Raman and Infrared Studies of Platinum-Based Drugs: Cisplatin

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A: New Tools and Methods in Experiment and Theory

Raman and Infrared Studies of Platinum-Based Drugs: Cisplatin, Carboplatin, Oxaliplatin, Nedaplatin and Heptaplatin Marjorie Torres, Sidrah Khan, Michael Duplanty, Hannah C. Lozano, Tyree J. Morris, Trang Nguyen, Yuri V Rostovtsev, Nathan J. DeYonker, and Nasrin Mirsaleh-Kohan J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/acs.jpca.8b04023 • Publication Date (Web): 02 Aug 2018 Downloaded from http://pubs.acs.org on August 8, 2018

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The Journal of Physical Chemistry

Raman and Infrared Studies of Platinum-Based Drugs: Cisplatin, Carboplatin, Oxaliplatin, Nedaplatin and Heptaplatin Marjorie Torres,1 Sidrah Khan,1 Michael Duplanty,1 Hannah C. Lozano,2 Tyree J. Morris,2 Trang Nguyen,1 Yuri V. Rostovtsev,3 Nathan J. DeYonker,*,2 Nasrin Mirsaleh-Kohan*,1

1

Department of Chemistry & Biochemistry, Texas Woman’s University, Denton TX 76204 2

3

Department of Chemistry, University of Memphis, Memphis, TN 38152

Center for Nonlinear Sciences and Department of Physics, University of North Texas, Denton, Texas 76203

* Corresponding authors Nathan J. DeYonker, The University of Memphis, Department of Chemistry 3744 Walker Avenue, Memphis, TN 38152, [email protected], Telephone: 901-678-2029 Nasrin Mirsaleh-Kohan, Texas Woman’s University, Department of Chemistry and Biochemistry, Denton, TX 76201, [email protected], Telephone: 940-898-2032

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ABSTRACT: This study reports the optimized structures and lowest energy conformations/stereochemistry of five currently used platinum-based drugs: cisplatin, carboplatin, nedaplatin, oxaliplatin and heptaplatin. Normal Raman and IR spectra of each drug are experimentally obtained and have been compared to various levels of Density Functional Theory (DFT). Although some combination of structure, reactivity, or spectroscopy for these drugs has been studied by various groups, there are no known experimental normal Raman and IR spectra for nedaplatin, oxaliplatin and heptaplatin in the literature. The detailed structural and vibration findings of these drugs are very important to understanding platinum behavior and drug dynamics. The following work explores the vibrational frequencies of these drugs particularly by focusing on the low-energy modes between 200-600 cm-1, where anharmonicity effects will have less influence on the accuracy of computed frequencies. Ideally, the Pt−N stretching modes provide vibrational diagnostics for each drug. Interestingly, a vibrational energy decomposition analysis (VEDA) suggests that oxaliplatin and heptaplatin Pt-N stretching modes are not Raman or IR active. Instead, C-C and Pt-O stretching frequencies in the various bidentate dioxo ligands might be more useful in characterizing new cisplatin derivatives. Analysis of anharmonicity effects was compared against (and in tandem with) dimer computations of four of the five drugs. Harmonic vibrational computations of the dimeric cisplatin derivatives provided greater qualitative improvement than that of the monomeric derivatives. Satisfying agreement with experimental Raman spectra was obtained, even without resorting to linear scale factors for the harmonic dimer frequencies.


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1. INTRODUCTION

Raman spectroscopy1 is a powerful technique that has been widely used in engineering, chemical, and biological applications. The sensitivity of coherent Raman scattering can be improved by applying femtosecond adaptive techniques to control maximal vibrational coherence to perform real time identification of biomolecules.2-5 The control of vibrational excitation is also interesting from the point of view of controlling chemical reactions. 6-11 For the realization of quantum control of chemical reactions, detailed information about Raman spectra is needed. Theoretical chemistry provides qualitative and quantitative measures of normal mode assignments. Another motivation to study the Raman spectra is application to medical treatment and diagnostics. As evidenced by clinical trials, concomitant treatment with chemotherapeutic drugs and radiotherapy is one of the more successful strategies in cancer treatment, and often leads to a higher rate of survival and local tumor control, compared to non-synchronous treatments. Platinum chemotherapeutic agents are one of the most widely used drugs in treatment of various cancers. Despite the great utility of platinum chemotherapeutic agents, there are several side effects such as nephrotoxicity, adverse effects on the peripheral nervous system as well as liver damage, severe emesis, and, drug resistant tumors.12 Side effects and tumor-resistance of these drugs have created a continuous momentum in designing platinum-based drugs. In spite of the great efforts, only a few drugs such as cisplatin, carboplatin, oxaliplatin, nedaplatin, lobaplatin, and heptaplatin, are successfully employed for clinical use. In order to design potentially active anticancer drugs and understand the interaction of rapidly synthesized new drugs with DNA, we need to examine the electronic structures of these drugs. Further analysis of similarities and



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differences between structural properties of these drugs could assist researchers with understanding the exact actions of these drugs with DNA. Though there have been efforts toward understanding cisplatin’s binding to biological ligands through IRMPD (infrared multiple photo dissociation spectroscopy), to completely understand the underlying mechanism of action of platinum (II), it is important to obtain detailed vibrational features of the drug.13,14 There are a few studies addressing molecular structures of the platinum-based drugs.15-21 For instance, Gao et al.22 have compared experimental X-ray crystal data from previous research with density functional theory (DFT) to calibrate predictions of the carboplatin vibration spectrum. These studies did not report experimental Raman or IR data. In another study, McNaughton and coworkers23 used DFT and surface enhanced Raman spectroscopy characterization of platinum-based drugs and reported that the B3LYP/LANL2DZ level of theory can be used as predictors for smaller platinum-based compounds; however, they mentioned this method fails for larger complexes. There have been other investigations focused on the structural characterization of cisplatin and oxaliplatin derivatives. An example is the work carried out by Štarha et al.24 where they determine the geometry of the platinum-based compounds, reporting cisplatin and oxaliplatin derivatives with a distorted square-planar geometry. Theoretical work by Wysokiński et al.25 compared the mPW1PW91 (mPW) DFT model using the LANL2DZ effective core potential and D95V(d,p) basis sets to FT-IR and FTRaman spectra of solid carboplatin, concluding the LANL2DZ results being more representative of the experimental findings. In this work, we have studied five currently used platinum-based drugs: cisplatin, carboplatin, nedaplatin, oxaliplatin and heptaplatin to obtain their optimized structures and


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lowest energy conformations/stereochemistry. Raman and IR spectra of each drug is experimentally measured and compared to the theoretical findings.

2. METHODS 2.1 Experimental. All anticancer drugs were purchased and used with no further purification. Cisplatin was purchased from Acros Organic BVBA. Carboplatin and oxaliplatin were obtained from TCL America, nedaplatin from LKB Laboratories, Inc. and heptaplatin from LKT Laboratories, Inc. The stated purities of cisplatin, carboplatin, oxaliplatin, nedaplatin and heptaplatin are 99.9%, ˃98.0%, ≥98.0%, 99.5%, and ˃98.0%, respectively. The Raman spectra were recorded with a Thermo Scientific DXR Raman Microscope; a research grade dispersive Raman microscope with a nominal spectral range between 50 to 3300 cm -1. Laser excitation of 532 nm was used to obtain the spectra. The spectral resolution was 5 cm -1. Infrared spectra were obtained through the use of Thermo Scientific Nicolet 6700 FT-IR with ATR attachment, and Mid-IR and Far-IR detectors. All the experimental data were recorded for the solid phase of the drugs and at room temperature (20 ◦C).

2.2 THEORETICAL All computations were performed with the Gaussian09.D01 software package.26 Two density functionals were tested throughout, the hybrid B3LYP27 and the dispersion-corrected B97D328,29 hybrid functional. In conjunction with DFT, a number of basis sets combinations were used, BS1 utilizes 6-31G(d')30,31 on the nonmetal atoms and the modified LANL2DZ effective core



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potential and basis set combination on the Pt atom.32 Computations with correlation consistent basis sets were performed with both aug-cc-pVDZ/aug-cc-pVDZ-PP, and aug-cc-pVTZ/aug-ccpVTZ-PP on non-metals/Pt33,34, respectively. To obtain vibrational spectra, the Hessian of the energy was computed at all stationary points, also allowing us to confirm the optimized geometries as minima on the potential energy surface. Through the course of this investigation, it was found that default DFT grid parameters provided optimized structures containing spurious imaginary vibrational frequencies. Using the “ultrafine” grid in Gaussian09, with 99 radial shells and 590 angular points per shell alleviated this issue. Using an in-house script, simulated Raman scattering and IR spectra were generated from Gaussian output files using a Gaussian lineshape and 5 cm-1 linewidths. Normal mode peak assignments (in the range of 400 – 1800 cm-1) of theoretical IR/Raman spectra at the B3LYP/ aug-cc-pVTZ + GD3BJ level of theory are provided in the SI of this paper (Tables S2, S4, S6, S8, S9, S10, S11) and for numbered peaks in the Figures 4-9, Pt-ligand stretching modes, or modes with large computed IR intensities (> 25 km/mol). Peak assignments were obtained by analysis of symmetrized internal coordinates35 provided by the potential energy distribution (PED) methodology. We employed the VEDA code of Jamróz.36 This code has previously been used by Michalska and coauthors to examine vibrational modes of the cisplatin derivative picoplatin.37 Normal mode analysis in this work was performed on a qualitative level; only the largest contributing PED element, without phase information, is provided. Numerical differentiation of the Hessian was performed for some molecules to compute anharmonic corrections to vibrational frequencies and IR/Raman intensities.38,39

3. RESULTS AND DISCUSSION 6 ACS Paragon Plus Environment

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3.1

Optimized Structures. Tables 1-5 show optimized computed bond lengths and

bond angles of all five platinum complexes using various levels of DFT. The corresponding structure of each drug with atomic labeling is also presented in Figure 1. We have compared these calculated values with experimental data if they are available. As seen in these tables, we have focused on the bond lengths and angles around Pt atom in each drug. The calculated bond lengths and bond angles for cisplatin are listed in Table 1 along with the experimental data taken from averaging the values for α- and β-polymorphs of cisplatin.40,41 Both B3LYP/ aug-cc-PVTZ w/GD3BJ and B97D3/ aug-cc-pVDZ show a decent description of Pt-Cl and N-H bond lengths, but all levels of theory seem to overestimate R(Pt-N) bond lengths, with a computed range of 2.093 – 2.119 Å versus the experimental value of 2.054 Å. For N−H, all levels of theory predict a slightly higher value compared to the experimental result. As shown in Table 1, the calculated N−Pt−N and Cl−Pt−Cl bond angles with DFT are overestimated compared to the experimental values by 4-8°. However, our computations underestimate the bond length of N−Pt−Cl by a value of 5°. It should be mentioned that similar overestimations for N−Pt−N and Cl−Pt−Cl bond angles and underestimation of bond angle for N−Pt−Cl have been reported by PW91 functional, HF and DFT results.40,42,43, 22 Overall discrepancies between experiment and theory for cisplatin and derivatives may be explained by the polymorphism and/or the formation of intramolecular interactions (H-Cl-bonding network) in the X-ray crystal structure which leads to conformational changes in the solid state.44 The optimized geometric parameters of carboplatin with various levels of DFT are given in Table 2. These values are compared with the experimental data obtained from X-ray results.45 DFT generally overestimates the bond lengths for Pt−N. The closest value to the experimental value of 2.021 Å, is reported using B3LYP/ aug-cc-PVDZ GD3BJ (2.083 Å). The computed



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bond lengths of Pt−O have been predicted to be slightly shorter than the experimental values Michalska and co-workers25 also reported slight shorter bond lengths for the Pt-O bond using MP2 and the mPW1PW91 functional. Geometric parameters computed here are similar to their work and the work from Wysokiński and Gao.25 However, their MP2 geometries were closer to the experimental values compared to the results presented in this work. As MP2 is expected to be more basis set dependent than DFT, the small basis set computations of Michalska may fortuitously show improvement over DFT for some geometric parameters [r(Pt-O)], while showing worse agreement than DFT for other bond distances. The bond angles predicted for N−Pt−N with DFT are larger than the experimental values by 7−10°. The calculated bond angles for the O−Pt−O are also over estimated by about 6° in comparison with the experimental value. Similar results have been reported in literature.22,25 The experimental value for the N−Pt−O bond angle is 87.1o. The DFT computations show smaller values of 79.4 – 80.8o, as shown in Table 2. In Table 3, the computed values for the bond lengths and angles of oxaliplatin along with the experimental results46 are listed. Overall, the calculated bond lengths from all the theoretical levels are in good agreement with the experiment; the largest difference less than 0.02 Å. Our results are also in good agreement with the computed values reported by Tyagi et. al.47 All computed bond angles agree with experiment to within 2 degrees. Oxaliplatin contains two chiral centers (atoms 16 and 17 in Figure 1c), and a cyclohexane moiety which can take form as a chair or twist-boat conformer. Previous studies have characterized the stereochemistry of oxaliplatin with DFT. Tyagi, Gahlot, and Kakkar47 previously distinguished cis for the (R,S) form referring to the planarity of the hydrogen atoms at each chiral center. Accordingly, one NH2R is equatorial on the cyclohexyl unit and the other is axial. Both NH2R ligands are equatorial from the cyclohexyl unit in the trans-oxaliplatin optical


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isomers, (R, R) and (R,S). Due to the cyclohexyl group breaking the plane of symmetry of the Pt-ethanedioate-O,O chelation, the (R, R) and (S, S) stereoisomers are not perfect mirror images. This is recognized in the nomenclature of Tyagi by further distinguishing the structures as transd (S, S), and trans-l (R, R). Johnstone48 reported a careful analysis of the crystallographic space group of oxaliplatin, confirming the (R, R) stereochemistry of the oxaliplatin global minimum. Curiously, Tyagi, Gahlot, and Kakkar47 compute the (S,S) configuration as the lowest energy stereoisomer, after correcting for zero-point vibrational energy. In Table 4, it can be seen that the (R,R) isomer is lowest in energy at all levels of theory. Our computations show that ∆E0 for (S,S) is less than +0.02 kcal mol-1 compared to the (R,R) isomer. With both B3LYP and B97D3 functionals, when correlation consistent basis sets and empirical dispersion corrections are employed, the (R, R) and (S, S) isomers have a difference in their ZPVE-corrected energy of less than 0.01 kcal mol-1. However, after thermal and entropic effects are included, the (R,R) isomer is more stable by 0.41 – 0.42 kcal mol-1 at the best levels of theory. The GD3BJ empirical dispersion correction stabilizes the relative energy of the (R,S) isomer considerably, but its ∆G is1.0 kcal mol-1 relative to the (R,R) configuration using the B3LYP/ aug-cc-pVTZ + GD3BJ level of theory. Table 5 demonstrates some selected optimized geometric parameters of nedaplatin computed employing various levels of DFT. We have mainly focused on the bond lengths and angles of oxygen and nitrogen atoms in close vicinity of the platinum atom; R(Pt–N4), R(Pt–N5), R(Pt– O2), R(Pt–O3), ∠(O2–Pt–N4), ∠(O3–Pt–N5), ∠(O2–Pt–O3), and ∠(N4–Pt–N5). Computed values are compared with the X-ray crystal structure analysis of nedaplatin.49 Table 5 shows that the experimental value for the bond length of Pt–N4 is slightly longer than the bond length of Pt–N5. A similar trend is observed for the computed values at all levels of theory. A comparison of the



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bond lengths of Pt–O2 and Pt–O3 also shows both experimental and computed values of Pt–O2 are somewhat longer than Pt–O3. All levels of theory provide bond lengths of Pt–N4, Pt–N5, Pt– O2 and Pt–O3 to be very close to the experimental values typically within 0.1 Å. Regarding the bond angles, all calculations underestimate the bond angles of O2–Pt–N4 and O3–Pt–N5 by 7.5° to 11.1°. For the ∠(O2–Pt–O3), the calculated values are found to be overestimated by 2.8 - 3.7° as compared to the experimental value. The largest discrepancy, 14.5 – 17.1°, was found comparing calculated values and the experimental value of the N4–Pt–N5 bond angle. Although, Alberto et. al50 have investigated hydrolysis mechanism of nedaplatin using DFT, they do not explicitly discuss structural and vibrational properties of nedaplatin. Banerjee51 also used DFT to analyze reactions of nedaplatin with thiosulfate rescue agents. Our computed bond lengths are in good agreement with those reported by Banerjee. With all levels of theory, a plane of symmetry is observed for nedaplatin (with a Cs point group). Table 6 demonstrates some selected optimized geometric parameters of heptaplatin computed employing various levels of DFT.

Structurally, heptaplatin is the most

stereochemically complex of the various platin derivatives, but also has the least amount of structural data available in the literature. Complicating discussion of structure even further is that the isopropyl moiety can adopt an anti or syn conformations with the bicyclic component. At the B3LYP/ aug-cc-pVTZ + GD3BJ level of theory, seven major low-lying conformations were characterized and relative energies are reported in Table 7. The (4S,5R)/(4R,5S)-anti conformations have Cs point group symmetry, while the (4S,5S)/(4R,5R)-anti conformations have no planes of molecular symmetry. Though supplies of heptaplatin drug are labelled as (4R,5R), there is no published crystallographic evidence of this in the literature. In the gas phase computations, we find that the (4S,5R) diastereomers are only 0.1 kcal mol-1 higher in energy,


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and actually 0.9 kcal mol-1 lower in free energy at 298.15 K. From Table 6, there are no structural features that distinguish between the two lowest energy diastereomers. It is surprising that multiple conformational possibilities exist for the lowest-energy conformer of heptaplatin. Without higher-level electronic structure theory, further speculation is not warranted. Indeed, when implicit solvation is included in the B3LYP aug-cc-pVTZ + GD3BJ computations via the SMD model52, the (4R,5R) configuration is 2.6 kcal mol-1 lower in free energy than (4S,5R) configuration. More on the stereochemistry of heptaplatin will be discussed below in section 3.2.5. 3.2 Vibrational Spectra. Figures 2a and 2b present normal Raman spectra of the five anticancer drugs; cisplatin, carboplatin, oxaliplatin, nedaplatin and heptaplatin focused on two regions; Figure 2a shows the peaks between 50 to 600 cm-1 and Figure 2b shows the region from 600 to 1800 cm-1. We have included the overall spectra from 50 to 3500 cm-1 in the supporting information of this paper (Figure S1). Figure 2a is special interest since most platinum-ligand stretching vibrations occur in the range from 50 to 600 cm-1. As seen from the figure, the region in Figure 2b has a very complicated spectrum for each drug and shows many high-intensity peaks. We will use our theoretical findings to attempt an assignment for each peak using various levels of theory. Figure 3 compares IR spectra of all five drugs between 500 to 2000 cm-1. The overall ranges for all the drugs have also been included in the SI of this paper (Figure S2). Some of the peaks with larger intensities have been marked as shown in Figure 3. Figures 4-7 compares the theoretical Raman vibrational frequencies (from 400 – 1800 cm-1) obtained from the four levels of theory with the experimental Raman spectra for all the drugs. We have shown the peaks between 400─1800 cm-1. In Figure 8, computed Raman spectra of the (4R,5R)-anti and (4R,5S)-anti conformers of heptaplatin are shown with the experimental



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spectrum. In Figures 4-8, there is no scaling of the computed vibrational frequencies for anharmonicity or for methodological errors. We seek to compare important common or unique features of the various cisplatin derivative spectra with acceptance of the systematic error that comes from the harmonic approximation to vibrational frequency computations. As many references in this contribution show, scaling factors are quite useful for calibration of theory and comparison to experiment. However, due to chemical diversity of cisplatin derivatives, universally accurate scale factors remain elusive. 3.2.1 Cisplatin. The theoretical and experimental normal Raman spectra of cisplatin are presented in Figure 4. An expanded view for the experimental frequencies between 700 to 1800 cm-1 is inset to show the frequencies in this region with smaller intensities. Table S1 presents Raman and IR intensities for various levels of theory. In Table S2 predicted Raman and IR intensities are given with assigned normal vibrational mode atom displacements at the B3LYP/ aug-cc-pVTZ+GD3BJ level of theory. All computations predict lower values for the experimentally observed peaks at 505 and 522 cm-1. In the computed spectra, the lower energy peak attributed to antisymmetric Pt-N stretching (Q10) has a 1:3 intensity ratio to the symmetric stretching peak (Q11) ~10 cm-1 higher in energy and appears as a shoulder in Figure 4. In agreement with experiment, Q11 is the vibrational mode with the largest computed Raman intensity value. For the peaks at 807 and 910 cm-1 most levels of theory predict lower values for the frequencies. However, the smaller basis sets (B3LYP/BS1 and B3LYP/BS1 + GD3BJ) match experiment fortuitously well with a 12 cm-1 difference. Polymorphism in solid cisplatin has been attributed to broadening in the noisy low-intensity peaks seen experimentally between 700 – 1100 cm-1. These broad peaks are attributed to NH3 rocking modes of the various conformations in thermal equilibrium. The polymorphism of cisplatin has been studied


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thoroughly (experimentally and theoretically) by other groups. Specifically, Marques, Batista de Carvalho, and coauthors explored temperature-dependent Raman spectroscopy to investigate the α-to-β polymorphic transition that occurs in cisplatin.53 Their work shows that clear resolving of ρ(NH3) bands in the α polymorph can only occur at temperatures of 150 K or lower. In this work, the experimental Raman spectrum of cisplatin, recorded at room temperature, matches well with that of Marques, Batista de Carvalho, and coauthors (c.f. Figure 3, reference 53). All higher energy Raman-active modes between 1200 and 1700 cm-1 correspond to various NH3 deformation modes. The smallest (BS1) and largest (aug-cc-pVTZ) basis sets are in reasonable agreement with experiment, but still red-shifted from the observed values of 1294 and 1312 cm-1. The antisymmetric mode (Q16) has a ~1:12 intensity ratio and is not visible in the computed spectra compared to Q17. Finally, the experimental peaks at 1535 and 1634 cm-1 are blue-shifted by theory. We do not observe clear functional and basis set quality dependence between computed and experimental Raman spectra for cisplatin (and the other platins discussed below). These results highlight the efforts of other groups to find viable harmonic frequency scale factors for cisplatin and derivatives. For example, Fiuza et. al have adjusted their computed frequencies with various scaling factors to compare better with experiments.43 Because there is no obvious decoupling of vibrational anharmonicity and methodological error, our discussion will account for discrepancies in computed harmonic frequencies and experimental fundamental frequencies for platin vibrational modes. In the literature, Gao et. al23 has reported an experimental Raman spectrum for the cisplatin. A comparison between their reported spectrum and the data presented here (Figures 2a, 2b and S1) shows our spectrum has a higher resolution, for example, the peak around 525 cm-1 in their spectra shows a slight shoulder, however we observe two resolved peaks (522 and 505 cm-



1

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) in our data. Furthermore, we have obtained the vibrational signature of cisplatin at a larger

frequency range (50−3600 cm-1). In the far-IR/low energy Raman region, the Pt-Cl stretching frequencies computed to be 338 and 349 cm-1 match quite well with the broad peak at 322 cm-1 in Figure 2a. The Cl-Pt-Cl bending mode also has appreciable intensity in the Raman computations. The computed frequency of 152 cm-1 is in excellent agreement with the experimental Raman value of 158 cm-1. Likely these low-energy peaks are less affected by the systematic error caused by anharmonicity and could be more appropriate as chemical diagnostics. Tasinato, Puzzarini, and Barone have recently published interesting work on the dimer of cisplatin, utilizing a harmonic force field with CCSD(T) and anharmonic corrections with dispersion-corrected B3PW91 and B2PLYP functionals.54 Their work showed that cisplatin dimer computations had a much smaller mean absolute deviation (15 cm-1) compared to experimentally observed Raman modes than monomer computations (45 cm-1). However, we find that no critical fundamental vibrational modes of cisplatin are qualitatively misassigned in their monomer calculations. Also, dimer computations at CCSD(T) or even MP2 would become prohibitively expensive for the larger platin drugs discussed in this work. 3.2.2

Carboplatin. Figure 5 illustrates the experimental and theoretical Raman spectra

in the range of 400-1800 cm-1. The spectra computed using B3LYP/aug-cc-pVDZ, B3LYP/augcc-pVDZ GD3BJ, B97D3/aug-cc-pVDZ, and B3LYP/aug-cc-pVTZ GD3BJ are shown in the figure; the other computed spectra are embedded in the SI.

All discussion of computed

carboplatin spectra will focus on the B3LYP aug-cc-pVTZ+GD3BJ level of theory. The peak around 545 cm-1 is the most intense in the experimental spectrum which has been previously reported.25 This band has been attributed to the symmetric stretching vibration of Pt-N (Tables S3 and S4). Curiously, the computed band in this energy region with the largest Raman intensity


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at 481 cm-1 is assigned to the C(6)-C(8) / C(7)-C(8) bond stretches. The computed Pt-N symmetric and antisymmetric stretches overlap at all levels of theory and are slightly lower in energy (460 and 463 cm-1, respectively), but still quite Raman active. The most intense band overall in the theoretical spectrum is at 1751 cm-1 representing the symmetric stretching of C(67), O(12,13), with the asymmetric carbonyl stretch occurring nearby at 1726 cm-1. As is well known in the literature, the carbonyl stretches in relevant solid phase cisplatin derivatives are strongly anharmonic, influenced by intermolecular hydrogen bonding between C=O groups and ammine ligands. The difference between the computed and experimental CO stretch is 142 cm-1 at the B3LYP/aug-cc-pVTZ+GD3BJ level of theory, implying a required vibrational scale factor of 0.919. This scale factor is quite smaller than the range of 0.94-0.98 typically recommended for most DFT computations with medium or large basis sets.55-58 Based on the qualitative agreement of the computed Raman with experiment within the range of 800-1200 cm-1, a single scale factor applied to all harmonic frequencies would be inappropriate for carboplatin. In the far-IR region, the experimental peak at 190 cm-1 has the largest intensity. Theoretically, this peak is assigned to overlapping N-Pt-O bending modes at 190 and 196 cm-1, but the computed intensity does not agree well with experiment. 3.2.3 Oxaliplatin. In Figure 6, comparison between four of the theoretical spectra with the experimental results is presented. The remaining levels of theory are shown in the SI of this paper (Figure S5). For discussion of peaks between 400 to 1800 cm-1, we have normalized the computed peaks to the lower-intensity peak of the pair at 1700-1800 in Figure 6. The SI contains the unnormalized experimental Raman spectrum of oxaliplatin (Figure S5). Table S6 in the SI of the paper displays the predicted Raman and IR intensities of oxaliplatin at the B3LYP/aug-ccpVTZ+GD3BJ level of theory. The peak around 1692 cm-1 is the most intense in the



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experimental spectrum in the 400-1800 cm-1 range, the theory predicts the highest peak to be around 1729 cm1. This peak corresponds again to carbonyl stretching. While the computed peak at 1652 cm-1 shows high intensity, this peak is actually assigned to a NH3 deformation mode. The computed carbonyl stretching frequencies are overestimated due to the harmonic approximation and appear at 1773 and 1796 cm-1. Overall in oxaliplatin, NH3 and H-N-C deformation modes show more proportional intensity to the carbonyl stretching frequency, which results in very crowded theoretical spectra. At the B3LYP/aug-cc-pVTZ+GD3BJ level, Raman active peaks nearly overlap at 563 and 575 cm-1, respectively. Tyagi and Kakkar47reported a computed peak at 551 cm-1 for Pt-N stretching. However, from the PED analysis of vibrational modes, assignment of the Pt-N stretching modes is not trivial due to severe mixing with other stretching coordinates. Surprisingly, the primary component of the peaks at 563 and 575 cm-1 is the C-C stretch of the dione. The experimentally observed peak at 216 cm-1 completely dominates the far-IR region of the Raman spectrum. Unlike other cisplatin derivatives in this study, this intense low-energy peak is also seen in the computed spectrum of oxaliplatin. The PED analysis attributes the corresponding mode at 187 cm-1 in the computations to belong to Pt-N-C bending. 3.2.4 Nedaplatin. Figure 7 presents the theoretical and experimental normal Raman spectra of nedaplatin between 400 to 1800 cm-1. Computed spectra of all levels of theory are included in Figure S6 (and Table S7). We have also listed our findings in Table S8 showing the B3LYP/aug-cc-pVTZ+GD3BJ levels of theory with predicted Raman and IR intensities. The experimental results show the most intense peak to be around 537 cm-1, however all levels of theory suggest that the Raman peak with the largest intensity is Q34 corresponding to the carbonyl stretch at 1754 cm-1. To the best of our knowledge, no computational or theoretical studies have investigated the vibrational frequencies of nedaplatin.


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The asymmetric stretching vibration of Pt-N is found to be 447 cm-1 with the asymmetric stretch is 462 cm-1 using the B3LYP/aug-cc-pVTZ+GD3BJ level of theory. Interestingly, these frequencies are found to be close to the values found for Pt-N stretching vibration in cisplatin and carboplatin, but about 100 cm-1 lower than that found for the same vibration in oxaliplatin. For the structure computed using B3LYP/aug-cc-pVTZ+GD3BJ, there are two peaks with low Raman intensity between 728-768 cm-1 that correspond to rocking/wagging motion of the NH bonds. In very good agreement between experiment and theory are the peaks that stick out of fluorescence background such as the peak at 929 cm-1, which corresponds to the O(2)-C(6) stretching mode computed at 904 cm-1. The carbonyl stretching modes have a large Raman intensity according to computation, but these peaks are not very large in the experimental Raman spectrum. The second highest intensity peak in the computed Raman spectra at 611 cm-1 is assigned to the Pt-O stretching motion. 3.2.5 Heptaplatin. Figure 8 presents the theoretical and experimental normal Raman spectra of heptaplatin between 400 to 1800 cm-1. Computed spectra of all levels of theory are included in the SI (Table S8). We have also listed our findings in Table S9 showing the B3LYP/aug-cc-pVTZ+GD3BJ levels of theory with predicted Raman and IR intensities. Figure 8 provides differences of (R, R) and (R, S) simulated Raman spectra compared to the experiment. Discussion will be limited to the (4R, 5R) diastereomer of heptaplatin unless otherwise specified. Similar to oxaliplatin, frequencies of carbonyl stretching heptaplatin have the largest Raman intensity at 1739 and 1755 for the antisymmetric and symmetric peaks, respectively. The peaks with the second largest intensity are at 1051 and 1066 cm-1 corresponding to C-C backbone symmetric/anti-symmetric stretching. In the region of 400 – 600 cm-1, there are clear differences in the computed Raman spectrum of the (4R, 5R) and (4R, 5S)



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configurations. Experimentally, a set of four peaks exists at 479, 490, 542, and 576 cm-1. With the peak at 479 cm-1 being the largest of the four and the peak at 490 cm-1 appearing to be an overlapping shoulder. Computationally, only two peaks in this region are evident for the (4R, 5R) diastereomer, while there are three for the (4R, 5S) diastereomer. For the (4R, 5R) configuration, the Raman peak corresponding to Pt-N symmetric stretching is at 495 cm-1. The Raman intensity of this computed peak is quite low compared to the similar Pt-N stretch at 492 cm-1 in the (4R,4S) diastereomer. The high intensity peak at 451 cm-1 in the (4R, 5R) configuration is a mix of several different normal coordinates in the VEDA that corresponds to primarily (but only with about a 10% contribution) to an H-C-C-O torsional motion. The peak at 558 cm-1 is much easier to assign, and belongs to symmetric C-C stretching. Unfortunately, there are no obvious differences to the computed Raman spectra in the 50 – 400 cm-1 region that would help us clearly identify the correct stereoconfiguration of heptaplatin.

Table S10

summarizes the low-energy modes with high Raman intensity (Raman active Pt-N/Pt-O stretching modes) for each drug. 3.2.6 Recommendations for Computational Studies of Platin Vibrational Spectroscopy. While discussion in previous sections has explicitly reported data obtained via the most “rigorous” methodology – B3LYP/ aug-cc-pVTZ + GD3BJ, it becomes evident from Figures 4-8 and Tables 1-6 that there is no qualitative difference in the structural data and harmonic vibrational spectra computed with B3LYP/ aug-cc-pVTZ + GD3BJ and B3LYP aug-cc-pVDZ + GD3BJ. Due to the energy convergence issues that manifested in the B3LYP/ aug-cc-pVTZ + GD3BJ heptaplatin computations, and the increased computational requirements for the larger platin derivatives, B3LYP/aug-cc-pVDZ + GD3BJ is recommended for future study of platin derivatives. This level of theory provides a balance between the stability of Kohn-Sham


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equations, tractability, and accuracy with respect to experiment. The B3LYP/aug-cc-pVDZ + GD3BJ level of theory will be employed in proceeding sections to compute the effects of intermolecular interactions and vibrational anharmonicity of the Pt-based drugs. 3.3 Dimer Computations. Thanks to an insightful Reviewer comment, the authors realized that an investigation of cisplatin and four Pt-centered derivatives with consistent spectroscopic methods does afford a unique opportunity to calibrate computational efforts against experiment. As previously mentioned, Tasinato, Puzzarini54, and Barone recently studied vibrational spectroscopy of cisplatin dimer using a slew of robust levels of theory. However, their findings may not be transferable to other platin derivatives due to the computational expense of double-hybrid functionals, MP2 and CCSD(T) methodologies. In Figures 9-12, Raman spectra of the dimers of cisplatin, nedaplatin, carboplatin, and oxaliplatin are respectively compared to the computed monomer and experimental solid-state spectra. These plots are computed at the B3LYP aug-cc-pVDZ + GD3BJ level of theory, and the range of 400 – 1800 cm-1 is shown. For cisplatin (Figure 9), geometry optimization of the dimer gives a C2 symmetric structure with a Pt-Pt bond length of 3.298 Å, and a dimer stabilization energy of 30.3 kcal mol-1. The Raman spectrum of the dimer shows a pronounced blue shift of all Raman active vibrational frequencies, and is in considerably better agreement with experiment than the monomer spectrum. Raman activities relative to experiment are also significantly improved, especially the various angle bending modes between 1500 and 1700 cm-1. Due justifiable compromises made in the level of theory reported here, dimeric structural parameters do not show the same improvement against experiment data that was reported by Tasinato, Puzzarini, and Barone54 with double-hybrid density functionals and aug-cc-pVTZ-quality basis sets. For example, the



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dimeric Pt-N bond lengths are computed to be 2.073 Å (versus 2.054 Å in experiment) and the Pt-Cl bond lengths are computed to be 2.342 Å (versus 2.318 Å in experiment). For the other Pt-based drugs, modeling the dimer has a much more complicated influence on the Raman spectroscopy (Figures 10-12). The geometry optimization of carboplatin reveals a Ci symmetric structure with an equilibrium Pt-Pt bond distance of 3.421 Å, and a dimer stabilization free energy of 40.9 kcal mol-1. Similar to cisplatin, blue-shifting of low-energy carboplatin peaks from 400 – 1000 cm-1 (Figure 10) improves agreement with experiment. The computed Raman activities of Q34 at 947 cm-1 [symmetric stretching of C(6)-C(8) and C(7)-C(8)] and Q35 at 964 cm-1 [symmetric bending of C(8)-C(11)-C(10) and C(9)-C(10)-C(11)] are a near perfect match with the experimentally observed mode at 945 cm-1. The computed line shapes of NH3 bending modes between 1619 and 1684 cm-1 are also in better qualitative agreement with the experimental spectrum. Curiously, the largest experimental Raman peak for carboplatin, at 545 cm-1 is still not well-represented computationally by the carboplatin dimer peak at 583 cm-1. In Figure 11, the computed oxaliplatin dimer Raman spectrum is compared to the monomer computations and experimental Raman spectrum. Again, the optimized structure belongs to the Ci point group. Because oxaliplatin has a more elongated structure with less access to hydrogen bonding between the two monomers, the Pt-Pt bond distance (4.040 Å) is quite longer than the other Pt-centered drugs. Interestingly, oxaliplatin has the largest dimerization free energy (46.6 kcal mol-1), perhaps due to dispersion effects. In Figure 11, the profile of Raman peaks in the dimer computations are in remarkably better agreement with experiment. For example, the dimer computation shows a Raman-active C-C stretching frequency at 855 cm-1, which matches very well with the experimental peak at 847 cm-1. Additionally, the overall lineshape of peaks between 750 – 950 cm-1 agree with experiment.


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From the theoretical oxaliplatin dimer Raman spectrum, carbonyl stretching frequencies are redshifted and in fantastic agreement with experiment. Figure 12 depicts the computed nedaplatin monomer and dimer Raman spectra, compared with experiment. Geometry optimization of nedaplatin dimer provides a Ci symmetric structure with an equilibrium Pt-Pt bond distance of 3.185 Å, and a dimer stabilization free energy of 30.5 kcal mol-1. Similar to the previous cisplatin derivatives, the nedaplatin dimer Raman spectrum is a significant improvement over the computed monomer spectrum. Relative peak heights of the nedaplatin dimer are closer to experiment. The profiles of the carbonyl stretching mode and NH3 deformation modes in the nedaplatin dimer agree with experiment in both intensity and frequency. 3.4 Anharmonicity Computations. The computational investigation of cisplatin dimer by Tasinato, Puzzarini, and Barone54 unfortunately does not separately report the contributions of dimerization and incorporation of anharmonic effects. In Figure 9, anharmonicity effects are shown for the computed Raman spectrum of the cisplatin monomer and dimer. Fundamental vibrational frequencies are plotted, along with any overtone and combination bands that show appreciable Raman activity. As seen in Figures S7 and S8 (for nedaplatin), inclusion of overtone and combination bands to the theoretical plots adds almost no visible effect or improvement to the Raman spectra. Meeting expectations, anharmonic vibrational frequencies for cisplatin monomer and dimer are red-shifted by various amounts. The Pt-N stretching frequencies predicted in the anharmonic dimer computations are in better agreement with experiment than the anharmonic monomer computations. However, the dimer Pt-N anharmonic stretches still deviate from experiment by ~50 cm-1. Additionally, the C-C stretching frequencies near 1300 cm-1 for the



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anharmonically corrected cisplatin dimer computations are in error by 80 cm-1, but again closer than the anharmonically corrected monomer spectrum. A case of being “right for the wrong reason” is observed in the harmonic C-C stretch of cisplatin dimer near 1300 cm-1. In Figure 12, the Raman spectrum for the anharmonically-corrected nedaplatin monomer and dimer are provided. For the nedaplatin monomer, inclusion of anharmonicity does surprisingly little to improve quality of the theoretical Raman spectrum. For example, barely any red-shift of the carbonyl stretch is observed, while NH3 bending modes artificially coalesce to overlapping peaks at 1599 and 1600 cm-1. Additionally, the O(2)-C(6) stretching frequency is shifted in the wrong direction (886 cm-1) compared to experiment. Adding anharmonicity corrections to the nedaplatin vibrational analysis also has a subtle effect on computed frequencies, though curiously large changes in Raman activities are present. This could be due to inappropriate treatment of vibrational resonance using default parameters of Gaussian09. All variations in the treatment of anharmonicity and intermolecular interactions fail to give an accurate prediction of the H(15)-C(7)-O(3) bending mode, experimentally observed at 1239 cm1

. The anharmonic dimer spectrum shows the best agreement with experimental NH3 bending

peaks. Analysis of Figures 9 and 12 allows us to make an unexpected prediction – excellent agreement with experimental Raman spectra is obtained at the B3LYP aug-cc-pVDZ + GD3BJ level of theory when dimeric harmonic vibrational computations are performed. Though the sample size is small, we predict that intermolecular interactions of platin dimers have a much more significant impact on the quality of theoretical vibrational spectra, much more so than including the effects of vibrational anharmonicity on the respective monomers. Computation of optimized dimer geometry and harmonic frequencies are expected to be competitive with


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anharmonic vibrational computations of the monomers in terms of required time and resources. Even using DFT, anharmonic VPT2 computations of platin dimers are likely intractable for drug candidates larger than nedaplatin. Even with formidable resources at University of Memphis, it is estimated that the carboplatin anharmonic vibrational frequency computation would require 8+ weeks of wall time. Overall, harmonic vibrational computations of platin dimers may give far more reliable simulated spectra than harmonic or anharmonic vibrational computations of the monomer.

4

CONCLUSIONS

In this work, we have presented the experimental vibrational signatures of five platinumanticancer drugs: cisplatin, carboplatin, nedaplatin, oxaliplatin and heptaplatin. Considering the importance of these drugs in treatment of cancer, it is important to examine chemical properties of these drugs such as structural characterizations, conformations, and vibrational frequencies. It is also helpful to compare structural information of these currently used drugs in order to synthesize new drugs. Although there are some theoretical computations in the literature for structure and vibrational spectroscopy of these drugs, only experimental characterization of IR or Raman spectra for cisplatin and carboplatin have been published. As discussed earlier, one of the challenges to compare theoretical and experimental vibrational frequencies is a transferable scheme for determining vibrational scaling factors. As seen in this work and others [20-24], this task has proven to be difficult. Often times, there are different scaling factors for various theoretical levels for different regions of the IR spectrum, and for different platinum drugs. Without a similar organic scaffold to the other four Pt-centered drugs studied here, vibrational scale factors derived from cisplatin should not be transferrable to 23 ACS Paragon Plus Environment


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more structurally complex derivatives. We have attempted to show a qualitative examination of unscaled harmonic vibrational frequencies with VEDA. Even without a comprehensive breakdown of normal mode mixing or phase, VEDA can provide a reasonable way to compare vibrational modes of cisplatin derivatives and provide new insight. We found that frequencies for the Pt-N stretching vibration in cisplatin, carboplatin, and nedaplatin are all Raman active and within a very small energy range of 444 – 463 cm-1. These three drugs have simple ammine (MNH3) ligands. Oxaliplatin and heptaplatin have more structurally complex M-NH2R ligands. Between 430 – 500 cm-1, Raman active vibrational peaks are highly mixed and interestingly are not dominated by Pt-N stretching modes. For these two cisplatin derivatives, CC and Pt-O stretching frequencies in the various bidentate dioxo ligands might be more useful in characterizing structurally similar candidate drugs. Our work highlights that Raman-active peaks between 200-600 cm-1 might serve as better diagnostics for Pt-DNA binding and anti-cancer activity. These normal modes will also be less influenced by errors from using the vibrational harmonic approximation. Harmonic vibrational spectra were computed for dimers of all candidate drugs except for the prohibitively large heptaplatin. For cisplatin and nedaplatin, harmonic dimer vibrational spectra were in better qualitative agreement with experiment compared to anharmonic vibrational computations of the monomers. Satisfying agreement with experimental Raman spectra was obtained, even without resorting to linear scale factors for the harmonic dimer frequencies. Vibrational spectra of cisplatin derivatives can be reliably computed using the B3LYP aug-cc-pVDZ + GD3BJ level of theory. The much larger aug-cc-pVTZ basis set resulted in only incremental improvement of spectral prediction, but greatly increased computational cost an exhibited SCF convergence issues with heptaplatin.


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The detailed structural and vibrational findings of all these drugs are very important for control of chemical reactions and diagnostics of the drug dynamics. The current research provides sufficient details for realization of several schemes of quantum control described in [8]. Also, the obtained results provide important spectroscopic data to guide future work monitoring or controlling the substances during medical treatment using laser Raman spectroscopy [3].

Supporting Information: We have included the overall spectra from 50 to 3500 cm-1 in the supporting information (SI) of this paper. Comparisons of the experimental Raman spectra and theoretical calculations for all seven levels of theory are also presented in the SI. Furthermore, see the SI of this paper for the low-energy modes of each drug with high Raman intensity (Raman active Pt-N/Pt-O stretching modes). Tables including the theoretical frequencies and their assignments are also included in the SI.

Acknowledgments This research was supported by the Robert H. Welch Foundation and Texas Woman’s University Research Enhancement Program. N.J.D. thanks the University of Memphis and Department of Chemistry for start-up funding. The High Performance Computing Center and the Computational Research on Materials Institute at The University of Memphis (CROMIUM) provided generous resources for this research.



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Cyclohexanediamine) and Pt (Malonato) ( 1R, 2R-Cyclohexane-Diamine). Inorg. Chem. Acta. 1984, 92, 279-284. 47. Tyagi, P.; Gahlot, P.; Kakkar, R. Structural Aspects of the Anti-Cancer Drug Oxaliplatin: A Combined Theoretical and Experimental Study. Polyhedron, 2008, 27, 3567-3574. 48. Johnstone, T. C. The Crystal Structure of Oxaliplatin: A Case of Overlooked Pseudo Symmetry. Polyhedron 2014, 67, 429-435. 49. Wang, Q.-K.; Pu, S.-P.; Cong, Y.-W.; Li, Y.-N.; Luan, C.-F. cis-Diammine (glycolato-k2O1, O2)-platinum(II). Acta Cryst. 2009, E65, M1687. 50. Alberto, M. E.; Lucas, M. F.; Pavelka, M.; Russo, N. The Second-Generation Anticancer Drug Nedaplatin: A Theoretical Investigation on the Hydrolysis Mechanism. J. Phys. Chem. B 2009, 113, 14473-14479. 51. Banerjee, S. Understanding the Ring‑Opening, Chelation and Non‑Chelation Reactions between Nedaplatin and Thiosulfate: a DFT Study Based on NBO, ETS‑NOCV and QTAIM. Theor. Chem. Acc. 2016, 20, 135:20. 52. Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. Universal Solvation Model Based on Solute Electron Density and on a Continuum Model of the Solvent Defined by the Bulk Dielectric Constant and Atomic Surface Tensions. J. Phys. Chem. B 2009, 113, 6378-96. 32 ACS Paragon Plus Environment

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53. Paula, M.; Marques, M.; Valero, R.; Parker, S. F.; Tomkinson, J. Batista de Carvalho, L. A E. Polymorphism in Cisplatin Anticancer Drug. J. Phys. Chem. B, 2013, 117, 6421–6429. 54. Tasinato, N.; Puzzarini, C.; Barone, V. Correct Modeling of Cisplatin: a Paradigmatic Case. Angew. Chem. Int. Ed. 2017, 56, 13838-13841. 55. https://cccbdb.nist.gov/vibscalejust. 56. Alecu, I. M.; Zheng, J.; Zhao, Y.; Truhlar, D. G. Computational Thermochemistry: Scale Factor Databases and Scale Factors for Vibrational Frequencies Obtained from Electronic Model Chemistries. J. Chem. Theory Comput. 2010, 6, 2872-2887. 57. J. Baker, J.; A. A. Jarzecki, A.A.; Pulay, P. Direct Scaling of Primitive Valence Force Constants: An Alternative Approach to Scaled Quantum Mechanical Force Fields. J. Phys. Chem. A, 1998, 102, 1412–1424. 58. Rauhut, G.; Pulay, P. Transferable Scaling Factors for Density Functional Derived Vibrational Force Fields. J. Phys. Chem. 1995, 99, 3093–3100.



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Figure 1. Structure and numbering schemes of (a) cisplatin, (b) carboplatin, (c) oxaliplatin, (d) nedaplatin, and (e) heptaplatin.


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Figure 2a Comparison between experimental Raman frequencies between 50 to 600 cm-1 for all five drugs. It should be mentioned that our spectral resolution is about 5 cm-1, therefore the values given are chosen at the maximum point of each peak. 35 ACS Paragon Plus Environment


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Figure 2b Comparison between experimental Raman frequencies between 600 to 1800 cm-1 for all five drugs. It should be mentioned that our spectral resolution is about 5cm-1, therefore the values given are chosen at the maximum point of each peak.



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Figure 3 Comparison between experimental IR frequencies between 500 to 2000 cm-1 for all five drugs. The x-axis shows wavenumber measured in cm-1 and the y-axis shows the intensity measured in arbitrary units.


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Figure 4 Comparison of the experimental Raman spectrum and the theoretical calculations for cisplatin. Raman Shifts are only shown from 400- 1800 cm-1. The computed vibrational frequencies are shown without linear scaling factors.


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Figure 5 Comparison of the experimental Raman spectrum and the theoretical calculations for carboplatin. Raman Shifts are only shown from 400- 1800 cm-1. The computed vibrational frequencies are shown without linear scaling factors.


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Figure 6 Comparison of the experimental Raman spectrum and the theoretical calculations for oxaliplatin. Raman Shifts are only shown from 400- 1800 cm-1. The computed vibrational frequencies are shown without linear scaling factors.


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Figure 7 Comparison of the experimental Raman spectrum and the theoretical calculations for nedaplatin. Raman Shifts are only shown from 400- 1800 cm frequencies are shown without linear scaling factors.

-1

. The computed vibrational

. 45

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Figure 8 Diastereomers comparison of the experimental Raman spectrum and the theoretical calculations for heptaplatin. Raman Shifts are only shown from 400- 1800 cm -1. The theoretical spectra are shown without scaling factor. Boltzmann averaging of (R,S) and (R,R) heptaplatin


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spectrum is obtained by Boltzmann weighting of the individual plots based on relative free energies in Table 7.



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Figure 9 Comparison of the experimental Raman spectrum and the theoretical calculations for cisplatin. Raman Shifts are only shown from 400-1800 cm-1. The computed vibrational frequencies are shown without linear scaling factors.


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Figure 10 Comparison of the experimental Raman spectrum and the theoretical calculations for carboplatin. Raman Shifts are only shown from 400- 1800 cm

-1


frequencies are shown without linear scaling factors. 49 ACS Paragon Plus Environment


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Figure 11 Comparison of the experimental Raman spectrum and the theoretical calculations for oxaliplatin. Raman Shifts are only shown from 400- 1800 cm

-1


frequencies are shown without linear scaling factors. 50 ACS Paragon Plus Environment

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Figure 12 Comparison of the experimental Raman spectrum and the theoretical calculations for nedaplatin. Raman Shifts are only shown from 400- 1800 cm -1. The computed vibrational frequencies are shown without linear scaling factors.



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Table 1. Comparison of Calculated Bond Lengths (in Å) and Bond Angles (in deg.) Calculated for Cisplatin with Various Levels of Theory

Geometry R(Pt–N) R(Pt–Cl) R(N4–H7) (1/3) R(N4–H6) (2/3) R(N–H) avg ∠(N–Pt–N) ∠(N–Pt–Cl) ∠(Cl–Pt–Cl) ∠(H6–N4–H7) (1/3) ∠(H6–N4–H10) (2/3) ∠(H–N–H) avg ∠(H7–N4–Pt) (1/3) ∠(H6–N4–Pt) (2/3) ∠(H–N–Pt) avg

Exp.

40,41

2.054 2.318

1.00 90.2 88.9 91.9

107

111

B3LYP BS1

B3LYP BS1 GD3BJ

B3LYP aug-ccpVDZ

2.119 2.346 1.026 1.019 1.021 98.2 83.2 95.3

2.114 2.342 1.026 1.019 1.021 98.1 83.3 95.3

2.098 2.318 1.027 1.019 1.022 98.2 83.1 95.5

B3LYP aug-ccpVDZ GD3BJ 2.093 2.314 1.027 1.019 1.022 98.1 83.2 95.5

B97D3 aug-ccpVDZ

B3LYP aug-ccpVTZ

2.094 2.314 1.031 1.022 1.025 98.2 83.2 95.5

2.100 2.307 1.022 1.015 1.017 98.1 83.2 95.5

B3LYP aug-ccpVTZ GD3BJ 2.095 2.304 1.022 1.014 1.017 98.0 83.2 95.5

108.5

108.5

108.1

108.1

108.2

108.4

108.4

109.1

109.2

108.5

108.6

108.6

108.7

108.8

108.9 102.6 113.9 110.1

109 102.6 113.8 110.1

108.4 102.4 114.6 110.5

108.4 102.4 114.5 110.5

108.5 102.6 114.4 110.5

108.6 102.3 114.4 110.4

108.6 102.3 114.2 110.2


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Table 2. Comparison of Calculated Bond Lengths (in Å) and Bond Angles (in deg.) Calculated for Carboplatin with Various Levels of Theory Geometry R(Pt–N4) R(Pt–N5) R(Pt–O2) R(Pt–O3) ∠(N4–Pt–N5) ∠(O2–Pt–O3) ∠(N5–Pt–O3) ∠(N4–Pt–O2) ∠(Pt–O3–C7) ∠(Pt–O2–C6)

Exp.

45

2.021 2.021 2.025 2.025 95.3 90.5 87.1 87.1

B3LYP BS1

B3LYP BS1 GD3BJ

B3LYP aug-ccpVDZ

2.115 2.116 2.004 2.005 104.7 96.2 79.5 79.5 123.0 122.7

2.110 2.111 2.003 2.005 104.9 96.2 79.4 79.4 122.0 121.6

2.088 2.089 1.986 1.987 103.2 96.1 80.3 80.3 123.3 122.8

B3LYP aug-ccpVDZ GD3BJ 2.083 2.083 1.986 1.987 103.3 96.1 80.3 80.3 122.2 121.8

B97D3 aug-ccpVDZ

B3LYP aug-ccpVTZ

2.088 2.089 1.994 1.995 102.8 95.7 80.7 80.8 121.6 121.2

2.089 2.089 1.981 1.981 103.1 95.9 80.5 80.5 123.7 123.3

B3LYP aug-ccpVTZ GD3BJ 2.084 2.084 1.980 1.981 103.2 95.9 80.4 80.4 122.7 122.3



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Table 3. Comparison of Calculated Bond Lengths (in Å) and Bond Angles (in deg.) Calculated for Oxaliplatin with Various Levels of Theory

Geometry

Exp.

R(Pt–N6) R(Pt–N5) R(Pt–O9) R(Pt–O8) ∠(O8–Pt–O9) ∠(N6–Pt–O9) ∠(N5–Pt–O9) ∠(N6–Pt–O8) ∠(N5–Pt–O8) ∠(N5–Pt–N6) ∠(C11–O9–Pt) ∠(C10–O8–Pt)

46

2.10 2.11 2.01 2.01 84.2 96.8 179.1 178.1 96.6 82.4 112 114

B3LYP BS1 GD3BJ

B3LYP BS1 2.117 2.117 2.011 2.011 83.8 97.0 179.1 179.1 97.0 82.1 113.1 113.1

2.110 2.110 2.009 2.009 84.0 96.8 179.1 179.1 96.8 82.4 113.0 113.0

B3LYP aug-ccpVDZ 2.085 2.085 1,991 1.991 84.1 96.5 179.3 179.3 96.5 82.8 113.4 113.4

B3LYP aug-ccpVDZ GD3BJ 2.081 2.081 1.991 1.991 84.2 96.5 179.3 179.3 96.5 82.9 113.3 113.3

B97D3 aug-ccpVDZ 2.084 2.084 2.001 2.001 84.4 96.4 179.1 179.1 96.4 82.8 113.0 113.0

B3LYP aug-ccpVTZ 2.086 2.086 1.985 1.985 84.0 96.6 179.3 179.3 96.6 82.8 113.7 113.7

B3LYP aug-ccpVTZ GD3BJ 2.081 2.081 1.985 1.985 84.0 96.5 179.3 179.3 96.5 82.9 113.6 113.6

Table 4. Relative ZPVE-corrected Energies and Gibbs Free Energies of the Oxaliplatin

(R,R)

PW91 631G** + ECP (Tyagi) ∆E0 0.3

B3LYP BS1

B3LYP BS1 GD3BJ

B3LYP augcc-pVDZ

B3LYP augcc-pVDZ GD3BJ

B97D3 aug-ccpVDZ

B3LYP aug-ccpVTZ

B3LYP augcc-pVTZ GD3BJ

∆E0 0.00

∆G 0.00

∆E0 0.00

∆G 0.00

∆E0 0.00

∆G 0.00

∆E0 0.00

∆G 0.00

∆E0 0.00

∆G 0.00

∆E0 0.00

∆G 0.00

∆E0 0.00

∆G 0.00

(S,S)

0.0

0.02

0.40

0.02

0.37

0.00

0.41

0.00

0.41

0.00

0.41

0.01

0.42

0.00

0.42

(R,S)

1.1

1.88

1.94

0.69

0.76

1.90

1.97

0.71

0.82

0.68

0.78

2.03

2.10

0.85

0.96

(R,R) twist boat

6.6

6.91

6.28

6.94

6.23

6.59

6.02

6.63

6.01

6.53

5.76

6.65

6.08

6.69

6.07

Stereoisomers (in kcal mol-1)


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Table 5. Comparison of Calculated Bond Lengths (in Å) and Bond Angles (in deg.)

Geometry R(Pt–N4) R(Pt–N5) R(Pt–O2) R(Pt–O3) ∠(O2–Pt–N4) ∠(O3–Pt–N5) ∠(O2–Pt–O3) ∠(N4–Pt–N5)

Exp.

49

2.038 2.017 2.013 2.01 93.18 94.6 83.82 88.4

B3LYP BS1

B3LYP BS1 GD3BJ

B3LYP aug-ccpVDZ

2.134 2.117 2.003 1.985 85.0 83.0 86.6 105.4

2.128 2.112 2.001 1.984 84.8 82.9 86.8 105.5

2.107 2.090 1.985 1.967 85.4 83.7 87.1 103.9

B3LYP aug-ccpVDZ GD3BJ 2.102 2.085 1.984 1.966 85.3 83.6 87.2 103.9

B97D3 aug-ccpVDZ

B3LYP aug-ccpVTZ

2.103 2.089 1.990 1.973 85.7 84.0 87.5 102.9

2.108 2.091 1.980 1.962 85.5 83.7 86.9 103.9

B3LYP aug-ccpVTZ GD3BJ 2.103 2.086 1.979 1.961 85.4 83.6 87.1 103.9

Calculated for Nedaplatin with Various Levels of Theory



Geometry R(Pt–N9) R(Pt–N10) R(Pt–O2) R(Pt–O3) ∠(O2–Pt–N9) ∠(O3–Pt–N10) ∠(O2–Pt–O3) ∠(N9–Pt–N10)

(4R,5S)-anti B3LYP aug ccB3LYP aug-ccpVDZ GD3BJ pVTZ GD3BJ 2.075 2.076 2.075 2.076 1.993 1.988 1.993 1.988 80.2 80.4 80.2 80.4 97.4 97.2 102.0 101.8

(4R,5R)-anti B3LYP aug ccB3LYP aug-ccpVDZ GD3BJ pVTZ GD3BJ 2.078 2.079 2.079 2.080 1.991 1.985 1.991 1.986 81.0 81.0 81.2 81.2 97.5 97.3 100.3 100.4

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Table 6. Compariso n of Calculated Bond Lengths (in Å) and Bond Angles (in

deg.) Calculated for Heptaplatin with Various Levels of Theory


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Table 7. Relative Energies (in kcal/mol) of Low-Lying Heptaplatin Conformers/Isomers at the B3LYP aug-ccpVTZ + GD3BJ ∆E ∆E0 ∆G (4R,5R)-anti 0.00 0.00 0.00 Level of Theory (4S,5S)-anti (4R,5R)-syn (4S,5R)-anti (4R,5S)-anti (4S,5S)-syn (4S,5R)-syn

0.00 0.05 0.14 0.14 0.23 1.13

0.00 0.06 0.37 0.37 0.31 1.35

0.00 0.10 -0.86 -0.86 0.34 0.56



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TOC


Raman and Infrared Studies of Platinum-Based Drugs: Cisplatin

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