Hetero Diels–Alder cycloadduct of Anti-Tumor (E)-3-X-indoline-2-thiones with C20 fullerene as drug delivery in solution vs. gas phase: A DFT survey

Abstract

Four commercially available asymmetric thioindoles including (E)-3-X-indoline-2-thiones (where X = phenyl, furan-2-yl, 1H-pyrrol-2-yl, and thiophene-2-yl, I to IV, respectively) are known as selective and potent inhibitors in contradiction of different receptors for tyrosine kinases. A specifically interesting report for these biologically active species is the effect of media on their stability and stereo-selectivity in inter-molecular cycloaddition as drug delivery involving I-IV hetero Diels–Alder (as diene) with [20]fullerene (as dienophile). Here, we have tackled this survey using the SCRF method in the gas phase, C7H8, CH2Cl2, MeOH, H2O, CH3CN and DMSO, at DFT. Stability of each solute (I-IV) and Diels–Alder cycloadducts (Ia-IVa) depends on the dielectric constant of the solvent, the possibility of the hydrogen bonding and dipole–dipole interactions. Formation of the endo isomer appears energetically less favorable due to the non-bonding electrostatic repulsions between the heteroatoms and C20 (nheteroatom ↔ πC20), also the π-π aromatic stackings among the substituted rings and C20 (πsubstituted ring ↔ πC20), which affect the stability of the transition states (TSs). Even though, the endo isomer appears thermodynamically more stable, we propose formation of the kinetically more stable exo isomer due to lack of π-π aromatic stackings. These appear completely comparable to interactions of the acyclic electron rich 1,3-dienes and dienophile C60 previously held responsible for the origin of region-selections in the exo [4 + 2] cycloadditions. Theoretical predictions are waiting for inter-molecular donor–acceptor experimental testing and verifications.