Comprehensive Vibrational Spectroscopic Investigation of trans,trans,trans-[Pt(N3)2(OH)2(py)2], a Pt(IV) Diazido Anticancer Prodrug Candidate

We report a detailed study of a promising photoactivatable metal-based anticancer prodrug candidate, trans,trans,trans-[Pt(N3)2(OH)2(py)2] (C1; py = pyridine), using vibrational spectroscopic techniques. Attenuated total reflection Fourier transform infrared (ATR-FTIR), Raman, and synchrotron radiation far-IR (SR-FIR) spectroscopies were applied to obtain highly resolved ligand and Pt-ligand vibrations for C1 and its precursors (trans-[Pt(N3)2(py)2] (C2) and trans-[PtCl2(py)2] (C3)). Distinct IR- and Raman-active vibrational modes were assigned with the aid of density functional theory calculations, and trends in the frequency shifts as a function of changing Pt coordination environment were determined and detailed for the first time. The data provide the ligand and Pt-ligand (azide, hydroxide, pyridine) vibrational signatures for C1 in the mid- and far-IR region, which will provide a basis for the better understanding of the interaction of C1 with biomolecules.


Table of contents
. Simplified representation of the octahedral complex C1. Figure S2. C 2v symmetry and vibrational modes of pyridine bound to platinum. Table S1. Selected bond distances (Å) and angles (°) for C1. Figure S3. X-ray structure and numbering of C1. Table S2. Selected bond distances (Å) and angles (°) for C2. Figure S4. X-ray structure and numbering of C2. Table S3. Selected bond distances (Å) and angles (°) for C3.         Extended ATR correction methodology. Figure S14. Processing schematic used to correct for anomalous dispersion by extended ATR correction. Figure S15. ATR-FTIR spectra of C1 before and after extended ATR and baseline correction. Figure S16. ATR-FTIR spectra of C2 before and after extended ATR and baseline correction. Figure S17. ATR-FTIR spectra of C3 before and after extended ATR and baseline correction. Table S4. ATR-FTIR, Raman, SR-FIR and theoretical vibrational bands of C1. Table S5. ATR-FTIR, Raman, SR-IR and theoretical vibrational bands of C2. Table S6. ATR-FTIR, Raman SR-FIR and theoretical vibrational bands of C3.
Comments on scaling of vibrational frequencies. Table S7. Selected bond distances and asymmetric stretching vibrations of C1, C2 and C3.
Cartesian coordinates of groundstate geometries of C1.
Cartesian coordinates of groundstate geometries of C2.
Cartesian coordinates of groundstate geometries of C3.
Calculated IR frequencies and intensities for C1, C2 and C3 (unscaled). Figure S1. Simplified representation of the octahedral complex C1. Hexagon = pyridine, large circle = platinum, small circle = ligands (azido, hydroxo and/or chloro). Arrows represent out-of-plane vibrations (out-of-plane bending, wagging and twisting) and in-plane vibrations (in plane bending, scissoring and rocking) are within the xy or xz plane respective of the ligands. The same approach is applied to square planar C2 and C3 complexes where the yz plane is ignored. Figure S2. C 2v symmetry and vibrational modes of pyridine bound to platinum, derived from Wilson's notation for benzene. 1    Figure S4. X-ray structure and numbering of C2. 3   Table S3. Selected bond distances (Å) and angles (°) for C3. 4 X-ray 4 Figure S5. X-ray structure and numbering of C3. 4 Figure S6. Raman spectra of C1 (solid) and C1' (dissolution of C1 in water followed by evaporation prior to measurements). Only selected peak labels are shown, see Table S4 for all peaks and assignments.    Table S4 for all peaks and assignments.  Table S5 for all peaks and assignments.  Table S6 for all peaks and assignments. Extended ATR correction methodology.
Diamond ATR-FTIR spectra of solid/crystalline C1, C2 and C3 exhibited anomalous dispersion (rapid changes to the refractive index of a sample whilst scanning through an absorption peak) resulting in asymmetric line shapes and shifts in absorption maxima to smaller wavenumber values 5 ( Figure S14A). Extended ATR correction (OPUS 7.2 software, Bruker Optics) designed to correct for anomalous dispersion was used. The algorithm is contained within the OPUS 7.2 license and cannot be disclosed. Please refer to the OPUS manual for the algorithm. Figure S14 shows the step-wise correction of the ATR-FTIR spectrum of C1. The ATR-FTIR spectra of C2 and C3 were likewise processed and the resulting corrections vs. no correction are shown in Figure S16 and S17 respectively.
The ATR-FTIR spectrum is first transformed to absorbance (AB) ( Figure S14A-B). Extended ATR correction (advanced) is then applied to the AB spectrum, varying the input of refractive index of the sample ( Figure S14C). The correction affects the band intensities, position and shape as highlighted in the inset shown in Figure S14D (from under-corrected for n = 1 to over-corrected for n = 2.2). An optimum correction was determined for each compound (C1: n = 2.025, C2: n = 1.970, C3: n = 1.700) and spectra were further baseline corrected (concave rubber-band) and vectornormalized. Initial ATR-FTIR spectra of solid C1, C2 and C3 vs. corrected ATR-FTIR spectra are shown in Figure S15, S16 and S17 respectively. Tables S4-6 contain wavenumber values of the ATR-FTIR spectra of C1, C2 and C3 before and after correction. The corrected ATR-FTIR spectrum of solid C1 was compared to the ATR-FTIR spectrum of C1' (dissolution of C1 in water followed by evaporation prior to measurements) and the major spectral band positions correspond well. Figure S14. ATR-FTIR processing schematic used to correct for anomalous dispersion by extended ATR correction (OPUS 7.2 software, Bruker optics). A) initial ATR-FTIR spectra of solid C1, small arrows indicate the effects of anomalous dispersion on the spectra; B) ATR spectra are transformed to absorbance; C) extended ATR correction screening by varying the refractive index input (n); D) Inset of overlapping spectral region (3700 -3450 cm -1 ) of extended ATR corrections, underlining the effect of increasing refractive index on the spectral band shape, position and intensity from under-(n = 1) to over-correction (n = 2.2).       Figure 6 and S11) due to anomalous dispersion and therefore the true maxima of these bands might be slightly shifted to larger wavenumbers. 5 Comments on scaling of vibrational frequencies.
Stretching vibrations are typically overestimated by DFT calculations and uniform scaling factors < 1.0 are commonly used to address the lack of anharmonicity in the DFT calculations. 6,7 However, the majority of platinum-ligand stretching vibrations are underestimated by both functionals, PBE and M06-2X, whereas their corresponding platinum-ligand bond lengths in their S 0 geometries are overestimated in most cases (Table S7). This suggests that both functionals underestimate the strength of the platinum-ligand coordination bonds in the studied complexes. As discussed in the paper for the individual complexes, the platinum-nitrogen or oxygen bonding is also strongly