Bis(triphenylphosphine)copper(I) Complexes of Orotate and L-Dihydroorotate

Full text of DOI:10.1021/ic980464m

Inorg. Chem. 1998, 37, 6125-6128
6125
As a further study into the various binding modes of orotic
acid derivatives with metals, we describe in this communication
the synthesis of a bis(triphenylphosphine)copper(I) orotate
complex, as well as a bis(triphenylphosphine)copper(I) dihy-
droorotate complex and examine their crystal structures. These
compounds are the first examples of orotic acid derivatives of
copper in the +1 oxidation state. Copper(I) is isoelectronic with
the biologically more relevant zinc(II) species, and this study
provides the first structural data of complexes containing the
same d10 metal fragment bound separately to the orotate and
dihydroorotate ligands.
Bis(triphenylphosphine)copper(I) Complexes of
Orotate and L-Dihydroorotate
Donald J. Darensbourg,* David L. Larkins, and
Joseph H. Reibenspies
Department of Chemistry, Texas A&M University,
P.O. Box 30012, College Station, Texas 77842
ReceiVed April 23, 1998
Introduction
Orotic acid derivatives and their complexes with metal ions
have recently been investigated by several research groups.1 The
importance of orotic acid as a metal ion carrier and as a
precursor in the biosynthesis of the pyrimidine nucleotides of
DNA has spawned this interest. The pathway of the biosyn-
thesis of thymidine and cytosine proceeds through the function
of several enzymes that have active sites containing various
metal ions. For instance, the enzyme dihydroorotase which
cyclizes the N-carbamyl-L-aspartase unit to form dihydroorotic
acid has an active site containing Zn,2 and investigations of the
binding of Zn to dihydroorotic acid have recently been published
by two research groups.3,4 Another example of an enzyme along
the biosynthetic pathway of orotic acid that contains a metal at
Experimental Section
Materials and Methods. All manipulations were performed on a
double-manifold Schlenk vacuum line under an atmosphere of argon
or in an argon-filled glovebox. All of the solvents used were dried
and deoxygenated by distillation from the appropriate reagent under a
nitrogen atmosphere. Infrared spectra were collected on a Matteson
6022 spectrometer with DTGS and MCT detectors in a 0.10-mm CaF2
cell. Copper(I) acetate and copper(I) bis(triphenylphosphine) acetate
were prepared according to previously reported methods.9 Orotic acid
monohydrate was purchased from Aldrich Chemical and used without
further purification. Triphenylphosphine was purchased from Lancaster
Synthesis, Inc., and used without further purification. L-Dihydroorotic
acid was purchased from Sigma Chemical and used as received.
Microanalyses were performed by Canadian Microanalytical Service,
Ltd. (Delta, B.C., Canada).
Synthesis of Cu(I) Bis(triphenylphosphine) Orotate, 1. The
synthesis of 1 was accomplished in yields in excess of 80% by the
reaction of 1 equiv of Cu(I) bis(triphenylphosphine) acetate with 1 equiv
of the orotic acid monohydrate in a 1:1 THF/methanol mixture. This
affords a greenish-yellow solution from which the solvent is removed,
leaving behind a pale greenish-yellow powder. Crystals of 1 were
obtained via slow diffusion of diethyl ether into the THF/methanol
the active site is that of dihydroorotate dehydrogenase.
A
recently obtained crystal structure of this enzyme by Nielsen
and co-workers has shown that this enzyme contains an iron-
sulfur cluster as a cofactor.5 In addition to the importance of
metal complexes of orotic acid derivatives in the biosynthesis
of pyrimidine nucleotides, some other metal complexes have
been found to show significant anticancer activity.6 Alternative
studies reported from our laboratories have examined the binding
of orotate and dihydroorotate derivatives in organometallic
derivatives, namely, group 6 metal carbonyls.7 These studies
have demonstrated that the chelated, deprotonated nitrogen of
the uracil ring can exhibit significant π-donating capability and
thus greatly enhance CO lability in these metal carbonyl
complexes.8 Yet, despite the obvious importance of metal
complexes of orotic acid and its derivatives, their coordination
chemistry heretofore has been relatively underexplored.
solution of
1 at -10 °C. Anal. Calcd for Cu(PC18H15)2-
(C5H3N2O4)‚MeOH [C42H37P2N2O5Cu]: C, 65.07; H, 4.81; N, 3.61.
Found: C, 64.67; H, 4.82; N, 3.62.
Synthesis of Cu(I) Bis(triphenylphosphine) Dihydroorotate, 2.
The synthesis of 2 was accomplished in yields in excess of 80% by
the reaction of 1 equiv of Cu(I) bis(triphenylphosphine) acetate with 1
equiv of L-dihydroorotic acid in 30 mL of methanol. The resulting
product is a clear, nearly colorless solution from which the solvent is
removed, leaving behind an off-white powder. Crystals of 2 were
obtained by concentrating the reaction solution to 5 mL and refrigerating
at 10 °C overnight. Anal. Calcd. for Cu(PC18H15)2(C5H5N2O4)‚MeOH
[C42H39P2N2O5Cu]: C, 64.90; H, 5.06; N, 3.60. Found: C, 64.37; H,
4.99; N, 3.64.
X-ray Crystallography of 1 and 2. Cu(PPh3)2(orotate), 1. Crystal
data and the details of data collection for 1 are given in Table 1. A
pale green block of 1 was mounted on glass fibers with epoxy cement
at room temperature and then cooled in a liquid-nitrogen cold stream.
X-ray diffraction data were collected on a Rigaku AFC5R X-ray
diffractometer (Cu KR, λ ) 1.541 78 Å radiation). Cell parameters
were calculated from the least-squares fitting of the setting angles for
24 reflections. Data were collected for 3.58° < θ < 50.00°. Three
control reflections, collected for every 97 reflections, showed no
significant trends. Lorentz and polarization corrections were applied
to 1895 reflections, and a total of 1766 unique reflections were used
in further calculations. The structure was solved by direct methods
[SHELXS program package, Sheldrick (1993)], and an empirical
absorption correction was applied (difabs). Full-matrix least-squares
anisotropic refinement for all non-hydrogen atoms yielded R ) 0.0956,
Rw ) 0.2090, and S ) 0.980 for 1. Hydrogen atoms were placed in
(1) Mutikainen, I. Ann. Acad. Sci. Fen. Ser. A. Chem. Soc.; 1988, 7. (b)
Burrows, A. D.; Mingos, M. P.; White, A. J. P.; Williams, D. J. J.
Chem. Soc.; Dalton Trans. 1996, 149. (c) Nepveu, F.; Gaultier, N.;
Korber, N.; Jaud, J.; Castan, P. J. Chem. Soc., Dalton Trans. 1995,
4005. (d) Kumberger, O.; Riede, J.; Schmidbaur, H. Chem. Ber. 1991,
124, 2739. (e) Bach, I.; Kumberger, O.; Schmidbaur, H. Chem. Ber.
1990, 123, 2267. (f) Castan, P.; Ha, T.; Nepveu, F.; Bernardinelli, G.
Inorg. Chim. Acta 1994, 221, 173.
(2) Lehninger, A. L.; Nelson, D. L.; Cox, M. M. Principles of Biochem-
istry; Worth Publishers: New York, 1993; p 721. (b) Christopherson,
R. I.; Lyons, S. D. Med. Res. ReV. 1990, 10, 505. (c) Kelly, R. E.;
Mally, M. I.; Evans, D. R. J. Biol. Chem. 1986, 261, 6073.
(3) Hambley, T. W.; Christopherson, R. I.; Zvargulis, E. S. Inorg. Chem.
1995, 34, 6550.
(4) Ruf, M.; Weis, K.; Vahrenkamp, H. Inorg. Chem. 1997, 36, 2130.
(5) Nielsen, F. S.; Anderson, P. S.; Jensen, K. F. J. Biol. Chem. 1996,
271, 29359. (b) Rowland, P.; Nielsen, F. S.; Jensen, K. F.; Larsen, S.
Acta Crystallogr., Sect. D 1997, 53, 802.
(6) Castan, P.; Colacio-Rodriguez, E.; Beauchamp, A. L.; Cros, S.;
Wimmer, J. J. Inorg. Biochem. 1990, 38, 225.
(7) Darensbourg, D. J.; Draper, J. D.; Larkins, D. L.; Frost, B. J.;
Reibenspies, J. H. Inorg. Chem. 1998, 37, 2538.
(8) Poulton, J. T.; Folting, K.; Streib, W. E.; Caulton, K. G. Inorg. Chem.
1992, 31, 3190. (b) Poulton, J. T.; Sigalas, M. P.; Folting, K.; Streib,
W. E.; Einstein, O.; Caulton, K. G. Inorg. Chem. 1994, 33, 1476. (c)
Brown, T. L.; Atwood, J. D. J. Am. Chem. Soc. 1976, 98, 3160. (d)
Lichtenberger, D. L.; Brown, T. L. J. Am. Chem. Soc. 1978, 100, 366.
(9) Darensbourg, D. J.; Holtcamp, M. W.; Longridge, E. M.; Klausmeyer,
K. K.; Reibenspies, J. H. Inorg. Chim. Acta 1994, 227, 223.
10.1021/ic980464m CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/24/1998

6126 Inorganic Chemistry, Vol. 37, No. 23, 1998
Notes
Table 1. Crystallographic Data for Complexes 1
infrared spectrum of complex 1 (KBr) exhibits four bands in
the ketone/carboxylate region. This four-band pattern at 1692,
1666, 1635, and 1354 cm-1 for the metal-bound orotic acid
species is assigned to the ν(CO)asym and ν(CO)sym (1692 and
1354 cm-1) of the carboxylate ligand and the ν(CO) stretches
(1666 and 1635 cm-1) of the carbonyl groups of the uracil ring.
These latter assignments are consistent with the corresponding
ν(CO) vibrational modes observed in uracilate derivatives.7 The
infrared spectrum of complex 2 (KBr) exhibits a similar pattern
with stretches at 1690, 1622, 1609, and 1391 cm-1. These
stretches also can be assigned to the ν(CO)asym and ν(CO)sym
(1690 and 1391 cm-1) of the carboxylate ligand and the ν(CO)
stretches (1622 and 1609 cm-1) of the carbonyl groups of the
ring.
1
2
empirical formula
C42H37CuN2O5P2 C42H39CuN2O5P2
FW
775.27
P21
1836.0(6)
2
777.23
P21
3702(2)
4
space group
V, Å3
Z
d
calc, g/cm3
1.390
1.395
a, Å
b, Å
c, Å
r, deg
â, deg
γ, deg
T, K
10.088(2)
14.727(3)
12.562(3)
90
100.34(3)
90
14.750(3)
14.846(6)
17.382(2)
90
103.452(11)
90
191(2)
191(2)
0.725
µ[Cu KR(1), Mo KR(2)], mm-1 2.058
wavelength, Å
1.54178
9.56
20.90
0.71073
5.75
The structure of complex 1 was determined by X-ray
crystallography, and a thermal ellipsoid drawing of the complex
is provided in Figure 1. The complex consists of an orotate
residue bound monodentate through one of its carboxylate
oxygens to the metal center. As seen in other orotate com-
plexes,11 the pyrimidine ring deviates from planarity by only
0.0255 Å. This is consistent with the pseudoaromatic nature
of the uracil ring. The Cu(1)-O(1) bond distance is a bit shorter
than that of a typical Cu(I) bis(triphenylphosphine) carboxylate
complex at 2.08(2) Å. Healy and co-workers have summarized
their work and work done in our laboratories with a comparison
of bond distances in 15 different monocarboxylate copper(I)
bis(triphenylphosphine) complexes.9,12,13 Among the monocar-
boxylate complexes, the Cu-O bond distance ranges from
2.051(3) to 2.244(7) Å with the average at 2.151 Å. The Cu-P
distances reported by Healy in these complexes range from
2.219(2) to 2.267(5) Å with the average at 2.237 Å. The Cu-
(1)-P(1) and the Cu(1)-P(1a) bond distances in complex 1 at
2.255(6) and 2.257(8) Å, respectively, are well within that range.
Another important comparison that we can make to other
monocarboxylate complexes is the metal to distal oxygen
distance. This distance ranges from 2.205(2) to 2.643(3) Å in
other monocarboxylates, but in complex 1, we observe no
interaction of the metal center with the distal oxygen at a
distance of 3.33(3) Å. The geometry at the metal center can
best be described as a distorted tetrahedron. The Cu lies out
of the plane formed by the two phosphorus atoms and the
carboxylate oxygen by 0.5617 Å. This tetrahedral distortion
arises from the rather strong interaction of the metal center with
one of the exocyclic oxygens on the orotate residue in a
neighboring unit cell at a distance of 2.28(2) Å. This interaction
coupled with the hydrogen bonding from the methanol solvate
as shown in Figure 2 explains why the complex is insoluble in
most solvent systems. The insolubility of the compounds
precludes further solution state characterization. This exocyclic
oxygen interaction also explains the unusually long distance
from the metal center to the distal carboxylate oxygen. In the
solid state, the copper atom has a full coordination sphere by
virtue of its interaction with the two phosphines, the orotate’s
carboxylate oxygen, and the exocyclic oxygen on a neighboring
orotate.
RF,a %
R
wF,b %
14.30
b
2
2
a RF ) ∑|Fo - Fc|/∑Fo. RwF ) {[∑w(Fo - Fc2)2]/(∑wFo )}1/2
.
idealized positions with isotropic thermal parameters fixed at 0.08.
Neutral atom scattering factors and anomalous scattering correction
terms were taken from International Tables for X-ray Crystallography.
Cu(PPh3)2(dihydroorotate), 2. Crystal data and the details of data
collection for 2 are given in Table 1. A colorless block of 2 was
mounted on glass fibers with epoxy cement at room temperature and
then cooled in a liquid-nitrogen cold stream. X-ray diffraction data
were collected on a Siemens P-4 X-ray diffractometer (Mo KR, λ )
0.710 73 Å radiation). Cell parameters were calculated from the least-
squares fitting of the setting angles for 24 reflections. Data were
collected for 2.06° < θ < 30.01°. Three control reflections, collected
for every 97 reflections, showed no significant trends. Lorentz and
polarization corrections were applied to 11 568 reflections, and a total
of 11 181 unique reflections were used in further calculations. The
structure was solved by direct methods [SHELXS program package,
Sheldrick (1993)], and an empirical absorption correction was applied
(difabs). Full-matrix least-squares anisotropic refinement for all non-
hydrogen atoms yielded R ) 0.0575, Rw ) 0.1430, and S ) 1.017 for
2. Hydrogen atoms were placed in idealized positions with isotropic
thermal parameters fixed at 0.08. Neutral atom scattering factors and
anomalous scattering correction terms were taken from International
Tables for X-ray Crystallography.
Results and Discussion
Synthesis and Spectral and Structural Characterization
of Cu(PPh3)2(orotate) and Cu(PPh3)2(dihydroorotate). The
title complexes were synthesized in greater than 80% yield by
the reaction of the appropriate acid with Cu(I)(PPh3)2(acetate).
The driving force for the reaction depicted in Scheme 1 is the
formation of acetic acid, which has a higher pKa (4.75) than
that of the carboxylic acid proton of either orotic acid (2.07)10
or dihydroorotic acid.
The product obtained in the reaction of orotic acid monohy-
drate is insoluble and usually precipitates out of the methanol/
THF mixture within 5 min. However, with the appropriate
concentrations of reactants crystals suitable for single-crystal
X-ray diffraction can be grown by the slow diffusion of diethyl
ether into the methanol/THF mixture at -10 °C. It should be
noted that although the crystals were suitable for X-ray analysis,
the overall quality of the crystals was poor. L-dihydroorotic
acid is more soluble in methanol than orotic acid, and the
product of the corresponding reaction depicted in Scheme 1 for
L-dihydroorotic acid remains in solution in methanol for up to
30 min. Concentration of this solution and cooling to 10 °C
affords suitable crystals for single-crystal X-ray diffraction. The
The X-ray structure of complex 2, which is shown in Figure
3, reveals characteristics similar to those observed in complex
1, with some minor deviations. One notable difference in the
structures is puckering of the uracil ring in complex 2. This is
(11) As evidenced by crystal structures from ref 1.
(12) Hart, R. D.; Healy, P. C.; Peake, M. L.; White, A. H. Aust. J. Chem.
1997, in press.
(13) Darensbourg, D. J.; Holtcamp, M. W.; Khandelwal, B.; Reibenspies,
J. H. Inorg. Chem. 1994, 33, 531. (b) Darensbourg, D. J.; Holtcamp,
M. W.; Reibenspies, J. H. Polyhedron 1996, 15, 2341.
(10) Kaneti, J. J.; Golovinski, E. Chem.-Biol. Interact. 1971, 3, 421. (b)
Maslowska, J.; Dortabialski, A. Pol. J. Chem. 1983, 57, 1089.

Notes
Inorganic Chemistry, Vol. 37, No. 23, 1998 6127
Scheme 1
for the bound carboxylate oxygen found in complex 2 are similar
to those found in 1 at 2.043(4) and 2.044(4) Å. The strong
copper-exocyclic oxygen interactions are still present at 2.200-
(3) and 2.245(4) Å for the respective molecules. The Cu-P
bond distances are typical for this type of compound, with the
average at 2.260 Å. It is also interesting to note that the
interaction of the metal center with the distal carboxylate oxygen
is absent as it was in complex 1 with the average distance of
3.30 Å.
The binding mode noted herein for the orotate and dihydro-
orotate ligands to the metal center in complexes 1 and 2 is rare.
Monodentate coordination through a carboxylate oxygen has
only been reported for four other orotates or dihydroorotates,
and only three of these have been structurally characterized.
2+
Terzis and co-workers14 reported the crystal structure of a UO2
Figure 1. Molecular structure of 1 with thermal ellipsoids at 50%
probability.
complex in which two orotic acid moieties were bound
monodentate through the carboxylate oxygens. More recently,
Vahrenkamp and co-workers4 have reported the synthesis of
tris(3-cumenyl-5-methylpyrazolyl)borate zinc orotate. This
compound could not be characterized crystallographically
because of the unavailability of suitable crystals. However
based on infrared spectroscopy, it was assumed to be the same
as the dihydroorotic acid analogue which was characterized by
X-ray crystallography and shown to contain a monodentate-
bound carboxylate ligand. It is of interest to note at this point
that in the pyrazolylborate zinc derivatives of dihydroorotate
the carbonyl stretch occurs at a much higher frequency (1663
cm-1) than that which we observed for the copper(I) derivative.
This may be the result of the copper(I) interaction with the
exocyclic oxygen on the dihydroorotate residue in a neighboring
molecule. An interaction of this type is unlikely in the zinc
complex because of the bulky pyrazolylborate ligand employed
in that study. One other dihydroorotic acid complex has been
shown crystallographically to bind monodentate. Hambley and
co-workers published the structure of [Zn(dihydroorotate)2-
(H2O)2] in 1995.3 This structure contains a zinc center bound
monodentate to two dihydroorotates and one from a neighboring
unit cell. The zinc also has two water molecules present to fill
the trigonal-bipyramidal coordination sphere. Our future plans
are to better characterize the solution-state properties of a variety
of more soluble metal orotate or dihydroorotate derivatives.
One aspect of our interest in copper(I) carboxylate derivatives
which we have not addressed herein is that of metal-catalyzed
decarboxylation processes.15 Currently, the mechanism of the
enzyme-catalyzed decarboxylation of orotic acid, which until
very recently was presumed not to involve a metal at the active
site,16 is receiving renewed attention.17 The documented cases
of copper(I) involvement in enhanced decarboxylation rates
Figure 2. Intermolecular interactions observed in the solid-state
structure of 1.
(14) Mentzafos, D.; Katsaros, N.; Terzis, A. Acta Crystallogr., Sect. C 1987,
43, 1905.
(15) Darensbourg, D. J.; Holtcamp, M. W.; Longridge, E. M.; Khandelwal,
B.; Klausmeyer, K. K.; Reibenspies, J. H. J. Am. Chem. Soc. 1995,
117, 318.
(16) Miller, B. G.; Traut, T. W.; Wolfenden, R. J. Am. Chem. Soc. 1998,
120, 2666.
(17) Beak, P.; Siegel, B. J. Am. Chem. Soc. 1976, 98, 3601. (b) Radzicka,
A.; Wolfenden, R. Science 1995, 267, 90. (c) Lee, J. K.; Houk, K. N.
Science 1997, 276, 942.
Figure 3. Molecular structure of 2 with thermal ellipsoids at 50%
probability.
expected because the hydrogenated carbons in the ring are now
sp3-hybridized. Another difference in the structures is that in
complex 2 there are two molecules of the complex in the
asymmetric portion of the unit cell. Both molecules have
essentially the same structural parameters. The Cu-O distances

6128 Inorganic Chemistry, Vol. 37, No. 23, 1998
Notes
indicate an electrophilic catalysis mechanism, e.g., the cy-
anoacetic acid decarboxylation catalyzed by copper(I) occurs
via a nitrile-bound copper(I) intermediate, (Ph3P)2CuNCCH2-
CO2.18,19 Although there are sites for metal binding to orotate
other than the carboxylate group, whether these interactions in
our complexes would survive the conditions necessary for
decarboxylation of orotic acid is presently unknown.20 Decar-
boxylation rates of orotic acid in the presence of copper(I)
complexes and their group 12 analogues are currently under
investigation in our laboratories.
Acknowledgment. The financial support provided for this
project by the National Science Foundation (Grant 96-15866)
and the Robert A. Welch Foundation is greatly appreciated.
Supporting Information Available: Packing diagrams for com-
plexes 1 and 2, and tables of anisotropic thermal parameters, bond
lengths, and bond angles for complexes 1 and 2 (22 pages). Ordering
and access information is given on any current masthead pages.
(18) Tsuda, T.; Chujo, Y.; Saegusa, T. J. Chem. Soc., Chem. Commun.
1995, 1, 963. (b) Tsuda, T.; Chujo, Y.; Saegusa, T. J. Am. Chem.
Soc. 1978, 100, 630. (c) Darensbourg, D. J.; Longridge, E. M.;
Holtcamp, M. W.; Klausmeyer, K. K.; Reibenspies, J. H. J. Am. Chem.
Soc. 1993, 115, 8839.
(19) The rate of decarboxylation of (Ph3P)2CuNCCH2CO2 is 400 times
faster than the corresponding rate of [PPN][NCCH2CO2] at 55.4 °C.
See ref 15.
IC980464M
(20) It should be emphasized that the uncatalyzed decarboxylation of
cyanoacetic acid occurs readily at 100 °C whereas the analogous
process involving orotic acid takes place slowly at 206 °C. See ref
17a.