Nickel-cysteine binding supported by phosphine chelates

Article abstract of DOI:10.1021/ic701150q

The effect of chelating phosphines was tested on the structure and pH-dependent stability of nickel-cysteine binding. (1,2-Bis(diphenylphosphino) ethane (dppe) and 1,1,1-tris[(diphenylphosphino)methyl]ethane (triphos) were used with three different cysteine derivatives (L-cysteine, Cys; L-cysteine ethyl ester, CysEt; cystamine, CysAm) to prepare complexes of the form (dppe)NiCysRⁿ⁺ and (triphos)NiCysRⁿ⁺ (n = 0 for Cys; n = 1 for CysEt and CysAm). Similar ³¹P {¹H} NMR spectra for all (dppe)NiCysRⁿ⁺ confirmed their square-planar P₂NiSN coordination spheres. The structure of [(dppe)NiCysAm]PF₆ was also confirmed by single-crystal X-ray diffraction methods. The (triphos)- NiCysAm⁺ and (triphos)NiCysEt⁺ complexes were fluxional at room temperature by ³¹P NMR. Upon cooling to -80°C, all gave spectra consistent with a P₂NiSN coordination sphere with the third phosphorus uncoordinated. Temperature-dependent ³¹P NMR spectra showed that a trans P-Ni-S π interaction controlled the scrambling of the coordinated triphos. In aqueous media, (dppe)NiCys was protonated at pH ～ 4-5, leading to possible formation of a nickel-cysteinethiol and eventual cysteine loss at pH < 3. The importance of N-terminus cysteine in such complexes was demonstrated by preparing (dppe)NiCys-bead and trigonal-bipyramidal Tp*NiCys-bead complexes, where Cys-bead represents cysteine anchored to polystyrene synthesis beads and Tp*^- = hydrotris(3,5-dimethylpyrazolyl)borate. Importantly, results with these heterogeneous systems demonstrated the selectivity of these nickel centers for cysteine over methionine and serine and most specifically for N-terminus cysteine. The role of Ni-S π bonding in nickel-cysteine geometries will be discussed, including how these results suggest a mechanism for the movement of electron density from nickel onto the backbone of coordinated cysteine.

Full text of DOI:10.1021/ic701150q

Inorg. Chem. 2007, 46, 9221−9233
Nickel−Cysteine Binding Supported by Phosphine Chelates
Patrick J. Desrochers,*,† Davis S. Duong,† Ariel S. Marshall,† Stacey A. Lelievre,† Bonnie Hong,†
Josh R. Brown,† Richard M. Tarkka,† Jerald M. Manion,† Garen Holman,† Jon W. Merkert,‡ and
|
David A. Vicic§,
Department of Chemistry, UniVersity of Central Arkansas, Conway, Arkansas 72035,
Department of Chemistry, The UniVersity of North Carolina at Charlotte, Charlotte,
North Carolina 28223, and Department of Chemistry and Biochemistry, UniVersity of Arkansas,
FayetteVille, Arkansas 72701
Received June 12, 2007
The effect of chelating phosphines was tested on the structure and pH-dependent stability of nickel−cysteine binding.
(1,2-Bis(diphenylphosphino)ethane (dppe) and 1,1,1-tris[(diphenylphosphino)methyl]ethane (triphos) were used with
three different cysteine derivatives (
L
-cysteine, Cys;
L
-cysteine ethyl ester, CysEt; cystamine, CysAm) to prepare
complexes of the form (dppe)NiCysRn and (triphos)NiCysRn (n
) 0 for Cys; n ) 1 for CysEt and CysAm).
+
+
Similar 31P
{
1H
}
NMR spectra for all (dppe)NiCysRn confirmed their square-planar P2NiSN coordination spheres.
+
The structure of [(dppe)NiCysAm]PF6 was also confirmed by single-crystal X-ray diffraction methods. The (triphos)-
NiCysAm+ and (triphos)NiCysEt+ complexes were fluxional at room temperature by 31P NMR. Upon cooling to
80
C, all gave spectra consistent with a P2NiSN coordination sphere with the third phosphorus uncoordinated.
Temperature-dependent 31P NMR spectra showed that a trans P
Ni interaction controlled the scrambling of
the coordinated triphos. In aqueous media, (dppe)NiCys was protonated at pH 5, leading to possible formation
of a nickel cysteinethiol and eventual cysteine loss at pH < 3. The importance of N-terminus cysteine in such
complexes was demonstrated by preparing (dppe)NiCys-bead and trigonal-bipyramidal Tp*NiCys-bead complexes,
where Cys-bead represents cysteine anchored to polystyrene synthesis beads and Tp*-
hydrotris(3,5-
−
°
−
−S π
∼
4−
−
)
dimethylpyrazolyl)borate. Importantly, results with these heterogeneous systems demonstrated the selectivity of
these nickel centers for cysteine over methionine and serine and most specifically for N-terminus cysteine. The
role of Ni
−S π bonding in nickel−cysteine geometries will be discussed, including how these results suggest a
mechanism for the movement of electron density from nickel onto the backbone of coordinated cysteine.
Introduction
genase,3 acetyl-coenzyme A (CoA) synthase,4 and a special
class of superoxide dismutases that utilize nickel (NiSOD).5
Notable exceptions without direct nickel-cysteine coordina-
tion include acireductone dioxygenase6 and methyl-
Complexes of nickel, hydrogen, and sulfur play a role in
important industrial and biochemical processes. The direct
coordination of one or more sulfur atoms to nickel is found
in the majority of redox-active bacterial nickel enzymes, and
in most cases, this sulfur is provided by cysteine.1 Examples
include [NiFe] hydrogenases,2 carbon monoxide dehydro-
(2) (a) Volbeda, A.; Garcin, E.; Piras, C.; de Lacey, A. L.; Fernandez, V.
M.; Hatchikian, E. C.; Frey, M.; Fontecilla-Camps, J. C. J. Am. Chem.
Soc. 1996, 118, 12989-12996. (b) Gu, Z.; Dong, J.; Allan, C. B.;
Choudhury, S. B.; Franco, R.; Moura, J. J. G.; Moura, I.; LeGall, J.;
Przybyla, A. E.; Roseboom, W.; Albracht, S. P. J.; Axley, M. J.; Scott,
R. A.; Maroney, M. J. J. Am. Chem. Soc. 1996, 118, 11155-11165.
(3) (a) Dobbek, H.; Svetlitchnyi, V.; Gremer, L.; Huber, R.; Meyer, O.
Science, 2001, 293, 1281-1285. (b) Feng, J.; Lindahl, P. A. J. Am.
Chem. Soc. 2004, 126, 9094-9100.
* To whom correspondence should be addressed. E-mail: patrickd@
uca.edu.
† University of Central Arkansas.
‡ The University of North Carolina at Charlotte.
§ University of Arkansas.
(4) (a) Tan, X.; Surovtsev, I. V.; Lindahl, P. A. J. Am. Chem. Soc. 2006,
128, 12331-12338. (b) Tan, X.; Loke, H.-K.; Fitch, S.; Lindahl, P.
A. J. Am. Chem. Soc. 2005, 127, 5833-5839.
| Current address: Department of Chemistry, University of Hawaii, 2545
McCarthy Mall, Honolulu, HI, 96822.
(1) (a) Thauer, R. K. Science, 2001, 293, 1264-1265. (b) Transition Metal
Sulfur Chemistry: Biological and Industrial; Steifel, E. I., Matsumoto,
K., Eds.; ACS Symposium Series 653; American Chemical Society:
Washington, DC, 1996; Chapter 4.
(5) Barondeau, D. P.; Kassmann, C. J.; Bruns, C. K.; Tainer, J. A.; Getzoff,
E. D. Biochemistry 2004, 43, 8038-8047.
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M. Inorg. Chem. 2004, 43, 3988-3997.
10.1021/ic701150q CCC: $37.00
Published on Web 09/14/2007
© 2007 American Chemical Society
Inorganic Chemistry, Vol. 46, No. 22, 2007 9221

Desrochers et al.
Figure 1. Nickel-cysteine coordination geometries resulting from different phosphorus- and nitrogen-donor chelates. Charges on the resulting complexes
vary from 1+, to 0, to 1-, depending on the ligand (dppe, triphos, or Tp*-) and cysteine derivative (Cys2-, CysEt-, or CysAm-) charges.
coenzyme M reductase (MCR), although MCR does involve
methyl thioether/thiyl radical association with nickel.7 Such
enzymes catalyze reactions that parallel commercially valu-
able processes including hydrogen consumption ([NiFe]
hydrogenases), hydrogen production via the water-gas shift
reaction (CODH), and the generation of methane from
biomass (CODH and MCR). Nickel-cysteine systems that
model characteristics of these enzymes remain a persistent
area of fruitful research.
Recent work by Riordan’s8 and Darensbourg’s9 groups has
explored the coordination of nickel with chelating cysteine
and phosphines. Both groups reported square-planar com-
plexes of nickel using the tripeptide Cys-Gly-Cys, leading
to NiN2S2 coordination spheres reminiscent of the distal
nickel site in acetyl-CoA synthase. In separate experiments,
they demonstrated the ability of cis-NiN2S2 groups to chelate
via bridging thiolates to secondary metals including Ni(dppe)
[where dppe ) 1,2-bis(diphenylphosphino)ethane],8 W(CO)4,9
Rh(CO)2,9 and Pd(Cl)(CH3).9 These results reinforced the
belief that the distal nickel site in acetyl-CoA synthase is
part of a supporting ligand for the proximal nickel center
where active acetyl synthesis takes place.10 Darensbourg’s
group anchored this Cys-Gly-Cys peptide to a heteroge-
neous support and showed that its chelation of nickel(II) was
unaltered.9
(3,5-dimethylpyrazolyl)borate; Figure 1) were used.12 Nickel(II)
ligated by Tp*- selectively bound cysteine and selenocys-
teine, producing analogous static five-coordinate geom-
etries.12,13 In contrast, the present results with triphos [a fac-
P3 donor; 1,1,1-tris[(diphenylphosphino)methyl]ethane] show
fluxional systems that exchange between four-coordinate P2-
NiSN and transient five-coordinate P3NiSN coordination
spheres. The Tp*Ni+ Lewis acid center also discriminated
between cysteine and homocysteine and the methyl thioether
of cysteine.13
Throughout all of the cysteine work to date, nickel-
cysteinethiol remains an elusive synthetic goal. Interest in
nickel-cysteine protonation stems from its invocation in
proposed catalytic cycles of [NiFe]Hase14 and NiSOD
enzymes,15 where it may also be coupled with electron
transport. Nickel-cysteine protonation coupled with electron
transport has been implicated in catalytic hydrogen genera-
tion in aqueous media.16 Work by Henderson’s group has
demonstrated that coordinated phosphines level the acidities
of Ni-SR groups (R ) Et and a variety of phenyls).17
Possible proton sharing between nickel and sulfur was
suggested in these systems, facilitated by phosphine back-
bonding that draws thiolate electron density onto nickel.17
The present work describes the effect of triphos on nickel-
cysteine geometries and the pH stability of cysteine coor-
dinated to (dppe)Ni2+. Considerable differences in coordi-
nation geometries between nickel and cysteine result when
triphos replaces Tp*-. Square-planar diamagnetic nickel-
cysteine complexes were not observed with tridentate
Tp*-,12,13 but these are described here for triphos. Experi-
Square-planar nickel-cysteine coordination spheres are the
norm in synthetic complexes;11 however, ancillary ligands
can alter this geometric pattern. Thermally stable five-
coordinate nickel-cysteine geometries resulted when tri-
dentate tris(pyrazolyl)borate chelates (i.e., Tp*-, hydrotris-
(7) (a) Craft, J. L.; Horng, Y.-C.; Ragsdale, S. W.; Brunold, T. C. J. Am.
Chem. Soc. 2004, 126, 4068-4069. (b) Ermler, U.; Grabarse, W.;
Shima, S.; Goubeaud, M.; Thauer, R. K. Science 1997, 278, 1457-
1462.
(12) Desrochers, P. J.; Cutts, R. W.; Rice, P. K.; Golden, M. L.; Graham,
J. B.; Barclay, T. M.; Cordes, A. W. Inorg. Chem. 1999, 38, 5690-
5694.
(13) Desrochers, P. J.; Abrams, M.; Nutt, D.; Arvin, M. E.; Phelps, A. L.
20th International Conference on the Organic Chemistry of Sulfur,
Northern Arizona University, Flagstaff, AZ, July 2002.
(14) (a) Fan, H.-J.; Hall, M. B. J. Am. Chem. Soc. 2002, 124, 394-395.
(b) Stadler, C.; de Lacey, A. L.; Montet, Y.; Volbeda, A.; Fontecilla-
Camps, J. C.; Conesa, J. C.; Ferna´ndez, V. M. Inorg. Chem. 2002,
41, 4424-4434.
(15) Pelmenschikov, V.; Siegbahn, P. E. M. J. Am. Chem. Soc. 2006, 128,
7466-7475.
(16) (a) Baˇnicaˇ, F. G. Bull. Soc. Chim. Fr. 1991, 128, 697-703. (b) Baˇnicaˇ,
F. G.; Diacu, E. Collect. Czech., Chem. Commun. 1991, 56, 140-
151.
(8) Krishnan, R.; Riordan, C. G. J. Am. Chem. Soc. 2004, 126, 4484-
4485.
(9) Green, K. N.; Jeffery, S. P.; Reibenspies, J. H.; Darensbourg, M. Y.
J. Am. Chem. Soc. 2006, 128, 6493-6498.
(10) Webster, C. E.; Darensbourg, M. Y.; Lindahl, P. A.; Hall, M. B. J.
Am. Chem. Soc. 2004, 126, 3410-3411.
(11) (a) Nivorozhkin, A. L.; Segal, B. M.; Musgrave, K. B.; Kates, S. A.;
Hedman, B.; Hodgon, K. O.; Holm, R. H. Inorg. Chem. 2000, 39,
2306-2313. (b) Baidya, N.; Ndreu, D.; Olmstead, M. M.; Mascharak,
P. K. Inorg. Chem. 1991, 30, 2448-2451. (c) Kozlowski, H.; Decock-
Le Re´ve´rend, B.; Ficheux, D.; Loucheux, C.; Sovago, I. J. Inorg.
Biochem. 1987, 29, 187-197.
(17) Clegg, W.; Henderson, R. A. Inorg. Chem. 2002, 41, 1128-1135.
9222 Inorganic Chemistry, Vol. 46, No. 22, 2007

Nickel-Cysteine Binding Supported by Phosphine Chelates
Expt (theory): C, 56.23 (58.10); H, 5.56 (5.35); N, 2.20 (2.19).
mental verification for the importance of π bonding between
triphos and the nickel-cysteine group is presented as a
driving force in this geometric variation. A limit on the pH-
dependent stability of nickel-cysteine chelation was deter-
mined for (dppe)NiCys.
Amino acids and short cysteine-peptides anchored to
polystyrene synthesis beads were also tested against Tp*Ni+
and (dppe)Ni2+ to determine the effect of Tp*- and dppe on
the selectivity of nickel for cysteine and related residues.
The spectroscopic results presented here confirm the geom-
etry of the heterogeneous products and demonstrate that the
heterogeneous systems are identical with their homogeneous
small-molecule counterparts.
13C {1H} NMR (CDCl3): δ 171.9 (-C(dO)-), 135-127 (Ph),
64.1 (d, CR, JCP ) 9.1 Hz), 61.7 (-C(O)CH2-), 33.9 (d, Câ, JCP
)
11.3 Hz), 27.7 (d/d, -PCH2-, JCP ) 16.0 and 31.9 Hz), 25.4 (d/d,
-PCH2-, JCP ) 11.8 and 32.6 Hz), 14.0 (-C(O)CH2CH3). 31P
NMR (Table 3). UV-vis (CHCl3): 382 nm (ꢀ ) 1110 M-1 cm-1),
492 sh (ꢀ ) 180).
Preparation of (dppe)NiCys. A total of 400 mg (0.76 mmol)
of (dppe)NiCl2 and 92 mg (0.76 mmol) of L-cysteine were placed
into separate Schlenk flasks under nitrogen. A total of 80 mL of
degassed methanol was added to (dppe)NiCl2, creating a red-orange
slurry. Degassed triethylamine (0.5 mL) was added to cysteine
dissolved in 10 mL of degassed methanol. This solution was stirred
vigorously and then transferred via a cannula needle to the flask
containing the (dppe)NiCl2/methanol mixture. A slight color change
from dark orange to light orange was observed after the cysteine
was added. The solution was allowed to stir for approximately 30
min, completing the dissolution and reaction of (dppe)NiCl2, and
then concentrated to a dark-orange syrup under nitrogen. Diethyl
ether was added to this residue to precipitate the light-orange
material. The solid was purified by column chromatography (70:
30 chloroform/methanol mobile phase, 3 cm × 18 cm column made
from 70-270 mesh, 60 Å silica gel as the stationary phase). The
solid extracted from the eluted residue was washed repeatedly with
diethyl ether to remove residual methanol. Yield: 200 mg. MS
(0.1% acetic acid/acetonitrile): m/z 576, (dppe)Ni(Cys)H+. IR
(KBr): 1102 cm-1 (m, C-N), 1450 (s), 1600 (s, R-CO2), 3045
(m, CdC-H), 3300 (w, R-NH2). 31P NMR: see Table 3. UV-
vis (CH3OH): 381 nm (ꢀ ) 730 M-1 cm-1), 495 sh (ꢀ ) 90).
Preparation of [(dppe)NiCysAm]PF6. This synthesis was
carried out following the same method as that of (dppe)NiCys using
2-aminoethanethiol hydrochloride (86 mg, 0.76 mmol). A concen-
trated solution of ammonium hexafluorophosphate (370 mg in 0.5
mL of deionized water) was added, the mixture was cooled in an
ice bath, and an additional 20 mL of deionized water was added to
induce precipitation of the product as a light-orange solid. The solid
was filtered and washed with deionized water and cold isopropyl
alcohol. Yield: 390 mg. Anal. Expt (theory): C, 49.60 (49.51); H,
4.47 (4.48); N, 2.07 (2.08). IR (KBr): 839 cm-1 (vs, PF6-), 1103
(m, C-N), 1436 (m), 3259 (m, R-NH2). 31P NMR: see Table 3.
UV-vis (CH3OH): 379 nm (ꢀ ) 810 M-1 cm-1), 494 sh (ꢀ )
90).
Experimental Section
Spectroscopy. Room-temperature Fourier transform (FT) NMR
spectra were recorded using a JEOL ECX 300 MHz spectropho-
tometer. This spectrometer is equipped with a variable-temperature
attachment. FTIR spectra were recorded for samples pressed as KBr
pellets using a Thermo Nicolet IR 100 spectrometer at ambient
temperature. UV-vis electronic spectra were recorded at room
temperature using a Cary 50 spectrometer and 1 cm path length
quartz cuvettes.
Mass Spectrometry. Spectra were recorded using a PE Biosys-
tem Mariner electrospray ionization time-of-flight mass spectrom-
eter. The sample was introduced via a direct-infusion syringe pump
(10 µL/min). Nozzle and skimmer voltages were optimized to
prevent fragmentation and solvent clustering. The nozzle was held
at a temperature of 125 °C. Prior to recording sample spectra, the
instrument was calibrated with Perceptive Biosystems Cal Mix
(containing bradykinin, angiotensin, and neutrotensin).
Synthesis of Nickel Complexes. All reagents, ligands, and
precursor complexes, (dppe)NiCl2, were obtained from Sigma-
Aldrich, unless otherwise noted. All solvents were obtained from
Fisher Scientific and used as received. The primary syntheses for
all of the (dppe)NiCysRn+ products were carried out under an inert
nitrogen atmosphere to retard oxidation of thiolate anion intermedi-
ates. Final workup and purification were performed open to the
air. All (triphos)NiCysR+ preparations and manipulations were
carried out under a constant nitrogen atmosphere to reduce oxidation
of the pendant uncoordinated phosphine. Elemental analyses were
performed by Atlantic Microlab, Norcross, GA.
Preparation of [(triphos)NiCysAm]PF6. The precursor complex
(triphos)NiCl2 was prepared, isolated under nitrogen, and then used
immediately to form the cysteine adducts. (Triphos)NiCl2 was
prepared according to literature methods18 using 200 mg (0.32
mmol) of triphos and 76 mg (0.32 mmol) of NiCl2‚6H2O. This
precursor was isolated upon removal of the reaction solvent under
nitrogen. Degassed methanol (15 mL) was added to the bright-
orange (triphos)NiCl2, giving a slurry of a green solution [solvated
(triphos)NiCl2] and an undissolved orange solid. In a separate
Schlenk flask was prepared a solution of 2-aminoethanethiol
hydrochloride (36 mg, 0.32 mmol) in 3 mL of methanol, and to
this solution was added 0.10 mL of degassed triethylamine. The
deprotonated aminoethanethiol/methanol solution was transferred
via a cannula needle to the (triphos)NiCl2/methanol mixture, leading
to a color change to light orange and the dissolution of all solids
after stirring for about 30 min. To this mixture was added a degassed
concentrated aqueous ammonium hexafluorophosphate solution
(630 mg in 2 mL), inducing immediate precipitation of the product
Synthesis and Purification of [(dppe)NiCysEt]Cl. A solution
of L-cysteine ethyl ester hydrochloride (71 mg, 0.38 mmol) was
prepared in 5 mL of degassed methanol, and 2.4 mol equiv of
degassed triethylamine (93 mg, 0.91 mmol) was added to depro-
tonate the amino acid ethyl ester in situ. This cysteine thiolate
solution was transferred via a cannula needle to a dark-orange slurry
of (dppe)NiCl2 (200 mg, 0.38 mmol) in 60 mL of methanol. The
mixture was stirred for an additional 30 min, affecting complete
dissolution of (dppe)NiCl2, and then stripped to dryness. Diethyl
ether added to the resultant residue induced the formation of a
microcrystalline solid. This solid was purified using column
chromatography: column dimensions ) 3 cm × 8 cm using 70-
270 mesh, 60 Å silica gel stationary phase (Aldrich); chloroform/
methanol mobile phase. For the first 2 h, a 90:10 chloroform/
methanol eluent was used. This was changed to an 80:20 mixture
for the final 2-3 h of separation. Leading bands were identified as
(dppe)O (31P NMR in CDCl3: -11.3 and 33.4 ppm) and occasion-
ally unreacted (dppe)NiCl2 (31P NMR: 58.2 ppm). The more polar
product eluted last as a dark-orange band. Yield: 150 mg. Anal.
(18) Kandiah, M.; McGrady, G. S.; Decken, A.; Sirsch, P. Inorg. Chem.
2005, 44, 8650-8652.
Inorganic Chemistry, Vol. 46, No. 22, 2007 9223

Desrochers et al.
as a pale-orange solid. The product was washed with deionized
water and dried in vacuo under nitrogen. Yield: 250 mg. Anal.
Expt (theory): C, 59.92 (61.03); H, 5.44 (5.36); N, 1.66 (1.66). IR
(KBr): 838 (vs, PF6-), 1097 (s, C-N), 1435 (s), 3250 (m, R-NH2).
31P NMR: see Table 3.
Preparation of [(triphos)NiCysEt]PF6. This synthesis was
carried out by the same method as that for [(triphos)NiCysAm]-
PF6 using 59 mg (0.32 mmol) L-cysteine ethyl ester hydrochloride.
The product was isolated as a light-orange solid. Yield: 260 mg.
Anal. Expt (theory): C, 56.75 (56.58); H, 5.13 (5.06); N, 1.46
(1.43). IR (KBr): 840 (vs, PF6), 1435 (s), 1735 (s, ester), 3248
and 3304 (R-NH2). 31P NMR: see Table 3.
Preparation of [(dppe)NiSeCysAm]Cl in Situ. A degassed
solution of methanol was added to a septum-fitted, purged bottle
containing 30 mg of selenocystamine dihydrochloride. This material
was purchased from ICN Biomedicals as a yellow diselenide. A
methanolic slurry of sodium borohydride was titrated into the yellow
diselenide solution until it was colorless, indicating complete
reduction to 2 equiv of the alkylselenide anion. This alkylselenide
solution was transferred to a waiting 50 mg sample of air-free
(dppe)NiCl2 in methanol using a gastight syringe. A slight im-
mediate color change was observed. The orange supernatant was
mL) were prepared under nitrogen, and degassed triethylamine (25
µL) was added to each in order to deprotonate cysteinethiols when
introduced to AAn-bead. Samples of AAn-bead were loaded into
septum-fitted vials and purged with nitrogen. The nickel-complex
solutions were added to each of the AAn-bead samples using a
gastight syringe. Reaction was noted by pronounced color changes,
indicative of the formation of green Tp*NiCys-AAn-bead and
orange (dppe)NiCys-AAn-bead whenever Cys was located at the
N-terminus site of the peptide sequence. These results are illustrated
in Figure 7.
In order to obtain spectroscopic confirmation for the bead-bound
product, a sample of (dppe)NiCys-bead was prepared in chloroform
following the procedure described above but with the Cys-beads
in a nitrogen-purged, septum-fitted NMR tube. A solution of (dppe)-
NiCl2 (10 mg and 50 µL of degassed triethylamine) in 0.6 mL of
degassed CDCl3 was prepared under a nitrogen atmosphere. The
originally colorless beads immediately became bright-orange when
(dppe)NiCl2 was added. Although the (dppe)NiCys-bead product
floated at the top of the reaction mixture, spinning while recording
the 31P NMR spectrum sufficiently homogenized the mixture,
adequate lock and shim was obtained, and a 31P {1H} NMR
spectrum was recorded on this slurry (Figure 8). The supernatant
containing unreacted (dppe)NiCl2 was removed, and the beads were
washed several times with fresh chloroform using a syringe through
the septum fitting. The bright-orange beads were resuspended in
fresh chloroform, and the spectrum of just the suspended (dppe)-
NiCys-bead product was recorded (Table 3 and Figure 8).
pH-Dependent 31P NMR of (dppe)NiCys. A series of aqueous
0.1 M phosphate buffers covering the pH range of 2-10 were
prepared from potassium phosphates and phosphoric acid and
calibrated using an Accumet model 20 (Fisher Scientific) pH meter.
Solutions of (dppe)NiCys (4 mg in 2 mL) were prepared in the
respective buffer, spectra were recorded, and the solutions were
referenced to a sealed capillary filled with 1 M phosphoric acid as
the internal standard.
X-ray Crystallography of [(dppe)NiCysAm]PF6. An orange
block crystal of [(dppe)NiCysAm]PF6 measuring 0.35 × 0.35 ×
0.30 mm was grown by slow evaporation of a methanol solution
of the compound. A total of 14 307 unique reflections (10 230 with
I > 2σ) were collected at 173(2) K temperature using a Rigaku
AFC8 Mercury CCD diffractometer. The structure was solved by
direct methods and expanded using Fourier techniques.20 All non-
hydrogen atoms were refined anisotropically. Hydrogen atoms were
included as riding atoms but not refined. The standard deviation
of an observation of the unit weight was calculated. All calculations
were performed using the software CrystalClear21 and Crystal-
Structure (version 1.3.6) from Rigaku22 and Crystals Issue 10 by
Watkin et al.23 except for refinement, which was performed using
SHELX-97. Refinement parameters are summarized in Table 1.
Selected bond distances and angles are presented in Table 2.
loaded into a septum-fitted NMR tube under nitrogen, and the 31
P
{1H} NMR spectrum was recorded as it was for the other samples.
NMR results are summarized in Table 3.
Synthesis of Bead-Supported Peptides. Argogel-NH2 poly-
styrene synthesis beads, with a functional group density of 0.40
mmol of -NH2 per 1 g of beads, were obtained from Aldrich. They
were thoroughly washed and swollen with a 50:50 mixture of N,N-
dimethylformamide (DMF)/CH2Cl2 prior to use. All other reagents
used in the synthesis of the oligopeptides on beads were used as
received. Fmoc-protected amino acids were obtained from Nova-
Biochem (EMD Biosciences). Piperidine, hydroxybenzotriazole
(HOBt), trifluoroacetic acid, diisopropylsilane, and diisopropylcar-
bodiimide (DIPCDI) were obtained from Aldrich. Kaiser test
reagents were obtained as a kit from Fluka.
Fmoc-protected amino acids were added to the synthesis beads
using the standard OBt ester formation protocol as described in
the 2006/2007 Novabiochem (EMD Biosciences) catalog, p 3.2.
Representative synthesis: 595 mg (2.0 mmol, 5-fold excess) of
Fmoc-protected glycine and 270 mg (2.0 mmol, 5-fold excess) of
HOBt were dissolved in 20 mL of a 50:50 mixture of DMF/CH2-
Cl2, after which DIPCDI (250 mg, 2.0 mmol, 5-fold excess) was
added. The mixture was stirred for about 10 min. The mixture was
added to 1.0 g of washed and swollen Argogel beads. The slurry
was rotated for several hours. Completeness of the addition of the
amino acid to the beads was tested using a standard Kaiser test as
described on p 3.4 of the 2006/2007 Novabiochem (EMD Bio-
sciences) catalog. The Fmoc protecting groups were removed by
rotating the beads for 30 min with 20 mL of a 20:80 mixture of
piperidine/DMF. This was done several times, after which the beads
were given a final wash with DMF. Removal of the Fmoc group
was confirmed with a Kaiser test. The trityl protecting group on
the cysteine residues and the tert-butyl protecting groups on serine
were both removed with a 95:5 mixture of trifluoroacetic acid/
triisopropylsilane.
Results and Discussion
Both of the chelating phosphines used in this work yielded
square-planar nickel-cysteine complexes. UV-vis electronic
(20) Beurskens, P. T.; Admiraal, G.; Beurskens, G.; Bosman, W. P.; de
Gelder, R.; Israel, R.; Smits, M. M. The DIRDIF-99 program system;
Technical Report of the Crystallography Laboratory, University of
Nijmegen; University of Nijmegen: Nijmegen, The Netherlands, 1999.
(21) Rigaku CrystalClear Software User’s Guide; Molecular Structure
Corp.: The Woodlands, TX, 1999.
(22) Rigaku and Rigaku/MSC, 3.6.0 ed.; Molecular Structure Corp.: The
Woodlands, TX, 2000-2004.
(23) Watkin, D. J.; Prout, C. K.; Carruthers, J. R.; Betteridge, P. W.
CRYSTALS Issue 10; Chemical Crystallography Laboratory, University
of Oxford, Oxford, U.K., 1996.
Reaction of (dppe)NiCl2 and Tp*NiNO3 with Bead-Bound
Peptides (AAn-bead). Tp*NiNO3 used in these experiments was
prepared according to literature methods.12,19 Separate methanolic
solutions of the two nickel precursors (10-15 mg of each in 2
(19) Han, R.; Looney, A.; McNeil, K.; Parkin, G.; Rheingold, A. L.;
Haggerty, B. S. J. Inorg. Biochem. 1993, 49, 105-121.
9224 Inorganic Chemistry, Vol. 46, No. 22, 2007

Nickel-Cysteine Binding Supported by Phosphine Chelates
Table 1. Crystal, Collection, and Refinement Parameters for
[(dppe)NiCysAm]PF6
as some differences in the rotation angles of the phosphine-
phenyl substituents. One of the phenyl rings is rotated such
that it is nearly coplanar with the P-Ni-S atom group
(phosphorus trans to sulfur). The origin of this phenyl ring
orientation must stem mostly from packing and steric effects
because both (dppe)NiCl2 and (dppe)NiBr2 showed this same
feature.24a,25 Considerable twist angles (16-18°) were ob-
served between planes defined by P-Ni-P and S-Ni-N
atom groups, implying a departure from perfect square-planar
coordination. Similar “Td” twists have been observed in other
square-planar nickel thiolates and (dppe)NiX2 complexes.26
Different Ni-P distances were observed in (dppe)-
NiCysAm+ depending on whether the phosphorus was trans
to nitrogen or sulfur. Somewhat shorter Ni-P distances were
observed, average Ni-P ) 2.146 Å, for the phosphorus trans
to nitrogen compared to those trans to sulfur, average Ni-P
) 2.169 Å. The shorter Ni-P distance trans to nitrogen and
the longer Ni-P distance trans to sulfur in (dppe)NiCysAm+
likely reflects a greater trans influence of sulfur over nitrogen
(as suggested by reviewer 2). Despite this difference, the
Ni-P distances in (dppe)NiCysAm+ are comparable to
values in other square-planar (dppe)Ni complexes.27
empirical formula
fw
C28H30F6NNiP3S
678.21
cryst size, mm3
T, K
0.42 × 0.42 × 0.35
173(2)
wavelength, Å
cryst syst, space group
unit cell dimens
a, Å
0.710 70
monoclinic, P21/n
19.919(6)
b, Å
13.482(4)
c, Å
22.577(7)
R, deg
90
92.851(7)
90
6056(3)
4, 1.49
0.925
2784
â, deg
γ, deg
V, Å3
Z, density (calcd), g/cm3
abs coeff, mm-1
F(000)
θ range for data collection
1.82-28.00
-25 e h e 26,
-17 e k e 17,
-29 e l e 20
56 029/14 307 [R(int) ) 0.0722]
97.7
0.7378 and 0.6974
14 307/0/738
1.101
limiting indices
reflns colld/unique
completeness to θ ) 28.00, %
max and min transmn
data/restraints/param
GOF on F2
R, Rwa [I > 2σ(I)]
0.0756, 0.1744
0.1063, 0.1994
1.007 and -0.689
R, Rwa (all reflns)
Ni-S distances in (dppe)NiCysAm+, average Ni-S )
largest diff peak and hole, e/Å3
2-
2.163 Å, are shorter than those in square-planar Ni(Cys)2
,
a R ) ∑[|(|Fo| - |Fc|)|]/∑|Fo|. Rw ) {∑[w(Fo2 - Fc )2]/∑[w(Fo )2]}1/2
.
2
2
average Ni-S ) 2.204 Å, in which the two sulfur atoms
are in a trans configuration.11b Longer distances for the trans
S-Ni-S arrangement in Ni(Cys)22- versus the trans P-Ni-S
arrangement in (dppe)NiCysAm+ likely result from more
repulsive Sπ donor-Ni-Sπ donor interactions coupled with ad-
ditional thiolate-Ni-thiolate anionic repulsive forces. Such
anionic repulsions are absent in (dppe)NiCysAm+, and there
is the added effect of a complementary Pπ acceptor-Ni-Sπ donor
interaction, both of which work to shorten the Ni-S bonds
in these cations. This hypothesis is independently supported
by a comparison to a longer average Ni-Cl distance in
(dppe)NiCl2, 2.200 Å,24a where comparable steric hindrance
from phosphine-phenyl substituents is expected. The shorter
Ni-S distance of (dppe)NiCysAm+, despite a somewhat
larger covalent radius for sulfur over chlorine, therefore
implies strong Ni-S bonding in this cation.
2
2
2
w ) 1/[σ2(Fo ) + (0.0709P)2 + 9.5772P], where P ) (Fo + 2Fc )/3.
Table 2. Selected Bond Distances (Å) and Angles (deg) for
(dppe)NiCysAm+ Cations
cation 1
cation 2
Ni(1)-N(1)
Ni(1)-S(1)
Ni(1)-P(1)
Ni(1)-P(2)
1.956(4)
Ni(2)-N(2)
Ni(2)-S(2)
Ni(2)-P(3)
Ni(2)-P(4)
1.948(4)
2.1663(13)
2.1518(13)
2.1663(13)
2.1591(14)
2.1406(14)
2.1719(14)
P(1)-Ni(1)-N(1)
P(2)-Ni(1)-S(1)
P(1)-Ni(1)-P(2)
N(1)-Ni(1)-S(1)
P(1)-Ni(1)-S(1)
P(2)-Ni(1)-N(1)
173.12(15)
165.71(5)
86.50(5)
89.46(13)
90.20(5)
P(3)-Ni(2)-N(2)
P(4)-Ni(2)-S(2)
P(3)-Ni(2)-P(4)
N(2)-Ni(2)-S(2)
P(3)-Ni(2)-S(2)
P(4)-Ni(2)-N(2)
167.49(14)
166.80(5)
87.60(5)
89.94(13)
89.41(5)
95.46(13)
95.73(13)
spectra were also consistent with those of square-planar P2-
NiSN coordination spheres for all complexes. Chelation of
cysteine to nickel invariably required deprotonation of the
thiol group prior to binding nickel. This S,N-donation was
a constant theme and extended to experiments when the
amino acid was anchored to heterogeneous supports. 31P
NMR spectra for the triphos system were complicated at
room temperature by phosphorus-atom scrambling charac-
teristic of this ligand; however, it was resolved at low
temperature.
Crystal and Molecular Structure of [(dppe)NiCysAm]-
PF6. A square-planar geometry was confirmed for the (dppe)-
NiCysAm+ cation, consistent with low-spin nickel(II) centers
and the diamagnetism demonstrated by NMR measurements
for all of the phosphine-nickel-cysteine complexes. Two
slightly different complex cations crystallized in the unit cell
(one is shown in Figure 2); average bond distances from
both cations are discussed below. These show slight differ-
ences in nickel-ligand bond distances and angles, as well
Ni-N distances in (dppe)NiCysAm+, average Ni-N )
1.951 Å, are longer than those in Ni(Cys)22-, average Ni-N
) 1.917 Å, and more similar to the distance in (bmedaco)-
Ni, 1.940 Å, a square-planar complex with a cis-N2NiS2
coordination sphere [bmedaco ) 1,5-bis(mercaptoethyl)-1,5-
diazacyclooctane].26a
(24) (a) Busby, R.; Hursthouse, M. B.; Jarrett, P. S.; Lehmann, C. W.;
Malik, K. M. A.; Phillips, C. J. Chem. Soc., Dalton Trans. 1993,
3767-3770. (b) Jarrett, P. S.; Sadler, P. J. Inorg. Chem. 1991, 30,
2098-2104.
(25) Rahn, J. A.; Delian, A.; Nelson, J. H. Inorg. Chem. 1989, 28, 215-
217.
(26) (a) Twist ) 13.3° in (bmedaco)Ni: Smee, J. J.; Miller, M. L.;
Grapperhaus, C. A.; Reibenspies, J. H.; Darensbourg, M. Y. Inorg.
Chem. 2001, 40, 3601-3605. (b) Twist ) 10-19° in (dppe)Ni-
(SPh′)2: Autissier, V.; Clegg, W.; Harrington, R. W.; Henderson, R.
A. Inorg. Chem. 2004, 43, 3098-3105. (c) Twist ) 4° in (dppe)-
NiBr2: ref 25.
24a
(27) Average Ni-P ) 2.153 Å in (dppe)NiCl2 and 2.149 Å in (dppe)-
NiBr2.25 Distances ranged from 2.158 to 2.189 Å in three different
(dppe)Ni(SPh′).26b
Inorganic Chemistry, Vol. 46, No. 22, 2007 9225

Desrochers et al.
Table 3. 31P{1H} NMR Results for Phosphine-Nickel-Cysteine Complexes
δ P, ppm
trans to N
compound
solvent
CDCl3
trans to S
59.8
other
[(dppe)NiCysEt]Cl
52.1
52.0
52.7
53.2
JPP ) 48.3 Hz
JPP ) 48.0 Hz
JPP ) 47.6 Hz
JPP ) 47.6 Hz
(dppe)NiCys-bead
(dppe)NiCys
CDCl3
CD3OD
CDCl3
CDCl3
59.7
61.2
62.0
[(dppe)NiCysAm]PF6
[(dppe)NiSeCysAm]Cl
PF6-, -143.8, septet
JPF ) 708 Hz
62.3
53.0
JPSe ) 54 Hzc
JPSe ) 40 Hzc
JPP ) 41 Hz
a,b
[(triphos)NiCysEt]PF6
trans
(CD3)2CO
17.8
18.4
18.6
17.5
6.7
7.6
9.0
7.0
-30.0, singletd
-32.6, singletd
-31.1, singletd
25.5, singlet, PdOd
JPP ) 83 Hz
JPP ) 86 Hz
JPP ) 83 Hz
JPP ) 81 Hz
cis
a,b
[(triphos)NiCysAm]PF6
[(triphos)NiCysAm]PF6
(CD3)2CO
(CD3)2CO
following aerial oxidation
a For comparison, (triphos)NiCl2 in CH2Cl2 at -50 °C gives two broad singlets at +13 and -30 ppm, assigned as nickel-coordinated and free phosphine,
c
based on respective 2:1 integration. b Recorded at -80 °C. 77Se, I ) 1/2, 7.6%. d Uncoordinated -PPh2 group. These samples also showed the characteristic
-
septet of PF6 as is reported for [(dppe)NiCysAm]PF6.
NiS2 coordination spheres of Ni(Cys-Gly-Cys)8 and Ni-
(bmedach) [bmedach ) N,N′-bis(2-mercaptoethyl)-1,4-
diazacycloheptane],26a respectively, and at 502 nm for NiN4
centers in Ni(L8py2)2+ [L8py2 ) 1,5-bis(2-pyridylmethyl)-
1,5-diazacyclooctane].30 The P2NiSN geometries in the
present complexes all show this transition near 495 nm.
These d to d transitions (ꢀ values range from 90 to 180 M-1
cm-1) appear as shoulders against a second dominant
transition near 380 nm assigned as a sulfur-to-nickel charge-
transfer band based on ꢀ values in the range from 730 to
1110 M-1 cm-1.
1H NMR Results for (dppe)NiCysEt+ That Support
P-Ni-S Long-Range Overlap. NMR (1H, 13C, and 31P)
measurements of (dppe)NiCysEt+ indicated significant long-
Figure 2. ORTEP diagram of the (dppe)NiCysAm+ complex cation, one
range coupling facilitated by the phosphorus-nickel-
cysteine bonding network. A 13C DEPT 135 experiment
(Figure S1 in the Supporting Information) unambiguously
identified the R-carbon resonance of the cysteine backbone
at 64.1 ppm. An HMQC experiment (Figure S2 in the
Supporting Information) indicated the single R-proton reso-
nance at 4.35 ppm and the two different â protons at 3.35
and 2.79 ppm. There has to date been some variation on the
assignment of R protons on cysteine ethyl ester chelated to
nickel(II) and cobalt(III). The R-proton resonance of square-
planar Ni(CysEt)2 was assigned to 2.75 ppm,11b and for six-
coordinate CoIII(en)2(CysEt)+, it was assigned to 4 ppm (en
) ethylenediamine).31 Both of the R- and â-carbon atoms
of cysteine couple significantly to the phosphorus atoms of
dppe, with JCP in the proton-decoupled 13C NMR spectrum
of 9.1 and 11.3 Hz, respectively. The coupling constants are
comparable to the two-bond JCP values observed for the
ethylene backbone of dppe (11.0 and 16.0 Hz). This through-
of two different cations in the unit cell. Ellipsoids are shown at the 50%
-
probability level. The PF6 counterion is omitted for clarity.
UV-Vis Electronic Spectra Confirm That Square-
Planar Coordination Persists in Solution. Room-temper-
ature electronic spectra for all of the phosphine-nickel-
cysteine complexes were consistent with those of square-
planar P2NiSN coordination spheres. This characteristic
persisted even in common donor solvents like water and
methanol. Square-planar nickel complexes typically have
their lowest-energy d to d transition at wavelengths shorter
1
1
than 600 nm, assigned as A1g f A2g.28 In general, this
transition is blue-shifted when sulfur donors are replaced by
nitrogen and phosphorus atoms. Accordingly, this transition
appears near 634 nm in NiS4 coordination spheres of Ni-
2-
(detc)2 and Ni(edt)2 (detc ) diethyldithiocarbamate and
edt ) 1,2-ethanedithiolate),29 near 550 and 457 nm in N2-
(28) Lever, A. B. P. Inorganic Electronic Spectroscopy; Elsevier: New
York, 1968; p 344.
(29) (a) Cavell, K. J.; Magee, R. J.; Hill, J. O. J. Inorg. Nucl. Chem. 1979,
41, 1281. (b) Snyder, B. S.; Rao, Ch. P.; Holm, R. H. Aust. J. Chem.
1986, 39, 963-974.
(30) Fox, D. C.; Fiedler, A. T.; Halfen, H. L.; Brunold, T. C.; Halfen, J.
A. J. Am. Chem. Soc. 2004, 126, 7627-7638.
(31) Sloan, C. P.; Krueger, J. H. Inorg. Chem. 1975, 14, 1481-1485.
9226 Inorganic Chemistry, Vol. 46, No. 22, 2007

Nickel-Cysteine Binding Supported by Phosphine Chelates
Figure 3. Temperature-dependent 31P NMR spectra of [(triphos)NiCysAm]PF6 in acetone-d6. Sharp resonances apparent in the 22 °C range are assigned
to adventitious oxidized material that does not participate in the proposed scrambling process. See Figure 4.
bond coupling indicates the influence of the nickel d orbital
delocalization onto the cysteine backbone of the complex.
This through-bond coupling results from the strong trans
influence of phosphorus and sulfur. Two additional NMR
experiments support this conclusion. The selenium analogue
of (dppe)NiCysAm+ was prepared using selenocystamine and
studied by 31P NMR in order to assign each phosphorus
signal to either the one trans to the chalcogen or the one
trans to nitrogen. The only peaks in the spectrum of this
sample were the two inequivalent 31P NMR signals of (dppe)-
NiSeCysAm+ at 62.3 and 53.0 ppm (JPP ) 41 Hz). The
similarity of this spectrum to the sulfur analogue, (dppe)-
NiCysAm+, recorded in the same protiomethanol medium,
confirms the same essential P2Ni(Se or S)N square-planar
geometry for both complexes. At the base of each phosphorus
doublet, there also appeared natural abundant 77Se NMR
plexes (Figures 3 and 5). The fluxional behavior of triphos
chelated to d8 metals like nickel(II)18,32 and platinum(II)33
has been well-documented. Accordingly, the two distinct
phosphorus resonances of square-planar (triphos)NiCl2 were
resolved in THF at -60 °C: -21.6 ppm (uncoordinated)
and -22.6 ppm (coordinated) versus a chemical shift of
-27.6 ppm for free triphos.18 This same fluxional behavior
was resolved for our own sample of (triphos)NiCl2 in CH2-
Cl2 at -50 °C: 13 ppm (coordinated, integral ) 2) and -30
ppm (uncoordinated, integral ) 1). This fluxional behavior
complicates air-free room-temperature spectra of (triphos)-
NiCysAm+ and (triphos)NiCysEt+, but once resolved, the
mechanism proposed to explain it (vide infra) supports the
importance of P-Ni-S π bonding in these complexes.
Variable-temperature 31P NMR spectra for [(triphos)-
NiCysAm]PF6 are summarized in Figure 3. At room tem-
perature under nitrogen, the primary visible resonance in this
1
multiplet satellites (I ) /2, 7.6%). The Se-P hyperfine
-
splittings were inequivalent for the two phosphorus signals.
The downfield 62.3 ppm resonance had JPSe ) 54 Hz, while
the upfield 53.0 ppm resonance had JPSe ) 40 Hz. This larger
JPSe implies that the phosphorus atom assigned to the
downfield resonance interacts more strongly with the chal-
cogen, a result of strong trans P-Ni-(S or Se) π interaction.
The more downfield resonance is therefore assigned to the
phosphorus trans to the chalcogen.
Temperature-Dependent Phosphorus Scrambling in
(triphos)NiCysAm+ and (triphos)NiCysEt+. The strong
trans P-Ni-S π overlap hinted at in (dppe)NiCysEt+ was
very evident in variable-temperature 31P NMR spectra of
fluxional (triphos)NiCysAm+ and (triphos)NiCysEt+ com-
sample is the sharp septet of the PF6 counterion at -144
ppm. A very broad coalesced resonance is also observable
around -8 ppm. As this sample is cooled, resonances
assignable to each of the three distinct phosphorus atoms of
(triphos)NiCysAm+ become apparent, and by -80 °C, these
resonances are completely resolved with 1:1:1:1 integration
-
relative to PF6 . Interestingly, the first resonance to emerge
from the coalesced group is the most downfield resonance
near 18 ppm (yellow highlight of Figure 3). This resonance
(32) (a) Bianchini, C.; Mealli, C.; Meli, A.; Scapacci, G. Organometallics
1983, 2, 141-143. (b) Bianchini, C.; Meli, A.; Orlandini, A.; Sacconi,
L. J. Organomet. Chem. 1981, 209, 219-231.
(33) Colton, R.; Tedesco, V. Inorg. Chim. Acta 1992, 202, 95-100.
Inorganic Chemistry, Vol. 46, No. 22, 2007 9227

Desrochers et al.
Scheme 1
assignments are supported by the resolved chemical shifts
of (triphos)NiCysAm+ (at -80 °C): uncoordinated P at -32
ppm (compared to -27 ppm for free triphos and to
uncoordinated P in our (triphos)NiCl2 sample), PS at 18 ppm,
and PN at 9 ppm. Also, PS is downfield-shifted and PN is
upfield-shifted from coordinated PCl in (triphos)NiCl2, in
agreement with changes seen when (dppe)NiCysRn+ are
formed from (dppe)NiCl2.
Oxidation of the uncoordinated phosphine group prevents
its participation in the scrambling process of Scheme 1 and
essentially locks the system into a square-planar geometry.
Again, this supports the proposed initial associative step in
Scheme 1. A similar result was observed in (triphos)Pt(S2)+,
where S2 represents chelating dithiocarbamates and dithio-
phosphites.33 Like (triphos)NiCl2, (triphos)Pt(S2)+ demon-
strated temperature-dependent fluxional behavior so long as
the apical phosphorus atom existed as a free phosphine.
Reaction of (triphos)Pt(S2)+ with elemental sulfur led to the
formation of (triphos/PdS)Pt(S2)+, where the free phosphine
was converted to the phosphine sulfide. Clear room-tem-
perature spectra were observed for (tripos/PdS)Pt(S2)+, con-
sistent with that of square-planar platinum(II), chelated by
two phosphorus atoms, and an uncoordinated PdS group.33
Figure 4 demonstrates how aerial oxidation of (triphos)-
NiCysAm+ stops the fluxional behavior of this complex
because the apical phosphine is converted to a phosphine
oxide. Some oxidized (triphos)NiCysAm+ is evident as an
adventitious impurity in the room-temperature spectrum
shown in Figures 3 and 4. At room temperature, therefore,
(triphos/PdO)NiCysAm+ gives a well-resolved spectrum
(Figure 4) consistent with square-planar nickel(II).
The same basic splitting patterns and temperature-depend-
ent fluxionality were also observed for (triphos)NiCysEt+
(Figure 5), supporting the same nickel coordination geometry
for this system. Here too, the resonance assigned to PS is
the first to become resolved at 0 °C, with eventual full
resolution of all resonances by -80 °C in comparison to
PF6- as an internal standard. Because of the chirality of the
cysteine ethyl ester, (triphos)NiCysEt+ exists in two diaster-
eomers, labeled cis and trans in Figure 5. Steric hindrance
should discourage the formation of the cis isomer because
the bulky apical -PPh2 group interacts with the -CO2Et
ester functional group in the cis configuration. This hindrance
is less in the trans isomer, and as a result, the trans form
predominates at -80 °C (70% trans vs 30% cis) when all
fluxionality is resolved.
first becomes distinct at 0 °C; the remaining two resonances
are not resolved until -40 °C, and all sharpen further with
additional cooling. The most downfield and first-resolved
resonance is assigned to a phosphorus atom that is impeded
from participation in scrambling at temperatures as high as
0 °C, while the other two phosphorus atoms continue to
scramble until they are cooled much further.
A mechanism for the scrambling of the three triphos
phosphorus atoms is outlined in Scheme 1. This proposal
invokes the common steps of Berry pseudorotation34 that
interconvert square-pyramidal (SP) and trigonal-bipyramidal
(TBP) coordination spheres. A key assumption in this process
is that the apical phosphorus (P of Scheme 1) binds to
produce an initial SP intermediate. This seems more likely
than a three-coordinate initial intermediate resulting from an
alternative dissociative step, because an associative initial
step is common for ligand substitution in square-planar
systems.35 Furthermore, reactions of the apical phosphorus
(vide infra) and the lack of scrambling when bidentate
phosphines are used, (dppe)NiCysRn+, all support the
proposed initial associative step described in Scheme 1. Berry
pseudorotation then accounts for subsequent conversion of
the SP intermediate into one of two possible secondary
intermediates, TBP1 or TBP2.
Two different routes exist for the TBP intermediates to
return to a square pyramid and regenerate a square-planar
product. In Scheme 1, geometry SP1 can become TBP1,
requiring disruption of the trans PS-Ni-S π overlap, or SP1
can become TBP2, leading to a retention of this favorable π
overlap. No similar trans π overlap is possible when the PN-
Ni-N angle is 180° (TBP1). TBP2 is therefore the preferred
TBP geometry during the scrambling mechanism, keeping
the PS-Ni-S angle closer to 180°, so that SP2 is more likely
to form. Ultimately, this mechanism explains the sluggishness
of PS to scramble with the apical P and further accounts for
the continued rapid exchange of the apical P and PN groups
long after the resonance assigned to PS has become well-
resolved. The self-consistency of this explanation and peak
pH Dependence of Cysteine Binding in (dppe)NiCys.
An attempt was made to determine the ability of cysteine to
accept protons when coordinated to nickel as (dppe)NiCys.
In our experience, initial cysteine coordination to nickel(II)
requires a cysteine thiolate formed by the addition of a base
prior to introducing the metal ion. For this reason, we
investigated the acid/base characteristics of nickel-cysteine
after the complex had formed. Figure 6 summarizes the effect
of variable pH on the 31P NMR chemical shift of (dppe)-
NiCys dissolved in aqueous phosphate buffers. These data
indicate that two different processes are occurring in these
mixtures. First, a monotonous downfield movement in the
(34) Casanova, D.; Cirera, J.; Llunell, M.; Alemany, P.; Avnir, D.; Alvarez,
S. J. Am. Chem. Soc. 2004, 126, 1755-1763.
(35) (a) Casares, J. A.; Espinet, P.; Mart´ınez-Ilarduya, J. M.; Mucientes,
J. J.; Salas, G. Inorg. Chem. 2007, 46, 1027-1032. (b) Cooper, J.;
Ziegler, T. Inorg. Chem. 2002, 41, 6614-6622. (c) Katakis, D.;
Gordon, G. Mechanisms of Inorganic Reactions; Wiley-Interscience:
New York, 1987; pp 191-195.
9228 Inorganic Chemistry, Vol. 46, No. 22, 2007

Nickel-Cysteine Binding Supported by Phosphine Chelates
Figure 4. Effect of atmospheric oxidation on the 31P NMR spectrum of [(triphos)NiCysAm]PF6 in acetone-d6. The bottom spectrum was recorded at room
temperature under nitrogen. The middle spectrum was recorded at -80 °C under nitrogen, demonstrating resolution of each of the three distinct phosphorus
signals. The top spectrum was recorded at room temperature after exhaustive aerial oxidation. All resonances in the -80 °C and oxidized spectra show 1:1
-
integration with the septet of PF6 that serves as an internal standard in these spectra.
phosphorus resonances is observed beginning at pH 6 and
continuing to below pH 3. Significantly, even at quite low
pH values, the characteristic doublets of (dppe)Ni(Cys)H+
are dominant resonances in the spectrum.
to nickel was observed in mer-(triphos)NiS(H)Et2+ (from a
pKa of 10.6 in free HSEt to 7.1 in the phosphine complex).17
A similar size decrease would be expected for cysteine thiol
versus (dppe)NiCysH+.37 (dppe)NiCysAm+ showed no simi-
lar pH-dependent shift, making the dangling carboxylate
group the likely initial protonation site on (dppe)NiCys. A
pKa of 2.4 was measured for coordinated cysteine in six-
coordinate (en)2CoIIICys+, and this was assigned to the
protonation of the uncoordinated carboxylate.38 It is not
surprising that cysteine loss was not reported in this system,
where cobalt(III)-cysteine bonds will be much less labile
than nickel(II)-cysteine. Similarly, bis(glycine dipeptide)
complexes of nickel(III) underwent ligand loss from nickel,
and an initial protonation at the dangling carboxylate was
proposed.39 Attempts to protonate any (dppe)NiCysRn+ with
acids possessing a coordinating conjugate base all resulted
in cysteine loss and the formation of the corresponding
(dppe)Ni(base) complexes, confirmed by 31P NMR [i.e.,
(dppe)NiCl2 from HCl and (dppe)Ni(O2CCR3)+ from HO2-
CCH3, HO2CCF3, and HO2CCCl3]. Similar acid-induced
A second reaction in this process is evident beginning at
pH 4. At this and lower pH values, a singlet assignable to
(dppe)2Ni+2 (δ ) 56.3 ppm)24b begins to emerge and grow
as still lower pH values are reached. The appearance of this
product of (dppe)NiCys degradation implies that, at some
point during the protonation process, a (dppe)Ni(Cys)H+
species must exist, and because of its weakened donor
strength toward nickel, this leads to cysteine loss and the
eventual formation of (dppe)2Ni+2 by scavenging dppe from
an adjacent metal center.
An initial protonation of cysteine dppeNiCys could occur
at either the carboxylate or the coordinated thiolate group
because of their available lone pairs; however, (dppe)-
NiCysAm+, which lacks the carboxylate group, showed no
similar pH-dependent shifts. The change in the chemical shift
with the pH suggests a pKa of 3-4 for protonated (dppe)-
NiCys. Free cysteine has respective functional group pKa’s
of 10.8 (-NH2), 8.3 (-SH), and 1.7 (-CO2H) by compari-
son.36 A 3.5 unit decrease in the thiol pKa when coordinated
(37) Hightower, K. E.; Huang, C.-c.; Casey, P. J.; Fierke, C. A. Biochemistry
1998, 37, 15555-15562.
(38) Herting, D. L.; Sloan, C. P.; Cabral, A. W.; Krueger, J. H. Inorg.
Chem. 1978, 17, 1649-1654.
(36) Stryer, L. Biochemistry, 4th ed.; W. H. Freeman and Co.: New York,
(39) Jacobs, S. A.; Margerum, D. W. Inorg. Chem. 1984, 23, 1195-
1201.
1995; p 23.
Inorganic Chemistry, Vol. 46, No. 22, 2007 9229

Desrochers et al.
Figure 5. Temperature-dependent 31P NMR spectra of [(triphos)NiCysEt]PF6 in acetone-d6. The two different diastereomers (based on L-cysteine) of the
complex are indicated by the two different resonances assignable to the uncoordinated phosphorus atom. These singlets integrate to about 70% of the trans
isomer and 30% of the cis isomer.
Figure 6. pH-dependent 31P NMR spectra of (dppe)NiCys in 0.1 M aqueous phosphate buffers. Spectra are close-ups of the 63-61 and 57-55 ppm
regions. The arrow near 56.3 ppm represents the singlet assigned to (dppe)2Ni2+ in the mixture. The heightened intensity is due to its coincidence with the
downfield half of the (dppe)NiCys(H)+ doublet.
thiolate losses were reported for (dppe)Ni(SPh′)2, where SPh′
respresents various para-substituted thiophenolates.26b
Protonation of the carboxylate in (dppe)NiCys does not
initially lead to cysteine loss from nickel. Rather, a second
intramolecular proton transfer to either sulfur or nitrogen
coordinated to nickel must follow, causing eventual scission
of cysteine from nickel. The amine group’s proximity to the
-CO2H group thus formed favors proton transfer to nitrogen;
however, the Ni-N bond would have to first weaken or
break to render the nitrogen lone pair more accessible to the
proton. The thiolate group is still within reach of the -CO2H
proton, and it should be possible to protonate one of the
sulfur lone pairs while retaining a measure of nickel-cysteine
integrity. Theoretical and experimental results on NiSOD
active sites and related models suggest that shorter nickel-
cysteine bonds result with sulfur protonation.40 Large Ni-S
force constants derived from NiSOD Raman measurements
described the strength of the nickel-cysteine bonds in these
systems, underscoring their stability if protonated.41 Mass
spectrometry confirmed the formation and integrity of (dppe)-
Ni(Cys)H+ in dispersed aerosols, where this was the primary
positive ion observed (m/e ) 576), including the correct
(40) Fiedler, A. T.; Bryngelson, P. A.; Maroney, M. J.; Brunold, T. C. J.
Am. Chem. Soc. 2005, 127, 5449-5462.
(41) Fiedler, A. T.; Brunold, T. C. Inorg. Chem. 2007, ASAP, Web Release
Date: Feb 13, 2007.
9230 Inorganic Chemistry, Vol. 46, No. 22, 2007

Nickel-Cysteine Binding Supported by Phosphine Chelates
Figure 7. Brightly colored (dppe)Ni-Cys-bead (A) and Tp*Ni-Cys-bead complexes (C) formed from colorless bead-supported cysteine (B). The orange
and green product beads have been thoroughly washed of residual reaction mixtures.
isotope distribution pattern. The more downfield 31P NMR
chemical shifts observed for (dppe)NiCysEt+ and protonated
(dppe)NiCys (also a monocation) are consistent with the
trend observed in the pH-dependent spectra of (dppe)NiCys.
The serine hydroxyl oxygen is a poor Lewis base43 with
nickel and the methyl thioether of Met-bead is a poorer donor
than the anionic thiolate sulfur of cysteine.44 Cysteine-nickel
binding in the present systems requires free deprotonated
sulfhydryl and amine groups. No binding of nickel to the
AA-beads was observed without the addition of triethy-
lamine. In this work, Fmoc-protected Cys-beads produced
no discernible reaction with Tp*NiNO3 or (dppe)NiCl2 under
inert atmospheres, when either the -SH or -NH2 cysteine
group was blocked by protecting groups.
Further proof of the coordinating role of the cysteine amine
nitrogen came from reactions with a series of cysteine/glycine
tripeptides in which the position of the cysteine was varied
from the C-terminus internal position immediately adjacent
to the bead tether (Gly-Gly-Cys-bead) to the N-terminus
end of the tripeptide chain. The C-terminus side of the
peptide forms an amide linkage with an amine pendant from
the bead. The formation of colored beads was only observed
for the variant with the Cys at the N-terminus of the tripeptide
(Cys-Gly-Gly-bead). The need for N-terminus cysteine to
coordinate nickel in these environments is in agreement with
previous reports by Darensbourg’s group.9
Hydrolysis of cysteine ethyl ester was observed in basic
conditions. At pH 10 (0.1 M phosphate buffer), the reso-
nances typical of (dppe)NiCysEt+ abruptly shift to the higher
values seen for (dppe)NiCys. Formation of (dppe)NiCys by
this reaction was confirmed by a comparison of the spectrum
of an original sample of (dppe)NiCys dissolved in the same
basic medium. This reactivity is consistent with the estab-
lished ability of nickel(II) to catalyze hydrolysis of carboxylic
acid esters.42
Nickel(II) Preference for Cys over Met and Ser on
Heterogeneous Supports. Nickel(II) ligated by dppe and
Tp*- demonstrated a clear affinity for cysteine versus other
amino acids when these amino acids were anchored to
polystyrene synthesis beads. A series of amino acids (AA
) Cys, Met, and Ser) anchored to Argogel beads were
exposed to Tp*NiNO3 in the presence of triethylamine
(Figure 7). The originally colorless beads developed a green
color when Cys was used, but they remained colorless for
Met and Ser forms. This green color is consistent with the
formation of a trigonal-bipyramidal Tp*NiCys-bead complex
based on a comparison with the small-molecule complex,
Tp*NiCysEt.12 The reaction of red-orange (dppe)NiCl2 with
the same set of beads led to orange beads, indicative of the
formation of (dppe)NiCys-bead (Figure 7).
The color changes observed when Tp*NiNO3 and (dppe)-
NiCl2 were reacted with bead-bound cysteine were the same
as those for homogeneous samples of (dppe)NiCysRn+ and
Tp*NiCysR, but spectroscopic comparisons between the two
forms were needed for definitive confirmation. 31P NMR
proved particularly useful in this regard; the only phosphorus
resonances resulted from (dppe)Ni species, either in solution
(42) (a) Wells, M. A.; Bruice, T. C. J. Am. Chem. Soc. 1977, 99, 5341-
5356. (b) Angelici, R. J.; Leach, B. E. J. Am. Chem. Soc. 1968, 90,
2499-2503. (c) Leach, B. E.; Angelici, R. J. J. Am. Chem. Soc. 1968,
90, 2504-2508.
(43) Rozema, D. B.; Poulter, C. D. Biochemistry 1999, 38, 13138-13146.
(44) Ochs, C.; Hahn, F. E.; Fro¨hlich, R. Chem.sEur. J. 2000, 6, 2193-
2199.
Inorganic Chemistry, Vol. 46, No. 22, 2007 9231

Desrochers et al.
The present results can be related to two properties in
nickel enzymes: electron movement through nickel-cysteine
manifolds and the stability of nickel-cysteinethiols. The
nickel center of the carbon cluster in carbon monoxide
dehydrogenase is known to be the site of CO coordination
and oxidation, but electron paramagnetic resonance3b and
L-edge X-ray absorption spectroscopy48 measurements sug-
gest that the electron density removed during this oxidation
is not localized on nickel. Electron movement during CO
oxidation could have them drawn from the Ni-CO unit onto
the associated iron-cysteine framework of the carbon cluster,
and the bonding manifold observed in the present phos-
phine-nickel-cysteine complexes suggests one route for this
process. ENDOR measurements on [NiFe] hydrogenases
detected the coupling of two different proton signals to nickel
unpaired electron spin density. One signal was exchangeable
with bulk protic media, and the other did not exchange.49
The nonexchangeable proton coupling has been assigned to
interaction with the â-methylene protons on the backbone
of the coordinated cysteine ligand.49,50 The strong JPC between
the phosphorus of dppe and the â-methylene of coordinated
cysteine in (dppe)NiCysEt+ points to a through-bond mech-
anism enhanced by Ni-S π bonding. A similar interaction
has been observed by paramagnetic NMR in cobalt- and
nickel-substituted rubredoxins51 and could also contribute to
the coupling of nickel spin density with the nonexchangeable
â-methylene protons observed for [NiFe] hydrogenases.
Figure 8. 31P{1H} NMR spectra of bead-supported (dppe)NiCys in CDCl3.
(Top) Reaction mixture of (dppe)Ni-Cys-bead and unreacted (dppe)NiCl2.
(Bottom) dppeNi-Cys-bead after washing to remove unreacted (dppe)-
NiCl2. These spectra were recorded for the orange bead sample pictured in
Figure 7. Phosphorus assignments are indicated (a-c).
or bound to the bead (Figure 8). 31P NMR spectra of the
(dppe)NiCys-bead/(dppe)NiCl2 slurry showed a resonance
at 58.2 ppm due to unreacted (dppe)NiCl2 in the bulk CDCl3
solution. Two new resonances, each with JPP ) 47 Hz, were
also observed at 61.1 and 52.5 ppm. After washing to remove
unreacted starting material, the orange beads gave only the
latter two doublets expected for (dppe)NiCys-bead. These
are assigned to the two inequivalent phosphorus atoms of
(dppe)NiCys-bead and are consistent with the independent
small-molecule results described above.
Conclusions
Because cysteinethiol in (dppe)NiCys shows only limited
integrity, postulated protonated Ni-S(H)Cys states for [NiFe]
hydrogenase and for NiSOD groups must benefit from
additional stabilizing influences. For both protein classes,
the nickel-cysteine site possesses multiple cysteinyl thiolates
coordinated to nickel. Multiple-sulfur coordination has been
shown to improve the stability of metal thiols in protected
protein environments52 and in synthetic models.53 Amide-
nitrogen-nickel coordination, as seen in NiSOD groups,
appears to offer no benefit for acid stability because bound
peptides are still displaced by protonation in Ni(Gly-Gly)2
that also possess amide-nitrogen-nickel bonds.39 It is likely
that the high dielectric aqueous environment used here
encouraged cysteine displacement in (dppe)NiCys with
protonation. Detailed pH-dependent stability studies of Ni-
(CysR)n and Ni(Cys-Xn-Cys) in variable dielectric media
are warranted to outline the limits of nickel-cysteinethiol
stability.
The present results demonstrate strong dπ-pπ bonding
involving sulfur, nickel, and the phosphorus atom trans to
sulfur in square-planar nickel complexes. This interaction
contributes to long-range dppe phosphorus coupling to the
ethylene backbone of the coordinated cysteine. With the
tridentate triphos ligand, this π interaction directs the rapid
scrambling of the three phosphorus atoms via an associative
initial step. In contrast, complementary experimental and
theoretical work with Tp*Ni+ has demonstrated the domi-
nance of N-Ni σ interactions in this coordination sphere.45
When dppe and pyrazolylborates (TpR-) or pyrazolyl-
methanes (TmR) are used simultaneously, low-spin NiIIP2N2
coordination spheres result,46 leading to κ2 TpR- or TmR
coordination. Bidentate TpR- leading to square-planar co-
ordination is a more common characteristic of second- and
third-row d8 platinum metal ions.47 For first-row nickel, this
again demonstrates the commanding π overlap of phosphorus
that tips the balance in favor of square-planar geometries.
The water solubility and acid-induced lability of the
phosphine-nickel-cysteine complexes encourage cytotox-
icity studies for the (dppe)NiCysRn+ class of compounds.
(45) Desrochers, P. J.; Telser, J.; Zvyagin, S. A.; Ozarowski, A.; Krzystek,
J.; Vicic, D. A. Inorg. Chem. 2006, 45, 8930-8941.
(46) (a) TpPhMeNi(dppe)+: Uehara, K.; Hikichi, S.; Akita, M. J. Chem.
Soc., Dalton Trans. 2002, 3529-3538. TpPhMe- ) hydrotris(3-phenyl-
5-methylpyrazolyl)borate. (b) We independently prepared a sample
of [TmNiII(dppe)](PF)2 as a bright-yellow solid and confirmed its
diamagnetic square-planar geometry by 31P NMR. Tm ) tripyrazolyl-
methane. Phelan, A.; Thompson, L.; Linz, T.; Tarkka, R. 233rd ACS
National Meeting, Chicago, IL, Mar 25-29, 2007, CHED 526.
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Ziolkowski, J. J. Organometallics 2003, 22, 1072-1080. (c) Reinartz,
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9232 Inorganic Chemistry, Vol. 46, No. 22, 2007

Nickel-Cysteine Binding Supported by Phosphine Chelates
Recently, labile (dppe)nCuI complexes were shown to exhibit
promising cytotoxicity,54 motivated in part by the success
of gold phosphines.55 Targeted binding is a common strategy
for metal-containing chemotherapeutic agents,56 and coor-
dinated cysteine has been investigated as a means of
improving water solubility and biorecognition.57 Some
cancers demonstrate the ability to thrive at abnormally low
pH levels, by inhibiting cell death normally triggered by
intracellular acidification.58 This more acidic tumor environ-
ment can help target anticancer therapies by exploiting pH-
dependent reactivity.59
The observed selectivity of Tp*Ni+ for bead-supported
N-terminus cysteine is a promising initial result for hetero-
geneous Tp*Ni+ work with amino acids and peptides. The
reluctance of Tp*Ni+ to bind homocysteine thiolate and a
readiness to bind cysteine thiolate13 could be exploited, for
example, as the basis for a colorimetric sensor for cysteine
in the presence of homocysteine. Plasma homocysteine
imbalance has been associated with a variety of pathologies.60
Analytical detection of homocysteine versus cysteine often
does not discriminate between these two major sulfur-
containing amino acids,61 so that selective homocysteine
detection in plasma typically requires a cysteine separation
step, prior to homocysteine detection.62 Heterogeneous work
involving Tp*Ni+ and more extensive cysteine peptides is
ongoing, motivated by the present preliminary results.
Acknowledgment. Financial support was provided by the
donors of the American Chemical Society Petroleum Re-
search Fund (39644-B3 to P.J.D.), including a PRF SUMR
Fellowship (to A.S.M.), and the University of Central
Arkansas Research Council (to P.J.D.). R.M.T. is grateful
to the BRIN program of the National Center for Research
Resources of the National Institute of Health (Grant P20 RR-
16460) for support. We recognize the assistance of
Blake Richardson in helping to prepare some of the bead-
bound peptide samples. Financial support was also provided
by the National Science Foundation (Grant CCLI 0125711
to J.M.M. and R.M.T.) for the purchase of the NMR
spectrometer.
(54) Sanghamitra, N. J.; Phatak, P.; Das, S.; Samuelson, A. G.; Soma-
sundaram, K. J. Med. Chem. 2005, 48, 977-985.
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Chem. 2004, 4, 49-60. (c) Gold: Mohamed, A. A.; Chen, J.; Bruce,
A. E.; Bruce, M. R.; Krause-Bauer, J. A.; Hill, D. T. Inorg. Chem.
2003, 42, 2203-2205.
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W. J. Cell Biochem. 1997, 67, 231-240. (c) Schornack, P. A.; Gillies,
R. J. Neoplasia 2003, 5, 135-145.
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Pharmacol. 2003, 66, 1207-1218.
Supporting Information Available: Complete listings of bond
distances, angles, and atomic anisotropic thermal parameters for
[(dppe)NiCysAm]PF6, crystallographic data for this compound in
CIF format, and DEPT 135 and HMQC NMR spectra with peak
assignments for [(dppe)NiCysEt]Cl in CDCl3. This material is
available free of charge via the Internet at http://pubs.acs.org.
(60) (a) Vitamin B12 deficiencies: Stangl, G. I.; Roth-Maier, D. A.;
Kirchgessner, M. J. Nutr. 2000, 130, 3038-3044. (b) Vacular
diseases: Marouf, R.; Zubaid, M.; Mojiminiyi, O. A.; Qurtom, M.;
Abdella, N. A.; Al Wazzan, H.; Al Humood, S. South. Med. J. 2006,
99, 811-816. (c) Renal failure: Baber, U.; Toto, R. D.; de Lemos, J.
A. Am. Heart J. 2007, 153, 471-477. Urquhart, B. L.; Freeman, D.
J.; Spence, J. D.; House, A. A. Am. J. Kidney Dis. 2007, 49, 109-
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IC701150Q
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Warner, I. M.; Dawan, F. B.; Lian, K.; Strongin, R. M. J. Am. Chem.
Soc. 2004, 126, 438-439.
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Inorganic Chemistry, Vol. 46, No. 22, 2007 9233