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Mono- and Binuclear Gold(I) Compounds Containing
Deprotonated Purines and Pyrimidines
Flavio Bonati, Alfredo Burini, and Bianca Rosa Pietroni*
Dipartimento di Scienze Chimiche dell’Universitä, Via S. Agostino 1, 1-62032 Camerino
Z. Naturforsch. 40b, 1749-1752 (1985); received June 18, 1985
Deprotonated Purines, Pyrimidines, Mono- and Binuclear Gold(I) Compounds
In the presence of alkali and LAuCl one or two —N H — groups of a purine or pyrimidine base can be transformed into -N (AuL)- groups giving stable and soluble compounds containing one or two two-coordinated gold(I) nuclei; mononuclear L A u-Q ' or binuclear LA u-Q -A uL with a monodentate Q " or an exobidentate O '" ligand, resp. (Q 'H = adenine, guanine, theobromine, theophylline, azaguanine or cytosine; Q H 2 - thymine or uracyl; L = triphenylphosphine).
Introduction
Much interest has recently been dedicated to the
chemistry of gold since this element in the oxidation
state + 1 has been found to provide compounds, such as
(2,3,4,6-tetra-O-acetyl-l-thio-ß-glucopyranosato-S)-
(triethylphosphine)gold(I) or triethylphosphine-
chlorogold(I), successfully used in the treatment of
rheumatoid arthritis [1]. The mode of action of this
or of other drugs actually used or undergoing clinical
tests of gold containing drugs [2] is extremely com
plex, and many more investigations will be required.
Our investigations in the field of gold chemistry
have been concerned with the interaction between
Au(I) and several nitrogen-containing heterocycles
such as pyrazoles [3], pyrazolones [4], indazoles,
imidazoles [5], triazoles, tetrazole [6], or pyridones
[7]. Isolation and characterization of several N- and
of a few C-(trisubstituted phosphine)gold(I) deriva
tives of the said molecules was reported. These were
found to be stable and soluble in organic solvents,
thus allowing spectroscopic investigations, whereas
the uncomplexed gold(I) derivatives are often insolu
ble coordination polymers or, at best, oligomers,
e.g.: l-gold-2-R-imidazole (R = /so-proypl [8] or
phenyl [9]) and tris(pyrazolato-N,N')trigold(I) [10],
respectively.
It was therefore decided to react with gold(I) cer
tain purine and pyrimidine bases of relevance to
biological systems. Here we report the isolation and
the characterization of stable and generally soluble
mono- or bis-aurated derivatives of purines or py
rimidines where gold(I)-nitrogen bonds are present.
* Reprint requests to Dr. B. R. Pietroni.
Verlag der Zeitschrift für Naturforschung, D-7400 Tübingen0340 - 5087/85/1200 -1749/$ 01.00/0
Results and Discussion
The reaction between a purine or pyrimidine base
(Q 'H or QH2), LAuCl and alkali was carried out in
homogeneous or heterogeneous phase, as detailed in
the experimental part, according to one of the fol
lowing patterns:
Q '-H + O H “ + LAuCl =
Q '-A uL + CP + H20
1, 4-8
Q - H 2 + 2 O H ' + 2 LAuCl =
Q(AuL )2 + 2 c r + 2 h 2o
2,3
The colourless, moisture- and air-stable solids
were characterized through elemental analyses, in
frared and proton NMR spectra (Tables I —III) .
These data confirmed that in several cases molecules
of solvents can be clathrated in the solids, a frequent
observation in the chemistry of the heterocyclic
derivatives of gold e.g.: l-(triphenylphosphinegold)-
6-methyl-2-pyridone [7] or l-tri(cyc/o-hexyl)phos-
phinegold-2-/so-propylimidazole [8]. The ligand L is
triphenylphosphine for several reasons: the starting
compound LAuCl is easily obtained and handled,
the corresponding products are generally soluble in
organic solvents, and the A u—P bond is not as easily
broken as, for example, the A u—As or the A u—Sb
bond of similar compounds having triphenylarsine or
triphenylstibine in the place of L [8, 11].
The reactivity of the molecules investigated is not
related to the number of nitrogen-bonded hydrogen
atoms available for the substitution by the LAu
group; in all the cases but two only mono-auration is
observed. Since no C-auration is observerd, even if
only one NH is present — as with theophylline or
theobromine (Q 'H) — a mono-aurated compound
1750 F. Bonati et al. ■ Mono- and Binuclear Gold(I) Compounds
Table I. Analytical and other data for compounds 1—8a. nh2 M ? m m
N ^ l p u . u n %N r CHru n u n u . 1Com- Meth- Yield m.p. Elemental analyses [%]b J 2 c f=H6 H2° J ch2c i2 h 2o i J c 6h6 2pound od [%] [°-C] C H N
1 A 73 227-229 48.32 3.94 6.31
2 A 77 258-260(47.93)44.49
(3.86)3.22
(6.71)2.59
3 A 79 268-270(44.04)48.78
(3.34)3.72
(2.44)2.40
4a A 72 271-273(48.73)45.70
(3.64)3.18
(2.47)11.80
4b B 51 271-273(45.86)45.83
(3.35)3.52
(11.63)11.47
5a A 42 >350(45.86)44.39
(3.35)3.11
(11.63)10.99
5b B 61 >350(44.67)45.02
(3.26)3.33
(11.32)11.47
6 A 73 320-321(44.67)42.74
(3.26)3.14
(11.32)13.70
7 B 82 267-268(42.66)46.78
(3.09)3.48
(13.57)8.56
8 B 78 273-274(47.03) 47.46(47.03)
(3.47) 3.53
(3.47)
(8.77) 8.98
(8.77)
a The methods A and B are described in the experimental part; b calculated values in brackets.
M M M
1 2
NHj 0
--------N u r\ ^ l l -------- N 1L 1 j l ' 2 H2 ° L J L I] ' Y H2 °
H ,N N N I 2 I
M rl
4a,4b 5a, 5b
oM
xn' 'n— nL jl II '7 n2L
M 'NN H
6
9 CH3 H3c j?N '^ r , ----N ---- N'J I J J II J
0 0 N^NI I
C H j CH3
7 8
M = AuPPh,
Table II. Proton nuclear magnetic resonance data for compound 1—8ab.
Compound Aromatic protons Other protons
1 7.90-7.10 m [19]; 5.55 d [1] j = 7 6.25-6.35 s, br [2]d; 3.65 s [2]d2 7.82-7.42 m [30]; 7.30 s [1] 5.75 s [2]d; 3.30 s [2]d; 1.72 s [3]3 7.90-7.30 m [37]; 5.45 d [1] j - 7 3.30 s [3]d4a, 4b 8.09 s [1]; 7.90 s [1]; 7.90-7.45 m [15] 6.70 s [2]d; 3.35 s [l]d5a, 5bc 7.90-7.30 m [16] 6.38 s [2]d; 3.35 s, br [2]d6 8-7.30 m [15] 10.5 s [l]d; 6.38 s [2]d; 3.32 s [l]d7 8-7.40 m [16] 3.92 s [3]; 3.44 s [3]8 7.90-7.30 m [16] 3.63 s [3]; 3.47 s [3]
a The data were recorded on a Varian instrument operating at 90 MHz using TMS as reference; they are in 6 units. Coupling constants in Hz; s = singlet, d = doublet, m = multiplet; [ ] denotes relative intensities; b the spectra were recorded in (CD3)2SO solution in all the cases but 8 (CDC13); 0 very little soluble in (CD 3)2SO; d disappears upon deuteration.
Compound v(OH; NH) 1500—1700 cm 1 region
1 3390 w, br 1620 s; 1595 m; 1585 m; 1570 s; 1565 s; 1510 m2 not evident 1642w; 1620s; 1610s; 1583w; 1572m; 1562m; 1595s3 not evident 1630 s; 1600 w; 1590 s; 1580 w; 1540 s4a, 4b 3660-3050 s, br 1630 s; 1590 s; 1550 m5a, 5b 3680-2500 s, br 1665 s; 1610 s; 1550 m6 3320 s, br; 3160 s, br 1685 s; 1670 s; 1615 m; 1560 w; 1529 w7 - 1660 s; 1650 s; 1625 s; 1585 m; 1545 m; 1530 m8 - 1690 s; 1640 s; 1530 s
Table III. dataa.
Selected infrared
Recorded as Nujol mull in the NaCl region with a Perkin- Elmer 297 instrument.
F. Bonati et al. • Mono- and Binuclear G o ld (I) Compounds 1751
Q' —AuL, 8 or 7, was obtained. The assignment gi
ven in the Figure is supported by the disappearance
of the NH absorptions and the shifting of the C = 0
vibrations in the infrared spectra as well as by the
presence of two methyl and of one =C H — signal in
the NMR spectra. In the case of the theophyllinato
complex the gold atom is assumed to be in the less
hindered 7-position rather than in the 9-position,
where it would be flanked by the 3-methyl group. In
the first preparation of this theophyllinato complex
the NMR spectrum of the crude product showed the
presence of both isomers (the 9-isomer being ca. 1/4),
but the following preparations failed to yield the
same result.
In the case of uracyl and of its C-methylated
homologue, thymine, two LAu replace the hydrogen
in both the NH groups, yielding 3 and 2, bulky
molecules where water and benzene or water and
dichloromethane are clathrated. Here, too, disap
pearance of NH bands, shifting of the C = 0 infrared
vibrations, and the presence of the required number
of methyl and CH signals rule out C-auration and are
in agreement with the formulae given in the figure.
Many structures are possible, in principle, for the
monoaurated derivatives of adenine, guanine, aza-
guanine, or cytosine (Q'H). For these purines sever
al tautomeric forms [12] may be written in each of
which a nitrogen bonded hydrogen may be replaced
by an LAu group. Actually, in the said bases only
mono-aurated derivatives have been isolated for
which the NMR spectra show an NH2 group. This
spectral evidence (together with the presence of a
C = 0 stretching group where required) rules out the
possibility of a substitution on the 1-position of cy
tosine and adenine and on the 3-position of guanine
and azaguanine. On this basis cytosine must be a 3-
aurated derivative, while in the case of adenine two
positions are still available, N(7) and N(9), the latter
being preferred because of less steric hindrance [12].
Three more types of substitutions are possible in the
case of guanine and of azaguanine (N (l), N(7) or
N(9)): they are all equally possible on the data avail
able. Therefore, in the absence of an X-ray crystal
structure determination, no definitive formula can be
assigned to 5 or 6, although in the Figure they are
depicted as 1-substituted derivatives because this is
the most acidic position available [13].
In conclusion, one or two LA u— moieties can be
attached to a purine or pyrimidine giving stable and
soluble compounds with A u—N bonds and two-coor
dinated Au(I) where the corresponding deproto-
nated nitrogen base may behave as a monodentate or
as an exobidentate (i.e. bidentate and bridging)
ligand. Previously only a few adducts of gold(I)
chloride with purine or nucleoside bases were re
ported: insoluble Au(nucl)2Cl (nucl is guanosine or
inosine) [14], to which a two-coordinated
N—>Au —Cl arrangement was assigned [15], or the
adduct (cytosine)AuCl, investigated only in solution
by proton NMR [16]. Our results show that the in
teraction between gold(I) and purine or pyrimidine
bases includes auration and is not limited to adduct
formation.
Experimental
Elemental analyses were performed by our Mi- croanalytical Laboratory (Perkin Elmer 240 Instrument) or by Mr. A. Canu (University of Sassari). Evaporation was always carried out under reduced
pressure.
Method A
To a methanol solution (20 ml) of cytosine (0.150 g; 1.35 mM), 1% sodium hydroxide (5.40 ml; 1.35 mM) in the same solvent and Ph3PAuCl (0.735 g; 1.48 mM) were added. After 8 h stirring at 40 °C the unreacted substrate was filtered, the solution evaporated to dryness, and the residue washed repeatedly with benzene, hexane and water to give the analytical sample 1 .
In the same way were prepared compounds 5 a and6 using as starting materials guanine and azaguanine, respectively. The compound 6 precipitated from methanol solution and was purified by several washings with water, methanol, benzene, and dichloromethane. The compound 2 was obtained by reaction
of thymine at r.t. and cristallization from CH2C12/ hexane of the residue left after evaporation. The
compound 3 was obtained by reaction of uracyl at r.t.; the residue after evaporation was extracted with CH2C12 and the evaporated residue was dissolved in benzene from which clathrated compound 3 precipitated nearly at once. The compound 4a was obtained as a precipitate from adenine at r.t. and was purified by means of several washings with water, methanol
and then hexane.
Method B
A dichloromethane solution (20 ml) of theobromine (0.150 g; 0.83 mM) and Ph3PAuCl (0.453 g;
1752 F. Bonati et al. • Mono- and Binuclear Gold(I) Compounds
0.92 mM) was added to an ice-cold suspension of tetra-n-butylammonium hydrogen sulphate (0.283 g;
0.83 mM) in 0.83 ml of 2 N aqueous sodium hydroxide. After 4 h stirring at r.t. the organic layer was
separated, washed with water till neutral washing, dried over sodium sulphate and evaporated to dry
ness. The residue was washed several times with ben
zene giving the analytical sample 7.The compound 8 was prepared as above starting
from theophylline and Ph3PAuCl. The residue was purified by cristallization from benzene/hexane.
The compounds 4 b and 5 b were obtained in the
same way starting from adenine on guanine and Ph3PAuCl, resp. The first product was cristallized
from dichloromethane/hexane and the former, insol
uble in dichloromethane, were filtered and purified by several washings with dichloromethane and
hexane.
We thank the “Ministero della Pubblica Is- truzione” and the “Consiglio Nazionale delle Ricerche” for financial support.
Note added in proof: After this work was accepted,
a paper became available to us in which several pal
lad ium ^), one rhodium(I), and some gold(I) derivatives were reported (Y. Rosopulos, U. Nagel, and W.
Beck, Chem. Ber. 118,931 (1985)). Amongst all these complexes only two are in common with those reported by us, though prepared in a different way. They are 1,3- bis(triphenylphosphinegold)uracyl and (triphenyl- phosphine)(adeninato-N(9))gold(I) for which an X-
ray crystal structure is also reported. The results of the German group agree fully with ours, and complete a
fieW of investigation where only scattered results had
been available.
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[2] S. J. Lippard (ed.): “Platinum, Gold, and other Metal Chemotherapeutic Agents” , ACS Symposium Series 209, American Chemical Society, Washington D .C., U.S.A. 1983.
[3] F. Bonati, Chim. Ind. (Milan) 62, 323 (1980); G. Min- ghetti, G. Banditelli, and F. Bonati, Inorg. Chem. 18, 658 (1979); F. Bonati, G. Minghetti, and G. Banditelli, J. Chem. Soc., Chem. Commun. 1974, 88 ; G. Banditelli, A. L. Bandini, G. Minghetti, and F. Bonati. Can. J. Chem. 59, 1241 (1981); J. R. Lechat, R. H. de Almeida Santos, G. Banditelli, and F. Bonati, Cryst. Struct. Commun. 11, 471 (1982).
[4] F. Bonati, A. Burini, B. R. Pietroni, and M. Felici. J. Organomet. Chem. 274, 275 (1984).
[5] F. Bonati, M. Felici, B. R. Pietroni, and A. Burini, Gazz. Chim. Ital. 112, 5 (1982).
[6] F. Bonati, A. Burini, M. Felici, and B. R. Pietroni, Gazz. Chim. Ital. 113, 105 (1983).
[7] F. Bonati, A. Burini, B. R. Pietroni, and B. Bovio, J. Organomet. Chem., accepted.
[8] B. Bovio, F. Bonati, A. Burini. and B. R. Pietroni, Z. Naturforsch. 39b, 1747 (1984).
[9] D. Leonesi, A. Lorenzotti, A. Cingolani, and F. Bonati, Gazz. Chim. Ital. I l l , 483 (1981).
[10] B. Bovio, F. Bonati, and G. Banditelli, Inorg. Chim. Acta 87, 25 (1984).
[11] Ref. [la], page 54.[12] D. J. Hodgson. Progr. Inorg. Chem. 23, 211 (1977).[13] Ref. [12], p. 221; T. J. Kistenmaker, Acta Crystallogr.
B30, 1610 (1974); T. J. Kistenmaker, L. G. Marzilli, and C. H. Chang, J. Am. Chem. Soc. 95, 5817 (1973).
[14] N. Hadjiliadis, G. Pneumaticakis, and R. Basosi, J. Inorg. Biochem. 14, 115 (1981).
[15] G. H. M. Calis and N. Hadjiliadis. Inorg. Chim. Acta 79, 241 (1983); ibid. 91, 203 (1984).
[16] M. Bressan, R. Ettorre, and P. Rigo, J. Magn. Reson. 26, 43 (1977).