Synthesis of neutral gold(III) pyrimidine-complexes and theoretical studies on the proton affinity of the coordinated ligands

Article abstract of DOI:10.1016/j.poly.2010.02.028

The neutral gold(III) complexes AuCl₃(pm) (pm = pyrimidine, 2-methylpyrimidine, 4-methylpyrimidine, 5-methylpyrimidine, 4,6-dimethylpyrimidine, 2-aminopyrimidine) have been synthesised and characterised. The proton affinity (PA) values of the free and coordinated N-heterocycles have been theoretically estimated on the basis of DFT calculations. The coordination to the AuCl₃ metal fragment causes a strong lowering of the basicity of the residual protonation sites, with PA variations around -25 kcal mol^-1. The lowering of PA caused by the bonding to the gold centre results related to the presence of space-demanding groups near the coordinating nitrogen atom and to the π-back donation of electron density from the metal to the protonated ligand.

Full text of DOI:10.1016/j.poly.2010.02.028

Polyhedron 29 (2010) 1833–1836
Contents lists available at ScienceDirect
Polyhedron
journal homepage: www.elsevier.com/locate/poly
Synthesis of neutral gold(III) pyrimidine-complexes and theoretical studies
on the proton affinity of the coordinated ligands
*
*
Marco Bortoluzzi , Bruno Pitteri
Department of Chemistry, Cà Foscari University of Venice, Calle Larga S. Marta, Dorsoduro 2137, 30123 Venice, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The neutral gold(III) complexes AuCl3(pm) (pm = pyrimidine, 2-methylpyrimidine, 4-methylpyrimidine,
5-methylpyrimidine, 4,6-dimethylpyrimidine, 2-aminopyrimidine) have been synthesised and character-
ised. The proton affinity (PA) values of the free and coordinated N-heterocycles have been theoretically
estimated on the basis of DFT calculations. The coordination to the AuCl3 metal fragment causes a strong
lowering of the basicity of the residual protonation sites, with PA variations around ꢀ25 kcal molꢀ1. The
lowering of PA caused by the bonding to the gold centre results related to the presence of space-demand-
Received 27 January 2010
Accepted 21 February 2010
Available online 24 February 2010
Keywords:
Gold(III)
Pyrimidines
Proton affinity
DFT
ing groups near the coordinating nitrogen atom and to the
metal to the protonated ligand.
p
-back donation of electron density from the
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
2. Experimental
Several square-planar gold(III) complexes stabilized by N-donor
heterocycles are potentially interesting species in biological sys-
tems and have been found to be anti-cancer and anti-parasitic
drugs [1]. Moreover, the chemical features of gold(III) complexes
stabilized by six-membered N-donor heterocycles are of current
interest in homogeneous catalysis. For example, Hashmi and co
workers reported in the last few years the use of pyridine-based
Au(III) complexes as efficient catalysts in organic syntheses [2].
Square–planar d8 gold complexes with monodentate N-donor het-
erocycles in their coordination sphere have been extensively stud-
ied also from kinetic and theoretical points of view, in order to give
insight into the Au–N bond [3]. The chemistry of gold(III)
complexes of nitrogen ligands has been recently reviewed by
M.A. Cinellu [4].
2.1. Materials and instruments
K[AuCl4]ꢁ2H2O was prepared following a standard procedure
from pure gold foils (99.9999%) purchased from CHIMET, Italy.
The pyrimidines (Aldrich) were used without further purifications.
Acetone, deuterated acetone and dimethylformamide (dmf) were
pure-grade Aldrich products. 1H NMR spectra were obtained with
Bruker Avance 300 and Bruker AC 200 spectrometers and are re-
ferred to internal tetramethylsilane. The organic ligands were
numerated following common conventions. The conductivity of
10ꢀ3 mol dmꢀ3 solutions in dmf and acetone at 25 °C was mea-
sured with a Radiometer CDM 83 instrument. Elemental analyses
(C, H, N, Cl) were performed by the Microanalytical Laboratory of
the Faculty of Pharmaceutical Science, University of Padua.
The pyrimidine ring is present in nucleic acids, several vitamins
and antibiotics and provides potential binding sites for Brønsted
and Lewis acids. In this paper the synthesis and characterisation
of several gold(III) complexes having general formula AuCl3(pm)
{pm = one of a number N-donor pyrimidines, namely: pyrimidine,
2-methylpyrimidine, 4-methylpyrimidine, 5-methylpyrimidine,
4,6-dimethylpyrimidine, 2-aminopyrimidine} is reported. The pro-
ton affinity (PA) values of the free and coordinated N-heterocycles
have been compared by means of DFT calculations, in order to esti-
mate the effects of the AuCl3 fragment on the basicity of these
polydentate ligands.
2.2. Preparation of the complexes
All the complexes were prepared following the same synthetic
strategy. In a typical procedure to a solution of 0.414 g (1.0 mmol)
of K[AuCl4]ꢁ2H2O in water (30 ml) was added drop by drop, under
stirring, a equimolar amount (1.0 mmol) of the proper pyrimidine
pm (pm = pyrimidine, 2-methylpyrimidine, 4-methylpyrimidine,
5-methylpyrimidine, 4,6-dimethylpyrimidine, 2-aminopyrimi-
dine) dissolved in methanol (1 ml). The bright yellow precipitate,
formed almost immediately, was filtered off, washed twice with
water and dried under vacuum. Yields were in all cases nearly
quantitative (>95%). Analytical and 1H NMR data are collected in
Tables S1 and S2 (Supplementary data) respectively.
* Tel.: +39 2348651; fax: +39 2348517.
E-mail address: markos@unive.it (M. Bortoluzzi).
0277-5387/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.poly.2010.02.028

1834
M. Bortoluzzi, B. Pitteri / Polyhedron 29 (2010) 1833–1836
2.3. DFT calculations
3. Results and discussion
The ground-state computational geometry optimisations of the
AuCl3(pm) complexes were carried out using the DFT B3LYP and
M06 functionals [5,6] without symmetry constrains, in combina-
tion with the LACVP** ECP-based basis set [7]. The LANL2DZ
pseudopotential used in this basis set was applied in the past by
our research group on gold(III) complexes with N-donor ligands
and the comparison between experimental and calculated geome-
tries was really good [8]. The geometry optimisations of the free li-
gands and of their conjugate acids [pmH]+ were carried out with
the B3LYP hybrid DFT functional [5] using Pople’s split-valence
3.1. Synthesis and characterisation of the gold(III) pyrimidine
complexes
The reaction of K[AuCl4]ꢁ2H2O with one of the pyrimidines (pm)
considered in this work in water at room temperature caused the
immediate formation of the corresponding neutral AuCl3(pm)
complexes in nearby quantitative yields. These species resulted
to be non-conductive in acetone or dmf solutions. Elemental anal-
yses and 1H NMR data agreed with the proposed formulations. All
the NMR spectra clearly showed the presence of a single isomer
(see Table S2), but for the ligands 4-methylpyrimidine and 2-ami-
nopyrimidine there is the possibility of different coordination
modes of the heterocycles to the metal fragment. 4-methylpyrim-
idine can coordinate the gold centre through the N-atom in ortho
or in para-position with respect to the methyl group, while the
Au–N bond in the 2-aminopyrimidine derivative can occur through
two chemically equivalent sp2 nitrogen atoms or through the ami-
no group. The energies of all the potential isomers have been there-
fore computed using the DFT and M06 functionals. The ZPVE was
also computed from the IR analysis on the B3LYP-optimised spe-
cies. All data are reported in Table 1. Energy calculations showed
that in the AuCl3(4-methylpyrimidine) complex the coordination
of the metal centre through the N-atom in para-position with re-
spect to the methyl group is slightly preferred. The 2-aminopyrim-
idine coordinates the gold(III) ion through a sp2 nitrogen atom of
the ring. The complexes considered in this work are sketched in
Scheme 1 for clarity.
**
double-f polarised 6-31G basis set [9]. The ‘‘restricted” formalism
was applied in all calculations and no solvation model was added.
All the resulting stationary points were characterised as true min-
ima (i.e., no imaginary frequencies). From the IR simulations, car-
ried out with the harmonic oscillator approximation, the zero-
point vibrational energy (ZPVE) values were computed. The ther-
mal contributions to enthalpy were calculated on the basis of sta-
tistical mechanical standard formulas (rigid-rotor approximation).
The proton affinities (PA) of the free and coordinated ligands were
computed on the basis of Eq. (1) as the total energy difference be-
tween the heterocycle pm (Epm) and its protonated counterpart
[pmH]+ (E(pmH)+). These energy values were corrected for zero-
point vibrational energies (ZPVE) and the thermal contributions
to enthalpy at 298 K (DH
0?298). Finally, the pressure-volume work
term ꢀRT, where R is the gas constant, which is equal to
ꢀ0.6 kcal molꢀ1 at 298 K, was added to Eq. (1) [10].
0!298
PA ¼ Epm þ ZPVEpm
þ
DH
ꢀ E½pmHꢂþ ꢀ ZPVE
½pmHꢂþ
pm
3.2. Proton affinity studies
0!298
ꢀ
D
H
ꢀ RT
ð1Þ
pmHþ
The pKa values for the conjugate acids of the pyrimidine,
4-methylpyrimidine, 4,6-dimethylpyrimidine, and 2-aminopyrimi-
dine ligands are reported in the literature [12]. The pKa values for
All calculations were carried out using a Intel Core-I7-based
x86-64 workstation. The software used was SPARTAN ’08 [11].
Table 1
Computed energy data (B3LYP and M06 DFT functionals) for the complexes AuCl3(4-methylpyrimidine) and AuCl3(2-aminopyrimidine).
Complex
Isomer
EB3LYP (a.u)
EM06 (a.u)
ZPVE (kcal molꢀ1
)
AuCl3(4-methylpyrimidine)
AuCl3(4-methylpyrimidine)
AuCl3(2-aminopyrimidine)
AuCl3(2-aminopyrimidine)
N1–Au
N3–Au
N1–Au
Nsp3–Au
ꢀ1819.7668
ꢀ1819.7655
ꢀ1836.8209
ꢀ1835.8045
ꢀ1819.4300
ꢀ1819.4278
ꢀ1835.4894
ꢀ1835.4716
78.1
78.1
71.3
71.7
Scheme 1. Sketches of the gold(III)–pyrimidine-complexes considered in this work.

M. Bortoluzzi, B. Pitteri / Polyhedron 29 (2010) 1833–1836
1835
the acids [pmH]+ derived from pyrimidine and methyl-substituted
pyrimidines are in the range 1.23–2.7, while the 2-aminopyrimi-
dine conjugate acid has a pKa value of 3.45. The proton affinity
(PA) values for the free ligands have been calculated in this work
the basis of Eq. (1). For the N-bases having different possible pro-
tonation sites, i.e. 4-methylpyrimidine and 2-aminopyrimidine,
all the possible conjugate acids have been considered.
The protonation of 4-methylpyrimidine appears to occur prefer-
entially on the N1 nitrogen atom. In the 2-aminopyrimidine ligand
the protonation of the ring nitrogen atoms results strongly favour-
able with respect to the NH2 groups. The comparison of the data
reported in Tables 1 and 2 show that the coordination to the gold
centre occurs through the most basic N-atom of the pyrimidine li-
gands. The maximum PA difference among the considered pyrimi-
dines is 8.7 kcal molꢀ1, corresponding to a pKa range of 2.22.
Table 3 reports the proton affinity values of the AuCl3-coordi-
**
on the basis of DFT B3LYP/6-31G calculations. A correlation be-
tween experimental and B3LYP/6-31G** computed proton affini-
ties for sixteen N-heterocycles [13] shows that the PA variations
from a nitrogen ligand to another one are correctly predicted on
this level of theory, even if the calculated absolute values are about
the 3% higher than real. Table 2 reports the PA values computed on
nated pyrimidines and the PA variation (DPA) of the ligands pro-
Table 2
DFT B3LYP calculated proton affinity values for the free pyrimidine ligands.
tonation sites after coordination. The lowering of proton affinity
of the non-coordinated N-atoms in the heterocycle rings caused
by the bonding is around ꢀ25 kcal molꢀ1. The PA of the NH2 group
of the 2-aminopyrimidine ligand results less affected by coordina-
Ligand
Protonation site
PA (kcal molꢀ1
)
Pyrimidine
N1–H
N1–H
N1–H
N3–H
N1–H
N1–H
N1–H
Nsp3–H
215.1
221.7
221.0
220.3
219.1
225.7
223.8
206.6
2-Methylpyrimidine
4-Methylpyrimidine
4-Methylpyrimidine
5-Methylpyrimidine
4,6-Dimethylpyrimidine
2-Aminopyrimidine
2-Aminopyrimidine
tion, with a calculated
D
PA of ꢀ17.6 kcal molꢀ1
.
A more careful analysis of Table 3 data allows observing that for
the ligands having space-demanding groups in ortho-position with
respect to the coordinating N-atom, i.e. 2-methylpyrimidine, 4,6-
dimethylpyrimidine and 2-aminopyrimidine, the lowering of PA
of the ring N-atoms caused by coordination is about 3 kcal molꢀ1
higher than that of the other pyrimidines. In other words, the basi-
city of pyrimidine, 4-methylpyrimidine and 5-methylpyrimidine
results less affected by coordination to AuCl3 than that of 2-meth-
ylpyrimidine, 2-aminopyrimidine and 4,6-dimethylpyrimidine. An
explanation for this difference between these two groups of li-
gands can be obtained from the geometry data of the neutral com-
plexes and their conjugate acids, reported in Table 4. The Au–N
bond lengths are increased after protonation and, more interest-
ingly, the protonated ligands tend to rotate itself around the Au–
N bond in order to become more coplanar to AuCl3, as observable
from the cisCl–Au–N–C dihedral angles. In the conjugate acids of
the AuCl3(pyrimidine), AuCl3(4-methylpyrimidine) and AuCl3(5-
methylpyrimidine) complexes these dihedral angles are in the
range 9.4–10.0°. The same angle is comprised between 47.8° and
66.0° for the AuCl3(2-methylpyrimidine), AuCl3(2-aminopyrimi-
dine) and AuCl3(4,6-dimethylpyrimidine) conjugate acids, because
of the bulk of the space-demanding groups near the Au–N bond.
The geometry difference between the two groups of complexes
leads to different interactions between the protonated ligand and
the gold complexes. An analysis of the molecular orbitals of two
strictly related complexes, [AuCl3(2-methylpyrimidine-H)]+ and
[AuCl3(4-methylpyrimidine-H)]+, shows that the most striking dif-
ference between the MOs of the two compounds occurs for the
HOMO-12 orbitals, depicted in Fig. 1.
Table 3
DFT B3LYP calculated proton affinity values for the AuCl3-coordinated pyrimidine
ligands and PA variation (DPA) of the protonation sites after coordination.
Complex
Protonation
site
PA
DPA
(kcal molꢀ1
)
(kcal molꢀ1
)
AuCl3(pyrimidine)
N3–H
N3–H
N3–H
N3–H
N3–H
N3–H
Nsp3–H
191.1
194.2
196.8
195.2
198.6
197.7
189.0
ꢀ24.0
ꢀ27.5
ꢀ24.2
ꢀ23.9
ꢀ27.1
ꢀ26.1
ꢀ17.6
AuCl3(2-methylpyrimidine)
AuCl3(4-methylpyrimidine)
AuCl3(5-methylpyrimidine)
AuCl3(4,6-dimethylpyrimidine)
AuCl3(2-aminopyrimidine)
AuCl3(2-aminopyrimidine)
Table 4
Selected B3LYP calculated geometry parameters (bond lengths r and dihedral angles
) for the AuCl3(pm) complexes and their conjugate acids.
x
Complex
Neutral form
Conjugate acid
rAu–N
xCl–Au–N–C
rAu–N
xCl–Au–N–C
(Å)
(°)
(Å)
(°)
AuCl3(pyrimidine)
2.124
2.107
2.120
2.112
2.104
2.118
41.8
83.1
41.3
42.6
81.3
59.4
2.266
2.200
2.253
2.261
2.191
2.236
9.4
66.0
9.6
10.0
59.5
47.8
AuCl3(2-methylpyrimidine)
AuCl3(4-methylpyrimidine)
AuCl3(5-methylpyrimidine)
AuCl3(4,6-dimethylpyrimidine)
AuCl3(2-aminopyrimidine)
The low cisCl–Au–N–C dihedral angle in [AuCl3(4-methylpyrim-
idine-H)]+ allows the overlap between a d orbital of Au(III) and
p
the
p-system of the aromatic ring. The same interaction is absent,
instead, for the [AuCl3(2-methylpyrimidine-H)]+ species. The
Fig. 1. HOMO-12 orbitals of AuCl3(2-methylpyrimidine) and AuCl3(4-methylpyrimidine).

1836
M. Bortoluzzi, B. Pitteri / Polyhedron 29 (2010) 1833–1836
Scheme 2. Effects of the position of the substituents on the
p
-back donation in the protonated complexes and on the PA variation of the pyrimidines after coordination.
(e) R. Wai-Yin Sun, C.-M. Che, Coord. Chem. Rev. 253 (2009) 1682;
HOMO-12 in [AuCl3(4-methylpyrimidine-H)]+ appears to enforce
(f) M. Navarro, Coord. Chem. Rev. 253 (2009) 1619.
[2] (a) A.S.K. Hashmi, J.P. Weyrauch, M. Rudolph, E. Kurpejovic, Angew. Chem., Int.
Ed. 43 (2004) 6645;
the
p-back donation of electron density from the metal centre to
the protonated pyrimidine. This result can explain why the proton
affinity of the pyrimidines not having space-demanding groups
near the coordinating N-atom results less affected by coordination
(b) A.S.K. Hashmi, M. Rudolph, J.P. Weyrauch, M. Wölfle, W. Frey, J.W. Bats,
Angew. Chem., Int. Ed. 44 (2005) 2798;
(c) A.S. K Hashmi, G.J. Hutchings, Angew. Chem., Int. Ed. 45 (2006) 7896;
(d) A.S.K. Hashmi, F.Ata, J.W. Bats, M.C. Blanco, W. Frey, M. Hamzic, M.
Rudolph, R. Salathè, S. Schäfer, M. Wölfle, Gold Bull. 40 (2007) 31;
(e) A.S.K. Hashmi, Chem. Rev. 107 (2007) 3180;
to AuCl3.The
p-back donation reduces the lowering of basicity
caused by the coordination to the gold centre if the AuCl3 fragment
and the pyrimidine ring are about on the same plane in the proton-
ated complexes. This interaction is not allowed if there are substit-
uents on the pyrimidine ring near the coordinating nitrogen atom,
therefore for these ligands the PA variation of the ring protonation
sites after coordination is higher. These conclusions are summa-
rised in Scheme 2.
(f) A.S.K. Hashmi, S. Rudolph, Chem. Soc. Rev. 37 (2008) 1766.
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4. Conclusions
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In this work the synthesis of several gold(III) complexes of
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role of space-demanding groups near the Au–N bond on the inter-
action between the gold fragment and the nitrogen ligands and the
consequent effect on the basicity of the residual protonation sites.
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Acknowledgements
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[10] A. El Hammadi, M. El Hammadi, J. Mol. Struct. (THEOCHEM) 497 (2000) 241.
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Simmonett, J.E. Subotnik, H.L. Woodcock III, W. Zhang, A.T. Bell, A.K.
Chakraborty, D.M. Chipman, F.J. Keil, A. Warshel, W.J. Hehre, H.F. Schaefer III,
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Financial support of Ca’ Foscari University of Venice (Ateneo
Fund 2008) is gratefully acknowledged.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.poly.2010.02.028.
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