Sulfoxides as response elements for fluorescent chemosensors

Article abstract of DOI:10.1021/ja407099a

Sulfoxides are shown to be viable reporting groups for fluorescent chemosensor development. Metal coordination of sulfoxide-appended fluorophores suppresses excited-state pyramidal inversion of the sulfoxide, leading to enhanced fluorescence emission. This new structural motif allows the construction of fluorescent chemosensors that do not require nitrogen coordination as part of the signaling process, that have a range of selectivities and affinities for oxophilic metal ions, and that can function in water.

Full text of DOI:10.1021/ja407099a

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Communication
Sulfoxides As Response Elements For Fluorescent Chemosensors
Rahul Singh Kathayat, and Nathaniel S. Finney
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja407099a • Publication Date (Web): 08 Aug 2013
Downloaded from http://pubs.acs.org on August 9, 2013
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Sulfoxides As Response Elements For Fluorescent
Chemosensors
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Rahul S. Kathayat and Nathaniel S. Finney*,†
Institute of Organic Chemistry, University of Zurich
Winterthurerstrasse 190, 8057 Zurich, Switzerland
Supporting Information Placeholder
ABSTRACT: Sulfoxides are shown to be viable reporting
groups for fluorescent chemosensor development. Metal
coordination of sulfoxideꢀappended fluorophores suppresses
excitedꢀstate pyramidal inversion of the sulfoxide, leading to
enhanced fluorescence emission. This new structural motif
allows the construction of fluorescent chemosensors that do
not require nitrogen coordination as part of the signaling
process, that have a range of selectivities and affinities for
oxophilic metal ions, and that can function in water
.
Figure 1. Sulfoxide fluorescent chemosensors 1ꢀ8.
Chemosensors that provide a fluorescence response
to reversible metal ion binding have broad potential
application for biological, medical and environmental
analyses.1 Numerous approaches to chemosensor
development have been described, but the most
common involve coordination to the lone pair of a
nitrogen atom attached to a proximal fluorophore such
that fluorescence emission is altered upon metal
binding.2 As effective as this approach has been, it
possesses limitations: acid sensitivity and direct
dependence of the fluorescence response on nitrogen
coordination chemistry. The discovery of new, nonꢀ
amine signaling motifs thus broadens the scope and
potential impact of chemosensor development.
Sulfoxides 1ꢀ8 have optical properties very similar to
those of pyrene, except that they have significantly
lower quantum yields (Table 1). While 1ꢀ4 have
limited metal ion affinity, their optical properties are
instructive. Titrations of 5ꢀ8 with various metal ions in
CH3CN reveal their efficacy as fluorescent
chemosensors (Table 2).
Table 1. Optical properties of 1ꢀ8.a
ε / 103 b φ c
ε / 103 b φ c
35.5
39.7
35.9
34.7
0.011
31.1
27.6
28.5
27.5
0.009
1
2
3
4
5
6
7
8
0.006
0.053
0.012
0.004
0.003
0.015
We describe the first use of sulfoxides as reporting
functional groups for the development of metalꢀ
responsive fluorescent chemosensors. Sulfoxides have
low intrinsic affinities and selectivities for metal ion
coordination,3 explaining in part why they have not
previously been studied as chemosensor response
elements.4 Despite this, we find that pyrenyl sulfoxides
exhibit enhanced emission upon metal binding, that the
metal binding properties of these chemosensors can be
readily altered by structural variation of the sulfoxide
probe (Figure 1), and that such probes can function in
water.5
a
All spectra measured in CH3CN. Emission spectra
acquired at 10 ꢁM. Longest λ absorption/excitation
maxima 349ꢀ352 nm; emission maxima 377ꢀ381 nm. b Mꢀ
1cmꢀ1. c Absolute quantum yields.
The low quantum yields of 1ꢀ8 are in keeping with
the established deactivation of aryl sulfoxides excited
states by pyramidal inversion of the sulfoxide.6 It is
believed that the barrier for excited state inversion is
greatly reduced by intramolecular charge transfer
(ICT) from the sulfoxide to the pendant aryl, which
lessens electrostatic repulsions associated with the
planar inversion transition state. Consistent with this,
in the phenyl pyrenyl series 1ꢀ3 an electron donating
substituent lowers the quantum yield (1 vs. 2) and an
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electron withdrawing substituent increases the
~104ꢀfold excess of TFA (0.15 M) – a small increase
compared to metalꢀinduced emission “turn on.”
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2
3
4
5
6
7
8
quantum yield (1 vs. 3): the pꢀH3CO group facilitates
ICT while pꢀF3C disfavors it.7
Appending sulfoxide 4 with more aggressively
metalꢀcoordinating groups increases metal affinity and
provides a measure of selectivity as well. The simple
extension of a methyl substituent to an ethylamino
group (5) has little influence on quantum yield in the
absence of metal ion,10 but leads to large increases in
metal ion affinity (Table 2): while there is still no
measurable affinity for Na+, Li+ affinity increases by
an order of magnitude, and logKds for the divalent
cations Mg2+, Ca2+ and Zn2+ are now ≤ꢀ5.3.
Elaboration to incorporate dipicolyl (6) or azacrown
(7) moieties further increases affinity and leads to the
emergence of a response to Na+,11 although the affinity
for divalent cations remains stronger. The strong
interaction of 7 and Mg2+ illustrates the limits of the
current analytical system: the measured logKd (ꢀ6.6)
represents a subꢀnM detection limit and the I/I0 of 140
corresponds to a final quantum yield (φmax) of 0.41.
Table 2. log(Kd) and I/I0 for titrations of 4ꢀ8.a-c
Li+
Na+
Mg2ꢀ
Ca2+
Zn2+
ꢀ0.8
–
ꢀ2.6 (33) ꢀ2.5 (26) ꢀ1.4 (36)
4
5
6
7
8
(13)d
ꢀ2.0
(33)
–
ꢀ5.7 (44) ꢀ5.7 (42) ꢀ5.3 (48)
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ꢀ5.2
(78)
ꢀ2.5
(20)
ꢀ5.7
ꢀ5.9
ꢀ5.3
(174)
(145)
(213)
ꢀ5.9
(90)
ꢀ4.0
(39)
ꢀ6.6
ꢀ6.4
ꢀ5.5
(140)
(140)
(160)
ꢀ2.1
(5)
ꢀ2.6
(3)
ꢀ3.6
(27)
ꢀ5.7
(27)
ꢀ1.9
(26)
a
Titrations in CH3CN at 10 ꢁM (4) or 0.5ꢁM (5ꢀ8)
b
c
chemosensor. Kd in M. I/I0 in parentheses. Entries
marked – indicate binding too weak to allow Kd
determination. Kd estimated from titrations that did not
d
Probe 8 most clearly illustrates two key aspects of
this new approach to fluorescence signaling, in that it
provides a strong (logKd = ꢀ5.7, I/I0 = 27, φmax = 0.40),
selective response to Ca2+ with no response to the
addition of acid and no requirement that nitrogen be
present in the molecule.12,13
reach saturation.
The quantum yields of the sulfoxides increase in
10% CH3CN/MOPS buffer (5 mM, pH 7.4),
presumably as the result of hydrogen bonding.14 The
quantum yields of 4 and 5 rise to ~ 0.50 and many of
the fluorescence responses seen in CH3CN simply can
not be observed in aqueous medium. However, this
effect is not uniformly overwhelming: the addition of
1.5 eq. ZnCl2 to 6 (10 ꢁM, φ0 = 0.025 in 10%
CH3CN/5mM MOPS) still provides
a
13ꢀfold
fluorescence enhancement with no reduction in
apparent affinity (logKd = ꢀ5.3).
Figure 2. Titration of 4 (10 ꢁM in CH3CN) with ZnCl2,
which is representative.
These chemosensors are unusual and advantageous
in not relying on nitrogen coordination to provide the
fluorescence response: while protonation of 5ꢀ7 in
acidic media is expected to impact metal binding, it
will not produce an increase in fluorescence emission
as a false positive. The oxophilic coordination
properties of sulfoxides are distinct from, and less well
described than, those of other functional groups
routinely used in small molecule chemosensors. The
ability to use sulfoxides to report metalꢀbinding events
is unprecedented, and the results described here
indicate that the modification of fluorophore and metal
recognition domains should provide useful and
interesting probes that function in water,15 with
selectivities and affinities complementary to those of
known systems.
The quantum yields of these sulfoxides, especially 5ꢀ
8, can be enhanced by the addition of metal ions,
making them viable fluorescent chemosensors. We
believe the enhancement is the result of coordination to
the sulfoxide oxygen, which withdraws electron
density and disfavors the deactivating ICT process.
The titration of 4 with ZnCl2 provides representative
emission spectra for this effect in the absence of other
metal binding functionality (Figure 2). Although the
binding is weak (logKd ~ 0.1 M),8 the fluorescence
enhancement is significant (I/I0 = 36).9 The response of
4 to oxophilic metals includes Li+, Mg2+ and Ca2+ as
well and occurs with similar fluorescence enhancement
(Table 2). Together, these observations delineate the
intrinsic binding affinities of an aryl sulfoxide in
CH3CN. The emission of 4 (10 ꢁM) shows no change
in the presence of a 103ꢀfold excess of TFA and
increases by only a factor of 2.6 in the presence of a
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6. For fundamental studies on the photochemistry of aryl
Supporting Information. Complete experimental
sulfoxides, see: a) Vos, B. W.; Jenks, W. S. J. Am. Chem. Soc.
2002, 124, 2544ꢀ2547. b) Cubbage, J. W.; Jenks, W. S. J. Phys.
Chem. A 2001, 105, 10588ꢀ10595. c) Lee, W.; Jenks, W. S. J. Org.
Chem. 2001, 66, 474ꢀ480. d) Guo, Y.; Jenks, W. J. J. Org. Chem.
1997, 62, 857ꢀ864. e) Cooke, R. S.; Hammond, G. S. J. Am. Chem.
Soc. 1970, 92, 2739ꢀ2745. f) Hammond, G. S.; Gotthard, H.; Coyne,
L. M.; Axelrod, M.; Rayner, D. R.; Mislow, K. J. Am. Chem. Soc.
1965, 87, 4959ꢀ4960.
7. We presume that the presence of the pꢀH3CO group increases
the driving force for excitedꢀstate ICT, while the pꢀF3C group
diminishes it. (This hypothesis is the subject of ongoing
computational study.) The proposed ICT excited state bears
resemblance to a sulfoxide radical cation, and we note that singleꢀ
electron oxidation of enantiomericallyꢀenriched aryl sulfoxides
dramatically increases rates of sulfoxide racemization: Aurisicchio,
C.; Baciocchi, E.; Gerini, M. F.; Lanzalunga, O. Org. Lett. 2007, 9,
1939ꢀ1942.
8. Binding constants were determined by nonꢀlinear leastꢀsquares
fitting of plots of emission intensity vs log[M] using the program
Prism6 (Graphpad, Inc., San Diego, CA). All ligand:metal
complexes were of 1:1 stoichiometry, as determined by the method
of continuous variation. See: Connors, K. A. Binding Constants
John Wiley & Sons: New York, 1987.
9. See Supporting Information for additional representative
titrations, emission spectra and binding constant determination.
10. From evaluation of the analogous sulfones, we believe that a
small degree of PET quenching from the N lone pair is also
occurring in 5ꢀ7. However, based on the quantum yields of 1ꢀ4,
significant fluorescent enhancement cannot occur without
suppression of the sulfoxide deactivation pathway, and this
“sulfoxideꢀgated PET” signaling cannot be a significant contributor
to the observed enhancements.
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details for compound synthesis and optical
measurements; copies of 1H NMR and 13C
spectra for all new compounds. This material is
available free of charge via the Internet at
http://pubs.acs.org/.
AUTHOR INFORMATION
Corresponding Author
9
Nathaniel S. Finney
nsfinney@ncsu.edu
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Present Addresses
†Department of Chemistry
North Carolina State University
Raleigh, NC 27610
Funding Sources
This work was supported by the Swiss National
Science Foundation and the Organic Chemistry
Institute (UZH).
ACKNOWLEDGMENT
We acknowledge important initial observations by
Dr. Sergey Malashikhin, and helpful discussions
with Profs. Jay Siegel and Kim Baldridge.
REFERENCES
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Bradshaw, J. S. Chem. Rev. 1991, 91, 1721ꢀ2085.
1. For representative reviews of fluorescent chemosensors and
probes, see: (a) Formica, M.; Fusi, V.; Giorgi, L.; Micheloni, M.
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Tetrahedron 2005, 61, 8551–8588. (e) Bell, T. W.; Hext, N. M.
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based on modulation of photoinduced electron transfer (PET) or
intramolecular charge transfer (ICT). For overviews of PETꢀbased
fluorescent chemosensors, see: (a) Bissell, R. A.; de Silva, A. P.;
Gunaratne, H. Q. N.; Lynch, P. L. M.; Maguire, G. E. M.; McCoy,
C. P.; Sandanayake, K. R. A. S. Top. Curr. Chem. 1993, 168, 223–
264. (b) da Silva, A. P.; Uchiyama, S. Top. Curr. Chem. 2011, 300,
1–28. For an overview of ICT signaling, and other approaches, see:
(c) Demchenko, A.P. Introduction to Fluorescence Sensing, Chapter
6, Springer Science: London, 2009; see also ref. 1.
12. Treatment of 8 (0.5 ꢁM, 90% CH3CN:H2O) with up to 105
equivalents of TFA produces no fluorescence response.
13. While the present system is almost unique in that oxygen
coordination leads to a direct perturbation of the excited state of a
single chromophore, it must be mentioned that there are other
oxygen coordinationꢀbased signaling motifs, such as polyether
coordination that leads to changes in the degree of excimer
formation between two pendant chromophores, or calixarene
coordination events that lead to displacement of a chromophore and
a subsequent solvatochromic shift in emission. (See refs 1 and 2.) In
what may be regarded as the first designed fluorescent
chemosensor, crown ethers containing an integrated naphthalene
group were found to respond to metal ion binding via changes in
fluorescence: Sousa, L. R.; Larson, J. M. J. Am. Chem. Soc. 1977,
99, 307ꢀ310.
14. Consistent with the posited Hꢀbonding, sulfoxides are known
to protonate selectively at oxygen in the presence of strong acid; see
ref. 3a.
15. While our experience has been that aryl sulfoxides are
consistently less emissive than the parent aryls, there are exceptions
to this trend that provide a cautionary note for fluorophore variation:
a) Christensen, P. R.; Nagle, J. K.; Bhatti, A.; Wolf, M. O. J. Am.
Chem. Soc. 2013, 135, 8109ꢀ8112. b) Dane, E. L.; King, S. B.;
Swager, T. B. J. Am. Chem. Soc. 2010, 132, 7758ꢀ7768.
3. For reviews of sulfoxide metal coordination, see: a) Calligaris,
M. Coord. Chem. Rev. 2004, 248, 351ꢀ375. b) Calligaris, M.;
Carugo, O. Coord. Chem. Rev. 1996, 153, 83ꢀ154.
4. For previous mention of the response of phenyl pyrenyl
sulfoxide in CH2Cl2 to added metal ions, see: Malashikhin, S.
Finney, N. S. J. Am. Chem. Soc. 2008, 130, 12846ꢀ12847.
5. See Supporting Information.
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