Molecular Modeling of the Raman and SERS Response of 6-Mercaptopurine: Tautomerism, Surface Coverage, and Charge Transfer

Surface-enhanced Raman spectroscopy (SERS) of 6-mercaptopurine (6-MP) was investigated by combining the experimental Raman measurements with Density Functional Theory calculations to clarify the effects of tautomerism, aggregation, adsorption geometry, and short-range charge transfer. In aqueous solution the thione forms, Thione(N1,N7) and Thione(N1,N9), are the only thermally accessible species, whereas the thiol forms are significantly less stable. X-ray derived dimeric models provide closer agreement with spontaneous Raman spectrum, showing that intermolecular interactions are essential for describing the solid-state spectrum; for the best Thione(N1,N9) dimer, the mean deviation is 1.1 ± 0.6%. For the adsorbed species, calculations on a tetrahedral Au20 cluster reveal that the thermodynamically preferred flat configurations do not provide the best match to the experimental SERS spectrum, which is instead more accurately reproduced by sulfur-bound vertex and center motifs. Increasing surface coverage and mixed-tautomer adsorption are further required to recover the experimental relative intensities, with a 3:1 Thione(N1,N9)/Thione(N1,N7) model giving the best agreement. Distance-dependent analysis further indicates a short-range chemical-enhancement regime below about 4 Å, marked by charge separation, HOMO stabilization, and selective amplification of vibrational modes localized at the molecule–gold adsorption interface. This work introduces a multitautomer modeling strategy that explicitly goes beyond the conventional single-molecule 1:1 adsorption paradigm, demonstrating that only the concurrent treatment of surface coverage, tautomeric coexistence, and short-range charge transfer yields a physically consistent and quantitatively accurate description of the SERS response.