Quantum Chemical Studies of cis-[M(NH₃)₂Cl₂] (M = Co^I, Rh^I, Ir^I, Ni^II, Pd^II, Pt^II, Cu^III, Ag^III, and Au^III): Structure, Bonding, and Hydrolysis

Abstract

To gain molecular-level insights into cisplatin and its metal analogs, we performed a comprehensive investigation of the geometric and electronic structures of cis-[M­(NH₃)₂Cl₂] (M = Co^I, Rh^I, Ir^I, Ni^II, Pd^II, Pt^II, Cu^III, Ag^III, and Au^III), along with their bonding characteristics and hydrolysis behaviors. All complexes adopt a planar, four-coordinate geometry, with the ${\mathrm{d}}_{x^2‐y^2}$ orbital predominantly involved in ligand interactions. EDA-NOCV analyses indicate that the total interaction energy increasing from Group 9 to 11 with σ-interactions dominates the metal–ligand bonding. cis-[M­(NH₃)₂Cl₂] with M = Co^I, Rh^I, and Ir^I were found to be unstable, exhibiting a tendency to form five-coordinated species. In contrast, cis-[M­(NH₃)₂Cl₂] complexes (M = Ni^II, Pd^II, Pt^II, Cu^III, Ag^III, and Au^III) undergo ligand exchange reactions via penta-coordinate trigonal-bipyramidal-like transition states. Their monoaquated derivatives all demonstrated high reactivity toward guanine. Considering their hydrolysis behaviors, cis-[Au^III(NH₃)₂Cl₂]⁺ emerges as a potential candidate for antitumor applications.

1. Introduction

The enduring interest in developing metallodrugs for cancer therapy arises from the well-established anticancer activity of cisplatin (cis-[Pt^II(NH₃)₂Cl₂]), first discovered by Rosenberg over five decades ago. Since then, numerous Pt^II complexes have been synthesized and tested. , However, only a few have progressed to clinical trials, with carboplatinthe second-generation cisplatin analogueand oxaliplatinthe third-generation derivativebeing the only globally approved platinum-based chemotherapeutics. ,

Beyond Pt^II, several other d⁸ transition metals, including Ni^II, Pd^II, and Au^III complexes, have also demonstrated promising antitumor activity both in vitro and in vivo. , In general, Ni^II and Pd^II complexes are thermodynamically and kinetically far less stable than those of Pt^II, making ligand design a critical factor in achieving biological efficacy. Their anticancer mechanisms are considered more diverse; in addition to DNA binding, inhibition of topoisomerase enzymes has been proposed. Although isoelectronic with Pt^II, Au^III complexes display distinct redox behaviors and are generally more prone to reduction ( ${E^0}_{{\mathrm{Au}}^{3+}/{\mathrm{Au}}^{+}}$ = +1.36 V vs ${E^0}_{{\mathrm{Pt}}^{2+}/{\mathrm{Pt}}^{+}}$ = +1.19 V). Hence, to prevent premature reduction before reaching biological targets, inert multidentate ligands such as porphyrin and pyridine derivatives are commonly employed to form cyclometalated species in the design of anticancer agents. −

Given the immense chemical diversity of metal-based compounds, experimentally assessing their full anticancer potential is practically impossible. Quantum chemical methods address this challenge by promoting molecular-level understanding of known anticancer drugs, thereby facilitating the rational design and high-throughput screening of potential candidates. To date, the structure and bonding of Pt^II anticancer drugs have been characterized, with Pt^II adopting a square-planar coordination, where the d _xy and ${\mathrm{d}}_{x^2‐y^2}$ orbitals form σ bonds with ligands, the d _xz and d _yz orbitals engage in π interactions, and the ${\mathrm{d}}_{z^2}$ orbital remains largely nonbonding. Subsequent studies have increasingly focused on their antitumor mechanisms, with hydrolysis followed by binding to DNA bases widely recognized as the primary pathway. ,

Despite these advances, most existing studies have focused on individual complexes and employed various computational methods and levels of theory. This lack of a unified and systematic computational framework hinders direct comparison of bonding characteristics and reactivity trends across transition-metal series, thereby limiting the rational design and screening of nonplatinum anticancer candidates. To address this gap, we extend our investigation beyond cisplatin to a series of cis-diamminedichloro complexes of group 9–11 transition metals, including Co^I, Rh^I, Ir^I, Ni^II, Pd^II, Cu^III, Ag^III, and Au^III. Their geometric and electronic structures, as well as bonding characters, are analyzed, followed by an assessment of their hydrolysis and reactivity toward guanine. These findings provide a deeper understanding of structure–reactivity relationships of cisplatin-type complexes and pave the way for the rational design of next-generation metal-based anticancer agents.

2. Computational Methods

Geometry optimization followed by harmonic vibrational frequency calculations was performed by the DFT methods with the pure Perdew–Burke–Ernzerhof (PBE) functional. − The Slater-type orbital basis sets with triple-ζ quality basis plus two polarization functions (TZ2P) were used for all atoms. The frozen-core approximation was applied to the inner shells [1s²-2p⁶] for Co, Ni, and Cu; [1s²-3d¹⁰] for Rh, Pd, and Ag; [1s²-4d¹⁰] for Ir, Pt, and Au; and [1s²] for C, N, and O. Scalar-relativistic (SR) effects were computed by the zero-order regular approximation (ZORA). Energy decomposition analysis coupled with natural orbital for chemical valence (EDA-NOCV) was employed to investigate the bonding characters between central metal and ligands using the geometries optimized at the same theoretical level. − In EDA, the total interaction energy (ΔE _int) between two fragments (here, the metal and ligand) is decomposed into three energy components:

$$\mathrm{\Delta }{E}_{\mathrm{int}}=\mathrm{\Delta }{E}_{\mathrm{elstat}}+\mathrm{\Delta }{E}_{\mathrm{Pauli}}+\mathrm{\Delta }{E}_{\mathrm{orb}}$$

where ΔE _elstat represents the quasi-classical electrostatic interaction between fragments with unperturbed electron densities. ΔE _Pauli arises from the requirement that the wave function obeys the Pauli exclusion principle. As the fragment electron densities overlap, electrons with the same spin cannot occupy the same spatial orbital. Therefore, the total wave function must be antisymmetrized, leading to an increase in energy. ΔE _orb corresponds to the stabilization arising from orbital relaxation and reorganization, which can be further decomposed into contributions from each irreducible representation of the point group.

Hydrolysis of cis-[M­(NH₃)₂Cl₂] (M = Co^I, Rh^I, Ir^I, Ni^II, Pd^II, Pt^II, Cu^III, Ag^III, and Au^III) and the subsequent binding to guanine were investigated by Gaussian 16 with the pure GGA PBE functional and the def2-TZVP basis set, including Grimme’s D3 dispersion correction with Becke–Johnson damping (GD3BJ). − Frequency analysis was further performed to identify the stationary points as either stable minima or transition states. The polarizable continuum solvent model of SMD was used to describe the aquatic solvation effect. The zero-point energy correction was included in the reported energies. The Gibbs free energy (G) was calculated according to Wertz’s correction, where the entropy contributions from translational and rotational degrees of freedom are scaled in the solvent:

$$G=H-T\times (S_{\mathrm{vib}}+0.5S_{\mathrm{rot}}+0.5S_{\mathrm{trans}})$$

where H is the enthalpy obtained from the calculation; T represents reaction temperature; S _vib, S _rot, and S _trans are the entropy contributed from the vibrational, rotational, and translational movements, respectively. The employed functionals and basis sets have been widely used and validated for the study of transition-metal complexes. −

3. Results and Discussion

3.1. Geometric Structure

The optimized geometric structures of cis-[M­(NH₃)₂Cl₂] are presented in Table S1 (at the PBE/TZ2P/SR level). In the case of cisplatin, as shown in Figure , the chlorine atoms, nitrogen atoms, and the central Pt^II are coplanar, with the Pt–N and Pt–Cl distances of 2.09 and 2.29 Å, respectively. Additionally, a Cl–H distance of 2.36 Å indicates the existence of an intramolecular hydrogen bond, which results in a reduced Cl–Pt–N angle of 82.6° and thus lowers the molecular symmetry to C_2v. Correspondingly, the Cl–Pt–Cl and N–Pt–N angles increase to 95.6° and 99.3°, respectively. Experimental data obtained from the solvent-free crystal of cisplatin show that the lengths of Pt–N and Pt–Cl are 2.01 ± 0.04 and 2.33 ± 0.01 Å, respectively, validating the theoretical methods used in this study.

1.

Bond lengths (Å) and angles (degree) as well as Hirshfeld atomic charges of cisplatin at the PBE/TZ2P/SR level.

The other complexes examined also exhibit C_2v symmetry, except for cis-[Cu­(NH₃)₂Cl₂]⁺, which has a C₁ symmetry (Figure S1). The M–Cl, M–N, and Cl–H bond lengths are in the range of 2.12–2.37, 1.95–2.15, and 2.29–2.55 Å, respectively. Within the same period, the M–Cl distance decreases whereas the M–N distance increases with an increasing atomic number. This suggests that the M–Cl bond is predominantly governed by electrostatic interactions since a higher valence leads to a shorter M–Cl distance. The angles of Cl–M–Cl, Cl–M–N, and N–M–N are 87.7–98.9°, 80.9–89.1°, and 93.1–99.5°, respectively. In general, the angle of Cl–M–Cl decreases from period 4 to 6, likely due to the decreasing atomic charges on the chlorine atoms, resulting in reduced repulsion (Table S2).

3.2. Electronic Structure

All the metals studied here primarily use their outer d orbitals to bond with ligands. In the C_2v point group, d orbitals split into four irreducible representations, i.e., a₁ ( ${\mathrm{d}}_{x^2‐y^2/z^2}$ ), a₂ (d _xy ), b₁ (d _xz ), and b₂ (d _yz ). − The ligand group orbitals (LGOs) originate from six Cl 3p orbitals and two N 2p orbitals, making a total of 8 LGOs. Hence, there are primarily 13 molecular orbitals (MOs) involved in the bonding between metals and (NH₃)₂Cl₂ ^2–.

Orbital interaction between metals and (NH₃)₂Cl₂ ^2– is analyzed using the MO energy-level correlation diagram, with cisplatin illustrated here as an example (Figure ). The Pt 5d _yz orbital interacts with 1b₂ LGO, which originates from the N 2p atomic orbital, to form the occupied σ-bonding MO 1b₂ and corresponding unoccupied antibonding 4b₂, which is the lowest unoccupied molecular orbital (LUMO) here. The Pt 5 ${\mathrm{d}}_{x^2‐y^2}$ interacts with the N-originated 1a₁ LGO, leading to the formation of 1a₁ and 4a₁ MOs with bonding and antibonding nature, respectively. The huge energy splitting of these two MO pairs reflects strong bonding interactions between the central platinum and (NH₃)₂ of the ligand. The MO pairs of 1a₂ and 2a₂ and 1b₁ and 2b₁ are originated from the π-interaction of Pt d _xy/xz with 1a₂ and 1b₁ LGOs, respectively. Interaction between the Pt 5 ${\mathrm{d}}_{z^2}$ and 3a₁ LGO results in the formation of 3a₁ and 5a₁ MOs. All these three MO pairs split slightly in energy between their bonding and antibonding orbitals, indicating the minor orbital interactions of central Pt and Cl₂ of the ligand. Three MOs, namely, 2a₁, 2b₂, and 3b₂, are Cl 3p-originated, which rarely interact with Pt atomic orbitals and exhibit nonbonding character. Additionally, five MOs, i.e., 4a₁, 5a₁, 2b₁, 2a₂, and 4b₂, are predominantly Pt 5d-based, among which the 4b₂ is unoccupied. Therefore, the oxidation state of Pt is best represented as divalent Pt^II (d⁸), and the ligand as dianion.

2.

MO energy-level correlation diagram (left panel) and frontier MOs (isovalue = 0.03 au, right panel) of cis-[Pt­(NH₃)₂Cl₂] at the SR-ZORA PBE/TZ2P level. The energy levels of Pt and (NH₃)₂Cl₂ ^2– fragments are shifted down as a whole by 0.85 and 10 eV, respectively, to align with their corresponding core molecular orbitals of cis-[Pt­(NH₃)₂Cl₂]. Occupied orbitals are shown in blue and red, while virtual orbitals are shown in orange and green.

Energy levels of complexes that belong to the same group are closely situated and decrease from Group 9 to 11 (Figure ). This trend can be attributed to the increase in effective nuclear charge across the series, which strengthens the attraction between the nucleus and electrons while reducing shielding effects, thereby leading to a general lowering of all molecular orbital energy levels. As all complexes involve similar d orbital interactions with the same ligands, their frontier molecular orbital (MO) contours are largely comparable, although slight variations in orbital ordering are observed (Figure S2). The highest occupied molecular orbitals (HOMOs) of cis-[Cu­(NH₃)₂Cl₂]⁺ and cis-[Ag­(NH₃)₂Cl₂]⁺ are derived from Cl 3p atomic orbitals and possess a nonbonding character. In contrast, for the remaining complexes, the HOMOs originate from π-interaction between metal d _xy or d _xz and LGOs. In the case of cis-[M­(NH₃)₂Cl₂] where M belongs to Groups 10 and 11, their LUMOs are formed from the σ-interaction between metal d _yz and N-originated LGOs. As to the Group 9 complexes, LUMOs are primarily LGO-originated. For all the complexes, four occupied MOs are metal d orbital-originated, suggesting that the oxidation states of the central metals are best represented as Co^I, Rh^I, Ir^I, Ni^II, Pd^II, Pt^II, Cu^III, Ag^III, and Au^III.

3.

Frontier MO energy of cis-[M­(NH₃)₂Cl₂] at the SR-ZORA PBE/TZ2P level. Their HOMOs were connected with red lines. The contours of HOMO and LUMO are shown in blue and red and in orange and green, respectively (isovalue = 0.3).

3.3. Chemical Bonding Analysis: EDA-NOCV

EDA-NOCV was performed for cis-[M­(NH₃)₂Cl₂] → M­(d⁸) + (NH₃)₂Cl₂ ^2–. In this study, ΔE _Pauli ranges from 179.62 to 390.15 kcal/mol (Table ). It increases down a group with an increasing atomic number, whereas it decreases across a period. Pauli repulsion originates from Coulombic exchange repulsion associated with the overlap of occupied orbitals. ,, Accordingly, the increase in atomic radius down a group leads to greater orbital overlap and thus enhanced Pauli repulsion. In contrast, across a period, the contraction of d orbitals with an increasing atomic number reduces orbital overlap, leading to a decrease in ΔE _Pauli. ΔE _elstat represents the Coulombic interaction between fragments, which increases with both the valence and the atomic number, resulting in the largest ΔE _elstat for cis-[Au­(NH₃)₂Cl₂]⁺ with a value of −1022.53 kcal/mol. ΔE _orb reflects the energy variation arising from polarization and charge transfer when two fragments become one. , Among these complexes, cis-[Cu­(NH₃)₂Cl₂]⁺ exhibits the highest ΔE _orb value of −830.07 kcal/mol, while cis-[Ag­(NH₃)₂Cl₂]⁺ and cis-[Au­(NH₃)₂Cl₂]⁺ have values of approximately −745 kcal/mol. For metals in the same Group of 9 and 10, ΔE _orb increases with the atomic number, of which the values are −217.62 to −316.55 and −390.65 to −443.34 kcal/mol, respectively. ΔE _orb is further decomposed into pairwise NOCV contributions. The contribution of σ-interaction is absolutely predominant, which accounts for more than 75% to the total ΔE _orb for all complexes.

1. EDA of cis-[M­(NH₃)₂Cl₂] at PBE/TZ2P (kcal/mol) .

metal	ΔEint	ΔEPauli	ΔEelstat	ΔEorb	ΔEta	ΔEσ
Co	–437.97	216.96	–437.31 (67%)	–217.62 (33%)	–654.93	–173.96 (80%)
Rh	–428.83	262.76	–462.93 (67%)	–228.65 (33%)	–691.58	–173.24 (76%)
Ir	–471.71	390.15	–545.30 (63%)	–316.55 (37%)	–861.85	–247.69 (78%)
Ni	–886.22	189.18	–684.77 (64%)	–390.65 (36%)	–1075.42	–292.05 (75%)
Pd	–860.28	243.58	–711.96 (65%)	–391.90 (36%)	–1103.86	–308.53 (79%)
Pt	–886.78	329.31	–772.72 (64%)	–443.34 (37%)	–1216.06	–344.89 (78%)
Cu	–1598.93	179.62	–948.51 (53%)	–830.07 (47%)	–1778.58	–673.07 (81%)
Ag	–1486.34	227.14	–968.32 (57%)	–745.19 (44%)	–1713.51	–611.49 (82%)
Au	–1468.45	301.20	–1022.53 (58%)	–747.07 (42%)	–1769.6	–601.55 (81%)

^aCalculations are performed for the process of cis-[M­(NH₃)₂Cl₂] → M­(d⁸) + (NH₃)₂Cl₂ ^2–. Each fragment is in a closed-shell configuration, and thus, the spin multiplicity is 1.

^bShown in parentheses are the percentage contributions to the total attractive interactions (ΔE _elstat + ΔE _orb).

^cShown in parentheses are the percentage contributions to the orbital interactions ΔE _orb.Here, ΔE _σ is determined by summing over all NOCV pairs with σ (a_1g, b_1g, and e_1u) symmetries, respectively.

The sum of ΔE _elstat and ΔE _orb gives rise to the total attractive interaction (ΔE _ta). Overall, Coulombic interaction plays a major role in all complexes, contributing approximately 53–67% to ΔE _ta. For cis-[Co­(NH₃)₂Cl₂]⁻, cis-[Rh­(NH₃)₂Cl₂]⁻, and cis-[Ir­(NH₃)₂Cl₂]⁻, due to their relatively weak electrostatic and orbital interactions and relatively large Pauli repulsion, their total interaction energies (ΔE _int), namely, the sum of ΔE _Pauli, ΔE _elstat, and ΔE _orb, are the smallest among all the studied complexes, with values of −437.97, −428.83, and −471.71 kcal/mol, respectively. For complexes featuring Ni, Pd, and Pt as the central metal, an ΔE _elstat of −684.77 to −772.72 kcal/mol accounts for more than 60% of ΔE _ta. Considering their relatively weak Pauli repulsion, the ΔE _int values fall within the range of −860.28 to −886.78 kcal/mol. In the case of Cu, Ag, and Au complexes, both electrostatic and orbital interactions are substantial, leading to the largest ΔE _int ranging from −1468.45 to 1598.93 kcal/mol.

We further summarized the variation patterns and analyzed the correlations among these structural and electronic parameters. Overall, these parameters do not vary monotonically with the atomic number but instead exhibit periodic trends (Figure S3). Specifically, the M–N bond lengths, ΔE _elstat, ΔE _orb, ΔE _ta, and ΔE _int increase across periods, whereas the M–Cl bond lengths, Cl–M–Cl angles, HOMO and LUMO energies, and ΔE _Pauli show the opposite trend. The LUMO energy, HOMO–LUMO gap, ΔE _elstat, ΔE _orb, ΔE _ta, and ΔE _Pauli increase down a group, while the remaining parameters exhibit a nonmonotonic trend, initially increasing and then decreasing. Pairwise scatter plots revealed that, except for the geometric parameters, data clustered by groups (Figure S4). Accordingly, correlation analysis was performed on the geometric parameters (Figure S5) and partial correlation analysis was conducted for all parameters using group as a covariate (Figure ). The M–Cl bond length shows a significant negative correlation with ΔE _elstat (r = −0.84, p < 0.01), suggesting that shorter M–Cl distances are associated with stronger electrostatic interactions. Interestingly, within the framework of the hard and soft acids and bases (HSAB) theory, Cl^– is generally considered a softer base than NH₃ and is therefore expected to exhibit relatively stronger covalent interactions. However, our results show the opposite trend. This discrepancy can be attributed to the anionic nature of Cl^–, which enhances Coulombic attraction with the metal center, thereby increasing the electrostatic contribution to the M–Cl interaction.

4.

Spearman partial correlation heatmap of geometric parameters and bonding characteristics of cis-[M­(NH₃)₂Cl₂] (M = Co^I, Rh^I, Ir^I, Ni^II, Pd^II, Pt^II, Cu^III, Ag^III, and Au^III). The color scale represents the correlation coefficient, with red and blue indicating positive and negative correlations, respectively. Statistical significance is denoted by *p < 0.05, **p < 0.01, and ***p < 0.001. Hirshfeld atomic charges are used in this analysis. Correlations among geometric parameters are calculated using Spearman correlation.

3.4. Reaction Behavior: Hydrolysis and Binding to Guanine

It is well-established experimentally that the primary antitumor mechanism of cisplatin involves an initial hydrolysis of one chlorine ion to form monoaquated species, cis-[Pt­(NH₃)₂ClH₂O]⁺, which subsequently binds to the N7 position of guanine bases, thereby suppressing DNA transcription and ultimately leading to cell death (Figure S6). − Accordingly, in this study, the first hydrolysis of cis-[M­(NH₃)₂Cl₂] and the binding of their monoaquated derivatives to guanine were investigated for better understanding of their antitumor potential.

The hydrolysis of cisplatin and its subsequent binding to guanine are both ligand exchange reactions, which proceed through penta-coordinate, trigonal-bipyramidal-like transition states. In this study, we observed a similar reaction pattern for the cis-[M­(NH₃)₂Cl₂] complexes (M = Ni^II, Pd^II, Pt^II, Cu^III, Ag^III, and Au^III) (Figure S7 and Table S3). For cis-[M­(NH₃)₂Cl₂] with M = Co^I, Rh^I, and Ir^I, our calculations indicate that these complexes are kinetically labile, as evidenced by the proton transfer from an NH₃ ligand to the central metal, resulting in a five-coordinated species (Figure S8). This transformation occurs with relatively low energy barriers (13.08, 18.47, and 13.98 kcal/mol for Co^I, Rh^I, and Ir^I, respectively), suggesting facile structural rearrangement (Table S4). We therefore speculate that these complexes follow an entirely different reaction pattern, and thus, they will not be discussed in the following section. It should be noted that, although cis-[M­(NH₃)₂Cl₂] (M = Co^I, Rh^I, and Ir^I) tend to undergo transformation to five-coordinate species, appropriate ligand design can stabilize square-planar geometries for these metal centers. In fact, a number of square-planar Co^I, Rh^I, and Ir^I complexes have been experimentally reported. , For example, acetylacetonate-1,5-cyclooctadiene Ir^I has been shown to exhibit anticancer activity. In addition, cis-[RhI₂(CO)₂]⁻ and cis-[IrI₂(CO)₂]⁻ are well-known square-planar intermediates in the Monsanto and Cativa processes for methanol carbonylation. , These observations suggest that the coordination number and stability of Co^I, Rh^I, and Ir^I complexes are highly dependent on the ligand environment. Therefore, through appropriate ligand design, it is possible to stabilize square-planar species and enable reactivity patterns analogous to those of cisplatin.

Regarding the first hydrolysis, a reactant complex (RC) with intramolecular hydrogen bonds is formed (Figure , detailed in Figure S7 and Table S3). The two chlorine ligands act as hydrogen-bond acceptors, while the water molecule serves as the donor. The hydrogen-bond distances range from 2.31 to 2.62 Å. This RC directly transforms into a penta-coordinate trigonal-bipyramidal TS, in which the leaving chlorine, the entering oxygen, and one of the nitrogen atoms are at the equatorial plane with the central metal. The O–M and Cl–M distances are 2.00–2.51 and 2.63–2.87 Å, respectively, and O–M–Cl angles range from 65.9° to 73.5°. Product complexes (PC) are formed with the leaving chlorine ion hydrogen-bonded to adjacent NH₃ and H₂O, with bond distances of 2.09–2.22 and 1.77–1.90 Å, respectively. For all metal complexes, formation of RC is exothermic, whereas dissociation of PC into infinitely separated products is endothermic. The Ni^II, Pd^II, Cu^III, and Ag^III complexes readily underwent hydrolysis, with the reaction barriers of 16.55, 18.91, 13.84, and 16.02 kcal/mol at 298.15 K, respectively (Figure and Table S5). In contrast, Pt^II and Au^III complexes exhibit relatively high barriers of 25.94 and 22.14 kcal/mol, respectively.

5.

Free energy profile for the first hydrolysis and binding to guanine at 298 K at the PBE/def2-TZVP level.

Lau et al. pointed out that the calculated reaction barriers are sensitive to the computational methodology and suggested that reactant complexes could be artifacts in aqueous solution, i.e., the attacking water molecule originates from the bulk solvent. , Accordingly, we further evaluated the reaction barriers using the separated reactants as the reference state and also performed calculations at the B3LYP/def2-TZVP level (Table S5). The results indicate that, when employing B3LYP/def2-TZVP with the separated reactants as the reference state, the calculated barrier is 23.72 kcal/mol at 298.15 K, in closest agreement with the experimental value (23.8 kcal/mol). , However, regardless of whether B3LYP or pure PBE is used and irrespective of the chosen reference state, the overall conclusions remain unchanged, i.e., the Ni^II, Pd^II, Cu^III, and Ag^III complexes undergo hydrolysis very readily, whereas the Pt^II and Au^III complexes exhibit relatively higher barriers.

The hydrolysis product forms hydrogen bonds with guanine, with oxygen and 7N of guanine acting as acceptors, and the H₂O and its cis-NH₃ as donors. The N–H and O–H distances are 1.08–1.55 and 1.80–1.95 Å, respectively. The TS are also of trigonal-bipyramidal shape, with the 7N of guanine, the oxygen of the leaving H₂O, the central metal, and one of the NH₃ ligand coplanar in the equatorial plane. The O–M and N–M distances are 2.11–2.51 and 2.22–2.59 Å, respectively, and the O–M–N angles range from 65.9° to 94.6°. For cis-[M­(NH₃)₂ClH₂O] (M = Ni^II, Pd^II, and Pt^II), the leaving H₂O forms a hydrogen bond with the chlorine ion, whereas for M = Cu^III, Ag^III, and Au^III, it binds to oxygen of guanine. All monoaquated complexes exhibit high reactivity toward guanine, with energy barriers of 7.73–21.58 kcal/mol at 298.15 K (Table S5), indicating that this step is not rate-limiting. Once the parent cis-[M­(NH₃)₂Cl₂] undergoes hydrolysis, the product promptly binds to guanine.

The reaction barriers of cis-[M­(NH₃)₂Cl₂] exhibit pronounced periodic trends across the transition-metal series (Figure S9). Specifically, within the same period, the activation barriers decrease with an increasing atomic number, whereas within the same group, the barriers increase upon descending the group. From a kinetic perspective, cis-[M­(NH₃)₂Cl₂] (M = Ni^II, Pd^II, Cu^III, and Ag^III) are unlikely to be antitumor candidates, as they hydrolyze so readily that they would be completely consumed before approaching tumor cells. In contrast, cisplatin hydrolyzes at a moderate rate, allowing sufficient time to enter tumor cells, and its hydrolysis product binds readily to guanine. These factors underlie cisplatin’s antitumor efficacy. Interestingly, cis-[Au­(NH₃)₂Cl₂]⁺ may serve as a potential antitumor candidate due to its overall similarity to cisplatin in both kinetic and thermodynamic aspects. Its hydrolysis barrier is moderate–sufficiently low to allow the reaction to proceed, yet not so low as to cause premature depletion in blood plasma prior to cellular uptake. In addition, the resulting monoaquated species can efficiently bind to guanine. It is important to note that in real biological systems, ligand exchange occurs within the full DNA environment, where additional steric constraints, base stacking interactions, and long-range electrostatic effects may be present. Therefore, a more complete description of anticancer drug interactions with DNA would require the use of larger DNA fragments in both experimental and computational studies.

Conclusions

The geometric and electronic structures of cis-[M­(NH₃)₂Cl₂] (M = Co^I, Rh^I, Ir^I, Ni^II, Pd^II, Pt^II, Cu^III, Ag^III, and Au^III) as well as their bonding characters were thoroughly examined in this study. All complexes exhibit C_2v symmetry except for cis-[Cu­(NH₃)₂Cl₂]⁺, which adopts C₁ symmetry. Intramolecular hydrogen bonds between Cl and H are present in all structures. For each metal center, the outmost ${\mathrm{d}}_{x^2‐y^2}$ orbital is primarily involved in bonding with ligands. Results of EDA indicate that the total interaction energy increases from Group 9 to 11, rising from approximately 400 to 1500 kcal/mol. Further NOCV analysis reveals that σ-interaction predominantly contributes to the total orbital interaction, accounting for about 75–82% of ΔE _orb.

The hydrolysis behavior of these complexes was also investigated. cis-[M­(NH₃)₂Cl₂] with M = Co^I, Rh^I, and Ir^I are unstable and tend to form five-coordinated species. In contrast, cis-[M­(NH₃)₂Cl₂] complexes (M = Ni^II, Pd^II, Pt^II, Cu^III, Ag^III, and Au^III) follow a similar ligand exchange reaction pattern, proceeding through the formation of penta-coordinate trigonal-bipyramidal-like transition states. The Ni^II, Pd^II, Cu^III, and Ag^III complexes are highly susceptible to hydrolysis, with reaction barriers below 19 kcal/mol at 298.15 K, whereas Pt^II and Au^III analogues exhibit relatively higher reaction barriers around 25 kcal/mol. All monoaquated derivatives show reactivity toward guanine with reaction barriers in the range of 7.73–21.58 kcal/mol. From the perspective of their hydrolysis behavior, cis-[Au­(NH₃)₂Cl₂]⁺ emerges as a potential antitumor candidate, as its reactivity closely resembles that of the Pt analogue. Further preclinical studies are warranted to evaluate its therapeutic potential in greater depth.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.6c01898.

• Geometric structures and frontier MO contours (Figures S1 and S2 and Tables S1 and S2), structural and electronic parameter analyses (Figures S3–S5), and geometries and reaction energies for hydrolysis and binding to guanine (Figures S6–S9 and Tables S3–S5) (PDF)

†.

W.-J.F., Y.-C.H., and Q.-K.L. contributed equally.

The authors declare no competing financial interest.