Lewis Acid Coordination Redirects S-Nitrosothiol Signaling Output

Article abstract of DOI:10.1002/anie.202001450

S-Nitrosothiols (RSNOs) serve as air-stable reservoirs for nitric oxide in biology. While copper enzymes promote NO release from RSNOs by serving as Lewis acids for intramolecular electron-transfer, redox-innocent Lewis acids separate these two functions

Full text of DOI:10.1002/anie.202001450

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Accepted Article
Title: Lewis Acid Coordination Redirects S-Nitrosothiol Signaling
Output
Authors: Valiallah Hosseininasab, Alison C. McQuilken, Abolghasem
(Gus) Bakhoda, Jeffery A. Bertke, Qadir K. Timerghazin, and
Timothy H. Warren
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202001450
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Lewis Acid Coordination Redirects S-Nitrosothiol Signaling
Output
Valiallah Hosseininasab,[a] Alison C. McQuilken,[a] Abolghasem (Gus) Bakhoda,[a] Jeffery A. Bertke,[a]
Qadir K. Timerghazin,[b]* and Timothy H. Warren[a]*
Figure 1. (A) Resonance representation of RSNO electronic
structure and its modulation by Lewis acid coordination. (B)
Known N-bound Lewis acid adducts of RSNOs.
Abstract: S-Nitrosothiols (RSNOs) serve as air-stable reservoirs for
nitric oxide in biology and are responsible for
a myriad of
physiological responses. While copper enzymes promote NO
release from RSNOs by serving as Lewis acids capable of
intramolecular electron-transfer, redox innocent Lewis acids
separate these two functions to reveal the effect of coordination on
structure and reactivity. The synthetic Lewis acid B(C6F5)3
coordinates to the RSNO oxygen atom in adducts RSNO-B(C6F5)3,
leading to profound changes in the RSNO electronic structure and
reactivity. Although RSNOs possess relatively negative reduction
potentials (-1.0 to -1.1 vs. NHE), B(C6F5)3 coordination increases
their reduction potential by over 1 V into the physiologically
accessible +0.1 V vs. NHE. Outer-sphere chemical reduction results
in formation of the Lewis acid stabilized hyponitrite dianion trans-
[LA–O–N=N–O–LA]2– (LA = B(C6F5)3) that releases N2O upon
acidification. Mechanistic and computational studies support initial
•
reduction to the [RSNO-B(C6F5)3]– radical-anion susceptible to N-N
coupling prior to loss of RSSR.
Nitric oxide (NO) is a key endogenous gasotransmitter
which plays crucial signaling roles in vasorelaxation,
neurotransmission and cytoprotection.[1] Nonetheless, NO has a
short lifetime under biological conditions, under assault by
omnipresent O2 and O2–.[2] S-nitrosothiols (RSNOs) serve as air-
stable NO reservoirs capable of facile NO release due to the
modest RS–NO bond strength (~30 kcal mol–1).[3] Circulating at
near micromolar levels, RSNOs such as S-nitrosoglutathione
serve as messengers themselves and participate in protein
control via S-nitrosation of proteins, an important post-
translational modification connected to health and disease [4] For
instance, S-nitrosation of hemoglobin at β-Cys93 is required for
proper blood oxygenation. [5]
Redox active copper enzymes such as CuZn-SOD
facilitate the release of NO from RSNOs.[6] Model studies
revealed that Lewis acid coordination of RSNO to a copper(I) ion
to form CuI-RSNO adducts precedes intramolecular electron
transfer that releases NO. For instance, addition of the synthetic
S-nitrosothiol Ph3CSNO to the tris(pyrazolyl)borate complex
MesTpCu results in MesTpCuI(κ1-N(O)SCPh3) that reversibly loses
NO with concomitant oxidation of the copper center to MesTpCuII-
SCPh3.[7] Given that the reduction potential of Ph3CSNO (-1.25 V
vs. NHE)[7] is dramatically more negative than the corresponding
[CuII]/[CuI] redox couple for a copper complex that releases NO
with formation of the corresponding copper(II) thiolate [CuII]-SR
(
iPr2TpCu(NCMe); E1/2 = 270 mV vs. NHE),[8] coordination of the
RSNO to the Lewis acid is clearly required to facilitate electron
transfer.[7]
RSNOs exist in a variety of protein environments, exposed
to a wide range of chemical stimuli including Lewis acids.[9]
These stimuli can have a dramatic effect on the –SNO group
properties owing to the unusual nature of the RSNO electronic
structure, whose description requires a combination of the three
resonance structures S, D, and I (Figure 1A). Two of these
structures, D and I, are antagonistic, i.e. have opposite bonding
patterns and formal charges on atoms.[10] This antagonistic
nature of RSNOs results in the paradoxical properties of the S–
N bond, which exhibits restricted rotation suggestive of a partial
double-bond character while being unusually long and weak,[11]
as well as dual reactivity pattern of RSNO reactions.[11-12]
The antagonistic nature of RSNOs also suggests that
Lewis acid coordination at N, S, or O atoms would radically alter
the RSNO reactivity by favoring one antagonistic structure at the
expense of the other (Figure 1A), an effect that may underline
the enzymatic control of the RSNO reactions in biological
environments.[10, 12b, 13] Due to the sensitive nature of RSNOs,
experimental support for Lewis acid modulation of RSNO
properties has lagged computational predictions.[11, 14] Seminal
studies by Doctorovich revealed that N-coordination of RSNO to
an IrIII center in [IrCl4(NCMe)(κ1-N(O)SR)]– (R = CH2Ph) to lead
to shortening of the S–N bond,[15] also seen in MesTpCuI(κ1-
N(O)SCPh3).[7] While the S–N distance in Ph3SNO is 1.792(5)
[a]
V. Hosseininasab, Dr. A. C. McQuilken, Dr. A. Bakhoda, Dr. J. A.
Bertke, Prof. Dr. T. H. Warren
Department of Chemistry, Georgetown University
Box 571227, Washington, DC 20057-1227 (USA)
E-mail: thw@georgetown.edu (T.H.W.)
Å,[16]
[IrCl4(NCMe)(κ1-N(O)SCH2Ph)]–1
and
MesTpCuI(κ1-
N(O)SCPh3) possess S–N distances of 1.737(8) and 1.755(4) Å,
each consistent with reduced I- and increased D-character of the
κ1-N-bound RSNO.
We experimentally find that O-coordination of a Lewis acid,
however, has an even more profound effect on the RSNO
reactivity due to the interaction with the oxygen atom which
bears a formal negative charge in resonance structure D (Figure
[b]
Prof. Dr. Q. K. Timerghazin
Department of Chemistry, Marquette University, P.O. Box 1881,
Milwaukee, WI 53201-1881 (USA)
Email: qadir.timerghazin@marquette.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/....
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Figure 2. Synthesis (A) and X-ray structures (B) of AdSNO-
B(C6F5)3 (3) and MesCH2SNO-B(C6F5)3 (4); H and F atoms are
not shown.
Figures S43-S44), with predicted 15N shifts at 755 and 605 ppm
(compared to O-anti at 838 ppm). This allows us to tentatively
assign the minor signals experimentally observed at δ 681 and
553 ppm to the O-syn and N-syn forms of 3, respectively.
A
B(C6F5)3
RSNO-B(C6F5)3
RSNO
Figure 3. Cyclic voltammogram of AdSNO-B(C6F5)3 (3) (7 mM)
pentane
in CH2Cl2 at 25 °C with [ nBu4N][BPh4] (0.1 M).
R = Ad, CH2Mes
B
3
4
S
S
anti
syn
N
N
O
O
B
B
AdSNO-B(C6F5)3 (3)
MesCH2SNO-B(C6F5)3 (4)
Besides the significant alteration of the RSNO geometry
and spectral properties, Lewis acid coordination has a dramatic
effect on the reduction potentials of RSNOs. Cyclic
voltammograms (CVs) of free RSNOs 1 and 2 in CH2Cl2 each
reveal two irreversible reduction features at rather negative
1A). Addition of the oxophilic Lewis acid B(C6F5)3 to synthetic
RSNOs AdSNO (1) and MesCH2SNO (2) in pentane at RT leads
to rapid color change from green to yellow for 1 or pink to
orange for 2. Crystallization from pentane provides Lewis acid
adducts AdSNO-B(C6F5)3 (3) and MesCH2SNO-B(C6F5)3 (4) in
80% and 71% yield, respectively (Figure 2). X-ray diffraction
analysis confirms short S–N bonds in these adducts of
1.6252(17) and 1.608(5) Å in the syn- and anti-conformers of 3
and 4, respectively.[17] The observed dramatic contraction of the
S–N bond is in agreement with DFT calculations at the
ωB97XD-PCM(CH2Cl2)/ma-def2-TZVPP level (Figures S42-S44).
At the same time, the experimental N–O bond lengths of
1.278(2) and 1.274(5) Å in 3 and 4 are longer than typical 1.18-
1.19 Å N-O distances in free RSNOs.[16, 18] These observations
are consistent with increased contribution of the resonance
component D in O-bound RSNO-B(C6F5)3 complexes: indeed,
calculations[19] suggest that the D weighting increases from
~30% in free RSNOs to ~55% in the B(C6F5)3 adducts 3 and 4.
Dramatic structural alterations of RSNOs induced by O-
coordination of a Lewis acid result in distinct spectroscopic
changes. Consistent with trends revealed through X-ray
structures, IR spectra report higher energy S–N stretches at 853
and 863 cm–1 for 3 and 4 relative to 645 and 630 cm–1 for the
corresponding free RSNOs 1 and 2. Conversely, the N–O
stretching frequencies decrease to 1257 and 1282 for 3 and 4
relative to 1486 and 1484 cm–1 in 1 and 2. Analysis of 15N
isotopomers of 1 - 4 confirms these assignments (Figures S5,
S9, S16 and S23 in SI). As the oxygen atom lone pair becomes
involved in dative bonding with B(C6F5)3, the n → π* adsorption
characteristic to the UV-visible spectra of RSNOs shifts to higher
energies. For instance, low intensity bands at 560 (5 M-1 cm-1)
and 600 nm (13 M-1 cm-1) for AdSNO (1) shift to 510 nm (9 M-1
cm-1) in AdSNO-B(C6F5)3 (3), (Figures S4 and S15).
potentials (Figures S24 and S28). The first corresponds to one-
•
electron reduction of the free RSNO to the [RSNO]– radical-
anion appearing at -1.13 and -1.01 V vs. NHE for 1 and 2,
respectively. The second peak in each at -1.32 V corresponds to
the reduction of free NO released from reduced RSNO.
Remarkably, AdSNO-B(C6F5)3 (3) exhibits a quasi-reversible
wave centered at +0.08 V vs. NHE, nearly 1 V higher than free
AdSNO (1) that is also present under CV conditions (Figure 3).
MesCH2SNO-B(C6F5)3 (4) also undergoes reduction at
a
potential ~1 V higher than free MesCH2SNO (2), but is largely
irreversible under these conditions signaled by a reduction wave
centered at +0.1 V vs. NHE (Figures S26 and S29).
To provide greater insight into the species generated
under CV conditions, we carried out chemical reduction with
outer-sphere reductants. Addition of Cp*Co (Ered = -1.24 V vs.
2
NHE in CH2Cl2)[20] to free RSNOs 1 and 2 results in NO
generation quantified in 82 and 71% yield, respectively (Figure
4A). This experimental finding is consistent with DFT
•
calculations that suggest the [RSNO]– structure as a weakly
bound complex of RS– and NO• (S–N distance >2.6 Å) with
Figure 4. (A) Outer-sphere reduction of RSNO (R = Ad,
MesCH2) by Cp2*Co. (B) Chemical reduction of AdSNO-B(C6F5)3
•
by Cp*Co. (C) Spin density plot of [AdSNO-B(C6F5)3]– (5). (D) X-
2
band EPR spectra of radical anions 5-14N and 5-15N recorded in
a mixture of fluorobenzene/pentane at 25 °C.
15N NMR spectra of RSNOs typically reveal two signals for
anti- and syn-conformers that require low temperature
acquisition due to a relatively low barrier for S–N bond rotation
(∆Gr‡ot = 10-14 kcal/mol).[16] For instance, the low temperature
15N NMR spectrum of AdS15NO in CD2Cl2 at -60 °C exhibits
major and minor signal at δ 845.4 and 786.6 ppm (relative to
NH3), attributed to anti and syn conformers. Low temperature
15N NMR spectra of crystallized adducts 3 and 4 dissolved in
CD2Cl2 each exhibit three upfield shifted resonances. The major
resonance for O-anti-AdSNO-B(C6F5)3 (3) appears at δ 741 ppm,
with two minor signals at 681 and 553 ppm. DFT calculations
suggest that among the possible forms of AdSNO-B(C6F5)3 the
O-syn and N-syn species are closest in energy to the most
stable O-anti form (enthalpies higher by 1.3 and 3.5 kcal/mol,
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>95% of spin density on the NO moiety (Figure S45).
•
Figure 6. Stepwise conversion of [RSNO-B(C6F5)3] – radical
The quasi-reversible reduction of AdSNO-B(C6F5)3 (3)
anions to dianion 7 and disulfide RS–SR. Reaction free energies
(in kcal/mol at 298 K) calculated at the ωB97XD-
PCM(CH2Cl2)/red-ma-def2-SV(P) level of theory.
observed by cyclic voltammetry suggests that the radical anion
•
[AdSNO-B(C6F5)3] – (5) may have a long enough lifetime to
enable characterization by EPR. Indeed, mixing a fluorobenzene
solution of 3 with a pentane solution of Cp*Co generates an
2
intermediate with a three-line EPR signal at g = 1.999 (Figure
4D). This resonance is consistent with an N-centered radical
anion predicted by DFT to exhibit extensive spin density on N
(0.7 e–, Figures 4C and S45B). The three-line pattern indicates
strong coupling to the 14N nucleus (I = 1; A(14N) = 45.0 MHz),
confirmed via isotopic substitution with 15N that gives a two line
pattern (I = ½; A(15N) = 62.5 MHz) (Figure 4D). Attempts to
DFT calculations suggest that the radical anions [RSNO-
•
observe [MesCH2SNO-B(C6F5)3]– by reduction of 4 with Cp*2Co
•
B(C6F5)3] – (R = Ad (5), MesCH2 (6)) formed by 1-electron
under similar conditions did not allow for EPR observation of the
corresponding radical anion consistent with its shorter lifetime
indicated by the irreversible reduction peak in the CV of 4.
reduction of 3 and 4 undergo thermodynamically favorable
dimerization via N–N bond formation to give dianions 8 and 9
(∆GR°= -6.5 and -6.7 kcal/mol, respectively). These di anions then
lose the corresponding disulfide RS–SR (∆GR°= -39.0 and -41.3
kcal/mol, respectively) to give the doubly borane-capped
hyponitrite dianion 7 (Figures 6 and S47-S48). Full reaction
pathway calculations for a small model system (Figure S49)
support the proposed mechanism with reasonably low barriers
(<17 kcal/mol) for the dimer formation and the subsequent RS–
elimination, and a barrierless RS– attack of to give disulfide RS–
SR and Lewis acid capped hyponitrite.
Although DFT calculations predict elongated S–N and N–O
•
bonds in [AdSNO-B(C6F5)3]– (5) (1.71 Å and 1.33 Å; Figure S45)
vs. AdSNO-B(C6F5)3 (3) (1.61 Å and 1.25 Å), 1-electron
reduction of AdSNO-B(C6F5)3 does not seem to destabilize the
S–N bond enough to encourage loss of NO• as occurs in the
reduction of free RSNOs (Figure 4A). Instead, reduction of Lewis
acid adducts 3 and 4 ultimately delivers the Lewis acid stabilized
hyponitrite dianion trans-[(C6F5)3BO–N=N–OB(C6F5)3]2– (7)
(Figure 5). Addition of Cp*Co to 3 or 4 gives dianion 7 charge-
2
stabilized by 2 equiv. Cp*2Co+ in 73% and 65% yield, respectively,
along with the corresponding disulfides AdS–SAd and
MesCH2S–SCH2Mes in 80 and 74% yield, respectively. Due to
the mild reduction potentials of 3 and 4, a range of metallocene
reductants provide [M]2[(C6F5)3BO–N=N–OB(C6F5)3] (7-[M]2; M =
Figure 7. Reaction of (7-[Cp*2Co]2) with trifluoroacetic acid
releases N2O.
2–
(C6F5)3B
N
O
+ 2 CF3COOH
N2O
O
N
B(C6F5)3
7
Cp2*Co +, Cp2Fe+). The X-ray crystal structure of [ Cp*Co+]2
+
2
Importantly, reaction of 7-[ Cp*Co
]
with 2 equiv.
2
2
[(C6F5)3BO–N=N–OB(C6F5)3]2– (7-[ Cp*Co +]2) reveals N-N
2
CF3COOH triggers release of N2O in 42-43% yield. Release of
N2O, the prototypical reactivity of hyponitrite upon protonation,[22]
underscores how Lewis acids can redirect the chemical outcome
of RSNO reduction which typically generates NO.
coupling to give a trans disposition of the [O–N=N–O]2–
hyponitrite core located at a center of inversion with N–N’ and O-
N distances of 1.257(9) and 1.381(6) Å, respectively. These
distances are similar to those found in other structures of the
Lewis acid coordination via the O atom of S-nitrosothiols
results in significant changes in the structure and chemical
properties of the RSNO by strongly promoting its RS+=N–O–
resonance component. Most profoundly, this mode of Lewis acid
coordination redirects reduction of RSNOs to the hyponitrite
dianion [ON=NO]2– rather than NO. Moreover, Lewis acid
coordination significantly raises the reduction potential of
RSNOs, enabling reduction by mild reductants. This represents
a general strategy to facilitate reduction of small molecules,
previously illustrated in the reduction of disulfides RSSR by
ferrocene that only occurs in presence of a Lewis acid such as
B(C6F5)3.[23] Thus, Lewis acids could serve as a signaling motif to
turn on outer sphere RSNO reduction in the vicinity of electron-
transfer proteins that function in the range of +700 to -800 mV vs.
NHE.[24] Future studies will examine connection between Lewis
acid strength and reduction potential, including Lewis acids that
serve as H-bond donors that could directly promote N2O
formation.
trans-hyponitrite anion.[21] 15N NMR analysis of 7-[ Cp*Co +]2
2
shows signals at δ 429.9 (major) and 384.9 (minor). We assign
these as the trans and cis isomers of 7 based on DFT-predicted
15N chemical shifts at δ 425 and 380 ppm, respectively. DFT
also indicates a small difference of 1.6 kcal/mol in free energies
for these isomers that favors the trans form (Figure S46).
Figure 5. (A) Reduction RSNO-B(C6F5)3 along with (B) the X-ray
structure of the trans-hyponitrite dianion [(C6F5)3B–ON=NO–
B(C6F5)3]2– (7); H and F atoms are not shown.
Acknowledgements
T.H.W. acknowledges the NIH (R01GM126205) and the
Georgetown Environment Initiative. Q.K.T. acknowledges NSF
CAREER award CHE–1255641, and Marquette University Way-
Klinger Sabbatical Award. V.H. thanks Mahdi Raghibi Boroujeni
and Dr. Pokhraj Ghosh for assistance with CV experiments. This
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S-Nitrosothiols (RSNOs) serve as air-
stable reservoirs for nitric oxide in
biology and are responsible for a
myriad of physiological responses. We
demonstrate that O-coordination by a
Lewis acid both dramatically facilitates
RSNO reduction as well as changes
its signaling output from NO to N2O
following protonation of the Lewis acid-
capped hyponitrite that forms upon
reduction.
Valiallah Hosseininasab,[a] Alison C.
McQuilken,[a] Abolghasem (Gus)
Bakhoda, Jeffery A. Bertke,[a] Qadir K.
Timerghazin,[b]* and Timothy H.
Warren[a]*
Page No. – Page No.
Lewis Acid Coordination Redirects
S-Nitrosothiol Signaling Output
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