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Anales de la Asociación Química Argentina

versión impresa ISSN 0365-0375

An. Asoc. Quím. Argent. v.92 n.1-3 Buenos Aires ene./jul. 2004



Structural Features Of Antitumor Gold(I)-Phosphine Derivatives Analyzed With Theoretical Methods

Caruso, F.;1 Rossi, M;2 Opazo, C2; Pettinari, C.3

1 Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Piazzale Aldo Moro 5, 00185, Roma, Italy;
Fax +39 06 49913628; email:
2 Vassar College, Department of Chemistry, Poughkeepsie NY 12604-0484, USA.
3 Università di Camerino, Dipartimento di Scienze Chimiche, Via S. Agostino, 1, 62032 Camerino (MC), Italy.

Received February, 02,2004. In final form April 01, 2004
Dedicated to Prof. Pedro J. Aymonino on the occasion of his 75th birthday

A Density Functional Theory (DFT) analysis of the mixed phosphine complexes Au(PPh3)(Ph2P(CH2)3PPh2)X shows a clear trend in the metal geometry as the anion X- is varied: the softer the anion, the more it is tetrahedral, or alternatively, the more ionic the complex, the more the complex geometry approaches trigonal planar. A strong (soft) donor as cyanide (X- = CN-) penetrates markedly the coordination sphere and establishes the most tetrahedral geometry. In the antitumor compound Au(PPh3)(Ph2P(CH2)3PPh2)Cl  (X- = Cl-), the weaker donor chloride is slightly displaced from the coordination sphere with consequent strengthening of Au-P bonds, thus stabilizing a more pyramidal geometry. If the anion is completely out of the coordination sphere, the cation [Au(PPh3)(Ph2P(CH2)3PPh2)]+ shows further strengthening of Au-P bonds and a geometry very close to the trigonal planar “AuP3” system. X-ray and DFT data for Au(PPh3)(Ph2P(CH2)3PPh2)Cl show generally good agreement; however, in the crystal the Au-Cl bond appears lengthened with consequent strong Au-P bonds. This is probably due to packing effects; nevertheless, the X-ray structure agrees with the trend mentioned above as well.

El análisis estructural teórico (DFT) de los complejos de coordinación Au(PPh3)(Ph2P(CH2)3PPh2)X muestra diferentes propiedades al variar el anion X-. Para aniones "blandos", por ejemplo X- = CN-, la geometria es tetraédrica y el anión está fuertemente unido al metal. En cambio para un anión fuera de la esfera de coordinación, el catión  [Au(PPh3)(Ph2P(CH2)3PPh2)]+ posee las uniones Au-P más fuertes y la geometria alrededor del metal es trigonal planar. Una configuración intermedia se verifica en el complejo antitumoral Au(PPh3)(Ph2P(CH2)3PPh2)Cl   (X = Cl-), debido a que el Cl- es menos "blando" que el CN-. Los datos estructurales de difracción de rayos X y DFT del Au(PPh3)(Ph2P(CH2)3PPh2)Cl muestran buen acuerdo, a pesar de un alargamiento de la unión Au-Cl y el reforzamiento de las uniones Au-P en el cristal. La estructura cristalográfica también sigue la tendencia descripta por los datos de DFT.


     When using soft ligands such as phosphines (PR3) the gold(I) cation has a marked tendency to establish linear compounds, (PR3)AuX, X- = anion,  in contrast with its homologue Ag(I) which prefers tetrahedral geometries, at least in the solid state, as in Ag(PR3)3X, {Ag[(PR3)]2X}2, [Ag(PR3)X]4 and [Ag(PR3)4]X [1-5]. In accordance, Ag(I) can be said to have the metal coordinatively saturated in a formal sp3 state, whereas Au can be described as having an sp state in PR3AuX. An example of these linear compounds is the orally administered anti-arthritic drug Auranofin® (1-thio-b-D-glucopyranosato-2,3,4,6-tetraacetato-S)(triethylphosphine)gold(I), (PEt3)AuL, whose anion L is a thio-glucose derivative.
     In contrast with Ag+, the Au+ cation is unstable but can be generated in situ from reduction by thiodiglycol of the Au(III) species Na[AuCl4] in aqueous solution [6]. Subsequent addition of PR3 stabilizes PR3AuX that can be easily isolated. The coordination number of Au(I) can be increased using this linear Au(I) species as starting material, and by reacting it in a different (organic) environment with addition of phosphine ligand. This technique has been used successfully to obtain a mixed phosphine gold complex [7]:

Au(PPh3)Cl + Ph2P(CH2)3PPh2 ® Au(PPh3)(Ph2P(CH2)3PPh2)Cl    (1)

     Therefore, a limiting coordination feature of Au(I) -its marked preference for linear geometry - can be used to obtain novel compounds where the metal is coordinated to different types of ligands. This is in contrast with Cu+ and Ag+ that saturate rapidly their coordination sphere with a unique ligand.
     Our interest in metal compounds with antitumor activity prompted us to synthesize this type of compound because it is closely related to active tetrahedral Au(I) complexes [Au(Ph2P(CH2)nPPh2)]Cl, n = 2, 3 [8]. The antitumor activity of Au(PPh3)(Ph2P(CH2)3PPh2)Cl (Fig.1) was confirmed in the first 2 protocols of the in vitro screening of the National Cancer Institute [7] and displayed marked sensitivity for melanoma tumors. In this article we analyze the structural effects resulting from variation of the Cl- ligand with theoretical methods.

Figure 1. DFT molecular structure of Au(PPh3)(Ph2P(CH2)3PPh2)Cl; ball and stick bonds for non-Ph atoms.


     The structural features of all compounds were analyzed as follows. Starting coordinates were obtained from the X-ray molecular structure of Au(PPh3)(Ph2P(CH2)3PPh2)Cl [7]. The optimized geometry of this compound was obtained through energy minimization with the Accelrys program Cerius 2.4.6, subroutine DMol3 [9] on an Octane SGI computer. Standard local density was the Perdew and Wang  (PWC) functional [10] using a double numeric basis set with polarization functions (DNP) [11] on all atoms. The same procedure was applied to (a) the cation [Au(PPh3)(Ph2P(CH2)3PPh2)]+, obtained by eliminating the Cl- anion from the Au(PPh3)(Ph2P(CH2)3PPh2)Cl Dmol3 minimized structure, and (b) Au(PPh3)(Ph2P(CH2)3PPh2)CN, obtained by replacing Cl- with a CN- moiety in Au(PPh3)(Ph2P(CH2)3PPh2)Cl.

Results And Discusion

     As seen in Table 1, comparison between X-ray and DFT molecular structures of Au(PPh3)(Ph2P(CH2)3PPh2)Cl show similar features, with the Au-P bonds shorter than Au-Cl, in agreement with X-ray structures of related Au(I)-phosphine compounds. For instance, Au(PPh3)3Cl has Au-P bonds (average) 2.41 Å and Au-Cl = 2.71 Å [12]. The marked affinity of Au(I) for soft ligands such as phosphines explains such a difference.

Table 1. Structural data in the coordination sphere of Au(PPh3)(Ph2P(CH2)3PPh2)X compounds, Ph2P(CH2)3PPh2 = DPPP.

























































































Note:  1Data obtained from ref [7]. Distances are provided in Å, angles in (°); <> stands for average value. Bold figures show data following the trend on metal geometry as the anion X- is varied: the softer the anion, the more it is tetrahedral, or alternatively, the more ionic the complex, the more the geometry is trigonal planar.

In addition, Table 1 shows that the åP-Au-P angles is close to 360° from the X-ray structure, suggesting that the Cl- anion is almost out of the coordination sphere. This pattern is very different from a pure tetrahedral structure, which would have åP-Au-P angles close to 3x109.5° = 328.5°.
     In the tetrahedral [Au(PPh2CH3)4]+ cation there are marked differences among P-Au-P bond angles, as the sum of 3 P-Au-P bond angle range is 328-342° [13], suggesting significant packing effects in the crystalline cell. Likewise, they may explain the different Au-Cl length in Au(PPh3)(Ph2P(CH2)3PPh2)Cl as obtained from X-rays (crystal, 2.928(2) Å) and DFT (isolated molecule, 2.613 Å).
     We also analyze anion effects by replacement of Cl- with the softer cyanide anion, which possesses marked affinity for M(I), M = Cu, Ag, Au. This is demonstrated in AgCN where it is impossible to remove the CN- when reacting this salt with excess of PR3, R = p-tolyl, and in fact, no more than 3 PR3 groups enter the coordination sphere stabilizing Ag(PR3)3CN [2]. This feature is in contrast with weaker donor anions such as nitrate, since [Ag(PR3)4]+ is easily obtained from silver nitrate.
     By replacing Cl- with CN- a lengthening of Au-P bonds is obtained, as shown in Table 1, in agreement with the softer character of CN- (in comparison with Cl-). That is, a competitive effect is present with the cyanide showing stronger bonding to Au(I) than Cl- with consequent withdrawal of P atoms from the coordination sphere. Another noticeable change is in the P-Au-P angle (average value of 109.6
° for Au(PPh3)(Ph2P(CH2)3PPh2)CN versus 112.7° for Au(PPh3)(Ph2P(CH2)3PPh2)Cl. Therefore a more tetrahedral character can be induced in Au(I) by substituting Cl- with appropriate (softer) anions. This DFT study shows that in Au(PPh3)(Ph2P(CH2)3PPh2)CN (Fig.2) the cyanide moiety is not linear as the bond angle Au-C-N is 156.8°. Several examples of this feature in the solid state show additional interaction with other units, e.g. from oligomerization due to interaction of the N lone pair with other units. This is not the case in the DFT structure of Au(PPh3)(Ph2P(CH2)3PPh2)CN as the isolated molecule is studied. The only example of non-linear terminal cyanide derivative studied with X-rays is the trimetallic cation [(Ph3P){AgS3WOCu}(CN)]+ [14] where the cyanide binds the Cu atom and has a Cu-C-N bond angle of 160°, which is of the same order in Au(PPh3)(Ph2P(CH2)3PPh2)CN.

Figure 2. DFT molecular structure of Au(PPh3)(Ph2P(CH2)3PPh2)CN

     The opposite structural effect than that caused by CN- in the coordination sphere, that is shortening of Au-P bonds and widening of P-Au-P angles, can be also obtained. For instance, replacing Cl- with weaker donors as NO3-, ClO4- or BF4-, should point only one atom towards the metal (O, O and F, respectively). We preferred to analyze the most extreme situation, corresponding to an anion completely out of the coordination sphere, for instance BPh4-, and therefore we performed a DFT study for the cation [Au(PPh3)(Ph2P(CH2)3PPh2)]+ (Fig.3), see Table 1. In comparison with the cyanide and chloride structures there are shorter Au-P bonds due to the increased s bond character (33%) at the metal because a pure “AuP3” system implies a sp2 hybrid. However, a perfectly planar geometry is not obtained through DFT in the minimization process, possibly because of a flattened shape at the bottom of the energy minimization curve.
     To conclude, a clear trend emerges when the anion X- is varied in Au(PPh3)(Ph2P(CH2)3PPh2)X molecules, a strong (soft) donor as cyanide penetrates markedly the coordination sphere establishing the most tetrahedral geometry with <P-Au-P> = 109.6
° and <P-Au-X> = 105.4°, which are close to the tetrahedral angle corresponding to 4 equal ligands (109.5°). The weaker donor chloride (X- = Cl-) is slightly displaced from the coordination sphere with consequent strengthening of Au-P bonds (<Au-P> is 2.524 Å for Cl- and 2.548 Å for CN-). Accordingly, a more pyramidal geometry is stabilized for Cl-, with <P-Au-P> = 112.7° or <P-Au-X> = 102.1°. When the anion is completely out of the coordination sphere, the DFT analysis of [Au(PPh3)(Ph2P(CH2)3PPh2)]+ shows further strengthening of Au-P bonds (<Au-P> = 2.498 Å) and a geometry (<P-Au-P> = 118.7°) very close to the trigonal planar “AuP3” system (<P-Au-P> = 120°). X-ray and DFT data for Au(PPh3)(Ph2P(CH2)3PPh2)Cl show good agreement, although in the crystal the Au-Cl bond appears lengthened with consequent strong Au-P bonds. This feature is probably associated with packing effects that are known to be important in Au-phosphine compounds as shown by [Au(PPh3)4]+, which was studied crystallographically in 2 different systems. Thus, tetrakis(triphenylphosphine)-gold(I) tetraphenylborate ethanol solvate [15], shows 2 Au-P bond lengths of 2.60 Å and 2 of 2.61 Å, whereas tetrakis(triphenylphosphine)-gold(I) tetraphenylborate acetonitrile solvate [15] has 2 Au-P bonds of 2.56 Å and 2 of 2.50 Å.


Figure 3. DFT molecular structure of [Au(PPh3)(Ph2P(CH2)3PPh2)]+       


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