The redox chemistry of sulfenic acids

Article abstract of DOI:10.1021/ja1083046

A persistent triptycenyl sulfenic acid is used as a model for cysteine-derived and other biologically relevant sulfenic acids in experiments which define their redox chemistry. EPR spectroscopy reveals that sulfinyl radicals are persistent and unreactive toward O₂, allowing the O-H bonding dissociation enthalpy (BDE) of the sulfenic acid to be readily determined by equilibration with TEMPO as 71.9 kcal/mol. The E° (RSO/RSO^-) and pK_a of this sulfenic acid are also reported.

Full text of DOI:10.1021/ja1083046

Published on Web 11/04/2010
The Redox Chemistry of Sulfenic Acids
Alaina J. McGrath,† Graham E. Garrett,† Luca Valgimigli,*,‡ and Derek A. Pratt*,†,§
Department of Chemistry, Queen’s UniVersity, 90 Bader Lane, Kingston, Ontario, Canada K7L 3N6, and
Department of Organic Chemistry “A. Mangini”, UniVersity of Bologna, Via San Giacomo 11,
40126, Bologna, Italy
Received September 14, 2010; E-mail: luca.valgimigli@unibo.it; dpratt@uottawa.ca
stabilized by an intramolecular hydrogen bondsand few other
Abstract: A persistent triptycenyl sulfenic acid is used as a model
for cysteine-derived and other biologically relevant sulfenic acids
in experiments which define their redox chemistry. EPR spec-
troscopy reveals that sulfinyl radicals are persistent and unreac-
examples have appeared since.15 The preparation, isolation, and
purification of three types of alkyl sulfenic acids have been
reportedsones derived from penicillins (4),16 and ones bearing
triptycene (5)17 and (E)-decalin (6)18 substitution. Since alkyl
tive toward O2, allowing the O-H bonding dissociation enthalpy
sulfenic acids are most appropriate models for 1, 2, and other
(BDE) of the sulfenic acid to be readily determined by equilibration
with TEMPO as 71.9 kcal/mol. The E° (RSO•/RSO-) and pKa of
this sulfenic acid are also reported.
biologically relevant sulfenic acids, we sought to prepare them and
determine their redox properties. The preparation of 5, modified
from the literature procedure17 as detailed in the Supporting
Information, was the most straightforward, and we describe our
investigations with this compound here.
Sulfenic acids figure prominently in biological and natural
product chemistry. For example, cysteine-derived sulfenic acids (1)
are key intermediates in signal transduction, responding to the redox
state of the cell and modulating gene transcription accordingly,1
and have also been shown to play both catalytic and structural roles
in enzymes,2 as well as nonenzymatic protein folding.7 Sulfenic
acids are proposed to be key intermediates in the metabolic
activation of antithrombotic agents, such as ticlopedine and
prasugrel,8 and, most tangibly, in the biosynthesis of the odorous
thiosulfinates in allium species, such as garlic, onions, leeks, and
shallots.9 Recently, we have shown that 2-propenesulfenic acid (2)
derived from allicin, the primary thiosulfinate giving garlic its
characteristic odor and flavor, is responsible for garlic’s potent
antioxidant activity.10
When a deoxygenated solution of 5 in benzene containing
5-10% (v/v) di-tert-butylperoxide was placed in the cavity of an
EPR spectrometer and irradiated for 10 s with UV light, an intense
single-line spectrum was obtained with the field center at g ) 2.0114
(black line, Figure 1).19 The radical was persistent under these
conditionssin contrast with other spectroscopically characterized
small-molecule-derived sulfinyl radicals (i.e., MeSO•20 and t-
BuSO•21),22 the latter of which was found to undergo a rapid
bimolecular self-reaction (2k ) 6 × 107 M-1 s-1) at -100 °C.23 In
fact, the same spectrum was obtained days after the initial
photolysis. More interestingly, the radical was found to be stable
to O2; introduction of air into the sample lead to significant
broadening of the signal (Figure 1, red line)sfrom a line width of
less than 0.4 G to close to 1.8 Gsowing to the paramagnetism of
O2. The original spectrum could be restored by sparging with N2.24
The potential for cysteine-derived sulfenic acids to be ubiquitous
in cell signaling processes has prompted the development of
numerous approaches for their detection and quantitation.11 Despite
the flurry of research that has ensued, revealing cysteine sulfenic
acid involvement in an ever increasing number of pathways, the
mechanisms responsible for the formation and reactions of these
intermediates remain unclear.2,4-10,12 This is compounded by the
fact that surprisingly little is known of the physicochemical
properties of this functional groupslargely because the preparation,
isolation, and purification of sulfenic acids is not a trivial en-
deavor.13
The first report of the preparation of a sulfenic acid was made
by Fries in 191314san anthraquinone-derived sulfenic acid (3)
Figure 1. EPR spectrum of 5• from irradiation of 5 in benzene and 5-10
mol % di-tert-butylperoxide in the absence of O2 (---), following exposure
to air (red line) and after being sparged with N2 to remove O2 (blue line).
† Queen’s University.
‡ University of Bologna.
The persistence of 5• allowed the determination of the O-H
bond dissociation enthalpy (BDE) of 5 by EPR using the radical
§ Current Address: Department of Chemistry, University of Ottawa, 10 Marie
Curie Pvt., Ottawa, Ontario, Canada K1N 6N5.
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C O M M U N I C A T I O N S
equilibration approach.25 Thus, 5 and TEMPO-H (N-hydroxy-
2,2,6,6-tetramethylpiperidine) were combined in a deoxygenated
benzene solution containing 5% (v/v) di-tert-butylperoxide and
irradiated in the cavity of an EPR spectrometer. The equilibrium
constant for exchange of an H-atom between 5• and TEMPO was
then obtained by integration of the spectral signals corresponding
to the two radicals. Since the O-H BDE of TEMPO-H is known
(69.6 kcal/mol),26 and assuming that the entropy change for the
equilibrium is negligible, the O-H BDE of 5 could be determined
to be 71.9 ( 0.3 kcal/mol. This value is in good agreement with
the value predicted by high-level theoretical calculations on smaller
alkyl sulfenic acids (∼69 kcal/mol) in some of our recent work.10
The substantially lower O-H BDE in sulfenic acids compared to
the (valence) isoelectronic hydroperoxides (∼88 kcal/mol) can be
ascribed to greater spin delocalization onto the S atom in the sulfinyl
radical (∼50%) compared to the internal O atom in the peroxyl
radical (∼30%).10,27
in this context. The persistence of the 9-triptycenesulfenic acid,
and sulfinyl radical derived therefrom, should prove useful for
carrying out model reactions of protein-bound cysteine sulfenic
acids; further, the physicochemical properties reported here should
be valuable to the interpretation of results obtained with them, as
well as with the actual biological systems, for which obtaining these
data is practically impossible.
Acknowledgment. We are grateful for the support of the
NSERC of Canada, the Ontario Ministry of Research and Innova-
tion, and the Canada Research Chairs program for grants to D.A.P.
and the University of Bologna for grants to L.V.
Supporting Information Available: Complete experimental details
for synthesis, EPR, electrochemical, and pKa studies. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
Cyclic voltammetry of CH3CN solutions of 5 revealed a broad,
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more oxidizing potentials, eventually becoming constant at 1.57
V, but still exhibiting irreversible behavior.29 Conversely, the
addition of 1 equiv of Bu4NOH shifted the anodic peak to ∼0.79
V and yielded quasi-reversible behavior, thereby allowing us to
estimate a standard potential of E° ) E1/2 ) 0.74 V versus NHE
for the RSO•/RSO- couple. For comparison, E° for the ROO•/
ROO- couple in neutral media is estimated to be 1.05 V vs NHE.30
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Figure 2. Cyclic voltammagrams corresponding to the oxidation of 5 mM
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additive (black), (b) 30 mM CF3SO3H (red), or (c) 5 mM Bu4NOH (blue)
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g14,32 indicating that sulfenic acids are indeed more acidic than
the isoelectronic hydroperoxides. Given that the pKa difference is
small relative to the difference in E°, the lability of the O-H bonds
in sulfenic acids can be said to derive more from the stability of
the sulfinyl radical than the sulfenate anion.
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(32) This was the maximum reliable value we could obtain with our pH probe.
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