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Complexes of palladium (II) with L-proline. Mixed L-prolinato nucleoside complexes of Palladium (II)
Polyhedron Vol. 3, No. I, pp. 9-15, hinted in Great Britain.
1984 0
0277-5387/84 1984 Pergamon
S3.00 + .OO Press Ltd.
COMPLEXES OF PALLADIUM (II) WITH LPROLINE. MIXED LPROLINATO NUCLEOSIDE COMPLEXES OF PALLADIUM (II) GEORGE PNEUMATIKAKIS University of Athens, Department of Chemistry, 13A Navarinou Greece
Street, Athens 144,
(Received 25 October 1982; accepted 22 June 1983) Abstract-The reaction of Palladium (II) chloride and L-proline (ProH) in aqueous solution gave the dimeric complex, (Pd(Pro)Cl},, which was characterized by elemental analysis, molecular weight, conductivity measurements and IR and NMR spectra. The complex, reacted further with the purine nucleosides inosine or guanosine (Nucl) and the complexes {Pd(Pro)(Nucl-H +)> were isolated from aqueous solution. The insolubility of these complexes suggested a rather polymeric structure in which the nucleoside bridges two adjacent palladium atoms through its N(7) and the exocyclic O(6) atoms. Reaction in dmso gave the complex (Pd(Pro)(Nucl)Cl} in which the nucleoside act as monodentate ligands with their N(7) atom as ligation site. In aqueous solutions these complexes are quantitatively transformed to the polymeric analogues with the liberation of HCl. The nucleoside adenosine (Ado) reacted in a different way giving only the dimeric complex {Cl(Pro)PdAdoPd(Pro)Cl} in which adenosine bridges two palladium atoms through its N(1) and N(7) atoms. Finally with the pyrimidine nucleoside cytidine (Cyd) the monomer Pd(Pro)(Cyd)Cl was isolated.
therapy. In this respect it is very important to study the interaction of Pd(I1) with a-amino-acids with the main purpose to prepare complexes with possible antitumour activity. It is also very important to investigate the interaction of these complexes with the nucleic acid constituents in order to note any similarities in their behaviour, with that of the well established antitumour agent cis-Pt(NH,),Cl, and the palladium analogue. This paper describes the synthesis and some properties of some complexes of Pd(I1) with L-proline, together with their interaction with nucleosides.
The Pd(I1) complexes are interesting in biological chemistry. For example, Kirschner and collaborators noted that cis-dichloropiperidine palladium (II) can induce filamental growth in E.Coli.’ The same effect was also noted by Charlon et al. with caesium cis-dichloro-L-serinato palladium (II).2 Kirschner and collaborators also reported that some Pd(I1) complexes with sulphur and nitrogen ligands, exhibit potential antitumour activity.3 It is clear from the active (against tumours) complexes discovered to date that cis displaceable ligands are necessary, and therefore the “carrier” ligand(s) should also occupy cis co-ordination sites in a four coordinate planar complex. When only monodentate “carrier” ligands are used one risks a cis complex isomerizing into the thermodynamically more stable trms configuration. Bidentate ligands remove this possibility of a drug deteriorating during storage. An L-amino-acid anion would seem to be an ideal choice of bidentate ligand for this task of conformation locking. Amino-acids may also be particularly useful “carrier” ligands because not only do cells have active transport processes for most of them but also, healthy cells tolerate them well and have means of using, or of disposing of, the amino-acids after
COOH
L-proline. a cyclic amino-acid widely distributed in nature, can form chelate and non-chelate complexes with various metals. Complexes are known for copper,ti cobalt,7-‘2 nickel,” palladium,1~‘6 rare earth,17 rhodium’* and platinum.‘“26 In these complexes Gproline acts either as unidentate (as molecule or anion) or as bidentate (as anion) ligand, 9
IO
G. PNEUMATIKAKIS
and coordination is effected through the imino group, or both, respectively. Unlike other optically active a -amino-acids, the optically active proline anion is coordinated stereospecifically with the metal ion in the formation of rings: the asymmetric environment of the donor nitrogen atom takes the obligatory S-absolute configuration. RESULTS AND DISCUSSION (1) Interaction
of palladium
(II)
chloride
with
L-proline
Anhydrous palladium (II) chloride is insoluble in water, but becomes soluble in presence of Lproline, in 1: 1 stoichiometry, and gave the dimeric complex (Pd(Pro)CI},, according to the eqn (1): 2PdC1, + 2ProH
n=
(Pd(Pro)Cll,
+ 2HC1.
(1)
The complex was a non-electrolyte in water and the analytical results were in agreement with the proposed formulation (see Table 1). Its dimeric nature was established by a molecular weight determination in ethanol (Found 5 17; Calc. 5 11.8). In the IR spectrum of the complex of palladium with L-proline there are three new bands, compared with the spectrum of L-proline alone. The first band at 485 cm - ’ is due to the metal-nitrogen vibrations. The second band at 305 cm-’ may be assigned to the Pol-Cl-P01 vibrations, since it disappears in the bromide analogue. The third band
at 295 cm-’ may be assigned to the metal-oxygen vibrations. The NH*+ bands at 1475 and 1380 cm-’ in the spectrum of L-proline do not appear in the spectrum of the complex, while the NH stretching vibrations shift from 3280 and 3190 cm-’ to 3340 and 3210 cm-‘. In addition the antisymmetric, symmetric, and deformation vibrations of the carboxylate group shift from 1610, 1415 and 680cm-’ to 1587, 1435 and 750cm-’ respectively (see Table 2).
These results are consistent with L-proline acting as a bidentate ligand, through its carboxylate group and the amino nitrogen in a chelate form. On the other hand the position of the v(Pd-Cl) band at (305-cm-‘), is consistent with the presence of chloride bridges in the complex, giving rise to the possible structure: 0
II
OC
c-o\p/t\w/ t./
\ct/
\NH
6
!J
The mode of L-proline coordination to palladium in this complex has further been confirmed by comparing the ‘H and 13CNMR spectra of the complexed and the free L-proline. The ‘H NMR chemical shifts of L-proline and
Table 1. Analytical and conductivity data of the complexes* r Compounds
%C
%H
%N
%Pd
I
-1 an2 MO1 -1 %.itn .. IO-3M
in dmf
-
7 in
10-3M
{Pd(Pro)C1)2
23.50 (23.44)
3.19 (3.13)
5.70 (5.47)
41.85 (41.56)
6
a
{Pd(Pro)Br}2
20.20 (19.98)
2.80 (2.66)
4.72 (4.66)
35.14 (35.43)
5
6
{Pd(Pro) (Ino)Clj
34.51 (34.34)
3.72 (3.82)
13.50 (13.36)
20.50 (20.30)
a
120
{Pd(Pro) (Ino-Ii+)
36.58 (36.91)
3.79 (3.90)
14.61 (14.36)
21.53 (21.82)
{Pd(Pro) (Guo)Clj
33.52 (33.38)
3.96
(3.89)
15.60 (15.29)
lg.48 (19.73)
7
115
{Pd(Pro) (Guo-H+)
35.60 (35.80)
(3.98)
16.00 (16.38)
21.42 (21.16)
(PatPro) (Cyd)Cl}
33.80 (33.661
4.35 (4.21)
11.50 (11.22)
21.50 (21.32)
tPd(ProjC112Ado
31.04 (30.81)
3.85 (3.72)
12.69 (12.58)
27.50 (27.32)
3.90
a
6
-* The
numbers
in parentheses
represent
the calculated
figures
H,(
Complexes of palladium (II) with L-proline Table 2. Some characteristic
IR bands of L-proline and {Pd(Pro)Cl}, (cm-‘)*
Compound
v(NH)
v,(Coo)
Vs(COO)
vae,fo33) 6@
L - Proline
3190
1610
1415
680
1475 1380
{Pd(Pro)Cl12
3340 3210
1587
1435
750
fPd(Pro)Br12
3210 3340
1583
1432
745
3280
11
its complex are given in Table 3. There is a downfield shift for all four kinds of protons, in the complex relatively to free ligand, but the ones at positions (2), (3) and (5) which are adjacent to the ligation sites are shifted the most, 1.50, 1.02 and 0.54 ppm respectively. This confirms coordination of L-proline to palladium through both the carboxylate group and the imino nitrogen, in agreement with the IR data. The 13CNMR spectra also confirm the above postulations. In Table 4 are given the 13CNMR chemical shifts of L-proline and the complex {Pd(Pro)Cl),. The most pronounced change was observed for the carboxyl carbon of the complex, which was shifted by 150ppm downfield with respect to the uncomplexed ligand. A large downfield shift was also observed for the carbons C(2) and C(5) (4.8 and 4.0 ppm respectively). This again confirms the participation of both the carboxylate group and
V(F+X)
v(W+a
-
-
-
-
485
305
295
-
487
252
297
the iminonitrogen in coordination, and is in agreement with the observation that the changes of chemical shift on chelation of a-amino-acids. to Co(II1) (H,N + RCOOH jchelate) were about 15 and 5 ppm for the carboxy-carbon and a-carbon respectively.*’ (2) Mixed prolinato-nucleoside complexes of palladium (II) The dimeric complex, {Pd(Pro)Cl),, prepared and characterized above, reacted with purine and pyrimidine nucleosides (Nucl) with the cleavage of the chloride bridges between the two palladium atoms, and monomeric complexes were formed, according, to eqn (1): (Pd(Pro)Cl}, + 2Nucl”“.
Z{Pd(Pro)(Nucl)Cl). (1)
The proposed formulae are in agreement with the
Table 3. ‘H NMR chemical shifts of L-proline and {Pd(Pro)Cl}, (ppm) Compound
H(2)
H(3)
H(4)
H(5)
Solvent
L - Proline
4.10
2.18
2.18
3.36
DzO
fPd(Pro)C112
5.60
3.20
2.43
3.90
DzO
Table 4. 13CNMR chemical shifts of L-proline and (Pd(Pro)Cl}, @pm) Compound
C=O
L-Proline
fPd(Pro)C1j2
v(PdG
C(2)
C(3)
C(4)
C(5)
174.2
63.6
29.5
23.9
50.5
189.2
68.4
31.7
25.0
54.5
G. PNEUMATIKAKIS
12
on the exocyclic O(6) atom; and (iii) the nucleophilic substitution of the coordinated chloride by this negatively charged oxygen atom. This behaviour is similar to that observed in reacting the dimeric complex (Pd(O-Mecys)Cl}, with nucleosides.3’ However it is in contrast to the behaviour of analogous platinum complexes, where attempts to prepare complexes with the O(6) atom of the nucleosides, participating in coordination, resulted in the destruction of the parent compounds.32 The binding sites of the nucleosides in these mixed ligand complexes were deduced from their ‘H NMR, r3C NMR and IR spectra. The ‘H NMR bands of the proline are not shown clearly because they coincide with some of the bands of the nucleosides. However, the bands in the aromatic proton region are very useful in assigning the coordination sites of the nucleosides, and they are given in Table 5. The complex Pd(Pro)(Ino)Cl gave two resonances at 8.79 and 8.20ppm assigned to H(8) and H(2) respectively. The downfield shift of the H(8) resonance by 0.57 ppm, is comparable to the one found in other similar cases28*33*34 and may be taken as a good indication of the N(7) coordination of inosine to Pd(I1). The complex Pd(Pro)(Guo)Cl shows one resonance at 8.46 ppm, assigned to H(8), and this again indicates N(7) coordination of guanosine to Pd(I1). The complex {Pd(Pro)Cl}, Ado shows two resonances at 8.70 and 8.9Oppm assigned to H(2) and H(8) respectively. The downfield shift of both H(2) and H(8) resonances by about 0.75 ppm as compared with the uncomplexed adenosine is consistent with the participation of both N( 1) and N(7) in coordination to Pd(II).28~32’33 In the complex
analytical results (see Table 1). These mixed ligand complexes are non-electrolytes in dmf, as well as other organic solvents, e.g. ethanol, acetone, etc. However, those complexes with one ionizable N( 1) H imino proton, e.g. inosine and guanosine, decompose in water giving insoluble yellow material and HCl, and consequently the mixtures develop high conductivities. These insoluble materials are free from chloride and correspond to the formulae; Pd(Pro)(Nucl-H). The decomposition reaction follows the equation: Pd(Pro)(Nucl)Cl-
“”
Pd(Pro)(Nucl-H)
+ HCl. (2)
In acidic solution the reaction (2) was reversed and the protonated complexes, Pd(Pro)(Nucl)Cl can be recovered. The deprotonated complexes, Pd(Pro)(Nucl-H) were also prepared by performing the reaction (1) in aqueous solutions: {Pd(Pro)Cl}, + 2Nucl-
W
2 Pd(Pro)(Nucl-H)
+ 2HCl.
(3)
Reaction (3) may proceed in two main steps. First the chloride bridges may be cleaved by the nucleosides, which then remain attached to palladium with their N(7) atom (as will be shown below) and this is seen by the formation of a transient clear yellow solution. In the second step, the compounds Pd(Pro)(Nucl-H) are precipitated, and this may involve: (i) the ionization of the N(l)-H iminoproton, due to the very large lowering of the pK, of this proton when the nucleosides are coordinated to metals and especially to Pd(II), through their N(7) atom;28-30(ii) the accumulation, due to resonance, of a negative charge
Table 5. H’ NMR chemical shifts of the mixed ligand complexes (ppm) Compounds
H(2)
H(5)
H(6)
H(8)
Inosine
8.11
-
-
0.22
6.03,
5.93
dmso-d6
{Pd(Pro) (Ino)Cll
82..@
-
-
8.79
5.85,
5.76
duo-d6
7.80
5.74,
5.60
dmso-d6
8.46
5.85,
5.78
dmso-d6
Guanosine fPd(Pro) (Guo)C11
-
Cytidine
-
Solvent
5.75,
5.66
7.78,
7.79
-
6.24,
6.17
dmso-d6
6.18,
6.19
8.11,
8.20
-
6.26,
6.24
dmso-d6
IPd(Pro) (Cyd)Clj
-
Adenosine
7.95
8.17
5.90,
5.80
dmso-d6
8.70
8.90
6.31,
6.23
dmso-d6
(Pd(Pro)C112
Ado
Complexes of palladium
{Pd(Pro)(Cyd)Cl}, both H(5) and H(6) shifted downfield, with the larger shift for H(5). This indicates that H(5) is closer to the coordination site on the ligand, probably the N(3) atom.33**) The postulations on the binding sites of nucleosides made from ‘HNMR spectra are further confirmed by the r3CNMR spectra of the complexes. The 13CNMR chemical shifts of the ligands and complexes are given in Table 6. In the complex {Pd(Pro)(Ino)Cl), the downfield shifts observed for the C(5) and C(8) resonances (2.3 and 3.8 ppm respectively) are consistent with N(7) coordination, since these carbons are adjacent to this nitrogen. The same sort of pattern was also observed in the i3C NMR spectra of the guanosine complex, suggesting again N(7) coordination. In the adenosine complex the resonances of all four carbon atoms, C(2), C(6), C(5) and C(8), adjacent to both N(1) and N(7) atoms are shifted downfield upon coordination, and this further supports the participation of both these nitrogens in coordination.32m35The resonances of the proline carbons in these mixed ligand complexes remain essentially at the same positions as in the parent dimeric complex. The deprotonated complexes Pd(Pro)(Nucl-H) are insoluble in all common solvents and the information concerning their structure was deduced only from their chemical behaviour and IR spectra.
(II) with L-proline
13
The preparation of these complexes from the complexes Pd(Pro)(Nucl)Cl and their reversible conversion to them suggested that the Pd-N(7) bonding, present in the latter complexes, exists also in the deprotonated complexes. These deprotonated complexes do not contain any chloride, and the v(Pd-Cl) vibration, which occurs at 305 cm-’ in the starting dimeric complex, {Pd(Pro)Cl}, and is shifted at about 330 cm -I in the complexes (Pd(pro)(Nucl)Cl} (the normal position for the stretching vibration of the Pd-Cl terminal group) is absent from the spectra of these complexes. On the other hand, the IR spectra of these complexes in the carbonyl stretching region, may give an indication for the exocyclic O(6) atom participating in bonding with Pd(II), in these deprotonated complexes. The v(C = 0) of the exocyclic carbonyl oxygen of the nucleosides inosine and guanosine appears at about 1700 cm - ’ and remains at the same frequency in the complexes Pd(Pro)(Nucl)Cl thus excluding its participation in bonding with palladium in these complexes.28*33,34,36 However in the complexes Pd(Pro)(Nucl-H+) this band is shifted to lower frequencies by about 75 cm -’ and appears at 1625cm-‘. This lowering of the v(C = 0) frequency may be taken as a good indication of the O(6) keto oxygen involvement in bonding with the metals.28,33,3qa)* 3638The shift to lower frequencies
Table 6. “C NMR chemical shifts of the mixed ligand complexes (ppm) L -
Zompounds c=o
(Ino)Cl}
Guanosine
lPd(Pro)
(Guo)Cl)
Cytidine
(PdfPro)
(CydJCl)
Adenosine
{Pd(Pro)C1)2
c2
carbons c1
c,
Nucleoside c5
_----
rnosine
fPd(Pro)
Proline
Ado
189.0
68.5
31.5
_
----
189.1
68.4
31.7
-
-
---
108.8
68.3
31.5
_
-
189.0
68.7
25.7
25.0
25.3
54.6
54.5
54.8
---
31.4
25.1
54.7
c*
cp
c,,
146.0
148.2
124.4
146.7
150.0
153.6
Carbons C6
C8
c,-
c2-
cj-
C.4.
c5-
156.5
138.7
87.4
74.0
70.2
85.6
61.2
126.8
157.5
142.5
88.2
74.5
70.0
85.9
60.8
151.3
116.6
156.7
135.6
86.3
73.7
70.3
85.1
61.7
154.6
152.6
118.7
158.2
139.0
87.1
74.0
69.7
85.6
61.1
152.9
163.7
99.6
148.6
-
90.8
74.6
69.8
03.8
61.3
156.5
166.0
98.0
147.2
-
90.7
74.9
69.7
84.0
61.0
148.5
147.0
114.5
152.0
135.8
60.4
71.0
73.9
86.3
61.0
156.0
147.6
116.9
157.0
143.5
68.6
71.3
74.3
86.8
61.3
14
G. PNEUMATIKAKIS
of the v(C = 0) band upon ionization of the N(1) H imino proton in inosine and guanosine, indicates the loss of the double bond character of the C = 0 group. 39v40This is more pronounced in the ionic salt of guanosine (shift to 1595 cm-L),38 and less whenever the metal-oxygen bonding is more covalent, as in the case of Pd(II).28v33Certainly, the double bond character of the C = 0 is also lowered when the oxygen interacts with a metal, without ionization of the N(l)H imino proton.3q*) Oxygen involvement in bonding with metals, following deprotonation of the imino proton, has also been found in the crystal structure of cisdiamminoplatinum a-pyridone blue:’ where both O- and N atoms bridge two platinum atoms. Kistenmacher et al.” have also found an SAg(1) interaction in the crystal structure of (nitrato) (1-methylcytosine) silver (1). Recently, Bau et ~1.~~ showed the participation of the exocyclic O(6) in coordination, in the crystal structure of a tetranuclear copper (II)--inosine monophosphate o-phenanthroline complex, where inosine acts as an O(6) N(7) bridging ligand with Cu-O(6) distance 1.956 A. Very recently, Marzilli et al.,4 have presented evidence for O(6) binding with metals mainly from 13CNMR spectra. In view of the above discussion, there must exist a strong O(6)--Pd interaction in the complexes Pd(Pro)(Nucl-H), which may be formulated as polymers with O(6) N(7) bridges: PrO
/
P\
0.5 mm01 (Pd(Pro)Cl}, and 1 mmol of the respective nucleoside were suspended in 3 cm3 dmso-d, and stirred for 1 hr at room temperature. The ‘H NMR spectra of the solution showed the existence of only one species in the solution and the compound was precipitated with excess acetone. Yield, 85-90x. (3) L-prolinato (guanosinato) palladium (III), Pd(pro)(Guo-H +) and L-prolinato (insosinato) palladium (II), Pd(pro)(Ino-H +) (a) 0.5 mmol {Pd(Pro)Cl), was dissolved in 10 cm3 Hz0 and to that was added 1 mmol of the respective nucleoside dissolved in 25 cm3 H20 (hot in the case of guanosine). The mixture was stirred at room temperature for 2 hr and the precipitate formed, was filtered, washed with hot water, ethanol, ether and dried at 80°C under vacuum. Yield, ea. 80%.
(b) 1 mmol of the respective complexes Pd(Pro)(Nucl)Cl (NucI = Ino or Guo) was suspended in 25 cm3 water and stirred for 2 hr at room temperature. The precipitate formed was filtered, washed with water, ethanol, ether and dried as above. Pro
0
/pd\ N(7) e-016) Nucl
The postulation that the bridging occurs with N(7) N(1) bridges, without participation of the carbonyl O(6) in bonding does not explain the large lowering of the v (C = 0) frequency, and does not seem very likely to occur. EXPERIMENTAL The experimental scribed elsewhere.33
(2) Chloro-(L-prolinato)(nucleoside) palladium (II), Pd(pro)(Nucl)Cl, (Nucl = Ino, Guo, Cyd)
FTO
Cl
O(6)
absolute ethanol and filtered. The compound was then precipitated with excess ether. Yield, 90%.
techniques
have been de-
Preparation of complexes palZadium (ZZ)-p-dichloro (1) L -Prolinato L-prolinato palladium (II), {Pd(pro)Cl},
Palladium (II) chloride (0.356 g, 2 mmoles) and L-proline (0.230 g, 2 mmoles) were suspended in 25 cm3 water and stirred at 60°C for 2 hr. The resulting clear red solution was roto-evaporated to dryness at 50°C. The residue was taken with 20 cm3
N(7) -O(6) Nucl
N(7)
_
(4) Chloro L -prolinato -palladium (II)-u -Adeno sine (Nl N7)-chloro L-prolinato palladium (II),
Cl(Pro)Pd Ado Pd (Pro)Cl 1 mmol {Pd(Pro)Cl), was dissolved in 10 cm3 H20 and to that was added 1 mmol Adenosine dissolved in 20 cm3 water and stirred for 2 hrs. The yellow precipitate formed, was filtered, washed with water, ethanol, ether and dried at 60°C under vacuum. Yield ca. 85%. REFERENCES 1. S. Kirschner, A. Maurer and D. Dragulesku, J. Clin. Hematol. Oncol. 1977, 7, 293. 2. A. J. Charlson, N. T. McArdle and E. C. Watton, Inorg. Chim. Acta 1981, 56, L35. 3. S. Kirschner, A. Maurer and C. Dragulescu, J. Clin. Hematol. Oncol 1977, 7, 190. 4. T. Yasui, J. Hidaka and Y. Shimura, J. Am. Chem. Sot. 1965, 87, 2762.
Complexes of palladium 5. T. Yasui, Bull. Chem. Sot. Japan 1965, 38, 1746. 6. A. M. Mathieson and K. H. Welsh, Acta Cryst. 1952, 5, 599. 7. R. G. Denning and T. S. Piper, Znorg. Chem. 1966, 5, 1056. 8. H. C. Freeman and J. E. Maxwell, Znorg. Chem. 1970, 9, 649. 9. T. Yasui, J. Hidaka and Y. Shimure, Bull. Chem. Sot. Japan 1966, 39, 2417. 10. T. Yasui, J. Fujita and Y. Shimure, Bull. Chem. Sot. Japan 1969, 42, 2081. 11. T. Yasui, J. Hidaka and Y. Shimure, Bull. Chem. Sot. Japan 1965, 38, 2025. 12. G. Brookes and L. D. Pettit, J. Chem. Sot., Chem. Commun. 1974, 813. 13. J. Hidaka and Y. Shimure, Bull. Chem. Sot. Japan 1970, 43, 2999. 14. K. Freund and H. Frye, Znorg. Nucl. Chem. L&t. 1971, 7, 107. 15. T. Ito, F. Marumo and J. Saito, Acta Cryst., Sect. B. 1971 27, 1062. 16. J. Kollmar, C. Schroeter and E. Hoyer, J. Prakt. Chem. 1975, 317, 515. 17. S. Zielinski, K. Lomozik and A. Wojciechowska, Russ. J. Znorg. Chem. 1980, 25, 1573. 18. A. E. Bukanova, I. V. Prokofeva, Ya. V. Salyn and L. K. Shubochkin, Russ. J. Znorg. Chem. 1981, 26, 82. 19. J. Fujita, K. Konya and K. Nakamoto, Znorg. Chem. 1970, 9, 2794. 20. K. Konya, J. Fujita and K. Nakamoto, Znorg. Chem. 1971, 10, 1699. 21. L. M. Volshtein and 0. P. Slyudkin, Russ. J. Znorg. Chem. 1972, 17, 236 and 1168. 22. L. M. Volshtein and 0. P. Slyudkin, Russ. J. Znorg. Chem. 1974, 19, 71. 23. R. D. Gillard and 0. P. Slyudkin, J. Chem. Sot. Dalton 1978, 152. 24. L. M. Volshkein, 0. P. Slyudkin and M. A. Kerzhentsev, Russ. J. Znorg. Chem. 1977, 22, 1506. 25. R. D. Gillard, S. M. Laurie, D. C. Price, D. A. Phipps and C. F. Weick, J. Chem. Sot. Dalton 1974, 1385.
POLY
Vol. 3. No.
I-B
(II) with L-proline
15
26. 0. P. Slyudkin and M. A. Kerzhentser, Russ. J. Znorg. Chem. 1979 24, 1695. 27. A. Tomoharu and Y. Takaji, Bull. Chem. Sot. Japan 1976, 49, 472. 28(a). G. Pneumatikakis, N. Hadjiliadis and T. Theophanides, Znorg. Chim. Acta 1977, 22, Ll. (b). G. Pneumatikakis, N. Hadjiliadis and T. Theophanides, Znorg. Chem. 1978, 17, 915. (c) N. Hadjiliadis and G. Pneumatikakis, J. Chem. Sot. Dalton 1978, 1691. 29. G. Y. H. Chu and R. S. Tobias, J. Am. Chem. Sot 1976, 98, 2641. 30. G. Y. H. Chu, S. Mansy, R. E. Duncan and R. S. Tobias, J. Am. Chem. Sot. 1978, 100, 593. 3 1. G. Pneumatikakis, Proc. XXII ZCCC, Vol. 2, p. 565, 23-27 August, Budapest, 1982. 32. N. Hadjiliadis and G. Pneumatikakis, Znorg. Chim. Acta 1980, 46, 255. 33. (a) G. Pneumatikakis, Znorg. Chim. Acta 1980, 46, 243. (b) Ibid. 1982, 66, 131. 34. (a) J. Dehand and J. Jordanov, J. Chem. Sot. Chem. Commun 1976, 598. (b) J. Dehand and J. Jordanov, J. Chem. Sot. Dalton 1977, 1588. 35. D. J. Nelson, P. I. Yeagle, T. I. Miller and R. B. Martin, Bioinorg. Chem. 1976, 5, 353. 36. M. Ogawa and T. Sakaguchi, Chem. Pharm. Bull. 1971, 19, 1650. 37. A. T. Tu and M. J. Heller, In Metal Ions in Biological Systems, Vol. 1, p. 1 (1974). 38. A. J. Canty and R. S. Tobias, Znorg. Chem. 1979, 18, 413. 39. R. M. Izatt, J. J. Christensen and J. H. Rytting, Chem. Rev. 1971, 71, 439. 40. R. Shapiro, Progr. Nucl. Acid Res. 1968, 73, 8. 41. J. K. Barton, H. N. Rabinowith, D. H. Szalda and R. S. Lippard, J. Am. Chem. Sot. 1977, 99, 2827. 42. T. J. Kistenmacher, M. Rossi and L. G. Marzilli, Znorg. Chem. 1979, 18, 240. 43. R. W. Gellert, B. E. Fischer and R. Bau, J. Am. Chem. Sot. 1980, 102, 7812. 44. L. G. Marzilli, C. Baltazar and C. Solorzano, J. Am. Chem. Sot. 1982, 104, 461.
1984 0
0277-5387/84 1984 Pergamon
S3.00 + .OO Press Ltd.
COMPLEXES OF PALLADIUM (II) WITH LPROLINE. MIXED LPROLINATO NUCLEOSIDE COMPLEXES OF PALLADIUM (II) GEORGE PNEUMATIKAKIS University of Athens, Department of Chemistry, 13A Navarinou Greece
Street, Athens 144,
(Received 25 October 1982; accepted 22 June 1983) Abstract-The reaction of Palladium (II) chloride and L-proline (ProH) in aqueous solution gave the dimeric complex, (Pd(Pro)Cl},, which was characterized by elemental analysis, molecular weight, conductivity measurements and IR and NMR spectra. The complex, reacted further with the purine nucleosides inosine or guanosine (Nucl) and the complexes {Pd(Pro)(Nucl-H +)> were isolated from aqueous solution. The insolubility of these complexes suggested a rather polymeric structure in which the nucleoside bridges two adjacent palladium atoms through its N(7) and the exocyclic O(6) atoms. Reaction in dmso gave the complex (Pd(Pro)(Nucl)Cl} in which the nucleoside act as monodentate ligands with their N(7) atom as ligation site. In aqueous solutions these complexes are quantitatively transformed to the polymeric analogues with the liberation of HCl. The nucleoside adenosine (Ado) reacted in a different way giving only the dimeric complex {Cl(Pro)PdAdoPd(Pro)Cl} in which adenosine bridges two palladium atoms through its N(1) and N(7) atoms. Finally with the pyrimidine nucleoside cytidine (Cyd) the monomer Pd(Pro)(Cyd)Cl was isolated.
therapy. In this respect it is very important to study the interaction of Pd(I1) with a-amino-acids with the main purpose to prepare complexes with possible antitumour activity. It is also very important to investigate the interaction of these complexes with the nucleic acid constituents in order to note any similarities in their behaviour, with that of the well established antitumour agent cis-Pt(NH,),Cl, and the palladium analogue. This paper describes the synthesis and some properties of some complexes of Pd(I1) with L-proline, together with their interaction with nucleosides.
The Pd(I1) complexes are interesting in biological chemistry. For example, Kirschner and collaborators noted that cis-dichloropiperidine palladium (II) can induce filamental growth in E.Coli.’ The same effect was also noted by Charlon et al. with caesium cis-dichloro-L-serinato palladium (II).2 Kirschner and collaborators also reported that some Pd(I1) complexes with sulphur and nitrogen ligands, exhibit potential antitumour activity.3 It is clear from the active (against tumours) complexes discovered to date that cis displaceable ligands are necessary, and therefore the “carrier” ligand(s) should also occupy cis co-ordination sites in a four coordinate planar complex. When only monodentate “carrier” ligands are used one risks a cis complex isomerizing into the thermodynamically more stable trms configuration. Bidentate ligands remove this possibility of a drug deteriorating during storage. An L-amino-acid anion would seem to be an ideal choice of bidentate ligand for this task of conformation locking. Amino-acids may also be particularly useful “carrier” ligands because not only do cells have active transport processes for most of them but also, healthy cells tolerate them well and have means of using, or of disposing of, the amino-acids after
COOH
L-proline. a cyclic amino-acid widely distributed in nature, can form chelate and non-chelate complexes with various metals. Complexes are known for copper,ti cobalt,7-‘2 nickel,” palladium,1~‘6 rare earth,17 rhodium’* and platinum.‘“26 In these complexes Gproline acts either as unidentate (as molecule or anion) or as bidentate (as anion) ligand, 9
IO
G. PNEUMATIKAKIS
and coordination is effected through the imino group, or both, respectively. Unlike other optically active a -amino-acids, the optically active proline anion is coordinated stereospecifically with the metal ion in the formation of rings: the asymmetric environment of the donor nitrogen atom takes the obligatory S-absolute configuration. RESULTS AND DISCUSSION (1) Interaction
of palladium
(II)
chloride
with
L-proline
Anhydrous palladium (II) chloride is insoluble in water, but becomes soluble in presence of Lproline, in 1: 1 stoichiometry, and gave the dimeric complex (Pd(Pro)CI},, according to the eqn (1): 2PdC1, + 2ProH
n=
(Pd(Pro)Cll,
+ 2HC1.
(1)
The complex was a non-electrolyte in water and the analytical results were in agreement with the proposed formulation (see Table 1). Its dimeric nature was established by a molecular weight determination in ethanol (Found 5 17; Calc. 5 11.8). In the IR spectrum of the complex of palladium with L-proline there are three new bands, compared with the spectrum of L-proline alone. The first band at 485 cm - ’ is due to the metal-nitrogen vibrations. The second band at 305 cm-’ may be assigned to the Pol-Cl-P01 vibrations, since it disappears in the bromide analogue. The third band
at 295 cm-’ may be assigned to the metal-oxygen vibrations. The NH*+ bands at 1475 and 1380 cm-’ in the spectrum of L-proline do not appear in the spectrum of the complex, while the NH stretching vibrations shift from 3280 and 3190 cm-’ to 3340 and 3210 cm-‘. In addition the antisymmetric, symmetric, and deformation vibrations of the carboxylate group shift from 1610, 1415 and 680cm-’ to 1587, 1435 and 750cm-’ respectively (see Table 2).
These results are consistent with L-proline acting as a bidentate ligand, through its carboxylate group and the amino nitrogen in a chelate form. On the other hand the position of the v(Pd-Cl) band at (305-cm-‘), is consistent with the presence of chloride bridges in the complex, giving rise to the possible structure: 0
II
OC
c-o\p/t\w/ t./
\ct/
\NH
6
!J
The mode of L-proline coordination to palladium in this complex has further been confirmed by comparing the ‘H and 13CNMR spectra of the complexed and the free L-proline. The ‘H NMR chemical shifts of L-proline and
Table 1. Analytical and conductivity data of the complexes* r Compounds
%C
%H
%N
%Pd
I
-1 an2 MO1 -1 %.itn .. IO-3M
in dmf
-
7 in
10-3M
{Pd(Pro)C1)2
23.50 (23.44)
3.19 (3.13)
5.70 (5.47)
41.85 (41.56)
6
a
{Pd(Pro)Br}2
20.20 (19.98)
2.80 (2.66)
4.72 (4.66)
35.14 (35.43)
5
6
{Pd(Pro) (Ino)Clj
34.51 (34.34)
3.72 (3.82)
13.50 (13.36)
20.50 (20.30)
a
120
{Pd(Pro) (Ino-Ii+)
36.58 (36.91)
3.79 (3.90)
14.61 (14.36)
21.53 (21.82)
{Pd(Pro) (Guo)Clj
33.52 (33.38)
3.96
(3.89)
15.60 (15.29)
lg.48 (19.73)
7
115
{Pd(Pro) (Guo-H+)
35.60 (35.80)
(3.98)
16.00 (16.38)
21.42 (21.16)
(PatPro) (Cyd)Cl}
33.80 (33.661
4.35 (4.21)
11.50 (11.22)
21.50 (21.32)
tPd(ProjC112Ado
31.04 (30.81)
3.85 (3.72)
12.69 (12.58)
27.50 (27.32)
3.90
a
6
-* The
numbers
in parentheses
represent
the calculated
figures
H,(
Complexes of palladium (II) with L-proline Table 2. Some characteristic
IR bands of L-proline and {Pd(Pro)Cl}, (cm-‘)*
Compound
v(NH)
v,(Coo)
Vs(COO)
vae,fo33) 6@
L - Proline
3190
1610
1415
680
1475 1380
{Pd(Pro)Cl12
3340 3210
1587
1435
750
fPd(Pro)Br12
3210 3340
1583
1432
745
3280
11
its complex are given in Table 3. There is a downfield shift for all four kinds of protons, in the complex relatively to free ligand, but the ones at positions (2), (3) and (5) which are adjacent to the ligation sites are shifted the most, 1.50, 1.02 and 0.54 ppm respectively. This confirms coordination of L-proline to palladium through both the carboxylate group and the imino nitrogen, in agreement with the IR data. The 13CNMR spectra also confirm the above postulations. In Table 4 are given the 13CNMR chemical shifts of L-proline and the complex {Pd(Pro)Cl),. The most pronounced change was observed for the carboxyl carbon of the complex, which was shifted by 150ppm downfield with respect to the uncomplexed ligand. A large downfield shift was also observed for the carbons C(2) and C(5) (4.8 and 4.0 ppm respectively). This again confirms the participation of both the carboxylate group and
V(F+X)
v(W+a
-
-
-
-
485
305
295
-
487
252
297
the iminonitrogen in coordination, and is in agreement with the observation that the changes of chemical shift on chelation of a-amino-acids. to Co(II1) (H,N + RCOOH jchelate) were about 15 and 5 ppm for the carboxy-carbon and a-carbon respectively.*’ (2) Mixed prolinato-nucleoside complexes of palladium (II) The dimeric complex, {Pd(Pro)Cl),, prepared and characterized above, reacted with purine and pyrimidine nucleosides (Nucl) with the cleavage of the chloride bridges between the two palladium atoms, and monomeric complexes were formed, according, to eqn (1): (Pd(Pro)Cl}, + 2Nucl”“.
Z{Pd(Pro)(Nucl)Cl). (1)
The proposed formulae are in agreement with the
Table 3. ‘H NMR chemical shifts of L-proline and {Pd(Pro)Cl}, (ppm) Compound
H(2)
H(3)
H(4)
H(5)
Solvent
L - Proline
4.10
2.18
2.18
3.36
DzO
fPd(Pro)C112
5.60
3.20
2.43
3.90
DzO
Table 4. 13CNMR chemical shifts of L-proline and (Pd(Pro)Cl}, @pm) Compound
C=O
L-Proline
fPd(Pro)C1j2
v(PdG
C(2)
C(3)
C(4)
C(5)
174.2
63.6
29.5
23.9
50.5
189.2
68.4
31.7
25.0
54.5
G. PNEUMATIKAKIS
12
on the exocyclic O(6) atom; and (iii) the nucleophilic substitution of the coordinated chloride by this negatively charged oxygen atom. This behaviour is similar to that observed in reacting the dimeric complex (Pd(O-Mecys)Cl}, with nucleosides.3’ However it is in contrast to the behaviour of analogous platinum complexes, where attempts to prepare complexes with the O(6) atom of the nucleosides, participating in coordination, resulted in the destruction of the parent compounds.32 The binding sites of the nucleosides in these mixed ligand complexes were deduced from their ‘H NMR, r3C NMR and IR spectra. The ‘H NMR bands of the proline are not shown clearly because they coincide with some of the bands of the nucleosides. However, the bands in the aromatic proton region are very useful in assigning the coordination sites of the nucleosides, and they are given in Table 5. The complex Pd(Pro)(Ino)Cl gave two resonances at 8.79 and 8.20ppm assigned to H(8) and H(2) respectively. The downfield shift of the H(8) resonance by 0.57 ppm, is comparable to the one found in other similar cases28*33*34 and may be taken as a good indication of the N(7) coordination of inosine to Pd(I1). The complex Pd(Pro)(Guo)Cl shows one resonance at 8.46 ppm, assigned to H(8), and this again indicates N(7) coordination of guanosine to Pd(I1). The complex {Pd(Pro)Cl}, Ado shows two resonances at 8.70 and 8.9Oppm assigned to H(2) and H(8) respectively. The downfield shift of both H(2) and H(8) resonances by about 0.75 ppm as compared with the uncomplexed adenosine is consistent with the participation of both N( 1) and N(7) in coordination to Pd(II).28~32’33 In the complex
analytical results (see Table 1). These mixed ligand complexes are non-electrolytes in dmf, as well as other organic solvents, e.g. ethanol, acetone, etc. However, those complexes with one ionizable N( 1) H imino proton, e.g. inosine and guanosine, decompose in water giving insoluble yellow material and HCl, and consequently the mixtures develop high conductivities. These insoluble materials are free from chloride and correspond to the formulae; Pd(Pro)(Nucl-H). The decomposition reaction follows the equation: Pd(Pro)(Nucl)Cl-
“”
Pd(Pro)(Nucl-H)
+ HCl. (2)
In acidic solution the reaction (2) was reversed and the protonated complexes, Pd(Pro)(Nucl)Cl can be recovered. The deprotonated complexes, Pd(Pro)(Nucl-H) were also prepared by performing the reaction (1) in aqueous solutions: {Pd(Pro)Cl}, + 2Nucl-
W
2 Pd(Pro)(Nucl-H)
+ 2HCl.
(3)
Reaction (3) may proceed in two main steps. First the chloride bridges may be cleaved by the nucleosides, which then remain attached to palladium with their N(7) atom (as will be shown below) and this is seen by the formation of a transient clear yellow solution. In the second step, the compounds Pd(Pro)(Nucl-H) are precipitated, and this may involve: (i) the ionization of the N(l)-H iminoproton, due to the very large lowering of the pK, of this proton when the nucleosides are coordinated to metals and especially to Pd(II), through their N(7) atom;28-30(ii) the accumulation, due to resonance, of a negative charge
Table 5. H’ NMR chemical shifts of the mixed ligand complexes (ppm) Compounds
H(2)
H(5)
H(6)
H(8)
Inosine
8.11
-
-
0.22
6.03,
5.93
dmso-d6
{Pd(Pro) (Ino)Cll
82..@
-
-
8.79
5.85,
5.76
duo-d6
7.80
5.74,
5.60
dmso-d6
8.46
5.85,
5.78
dmso-d6
Guanosine fPd(Pro) (Guo)C11
-
Cytidine
-
Solvent
5.75,
5.66
7.78,
7.79
-
6.24,
6.17
dmso-d6
6.18,
6.19
8.11,
8.20
-
6.26,
6.24
dmso-d6
IPd(Pro) (Cyd)Clj
-
Adenosine
7.95
8.17
5.90,
5.80
dmso-d6
8.70
8.90
6.31,
6.23
dmso-d6
(Pd(Pro)C112
Ado
Complexes of palladium
{Pd(Pro)(Cyd)Cl}, both H(5) and H(6) shifted downfield, with the larger shift for H(5). This indicates that H(5) is closer to the coordination site on the ligand, probably the N(3) atom.33**) The postulations on the binding sites of nucleosides made from ‘HNMR spectra are further confirmed by the r3CNMR spectra of the complexes. The 13CNMR chemical shifts of the ligands and complexes are given in Table 6. In the complex {Pd(Pro)(Ino)Cl), the downfield shifts observed for the C(5) and C(8) resonances (2.3 and 3.8 ppm respectively) are consistent with N(7) coordination, since these carbons are adjacent to this nitrogen. The same sort of pattern was also observed in the i3C NMR spectra of the guanosine complex, suggesting again N(7) coordination. In the adenosine complex the resonances of all four carbon atoms, C(2), C(6), C(5) and C(8), adjacent to both N(1) and N(7) atoms are shifted downfield upon coordination, and this further supports the participation of both these nitrogens in coordination.32m35The resonances of the proline carbons in these mixed ligand complexes remain essentially at the same positions as in the parent dimeric complex. The deprotonated complexes Pd(Pro)(Nucl-H) are insoluble in all common solvents and the information concerning their structure was deduced only from their chemical behaviour and IR spectra.
(II) with L-proline
13
The preparation of these complexes from the complexes Pd(Pro)(Nucl)Cl and their reversible conversion to them suggested that the Pd-N(7) bonding, present in the latter complexes, exists also in the deprotonated complexes. These deprotonated complexes do not contain any chloride, and the v(Pd-Cl) vibration, which occurs at 305 cm-’ in the starting dimeric complex, {Pd(Pro)Cl}, and is shifted at about 330 cm -I in the complexes (Pd(pro)(Nucl)Cl} (the normal position for the stretching vibration of the Pd-Cl terminal group) is absent from the spectra of these complexes. On the other hand, the IR spectra of these complexes in the carbonyl stretching region, may give an indication for the exocyclic O(6) atom participating in bonding with Pd(II), in these deprotonated complexes. The v(C = 0) of the exocyclic carbonyl oxygen of the nucleosides inosine and guanosine appears at about 1700 cm - ’ and remains at the same frequency in the complexes Pd(Pro)(Nucl)Cl thus excluding its participation in bonding with palladium in these complexes.28*33,34,36 However in the complexes Pd(Pro)(Nucl-H+) this band is shifted to lower frequencies by about 75 cm -’ and appears at 1625cm-‘. This lowering of the v(C = 0) frequency may be taken as a good indication of the O(6) keto oxygen involvement in bonding with the metals.28,33,3qa)* 3638The shift to lower frequencies
Table 6. “C NMR chemical shifts of the mixed ligand complexes (ppm) L -
Zompounds c=o
(Ino)Cl}
Guanosine
lPd(Pro)
(Guo)Cl)
Cytidine
(PdfPro)
(CydJCl)
Adenosine
{Pd(Pro)C1)2
c2
carbons c1
c,
Nucleoside c5
_----
rnosine
fPd(Pro)
Proline
Ado
189.0
68.5
31.5
_
----
189.1
68.4
31.7
-
-
---
108.8
68.3
31.5
_
-
189.0
68.7
25.7
25.0
25.3
54.6
54.5
54.8
---
31.4
25.1
54.7
c*
cp
c,,
146.0
148.2
124.4
146.7
150.0
153.6
Carbons C6
C8
c,-
c2-
cj-
C.4.
c5-
156.5
138.7
87.4
74.0
70.2
85.6
61.2
126.8
157.5
142.5
88.2
74.5
70.0
85.9
60.8
151.3
116.6
156.7
135.6
86.3
73.7
70.3
85.1
61.7
154.6
152.6
118.7
158.2
139.0
87.1
74.0
69.7
85.6
61.1
152.9
163.7
99.6
148.6
-
90.8
74.6
69.8
03.8
61.3
156.5
166.0
98.0
147.2
-
90.7
74.9
69.7
84.0
61.0
148.5
147.0
114.5
152.0
135.8
60.4
71.0
73.9
86.3
61.0
156.0
147.6
116.9
157.0
143.5
68.6
71.3
74.3
86.8
61.3
14
G. PNEUMATIKAKIS
of the v(C = 0) band upon ionization of the N(1) H imino proton in inosine and guanosine, indicates the loss of the double bond character of the C = 0 group. 39v40This is more pronounced in the ionic salt of guanosine (shift to 1595 cm-L),38 and less whenever the metal-oxygen bonding is more covalent, as in the case of Pd(II).28v33Certainly, the double bond character of the C = 0 is also lowered when the oxygen interacts with a metal, without ionization of the N(l)H imino proton.3q*) Oxygen involvement in bonding with metals, following deprotonation of the imino proton, has also been found in the crystal structure of cisdiamminoplatinum a-pyridone blue:’ where both O- and N atoms bridge two platinum atoms. Kistenmacher et al.” have also found an SAg(1) interaction in the crystal structure of (nitrato) (1-methylcytosine) silver (1). Recently, Bau et ~1.~~ showed the participation of the exocyclic O(6) in coordination, in the crystal structure of a tetranuclear copper (II)--inosine monophosphate o-phenanthroline complex, where inosine acts as an O(6) N(7) bridging ligand with Cu-O(6) distance 1.956 A. Very recently, Marzilli et al.,4 have presented evidence for O(6) binding with metals mainly from 13CNMR spectra. In view of the above discussion, there must exist a strong O(6)--Pd interaction in the complexes Pd(Pro)(Nucl-H), which may be formulated as polymers with O(6) N(7) bridges: PrO
/
P\
0.5 mm01 (Pd(Pro)Cl}, and 1 mmol of the respective nucleoside were suspended in 3 cm3 dmso-d, and stirred for 1 hr at room temperature. The ‘H NMR spectra of the solution showed the existence of only one species in the solution and the compound was precipitated with excess acetone. Yield, 85-90x. (3) L-prolinato (guanosinato) palladium (III), Pd(pro)(Guo-H +) and L-prolinato (insosinato) palladium (II), Pd(pro)(Ino-H +) (a) 0.5 mmol {Pd(Pro)Cl), was dissolved in 10 cm3 Hz0 and to that was added 1 mmol of the respective nucleoside dissolved in 25 cm3 H20 (hot in the case of guanosine). The mixture was stirred at room temperature for 2 hr and the precipitate formed, was filtered, washed with hot water, ethanol, ether and dried at 80°C under vacuum. Yield, ea. 80%.
(b) 1 mmol of the respective complexes Pd(Pro)(Nucl)Cl (NucI = Ino or Guo) was suspended in 25 cm3 water and stirred for 2 hr at room temperature. The precipitate formed was filtered, washed with water, ethanol, ether and dried as above. Pro
0
/pd\ N(7) e-016) Nucl
The postulation that the bridging occurs with N(7) N(1) bridges, without participation of the carbonyl O(6) in bonding does not explain the large lowering of the v (C = 0) frequency, and does not seem very likely to occur. EXPERIMENTAL The experimental scribed elsewhere.33
(2) Chloro-(L-prolinato)(nucleoside) palladium (II), Pd(pro)(Nucl)Cl, (Nucl = Ino, Guo, Cyd)
FTO
Cl
O(6)
absolute ethanol and filtered. The compound was then precipitated with excess ether. Yield, 90%.
techniques
have been de-
Preparation of complexes palZadium (ZZ)-p-dichloro (1) L -Prolinato L-prolinato palladium (II), {Pd(pro)Cl},
Palladium (II) chloride (0.356 g, 2 mmoles) and L-proline (0.230 g, 2 mmoles) were suspended in 25 cm3 water and stirred at 60°C for 2 hr. The resulting clear red solution was roto-evaporated to dryness at 50°C. The residue was taken with 20 cm3
N(7) -O(6) Nucl
N(7)
_
(4) Chloro L -prolinato -palladium (II)-u -Adeno sine (Nl N7)-chloro L-prolinato palladium (II),
Cl(Pro)Pd Ado Pd (Pro)Cl 1 mmol {Pd(Pro)Cl), was dissolved in 10 cm3 H20 and to that was added 1 mmol Adenosine dissolved in 20 cm3 water and stirred for 2 hrs. The yellow precipitate formed, was filtered, washed with water, ethanol, ether and dried at 60°C under vacuum. Yield ca. 85%. REFERENCES 1. S. Kirschner, A. Maurer and D. Dragulesku, J. Clin. Hematol. Oncol. 1977, 7, 293. 2. A. J. Charlson, N. T. McArdle and E. C. Watton, Inorg. Chim. Acta 1981, 56, L35. 3. S. Kirschner, A. Maurer and C. Dragulescu, J. Clin. Hematol. Oncol 1977, 7, 190. 4. T. Yasui, J. Hidaka and Y. Shimura, J. Am. Chem. Sot. 1965, 87, 2762.
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