Search

A theoretical investigation on the regio- and stereoselective outcomes of the hydroformylation reaction with an unmodified rhodium catalyst (H—Rh(CO)3) was carried out at the B3LYP/SBK(d) level on related chiral olefins, namely (1-vinyloxy-ethyl)-benzene (1) and (1-methyl-but-3-enyl)-benzene (2). A thorough and computationally expensive examination of the various possible H—Rh(CO)3-olefin complex intermediates was performed, in order to determine, interpret, and eventually predict, the regio- and stereoselectivity of the aforementioned reactions, whose products are a mixture of the linear aldehyde and of two diastereomers of the branched aldehyde. Regio- and diastereoselectivity of the reaction have been experimentally determined via hydroformylation runs at 20° and 100° C for 1 and at 20° C for 2. The theoretical results obtained are in good agreement with the experimental ones, which put forward a high chiral discrimination for chiral vinyl ether substrates in contrast to the lack of regio- and diastereo-selectivity observed in the hydroformylation of 2. For the hydroformylation of 1, a regioselectivity ratio (B:L) of 72:28 and a diastereoselectivity ratio (b:b’) of 97:3 have been computed which compare well to the corresponding experimental results (85:15 and 88:12). Therefore, theoretical calculations can give reliable estimates of regio- and diastereoselectivity provided a careful and accurate surface scan is performed for the alkyl-rhodium intermediates and the reaction is carried out at room temperature and, hence, in the absence of branched to linear alkyl isomerization.

The catalytic effect of explicit water molecules on the keto-enol tautomerism in a system of biological interest (enolpyruvate) has been investigated at the B3LYP/6-31++G** level by exploring the potential energy surface in the presence of 1 or 2 water molecules and comparing the energy profiles to the direct tautomerisation one. The water-assisted mechamisms turned out to be more favourable than the direct ones, in agreement with what occurred for the acetylacetone tautomerism in the presence of a single water molecules. To compare the behaviour of water in pyruvate and in acetylacetone, the two-water-assisted mechanism has been also examined for the latter at the B3LYP/6-31G* level. A number of stationary points for both compounds in vacuo and in the presence of explicit water molecules have been computed with DFT coupled to larger basis sets and at the MP2 level. Two diketo forms more stable than any of the ketoenol tautomers have been located, while for pyruvate the keto form is always more favourable than the enol one. The equilibrium constant for acetylacetone tautomerisation has been computed with high accuracy, performing complete basis set extrapolation for the relative internal energy, to determine whether the quality of the method/basis set is responsible for the earlier modest agreement with the experimental value. Monte Carlo and molecular dynamics simulations helped characterize the solution structure and association features in the 0.03-0.22 molar concentration range.

The approaching path of CO to the alkyl-Rh(CO)3 intermediate, considered for 1,1-diphenylethene as a test case to investigate the reason of its failure to produce quaternary aldehydes in hydroformylation reactions, shows a remarkable activation barrier in DFT calculations for the branched alkyl-Rh intermediate, but not for the linear one. Consideration of the free energy associated to this step strengthens this result, whereas the other steps remain fairly comparable. The path leading to the branched aldehyde is thus abandoned early, and this species then returns to the catalyst and the olefin, with subsequent reformation of the branched and linear alkyl-Rh intermediates until consumption of the olefin. The branched backward pathway is more favourable indeed than the forward one, as can be inferred from its free energy reaction profile. The heuristic value of theoretical/computational methods in exploring experimentally inaccessible species and in rationalizing the results, together with the importance of the organic part structure in organometallic complexes, is also put forward.

The conformational landscape of the prenylchalcone plicatin B and some of its tautomers has been investigated at the B3LYP/6-31G* level in analogy to prior studies of ours on two structurally related prenylated pterocarpans. Since the antioxidant activity of these natural compounds is supposed to be related to their copper chelation ability, several complexes with Cu(I) and Cu(II) metal cations, Cu+ and Cu2+, have been taken into account with the metal ions described by effective core potentials in the LANL2DZ valence basis set. The preferred binding sites on low-energy conformers of E and Z plicatin B have been determined and their metal ion affinity (MIA) values have been compared. Both cations give stable complexes with plicatin B, but the stability order of the metalated species at the various coordination sites strongly depends on the cation nature. In particular, for the E configuration the most stable Cu+-plicatin B ground-state structure features the metal cation bridged between the hydroxy O lone pairs and the prenyl À density, while in the most stable Cu2+ complex the cation is coordinated with the inner lone pairs of the oxygens in the methyl ester moiety bearing an anti methyl group. For the Z configuration, in contrast, the most stable Cu2+ complexes are found with the metal ions dentated between the Z ester side chain and the prenyl pi-density, while Cu+ in addition is close to the aromatic ring density as well. Comparison of the Cu+ and Cu2+ affinity values demonstrates however that the affinity to Cu2+ is decidedly much higher (by a factor of 3-4, depending on the arrangement type) than that to Cu+, even including the possible B3LYP overestimate of the Cu2+ binding energy with respect to BHLYP. A tentative evaluation of MIA in aqueous solution using the polarizable continuum model of the solvent shows a remarkable decrease for Cu(II).

The antioxidant activity of 3,9-dimethoxy-4-prenylpterocarpan (bitucarpin A) and 3,9-dihydroxy-4,8-diprenylpterocarpan (erybraedin C) is supposed to be related to their copper coordination ability. Therefore several complexes with Cu2+ of low-energy conformers of these two prenylated pterocarpans, whose conformational landscape was the subject of a prior B3LYP/6-31G* study (Alagona, Ghio, Monti Phys. Chem. Chem. Phys. 2004, 6, 2849), have been taken into account at the same computational level, with the metal ion described by effective core potentials in the LanL2DZ valence basis set. Their metal ion affinity (MIA) values have been determined and compared with the results obtained earlier with the same methods for the preferred binding sites of plicatin B, a prenylchalcone that can exist in E and Z configurations as well as in tautomeric forms. The stability order of the metalated species at the various coordination sites strongly depends on their position and nature. The spin density of the cation upon ligand coordination becomes vanishingly small, whereas the ligand spin density approaches 1. Thus the ligand is oxidized to a radical cation (Ligand•+), while Cu(II) is reduced to Cu(I). A very favorable MIA is obtained in vacuo when Cu2+ is chelated between the prenyl and O lone pair moieties for both pterocarpans (MIA ) 370 and 380 kcal/mol for bitucarpin A and erybraedin C, respectively). High affinity values are found also when the cation is sequestered within the two end groups (prenyl À density and D ring) in the Ot configuration (MIA ) 371 and 373 kcal/mol for bitucarpin A and erybraedin C, respectively). In aqueous solution, the solvent effect dampens the free energy differences and reduces the MIA especially when the ion is remarkably exposed to the solvent. Conversely, when Cu2+ is sequestered, the MIA decrease in solution is limited (MIA ) 327 and 360 kcal/mol for bitucarpin A and erybraedin C, respectively). The solvent effect is significantly larger in plicatin B, where the MIA is lowered by 80 to 140 kcal/mol, probably because (a) the screening ability of the substituted phenolic ring is lower and (b) the positive charge on the ligand is less efficiently delocalized than in the four fused ring system of pterocarpans.

The Wittig reaction of the unsubstituted triphenylphosphonium ylide (Ph3PCH2) on an aldehyde with two stereogenic centres (2S,3R)-2,4-dimethyl-3-pyrrol-1-yl-pentanal) has been investigated with a density functional (DF) approach at the B3P86/6-31G* level in vacuo and in tetrahydrofuran (THF) to shed some light on the mechanistic details when bulky chiral substrates are employed in the absence of E/Z selectivity issues. The interest is focused on the reaction intermediates, primarily on those that cannot be observed spectroscopically. Both the concerted mechanism (with a four-centre transition state (TS)) and the stepwise one (occurring via a betaine-type zwitterionic intermediate) have been explored, examining the potential energy profiles as well as the free energy ones. The solvent effect in the integral equation formalism-polarizable continuum model (IEF-PCM) framework has been also considered for THF. Interestingly, the early TS found in vacuo for both mechanisms becomes vanishingly small in THF, while the reactant adducts turn out to be somewhat destabilized, with an overall similarity in the relevant profiles.

DFT geometry optimizations have been performed at the B3LYP/6-31G* level in the gas phase and at the IEF-PCM/B3LYP/6-31G* level in tetrahydrofuran (THF) and aqueous solutions using scaled Bondi radii for the diketo and ketoenol forms of acetylacetone and cyclohexanedione. To evaluate basis set effects, starting from the aforementioned minima, the 6-311++G** optimized structures have been obtained. A number of complexes of both systems including one explicit water molecule have been considered up to the B3LYP/6-311++G** level, for cyclohexanedione taking into account the B3LYP/6-31G* basis set superposition errors as well. The diketo-ketoenol interconversion mechanisms have been investigated at the B3LYP/6-31G* level in vacuo. Interestingly, the geometric constraint due to the presence of the ring facilitates the description of the reaction mechanism in cyclohexanedione. Despite the very different flexibility of the two systems that in the case of acetylacetone prevents a straightforward interconversion of the diketo to the most stable of its ketoenol forms, both reactions occur with a very high barrier (about 62-63 kcal/mol), unaffected by continuum solvents, that decreases by 2.5-3.5 kcal/mol after the inclusion of thermal corrections. The barriers are almost halved, becoming ~31-35 kcal/mol, for the addition of a single water molecule according to various model reaction paths. Thermal corrections are limited (0.8-1.6 kcal/mol) for those adducts. The formation of a 1,1-diol, explored in the case of acetylacetone, might facilitate the obtainment of the most stable diketo conformation, featuring the carbonyl groups in distinct orientations. Inclusion of dispersion and basis set effects via the G2MP2 protocol does not alter the relative stability of both system tautomers. In contrast, the G2MP2 interconversion barriers for the isolated systems in vacuo are close to the B3LYP ones, whereas they turn out to be somewhat higher than the free energy based B3LYP barriers in the presence of a catalytic water molecule.

The three-dimensional structure of an optically active substituted s-triazine derivative, 2-chloro-4-methoxy-6-[(R)-1-phenylethylamino]-1,3,5- triazine, has been studied by conformational analysis using density functional theory (DFT) both in vacuo and in acetonitrile solution in the polarizable continuum model integral equation formalism framework. Time-dependent DFT methods have been used to investigate the molecular electronic CD and absorption UV spectra. Comparison with experimental results allowed the reliability of the theoretical predictions to be enhanced and suggested a possible interpretation of the measured data.

The conformational landscape of the N-protonated form of adrenaline (epinephrine in the U.S.) has been considered at both the B3LYP/6-31G* and 6-311++G** levels, with full geometry optimization in the gas phase and in aqueous solution, using the integral equation formalism for the polarizable continuum model (IEF-PCM). All stable orientations of the two catecholic hydroxy groups as well as the interconversion pathways between them have been taken into account. The dependence of the potential energy profile for the –[NH2CH3]+ group rotation on the catechol ring and side-chain OH group orientation has been also examined. B3LYP/6-31G* stationary points have been confirmed with frequency calculations (at 310 K and 1 atm) allowing thermal corrections and IR spectra to be evaluated. Basis set effects do not alter the relative stability of the various forms that is maintained also when MP2 correlation corrections are included. The role of the internal structures either embedding in aqueous solution the conformers kept rigid at their in vacuo geometries or allowing the structure to relax has been examined at the IEF-PCM/B3LYP/6-31G* and 6-311++G** levels and compared to the IEF-PCM/MP2/6-31G* results. In vacuo the G1 conformers are favored with respect to the T and G2 ones, while in water the stability ordering changes, T becoming significantly more stable than both gauche forms. This occurs even for the gas-phase structures, including or not thermal corrections. The addition of a single water molecule to N-protonated adrenaline caused the intramolecular H-bond within the side chain to weaken till formation of two H-bonds with water. This fact, coupled to the strain relaxation, further stabilized the G1 and T conformers. The maximum intensity of the IR spectra increases in solution, especially for monohydrated adducts, where a significant red shift in the vibration of the NH involved in a H-bond to the water O is found.

The regioselectivity of the hydroformylation reaction of 2-methyl-3-(3-acetyl pyrrol-1-yl)prop-1-ene catalyzed by an unmodified Rh catalyst has been investigated at the B3LYP/6-31G* level with Rh described by effective core potentials in the LANL2DZ valence basis set. Considering the population of all the H–Rh(CO)3-olefin transition state complexes, a regioselectivity ratio (B:L) of 12:88 has been obtained, in satisfactory agreement with the experiment producing the chiral linear aldehyde as the only product. The aldehyde, after complete diastereoselective cyclization, yields a 1:1 mixture of 1-acetyl-6R(S)-methyl-8R(S)-hydroxy-5,6,7,8-tetrahydroindolizine (having the same configuration on both stereogenic carbon atoms) and 2-acetyl-6-methyl-5,6-dihydroindolizine [Lett Org Chem (2006) 3:10–12]. The reason for such a high degree of diastereoselectivity has been elucidated examining the B3LYP/6-31G* potential energy surface for the reactions leading to the RR and RS diastereomers on a model system (without the acetyl substituent) and the actual compound. In the absence of a catalyst, a very high barrier is found along the reaction pathway, whereas spontaneous annulation occurs to a protonated pentahydroindolizine in the presence of H+. When a counterion (F–) is added, the proton on the newly formed tetrahedral carbon is abstracted, obtaining a structure closer to the final product (tetrahydroindolizine). Replacing H+ with Rh+, an initial adduct along the RS path much more favorable than any of those computed along the RR one is located because of the presence of the acetyl group. Tentative approaching paths obtained using [Rh(CO)3]+, bound to the aldehyde O, feature a higher barrier along the RS one, and offer a convincing explanation for the observed diastereoselectivity.

The ability to cross the intestinal cell membrane is a fundamental prerequisite of a drug compound. However, the experimental measurement of such an important property is a costly and highly time consuming step of the drug development process because it is necessary to synthesize the compound first. Therefore, in silico modelling of intestinal absorption, which can be carried out at very early stages of drug design, is an appealing alternative procedure which is based mainly on multivariate statistical analysis such as partial least squares (PLS) and neural networks (NN). Our implementation of neural network models for the prediction of intestinal absorption is based on the correlation of Caco-2 cell apparent permeability (P(app)) values, as a measure of intestinal absorption, to the structures of two different data sets of drug candidates. Several molecular descriptors of the compounds were calculated and the optimal subsets were selected using a genetic algorithm; therefore, the method was indicated as Genetic Algorithm–Neural Network (GA-NN). A methodology combining a genetic algorithm search with neural network analysis applied to the modelling of Caco-2 P(app) has never been presented before, although the two procedures have been already employed separately. Moreover, we provide new Caco-2 cell permeability measurements for more than two hundred compounds. Interestingly, the selected descriptors show to possess physico-chemical connotations which are in excellent accordance with the well known relevant molecular properties involved in the cellular membrane permeation phenomenon: hydrophilicity, hydrogen bonding propensity, hydrophobicity and molecular size. The predictive ability of the models, although rather good for a preliminary study, is somewhat affected by the poor precision of the experimental Caco-2 measurements. Finally, the generalization ability of one model was checked on an external test set not derived from the data sets used to build the models. The result obtained is of interesting practical application and underlines that the successful model construction is strictly dependent on the structural space representation of the data set used for model development.

All possible combinations of stable dihedral values have been considered in vacuo at the B3LYP/6-31G* level for 3,9-dihydroxy-4,8-diprenylpterocarpan (erybraedin C), whose hydroxy out-out conformation had been examined earlier together with the conformational preferences of 3,9-dimethoxy-4- prenylpterocarpan (bitucarpin A) at the same level (Phys. Chem. Chem. Phys. 2004, 6, 2849). The structure with O5 trans with respect to H6a (Ot) is about 2 kcal/mol less stable in vacuo than that with one of the H6 trans to it (Ht); in aqueous solution its energy gap is nearly conserved. The in-in arrangement of the hydroxyl groups of erybraedin turns out to be preferred in vacuo (even considering zero point and thermal effects), where pseudo H-bonds are formed between hydroxy hydrogens and ð electron distributions of prenyl groups. The continuum solvent effect (water) at the IEF-PCM/B3LYP/6-31G* level on the relative stability of the various rotamers is very limited both on bitucarpin and erybraedin. Considering the dihydrated derivatives, significant differences in the solvation energy are found between the distinct hydration sites, increasing in the order: methoxy O, ring O, hydroxy O, and hydroxy H. In hydroxy-water interactions, in fact, water prefers to behave as an H-bond acceptor unless nearby bulky groups prevent its approach. Interestingly enough, a bridging water molecule between the hydroxy H of erybraedin and the prenyl group can be found. The inclusion of BSSE corrections in hydroxy-water interactions decidedly favors out-out hydrated arrangements, followed by out-in and in-out ones. Bulk solvent effects with IEF-PCM about the dihydrated systems almost invert the stability order found in vacuo. When a four-water cluster is considered using QM methods, waters gather in H-bonded pairs around the solute OH groups. MD simulations, carried out on a pterocarpan solute (J. Phys. Chem. B 2005, 109, 16918), supply water adducts consistent with a liquid state that have also been embedded in the continuum solvent.

The conformational landscape of protonated serotonin has been explored in the gas phase and aqueous solution (IEF-PCM) with full geometry optimization at the HF and MP2 levels using the 6-31G* basis set. Single point calculations carried out up to the QCISD(T)/6-31G* level on the HF/6-31G* optimized structures find two low energy gauche conformations (G2 and G1) and a trans conformation (T) higher in energy by about 6 kcal/mol. Optimized calculations up to the HF/6-311++G** level somewhat reduce the barrier heights with respect to the HF/6-31G* ones of G2 and G1 to T (7–8.5 kcal/mol) whose relative energy is about 4.5 kcal/mol less favorable than the gauche conformers. Both trends are smoother than that obtained including MP2 correlation corrections at the 6-31G* level, where the T structure turns out about 7.3 kcal/mol higher in energy than the most stable gauche conformation (G2) with barrier heights of about 10–12 kcal/mol. In aqueous solution G1 and primarily T are significantly stabilized with respect to G2, that becomes the least stable minimum according to IEF-PCM/HF and MP2/6-31G* continuum solvent calculations in water, while the barriers decrease to 3–5 kcal/mol. The results obtained have been compared to earlier DFT results at the B3LYP/6-31G* level [J. Chem. Theory Comput. 1 (2005) 801]. Singly hydrated adducts have been considered both at the CP-corrected level or not, the latter embedded in the continuum solvent as well. Geometry optimizations in solution of monohydrated complexes put forward non-negligible solvent effects on the supermolecule structure and the related differential stabilization due to bulk solvent.

Conformational analyses have been performed for protonated serotonin in the gas phase, aqueous solution, and in the binding cavity of a 5-HT2A receptor model. DFT geometry optimizations have been performed in the gas phase at the B3LYP/6-31G* levels. Optimized calculations up to the B3LYP/6-311++G** level find two low-energy gauche conformations separated by 8-10 kcal/mol barriers from a trans conformation with relative energy of about 6 kcal/mol. In aqueous solution as concluded from IEF-PCM/B3LYP/6-31G* and IEF-PCM/MP2/6-31G*//IEF-PCM/B3LYP/6-31G* continuum solvent calculations as well as Monte Carlo free energy perturbation simulations with explicit solvent molecules, those barriers decrease to 2-7 kcal/mol, while the two gauche and one trans conformers are within a 3 kcal/mol relative free energy range. The solute is strongly hydrated by about three water molecules around the -NH3+ group and by one water molecule for each of the pyrrole and phenolic hydrogen atoms. Docking studies of the protonated ligand predicted both gauche and trans ligand conformers to favorably interact with the 5-HT2A receptor in its hypothesized binding cavity. The theoretical studies confirm the experimental results regarding strong interactions with the Asp155 and Ser159 residues (TM helix III) and the interactions of the indole ring with Phe, Trp, and Tyr side chains in TM V, VI, and VII helices within a 24 kcal/mol range for the relative interaction energies.

A theoretical investigation on the stability of the alkyl rhodium transition states as the key-step determining the regio- and diastereoselective outcomes of the hydroformylation reaction with an unmodified rhodium catalyst (H—Rh(CO)3) has been carried out. The results obtained employing effective core potentials for Rh in the LANL2DZ valence basis set, with the other atoms described at the B3P86/6-31G* level, have been compared to those computed with B3LYP/SBK(d), using effective core potentials for Rh and main group atoms. A number of contaminations between those levels or additional basis functions have also been used. The substrates considered are three related chiral olefins, namely (1-vinyloxy-ethyl)-benzene (1), (1-methyl-but-3-enyl)-benzene (2), and (1-methyl-allyl)-benzene (3). The structural features of the various possible complexes, which show a second chiral center at the inner olefin carbon upon complexation, do not present major changes among the various computational descriptions for each substrate. Significant differences in relative stabilities of the lowest energy transition states can be detected in the case of the ethereal substrate (1), whereas for both chiral alkenes (2 and 3) only very small energy gaps have been computed. In the case of 1 and 2, a quantitative agreement with available experimental results is obtained at the B3P86/6-31G* level, that should allow the prediction of regio- and stereoselectivity for chiral olefins not already screened. The B3LYP/SBK(d) values are comparable to the B3P86/6-31G* ones, although in the case of vinylether (1) the B3LYP/SBK(d) regioisomeric ratio turns out to be critical.

The intramolecular mechanism for the second proton transfer in TIM has been subjected to quantum mechanics (QM)/free energy perturbation (FEP) simulations in the presence of the protein environment with His95 in its e form. The results confirm and eventually strengthen earlier FEP simulations in the presence of d-His95 [G. Alagona, C. Ghio, P.A. Kollman, J. Comp. Chem. 24 (2003) 46] producing a shallow energy profile for the intramolecular path. Attempts to model the His-assisted pathway ab initio for determining the parameters to be used in subsequent intermolecular FEP simulations failed, because HF/6-31+G* calculations in vacuo suggested Glu165 instead as the only proton acceptor/donor in the active site. In order to assess whether the intramolecular mechanism modeled in the FEP simulations produced an unwanted bias, Car-Parrinello molecular dynamics simulations (including in the QM model the substrate intermediate, GluH165, His95 and Lys12), coupled to a classical description of the protein environment, have been carried out. The His95-assisted mechanism turns out to be the preferential pathway regardless which model of the environment is considered. Barrier heights, obtained using the blue moon ensemble method, indicate that the intramolecular proton transfer is about twice as much less favorable than the His95-assisted one.

Free energies of hydration (FEH) have been computed for thirteen neutral and nine ionic species as a difference of theoretically calculated Gibbs free energies in solution and in the gas phase. In-solution calculations have been performed using both SCIPCM and PCM polarizable continuum models at the DFT/B3LYP and ab initio Hartree-Fock levels with two basis sets (6-31G* and 6-311++G**). Good linear correlation has been obtained for calculated and experimental gas-phase dipole moments, with an increase by about 30% upon solvation due to solute polarization. The geometry distortion in solution turns out to be small, whereas solute polarization energies are up to 3 kcal/mol for neutral molecules. Calculation of free energies of hydration with PCM provides a balanced set of values with 6-31G* and 6-311++G** basis sets for neutral molecules and ionic species, respectively. Explicit solvent calculations within Monte Carlo simulations applying free energy perturbation methods have been considered for twelve neutral molecules. Four different partial atomic charge sets have been studied, obtained by a fit to the gas-phase and in-solution molecular electrostatic potentials at in-solution optimized geometries. Calculated FEH values depend on the charge set and the atom model used. Results indicate a preference for the all-atom model and partial charges obtained by a fit to the molecular electrostatic potential of the solute computed at the SCIPCM/B3LYP/6-31G* level.

The reductions of ketones by borane (BH3) with the Corey, Bakshi and Shibata (CBS) catalyst are important tools in asymmetric synthesis. Since substantial differences emerged depending on the method and basis set adopted in a theoretical study of the acetophenone reduction, the weak interaction responsible for the formation of the acetophenone-CBS complex was studied in model systems, with the aim to find the best compromise between quality of the description and computational costs. The major chosen model contained the most important elements of the acetophenone-CBS-BH3 complexes, that is the 1,3,2-oxazaborolidine ring with both a molecule of BH3 and acetone, the smallest possible ketone, coordinated to it. The effect of basis set and method on the description of the ketone-oxazaborolidine interaction along the B···O approaching path was investigated with several methods (HF, DFT-B3LYP, MP2) and basis sets (3-21G, 6-31G, 6-31G*, 6-31G**, 6-31+G**), taking into account basis set superposition errors, which can be significant even in the case of interactions involving two relatively large systems. Due to the remarkable structural changes occurring in the process, the effects of geometry deformation were also considered. The complexation of acetone is basically due to the electrostatic interaction between a Lewis acid/base couple, respectively the endocyclic boron and the carbonyl oxygen. Thus the electronic density drawn away from the C=O double bond makes the carbon atom more subject to hydride transfer, while the presence of the ring keeps the system rigid. The MP2 results turn out to be the closest to the QCISD(T) ones from QCISD(T)/6-31G*//HF/6-31G* calculations. In order to better analyze the nature of the interactions taking place in the complex, several dimers, smaller than the aforementioned model, were also considered. The solvent (tetrahydrofuran) effect on the adduct stability as well as on the association energy in the polarizable continuum model framework was taken into account at the 6-31G* level.