pubs.acs.org/Organometallics Published on Web 05/21/2009 r 2009 American Chemical Society

3906 Organometallics 2009, 28, 3906–3915

DOI: 10.1021/om900208r

Organoplatinum(II) and -palladium(II) Complexes of Nucleobases and

Their Derivatives

Katharina Butsch,† Sait Elmas,† Nalinava Sen Gupta,† Ronald Gust, ) Frank Heinrich,†

Axel Klein,*,† Yvonne von Mering,† Michael Neugebauer,† Ingo Ott,^ Mathias Sch::afer,‡

Harald Scherer,†,§ and Thilo Schurr†

†Institut f::ur Anorganische Chemie, Department f

::ur Chemie, Universit

::at zu K

::oln, Greinstrasse 6, D-50939 K

::oln,

Germany, )Institut f::ur Pharmazie, Pharmazeutische Chemie, Freie Universit

::at Berlin,

K::onigin-Luise-Strasse 2+4, D-14195 Berlin, Germany, ^Institut f

::ur Pharmazeutische Chemie,

Technische Universit::at Braunschweig, Beethovenstrasse 55, D-38106 Braunschweig, Germany, and ‡Institut f

::ur

Organische Chemie, Department f::ur Chemie, Universit

::at zu K

::oln, Greinstrasse 4, D-50939 K

::oln, Germany.

§Present address: Institut f::ur Anorganische and Analytische Chemie, Albert-Ludwigs Universit

::at Freiburg,

Albertstrasse 21, D-79104 Freiburg i. Br

Received March 19, 2009

The [(COD)M(R)] 14 VE complex fragments (COD = 1,5-cyclooctadiene, R = methyl orneopentyl (2,2-dimethylpropyl), M = Pd or Pt) bind to the nucleobases cytosine (Cyt) or uracil(Ura), to the methylated nucleobase derivatives 1-methylcytosine (1MeCyt) or 1-methyluracil(1MeUra), and to the related ligand caffeine (Caf) (1,3,7-trimethylxanthine). From the potentiallybridging cytosinate ligand a binuclear platinum complex [(COD)(Me)Pt(N3-cytosinate-N1)Pt(Me)-(COD)]+ was obtained. The solubility of the corresponding complexes in organic solvents allowedtheir characterization by multiple (1H, 13C, and 195Pt) NMR spectroscopy and in some cases bycrystal structure analysis. Relative ligand-metal bond strength were discussed in view of 1H-195PtNMR coupling constants. Further focus lies on the observation of binding isomers, the formation ofbinuclear species, multiple substitution, and the observed differences between Pt and Pd derivatives.Cytotoxicity experiments on HT-29 colon carcinoma and MCF-7 breast cancer cell lines revealedpromising activities for selected platinum COD complexes.

Introduction

The potential applications of organoplatinum(II) com-plexes [(COD)Pt(R)(L)] (R = alkyl, alkynyl or aryl; L =other ligands) with the COD (1,5-cyclooctadiene) chelateligand are widespread. Originally designed as precursors formono- and polynuclear organometallic platinum(II) com-pounds (due to the ease of exchange of COD with otherneutral ligands),1-3 these compounds have been investigatedalso in the field of catalysis4 and for chemical vapor deposition(CVD) of platinum.5 Also their use as antitumor agents hasbeen proposed by Komiya et al. some years ago.6 A series ofcomplexes [(COD)Pt(Me)(Nuc)](NO3) (Nuc = guanosine,cytidine, adenosine, or thymidine nucleosides) have been

synthesized and examined by 1H and 13CNMR spectroscopy,and the preference of platinum binding to guanosine wasshown by exchange reactions using the three nucleosides.Furthermore, preliminary cell tests using P388 leukemia cellsshowed “considerable cytotoxic activities”.6 Unfortunately,these studieswere neither continued nor driven to a conclusiveend. The reason seems to be the presence of the hydrophobicCOD ligand, which seems not very suitable to deliver into acell. On the other hand, we have recently shown the suitabilityof the [(COD)M(Me)] fragments (M= Pt7 or Pd8 to coordi-nate various ligands. Most importantly, the concept of intro-ducing biorelevant ligands in platinum anticancer drugs9

makes complexes of the type [(COD)M(R)(L)]n+ (R= alkyl,alkynyl or aryl; M = Pd or Pt; L = (bio)ligand) veryinteresting precursor molecules.

*To whom correspondence should be addressed. E-mail: axel.klein@uni-koeln.de.(1) Clark, H. C.; Manzer, L. E. J. Organomet. Chem. 1973, 59, 411.(2) (a) Holtcamp, M. W.; Labinger, J. A.; Bercaw, J. E. Inorg. Chim.

Acta 1997, 265, 117. (b) Dawoodi, Z.; Eaborn, C.; Pidcock, A.J. Organomet. Chem. 1979, 179, 95. (c) Chaudhury, N.; Puddephatt,R. J. J. Organomet. Chem. 1975, 84, 105.(3) (a) Lin, M.; Fallis, K. A.; Anderson, G. K.; Rath, N. P.; Chiang,

M. Y. J. Am. Chem. Soc. 1992, 114, 4687. (b) Sutcliffe, V. F.; Young, G.B. Polyhedron 1984, 3, 87. (c) Bochmann,M.;Wilkinson, G.; Young, G.B. J. Chem. Soc., Dalton Trans. 1980, 1879.(4) Lee, T. R.; Whitesides, G. M. J. Am. Chem. Soc. 1991, 113, 2576.(5) Cumar, R.; Roy, S.; Rashidi, M.; Puddephatt, R. J. Polyhedron

1989, 8, 551.(6) Komiya, S.; Mizuno, Y.; Shibuya, T. Chem. Lett. 1986, 1065.

(7) Klein, A.; Klinkhammer, K.-W.; Scheiring, T. J. Organomet.Chem. 1999, 592, 128.

(8) Klein, A.; Dogan, A.; Feth,M.; Bertagnolli, H. Inorg. Chim. Acta2003, 343, 189.

(9) (a) Van Zutphen, S.; Pantoia, E.; Soriano, R.; Soro, C.; Tooke,D. M.; Spek, A. L.; Den Dulk, H.; Brouwer, J.; Reedijk, J. DaltonTrans. 2006, 1020. (b) Anzelotti, A.; Stefan, S.; Gibson, D.; Farrell, N.Inorg. Chim. Acta 2006, 359, 3014. (c) Arandjelovic, S.; Tesic, Z.;Radulovic, S. Med. Chem. Rev. 2005, 2, 415. (d) Margiotta, N.;Papadia, P.; Lazzaro, F.; Crucianelle, M.; De Angelis, F.; Pisano,C.; Vesci, L.; Natile, G. J. Med. Chem. 2005, 48, 7821. (e) Ma, D.-L.;Shum, T. Y.-T.; Zhang, F.; Che, C.-M.; Yang, M. Chem. Commun.2005, 4675. (f) Siu, P. K.-M.; Ma, D.-L.; Che, C.-M. Chem. Commun.2005, 1025.

Article Organometallics, Vol. 28, No. 13, 2009 3907

Therefore, we started an investigation with the aim oftesting various biorelevant ligands in the system [(COD)M-(R)(L)]n+ (L = (bio)ligand; M = Pd or Pt; R = methyl orneopentyl (2,2-dimethylpropyl) Scheme 1), focusing on theirbinding properties (bond strength or binding options, if theywere ambident). As a first example we have recently presenteda thorough investigation of the water-soluble and water-stable organoplatinum complex [(COD)Pt(Me)(Cyt)](SbF6)(Cyt= cytosine) including its crystal and molecular structureand detailed NMR spectroscopic investigations.10

In the complex cation [(COD)Pt(Me)(Cyt)]+ an organo-platinum fragment [(COD)Pt(Me)] binds to the ambivalentligand cytosine forming theN3andN1 stereoisomers in a ratioof 5:1. The organometallic approach (organometallic plati-num complex fragments binding to cytosine) allowed a verydetailed spectroscopic and structural characterization of thecomplex, due to the solubility in almost any organic solvent,revealing, for example, the strength of the N3 (biologicallyimportant) orN1 binding in comparison to other ligands suchas H2O, OH-, or Cl-. Other properties such as the 5:1preference of the N3 over the N1 coordination and essentialbinding parameters in the structure of [(COD)Pt(Me)(Cyt)](SbF6) 3 0.5H2O are similar to nonorganometallic related spe-cies,11-13 confirming the biological relevance of our results.In this paper we wish to report on the complete study,

extending the organometallic approach to complexes of thenucleobases cytosine and uracil, their methylated derivatives1-methylcytosine and 1-methyluracil, and the related ligandcaffeine (1,3,7-trimethylxanthine). While most of the com-pounds contain the very stable methyl co-ligand (R =Me) inthe organometallic complex fragments [(COD)M(R)] (COD=1,5-cyclooctadiene;M=Pdor Pt), for a number of derivativeswe replaced methyl by neopentyl (2,2-dimethylpropyl) toachieve better solubility for the resulting complexes (Scheme1).Furthermore, we have tested some of the complexes for theirtoxicity against cancer cell lines (HT-29 colon carcinoma andMCF-7 breast cancer), on which we also wish to report.

Results and Discussion

Preparation. Starting from the precursor complexes[(COD)M(R)X] (for M= Pt or Pd; R =methyl or neopen-tyl; X = Cl, Br) ligand exchange reactions were performed.The halogenido ligands were cleaved using AgSbF6 andformed insoluble AgCl. The resulting solvent complexes[(COD)M(R)(Solv)]+ were not isolated but directly reactedwith the corresponding biorelevant ligands (details in theExperimental Section). The reaction products are all color-less powders with good to excellent solubility in organicsolvents. As expected, the neutral complexes [(COD)Pt(Me)-(Ura)], [(COD)M(Me)(1MeUra)] (M = Pd or Pt), and[(COD)Pd(neop)Br] exhibit excellent solubility. The synth-esis of the palladium derivatives was performed with highyields and excellent purities; however, most of the organo-metallic palladium complexes tend to decompose uponprolongated standing in solution, yielding black material(presumably elemental Pd). Compared to this, platinumderivatives exhibit far higher stability. Furthermore, theplatinum compounds generally exhibit better solubilityand higher stability in water for a longer period of time(>2weeks).As expected, fromourpreliminarywork,10whichshowed that cytosine can bind by both its N3 or N1 atom to[(COD)Pt(Me)], the reaction of 2 equiv of the platinumprecursor [(COD)Pt(Me)(Solv)]+ with 1 equiv of cytosineyielded the binuclear complex [(COD)Pt(Me)(N3-cytosi-nate-N1)Pt(Me)(COD)]+, depicted in Scheme 2. 195Pt NMRspectra (see Table 3) reveal unequivocally the magnetic in-equivalence of the twoplatinumatoms, resulting frombindingto two different N atoms in the bridging cytosine.Crystal and Molecular Structures in the Solid. From the

compounds [(COD)M(Me)(Caf)](SbF6) (M = Pd or Pt)and [(COD)Pt(Me)(1MeUra)] 3 3H2O single crystals wereobtained and submitted to XRD experiments. The com-plexes [(COD)Pd(Me)(Caf)](SbF6) and [(COD)Pt(Me)-(Caf)](SbF6) were found to crystallize both in themonoclinicspace groupP21/c, while the structure of the neutral complex[(COD)Pd(Me)(1MeUra)] 3 3H2O was solved in triclinic P1.Figure 1 shows two representative molecular structures forthe three complexes, In Figure 2 the crystal structure of[(COD)Pt(Me)(1MeUra)] 3 3H2O is displayed, while Tables 1

Scheme 2

Scheme 1

(10) Klein, A.; Schurr, T.; Scherer, H.; Sen Gupta, N. Organometal-lics 2007, 26, 230.(11) (a) Br

::uning, W.; Freisinger, E.; Sabat, M.; Sigel, R. K. O.;

Lippert, B. Chem.;Eur. J. 2002, 8, 4681. (b) Br::uning, W.; Sigel, R. K.

O.; Freisinger, E.; Lippert, B. Angew. Chem., Int. Ed. Engl. 2001, 40,3397. (c) Br

::uning, W.; Ascaso, I.; Freisinger, E.; Sabat, M.; Lippert, B.

Inorg. Chim. Acta 2002, 339, 400. (d) Jaworski, S.; Sch::ollhorn, H.;

Eisenmann, P.; Thewald,U.; Lippert, B. Inorg. Chim.Acta 1988, 153, 31.(12) Hollis, L. S.; Amundsen, A.R.; Stern, E.W. J.Med. Chem. 1989,

32, 128.(13) (a) Cosar, S.; Janik, M. B. L.; Flock, M.; Freisinger, E.; Farkas,

E.; Lippert, B. J. Chem. Soc., Dalton Trans. 1999, 2329. (b) M::uller, J.;

Glah�e, F.; Freisinger, E.; Lippert, B. Inorg. Chem. 1999, 38, 3160. (c)Lippert, B.; Thewalt, U.; Sch

::ollhorn, H.; Goodgame, D.M. L.; Rollins,

R. W. Inorg. Chem. 1984, 23, 2807. (d) Faggiani, R.; Lippert, B.; Lock,C. J. L. Inorg. Chem. 1982, 21, 3210.

3908 Organometallics, Vol. 28, No. 13, 2009 Butsch et al.

and 2 list the crystal properties and selected molecularbonding parameters.

The crystal structures of the two isostructural cationic com-plexes [(COD)M(Me)(Caf)](SbF6) exhibit a number ofF 3 3 3H-C=(COD), F 3 3 3H-C(3)(Caf), and F 3 3 3H-CH2

(COD) contacts ranging between 2.47(1) and 2.52(1) A (detailsin the Supporting Information). For [(COD)Pt(Me)(Caf)]-(SbF6) additionally CdO(6) 3 3 3H-C(1)(Caf) (2.37(1) A) andCdO(2) 3 3 3H-C(methyl) (2.56(1) A) contacts were observed.

However, all of them are considered to be rather weak14 andvery probably do not have an impact on the molecular struc-ture. In contrast to this, in the crystal structure of [(COD)Pt-(Me)(1MeUra)] 33H2O markedly stronger H-bridges werefound (Figure 2). The three water molecules bridge be-tween keto-functions of different 1-methyl uracilato ligands.Their H 3 3 3O distances are 1.96(1) or 1.97(1) A for the

Figure 1. ORTEP representation of the complex molecules in the structures of [(COD)Pd(Me)(Caf)](SbF6) (left) and [(COD)Pt-(Me)(1MeUra)] 3 3H2O (right) at the 30% probability level; protons, counterions (SbF6)

-, and cocrystallized H2O molecules wereomitted for clarity.

Figure 2. Crystal structure of [(COD)Pt(Me)(1MeUra)] 3 3H2O showing various intermolecular H-bonding interactions.

(14) Steiner, T. Angew. Chem., Int. Ed. Engl. 2002, 41, 48.

Article Organometallics, Vol. 28, No. 13, 2009 3909

CdO 3 3 3H-OH bridges (distances O 3 3 3O: about 2.79 A;angles O-H 3 3 3O: about 165�), and intermolecular distancesbetween the water molecules range from 2.14(1) to 2.47(1) A(2.73 to 2.94 A for distances O 3 3 3O). Together they form anetwork of H-bridges, which is dominating largely the crystalstructure (see Figure 2). H-bridges have also been observed inthe recently reported complex [(COD)Pt(Me)(Cyt)](SbF6) 30.5H2O.10 However they differ largely from the above-de-scribed ones, since the strongest bridges in [(COD)Pt(Me)-(Cyt)](SbF6) 3 0.5H2O were observed between the N-H

function of one cytosine ligand and the CdO function of aneighboring cytosine complex. Additionally, there wereshort contacts between the cocrystallized water and theN(3)-H amino function. In the present complexes therewere no such amino functions available.

The bonding parameters M-N and M-C(10) aroundthe platinum atom are quite similar to those reported forthe crystal structure of [(COD)Pt(Me)(Cyt)](SbF6) 3 0.5H2O.10 Also the coordination plane around the M atomis completely planar in all cases, and the bite angles of theCOD ligand, expressed by X(1)-M-X(2), and otherangles around M are quite similar. Although most of thecorresponding bond lengths and angles of all three com-pounds are essentially identical within error limits, anumber of trends in these values are worth mentioning.First, the neutral complex [(COD)Pt(Me)(1MeUra)]shows the shortest M-C, M-N, or M-X bonds in theseries, with a very short M-X(1) bond. Second, the M-Xbonds trans to the strong donor co-ligand methyl aremarkedly longer than the corresponding cis-M-X bonds,as expected from the trans influence of the methyl co-ligand. Finally, the bond lengths around Pd in [(COD)Pd-(Me)(Caf)]+ all exceed their counterparts in the Pt deri-vative (Pd2+ is larger than Pt2+) with the exception of theM-CH3 bond, pointing to a rather strong Pd-Me bond.Similar bonding parameters as found for these three com-plexes have also been observed for related complexespreviously.7

NMR Spectroscopy. Apart from being an important ana-lytical tool in our study, detailedmultinuclearNMRspectro-scopy allowed us to address a number of important questionsconcerning the constitution of the complexes in solution andtheir reactivity and in case of the platinum derivativesenabled us also to determine relative bond strengths of the(bio)ligands L. It is well established since the 1970s that thetrans influence of a ligand and thus its strength correlate wellwith metal-ligand coupling constants. For platinum com-plexes coupling of the 195Pt isotope to 1H, 31P, 13C, or 15N

Table 1. Parameters of Crystal Structure Measurements and Refinements of [(COD)Pd(Me)(Caf)](SbF6), [(COD)Pt(Me)(Caf)](SbF6),

and [(COD)Pt(Me)(1MeUra)] 3 3H2Oa

[(COD)Pd(Me) (Caf)](SbF6) [(COD)Pt(Me)(Caf)](SbF6) [(COD)Pt(Me) (1MeUra)] 3 3H2O

formula C17H25N4O2F6PdSb C17H25N4O2F6PtSb C14H26N2O5Ptweight (g 3mol-1) 659.59 748.25 497.46cryst syst monoclinic monoclinic triclinicspace group P21/c (No. 14) P21/c (No. 14) P1 (No. 2)temperature (K) 273(2) 203(2) 203(2)a (A) 7.223(3) 7.2229(5) 7.8994(14)b (A) 32.855(5) 32.523(4) 10.1745(19)c (A) 9.292(5) 9.3269(11) 10.774(2)R (deg) 90 90 79.317(15)β (deg) 90.00(2) 90.00(2) 76.340(15)γ (deg) 90 90 86.445(15)V (A3)/Z 2205/4 2191/4 826.7(3)/2Fcalc (g cm-3) 1.987 2.268 1.998μ (mm-1)/F(000) 2.112/1288 7.683/1416 8.511/484limiting indices -8 < h < 8, -8 < h < 9, -10 < h < 10,

-38 < k < 38, -41 < k < 41, -14 < k < 14,-11 < l < 11 -12 < l < 12 -14 < l < 14

reflns coll/uniq 20 104/2110 18 495/4636 11 940/4556Rint 0.081 0.0622 0.0837data/restraints/params 3886/0/285 4636/0/285 4556/9/226Goof on F2 0.778 1.107 1.310final R1/wR2 [I > 2σ(I)] 0.0394/0.0860 0.0381/0.0881 0.0738/0.1840R1/wR2 (all data) 0.0755/0.0941 0.0449/0.0911 0.0879/0.1938larg diff peak/hole (e 3 A

-3) 0.727/-1.162 1.478/-1.378 3.684/-1.113

aRadiation wavelength λ = 0.71073 A; refinement method: full-matrix least-squares on F2.

Table 2. Selected Distances (A) and Angles (deg) of Complexes

[(COD)Pd(Me)(Caf)](SbF6), [(COD)Pt(Me)(Caf)](SbF6), and

[(COD)Pt(Me)(1MeUra)] 3 3H2O

[(COD)Pd(Me)-(Caf)](SbF6)

[(COD)Pt(Me)-(Caf)](SbF6)

[(COD)Pt(Me)-(1MeUra)] 3 3H2O

Distances

M-N 2.102(5) 2.084(5) 2.077(9)M-C(10) 2.040(7) 2.064(7) 2.046(12)M-C(11) 2.187(7) 2.145(7) 2.126(12)M-C(12) 2.199(7) 2.160(6) 2.130(11)M-C(15) 2.376(7) 2.283(7) 2.239(13)M-C(16) 2.385(7) 2.308(7) 2.261(13)M-X(1)a 2.085(8) 2.037(3) 2.006(6)M-X(2)a 2.286(7) 2.194(3) 2.143(6)

Angles

C(10)-M-N 88.7(2) 88.2(2) 86.9(5)C(10)-M-X(1) 90.7(2) 91.48(18) 92.5(3)C(10)-M-X(2) 175.1(2) 177.30(18) 178.0(3)N-M-X(1) 177.75(14) 178.60(14) 178.9(2)N-M-X(2) 95.43(13) 94.12(14) 93.0(2)X(1)-M-X(2) 85.2(2) 86.30(18) 87.6(2)P

of anglesaround M

360.0(2) 360.1(2) 360.0(3)

coord planeb/ligand plane

69.00(6) 66.20(5) 93.10(9)

aCentroids X(1) and X(2) are defined as the average olefinic bondsbetween C(11) and C(12) or C(15) and C(16), respectively. bThecoordination plane is defined by X(1)X(2)C(10)NM; the ligand planeis the (bio)ligands’ planar heteroaromatic system.

3910 Organometallics, Vol. 28, No. 13, 2009 Butsch et al.

nuclei has been widely used.15,16 We have applied success-fully this correlation for a large number of complexes[(COD)Pt(Me)L]n+,7,10 mainly by using the 2JPt-H(COD)

cou-pling constant as a measure for the bond strength of thecorresponding trans-oriented co-ligand R or (bio)ligand L.In Table 3 these values were collected for the new complexes,revealing almost uniform values around 30 Hz for theolefinic protons trans to the strong σ-donor co-ligand R.The corresponding coupling constants of the olefinic protonstrans to the (bio)ligandL vary from 67 to 78Hz. These valuesindicate that all used (bio)ligands L can be ranked within agroup of medium strong ligands such as Cl- (74.3 Hz), OH-

(73.7 Hz), and pyridine (72.1 Hz)7,10 and that they are farstronger ligands than H2O (89.3 Hz). From this we cansuppose that in practical terms all (bio)ligands L might bereplaced by Cl- or OH- in solution, but the complexes arestable toward hydrolysis (replacement by water). For thepalladium derivatives such information from coupling con-stants is not available and we have to rely on the assumptionthat shift similarities between palladium and platinumcomplexes represent similarities in the bonding situation.

Comparison of the chemical shifts of specific protons inplatinum and palladium homologues reveals a general low-field shift for the signals of the [(COD)M(R)] fragment forthe palladium derivatives compared to the platinum analo-gues, while the protons of the (bio)ligands are high-fieldshifted. However, the differences are not very pronounced,and since in this case it can be assumed that electron-with-drawing (high-field) and electron-donating (low-field shift)effects through bonds are superimposed by ligand-ligandinteractions through space, we refrain from discussing thesedifferences. Nevertheless, it seems justified to state that thebonding situation is quite similar for corresponding palla-dium and platinum derivatives. For example, from thewealth of NMR data (including 2D experiments) we are

confident that in both the Pt and the Pd derivative of thecomplex [(COD)M(Me)(1MeCyt)]+ the 1MeCyt ligand co-ordinates exclusively via the N3 atom to the metal and notthrough the NH2 function, as found by Lippert et al. for thecomplex trans-[Pt(NH3)2(1MeCytN4)2]

2+.17 In contrast tothis, we can only speculate on the platinum binding site inthe complex [(COD)Pt(Me)(Ura)]. Comparison with themethylated derivative shows similar chemical shifts for theH5,6-COD and the H6-Ura protons, which suggests the samesurrounding and thus identical binding sites.

Interestingly, for the complex [(COD)Pt(neop)(Caf)]+ thefour olefinic COD protons show individual signals, and alsotwo signals for the neopentyl -CH2- group are observed(seeTable 3 andExperimental Section). Since there is onlyone195Pt resonance, we can exclude the possibility of isomers(syn or anti)18 and have to conclude that the strong intramo-lecular contacts between the neopentyl-CH2- group and theCOD olefinic protons lead to the obvious loss of magneticequivalence. NOESY experiments confirm this conclusionand allow the detailed assignment of all four olefinic CODprotons (see Experimental Section; a 1HNOESY spectrum issupplied in the Supporting Information).Ligand Exchange Reactions. Besides all structural and

electronical similarities of palladium and platinum com-plexes, an important difference between the two metals canbe expected concerning the rate of ligand exchange reactions.Palladium is supposed to exhibit far higher reactivity.19 As aconsequence for the studied [(COD)M(R)] systems, the Pdderivatives might undergo multiple substitution includingthe replacement of the COD ligand. Such reactions havebeen described already for the system [(COD)Pd(Me)-(Solv)]+ using nitrogen ligands such as iPrNH2,

tBuNH2,

Table 3. Selected 1H and 195Pt NMR Data of Palladium and Platinum Complexesa

δH1,2- CODtrans L

2JPt-HH1,2-CODtrans L

δH56-CODtrans R

2JPt-HH5,6-CODtrans R δM-CH3 δL δ195Pt

[(COD)Pt(Me)(Ura)] b 4.70 74.4 5.34 39.6 0.68 5.62/7.34 -3346[(COD)Pd(Me)(1MeUra)] 5.22 5.77 0.96 5.64/7.05[(COD)Pt(Me)(1MeUra)] 4.57 71 5.36 36 0.63 5.40/7.33 -3436[(COD)Pd(Me)(Cyt)]+ N3b,c 5.42 5.73 0.99 5.97/7.54[(COD)Pd(Me)(Cyt)]+ N1b,c 5.42 5.73 0.99 5.94/7.49[(COD)Pt(Me)(Cyt)]+ N3d 5.03 74 5.53 31 0.78 6.19/7.81 -3593[(COD)Pt(Me)(Cyt)]+ N1d 4.88 67 5.52 31 0.73 6.06/7.74 -3553[(COD)Pd(Me)(Caf)]+ 5.64 5.89 1.12 8.40[(COD)Pt(Me)(Caf)]+ 5.34 78 5.59 30 0.85 8.71 -3010[(COD)Pd(Me)(1MeCyt)]+ 5.21 5.77 1.00 e

[(COD)Pt(Me)(1MeCyt)]+ 5.01 76 5.56 31 0.76 5.95/7.71 -3596[{(COD)Pt(Me)}2(Cyt)]

+ N3 f 4.90 70 5.50 31 0.73 7.72/6.95 -3556N1f 4.87 74 5.50 31 0.72 6.04 -3549[(COD)Pt(Me)Cl] 4.51 74.3 5.39 32.5 0.76 -3501[(COD)Pd(Me)Cl] 5.21 5.77 1.00[(COD)Pt(neop)Br] 4.62 75.7 5.50 34.5 1.90g -3580[(COD)Pd(neop)Br] 5.34 5.81 2.34g

[(COD)Pt(neop)(Caf)]+ 5.39, 5.31 72, 74 5.69, 5.59 34, 32 1.89g, 1.72g 8.95 -3605

a 1H or 195Pt NMR shifts [ppm] and selected 195Pt-H coupling constants [Hz], measured in acetone-d6, counterion is (SbF6)-. b Measured in

methanol-d4.cThe two binding isomersN3 andN1were assigned in analogywith the correspondingPt analogue.10 dFrom ref 10. eNot assignable due to

multiple substitution products (see text). fDifferent signals are attributable toN3- orN1-bound [(COD)Pt(Me)] fragments. gNeopentyl-CH2- group.

(15) Appleton, T. G.; Clark, H. C.; Manzer, L. E. Coord. Chem. Rev.1973, 10, 335.(16) (a) Appleton, T. G.; Hall, J. R.; Ralph, S. F. Inorg. Chem. 1985,

24, 673. (b) Appleton, T.G.; Hall, J. R.; Ralph, S. F. Inorg. Chem. 1985,24, 4685.

(17) M::uller, J.; Zangrando, E.; Pahlke,N.; Freisinger, E.; Randaccio,

L.; Lippert, B. Chem.;Eur. J. 1998, 4, 397.(18) Syn or anti refers to the orientation of the neopentyl co-ligand

and the Caf ligand toward the square-planar binding plane. An exampleof syn and anti isomers can be found in: Klein, A.; Schurr, T.; Kn

::odler,

A.; Gudat, D.; Klinkhammer, K.-W.; Jain, V. K.; Z�ali�s, S.; Kaim, W.Organometallics 2005, 24, 4125.

(19) Huheey, J. E.; Keiter, E. A.; Keiter, R. L. Inorganic Chemistry:Principles of Structure and Reactivity, 4th ed.; Prentice Hall: UpperSaddle River, NJ, 1993.

Article Organometallics, Vol. 28, No. 13, 2009 3911

or pyridine.8However, it has also been found in this previouswork that for the bulkier pyridine derivative collidine(2,4,6-trimethylpyridine) multiple substitution is hamperedand the complex [(COD)Pd(Me)(collidine)]+ is stable evenin the presence of excess collidine.8

When studying corresponding reactions using 1MeCytand [(COD)Pd(Me)(Solv)]+ in various ratios, in all casesmixtures of species [(COD)Pd(Me)(1MeCyt)]+ / [Pd(Me)-(1MeCyt)2(Solv)]

+ / [Pd(Me)(1MeCyt)3]+ could be ob-

served by NMR spectroscopy. This is in contrast to ourpreliminary experiments, where, for very short reactiontimes, the monosubstituted product was dominant (or ex-clusively formed).8 Even the use of a substoichiometricamount of 1MeCyt ligand in a 5 min room-temperaturereaction yielded a product mixture containing all threespecies. A corresponding NMR titration experiment gavethe same result (Figure S1, Supporting Information). In thisexperiment we dissolved a small portion (2.5 mg) of theprecursor [(COD)Pd(Me)(acetone)](SbF6) in methanol-d4and added different amounts of solid 1MeCyt. After addingthe ligand, each mixture was immediately analyzed byNMRspectroscopy. The spectra showed an emerging signal for freeCOD already upon adding 0.3 equiv of 1MeCyt.

Figure 3 shows two sections of 1HNMR spectra, focusingon the olefinic 1MeCyt protons, recorded after the additionof 1.5 equiv of 1MeCyt ligand. Since at ambient temperaturethe spectral resolution was not sufficient, also low-tempera-ture spectra were recorded. At low temperatures we canclearly see that the reaction mixture contains four indepen-dent 1MeCyt signals. None of them can be assigned tounbound 1MeCyt. Therefore, 1-, 2-, and 3-fold substitutedcomplexes are coexisting. According to the complex symme-try the monosubstituted and the 2-fold substituted com-pound should show only one NMR signal set each, and the3-fold substituted species is expected to exhibit two signalsets (rel intensity 1:2). By comparison of the spectra inFigure 3 with the spectrum of the 3-fold substituted complex(see below), the signals at 7.72 and 7.65 ppm can be assignedto the 3-fold substituted complex. Unfortunately there is noH,H-correlation between 1MeCyt and the methyl group,which could be detected by 1H1H NOESY experiments.Therefore it remains unclear which signal belongs to the

2-fold substituted and which can be assigned to the singlysubstituted compound.

Complete replacement of the COD ligand was observedupon adding an excess (4-fold) of 1MeCyt, leading to theisolation of [Pd(Me)(1MeCyt)3](SbF6) (see ExperimentalSection). The NMR spectroscopic investigation of this com-plex allowed not only to trace the species in the complexmixtures (as in Figure 3) but also supported our assumptionthat syn or anti isomers arising from the orientation of the(bio)ligands in 2- or 3-fold substituted complexes cannot bediscriminated in the 1H NMR spectra and thus do notfurther complicate the assignment of species observed inthe NMR spectra. Scheme 3 depicts the postulated mechan-ism for the substitution reactions.

In the first step the solvent ligand (Solv) is replaced by a1MeCyt ligand. The resulting monosubstituted complex[(COD)Pd(Me)(1MeCyt)]+ readily adds another 1MeCytligand, while COD is completely (Scheme 3, A) or partly(Scheme 3, B) replaced. Unfortunately, our efforts to trace

Figure 3. 1HNMR spectra (400MHz) of amixture of [(COD)Pd-(Me)(Solv)]+ and 1MeCyt (1:1.5 equiv) in methanol-d4, at varioustemperatures. The sections focus on the olefinic 1MeCyt protons(the low-field signal of the olefinic CODprotons ismarkedwith anasterisk).

Scheme 3

3912 Organometallics, Vol. 28, No. 13, 2009 Butsch et al.

one of these two intermediates by NMR spectroscopy wereunsuccessful. Neither signals for bound solvent molecules(for A) nor resonances for singly bound COD were found inthe NMR spectra. In contrast to this, ESI-MS of suchsolutions showed a fragment withm/z= 371 correspondingto [Pd(Me)(1MeCyt)2]

+ as the simulation shows (Figure S2,Supporting Information), giving strong evidence for the2-fold substituted species. In any case, it seems that theincoming 1MeCyt ligand in the monosubstituted complexis labilizing the COD ligand, leading to very fast consecutivereactions. This is probably due to the stronger trans effectexerted by the 1MeCyt ligand in comparison to the (Solv)ligand. Since the olefin group of the COD trans to the verystrong methyl co-ligand is already largely labilized (see forcrystal structures), this might explain why multiple substitu-tion is favored over the formation of the singly substitutedproducts [(COD)Pd(Me)L]+.

Comparable reactions of [(COD)Pd(Me)(Solv)]+ andcaffeine (Caf) revealed no evidence for multiple substitution,and the monosubstituted complex [(COD)Pd(Me)(Caf)](SbF6) could be isolated (crystal structure shown above).

In contrast to this, parallel work using the precursorcomplex [(COD)Pd(neop)(Solv)](SbF6), containing the verystrong σ-donor co-ligand neopentyl (2,2-dimethylpropyl),revealed a marked degree of 2-fold substitution. In a sub-stoichiometric reaction of the precursor (0.4 mmol) andcaffeine (Caf) in acetone solution the main product was [Pd(neop)(Caf)2(acetone)]

+ instead of [(COD)Pd(neop)(Caf)]+

(for details see Experimental Section). A similar reaction(1:1 ratio) using 4-picoline (4-Pic) yielded mainly (26%)[Pd(neop)(4-Pic)3]

+, while 62% of the precursor remainedunreacted. Supposing an analogous substitution mechanismalso for this reaction, we can conclude that the neopentyl co-ligand accelerates the COD replacement, compared to themethyl co-ligand. Furthermore, it is interesting to note thatfor L=Caf the 2-fold substituted complex could be isolated,and a 3-fold substitution was not observed, which is prob-ably due to the larger steric strain imposed by the neopentylco-ligand. The complex [Pd(neop)(Caf)2(acetone)](SbF6)was also crystallized, but unfortunately the obtained crystalstructure exhibits a strong disorder of the acetone and theneopentyl co-ligands. Therefore the structure could not besolved completely. Since essentially the [Pd(Caf)2] unit wasinteresting to us, we decided to squeeze the remainingelectron density and refine themain structuremotif. Figure 4shows the molecule fragment, and Table S2 in the Support-ing Information summarizes the structure parameters for theincomplete crystal structure.

The Pd-N distances are similar to those in a mono-substituted Pd complex (see above). The N1-Pd-N2 angleis 177.1(2)� and is also close to the ideal angle of 180� in asquare-planar coordination geometry.With a dihedral angleof 9.0(2)� the two trans-oriented caffeine ligands are nearlycoplanar and exhibit the expected E configuration.

Therefore, our preliminary assumption that sterical effectslargely influence the probability of multiple substitution isconfirmed by these results. The degree of multiple substitu-tion can be lowered by using larger (bio)ligands and co-ligands (e.g., neop instead ofMe). However, this might not bethe only important parameter, since it is hard to believe thatthe two ortho-CH3 substituents of collidine (2,4,6-trimethyl-pyridine) exert much larger steric bulk (no multiple substitu-tion) than the -NH2 and dO substituents of 1MeCyt(complete substitution), while caffeine takes amiddle position

in this respect. Presumably, other factors such as the feasibilityof residing and incoming ligands to form H-bridges play animportant role.Cytotoxicity. The platinum compounds [(COD)PtCl2],

[(COD)Pt(Me)Cl], and [(COD)Pt(Me)(Cyt)](SbF6) weretested exemplarily for their cell growth inhibitory effects onHT-29 colon carcinoma and MCF-7 breast cancer cells (seeTable 4). Whereas [(COD)PtCl2] was not significantly active(IC50 values above 100 μM in both cell lines), [(COD)Pt-(Me)Cl] and [(COD)Pt(Me)(Cyt)](SbF6) exhibited promis-ing antiproliferative effects, with IC50 values in the range8.3-17.5 μM. Compared to the established inorganic antic-ancer drug cisplatin, these values represent a good startingpoint for further drug development of COD complexes,probably leading to species with a more pronounced cyto-toxicity profile. From this preliminary bioactivity study thefollowing conclusion can be drawn: replacement of at leastone Cl of [(COD)PtCl2] leads to active agents. Since thepresented results confirm the early trials of Komiya et al.,6

and in view of related findings by Deacon et al.,20 we suggestthat optimizing the ligand set in such organometallic plati-num complexes might yield complexes with superior cyto-toxicity compared to nonorganometallic derivatives. Furthercomparative tests will thus be undertaken in the future.

Conclusions

The [(COD)M(R)] 14 VE complex fragments (COD=1,5-cyclooctadiene,R=methyl or neopentyl,M=PdorPt) bindeffectively to the nucleobase cytosine (Cyt) or uracil (Ura),

Figure 4. ORTEP of the incomplete [Pd(neop)(Caf)2(acetone)]+

fragment at the 30% probability level; protons were omitted, thecounterion SbF6

- was assigned but is also not shown for the sakeof clarity.

Table 4. Cytotoxicity of Selected Compounds in HT-29 and

MCF-7 Cells Expressed as IC50 Values Obtained in Two Inde-

pendent Experiments

IC50 HT-29 IC50 MCF-7

[(COD)PtCl2] >100 μM >100 μM[(COD)Pt(Me)Cl] 8.3 ( 3.0 μM 11.2 ( 1.4 μM[(COD)Pt(Me)(Cyt)](SbF6) 13.5 ( 7.2 μM 17.5 ( 1.2 μMcisplatina 7.0 ( 2.0 μM 2.0 ( 0.3 μM

aFrom ref 21.

(20) (a) Deacon, G. B. In Platinum and Other Metal CoordinationCompounds in Cancer Chemotherapy; Howell, S. B., Ed.; Plenum Press:New York, 1992; p 139. (b) Cullinane, C.; Deacon, G. B.; Drago, P. R.;Hambley, T. W.; Nelson, K. T.; Webster, L. K. J. Inorg. Biochem. 2002,89, 293.

(21) Sch::afer, S.; Ott, I.; Gust, R.; Sheldrick, W. S. Eur. J. Inorg.

Chem. 2007, 3034.

Article Organometallics, Vol. 28, No. 13, 2009 3913

to their methylated derivatives 1-methylcytosine (1MeCyt)and 1-methyluracil (1MeUra), and to caffeine (Caf) (1,3,7-trimethylxanthine). From the potentially bridging cytosinateligand a binuclear platinum complex, [(COD)(Me)Pt(N3-cytosinate-N1)Pt(Me)(COD)]+, was synthesized and spectro-scopically characterized. The synthesized platinum and palla-dium compounds are very similar in geometry and electronicdistribution (XRD and multinuclear NMR). The main dif-ference between the two metals arises from the far higherreactivity of Pd(II) compared to Pt(II). The correspondingpalladium compounds of our series are very reactive and, as aconsequence, able to formmultiple substitution products. Forthe degree of multiple substitution the steric bulk of theligands but presumably also their ability to form H-bridgesplays a major role. At the same time, the Pd complexes aremarkedly more labile (decomposition to elemental Pd) insolution than corresponding Pt(II) derivatives. Cell growthinhibitory effects on HT-29 colon carcinoma and MCF-7breast cancer cells give some indication for the enhancedtoxicity of organometallic complexes over nonorganometallicderivatives.

Experimental Section

Instrumentation. The NMR spectra were recorded on a BrukerAvance II 300 MHz (1H: 300.13 MHz, 13C: 75.47 MHz)/BrukerAvance 400 spectrometer (1H: 400.13 MHz, 13C: 100.61 MHz, 195Pt:86.01 MHz) using a triple-resonance 1H,19F,BB inverse probeheadand on a Bruker Avance II 600 spectrometer (1H: 600.13 MHz). Theunambiguous assignment of the 1H, 13C, and 195Pt resonances wasobtained from 1H TOCSY, 1H COSY, gradient selected 1H, 13CHSQC, HMQC, andHMBC, and gradient selected 1H, 195Pt HMBC,and 1H NOESY experiments. All 2D NMR experiments wereperformed using standard pulse sequences from the Bruker pulseprogram library. Chemical shifts were relative to TMS for 1H and 13Cand Na2[PtCl6] in D2O for 195Pt. The spectral analyses were per-formed using Bruker TopSpin 2 software. The ESI-MS spectra weremeasured with a Finnigan MAT 900 S, while FAB mass spectra wererecorded on a Finnigan MAT 95. Simulations were obtained usingISOPRO 3.0. Elemental analyses were carried out on a HekatechCHNS EuroEA 3000 analyzer.Crystal Structure. The data collection was performed at T =

173(2) or 293(2) K on a STOE IPDS I diffractometer with Mo KRradiation (λ = 0.71073 A) employing the ω-2θ scan technique. Thestructure was solved by direct methods using the SHELXTL pack-age,22 and refinement was carried out with SHELXL97 employingfull-matrix least-squares methods on F2 18 with Fo

2 g 2σ(Fo2). All non-

hydrogen atoms were treated anisotropically, and hydrogen atomswere included by using appropriate riding models. CCDC 723677[(COD)Pd(Me)(Caf)](SbF6), -723678 [(COD)Pt(Me)(Caf)](SbF6),and -723679 [(COD)Pd(Me)(Ura)] 3 3H2O contain the full crystal-lographic information. These data can be obtained free of charge atwww.ccdc.cam.ac.uk/conts/retrieving.html or from the CambridgeCrystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZUK. Fax: + 44-1223-336-033; e-mail: deposit@ccdc.cam.ac.uk.Cytotoxicity. The antiproliferative effects of the compounds were

determined following an established procedure.21 In short, cells weresuspended in cell culture medium (HT-29: 2850 cells/mL, MCF-7:10 000 cells/mL), and 100 μL aliquots thereof were plated in 96-wellplates and incubated at 37 �C: 5% CO2 for 48 h (HT-29) or 72 h(MCF-7). Stock solutions of the compounds in dimethylformamide(DMF) were freshly prepared and diluted with cell culture medium tothe desired concentrations (final DMF concentration: 0.1% v/v).

The medium in the plates was replaced with medium containingthe compounds in graded concentrations (six replicates). Afterfurther incubation for 72 h (HT-29) or 96 h (MCF-7) the cell biomasswas determined by crystal violet staining, and the IC50 valueswere determined as those concentrations causing 50% inhibition ofcell proliferation. Results were calculated from two independentexperiments.

Materials and Procedures. All reagents were of commercialquality, and all reactions and manipulations were carried out in drysolvents (MBRAUN MB SPS-800, M. Braun Inertgas-SystemeGmbH, Garching) and under an atmosphere of argon. Merck silicagel 60 (230-400 mesh) was used for flash chromatography. [(COD)Pt-(Me)Cl],23 [(COD)Pd(Me)Cl], and 1MeCyt24 were synthesized accord-ing to literature procedures. [(COD)Pt(neop)Cl] was synthesizedfrom [(COD)Pt(neop)2] and acetyl chloride/methanol as describedrecently.25Yield: 78%.Elemental analysis: found (calc for C13H23ClPt)C 38.08 (38.10); H 5.64 (5.66). 1H NMR (acetone-d6): δ 5.47 (m, 2H,2JPtH = 33.3 Hz, H5,6(COD)), 4.53 (m, 2H, 2JPtH = 74.9 Hz, H1,2COD),2.60-2.26 (m, 8HH3,4,7,8COD), 1.72 (s, 2H, 2JPtH= 80.6 Hz, CH2neop),1.07 (s, 9H, 4JPtH = 4.1 Hz, Meneop).

195Pt-1H HMBC (acetone-d6):δ -3523. EI-MS: 410 [M]+, 373 [M - Cl,H]+, 339 [M - neop]+,303 [M - neop,Cl]+, 71 [neop]+, 43 [C3H7]

+.Synthesis of [(COD)Pt(neop)Br]. A solution of 607 mg (1.481

mmol) of [(COD)Pt(neop)Cl] dissolved in 50 mL of acetone wasmixed with 220 mg (2.138 mmol) of NaBr. The mixture was stirredovernight, the resulting NaCl filtered off, and the filtrate evaporatedto dryness. The remaining solid was recrystallized from CH2Cl2,giving 536 mg (1.18 mmol) of a faint yellow microcrystalline material.Yield: 79.7%. Elemental analysis: found (calc for C13H23BrPt) C34.40 (34.37); H 5.14 (5.10). 1H NMR (acetone-d6): δ 5.50 (m, 2H,2JPtH = 34.5 Hz, H5,6COD), 4.62 (m, 2H, 2JPtH = 75.7 Hz, H1,2COD),2.67-2.20 (m, 8H H3,4,7,8COD), 1.90 (s, 2H, 2JPtH = 81.9 Hz,CH2neop), 1.09 (s, 9H, Meneop).

195Pt-1H HMBC (acetone-d6): δ -3580. EI-MS: 454 [M]+.

Synthesis of [(COD)Pd(neop)Br].A 195 mg (8.01 mmol, 1 equiv)amount of magnesium and 1.21 g (8.01 mmol) of neopentyl bromidein diethyl ether were heated to reflux for 2 h to form (neop)MgBr.In a separate flask a suspension of 1.5 g (4.01 mmol, 0.5 equiv) of[(COD)PdBr2] in diethyl ether was prepared and cooled to -78 �C.The solution of (neop)MgBr was slowly added to the precursorsuspension. Then the ice bath was removed and the mixture wasstirred at room temperature for 2 h. The thus formed solids werefiltered off, and 10 mL of water was added slowly to the remainingsolution. After phase separation, the water phase was washed withdiethyl ether and the combined organic solutions were dried overMgSO4. Removal of the solvent gave an off-white crystallinesolid. Yield: 1.01 g (2.76 mmol, 69%). Elemental analysis: found(calc for C13H23BrPd) C 42.70 (42.71); H 6.40 (6.43). 1H NMR(chloroform-d1): δ 5.90 (m, 2H, H5,6COD), 5.23 (m, 2H, H1,2COD),2.67-2.37 (m, 8H, H3,4,7,8COD), 2.40 (s, 2H, CH2neop), 1.11 (s, 9H,Meneop).

13C NMR (acetone-d6): δ 126 (C1,2COD), 104.5 (C5,6COD),44 (CH2neop), 36 (CMe3neop), 33.8 (CCH3neop 31.7 (C3,8COD),28.2 (C,4,7COD).

General Procedure for [(COD)Pd(Me)(L)](SbF6) (L = 1Me-Cyt, Cyt, or Caf). A 150 mg (0.57 mmol, 1 equiv) amount ofprecursor complex [(COD)Pd(Me)Cl] was dissolved in 50 mL ofTHF. Then 196 mg (0.57 mmol, 1 equiv) of Ag(SbF6) was added as asolid, and themixture was stirred for 30min excluding intense light. A5 mL amount of CH2Cl2 was added to the reaction mixture tocomplete precipitation of AgCl, and after 10 min the solid wasremoved by filtration. To the resulting solution was added 1 equivof the (bio)ligand L dissolved in acetone (or methanol in the caseof 1MeCyt), and the mixture was stirred for 90 min. The solventswere removed under vacuum at 0-20 �C, and the residues were

(22) (a) Sheldrick, G. M. SHELXS-97: A Program for CrystalStructure Solving; University of G

::ottingen, 1997. (b) Sheldrick, G. M.

SHELXL-97: A Program for the Refinement of Crystal Structures;University of G

::ottingen, 1997.

(23) R::ulke, R. E.; Ernsting, J. M.; Spek, A. L.; Elsevier, C. J.;

van Leeuwen, P.; Vrieze, K. Inorg. Chem. 1993, 32, 5769.(24) Kistenmacher, T. J.; Rossi, M.; Caradonna, J. P.;Marzilli, L. G.

Adv. Mol. Relax. Interact. Processes 1979, 15, 119.(25) Klein, A.; van Slageren, J.; Z�ali�s, S. J. Organomet. Chem. 2001,

620, 202.

3914 Organometallics, Vol. 28, No. 13, 2009 Butsch et al.

washed with diethyl ether. The resulting products were colorlessmicrocrystals. [(COD)Pd(Me)(1MeCyt)](SbF6): No yield was deter-mined for the obtained mixture of complexes. However, a number ofcrystals could be separated for analytical purposes. 1H NMR (acet-one-d6) δ: 7.71 (d, 1H, H6-1MeCyt), 5.95 (d, 1H, H5-1MeCyt), 5.77 (m,2H, H5,6COD), 5.21 (m, 2H, H1,2COD), 3.42 (s, 3H, HMe-1MeCyt), 2.71-2.42 (m, 8H, H3,4,7,8COD), 1.00 (s, 3H, HMe-Pd). No signal wasobserved for the protons of the NH2-1-MeCyt group. [(COD)Pd(Me)

(Cyt)](SbF6): Yield: 200 mg (0.41 mmol, 80%). Elemental analysis:found (calc. for C13H20N3O1Pd1Sb1F6) C 26.98 (27.09); H 3.49 (3.50);N 7.29 (7.29). 1H NMR (methanol-d4) the two isomers N3 and N1(ratio: 6:4) were assigned in analogy with the Pt derivative; δ 7.54(d, 1H, H6Cyt,N3), 7.49 (d, 1H, H6Cyt,N1), 5.97 (d, 1H, H5Cyt,N3), 5.94(d, 1H, H5Cyt,N1), for all other signals no discrimination betweenN3 and N1 isomers was possible: 5.73 (m, 2H, H5,6COD), 5.42 (m, 2H,H1,2COD), 2.81-2.50 (m, 8H, H3,4,7,8COD), 0.99 (s, 3H, HMe-Pd). Nosignals were observed for the protons of theNH2Cyt groups. [(COD)Pd-(Me)(Caf)](SbF6): Yield: 43%. Elemental analysis: found (calc forC17H25N4O2Pd1Sb1F6) C 30.90 (30.96); H 3.79 (3.83); N 8.40 (8.49).1H NMR (acetone-d6): δ 8.55 (s, 1H, H8Caf), 5.88 (m, 2H, H5,6COD),5.68 (m, 2H, H1,2COD), 4.11 (s, 3H, H7Caf), 3.94 (s, 3H, H3Caf),3.31 (s, 3H, H1Caf), 2.82 (m, 4H, H3,4COD), 2.65 (m, 4H, H7,8COD),1.12 (s, 3H, HMe-Pd).General Procedure for [(COD)Pt(Me)(L)](SbF6) (L = Caf or

1MeCyt). A solution of 102 mg (0.29 mmol, 1 equiv) of [(COD)Pt-(Me)Cl] in 20 mL of acetone was mixed with 101 mg (0.29 mmol, 1equiv) of Ag(SbF6) dissolved in 7 mL of acetone. AgCl immediatelyprecipitated, yielding an opaque solution. Stirring was continued for10min, and thenAgCl was filtered off. The filtrate was combined witha solution of the (bio)ligand L (0.29 mmol, 1 equiv) in 10 mL ofacetone and stirred for 30min, and then the solvent was removed at 50�C, leaving an off-white material, which was recrystallized fromacetone. [(COD)Pt(Me)(Caf)](SbF6): Yield: 60%. Elemental analysis:found (calc for C17H25N4O2Pt1Sb1F6) C 25.23 (27.29); H 3.27 (3.37);N 7.62 (7.49). 1H NMR (acetone-d6): δ 8.72 (s, 1H, H8Caf), 5.59(m, 2H, 2JPtH = 29.6 Hz, H5,6COD), 5.34 (m, 2H, 2JPtH = 77.8 Hz,H1,2COD), 4.14 (s, 3H, HMe-N7Caf), 4.07 (s, 3H, HMe-N3Caf), 3.33 (s, 3H,HMe-N1Caf), 2.80-2.48 (m, 8H, H3,4,7,8COD), 0.86 (s, 3H, 2JPtH = 70.0Hz, HMe-Pt).

195Pt-1H HMBC (acetone-d6): δ -3010. [(COD)Pt(Me)-(1MeCyt)](SbF6): Yield: 91%. Elemental analysis: found (calc forC14H22N3O1Pt1Sb1F6) C 24.78 (24.76); H 3.29 (3.27); N 6.19 (6.19).1H NMR (acetone-d6): δ 8.01, 7.29 (each s, 1H, HNH2-1-MeCyt),7.90-7.88 (d, 1H, H6-1MeCyt), 6.18-6.15 (d, 1H, H5-1MeCyt,2JPtH = 28 Hz), 5.56 (s, 2H, H1,2COD,

2JPtH = 31 Hz), 5.01 (s, 2H,H5,6COD,

2JPtH = 76 Hz), 3.47 (s, 3H, H1-1MeCyt), 2.70-2.39 (m, 8H,H3,4,7,8COD), 0.76 (s, 3H, HMe-Pt,

2JPtH = 72 Hz). 195Pt-1H HMBC(acetone-d6): δ -3596.General Procedure for [(COD)M(Me)(1MeUra)] (M = Pt or

Pd). A solution of the precursor complex [(COD)M(Me)Cl](0.5 mmol) in 25 mL of methanol was mixed with 93 mg (0.55 mmol)of AgNO3 dissolved in 10 mL of methanol. AgCl immediatelyprecipitated, yielding an opaque solution. Stirring was continuedfor 30 min, and AgCl was filtered off. The filtrate was added toa solution of 69 mg (0.55 mmol) of 1-methyluracile and 62 mg(0.55 mmol) of KOtBu in 20 mL of methanol, stirred for 30 min,and evaporated. The residues were dissolved in CH2Cl2, KNO3 wasremoved by filtration, and the off-white products were obtained byslow crystallization. [(COD)Pt(Me)(1MeUra)]: Yield: 77%. Elemen-tal analysis: found (calc for C14H20N2O2Pt1) C 37.98 (37.92); H 4.49(4.55); N 6.38 (6.32). 1H NMR (acetone-d6): δ 7.33 (d, 1H, 3JH5H6 =7.4 Hz, H6-1MeUra), 5.40 (d, 1H, H5-1MeUra), 5.38 (m, 2H, 2JPtH =36.5 Hz, H5,6COD), 4.57 (m, 2H, 2JPtH = 71.0 Hz, H1,2COD), 3.27(s, 3H, HMe-1MeUra), 2.6-2.2 (m, 8H, H3,4,7,8COD), 0.65 (s, 2JPtH =74.0 Hz, HMe-Pt).

195Pt-1H HMBC (acetone-d6): δ-3436. 13C NMR(acetone-d6): δ 169 (C4-1MeU), 155 (C2-1MeUra), 143 (C6-1MeUra), 108(1JPtC = 41.6 Hz, C1,2COD), 102 (1JPtC = 30.0 Hz, C5-1MeUra),85 (C5,6COD), 35 (CMe-1MeUra), 30-28 (C3,4,7,8COD), 0 (CMe-Pt).[(COD)Pd(Me)(1MeUra)]: Yield: 32%. Elemental analysis: found(calc for C14H20N2O2Pd1) C 47.48 (47.40); H 5.49 (5.68); N 7.79(7.90). 1HNMR (acetone-d6): δ 7.05 (d, 1H, H6-1MeUra), 5.77 (m, 2H,

H5,6COD), 5.64 (d, 1H,H5-1MeUra), 5.22 (m, 2H, H1,2COD), 3.34 (s, 3H,HMe-1MeUra), 2.80-2.37 (m, 8H, H3,4,7,8COD), 0.96 (s, 3H, HMe-Pd).

Synthesis of [(COD)Pt(Me)(Ura)]. A solution of the precursorcomplex [(COD)Pt(Me)Cl] (127 mg, 0.5 mmol) in 25 mL of methanolwas mixed with 90 mg (0.53 mmol) of AgNO3 dissolved in 10 mL ofmethanol. AgCl immediately precipitated, yielding an opaque solu-tion, which was stirred for 30 min, and then the AgCl was filtered off.The filtrate was added to a solution of 62 mg of uracil (0.55 mmol)and 63 mg of KOtBu (0.56 mmol) in 20 mL of methanol, stirred for 30min, and evaporated to dryness. The residue was suspended inCH2Cl2, KNO3 was removed by filtration, and the filtrate wasevaporated to dryness, leaving an off-white powder, which wasrecrystallized several times from CH2Cl2. Yield: 75% Elementalanalysis: found (calc for C13H18N2O2Pt1) C 36.48 (36.36); H 4.29(4.23); N 6.49 (6.52). 1HNMR (methanol-d4): δ 7.34 (d, 1H, 3JH5H6=7.5 Hz, H6-Ura), 5.62 (d, 1H, H5-Ura), 5.34 (m, 2H, 2JPtH = 39.6 Hz,H5,6COD), 4.70 (m, 2H, 2JPtH = 74.4 Hz, H1,2COD), 2.7-2.2 (m, 8H,H3,4,7,8COD), 0.68 (s, 2JPtH = 74.0 Hz, HMe-Pt).

195Pt-1H HMBC(methanol-d4): δ -3346.

Synthesis of [{(COD)Pt(Me)}2(Cyt)](SbF6). A 100 mL flaskwas chargedwith 230mg (0.65mmol) of [(COD)Pt(Me)Cl] and 20mLof methanol. On addition of 223 mg (0.65 mmol) of Ag(SbF6)dissolved in methanol a precipitate of AgCl was formed and filteredoff, after 15 min of stirring. The filtrate was added to a flask, in which36 mg (0.325 mmol) of cytosine, dissolved in methanol, was depro-tonated using 36.5 mg (0.325 mmol) of KOtBu. After 30 min stirring,all volatiles were removed under reduced pressure. The product wasobtained as a white solid from recrystallization from acetone/n-heptane (5:1). Yield: 33%. Elemental analysis: found (calc forC22H34N3O1Pt2Sb1F6) C 28.17 (26.90); H 3.72 (3.49); N 4.21 (4.28).1H NMR (acetone-d6): cytosine ligand, δ 7.72 (d, 1H, 3JH5H6COD =6.6 Hz, 3JPtH = 48 Hz, H6Cyt), 6.95 (m, 2H, HNH2Cyt), 6.04 (d, 1H,4JPtH = 27 Hz, H5Cyt); N1 bound [(COD)Pt(Me)], δ: 5.50 (m, 2H,2JPtH = 31 Hz. H5,6COD), 4.87 (m, 2H, 2JPtH = 74 Hz, H1,2COD),2.73-2.36 (m, 8H, H3,4,7,8COD), 0.72 (s, 3H, 2JPtH = 72 Hz, HMe-Pt);N3 bound [(COD)Pt(Me)]: δ 5.50 (m, 2H, 2JPtH = 31 Hz. H5,6COD),4.90 (m, 2H, 2JPtH = 70 Hz, H1,2COD), 2.73-2.36 (m, 8H,H3,4,7,8COD), 0.73 (s, 3H, 2JPtH = 70 Hz, HMe-Pt).

195Pt-1H HMBC(acetone-d6): δ -3556 (PtonN3Cyt), -3549 (Pt1onN1Cyt).

Synthesis of [(COD)Pt(neop)(Caf)](SbF6).A solution of 147mg(0.36 mmol) of [(COD)Pt(neop)Cl] dissolved in 30 mL of acetone wasmixed with 135 mg (0.392 mmol) of AgSbF6 dissolved in 10 mL ofacetone. After stirring the mixture for 10 min, the resulting AgCl wasfiltered off and the filtrate was admixed to a solution of 76 mg(0.392 mmol) of caffeine dissolved in 10 mL of acetone. The reactionmixture was stirred for 45 min, and then all volatiles were removedunder vacuum. The remaining grayish solid was recrystallized fromCH2Cl2/n-heptane (10:1), giving 232 mg (0.288 mmol, 80%) of acolorless microcrystalline material. Elemental analysis: found (calcfor C21H33N4O2Pt1Sb1F6) C 31.90 (31.36); H 4.30 (4.14); N 6.83(6.97). 1H NMR (acetone-d6): δ 8.95 (q, 1H, 4JHH = 0.6 Hz, 2JPtH =16Hz,H8Caf), 5.69 (m, 1H, 2JPtH= 34Hz, H6COD), 5.59 (m, 1H, 2JPtH= 32 Hz, H5COD), 5.39 (m, 1H, 2JPtH = 74 Hz, H2COD), 5.31 (m, 1H,2JPtH = 72 Hz, H1COD), 4.17 (d, 3H, H7Caf), 4.13 (s, 3H, H3Caf),3.33 (s, 3H, H1Caf), 2.81 (m, 2H, H8COD), 2.74 (m, 2H, H3COD), 2.58(m, 2H, H4COD), 2.53 (m, 2H, H7COD), 1.89 (d, 1H, 2JHH = 10 Hz,2JPtH = 65 Hz, CH2neop), 1.72 (d, 1H, 2JHH = 10 Hz, 2JPtH = 82 Hz,CH2neop), 0.84 (s, 9H, Meneop),

13C NMR (acetone-d6): δ 154 (C4Caf),151 (C2Caf), 145 (C6Caf), 141 (C8Caf), 118 (C6COD), 114 (C5COD), 108(C5Caf), 95 (C2COD), 90 (C1COD), 37 (CH2neop), 35 (CMe3neop),34.5 (C7Caf), 32.7 (C3Caf), 32 (CCH3neop), 31 (C8COD), 30 (C3COD),28 (C4COD), 27 (C7COD), 27.3 (C1Caf),

195Pt-1H HMBC (acetone-d6):δ -3605.

Synthesis of [Pd(Me)(1MeCyt)3](SbF6). To a 150 mg(0.57 mmol) amount of [(COD)Pd(Me)Cl] dissolved in 50 mL ofMeOH was added 196 mg (0.57 mmol) of Ag(SbF6), and the mixturewas stirred for 30 min, excluding intense light. A 5 mL amountof CH2Cl2 was added to the reaction mixture to complete precipita-tion of AgCl. After 10 min the solid was removed by filtration.To the resulting solution was added 285 mg (2.28 mmol, 4 equiv)

Article Organometallics, Vol. 28, No. 13, 2009 3915

of 1MeCyt in methanol. After stirring the reaction mixture for90 min, the solvents were removed under vacuum at 0-20 �C andthe residue was recrystallized from acetone. The resulting product wasa colorless powder. Yield: 94% (392 mg, 0.54 mmol). Elementalanalysis: found (calc for C16H24N9O3Pd1Sb1F6) C 26.20 (26.23);H 3.27 (3.30); N 17.09 (17.21). 1H NMR (DMF-d7): δ 7.85 (d, 1H,H6,trans), 7.65 (d, 2H, H6-1MeCyt,cis), 6.03 (d, 1H, H5-1MeCyt,trans),5.79 (d, 2H, H5-1MeCyt,cis), 3.43 (s, 3H, HMe-1MeCyt,trans), 3.30 (s, 6H,HMe-1MeCyt,cis), 0.16 (s, 3H, HPd-Me).Synthesis of [Pd(Caf)2(neop)(acetone)](SbF6). To a 150 mg

(0.41 mmol) amount of [(COD)Pd(neop)Br] dissolved in 20 mL ofTHF was added 141 mg (0.41 mmol) of AgSbF6, and the reactionmixture was stirred for a few minutes, before the precipitate wasfiltered off and the remaining solution was mixed with a solution of76 mg (0.39 mmol) of caffeine in 5 mL of THF. The reaction mixturewas stirred for 2.5 h, and the thus formed solid was isolated byfiltration. The crude product was recrystallized from acetone/n-heptane at-25 �C to yield 62 mg (0.07 mmol) or 36% of a colorlesssolid. Elemental analysis: found (calc for C24H37N8O5Pd1Sb1F6)C 33.51 (33.53); H 4.44 (4.34); N 13.03 (13.03). 1H NMR (acetone-d6): δ 8.87 (s, 2H, H8Caf), 4.51 (s, 6H, H7Caf), 4.12 (d, 6H, H3Caf,4JH2,H1 = 0.6 Hz), 3.30 (s, 6H, H1Caf), 2.35 (s, 2H, CH2neop), 2.09(s, 6H, Hacetone), 0.82 (s, 9H, Meneop).Synthesis of [Pd(neop)(4-Pic)3](SbF6). To a 150 mg (0.41 mmol)

amount of [(COD)Pd(neop)Br] dissolved in 20 mL of THF wasadded 141 mg (0.41 mmol) of Ag(SbF6), and the mixture was stirredfor 30 min excluding intense light. After removing the solid AgClby filtration, to the resulting solution was added 36 mg (0.39 mmol,0.38 mL) of 4-picoline. After stirring the reaction mixture for45 min all volatiles were removed under vacuum and the residual

oily solid was washed with several portions of n-pentane andsubsequently recrystallized from CH2Cl2, yielding a faint yellowmicrocrystalline material. Yield: 26% (74 mg, 0.11 mmol). Elemen-tal analysis: found (calc for C23H32N3Pd1Sb1F6) C 40.01 (39.88);H 4.61 (4.66); N 6.04 (6.07). 1H NMR (acetone-d6): δ 8.87 (m, 4H,H2,6Pic-cis), 8.60 (m, 2H, H2,6Pic-trans), 7.42 (m, 4H, H3,5Pic-cis),7.26 (m, 2H, H3,5Pic-trans) 2.42 (s, 6H, MePic-cis), 2.31 (s, 3H,MePic-trans), 1.87 (s, 2H, CH2neop), 0.77 (s, 9H, Meneop). Fromthe combined n-pentane filtrates 92 mg (0.25 mmol) of [(COD)Pd-(neop)Br] was isolated.

Acknowledgment. We gratefully acknowledge JohnsonMatthey PLC for a loan of K2PtCl4 and K2PdCl4. Wealso thank Dr. Ingo Pantenburg and Ms. Ingrid M

::uller

(University of Cologne) for crystal data collection.

Supporting Information Available: NMR titration spectra of1-methylcytosine (1MeCyt) added to [(COD)Pd(Me)(Solv)]+ inmethanol-d4, the ESI-MS peak pattern of [Pd(Me)(Caf)2]

+,together with a simulation and a 1H NOESY spectrum of[(COD)Pt(neop)(Caf)]+ in acetone-d6 are provided. Further-more, detailed XRD data for [(COD)Pd(Me)(Caf)](SbF6),[(COD)Pt(Me)(Caf)](SbF6), and [(COD)Pt(Me)(1MeUra)] 3 3H2O together with figures representing the molecule packingin the unit cell and the molecular structure of [(COD)Pt(Me)-(Caf)](SbF6) are given. Also, crystal data of [Pd(Caf)2](SbF6), afragment of [Pd(Me)(Caf)2(acetone)](SbF6), are summarized.This material is available free of charge via the Internet athttp://pubs.acs.org.