Bismercaptoethanediazacyclooctane as a N2S2 chelating agent and Cys-X-Cys mimic for Fe(NO) and Fe(NO)2

Article abstract of DOI:10.1021/ja049627y

The N-protonated bismercaptoethanediazacyclooctane serves as a bidentate dithiolate ligand to oxidized Fe(NO)₂ of Enemark-Feltam notation, E-F {Fe(NO)₂},⁹ mimicking Cys-X-Cys binding of Fe(NO) ₂ to proteins or thio-biomolecules. The neutral compound is characterized by the well-known g = 2.03 EPR signal which is a hallmark of dinitrosyl iron complexes, DNIC's. The Fe(NO)₂ unit can be removed from the chelate by excess PhS^-, producing (PhS)₂Fe(NO) ₂^-. Transfer of NO from Fe(H⁺bme-daco)(NO) ₂ (ν(NO) = 1740, 1696 cm^-1) to Fe^II of [(bme-daco)Fe]₂ yields the five-coordinate, square-pyramidal N ₂S₂-Fe(NO) (ν(NO) = 1649 cm^-1), where NO is in the apical position. Its isotropic EPR signal at g = 2.05 is consistent with E-F {Fe(NO)}⁷ formulation. In excess NO, Roussin's red ester-type molecules are formed as dinuclear or tetranuclear species, {(μ-SRS)[Fe ₂(NO)₄]}_n (n = 1,2). These well-characterized molecules furnish reference points for positions and patterns in ν(NO) vibrational spectroscopy expected to be useful for in vivo studies of NO degradation of iron-sulfur clusters in ferredoxins.

Full text of DOI:10.1021/ja049627y

Published on Web 08/11/2004
Bismercaptoethanediazacyclooctane as a N2S2 Chelating
Agent and Cys-X-Cys Mimic for Fe(NO) and Fe(NO)2
Chao-Yi Chiang, Matthew L. Miller, Joseph H. Reibenspies, and
Marcetta Y. Darensbourg*
Contribution from the Department of Chemistry, Texas A&M UniVersity,
College Station, Texas 77843
Received January 21, 2004; E-mail: marcetta@mail.chem.tamu.edu
Abstract: The N-protonated bismercaptoethanediazacyclooctane serves as a bidentate dithiolate ligand
to oxidized Fe(NO)2 of Enemark-Feltam notation, E-F {Fe(NO)2},9 mimicking Cys-X-Cys binding of
Fe(NO)2 to proteins or thio-biomolecules. The neutral compound is characterized by the well-known g )
2.03 EPR signal which is a hallmark of dinitrosyl iron complexes, DNIC’s. The Fe(NO)2 unit can be removed
from the chelate by excess PhS-, producing (PhS)2Fe(NO)2-. Transfer of NO from Fe(H+bme-daco)(NO)2
(ν(NO) ) 1740, 1696 cm-1) to FeII of [(bme-daco)Fe]2 yields the five-coordinate, square-pyramidal N2S2-
Fe(NO) (ν(NO) ) 1649 cm-1), where NO is in the apical position. Its isotropic EPR signal at g ) 2.05 is
consistent with E-F {Fe(NO)}7 formulation. In excess NO, Roussin’s red ester-type molecules are formed
as dinuclear or tetranuclear species, {(µ-SRS)[Fe2(NO)4]}n (n )1, 2). These well-characterized molecules
furnish reference points for positions and patterns in ν(NO) vibrational spectroscopy expected to be useful
for in vivo studies of NO degradation of iron-sulfur clusters in ferredoxins.
-
Introduction
of iron-sulfur clusters to produce (protein-Cys-S)2Fe(NO)2
,
B, which was discovered in studies of 2Fe2S and 4Fe4S
ferredoxins, in the presence of excess NO.11-14 A repair process
established by Ding et al. requires L-cysteine and cysteine
desulfurase to remove NO and provide sulfur for the regenera-
tion of the iron-sulfur clusters.12-14 An undetermined issue is
whether, or the conditions under which, the protein-bound DNIC
may be mobilized by reaction with plasma thiols such as
glutathione or free cysteine, thereby becoming potential NO
carriers, C.15 In this connection, DNIC’s have been suggested
to serve as labile NO sources similarly to RSNO’s, showing
the same biological activities such as vasodilation.16,17 As yet
another possible physiological action, the intracellular formation
of DNIC’s has been suggested to reduce NO cytotoxicity.18 The
scope of these processes has inspired us to examine the
inorganic/organometallic precedents of import to DNIC’s.
The inorganic literature finds precedents for small molecule
DNIC’s in two oxidation levels of the Fe(NO)2 unit. A
diamagnetic, reduced form is stabilized by soft donor ligands
The interactions of NO with sulfur of natural thiols, forming
nitrosothiols (RSNO′S),1-3 and with heme iron in hemoglobin
or myoglobin, forming nitrosylated or RS-nitrosylated heme,3-5
have been intensely studied by chemists and biochemists. Also
well known in bioinorganic chemistry is the iron-nitrosyl found
in the NO-deactivated form of iron-nitrile hydratase.6,7 The
unusual binding site is composed of deprotonated carboxamido
nitrogens in a cysteine-serine-cysteine sequence within the
protein, resulting in a planar array of N2S2 donor sites. As shown
in structure A, two of the cysteine sulfurs in the N2S2 moiety
are further modified as S-oxygenates. Photolabilization of the
NO is required for enzyme activity.
Yet another “natural” Fe-NO complex, a tetrahedral, S-
bound iron dinitrosyl, has been known for decades.8,9 Interest
in sulfur-bound dinitrosyl iron complexes (DNIC’s) derives from
their fundamental properties and the possibility of physiologi-
cally significant chemistry.9,10 The latter includes degradation
such as CO and PR3 in neutral L2Fe(NO)2 complexes;19,20
a
(1) Williams, D. L. H. Acc. Chem. Res. 1999, 32, 869-875.
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140.
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9
10.1021/ja049627y CCC: $27.50 © 2004 American Chemical Society
J. AM. CHEM. SOC. 2004, 126, 10867-10874
10867

A R T I C L E S
Chiang et al.
-
SR)2Fe(NO)2 is dependent on the oxidation state of Ni, thus
placing the Ni(0) derivative, [(ON)Ni0(µ-S(CH2)2S(CH2)2S)Fe-
(NO)2], in the same class as the paramagnetic, g ) 2.03,
oxidized version of (RS)2Fe(NO)2-. In contrast, the Ni(II)
derivatives using the N2S2 dithiolate ligands such as (bismer-
captoethanediazacyclooctane)nickel(II), (bme-daco)Ni(II), as the
metallothiolate ligand to {Fe(NO)2} generated the neutral,
reduced L2Fe(NO)2 complexes, similarly to diphosphine deriva-
tives, (Ph2PCH2CH2PPh2)Fe(NO)2.28
The following report is of chemistry developing from our
attempts to generate the nickel-free versions of [(-S(CH2)2S-
(CH2)2S-)Fe(NO)2]- and (bme-daco)Fe(NO)2- which have led
to unique structural forms. For the former, a tetranuclear dimer
of dimers defines a Roussin’s red “ester” with a symmetrical
orientation of µ-SR units. The latter demonstrates a novel
configuration of the structurally reinforced diaza ligand that can
halide, pseudo-halide, and thiolate ligands.21,22 The latter is
characterized by an isotropic EPR signal of g ) 2.03-2.04; in
fact, it was this spectroscopic feature that first linked the
inorganic models to the biological DNIC’s.23 The Fe(NO)2 units
-
in these as well as in the (RS)2Fe(NO)2 complexes are
-
accommodate a tetrahedral (RS)2Fe(NO)2 structure, an ana-
computed to carry a +1 charge and are designated according
to the Enemark-Feltham (E-F) notation (a summation of Fen
d-electrons and the number of NO ligands) as {Fe(NO)2}9.24
The reduced, diamagnetic form, denoted as E-F {Fe(NO)2}10,
has a charge of 0 in the neutral L2Fe(NO)2 complexes where L
is a soft donor. Borderline hard/soft donors such as nitrogen in
imidazoles produce the Fe(NO)2 unit in forms that appear to
logue of biological (Cys-X-Cys)2Fe(NO)2-. Transfer of one
NO to an NO acceptor shifts the remaining FeNO unit into the
N2S2 core. The preparation and characterization of these
structural types of nitrosyl iron complexes, including explora-
tions of an RS- ligand exchange process and NO transfer from
(H+bme-daco)[Fe(NO)2], are described below. Notably this
well-characterized series provides vibrational spectroscopic
reference points and uses vibrational spectroscopy as a monitor
for reaction pathways of iron nitrosyls in biologically significant
sulfur-rich coordination.
easily convert between oxidized and reduced redox levels.25
A
pertinent example comes from DNIC’s derived from histidine
mimics such as that of Li and co-workers.25
Because of its sensitivity at low concentrations, EPR spec-
troscopy is the most frequently used diagnostic for biological
DNIC species. However, a review of the available data shows
little differences in the g values for potential model species of
quite different compositions, including those that, based on bulk
composition and structures, should be diamagnetic. The latter
discrepancy results from solution studies where small amounts
of the complex may be solvated leading to oxidation and EPR
activity.26,27 A further complicating feature of DNIC detection
and characterization is that further oxidation in solution forms
the stable and EPR silent Roussin’s red “esters” of formulation
(µ-SR)2Fe2(NO)4. Hence, it is important to develop an auxiliary
technique for DNIC identification and study; ν(NO) vibrational
spectroscopy is an obvious choice.
Experimental Section
Materials and Techniques. Solvents were of reagent grade and
purified as follows: Dichloromethane was distilled over P2O5 under
N2. Acetonitrile was distilled once from CaH2, once from P2O5, and
freshly distilled from CaH2 immediately before use. Diethyl ether,
toluene, THF, and hexane were distilled from sodium/benzophenone
under N2. Syntheses of PPN[FeI2(NO)2],21 Na2(SCH2CH2SCH2CH2S),29
N,N′-bis(2-mercaptoethyl)-1,5-diazacyclooctane (H2bme-daco),30 and its
iron complex, [(bme-daco)Fe]2,31 were according to published proce-
dures. NO gas (98.5%) and 2-mercaptoethyl sulfide (90%) were
purchased from Aldrich Chemical Co. and were used as received.
Syntheses and manipulations were performed using standard Schlenk-
line and syringe/rubber septa techniques under N2 or in an argon
atmosphere glovebox. Filtrations of solutions used airless-ware glass
frits typically with 1-2 cm pads of Celite.
Infrared spectra were recorded on a Mattson 6022 spectrometer in
a CaF2 cell of 0.1 mm path length. UV/vis spectra were recorded on a
Hewlett-Packard HP8452A diode array spectrophotometer. Elemental
analyses were performed by Canadian Microanalytical Systems in Delta,
British Columbia, Canada. Electro-spray ionization mass spectrometry
data were obtained at the Laboratory for Biological Mass Spectrometry,
Texas A&M University, College Station, Texas, using a MDS Series
Qstar Pulsar with a spray voltage of 5 keV. The EPR spectrum was
recorded on a Bruker X-band EPR spectrometer (model ESP 300E)
with an Oxford Liquid Helium/Nitrogen cryostat at 77 K in CH2Cl2, 1
mW power, and 0.1 mT modulated amplitude.
We have explored the use of {Fe(NO)2} as a redox active
reporter unit in heterometallic complexes based on (RS)2Fe-
- 28
(NO)2
.
The oxidation level of the {Fe(NO)2} unit in Ni(µ-
(19) (a) Brockway, L. O.; Anderson, J. S. Trans. Faraday Soc. 1937, 33, 1233-
1239. (b) Hedberg, L.; Hedberg, K.; Satija, S. K.; Swanson, B. I. Inorg.
Chem. 1985, 24, 2766-2771.
(20) Albano, V. G.; Araneo, A.; Bellon, P. L.; Ciani, G.; Manassero, M. J.
Organomet. Chem. 1974, 67, 413-422.
(21) Connelly, N. G.; Gardner, C. J. Chem. Soc., Dalton Trans. 1976, 1525-
1527.
(22) Strasdeit, H.; Krebs, B.; Henkel, G. Z. Naturforsch. 1986, 41b, 1357-
1362.
(23) (a) Butler, A. R.; Glidewell, C.; Johnson, I. L.; Walton, J. C. Polyhedron
1987, 6, 2085-2090. (b) McDonald, C. C.; Phillips, W. D.; Mower, H. F.
J. Am. Chem. Soc. 1965, 87, 3319-3326. (c) Basosi, R.; Gaggelli, E.;
Tiezzi, E.; Valensin, G. J. Chem. Soc., Perkin Trans. 2 1975, 423-428.
(d) Jezowska-Trezebiatowska, B.; Jezierski, A. J. Mol. Struct. 1973, 19,
635-640. (e) Bryar, T. R.; Eaton, D. R. Can. J. Chem. 1992, 70, 1917-
1926.
Preparations. (H+bme-daco)Fe(NO)2, Complex 1. In a typical
synthesis, a 0.268 g (1.15 mmol) portion of H2bme-daco dissolved in
(24) Enemark, J. H.; Feltham, R. D. Coord. Chem. ReV. 1974, 340-404.
(25) (a) Reginato, N.; McCrory, C. T. C.; Pervitsky, D.; Li, L. J. Am. Chem.
Soc. 1999, 121, 10217-10218. (b) Li, L. Comments Inorg. Chem. 2000,
23, 335-353.
(29) Yogi, S.; Hokama, K.; Tsuge, O. Bull. Chem. Soc. Jpn. 1987, 60, 335-
342.
(30) Mills, D. K.; Font, I.; Farmer, P. J.; Tuntulani, T.; Buonomo, R. M.;
Goodman, D. C.; Musie, G.; Grapperhaus, C. A.; Maguire, M. J.; Lai, C.-
H.; Hatley, M. L.; Smee, J. J.; Bellefeuille, J. A.; Darensbourg, M. Y. Inorg.
Synth. 1998, 32, 89-98.
(26) Burlamacchi, L.; Martini, G.; Tiezzi, E. Inorg. Chem. 1969, 8, 2021-2025.
(27) Li, L.; Morton, J. R.; Preston, K. F. Magn. Reson. Chem. 1995, 33, S14-
S19.
(28) Liaw, W.-F.; Chiang, C.-Y.; Lee, G.-H.; Peng, S.-M.; Lai, C.-H.; Darens-
bourg, M. Y. Inorg. Chem. 2000, 39, 480-484.
(31) Mills, D. K.; Hsiao, Y. M.; Farmer, P. J.; Atnip, E. V.; Reibenspies, J. H.;
Darensbourg, Y. D. J. Am. Chem. Soc. 1991, 113, 1421-1423.
9
10868 J. AM. CHEM. SOC. VOL. 126, NO. 35, 2004

Bismercaptoethanediazacyclooctane
A R T I C L E S
Scheme 1
10 mL of THF was transferred into a 50 mL Schlenk flask containing
a stir bar and 0.365 g (0.40 mmol) of PPN[FeI2(NO)2], which was
immersed in a 0 °C bath. The reaction mixture was maintained at 0 °C
with stirring for 2 h. The solvent was removed under vacuum, and the
resulting brown green oil was redissolved in MeOH. Under air-free
conditions, degassed water was added and the solid which precipitated
was collected on a filter frit. The solid was redissolved in THF, and
trace H2O was removed by adding MgSO4. The solution was decanted
from the drying agent, and the solvent was removed under vacuum.
The resulting solid was washed with hexane before being redissolved
in THF and filtered through Celite to remove PPN+I-. After removal
of the solvent, crude solid (0.062 g, 44%) was collected. Brown-red
crystals suitable for X-ray diffraction analysis were obtained by
diffusion of pentane vapor into a THF solution of compound at 5 °C.
Infrared spectrum (νNO): 1695(s), 1739(m) cm-1 (THF). The synthesis
worked equally well with Et4N[FeI2(NO)2] as starting material from
which purer bulk samples were obtained, affording acceptable elemental
analyses. Mass spectrum: m/z ) 350.05 (complex 1 + H+); 334.04
(complex 1 - (N + H)); 320 (complex 1 - NO). Also present m/z )
465 (complex 3 + H+); 434 (complex 3H+ - NO); 404 (complex 3H+
- 2NO). Anal. Calcd for C10H21O2N4FeS2: C, 34.39; H, 6.06; N, 16.04.
Found: C, 34.10; H, 5.87; N, 15.14.
rick),35 and molecular graphics and preparation of material for publica-
tion, SHELXTL-Plus, version 5.1 or later (Bruker).36
Results and Discussion
Syntheses and Molecular Structures. Among several avail-
able routes for the synthesis of (RS)2Fe(NO)2- complexes, the
method presented in Scheme 1 was selected for the N2S2 bme-
daco derivatives. Following the procedure of Connelly and
Gardner, reductive nitrosylation of Fe(CO)5 followed by oxida-
tive addition of I2 yields the [I2Fe(NO)2]- anion, isolated as its
PPN+ salt.21 Reaction with excess of the dithiol, H2bme-daco,
in THF solution at 0 °C results in iodide displacement by the
dithiolate and precipitation of PPN+I-. For mass balance, a mole
of HI should be released. The brown-green complex 1 is
obtained as a solid following removal of THF, redissolving in
MeOH, precipitation on addition of H2O, and recrystallization
(THF/hexane or THF/pentane). The solid may be stored
indefinitely in an Ar-filled glovebox freezer held at -35 °C.
Long-term exposure (hours) of solutions of 1 to air, water, or
heat leads to slow decomposition with formation of (bme-daco)-
Fe(NO), complex 2, or the Roussin’s red ester complex, [(bme-
daco)[Fe(NO)2]2]n, n ) 1 or 2.
(bme-daco)Fe(NO), Complex 2. A 1.34 g (2.34 mol) portion of
[(bme-daco)Fe]2 was dissolved in 70 mL of MeOH in a 100 mL Schlenk
flask at 60 °C under argon. Under NO gas (1 atm), the solution color
changed from purple-brown to green within 30 min. The solvent was
removed under vacuum. The solid was redissolved in 50 mL of CH2-
Cl2 and filtered through Celite. The green filtrate was concentrated to
5 mL under vacuum, and addition of 30 mL of pentane resulted in
precipitation of a green solid; yield 1.27 g, 86%. Green crystals of
X-ray diffraction quality were obtained by diffusion of pentane vapor
into a CH2Cl2 solution of complex 2 maintained at 5 °C. IR (νNO):
1649(s) cm-1 (CH2Cl2). Anal. Calcd for C10H20ON3FeS2: C, 37.74; H,
6.33; N, 13.20. Found: C, 37.27; H, 6.26; N, 12.87.
PPN[(S3′)Fe(NO)2], Complex 4, and Fe4(S3′)2(NO)8 (S3′ ) S(CH2)2S-
(CH2)2S), Complex 5. The reaction of PPN[FeI2(NO)2] (0.363 g, 0.40
mmol) with Na2S3′, Na2(SCH2CH2SCH2CH2S), (0.156 g, 0.80 mmol)
in a 1:1 mixture of MeOH/THF resulted in a green solution with ν(NO)
) 1694, 1739 cm-1. All attempts to isolate and crystallize the presumed
PPN[(S3′)Fe(NO)2] salt resulted in conversion to a red-brown product
with ν(NO) ) 1751, 1777 cm-1, THF solvent. In solution, even at
-20 °C, the green PPN[(S3′)Fe(NO)2], 4, slowly changed to the red
complex 5. This product was determined by X-ray crystallography to
be the tetranuclear Fe4(S3′)2(NO)8. As a solid, it is both thermally and
air stable (for short periods); however, solutions should be kept under
Ar or N2. It is soluble in THF and CH2Cl2. Anal. Calcd for C8H16O8N8-
Fe4S6‚CH3OH: C, 13.51; H, 2.52; N, 14.01. Found: C, 14.0; H, 2.31;
N, 13.8.
Optimal conditions for production of complex 1 in near
quantitative yields as determined by solution ν(NO) IR spec-
troscopy via Scheme 1 employ a ratio of H2bme-daco to
PPN+[I2Fe(NO)2]- of ca. 3:1 in THF. Other solvents, CH3CN,
CH2Cl2, and MeOH, may be used; however, at lower L:Fe ratios,
a minor product is observed with ν(NO) ) 1649 cm-1. A direct
route to this green product, (bme-daco)Fe(NO), complex 2, is
outlined in Scheme 2, beginning with the synthesis of dimeric
[(bme-daco)Fe]2.31 The reaction of [(bme-daco)Fe]2 with either
-
NO+PF6 or NO(g) in warm MeOH (60 °C) results in a color
change from red-brown to green and, ultimately, precipitation
of a green solid. The single ν(NO) stretch at 1649 cm-1 is
similar to that observed by Baltusis et al., for a related open
chain (N2S2)Fe(NO) complex.37 The purified complex 2 is
thermally and air stable as a solid. As a precaution, solutions
were prepared and maintained air free. Air sensitivity, however,
is not great even in solution.
Although [(bme-daco)Fe]2 is largely insoluble in CH2Cl2 and
CH3CN, reaction with NO gas draws the compound into these
solvents as green complex 2, in which case further reaction with
X-ray Structure Determinations. X-ray data were obtained on an
Apex CCD difractometer and covered a hemisphere of space upon
combining three sets of exposures. The space groups were determined
on the basis of systematic absences and intensity statistics. The
structures were solved by direct methods. Anisotropic displacement
parameters were determined for all non-hydrogen atoms. Hydrogen
atoms were added at idealized positions and refined with fixed isotropic
displacement parameters equal to 1.2 (1.5 for methyl protons) times
the isotropic displacement parameters of the atoms to which they were
attached. Atoms which proved to be nonpositive definite were corrected
by including the command ISOR with the “s” parameter set at 0.05 in
the instruction file. Programs used for data collection and cell
refinement, SMART;32 data reduction, SAINT-Plus;33 structure solution,
SHELXS-86 (Sheldrick);34 structure refinement, SHELXL-97 (Sheld-
(34) Sheldrick, G. SHELXS-86: Program for Crystal Structure Solution; Institu¨t
fu¨r Anorganische Chemie, Universita¨t Gottingen: Gottingen, Germany,
1986.
(35) Sheldrick, G. SHELXL-97: Program for Crystal Structure Solution; Institu¨t
fu¨r Anorganische Chemie, Universitat Gottingen: Gottingen, Germany,
1997.
(36) SHELXTL, version 5.1 or later; Bruker: Madison, WI, 1998.
(37) Baltusis, L. M.; Karlin, K. D.; Rabinowitz, H. N.; Dewan, J. C.; Lippard,
S. J. Inorg. Chem. 1980, 19, 2627-2632.
(32) Smart 1000 CCD; Bruker Analytical X-ray Systems: Madison, WI, 1999.
(33) SAINT-Plus, version 6.02; Bruker: Madison, WI, 1999.
9
J. AM. CHEM. SOC. VOL. 126, NO. 35, 2004 10869

A R T I C L E S
Chiang et al.
Scheme 2
Molecular Structures from X-ray Crystallography. Crys-
tals of complexes 1, 2, and 5 were obtained as described in the
Experimental Section. Crystallographic data for the structures
are given in Table 1. As expected from solubility characteristics,
the molecular structure of complex 1 shows no counteranion,
which implies a protonated ligand, represented as nitrogen
protonation, in Figure 1. Two views of the (H+bme-daco)Fe-
(NO)2 species are given in Figure 1a and 1b. All atoms of the
Fe(NO)2 unit lie in a plane which bisects that of the FeS2 portion
of the complex; the N-Fe-N of 115.3(3)° and the S-Fe-S
of 111.9(1)° are consistent with the nearly regular tetrahedral
coordination environment about Fe. The Fe-N-O angles of
168.9° and 166.9° with O-Fe-O ) 105.5° are hallmarks of
the so-called “attracto” conformation in which O atoms are
drawn in toward each other within the Fe(NO)2 plane.39 Iron-
sulfur and Fe-N bond distances are given in Table 2 and
compare well with the (PhS)2Fe(NO)2- species whose structure
was determined as its Et4N+ salt.22 Differences of note are
largely in the S-C distances, which are ca. 0.07 Å shorter in
Scheme 3
the (PhS)2Fe(NO)2 complex.22
-
The orientation of complex 1 shown in Figure 1b emphasizes
the conformation of the diazacyclooctane ring which, when
N-bonded to metals (as seen in complex 2), forms classic six-
membered metal-diazacyclohexane rings resulting in chair-boat
conformations. Figure 1b shows the same conformation is
maintained in the absence of a transition metal bound to the
two nitrogens. The final density map finds a single proton bound
to one nitrogen, N(4). This single protonation site was cor-
roborated by the different N-C distances in the N(4) ammonium
ion versus the neutral N(3) amine. The geometries of the
nitrogens are largely the same according to the C-N-C
angles surrounding N(3) and N(4). The conformation of the
ethylene sulfide arms that orient sulfurs to accommodate
tetrahedral binding to iron is the first of this type observed for
the bme-daco ligand. Typically, the N2S2 donor sites of bme-
daco support square-planar and square-pyramidal binding.31,40
A similar observation has been made for the open chain N2S2
ligand, N,N′-dimethyl-N,N′-bis(2-mercaptoethyl)1,3-propanedi-
amine, in the iron-dinitrosyl complex, (H+bme-pda)Fe(NO)2,
whose structure was determined on a mixture which was
cocrystallized with (bme-pda)Fe(NO).37 The Fe-S and Fe-N
distances as well as the coordination angles of the open chain
(H+N2S2)Fe(NO)2 and the more constrained complex 1 are
approximately the same, despite the more rigid framework of
complex 1. Overlays of the structures of the open chain and
the reinforced diazacycle forms of (H+N2S2)Fe(NO)2 complexes,
and a comparison of the metric data, are given in the Supporting
Information.
excess NO readily (within minutes) occurs yielding red-brown
derivatives with ν(NO) absorptions of 1780, 1755 cm-1. In
MeOH, complex 2 is more stable toward excess NO, requiring
reaction times of ∼4 h to produce the same red-brown species.
The ν(NO) bands in the 1750-1780 cm-1 region are
characteristic of Roussin’s red “ester”, (µ-SR)2[Fe(NO)2]2;23,38
they are assigned to complex 3 in Scheme 2. Infrared absorptions
in this region were also observed in the ultimate reaction product
The molecular structure of complex 2, (bme-daco)Fe(NO),
given in Figure 2 is that of a square pyramid with an N2S2 base
and an apical NO group. The iron nitrosyl is substantially bent,
Fe-N-O ) 151.7(5)°, and the NO vector is oriented in the
direction of the basal sulfur atoms. The diazacyclooctane ring
adopts its common chair/boat conformations of the fused
metallodiazacyclohexane rings, and the ethylene sulfide arms
are eclipsed with respect to the N2S2Fe coordination group.
While the average deviations of N and S atoms from a best
planes calculation for the N2S2 group are <0.1 Å, the iron atom
-
of I2Fe(NO)2 with the 2-mercaptoethyl sulfide ligand, S3′.
Reaction of the sodium salt of -SCH2CH2SCH2CH2S- initially
produced a green product assigned to the dinitrosyl complex
indicated in Scheme 3. All attempts to grow crystals of this
presumed monomeric species either at -20 or at 22 °C resulted
in a transformation to the red-brown tetranuclear, Roussin’s red
type species as shown in Scheme 3.
(38) (a) Thomas, J. T.; Robertson, J. H.; Cox, E. G. Acta Crystallogr. 1958, 11,
599-604. (b) Glidewell, C.; Lambert, R. J. J. Chem. Soc., Dalton Trans.
1989, 2061-2064. (c) Glidewell, C.; Harman, M. E.; Bursthouse, M. B.;
Johnson, I. L.; Motevalli, M. J. Chem. Res., Synop. 1988, 212-213, 1676-
1690. (d) Cai, J.; Mao, S. Jiegou Huaxue 1983, 2, 263-267.
(39) Martin, R. L.; Taylor, D. Inorg. Chem. 1976, 15, 2970-2976.
(40) Musie, G.; Lai, C.-H.; Reibenspies, J. H.; Sumner, L. W.; Darensbourg,
M. Y. Inorg. Chem. 1998, 37, 4086-4093.
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10870 J. AM. CHEM. SOC. VOL. 126, NO. 35, 2004

Bismercaptoethanediazacyclooctane
A R T I C L E S
Table 1. Crystallographic Data for the Fe(NO)/Fe(NO)2 Complexes
+
(H bme-daco)Fe(NO)2a
(bme-daco)Fe(NO)b
Fe4(S ′)(NO)8b
3
formula
C10H21N4O2S2Fe
349.28
orthorhombic
Pbca
C10H20FeN3OS2
318.26
monoclinic
P21/n
C8H16Fe4N8O8S6
768.05
triclinic
fw (g/mol)
crystal system
space group
unit cell
P1
a (Å)
b (Å)
c (Å)
16.448(10)
12.384(8)
28.996(17)
90
90
90
5906(6)
16
5.81, 12.19
15.46, 14.81
7.665(6)
23.861(18)
7.803(6)
90
112.869(14)
90
1315.0(18)
4
6.40, 14.76
9.01, 16.61
7.7217(8)
11.3593(11)
15.5075(15)
98.959(2)
97.956(2)
104.367(2)
1279.1(2)
2
R (deg)
â (deg)
γ (deg)
volume (Å3)
Z
R1,c wR2d (%) [I > 2σ(I)]
R1,c wR2d (%) all data
4.43, 11.79
4.84, 12.24
a Obtained using graphite-monochromatized Mo KR radiation (λ ) 0.71073 Å) at 293 K. b Obtained using graphite-monochromatized Mo KR radiation
(λ ) 0.71073 Å) at 110 K. c R1 ) ∑||Fo| - |Fc||/∑Fo. d wR2 ) [∑[w(Fo - Fc )2]/∑w(Fo )2]1/2
.
2
2
2
Table 2. Selected Distances and Angles of Complexes 1, (H+
bme-daco)Fe(NO)2, and 5, Fe4(S3′)2(NO)8 (See Figures 1 and 3)
1
5
Fe-N1 (Å)
Fe-N2
1.657(6)
1.681(6)
2.270(2)
2.285(3)
1.196(7)
1.175(7)
1.837(7)
1.824(7)
1.669(2)
1.681(3)
2.255(1)
2.249(1)
1.172(3)
1.164(3)
1.837(3)
1.830(3)
2.677(6)
6.861(1)
3.618(1)
Fe-S1
Fe-S2
N1-O1
N2-O2
S1-C1
S2-C10
Fe-Feavg
Fe----Fe
S----S
3.769(1)
4.113(1)
115.3(3)
107.6(2)
167.9(6)
111.8(1)
Fe----N(R2)avg
N1-Fe-N2 (deg)
N-Fe-Savg
Fe-N-Oavg
S1-Fe-S2
Fe-S-Fe
Fe-S-Cavg
119.1(1)
107.3(9)
171.5(2)
107.0(3)
72.9(3)
108.3(3)
108.0(1)
Figure 1. Two views of the molecular structure of complex 1, (H+bme-
daco)Fe(NO)2, with thermal ellipsoids drawn at the 50% probability level.
Selected distances and angles are given in Table 2.
is displaced by 0.476 Å out of the plane and toward the apical
NO. This is similar to the open chain analogues, (bme-pda)-
Fe(NO) and N,N′-dimethyl-N,N′-bis(2-mercaptoethyl)ethylene-
diamine iron nitrosyl or (bme-eda)Fe(NO), in which the Fe is
displaced by 0.55 and 0.415 Å, respectively, from the N2S2 basal
planes.37,41 Interestingly, the displacement of Fe from the N2S2
plane toward the apical S in the dimeric [(bme-daco)Fe]2
complex which is the precursor to the (bme-daco)Fe(NO) is
even greater, 0.59 Å.40 The iron to nitrogen distance of Fe-
NO is 1.707(6) Å in complex 2; this is 0.3 Å less than the Fe-N
distances to the N2S2 ligand.
Figure 2. Molecular structure of complex 2, (bme-daco)Fe(NO), with
thermal ellipsoids drawn at the 50% probability level. Selected distances,
Å: Fe-N1, 2.069(5); Fe-N2, 2.072(5); Fe-N3, 1.707(6); Fe-S1, 2.239-
(2); Fe-S2, 2.253(2); N3-O1, 1.165(6); S-Navg, 1.824(6). Selected angles,
deg: N1-Fe-N2, 87.0(2); N1-Fe-N2, 87.0(2); N1-Fe-S1, 87.8-
(2); N1-Fe-S2, 149.4(1); Fe-N-O, 151.7(5); S1-Fe-S2, 88.11(8).
SCH2CH2S-, and serves to link individual Fe2(NO)4 units,
Figure 3a. The alternate view of the molecular structure in Figure
3b emphasizes that all 4 iron, 8 nitrogen, and 8 oxygen atoms
are in the same plane. The planar 2Fe2S core of the (µ-SR)2-
[Fe(NO)2]2 units is diamond-shaped with S-Fe-S of 107.0°
and Fe-S-Fe of 72.9°; the Fe-Fe distance averages to 2.68
The tetranuclear complex 5 consists of a dimer of (µ-SR)2-
[Fe(NO)2]2 units in which the µ-SR is a dithiolate, -SCH2CH2-
(41) Karlin, K. D.; Rabinowitz, H. N.; Lewis, D. L.; Lippard, S. J. Inorg. Chem.
1977, 16, 3262-3267.
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A R T I C L E S
Chiang et al.
Scheme 4
Cl2), and the S3′Fe(NO)2-, complex 4, where ν(NO) ) 1739
and 1694 cm-1 in THF/MeOH. The shifts of ν(NO) to lower
wavenumbers in the aryl and alkanethiolates as compared to
the halides are consistent with the better donor character,
specifically the better π-donor ability, of the thiolate sulfurs as
compared to that of the halides.
Figure 3. (a) Molecular structure of complex 5, Fe4(S′3)2(NO)8, with
thermal ellipsoids drawn at the 50% probability level. Selected distances
and angles are given in Table 2. (b) Alternate view, perpendicular to the
Fe-Fe bond vector, using the ball-and-stick representation.
Å. The 2Fe2S plane of each (µ-SR)2[Fe(NO)2]2 unit bisects the
Fe(NO)2 planes, yielding pseudo-tetrahedral coordination ge-
ometry about each iron. The N-Fe-N of 119.1° is 4° greater
than that of the Fe(NO)2 unit of complex 1. The 2Fe2S planes
of individual (µ-SR)2[Fe(NO)2]2 units are parallel and eclipsed
with Fe....Fe spacings across the 16-membered ring of 6.86 Å.
Complex 5 is a dimeric form of Roussin’s red ester, (µ-SR)2-
[Fe2(NO)4], known to exist in solution as a mixture in C2h and
C2V isomer forms.42 While the known crystal structures of
dimeric Roussin’s red esters are of the C2h isomeric forms with
µ-RS groups in the anti-conformation,43 the linking of individual
units in complex 5 by µ-SCH2CH2SCH2CH2S-µ dithiolate
restricts the geometry to the syn orientation of all µ-S-C bonds.
Spectral Characterizations: ν(NO) Infrared Data. The
ν(NO) IR values for the new complexes are listed in the
schemes. Literature precedents for the oxidized monomeric {Fe-
(NO)2}9 units may be found in the anionic halide series
X2Fe(NO)2- which vary little with X- in CH2Cl2 solutions (X
) Cl, 1781, 1708 cm-1; Br, 1780, 1710 cm-1; I, 1778, 1719
cm-1).21 Reported ν(NO) IR data for thiolate derivatives are,
to our knowledge, very limited. We find the ν(NO) values for
the CH2Cl2 solution spectrum of the (PhS)2Fe(NO)2- derivative
as its PPN+ salt are at 1745 and 1697 cm-1 (1737 and 1693
cm-1 in THF). These values compare well to the two alkane-
thiolates of our study, (H+bme-daco)Fe(NO)2, complex 1, with
ν(NO) ) 1739 and 1695 cm-1 (THF); 1746, 1698 cm-1 (CH2-
Shown in Scheme 4 are the ν(NO) spectral changes which
occur on attaching nickel to the thiolate sulfurs which bind the
Fe(NO)2 units in monomeric (SRS)Fe(NO)2-. The dashed line
arrows in Scheme 4A represent Gedanken (thought) experiments
only as the known syntheses of the NiFe complexes are via the
alternate routes represented by the solid line arrows. That is,
we have not been able to displace the proton in complex 1 by
insertion of a Ni2+ into the N2S2 binding site. In fact, as noted,
the IR spectral data imply the Fe(NO)2 units are in different
oxidation levels in the nickel-free versus the nickel-bound forms
of (bme-daco)Fe(NO)2.28 The former is analogous to that of the
X- and PhS- derivatives which stabilize the oxidized form or
{Fe(NO)2}9, while the latter supports the reduced {Fe(NO)2}10
form. Thus, the formal displacement of a proton by Ni2+ would
have to be accompanied by a conformational change of the N2S2
ligand as well as addition of an electron which serves to reduce
the {Fe(NO)2}9 to {Fe(NO)2}10 . The latter conclusion is
supported both by the lower ν(NO) stretching frequencies as
well as by the similarity of the IR data to diphosphine derivatives
of {Fe(NO)2}.10
Equation B of Scheme 4 shows that the ν(NO) spectral
changes on binding the nickel-zero containing fragment Ni-
(NO)+ to the metal-free S3′Fe(NO)2 result in shifts to higher
-
energies, implying the electron density available from the
thiolate donors has been diminished by interaction with the Ni-
(NO)+ moiety. The values for the Ni0-metalated dithio-DNIC
-
are relatively close to those for the iodide complex, I2Fe(NO)2
,
(42) Butler, A. R.; Glidewell, C.; Johnson, I. L. Polyhedron 1987, 6, 1147-
1148.
vide supra, which also contains the oxidized version of {Fe-
(NO)2}.9
(43) Butler, A. R.; Glidewell, C.; Hyde, A. R.; Walton, J. C. Polyhedron 1985,
4, 797-809.
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Bismercaptoethanediazacyclooctane
A R T I C L E S
Scheme 5
Scheme 6
are extremely close in solution, necessitating extensive control
experiments for credible interpretation. In comparative studies,
THF solution samples of (a) pure complex 1, (b) complex 1
plus PPN+SPh-, and (c) pure PPN+[(PhS)2Fe(NO)2]- were
prepared at 0 °C, and their ν(NO) IR spectra and UV/vis spectra
were recorded. The pure sample of complex 1, over the extended
time-course of this experiment, showed only a slight decom-
position (ca. 5%) to the Roussin’s red derivative [(bme-daco)-
[Fe(NO)2]2]n. Immediately on addition of 2 equiv of PPN+SPh-
(in THF/CH3CN ) 10/1 mixture) to complex 1, the solution
color changed from the brown-green to the brown-red charac-
teristic of the PPN+[(PhS)2Fe(NO)2]- sample. The ν(NO) bands
shifted from those observed for the pure complex 1 to the more
negative values of PPN+[(PhS)2Fe(NO)2]-. After 3 h at 0 °C
and on warming to 25 °C and holding for 10 h, the color did
not change and the IR spectrum indicated [(PhS)2Fe(NO)2]-
was the major product. There was no ν(NO) band at ∼1650
cm-1, which would have indicated the presence of mono-nitrosyl
product. Under similar conditions, no reaction was observed
with PhSH in a 10-fold excess.
Thiolate and thiol ligand exchange processes of Roussin’s
red esters have previously been reported by Glidewell et al.43
Studies of diamagnetic, dimeric ((µ-SR′)2Fe2(NO)4 found solvent
dependencies and paramagnetic mononuclear solvated products
which implicated highly complex reaction pathways.43
Complex 1 was found to react with [(bme-daco)Fe]2 in
stoichiometric amounts as described in Scheme 6. A mixed-
solvent system, MeOH/[(bme-daco)Fe]2 and CH2Cl2-MeOH/
complex 1, was required for solubilization. On mixing such
solutions at 0 °C, no change was observed over 1 h. Upon
warming the solutions to 22 °C and stirring for 4 h, the color
changed to green and a single band in the IR spectrum, at 1649
cm-1 for the mono-nitrosyl, grew in. The final IR spectrum (after
the solution was left overnight at 22 °C) showed only complex
2. It should be noted that complex 1 is stable in solution over
the same time period, decomposing over a longer time to the
Roussin’s red ester described above.
Figure 4. (a) EPR spectrum of complex 1 in CH2Cl2 at 10 K; (b) of
complex 2 in CH2Cl2 at 77 K.
Magnetism and EPR Data. Complexes 1 and 2 are
paramagnetic and show a single isotropic signal in their EPR
spectra with g-values of 2.03 and 2.05, respectively, Figure 4.
The former value is typical of dinitrosyl iron complexes in which
the Fe(NO)2 unit is in the oxidized form, that is, {Fe(NO)2}9.23
The latter has precedent in the open chain, mononitrosyl
complex, that is, the N2S2Fe(NO) complexes reported by
Lippard et al., which implicates an electronic configuration of
{Fe(NO)}7.41 While the Roussin’s red ester dimer, complex 5,
as well as the presumed (µ-bme-daco)2[Fe2(NO)4]2 should be
diamagnetic, complicated EPR signals are observed. These are
assumed to arise from paramagnetic species formed from various
solvent interactions.
Chemical Reactivity. As background for establishing reaction
patterns which might relate to the biological significance of iron
dinitrosyl complexes, we have explored the reactivity of (H+-
bme-daco)Fe(NO)2, as a model for a protein-bound DNIC, with
a thiolate and a thiol, PhS- and PhSH, respectively. Two major
reaction paths were anticipated for PhS-. (1) PhS- might
displace the -SRS- dicysteine mimic, generating the known
and presumably more stable (PhS)2Fe(NO)2-. (2) Alternatively,
PhS- might remove NO from iron in a nucleophilic attack
process, generating PhSNO, with the remaining FeNO shifting
into the N2S2 binding site. With removal of both NO’s, the
[(bme-daco)Fe]2 might be reclaimed.
Summary and Comments
The chelating dithiolate based on the structurally reinforced
bme-daco has been demonstrated to serve as a bidentate ligand
to the tetrahedral iron of the Fe(NO)2 unit, forming overall a
12-membered ring system. In a different conformation, the
ligand captures Fe(NO) within its N2S2 core to yield a square
Scheme 5 presents the results of IR and UV/vis monitors of
the reaction of complex 1 with PPN+SPh-. Note that the ν(NO)
values of the reactant 1 and the expected product (PhS)2Fe(NO)2-
9
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A R T I C L E S
Chiang et al.
pyramid with apical NO. Excess NO readily leads to the
thermodynamically stable Roussin’s red esters, typically for-
mulated as (µ-SR)2Fe2(NO)4. While the [(bme-daco)Fe2(NO)4]n
complex could not be crystallized, its distinctive ν(NO) bands
are similar to those of the (µ-SCH2CH2SCH2CH2S)2[Fe2(NO)4]2,
complex 5.
Our work establishes that the major chemical components
of iron nitrosyl complexes involving N2S2 coordination sites
may be distinguished by ν(NO) IR spectroscopy. This result
was useful in preliminary studies of thiolate ligand exchange
and NO transfer from Fe. To our knowledge and as of this
writing, the controversy regarding iron dinitrosyls as possible
NO carriers in vivo, versus their being irrevocably protein
bound, has not been resolved. Our results indicate that the Fe-
(NO)2 is indeed transferable as a unit to a different thiolate
ligand as implicated in the biological studies of Vanin et al.44
As the role of NO in physiology continues to expand, such
spectroscopic and reaction model studies as those above are a
vital requirement for deciphering and predicting potential
reaction pathways.
Acknowledgment. We acknowledge the financial support of
the National Science Foundation (grants CHE 01-11629 to
M.Y.D. for this work, CHE 00-92010 for the EPR instrument,
and CHE 98-07975 for the purchase of X-ray equipment) and
contributions from the Robert A. Welch Foundation. We
appreciate the assistance of Dr. J. C. Yarbrough, M. V.
Rampersad, and Dr. D. Chong. Collaborations with Dr. W.-F.
Liaw, National Tsing Hua University, Taiwan, initiated this
project.
Supporting Information Available: Tables of crystal data and
experimental conditions for the X-ray studies, atomic coordi-
nates, and Beq values, complete listings of bond lengths and
bond angles, and anisotropic temperature factors for complexes
1, 2, and 5 (PDF, CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
(44) Mu¨lsch, A.; Mordvintcev, P.; Vanin, A. F.; Busse, R. FEBS Lett. 1991,
294, 252-256.
JA049627Y
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