Purines bearing phenanthroline or bipyridine ligands and their RuII complexes in position 8 as model compounds for electrochemical DNA labeling - Synthesis, crystal structure, electrochemistry, quantum chemical calculations, cytostatic and antiviral activity

FULL PAPER

DOI: 10.1002/ejic.200700030

Purines Bearing Phenanthroline or Bipyridine Ligands and Their Ru^II

Complexes in Position 8 as Model Compounds for Electrochemical DNA

Labeling – Synthesis, Crystal Structure, Electrochemistry, Quantum Chemical

Calculations, Cytostatic and Antiviral Activity

[a]

[b]

[a]

ˇ

Milan Vrábel, Michal Hocek,* Ludek Havran, Miroslav Fojta,* Ivan Votruba,

[a]

[c]

ˇ

Blanka Klepetárová, Radek Pohl, Lubomír Rulísek, Lucie Zendlová, Pavel Hobza,

I-hung Shih,^[d]Eric Mabery,^[d]and Richard Mackman^[d]

Keywords: Purines / Nucleobases / Bipyridines / Phenanthrolines / Ru complexes / Electrochemistry

A series of ethynyl- or (4-boronophenyl)bipyridines and

-phenanthrolines were prepared as versatile building blocks

for attachment of bidentate N-ligands to other molecules via

cross-coupling reactions. Their complexation with Ru(bpy)₂-

Cl₂gave the corresponding Ru^IIcomplexes. 9-Benzyladenine

acids. The crystal structures of two Ru complexes were deter-

mined by X-ray diffraction. The electrochemistry of the

model purines bearing the phenanthroline or bipyridine li-

gands and the Ru complexes was studied by means of cyclic

or square-wave voltammetry with carbon paste and mercury

derivatives bearing the bipyridine or phenanthroline com- electrodes. The experimental redox potentials of the title

plexes in position 8, attached via a conjugate acetylene or

phenylene linker were prepared by cross-coupling reactions

of the ethynyl- or 4-boronophenylbipyridines and -phenan-

throlines with 9-benzyl-8-bromoadenine. Their complexation

with Ru(bpy)₂Cl₂afforded the corresponding Ru complexes

as model compounds for electrochemical DNA labeling. The

same compounds were also prepared directly by cross-

coupling of 9-benzyl-8-bromoadenine with Ru complexes of

compounds were compared with quantum chemical calcula-

tions. A very good agreement between experiment and

theory was obtained, with a standard deviation of 0.13 V. It

was shown that theoretical calculations can be of a limited

predictive power for new Ru^IIcomplexes, though it was diffi-

cult to reproduce differences smaller than 0.05 V. Several

compounds of this series exhibited a considerable cytostatic

effect and activity against the hepatitis C virus (HCV).

the alkynes and boronic acids. Both approaches are com- (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,

pared in terms of potential applications for labeling of nucleic

Germany, 2007)

gene expression, etc. DNA damage and interaction of DNA

with different toxic or biologically active species can also be

detected by DNA sensors. In addition to optical methods

involved in most of the commercially available systems, elec-

trochemical detection has attracted attention as a less ex-

pensive alternative offering comparable sensitivity.

Nucleic acids are electroactive species producing analyti-

cally useful oxidation and reduction signals at mercury or

solid electrodes.^[2,3]In addition to label-free DNA detec-

tion, different electroactive (or enzyme) tags tethered to tar-

get DNAs or hybridization probes are used to improve sen-

sitivity and/or specificity of the analysis.^[3]For example,

Introduction

DNA biosensors and chips^[1]are increasingly utilized in

current molecular biology, biochemistry, biomedicine and

related disciplines. On the basis of DNA hybridization,

these devices are used to analyze nucleotide sequences of

DNAs or RNAs, searching for mutations, monitoring of

[a] Gilead & IOCB Research Center, Institute of Organic Chemis-

try and Biochemistry, v. v. i., Academy of Sciences of the Czech

Republic,

Flemingovo nám. 2, 16610 Prague 6, Czech Republic

Fax: +420-220183559

E-Mail: hocek@uochb.cas.cz

[b] Institute of Biophysics, v. v. i., Academy of Sciences of the ferrocene-labeled oligonucleotides (ON) were used as re-

porter (signaling) probes^[4]or as an electrochemical variant

Czech Republic,

Královopolská 135, 61265 Brno, Czech Republic

E-Mail: fojta@ibp.cz

of a “molecular beacon.”^[5]Osmium tetroxide complexes re-

[c] Center for Complex Molecular Systems and Biomolecules, In-

stitute of Organic Chemistry and Biochemistry, Academy of

Sciences of the Czech Republic,

acting selectively with thymine residues were applied in re-

cently proposed double-surface (biomagnetic) electrochemi-

cal DNA hybridization techniques.^[3,6]In analogy with the

multicolor optical coding, combination of electrochemical

tags yielding different signals makes it possible to detect

several target DNA sequences in parallel.^[7]

Flemingovo nám. 2, 16610 Prague 6, Czech Republic

[d] Gilead Sciences, Inc.,

333 Lakeside Drive, Foster City, CA 94404, USA

Supporting information for this article is available on the

WWW under http://ww w .eurjic.org or from the author.

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Ru-Labelled Purines

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Complexes of transition metals, for instance ferrocene,^[8]needed the acetylene and boronic acid derivatives of the

or complexes of bidentate N-ligands^[9](in particular phen- bidentate N-ligands.

anthrolines and bipyridines) with transition metals (Ru, Rh,

Synthesis of Ligand Building Blocks

Ni, Cu, Co, Pt, Pd, Os etc.) possess unique electrochemical

1,10-Phenanthroline (phen), 2,2Ј-bipyridine (bpy), and

2,2Ј:6Ј,2"-terpyridine (tpy) are the most commonly used

polypyridine ligands in the chemistry of coordinating com-

pounds^[15]and are often used as building blocks for the

construction of molecular and supramolecular devices.^[16]

Cross-coupling reactions are the most versatile tools for

construction of molecules containing these ligands con-

nected via conjugate (and thus charge conducting) acetyl-

ene or phenylene linkers. However, the chemistry of the cor-

responding synthetic equivalents for cross-coupling reac-

tions, i.e. boronic acids and acetylene derivatives of oligopy-

ridine ligands, is still underdeveloped and rather difficult.

Therefore our first task was to prepare a series of such rea-

gents (some of them were hitherto unknown compounds)

not only by application but also by modification and opti-

mization of known methods.

Common starting compounds in the synthesis of the

building blocks were halogenated phenanthrolines and bi-

pyridines 1. 2-Chloro-1,10-phenanthroline (1a) was pre-

pared^[17]in four steps from the commercially available

phenanthroline monohydrate. The Sonogashira cross-

coupling reaction of 1a with (trimethylsilyl)acetylene and

subsequent deprotection of the TMS group by treatment

with KF in MeOH/THF mixture, led to the desired new 2-

ethynyl-1,10-phenanthroline (2a) (Scheme 1). Known 6-

(ethynyl)-2,2Ј-bipyridine (2b) and 5-(ethynyl)-2,2Ј-bipyri-

dine (2c) were prepared by analogous literature pro-

cedures^[18]from 6-bromo-2,2Ј-bipyridine (1b) and 5-bromo-

2,2Ј-bipyridine (1c), respectively (Scheme 1, Table 1).

and photophysical properties. Some of the phenanthroline

complexes, which are also efficient DNA intercallators, have

been extensively used as luminescent and electroactive

DNA labels.^[10]Attachment of probes based on metal com-

plexes directly to a nucleobase via conjugate linkers should

increase the efficiency of the charge transfer and thus en-

hance sensitivity. There are many examples of such probes

connected to pyrimidine nucleobases. 5-(Ferrocenylethyn-

yl)pyrimidine nucleosides were synthesized by Sonogashira

coupling of 5-iodopyrimidines with ethynylferrocene and

incorporated into DNA as electroactive redox markers.^[11]

Covalently bound conjugates of pyrimidine nucleotides and

phenanthroline complexes of Ru and Os have been

studied^[12]as fluorescence probes for DNA hybridization

and charge transfer through DNA. However, there are very

few reports of probes conjugated to purines, presumably

due to the greater difficulty in preparation and incorpora-

tion. Recently, we have reported^[13]on the synthesis of

model 9-benzyl-8-(ferrocenylethynyl)adenine by cross-

coupling of ethynylferrocene with 8-bromoadenine. Prelimi-

nary electrochemical and quantum chemical studies showed

that even small electronic changes are effectively transferred

through the conjugated system and are electrochemically

detectable. Moreover, these effects could be reliably calcu-

lated and predicted using ab initio calculations. However,

the corresponding protected phosphoramidite of 8-(ferro-

cenylethynyl)-2Ј-deoxyadenosine was not efficiently incor-

porated to oligonucleotides^[14]presumably due to oxidation

of ferrocene followed by nucleophilic displacement. There-

fore, our next probes of choice for labeling purines are com-

plexes (Ru and Os) of bipyridine and phenanthroline. Here

we describe the synthesis of model adenine derivatives by

two different approaches and the study of their electro-

chemical properties in order to verify applicability of such

complexes as probes for labeling nucleic acids. We were also

interested in the biological activity of these novel types of

adenine derivatives and metal complex conjugates.

Scheme 1. Synthesis of the ligands: i) 1. [Pd(PPh₃)₂Cl₂] (5–10 mol-

%), CuI (10 mol-%), TMSA (2.2 equiv.), Et₃N (3.2 equiv.), DMF

or THF, 60–70 °C; 2. MeOH/THF KF (2 equiv.).

Results and Discussion

Synthesis

Table 1. Synthesis of the ethynyl ligands 2.

Two different approaches to the synthesis of target 9-

benzyladenines bearing phenanthroline complexes Ru^IIand

Os^IIin position 8 have been designed and verified in terms

of their efficiency, practicability, and compatibility with

rather labile nucleic acids. The first one consisted of cross-

coupling of 8-bromoadenine with ethynyl- or (4-borono-

Entry

R-hal

Product

Yield [%]

1

2

3

1a

1b

1c

2a

2b

2c

60

82

83

(4-Bromophenyl)bipyridines, -phenanthroline and -terpy-

phenyl)-2,2Ј-bipyridines or -phenanthrolines followed by ridine 3a–3d were the key intermediates for the synthesis of

complexation of the resulting purine-ligand conjugates with the corresponding boronates 4a–4d. 2-(4-Bromophenyl)-

a metal. The second approach was based on direct cross- phenanthroline (3a) was prepared in 69% yield by a

coupling of 8-bromoadenine with preformed Ru complexes known^[19]procedure involving addition of 4-bromophen-

of the ligand building blocks. For both approaches we yllithium to phenanthroline monohydrate followed by oxi-

Eur. J. Inorg. Chem. 2007, 1752–1769

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M. Hocek, M. Fojta et al.

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dation with MnO₂. The Suzuki cross-coupling reactions of refluxing the mixture for several hours under an inert atmo-

6-bromo-2,2Ј-bipyridine or 5-bromo-2,2Ј-bipyridine with 4- sphere, afforded the desired products 5 and 6 in poor yields

bromophenylboronic acid afforded the p-bromophenylene- (12–30%) accompanied by some byproducts. When ethyl-

substituted bipyridines 3b and 3c (compound 3c was re- ene glycol was used as the solvent,^[27]the yields were im-

ported earlier via heterocyclizations^[20]). 4Ј-(p-Bromo- proved up to 66% (Scheme 3, Table 3) and the amounts of

phenyl)-2,2Ј:6Ј,2"-terpyridine 3d was prepared by a known byproducts significantly decreased. A typical procedure in-

multistep procedure^[21]from 2-acetylpyridine and 4-bro- volved a suspension of the starting compounds in ethylene

mobenzaldehyde. All these bromo derivatives 3a–3d were glycol heating the mixture at 150 °C for 2 h, distillation of

subjected to cross-coupling reactions with bis(pinacolato)- the solvent and anion exchange precipitation from aqueous

diboron^[22]in the presence of Pd(dppf)Cl₂and KOAc in di- solution by treatment with NH₄PF₆. The solid was further

oxane at 80 °C to give the series of pinacol boronates 4a– purified on a silica gel column using a mixture of acetoni-

4d in good yields of 60–91% (Scheme 2, Table 2). Com- trile, water, and saturated KNO₃as the eluent. However,

pounds 4a and 4b were new, while known compounds 4c^[23]during this separation, partial anion exchange occurred and

and 4d^[21a]were prepared by this method in much higher therefore it was crucial to re-precipitate the final product

yields (91 and 81%, respectively) than alternative methods once again from its aqueous solution by treatment with

reported in the literature (30 and 42%, respectively).

NH₄PF₆. Only after this procedure and final re-crystalli-

zation were pure samples of hexafluorophosphate salts 5b–

5c and 6a–6c isolated. In the case of terpyridine derivative

4d, Ru(tpy)Cl₃complex^[28]was used as the complexation

agent under the same conditions as described above to yield

the complex 6d. It should be mentioned that all the pinacol

esters of boronate ligands 4a–4d were cleaved simulta-

neously during the complexation to afford free boronic ac-

ids 6a–6d.

Scheme 2. Synthesis of the ligands: i) bis(pinacolatodiboron)

(1.2 equiv.), [Pd(dppf)Cl₂] (5 mol-%), KOAc (1.5 equiv.), dioxane,

80 °C.

Table 2. Synthesis of the phenylene-bridged ligands.

Entry

Bromo derivative Product

Yield [%]

1

2

3

4

3a

3b

3c

3d

4a

4b

4c

4d

60

86

91

81

Synthesis of Ru Complex-Containing Building Blocks

Among many transition metals used in coordination

chemistry of bipyridine-type ligands, Ru^IIcomplexes are

one of the most popular due to their chemical stability and

favorable redox and photophysical properties.^[24]Surpris-

ingly, acetylene or boronic acid building blocks containing

the Ru^IIcomplexes, ready for a single-step attachment to

any aromatic skeleton by cross-coupling reactions, are vir-

Scheme 3. Complexation reactions: i) 1. ethylene glycol, 150 °C,

2 h; 2. saturated aqueous solution of NH₄PF₆.

Table 3. Complexations of the ligands 2 and 4.

tually unknown with the exception of (3- and 4-ethynyl-

Entry

Ligand

Complex

Yield [%]^[a]

– [25]

1,10-phenanthroline)Ru²⁺(bipy)₂·2PF₆.

We have pre-

1

2

3

4

5

6

2b

2c

4a

4b

4c

4d

5b

5c

6a

6b

6c

6d

49

32

66

47

42

69

pared the whole series of Ru^IIcomplexes of the ligands 2b–

2c and 4a–4d.

Commercially available Ru(bpy)₂Cl₂·2H₂O was the com-

pound of choice for the complexation reactions. Its com-

plexation with ligands 2 and 4a–4c under standard condi-

tions,^[26]e.g. mixing of the reagents in MeOH or EtOH and [a] Yields after crystallization.

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Ru-Labelled Purines

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Synthesis of Adenine–Ligand Conjugates

catalysts by the oligopyridine moiety and by some loss dur-

ing the silica gel chromatography of the quite polar sub-

strates.

Cross-coupling reactions are often used for introduction

of C-substituents to position 8 of purines.^[29]The Suzuki–

Miyaura reactions with arylboronic acids are usually

used^[30]for attachment of an aryl group while the Sonoga-

shira reactions with terminal acetylenes are used^[13,31]for

alkynyl groups. Therefore, these reactions were our methods

of choice for the synthesis of the conjugates of adenine with

oligopyridine-type ligands connected via acetylene or phen-

ylene bridges.

The Sonogashira cross coupling reactions of 9-benzyl-8-

bromoadenine (7) with the terminal alkynes 2a–2c in the

presence of [Pd(dppf)Cl₂], CuI, and Et₃N in DMF at 90 °C

afforded the corresponding acetylene-bridged conjugates

8a–8c in the yields of ca. 55% after crystallization

(Scheme 4, Table 4). The Suzuki–Miyaura cross coupling

reaction of bromoadenine 7 with pinacol boronates 4a–4d

gave the phenylene-linked conjugates 9a–9d (Scheme 4) in

ca. 50% yield. All the cross-coupling reactions proceeded

very well and quite cleanly. Their moderate isolated yields

may have been caused by partial complexation of the Pd-

Synthesis of Adenine–Complex Conjugates by

Complexation

One of the approaches to the desired title model conju-

gates of adenine and Ru^IIcomplexes is the complexation of

the adenine-ligand conjugates 8 and 9 (Scheme 5, Table 5).

The complexation reactions with either Ru(bpy)₂-

Cl₂·2H₂O or the Ru(tpy)Cl₃complex were performed in

ethylene glycol in analogy to the synthesis of the building

blocks 5 and 6. Once again problems were encountered with

anion exchange during chromatography and the desired

Ru^IIcomplexes 10a–10c and 11a–11d could only be isolated

in good yields of 65–81% after re-precipitation and re-

crystallization (Table 5). There was no significant difference

in the rate and yield of complexation between the less steri-

cally hindered 5-substituted bipyridines 8c,9c and the more

hindered 6-substituted bipyridines 8b,9b.

Scheme 4. Synthesis of the conjugates: i) [Pd(dppf)Cl₂] (5 mol-%),

CuI (5 mol%), Et₃N (8 equiv.), DMF, 90 °C; ii) [Pd(dppf)Cl₂]

(5 mol-%), K₂CO₃(4 equiv.), DMF, 90 °C.

Scheme 5. Complexations of the conjugates: i) 1. ethylene glycol,

150 °C, 2 h; 2. saturated aqueous solution of NH₄PF₆.

Table 4. Synthesis of the conjugates.

Entry

Ligand

Conjugate

Yield [%]^[a]

1

2

3

4

5

6

7

2a

2b

2c

4a

4b

4c

4d

8a

8b

8c

9a

9b

9c

9d

55

58

56

47

53

52

46

In order to compare the chemical and electrochemical

properties of the Ru^IIcomplexes with the corresponding

Os^IIwe have prepared the Os complex 12b (Scheme 6),

[32]

using the complexation of 8b with Os(bipy)₂Cl₂

under

the same conditions as for Ru complexes. In this case the

[a] Yields after crystallization.

Os complex 12b was obtained in good yield of 74%.

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M. Hocek, M. Fojta et al.

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Table 5. Complexation of conjugates.

Entry

Conjugate

Complex

Yield [%]

1

2

3

4

5

6

7

8a

8b

8c

9a

9b

9c

9d

10a

10b

10c

11a

11b

11c

11d

69

80

75

72

74

81

65

Scheme 7. Cross coupling reactions with complexes. i) [Pd(OAc)₂]

(10 mol-%), P(Ph-SO₃Na)₃(50 mol-%), Cs₂CO₃(3 equiv.),

CH₃CN/H₂O (1:1).

Table 6. Cross coupling reactions with Ru complexes.

Entry

Ru complex

Product

Yield [%]

1

2

3

4

6a

6b

6c

6d

11a

11b

11c

11d

40

24

53

63

Crystal Structures

Complexes 5b and 10b gave monocrystals suitable for X-

ray diffraction. However, the crystals of 10b diffracted

rather poorly, which resulted in weak reflections. Conse-

Scheme 6. Synthesis of the Os^IIcomplex: i) 1. ethylene glycol, quently, the precision of the structure determination is not

150 °C, 2 h; 2. saturated aqueous solution of NH₄PF₆.

excellent, but it still describes reasonably well all the main

structural features of this Ru complex. The structures of

complexes 5b and 10b are depicted in Figure 1.

Synthesis of Adenine–Complex Conjugates by Direct Cross-

Coupling

The second approach to the title conjugates 10 and 11

was based on direct cross-coupling reactions of 7 with Ru

complex containing building blocks 5 and 6. At first we

tried to apply the same cross-coupling conditions utilized

in the synthesis of ligand conjugates 8 and 9 (reactions in

DMF, Pd(dppf)Cl₂as catalyst and CuI, Et₃N for the ter-

minal alkynes and K₂CO₃for the boronic acids). Unfortu-

nately, none of these reactions proceeded and partial de-

composition of the starting materials was observed under

prolonged reaction times. Therefore, we tried to apply the

aqueous-phase cross-coupling reactions that have been re-

cently successfully used in the attachment of aryl groups^[33]

including hydrophilic amino acid residues^[34]to the 8-

position of purine nucleosides. The cross-coupling reactions

of 7 with boronic acids 6a–6d using Pd(OAc)₂as the cata-

lyst, water soluble P(Ph–SO₃Na)₃ligand and Cs₂CO₃as a

base in a mixture of acetonitrile/water (1:1) proceeded rela-

tively well to give the desired products 11a–11d in moderate

yields 24–63% (Scheme 7, Table 6). Application of the

aqueous conditions for the Sonogashira cross coupling re-

actions of 7 with acetylenes 5 was not successful. In conclu-

sion, direct cross-coupling of 8-bromoadenine with Ru

complex-containing organometallics is possible with the ap-

plication of aqueous-phase conditions for attachment of

aryl groups by the Suzuki–Miyaura reaction. Presumably,

Figure 1. ORTEP diagram of 5b (a) and 10b (b) (thermal ellipsoids

due to the relatively mild conditions and tolerance to un-

drawn at the 30% probability level).

protected functional groups,^[34]this could be the method of

choice for direct labeling of nucleotides and oligonucleo-

tides with complexes containing phenylene linkers but not parable to those of the parent ion [Ru(bpy)₃]²⁺(2.055 Å),^[35]

for the attachment of acetylenes. with the exception of the shorter bond Ru1–N50 [10b,

The Ru–N bond lengths of 10b and 5b are generally com-

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Eur. J. Inorg. Chem. 2007, 1752–1769

Ru-Labelled Purines

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2.013(9) Å], Ru1–N33 [5b, 2.097(10) Å] and especially the acetylene moiety, two cathodic peaks were observed. As ex-

significantly elongated bonds Ru1–N20 [10b, 2.109(9) Å] pected,^[38]reduction of the triple bond was easier in the

and the corresponding bond Ru1–N3 [5b, 2.110(6) Å]. This conjugate 10c (involving disubstituted acetylene) than in the

elongation is caused by the steric hindrance of the adjacent building block 5c (monosubstituted acetylene).

9-benzyl-8-ethynyladenine (10b) or acetylene (5b) groups

With respect to the prospective utilization of the conju-

and seems to be typical for all structures containing any gates as DNA labels, our attention was focused mainly on

group attached to the C25 carbon that were found in the processes related to the metal complexes. Cyclic voltamme-

Cambridge Structural Database.^[36]The structure of the try (CV) at a carbon paste electrode (CPE) revealed couples

central octahedron in both complexes is more or less the of reversible redox signals for all ruthenium complexes at

same, but the bipyridine units are slightly shifted due to the potentials around +1.2 V (not shown). The CV peaks were,

presence of substituents (see Figure S1 in the Supporting however, relatively poorly developed due to their occurrence

Information).

at rather positive potentials close to background discharge.

We therefore chose square-wave voltammetry (SWV), a

technique offering better separation of signals from the

background,^[40]in further experiments. Peak potentials due

to the ruthenium complexes resulting from these measure-

ments are summarized in Table 7. All compounds involving

the bipyridine ligand covalently linked to the adenine moi-

ety, regardless of the bridge type or position of the bipyri-

dine substitution, produced net SWV peaks at +1.21 V

(compounds 10b, 10c, 11b, and 11c; in Figure 2 shown for

Electrochemistry

The conjugates 10a–10c, 11a–11d, and 12b involve sev-

eral electrochemically active centers, including the adenine

moiety (potentially reducible at mercury and oxidizable at

carbon electrodes^[37]), triple bond of the ethynyl bridge (re-

ducible at mercury electrodes^[38]) as well as the ruthenium

or osmium chelates (expected to undergo reversible one-

electron Ru^II/Ru^IIIor Os^II/Os^IIIoxidation^[39]). Using the

hanging mercury drop electrode (HMDE), we observed

cathodic signals attributable to the adenine (with all conju-

gates) as well to the triple bond (with 10a–10c and 12b,

see Table 7). Potentials of 9-benzyladenine reduction were

influenced by the substituents to some extent. In general,

the adenine moiety was reduced more easily in bipyridine

conjugates with the phenylene linker than in analogues with

the ethynyl linker (10b vs. 11b and 10c vs. 11c), in the phen-

anthroline conjugates (10a vs. 11a), the opposite was true.

The potential of the adenine signal in the bipyridine conju-

gates was also influenced by the position of the bipyridine

substitution, being markedly more negative for the 5-substi-

tuted (b) than for 6-substituted (c) bipyridines. The ethynyl

linker produced a single reduction peak in conjugates of

phenanthroline (a) and 6-substituted bipyridine (b). In the

Figure 2. Sections of square-wave voltammograms of unsubstituted

complex [Ru(bipy)₃]²⁺(solid), compound 5b (dash) and compound

10b (dash-dot-dot) measured at the CPE. Inset shows the same

5-substituted bipyridine compounds (a) involving the voltammograms after baseline subtraction.

Table 7. Potentials of electrochemical signals of the synthesized compounds.

Oxidation at PGE

Reduction at HMDE

E^{net [a]}[V]

∆E^{net [b]}[mV]

E^{ade [c]}[V]

∆E^{ade [d]}[mV]

E^{eth [e]}[V]

[Ru(bipy)₃]²⁺

9-benzyladenine

5c

1.095

–

0

–

0

–

7

–52

–

46

–16

–10

36

–

–1.362

–

–1.355

–1.414

–

–1.316

–1.378

–1.372

–1.326

–

1.175

1.210

1.165

1.210

1.220

1.215

1.265

0.790

80

115

70

115

–

–1.263; –1.362

–0.810; –0.886

10c

10b

6c

11c

11b

10a

11a

11d

12b

–1.062

–

–0.950

–

–1.390

–28

–1.024

[a] E^netis the apparent redox potential of the Ru^II/Ru^IIIor Os^II/Os^IIIcouple measured on the net square-wave voltammogram (CPE). [b]

∆E^netis the potential shift relative to unsubstituted [Ru(bipy)₃]²⁺complex. [c] E^adeis the potential of reduction of the 9-benzyladenine

moiety in the conjugate measured by linear scan voltammetry (HMDE). [d] ∆E^adeis the potential shift relative to unsubstituted 9-

benzyladenine. [e] E^ethare potentials of peaks related to reduction of the ethynyl linker triple bond (HMDE). All potentials are measured

against a Ag/AgCl/3  KCl reference electrode.

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M. Hocek, M. Fojta et al.

FULL PAPER

10b). Apparent redox potentials of complexes with coval- 200 mV on a small model complex),^[41](ii) the single refer-

ently coupled phenanthroline ligands 10a,11a were slightly ence treatment of the triple (quasi)degenerate ground state

more positive (+1.220 or +1.215 V, respectively) than those in [Ru(bipy)₃]³⁺complexes, (iii) the uncertainty in the abso-

of the bipyridine analogues, while the complex 11d (with lute potential of SHE, (iv) the difference between the theo-

ruthenium coordinated by two terpyridines) yielded a peak retical calculations and the experimental setup (presence of

at +1.265 V. The osmium complex 12b underwent reversible counterions and the adsorption of complexes on the elec-

oxidation at +0.79 V, in agreement with a less positive redox trode).

potential of the Os^II/Os^IIIcouple, compared to Ru^II/

Ru^{III [39]}(not shown).

Table 8. The calculated redox potentials of the synthesized com-

pounds (vs. Ag/AgCl/3  KCl reference electrode).

Compared to unsubstituted [Ru(bipy)₃]²⁺, the apparent

redox potentials of compounds 10b–c and 11b–c were sig-

nificantly more positive (see Table 7). This phenomenon

can be explained by electron-withdrawing effects of the ade-

nine residue linked via the unsaturated bridges. Reducing

electron density at ruthenium results in its more difficult

oxidation. Similar effects were recently observed^[13]with

ferrocenylethyne–adenine conjugates in which the iron oxi-

dation was found to be more difficult, compared to unsub-

stituted ferrocene or to ferrocene linked to the adenine moi-

ety via a saturated bridge, due to electronic coupling be-

tween ferrocene and adenine via the alkyne bridge. Influ-

ence of conjugated unsaturated substituents on electro-

chemical properties of the ruthenium complex is evident

from the series [Ru(bipy)₃]²⁺–5b–10b (Table 7, Figure 2)

and series [Ru(bipy)₃]²⁺–6b–11b (Table 7). The ethynyl (5b)

or phenylene (6b) groups themselves cause shifts in the re-

dox potential of the ruthenium complex by 80 or 70 mV,

respectively, towards more positive values. Attachment of

the purine moiety offering further electronic conjugation re-

sulted in higher positive potential shifts (about 115 mV rela-

tive to the [Ru(bipy)₃]²⁺for both 10b and 11b as well as 10c

and 11c which involve 5-substituted bipyridine instead of 6-

substituted bipyridine present in the series b). Similar shifts

Oxidation Ru^2+/3+(Os^2+/3+

[V]^[a]∆E⁰[mV]^[b]∆E⁰[mV]^[c]E⁰

calc

)

Reduction

[V]

E⁰

calc

exp

[Ru(bipy)₃]²⁺

5c

1.082a

1.074

1.183

1.238

1.368

0.987

1.130

1.165

1.189

0.960

1.127

0

80

115

70

115

(125)

(120)

(170)

(–305)

–1.450

–1.557

–1.144

–1.357

–1.429

–1.292

–1.411

–1.234

–1.484

–1.389

–1.498

–8

101

156

286

–95

48

10c

10b

6c

11c

11b

10a

11a

11d

12b

83

107

–122

45

[a] E⁰

were calculated using the B3LYP/def2-TZVP//PBE/def2-

calc

SVP energies, PBE/def2-SV(P) frequencies, ideal gas approximation

for thermodynamic functions, the COSMO solvation model, 4.34 V

as the absolute potential of the SHE, and 0.207 V as the potential

of the reference electrode used in the electrochemical measurements

(Table 7). [b] ∆E⁰_calc/exp(X) = E⁰_calc/exp(X) – E⁰_calc/exp([Ru(bipy)₃]²⁺).

[c] Experimental data taken from Table 7; values in parentheses

have not been presented in Table 7 (showing effects of conjugated

unsaturated substituents on the [Ru(bipy)₃]^2+/3+redox potential)

because compounds 10a, 11a, 11d and 12b involve complexes of

different types.

To account for these systematic errors, we further discuss

of the Ru^II/Ru^IIIredox potential were observed also with the values of ∆E⁰[∆E⁰(X) = E⁰(X) – E⁰([Ru(bipy)₃]²⁺)],

compounds in which the adenine moiety was replaced by though it can be noted that an excellent agreement between

another aromatic system (p-tolyl, not shown). More details the calculated and experimental values of E⁰([Ru(bipy)₃]²⁺

)

about the electrochemistry of the conjugates and/or the has been obtained (E⁰

= 1.082 V vs. E⁰= 1.095 V).

exp

calc

building blocks at carbon or mercury electrodes will be

published elsewhere.

Considering that 100 mV corresponds to ca. 10 kJmol^–1,

we can see that most of the calculated values are within an

error bar of the quantum chemical methods. Specifically,

the values of ∆E⁰for four studied complexes (10c, 11b, 10a,

11a) are within 42 mV of the experimental values, which

can be considered an excellent agreement between theory

and experiment. Another two complexes, 5c and 11b, devi-

Quantum Chemical Calculations of the Redox Potentials of

the Studied Complexes

DFT calculations have been performed in order to verify ate by 88 and 67 mV, respectively, which is still a very good

the potential utilization of these methods for theoretical agreement. The largest errors are found for 6c (+216 mV),

prediction of redox potentials of the title complexes. Listed 11c (–210 mV), and 11d (–292 mV). However, an analysis

in Table 8 are the calculated values of redox potentials for of the spin densities have shown that for the latter two com-

the synthesized compounds, using Equations (1) and (2) plexes, the unpaired electron is not localized on the Ru

(see Experimental Section). It can be seen that the calcu- atom (Figure 3), but rather resides on the adenine moiety.

lated and experimental results are in good agreement (with This finding explains the observed discrepancy between the

a standard deviation of 130 mV). The systematic (mean) er- calculations and experimental data. Whether this is an arti-

ror of –60 mV can be attributed to several factors: (i) ne- fact of the DFT method or an observable phenomenon is

glect of spin-orbit coupling (SOC) in the nonrelativistic a subject of subsequent study.^[41]As mentioned above, the

treatment which has been estimated to account for approxi- discrepancy of +350 mV for 12b (Os^2+/3+complexes) can be

mately +30 mV on the model Ru^2+/3+complex^[41](this ef- mostly attributed to spin-orbit coupling effects, which are

fect is by one order of magnitude greater for Os^IIcom- not included in the DFT calculations. This is a general ef-

plexes, viz. Table 8, and has been calculated to account for fect exercised in octahedral Os^2+/3+complexes and may ex-

1758

www.eurjic.org

Eur. J. Inorg. Chem. 2007, 1752–1769

Ru-Labelled Purines

FULL PAPER

plain the lower redox potential of the Os^2+/3+pair (com-

pared to Ru^2+/3+).

In summary, it has been demonstrated that the theoreti-

cal calculations can satisfactorily reproduce the experimen-

tal data and can serve for prediction of redox potentials of

new molecules with a reasonable level of fidelity. However,

the anticipated differences in redox potential should be

higher than ca. 100 mV (which has been shown as an error

bar of the method), and care must be taken when interpret-

ing the calculated data, i.e., to formally assign oxidation

states and check whether they correspond to the experimen-

tally observed process.

Biological Activity

HCV chronically infects about 170 million people and

the only approved therapy (a combination of interferon-α

and ribavirin) is expensive and effective in only 50–60% of

patients infected with HCV genotype 1. Development of

effective antivirals for combating this pathogen is of great

interest within pharmaceutical research. Common nucleo-

side anti-HCV agents are intracellularly phosphorylated to

their triphosphates and then inhibit viral RNA synthesis

mediated by the HCV RNA-dependent RNA polymer-

ase.^[42]Apart from that, there are numerous non-nucleoside

inhibitors of this enzyme under current study.^[43]Ru com-

plexes of oligopyridine ligands are known to bind to DNA

and thus exert antitumor and antiparasitic activity.^[44]Some

other types of Ru complexes are inhibitors of protein kin-

ases.^[45]To the best of our knowledge, neither oligopyridine

Figure 3. The equilibrium geometry of 11d. Denoted are the calcu-

lated spin densities for the oxidized Ru^IIIcomplex demonstrating

that the unpaired electron is localized on the adenine moiety rather

than on the Ru atom.

Structurally, we can observe only very small geometry ligands nor their transition metal complexes have been re-

changes associated with the Ru^2+/3+oxidation and ported to possess anti-HCV activity. Therefore, we have also

Ru^2+/1+reduction. The most important parameters, the Ru– studied the biological activity (cytostatic effect and anti-

N distances, are shortened by ca. 0.004 Å upon the re- HCV activity) of the model adenine-ligand and adenine

duction and lengthened by ca. 0.006 Å upon oxidation. All complex conjugates.

the values of the Ru–N distances are summarized in Table

S1 (see supporting information).

Selected compounds and their respective Ru or Os com-

plexes were evaluated in the HCV subgenomic replicon as-

Also listed in Table 8 are the values of redox potentials say and their activity is presented in Table 9.^[46]In general,

for the reduction of the studied compounds. The interpret- the Ru and Os complex-based inhibitors displayed similar

ation of these values, i.e., the assignment of the formal re- or weaker antiviral activity than their corresponding pre-

dox states to subsystems in the studied complexes, is more cursors with the exception of 10c. However, analog 10c de-

complicated. In general, the calculated data are in the range spite improved antiviral activity compared to its precursor

of the experimental values: (–1.144, –1.557 V) vs. (–0.810, 8c also showed less than 5-fold selectivity thereby con-

–1.414 V). The spin densities are strongly delocalized on the founding further interpretation of the data. Two of the most

ligands, which suggests that these redox potential values do potent compounds were the structurally related analogs 9a

not refer to the reduction of the metal center, in agreement and 8a in which the main structural difference is the bridg-

with the experimental data (Table 7).

ing group between the purine and metal chelating motif

Table 9. Replicon activity and NS5B 1b enzymatic potency of selected compounds.

Replicon EC₅₀/µM

Huh-7 CC₅₀/µM

NS5B 1b IC₅₀/µM Ru/Os salt complex Replicon EC₅₀/µM

Huh-7 CC₅₀/µM

8a^[a]

8b

0.73

5

Ͼ50

0.49

3.0

2

n.d.

Ͼ2

n.d.

Ͼ2

10a

10b

10c

11a

11b

12b

11c

11d

17

28

10

27

1.0

2.0

11

28

100

cytostatic

50

Ͼ100

28

Ͼ50

0.89

14

8c

9a

9b

32

9c

9d

4.0

0.23

50

Ͼ50

n.d.

Ͼ2

cytostatic

23

[a] Compound required low pH for dissolution in DMSO; n.d. = not determined.

Eur. J. Inorg. Chem. 2007, 1752–1769

www.eurjic.org

1759

M. Hocek, M. Fojta et al.

FULL PAPER

(alkynyl or phenyl). Unfortunately, both of these analogs and 6 will certainly be useful in labeling of other types of

also displayed poor selectivity (less than 3-fold). Analog 9d molecules by a direct cross-coupling.

was the most potent and selective (at least 200-fold) inhibi-

The model compounds have been systematically studied

tor in the series.

by several methods. Electrochemistry revealed both oxi-

Several compounds, including 9d, were tested for inhibi- dation and reduction patterns with relatively minor substit-

tion toward HCV NS5B polymerase 1b (Table 9).^[47]None uent effects. Quantum-chemical calculations were able to

of the noncomplexed analogs demonstrated activity up to predict the values of redox potentials with the precision of

2 µ. Because of poor solubility in the assay buffer, inhibi- ca. 100 mV, which might not always be sufficient for the

tory activity beyond 2 µ could not be measured. There- prediction of differences in redox potentials in DNA. De-

fore, determination of whether 9d inhibits HCV NS5B spite these problems, we will continue our efforts in the syn-

weakly through an allosteric mechanism, or whether it has thesis of oligonucleotide probes bearing such transition

other cellular or viral targets will require further study.

metal complexes. The most interesting (and rather unexpec-

The in vitro evaluation of the cell growth inhibition was ted) finding was the significant antiviral activity against

estimated in mouse lymphocytic leukemia L1210 cells HCV of the adenine–oligopyridine conjugates, which is un-

(ATCC CCL 219), CCRF-CEM T lymphoblastoid cells fortunately accompanied by considerable cytotoxicity. Nev-

(human acute lymphoblastic leukemia, ATCC CCL 119), ertheless, these compounds represent a completely new

human promyelocytic leukemia HL-60 cells (ATCC CCL structural lead in the search for novel antiviral agents.

240), and human cervix carcinoma HeLa S3 cells (ATCC

CCL 2.2). Significant cytostatic activity was found only in

Experimental Section

compounds 8a and 9d. Surprisingly, compound 9a in con-

trast to Huh-7 hepatocytes does not exert any cytotoxicity

at 10 µmolL^–1. This discrepancy was rechecked by the

analysis of the cell cycle course using flow cytometry. The

data revealed that 0.7 µ compound 8a considerably influ-

ences the cell cycle profile, which is characterized by

apoptosis inducing activity and reduced proportion of G1

(from 49.4 to 17.5%) and G2/M phases (from 19.7 to 4.9%)

compensated by an increase of the S phase (from 30.8 to

77.6%). On the other hand, compound 9a does not affect

the cell cycle pattern even at 2 µ, which represents more

than twice the Huh7 CC₅₀value. These results indicate dif-

ferent susceptibilities of various cell lines towards the model

adenine ligands (Table 10).

General Remarks: All cross-coupling reactions were performed un-

der argon. Et₃N was degassed in vacuo and stored over molecular

sieves under argon. Compounds 1a [ref.^[17]], 1b, 1c, 2b, 2c [ref.^[18]],

3a [ref.^[19]], and 3d [ref.^[20]] were prepared according to literature

procedures. Other chemicals were purchased from commercial sup-

pliers and used as received. NMR spectra were recorded with

Bruker Avance 500 (500 MHz for H and 125.8 MHz for ¹³C) and

1

Bruker Avance 400 (¹H at 400, ¹³C at 100.6 MHz) spectrometers in

CDCl₃, [D₆]DMSO, or [D₆]acetone. Chemical shifts (in ppm, δ

scale) were referenced to TMS (for ¹H NMR spectra in CDCl₃)

and/or to the solvent signal (CDCl₃δ = 7.26 ppm for ¹H NMR

and δ = 77.0 ppm for ¹³C NMR; [D₆]DMSO for ¹H NMR (δ =

2.5 ppm) and for ¹³C NMR (δ = 39.7 ppm), [D₆]acetone for ¹H

NMR (δ = 2.05 ppm) and for ¹³C NMR (δ = 29.8 ppm, CD₃

group), coupling constants J are given in Hz. The assignment of

proton and carbon signals was based on H,H-COSY, H,C-HSQC,

and H,C-HMBC experiments. Melting points were determined on

a Kofler block and are uncorrected. Mass spectra were measured

on a ZAB-EQ (VG Analytical) spectrometer using FAB (ionization

by Xe, accelerating voltage 8 kV, glycerol matrix) or on a LCQ

classic spectrometer using electrospray ionization (ESI). X-ray crys-

tallographic analysis of single crystals of 10b (red,

0.03ϫ0.14ϫ0.27 mm) and 5b (red, 0.08ϫ0.31ϫ0.40 mm) was

performed with Xcalibur X-ray diffractometer with Cu-K_α(λ =

1.54180 Å), data collected at 150 K (10b) and 295 K (5b).

Table 10. Cytostatic activity of selected compounds.

IC₅₀, µmolL^–1

L1210

HL60

HeLa S3

1.10Ϯ0.08 1.40Ϯ0.10

Ͼ 20 1.65Ϯ0.11

CCRF-CEM

8a

9d

0.88Ϯ0.06

0.97Ϯ0.08

0.57Ϯ0.05

1.40Ϯ0.08

Conclusions

2-Ethynyl-1,10-phenanthroline (2a): A solution of 2-chloro-1,10-

phenanthroline (0.5 g, 2.3 mmol), bis(triphenylphosphane)palla-

dium dichloride (160 mg, 0.23 mmol), CuI (44 mg, 0.23 mmol),

Et₃N (1 mL, 7.2 mmol), and (trimethylsilyl)acetylene (0.7 mL,

9-Benzyladenine derivatives bearing Ru complexes in po-

sition 8 were prepared as model compounds for electro-

chemical DNA labeling. Two strategies of synthesis have 5.16 mmol) in DMF (5 mL) was stirred at 60 °C under argon for

12 h. The solvent was removed under reduced pressure, the residue

was dissolved in CHCl₃, and washed with a saturated solution of

EDTA. The organic layers were collected and the solvents evapo-

rated to dryness. The crude intermediate was diluted in methanol

(5 mL) and K₂CO₃(2.17 mmol, 300 mg) was added. The mixture

was stirred for 6 h at room temperature. After evaporation of the

solvent under reduced pressure, the crude product was purified by

column chromatography (ethyl acetate/hexanes, 1:1) to give 285 mg

of 1a (60%) as brownish crystals with m.p. 52–58 °C. ¹H NMR

(400 MHz, CDCl₃): δ = 3.27 (s, 1 H, HCϵC–), 7.65 (dd, J_8,7= 8.1,

been explored: (i) synthesis of adenine derivatives of bipyri-

dine ligands followed by complexation with Ru or (ii) cross-

coupling of 8-bromoadenine derivatives with boronic acids

derived from Ru complexed ligands. None of the two ap-

proaches is truly efficient but, due to the relatively harsh

conditions, difficult separation, and moderate yields of the

complexation in the first approach, the second approach

seems to be more suitable for applications in labile nucleo-

sides or oligonucleotides despite its moderate yields. The

new Ru-containing acetylene or boronate building blocks 5 J_8,9= 4.4, 1 H, 8-H), 7.77 (d, J_5,6= 8.8, 1 H, 5-H), 7.79 (d, J_3,4

=

1760 Eur. J. Inorg. Chem. 2007, 1752–1769

www.eurjic.org

Ru-Labelled Purines

FULL PAPER

8.2, 1 H, 3-H), 7.81 (d, J_6,5= 8.8, 1 H, 6-H), 8.22 (d, J_4,3= 8.2, 1

(m, 2 H, H^ophenylene), 9.26 (dd, J_9,8= 4.4, J_9,7= 1.7, 1 H, 9-

H, 4-H), 8.25 (dd, J_7,8= 8.1, J_7,9= 1.8, 1 H, 7-H), 9.23 (dd, J_9,8

=

H) ppm. ¹³C NMR (100.6 MHz, CDCl₃): δ = 24.92 (CH₃dioxabor-

4.4, J_9,7= 1.8, 1 H, 9-H) ppm. ¹³C NMR (100.6 MHz, CDCl₃): δ olane), 83.88 (C dioxaborolane), 120.86 (C-3), 122.89 (C-8), 126.38

= 78.43 (HCϵC–), 83.56 (–CϵCH), 123.31 (C-8), 126.04 (C-5), and 126.40 (C-5 and C-6), 127.14 (C^ophenylene), 127.73 (C-4a),

126.54 (C-3), 127.43 (C-6), 127.91 (C-4a), 128.89 (C-6a), 135.95 (C- 129.08 (C-6a), 135.22 (C^mphenylene), 136.14 (C-7), 136.83 (C-4),

7), 136.12 (C-4), 142.56 (C-2), 145.66 (C-10a), 146.28 (C-10b),

141.94 (Cⁱphenylene), 146.13 (C-10b), 146.42 (C-10a), 150.45 (C-

9), 157.36 (C-2) ppm; C^pphenylene signal not observed. FAB MS:

150.70 (C-9) ppm. FAB MS: m/z (%) = 205 (100) [M⁺+ H]. HRMS

(FAB): for C₁₄H₉N₂calcd. 205.0766; found 205.0769. IR (CHCl₃): m/z (%) = 282.1 (70), 382.2 (100) [M⁺]. HRMS (FAB): for

ν = 3304, 3049, 2968, 2835, 1505, 853 cm^–1. C H N ·H O (222.24):

C₂₄H₂₄BN₂O₂calcd. 383.1931; found 383.1924. IR (CHCl ): ν =

˜

14

8

2

3

calcd. C 75.66, H 4.54, N 12.6; found C 75.71, H 4.88, N 12.3.

3010, 2981, 1610, 1522, 1360, 1144, 1089, 1017, 858, 842, 662,

650 cm^–1. C₂₄H₂₃BN₂O₂·1/3H₂O (400.28): calcd. C 74.53, H 6.12,

N 7.24; found C 74.74, H 6.07, N 6.99.

6-(4-Bromophenyl)-2,2Ј-bipyridine (3b): A mixture of 6-bromo-2,2Ј-

bipyridine (1 g, 4.25 mmol), (4-bromophenyl)boronic acid (1.28 g,

5.3 mmol, 1.5 equiv.), K₂CO₃(1.18 g, 8.5 mmol, 2 equiv.), and

Pd(PPh₃)₄(245 mg, 0.21 mmol, 5 mol-%) in toluene (5 mL) was

stirred under argon for 8 h at 100 °C. After evaporation of the sol-

vent the residue was dissolved in chloroform, washed with satu-

rated solution of EDTA and dried with MgSO₄. The product was

purified by silica gel column chromatography (ethyl acetate/

Pinacol [4-(2,2Ј-Bipyridin-6-yl)phenyl]boronate (4b): The product

was obtained as white crystals in 86% yield (Method A). M.p. 121–

123 °C. ¹H NMR (500 MHz, CDCl₃): δ = 1.38 (s, 12 H, CH₃diox-

aborolane), 7.33 (ddd, J_5Ј,4Ј= 7.5, J_5Ј,6Ј= 4.8, J_5Ј,3Ј= 1.2, 1 H, 5Ј-

H), 7.81 (dd, J_5,4= 7.8, J_5,3= 1.1, 1 H, 5-H), 7.86 (td, J_4Ј,3Ј= 8.0,

J_4Ј,5Ј= 7.5, J_4Ј,6Ј= 1.8, 1 H, 4Ј-H), 7.89 (t, J_4,5= 7.8, J_4,3= 7.8, 1

H, 4-H), 7.95 (m, 2 H, H^mphenylene), 8.16 (m, 2 H, H^ophenylene),

8.39 (dd, J_3,4= 7.8, J_3,5= 1.1, 1 H, 3-H), 8.64 (dt, J_3Ј,4Ј= 8.0, J_3Ј,5Ј

= 1.2, J_3Ј,6Ј= 1.0, 1 H, 3Ј-H), 8.70 (ddd, J_6Ј,5Ј= 4.8, J_6Ј,4Ј= 1.8,

J_6Ј,3Ј= 1.0, 1 H, 6Ј-H) ppm. ¹³C NMR (125.8 MHz, CDCl₃): δ =

24.89 (CH₃dioxaborolane), 83.88 (C dioxaborolane), 119.57 (C-3),

120.58 (C-5), 121.34 (C-3Ј), 123.75 (C-5Ј), 126.13 (C^ophenylene),

135.17 (C^mphenylene), 136.89 (C-4Ј), 137.67 (C-4), 141.81 (Cⁱ

phenylene), 149.04 (C-6Ј), 155.80 (C-2), 156.23 (C-6), 156.31 (C-

2Ј) ppm; C^pphenylene signal not observed. FAB MS: m/z (%) =

258.1 (65), 358.2 (100) [M⁺]. HRMS (FAB): for C₂₂H₂₄BN₂O₂

hexanes, 1:10). The product was obtained as a colorless solid

1

(1.14 g, 86%). H NMR (500 MHz, CDCl₃): δ = 7.33 (ddd, J_5Ј,4Ј

=

7.5, J_5Ј,6Ј= 4.8, J_5Ј,3Ј= 1.2, 1 H, 5Ј-H), 7.63 (m, 2 H, H^mphenyl-

ene), 7.74 (dd, J_5,4= 7.8, J_5,3= 1.0, 1 H, 5-H), 7.85 (ddd, J_4Ј,3Ј

8.0, J_4Ј,5Ј= 7.5, J_4Ј,6Ј= 1.8, 1 H, 4Ј-H), 7.89 (t, J_4,5= 7.8, J_4,3

=

7.8, 1 H, 4-H), 8.03 (m, 2 H, H^ophenylene), 8.39 (dd, J_3,4= 7.8,

J_3,5= 1.0, 1 H, 3-H), 8.60 (dt, J_3Ј,4Ј= 8.0, J_3Ј,5Ј= 1.2, J_3Ј,6Ј= 0.9,

1 H, 3Ј-H), 8.70 (ddd, J_6Ј,5Ј= 4.8, J_6Ј,4Ј= 1.8, J_6Ј,3Ј= 0.9, 1 H, 6Ј-

H) ppm. ¹³C NMR (125.8 MHz, CDCl₃): δ = 119.64 (C-3), 120.01

(C-5), 121.25 (C-3Ј), 123.45 (C^pphenylene), 123.84 (C-5Ј), 128.49

(C^ophenylene), 131.85 (C^mphenylene), 136.88 (C-4Ј), 137.84 (C-

4), 138.21 (Cⁱphenylene), 149.11 (C-6Ј), 155.23 (C-6), 155.88 (C-

calcd. 359.1931; found 359.1938. IR (CHCl ): ν = 3010.2998, 2983,

˜

3

1611, 1566, 1430, 1391, 1361, 1321, 1144, 1088, 1018, 859,

662 cm^–1. C₂₂H₂₃BN₂O₂(358.24): calcd. C 73.76, H 6.47, N 7.82;

found C 73.58, H 6.47, N 7.60.

2), 156.12 (C-2Ј) ppm. IR (CHCl ): ν = 3011, 2985, 1582, 1562,

˜

3

1454, 1431, 1009, 817, 637 cm^–1. FAB MS: m/z (%) = 311 (100).

HRMS (FAB): for C₁₆H₁₂BrN₂calcd. 311.0184; found 311.0179.

C₁₆H₁₁BrN₂(311.18): calcd. C 61.76, H 3.56, N 9.00; found C

61.82, H 3.61, N 9.05.

Pinacol [4-(2,2Ј-Bipyridin-5-yl)phenyl]boronate (4c): The product

was obtained as white crystals in 91% yield (Method A) which gave

analytical data identical to those previously reported.^{[23] 1}H NMR

(400 MHz, CDCl₃): δ = 1.38 (s, 12 H, CH₃dioxaborolane), 7.33

(ddd, J_5Ј,4Ј= 8.0, J_5Ј,6Ј= 4.8, J_5Ј,3Ј= 1.2, 1 H, 5Ј-H), 7.67 (m, 2 H,

H^ophenylene), 7.84 (td, J_4Ј,3Ј= J_4Ј,5Ј= 8.0, J_4Ј,6Ј= 1.9, 1 H, 4Ј-H),

7.94 (m, 2 H, H^mphenylene), 8.05 (dd, J_4,3= 8.3, J_4,6= 2.4, 1 H,

4-H), 8.45 (dt, J_3Ј,4Ј= 8.0, J_3Ј,5Ј= 1.2, J_3Ј,6Ј= 1.0, 1 H, 3Ј-H), 8.48

(dd, J_3,4= 8.3, J_3,6= 0.9, 1 H, 3Ј-H), 8.71 (ddd, J_6Ј,5Ј= 4.8, J_6Ј,4Ј

= 1.9, J_6Ј,3Ј= 1.0, 1 H, 6Ј-H), 8.94 (dd, J_6,4= 2.4, J_6,3= 0.9, 1 H,

6-H) ppm. ¹³C NMR (100.6 MHz, CDCl₃): δ = 24.87 (CH₃diox-

aborolane), 83.95 (C dioxaborolane), 120.96 and 121.10 (C-3 and

C-3Ј), 123.72 (C-5Ј), 126.32 (C^ophenylene), 135.29 (C-4), 135.52

(C^mphenylene), 136.30 (C-5), 136.95 (C-4Ј), 140.20 (Cⁱphenylene),

147.72 (C-6), 149.23 (C-6Ј), 155.14 (C-2), 155.84 (C-2Ј) ppm; C^p

phenylene signal not observed.

5-(4-Bromophenyl)-2,2Ј-bipyridine (3c): A mixture of 5-bromo-2,2Ј-

bipyridine (1 g, 4.25 mmol), (4-bromophenyl)boronic acid (1.03 g,

5.1 mmol, 1.2 equiv.), K₂CO₃(1.18 g, 8.5 mmol, 2 equiv.), and

Pd(PPh₃)₄(245 mg, 0.21 mmol, 5 mol-%) in DMF (5 mL) was

stirred under argon for 8 h at 100 °C. After evaporation of the sol-

vent the residue was dissolved in chloroform, washed with satu-

rated solution of EDTA, and dried with MgSO₄. The product was

purified by silica gel column chromatography (ethyl acetate/

hexanes, 1:10). The product was obtained as a colorless solid

(780 mg, 59%), which gave analytical data identical to those pre-

viously reported.^[20]

General Procedure for Preparation of the Pinacolboronates. Method

A: A bromo derivative (3a/3d) (3.5 mmol), bis(pinacolato)diboron

(4.2 mmol, 1.2 equiv.), PdCl₂(0.175 mmol, 5 mol-%), dppf

(0.175 mmol, 5 mol-%), and KOAc (5.25 mmol, 1.5 equiv.) were

combined and stirred under argon in dry dioxane at 80 °C until the

TLC showed complete consumption of the starting material. After

evaporation of the solvent the residue was dissolved in chloroform,

washed with a saturated solution of EDTA and purified by silica

gel column chromatography (ethyl acetate/hexanes).

Pinacol [4-(2,2Ј:6Ј,2"-Terpyridine-4Ј-yl)phenyl]boronate (4d): The

product was isolated as white crystals in 81% yield (Method A).

1

M.p. 187–196 °C. H NMR (400 MHz, CDCl₃): δ = 1.39 (s, 12 H,

CH₃dioxaborolane), 7.36 (ddd, J_5Ј,4Ј= 7.5, J_5Ј,6Ј= 4.8, J_5Ј,3Ј= 1.2,

2 H, 5Ј-H), 7.88 (td, J_4Ј,3Ј= 8.0, J_4Ј,5Ј= 7.5, J_4Ј,6Ј= 1.8, 2 H, 4Ј-

H), 7.92 (m, 2 H, H^ophenylene), 7.96 (m, 2 H, H^mphenylene),

8.68 (dt, J_3Ј,4Ј= 8.0, J_3Ј,5Ј= 1.2, J_3Ј,6Ј= 0.9, 2 H, 3Ј-H), 8.74 (ddd,

Pinacol [4-(1,10-Phenanthroline-3-yl)phenyl]boronate (4a): The J_6Ј,5Ј= 4.8, J_6Ј,4Ј= 1.8, J_6Ј,3Ј= 0.9, 2 H, 6Ј-H), 8.76 (s, 2 H, 3-

product was obtained as brownish crystals in 60% yield (Method

A). M.p. 192–193 °C. ¹H NMR (400 MHz, CDCl₃): δ = 1.39 (s, 12

H, CH₃dioxaborolane), 7.65 (dd, J_8,7= 8.0, J_8,9= 4.4, 1 H, 8-H),

7.79 (d, J_6,5= 8.8, 1 H, 6-H), 7.83 (d, J_5,6= 8.8, 1 H, 5-H), 7.99

H) ppm. ¹³C NMR (100.6 MHz, CDCl₃): δ = 24.93 (CH₃dioxabor-

olane), 83.98 (C dioxaborolane), 118.94 (C-3), 121.42 (C-3Ј), 123.85

(C-5Ј), 126.59 (C^ophenylene), 135.37 (C^mphenylene), 136.90 (C-

4Ј), 140.98 (Cⁱphenylene), 149.15 (C-6Ј), 150.15 (C-4), 155.98 (C-

(m, 2 H, H^mphenylene), 8.15 (d, J_3,4= 8.4, 1 H, 3-H), 8.27 (dd, 2), 156.26 (C-2Ј) ppm; C^pphenylene signal not observed. FAB MS:

J_7,8= 8.0, J_7,9= 1.7, 1 H, 7-H), 8.32 (d, J_4,3= 8.4, 1 H, 4-H), 8.36

m/z (%) = 336 (25), 436 (100) [M⁺+ H]. HRMS (FAB): for

Eur. J. Inorg. Chem. 2007, 1752–1769

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1761

M. Hocek, M. Fojta et al.

FULL PAPER

C H BN O : calcd. 436.2196; found 436.2187. IR (CHCl ): ν =

9-Benzyl-8-[(2,2Ј-bipyridine-5-yl)ethynyl]adenine (8c): 8-Bromo-9-

benzyladenine (0.5 g, 1.64 mmol), 5-ethynylbipyridine (355 mg,

1.97 mmol, 1.2 equiv.), PdCl₂(14.5 mg, 0.082 mmol, 5 mol-%),

dppf (45.5 mg, 0.082 mmol, 5 mol-%), CuI (16 mg, 0.082 mmol,

5 mol-%), and Et₃N (2 mL, 14.3 mmol) were combined in DMF

(5 mL) and stirred under argon at 85 °C for 12 h. The workup was

performed in the same way as for 8a. Crystallization of crude prod-

uct from CHCl₃(plus a few drops of MeOH)/heptane gave 8c as a

white solid (373 mg, 56%). M.p. 273–278 °C. ¹H NMR (400 MHz,

[D₆]DMSO): δ = 5.55 (s, 2 H, CH₂), 7.29 (m, 1 H, H^pphenylene),

˜

27 27

3

2

3

3010, 2983, 1603, 1586, 1469, 1388, 1364, 1144, 1092, 1019, 859,

787, 662 cm^–1.

9-Benzyl-8-[(1,10-Phenanthroline-2-yl)ethynyl]adenine (8a): 9-Ben-

zyl-8-bromoadenine (0.5 g, 1.64 mmol), 2-ethynylphenanthroline

(402 mg, 1.97 mmol, 1.2 equiv.), PdCl₂(14.5 mg, 0.082 mmol,

5 mol-%), dppf (45.5 mg, 0.082 mmol, 5 mol-%), CuI (16 mg,

0.082 mmol, 5 mol-%), and Et₃N (2 mL, 14.3 mmol) were com-

bined in dry DMF (5 mL) and stirred under argon at 90 °C for

12 h. The solvent was removed under reduced pressure, the residue

was dissolved in chloroform, washed with a saturated solution of

EDTA, evaporated, and purified by silica gel column chromatog-

raphy (CHCl₃+ 1–10% MeOH). Crystallization from CHCl₃(plus

a few drops of MeOH) and heptane gave the product as a yellowish

7.33–7.41 (m, 4 H, H^m,ophenylene), 7.51 (ddd, J_5Љ,4Љ= 7.5, J_5Љ,6Љ

=

4.7, J_5Љ,3Љ= 1.2, 1 H, 5Љ-H), 7.60 (br. s, 2 H, NH₂), 8.00 (td, J_4Љ,3Љ

= 7.9, J_4Љ,5Љ= 7.5, J_4Љ,6Љ= 1.8, 1 H, 4Љ-H), 8.22 (dd, J_4Ј,3Ј= 8.3,

J_4Ј,6Ј= 2.2, 1 H, 4Ј-H), 8.25 (s, 1 H, H-2), 8.43 (dt, J_3Љ,4Љ= 7.9,

J_3Љ,5Љ= 1.2, J_3Љ,6Љ= 0.9, 1 H, 3Љ-H), 8.49 (dd, J_3Ј,4Ј= 8.3, J_3Ј,6Ј

=

1

solid (385 mg, 55%). M.p. 288–291 °C. H NMR (500 MHz, [D₆]-

0.9, 1 H, 3Ј-H), 8.74 (ddd, J_6Љ,5Љ= 4.7, J_6Љ,4Љ= 1.8, J_6Љ,3Љ= 0.9, 1 H,

6Љ-H), 8.94 (dd, J_6Ј,4Ј= 2.2, J_6Ј,3Ј= 0.9, 1 H, 6Ј-H) ppm. ¹³C NMR

(125.8 MHz, [D₆]DMSO): δ = 46.39 (CH₂), 83.01 (pur-CϵC-),

91.58 (bipy-CϵC-), 117.69 (C-5Ј), 119.28 (C-5), 120.34 (C-3Ј),

121.25 (C-3Љ), 125.04 (C-5Љ), 127.82 (C^ophenylene), 128.06 (C^p

phenylene), 128.96 (C^mphenylene), 132.66 (C-8), 136.83 (Cⁱphenyl-

ene), 137.75 (C-4Љ), 140.36 (C-4Ј), 149.66 (C-4), 149.78 (C-6Љ),

152.01 (C-6Ј), 154.28 (C-2Љ), 154.44 (C-2), 155.58 (C-2Ј), 156.21 (C-

DMSO): δ = 5.60 (s, 2 H, CH₂), 7.29 (m, 1 H, H^pphenylene), 7.37

(m, 2 H, H^mphenylene), 7.49 (m, 2 H, H^ophenylene), 7.62 (br. s,

2 H, NH₂), 7.83 (dd, J_8Ј,7Ј= 8.1, J_8Ј,9Ј= 4.3, 1 H, 8Ј-H), 8.05 (d,

J_5Ј,6Ј= 8.8, 1 H, 5Ј-H), 8.06 (d, J_3Ј,4Ј= 8.3, 1 H, 3Ј-H), 8.09 (d,

J_6Ј,5Ј= 8.8, 1 H, 6Ј-H), 8.27 (s, 1 H, H-2), 8.54 (dd, J_7Ј,8Ј= 8.1,

J_7Ј,9Ј= 1.8, 1 H, 7Ј-H), 8.63 (d, J_4Ј,3Ј= 8.3, 1 H, 4Ј-H), 9.15 (dd,

J_9Ј,8Ј= 4.3, J_9Ј,7Ј= 1.8, 1 H, 9Ј-H) ppm. ¹³C NMR (125.8 MHz,

[D₆]DMSO): δ = 46.61 (CH₂), 78.45 (pur-CϵC), 94.32 (phen-

CϵC), 119.45 (C-5), 124.08 (C-8Ј), 126.44 and 126.63 (C-3Ј, C-5Ј),

127.98 (C^ophenylene), 128.08 (C^pphenylene), 128.46 (C-4aЈ),

128.52 (C-6Ј), 128.99 (C^mphenylene), 129.12 (C-6aЈ), 132.41 (C-8),

136.57 (C-7Ј), 136.68 (Cⁱphenylene), 137.37 (C-4Ј), 140.44 (C-2Ј),

145.02 (C-10aЈ), 146.03 (C-10bЈ), 149.65 (C-4), 150.61 (C-9Ј),

154.57 (C-2), 156.27 (C-6) ppm. FAB MS: m/z (%) = 428 (25) [M⁺

6) ppm. FAB MS: m/z (%) = 93 (100), 259 (5), 404.2 (10) [M⁺

H]. HRMS (FAB): for C₂₄H₁₈N₇calcd. 404.1624 found 404.1614.

+

IR (KBr): ν = 3421, 3321, 3032, 1660, 1586, 1325, 1021, 195,

˜

745 cm^–1. UV/Vis (MeOH): λ_max(ε) = 336 (21515), 257 (5228) nm.

C₂₄H₁₇N₇·1H₂O (421.45): calcd. C 69.89, H 4.40, N 23.77; found

C 70.20, H 4.15, N 23.63.

+ H], 231 (80). HRMS (FAB): for C₂₆H₁₈N₇calcd. 428.1623; found 9-Benzyl-8-[4-(1,10-phenanthroline-2-yl)phenyl]adenine (9a): 9-Ben-

428.1630. IR (KBr): ν = 3481, 3413, 3034, 1631, 1572, 1486, 1287,

zyl-8-bromoadenine (0.215 g, 0.7 mmol), 4-(1,10-phenanthroline-3-

yl)pinacolboronate (270 mg, 0.7 mmol, 1 equiv.), PdCl₂(6 mg,

˜

850, 732 cm^–1. UV/Vis (MeOH): λ_max(ε) = 364 (24345), 333

(25380), 279 (21220) nm. C₂₆H₁₇N₇·1/2CHCl₃(487.15): calcd. C 0.035 mmol, 5 mol-%), dppf (19 mg, 0.035 mmol, 5 mol-%), K₂CO₃

65.34, H 3.62, N 20.13; found C 65.95, H 3.62, N 20.15.

(390 mg, 2.8 mmol, 4 equiv.) were combined in DMF (4 mL) and

three drops of water and stirred under argon at 90 °C for 10 h. The

workup was performed in the same way as for 8a. Crystallization

of crude product from CHCl₃(plus a few drops of MeOH)/heptane

9-Benzyl-8-[(2,2Ј-bipyridine-6-yl)ethynyl]adenine (8b): 9-Benzyl-8-

bromoadenine (0.5 g, 1.64 mmol), 6-ethynylbipyridine (355 mg,

1.97 mmol, 1.2 equiv.), PdCl₂(14.5 mg, 0.082 mmol, 5 mol-%),

dppf (45.5 mg, 0.082 mmol, 5 mol-%), CuI (16 mg, 0.082 mmol,

5 mol-%), and Et₃N (2 mL, 14.3 mmol) were combined in DMF

(3 mL) and stirred under argon at 90 °C for 8 h. The workup was

performed in the same way as for 8a. Crystallization of the crude

product from CHCl₃(plus a few drops of MeOH)/heptane gave 8b

as a colorless solid (384 mg, 58%). M.p. 242–244 °C. ¹H NMR

(500 MHz, [D₆]DMSO): δ = 5.44 (s, 2 H, CH₂), 7.29 (m, 1 H, H^p

phenylene), 7.35 (m, 2 H, H^mphenylene), 7.47 (m, 2 H, H^ophenyl-

ene), 7.52 (ddd, J_5Љ,4Љ= 7.5, J_5Љ,6Љ= 4.7, J_5Љ,3Љ= 1.2, 1 H, 5Љ-H), 7.62

(br. s, 2 H, NH₂), 7.83 (dd, J_5Ј,4Ј= 7.7, J_5Ј,3Ј= 1.1, 1 H, 5Ј-H), 8.01

1

gave 9a as a yellowish solid (160 mg, 47%). M.p. 286–293 °C. H

NMR (400 MHz, [D₆]DMSO): δ = 5.62 (s, 2 H, CH₂), 7.07 (m, 2

H, H^ophenylene), 7.24 (m, 1 H, H^pphenylene), 7.30 (m, 2 H, H^m

phenylene), 7.46 (br. s, 2 H, NH₂), 7.81 (dd, J_8Ј,7Ј= 8.1, J_8Ј,9Ј

=

4.3, 1 H, 8Ј-H), 7.94 (m, 2 H, H^ophenylene), 8.01 (d, J_6Ј,5Ј= 8.8,

1 H, 6Ј-H), 8.05 (d, J_5Ј,6Ј= 8.8, 1 H, 5Ј-H), 8.22 (s, 1 H, H-2), 8.48

(d, J_3Ј,4Ј= 8.5, 1 H, 3Ј-H), 8.52 (dd, J_7Ј,8Ј= 8.1, J_7Ј,9Ј= 1.8, 1 H,

7Ј-H), 8.58 (m, 2 H, H^mphenylene), 8.61 (d, J_4Ј,3Ј= 8.5, 1 H, 4Ј-

H), 9.18 (dd, J_9Ј,8Ј= 4.3, J_9Ј,7Ј= 1.8, 1 H, 9Ј-H) ppm. ¹³C NMR

(100.6 MHz, [D₆]DMSO): δ = 46.46 (CH₂), 118.89 (C-5), 120.42

(C-3Ј), 123.66 (C-8Ј), 126.53 (C^ophenylene), 126.59 (C-5Ј), 127.06

(C-6Ј), 127.71 (C^pphenylene, C^mphenylene), 127.95 (C-4aЈ), 128.96

(C^mPh), 129.10 (C-6aЈ), 129.38 (C^ophenylene), 130.90 (Cⁱphenyl-

ene), 136.54 (C-7Ј), 137.24 (CⁱPh), 137.74 (C-4Ј), 139.98 (C^pphen-

ylene), 145.51 (C-10bЈ), 145.76 (C-10aЈ), 149.51 (C-8), 150.24 (C-

9Ј), 151.76 (C-4), 153.15 (C-2), 154.67 (C-2Ј), 156.13 (C-6) ppm.

FAB MS: m/z (%) = 282 (5%), 390 (8%) 480 (35) [M⁺]. HRMS

(td, J_4Љ,3Љ= 8.0, J_4Љ,5Љ= 7.5, J_4Љ,6Љ= 1.8, 1 H, 4Љ-H), 8.09 (t, J_4Ј,3Ј

8.0, J_4Ј,5Ј= 7.7, 1 H, 4Ј-H), 8.27 (s, 1 H, H-2), 8.42 (dt, J_3Љ,4Љ= 8.0,

J_3Љ,5Љ= 1.2, J_3Љ,6Љ= 1.0, 1 H, 3Љ-H), 8.49 (dd, J_3Ј,4Ј= 8.0, J_3Ј,5Ј

=

1.1, 1 H, 3Ј-H), 8.73 (ddd, J_6Љ,5Љ= 4.7, J_6Љ,4Љ= 1.8, J_6Љ,3Љ= 1.0, 1 H,

6Љ-H) ppm. ¹³C NMR (125.8 MHz, [D₆]DMSO): δ = 46.54 (CH₂),

77.94 (pur-CϵC-), 93.58 (bipy-CϵC-), 119.31 (C-5), 120.86 (C-3Љ),

121.55 (C-3Ј), 125.00 (C-5Љ), 128.03 (C^ophenylene), 128.16 (C^p

phenylene), 128.27 (C-5Ј), 128.95 (C^mphenylene), 132.40 (C-8),

136.74 (Cⁱphenylene), 137.78 (C-4Љ), 138.63 (C-4Ј), 140.32 (C-6Ј),

149.62 (C-4), 149.66 (C-6Љ), 154.33 (C-2Љ), 154.56 (C-2), 156.27 (C-

6), 156.34 (C-2Ј) ppm. FAB MS: m/z (%) = 79.1 (100), 187.0 (20),

279.1 (20), 404.2 (10) [M⁺+ H]. HRMS (FAB): for C₂₄H₁₈N₇

(FAB): for C H N calcd.480.1937 found 480.1945. IR (KBr): ν

˜

30 22

7

= 3438, 3133, 1666, 1292, 1113 cm^–1. UV/Vis (MeOH): λ_max(ε) =

355 sh (9720), 321 (21792), 303 sh (21792), 233 (26572) nm.

C₃₀H₂₁N₇·1H₂O (497.55): calcd. C 72.42, H 4.66, N 19.71; found

C 72.40, H 4.19, N 19.53.

calcd. 404.1624; found 404.1628. IR (KBr): ν = 3430, 3316, 1649,

9-Benzyl-8-[4-(2,2Ј-bipyridine-6-yl)phenyl]adenine (9b): 9-Benzyl-8-

˜

1559, 1425, 775 cm^–1. UV/Vis (MeOH): λ_max(ε) = 327 (23755), 282 bromoadenine (0.5 g, 1.64 mmol), 4-(2,2Ј-bipyridin-6-yl)pinacol-

(15335) nm. C₂₄H₁₇N₇·1/2H₂O (421.45): calcd. C 69.89, H 4.40, N

23.77; found C 70.08, H 4.06, N 23.79.

boronate (600 mg, 1.8 mmol, 1.1 equiv.), PdCl₂(14.5 mg,

0.082 mmol, 5 mol-%), dppf (45.5 mg, 0.082 mmol, 5 mol-%), and

1762

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Eur. J. Inorg. Chem. 2007, 1752–1769

Ru-Labelled Purines

FULL PAPER

K₂CO₃(905 mg, 6.56 mmol, 4 equiv.) were combined in DMF

(5 mL) and three drops of water and stirred under argon at 90 °C

for 8 h. The workup was performed in the same way as for 8a.

Crystallization of crude product from CHCl₃(plus a few drops of

MeOH)/heptane gave 9b as a white solid (401 mg, 53%). M.p. 252–

MeOH)/heptane gave 9d as a white solid (283 mg, 46%). M.p. 269–

1

271 °C. H NMR (400 MHz, [D₆]DMSO): δ = 5.60 (s, 2 H, CH₂),

7.06 (m, 2 H, H^oPh), 7.42 (m, 1 H, H^pPh), 7.30 (m, 2 H, H^mPh),

7.46 (br. s, 2 H, NH₂), 7.54 (ddd, 2 H, J_5Љ,4Љ= 7.5, J_5Љ,6Љ= 4.8, J_5Љ,3Љ

= 1.2, 2 H, 5Љ-H), 7.92 (m, 2 H, H^ophenylene), 8.04 (ddd, J_4Љ,3Љ

=

1

255 °C. H NMR (500 MHz, [D₆]DMSO): δ = 5.58 (s, 2 H, CH₂),

8.0, J_4Љ,5Љ= 7.5, J_4Љ,6Љ= 1.8, 2 H, 4Љ-H), 8.07 (m, 2 H, H^mphenyl-

7.05 (m, 2 H, H^oPh), 7.24 (m, 1 H, H^pPh), 7.29 (m, 2 H, H^mPh), ene), 8.21 (s, 1 H, H-2), 8.68 (dt, J_3Љ,4Љ= 8.0, J_3Љ,5Љ= 1.2, J_3Љ,6Љ

=

7.40 (br. s, 2 H, NH₂), 7.49 (ddd, J_5Љ,4Љ= 7.5, J_5Љ,6Љ= 4.7, J_5Љ,3Љ

=

0.9, 2 H, 3Љ-H), 8.76 (s, 2 H, H-3Ј), 8.76 (ddd, J_6Љ,5Љ= 4.8, J_6Љ,4Љ

1.2, 1 H, 5Љ-H), 7.88 (m, 2 H, H^ophenylene), 8.00 (td, J_4Љ,3Љ= 7.9,

1.8, J_6Љ,3Љ= 0.9, 2 H, 6Љ-H) ppm. ¹³C NMR (100.6 MHz, [D₆]-

J_4Љ,5Љ= 7.5, J_4Љ,6Љ= 1.8, 1 H, 4Љ-H), 8.07 (t, J_4Ј,5Ј= 7.9, J_4Ј,3Ј= 7.7, DMSO): δ = 46.51 (CH₂), 118.14 (C-3Ј), 118.93 (C-5), 121.22 (C-

1 H, 4Ј-H), 8.13 (br. d, J_5Ј,4Ј= 7.9, 1 H, 5Ј-H), 8.21 (s, 1 H, H-2),

8.38 (m, 2 H, H^mphenylene), 8.39 (dd, J_3Ј,4Ј= 7.7, J_3Ј,5Ј= 1.1, 1

H, 3Ј-H), 8.60 (dt, J_3Љ,4Љ= 7.9, J_3Љ,5Љ= 1.2, J_3Љ,6Љ= 0.9, 1 H, 3Љ-H),

3Љ), 124.88 (C-5Љ), 126.58 (C^oPh), 127.49 (C^mphenylene), 127.73

(C^pPh), 128.99 (C^mPh), 129.86 (C^ophenylene), 130.91 (Cⁱphenyl-

ene), 137.19 (CⁱPh), 137.77 (C-4Љ), 138.72 (C^pphenylene), 148.65

8.72 (ddd, J_6Љ,5Љ= 4.7, J_6Љ,4Љ= 1.8, J_6Љ,3Љ= 0.9, 1 H, 6Љ-H) ppm. ¹³C (C-4Ј), 149.29 (C-8), 149.59 (C-6Љ), 151.78 (C-4), 153.22 (C-2),

NMR (125.8 MHz, [D₆]DMSO): δ = 46.43 (CH₂), 118.88 (C-5), 155.05 (C-2Љ), 156.06 (C-2Ј), 156.16 (C-6) ppm. FAB MS: m/z (%)

119.82 (C-3Ј), 120.97 (C-3Љ, C-5Ј), 124.59 (C-5Љ), 126.45 (C^oPh),

127.04 (C^mphenylene), 127.66 (C^pPh), 128.95 (C^mPh), 129.36 (C^o

phenylene), 130.65 (Cⁱphenylene), 137.20 (CⁱPh), 137.61 (C-4Љ),

= 91 (90), 336 (35), 436 (100), 533 (15) [M⁺]. HRMS (FAB): for

C₃₃H₂₅N₈calcd. 533.2202 found 533.2231. IR (KBr): ν = 3401,

˜

3299, 3060, 1637, 1584, 1390, 1330, 842, 792 cm^–1. UV/Vis

138.80 (C-4Ј), 139.61 (C^pphenylene), 149.51 (C-6Љ, C-8), 151.69 (MeOH): λ_max(ε) = 318 sh (30620), 285 (34170), 248 (32715) nm.

(C-4), 153.11 (C-2), 154.56 (C-6Ј), 155.32 (C-2Ј, C-2Љ), 156.10 (C- C₃₃H₂₄N₈·H₂O (550.6): calcd. C 71.98, H 4.74, N 20.35; found C

6) ppm. FAB MS: m/z (%) = 91 (100), 258 (10), 366 (15), 456 (75%)

71.24, H 4.47, N 20.31.

[M⁺+ H]. HRMS (FAB): for C₂₈H₂₂N₇calcd.456.1937 found

General Procedure for the Complexation Reactions. Method B:

Compounds 2b–2c, 4a–4c, 8a–8c or 9a–9c (1.5 mmol) were com-

bined with commercially available Ru(bipy)₂Cl₂·2H₂O (1.65 mmol,

1.1 equiv.) or 4d or 9d with Ru(terpy)Cl₃(1.65 mmol, 1.1 equiv.) in

ethylene glycol and were then heated for 2 h at 150 °C. The solvent

was distilled off under reduced pressure. The residue was dissolved

in water and saturated solution of NH₄PF₆was added to the mix-

ture. The precipitate thus formed was collected by filtration. The

crude product was purified by silica gel column chromatography

using a mixture of CH₃CN/H₂O/saturated KNO₃(10:1:0.1) as elu-

ent. The corresponding fractions were combined and the solvent

removed in vacuo. The residue was dissolved in a small amount of

EtOH and the KNO₃was filtered off. The product was dissolved in

water and a saturated solution of NH₄PF₆was added. The product

precipitated as hexafluorophosphate salts from the solution. The

solid was filtered off. Crystallization from acetone or acetonitrile/

iPrOH gave pure desired products 5, 6, 10 or 11.

456.1927. IR (KBr): ν = 3444, 3062, 1649, 1582, 1429, 755 cm^–1.

˜

UV/Vis (MeOH): λ_max(ε)

C₂₈H₂₁N₇·H₂O (473.53): calcd. C 71.02, H 4.90, N 20.71; found C

71.24, H 4.55, N 20.59.

= 310 (26420), 238 (21188) nm.

9-Benzyl-8-[4 -(2,2Ј-bipyridine-5-yl)phenyl]adenine (9c): 9-Benzyl-8-

bromoadenine (0.5 g, 1.64 mmol), 4-(2,2Ј-bipyridin-5-yl)pinacol-

boronate (600 mg, 1.8 mmol, 1.1 equiv.), PdCl₂(28 mg,

0.165 mmol, 10 mol-%), dppf (90 mg, 0.165 mmol, 5 mol-%), and

K₂CO₃(905 mg, 6.56 mmol, 4 equiv.) were combined in DMF

(9 mL) and three drops of water and stirred under argon at 90 °C

for 8 h. The workup was performed in the same way as for 8a.

Crystallization of crude product from CHCl₃(plus a few drops of

MeOH)/heptane gave 9c as a white solid (400 mg, 52%). M.p. 267–

1

272 °C. H NMR (400 MHz, [D₆]DMSO): δ = 5.58 (s, 2 H, CH₂),

7.04 (m, 2 H, H^oPh), 7.22–7.33 (m, 4 H, H^m,pPh), 7.43 (br. s, 2

H, NH₂), 7.48 (ddd, J_5Љ,4Љ= 7.5, J_5Љ,6Љ= 4.8, J_5Љ,3Љ= 1.2, 1 H, 5Љ-

H), 7.86 (m, 2 H, H^ophenylene), 7.95–8.01 (m, 3 H, 4Љ-H and H^m

phenylene), 8.20 (s, 1 H, H-2), 8.34 (dd, J_4Ј,3Ј= 8.3, J_4Ј,6Ј= 2.4, 1

H, 4Ј-H), 8.44 (dt, J_3Љ,4Љ= 7.9, J_3Љ,5Љ= 1.2, J_3Љ,6Љ= 1.0, 1 H, 3Љ-H),

8.49 (dd, J_3Ј,4Ј= 8.3, J_3Ј,6Ј= 0.9, 1 H, 3Ј-H), 8.79 (ddd, J_6Љ,5Љ= 4.8,

Complex 5b: The product was isolated as a red solid in 49% yield

(Method B). M.p. 265–274 °C (decomposition). ¹H NMR

(400 MHz, [D₆]acetone): δ = 3.60 (s, 1 H, HCϵC), 7.43 (ddd, J_5,4

= 7.6, J_5,6= 5.7, J_5,3= 1.4, 1 H, 5-H bipy), 7.51–7.59 (m, 3 H, 5Ј-

H and 2ϫ5-H bipy), 7.63 (ddd, J_5,4= 7.6, J_5,6= 5.7, J_5,3= 1.4, 1

H, 5-H bipy), 7.82 (dd, J_5,4= 7.8, J_5,3= 1.3, 1 H, 5-H), 7.91–7.97

(m, 4 H, 6Ј-H and 3 ϫ6-H bipy), 8.08 (ddd, J_4,3= 8.1, J_4,5= 7.6,

J_4,6= 1.5, 1 H, 4-H bipy), 8.18–8.27 (m, 5 H, 4-H, 4Ј-H and 3 ϫ4-

H bipy), 8.33 (ddd, J_6,5= 5.7, J_6,4= 1.5, J_6,3= 0.8, 1 H, 6-H bipy),

8.71 (ddd, J_3,4= 8.1, J_3,5= 1.4, J_3,6= 0.8, 1 H, 3-H bipy), 8.78–

J_6Љ,4Љ= 1.8, J_6Љ,3Љ= 1.0, 1 H, 6Љ-H), 9.10 (dd, J_6Ј,4Ј= 2.4, J_6Ј,3Ј

=

0.9, 1 H, 6Ј-H) ppm. ¹³C NMR (125.8 MHz, [D₆]DMSO): δ =

46.42 (CH₂), 118.88 (C-5), 120.67 and 120.70 (C-3Ј and C-3Љ),

124.51 (C-5Љ), 126.39 (C^oPh), 127.22 (C^mphenylene), 127.65 (C^p

Ph), 128.95 (C^mPh), 129.60 (C^ophenylene), 129.80 (Cⁱphenylene),

134.69 (C-5Ј), 135.43 (C-4Ј), 137.19 (CⁱPh), 137.57 (C-4Љ), 137.96

(C^pphenylene), 147.59 (C-6Ј), 149.41 (C-8), 149.60 (C-6Љ), 151.69

(C-4), 153.09 (C-2), 154.76 (C-2Ј), 154.97 (C-2Љ), 156.08 (C-6) ppm.

FAB MS: m/z (%) = 456.2 (45%) [M⁺]. HRMS (FAB): for

8.84 (m, 4 H, 3Ј-H and 3 ϫ3-H bipy), 8.84 (dd, J_3,4= 8.2, J_3,5

=

1.3, 1 H, 3-H) ppm. ¹³C NMR (100.6 MHz, [D₆]acetone): δ = 79.31

(CϵCH), 88.56 (HCϵC), 124.92, 124.98, 125.02, 125.50 and 125.53

(C-3Ј and C-3 bipy), 126.04 (C-3), 128.45, 128.50, 128.70, 128.79

and 129.08 (C-5Ј and C-5 bipy), 135.16 (C-5), 138.88, 138.97,

139.04, 139.10, 139.14 and 139.33 (C-4, C-4Ј and C-4 bipy), 148.19

(C-6), 152.39, 152.44, 152.52, 152.91 and 153.75 (C-6Ј and C-6

bipy), 158.03, 158.17, 158.25 and 158.32 (C-2 bipy), 158.79 (C-2Ј),

C₂₈H₂₂N₇calcd.456.1937 found 456.1921. IR (KBr): ν = 3446,

˜

1643, 1589, 1330, 1001, 753 cm^–1. UV/Vis (MeOH): λ_max(ε) = 315

(20980), 259 (6656) nm. C₂₈H₂₁N₇·CHCl₃(574.89): calcd. C 60.59,

H 3.86, N 17.05; found C 60.43, H 3.36, N 16.73.

9-Benzyl-8-[4Ј-(2Ј,2": 6Ј,2"-terpyridine-1Ј-yl)phenyl]adenine (9d): 9-

Benzyl-8-bromoadenine (0.35 g, 1.15 mmol), 4Ј-phenylene-

2,2Ј:6Ј,2ЈЈ-terpyridine (500 mg, 1.15 mmol, 1 equiv.), PdCl₂(10 mg,

0.058 mmol, 5 mol-%), dppf (32 mg, 0.058 mmol, 5 mol-%), and

K₂CO₃(475 mg, 3.45 mmol, 3 equiv.) were combined in DMF

(5 mL)and three drops of water and stirred under argon at 85 °C

for 10 h. The workup was performed in the same way as for 8a.

Crystallization of crude product from CHCl₃(plus a few drops of

159.22 (C-2) ppm. ESI MS: m/z (%) = 739 (65) [M⁺+ PF₆], 297

–

(100) [M²⁺– 2PF ]. IR (KBr): ν = 3435, 3280, 2118 1568, 1466,

–

˜

6

1426, 839, 558 cm^–1. C₃₂H₂₄F₁₂N₆P₂Ru·H₂O (901.6): calcd. C

42.63, H 2.91, N 9.32; found C 43.18, H 3.07, N 9.01.

Complex 5c: The product was isolated as a red solid in 32% yield

1

(Method B). M.p. 185–193 °C. H NMR (500 MHz, [D₆]acetone):

Eur. J. Inorg. Chem. 2007, 1752–1769

www.eurjic.org

1763

M. Hocek, M. Fojta et al.

FULL PAPER

δ = 4.12 (s, 1 H, HCϵC), 7.55–7.62 (m, 5 H, 5Љ-H and 4ϫ5-H (ddd, J_3,4= 8.2, J_3,5= 1.3, J_3,6= 0.7, 1 H, 3-H bipy), 8.37 (ddd,

bipy), 7.99–8.10 (m, 6 H, 6Ј-H, 6Љ-H and 4ϫ6-H bipy), 8.17–8.27 J_6,5= 5.6, J_6,4= 1.5, J_6,3= 0.7, 1 H, 6-H bipy), 8.64, 8.71 and 8.73

(m, 6 H, 4Ј-H, 4Љ-H and 4ϫ4-H bipy), 8.78–8.85 (m, 6 H, 3Ј-H, (3ϫddd, J_3,4= 8.2, J_3,5= 1.3, J_3,6= 0.7, 3ϫ1 H, 3ϫ3-H bipy),

3Љ-H, 4ϫ3-H bipy) ppm. ¹³C NMR (125.8 MHz, [D₆]acetone): δ =

8.89 (ddd, J_3Ј,4Ј= 8.2, J_3Ј,5Ј= 1.3, J_3Ј,6Ј= 0.7, 1 H, 3Ј-H), 8.93 (dd,

78.97 (CϵCH), 86.89 (HCϵC), 123.71 (C-5Ј), 124.89, 125.29, J_3,4= 8.2, J_3,5= 1.4, 1 H, 3-H) ppm. ¹³C NMR (100.6 MHz, [D₆]-

125.33, 125.36, 125.46 and 125.93 (C-3Ј, C-3Љ and C-3 bipy),

128.71, 128.74, 128.80 and 129.04 (C-5Љ and C-5 bipy), 138.97,

139.04 and 139.06 (C-4Љ and C-4 bipy), 141.42 (C-4Ј), 152.58,

152.73, 152.82, 152.84 and 153.09 (C-6Љ and C-6 bipy), 154.81 (C-

6Ј), 157.50 (C-2Ј), 157.79, 158.00, 158.09, 158.12 and 158.17 (C-2Љ

acetone): δ = 124.27 (C-3 bipy), 124.48 (C-3), 125.18, 125.36 and

125.39 (C-3 bipy), 125.97 (C-3Ј), 127.57 and 128.08 (C-5 bipy),

128.18 (C^mphenylene), 128.27 (C-5Ј), 128.80 (C^mphenylene),

128.86 and 128.93 (C-5 bipy), 129.31 (C^ophenylene), 130.59 (C-

5Ј), 137.07 (C-4 bipy), 138.94, 138.97, 139.05 and 139.07 (C-4Ј and

C-4 bipy), 139.18 (C-4), 139.82 (C^pphenylene), 151.90 (C-6 bipy),

152.58 (C-6Ј), 152.70 and 153.78 (C-6 bipy), 157.30, 158.16 and

and C-2 bipy) ppm. ESI MS: m/z (%) = 738.9 (35) [M⁺+ PF₆],

–

297 (100) [M²⁺– 2PF ]. IR (KBr): ν = 3435, 3270, 2117 1559,

–

˜

6

1466, 1465, 839, 558 cm^–1. C₃₂H₂₄F₁₂N₆P₂Ru·H₂O (901.6): calcd. 158.26 (C-2 bipy), 158.61, 159.06 and 159.10 (C-2, C-2Ј and C-2

C 42.63, H 2.91, N 9.32; found C 42.80, H 3.06, N 9.10.

bipy), 167.75 (C-6) ppm; Cⁱphenylene signal not observed. ESI

MS: m/z (%) = 834 (5) [M⁺+ PF₆], 345 (15) [M²⁺– 2PF₆]. IR

–

Complex 6a: The product was isolated as a red solid in 66% yield

(KBr):

ν

˜

=

3437, 3083, 2342, 1242, 1225, 842, 558 cm^–1.

1

(Method B). M.p. 182–188 °C. H NMR (400 MHz, [D₆]acetone):

C₃₆H₂₉BF₁₂N₆O₂P₂Ru (979.5): calcd. C 44.15, H 2.98, N 8.58;

found C 44.11, H 3.16, N 8.29.

δ = 6.24 (br. m, 1 H, H^mphenylene), 6.94 (ddd, J_5,4= 7.6, J_5,6

=

5.6, J_5,3= 1.3, 1 H, 5-H bipy), 7.22 (s, 2 H, B(OH)₂), 7.28 (br. m,

1 H, H^ophenylene), 7.31 (ddd, J_6,5= 5.6, J_6,4= 1.5, J_6,3= 0.7, 1

H, 6-H bipy), 7.40, 7.47 and 7.50 (3ϫddd, J_5,4= 7.6, J_5,6= 5.6,

J_5,3= 1.3, 3ϫ1 H, 3ϫ5-H bipy), 7.55 (br. m, 1 H, H^mphenylene),

7.60 (br. m, 1 H, H^ophenylene), 7.68 (td, J_4,3= 8.2, J_4,5= 7.6, J_4,6

= 1.5, 1 H, 4-H bipy), 7.79 and 7.83 (2ϫddd, J_6,5= 5.6, J_6,4= 1.5,

J_6,3= 0.7, 2ϫ1 H, 2ϫ6-H bipy), 7.84 (d, J_3,4= 8.3, 1 H, 3-H),

7.85 (dd, J_8,9= 8.3, J_8,7= 5.3, 1 H, 8-H), 8.12, 8.14 and 8.23

(3ϫddd, J_4,3= 8.2, J_4,5= 7.6, J_4,6= 1.5, 3ϫ1 H, 3ϫ4-H bipy),

8.26 (dd, J_9,8= 5.3, J_9,7= 1.3, 1 H, 9-H), 8.28 (ddd, J_6,5= 5.6, J_6,4

= 1.5, J_6,3= 0.7, 1 H, 6-H bipy), 8.32 (ddd, J_3,4= 8.2, J_3,5= 1.3,

J_3,6= 0.7, 1 H, 3-H bipy), 8.45 (d, J_6,5= 8.9, 1 H, 6-H), 8.50 (d,

Complex 6c: The product was isolated as a red solid in 42% yield

(Method B). M.p. 151–172 °C. H NMR (500 MHz, [D₆]acetone):

1

δ = 7.35 (s, 1 H, B–OH), 7.44 (m, 2 H, H^mphenylene), 7.55–7.65

(m, 5 H, 5Љ-H and 4ϫ5-H bipy), 7.89 (m, 2 H, H^ophenylene),

8.07, 8.08 and 8.10 (3ϫddd, J_6,5= 5.6, J_6,4= 1.5, J_6,3= 0.7, 3ϫ1

H, 3ϫ6-H bipy), 8.11 (dd, J_6,4= 2.1, J_6,3= 0.6, 1 H, 6Ј-H), 8.17

(ddd, J_6,5= 5.6, J_6,4= 1.5, J_6,3= 0.7, 1 H, 6-H bipy), 8.18–8.28

(m, 6 H, 6Љ-H, 4Љ-H and 4ϫ4-H bipy), 8.50 (dd, J_4Ј,3Ј= 8.6, J_4Ј,6Ј

= 2.1, 1 H, 4Ј-H), 8.70, 8.83, 8.835 and 8.84 (4ϫdt, J_3,4= 8.3, J_3,5

= 1.3, J_3,6= 0.7, 4H 4ϫ3-H bipy), 8.86 (dt, J_3,4= 8.3, J_3,5= 1.3,

J_3,6= 0.7, 4 H, 3Љ-H), 8.89 (dd, J_3Ј,4Ј= 8.6, J_3Ј,6Ј= 0.6, 1 H, 3Ј-

H) ppm. ¹³C NMR (125.8 MHz, [D₆]acetone): δ = 125.24, 125.31,

125.36 and 125.45 (C-3Ј, C-3Љ and C-3 bipy), 126.88 (C^mphenyl-

ene), 128.64, 128.68, 128.72 and 128.81 (C-5Љ and C-5 bipy), 135.91

(C^ophenylene), 136.65 (C-4Ј), 137.14 (C^pphenylene), 138.88 and

138.92 (C-4Љ and C-4 bipy), 140.77 (C-5Ј), 149.90 (C-6Ј), 152.64,

152.68, 153.02 and 153.07 (C-6Љ and C-6 bipy), 156.79 (C-2Ј),

157.91, 158.03, 158.09, 158.15 and 158.27 (C-2Љ and C-2 bipy) ppm;

Cⁱphenylene signal not observed. ESI MS: m/z (%) = 835 (100)

J_5,6= 8.9, 1 H, 5-H), 8.67, 8.70 and 8.73 (3ϫdt, J_3,4= 8.2, J_3,5

1.3, J_3,6= 0.7, 3ϫ1 H, 3ϫ3-H bipy), 8.81 (dd, J_7,8= 8.3, J_7,9

=

1.3, 1 H, 7-H), 8.92 (d, J_4,3= 8.3, 1 H, 4-H) ppm. ¹³C NMR

(100.6 MHz, [D₆]acetone): δ = 124.18, 125.16, 125.19 and 125.28

(C-3 bipy), 126.77 (C-8Ј), 126.96 (C^mphenylene), 127.54 (C-5 bipy),

127.81 (C^mphenylene), 127.97, 128.67, 128.95 and 128.97 (C-6 and

C-5 bipy), 129.34 and 129.36 (C-3 and C-5), 131.27 (C-4a), 132.60

(C-6a), 134.86 (C^ophenylene), 135.28 (Cⁱphenylene), 136.90 (C-4

bipy), 137.89 (C-7), 138.53 (C-4), 138.91 and 139.11 (C-4 bipy),

141.28 (C^pphenylene), 148.55 (C-10b), 149.03 (C-10a), 152.13,

152.89 and 152.94 (C-6 bipy), 153.46 (C-9Ј), 153.81 (C-6 bipy),

157.56, 158.11, 158.43 and 159.03 (C-2 bipy), 168.67 (C-2Ј) ppm.

[M⁺+ PF₆], 345 (30) [M²⁺– 2PF ]. IR (KBr): ν = 3435, 3083,

–

˜

6

2981, 1244, 1222, 840, 558 cm^–1. C₃₆H₂₉BF₁₂N₆O₂P₂Ru (979.5):

calcd. C 44.15, H 2.98, N 8.58; found C 44.58, H 3.51, N 8.13.

ESI MS: m/z (%) = 859 (65) [M⁺+ PF₆], 357 (70) [M²⁺– 2PF₆].

–

Complex 6d: The product was isolated as a red solid in 69% yield

(Method B). M.p. Ͼ310 °C. ¹H NMR (500 MHz, [D₆]acetone): δ

= 7.33 and 7.34 (2ϫddd, J_5Ј,4Ј= 7.5, J_5Ј,6Ј= 5.5, J_5Ј,3Ј= 1.3, 2ϫ2

H, 5Ј-H terpy and 5Ј-H Ph-terpy), 7.52 (br. s, 1 H, B–OH), 7.72

(ddd, J_6Ј,5Ј= 5.5, J_6Ј,4Ј= 1.5, J_6Ј,3Ј= 0.7, 2 H, 6Ј-H Ph-terpy), 7.81

(ddd, J_6Ј,5Ј= 5.5, J_6Ј,4Ј= 1.5, J_6Ј,3Ј= 0.7, 2 H, 6Ј-H terpy), 8.08

and 8.09 (2ϫddd, J_4Ј,3Ј= 8.2, J_4Ј,5Ј= 7.5, J_4Ј,6Ј= 1.5, 2ϫ2 H, 4Ј-

H terpy and 4Ј-H Ph-terpy), 8.22 (m, 2 H, H^ophenylene), 8.33 (m,

2 H, H^mphenylene), 8.58 (t, J_4,3&5= 8.2, 1 H, 4-H terpy), 8.82

(ddd, J_3Ј,4Ј= 8.2, J_3Ј,5Ј= 1.3, J_3Ј,6Ј= 0.7, 2 H, 6Ј-H terpy), 9.07

(ddd, J_3Ј,4Ј= 8.2, J_3Ј,5Ј= 1.3, J_3Ј,6Ј= 0.7, 2 H, 6Ј-H Ph-terpy), 9.08

(d, J_3&5,4= 8.2, 2 H, 3,5-H terpy), 9.45 (s, 2 H, 3,5-H Ph-

terpy) ppm. ¹³C NMR (125.8 MHz, [D₆]acetone): δ = 122.30 (C-

3,5 Ph-terpy), 124.78 (C-3,5 terpy), 125.41 (C-3Ј terpy), 125.65 (C-

IR (KBr): ν = 3435, 3082, 2924, 1242, 1202, 840, 558 cm^–1.

˜

C₃₈H₂₉BF₁₂N₆O₂P₂Ru·H₂O (1021.5): calcd. C 44.68, H 3.06, N

8.23; found C 44.65, H 2.90, N 8.32.

Complex 6b: The product was isolated as a red solid in 47% yield

1

(Method B). M.p. 180–200 °C. H NMR (400 MHz, [D₆]acetone):

δ = 6.15 (br. m, 1 H, H^mphenylene), 6.78 (br. m, 1 H, H^ophenyl-

ene), 6.97 (ddd, J_5,4= 7.6, J_5,6= 5.6, J_5,3= 1.3, 1 H, 5-H bipy),

7.06 (br. m, 1 H, H^ophenylene), 7.27 (ddd, J_6,5= 5.6, J_6,4= 1.5,

J_6,3= 0.7, 1 H, 6-H bipy), 7.41 (ddd, J_5,4= 7.6, J_5,6= 5.6, J_5,3

=

1.3, 1 H, 5-H bipy), 7.45 (br. m, 1 H, H^mphenylene), 7.48 (dd, J_5,4

= 7.7, J_5,3= 1.4, 1 H, 5-H), 7.50 (ddd, J_5Ј,4Ј= 7.6, J_5Ј,6Ј= 5.6, J_5Ј,3Ј

= 1.3, 1 H, 5Ј-H), 7.61 (ddd, J_5,4= 7.6, J_5,6= 5.6, J_5,3= 1.3, 1 H,

5-H bipy), 7.67 (ddd, J_6,5= 5.6, J_6,4= 1.5, J_6,3= 0.7, 1 H, 6-H

bipy), 7.70 (ddd, J_5,4= 7.6, J_5,6= 5.6, J_5,3= 1.3, 1 H, 5-H bipy), 3Ј Ph-terpy), 127.57 (C^mphenylene), 128.60 (C-5Ј Ph-terpy and C-

7.73 (ddd, J_4,3= 8.2, J_4,5= 7.6, J_4,6= 1.5, 1 H, 4-H bipy), 7.89

5Ј terpy), 136.08 (C^ophenylene), 138.97 (C^pphenylene), 139.05 and

(ddd, J_6Ј,5Ј= 5.6, J_6Ј,4Ј= 1.5, J_6Ј,3Ј= 0.7, 1 H, 6Ј-H), 8.07 (ddd, J_4,3139.12 (C-4Ј Ph-terpy and C-4Ј terpy), 149.13 (C-4 Ph-terpy),

= 8.2, J_4,5= 7.6, J_4,6= 1.5, 1 H, 4-H bipy), 8.13 (ddd, J_6,5= 5.6,

J_6,4= 1.5, J_6,3= 0.7, 1 H, 6-H bipy), 8.21 (ddd, J_4,3= 8.2, J_4,5

7.6, J_4,6= 1.5, 1 H, 4-H bipy), 8.22 (ddd, J_4Ј,3Ј= 8.2, J_4Ј,5Ј= 7.6,

J_4Ј,6Ј= 1.5, 1 H, 4Ј-H), 8.28 (ddd, J_4,3= 8.2, J_4,5= 7.6, J_4,6= 1.5,

1 H, 4-H bipy), 8.31 (t, 1 H, J_4,3= 8.2, J_4,5= 7.7, 1 H, 4-H), 8.32

153.41 and 153.48 (C-6Ј Ph-terpy and C-6Ј terpy), 156.41 (C-2,6

terpy), 156.65 (C-2,6 Ph-terpy), 159.20 (C-2Ј terpy), 159.36 (C-2Ј

Ph-terpy) ppm; Cⁱphenylene signal not observed. ESI MS: m/z (%)

=

–

= 833 (50) [M⁺+ PF₆], 344 (40) [M²⁺– 2PF₆], 687 (75) [M⁺

–

2PF ]. IR (KBr): ν = 3435, 3083, 2981, 1244, 1222, 840, 558 cm^–1.

–

˜

6

1764

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Eur. J. Inorg. Chem. 2007, 1752–1769

Ru-Labelled Purines

FULL PAPER

C₃₆H₂₇BF₁₂N₆O₂P₂Ru·H₂O (995.5): calcd. C 43.44, H 2.94, N 8.60; MS: m/z (%) = 816 (15) [M⁺– 2PF₆], 408 (100) [M²⁺– 2PF₆]. IR

found C 43.63, H 2.95, N 8.23.

–

(KBr): ν = 2218, 1639, 841, 558 cm^–1. UV/Vis (MeOH): λ

(ε) =

˜

max

442

(17095),

355

sh

(26410),

287

(88079) nm.

Complex 10a: The product was isolated as an orange solid in 69%

yield (Method B). M.p. 261–264 °C. ¹H NMR (500 MHz, [D₆]ace-

tone): δ = 5.28 and 5.42 (2ϫd, J_gem= 15.5, 2 H, CH₂Ph), 6.91 (br.

s, 1 H, NH), 6.99 (ddd, J_5,4= 7.6, J_5,6= 5.6, J_5,3= 1.4, 1 H, 5-H

bipy), 7.23 (m, 2 H, H^oPh), 7.25–7.32 (m, 3 H, H^m,pPh), 7.37 and

7.51 (2ϫddd, J_5,4= 7.6, J_5,6= 5.6, J_5,3= 1.4, 2ϫ1 H, 2ϫ5-H

bipy), 7.52 (ddd, J_4,3= 8.3, J_4,5= 7.6, J_4,6= 1.5, 1 H, 4-H bipy),

7.56 (ddd, J_5,4= 7.6, J_5,6= 5.6, J_5,3= 1.4, 1 H, 5-H bipy), 7.71 and

7.86 (2ϫddd, J_6,5= 5.6, J_6,4= 1.5, J_6,3= 0.7, 2ϫ1 H, 2ϫ6-H

bipy), 7.91 (dd, J_8Ј,9Ј= 8.2, J_8Ј,7Ј= 5.3, 1 H, 8Ј-H), 7.97 (ddd, J_6,5

= 5.6, J_6,4= 1.5, J_6,3= 0.7, 1 H, 6-H bipy), 8.17 (d, J_3Ј,4Ј= 8.4, 1

H, 3Ј-H), 8.18–8.24 (m, 4 H, 6-H bipy and 3ϫ4-H bipy), 8.29 (s,

1 H, H-2), 8.33 (dd, J_9Ј,8Ј= 5.3, J_9Ј,7Ј= 1.3, 1 H, 9Ј-H), 8.44 (d,

J_5Ј,6Ј= 8.9, 1 H, 5Ј-H), 8.47 (d, J_6Ј,5Ј= 8.9, 1 H, 6Ј-H), 8.56 (ddd,

J_3,4= 8.3, J_3,5= 1.4, J_3,6= 0.7, 1 H, 3-H bipy), 8.78–8.84 (m, 4 H,

7Ј-H and 3ϫ3-H bipy), 8.91 (d, J_4Ј,3Ј= 8.4, 1 H, 4Ј-H) ppm. ¹³C

NMR (125.8 MHz, [D₆]acetone): δ = 47.33 (CH₂Ph), 89.14 (CϵC

pur), 90.68 (CϵC pur), 120.07 (C-5), 125.23, 125.44, 125.49 and

125.51 (C-3 bipy), 127.33 (C-8Ј), 128.26 and 128.57 (C-5 bipy),

128.61 (C^oPh), 128.81 (C-5 bipy), 128.97 (C^pPh), 129.10 and

129.13 (C-5Ј and C-5 bipy), 129.65 (C^mPh), 130.02 (C-6Ј), 131.60

(C-4aЈ), 132.12 (C-8), 132.77 (C-6aЈ), 133.60 (C-3Ј), 137.29 (CⁱPh),

137.67 (C-4 bipy), 138.07 (C-7Ј), 138.39 (C-4Ј), 139.07, 139.15 and

139.41 (C-4 bipy), 147.60 (C-2Ј), 148.65 (C-10aЈ), 149.59 (C-10bЈ),

150.77 (C-4), 152.30, 152.45 and 152.73 (C-6 bipy), 153.67 (C-3Ј),

153.77 (C-9Ј), 155.79 (C-2), 157.29 (C-6), 157.82, 158.01, 158.19

C₄₄H₃₃F₁₂N₁₁P₂Ru·H₂O (1124.8): calcd. C 46.98, H 3.14, N 13.7;

found C 46.83, H 3.03, N 13.56.

Complex 10c: The product was isolated as an orange solid in 75%

yield (Method B). M.p. 284–291 °C. ¹H NMR (500 MHz, [D₆]ace-

tone): δ = 5.45 (s, 2 H, CH₂Ph), 6.88 (br. s, 2 H, NH₂), 7.26–7.34

(m, 5 H, H-o,m,p-Ph), 7.54–7.63 (m, H-5Љ, 5 H, 4ϫ5-H bipy), 8.00,

8.04 and 8.07 (3ϫddd, J_6,5= 5.6, J_6,4= 1.4, J_6,3= 0.6, 1 H, 3ϫ6-

H bipy), 8.09 (ddd, J_6Љ,5Љ= 5.6, J_6Љ,4Љ= 1.4, J_6Љ,3Љ= 0.6, 1 H, 6Љ-H),

8.14–8.25 (m, 6 H, 4Љ-H, 4ϫ4-H bipy and 6-H bipy), 8.25 (s, 1 H,

H-2), 8.29 (dd, J_6Ј,4Ј= 1.9, J_6Ј,3Ј= 0.7, 1 H, 6Ј-H), 8.39 (dd, J_4Ј,3Ј

= 8.5, J_4Ј,6Ј= 1.9, 1 H, 4Ј-H), 8.78, 8.81, 8.82 and 8.86 (4ϫdt, J_3,4

= 8.3, J_3,5= 1.5, J_3,6= 0.6, 5 H, 3Љ-H and 4ϫ3-H bipy), 8.90 (dd,

J_3Ј,4Ј= 8.5, J_3Ј,6Ј= 0.7, 1 H, 3Ј-H) ppm. ¹³C NMR (100.6 MHz,

[D₆]acetone): δ = 47.21 (CH₂Ph), 86.09 (CϵC pur), 89.84 (CϵC

pur), 120.62 (C-5), 122.55 (C-5Ј), 125.00 (C-3Ј), 125.33, 125.46 and

126.18 (C-3Љ and C-3 bipy), 128.50 (C^oPh), 128.2, 128.75, 128.82,

128.84 and 129.18 (C^pPh, C-5Љ and C-5 bipy), 129.63 (C^mPh),

133.26 (C-8), 137.50 (CⁱPh), 138.98, 139.03 and 139.10 (C-4Љ and

C-4 bipy), 141.03 (C-4Ј), 150.89 (C-4), 152.54, 152.77, 152.84,

152.88 and 153.09 (C-6Љ and C-6 bipy), 154.66 (C-6Ј), 155.50 (C-

2), 157.10 (C-6), 157.37 (C-2Ј), 157.99, 158.04, 158.12, 158.04 and

158.30 (C-2Љ and C-2 bipy) ppm. ESI MS: m/z (%) = 816 (5) [M⁺

–

2PF₆], 408 (100) [M²⁺– 2PF ]. IR (KBr): ν = 2221, 1635, 840,

˜

6

558 cm^–1. UV/Vis (MeOH): λ_max(ε) = 442 sh (18007), 365 (34598),

286 (85546) nm. C₄₄H₃₃F₁₂N₁₁P₂Ru·H₂O (1124.8): calcd. C 46.98,

H 3.14, N 13.7; found C 46.26, H 3.08, N 13.35.

and 158.76 (C-2 bipy) ppm. ESI MS: m/z (%) = 840 (50) [M⁺

–

2PF₆], 420 (100) [M²⁺– 2PF ]. IR (KBr): ν = 2220, 1637, 840,

˜

6

General Procedure for Cross-Coupling of Complexes 6a–6d with 7 -

Method C

558 cm^–1. UV/Vis (MeOH): λ_max(ε) = 439 (14454), 373 (19412),

285 (81332) nm. C₄₆H₃₃F₁₂N₁₁P₂Ru·H₂O (1148.9): calcd. C 48.09,

H 3.07, N 13.41; found C 48.40, H 3.29, N 13.09.

9-Benzyl-8-bromoadenine (20 mg, 0.065 mmol), the corresponding

complex (6a–6d) (0.072 mmol, 1.1 equiv.), and Cs₂CO₃(64 mg,

0.195 mmol, 3 equiv.) were combined and a mixture of degassed

CH₃CN/H₂O (1:1, 1 mL) was added. To this mixture was added a

solution of Pd(OAc)₂(0.0065 mmol, 10 mol-%) and water soluble

P(Ph-mSO₃Na)₃(0.0325 mmol, 5 equiv. to Pd, 50 mol-%) in

CH₃CN/H₂O (1:1, 0.5 mL). The whole mixture was degassed and

the flask filled with argon. The mixture was stirred under argon at

95 °C for 7 h. The solvent was than evaporated and the products

were purified by silica gel column chromatography using a mixture

of CH₃CN/H₂O/saturated KNO₃(10:1:0.1) as eluent. The crystalli-

zation from acetonitrile or acetone/iPrOH, diethylether gave the

desired products 11a–11d.

Complex 10b: The product was isolated as an orange solid in 80%

yield (Method B). M.p. 295–301 °C. ¹H NMR (500 MHz, [D₆]ace-

tone): δ = 5.22 and 5.34 (2ϫd, J_gem= 15.5, CH₂Ph), 6.87 (br. s, 1

H, NH), 6.91 (ddd, J_5,4= 7.6, J_5,6= 5.6, J_5,3= 1.3, 1 H, 5-H bipy),

7.20 (m, 2 H, H^oPh), 7.27–7.31 (m, 3 H, H^m,pPh), 7.47 (ddd, J_4,3

= 8.5, J_4,5= 7.6, J_4,6= 1.5, 1 H, 4-H bipy), 7.50 (ddd, J_5,4= 7.6,

J_5,6= 5.6, J_5,3= 1.3, 1 H, 5-H bipy), 7.56 (ddd, J_5Љ,4Љ= 7.6, J_5Љ,6Љ

= 5.6, J_5Љ,3Љ= 1.3, 1 H, 5Љ-H), 7.58 and 7.69 (2ϫddd, J_5,4= 7.6,

J_5,6= 5.6, J_5,3= 1.3, 2ϫ1 H, 5-H bipy), 7.78 and 7.88 (2ϫddd,

J_6,5= 5.6, J_6,4= 1.5, J_6,3= 0.7, 2ϫ1 H, 6-H bipy), 7.92 (dd, J_5Ј,4Ј

= 7.8, J_5Ј,3Ј= 1.4, 1 H, 5Ј-H), 7.94 (ddd, J_6Љ,5Љ= 5.6, J_6Љ,4Љ= 1.5,

J_6Љ,3Љ= 0.7, 1 H, 6Љ-H), 7.97 (ddd, J_6,5= 5.6, J_6,4= 1.5, J_6,3= 0.7,

1 H, 6-H bipy), 8.17 (ddd, J_4,3= 8.5, J_4,5= 7.6, J_4,6= 1.5, 1 H, 4-

H bipy), 8.23 (ddd, J_4Љ,3Љ= 8.5, J_4Љ,5Љ= 7.6, J_4Љ,6Љ= 1.5, 1 H, 4Љ-H),

8.26 (ddd, J_4,3= 8.5, J_4,5= 7.6, J_4,6= 1.5, 1 H, 4-H bipy), 8.27 (s,

1 H, H-2), 8.28 (ddd, J_4,3= 8.5, J_4,5= 7.6, J_4,6= 1.5, 1 H, 4-H

Complex 11a: The product was isolated as an orange solid in 72%

yield (Method B) and in 40% yield (Method C). M.p. 210–215 °C.

¹H NMR (500 MHz, [D₆]acetone): δ = 5.57 and 5.62 (2ϫd, J_gem

= 16.7, 2 H, CH₂Ph), 6.38 (br. m, 1 H, H^mphenylene), 6.98 (ddd,

J_5,4= 7.7, J_5,6= 5.6, J_5,3= 1.3, 1 H, 5-H bipy), 7.10 (m, 2 H, H^o

Ph), 7.22 (br. m, 1 H, H^ophenylene), 7.29–7.37 (m, 3 H, H^m,pPh),

7.37 (ddd, J_6,5= 5.6, J_6,4= 1.4, J_6,3= 0.7, 1 H, 6-H bipy), 7.41,

7.46 and 7.47 (3ϫddd, J_5,4= 7.7, J_5,6= 5.6, J_5,3= 1.3, 3ϫ1 H,

bipy), 8.32 (t, J_4Ј,3Ј= 8.3, J_4Ј,5Ј= 7.8, 1 H, 4Ј-H), 8.40 (ddd, J_6,5

=

5.6, J_6,4= 1.5, J_6,3= 0.7, 1 H, 6-H bipy), 8.49, 8.77 and 8.83

(3ϫddd, J_3,4= 8.5, J_3,5= 1.3, J_3,6= 0.7, 3ϫ1 H, 3ϫ3-H bipy),

8.87 (ddd, J_3Љ,4Љ= 8.5, J_3Љ,5Љ= 1.3, J_3Љ,6Љ= 0.7, 1 H, 3Љ-H), 8.92 (dd,

J_3Ј,4Ј= 8.3, J_3Ј,5Ј= 1.4, 1 H, 3Ј-H) ppm. ¹³C NMR (125.8 MHz, 3ϫ5-H bipy), 7.51 (br. m, 1 H, H^ophenylene), 7.72 (br. m, 1 H,

[D₆]acetone): δ = 47.27 (CH₂Ph), 87.58 (CϵC pur), 90.40 (CϵC

pur), 118.92 (C-5), 125.31, 125.37, 125.44, 125.57 and 126.19 (C-

3Ј, C-3Љ and C-3 bipy), 128.42 and 128.44 (C-5 bipy), 128.59 (C^o

Ph), 128.75 (C-5 bipy), 128.94 (C^pPh and C-5 bipy), 129.06 (C-5Љ),

H^mphenylene), 7.75 (td, J_4,3= 8.1, J_4,5= 7.7, J_4,6= 1.5, 1 H, 4-H

bipy), 7.77 (ddd, J_6,5= 5.6, J_6,4= 1.4, J_6,3= 0.7, 1 H, 6-H bipy),

7.85 (dd, J_8Ј,9Ј= 8.2, J_8Ј,7Ј= 5.3, 1 H, 8Ј-H), 7.88 (d, J_3Ј,4Ј= 8.3, 1

H, 3Ј-H), 7.89 (ddd, J_6,5= 5.6, J_6,4= 1.4, J_6,3= 0.7, 1 H, 6-H bipy),

129.63 (C^mPh), 132.23 (C-8), 135.78 (C-5Ј), 137.26 (CⁱPh), 137.39, 8.11, 8.13 and 8.20 (3ϫddd, J_4,3= 8.1, J_4,5= 7.7, J_4,6= 1.5, 3ϫ1

139.03, 139.14, 139.22, 139.25 and 139.37 (C-4Ј, C-4Љ and C-4 H, 3ϫ4-H bipy), 8.20 (ddd, J_6,5= 5.6, J_6,4= 1.4, J_6,3= 0.7, 1 H,

bipy), 147.41 (C-6Ј), 150.72 (C-4), 152.21, 152.23, 152.44, 152.67 6-H bipy), 8.25 (dt, J_3,4= 8.1, J_3,5= 1.3, J_3,6= 0.7, 1 H, 3-H bipy),

and 153.76 (C-6Љ and C-6 bipy), 155.70 (C-2), 157.27 (C-6), 157.97, 8.27 (dd, J_9Ј,8Ј= 5.3, J_9Ј,7Ј= 1.3, 1 H, 9Ј-H), 8.37 (s, 1 H, H-2),

158.01 and 158.79 (C-2Љ and C-2 bipy), 159.72 (C-2Ј) ppm. ESI

8.46 (d, J_6Ј,5Ј= 8.9, 1 H, 6Ј-H), 8.51 (d, J_5Ј,6Ј= 8.9, 1 H, 5Ј-H),

Eur. J. Inorg. Chem. 2007, 1752–1769

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1765

M. Hocek, M. Fojta et al.

FULL PAPER

8.59, 8.66 and 8.69 (3ϫdt, J_3,4= 8.1, J_3,5= 1.3, J_3,6= 0.7, 3ϫ1

H, 3ϫ3-H bipy), 8.82 (dd, J_7Ј,8Ј= 8.2, J_7Ј,9Ј= 1.3, 1 H, 7Ј-H), 8.95

(d, J_4Ј,3Ј= 8.3, 1 H, 4Ј-H) ppm. ¹³C NMR (125.8 MHz, [D₆]ace-

bipy), 8.24 (s, 1 H, H-2), 8.26 (td, J_4,3= 8.3, J_4,5= 7.6, J_4,6= 1.5,

1 H, 4-H bipy), 8.54 (dd, J_4Ј,3Ј= 8.6, J_4Ј,6Ј= 2.1, 1 H, 4Ј-H), 8.79,

8.82, 8.83 and 8.88 (4ϫdt, J_3,4= 8.3, J_3,5= 1.5, J_3,6= 0.7, 5 H,

tone): δ = 47.61 (CH₂Ph), 117.89 (C-5), 124.45, 125.16, 125.18 and 3Љ-H and 4ϫ3-H bipy), 8.91 (dd, J_3Ј,4Ј= 8.6, J_3Ј,6Ј= 0.6, 1 H, 3Ј-

125.25 (C-3 bipy), 126.85 (C-8Ј), 127.29 (C^oPh), 127.86, 128.04,

H) ppm. ¹³C NMR (100.6 MHz, [D₆]acetone): δ = 47.35 (CH₂Ph),

120.09 (C-5), 125.24, 125.31, 125.34, 125.45 and 125.48 (C-3Ј, C-

128.52, 128.62, 128.74, 128.99, 129.11, 129.30, 129.39, 129.47 and

129.56 (C-3Ј, C-5Ј, C-6Ј, C-5-bipy, C^o,mphenylene and C^pPh), 3Љ and C-3 bipy), 127.32 (C^oPh), 128.16 (C^mphenylene), 128.42

129.74 (C^mPh), 131.10 (Cⁱphenylene), 131.36 (C-4aЈ), 132.60 (C-

6aЈ), 137.64 (CⁱPh), 137.80 (C-7Ј), 137.93 (C-4 bipy), 138.69 (C- Ph), 130.55 (C^ophenylene), 132.21 (Cⁱphenylene), 136.75 (C-4Ј),

4Ј), 138.92 and 139.15 (C-4 bipy), 141.15 (C^pphenylene), 148.75 136.88 (C^pphenylene), 137.99 (CⁱPh), 138.94 (C-4Љ and C-4 bipy),

(C^pPh), 128.69, 128.72 and 128.81 (C-5Љ and C-5 bipy), 129.58 (C^m

(C-10bЈ), 148.95 (C-10aЈ), 151.04 (C-8), 151.34 (C-2), 152.10 (C-6 139.81 (C-5Ј), 150.02 (C-6Ј), 150.37 (C-8), 152.62 and 152.66 (C-6

bipy), 152.62 (C-4), 152.64 and 153.15 (C-6 bipy), 153.46 (C-9Ј), bipy), 153.00 (C-4), 153.03 and 153.08 (C-6Љ and C-6 bipy), 153.80

153.67 (C-6 bipy), 155.17 (C-6), 157.40, 158.01, 158.38 and 158.79

(C-2 bipy), 167.55 (C-2Ј) ppm. ESI MS: m/z (%) = 892 (25)

(C-2), 156.73 (C-6), 157.12 (C-2Ј), 157.82, 158.00, 158.10, 158.14

and 158.26 (C-2Љ and C-2 bipy) ppm. ESI MS: m/z (%) = 1014 (70)

[M⁺– 2PF₆], 447 (100) [M²⁺– 2PF ]. IR (KBr): ν = 1636, 840,

[M⁺– PF₆], 434 (100) [M²⁺– 2PF ]. IR (KBr): ν = 1635, 840,

–

˜

6

558 cm^–1. UV/Vis (MeOH): λ_max(ε) = 446 (15810), 287 (72639),

268 sh (63625) nm. C₅₀H₃₇F₁₂N₁₁P₂Ru·2H₂O (1218.9): calcd. C

49.27, H 3.39, N 12.64; found C 49.34, H 3.06, N 12.52.

558 cm^–1. UV/Vis (MeOH): λ_max(ε) = 451 (13145), 320 sh (34814),

286 (77563) nm. C₄₈H₃₇F₁₂N₁₁P₂Ru·2H₂O (1194.9): calcd. C 48.25,

H 3.46, N 12.89; found C 48.10, H 3.24, N 12.84.

Complex 11b: The product was isolated as an orange solid in 74%

yield (Method B) and in 24% yield (Method C). M.p. 208–210 °C.

¹H NMR (500 MHz, [D₆]acetone): δ = 5.52 and 5.54 (2ϫd, J_gem

= 16.8, 2 H, CH₂Ph), 6.25 (br. m, 1 H, H^mphenylene), 6.95 (ddd,

Complex 11d: The product was isolated as an orange solid in 65%

yield (Method B) and in 63% yield (Method C). M.p. Ͼ320 °C. ¹H

NMR (500 MHz, [D₆]acetone): δ = 5.74 (s, 2 H, CH₂Ph), 6.82 (br.

s, 2 H, NH₂), 7.19 (m, 2 H, H^oPh), 7.29–7.39 (m, 7 H, 5Ј-H terpy,

J_5,4= 7.7, J_5,6= 5.6, J_5,3= 1.3, 1 H, 5-H bipy), 7.07 (m, 2 H, H^o5Ј-H Ph-terpy, H^m,pPh), 7.73 (ddd, J_6Ј,5Ј= 5.6, J_6Ј,4Ј= 1.5, J_6Ј,3Ј

=

Ph), 7.13 (br. m, 2 H, H^ophenylene), 7.27–7.36 (m, 4 H, 6-H bipy

and H^m,pPh), 7.41 (ddd, J_5,4= 7.7, J_5,6= 5.6, J_5,3= 1.3, 1 H, 5-H

0.6, 2 H, 6Ј-H Ph-terpy), 7.81 (ddd, J_6Ј,5Ј= 5.6, J_6Ј,4Ј= 1.5, J_6Ј,3Ј

0.6, 2 H, 6Ј-H terpy), 8.08 (ddd, J_4Ј,3Ј= 8.2, J_4Ј,5Ј= 7.5, J_4Ј,6Ј

bipy), 7.42 (br. m, 1 H, H^mphenylene), 7.51 (ddd, J_5Љ,4Љ= 7.7, J_5Љ,6Љ1.5, 2 H, 4Ј-H Ph-terpy), 8.09 (ddd, J_4Ј,3Ј= 8.2, J_4Ј,5Ј= 7.5, J_4Ј,6Ј

= 5.6, J_5Љ,3Љ= 1.3, 1 H, 5Љ-H), 7.92 (dd, J_5Ј,4Ј= 7.7, J_5Ј,3Ј= 1.3, 1

H, 5Ј-H), 7.61 (ddd, J_5,4= 7.7, J_5,6= 5.6, J_5,3= 1.3, 1 H, 5-H bipy),

7.65 (ddd, J_6,5= 5.6, J_6,4= 1.5, J_6,3= 0.7, 1 H, 6-H bipy), 7.68

(ddd, J_5,4= 7.7, J_5,6= 5.6, J_5,3= 1.3, 1 H, 5-H bipy), 7.73 (ddd,

1.5, 2 H, 4Ј-H terpy), 8.10 (m, 2 H, H^ophenylene), 8.48 (m, 2 H,

H^mphenylene), 8.59 (t, J_4,3&5= 8.2, 1 H, 4-H terpy), 8.82 (ddd,

J_3Ј,4Ј= 8.2, J_3Ј,5Ј= 1.3, J_3Ј,6Ј= 0.6, 2 H, 6Ј-H terpy), 9.06 (ddd,

J_3Ј,4Ј= 8.2, J_3Ј,5Ј= 1.3, J_3Ј,6Ј= 0.6, 2 H, 6Ј-H Ph-terpy), 9.09 (d,

J_3&5,4= 8.2, 2 H, 3,5-H terpy), 9.49 (s, 2 H, 3,5-H Ph-terpy) ppm.

¹³C NMR (125.8 MHz, [D₆]acetone): δ = 47.48 (CH₂Ph), 120.24

(C-5), 122.26 (C-3,5 Ph-terpy), 124.81 (C-3,5 terpy), 125.43 (C-3Ј

J_4,3= 8.2, J_4,5= 7.7, J_4,6= 1.5, 1 H, 4-H bipy), 7.91 (ddd, J_6Љ,5Љ

=

5.6, J_6Љ,4Љ= 1.5, J_6Љ,3Љ= 0.7, 1 H, 6Љ-H), 8.07 (ddd, J_4,3= 8.2, J_4,5

= 7.7, J_4,6= 1.5, 1 H, 4-H bipy), 8.17 (ddd, J_6,5= 5.6, J_6,4= 1.5,

J_6,3= 0.7, 1 H, 6-H bipy), 8.19–8.28 (m, 4 H, 4Љ-H, 3-H bipy, 2ϫ4- terpy), 125.71 (C-3Ј-Ph_terpy), 127.41 (C^oPh), 128.50 (C^pPh),

H bipy and 6-H bipy), 8.31 (s, 1 H, H-2), 8.34 (t, J_4Ј,3Ј= 8.2, J_4Ј,5Ј

= 7.7, 1 H, 4Ј-H), 8.58, 8.62 and 8.70 (3ϫddd, J_3,4= 8.2, J_3,5

128.62 and 128.67 (C-5Ј Ph-terpy and C-5Ј terpy), 128.80 (C^m

phenylene), 129.69 (C^mPh), 133.02 (CⁱPh), 137.08 (C^ophenylene),

138.16 (CⁱPh), 138.60 (C^pphenylene), 139.07 and 139.16 (C-4Ј Ph-

terpy and C-4Ј terpy), 147.88 (C-4 Ph-terpy), 150.44 (C-8), 153.15

(C-4), 153.45 and 153.48 (C-6Ј Ph-terpy and C-6Ј terpy), 154.14

(C-2), 156.38 (C-2,6 terpy), 156.77 (C-2,6 Ph-terpy), 157.02 (C-6),

159.18 and 159.29 (C-2Ј terpy and C-2Ј Ph-terpy) ppm. ESI MS:

=

1.3, J_3,6= 0.7, 3ϫ1 H, 3ϫ3-H bipy), 8.88 (ddd, J_3Љ,4Љ= 8.2, J_3Љ,5Љ

= 1.3, J_3Љ,6Љ= 0.7, 1 H, 3Љ-H), 8.93 (dd, J_3Ј,4Ј= 8.2, J_3Ј,5Ј= 1.3,

1 H, 3Ј-H) ppm. ¹³C NMR (100.6 MHz, [D₆]acetone): δ = 47.45

(CH₂Ph), 120.18 (C-5), 124.49 (C-3 bipy), 124.61 (C-3Ј), 125.13,

125.29 and 125.36 (C-3 bipy), 125.94 (C-3Љ), 127.24 (C^oPh), 127.73

and 128.12 (C-5 bipy), 128.34 (C-5Љ), 128.44 (C^mphenylene), 128.54 m/z (%) = 866 (15) [M⁺– PF₆], 433 (100) [M²⁺– 2PF₆]. IR (KBr):

–

(C^pPh), 128.93 and 128.97 (C-5 bipy), 129.37 (C^mphenylene),

129.49 (C^ophenylene), 129.70 (C^mPh), 130.41 (C-5Ј), 131.12 (Cⁱ

phenylene), 137.67 (C-4 bipy), 137.85 (CⁱPh), 138.95, 138.98,

139.06 and 139.08 (C-4Љ and C-4 bipy), 139.35 (C-4Ј), 140.96 (C^p

phenylene), 150.52 (C-8), 151.83 (C-6 bipy), 152.41 (C-2), 152.57

(C-6Љ), 152.76 (C-4), 152.90 and 153.62 (C-6 bipy), 155.98 (C-6),

157.11, 158.07 and 158.21 (C-2 bipy), 158.88 and 158.92 (C-2Ј, C-

2Љ and C-2 bipy), 166.81 (C-6Ј) ppm. ESI MS: m/z (%) = 868 (5)

ν = 1633, 842, 558 cm^–1. UV/Vis (MeOH): λ

(ε) = 490 (32975),

˜

max

333 sh (60225), 311 (71050), 283 (60350), 275 sh (59375) nm.

C₄₈H₃₅F₁₂N₁₁P₂Ru·3H₂O (1210.9): calcd. C 47.61, H 3.41, N 12.72;

found C 47.70, H 3.21, N 12.70.

Complex 12b: The complex was prepared according to general pro-

cedures for complexation (Method B) using Os(bipy)₂Cl₂as the

complexation agent. The product was isolated as a dark green solid

1

in 74% yield. M.p. Ͼ320 °C. H NMR (500 MHz, [D₆]acetone): δ

–

[M⁺– 2PF₆], 434 (65) [M²⁺– 2PF ]. IR (KBr): ν = 1634, 841,

˜

6

= 5.21 and 5.34 (2ϫd, J_gem= 15.4, CH₂Ph), 6.86 (ddd, J_5,4= 7.4,

J_5,6= 5.7, J_5,3= 1.4, 1 H, 5-H bipy), 6.87 (br. s, 1 H, NH), 7.19

(m, 2 H, H^oPh), 7.26–7.31 (m, 4 H, 4-H bipy and H^m,pPh), 7.44

(ddd, J_5,4= 7.4, J_5,6= 5.7, J_5,3= 1.4, 1 H, 5-H bipy), 7.46 (ddd,

J_5Љ,4Љ= 7.4, J_5Љ,6Љ= 5.7, J_5Љ,3Љ= 1.4, 1 H, 5Љ-H), 7.50 and 7.59

(2ϫddd, J_5,4= 7.4, J_5,6= 5.7, J_5,3= 1.4, 2ϫ1 H, 2ϫ5-H bipy),

7.65, 7.73 and 7.81 (3ϫddd, J_6,5= 5.7, J_6,4= 1.5, J_6,3= 0.7, 3ϫ1

H, 3ϫ6-H bipy), 7.84 (dd, J_5Ј,4Ј= 7.8, J_5Ј,3Ј= 1.4, 1 H, 5Ј-H), 7.87

(ddd, J_6Љ,5Љ= 5.7, J_6Љ,4Љ= 1.5, J_6Љ,3Љ= 0.7, 1 H, 6Љ-H), 7.99 (ddd, J_4,3

= 8.4, J_4,5= 7.4, J_4,6= 1.5, 1 H, 4-H bipy), 8.02 (ddd, J_4Љ,3Љ= 8.4,

558 cm^–1. UV/Vis (MeOH): λ_max(ε) = 448 (10816), 289 (63986) nm.

C₄₈H₃₇F₁₂N₁₁P₂Ru·3H₂O (1212.9): calcd. C 47.53, H 3.57, N 12.7;

found C 47.62, H 3.09, N 12.58.

Complex 11c: The product was isolated as an orange solid in 81%

yield (Method B) and in 53% yield (Method C). M.p. 280–283 °C.

¹H NMR (500 MHz, [D₆]acetone): δ = 5.58 (s, 2 H, CH₂Ph), 6.76

(br. s, 2 H, NH₂), 7.06 (m, 2 H, H^oPh), 7.23–7.30 (m, 3 H, H^m,p

Ph), 7.54–7.65 (m, 7 H, 5Љ-H, 4ϫ5-H bipy and H^mphenylene),

7.79 (m, 2 H, H^ophenylene), 8.05 (ddd, J_6,5= 5.6, J_6,4= 1.5, J_6,3

= 0.7, 1 H, 6-H bipy), 8.08 (ddd, J_6Љ,5Љ= 5.6, J_6Љ,4Љ= 1.5, J_6Љ,3Љ

0.7, 1 H, 6Љ-H), 8.10 (ddd, J_6,5= 5.6, J_6,4= 1.5, J_6,3= 0.7, 1 H, 6-

H bipy), 8.16–8.24 (m, 7 H, 6Ј-H, 4Љ-H, 3ϫ4-H bipy and 2ϫ6-H

=

J_4Љ,5Љ= 7.4, J_4Љ,6Љ= 1.5, 1 H, 4Љ-H), 8.08 and 8.09 (2ϫddd, J_4,3

8.4, J_4,5= 7.4, J_4,6= 1.5, 2ϫ1 H, 2ϫ4-H bipy), 8.13 (t, J_4Ј,3Ј

8.3, J_4Ј,5Ј= 7.8, 1 H, 4Ј-H), 8.27 (s, 1 H, H-2), 8.31 (ddd, J_6,5

=

1766

www.eurjic.org

Eur. J. Inorg. Chem. 2007, 1752–1769

Ru-Labelled Purines

FULL PAPER

5.6, J_6,4= 1.5, J_6,3= 0.7, 1 H, 6-H bipy), 8.49, 8.77, 8.79 and 8.81

(4ϫddd, J_3,4= 8.4, J_3,5= 1.4, J_3,6= 0.7, 4ϫ1 H, 4ϫ3-H bipy),

8.86 (ddd, J_3Љ,4Љ= 8.4, J_3Љ,5Љ= 1.4, J_3Љ,6Љ= 0.7, 1 H, 3Љ-H), 8.90 (dd,

J_3Ј,4Ј= 8.3, J_3Ј,5Ј= 1.4, 1 H, 3Ј-H) ppm. ¹³C NMR (125.8 MHz,

[D₆]acetone): δ = 47.29 (CH₂Ph), 88.05 (CϵC pur), 90.45 (CϵC

SV(P) level, 298 K and 1 atm pressure, using an ideal-gas approxi-

mation.^[56]

)

The redox potentials were then calculated according to the equa-

tion (2)

pur), 120.12 (C-5), 125.34, 125.41, 125.48, 125.57 and 125.76 (C-3Ј E⁰[V] = 27.21(G_ox[a.u.] – G_red[a.u.]) – 4.34 V

and C-3 bipy), 126.35 (C-3Љ), 128.59 (C^oPh), 128.74, 128.92,

(2),

128.94, 129.12, 129.40 and 129.46 (C-5Љ C-5-bipy and C^pPh),

129.63 (C^mPh), 132.25 (C-8), 135.97 (C-5Ј), 136.83 (C-4 bipy),

where G_ox/redare free energy values calculated according to Equa-

tion (1), and 4.34 V is an absolute redox potential of the standard

137.26 (CⁱPh), 138.36, 138.47, 138.64 and 139.09 (C-4Ј, C-4Љ and hydrogen electrode (SHE).^[57]

C-4 bipy), 146.91 (C-6Ј), 150.72 (C-4), 151.15, 151.19 and 151.40

X-ray Diffraction: X-ray crystallographic analysis of single crystals

(C-6 bipy), 151.99 (C-6Љ), 153.33 C-6 bipy), 155.68 (C-2), 157.24

(C-6), 159.02, 159.79, 159.92 and 160.64 (C-2Љ and C-2 bipy),

of

10b

(red,

0.03ϫ0.14ϫ0.27 mm)

and

5b

(red,

0.08ϫ0.31ϫ0.40 mm) was performed with the Xcalibur X-ray dif-

fractometer with Cu-K_α(λ = 1.54180 Å), data collected at 150 K

(10b) and 295 K (5b). Both structures were solved by direct meth-

ods with SIR92^[58]and refined by full-matrix least-squares methods

based on F with CRYSTALS.^[59]Friedel pairs were not merged.

Hydrogen atoms were located in a difference map, but those at-

tached to carbon atoms were repositioned geometrically and then

refined with riding constraints, all other atoms were refined aniso-

tropically in both cases.

–

162.53 (C-2Ј) ppm. ESI MS: m/z (%) = 1052 (100) [M⁺– PF₆], 453

(15) [M²⁺

–

2PF₆]. IR (KBr):

ν

˜

=

1635, 842, 558 cm^–1.

–

C₄₄H₃₃F₁₂N₁₁OsP₂(1197.2): calcd. C 44.19, H 2.78, N 12.88; found

C 44.15, H 2.74, N 12.83.

Electrochemistry: All voltammetric measurements were performed

with an Autolab analyzer (Eco Chemie, The Netherlands) in con-

nection with VA-Stand 663 (Metrohm, Switzerland). The three-

electrode system was always used. Carbon paste electrodes (CPE)

or hanging mercury drop electrodes (HMDE) were used as working

electrodes, a Ag/AgCl/3  KCl electrode as reference and platinum

wire as the auxiliary electrode. The CPE was prepared by hand

mixing of graphite powder CR-5 (Tesla, Czech Republic) with min-

eral oil (Sigma) in a weight ratio of 70/30 and filled in a Teflon

electrode body. The surface of the CPE was renewed by wiping

with wet filtration paper. Square-wave voltammetric measurements

at the CPEs were performed with the following settings: frequency

200 Hz, amplitude 25 mV, potential step 5 mV, scan rate: 1 Vs^–1,

initial potential: –1.0 V, end potential: +1.6 V. For measurements

at the HMDE, linear sweep or cyclic voltammetry was used: scan

rate: 1 Vs^–1, potential step 5 mV, initial potential: 0.0 V, end

(switching) potential: –1.6 V. All measurements were performed in

0.2 acetate buffer (pH 5.0) at room temperature (22 to 25 °C). Be-

fore each measurement at the HMDE, the solution of the back-

ground electrolyte was deaerated with argon.

Crystal Data for 10b: C₄₄H₃₃F₁₂N₁₁P₂Ru₁, monoclinic, space group

P2₁/n, a = 9.041(4), b = 11.983(4), c = 45.72(2) Å, β = 94.34(4)°, V

= 4939(3) Å³, Z = 4, M = 1106.81, 73413 reflections measured,

18674 independent reflections. Final R = 0.0866, wR = 0.0701 for

5598 reflections with I Ͼ 1.96σ(I) and 694 parameters. Several ther-

mal similarity restraints were used in the refinement of the bipyri-

dine units and the hexafluorophosphate anions. The two hexafluo-

rophosphate anions were found to be disordered in three positions

with their site occupation factors being 0.75, 0.75, and 0.50.

Crystal Data for 5b: C₃₄H₂₄F₁₂N₆P₂Ru₁, orthorhombic, space

group Pna2₁, a = 13.5397(2), b = 25.6956(3), c = 10.0094(2) Å, V

= 3482.38(10) Å³, Z = 4, M = 883.58, 56076 reflections measured,

7377 independent reflections. Final R = 0.0331, wR = 0.0380 for

2940 reflections with I Ͼ 1.96σ(I) and 478 parameters.

CCDC-628693 (for 10b) and -629224 (for 5b) contain the supple-

mentary crystallographic data for this paper. These data can be

obtained free of charge from The Cambridge Crystallographic

Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

Computational Details: All density functional theory (DFT) calcu-

lations reported in the study were carried out using the Turbomole

5.8 program.^[48]The Perdew–Burke–Ernzerhof (PBE)^[49]and hybrid

three-parameter Becke’s^[50](B3LYP) functionals were used

throughout. The calculations were expedited by expanding the

Coulomb integrals in an auxiliary basis set, the resolution-of-ident-

ity (RI-J) approximation.^[51,52]All the geometry optimizations were

carried out using the def2-SVP basis set,^[53]whereas the single point

energies were recomputed in a larger basis set, def2-TZVP (triple-

zeta valence with two polarization functions on each atom).^[53]

Biological Activity Screening: The HCV subgenomic replicon assay

was performed according to the published procedure.^[46]Inhibition

of HCV NS5B polymerase 1b assay was performed according to

ref.^[47]Cytostatic activity screening was done according to ref.^[60]

The cell cycle analysis was carried out by the propidium iodide

method^[61]and evaluated by means of ModFit LT software (Verity

Software House, Topsham, ME, USA).

To account for solvation effects, the conductor-like screening model

(COSMO) method^[54,55]was used with the dielectric constant corre-

sponding to an equimolar mixture of water and acetonitrile (ε_r=

57). The Gibbs free energy was then calculated as the sum of these

contributions [Equation (1)]

Acknowledgments

This work is a part of the research project Z4 055 0506. It was

supported by EC Specific Targeted Research Project, Control of

Assembly and Charge Transport Dynamics of Immobilized DNA

(CIDNA) (to M. V. and M. H.), by the Grant Agency of the Czech

Republic (a grant No. 203/05/0043 to M. V., M. H., L. H., and

M. F. and 203/05/H001 to L. Z.), by the Czech Ministry of Educa-

tion LC512 and LC06035 (to L. R., L. Z., P. H. and L. H., M. F.,

respectively) and by Gilead Sciences, Inc. (Foster City, CA, USA).

G = E_el+ G_solv+ (E_ZPE+ nRT – TS)

(1)

where E_elis the in vacuo energy of the system (at the B3LYP/def2-

TZVP level and the geometry optimized at the RI-PBE/def2-SVP

level), G_solvis the solvation free energy (at the RI-PBE/def2-SVP

level) and the (E_ZPE+ nRT – TS) term is the zero-point energy,

thermal correction to the Gibbs free energy, and entropic term (ob-

tained from a frequency calculation with the same method and

software as for the geometry optimizations at the RI-PBE/def2-

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Received: November 30, 2006

Published Online: March 6, 2007

Eur. J. Inorg. Chem. 2007, 1752–1769

www.eurjic.org

1769

Article Doi

Purines bearing phenanthroline or bipyridine ligands and their RuII complexes in position 8 as model compounds for electrochemical DNA labeling - Synthesis, crystal structure, electrochemistry, quantum chemical calculations, cytostatic and antiviral activity

DOI: 10.1002/ejic.200700030

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