Copper(I) nitrosyls from reaction of copper(II) thiolates with S-nitrosothiols: Mechanism of NO release from RSNOs at Cu

Article abstract of DOI:10.1021/ja406476y

S-nitrosothiols (RSNOs) serve as ready sources of biological nitric oxide activity, especially in conjunction with copper centers. We report a novel pathway for the generation of NO within the coordination sphere of copper model complexes from reaction of copper(II) thiolates with S-nitrosothiols. Reaction of tris(pyrazolyl)borate copper(II) thiolates ^iPr2TpCu-SR (R = C ₆F₅ or CPh₃) with ^tBuSNO leads to formation of ^iPr2TpCu(NO) and the unsymmetrical disulfide RS-S ^tBu. Quantum mechanical investigations with B3LYP-D3/6-311G(d) suggest formation of a κ¹-N-RSNO adduct ^iPr2TpCu(SR) (R′SNO) that precedes release of RSSR′ to deliver ^iPr2TpCu(NO). This process is reversible; reaction of ^iPr2TpCu(NO) (but not ^iPr2TpCu(NCMe)) with C ₆F₅S-SC₆F₅ forms ^iPr2TpCu-SC₆F₅. Coupled with the facile, reversible reaction between ^iPr2TpCu(NO) and C₆F ₅SNO to give ^iPr2TpCu-SC₆F₅ and 2 equiv NO, we outline a new, detailed catalytic cycle for NO generation from RSNOs at Cu.

Full text of DOI:10.1021/ja406476y

Communication
pubs.acs.org/JACS
Copper(I) Nitrosyls from Reaction of Copper(II) Thiolates with
S‑Nitrosothiols: Mechanism of NO Release from RSNOs at Cu
Shiyu Zhang,‡ Nihan C
̧
elebi-Olcu
̧
m,*,§,∥ Marie M. Melzer,‡,† K. N. Houk,§ and Timothy H. Warren‡,*
̈
̈
‡Department of Chemistry, Georgetown University, Box 571227-1227, Washington, DC 20057, United States
§Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569
∥Department of Chemical Engineering, Yeditepe University, Istanbul 34755, Turkey
S
* Supporting Information
Scheme 1. Copper-Mediated Reactions with S-Nitrosothiols
ABSTRACT: S-nitrosothiols (RSNOs) serve as ready
sources of biological nitric oxide activity, especially in
conjunction with copper centers. We report a novel
pathway for the generation of NO within the coordination
sphere of copper model complexes from reaction of
copper(II) thiolates with S-nitrosothiols. Reaction of
tris(pyrazolyl)borate copper(II) thiolates iPr2TpCu−SR
t
(R = C6F5 or CPh3) with BuSNO leads to formation of
iPr2TpCu(NO) and the unsymmetrical disulfide RS−StBu.
Quantum mechanical investigations with B3LYP-D3/6-
311G(d) suggest formation of a κ1-N−RSNO adduct
iPr2TpCu(SR)(R′SNO) that precedes release of RSSR′ to
deliver iPr2TpCu(NO). This process is reversible; reaction
of iPr2TpCu(NO) (but not iPr2TpCu(NCMe)) with
C6F5S−SC6F5 forms iPr2TpCu−SC6F5. Coupled with the
facile, reversible reaction between iPr2TpCu(NO) and
C6F5SNO to give iPr2TpCu−SC6F5 and 2 equiv NO, we
outline a new, detailed catalytic cycle for NO generation
from RSNOs at Cu.
[Me2NN]Cu−SCPh3 (Scheme 1).8 Release of NO from E−
NO at a Cu(I) center is the microscopic reverse of reductive
nitrosylation, which occurs at Cu(II) centers [CuII]−E with
concomitant formation of the organonitroso compound E−
NO.9 Related reductive nitrosylation reactions involving the
formation of O−NO bonds has been observed in laccase10 and
other enzymes.11 The formation of N−NO bonds with NO is a
common pathway in reaction of copper(II) amine complexes12
and has been used as the basis for NO detection.13
Copper(II) thiolates are ubiquitous in biology, especially in
“blue copper” type 1 Cu sites possessing strong absorbances
near λ = 600 nm (ε ≈ 3000−4000 M−1 cm−1)14 that mediate
electron transfer in a number of enzymes. Ceruloplasmin, the
most abundant source of copper in the plasma (∼1.5 − 3.1
μM),15 contains three type 1 Cu sites, two with Met donors
and one without. Coupled with the relatively high concen-
tration of low molecular weight S-nitrosothiols (0.2 − 0.3 μM)
in the plasma,2 the possibility of interaction between copper(II)
thiolates related to type 1 Cu with RSNOs is of interest,
especially since ceruloplasmin has been shown to generate
RSNOs from NO and thiols such as glutathione.16
In this study, we employ copper(II) thiolates supported by
tris(pyrazolyl)borates, which have been used as structural17 and
spectroscopic17,18 models for type 1 Cu sites. These biological
copper centers feature two histidine N-donors, an anionic
cysteine S-donor in addition to a weak donor such as
methionine that results in only a slightly distorted trigonal
environment at copper. X-ray structures of TpCu−SR species
generally reveal two shorter Cu−N (1: 1.930(9), 2.037(9);17a
2: 1.97(5), 2.03(4))17b and one modestly longer Cu−N (1:
2.119(8); 2: 2.05(4)) distances with a relatively short Cu−S
distance (1: 2.176(4); 2: 2.12(2)).
S-nitrosothiols, RSNOs, serve both as ready reservoirs of NO
activity and active agents in the post-translational modification
of proteins through S-transnitrosation of cysteine SH residues.1
Low-molecular weight RSNOs such as S-nitrosoglutathione
(GSNO) are present at submicromolar concentrations in the
plasma2 and exhibit a number of beneficial physiological effects1
such as protection against myocardium3 and lung/airway3
injuries. Due to the modest RS-NO bond strength (20−32
kcal/mol),4 RSNOs serve as air-stable reservoirs of NO.
Offering the prospect of controlled, triggered NO release in
biological environments, copper ions are effective in catalyzing
RSNO decomposition to NOgas and disulfides RSSR (Scheme
1).5 CuZnSOD which represents the most abundant source of
copper in red blood cells releases NO from GSNO.6 NO
release may be inhibited with neocuproine, a Cu+-specific
chelator.6 Taking advantage of endogenous RSNOs in the
plasma, Cu2+ ions embedded into medical polymers can serve
as long-lived NO generating devices.7 Thus, copper complexes
starting in both the Cu(I) and Cu(II) oxidation states can be
effective for release of NO from RSNOs.
We recently reported the formation of NO in the reaction of
an electron-rich β-diketiminato copper(I) complex
[Me2NN]Cu with Ph3CSNO to give the copper(II) thiolate
Received: June 28, 2013
Published: October 10, 2013
© 2013 American Chemical Society
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To examine the reaction between copper(II) thiolates and
RSNOs, we employed the previously reported iPr2TpCu−SR (R
= C6F5 (1) and CPh3 (2)) which possess reasonable thermal
stability. Reaction of 1 with C6F5SNO (prepared in situ from
[NO]BF4 and TlSC6F5) in CH2Cl2 (at 0 °C over 12 min) led
to partial consumption of 1 (12%) as judged by the loss of the
strong band of 1 at λmax = 666 nm (ε ≈ 5900 M−1 cm−1) with
formation of a new band at λmax = 495 nm. GC/MS and 19F
NMR analysis indicates formation of the disulfide C6F5S−
SC6F5 in 18% yield (Scheme 2). Addition of the much larger S-
kinetic study via initial rates identifies that the reaction is clearly
t
first order in BuSNO when the initial iPr2TpCu−SCPh3
concentration is held constant (Scheme S4).
The absence of the symmetric disulfides C6F5S−SC6F5 and
Ph3CS−SCPh3 (<5%) in these reactions suggested that S-
transnitrosation does not compete with Cu−NO and RS−SR
bond formation. This is in contrast to the closely related zinc
thiolates iPr2TpZn-SR′ which react with RSNO to cleanly
undergo S-transnitrosation to give equilibrium mixtures of
iPr2TpZn-SR and R′SNO (Scheme 4).20 The later reaction
Scheme 2. Reactivity of iPr2TpCu−SR with RSNO
Scheme 4. Reactivity of Thiolates with S-nitrosothiols
nitrosothiol Ph3CSNO to the bulky copper(II) thiolate iPr2Tp-
Cu−SCPh3 (λmax = 625 nm; ε ≈ 6600 M−1 cm−1) gave no
reaction under similar conditions.
appears to be a zinc-mediated transnitrosation of thiolate
anions R′S− with S-nitrosothiols RSNO which have been
shown by experiment21a and theory21b to proceed via nitroxyl
disulfide intermediates [R′S(NO)SR]− (Scheme 4).
The new optical band at λmax = 495 nm in the reaction of 1
with C6F5SNO is the copper(I) nitrosyl iPr2TpCu(NO) (3)
which may be generated independently by reaction of iPr2TpCu
We used dispersion-corrected density functional theory
(DFT-D3)22 and Gaussian 0923 to investigate the reactivity of
Cu(II) thiolates with S-nitrosothiols. For computational
efficiency, we considered iPrTpCu−SC6F5, a steric model of 1
that involves only the isopropyl substituent on each pyrazolyl
ring that flanks the coordination pocket. Optimization results in
two short and one long Cu−N distance (1.99 Å and 2.24 Å,
respectively) and a Cu−S distance of 2.22 Å at the B3LYP/6-
311G(d) level, in good agreement with the X-ray structure of 1.
Dispersion corrected energies suggest a slightly endothermic
reaction between iPrTpCu−SC6F5 and C6F5SNO (ΔHr = 1.2
kcal/mol) in accordance with the experimentally observed
reversibility of the reaction (Scheme 2). The reaction of
with excess NO (λmax = 495 nm (ε ≈ 960 M−1 cm−1)); νNO
=
1704 cm−1) at −40 °C. While it is clear that iPr2TpCu(NO) (3)
forms in the reaction of iPr2TpCu−SC6F5 and C6F5SNO, 3 is
difficult to quantify because of its relative instability. Related
tris(pyrazolyl)borate copper(I) nitrosyls TpCu(NO) feature
labile binding of NO which may also disproportionate over
time to TpCu(NO2) and N2O.19 Nonetheless, addition of the
disulfide C6F5S−SC6F5 to iPr2TpCu(NO) (3) (in situ generated
at −40 °C in CH2Cl2) at 0 °C results in the formation of
iPr2TpCu−SC6F5 (1) (68% yield; UV−vis) and C6F5SNO,
indicating an equilibrium (Scheme 2). Monitoring over the
temperature range −70 °C to −40 °C gives the thermodynamic
parameters ΔHr = −2.3(2) kcal/mol and ΔSr = −14.5(8) for
this reversible transformation (Figure S5).
t
iPrTpCu−SC6F5 with BuSNO is predicted to be slightly
exothermic (ΔHr = −2.1 kcal/mol). These are close to values
measured by experiment (−2.3(2) kcal/mol and −1.7(1) kcal/
mol, respectively).
To better understand the fate of the S-residues in the
reaction of iPr2TpCu−SR with S-nitrosothiols, we added the
We first considered the possibility of a nitroxyl disulfide
anion [RS(NO)SR′]− bound to a copper(II) center in
iPr2TpCu(κ2-SR(NO)SR′) along the reaction pathway. This
was especially attractive, since theoretical studies on nitroxyl
disulfides have suggested that these are rather unstable toward
oxidation to NO and the corresponding disulfide (Scheme 4).
For instance, the aqueous oxidation potential of [MeS(NO)-
SMe]− anion was estimated as +0.31 vs NHE21b and the
oxidation potential of iPr2TpCu(NCMe) is +0.64 V in MeCN.24
Quantum mechanical investigations on a small model system
employing MeSNO with TpCu−SMe possessing the unsub-
stituted tris(pyrazolyl)borate ligand were performed at the
B3LYP-D3/6-311+G(d) level of theory (Scheme 5). Formation
of the symmetric nitroxyl disulfide intermediate TpCu(κ2-
MeS(NO)SMe) (4) is predicted to be exothermic with respect
to the starting materials (ΔHr = −14.2 kcal/mol and ΔGr = 0.7
kcal/mol). The optimized structure of 4 shown in Scheme 5,
however, suggests a sterically unfavorable orientation of the
alkyl groups of the nitroxyl disulfide toward the Tp ligand,
which is partly compensated by favorable dispersion
interactions. Indeed, inclusion of the steric bulk around the
reaction center using the steric model iPrTpCu revealed that
t
distinct S-nitrosothiol BuSNO to 1 and 2 at 25 °C in CH2Cl2
(Scheme 3). In each case, the predominant S-containing
Scheme 3. Reactivity of iPr2TpCu−SR with tBuSNO at 25 °C
product is the unsymmetrical disulfide RS−StBu. Following the
reaction of 1 equiv tBuSNO to iPr2TpCu−SC6F5 (1) by UV−vis
spectroscopy results in the decay of 1 and formation of
iPr2TpCu(NO) (3). 19F NMR analysis following reaction in
benzene-d6 reveals that the unsymmetrical disulfide C6F5S−
StBu is the sole fluorine-containing product; the disulfide
tBuS−StBu accounts for the remainder of the tBuSNO
employed. The reaction between iPr2TpCu−SCPh3 (2) and
tBuSNO proceeds similarly with loss of 2, formation of 3, and
identification of Ph3CS−StBu as the major new S-containing
t
product with BuS−StBu as the remainder. A preliminary
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conversion of 7 to the corresponding TpCu(NO) and RSSR′
species proceeds smoothly via the transition state TS7 with an
activation enthalphy of 5.9 kcal/mol (ΔG⧧ (298 K) = 19.4
kcal/mol) with respect to the starting materials (Scheme 7).
Scheme 5. Energetics of Reactions of Model TpCu−SMe
a
with MeSNO Calculated with B3LYP-D3/6-311+G(d)
Scheme 7. Conversion of iPrTpCu(SR)(N(O)SR′) to
iPrTpCu(NO) and RSSR′ Calculated with B3LYP-D3/6-
a
311G(d)
a
Non-dispersion corrected B3LYP enthalpies are given in parentheses.
formation of the corresponding nitroxyl disulfide 6 from
t
iPrTpCu−SC6F5 and BuSNO is sterically more challenging
(ΔHr = −1.1 kcal/mol and ΔGr (298 K) = 12.5 kcal/mol;
Scheme 6).
Scheme 6. Energetics of Reactions of Steric Model iPrTpCu−
t
SC6F5 with BuSNO Calculated with B3LYP-D3/6-
a
311G(d)
a
Non-dispersion corrected B3LYP enthalpies are given in parentheses.
The concerted cleavage of the RS−NO and Cu−SR bonds with
the simultaneous formation of the RS−SR bond in the κ1-N−
RSNO adduct iPrTpCu(SR)(R′SNO) as depicted in TS7
accounts for the experimental formation of only unsymmetrical
disulfides.
The dispersion energy correction terms calculated with DFT-
D3 contributes 8−16 kcal/mol to the formation enthalpies of
4-7. This clearly suggests the importance of dispersion
interactions in stabilizing these intermediates and demonstrates
the necessity of the accurate treatment of dispersion effects in
these calculations.
The reaction of [CuII]−SR with RSNO to form [CuI](NO)
and RS−SR closes a catalytic cycle for release of NO from S-
nitrosothiols provided that copper(II) thiolates [CuII]−SR are
formed upon reaction of copper(I) complexes [CuI] and
RSNOs (Schemes 1 and 8). Reaction of iPr2TpCu(NO) (3)
a
Non-dispersion corrected B3LYP enthalpies are given in parentheses.
Scheme 8. Copper-Catalyzed Release of NO from RSNOs
We also considered direct attack of an RSNO at the metal
center that leads to a Cu−N interaction in TpCu(SMe)(κ1-
N(O)SMe) (Scheme 5). While this κ1-N binding mode for
MeSNO at a naked Cu+ ion previously has been theoretically
considered,25 isolable complexes bearing S-nitrosothiols coor-
dinated to transition metal ions are exceedingly rare and are
limited to a few kinetically inert, low-spin Ir(III) species.26
Although κ1-N coordination of MeSNO to TpCu−SMe to give
5 (ΔHr = −4.9 kcal/mol, ΔGr = 7.4 kcal/mol) is predicted to
be less favorable than 4, we find that κ1-N coordination of the
with 1 equiv C6F5SNO at −40 °C in CH2Cl2 leads to
incomplete consumption of 3 with formation of iPr2TpCu−
SC6F5 (1). Using the steric model iPrTpCu, calculations predict
this reaction to be mildly favorable with ΔHr = +1.9 kcal/mol
and ΔGr (298 K) = −6.7 kcal/mol. This reaction is reversible;
addition of excess NO to iPr2TpCu−SC6F5 at −40 °C forms
iPr2TpCu(NO) (3) (Scheme 8). Thus, addition of excess
C6F5SNO to 1 or 3 at −40 °C results in the facile Cu-catalyzed
t
much bulkier BuSNO to iPrTpCu−SC6F5 in 7 is substantially
more stable (ΔHr = −8.8 kcal/mol, ΔGr(298 K) = 5.3 kcal/
mol) than its nitroxyl disulfide counterpart 6. Unfavorable
steric interactions at the Cu center in 6 between bulky thiolate
tert-butyl and TpCu isopropyl substituents are significantly
t
relieved by the κ1-N binding mode of BuSNO in 7. The
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental, characterization, and calculational details. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
nihan.olcum@yeditepe.edu.tr
thw@georgetown.edu
Present Address
†Old Dominion University, Department of Chemistry and
Biochemistry, 4541 Hampton Boulevard, Norfolk, VA 23529-
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
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T.H.W. thanks NSF (CHE-0957606). N.C
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