2.1 Introduction
37
and presence of Cu(II) coordination at the quinonoid group (5,6-carbonyl groups)
of dopachrome. When Cu(II) is coordinated to the quinonoid group, the activation
barriers for α-deprotonation, β-deprotonation, and decarboxylation are all reduced.
Without Cu(II) coordination, the dissociated proton (from β-carbon) would be reprotonated at 5-carbon to form the metastable quinone methide intermediate. This
quinone methide intermediate shows significantly reduced activation barriers for
decarboxylation and α-deprotonation, as compared to those of the initial state of the
reaction. When the 6-oxygen of the quinone methide is further protonated, the activation barrier for decarboxylation is drastically reduced, and then DHI is formed as the
product. At a basic pH, this O6-protonation rate must decrease, and α-deprotonation
rate should increase instead, generally indicating that this is a favorable condition
for the formation of DHICA. In the presence of Cu(II) coordination at the quinonoid
group, this reprotonation becomes energetically favorable at α-carboxyl group rather
than at quinonoid group. This results in selective formation of DHICA. Since the
rate-limiting step of dopachrome conversion is β-deprotonation based on its activation barriers with and without Cu(II) coordination, our calculated results confirm the
reported base-catalyzed nature of this reaction. These calculations emphasize that
protection of the quinonoid group from protonation is important for the selective
formation of DHICA.
2.2 Calculation Methods and Models for Simulating
Dopachrome Conversion
We conducted first principles calculations based on density functional theory [23, 24].
All calculations were performed using Gaussian09, which is a widely used quantum
chemical calculation package [25]. The exchange correlation energy was calculated
using a hybrid functional B3LYP [26, 27] and the basis set was 6–31 ++G(d, p). The
natural atomic orbital analysis was performed to estimate the atomic charge [28].
Furthermore, the interaction with water was described using a polarizable
continuum model (PCM) [29, 30]. To calculate the solvation energy by means
of dielectric response, PCM approximates the solvent as a continuous dielectric
medium with spherical cavities, which are introduced around the solute atoms (The
cavity volume is approximately 1.1 times larger than the van der Waals volume). At
the boundary between the cavities (vacuum) and the dielectric medium (water), the
dielectric constant changes discontinuously so that apparent surface charges appear.
The solvation energy can be calculated based on the interaction between this surface
charge and the calculated electron density.
In order to calculate the activation barriers for elementary processes, potential
energy curves are calculated along the direction in which the C –H or C–C bond length
increases with a step size increment of 0.05 or 0.10 Å. For each point of the potential
energy curve, the molecular geometry was optimized except for the dissociating
bond length. However, in the cases of decarboxylation, “immediate rotation” of the
37
and presence of Cu(II) coordination at the quinonoid group (5,6-carbonyl groups)
of dopachrome. When Cu(II) is coordinated to the quinonoid group, the activation
barriers for α-deprotonation, β-deprotonation, and decarboxylation are all reduced.
Without Cu(II) coordination, the dissociated proton (from β-carbon) would be reprotonated at 5-carbon to form the metastable quinone methide intermediate. This
quinone methide intermediate shows significantly reduced activation barriers for
decarboxylation and α-deprotonation, as compared to those of the initial state of the
reaction. When the 6-oxygen of the quinone methide is further protonated, the activation barrier for decarboxylation is drastically reduced, and then DHI is formed as the
product. At a basic pH, this O6-protonation rate must decrease, and α-deprotonation
rate should increase instead, generally indicating that this is a favorable condition
for the formation of DHICA. In the presence of Cu(II) coordination at the quinonoid
group, this reprotonation becomes energetically favorable at α-carboxyl group rather
than at quinonoid group. This results in selective formation of DHICA. Since the
rate-limiting step of dopachrome conversion is β-deprotonation based on its activation barriers with and without Cu(II) coordination, our calculated results confirm the
reported base-catalyzed nature of this reaction. These calculations emphasize that
protection of the quinonoid group from protonation is important for the selective
formation of DHICA.
2.2 Calculation Methods and Models for Simulating
Dopachrome Conversion
We conducted first principles calculations based on density functional theory [23, 24].
All calculations were performed using Gaussian09, which is a widely used quantum
chemical calculation package [25]. The exchange correlation energy was calculated
using a hybrid functional B3LYP [26, 27] and the basis set was 6–31 ++G(d, p). The
natural atomic orbital analysis was performed to estimate the atomic charge [28].
Furthermore, the interaction with water was described using a polarizable
continuum model (PCM) [29, 30]. To calculate the solvation energy by means
of dielectric response, PCM approximates the solvent as a continuous dielectric
medium with spherical cavities, which are introduced around the solute atoms (The
cavity volume is approximately 1.1 times larger than the van der Waals volume). At
the boundary between the cavities (vacuum) and the dielectric medium (water), the
dielectric constant changes discontinuously so that apparent surface charges appear.
The solvation energy can be calculated based on the interaction between this surface
charge and the calculated electron density.
In order to calculate the activation barriers for elementary processes, potential
energy curves are calculated along the direction in which the C –H or C–C bond length
increases with a step size increment of 0.05 or 0.10 Å. For each point of the potential
energy curve, the molecular geometry was optimized except for the dissociating
bond length. However, in the cases of decarboxylation, “immediate rotation” of the