends, kinetic stability based on ∆EL‐H of Ia, develops in opposite to that of ε. The more stability of Ia is attributed to its H―bonding, and dipole–dipole interaction in water. The energy barrier of exo transition states (TS) is low; hence, cycloaddition is recommended to be of synthetically interest for preparation of asymmetric nano compound. Moreover, the π‐π aromatic stacking among the substituted phenyl ring and C20 (πsubstituted phenyl ring ↔ πC20) has significant effect on destabilization of endo TS. This DA reaction have polar nature according to one‐step mechanism, that comprises an initial hetero‐DA reaction yielding Ia, which experiences a subsequent [3,3] sigmatropic shift to yield the expected formal cycloadduct. This is a consequence of more polar nature of reaction, due to lower nucleophilicity (N), higher electrophilicity (ω), higher maximum electronic charge (ΔNmax), more polarity (μ), and more global electron density transfer (GEDT) of Ia in polar solvents (especially in water) in comparison to gas phase. This polar character is given by the electrophilic character of the C20 dienophile (ω = 5.29 eV) and nucleophilic character of the 1,3‐diene molecule (I) (N = 3.70 eV). Additionally, molecular mechanism of the considered reaction is substantially different from the DA reactions between simple 1,3‐diene and dienophiles.

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