Reversible RS-NO bond cleavage and formation at copper(i) thiolates

Article abstract of DOI:10.1039/b911643e

Two coordinate copper(i) thiolates IPrCu-SR undergo rapid, reversible transnitrosation with S-nitrosothiols RSNOs without catalyzing the loss of NO_gas from these biological carriers of NO.

Full text of DOI:10.1039/b911643e

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Reversible RS–NO bond cleavage and formation at copper(I) thiolatesw
Marie M. Melzer, Ercheng Li and Timothy H. Warren*
Received (in Berkeley, CA, USA) 16th June 2009, Accepted 21st August 2009
First published as an Advance Article on the web 8th September 2009
DOI: 10.1039/b911643e
Two coordinate copper(I) thiolates IPrCu-SR undergo rapid,
reversible transnitrosation with S-nitrosothiols RSNOs without
catalyzing the loss of NOgas from these biological carriers
of NO.
copper(I). Copper catalysis also forms the basis of long-lived
NO generation from medical devices containing polymer-
bound Cu2+ ions which release NO upon contact with
endogenous RSNOs in the plasma.23,24
To synthetically explore interactions between copper ions
and RSNOs, we chose low-coordinate copper(I)-thiolates
IPrCu-SR based on N-heterocyclic carbenes first reported by
Gunnoe et al.25 The unusually low coordination number
of these metal-thiolates would appear to provide a clear
opportunity for association of an RSNO with the copper
center. In addition, copper(I)-thiolates would be expected to
be considerably more thermally stable than the corresponding
copper(II)-thiolates [CuII]-SR owing to their generally facile
loss of disulfide RSSR with concomitant reduction to [CuI]
species.
S-Nitrosothiols RS–NO, first synthesized in 1909,1 were not
recognized until the 1990s as a biological source of nitric
oxide.2–4 They exhibit biological activities similar to NO itself
including vasodilation and anti-platelet activity.3,5 In contrast
to NO which has a short lifetime (3–5 s) in the plasma owing to
ready reaction with O2 and O2-carrying enzymes, cysteine- and
peptide-based RSNOs circulate at near micromolar6,7 levels
(e.g. CysNO8,9 E 0.2–0.3 mM). Consistent with their modest
RS–NO homolytic dissociation enthalpies of 20–32 kcal molꢀ1
determined by both theory and experiment,10,11 these
compounds are thermally and photochemically sensitive,
releasing NOgas and the disulfide RSSR (Scheme 1a).12,13
S-Nitrosothiols may also serve as formal sources of NO+ as
in transnitrosation reactions between RSNOs and thiolate
anions R0Sꢀ which proceed through nitroxyl disulfide inter-
mediates [RSNOSR0]ꢀ (Scheme 1b).14,15
Reaction of IPrCu-Cl26 with TlSR in THF provides the
t
two-coordinate IPrCu-SR (R = Bn25 (1), Bu (2), CH2ArtBu
(3)) complexes in good yields (70–78%) (Scheme 2). The X-ray
structure of IPrCu-SCH2ArtBu (3)z features a nearly linear
C–Cu–S linkage (172.90(6)1) with a Cu–S distance of 2.130(1) A,
nearly identical to parameters reported in the X-ray
determination of 1.25
Copper ions can be extremely efficient catalysts for the
decomposition of S-nitrosothiols RSNOs to NOgas and the
corresponding disulfides RSSR (Scheme 1a).12,16 In aqueous
solution, Williams et al. have found that adventitious copper
ions present in buffer solutions accelerate the rate of RSNO
decomposition while the use of a Cu2+ chelator such as EDTA
significantly halts this catalysis.16,17 Copper containing
enzymes also catalyze loss of NO from RSNOs and play a
role in vasodilation,18 anti-platelet aggregation19 and regulation
of intracellular RSNO levels.20 For instance, CuZn-superoxide
dismutase has been shown to catalyze the decomposition of
RSNOs to NO.21,22 This process is interrupted with neocuproine
The addition of 1 equiv. BnSNO to IPrCu-SBn (1) or
tBuSNO to IPrCu-StBu (2) (each at ca. 55 mM) at room
temperature in CDCl3 results in no net change when
monitored by 1H NMR spectroscopy. Importantly, degradation
of the S-nitrosothiols to the corresponding disulfides does not
rapidly ensue. Addition of 1 equiv. BnSNO to IPrCu-StBu (2),
however, results in the immediate appearance of tBuSNO and
IPrCu-SBn (1) with incomplete consumption of 2 and BnSNO.
Thus a transnitrosation equilibrium is set up favoring 2 and
BnSNO (Keq = 0.25(5)) (Scheme 3).
Analogous transnitrosation reactions are significantly faster
in benzene-d6. In the degenerate exchange between 1 equiv.
(2,9-dimethyl-1,10-phenanthroline),
a potent chelator for
Scheme 1
Department of Chemistry, Georgetown University, Box 571227,
Washington, DC 20057-1227, USA. E-mail: thw@georgetown.edu;
Fax: +1 202 687 6362; Tel: +1 202 687 6362
w Electronic supplementary information (ESI) available: Synthetic
and experimental procedures with spectroscopic characterization
details; complete crystallographic details for 3, 4, and 5. CCDC
736333–736335. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/b911643e
Scheme 2
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the corresponding RSNO species in methanol.15 S-nitrosothiols
exhibit syn–anti isomerization with a low barrier of S–N bond
rotation of ca. 10 kcal molꢀ1 11,27
.
No reaction between these copper(I) thiolates occurs in the
presence of 1–10 equiv. anaerobic NOgas in CDCl3. Addition
of nitrosonium (NO+) as NOBF4, however, to colorless
solutions of IPrCu-SBn (1) and IPrCu-StBu (2) in CDCl3
results in immediate formation of red and green solutions.
These are the respective colors of the S-nitrosothiols BnSNO
and tBuSNO. 1H NMR spectroscopy verifies the formation of
each S-nitrosothiol along with one new copper-containing
species in each case (Scheme 4).
Scheme 3
The new copper complexes are the dinuclear thiolates
t
[{IPrCu}2(m-SR)]BF4 (R = Bn (4) or Bu (5)) which may be
crystallized from each reaction mixture. Despite the bridging
interaction, the Cu–S distances in 4z (2.146(2) and 2.157(2) A)
and 5z (2.185(5) and 2.164(4) A) are not markedly different
than found in the thiolates 1 (2.127(1) A) and 3 (2.130(1) A).
The copper centers are separated by 3.575(1) and 3.732(1) A
with Cu–S–Cu angles of 112.34(7)1 and 118.19(18)1. 1H NMR
spectra reveal upfield shifted thiolate resonances at d 2.93 ppm
(SCH2Ph) and d 0.58 ppm (StBu), likely due to the ring current
of the NHC ligands.
Fig. 1 1H NMR spectra (300 MHz, benzene-d6, RT) illustrating fast,
reversible transnitrosation between IPrCu-SCH2Ph and PhCH2SNO
with increasing PhCH2SNO : IPrCu-SCH2Ph ratio (bottom to top).
each BnSNO and IPrCu-SBn (1) (40 mM in each component),
only one broad resonance is observed for the combined
SCH2Ph resonances of the benzyl groups. Increasing the
BnSNO : IPrCu-SBn (1) ratio results in a monotonic shift of
the coalesced peak from d 3.82 ppm (for 1) to d 4.08 ppm (for
PhCH2SNO) supporting fast exchange between these two
species on the NMR timescale (Fig. 1). The rate of exchange
is qualitatively related to the size of the S-substituent.
Broadened, though still distinct, StBu resonances are observed
Based on these findings, reaction of NO+ with 1 and 2 may
generate an equivalent of S-nitrosothiol RSNO within
the coordination sphere of copper (not spectroscopically
observed) which could be formally displaced by another
equivalent of IPrCu-SR to form dinuclear 4 and 5. Consistent
28
with this suggestion, reaction of {IPrCu(NCMe)}BF4 with
t
IPrCu-SR results in displacement of NCMe and isolation of
4 and 5 in 86 and 89% yield (Scheme 4).
at d 1.52 and 1.49 ppm in a 1 : 1 mixture of BuSNO and
IPrCu-StBu (2) at RT (55 mM in each component). This
indicates that transnitrosation is much slower owing to the
considerably larger S-substituents.
Despite the important biological role of copper ions in
the interconversion of NOgas and RSNOs,18–22,29,30 these
two-coordinate Cu(I) thiolates IPrCu-SR allow clean trans-
nitrosation equilibria to be observed with RSNOs without
catalyzing the loss of NOgas. Moreover, we find that rate of
transnitrosation is enhanced in non-polar solvents. The use of
nitrosonium cation leads to the loss of RSNO from IPrCu-SR
and generation of novel two-coordinate dicopper cations
[{IPrCu}2(m-SR)]+. Current studies target the interactions of
RSNOs with other copper model complexes to illuminate the
role of the copper coordination environment and oxidation
state in the release of NOgas from RSNOs.
In an attempt to identify an intermediate in degenerate
transnitrosation such as a nitroxyl disulfide [RSNOSR]ꢀ, we
carried out low temperature 15N NMR studies in toluene-d8
and chloroform-d1 on both 1 and 3 in the presence of the
respective 15N-labeled S-nitrosothiols PhCH2S15NO and
tBuArCH2S15NO. We see no evidence for new 15N-containing
species other than syn and anti isomers of the respective
S-nitrosothiols. In contrast, Estrin et al. observed a new
upfield shifted 15N-signal corresponding to a nitroxyl disulfide
intermediate in a mixture of the cysteine ethyl ester anion with
Scheme 4
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We thank Georgetown University, the NSF (CHE-0726304)
and ACS-PRF (43048-AC3) for financial support of this work.
MMM is grateful to the Clare Booth Luce foundation for a
predoctoral fellowship.
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=
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