Building Blocks of Eumelanin:  Relative Stability and Excitation Energies of Tautomers of 5,6-Dihydroxyindole and 5,6-Indolequinone

Abstract

Computation methods were used to examine the tautomerization equilibria for 5,6-dihydroxyindole (DHI, 2) and 5,6-indolequinone (IQ, 3). Relative energies were calculated at the B3LYP and PBE0 level of theory; solvent effects were modeled by using the CPCM method. Nine tautomers of 2 were examined. Our data showed that the generally accepted molecular structure of 2 corresponds to the most stable tautomer in both gas phase and aqueous solution. In aqueous solution, the quinone methide tautomer was the second most stable structure, being destabilized by 6 kcal mol -1 . In contrast, gas-phase DFT calculations on four tautomers of 3 suggest this compound exists as a mixture of two tautomers, the quinone and the quinone methide. The relative concentration of the quinone methide is predicted to be sufficient to be detected experimentally. The energy difference between these two tautomers increases in solution so concentration of quinone methide should be negligible in polar solvents. Vertical excitation energies for tautomers of 2 and 3 in solutions were obtained by combining TD-DFT techniques with the SCRF-CPCM calculations. Simulated absorption spectra in water were in semiquantitative agreement with available experimental data. Relatively strong absorption in near-IR range was predicted for 3. This spectral feature might be used to clarify the complex mechanisms of dihydroxyindole oxidation.

5,6-Dihydroxyindole-2-carboxylic acid: a first principles density functional study

“…Therefore we have also employed the ∆SCF method [33] to calculate the HOMO-LUMO gap. We have previously shown that equivalent results for DHI reproduce the trends found in time dependent DFT calculations [23]. In table IV we compare the HOMO-LUMO gap found from a simple interpretation of the Kohn-Sham eigenvalues with those found by the ∆SCF method.…”

“…Despite the widespread agreement that natural eumelanin contains both DHI and DHICA, previous quantum chemical studies [14,15,17,18,19,20,21,22,23] have only considered DHI. This is in part due to the greater chemical complexity of DHICA, but also in part due to assumption that the carboxylation of DHI does not play a significantly role in determining the properties eumelanin.…”

5,6‐Dihydroxyindole Chemistry: Unexplored Opportunities Beyond Eumelanin

“…Relative calculated energies for selected tautomers of the indole and quinone are shown. [9] As mentioned earlier, the indole 1 in its reduced state is characterized by a marked facility for oxidation, particularly in solution, thus sharing a notorious intractability with reactive catechols. Most of the difficulties involved in the study of 5,6-dihydroxyindole chemistry, however, have been circumvented by the adoption of suitable catechol protection strategies, based mainly on acetylation and benzylation.…”

“…[20][21][22][23] All these studies concurred to indicate that 1 exists exclusively in the catechol form, with other tautomers appearing to be destabilized both in the gas phase and in solution. [9] With regard to 5,6-indolequinone, in solution the oquinone is the most stable tautomer but in the gas phase the quinonemethide is close in energy, indicating that in the gas phase it might constitute up to 25 % of 5,6-indolequinone.…”

Quantitative fluorescence spectra and quantum yield map of synthetic pheomelanin

“…Eumelanin is derived by oxidation of dihydroxyphenylalanine (dopa) via the Raper-Mason scheme, and pheomelanin is produced via a similar pathway when cysteine is present. 7 Whereas eumelanin is believed to be comprised of aggregates of indolic monomers dihydroxyindole (DHI), [also known as hydroquinone (HQ)], its partially oxidized form semiquinone (SQ), and its fully oxidized form indolequinone (IQ), 8,9 pheomelanin is understood to consist of benzothiazine intermediates.…”