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Inorganica Chimica Acta 358 (2005) 3927–3936

Hydrogen bonding in diruthenium(II,III) tetraacetate complexeswith biologically relevant axial ligands

Brendan R.A. Bland a, Heather J. Gilfoy a, George Vamvounis a, Kathy N. Robertson b,T. Stanley Cameron b, Manuel A.S. Aquino a,*

a Department of Chemistry, St. Francis Xavier University, P.O. Box 5000, Antigonish, NS, Canada B2G 2W5b Department of Chemistry, Dalhousie University, Halifax, NS, Canada B3H 4J3

Received 6 May 2005; received in revised form 13 June 2005; accepted 13 June 2005Available online 26 July 2005

Abstract

Three diadduct complexes of the mixed-valent form of diruthenium tetraacetate, [Ru2(l-O2CCH3)4L2](PF6), where L are thebiologically relevant ligands imidazole, 1, 7-azaindole, 2, and caffeine, 3, were synthesized and characterized by elemental anal-ysis, IR and UV–Vis spectroscopy and X-ray crystallography. In order to further elucidate the potential interactions of thesedimers with DNA, the nature of the ligand coordination and the secondary inter- and intramolecular hydrogen-bonding inter-actions in all three complexes were assessed. Complex 1 Æ CH2Cl2 shows, exclusively, intermolecular interactions with the PF6

�

counterion whereas complexes 2 Æ ClCH2CH2Cl and 3 Æ OC(CH3)2 Æ H2O, in addition to extensive intermolecular interactions,show intramolecular hydrogen bonding from the axial ligand to the bridging acetate oxygens, locking the ligand mean planesin place between the bridging acetate mean planes. In addition, all three complexes display p–p stacking of axial ligand rings onadjacent diadduct units.� 2005 Elsevier B.V. All rights reserved.

Keywords: Diruthenium tetracarboxylates; X-ray crystal structures; Hydrogen bonding; p–p stacking

1. Introduction

Dinuclear metal carboxylate complexes have showngreat promise as potential anti-tumour agents, however,the vast majority of studies, starting as far back as theearly 1970s, have focused on the dirhodium(II,II) com-plexes with only a few accounts of the activity of dirhe-nium(III,III) and the mixed-valent diruthenium(II,III)species [1]. Recent [2] and past [3] studies have indicateda certain degree of cytotoxicity in complexes with themixed-valent [Ru2(l-O2CR)4]

+ core and, as with theirdirhodium cousins, it has been postulated that their

0020-1693/$ - see front matter � 2005 Elsevier B.V. All rights reserved.

doi:10.1016/j.ica.2005.06.023

* Corresponding author.E-mail address: maquino@stfx.ca (M.A.S. Aquino).

mode of action may involve direct axial binding to thenucleotide bases on DNA. The choice of binding siteand its stability may be partly dictated by hydrogen-bonding interactions between other moieties on thenucleotide/nucleoside and the tetracarboxylate core.Two examples of such stabilization in dirhodium(II,II)species serve to illustrate this latter feature. In [Rh2(l-O2CCH3)4(1-MeAdo)2] (1-MeAdo = 1-methyladeno-sine), axial coordination takes place through N-7 andthere is additional stabilization due to a hydrogen bondformed between the purine exocyclic NH2 group (in the6 position) and the oxygen atom of the bridging carbox-ylate on the dirhodium unit [4]. However, attempts tobind guanine to the [Rh2(l-O2CCH3)4] core have notbeen possible due to an electrostatic repulsion betweenthe purine oxygen (at site 6) and the carboxylate oxygen.

3928 B.R.A. Bland et al. / Inorganica Chimica Acta 358 (2005) 3927–3936

Stabilization of axial guanine was achieved by substitut-ing two of the bridging carboxylates by acetamidateswhich contain the hydrogen-bond donor NH groupswhich can easily hydrogen bond to the purine oxygens[5].

Over the past 35 years a large number of mixed-valent diruthenium(II,III) tetracarboxylate diadductsof the form [Ru2(l-O2CR)4L2]

+ (where the axial ligand,L, is normally a Lewis base) have been synthesized andstructurally characterized [6–9]. Despite this large num-ber very few have contained axial ligands with signifi-cant biological relevance.

Adenine and adenosine adducts of [Ru2(l-O2CCH3)4]

+ were synthesized and partly characterizedbut no X-ray structures were reported [10]. It wasconcluded from NMR data that the adenine derivativewas a polymer of the form, [Ru2(l-O2CCH3)4(ade-nine)]x, in which the adenine bridged adjacent diruthe-nium dimers via N-9 and N-3 (or N-1) and that theadenosine complex was a distinct diadduct, [Ru2(l-O2CCH3)4(adenosine)2]Cl, in which the adenosinecoordinated through N-7.

Three examples of structurally characterizedcomplexes have been reported. The first involves ureain the co-crystallized [Ru2(l-O2CCH3)4(urea)2][Ru2(l-O2CCH3)4(1-propanol)2](PF6)2 complex [11]. Here,the axially bound urea interacts via a weak intermo-lecular hydrogen bond from the urea nitrogen to acarboxylate oxygen of an adjacent 1-propanol diad-duct (N–H� � �O distance = 3.18 A). The secondinvolves the 2-methylimidazole (2-mimH) adduct,[Ru2(l-O2CC6H4-p-OCH3)4(2-mimH)2](ClO4), whichbinds through the imine nitrogen and shows a weakhydrogen bond between the amine nitrogen and theperchlorate counterion [12]. Finally, our lab recentlyreported the structure of [Ru2(l-O2CCH3)4(quino-line)2](PF6) which showed an anti orientation of theaxial quinoline ligands and two weak but stabilizing(C–H� � �O) hydrogen bonding interactions betweenthe quinoline and the oxygens on the bridging acetates[13].

Because of the difficulty in synthesizing and, inparticular, structurally characterizing the nucleotide/nucleoside diadducts directly [10], we have under-taken a study to prepare and structurally characterizea series of diadducts involving various ligands thatdisplay some of the features of nucleotide bases.Once these complexes have been structurally charac-terized we can assess the nature of the axial coordi-nation in terms of the ligand donor atom as wellas any role hydrogen bonding may play in dictatingthe orientation (conformation) and stabilization ofthe axial ligand with respect to the [Ru2(l-O2CR)4-L2]

+ core. We report here on three such diadductsinvolving the axial ligands imidazole, 7-azaindoleand caffeine.

2. Experimental

2.1. General procedures

2-Propanol, diethyl ether and acetone were used asreceived. Dichloromethane and 1,2-dichloroethanewere distilled from CaH2 prior to use. Imidazole, 7-azaindole and caffeine were used as received (Aldrich)and [Ru2(l-O2CCH3)4(H2O)2](PF6) was prepared usinga literature procedure [14]. Infrared spectra were re-corded on a Bio-Rad FTS-175 spectrophotometer asKBr discs. UV–Vis spectra were obtained usingmatched 1 cm Hellma quartz cells on a Varian 100UV–Vis spectrophotometer. Effective magnetic mo-ments, leff, were determined at room temperature usinga Johnson Matthey MSB-1 magnetic susceptibilitybalance. Elemental analyses were performed by Cana-dian Microanalytical Service Ltd., Delta, BC, Canada.X-ray data were collected and the structures solved atthe DalX X-ray facility, Dalhousie University, Halifax,NS, Canada.

2.2. Preparation of [Ru2(l-O2CCH3)4(ImH)2](PF6)

(1)

[Ru2(l-O2CCH3)4(H2O)2](PF6) (0.100 g, 0.16 mmol)was dissolved in a minimum amount of 2-propanol(�10 ml). Imidazole (0.022 g, 0.32 mmol) in �2 ml of2-propanol was added dropwise to the above solution.A golden yellow precipitate appeared after approxi-mately 5 min. The reaction was allowed to proceed fora total of no more than 10 min and the precipitatewas filtered, washed with cold 2-propanol and dried invacuo. Crystallization can be afforded by diffusingdiethylether into a dichloromethane solution of thecrude product. Yield: 0.062 g (53%). IR (cm�1): 3414m, 3142 m, 2945 w, 1443 s, 1401 s, 1067 s, 847 s, 691s, 558 m. Anal. Calc. for C14H20N4O8PF6Ru2: C,23.30; H, 2.80; N, 7.77. Found: C, 23.62; H, 2.83; N,7.43%.

2.3. Preparation of [Ru2(l-O2CCH3)4(7-azaindole)2]

(PF6) (2)

This complex was prepared in a similar fashion to 1

except that 7-azaindole (0.038 g, 0.32 mmol) in approx-imately 10 ml of 2-propanol was used. A mustard col-oured precipitate formed immediately and could berecrystallized from dichloromethane or 1,2-dichloroeth-ane. Yield: 0.123 g (92%). IR (cm�1): 3435 m, 2975 w,1590 m, 1443 s, 1402 s, 1354 m, 1278 m, 849 s, 691 s,559 m. Anal. Calc. for C22H24N4O8PF6Ru2 Æ 0.5CH2Cl2: C, 31.34; H, 2.92; N, 6.50. Found: C, 31.79;H, 2.91; N, 6.61%.

B.R.A. Bland et al. / Inorganica Chimica Acta 358 (2005) 3927–3936 3929

2.4. Preparation of [Ru2(l-O2CCH3)4(caffeine)2](PF6)

(3)

This complex was prepared in a similar fashion to 1

except that caffeine (0.063 g, 0.32 mmol) in 10–15 mlof 2-propanol was added and no precipitate formedupon addition of the ligand. The red solution that re-sulted was filtered and allowed to slowly evaporate untilcrystals began to form. These were collected by filtrationjust prior to the solution running dry. Crystals suitablefor X-ray diffraction were grown by diffusion of acetoneinto an aqueous solution of the product. Yield: 0.144 g(83%). IR (cm�1): 3447 s, 2933 w, 1706 s, 1652 s, 1447s, 1354 m, 1235 m, 865 s, 691 m. Anal. Calc. (%) forC24H32N8O12PF6Ru2 Æ (CH3)2CHOH: C, 31.43; H,3.91; N, 10.86. Found: C, 31.23; H, 3.88; N, 10.77%.

2.5. X-ray crystallography

Crystals were mounted on a glass fiber on a RigakuAFC5R diffractometer with graphite monocromatedCu Ka (1 Æ CH2Cl2) or Mo Ka (2 Æ ClCH2CH2Cl and3 Æ OC(CH3)2 Æ H2O) radiation and a rotating anode gen-erator. Procedures for crystal indexing, data collectionand data reduction for this instrument were routineand have been described elsewhere [14]. Correctionswere made for the effects of absorption anisotropy aswell as Lorentz and polarization effects. A correctionfor secondary extinction was applied in all cases.

Table 1Crystal data and structure refinement parameters

Empirical formula C15H22O8N4Ru2PF6Cl2(1 Æ CH2Cl2)

MW 804.37Space group Pnma

Unit cell dimensions

a (A) 10.130(2)b (A) 20.301(2)c (A) 13.257(2)a (�) 90.0b (�) 90.0c (�) 90.0

V (A)3 2726.4(6)Z value 4T (K) 296(1)Dcalc (g cm

�1) 1.959Crystal size (mm) 0.06 · 0.09 · 0.40l 121.66 cm�1

k (A) 1.54178Number of unique data 2286R1

a (I > 2r(I)) 0.042WR2

b 0.148Rc

Rwd

Goodness-of-fit 0.99

a R1 ¼PjðF 2

oÞ � ðF 2cÞj=

PðF 2

oÞ.b wR2 ¼ ½

PwðF 2

o � F 2cÞ

2=P

wðF 2oÞ

2�1=2.c R ¼

PkF oj � jF ck=

PjF oj.

d Rw ¼ ½ðP

wðjF oj � jF cjÞ2=P

wF 2o�

1=2.

All structures were solved by direct methods [15]and expanded using Fourier techniques [16]. Thenon-hydrogen atoms were refined anisotropically andthe hydrogen atoms were included but not refined asthey were determined at calculated positions. Neutralatom scattering factors were taken from Cromer andWaber [17]. Anomalous dispersion effects were in-cluded in Fcalc [18], the values for Df 0 and Df00 werethose of Creagh and McAuley [19]. The values forthe mass attenuation coefficients are those of Creaghand Hubbell [20]. All calculations were performedusing the TEXSAN [21] crystallographic software pack-age from Molecular Structure Corporation except forthe refinement of 1 which was performed usingSHELXL-97 [22].

The PF6� anion in 2 Æ ClCH2CH2Cl was found to be

disordered and two of the fluorine ligands were allowedto occupy two positions, each with occupancy of 0.5,and with equal atomic displacement parameters for eachA/B pair. The fluoride A/B distances were fixed at0.90(0.02) A and the P–F distances to 1.58(0.015) A.The incorporated solvent molecule of 1,2-dichloroeth-ane was also found to be disordered. The carbon andchlorine atoms of the solvent were allowed to occupytwo positions equally, with equal atomic displacementparameters for each pair. The C–C bond length in thesolvent was fixed at 1.53(0.015) A and the C–Cl bondlength to 1.80(0.015) A. The A/B distance between thecarbon atoms was fixed at 1.20(0.02) A and that between

C22H28O8N4Ru2PF6Cl4(2 Æ ClCH2CH2Cl)

C27H40O14N8Ru2PF6

(3 Æ H2O Æ (CH3)2CO)918.52 1047.77P�1 P�1

10.642(2) 10.035(8)11.635(5) 12.754(5)7.990(2) 9.053(3)108.30(3) 95.36(3)104.85(2) 99.63(5)101.23(3) 69.27(5)866.2(6) 1068(1)2 2296(1) 193(1)1.761 1.7480.90 · 0.70 · 0.30 0.05 · 0.18 · 0.071.153 mm�1 8.48 cm�1

0.7107 0.71074797 32740.05820.1485

0.0490.058

0.953 1.11

Table 2Selected bond lengths (A) and angles (�) for [Ru2(lO2CCH3)4-(ImH)2](PF6) Æ CH2Cl2 (1 Æ CH2Cl2)

3930 B.R.A. Bland et al. / Inorganica Chimica Acta 358 (2005) 3927–3936

the chlorine atoms was fixed at 0.70(0.02) A. Finally thedistance between the two chlorine atoms was restrainedto be the same in all molecules.

Ru(1)–Ru(1A) 2.2839(16)Ru(1)–O(1) 2.026(6)Ru(1)–O(2) 2.024(6)Ru(1)–O(3) 2.027(6)Ru(1)–O(4) 2.006(6)Ru(1)–N(1) 2.273(9)O(1)–C(1) 1.288(12)O(2)–C(3) 1.288(13)C(1)–C(2) 1.488(13)C(3)–C(4) 1.495(14)N(1)–C(5) 1.293(13)N(1)–C(7) 1.386(14)N(2)–C(5) 1.336(14)N(2)–C(6) 1.363(15)C(6)–C(7) 1.350(16)

O(4)–Ru(1)–O(2) 178.9(3)O(2)–Ru(1)–O(1) 90.0(3)O(4)–Ru(1)–N(1) 90.4(3)O(4)–Ru(1)–Ru(1A) 89.8(2)N(1)–Ru(1)–Ru(1A) 176.5(2)C(3)–O(4)–Ru(1) 120.0(7)C(5)–N(1)–Ru(1) 128.1(8)C(5)–N(2)–C(6) 109.2(10)C(7)–C(6)–N(2) 104.9(10)O(1)–C(1)–C(2) 118.2(10)O(1)–C(1)–O(3A) 121.1(9)O(4)–Ru(1)–O(1) 90.2(3)O(1)–Ru(1)–O(3) 178.2(3)O(2)–Ru(1)–N(1) 90.8(3)O(2)–Ru(1)–Ru(1A) 89.1(2)C(1)–O(1)–Ru(1) 120.6(6)C(5)–N(1)–C(7) 106.8(10)C(7)–N(1)–Ru(1) 124.5(8)N(1)–C(5)–N(2) 110.0(11)C(6)–C(7)–N(1) 109.0(10)O(2)–C(3)–C(4) 118.6(11)O(2)–C(3)–O(4A) 121.4(10)

3. Results and discussion

3.1. Synthesis

All three complexes were prepared in a similarfashion using a rapid precipitation technique we haveemployed before [23] whereby a two molar equivalentof the ligand is added to the starting complex, [Ru2(l-O2CCH3)4(H2O)2](PF6), in 2-propanol. The productprecipitates almost immediately (or within 5 min) thusavoiding any equatorial acetate substitution whicheven modest p-acids such pyridine or pyrimidine li-gands are prone to do over longer periods [8].

Each complex required a slightly different recrystal-lization technique to afford X-ray quality crystals.Complex 1 was recrystallized as a dichloromethanesolvate (1 Æ CH2Cl2) from diethylether/dichlorometh-ane. Crystals of 2 Æ ClCH2CH2Cl were grown from1,2-dichloroethane and 3 Æ OC(CH3)2 Æ H2O was ob-tained by diffusion of acetone into an aqueous solu-tion of 3.

3.2. Physico-chemical measurements

All of the complexes gave satisfactory elemental anal-yses. The formulations differ somewhat from the crystalstructures as thoroughly dried samples were usedwhereas drying the actual crystals used for X-ray analy-sis often compromised their integrity and consequentlysome additional molecules of solvation are present in

Fig. 1. Molecular structure of [Ru2(l-O2CCH3)4(ImH)2](PF6) Æ CH2Cl2 (1 Æ CH2Cl2).

Table 3Selected bond lengths (A) and angles (�) for [Ru2(l-O2CCH3)4(7-azaindole)2](PF6) Æ ClCH2CH2Cl (2 Æ ClCH2CH2Cl)

Ru(1)–Ru(1A) 2.282(2)Ru(1)–O(1) 2.027(7)Ru(1)–O(2A) 2.006(7)Ru(1)–O(3) 2.018(6)Ru(1)–O(4A) 2.018(7)Ru(1)–N(1) 2.288(9)O(1)–C(1) 1.287(12)O(2)–C(1) 1.273(12)O(3)–C(3) 1.298(12)O(4)–C(3) 1.276(11)C(1)–C(2) 1.492(14)C(3)–C(4) 1.476(14)N(1)–C(5) 1.331(13)N(1)–C(11) 1.346(13)N(2)–C(11) 1.320(13)N(2)–C(10) 1.361(13)C(5)–C(6) 1.368(14)C(6)–C(7) 1.39(2)C(7)–C(8) 1.39(2)C(8)–C(11) 1.416(13)C(8)–C(9) 1.44(2)C(9)–C(10) 1.33(2)

O(2A)–Ru(1)–O(3) 90.0(3)O(2A)–Ru(1)–O(4A) 89.7(3)O(3)–Ru(1)–O(4A) 179.2(3)

B.R.A. Bland et al. / Inorganica Chimica Acta 358 (2005) 3927–3936 3931

the crystal structures. We will only include the specificmolecules of solvation when we discuss the crystal struc-tures, otherwise we will just refer to the complexes as 1,2 and 3.

The major infrared bands are listed in Section 2 andare consistent with the formulations presented. Bandsobserved in all of the complexes include C–H stretching(2933–2095 cm�1), asymmetric and symmetric CO2

stretching (1401–1447 cm�1), C–N ring stretching(1235–1277 cm�1), P–F bending (847–865 cm�1) andC–CH3 out-of-plane bending (691 cm�1). There are alsosome bands unique to each complex. For 1 and 2 we seethe distinct N–H stretching vibrations originating on theunbound nitrogen at 3414 cm�1 for 1 and 3435 cm�1 for2. For the caffeine adduct, 3, we see two strong bands at1705 and 1651 cm�1 corresponding to the two carbonylmoieties.

The electronic spectrum of all three complexes wasmeasured in 1,2-dichloroethane and the characteristicp*(Ru) p (RuO, Ru) transition is seen for all ataround 430 nm with molar absorptivities ranging from700 to 1000 M�1cm�1. Room temperature magnetic sus-ceptibility measurements show leff values ranging from4.0 to 4.2 B.M. consistent with 3 unpaired electronsper Ru2 dimer [8].

3.3. X-ray structures

The structures of all three complexes were determinedby single-crystal X-ray diffraction and showed the li-gands to be coordinated through their unprotonated

Fig. 2. Molecular structure of [Ru2(l-O2CCH3)4(7-azaindole)2](PF6)(2 Æ ClCH2CH2Cl).

(or unmethylated) nitrogens as well as displaying vary-ing degrees of hydrogen bonding. The crystal data forcomplexes 1–3 are given in Table 1. We will look atthe specifics of each structure in turn and then discussthe hydrogen bonding.

O(2A)–Ru(1)–O(1) 179.0(3)O(3)–Ru(1)–O(1) 90.6(3)O(4A)–Ru(1)–O(1) 89.7(3)O(3)–Ru(1)–Ru(1A) 89.1(2)O(1)–Ru(1)–Ru(1A) 89.4(2)O(3)–Ru(1)–N(1) 87.9(3)O(1)–Ru(1)–N(1) 92.0(3)Ru(1A)–Ru(1)–N(1) 176.7(3)C(1)–O(1)–Ru(1) 118.2(7)C(3)–O(3)–Ru(1) 119.4(6)C(5)–N(1)–C(11) 116.7(10)C(5)–N(1)–Ru(1) 118.5(8)C(11)–N(1)–Ru(1) 124.6(7)C(11)–N(2)–C(10) 108.3(10)O(2)–C(1)–O(1) 123.3(10)O(1)–C(1)–C(2) 117.7(10)O(4)–C(3)–O(3) 122.4(9)O(3)–C(3)–C(4) 117.8(9)N(1)–C(5)–C(6) 125.0(12)C(5)–C(6)–C(7) 118.5(12)C(8)–C(7)–C(6) 118.7(10)C(7)–C(8)–C(11) 118.0(11)C(7)–C(8)–C(9) 137.1(11)C(11)–C(8)–C(9) 104.7(10)C(10)–C(9)–C(8) 106.2(11)C(9)–C(10)–N(2) 111.5(12)N(2)–C(11)–N(1) 127.9(9)N(2)–C(11)–C(8) 109.2(10)N(1)–C(11)–C(8) 122.7(10)

3932 B.R.A. Bland et al. / Inorganica Chimica Acta 358 (2005) 3927–3936

3.3.1. Structure of [Ru2(l-O2CCH3)4(ImH)2]

(PF6) Æ CH2Cl2 (1 Æ CH2Cl2)

Complex 1 Æ CH2Cl2 crystallizes in an orthorhombicsystem (Pnma) and the molecule lies on an inversioncenter. Selected bond lengths and angles are listed inTable 2 and a structural diagram can be seen inFig. 1. All of the bond lengths and angles are typicalfor such complexes [8]. The diagram clearly shows thetypical [Ru2(l-O2CCH3)4]

+ core with imidazole groupsaxially bound through the N-3 nitrogen (labeled N(1)in Fig. 1). The imidazole rings are essentially planarwith respect to each other (dihedral angle of less than6�) with the protonated N-1 (labeled N(2) in Fig. 1)nitrogens oriented anti to each other. They are alsoparallel with respect to the planes formed by two ofthe bridging carboxylates defined by Ru(1)–O(1)–C(1)–O(3A)–Ru(1A) and Ru(1)–O(3)–C(1A)–O(1A)–Ru(1A) (with dihedral angles of less than 3�).

3.3.2. Structure of [Ru2(l-O2CCH3)4 (7-azaindole)2]

(PF6) Æ ClCH2CH2Cl (2 Æ ClCH2CH2Cl)

Complex 2 Æ ClCH2CH2Cl crystallizes in a triclinicsystem ðP�1Þ and the molecule lies on an inversion cen-ter. A structural diagram is shown in Fig. 2 and se-lected bond lengths and angles are given in Table 3.Again we see the typical [Ru2(l-O2CCH3)4]

+ core,here with 7-azaindole groups coordinated throughtheir N-3 nitrogens (labeled N(1) in Fig. 2) and ori-ented parallel (dihedral angle of less than 1�) but antiwith respect to each other. Contrary to the situationwith the imidazole adduct, however, the planes definedby the 7-azaindole ligands almost perfectly bisect

(dihedral angle of 43�) the perpendicular planes ofany two cis oriented carboxylate bridges (e.g.,Ru(1)–O(3)–C(3)–O(4)–Ru(1A) and Ru(1)–O(1)–C(1)–O(2)–Ru(1A)). This is almost certainly due to the

Fig. 3. Molecular structure of [Ru2(l-O2CCH3)4(caffein

involvement of the protonated N-1 nitrogen (labeledN(2) in Fig. 2) in hydrogen bonding with the carbox-ylate bridges (see later).

3.3.3. Structure of [Ru2(l-O2CCH3)4(caffeine)2]

(PF6) Æ OC(CH3)2 Æ H2O (3 Æ OC(CH3)2 Æ H2O)Complex 3 Æ OC(CH3)2 Æ H2O crystallizes in a triclinic

system ðP�1Þ with the molecule lying on an inversion cen-ter and includes an acetone and a water molecule of sol-vation. A diagram is shown in Fig. 3 with selected bondlengths and angles listed in Table 4. The caffeine ligandsare bound to the diruthenium core through their N-9nitrogens (labeled N(4) in Fig. 3) and are oriented antiand essentially parallel (dihedral angle = 5�) with re-spect to each other. In a similar fashion to the 7-azain-dole derivative the mean-plane of the caffeine ringsystems bisect the planes defined by two perpendicularacetate bridges by an angle of 40�.

3.4. Hydrogen bonding

Hydrogen-bonding interactions involving the axialligands in compounds 1–3 can be manifested in fourdifferent ways: (1) intramolecular interactions withthe diruthenium tetraacetate core; (2) intermolecularinteractions with the PF6

� counterion; (3) intermolec-ular interactions with any molecules of solvation thatmay be present and; (4) intermolecular interactionswith adjacent diruthenium diadduct units. Most ofour discussion will be limited to the first two typesof interactions. These would be the most likely inter-actions one would see when these dimers bind to thenucleotide bases on DNA. A summary of these rele-vant hydrogen-bonding interactions out to an H� � �Bmaximum distance of 2.75 A in complexes 1–3 isgiven in Table 5.

e)2](PF6) Æ OC(CH3)2 ÆH2O (3 Æ OC(CH3)2 Æ H2O).

Table 4Selected bond lengths (A) and angles (�) for [Ru2(l-O2CCH3)4(caf-feine)2](PF6) Æ OC(CH3)2 Æ H2O (3 Æ OC(CH3)2 Æ H2O)

Ru(1)–Ru(1A) 2.283(4)Ru(1)–O(1) 2.01(1)Ru(1)–O(3) 2.01(1)Ru(1)–N(4) 2.34(2)O(1)–C(1) 1.25(2)O(2)–C(3) 1.29(2)O(5)–C(8) 1.22(2)O(6)–C(5) 1.23(2)N(1)–C(5) 1.39(2)N(1)–C(8) 1.37(2)N(1)–C(10) 1.48(2)N(2)–C(5) 1.38(2)N(2)–C(6) 1.37(2)N(2)–C(11) 1.49(2)N(3)–C(7) 1.43(2)N(3)–C(9) 1.35(2)N(3)–C(12) 1.47(2)N(4)–C(6) 1.38(2)N(4)–C(9) 1.32(2)C(1)–C(2) 1.52(2)C(6)–C(7) 1.42(2)C(7)–C(8) 1.35(2)

Ru(1A)–Ru(1)–O(1) 89.1(4)Ru(1)–Ru(1A)–O(3) 88.9(4)Ru(1A)–Ru(1)–N(4) 175.6(6)O(1)–Ru(1)–O(2) 89.4(5)O(1)–Ru(1)–O(3A) 178.0(6)O(1)–Ru(1)–O(4A) 90.0(5)O(1)–Ru(1)–N(4) 86.4(6)O(2)–Ru(1)–O(3A) 91.1(5)O(2)–Ru(1)–O(4A) 178.8(6)O(2)–Ru(1)–N(4) 90.5(6)Ru(1)–O(1)–C(1) 118(1)Ru(1)–O(2)–C(3) 118(1)C(5)–N(1)–C(8) 126(1)C(5)–N(1)–C(10) 117(1)C(8)–N(1)–C(10) 117(1)C(5)–N(2)–C(6) 120(1)C(5)–N(2)–C(11) 117(1)C(6)–N(2)–C(11) 122(1)C(7)–N(3)–C(9) 108(1)C(7)–N(3)–C(12) 125(1)C(9)–N(3)–C(12) 127(1)Ru(1)–N(4)–C(6) 143(1)Ru(1)–N(4)–C(9) 113(1)C(6)–N(4)–C(9) 103(2)O(1)–C(1)–O(3) 125(2)O(1)–C(1)–C(2) 117(2)O(6)–C(5)–N(1) 122(2)O(6)–C(5)–N(2) 120(2)N(1)–C(5)–N(2) 118(1)N(2)–C(6)–C(7) 117(2)N(3)–C(7)–C(6) 101(1)C(6)–C(7)–C(8) 126(2)O(5)–C(8)–C(7) 125(2)N(3)–C(9)–N(4) 114(2)N(2)–C(6)–N(4) 129(2)N(4)–C(6)–C(7) 114(2)N(3)–C(7)–C(8) 133(2)O(5)–C(8)–N(1) 122(2)N(1)–C(8)–C(7) 113(2)

Table 5

Selected hydrogen bonding parameters for complexes 1–3

A–H� � �B A� � �B (A) A� � �H (A) H� � �B (A) \A–H� � �B (�)

Complex 1

N(2)–H(8)� � �F(5) 2.984 0.94 2.15 147.4

N(2)–H(8)� � �F(7) 2.943 0.94 2.27 128.5

Complex 2

N(2)–H(2)� � �O(1) 3.279 0.86 2.73 122.6

N(2)–H(2)� � �O(3) 3.047 0.86 2.53 119.7

N(2)–H(2)� � �F(2A) 2.90 0.86 2.15 144.6

N(2)–H(2)� � �F(2B) 3.35 0.86 2.54 158.0

Complex 3

C(9)–H(7)� � �O(1) 2.978 0.95 2.54 108.4

C(11)–H(12)� � �O(2) 3.313 0.95 2.45 151.5

C(11)–H(11)� � �O(3A) 3.193 0.95 2.58 122.2

C(11)–H(13)� � �O(6) 2.705 0.95 2.26 107.7

C(10)–H(9)� � �O(6) 2.726 0.95 2.30 106.9

C(12)–H(15)� � �O(5) 3.121 0.95 2.53 120.6

C(10)–H(8)� � �F(3B) 3.396 0.95 2.61 140.1

C(9)–H(7)� � �F(1A) 3.527 0.95 2.70 146.4

C(12)–H(16)� � �F(3) 3.230 0.95 2.65 120.1

B.R.A. Bland et al. / Inorganica Chimica Acta 358 (2005) 3927–3936 3933

In complex 1 Æ CH2Cl2 only intermolecular interac-tions between the protonated, unbound imidazole nitro-gen, and the PF6

� counterion are observed and these areshown in Fig. 4. Here the N–H bond interacts with twofluorine atoms and essentially bifurcates the F(5)–P(1)–F(7) bond angle.

In complex 2 Æ ClCH2CH2Cl (see Fig. 5) we see a sim-ilar N–H� � �F interaction between the protonated, un-bound nitrogen (N-1 of the 7-azaindole) and theaveraged fluorine positions F(2A)/F(2B) on the PF6

�

counterion. (An additional, weaker interaction, is seenfrom C(10)–H(10) to the averaged F(3A)/F(3B) fluorineon the counterion). More biologically relevant is theintramolecular interaction of the same N–H group withthe two oxygens (O(1) and O(3)) on the bridgingcarboxylate groups. These interactions are relativelysymmetrical N(2)–H(2)� � �O(1) = 3.28 A and N(2)–H(2)� � �O(3) = 3.05 A, with similar bond angles. Despitethe weakness of the interaction to O(1), these interac-tions of the bound indole group with the dirutheniumtetraacetate core almost certainly assists in stabilizingthe overall binding and in orienting the entire 7-azain-dole so as to almost perfectly bisect the planes formedby the two perpendicular acetate groups (dihedral an-gle = 43�, see above).

Complex 3 Æ OC(CH3)2 Æ H2O displays a wide varietyof hydrogen bonding. Three intramolecular hydrogenbonds: C(9)–H(7)� � �O(1), C(11)–H(11)� � �O(3A) andC(11)–H(12)� � �O(2), all appear to serve to ‘‘lock’’ thecaffeine ligand into place as well as almost evenly bisect-ing the planes formed by perpendicular acetate bridgeson the diruthenium tetraacetate core (dihedralangle = 40�), as in 2 Æ ClCH2CH2Cl. Three additionalpossible hydrogen bonds are seen within the caffeine

Fig. 4. Hydrogen-bonding interactions in complex 1 Æ CH2Cl2. The close Cl� � �F distance of 3.123 A is also shown.

3934 B.R.A. Bland et al. / Inorganica Chimica Acta 358 (2005) 3927–3936

ligands themselves: C(10)–H(9)� � �O(6), C(11)–H(13)� � �O(6) and C(12)–H(15)� � �O(5) (see Fig. 6).

In addition to these intramolecular interactions thereare also three hydrogen bonds between the caffeine andthe PF6

� counterion shown in Fig. 7, however it is unli-kely these would play as significant a biological role.

Another interesting feature which appears in all threestructures is the p–p stacking interactions that take place

Fig. 5. Hydrogen-bonding interactions in complex 2 Æ ClCH2CH2Cl.

between the axial ligands of adjacent dimers. In1 Æ CH2Cl2 the distance between the two imidazole ringcentroids is 3.489 A with a tilt angle of the two ringsat 12.2�. There is a close contact between C(4)–H(4)and the ring plane with a H� � �ring centroid distance of2.54 A and an angle of 160�. In 2 Æ ClCH2CH2Cl, thetwo pyridine (6-membered) rings overlap with a distancebetween the centroids of 3.626 A and a tilt angle of 18.1�while the distance between the centroids of the 5 and 6-membered rings is 3.614 A, with a tilt angle of 17�.Finally in the caffeine adduct, 3 Æ OC(CH3)2 Æ H2O, thetwo 6-membered rings stack the closest of the threeadducts with a centroid distance of 3.483 A and a tilt an-gle of 16.3�. There is also a weak hydrogen bond be-tween one of the methyl groups on one caffeine andthe bound nitrogen on the methylimidazole ring of theother caffeine, C(10)–H(10)� � �N(4) = 3.517 A and the\C(10)–H(10)� � �N(4) = 158�. Diagrams of these threep–p stacking interactions are included in the Supplemen-tary Material (Figures S1–S3).

4. Conclusions

We have successfully synthesized and structurallycharacterized three mixed-valent diruthenium tetraace-tate complexes with biologically relevant axial donor li-gands. In all three cases coordination occurs, notsurprisingly, through the deprotonated nitrogen (i.e.the most basic site). However, it is the nature of thehydrogen bonding that is more subtle and appears to

Fig. 6. Intramolecular hydrogen-bonding interactions in complex 3 Æ OC(CH3)2H2O.

Fig. 7. Hydrogen-bonding interactions between the caffeine ligands and the PF6� counterions in complex 3 Æ OC(CH3)2 Æ H2O.

B.R.A. Bland et al. / Inorganica Chimica Acta 358 (2005) 3927–3936 3935

lead to additional stabilization, not only of the ligandbinding, but also of certain conformers over others.The bis-imidazole adduct, 1 Æ CH2Cl2, shows no signifi-cant intramolecular hydrogen bonding (possibly due tothe fact that there is no secondary ring structure) andit assumes a conformation essentially parallel to a planeformed by two trans-oriented acetate groups. This paral-lel alignment of ligands with a single ring structure is nota unique conformation as a series of pyridine derivativeswe reported in an earlier paper [23] show a wide varietyof conformations with respect to the acetate rings, fromeclipsed, as in 1 Æ CH2Cl2, to staggered (bisecting theacetate mean planes), with both conformers evenappearing in the same unit cell for [Ru2(l-O2CCH3)4(pyridine)2](PF6) and [Ru2(l-O2CCH3)4(4-phenylpyridine)2](PF6).

The situation appears to be different when there is anadditional ring adjacent to the one that contains thecoordinating nitrogen. In 2 Æ ClCH2CH2Cl, where coor-dination takes place through the pyridyl nitrogen,

hydrogen bonding from the N–H group on the indolering to oxygens on adjacent perpendicular acetatebridges serves to orient the entire 7-azaindole ligand ina staggered fashion. We have seen this even in the ab-sence of an N–H group in [Ru2(l-O2CCH3)4(quino-line)2](PF6) where C–H� � �O bonds also serve tostagger the quinoline ligand with respect to the acetatebridges [13]. In 3 Æ OC(CH3)2 Æ H2O the effect is similar,even though it is a nitrogen atom on the imidazole ringthat is coordinating and a methyl group on the 6-mem-bered ring that hydrogen bonds to the oxygens on adja-cent acetates. A much earlier study on the caffeinediadduct of dirhodium(II,II) tetracetate, Rh2(l-O2CCH3)4(caffeine)2, where the caffeine binds throughthe N-9 nitrogen as is the case here, also showed a sim-ilar bisecting of the acetate bridge planes by the plane ofthe caffeine [24]. Interestingly, the authors of that studybelieved this to be due to base stacking of the caffeine li-gands with respect to each other in the crystal lattice andmention little of any intramolecular (caffeine/acetate

3936 B.R.A. Bland et al. / Inorganica Chimica Acta 358 (2005) 3927–3936

bridge) hydrogen bonding. As we have also seen signif-icant p–p stacking in all three of our complexes theinterplay of both of these types of interactions andhow they effect the ligand orientation need to beinvestigated.

While it may be premature to generalize any of theseeffects to what may happen when diruthenium tetracarb-oxylates (and other tetrabridged dimetal complexes)bind to DNA, they are certainly worthy of further study.Investigations in this direction on other diadducts areongoing in our lab.

Appendix A. Supplementary data

Three figures showing p–p stacking interactions incompounds 1–3. Crystallographic data in the CIF formatfor the structural analyses have been deposited with theCambridge Data Centre, CCDC Nos. 270639–270641for compounds 1–3, respectively. Copies of the CIF infor-mationmay be obtained free of charge fromTheDirector,CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK, fax:+44 1223 336 033; email: deposit@ccdc.cam.ac.uk or onthe web http://www.ccdc.cam.ac.uk.

Supplementary data associated with this article can befound in the online version at doi:10.1016/j.ica.2005.06.023.

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