A copper(II) thiolate from reductive cleavage of an S-nitrosothiol

Article abstract of DOI:10.1021/ic301356h

S-Nitrosothiols RSNO represent circulating reservoirs of nitric oxide activity in the plasma and play intricate roles in protein function control in health and disease. While nitric oxide has been shown to reductively nitrosylate copper(II) centers to form copper(I) complexes and ENO species (E = R ₂N, RO), well-characterized examples of the reverse reaction are rare. Employing the copper(I) β-diketiminate [Me₂NN]Cu, we illustrate a clear example in which an RS-NO bond is cleaved to release NO _gas with formation of a discrete copper(II) thiolate. The addition of Ph₃CSNO to [Me₂NN]Cu generates the three-coordinate copper(II) thiolate [Me₂NN]CuSCPh₃, which is unstable toward free NO.

Full text of DOI:10.1021/ic301356h

Communication
pubs.acs.org/IC
A Copper(II) Thiolate from Reductive Cleavage of an S‑Nitrosothiol
Marie M. Melzer,† Susanne Mossin,§ Allan Jay P. Cardenas,† Kamille D. Williams,† Shiyu Zhang,†
Karsten Meyer,§ and Timothy H. Warren*,†
†Department of Chemistry, Georgetown University, Box 571227-1227, Washington, D.C. 20057, United States
§Department of Chemistry and Pharmacy, Friedrich-Alexander-University, Erlangen-Nuremberg, Egerlandstrasse 1, 91058 Erlangen,
Germany
S
* Supporting Information
Scheme 2. Redox Interconversion of RSNO and NO
ABSTRACT: S-Nitrosothiols RSNO represent circulating
reservoirs of nitric oxide activity in the plasma and play
intricate roles in protein function control in health and
disease. While nitric oxide has been shown to reductively
nitrosylate copper(II) centers to form copper(I) com-
plexes and ENO species (E = R2N, RO), well-
characterized examples of the reverse reaction are rare.
Employing the copper(I) β-diketiminate [Me2NN]Cu, we
illustrate a clear example in which an RS−NO bond is
cleaved to release NOgas with formation of a discrete
copper(II) thiolate. The addition of Ph3CSNO to
[Me2NN]Cu generates the three-coordinate copper(II)
Ceruloplasmin, the enzyme carrying ca. 95% of all copper in the
plasma,11 generates GSNO from NO.12 In other environments,
NO reduces copper(2+) in cytochrome c oxidase13 and
laccase14 with concomitant N−O bond formation to give
nitrite upon the formal attack of water on NO+. In a related
thiolate [Me2NN]CuSCPh3, which is unstable toward free
fashion, Cu(dmp)2(H2O)2+ reacts with NO in MeOH to give
NO.
Cu(dmp)2 and MeONO.15 Intramolecular nitrosylation of a
+
coordinated amine ligand bound to copper(2+) upon exposure
16
of NOgas
represents a chemical trigger in turn-on
S-Nitrosothiols RSNO play an intricate role in the control of
protein function in health and disease through the post-
translational modification of cysteine SH residues.1 Low-
molecular-weight S-nitrosothiols such as S-nitrosoglutathione
(GSNO) represent circulating reservoirs of nitric oxide activity
typically present at submicromolar concentrations in the
plasma,2 which have protective effects against myocardial3
and lung/airway3 injuries among other functions.1 RSNO
compounds are prone to homolytic loss of NO due to the
relative weakness of the RS−NO bond (20−32 kcal/mol)4 and
the strength of the RS−SR bond (65−66 kcal/mol).5
fluorescence-based approaches to sense NO.17
We recently reported the microscopic reverse of this process
in the reductive cleavage of the N−NO bond in the
nitrosamine Ph2NNO by an electron-rich β-diketiminato
copper(I) complex to give the copper(II) amide [Me2NN]-
CuNPh2.18 We describe herein cleavage of the RS−NO bond of
a synthetic S-nitrosothiol by copper(I) to form a discrete
copper(II) thiolate connected to the copper-promoted
generation of NO from this important class of NO donors.
The addition of 2 equiv of Ph3CSNO to {[Me2NN]Cu}2 (1)
in toluene (ca. 0.1 M) at 0 °C results in the rapid (ca. 10 s)
formation of a new blue species, [Me2NN]CuSCPh (2), with
λmax = 731 nm that is unstable under the reaction conditions.
Over the course of ca. 30 min, the solution turns green because
of the final major product [Me2NN]Cu(ON[Me2NN]) (3)
with λmax = 647 nm.
Trace amounts of copper ions serve as efficient catalysts for
RSNO decomposition to form NOgas and RSSR (Scheme 1).6
Scheme 1. Copper-Catalyzed Release of NO from RSNO
Compounds
Crystallization of the reaction mixture involving 1 and
Ph3CSNO allows for identification of the final green species 3.
The highly soluble 3 [λmax = 647 nm (1700 M−1cm−1)] is
isolated in 70% yield as green crystals from ether/
hexamethyldisiloxane (Scheme 3). X-ray characterization of 3
(Figure 1) reveals a distorted square-planar copper(II) species
with one “normal” and one nitrosated anionic β-diketiminate
ligand in which the backbone methine hydrogen atom has
undergone formal substitution by NO.18,19 The π-delocalized
nitrosated ligand coordinates through two different types of
CuZnSOD is the most abundant source of copper in red blood
cells and is effective at releasing NO from GSNO.7 It may be
inhibited with neocuproine, a copper(+) chelator, suggesting
copper(I) as an active oxidation state for NO loss.7 Moreover,
medical polymers with imbedded copper(2+) ions serve as
long-lived NO-generating devices via the copper-catalyzed
decomposition of endogenous S-nitrosothiols.8
Copper enzymes also generate RS−NO bonds from NO via
reductive nitrosylation (Scheme 2).9 CuZnSOD has been
shown to specifically S-nitrosylate β-Cys93 of hemoglobin.10
Received: June 25, 2012
Published: August 7, 2012
© 2012 American Chemical Society
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Inorganic Chemistry
Communication
paramagnetic resonance (EPR) spectrum [2, g1 = 2.165(3), g2 =
2.039(8), g3 = 2.031(8); 4, g1 = 2.233(5), g2 = 2.06(1), g3 =
2.04(1); Figures S15 and S17 in the Supporting Information,
SI]. The pseudoaxial hyperfine contribution from copper in
alkoxide 4 [A1(Cu) = 372(5) MHz], however, is greater than
that in thiolate 2 [A1(Cu) = 332(5) MHz], suggesting greater
delocalization of the unpaired electron away from copper in the
case of thiolate 2. Density functional theory calculations
corroborate this picture, indicating that thiolate 2 possesses
greater spin density on the sulfur atom (Cu, 0.31 e−; S, 0.39 e−)
than on the oxygen atom in alkoxide 4 (Cu, 0.40 e−; O, 0.28
e−). These trends may be rationalized by the higher orbital
energies of sulfur versus oxygen that result in greater covalency
in the Cu−SR interaction (Figures 2 and S12 and S13 in the
Scheme 3. Reactivity of Ph3CSNO with 1
nitrogen atoms, including the nitrogen derived from NO [Cu−
N3 = 2.037(3) Å; Cu−N5 = 1.962(3) Å], while the “normal” β-
diketiminate coordination is unremarkable [Cu−N1 = 1.940(3)
Å; Cu−N2 = 1.928(3) Å]. The square-planar structure is
maintained in a toluene solution as judged by the large
isotropic copper hyperfine Aiso = 223(5) MHz, which largely
results from the high value of the axial parameter in the
pseudoaxial frozen glass spectrum of 3 [g1 = 2.192(3); A1(Cu)
= 567(5) MHz].
Because we anticipated the formation of 2 in the reaction of
1 with Ph3CSNO, we sought a convenient route for its
independent synthesis. The addition of 1 equiv of tBuOOtBu to
1 in toluene allows for the isolation of [Me2NN]CuOtBu (4)
on a preparative scale in 86% yield (Scheme 3) as red crystals
from pentane [λmax = 409 nm (1500 M−1cm−1) in toluene].
The X-ray crystal structure of 4 (Figure 1) reveals a planar,
three-coordinate copper center due to the steric bulk of the tert-
butoxy ligand. Related to Tolman’s β-diketiminato copper(II)
phenoxides20 and our [Cl2NN]CuOtBu,21 4 possesses partic-
ularly short Cu−O [1.788(2) Å] and Cu−Nβ‑dik [1.879(2) and
1.890(2) Å] distances with a Cu−O−C22 angle of
123.82(12)°. The reaction of 4 with HSCPh3 in toluene
provides a smooth, quantitative conversion to 2 [λmax = 731 nm
(5800 M−1cm−1)]. Crystals of thermally sensitive 2 may be
obtained from ether at −35 °C. The X-ray structure of 2
(Figure 1) features a trigonally coordinated copper center with
Cu−S [2.137(1) Å] and Cu−Nβ‑dik distances [1.896(2) and
1.907(2) Å] along with a Cu−S−C angle of 116.80(7)° closely
related to metrical parameters in Tolman’s [CuII]SCPh3
complex employing an o-isopropyl-N-aryl variant of the β-
diketiminate ligand.22a
Figure 2. Orbital interactions in trigonal copper(II) thiolates and
alkoxides.
SI).23,24 Quasi-reversible cyclic voltammetry of 2 and 4 in
tetrahydrofuran reveals that thiolate 2 is considerably easier to
reduce (E1/2 = −0.18 V vs NHE) than alkoxide 4 (E1/2 = −0.52
V; Figures S10 and S11 in the SI).
The rapid conversion of 2 to other species under its synthesis
conditions from Ph3CSNO that leads to NOgas formation
suggests that 2 is unstable toward NO (Scheme 3). We find
that when the addition of 2 equiv of Ph3CSNO to 1 at 0 °C in
toluene is followed by the immediate flushing of the solution
with N2 to remove all NOgas formed in the reaction, 2 may be
observed in 73% spectroscopic yield (Scheme 4). Importantly,
the addition of 2 equiv of NO to pure 2 leads to 3 (79% yield)
and Ph3CSSCPh3 (83% yield) (Scheme 4). We have not
detected any intermediates by UV−vis spectroscopy at −80 °C
in toluene during the addition of Ph3CSNO to 1.
Conceptually related, the tertiary thiolate 2 and alkoxide 4
possess subtle but important differences in their electronic
structure. Each exhibits a nearly axial frozen-glass electron
In conclusion, an electron-rich copper(I) complex reacts with
RSNO species to give a well-defined [CuII]SR complex with the
Figure 1. X-ray structures of 3, 2, and 4.
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Inorganic Chemistry
Communication
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ASSOCIATED CONTENT
* Supporting Information
Experimental, characterization, and calculational details and X-
ray crystallographic data in CIF format. This material is
available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: thw@georgetown.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
T.H.W. thanks the NSF (Grant CHE-0957606) and K.M.
acknowledges the DFG (Grant SFB-583) for funding. George-
town University thanks the NSF (Grant CHE-0840453) for an
EPR spectrometer.
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