for a complete rotation (360°) of the bond with a 15° pace. A conformer without
O−H⋯π interaction between the moieties (a conformer with the O43−H52⋯O42
and O44−H54⋯O45 IHBs) was chosen as input, to avoid the effect of the removal
of the interaction during the rotation. The scan highlighted five minima (Fig. 2,
considering that angles differing by 360° are the same). Each of the corresponding
geometries was optimized to find the actual geometry corresponding to a given
minimum (as the optimization involves fully relaxed geometry). Since interactions
between S and S′ were not present in the input, this provides information only on
the preferences for the mutual orientations of the moieties and identifies five different combinations of orientations. More conformers were then identified by
changing the IHB patterns in each of the five conformers obtained from the
potential energy profile.
Calculations in solution utilized the Polarizable Continuum Model (PCM, [21–
26]). In this model, the solvent is considered immeasurable and is modelled by a
continuous isotropic dielectric into which the solute is inserted. Thus, the solute
molecule is embedded in a cavity surrounded by the continuum solvent. The
geometry of the cavity follows the geometry of the solute molecule, considering its
solvent accessible surface. The calculations utilised the default settings of Gaussian03 [27] for PCM, namely, Integral Equation Formalism model (IEF, [23–26])
and Gepol model for building the cavity around the solute molecule [28–30], with
simple United Atom Topological Model (UAO) for the atomic radii and 0.200 Å
2
for the average area of the tesserae into which the cavity surface is subdivided.
The SCFVAC option was selected to obtain more thermodynamic data.
Calculations in solution were performed as single point (SP) calculations on the
in-vacuo optimised geometries, with the same levels of theory utilised in vacuo. It
was opted to use SP calculations because the size of the molecule makes
re-optimisation in solution computationally expensive. Although SP calculations
cannot provide information on the geometry changes caused by the solvent, they
can provide reasonable information on the energetics, such as the conformers’
relative energies in solution and the energy aspects of the solution process (the free
energy of solvation, ΔG solv , and its components).
The three solvents considered (chloroform, acetonitrile and water) cover the
ranges of polarity and of hydrogen bonding abilities interesting for biologically
active molecule. Chloroform is an apolar aprotic solvent with low relative permittivity (ε r = 4.90) and low dipole moment (µ = 1.04 D [31]). Acetonitrile is a
dipolar aprotic solvent with large relative permittivity (ε r = 36.64) and high dipole
moment (µ = 3.92 D [31]). Water is a protic solvent with high relative permittivity
(ε r = 78.39) and a sizeable dipole moment (µ = 1.83 D [31]).
Calculations were performed using GAUSSIAN 03, Revision D 01 [27].
All the energy values reported are in kcal/mol and all the distances are in Å.
Acronyms are utilized for the calculation methods and for the media, for conciseness sake on reporting values: HF for HF/6-31G(d,p), DFT for DFT/B3LYP/
6-31+G(d,p), ‘vac’ for vacuum, ‘chlrf’ for chloroform, ‘actn’ for acetonitrile and
‘aq’ for water. Tables with all the numerical values of the properties of the calculated conformers (relative energy, dipole moments, free energy of solvation in the
Computational Study of Jozimine A 2 , a Naphthylisoquinoline …
309
O−H⋯π interaction between the moieties (a conformer with the O43−H52⋯O42
and O44−H54⋯O45 IHBs) was chosen as input, to avoid the effect of the removal
of the interaction during the rotation. The scan highlighted five minima (Fig. 2,
considering that angles differing by 360° are the same). Each of the corresponding
geometries was optimized to find the actual geometry corresponding to a given
minimum (as the optimization involves fully relaxed geometry). Since interactions
between S and S′ were not present in the input, this provides information only on
the preferences for the mutual orientations of the moieties and identifies five different combinations of orientations. More conformers were then identified by
changing the IHB patterns in each of the five conformers obtained from the
potential energy profile.
Calculations in solution utilized the Polarizable Continuum Model (PCM, [21–
26]). In this model, the solvent is considered immeasurable and is modelled by a
continuous isotropic dielectric into which the solute is inserted. Thus, the solute
molecule is embedded in a cavity surrounded by the continuum solvent. The
geometry of the cavity follows the geometry of the solute molecule, considering its
solvent accessible surface. The calculations utilised the default settings of Gaussian03 [27] for PCM, namely, Integral Equation Formalism model (IEF, [23–26])
and Gepol model for building the cavity around the solute molecule [28–30], with
simple United Atom Topological Model (UAO) for the atomic radii and 0.200 Å
2
for the average area of the tesserae into which the cavity surface is subdivided.
The SCFVAC option was selected to obtain more thermodynamic data.
Calculations in solution were performed as single point (SP) calculations on the
in-vacuo optimised geometries, with the same levels of theory utilised in vacuo. It
was opted to use SP calculations because the size of the molecule makes
re-optimisation in solution computationally expensive. Although SP calculations
cannot provide information on the geometry changes caused by the solvent, they
can provide reasonable information on the energetics, such as the conformers’
relative energies in solution and the energy aspects of the solution process (the free
energy of solvation, ΔG solv , and its components).
The three solvents considered (chloroform, acetonitrile and water) cover the
ranges of polarity and of hydrogen bonding abilities interesting for biologically
active molecule. Chloroform is an apolar aprotic solvent with low relative permittivity (ε r = 4.90) and low dipole moment (µ = 1.04 D [31]). Acetonitrile is a
dipolar aprotic solvent with large relative permittivity (ε r = 36.64) and high dipole
moment (µ = 3.92 D [31]). Water is a protic solvent with high relative permittivity
(ε r = 78.39) and a sizeable dipole moment (µ = 1.83 D [31]).
Calculations were performed using GAUSSIAN 03, Revision D 01 [27].
All the energy values reported are in kcal/mol and all the distances are in Å.
Acronyms are utilized for the calculation methods and for the media, for conciseness sake on reporting values: HF for HF/6-31G(d,p), DFT for DFT/B3LYP/
6-31+G(d,p), ‘vac’ for vacuum, ‘chlrf’ for chloroform, ‘actn’ for acetonitrile and
‘aq’ for water. Tables with all the numerical values of the properties of the calculated conformers (relative energy, dipole moments, free energy of solvation in the
Computational Study of Jozimine A 2 , a Naphthylisoquinoline …
309