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TD-DFT studies on electronic and photophysical properties of Auranofin: A reference Au(I) complex
Journal Pre-proofs DFT/TD-DFT studies on electronic and photophysical properties of Auranofin: A reference Au(I) complex Pedro Francisco Santiago, Jorge Ramón Soto Mercado, Bertha Molina Brito PII: DOI: Reference:
S0277-5387(19)30707-7 https://doi.org/10.1016/j.poly.2019.114262 POLY 114262
To appear in:
Polyhedron
Received Date: Revised Date: Accepted Date:
27 August 2019 15 November 2019 4 December 2019
Please cite this article as: P. Francisco Santiago, J. Ramón Soto Mercado, B. Molina Brito, DFT/TD-DFT studies on electronic and photophysical properties of Auranofin: A reference Au(I) complex, Polyhedron (2019), doi: https:// doi.org/10.1016/j.poly.2019.114262
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DFT/TD-DFT studies on electronic and photophysical properties of Auranofin: A reference Au(I) complex Pedro Francisco Santiago,a,b Jorge Ramón Soto Mercado,a and Bertha Molina Britoa* aDepartamento
de Física, Facultad de Ciencias, Universidad Nacional Autónoma de México, Circuito Exterior S/N, Ciudad Universitaria, Ciudad de México, México, C.P. 04510 bInstituto de Investigaciones en Materiales, Universidad Nacional Autónoma de México, Circuito Exterior S/N, Ciudad Universitaria, Ciudad de México, México, C.P. 04510. *Corresponding author. E-mail addresses: [email protected] Abstract A systematic analysis based on DFT and TD-DFT calculations of the structural, electronic and photophysical properties was performed for auranofin, a drug commonly used as reference compound for medicinal applications. A correspondence was found between DFT optimized structural parameters and X-ray data. IR calculations indicate that this spectroscopy cannot differentiate between isomers obtained with and without dispersion for this gold(I) compound. However, from UV-vis, their geometrical structural differences appear as different features when their spectra are compared. It is also shown that this molecule is photosensitive in such a way that the excitation-emission process induces a bending of the P-Au-S motif, giving place to a phosphorescence phenomenon, described from TD-DFT calculations including spin-orbit.
Keywords: Auranofin, Phosphorescence, IR-spectra, UV-vis spectra, TD-DFT 1. Introduction The expectation generated in the last decades by the probable therapeutic application of the known gold(I) complexes against some the most challenging diseases, such as the acquired immune deficiency syndrome (AIDS), cancer, and others [1-10], has driven the synthesis of new gold complexes with equally important biological activity [10,11]; however, despite the numerous efforts to identify effective drugs based on gold, it seems the right compound must still be synthetized. Different strategies have been implemented or suggested in order to design or identify a better drug with respect to those known. Very often, in the design process, a drug with recognized biological activity is modified or used
as reference to assess the biological properties of the new drug. Surprisingly, the structural, electronic and optical properties of the reference gold complexes are often poorly characterized. In fact, very few gold(I) complexes structures have been solved, mainly due to poor crystallinity and solubility of the samples; factors that prevent X-ray measurements [12]. Because this, the gold complexes are mostly characterized by indirect methods, such as NMR, or vibrational or electronic spectroscopy [13]; however, given the limited details available on these compounds in literature from the molecular point of view, their spectra are interpreted inaccurately. At this point it should be said that, in the field of nanoparticles, the experimental far infrared and UV-vis spectra in joint with density functional theory (DFT) calculations in the first case, and time-dependent density functional (TD-DFT) calculations in the second case, are successful methodologies, very useful in the characterization of these nanostructures, including their geometrical configurations [14-16]. Although this combination of methodologies is so usual for clusters and macromolecules, it seems that it is still little used in drug design. In this context, it is worthwhile to make a theoretical reexamination of the different properties of the gold complexes typically used as reference compounds. Auranofin [2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopiranosato-S-(triethylphosphine) gold(I)] is probably the gold complex [9,17-19] most used in literature as a reference compound, because it is the only one approved by the FDA (Food and Drug Administration), used to treat psoriatic rheumatism [19,20]; besides, today it is the main gold complex studied in clinical phase II as an anti-Lymphocytic Leukemia agent [8], and recent results points it out as a potential anti-HIV drug [9,20,21]. The geometrical structure for the so-termed form A of the auranofin is well determined from X-ray spectroscopy [22], which consists of a 2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranose ring bonded to one sulfur atom coordinated to the (triethylphosphoranylidene)gold group, with the acetyl groups equatorial oriented, and the carbohydrate ring in chair configuration. Experimental vibrational, and electronic characterizations of this compound were made through infrared (IR), and electronic absorption [23] and emission [24] spectra, although only in preliminary form, because there were no specific theoretical spectra for comparison. In particular, the photophysical and photochemical properties of auranofin are poorly explained. The light sensitivity of gold compounds has been known for a long time [25] and has been widely studied in the last decades. Based on these studies, the photoluminescence properties of discrete, mononuclear two-coordinate gold(I) compounds were concluded to be induced from electronic transitions as follows: metal centered (MC), intraligand charge transfer (ILCT), metal-to-metal charge transfer (MMCT), ligand-to-ligand charge transfer (LLCT), ligand-to-metal charge transfer (LMCT), and metal-to-ligand charge transfer (MLCT). For these kinds of compounds there is evidence showing that Au···Au interactions or ligand coordination at gold can alter their emission properties, changing the intensity or the band position [25,26]. Also, the intense emission of monomeric [AuL3]+ complexes has been reported as a consequence of an excited-state distortion compared to the ground state [26,27], although the photolysis could also be a consequence of the
excitation process [24]. Distortion at the excited state of the systems [Au(PR3)3]+ and (TPA)AuSCH(CH3)2 were supported by theoretical predictions from DFT and TD-DFT calculations [26,28]. For auranofin, emission spectra for samples in solid state at 77 K were reported, while these emissions are quenched at room temperature. Because the origin of this luminescent characteristic of auranofin is not yet completely understood, some suppositions were made about these spectra. On the one hand, it was assumed that the Au···Au interactions are negligible and the emissive state is of a mixed ds/LMCT character [24]. On the other hand, the lowest-energy excited state in the absorption spectra was assumed to be responsible of the emissive peak [24], but, evidently, the possible spin multiplicity change towards triplet state, which is fundamental to identify luminescent emission as phosphorescence, was not considered. Given that gold is a heavy atom, it is very plausible that the longest-wavelength emission of auranofin is of this type. At this point it should be said that, while the photophysics and photochemistry of the gold complexes are topics quite intriguing in their own right, there is an additional interest on them due to these compounds typically exhibiting luminescent properties, and the fluorescence microscopy is a technic which has been highly recommended to scan the cellular uptake and cellular distribution of these drugs [11]. In this work a systematic theoretical analysis of the structural, electronic and photophysical properties of auranofin is reported. The analysis was based on DFT and TDDFT calculations including dispersion correction. The resulting theoretical structural parameters obtained for the stable isomers were compared with X-ray data. IR and UV-vis spectra were calculated and compared with previous experimental characterizations for auranofin. The excitation-emission process was studied from spin-orbit TD-DFT calculations in order to evaluate the nature of the emission. . 2. Computational methods We used the experimental X-ray data from reference [22] to build the full geometrical structure of the auranofin molecule. Bearing in mind that relativistic effects are important in the gold atom, we used the scalar relativistic (SR) and spin orbit (SO) Zero Order Regular Approximation (ZORA) [29-31] Hamiltonians as they are implemented in the Amsterdam Density Functional (ADF2013.01) [32] package in order to optimize the structure built. For all calculations, the exchange and correlation terms were approached through the Perdew−Burke−Ernzerhof [33] (PBE) Generalized Gradient Approximation (GGA) functional, which has had good performance in the calculations and prediction of optical properties of thiolate gold clusters [16]. Additionally, in order to explore the dispersive interaction into the molecule here studied, we performed optimization calculations at the SR-ZORA level including the Grimme’s dispersion-energy (GD3) [34] correction to the PBE functional. All structures were optimized in the gas phase. For all atoms in all calculations, the standard Slater-type orbital basis sets with quality of triple-
zeta plus one polarization function (TZP) were used, which leaves 19 valence electrons for gold, 5 for phosphorus, 6 for sulfur, 6 for oxygen, and 4 for the carbon atom. For the SCF convergence an accuracy of 10−5 Hartree and a gradient maximum limit of 10−4 Hartree/Å were selected. In order to assess its stability, for each optimized structure we performed a frequencies calculation at the same level of theory used for the geometrical optimization. In order to obtain the absorption/excitation spectrum, the first 200 allowed singletsinglet electronic transitions were computed using TDDFT at the (SR, SO)ZORA/PBE/TZP and SR-ZORA/PBE-GD3/TZP level as they are implemented in ADF2013.01. Based on the Kasha’s rule we expect the emission to come from the lowest excited state; then, in order to model the emissive state, we monitored the evolution of the two lowest singlet and triplet states using the TDDFT gradient scheme implemented in ADF2013.01, which is only programed for the SR-ZORA Hamiltonian with a TZP basis set without core; the convergence criteria for energy and gradient were employed as before. Finally, we carried out TDDFT calculations at the restricted SO-ZORA/PBE/TZP level on the emissive states predicted, in order to compute their 200 lowest excited states and their respective radiative lifetimes. These radiative lifetimes are computed in ADF using the relationship derived by Strickler and Berg [35] between this parameter and the transition dipole moment in the x, y or z direction. 3. Results and Analysis 3.1 Electronic and structural analysis In Figure 1.a the molecular drawing of auranofin obtained after of the optimization using the SR-ZORA Hamiltonian can be seen. In these representations H atoms were omitted for clarity. As we expected, and in good agreement with previous descriptions [22], the gold atom is nearly linearly coordinated to the P and S atoms on either side; the four acetyl groups are equatorial coordinated on the glucopyranose ring; the C-S bond adopts a -configuration and, as Figure 1.b shows, the glucopyranose ring displays its characteristic chair conformation, with H atoms axially arranged. It is important to note that the equatorial plane of the sugar ring is predicted quasi-parallel to the S-Au-P motif.
Figure 1.a) Molecular drawing of auranofin obtained after the optimization using the SRZORA/PBE/TZP. The H atoms were omitted for clarity; b) glucopyranose ring and its torsion angles D1 = O1-C11-C10-C9 and D2 = O1-C7-C8-C9; the first value corresponds to PBE and the second to PBE-GD3. In order to assess the good performance of our calculation methods in the prediction of the structural parameters for this kind of compounds, we proceed to compare the relevant bond lengths and angles computed for auranofin with the corresponding experimental and theoretical values in the literature (selected bond lengths and angles can be seen in Table 1). In Table 1 we omitted our SO-ZORA results because they are practically the same as SRZORA, which indicates that the SO coupling does not play an important role in the ground state structural properties. Note that the larger differences between the bond lengths computed with and without the GD3 term are found for Au-P and Au-S distances, 0.008 and 0.026 Å respectively; these results indicate that the dispersive forces produce a repulsive effect between Au and S atoms, slightly increasing the distance between them; instead, a more moderated attractive effect is predicted between Au and P atoms due to this kind of interactions. However, very different values are computed with and without the dispersion term for torsion angle Au-S-C7-C8 (287.34 and 189.4 degree respectively) and bond angle Au-S-C7 (95.6 and 103.3 degree respectively). A detailed inspection on the SRZORA/PBE-GD3 structure reveals the equatorial plane of the sugar ring in a quasiperpendicular arrangement relative to the S-Au-P motif, with the four acetyl groups still equatorial coordinated on the glucopyranose ring. Also, with the dispersion term a greater bending is computed for the bond angle P-Au-S (170.5 vs 174.6 degrees without the dispersion term) and therefore, different torsion angles Au-P-C1-C2 (60.37 and 55.7 degrees with and without the GD3 term, respectively) are obtained too. Hence, two different isomers were obtained. It should be said that we tried the reoptimization of the
Table 1. Structural parameters for auranofin and their comparison with theoretical and experimental values in literature. TZP basis were used for all cases in this table. Bond lengths (Å)
Au-P Au-S S-C7 P-C1 P-C3 P-C5 C7-O1 C11-O1 C7-C8 C8-C9 C9-C10 C10-C11 P-S’ Au···Au’ S···P’
SRZORA/ PBE
SRZORA/PBEGD3[a]
2.296 2.330 1.826 1.854 1.854 1.856 1.441 1.433 1.539 1.530 1.526 1.537
2.288 2.356 1.823 1.850 1.847 1.854 1.442 1.428 1.537 1.529 1.523 1.532
B3LYP/ (6-31G*, SD)/S[c] 2.341 2.382
B3PW91/ LANL2DZ[d] 2.416 2.390
Exp. from ref. [22] 2.259 2.293 1.788 1.863 1.787 1.821 1.427 1.420 1.523 1.521 1.502 1.517 5.006 6.498 9.25
Bond angles (Degree) P-Au-S 174.6 170.5 173.6 178.6 175 Au-S-C7 103.3 95.6 105.6 103.6 96.2 P-C1-C2 113.6 110.0 115 P-C3-C4 113.8 115.2 114 P-C5-C6 117.2 114.1 117 Au-P-C1 114.4 110.0 111.3 112.9 Au-P-C3 115.7 115.2 111.6 Au-P-C5 111.5 114.1 115.8 Au-P-C1-C2 55.73 60.37 47.270 Au-P-C3-C4 57.51 58.58 54.037 Au-P-C5-C6 181.78 183.67 179.498 Au-S-C7-O1 51.36 47.23 -51.405 -72.1 Au-S-C7-C8 189.40 287.34 -169.287 C8-O2-C12-O3 3.69 7.60 6.30 C9-O4-C14-O5 184.08 181.89 -9.26 [a] SR is acronym for scalar relativistic, GD3 for dispersion term, SD for Sttutgard-Dresden bases and S for solvent; [b] data from reference [37]; [c] data from reference [36].
SR-ZORA/PBE structure taking into account the dispersion term, and the resulting structure was the previously obtained SR-ZORA/PBE-GD3 molecule; and vice versa, we tried the reoptimization of the SR-ZORA/PBE-GD3 structure without dispersion correction, and convergence was found for a similar structure to SR-ZORA/PBE-GD3, but one high imaginary frequency was computed. Comparing with theoretical results in
literature, we note the bond angle Au-S-C7 predicted by Howell (96.2 degree) [36] using Kohn-Sham Hamiltonian (B3PW91/LANL2DZ method) only differs 0.6 degrees compared to our corresponding SR-ZORA/PBE-GD3 value, although Howell simplified the auranofin structure removing the acetyl groups and replacing the triethylphosphine by trimethylphosphine groups. Conversely, Dos Santos et al [37] computed the full structure (using B3LYP/ Sttutgard-Dresden bases), however, the torsion angle Au-S-C7-O1 (-72.1 degree) reported by them suggests a different isomer as compared with the isomers calculated in this work (see Table 1). Note that SR-ZORA Hamiltonians using PBE functional predict slightly lower values of the P-Au-S angles and shorter Au-P and Au-S distances than Kohn-Sham Hamiltonians using hybrid functionals and relativistic pseudopotentials [36,37] (see Table 1); comparisons with X-ray data show that our results are in better agreement with experimental values. A complete contrast between our SR-ZORA-PBE structural parameters and X-ray data shows good agreement between the two sets of parameters, with the following maximum differences: 0.067 Å for P-C3 distance, 4.3 degree for the bond angle Au-P-C5, and 8.4 degree for the torsion angle Au-P-C1-C2. See Tables S1 and S2 in Supplementary Information (SI) for a more detailed comparison with experimental data [22], including overall errors. It is important to note that the inclusion of the dispersion term does not necessarily improve the agreement with specific geometrical parameters. Often, the HOMO-LUMO (the highest occupied and lowest unoccupied molecular orbital, HOMO and LUMO respectively) energy difference is used as an indicative parameter of molecular chemical stability. Using this parameter, practically the same chemical stability is predicted for both SR-ZORA/PBE (3.37 eV) and SR-ZORA/PBE-GD3 (3.29 eV) structures, whose HOMO and LUMO orbitals also present the same form and distribution (see Figures 2 and 1S in Supplementary Information); the HOMO is dominated by a pz orbital centered on the sulfur atom with a non-negligible dxz contribution on the gold atom. The LUMO is a π-bonding orbital between the gold and phosphorus atoms, oriented in the yz-plane with a slight contribution px of the sulfur.
Figure 2. HOMO and LUMO for the ground state of Auranofin.
In fact, the reactivity properties of auranofin can be analyzed from the calculated ground state electronic wave-function using estimators as the average local ionization energy (ALIE) and the local electron attachment energy (LEAE), which are also good indicators of basicity/acidity of organic and inorganic compounds [38]. See SI for the ALIE and LEAE definitions. The existence of ALIE surface minima at low electronic densities (usually 0.001 a.u.) correspond to localized regions around the molecule, where interaction with electrophilic moieties (Lewis acids) is largest. The LEAE surface minima are regions susceptible to nucleophilic attack (Lewis basis). The resulting surfaces for these properties calculated from our SR-ZORA/PBE and SR-ZORA/PBE-GD3 wave-functions are presented in SI (Figures 2S and 3S in SI). The colored surfaces have very similar features around the P-AuS bond regardless of the employed method. A localized region around the Au-S bond can be identified as an important Lewis basic zone from the ALIE colored surface, which is the most prone to interact with electron-acceptors at different Lewis acids. The LEAE characteristics reveal that auranofin is a soft Lewis acid as might be expected for an Au(I) complex. The localized regions of minimum LEAE at the 0.004 isodensity surface are mainly localized on a saddle surface enclosing Au and the interstitial region between S and the thioglucose ligand with a hole on top S and on three small basins around the phosphorus atom, behind the bonds with the ethyl groups. The LEAE main contributions (see Table 3S in SI) are from LUMO (around P) and from LUMO+1 to LUMO+9 (the saddle surface). Dos Santos [37] found that tetraaceytylthioglucose replacement is the most favorable reaction occurring when auranofin reacts with S-, Se- and N- containing amino acids (AA). A proton transfer upon the nucleophilic AA attack to the S-auranofin promotes this reaction and is indeed favored in the wide region between the S-atom and the glucose moiety found with aid of LEAE. The replacement of the triethylphosphane moiety reacting with the AA was predicted as unfavorable [37] in agreement with the LEAE colored isosurface that shows just three small point regions susceptible to nucleophilic attack around the P atom. 3.2 IR-spectra analysis and comparison with experiment The simulated IR spectra for both isomers of auranofin computed with and without dispersion correction are displayed superimposed in Figure 3.a. Note that both spectra exhibit very similar shapes, with appreciable changes mainly in the height of their peaks, higher in the SR-ZORA/PBE IR spectrum than the other one. Hence, we concluded that the structural differences between the two isomers, discussed above, do not turn on or off any IR modes of vibration.
Figure 3. a) Theoretical IR spectra for the auranofin molecule; (b) experimental IR spectrum for form A of the auranofin from reference [23] and superimposed our PBE/TZP IR spectrum between 2000 - 350 cm-1; here a shift of 3 cm-1 was applied. When comparing with experimental IR spectra in literature, we note that the shape of the peaks in our IR spectra for auranofin look like those of Baran et al [23] (see Figure 3.b), while a blue- shift of approximately 3 cm-1, leave 4 of the 7 main peaks superimposed. At this point it should be said that Baran et al confirmed the presence of the A polymorph based on melting-point studies. In our spectra a doublet at 3028/2961 cm-1 (see Figure 3.a) can be localized, which corresponds to vibration modes from the ethyl groups from the PEt3 ligand: stretching of C-H, asymmetric stretching of CH2, and waging, stretching, and asymmetric stretching of CH3. This doublet is in agreement with that reported by Baran et al at 2966/2870 cm-1, although they also assign vibrations from acetate moieties to this doublet [23]. The band at 1745 cm-1 is dominated by vibrations from acetyl groups: δ(acetyl) bending, ν(C=O) stretching, and γ(CH3) waging; although asymmetric stretching of the OCH on the ring is also registered. This is in very good agreement with Baran et al, who describe one band at 1747 cm-1, corresponding to carbonyl groups.
The band at 1428 cm-1 was assigned to δ(P-CH2) bending and γ(CH3) waging modes from the acetyl groups. In the next band localized at 1337 cm-1 complex vibrations deforming the sugar ring, stretching vibrations of ring-O-acetyl moiety, asymmetric stretching of the acetyl groups, and stretching of C-C from acetyl group and sugar ring can be observed. Note the similar shape and the much lower heights obtained for the peaks at 1428 and 1337 cm-1 as compared to the experimental one (1452 and 1373 cm-1 respectively [23]). The higher heights in the experimental peaks could be due to the vibrations in these bands, and might be favored by intermolecular interactions between acetyl moieties. Clearly the effects of these intermolecular interactions in our IR-spectra are missing because our calculations are in gas phase. Note that these bands are scarcely described by Baran et al, and according to their assignments, the vibration modes of the ring-O-acetyl moiety and C-C stretching should be expected until the band at 1032 cm-1. Again, the band at 1190 cm-1 is dominated by complex vibrations and coupling of the ring, thus, there are registered twisting and beating of the ring, asymmetric stretching of the ring-O-acetyl, ring-CH2-O-Acetyl and ring-S moieties. Contributions from these three last moieties are also registered in the band at 997 cm-1, with additional asymmetric stretching of the acetyl and PEt3 groups. The weak band at 736 cm-1 also contains complex coupled vibrations from all moieties constituting the molecule, thus, we can observe bending mode of the PEt3 and asymmetric stretching of the ring-O-Acetyl, acetyl and ring-S-Au. In the analogue experimental band Baran et al only assign vibrations for the triethylphosphine moiety. Also, by comparison with literature they tentatively assigned the υ(C–S) mode to the band at 630 cm-1. The next weak band at 569 cm-1 is also dominated by asymmetric stretching of the ring, ring-O-Acetyl, ring-CH2-O-Acetyl and Au-S-ring, while the band at 403 cm-1 contains uncoupled and asymmetric stretching of the Au-P and Au-S (at 413 and 315 cm-1 respectively), both stretchings coupled to vibrations from Et3 and acetylglucopyranose (Atg) ring moieties respectively. In contrast, Baran et al reported υ(P–Au) stretching vibration and δ(Au-P) mode at 382 and 301 cm-1. Finally, we observe a bending mode of PAu-S coupled to both ligands at 50 cm-1. Readers interested in a more detailed description of these bands see Table 4S in SI. 3.3 UV-vis spectrum for Auranofin and comparison with experiment The UV-vis spectra computed using TDDFT SR-ZORA/(PBE, PBE-DG3) methods are superimposed in Figure 4. To simulate these spectra, we use a gaussian functions superposition with a width of 6 nm. Counter to the IR-spectra, the absorption/excitation spectra with and without the dispersion correction exhibit different features: the spectrum computed without dispersion term presents one main peak, two shoulders and one peak with very low intensity in the energy window from 160 to 300 nm; for the geometrical structure calculated using the SR-ZORA/PBE-GD3 method, only a wide main peak without shoulders and two peaks with very low intensity are obtained. Clearly, our SR-ZORA/PBE
absorption spectrum is in excellent agreement with the experimental electronic spectrum (showed at inset in Figure 4) obtained for an aqueous solution of auranofin by Baran et al [23]: our main peak and the two first shoulders are located at 195, 213, and 223 nm compared with 196, 210, and 222 nm, respectively in the experimental case; the third experimental shoulder (246 nm) is imperceptible in our UV-vis curve; however, the small peak at 255 nm is in good agreement with the tail observed at the same energy in the experimental spectrum.
Figure 4. Theoretical UV-vis spectra for the Auranofin molecule. At inset the experimental UV-vis spectrum for form A of the auranofin from reference [23]. In Tables 5S and 6S and Figures 4S-7S (see SI) the characteristics (energy, oscillator strength, molecular orbitals and weight of the transition) of the most intense and probable electronic transitions contributing to the configuration of each peak in the SR-ZORA/(PBE, PBE-GD3) UV-vis spectra are shown. In these Tables and Figures the main peak is named a; the two shoulders, b and c; and the less intensive peak, d. According to these results, in the SR-ZORA/PBE spectrum the three most intense transitions in band a (see Table 5S and Figures 4S and 5S) mainly come from charge transfer from PAuSATg to the SAuPEt3 as well as from the electron back bonding in SAuPC to SAuPEt3 and SAuPEt3 to acetyl group, not only from the C-S bond as Baran et al suggested. In band b the three most intense transitions come from charge transfer from PAuSC to acetyl groups and PAuSAtg to SAuPEt3 moiety. Also, the shoulder at 223 nm (band c) mainly comes from two transitions with strong contributions, HOMO-1 → LUMO+9 and HOMO → LUMO+16, the HOMO and HOMO-1were mainly localized on the S-P bond. The peak d at 255 nm is an HOMO2→ LUMO+1 transition. In the SR-ZORA/PBE-GD3 spectrum (see Table 6S and Figure 6S and 7S) the most intense transitions in band a are localized at 196 and 205 nm, while band b is found at 240
nm, all of them coming from charge transfer from SAuP to all molecule. Band c at 279 nm comes from CSAu to SAuPEt3 moiety. Note the relatively good agreement between these transition energies with those of Baran et al; however, the electronic transitions around 222 nm are mostly off (see Figure 6S). It is important to highlight that HOMO→ LUMO+1 is missing in the SR-ZORA/PBE spectrum (see Table 5S), while the three firsts transitions HOMO→ LUMO are localized at 363, 350 and 330 nm. On the other hand, for the SR-ZORA/PBE-GD3 structure, the HOMO→ LUMO is missing in the window of energies reported (see Table 6S), but one transition HOMO→ LUMO+1 is obtained at 348 nm. These characteristics must be specially considered, because they could be important in explaining the phosphorescence of auranofin, property studied by Kunkely et al [24], whom also studied the photolysis of auranofin in acetonitrile using an irradiation of 254 nm. Comparing their absorption spectrum at t = 0 s with our spectra, once again a better concordance is found with the SRZORA/PBE spectrum, since their peaks at 196, 210, 224, 244, and 276 nm are in good agreement with our peaks at 195, 213, 223, 255, and 289 nm. Instead, as before, the transition at 224 nm is missing for the PBE-GD3 spectrum (see Table 6S). Another feature missing in this spectrum is the observed decay in the experimental curves around 250 nm. Because a better agreement between our SR-ZORA/PBE UV-vis spectrum and the experimental ones was found, we selected the structure resulting from this method to study the phosphorescence properties of auranofin. 3.4 Phosphorescence emission for auranofin The emission spectrum of auranofin shows phosphorescence with max = 594 nm in the solid state at 77 K [24]. This emission behavior is possible due to the heavy atom effect of gold. Given the large intermolecular Au···Au separation (6.498 Å) reported by Hill et al (see Table 1), we assumed that these phosphorescence properties cannot be altered by possible gold-gold interactions, which justifies the use of auranofin in the gas phase in order to study these properties. In general, phosphorescence involves a spin-forbidden radiative transition between states of different multiplicity, usually from the lowest excited singlet S1 or triplet state T1, according to Kasha’s rule. The triplet-excited state can be accessed from the singlet-excited state S1 or vice versa only if the molecule or its environment favors the intersystem crossing (ISC) process. The presence of gold in auranofin enhances the rate of ISC by increasing the spin-orbit coupling between ground and lowest-energy excited states. In order to achieve a deeper understanding on this phenomenon in auranofin, the low-energy singlet and triplet transitions from its theoretical UV-vis spectrum were analyzed. In Table 7S both are reported, the low-energy singlet and triplet transitions (left and right sides respectively) for auranofin computed using SR-ZORA/PBE as well as the corresponding oscillator strengths and the transition states with their respective weights. The transitions to triplet appear with zero oscillator strength because these types of transitions are spin-
forbidden in SR-ZORA. In Table 7S, the first S1 excited state corresponds to a HOMOLUMO transition with an energy of 3.42 eV, while the T1 is a lower-energy state at 3.33 eV between the same states. The next transitions S2 and T2 (at 3.50 and 3.48 eV respectively) are predominantly HOMOLUMO+1, with some mixing with HOMOLUMO+2. Based on the HOMO and LUMO descriptions (Figure 2), the lowest energy transition of auranofin can be classified as LMCT (ligand-to-metal charge transfer) with some non-negligible MC (metal-centered) contribution. For the next transition, the charge transfer to ligands, is involved (see Figure 1S in SI). Due to a large component centered on gold in the transition orbitals, it is important to study the spin-orbit effect in the lowest energy transition. In order to accomplish this task, we analyze the SO-ZORA optimization results for the ground state. As we mentioned in Sect. 3.1, there are no important structural modifications when the spin-orbit coupling is incorporated to the calculations, hence there are no significant changes expected for the transition energies. In Table 8S the spin-orbit coupled excitation energies for auranofin are reported, including oscillator strengths, states involved, and their weights and transition lifetimes. In this transitions list it is not possible to distinguish if the transition is to triplet or singlet, however comparison with the list of Table 7S is valid, because there are negligible structural changes between the two ground states (SR, SO)/ZORA. Therefore, the three lowest transitions in Table 8S correspond to T1 and the 4th corresponds to S1. The consistency of this assumption can be confirmed comparing the oscillator strengths for S1 in Table 7S (0.0062) with that of the 4th state in Table 8S (0.007), also, both are HOMOLUMO transitions. Note that the first three excitations have oscillator strengths one order of magnitude lower, but now are not spin-forbidden. The next four excitations in Table 8S (5-8) are not mixed as in Table 7S and correspond to HOMOLUMO+1 transitions. Since the HOMOLUMO transition involves the heavy gold atom, as it was shown above, it is very probable that the spin-orbit coupling will be large enough between these states, in such a way that the ISC from S1 to T1 will take place. In order to explore this possibility, we tried the optimization of the molecule in the S1 and T1 excited states at the SR-ZORA level (SO-ZORA optimizations for exited states are not supported in ADF2013.01), but we did not get convergence in the calculations; in fact, whenever we started the optimization from the ground state structure, a cleavage of the S-C bond was obtained, which finally leads to the dissociation of the molecule. Therefore, we proceeded to optimize the second excited states S2 and T2, obtaining the structures displayed in Figure 5.
Figure 5. SR-ZORA structure for auranofin in the second excited states a) S2 and b) T2. The most important geometrical change in both excited states structures is observed in the bond angle P-Au-S, which suffers a bending from 175 (S0) to 168 (S2) and 159 (T2) degree; in Table 2, the main geometrical parameters characterizing both structures are reported. An elongation of around 0.1 Å for the Au-S bond length with respect to the ground state was found for both excited structures, accompanied by a lower elongation of the P-Au bonds length (0.02 and 0.03 Å for singlet and triplet respectively). Besides of the P-Au-S angle, these bond and dihedral angles, which include the Au-S moiety, suffer important changes, while those involving the Au-P fragment do not change in average (see Table 2). Table 2. Structural parameters from SR-ZORA/PBE for Auranofin in the ground state and their comparison with those of the second excited states S2 and T2. Bond lengths (Å) Bond angles (Degree) Au-P Au-S S-C7 P-C1 P-C3 P-C5 C7-O1 C11-O1 C7-C8 C8-C9 C9-C10 C10-C11
Singlet
Triplet
2.319 2.427 1.840 1.854 1.888 1.858 1.404 1.453 1.545 1.528 1.533 1.543
2.334 2.412 1.842 1.852 1.874 1.855 1.405 1.453 1.545 1.528 1.534 1.543
P-Au-S Au-S-C7 P-C1-C2 P-C3-C4 P-C5-C6 Au-P-C1 Au-P-C3 Au-P-C5 Au-P-C1-C2 Au-P-C3-C4 Au-P-C5-C6 Au-S-C7-O1 Au-S-C7-C8 C8-O2-C12-O3 C9-O4-C14-O5
Singlet
Triplet
167.5 115.3 115.1 113.1 116.8 108.6 127.3 106.4 52.75 57.17 184.07 38.82 197.03 7.66 178.02
159.1 115.1 114.6 113.5 116.8 109.1 125.1 107.0 54.41 58.17 186.84 38.11 197.55 7.48 177.69
For the excited state T2 there is an exchange between LUMO and LUMO+1 with respect to the ground state, the latter being a gold-ligands orbital (see Figure 8S in SI). It is important to note the change in the LUMO+1 orbital due to the bending of the P-Au-S angle becoming predominantly s gold-centered, hybridized with π (Au-P) and π*(P-C), and a lower contribution from py(S). This type of orbital was computed by Aikens et al [28] for the S1 excited state of (TPA)AuSCH(CH3) complex, which suffers a similar bending of the P-Au-S angle (160 degree). According to the El-Sayed selection rules, the ISC rate is increased from the lowest singlet state to the triplet manifold when the transition involves a change of the orbital type [39]. In this case, the orbital changes from ground to excited state produced by the P-Au-S bending, favors the ISC. In Table 9S the excitation energies calculated using SR-ZORA on the T2 excited state geometry are summarized. Note that for this excited state, the two lowest-energy transitions to singlet and triplet are degenerated and correspond to combinations between HOMOLUMO+1 and HOMOLUMO. This mixing of states is probably the reason why it is not possible to optimize the S1 and T1 states within the framework of the TDDFT, assuming both states close to S2 and T2. Similar behavior was found by Guidez and Aikens [28] for some gold-phosphine-thiolates complexes simpler than auranofin, computing several state crossings of the excited energies as a function of the P-Au-S angle. Instead, we note that for auranofin the mixing and the degeneration between the (1-4) -(5-6) states (see Table 10S) disappear when the spin-orbit coupled TDDFT calculation is performed on the SR-ZORA excited structure. In this case, from Tables 9S and 10S it is not possible to establish a singlet-triplet correspondence, because the inclusion of the spin-orbit coupling breaks the accidental degeneracy of the states, and changes the oscillator strengths’ values. Naturally, we can assume that 5th to 7th excited states are preferred for the ISC nonradiative transition, since they are related to the gold predominant orbital transition (see LUMO+1 in Fig. 1S). Besides, considering that LUMO and LUMO+1 can be exchanged for the lowest excited state T1 (supported by the degeneration breaking T1-T2 induced by spin-orbit coupling), the computed emission energy would be lower than 2.29 eV (540 nm) which is in agreement with the peak (594 nm) measured by Kunkely et al [24]. The predicted lifetime for these excited states falls within the range (14 – 795 s), which corresponds to a phosphorescence radiative emission; however, these values must still be corroborated experimentally. Conclusions In conclusion, we have presented a systematic theoretical study on the structural, electronic and photophysical properties of auranofin, a molecule of reference for the phosphine-gold(I) complexes. This study was based on SR and SO ZORA-DFT and TDDFT calculations on the X-ray structure of auranofin reported in the literature. After the optimization calculations, we found good agreement between structural parameters calculated using the SR- ZORA/PBE method and X-ray data. Inconsistences between some
bond and torsional angles are obtained as compared with the corresponding experimental parameters, when the GD3 dispersion correction is applied to the GGA-PBE functional. According to our results, the spin orbit coupling is negligible in the structural properties of this gold compound in the ground state. The calculated ground state wave-functions for auranofin allowed us to evaluate the isosurfaces LEAE and ALIE, and to characterize the reactivity for this molecule. The regions susceptible to nucleophilic and electrophilic attacks can be identified locating the minima of these quantities in their constant low density isosurfaces. For auranofin, the minima of LEAE were located at sites between the S atom and the thioglucose moiety, while for ALIE they were observed around Au-S. Also, LEAE showed that the region around the P atom is mostly inactive. Therefore, calculations of these surfaces are recommended for these types of compounds, prior to catalysis applications; this could be relevant in the design of new drugs, because these surfaces can be used to guide exchange reactions calculations, for example. In principle, both optimized structures for auranofin, with and without dispersion term, yield almost the same IR spectra, being this technique insensitive to the structural changes found such as the orientation of the equatorial plane of the sugar ring with respect to the P-Au-S motif. Our spectra showed good agreement with the experimental one. After a careful revision of the calculated vibrational modes, we proposed a reassignation of some modes and we completed the description for the different bands in the experimental spectrum. For example, unlike to previous experimental assignment, we do not observe contributions from acetate moieties to the doublet at 2966/2870 cm-1; the experimental description puts the vibrational modes of the ring-O-acetyl moiety and C-C stretching in the band at 1032 cm-1, instead we observe these vibrational modes in the band at 1428 cm-1. Also, we registered an asymmetric stretching of the ring-S-Au in the bands at 736 and 569 cm-1, while the experimental group only assigned υ(P–Au) and δ(Au-P) vibration modes at 382 and 301 cm-1 respectively. Note that they either report the bending mode of P-Au-S located at 50 cm-1. As evidence of the photosensitivity of these compounds, correlated to changes in its geometrical structure, we highlighted the lack of two shoulders in the UV-vis spectrum calculated for the SR-ZORA/PBE-GD3 isomer, which can be seen in the SRZORA/PBE and experimental UV-vis spectra. This fact was decisive in selecting the method without dispersion to study the phosphorescence properties of auranofin. Our results show that the scalar relativistic approximation is a good level of theory to predict its structural parameters and their IR and UV-vis spectra; however, a spin-orbit approximation must be used for the prediction of its phosphorescence properties. According to our analysis, a bending of the bond angle P-Au-S is induced by the excitation to the lowest triplet state, giving place to a phosphorescence radiative emission with an energy around 540 nm and lifetime in the range of 14 – 795 s. The lowest energy transition for auranofin can be classified as LMCT with MC contributions. We hope this work encourages more detailed emission experiments and can be used as a starting point for new studies oriented to catalysis and drug design based on mononuclear gold(I) compounds.
Declarations of interests: none. Acknowledgements The authors acknowledge the Dirección General de Cómputo y de Tecnologías de la Información (DGTIC-UNAM) for providing Supercomputing resources on “Miztli” through the Project LANCAD-UNAM-DGTIC-298. B. Molina acknowledges the support by PAPIIT-DGAPA, UNAM IN115515. Appendix A. Supplementary data Supplementary data to this article can be found online at … References [1] S. Medici, M. Peana, V.M. Nurchi, J.I. Lachowicz, G. Crisponi, M.A. Zoroddu, Coord. Chem. Rev. 284 (2015) 329-350. [2] S. Parveen, F. Arjmand, S. Tabassum, Eur. J. Med. Chem. 175 (2019) 269-286. [3] B. Bertrand, A. Casini, Dalton Trans. 43 (2014) 4209-4219. [4] I. Romero-Canelon, P.J. Sadler, Inorg. Chem. 52 (2013) 12276−12291. [5] M. Ravera, E. Moreno-Viguri, R. Paucar, S. Perez-Silanes, E. Gabano, Eur. J. Med. Chem. 155 (2018) 459-482. [6] G. Faa, C. Gerosa, D Fanni, J.I. Lachowicz, V.M. Nurchi, Current Med. Chem. 25 (2018) 75-84. [7] A. Ssemaganda, L.M. Low, K.R. Verhoeft, M. Wambuzi, B. Kawoozo, S.B. Nabasumba, J Mpendo, B.S. Bagaya, N. Kiwanuka, D.I. Stanisic, S.J. Berners-Price, M.F. Good, Metallomics 10 (2018) 444-454. [8] B. Dominelli, J.D.G. Correia, F.E. Kühn, J. Organometal. Chem. 866 (2018) 153-164. [9] S.J. Berners-Price, A. Filipovska, Metallomics 3 (2011) 863–873. [10] P. Fonteh, D. Meyer, Metallomics 1 (2009) 427-433. [11] J.C. Lima, L. Rodríguez, Anti-Cancer Agents in Med. Chem. 11 (2011) 921-928. [12] D.T. Hill, B.M. Sutton, A.A. Isab, T. Razi, P.J. Sadler, J. M. Trooster, G.H.M. Calis, Inorg. Chem. 22 (1983) 2936-2942. [13] P.J. Sadler, R.E. Sue, Met.-Based Drugs 1 (1994) 107 – 144. [14] P. Gruene, D.M. Rayner, B. Redlich, A.F.G. van der Meer, J.T. Lyon, G. Meijer, A. Fielicke, Science 321 (2008) 674-676. [15] A. Tlahuice-Flores, U. Santiago, D. Bahena, E. Vinogradova, C.V. Conroy, T. Ahuja, S.B.H. Bach, A. Ponce, G. Wang, M.J. Yacamán, R.L. Whetten, J. Phys. Chem. A, 17 (2013) 10470-10476.
[16] B. Molina, A. Sánchez-Castillo, S. Knoppe, I.L. Garzón, T. Bürgi, A. Tlahuice-Flores, Nanoscale, 5 (2013) 10956-10962. [17] B.M. Sutton, E. McGusty, D.T. Walz, M.J. DiMartino, J. Med. Chem. 15 (1972) 1095-1098. [18] S.-J. Park, I.-S. Kim, Brit. J. Pharmacol. 146 (2005) 506–513. [19] D.L. Shapiro, J.R. Masci, J. Rheumatol. 23 (1996) 1818–1820. [20] B. Chirullo, R. Sgarbanti, D. Limongi, I.L. Shytaj, D. Alvarez, B. Das, A. Boe, S. DaFonseca, N. Chomont, L. Liotta, E. III Petricoin, S. Norelli, E. Pelosi, E. Garaci, A. Savarino, A.T. Palamara, Cell Death and Dis. 4 (2013) e944. [21] I. L. Shytaj, B. Chirullo, W. Wagner, M.G. Ferrari, R. Sgarbanti, A. Della Corte, C. LaBranche, L. Lopalco, A.T. Palamara, D. Montefiori, M.G. Lewis, E. Garaci, A. Savarino, Retrovirology 10 (2013) 1-15. [22] D.T. Hill, B.M. Sutton, Cryst. Struct. Commun. 9 (1980) 679. [23] E.J. Baran, G.E. Tobón-Zapata, S.B. Etcheverry, Spectrochimica Acta Part A 55 (1999) 1569–1573. [24] H. Kunkely, A. Vogler, Zeitschrift für Naturforschung B 51 (1996) 1067–1071. [25] A. Vogler, H. Kunkely, Coord. Chem. Rev. 219–221 (2001) 489–507. [26] C.-M. Che, S.-W. Lai, Lumi, Gold Chemistry, Application and Future Directions in the Life Sciences, Chapter 5; edited by F. Mohr, Wiley-VCH, Germany (2009) 249-281. [27] Z. Assefa, J.M. Forward, T.A. Grand, R. J. Staples, B.E. Hanson, A.A. Mohamed, J.P. Jr. Flacker, Inorg. Chimica Acta (2003) 31-45. [28] E.B. Guidez, C.M. Aikens, J. Phys. Chem. A 119 (2015) 337-347. [29] E. van Lenthe, E.J. Baerends, J.G. Snijders, J. Chem. Phys. 99 (1993) 4597. [30] E. van Lenthe, E.J. Baerends, J.G. Snijders, J. Chem. Phys. 101 (1994) 9783. [31] E. van Lenthe, J.G. Snijders, E.J. Baerends, J. Chem. Phys. 105 (1996) 6505. [32] ADF 2013.01 SCM. Theoretical Chemistry, Vrije Universiteit: Amsterdam, The Netherlands. Available at: http://www.scm.com. [33] J.P. Perdew, K. Burke, M. Ernzerhof, Phys. Rev. Lett. 77 (1996) 3865. [34] S. Grimme, J. Antony, S. Ehrlich, H. Krieg, J. Chem. Phys. 132 (2010) 154104. [35] K. Mori, T.P.M. Goumans, E. van Lenthe, F. Wang, Phys. Chem. Chem. Phys. 16 (2014) 14523−14530. [36] J.A.S. Howell, J. Organomet. Chem. 694 (2009) 868–873. [37] H.F. Dos Santos, Comput. Theor. Chem. 1048 (2014) 95–101. [38] T. Brinck, J.H. Stenlid, Adv. Theory Simul. 2 (2019) 1800149. [39] C. M. Marian, WIREs Comput. Mol. Sci. 2 (2012) 187–203.
DFT and TD-DFT calculations of the structural, electronic and photophysical properties were performed for auranofin, a drug commonly used as a reference compound. IR spectroscopy cannot differentiate between isomers obtained while UV-vis does. Calculations including spin-orbit predict auranofin lowest excitation induces a bending of its P-Au-S motif, which explains its phosphorescence.
S0277-5387(19)30707-7 https://doi.org/10.1016/j.poly.2019.114262 POLY 114262
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Please cite this article as: P. Francisco Santiago, J. Ramón Soto Mercado, B. Molina Brito, DFT/TD-DFT studies on electronic and photophysical properties of Auranofin: A reference Au(I) complex, Polyhedron (2019), doi: https:// doi.org/10.1016/j.poly.2019.114262
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DFT/TD-DFT studies on electronic and photophysical properties of Auranofin: A reference Au(I) complex Pedro Francisco Santiago,a,b Jorge Ramón Soto Mercado,a and Bertha Molina Britoa* aDepartamento
de Física, Facultad de Ciencias, Universidad Nacional Autónoma de México, Circuito Exterior S/N, Ciudad Universitaria, Ciudad de México, México, C.P. 04510 bInstituto de Investigaciones en Materiales, Universidad Nacional Autónoma de México, Circuito Exterior S/N, Ciudad Universitaria, Ciudad de México, México, C.P. 04510. *Corresponding author. E-mail addresses: [email protected] Abstract A systematic analysis based on DFT and TD-DFT calculations of the structural, electronic and photophysical properties was performed for auranofin, a drug commonly used as reference compound for medicinal applications. A correspondence was found between DFT optimized structural parameters and X-ray data. IR calculations indicate that this spectroscopy cannot differentiate between isomers obtained with and without dispersion for this gold(I) compound. However, from UV-vis, their geometrical structural differences appear as different features when their spectra are compared. It is also shown that this molecule is photosensitive in such a way that the excitation-emission process induces a bending of the P-Au-S motif, giving place to a phosphorescence phenomenon, described from TD-DFT calculations including spin-orbit.
Keywords: Auranofin, Phosphorescence, IR-spectra, UV-vis spectra, TD-DFT 1. Introduction The expectation generated in the last decades by the probable therapeutic application of the known gold(I) complexes against some the most challenging diseases, such as the acquired immune deficiency syndrome (AIDS), cancer, and others [1-10], has driven the synthesis of new gold complexes with equally important biological activity [10,11]; however, despite the numerous efforts to identify effective drugs based on gold, it seems the right compound must still be synthetized. Different strategies have been implemented or suggested in order to design or identify a better drug with respect to those known. Very often, in the design process, a drug with recognized biological activity is modified or used
as reference to assess the biological properties of the new drug. Surprisingly, the structural, electronic and optical properties of the reference gold complexes are often poorly characterized. In fact, very few gold(I) complexes structures have been solved, mainly due to poor crystallinity and solubility of the samples; factors that prevent X-ray measurements [12]. Because this, the gold complexes are mostly characterized by indirect methods, such as NMR, or vibrational or electronic spectroscopy [13]; however, given the limited details available on these compounds in literature from the molecular point of view, their spectra are interpreted inaccurately. At this point it should be said that, in the field of nanoparticles, the experimental far infrared and UV-vis spectra in joint with density functional theory (DFT) calculations in the first case, and time-dependent density functional (TD-DFT) calculations in the second case, are successful methodologies, very useful in the characterization of these nanostructures, including their geometrical configurations [14-16]. Although this combination of methodologies is so usual for clusters and macromolecules, it seems that it is still little used in drug design. In this context, it is worthwhile to make a theoretical reexamination of the different properties of the gold complexes typically used as reference compounds. Auranofin [2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopiranosato-S-(triethylphosphine) gold(I)] is probably the gold complex [9,17-19] most used in literature as a reference compound, because it is the only one approved by the FDA (Food and Drug Administration), used to treat psoriatic rheumatism [19,20]; besides, today it is the main gold complex studied in clinical phase II as an anti-Lymphocytic Leukemia agent [8], and recent results points it out as a potential anti-HIV drug [9,20,21]. The geometrical structure for the so-termed form A of the auranofin is well determined from X-ray spectroscopy [22], which consists of a 2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranose ring bonded to one sulfur atom coordinated to the (triethylphosphoranylidene)gold group, with the acetyl groups equatorial oriented, and the carbohydrate ring in chair configuration. Experimental vibrational, and electronic characterizations of this compound were made through infrared (IR), and electronic absorption [23] and emission [24] spectra, although only in preliminary form, because there were no specific theoretical spectra for comparison. In particular, the photophysical and photochemical properties of auranofin are poorly explained. The light sensitivity of gold compounds has been known for a long time [25] and has been widely studied in the last decades. Based on these studies, the photoluminescence properties of discrete, mononuclear two-coordinate gold(I) compounds were concluded to be induced from electronic transitions as follows: metal centered (MC), intraligand charge transfer (ILCT), metal-to-metal charge transfer (MMCT), ligand-to-ligand charge transfer (LLCT), ligand-to-metal charge transfer (LMCT), and metal-to-ligand charge transfer (MLCT). For these kinds of compounds there is evidence showing that Au···Au interactions or ligand coordination at gold can alter their emission properties, changing the intensity or the band position [25,26]. Also, the intense emission of monomeric [AuL3]+ complexes has been reported as a consequence of an excited-state distortion compared to the ground state [26,27], although the photolysis could also be a consequence of the
excitation process [24]. Distortion at the excited state of the systems [Au(PR3)3]+ and (TPA)AuSCH(CH3)2 were supported by theoretical predictions from DFT and TD-DFT calculations [26,28]. For auranofin, emission spectra for samples in solid state at 77 K were reported, while these emissions are quenched at room temperature. Because the origin of this luminescent characteristic of auranofin is not yet completely understood, some suppositions were made about these spectra. On the one hand, it was assumed that the Au···Au interactions are negligible and the emissive state is of a mixed ds/LMCT character [24]. On the other hand, the lowest-energy excited state in the absorption spectra was assumed to be responsible of the emissive peak [24], but, evidently, the possible spin multiplicity change towards triplet state, which is fundamental to identify luminescent emission as phosphorescence, was not considered. Given that gold is a heavy atom, it is very plausible that the longest-wavelength emission of auranofin is of this type. At this point it should be said that, while the photophysics and photochemistry of the gold complexes are topics quite intriguing in their own right, there is an additional interest on them due to these compounds typically exhibiting luminescent properties, and the fluorescence microscopy is a technic which has been highly recommended to scan the cellular uptake and cellular distribution of these drugs [11]. In this work a systematic theoretical analysis of the structural, electronic and photophysical properties of auranofin is reported. The analysis was based on DFT and TDDFT calculations including dispersion correction. The resulting theoretical structural parameters obtained for the stable isomers were compared with X-ray data. IR and UV-vis spectra were calculated and compared with previous experimental characterizations for auranofin. The excitation-emission process was studied from spin-orbit TD-DFT calculations in order to evaluate the nature of the emission. . 2. Computational methods We used the experimental X-ray data from reference [22] to build the full geometrical structure of the auranofin molecule. Bearing in mind that relativistic effects are important in the gold atom, we used the scalar relativistic (SR) and spin orbit (SO) Zero Order Regular Approximation (ZORA) [29-31] Hamiltonians as they are implemented in the Amsterdam Density Functional (ADF2013.01) [32] package in order to optimize the structure built. For all calculations, the exchange and correlation terms were approached through the Perdew−Burke−Ernzerhof [33] (PBE) Generalized Gradient Approximation (GGA) functional, which has had good performance in the calculations and prediction of optical properties of thiolate gold clusters [16]. Additionally, in order to explore the dispersive interaction into the molecule here studied, we performed optimization calculations at the SR-ZORA level including the Grimme’s dispersion-energy (GD3) [34] correction to the PBE functional. All structures were optimized in the gas phase. For all atoms in all calculations, the standard Slater-type orbital basis sets with quality of triple-
zeta plus one polarization function (TZP) were used, which leaves 19 valence electrons for gold, 5 for phosphorus, 6 for sulfur, 6 for oxygen, and 4 for the carbon atom. For the SCF convergence an accuracy of 10−5 Hartree and a gradient maximum limit of 10−4 Hartree/Å were selected. In order to assess its stability, for each optimized structure we performed a frequencies calculation at the same level of theory used for the geometrical optimization. In order to obtain the absorption/excitation spectrum, the first 200 allowed singletsinglet electronic transitions were computed using TDDFT at the (SR, SO)ZORA/PBE/TZP and SR-ZORA/PBE-GD3/TZP level as they are implemented in ADF2013.01. Based on the Kasha’s rule we expect the emission to come from the lowest excited state; then, in order to model the emissive state, we monitored the evolution of the two lowest singlet and triplet states using the TDDFT gradient scheme implemented in ADF2013.01, which is only programed for the SR-ZORA Hamiltonian with a TZP basis set without core; the convergence criteria for energy and gradient were employed as before. Finally, we carried out TDDFT calculations at the restricted SO-ZORA/PBE/TZP level on the emissive states predicted, in order to compute their 200 lowest excited states and their respective radiative lifetimes. These radiative lifetimes are computed in ADF using the relationship derived by Strickler and Berg [35] between this parameter and the transition dipole moment in the x, y or z direction. 3. Results and Analysis 3.1 Electronic and structural analysis In Figure 1.a the molecular drawing of auranofin obtained after of the optimization using the SR-ZORA Hamiltonian can be seen. In these representations H atoms were omitted for clarity. As we expected, and in good agreement with previous descriptions [22], the gold atom is nearly linearly coordinated to the P and S atoms on either side; the four acetyl groups are equatorial coordinated on the glucopyranose ring; the C-S bond adopts a -configuration and, as Figure 1.b shows, the glucopyranose ring displays its characteristic chair conformation, with H atoms axially arranged. It is important to note that the equatorial plane of the sugar ring is predicted quasi-parallel to the S-Au-P motif.
Figure 1.a) Molecular drawing of auranofin obtained after the optimization using the SRZORA/PBE/TZP. The H atoms were omitted for clarity; b) glucopyranose ring and its torsion angles D1 = O1-C11-C10-C9 and D2 = O1-C7-C8-C9; the first value corresponds to PBE and the second to PBE-GD3. In order to assess the good performance of our calculation methods in the prediction of the structural parameters for this kind of compounds, we proceed to compare the relevant bond lengths and angles computed for auranofin with the corresponding experimental and theoretical values in the literature (selected bond lengths and angles can be seen in Table 1). In Table 1 we omitted our SO-ZORA results because they are practically the same as SRZORA, which indicates that the SO coupling does not play an important role in the ground state structural properties. Note that the larger differences between the bond lengths computed with and without the GD3 term are found for Au-P and Au-S distances, 0.008 and 0.026 Å respectively; these results indicate that the dispersive forces produce a repulsive effect between Au and S atoms, slightly increasing the distance between them; instead, a more moderated attractive effect is predicted between Au and P atoms due to this kind of interactions. However, very different values are computed with and without the dispersion term for torsion angle Au-S-C7-C8 (287.34 and 189.4 degree respectively) and bond angle Au-S-C7 (95.6 and 103.3 degree respectively). A detailed inspection on the SRZORA/PBE-GD3 structure reveals the equatorial plane of the sugar ring in a quasiperpendicular arrangement relative to the S-Au-P motif, with the four acetyl groups still equatorial coordinated on the glucopyranose ring. Also, with the dispersion term a greater bending is computed for the bond angle P-Au-S (170.5 vs 174.6 degrees without the dispersion term) and therefore, different torsion angles Au-P-C1-C2 (60.37 and 55.7 degrees with and without the GD3 term, respectively) are obtained too. Hence, two different isomers were obtained. It should be said that we tried the reoptimization of the
Table 1. Structural parameters for auranofin and their comparison with theoretical and experimental values in literature. TZP basis were used for all cases in this table. Bond lengths (Å)
Au-P Au-S S-C7 P-C1 P-C3 P-C5 C7-O1 C11-O1 C7-C8 C8-C9 C9-C10 C10-C11 P-S’ Au···Au’ S···P’
SRZORA/ PBE
SRZORA/PBEGD3[a]
2.296 2.330 1.826 1.854 1.854 1.856 1.441 1.433 1.539 1.530 1.526 1.537
2.288 2.356 1.823 1.850 1.847 1.854 1.442 1.428 1.537 1.529 1.523 1.532
B3LYP/ (6-31G*, SD)/S[c] 2.341 2.382
B3PW91/ LANL2DZ[d] 2.416 2.390
Exp. from ref. [22] 2.259 2.293 1.788 1.863 1.787 1.821 1.427 1.420 1.523 1.521 1.502 1.517 5.006 6.498 9.25
Bond angles (Degree) P-Au-S 174.6 170.5 173.6 178.6 175 Au-S-C7 103.3 95.6 105.6 103.6 96.2 P-C1-C2 113.6 110.0 115 P-C3-C4 113.8 115.2 114 P-C5-C6 117.2 114.1 117 Au-P-C1 114.4 110.0 111.3 112.9 Au-P-C3 115.7 115.2 111.6 Au-P-C5 111.5 114.1 115.8 Au-P-C1-C2 55.73 60.37 47.270 Au-P-C3-C4 57.51 58.58 54.037 Au-P-C5-C6 181.78 183.67 179.498 Au-S-C7-O1 51.36 47.23 -51.405 -72.1 Au-S-C7-C8 189.40 287.34 -169.287 C8-O2-C12-O3 3.69 7.60 6.30 C9-O4-C14-O5 184.08 181.89 -9.26 [a] SR is acronym for scalar relativistic, GD3 for dispersion term, SD for Sttutgard-Dresden bases and S for solvent; [b] data from reference [37]; [c] data from reference [36].
SR-ZORA/PBE structure taking into account the dispersion term, and the resulting structure was the previously obtained SR-ZORA/PBE-GD3 molecule; and vice versa, we tried the reoptimization of the SR-ZORA/PBE-GD3 structure without dispersion correction, and convergence was found for a similar structure to SR-ZORA/PBE-GD3, but one high imaginary frequency was computed. Comparing with theoretical results in
literature, we note the bond angle Au-S-C7 predicted by Howell (96.2 degree) [36] using Kohn-Sham Hamiltonian (B3PW91/LANL2DZ method) only differs 0.6 degrees compared to our corresponding SR-ZORA/PBE-GD3 value, although Howell simplified the auranofin structure removing the acetyl groups and replacing the triethylphosphine by trimethylphosphine groups. Conversely, Dos Santos et al [37] computed the full structure (using B3LYP/ Sttutgard-Dresden bases), however, the torsion angle Au-S-C7-O1 (-72.1 degree) reported by them suggests a different isomer as compared with the isomers calculated in this work (see Table 1). Note that SR-ZORA Hamiltonians using PBE functional predict slightly lower values of the P-Au-S angles and shorter Au-P and Au-S distances than Kohn-Sham Hamiltonians using hybrid functionals and relativistic pseudopotentials [36,37] (see Table 1); comparisons with X-ray data show that our results are in better agreement with experimental values. A complete contrast between our SR-ZORA-PBE structural parameters and X-ray data shows good agreement between the two sets of parameters, with the following maximum differences: 0.067 Å for P-C3 distance, 4.3 degree for the bond angle Au-P-C5, and 8.4 degree for the torsion angle Au-P-C1-C2. See Tables S1 and S2 in Supplementary Information (SI) for a more detailed comparison with experimental data [22], including overall errors. It is important to note that the inclusion of the dispersion term does not necessarily improve the agreement with specific geometrical parameters. Often, the HOMO-LUMO (the highest occupied and lowest unoccupied molecular orbital, HOMO and LUMO respectively) energy difference is used as an indicative parameter of molecular chemical stability. Using this parameter, practically the same chemical stability is predicted for both SR-ZORA/PBE (3.37 eV) and SR-ZORA/PBE-GD3 (3.29 eV) structures, whose HOMO and LUMO orbitals also present the same form and distribution (see Figures 2 and 1S in Supplementary Information); the HOMO is dominated by a pz orbital centered on the sulfur atom with a non-negligible dxz contribution on the gold atom. The LUMO is a π-bonding orbital between the gold and phosphorus atoms, oriented in the yz-plane with a slight contribution px of the sulfur.
Figure 2. HOMO and LUMO for the ground state of Auranofin.
In fact, the reactivity properties of auranofin can be analyzed from the calculated ground state electronic wave-function using estimators as the average local ionization energy (ALIE) and the local electron attachment energy (LEAE), which are also good indicators of basicity/acidity of organic and inorganic compounds [38]. See SI for the ALIE and LEAE definitions. The existence of ALIE surface minima at low electronic densities (usually 0.001 a.u.) correspond to localized regions around the molecule, where interaction with electrophilic moieties (Lewis acids) is largest. The LEAE surface minima are regions susceptible to nucleophilic attack (Lewis basis). The resulting surfaces for these properties calculated from our SR-ZORA/PBE and SR-ZORA/PBE-GD3 wave-functions are presented in SI (Figures 2S and 3S in SI). The colored surfaces have very similar features around the P-AuS bond regardless of the employed method. A localized region around the Au-S bond can be identified as an important Lewis basic zone from the ALIE colored surface, which is the most prone to interact with electron-acceptors at different Lewis acids. The LEAE characteristics reveal that auranofin is a soft Lewis acid as might be expected for an Au(I) complex. The localized regions of minimum LEAE at the 0.004 isodensity surface are mainly localized on a saddle surface enclosing Au and the interstitial region between S and the thioglucose ligand with a hole on top S and on three small basins around the phosphorus atom, behind the bonds with the ethyl groups. The LEAE main contributions (see Table 3S in SI) are from LUMO (around P) and from LUMO+1 to LUMO+9 (the saddle surface). Dos Santos [37] found that tetraaceytylthioglucose replacement is the most favorable reaction occurring when auranofin reacts with S-, Se- and N- containing amino acids (AA). A proton transfer upon the nucleophilic AA attack to the S-auranofin promotes this reaction and is indeed favored in the wide region between the S-atom and the glucose moiety found with aid of LEAE. The replacement of the triethylphosphane moiety reacting with the AA was predicted as unfavorable [37] in agreement with the LEAE colored isosurface that shows just three small point regions susceptible to nucleophilic attack around the P atom. 3.2 IR-spectra analysis and comparison with experiment The simulated IR spectra for both isomers of auranofin computed with and without dispersion correction are displayed superimposed in Figure 3.a. Note that both spectra exhibit very similar shapes, with appreciable changes mainly in the height of their peaks, higher in the SR-ZORA/PBE IR spectrum than the other one. Hence, we concluded that the structural differences between the two isomers, discussed above, do not turn on or off any IR modes of vibration.
Figure 3. a) Theoretical IR spectra for the auranofin molecule; (b) experimental IR spectrum for form A of the auranofin from reference [23] and superimposed our PBE/TZP IR spectrum between 2000 - 350 cm-1; here a shift of 3 cm-1 was applied. When comparing with experimental IR spectra in literature, we note that the shape of the peaks in our IR spectra for auranofin look like those of Baran et al [23] (see Figure 3.b), while a blue- shift of approximately 3 cm-1, leave 4 of the 7 main peaks superimposed. At this point it should be said that Baran et al confirmed the presence of the A polymorph based on melting-point studies. In our spectra a doublet at 3028/2961 cm-1 (see Figure 3.a) can be localized, which corresponds to vibration modes from the ethyl groups from the PEt3 ligand: stretching of C-H, asymmetric stretching of CH2, and waging, stretching, and asymmetric stretching of CH3. This doublet is in agreement with that reported by Baran et al at 2966/2870 cm-1, although they also assign vibrations from acetate moieties to this doublet [23]. The band at 1745 cm-1 is dominated by vibrations from acetyl groups: δ(acetyl) bending, ν(C=O) stretching, and γ(CH3) waging; although asymmetric stretching of the OCH on the ring is also registered. This is in very good agreement with Baran et al, who describe one band at 1747 cm-1, corresponding to carbonyl groups.
The band at 1428 cm-1 was assigned to δ(P-CH2) bending and γ(CH3) waging modes from the acetyl groups. In the next band localized at 1337 cm-1 complex vibrations deforming the sugar ring, stretching vibrations of ring-O-acetyl moiety, asymmetric stretching of the acetyl groups, and stretching of C-C from acetyl group and sugar ring can be observed. Note the similar shape and the much lower heights obtained for the peaks at 1428 and 1337 cm-1 as compared to the experimental one (1452 and 1373 cm-1 respectively [23]). The higher heights in the experimental peaks could be due to the vibrations in these bands, and might be favored by intermolecular interactions between acetyl moieties. Clearly the effects of these intermolecular interactions in our IR-spectra are missing because our calculations are in gas phase. Note that these bands are scarcely described by Baran et al, and according to their assignments, the vibration modes of the ring-O-acetyl moiety and C-C stretching should be expected until the band at 1032 cm-1. Again, the band at 1190 cm-1 is dominated by complex vibrations and coupling of the ring, thus, there are registered twisting and beating of the ring, asymmetric stretching of the ring-O-acetyl, ring-CH2-O-Acetyl and ring-S moieties. Contributions from these three last moieties are also registered in the band at 997 cm-1, with additional asymmetric stretching of the acetyl and PEt3 groups. The weak band at 736 cm-1 also contains complex coupled vibrations from all moieties constituting the molecule, thus, we can observe bending mode of the PEt3 and asymmetric stretching of the ring-O-Acetyl, acetyl and ring-S-Au. In the analogue experimental band Baran et al only assign vibrations for the triethylphosphine moiety. Also, by comparison with literature they tentatively assigned the υ(C–S) mode to the band at 630 cm-1. The next weak band at 569 cm-1 is also dominated by asymmetric stretching of the ring, ring-O-Acetyl, ring-CH2-O-Acetyl and Au-S-ring, while the band at 403 cm-1 contains uncoupled and asymmetric stretching of the Au-P and Au-S (at 413 and 315 cm-1 respectively), both stretchings coupled to vibrations from Et3 and acetylglucopyranose (Atg) ring moieties respectively. In contrast, Baran et al reported υ(P–Au) stretching vibration and δ(Au-P) mode at 382 and 301 cm-1. Finally, we observe a bending mode of PAu-S coupled to both ligands at 50 cm-1. Readers interested in a more detailed description of these bands see Table 4S in SI. 3.3 UV-vis spectrum for Auranofin and comparison with experiment The UV-vis spectra computed using TDDFT SR-ZORA/(PBE, PBE-DG3) methods are superimposed in Figure 4. To simulate these spectra, we use a gaussian functions superposition with a width of 6 nm. Counter to the IR-spectra, the absorption/excitation spectra with and without the dispersion correction exhibit different features: the spectrum computed without dispersion term presents one main peak, two shoulders and one peak with very low intensity in the energy window from 160 to 300 nm; for the geometrical structure calculated using the SR-ZORA/PBE-GD3 method, only a wide main peak without shoulders and two peaks with very low intensity are obtained. Clearly, our SR-ZORA/PBE
absorption spectrum is in excellent agreement with the experimental electronic spectrum (showed at inset in Figure 4) obtained for an aqueous solution of auranofin by Baran et al [23]: our main peak and the two first shoulders are located at 195, 213, and 223 nm compared with 196, 210, and 222 nm, respectively in the experimental case; the third experimental shoulder (246 nm) is imperceptible in our UV-vis curve; however, the small peak at 255 nm is in good agreement with the tail observed at the same energy in the experimental spectrum.
Figure 4. Theoretical UV-vis spectra for the Auranofin molecule. At inset the experimental UV-vis spectrum for form A of the auranofin from reference [23]. In Tables 5S and 6S and Figures 4S-7S (see SI) the characteristics (energy, oscillator strength, molecular orbitals and weight of the transition) of the most intense and probable electronic transitions contributing to the configuration of each peak in the SR-ZORA/(PBE, PBE-GD3) UV-vis spectra are shown. In these Tables and Figures the main peak is named a; the two shoulders, b and c; and the less intensive peak, d. According to these results, in the SR-ZORA/PBE spectrum the three most intense transitions in band a (see Table 5S and Figures 4S and 5S) mainly come from charge transfer from PAuSATg to the SAuPEt3 as well as from the electron back bonding in SAuPC to SAuPEt3 and SAuPEt3 to acetyl group, not only from the C-S bond as Baran et al suggested. In band b the three most intense transitions come from charge transfer from PAuSC to acetyl groups and PAuSAtg to SAuPEt3 moiety. Also, the shoulder at 223 nm (band c) mainly comes from two transitions with strong contributions, HOMO-1 → LUMO+9 and HOMO → LUMO+16, the HOMO and HOMO-1were mainly localized on the S-P bond. The peak d at 255 nm is an HOMO2→ LUMO+1 transition. In the SR-ZORA/PBE-GD3 spectrum (see Table 6S and Figure 6S and 7S) the most intense transitions in band a are localized at 196 and 205 nm, while band b is found at 240
nm, all of them coming from charge transfer from SAuP to all molecule. Band c at 279 nm comes from CSAu to SAuPEt3 moiety. Note the relatively good agreement between these transition energies with those of Baran et al; however, the electronic transitions around 222 nm are mostly off (see Figure 6S). It is important to highlight that HOMO→ LUMO+1 is missing in the SR-ZORA/PBE spectrum (see Table 5S), while the three firsts transitions HOMO→ LUMO are localized at 363, 350 and 330 nm. On the other hand, for the SR-ZORA/PBE-GD3 structure, the HOMO→ LUMO is missing in the window of energies reported (see Table 6S), but one transition HOMO→ LUMO+1 is obtained at 348 nm. These characteristics must be specially considered, because they could be important in explaining the phosphorescence of auranofin, property studied by Kunkely et al [24], whom also studied the photolysis of auranofin in acetonitrile using an irradiation of 254 nm. Comparing their absorption spectrum at t = 0 s with our spectra, once again a better concordance is found with the SRZORA/PBE spectrum, since their peaks at 196, 210, 224, 244, and 276 nm are in good agreement with our peaks at 195, 213, 223, 255, and 289 nm. Instead, as before, the transition at 224 nm is missing for the PBE-GD3 spectrum (see Table 6S). Another feature missing in this spectrum is the observed decay in the experimental curves around 250 nm. Because a better agreement between our SR-ZORA/PBE UV-vis spectrum and the experimental ones was found, we selected the structure resulting from this method to study the phosphorescence properties of auranofin. 3.4 Phosphorescence emission for auranofin The emission spectrum of auranofin shows phosphorescence with max = 594 nm in the solid state at 77 K [24]. This emission behavior is possible due to the heavy atom effect of gold. Given the large intermolecular Au···Au separation (6.498 Å) reported by Hill et al (see Table 1), we assumed that these phosphorescence properties cannot be altered by possible gold-gold interactions, which justifies the use of auranofin in the gas phase in order to study these properties. In general, phosphorescence involves a spin-forbidden radiative transition between states of different multiplicity, usually from the lowest excited singlet S1 or triplet state T1, according to Kasha’s rule. The triplet-excited state can be accessed from the singlet-excited state S1 or vice versa only if the molecule or its environment favors the intersystem crossing (ISC) process. The presence of gold in auranofin enhances the rate of ISC by increasing the spin-orbit coupling between ground and lowest-energy excited states. In order to achieve a deeper understanding on this phenomenon in auranofin, the low-energy singlet and triplet transitions from its theoretical UV-vis spectrum were analyzed. In Table 7S both are reported, the low-energy singlet and triplet transitions (left and right sides respectively) for auranofin computed using SR-ZORA/PBE as well as the corresponding oscillator strengths and the transition states with their respective weights. The transitions to triplet appear with zero oscillator strength because these types of transitions are spin-
forbidden in SR-ZORA. In Table 7S, the first S1 excited state corresponds to a HOMOLUMO transition with an energy of 3.42 eV, while the T1 is a lower-energy state at 3.33 eV between the same states. The next transitions S2 and T2 (at 3.50 and 3.48 eV respectively) are predominantly HOMOLUMO+1, with some mixing with HOMOLUMO+2. Based on the HOMO and LUMO descriptions (Figure 2), the lowest energy transition of auranofin can be classified as LMCT (ligand-to-metal charge transfer) with some non-negligible MC (metal-centered) contribution. For the next transition, the charge transfer to ligands, is involved (see Figure 1S in SI). Due to a large component centered on gold in the transition orbitals, it is important to study the spin-orbit effect in the lowest energy transition. In order to accomplish this task, we analyze the SO-ZORA optimization results for the ground state. As we mentioned in Sect. 3.1, there are no important structural modifications when the spin-orbit coupling is incorporated to the calculations, hence there are no significant changes expected for the transition energies. In Table 8S the spin-orbit coupled excitation energies for auranofin are reported, including oscillator strengths, states involved, and their weights and transition lifetimes. In this transitions list it is not possible to distinguish if the transition is to triplet or singlet, however comparison with the list of Table 7S is valid, because there are negligible structural changes between the two ground states (SR, SO)/ZORA. Therefore, the three lowest transitions in Table 8S correspond to T1 and the 4th corresponds to S1. The consistency of this assumption can be confirmed comparing the oscillator strengths for S1 in Table 7S (0.0062) with that of the 4th state in Table 8S (0.007), also, both are HOMOLUMO transitions. Note that the first three excitations have oscillator strengths one order of magnitude lower, but now are not spin-forbidden. The next four excitations in Table 8S (5-8) are not mixed as in Table 7S and correspond to HOMOLUMO+1 transitions. Since the HOMOLUMO transition involves the heavy gold atom, as it was shown above, it is very probable that the spin-orbit coupling will be large enough between these states, in such a way that the ISC from S1 to T1 will take place. In order to explore this possibility, we tried the optimization of the molecule in the S1 and T1 excited states at the SR-ZORA level (SO-ZORA optimizations for exited states are not supported in ADF2013.01), but we did not get convergence in the calculations; in fact, whenever we started the optimization from the ground state structure, a cleavage of the S-C bond was obtained, which finally leads to the dissociation of the molecule. Therefore, we proceeded to optimize the second excited states S2 and T2, obtaining the structures displayed in Figure 5.
Figure 5. SR-ZORA structure for auranofin in the second excited states a) S2 and b) T2. The most important geometrical change in both excited states structures is observed in the bond angle P-Au-S, which suffers a bending from 175 (S0) to 168 (S2) and 159 (T2) degree; in Table 2, the main geometrical parameters characterizing both structures are reported. An elongation of around 0.1 Å for the Au-S bond length with respect to the ground state was found for both excited structures, accompanied by a lower elongation of the P-Au bonds length (0.02 and 0.03 Å for singlet and triplet respectively). Besides of the P-Au-S angle, these bond and dihedral angles, which include the Au-S moiety, suffer important changes, while those involving the Au-P fragment do not change in average (see Table 2). Table 2. Structural parameters from SR-ZORA/PBE for Auranofin in the ground state and their comparison with those of the second excited states S2 and T2. Bond lengths (Å) Bond angles (Degree) Au-P Au-S S-C7 P-C1 P-C3 P-C5 C7-O1 C11-O1 C7-C8 C8-C9 C9-C10 C10-C11
Singlet
Triplet
2.319 2.427 1.840 1.854 1.888 1.858 1.404 1.453 1.545 1.528 1.533 1.543
2.334 2.412 1.842 1.852 1.874 1.855 1.405 1.453 1.545 1.528 1.534 1.543
P-Au-S Au-S-C7 P-C1-C2 P-C3-C4 P-C5-C6 Au-P-C1 Au-P-C3 Au-P-C5 Au-P-C1-C2 Au-P-C3-C4 Au-P-C5-C6 Au-S-C7-O1 Au-S-C7-C8 C8-O2-C12-O3 C9-O4-C14-O5
Singlet
Triplet
167.5 115.3 115.1 113.1 116.8 108.6 127.3 106.4 52.75 57.17 184.07 38.82 197.03 7.66 178.02
159.1 115.1 114.6 113.5 116.8 109.1 125.1 107.0 54.41 58.17 186.84 38.11 197.55 7.48 177.69
For the excited state T2 there is an exchange between LUMO and LUMO+1 with respect to the ground state, the latter being a gold-ligands orbital (see Figure 8S in SI). It is important to note the change in the LUMO+1 orbital due to the bending of the P-Au-S angle becoming predominantly s gold-centered, hybridized with π (Au-P) and π*(P-C), and a lower contribution from py(S). This type of orbital was computed by Aikens et al [28] for the S1 excited state of (TPA)AuSCH(CH3) complex, which suffers a similar bending of the P-Au-S angle (160 degree). According to the El-Sayed selection rules, the ISC rate is increased from the lowest singlet state to the triplet manifold when the transition involves a change of the orbital type [39]. In this case, the orbital changes from ground to excited state produced by the P-Au-S bending, favors the ISC. In Table 9S the excitation energies calculated using SR-ZORA on the T2 excited state geometry are summarized. Note that for this excited state, the two lowest-energy transitions to singlet and triplet are degenerated and correspond to combinations between HOMOLUMO+1 and HOMOLUMO. This mixing of states is probably the reason why it is not possible to optimize the S1 and T1 states within the framework of the TDDFT, assuming both states close to S2 and T2. Similar behavior was found by Guidez and Aikens [28] for some gold-phosphine-thiolates complexes simpler than auranofin, computing several state crossings of the excited energies as a function of the P-Au-S angle. Instead, we note that for auranofin the mixing and the degeneration between the (1-4) -(5-6) states (see Table 10S) disappear when the spin-orbit coupled TDDFT calculation is performed on the SR-ZORA excited structure. In this case, from Tables 9S and 10S it is not possible to establish a singlet-triplet correspondence, because the inclusion of the spin-orbit coupling breaks the accidental degeneracy of the states, and changes the oscillator strengths’ values. Naturally, we can assume that 5th to 7th excited states are preferred for the ISC nonradiative transition, since they are related to the gold predominant orbital transition (see LUMO+1 in Fig. 1S). Besides, considering that LUMO and LUMO+1 can be exchanged for the lowest excited state T1 (supported by the degeneration breaking T1-T2 induced by spin-orbit coupling), the computed emission energy would be lower than 2.29 eV (540 nm) which is in agreement with the peak (594 nm) measured by Kunkely et al [24]. The predicted lifetime for these excited states falls within the range (14 – 795 s), which corresponds to a phosphorescence radiative emission; however, these values must still be corroborated experimentally. Conclusions In conclusion, we have presented a systematic theoretical study on the structural, electronic and photophysical properties of auranofin, a molecule of reference for the phosphine-gold(I) complexes. This study was based on SR and SO ZORA-DFT and TDDFT calculations on the X-ray structure of auranofin reported in the literature. After the optimization calculations, we found good agreement between structural parameters calculated using the SR- ZORA/PBE method and X-ray data. Inconsistences between some
bond and torsional angles are obtained as compared with the corresponding experimental parameters, when the GD3 dispersion correction is applied to the GGA-PBE functional. According to our results, the spin orbit coupling is negligible in the structural properties of this gold compound in the ground state. The calculated ground state wave-functions for auranofin allowed us to evaluate the isosurfaces LEAE and ALIE, and to characterize the reactivity for this molecule. The regions susceptible to nucleophilic and electrophilic attacks can be identified locating the minima of these quantities in their constant low density isosurfaces. For auranofin, the minima of LEAE were located at sites between the S atom and the thioglucose moiety, while for ALIE they were observed around Au-S. Also, LEAE showed that the region around the P atom is mostly inactive. Therefore, calculations of these surfaces are recommended for these types of compounds, prior to catalysis applications; this could be relevant in the design of new drugs, because these surfaces can be used to guide exchange reactions calculations, for example. In principle, both optimized structures for auranofin, with and without dispersion term, yield almost the same IR spectra, being this technique insensitive to the structural changes found such as the orientation of the equatorial plane of the sugar ring with respect to the P-Au-S motif. Our spectra showed good agreement with the experimental one. After a careful revision of the calculated vibrational modes, we proposed a reassignation of some modes and we completed the description for the different bands in the experimental spectrum. For example, unlike to previous experimental assignment, we do not observe contributions from acetate moieties to the doublet at 2966/2870 cm-1; the experimental description puts the vibrational modes of the ring-O-acetyl moiety and C-C stretching in the band at 1032 cm-1, instead we observe these vibrational modes in the band at 1428 cm-1. Also, we registered an asymmetric stretching of the ring-S-Au in the bands at 736 and 569 cm-1, while the experimental group only assigned υ(P–Au) and δ(Au-P) vibration modes at 382 and 301 cm-1 respectively. Note that they either report the bending mode of P-Au-S located at 50 cm-1. As evidence of the photosensitivity of these compounds, correlated to changes in its geometrical structure, we highlighted the lack of two shoulders in the UV-vis spectrum calculated for the SR-ZORA/PBE-GD3 isomer, which can be seen in the SRZORA/PBE and experimental UV-vis spectra. This fact was decisive in selecting the method without dispersion to study the phosphorescence properties of auranofin. Our results show that the scalar relativistic approximation is a good level of theory to predict its structural parameters and their IR and UV-vis spectra; however, a spin-orbit approximation must be used for the prediction of its phosphorescence properties. According to our analysis, a bending of the bond angle P-Au-S is induced by the excitation to the lowest triplet state, giving place to a phosphorescence radiative emission with an energy around 540 nm and lifetime in the range of 14 – 795 s. The lowest energy transition for auranofin can be classified as LMCT with MC contributions. We hope this work encourages more detailed emission experiments and can be used as a starting point for new studies oriented to catalysis and drug design based on mononuclear gold(I) compounds.
Declarations of interests: none. Acknowledgements The authors acknowledge the Dirección General de Cómputo y de Tecnologías de la Información (DGTIC-UNAM) for providing Supercomputing resources on “Miztli” through the Project LANCAD-UNAM-DGTIC-298. B. Molina acknowledges the support by PAPIIT-DGAPA, UNAM IN115515. Appendix A. Supplementary data Supplementary data to this article can be found online at … References [1] S. Medici, M. Peana, V.M. Nurchi, J.I. Lachowicz, G. Crisponi, M.A. Zoroddu, Coord. Chem. Rev. 284 (2015) 329-350. [2] S. Parveen, F. Arjmand, S. Tabassum, Eur. J. Med. Chem. 175 (2019) 269-286. [3] B. Bertrand, A. Casini, Dalton Trans. 43 (2014) 4209-4219. [4] I. Romero-Canelon, P.J. Sadler, Inorg. Chem. 52 (2013) 12276−12291. [5] M. Ravera, E. Moreno-Viguri, R. Paucar, S. Perez-Silanes, E. Gabano, Eur. J. Med. Chem. 155 (2018) 459-482. [6] G. Faa, C. Gerosa, D Fanni, J.I. Lachowicz, V.M. Nurchi, Current Med. Chem. 25 (2018) 75-84. [7] A. Ssemaganda, L.M. Low, K.R. Verhoeft, M. Wambuzi, B. Kawoozo, S.B. Nabasumba, J Mpendo, B.S. Bagaya, N. Kiwanuka, D.I. Stanisic, S.J. Berners-Price, M.F. Good, Metallomics 10 (2018) 444-454. [8] B. Dominelli, J.D.G. Correia, F.E. Kühn, J. Organometal. Chem. 866 (2018) 153-164. [9] S.J. Berners-Price, A. Filipovska, Metallomics 3 (2011) 863–873. [10] P. Fonteh, D. Meyer, Metallomics 1 (2009) 427-433. [11] J.C. Lima, L. Rodríguez, Anti-Cancer Agents in Med. Chem. 11 (2011) 921-928. [12] D.T. Hill, B.M. Sutton, A.A. Isab, T. Razi, P.J. Sadler, J. M. Trooster, G.H.M. Calis, Inorg. Chem. 22 (1983) 2936-2942. [13] P.J. Sadler, R.E. Sue, Met.-Based Drugs 1 (1994) 107 – 144. [14] P. Gruene, D.M. Rayner, B. Redlich, A.F.G. van der Meer, J.T. Lyon, G. Meijer, A. Fielicke, Science 321 (2008) 674-676. [15] A. Tlahuice-Flores, U. Santiago, D. Bahena, E. Vinogradova, C.V. Conroy, T. Ahuja, S.B.H. Bach, A. Ponce, G. Wang, M.J. Yacamán, R.L. Whetten, J. Phys. Chem. A, 17 (2013) 10470-10476.
[16] B. Molina, A. Sánchez-Castillo, S. Knoppe, I.L. Garzón, T. Bürgi, A. Tlahuice-Flores, Nanoscale, 5 (2013) 10956-10962. [17] B.M. Sutton, E. McGusty, D.T. Walz, M.J. DiMartino, J. Med. Chem. 15 (1972) 1095-1098. [18] S.-J. Park, I.-S. Kim, Brit. J. Pharmacol. 146 (2005) 506–513. [19] D.L. Shapiro, J.R. Masci, J. Rheumatol. 23 (1996) 1818–1820. [20] B. Chirullo, R. Sgarbanti, D. Limongi, I.L. Shytaj, D. Alvarez, B. Das, A. Boe, S. DaFonseca, N. Chomont, L. Liotta, E. III Petricoin, S. Norelli, E. Pelosi, E. Garaci, A. Savarino, A.T. Palamara, Cell Death and Dis. 4 (2013) e944. [21] I. L. Shytaj, B. Chirullo, W. Wagner, M.G. Ferrari, R. Sgarbanti, A. Della Corte, C. LaBranche, L. Lopalco, A.T. Palamara, D. Montefiori, M.G. Lewis, E. Garaci, A. Savarino, Retrovirology 10 (2013) 1-15. [22] D.T. Hill, B.M. Sutton, Cryst. Struct. Commun. 9 (1980) 679. [23] E.J. Baran, G.E. Tobón-Zapata, S.B. Etcheverry, Spectrochimica Acta Part A 55 (1999) 1569–1573. [24] H. Kunkely, A. Vogler, Zeitschrift für Naturforschung B 51 (1996) 1067–1071. [25] A. Vogler, H. Kunkely, Coord. Chem. Rev. 219–221 (2001) 489–507. [26] C.-M. Che, S.-W. Lai, Lumi, Gold Chemistry, Application and Future Directions in the Life Sciences, Chapter 5; edited by F. Mohr, Wiley-VCH, Germany (2009) 249-281. [27] Z. Assefa, J.M. Forward, T.A. Grand, R. J. Staples, B.E. Hanson, A.A. Mohamed, J.P. Jr. Flacker, Inorg. Chimica Acta (2003) 31-45. [28] E.B. Guidez, C.M. Aikens, J. Phys. Chem. A 119 (2015) 337-347. [29] E. van Lenthe, E.J. Baerends, J.G. Snijders, J. Chem. Phys. 99 (1993) 4597. [30] E. van Lenthe, E.J. Baerends, J.G. Snijders, J. Chem. Phys. 101 (1994) 9783. [31] E. van Lenthe, J.G. Snijders, E.J. Baerends, J. Chem. Phys. 105 (1996) 6505. [32] ADF 2013.01 SCM. Theoretical Chemistry, Vrije Universiteit: Amsterdam, The Netherlands. Available at: http://www.scm.com. [33] J.P. Perdew, K. Burke, M. Ernzerhof, Phys. Rev. Lett. 77 (1996) 3865. [34] S. Grimme, J. Antony, S. Ehrlich, H. Krieg, J. Chem. Phys. 132 (2010) 154104. [35] K. Mori, T.P.M. Goumans, E. van Lenthe, F. Wang, Phys. Chem. Chem. Phys. 16 (2014) 14523−14530. [36] J.A.S. Howell, J. Organomet. Chem. 694 (2009) 868–873. [37] H.F. Dos Santos, Comput. Theor. Chem. 1048 (2014) 95–101. [38] T. Brinck, J.H. Stenlid, Adv. Theory Simul. 2 (2019) 1800149. [39] C. M. Marian, WIREs Comput. Mol. Sci. 2 (2012) 187–203.
DFT and TD-DFT calculations of the structural, electronic and photophysical properties were performed for auranofin, a drug commonly used as a reference compound. IR spectroscopy cannot differentiate between isomers obtained while UV-vis does. Calculations including spin-orbit predict auranofin lowest excitation induces a bending of its P-Au-S motif, which explains its phosphorescence.