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Article Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX

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Water-Soluble Silver(I) Complexes Featuring the Hemilabile 3,7Dimethyl-1,3,5-triaza-7-phosphabicyclo[3.3.1]nonane Ligand: Synthesis, Characterization, and Antimicrobial Activity Declan Armstrong,† Sarah M. Kirk,† Cormac Murphy,‡ Antonella Guerriero,§ Maurizio Peruzzini,§,∥ Luca Gonsalvi,§ and Andrew D. Phillips*,†,§ †

School of Chemistry and ‡School of Microbiology, University College Dublin, Belfield Campus, Co. Dublin, Ireland, D4 § Istituto di Chimica dei Composti Organometallici (ICCOM), Consiglio Nazionale delle Ricerche (CNR), Via Madonna del Piano 10, 50019 Sesto Fiorentino, Florence, Italy ∥ Dipartimento di Scienze Chimiche e Tecnologia dei Materiali (DSCTM), Consiglio Nazionale delle Ricerche (CNR), Via dei Taurini 19, 00185 Rome, Italy S Supporting Information *

ABSTRACT: This paper describes the preparation and comprehensive characterization of a series of water-soluble cationic silver(I)-centered complexes featuring the hemilabile P,N-ligand known as 3,7-dimethyl-1,3,5-triaza-7phosphabicyclo[3.3.1]nonane (herein abbreviated as PTN(Me)) and differing types of monoanionic counterions including known biologically active sulfadiazine and triclosan. The complexes primarily differed though the number of coordinating PTN(Me) ligands. The bis-substituted Ag(I) complexes revealed P,N bidentate coordination, while the only P-monocoordination of the metal center was observed for the tris-substituted systems. The bis-ligated silver compounds were observed to quickly degrade upon photoexposure or in contact with air. In contrast, the tris-ligated complexes demonstrated greater stability, in particular, a high resistance to photodecomposition. Calculated geometry optimized models using the density functional theory method (BP86) revealed for the bissubstituted PTN(Me) Ag(I) species that the total enthalpy of the tetrahedral C2-symmetric structure is marginally lower by −0.6 kcal mol−1 compared to the planar C2h structure, which is analogous for the corresponding [Au(PTN(Me))2]+ complex with ΔH = −0.5 kcal mol−1. Hence both types of complexes feature free rotation of the PTN ligand about the M−P bond axis. This series of Ag(I) and bis-PTN(Me) Au(I) complexes were evaluated using the agar well diffusion test for potential antimicrobial and antifungal activity. The nature of the counterion was found to have a strong correlation with the area of microbiological growth inhibition. Silver(I) complexes bearing the deprotonated triclosan as the counterion demonstrated the greatest activity, with large zones of growth inhibition, with the tris-ligated triclosan complex obtaining of a high clearance of 42 mm against the Gramnegative Escherichia coli. In contrast, the previously reported [Au(PTN(Me))2]Cl complex demonstrated activity only against E. coli, which is lower than that observed for the silver(I) PTN(Me) species.

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provided through NHC supported complexes.13,14 The ligand 1,3,5-triaza-7-phosphaadamantane (commonly abbreviated as PTA), has been employed with silver for these applications.15−17 This entirely alkyl-based water-soluble phosphine is particularly exceptional for its high stability in both air and water. The relatively small Tolman cone angle (103.2° in dichloromethane) compared to other types of phosphine ligands affords complexes that can undergo exchange in solution.18 More recently, several modifications to the parent PTA structure have been developed over the years, including functionalization of the “upper rim” (P-bonded methylene

INTRODUCTION Antimicrobial resistance is one of the major healthcare concerns for the 21st century, exacerbated by an increasing rate coupled with a slowing rate of new treatments being discovered, produced, and evaluated.1 While new pharmaceutical organic compounds are being developed to combat resistance, metal complexes also have a role to play in solving this global problem. Compounds featuring Cu(II),2,3 Zn(II),4 Pd(II),5,6 Co(II),7 Fe(III),8 Ru(II),9 Ag(I)10,11 metal centers, among others, have been shown to have antimicrobial activity. Of particular interest is silver, due to its antimicrobial activity against a broad range of unicellular organisms.12 A wide variety of ligands have been employed in an effort to precisely tune the release of Ag(I) ions, for which significant developments are © XXXX American Chemical Society

Received: January 25, 2018

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DOI: 10.1021/acs.inorgchem.8b00227 Inorg. Chem. XXXX, XXX, XXX−XXX

Article

Inorganic Chemistry Scheme 1. PTA and Selected Examples of Functionalized PTA Derivatives19

Scheme 2. Synthesis of the PTN(Me) Ligand from the Tris-hydroxymethyl-methyl Phosphonium Salt

Scheme 3. Selected Examples of Transition Metal Complexes Bound by the PTN(Me) Ligand Featuring the κ1-P and κ2-P,N Metal Binding Modes

groups), “lower rim” (N−C−N), in addition to direct N- and P-substitution. Examples of modified PTA ligands are shown in Scheme 1.19 A previously reported upper and lower rim modified version of PTA is 7-phospha-3,7-dimethyl-1,3,5-triazabicyclo[3.3.1]nonane (herein abbreviated as PTN) was first described by Schmidbaur and is the subject of this report.20 The synthetic route first requires the cyclization of tris-P-hydroxymethyl-Pmethyl phosphonium salt to afford a P-methyl substituted PTA salt, followed by Birch reduction conditions. Employing sodium as the reducing reagent converts P-methyl-PTA+ into PTN(Me) via cleavage of a phosphorus−carbon bond (Scheme 1).20 The reaction is not entirely selective, and PTA is also formed as a coproduct, but PTN(Me) is easily separated through low temperature, static vacuum sublimation. PTN(Me) has a bulkier structure than the closed structure analogue PTA, with a methyl functionality both on the phosphorus and terminal nitrogen center. The PTN(Me) ligand has previously been employed as a supporting ligand for a series of η6-arene ruthenium and osmium chloride anticancer complexes featuring cytotoxicity comparable to the related RAPTA type compounds.21 It was found that the PTN(Me) ligand always coordinated in a κ2-P,N

fashion with the metal centers, forming highly water-soluble complexes that readily hydrolyzed exclusively through the cleavage of the M−Cl bond, which enabled strong metal binding with the protein ubiquitin, and short sequence DNA oligonucleotides. The ruthenium PTN(Me) complexes were found to be significantly more cytotoxic in vitro than the corresponding osmium analogue, a trend that had also been observed in comparable complexes with PTA ligands. This study also demonstrated that uncomplexed form of PTN(Me) has negligible cytotoxicity, comparable to that reported for PTA.21 Other transition metal complexes featuring the PTN(R) ligand (R = Me or Ph) include metals such as Mo(0), Rh(I), Pd(II), Au(I), and Au(III) (Scheme 3). For the synthesis of water-soluble PTN(Me) complexes with either a rhodium(III), palladium(II) or gold(III) center, it was found that PTN(Me) engaged in κ1-P coordination mode. However, in a few cases, a hemilabile κ2-P,N binding mode could be accessed, when the Cl substituent attached to the metal center was extracted by counterion exchange.22,23 Schmidbaur et al., reported both mono- and bis-coordinated PTN(Me) gold(I) complexes for which the chelating κ2-P,N binding mode was not fully realized. Only the significant more Lewis acidic Au(III) dimethyl substituted complex features a fully chelated B


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Inorganic Chemistry

methanol and 2 mL of chloroform for 16 h with strict exclusion of light. A colorless solution was afforded after some time. The solvent was reduced under a stream of nitrogen to approximately 2 mL, followed by the addition of antisolvent (15 mL of diethyl ether) yielding a colorless precipitate. This solid was isolated through filtration, washed with 2 × 5 mL of diethyl ether, and air-dried. Yield: 85.3%. Elemental analysis for C26H38AgCl3N6O2P2: Calculated C 42.04%, H 5.16%, N 11.31%, found C 41.70%, H 4.84%, N 11.12%. ESI-MS (positive mode, CH2Cl2): 454.37 m/z, calculated (M+ + H+) 453.12 m/z, (negative mode, CH2Cl2): 286.90 m/z, calculated for C12H7Cl3O2: 286.94 m/z. 1 H NMR (500 MHz, CDCl3, 25 °C) δ 2.11 (s, 6H, PCH3), 1.24 (s, 6H, NCH3), 3.51 (d, 4H, 2JHH = 11.0 Hz, HF), 3.57 (d, 2H, 2JHH = 7.5 Hz, HC), 3.84 (d, 4H, 2JHH = 13.3 Hz, HA) 3.91 (d, 4H, 2JHH = 13.3 Hz, HB), 3.94 (d, 2H, 2JHH = 7.5 Hz, HD), 4.03 (d, 4H, 2JHH = 11.0 Hz, HE), 6.48 (dd, 1H, 3JHH = 8.0 Hz, 4JHH = 1.7 Hz, H8), 6.79 (d, 1H, 3 JHH = 8.3 Hz, H6), 6.73 (d, 1H, 3JHH = 8.5 Hz, H9), 6.85 (d, 1H, 4JHH = 1.6 Hz, H11), 7.10 (dd, 1H, 3JHH = 9.4 Hz, 4JHH = 2.3 Hz, H5), 7.34 (d, 1H, 4JHH = 1.5 Hz, H3). 13C{1H} NMR (126 MHz, CDCl3, 25 °C) δ 15.53 (s, PCH3), 39.02 (s, NCH3), 54.54 (s, Cα), 70.45 (s, Cβ), 76.77 (s, Cγ), 117.46 (s, C8), 119.30 (s, C6), 122.13 (s, C9), 122.96 (s, C5), 126.19 (s, C4), 127.34 (s, C5), 129.18 (s, C3), 130.73 (s, C10), 142.51 (s, C7), 147.17 (s, C12), 153.07 (s, C1), C2 is not observed. 31P{1H} NMR (162 MHz, CDCl3, 25 °C) δ −69.16 (br s). 2a: AgOAc (25.7 mg, 0.142 mmol) and PTN(Me) (80.0 mg, 0.462 mmol) were combined and stirred in 2 mL of methanol and 2 mL of chloroform for 4 h to form a colorless solution. The solvent was reduced under a stream of nitrogen to approximately 2 mL, followed by the addition of 15 mL of diethyl ether to produce a colorless precipitate. The solid was isolated by filtration, washing with 2 × 5 mL of diethyl ether and air drying. Yield: 92.1%. S(H2O, 25 °C) = 0.553 g mL−1. Elemental analysis for C23H51AgN9O2P3·0.1CHCl3: Calculated C 39.72%, H 7.37%, N 18.05%, found C 39.64% H 7.65% N 17.77%. ESI-MS (positive mode, CH2Cl2): 454.22 m/z, calculated (M+ + H+ PTN(Me)) 626.23 m/z. 1 H NMR (500 MHz, D2O, 25 °C): 1.97 (s, 3H, O2CCH3), 1.41 (d, 9H, 2JPH = 2.8 Hz, PCH3), 2.23 (s, 9H, NCH3), 3.67 (d, 6H, 2JHH = 11.5 Hz, HF), 3.79 (d, 6H, 2JHH = 17.2 Hz, HA), 3.88 (d, 6H, 2JHH = 13.6 Hz, HC), 3.98 (d, 6H, 2JHH = 17.2 Hz, HB), 4.05 (d, 6H, 2JHH = 13.6 Hz, HD), 4.08 (d, 6H, 2JHH = 11.5 Hz, HE). 13C{1H} NMR (126 MHz, D2O, 25 °C): 13.97 (d, 1JPC = 3.7 Hz, PCH3), 23.31 (s, O2CCH3), 39.23 (s, NCH3), 52.35, (d, 1JPC = 6.8 Hz, Cβ), 67.93 (d, 3 JPC = 11.2 Hz, Cα), 75.32 (s, Cγ), 181.37 (s, CO2). 31P{1H} NMR (121 MHz, D2O, 25 °C): δ −64.60 (br s). 2f: Ag2O (17.5 mg, 0.077 mmol), PTN(Me) (80.0 mg, 0.462 mmol), and triclosan (45.1 mg, 0.154 mmol) were combined and stirred in 2 mL of methanol and 2 mL of chloroform for 16 h to form a colorless solution. The solvent was reduced under a stream of nitrogen to approximately 2 mL, followed by the addition of 15 mL of diethyl ether to produce a colorless precipitate. This solid was isolated by filtration, washing with 2 × 5 mL of diethyl ether and air-dried. Yield: 89.6%. S(H2O, 25 °C) = 0.035 g mL−1.· Elemental analysis for C33H54AgCl3N9O2P3·0.1 CHCl3: Calculated C 42.84%, H 5.88%, N 13.58%, found C 42.63%, H 6.16%, N 13.37%. ESI-MS (positive mode, CH2Cl2): 454.64 m/z, calculated (M+ + H+ - PTN(Me)) 626.23 m/z, (negative mode, CH2Cl2): 286.88 m/z, calculated for C12H7Cl3O2: 286.94 m/z. 1 H NMR (500 MHz, CDCl3, 25 °C): 1.14 (d, 9H, 3JPH = 2.6 Hz, PCH3), 2.07 (s, 9H, NCH3), 3.48 (d, 6H, 2JHH = 8.6 Hz, HF), 3.49 (d, 6H, 2JHH = 9.5 Hz, HA), 3.82 (d, 6H, 2JHH = 9.5 Hz, HD), 3.84 (d, 6H, 2 JHH = 9.5 Hz, HB), 3.92 (d, 6H, 2JHH = 9.5 Hz, HC), 3.94 (d, 6H, 2JHH = 8.6 Hz, HE), 6.50 (dd, 1H, 3JHH = 8.4 Hz, 4JHH = 1.6 Hz, H8), 6.72 (d, 1H, 3JHH = 8.8 Hz, H6), 6.81 (d, 1H, 3JHH = 8.4 Hz, H9), 6.84 (d, 1H, 4JHH = 1.6 Hz, H11), 7.07 (dd, 1H, 3JHH = 8.8 Hz, 4JHH = 2.4 Hz, H5), 7.33 (d, 1H, 4JHH = 2.4 Hz, H3). 13C{1H} NMR (126 MHz, CDCl3, 25 °C): δ 15.89 (s, PCH3), 38.94 (s, NCH3), 54.93 (s, Cβ), 70.32 (d, 3JPC = 11.5 Hz, Cα), 76.58 (s, Cγ), 115.25 (s, C8), 117.49 (s, C6), 119.28 (s, C11), 122.09 (s, C9), 122.88 (s, C5), 126.24 (s, C4), 127.65 (s, C5), 129.47 (s, C3), 130.73 (s, C10), 142.49 (s, C7), 147.25

PTN(Me) ligand. Other transition metal based complexes such as the η4-1,5-cyclooctadiene Rh(I) species with a chelating PTN(R) ligand (R = Me or Ph) have moderate activity as water-soluble homogeneous catalysts for the hydroformylation of styrene and 1-hexene under biphasic aqueous conditions. Similarly, chelating PTN(Me)-dichloro- or diacetato palladium(II) complexes were shown to be an active catalyst for Suzuki C−C coupling for different aryl halides under aqueous biphasic conditions.6 Thus far, no silver complexes featuring the open cage PTN(Me) ligand have been reported in the literature, nor have any complexes featuring this ligand been evaluated for antimicrobial activity.

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EXPERIMENTAL SECTION

The PTN(Me) ligand was synthesized following the detailed method reported by Caporali et al.24 All other reagents were used as received from commercial sources. Additionally, information including procedures for determining the minimum inhibitory concentration are found in the Supporting Information. Synthetic procedures for 1b−1e and 2b−2d follow those described below for 1a and 2a, respectively. The hydrogen and carbon labeling scheme for the PTN(Me) ligand is provided in Scheme 4, whereas the labeling schemes for the sulfadiazine and triclosan anion are given in the Supporting Information.

Scheme 4. PTN(Me) Hydrogen or Carbon Atom Labelling Scheme

1a: AgOAc (38.6 mg, 0.231 mmol) and PTN(Me) (80.0 mg, 0.462 mmol) were combined and stirred in a mixture of 2 mL of methanol and 2 mL of chloroform for 4 h, with strict exclusion of light, yielding a colorless solution over time. The solvent was reduced under a stream of nitrogen to approximately 2 mL, followed by the addition of 15 mL of the antisolvent (diethyl ether) affording a colorless precipitate. The precipitate was isolated by filtration, washed with 2 × 5 mL of diethyl ether, and air-dried for several hours. Yield: 91.4%. S(H2O, 25 °C) = 0.027 g mL−1. Elemental analysis for C16H35AgN6O2P2·0.15 CHCl3: Calculated C 36.51%, H 6.67%, N 15.82%, found C 35.96%, H 6.31%, N 16.26%. ESI-MS (positive mode, CH2Cl2): 454.36 m/z, calculated (M+ + H+), 453.12 m/z. 1 H NMR (500 MHz, CHCl3, 25 °C): δ 1.19 (d, 6H, 3JPH = 2.4 Hz, PCH3), 1.98 (s, 3H, O2CCH3), 2.23 (s, 6H, NCH3), 3.50 (d, 2H, 2JHH = 11.3 Hz, HF), 3.54 (dd, 4H, 2JHH = 9.1 Hz, 3JPH = 17.5, HA), 3.83 (d, 4H, 2JHH = 14.6 Hz, HC), 3.90 (d, 4H, 2JHH = 9.1 Hz, HB), 3.96 (d, 4H, 2 JHH = 14.6 Hz, HD), 3.96 (d, 2H, 2JHH = 11.3 Hz, HE). 1H NMR (600 MHz, D2O, 25 °C): δ 1.89 (d, 6H, 3JPH = 2.7 Hz, PCH3), 1.99 (s, 3H, O2CCH3), 2.11 (s, 6H, NCH3), 3.49 (d, 4H, 2JHH = 5.4 Hz, HF), 3.53 (dd, 4H, 2JHH = 7.5 Hz, 3JPH = 5.1, HA), 3.83 (d, 2H, 2JHH = 5.6 Hz, HC), 3.90 (dd, 4H, 2JHH = 7.5 Hz, 3JPH = 4.5, HB), 3.93 (d, 2H, 2JHH = 5.6 Hz, HD), 3.96 (d, 4H, 2JHH = 5.4 Hz, HE). 13C{1H} NMR (126 MHz, D2O, 25 °C): δ 15.75 (s, PCH3), 22.98 (s, O2CCH3), 36.42 (s, NCH3), 52.52 (d, 1JPC = 9.7 Hz, Cα), 77.14 (s, Cγ), 69.43 (d, 3JPC = 5.7 Hz, Cβ), 178.45 (s, CO2). 31P{1H} NMR (121 Mhz, 25 °C, CHCl3): δ −70.8 (br s). 31P{1H} NMR (162 MHz, D2O, 25 °C): δ −62.8 (br s). 1f: Ag2O (26.3 mg, 0.116 mmol), PTN(Me) (80.0 mg, 0.462 mmol) and triclosan (67.65 mg, 0.154 mmol) were combined in a small round-bottom flask, and the mixture was stirred in 2 mL of C


Article

Inorganic Chemistry

Scheme 5. Synthesis of 1a−1e and 2a−2d Using Silver(I) Salt Precursors and Different Equivalents of the PTN(Me) Ligand

Scheme 6. Synthesis of 2f Using Silver(I) Oxide, Triclosan and 3 equiv of the PTN(Me) Ligand

(s, C12), 153.12 (s, C1), C2 not observed. 31P{1H} NMR (121 MHz, CDCl3, 25 °C): δ −72.80 (br s). 3: Au(Me2S)Cl (68.0 mg, 0.231 mmol) and PTN(Me) (80.0 mg, 0.462 mmol) were combined and stirred in 2 mL of methanol and 2 mL of chloroform for 4 h. Over several hours, a colorless solution slowly developed. After 6 h, the solvent was reduced under a stream of nitrogen to approximately 2 mL, followed by the addition of 15 mL of diethyl ether to produce a white precipitate. The precipitate was isolated by filtration, washing with 2 × 5 mL of diethyl ether and airdried for several hours. Colorless crystals suitable for X-ray diffraction were grown through the slow evaporation of a saturated aqueous solution. Yield: 114.3 mg, 85.5%. S(H2O, 25 °C) = 0.274 g mL−1. Elemental analysis for C14H32AuCl1N6P2·2H2O: Calculated C 27.35%, H 5.90%, N 13.67%, found C 27.22%, H 5.68%, N 13.45%. ESI-MS (positive mode, CH2Cl2): 542.62 m/z, calculated (M+ − Cl)− 578.81 m/z. 1 H NMR (300 MHz, CDCl3, 25 °C): 1.48 (s, 6H, PCH3), 2.14 (s, 6H, NCH3), 3.55 (d, 4H, 2JHH = 11.6 Hz, HF), 3.86 (d, 4H, 2JHH = 13.2 Hz, HA), 3.95 (d, 4H, 2JHH = 13.2 Hz, HB), 4.08 (d, 2H, 2JHH = 11.5 Hz, HC), 4.45 (d, 2H, 2JHH = 11.5 Hz, HD), 4.60 (d, 2H, 2JHH = 11.6 Hz, HE). 1H NMR (300 MHz, D2O, 25 °C): 1.48 (s, 6H, PCH3), 2.16 (s, 6H, NCH3), 3.46 (dd, 4H, 2JHH = 9.6 Hz, 3JPH = 19.3 Hz, HA), 3.55 (d, 4H, 2JHH = 14.4 Hz, HF), 3.86 (d, 2H, 2JHH = 10.0 Hz, HC), 3.85 (d, 4H, 2JHH = 9.6 Hz, 3JPH = 12.0 Hz, HB), 4.11 (d, 4H, 2JHH = 14.4 Hz, HE), 4.27 (d, 2H, 2JHH = 10.0 Hz, HD). 13C{1H} NMR (101 MHz, CDCl3, 25 °C): δ 16.89 (d, 1JPC = 10.9 Hz, PCH3), 39.19 (s, NCH3), 55.02 (d, 1JPC = 10.0 Hz, Cα), 70.01 (br s, Cβ), 76.56 (s, Cγ). 31 1 P{ H} NMR (162 MHz, CDCl3, 25 °C): δ −31.87 (s). 31P{1H} NMR (162 MHz, D2O, 25 °C): δ −31.42 (br s, ω1/2 = 129.5 Hz).

PTN(Me) ligand, both bis- and tris-coordinated complexes were afforded as colorless microcrystalline solids in high purity. However, in contrast to [Ag(PTA)4]+ it was not possible to synthesize a tetrakis-PTN silver complex, as tris-coordinated species formed when 4 equivalents of PTN were utilized. Likely this is due to the increased steric bulk of the more open PTN(Me) system. In contrast, with the closed-ring structure of PTA ligand, having a smaller Tolman cone angle, the tetrakisPTA complex is more easily formed. The [Ag(PTN(Me))n]An (n = 2 or 3) complexes were synthesized with various types of counterions, which included An = acetate, lactate, nitrate, hexafluorophosphate, and the biologically active sulfadiazine (Scheme 5). The bis-coordinated PTN(Me) Ag(I) complexes (excluding An = sulfadiazine, 1c) were found to be photochemically sensitive, decomposing to elemental silver within several hours, both in solution and in the solid state. The unusual higher photostability of 1c is attributed to a potentially greater interaction between the Ag+ center and sulfadiazine anion as compared to the other types of counterions. In contrast, the tris-coordinated PTN(Me) Ag(I) complexes were found to be initially stable when exposed to light, air and moisture; however, the complexes slowly degraded over prolonged periods (days) under normal conditions. The decomposition of a bis-PTN(Me) silver complex, 1a was monitored over several weeks using 31P{1H} NMR spectroscopy and revealed several emerging compounds with the principal species being tentatively assigned as the P-oxide of PTN(Me), which has a deshielded signal of 4.85 ppm, a region typically associated with phosphine oxides, i.e., P-oxide of PTA δ(31P) = −1.92 ppm. The relative stabilities of the [Ag(PTN(Me)) 3 ]+ species match those of the related gold(I)

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RESULTS AND DISCUSSION A series of silver(I) PTN(Me) complexes were synthesized using a simple one-pot procedure, depicted in Scheme 5. By precisely controlling the molar ratio between the Ag(I) salt and D


Article

Inorganic Chemistry

Figure 1. ORTEP representation of complex 1e. Thermal ellipsoids are drawn on the 50% probability level. The PF6 counterion has been omitted for clarity. Selected bond angles and lengths are given in Table 1.

complexes.20 Interestingly, the greater liability of the PTN(Me) ligand in the tris-coordinated complexes can be demonstrated by reacting 2a with half an equivalent of silver acetate in D2O, as the bis-PTN(Me) complex 1a was quatitative formed as indicated through 31P{1H} NMR. Complexes featuring deprotonated triclosan as the counterion were also synthesized, using Ag2O as the silver precursor (Scheme 6). Triclosan (5-chloro-2-(2,4-dichlorophenoxy)phenol) is a broad-spectrum antibiotic that exhibits activity against bacteria, fungi, and viruses.25 Initial attempts to synthesize the triclosan complex by first forming a silver(I) triclosan precursor proved unsuccessful, so a one-pot method was employed, with the Lewis-basic silver oxide able to deprotonate 2 equivalents of triclosan to form the counterion. A tris-ligated complex featuring a triclosan counterion was also synthesized using this method and is hereafter referred to as 2f. Solution ESI-MS confirmed the presence of the deprotonated triclosan anion for both 1f and 2f. For comparative purposes the bis-substituted gold(I) complex, [Au(PTN(Me))2]Cl (3) was prepared according the procedure outlined by Schmidbaur et al.26 All complexes were fully characterized by NMR spectroscopy, ESI mass spectrometry, and microanalysis. The aqueous solubility of the resulting silver PTN(Me) complexes varied and depended primarily on the number of coordinating PTN(Me) ligands. For example, the bis-PTN(Me) species 1a is significantly less soluble (0.027 g mL−1) than the corresponding tris analog (2a) at 0.553 g mL−1, whereas 2f featuring the more lipophilic triclosan anion decreased significantly with S (25 °C) = 0.035 g mL−1. The bis-PTN(Me) gold complex 3 demonstrated a higher degree of water solubility than the analogous silver complexes (0.274 g mL−1). Solid state structures for 1b, 1e, and 2d were obtained by single crystal X-ray diffraction (Figure 1), with selected bond distances and angles displayed in Table 1. For comparative purposes, the structure of [Au(PTN(Me))2]Cl (3) was redetermined and features no disorder between the P- and N-terminal positions of the coordinated PTN(Me) ligand. The bis-coordinated PTN(Me) Ag(I) complex 1e crystallizes in a monoclinic space group (P21/n) and features a linear geometry at the Ag(I) center as defined by two PTN(Me) ligands coordinating κ2-P,N mode (Figure 1). The PF6 counterion is positioned at almost right angles to the PTN(Me) ligands and forms a close contact between the Ag and F centers 3.074(2) Å. However, other shorter contacts are present between the F atoms of the counterion and the H atoms of the ligands. The PTN(Me) ligands are trans-positioned to another, with a P− Ag−P angle of 176.91(2)°. The PTN(Me) ligands are orientated in a staggered conformation about the P−Ag bond

Table 1. Selected Bond Distances (Å) and Bond Angles (deg) for 1b, 1e, 2d, and 3 complex parameter

1e

1b

2d

3

metal M−P (Å)

Ag(I) 2.391(1) 2.388(1)

Ag(I) 2.397(2) 2.390(2)

Au(I) 2.309(1) 2.309(1)a

M···Nterminal (Å)

3.029(2) 3.122(2)

3.004(6) 3.103(6)

P···Nterminal (Å)

2.942(2) 2.926(2)

2.932(5) 2.910(5)

P−M−P (deg)

176.91(2)

160.99(5)

Ag(I) 2.475(1) 2.491(1) 2.452(1) 3.707(2) 3.174(2) 2.999(2) 3.026(2) 2.845(2) 2.947(2) 111.53(1) 119.06(2) 129.24(2)

3.152(2) 3.153(2)a 2.968(2) 2.917(2)a 180b 180a,b

a

Two crystallographically independent molecules contained within the unit cell. bCrystallographically defined bond angle caused by the presence of an inversion center.

axis with both N−C(H3) bonds aligned with the plane defined by the Ag and two P centers. The Ag−P distances of 2.3910(6) and 2.3878(6) Å are shorter than the median value of 2.412 Å for all structures reported in the CSD featuring a [Ag(PR3)2]+ unit, but are similar to other species featuring bulky alkyl-based phosphines, including [Ag(P(cyclohexyl)3)2]+ (2.394(7) Å).27 The distances between the Ag center and the terminal nitrogen centers of the PTN(Me) ligand are 3.029(2) Å and 3.122(2) Å. Although well beyond a typical covalent Ag−N(C3) bond length of 2.412 Å,26 these values are less than the combined sum of van der Waals radii for Ag and N (i.e., 3.7 Å),27 and this suggests the presence of marginal bonding interactions between the metal and this part of the PTN(Me) ligand. This is in contrast to previous examples of gold,26 palladium,6 rhodium,23 ruthenium,21 and molybdenum26 complexes where a well defined κ2-P,N coordination mode for the PTN(Me) ligand has been observed. A second version of the bis-coordinating PTN(Me) silver complex, 1b crystallizes in the orthorhombic (P21212) space group. In contrast to the coordinative unsaturated complex 1e, the Ag(I) center in 1b is additionally coordinated by a lactate group. For 1b, the central metal adopts a highly distorted tetrahedral geometry as defined by the two phosphorus centers and the two oxygen centers of the carboxylate group belonging to the lactate (Figure 2). Both the PTN(Me) and lactate ligands are disordered over two positions in a ratio of 0.66 to 0.34. Analogous with 1e, the phosphine ligands are trans-positioned to one another. E


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Inorganic Chemistry

Figure 2. ORTEP representation of complex 1b. Thermal ellipsoids are drawn on the 50% probability level. Only one set of the disordered PTN(Me) ligands is shown. Solvates are omitted for clarity. Selected bond angles and distances are given in Table 1.

Figure 3. ORTEP representation of complex 2d. Thermal ellipsoids are drawn on the 50% probability level. The NO3 counterion has been omitted for clarity. Selected bond angles and distances are given in Table 1.

However, the presence of the lactate group perturbs the P− Ag−P bond angle to 160.99(5)°, with one Ag−P bond equivalent to that in 1e, 2.390(2) and the other only slightly longer, 2.397(2) Å. The orientation of the PTN(Me) ligands, as defined by the P−C(H3) bond axis, is inverted with respect to another. The lactate group is a bidentate κ2-O,O’ chelating ligand, exhibited by the highly uneven bond distances of Ag−O 2.448(6) Å and 2.813(9) Å, respectively, indicating a significant tilting of the CO2 group, affording one oxygen center with stronger metal coordination (i.e., Ag−O−C 108.5(4)° versus 88.00(5)°). This mode of binding is slightly different from the other only bis-coordinating phosphine silver(I) complex with a lactate group which features an overall stronger chelation of the Ag center, the Ag−O distances are 2.425(3) Å and 2.509(4) Å, and the Ag−O−C bond angles are 91.0(5)° and 94.8(3)°, respectively.29 In contrast to the almost linear P−Ag−P bond angle in 1b, the same angle in [Ag(PPh3)2]+ is significantly narrower (126.15(3)°) with the lactate forming an O−Ag−O angle of 51.3(1)° versus 46.20(2)° in 1b. Similar to complex 1e, the distances between the Ag center and the terminal nitrogen centers of the PTN(Me) ligands are considerably long, 3.004(6) Å and 3.103(6) Å, and thus represent minimal bonding interactions. The [Ag(PTN(Me))3]NO3 compound 2d crystallizes in the monoclinic P21/n space group and features a Ag(I) center bonded by only three PTN(Me) ligands in the κ1-P mode, and features a noncoordinating nitrate counterion (Figure 3). Two of the PTN(Me) ligands are orientated with the P-substituted methyl groups orientated in roughly the same direction, while the third PTN(Me) aligns in the opposite direction. The Ag−P distances, 2.452(1) Å, 2.476(1) Å, 2.491(1) Å are significantly longer than those in 1b, but shorter than the Ag−P values found in [Ag(PPh3)3]NO3, (i.e., 2.525(2), 2.545(2), 2.630(2) Å).30 The metal center has a distorted trigonal planar geometry exemplified by the bond angles P−Ag−P (129.24(2)°, 119.06(2)°, 111.54(2)°). The sum of the angles totals 359.83(3)° indicating an almost trigonal planar Ag center, which is in contrast to the pyramidal geometry of the metal center in [Ag(PPh3)3]NO3.29 The orientation and natural curvature of the PTN(Me) ligand position the terminal methyl groups in a way that affords significant steric protection around

the metal center, preventing access to potential vacant coordination sites. Similar to 1b, the distances between the terminal nitrogen centers of the three PTN(Me) ligands and Ag are 3.7071(16) Å, 3.1744(17) Å, 2.9991(15) Å, which are considerably longer than a standard covalent value, but two of which are less than the sum of van der Waals radius for Ag and N, which suggests that only very weak bonding interactions are maintained. In all herein described Ag-PTN(Me) complexes, the C(H2)−P−C(H2) bond angle falls within a narrow range of 97° to 98°, which is wider than the 93.43(10)° found within free PTN(Me)26 and indicates strong Ag−P binding as confirmed by density functional theory (DFT) calculations. Complex 3 crystallizes in the triclinic P1̅ space group and features two crystallographic independent [Au(PTN(Me))2]+ molecules in the unit cell along with two water solvates and two chloride counterions (Figure 4). The previously reported crystal structure presented with no solvates in the unit cell, but featured significant disorder of the PTN(Me) ligand over the P

Figure 4. ORTEP representation of complex 3. Thermal ellipsoids are drawn on the 50% probability level. Solvates and the Cl counterion have been omitted for clarity. Selected bond angles and distances are given in Table 1. F


Article

Inorganic Chemistry and terminal N positions.11 The Au(I) center is coordinatively unsaturated with a linear, trans-orientation of the PTN(Me) ligands coordinated in a κ1-P mode and is structurally analogous to the bis-coordinated PTN(Me) silver complex 1e. The essential differences between the two Au(I) cations is that one molecule features hydrogen bonding to the water solvates, while the other maintains only long-distance interactions. Both bent and linear geometries are typically observed for gold(I) phosphine complexes, with the P−Au−P bond angles ranging from 150° to 180°.27 In the case of 3, a linear geometry is observed with the P−Au−P bond angles set at 180° due to the presence of a crystallographic inversion center, thus defining C2h symmetry with respect to the metal center. The PTN(Me) ligands are coordinated equidistant from the Au center due to a 2-fold mirror plane bisecting the inversion center. The Au−P distances are 2.3087(4) Å and 2.3099(4) Å, both lengths being less than the median value of 2.423 Å as indicated by the CSD for the [Au(PR3)2]+ subset. Interestingly, the structure of the [Au(PTA)2]Cl complex reported by Fackler et al., also features a P−Au−P bond angle of 180°, but considerably shorter Au−P bond distances of 2.261(5) Å, which is probably due to the reduced steric profile of PTA versus PTN(Me).31 For complex 3, both PTN(Me) ligands align parallel to each other through this plane with the orientation reversed with respect to another. The distances between the terminal nitrogen centers and the Au(I) are 3.152(2) Å. This implies that the PTN(Me) ligands are not adopting the κ2-P,N chelating mode. However, these distances are shorter than the sum of the van der Waals radii of Au (2.32 Å)28 and N (1.66 Å),28 totalling 3.98 Å. Hence a marginal bonding interaction can be considered present between the terminal N centers of PTN(Me) and the metal. An additional feature is that one of the [Au(PTN(Me))2]+ complexes is that a side N center of the PTN(Me) ligand forms a hydrogen bond to a water solvate with a bond distance of 2.17 Å. This ability to hydrogen bond analogous to numerous complexes featuring PTA. However, in all of the herein described structures, the terminal N centers of the coordinated PTN(Me) ligands do not engage in any long-range contacts, presumably due to the curved and rigid structure of the PTN(Me) ligand that restricts the space around these nitrogen atoms. Solution NMR spectroscopy confirms the structure of the bis- and tris-substituted PTN Ag complexes as indicated by the X-ray diffraction studies in the solid state. Due to the fixed conformation of PTN(Me) this affords inequivalent protons, thus all methylene groups exhibit second order coupling, and in some cases, the signals are overlapping. Hence definitive assignment was performed through 15N−1H and 13C−1H HETCOR 2D NMR techniques. These methods were employed previously to assign the CH2 groups in the free ligand.23 Moreover, we have employed the 2D NMR 1H−1H NOESY technique to assign specific protons of the methylene groups by through space interactions. The labeling scheme of the protons in the PTN(Me) ligand is shown in Figure 5. Figure 6 shows the methylene regions in the 1H NMR spectra of complexes 1d, 2d, 2e, and 3, alongside uncomplexed PTN(Me) in deuterated chloroform and D2O. Upon complexation to the silver(I) ion, all protons associated with the PTN(Me) ligand are deshielded to varying degrees, most notably exemplified by the CH3(P) resonances which shifts from δ(1Η) = 0.91 ppm to 1.17 ppm for 2d. The bis-PTN(Me) complexes 1a−f exhibit greater deshielding for the methylene protons versus the tris-substituted species, a comparison of

Figure 5. Methylene proton labeling scheme and inter-methylene proton through space relationship as established by 1H−1H NOESY.

δ(1H) values is provided in Table 2. Moreover, greater deshielding is observed when all complexes are dissolved in D2O as compared to CDCl3, indicating that the coordinated PTN(Me) ligand is significantly affected by hydrogen bonding with the solvent. Due to the rigid structure of the PTN(Me), some methylene protons experience greater deshielding upon P-coordination, due to the orientation of the ligands around the metal center. For example, δ(1H) of HB changes from 3.34 to 3.73 ppm for 1d, and to 3.79 ppm for 2d in D2O. Other protons on the ligand do not experience such strong deshielding effects upon complexation, for example, δ(1H) of HF only changes by 0.03 ppm in the aprotic solvent CDCl3. Figure 7 shows the 31P{1H} NMR spectrum for 1e, which presents with two sets of doublets. This splitting pattern is manifested by coupling to the I = 1/2 Ag(I) center. The very large coupling constants of 546.6 and 627.2 Hz are effectuated by the two isotopes of silver, 107Ag and 109Ag. Accounting for the difference in the gyromagnetic ratios between two isotopes, the average reduced coupling is 1K(107Ag,31P) = −2.76 × 1022 T2 J−1 equivalent to the standard one-bond coupling value of 1 107 J( Ag,31P) of 546.0 Hz. The magnitude of the coupling constants is typical for complexes bearing only two phosphine ligands (i.e., [Ag(PPh3)2]PF6 1J(107Ag,31P) = 507 Hz).32 The effect of incorporating electronegative nitrogen atoms into the PTN(Me) ligand serves to also increase the magnitude of the coupling constant.33 Interestingly, Ag-coupling31 was not observed with the tris-ligated complexes 2a−f, with only singlet resonances appearing in the 31P spectra. This can be attributed to rapid intermolecular exchange of the ligands, which effectively decouples the phosphorus from the silver atom. This is further supported by the ESI-MS data of 2f, which reveals only a signal corresponding to Ag(I) with two PTN(Me) ligands, suggesting highly lability of the third PTN(Me) ligand in solution. As with the proton NMR spectra, the 31P{1H} spectra demonstrated greater deshielding in the complexes than the free ligand. However, no clear trend regarding δ(31P) values between the bis- and tris-substituted PTN complexes was observed.

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COMPUTATIONAL ANALYSIS Both the bis- and tris-PTN(Me) coordinated silver(I) complexes, and the bis-coordinated PTN(Me) Au(I) species were modeled by DFT calculations at the BP86 level of theory using the quasi-relativistic Stuttgart large-core basis set for the metals.34 For the bis-coordinate cationic species (1f and 3), both C2 and C2h symmetric structures were geometry optimized to energy minimums (Figure 8). In all cases, the C2 structures, whereby the Nterminal−P−P−Nterminal torsional angle is 88.4° (M = Ag) or 105.8° (M = Au), are marginally lower in energy than the C2h version (Nterminal−P−P-Nterminal is fixed as 180°) by −0.6 and −0.5 kcal mol−1, respectively. The minuscule energy difference between the two geometry-types indicates that the G


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Inorganic Chemistry

Figure 6. 1H NMR (methylene region only) of PTN(Me) in CDCl3, D2O, complexes 1d (CDCl3, D2O), 1e (CDCl3), 2d (CDCl3, D2O), and 3 (CDCl3). Peak labels correspond to the scheme shown in Figure 5.

been previously employed to demonstrate that considerable strain is created when the PTN(Me) ligand engages in the κ2P,N chelation mode.23 As expected, the metal-phosphine interaction is strong, with the gold complex having the strongest of the series. The greater strength of the Au−P bond over Ag−P or Cu−P bonds is well documented in the literature and has been cited as a rationale for the preference for bis-coordinate linear geometry.36 Inclusion of the lactate group to [Ag(PTN(Me))2]+ serves to weaken the Ag−P bonds with the binding of electronegative oxygen atoms increasing the charge on the metal center. Similarly, the addition of a third PTN(Me) ligand to [Ag(PTN(Me))2]+ individually weakens each Ag−P bond; however, the combined bond strength about the Ag(I) center is considerably greater than in the biscoordinated PTN(Me) complex, which greatly enhances complex stability. The lower MBI value of the Ag−P bond in the tris-PTN(Me) species supports the experimentally observed

PTN(Me) ligand freely rotates about the M−P bond axis, further supporting the apparent weakness of the bonding interaction between the terminal N and metal center. When the lactate group is added to the [Ag(PTN(Me))2]+ complex, a more accurate representation of the solid state structure (1d) is obtained, including the rotation of the CO2 functional group that enables one of the oxygen centers to bind more strongly with the Ag(I) (Figure 8). A complete comparison of bond lengths and angles between the DFT calculated gas phase models and experimental solid state structures is provided in the Supporting Information. As an initial foray to understanding the internal bonding within the modeled complexes, Mayer bond indices (MBI) were calculated for the C2h symmetric [M(PTN(Me))2]+ (M = Ag, Au) and [Ag(PTN(Me))3]+ (C1 symmetry) with the values summarized in Table 3.35 MBI provides a standardized measure of bond strength through integration of orbital overlap and has H


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Inorganic Chemistry

Table 2. 1H and 31P{1H} Chemical Shifts (δ, ppm) and Coupling Constants (J, Hz) of the Uncoordinated PTN(Me) and the PTN(Me) Ligand within the Complexes Recorded in Aprotic (CDCl3) and Protic (D2O) Solvents

a

P{1H}

31

compound (solvent)

P-CH3

N−CH3

HA

HB

HC

HD

HE

HF

PTN(Me) (CDCl3) PTN(Me) (D2O) 1d (CDCl3) 1d (D2O) 2d (CDCl3) 2d (D2O) 3 (CHCl3) 3 (D2O)

0.91

2.10

3.65

3.29

3.79

3.86

3.82

3.50

−89.50 (s)

0.96

2.08

3.62

3.23

3.74

3.90

3.89

3.36

−92.2 (s)

1.28

2.14

3.63

3.71

3.83

3.89

3.87

3.49

−69.58 (d 1J = 587 Hz)a

1.28

2.14

3.73

3.73

3.83

3.92

3.89

3.48

−62.57, d, 1J = 600 Hz)a

1.17

2.09

3.53

3.86

3.94

3.89

3.97

3.53

−70.66 (s)

1.23

2.02

3.62

3.67

3.83

3.91

3.78

3.48

−66.81 (s)

1.48

2.14

3.86

3.95

3.95

4.25

4.09

3.54

−31.19 (s)

1.48

2.16

3.47

3.85

3.86

4.27

4.11

3.55

−31.93 (br s)

Refers to the 1J(109Ag,31P) coupling constant.

Figure 7. 31P{1H} NMR spectrum of 1e. δ = −62.60 (d, 1J(109Ag, 31P) = 627.2 Hz), −62.61 (d, 1J(107Ag, 31P) = 546.6 Hz). 1K(31P,107Ag) = −2.76 × 1022 T2 J−1.

C(H2) bond angles are constrained by the rigid framework of the PTN(Me) cage structure, these bonds weaken, and the rest of the core bonds within the PTN(Me) ligands adjust slightly to compensate for the small amount of induced strain. In order to gain further insight into the nature of the metal PTN(Me) bonding, charge decomposition analysis (CDA) was performed by dividing the complexes into separate metal and ligand fragments and analyzing the amount of electron transfer and molecular orbital overlap between the FMOs.38 For CDA analysis, only the C2h symmetric [M(PTN(Me))2]+ (M = Ag and Au) and [Ag(PTN(Me))3]+ species were examined. Employing the methodology devised by Frenking et al.,39 as implemented through the AOMIX program,40 the relevant fragment molecular orbitals (FMOs) which contribute to metal bonding are identified. Moreover, the degree of forward- versus back-ligand to metal electron donation is readily quantified through the f/b ratio.41−43 Specific values of ligand to metal forward e− donation, back e− donation, and f/b ratios are given in Table 4. Both Ag(I) and Au(I) free ions feature a formally

conversion of 2a into the bis-PTN(Me) complex 1a with the addition of a half equivalent of silver acetate. The calculations confirm the weak interaction between the terminal N center of the PTN(Me) ligand and the metal in the [M(PTN(Me))2]+ species with the values roughly representing 15.7% of the M−P bond, in the case of Ag(I) and 11.5% for Au(I). The q(Nterminal) values for the entire series indicate no variance, and hence a M−N bonding interaction is present but contributes minimally to stabilization of the metal center. Comparison of the MBI values between the uncoordinated and coordinated PTN(Me) reveals the greatest change occurs with the methylene P−C(H2) bonds with the C2h symmetric Ag(I) and Au(I) complexes showing the greatest reduction in bond strength, while the methyl P−C(H3) generally increases in strength (Table 3). Conversely, the methylene N−C bonds of the bridge-head position also weaken. These changes are consistent with a change of hybridization at the phosphorus center upon coordination, whereby the amount of 3s character increases for all three P−C bonds. However, as the C(H2)−P− I


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Inorganic Chemistry

Figure 8. Ball and stick diagrams of DFT calculated gas-phase model complexes which are geometry optimized to energy minima. Dotted line indicates weak bonding interactions.

Table 3. Calculated Fitted Atomic Charges (q, CM5 Method37) and Selected MBI Values for the Modelled Complexes compound parameter

a

PTN

[Ag(PTN(Me))2]

+a

Ag(PTN(Me))2 lactate

[Ag(PTN(Me))3]+

[Au(PTN(Me))2]+a

Ag 0.349 −0.084 −0.084

Ag 0.334 −0.085 −0.085 −0.086 −0.347 −0.347 −0.350 0.474 0.492 0.493 0.078 0.067 0.072 0.971 0.928 1.008 0.972 1.003 0.902 0.975

Au 0.236 −0.055

M q(M) q(P)

n/a −0.097

Ag 0.306 −0.078

q(Na)

−0.345

−0.347

−0.347 −0.347

P−M

n/a

0.589

0.509 0.470

N−M

n/a

0.093

0.071 0.066

Na−C(H3) Na−C(H2)Nb Nb−C(H2)−Na Nb−C(H2)−Nb Nb−C(H2)P P−C(H2) P−C(H3) M−O

0.988 0.939 1.016 0.985 0.982 0.938 0.993

0.962 0.923 1.003 0.969 1.008 0.907 1.003

0.958 0.967 0.999 0.981 0.997 0.918 0.993 0.396 0.210

−0.348

0.719

0.083

0.965 0.929 0.997 0.969 1.010 0.905 1.004

C2h symmetric model only.

filled d10 core with the higher level s- and p-orbitals energetically accessible for receiving electron density from the coordinating ligands. Figures 9 and 10 show the molecular orbital energy interaction diagrams between the PTN(Me)

ligand and the metal(I) ions for the bis-coordinated species, with the MOs that represent the most significant bonding interactions highlighted. The corresponding diagram for the tris-PTN(Me) Ag(I) species is given in the Supporting J


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Inorganic Chemistry

Table 4. Comparison of CDA Derived Ligand to Metal Forward and Back Electron Donation for Bis- and Tris-Coordinating PTN(Me) Ag(I) Complexes and the Bis-Substituted PTN(Me) Au(I) Species complex [Ag(PTN(Me))2]+ C2h [Au(PTN(Me))2]+ C2h [Ag(PTN(Me))3]+ C1

PTN → M total forward e− donation (per ligand)

PTN ← M total back e−donation (per ligand)

forward/back f/b ratio

interaction energy (kcal mol−1) total (per ligand)

0.981 (0.491)

0.150 (0.075)

6.54

−151.02 (−75.5)

0.983 (0.492)

0.259 (0.130)

3.80

−205.20 (−102.6)

1.248 (0.416)

0.183 (0.061)

6.82

−167.27 (−55.8)

Figure 9. Molecular orbital interaction energy diagram for [Ag(PTN(Me))2]+ in C2h symmetry as calculated using a DFT method (B86 level of theory). Selected interactions between fragments that contribute (≥10%) to bonding or antibonding are shown. Fragment AOs and MOs are drawn with an isodensity of 0.04 au.

Information. Both complexes share a similar MO composition whereby HOMO-5 and HOMO-6 comprise the primary bonding interaction with a significant degree of overlap between the metal s-orbital and the PTN(Me) ligand (see Supporting Information). Not surprisingly, these MOs feature the greatest amount of charge transfer from the ligand to metal. Cationic Ag(I) and Au(I) complexes bearing NHC-type ligands differ significantly from [M(PR3)2]+, in that the primary ligand to metal bonding occurs mainly through the metal p-orbitals with a lower degree of s-orbital involvement. The greater sorbital participation in the phosphine-bearing complexes is due to a better energy matching of the electron donating MOs associated with the PTN(Me) (and phosphines in general) ligand in comparison to NHCs. For the calculated models, the

metal p-orbitals only contribute to the low energy LUMOs. The most significant difference between the silver and gold biscoordinating PTN(Me) complexes is a higher degree of electron donation into the 6s orbital of Au(I), where, due to relativistic effects, the 6s is closer in energy to the 5d orbitals. This observation is supported by almost equal forward e− donation values as shown in Table 4, whereby the two complexes significantly differ in the degree of back e− donation, the Au(I) species having almost twice that of the Ag(I) species. The back e− donation for the Ag(I) species occurs in HOMO10 (Ag) and HOMO-11 (Bg), HOMO-11 (Bg) in the Au(I) complex and involves the well-known mechanism of filled metal d-orbital e− donation into the σ*(P−C) bonds of the PTN(Me) ligand,44,45 which also contributes to weakening of K


Article

Inorganic Chemistry

Figure 10. Molecular orbital interaction energy diagram for [Au(PTN(Me))2]+ in C2h symmetry as calculated using a DFT method (B86 level of theory). Selected interactions between fragments that contribute (≥10%) to bonding or antibonding are shown. Fragment AOs and MOs are drawn with an isodensity of 0.04 au.

Table 5. Diameter of Zone of Inhibition (mm) at the Minimum Inhibitory Concentration, MICb

a

compound

conc μmol/mL

S. aureus

E. coli

A. niger

A. f lavus

C. albicans

P. spinulosum

[Ag] acetate [Ag] lactate [Ag] sulfadiazinea [Ag] nitrate triclosana 1a 1b 1c 1d 1f 2a 2b 2c 2d 2f 3

5.991 5.077 2.800 5.887 0.345 1.948 1.841 1.421 1.937 1.346 1.457 1.396 2.281 1.450 1.092 1.728

12 0 0 21 46 0 0 0 0 37 11 11 0 0 38 0

19 20 0 21 37 17 0 18 19 38 13 12 0 13 42 16

0 0 0 0 15 19 0 0 0 20 15 16 0 0 0 0

0 0 0 0 15 18 0 0 0 20 16 19 0 0 12 0

0 0 0 0 13 18 0 0 0 21 19 0 0 0 11 0

0 0 0 0 0 0 0 0 0 16 0 0 0 0 0 0

Dissolved in DMSO. bAll experiments carried out in water unless otherwise specified.

the P−C(H2) bonds. The increased e− back-donation contribution, particularly in the Au(I) species dramatically increases the M−P bond strength and hence overall stability of the complexes. In the tris-substituted PTN(Me) Ag(I) complex, HOMO-11 represents the main bonding interaction which involves both 5s and 4d orbitals of Ag. As indicated by the MBI values, the forward e− donation by each PTN(Me) fragment is less, but interestingly, the f/b ratio is comparable to

bis-coordinated PTN(Me) Ag(I) complex. Hence the f/b ratios for the PTN(Me) ligand (Table 4) are significantly lower than those of NHC-type ligands which roughly range from 11 to 13 for Ag(I) complexes and 5 to 6 for Au(I).42 The DFT calculations predicts that the bis-coordinating PTN(Me) Ag species has a larger 1J(107/109Ag-31P) coupling constant than the tris-coordinating PTN(Me) complex. The Fermi contact mechanism indicates that the magnitude of a coupling constant L


Article

Inorganic Chemistry

complexes 1a-b,d-e were found to be light-sensitive and decompose within hours in the solid state. All of the complexes were soluble in water. Analysis of compounds by solid-state Xray crystallography showed that coordination to the silver metal center occurs primarily through the phosphorus atom; however very weak bonding is observed between the metal center and the terminal nitrogen in the bis-ligated complexes 1b and 1e. In tris-ligated complex 2d, the ligand coordinated to the silver center in a pseudo κ2-P,N binding mode, where complete metal coordination by the terminal N center is significantly restricted. It is thought that the bulky methyl groups on the ligand prevent the formation of a tetrakis-ligated complex. DFT studies also confirmed the negligible M−N bonding and that the greater mixing between the 5d and 6s orbitals contributes to strong bonding with the PTN(Me) ligand; hence, this equates to a higher stability for bis-PTN(Me) gold complex versus the silver counterpart. When tested for antimicrobial activity, it was found that stand alone triclosan performed overall the best of the precursor compounds; however, complexes 1f and 2f had similar or enhanced activity to triclosan, depending on the microorganism tested against. This indicates that the presence of silver may contribute to the antimicrobial effect. However, the activity was diminished for the other silver complexes tested, which indicates that the presence of the triclosan anion is the highest factor in preventing microbial growth.

is proportional to the amount of s orbital participation. CDA shows for the total Ag−P bonding, greater 5s orbital character is present in the bis-PTN(Me) complex, 27.8% versus only 12.5% in the tris-substituted species. Examination of the higher energy HOMOs in all complexes shows a minor degree of orbital overlap between the Nterminal and metal centers, suggesting an almost negligible amount of e− transfer.

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ANTIMICROBIAL EVALUATION The complexes were assessed in vitro for possible antimicrobial activities against a variety of organisms including fungi, Grampositive and Gram-negative bacteria using the agar well diffusion test which involves diffusion of the compounds through the growth medium agar. Table 5 shows the observed diameter (in units of mm) associated with the zone of growth inhibition (ZOI) for the complexes against six commonly found pathogenic organisms: Staphylococcus aureus, E. coli, Aspergillus niger, A. f lavus, Candida albicans, and Penicillium spinulosum. The antibiological activities of the silver precursors and triclosan were also evaluated to provide a baseline comparison. Further information on testing and resulting data is included in the Supporting Information. Examination of the Ag(PTN(Me)) complexes indicates that those bearing the triclosan counterion (1f and 2f) showed the greatest activity against S. aureus and E. coli. Interestingly, triclosan on its own showed the highest activity overall of any Ag or Au complex tested against S. aureus, with a ZOI of 46 mm at a low concentration of 0.345 μmol/mL. Although triclosan is the most antibiotic of all compounds tested, it should be noted that complexes 1f and 2f are more soluble in water, in contrast to triclosan which required DMSO to solubilize. Complex 1f is the only compound to show activity against the fungus P. spinulosum, with a ZOI of 16 mm at 1.346 μmol/mL. This complex also shows increased activity against A. niger, A. f lavus, and C. albicans over triclosan alone, albeit at a higher concentration. Silver lactate shows activity only against E. coli, whereas the corresponding [Ag(PTN(Me))3] lactate complex 2b also exhibits activity against S. aureus, A. niger, and A. f lavus. As lactate is a common biological molecule that is routinely metabolized, it is probable that the silver cation initiates this activity. Conversely, the bis-PTN(Me) analogue 1b shows no activity which is attributed to the relative stabilities of the two complexes. Unexpectedly, silver sulfadiazine showed no activity against any of the microorganisms, nor did complex 2c. This is unexpected as silver sulfadiazine is used as a topical antibiotic in medicine.46 Complexes 1c, 1d, and 2d showed activity only against the Gram-negative bacteria E. coli. Furthermore, all silver complexes demonstrated higher activity against Gramnegative E. coli than Gram-positive S. aureus. This can be attributed to the water-solubility of the complexes allowing the compounds to pass the aqueous periplasm located near the cell membrane associated with the morphology of Gram-negative bacteria. This observation is in agreement with the observed higher activity of the lipophilic triclosan in S. aureus, which has a thicker peptidoglycan layer. For the gold(I) complex [Au(PTN(Me))2]Cl (3), the only activity observed was against E. coli, with a ZOI of 16 mm. This result is comparable with the silver(I) nitrate complexes, 1d and 2d.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.inorgchem.8b00227. Experimental, X-ray structure elucidation, synthetic procedures, NMR spectra, 1H-1H NOESY spectrum, tables of crystallographic data, biological preparations, MIC calculations, biological data, DFT calculations, molecular orbital interaction energy diagram, selected molecular orbitals, comparison of selected bond distances, angles, and dihedrals, optimized geometry coordinates (PDF) Accession Codes

CCDC 1819476−1819479 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Luca Gonsalvi: 0000-0002-5996-6307 Andrew D. Phillips: 0000-0001-5599-6499 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was partially funded by a grant from Science Foundation Ireland (SFI), Project No. 16/TIDA/3992. The authors are grateful for the access to computing facilities owned

CONCLUSIONS A series of bis- and tris-ligated PTN-Me silver(I) complexes with varying counterions were synthesized. The bis-ligated M


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Inorganic Chemistry

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