sine.8 These latter examples are highly comparable to the case
O
N
Me
O
HN
N
Me
of 3, particularly the complexes trans,trans,trans-[Pt(NH3)2-
(OH)2(1-MeCyt-N4)2]2ϩ and trans-[Pt(NH3)2(1-MeCyt-N4)2]2ϩ
(1-MeCyt = 1-methylcytosine).8 The authors have discussed
the biological implications of these metal-stabilized tautomers
with respect to DNA base-pair mismatching, and it is of inter-
est to consider such effects here. Stabilization of the iminooxo
form should preclude base-pairing with guanine but allow for
mismatching with adenine or thymine for example (Fig. 7). The
data presented here further indicate that PdII binding at the
exocyclic nitrogen donors can stabilize the iminooxo form.8
N
N
HN
OH
OH
NH2
NH2
II
I
Fig. 6 Aminooxo (I) and iminooxo (II) tautomeric forms of L
Conclusion
O
HN
HN
N
The substituted pyrimidine, 1-(2-hydroxyethyl)-(2-aminoethyl-
N2)-5-methylisocytosine, has been shown to bind metal ions as
a mono-, di- and tri-dentate ligand, the last two examples being
observed for PdII. In addition to exhibiting different modes of
co-ordination, the pyrimidine moiety in the two PdII complexes
exists in different tautomeric forms, with the iminooxo form
associated with the tridentate binding mode involving co-
ordination to the N(2) amino group. This result further indi-
cates that metal-ion binding at the exocyclic nitrogen atoms of
nucleobases may induce nucleobase tautomerism and is thus
implicated as a mechanism for metal-based mutagenicity.
N
NH
N
N
O
HNH
O
HNH
N
N
N
HN
HN
N
Experimental
The NMR data were measured on a JEOL Lambda 500
instrument with either D2O or (CD3)2SO as solvent.
N
Fig. 7 Incompatible hydrogen-bonding interactions for the G᎐C pair
(top) containing the iminooxo tautomer, and mismatched base pair
between A᎐C (bottom)
Syntheses
1-(2-Hydroxyethyl)-(2-aminoethyl-N2)-5-methylisocytosine
hydrochloride [LH]ϩClϪ. 1-(2-Chloroethyl)thymine11 (1.00 g,
5.79 mmol) was stirred with an excess of ethylenediamine
(5 ml, 75 mmol) at room temperature under an atmosphere
of nitrogen for 24 h. Excess ethylenediamine was removed
under reduced pressure, the resultant yellow viscous liquid was
taken up in ethanol (10 ml). The mixture was warmed gently,
after a short time a white solid precipitated. The resultant
crude product was recrystallized from ethanol (25 ml). The
white solid (0.89 g, 62%) was collected by filtration, washed
A search of the Cambridge Structural Database12 reveals
that complexes of 1-alkylcytosine generally prefer N3 as the
binding site.20 However, other modes of co-ordination involving
N4 are known.22 Bond lengths for the exocyclic amino group of
cytosine binding to PdII as an anionic donor group lie in the
range 1.973–2.014 Å and compare with a Pd᎐N(2) distance of
2.040(7) Å in 3.22
A significant difference in 3 compared to 1 and 2 is that the
pyrimidine ring exists in a different tautomeric form. Two prin-
cipal resonance structures, I and II, may be written for the
pyrimidine (Fig. 6). Evidence suggestive of the iminooxo
tautomer in 3 was obtained by consideration of the bond
lengths within the pyrimidine ring (refer to Table 1). The
C(2)᎐N(3) bond in 3 is longer [1.364(11) Å] than that observed
in 1 and 2 [1.332(5) and 1.351(6) Å, respectively]. The greater
bond length in 3 is indicative of single bond character, and
conversely in both 1 and 2 greater double bond character is
apparent. It should be noted that due to the effect of N(3)
metallation the bond length is greater in 2 than in 1. The
C(2)᎐N(2) bond length in 3 [1.323(10) Å] is shorter than that
observed in 1 [1.343(5) Å] and 2 [1.332(7) Å]. Again these bond
length data are consistent with the pyrimidine existing as the
iminooxo tautomer in 3 and the aminooxo tautomer in both 1
and 2. Further support for the existence of L as the iminooxo
tautomer in 3 is gained from the bond angle data of the three
complexes. The large value of the angle at N(3) [126.1(7)Њ] in 3
agrees with a proton being bonded to this nitrogen. Generally
the angle is significantly smaller in cases where the N(3) site
carries no proton, as in isocytosine (119.7Њ) for example. In 1
the angle is 119.6(4)Њ, again as expected for form I. Finally, an
analysis of difference electron density maps gave a clear indi-
cation as to the location of indicative protons in the three struc-
tures: N(2) in 1 with no peak near N(3), a single proton on N(2)
in 2 and a single proton on N(3) for both molecules in the
structure of 3.
1
with cold ethanol and air dried. H NMR [(CD3)2SO]: δ 1.73
(s, 3 H, pyrimidine CH3), 2.99 (t, 2 H, CH2NH3ϩ), 3.50 (t, 2 H,
NHCH2CH2), 3.62 (t, 2 H, CH2OH), 3.79 (t, 2 H, CH2CH2OH),
7.13 (s, br, 1 H, pyrimidine NH), 7.27 (s, 1 H, C6H); 13C NMR
[(CD3)2SO]: δ 13.18 (pyrimidine CH3), 38.55 (NHCH2CH2),
38.68 (CH2NH3), 51.89 (CH2CH2OH), 58.74 (CH2OH), 140.55
(C6), 112.61, 153.29, 170.36 (C2, C5, C4) (Found: C, 40.69; H,
6.26; N, 20.68. Calc. for C9H19ClN4O3: C, 40.53; H, 7.18; N,
21.01%). Infrared; ν (cmϪ1) 3352, 3280 (N᎐H) and 1660 (C᎐O).
᎐
[ZnCl3(LH)] 1. To a solution of zinc chloride (0.14 g, 1.00
mmol) in H2O (15 ml) was added with stirring an aqueous solu-
tion (15 ml) of 1-(2-hydroxyethyl)-(2-aminoethyl-N2)-5-methyl-
isocytosine hydrochloride (0.25 g, 1.00 mmol), the mixture was
allowed to stir overnight. The colourless solution was concen-
trated to a minimum volume on a rotary evaporator, ethanol
(60 ml) was added and the mixture was allowed to stand
undisturbed overnight. Complex 1 crystallized as colourless
crystals which were found to be suitable for a single-crystal
X-ray structure analysis (Found: C, 27.35; H, 4.45; N, 14.14.
Calc. for C9H17Cl3N4O2Zn: C, 28.23; H, 3.95; N, 14.63%).
Infrared; ν (cmϪ1) 3471, 3293 (N᎐H) and 1654 (C᎐O).
᎐
[PdCl2L] 2. To a refluxing solution of PdCl2 (0.18 g, 1.0
mmol) in acetonitrile (25 ml) was added dropwise an aqueous
(25 ml) solution of 1-(2-hydroxyethyl)-(2-aminoethyl-N2)-5-
methylisocytosine hydrochloride (0.25 g, 1.0 mmol). The mix-
ture was allowed to remain at reflux for 24 h. The cooled solu-
Lippert and co-workers have reported on various metal-
stabilized rare tautomers of the nucleobases adenine7 and cyto-
2004
J. Chem. Soc., Dalton Trans., 1998, Pages 2001–2006