The project ‘Molecular Computational Chemistry’ employs theoretical chemistry methodologies to elucidate structural, thermochemical and reactivity aspects of molecular and supramolecular materials. The methodologies are chosen in respect to molecular size and range from semi-empirical (PM3, PM7) for large supramolecular entities to those involving density functional theory (B3LYP, B3P86) and ab-initio (MP2, CCSD(T)) for progressively smaller molecules.

Research Activities

Allylic substitution reactions of Morita–Baylis–Hillman acetates with phosphinic nucleophile

Phosphinic pseudopeptides are of great importance in medicinal chemistry as zinc-metalloprotease inhibitors. In order to explore efficient synthetic routes of these pharmaceuticals, a model system was considered involving the reaction of phosphinic nucleophiles with Morita–Baylis–Hillman acetates (MBHA) possessing a variety of substituents, as shown in Scheme 1.

The reaction rates and the E/Z stereochemistry of the final products were monitored by 31P-NMR. In order to address the experimentally observed stereoselectivity dependence on R2 and R3, a theoretical investigation was performed by density functional theory (DFT), at the B3LYP/6-31G(d’) and B3LYP/6-311++G(3df,2p) levels of theory, including the treatment of solvent (CH2Cl2) effects using the Integral Equation Formalism of the Polarizable Continuum Model (IEF-PCM). The work was performed in collaboration with Prof. D. Georgiadis (Univ. of Athens) and Dr. A. Papakyriakou. For R4 = Ph and R5 = SiMe3, the experimental stereoselectivity correlates with reactants energies in the case of R3 = CN (nitriles), whereas in the case of R3 = COOEt (esters) it correlates with product energies, suggesting ‘early’ and ‘late’ rate-determining transition states (TS), respectively. This was pursued by attempting to locate the corresponding TS in a chemically similar system with R4 = OMe and R5 = Me, having less complexity and computational requirements. The structures and the relative energies of the corresponding TS support the above suggestion (Chem. Eur. J (2015), 21, 3278-3289), and their geometries for R2 = Ph are shown in Figure 1.

Figure 1. Structure of the rate-determining transition states for the reactions of P(OMe)3 with nitrile and ester MBHAs at the B3P86/6-31G(d’) level of theory.

Staudinger ligation of β-cyclodextrin

Dimers and oligomers of cyclodextrins (CD) possess potential advantages in respect to the corresponding monomers due to an enhanced binding affinity for pharmaceuticals combined with superior molecular recognition properties. The theoretical investigation of Staudinder-ligated β-CD, in respect to self-inclusion and encapsulation of guest molecules was completed (Beilstein J. Org. Chem. (2014), 10, 774-783). The work was performed in collaboration with Dr. K. Yannakopoulou. The semiempirical PM3 level of theory was chosen, with the Conductor-like Screening Model (COSMO) treatment of solvent effects in aqueous solution. The computational results indicate the formation of intra- as well as intermolecular self-inclusion complexes, sufficiently flexible to permit the inclusion of the protonated form of 1-adamantylamine with a binding energy of 45 kJ/mol. The reliability of the structural parameters calculated semiempirically was verified by benchmark calculations using DFT at the B3P86/6-31G(d’,p’) level of theory. A schematic of the open and closed (self-inclusion) conformations for dimers of β-CD is shown in Figure 2.

Figure 2. Structures of the open and closed forms of Staudinger-ligated β-CD dimers at the PM3(COSMO) level of theory.

Interaction of cyanotoxins with α-, β- and γ- cyclodextrin

Cyanotoxins are considered to be a major environmental threat, due to their extreme toxicity for most life forms. Various classes of cyanotoxins have been detected worldwide, especially in lakes. Removal of particularly stable cyanotoxins from irrigation or drinking water is a challenging project, done primarily by nanofiltration, adsorption or chemical oxidation. The prospect of removal using cyclodextrins (CD) has been recently considered. The interactions of three abundant and powerful toxins, microcystin-LR, microcystin-RR and nodularin-R with α-, β- and γ- CDs in aqueous solutions were examined at the semiempirical PM7(COSMO) level of theory, in the framework of an ongoing collaboration with Prof. C. Laspidou and Prof. K. Kormas (Univ. of Thessaly). The results indicate that these cyclic peptide toxins interact with CDs in a similar fashion, namely by insertion of their phenylalkyl side chain into the hydrophobic CD cavity, preferably via the secondary side of CD. Furthermore, the interaction strength was found to increase with the size of cyclodextrin. The theoretical data agree with experimental data obtained by 1H-NMR, suggesting that PM7 is a computationally affordable theoretical method for the study of cyanotoxins interactions with CDs. The structure of the most stable complex between microcystin-LR with β-CD is shown in Figure 3.

Figure 3. Structure of the most stable complex between microcystin-LR with β-CD in aqueous solution at the PM7(COSMO) level of theory.