Cyanide detection using a triazolopyridinium salt

Article abstract of DOI:10.1021/ol4008298

A triazolopyridinium salt chemodosimeter has been developed that displays a 60-fold enhancement in fluorescence upon reaction with cyanide. The novel, fast, selective and sensitive reaction-based indicator relies on the pseudopericyclic ring opening of the bridgehead nitrogen-containing detector.

Full text of DOI:10.1021/ol4008298

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Cyanide Detection Using a
Triazolopyridinium Salt
Thomas F. Robbins, Hai Qian, Xin Su, Russell P. Hughes, and Ivan Aprahamian*
Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755,
United States
ivan.aprahamian@dartmouth.edu
Received March 26, 2013
ABSTRACT
A triazolopyridinium salt chemodosimeter has been developed that displays a 60-fold enhancement in fluorescence upon reaction with cyanide.
The novel, fast, selective and sensitive reaction-based indicator relies on the pseudopericyclic ring opening of the bridgehead nitrogen-containing
detector.
Despite its toxicity,1,2 cyanide (CNꢀ) is still widely used
in mining, metallurgy, and various chemical industries,
inevitably resulting in the pollution of water supplies.3,4 As
a result, considerable attention has been devoted in recent
years to the development of CNꢀ sensors.5 Traditionally,
hydrogen bonding or supramolecular interactions have
been used in the detection of low concentrations of cyanide
in solution.6ꢀ8 These approaches, however, usually result
in poor selectivity over other common anions.9 The bur-
geoning field of reaction-based indicators has made prog-
ress in this area because of the unique reactivity of CNꢀ
toward a variety of organic functional groups10,11 including
CdO,9,11b,11h,11j CdN,11f,g and CdC.11k,i Other advantages
of this approach include the irreversible formation of chemi-
cal bonds that can provide chemodosimetric information10c
and lead to remediation as well as detection.9b There is an
ever-present need to develop new reaction-based CNꢀ sen-
sors, as these can help overcome lingering obstacles in its
detection,10 such as selectivity, sensitivity, response times,
sensor stability, reaction conditions, etc.11 Here we report a
(1) World Health Organization. Concise International Chemical Assess-
ment Document 61. Hydrogen cyanide and cyanides: human health aspects;
Geneva, 2004; 4ꢀ5. http://www.who.int/ipcs/publications/cicad/en/cicad61.
pdf (accessed Sep. 17, 2012).
(2) Taylor, J.; Roney, N.; Harper, C.; Fransen, M.; Swarts, S.
Toxicological Profile for Cyanide; U.S. Department of Health and Human
Services: Atlanta, GA, 2006; 6ꢀ7.
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J.; Hu, M.; Fan, J.; Peng, X. Chem. Soc. Rev. 2012, 41, 4511. (d) Chan, J.;
Dodani, S. C.; Chang, C. J. Nat. Chem. 2012, 4, 973.
(3) The United States Environmenꢀtal Protection Agency has set the
maximum contaminant level for CN in drinking water at 0.2 ppm:
Kulig, K. W. Cyanide Toxicity; U.S. Department of Health and Human
Services: Atlanta, GA, 1991.
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Sun, Y.; Wang, G.; Guo, W. Tetrahedron 2009, 65, 3480. (c) Kim, D.-S.;
Chung, Y.-M.; Jun, M.; Alm, K. H. J. Org. Chem. 2009, 74, 4849. (d)
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r
10.1021/ol4008298
XXXX American Chemical Society

new fluorescence turn-on chemodosimeter that exhibits fast,
sensitive, and selective detection of CNꢀ under mild condi-
tions. The reaction-based system relies on a well established
and studied ring-opening reaction of bridgehead nitrogen-
containing azolopyridinium salts (Scheme 1).12
has led us to compound 1, which was synthesized in a few
simple steps (Scheme 2): p-Anisidine was treated with conc.
HCl in H2O and then with NaNO2 at 0 °C to give the
p-anisidenediazonium chloride salt. A solution of ethy1ꢀ2-
(pyridin-2-yl)acetate that was pretreated with sodium acetate
was then added to this solution to afford the hydrazone
precursor. The latter was subsequently oxidized with 4 equiv
Scheme 1. Reaction-Based Detection of CNꢀ Using the
Triazolopyridinium Salt 1
of Cu(ClO4)2 6H2O in CH3CN at 55 °C to give 1 as an off-
3
white solid in 46% yield. Both 1 and the hydrazone precursor
were characterized using NMR spectroscopy and ESI-MS
(Supporting Information).
Scheme 2. Synthetic Route towards the Triazolopyridinium
Salt 1
We have recently reported the synthesis and photophys-
ical properties of water-soluble triazolopyridinium salts13
derived from our hydrazone-based switches.14 We hy-
pothesized that the ring-opening reaction in these systems
would lead to conjugated triazole-based derivatives that can
potentially be emissive15 and, hence, used in CNꢀ sensing.
Our choice of a sensor was based on how the emission
properties of the newly formed cyano-containing triazole
derivative might be best distinguished from the emission
properties of the starting material. The triazolopyridinium
salts emit blue light upon excitation,13 and we anticipated
that the extended π-conjugation in the cyano adduct will lead
to a bathochromic shift. A recent report showed that having
a p-OMe substituted phenyl ring at the N-2 position of the
triazole ring can lead to enhanced emission.15a On the other
hand, and based on our previous results,13 this substituent
was expected to quench the emission of the triazolopyridi-
nium dye through charge transfer. Hence, we decided to
incorporate a p-OMe substituent in our design (Scheme 2) to
enhance the change in emission upon reaction with CNꢀ.
Moreover, we added an ethyl ester group at position C-5 to
increase the conjugation in the system. This rational design
Figure 1. 1H NMR spectra (DMSO-d6 at 294 K) of (a) 1 and (b) a
crude mixture of E/Z isomers of 2, obtained after adding 1 equiv
of NaCN to 1.
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1H NMR spectroscopy studies in DMSO-d6 suggest that
the ring-opening reaction reported in the literature for
analogous azolopyridinium salts12 occurs rapidly with 1
as well. The 1H NMR spectrum changes immediately upon
the addition of 1 equiv of NaCN to 1 (Figure 1). The
appearance of upfield alkene signals implies the formation
of 2 (Scheme 1), which equilibrates over time to give an
85:15 mixture of the Z and E isomers, respectively. This
assignment was inferred from the coupling constants of the
signals at 5.94 and 6.17 ppm, J = 10.9 and 16.1 Hz, respec-
tively (Supporting Information, Figure S4). Compound 2
was isolated as an inseparable mixture of Z and E isomers
and characterized by NMR spectroscopy and ESI-MS
(Supporting Information).
ꢀ
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Riedl, Z.; Hajos, G. J. Organomet. Chem. 2010, 695, 2673.
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4160.
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18269. (b) Su, X.; Aprahamian, I. Org. Lett. 2011, 13, 30. (c) Su, X.;
Robbins, T. F.; Aprahamian, I. Angew. Chem., Int. Ed. 2011, 50, 1841.
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Elhabiri, M.; Goddard, W. A., III; Aprahamian, I. J. Am. Chem. Soc.
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Chem. 2012, 8, 872. (f) Ray, D.; Foy, J. T.; Hughes, R. P.; Aprahamian,
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Aprahamian, I. Chem. Commun. 2012, 48, 10490. (h) Yang, Y.; Hughes,
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B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 3. Pseudopericyclic Pathway for Ring Opening/Closing
transfer from the phenyl ring to the triazolopyridinium
subunit. The addition of 2 equiv of NaCN to 1 affords 2,
which upon excitation at330 nm yields a 60-fold increasein
fluorescence relative to 1 at λmax = 504 nm (Figure 3a).
Compound 2 has a broad emission ranging from 400ꢀ
620 nm and a quantum yield of 0.45 ( 0.02, which is
15 times higher than that of 1 (0.03 ( 0.02). An accurate
estimation of the Stokes shift was precluded by the absorp-
tion of DMSO below 350 nm. However, when the spectro-
scopic analysis was carried out in acetonitrile a “mega”
Figure 2. Free energy landscape calculated (DFT/B3LYP-D3/
6-311þþG**)(DMSO) for opening of cyanotriazole intermedi-
ate via pseudopericyclic pathways to give Z- and E-products.
(larger than 100 nm)19 Stokes shift of 177 nm (56,500 cmꢀ1
)
Values of ΔG are in kcal molꢀ1. The ester and aryl groups were
(Supporting Information, Figure S10) was measured. Such
large Stokes shifts and broad emission profiles have been
reported previously for other triazole-based systems.15a
Compound 1 exhibits a turn-on response upon the
addition of NaCN, enabling its visual detection upon
excitation in the UV range (Figure 3b). Because of the
unique fluorescent properties of 2, a limit of detection
(LOD) of 0.2 ppm (8.46 μM) in DMSO/H2O (99:1) was
determined for CNꢀ (Supporting Information, Figure S7),
which is at the level set by the United States Environmental
Protection Agency.3 Moreover, the reaction between 1 and
3
removed for the sake of clarity. See Supporting Information
Figure S19 for full structures.
To better understand the energetics and stereochemistry
of the ring-opening reaction (Scheme 1) DFT calculations
(B3LYP-D3/6311þþG**) were carried out using a DMSO
solvent model.16,17 The energetics are summarized in
Figure2. The ring opening is thermodynamically favorable
by 34.5 kcal/mol for both Zand Eisomers. However, opening
to give the Z isomer is kinetically favored by 0.8 kcal molꢀ1
3
with very large barriers for reclosure, consistent with the
observed Z/E isomer ratio of 85:15 being kinetically
controlled. Application of NBO techniques (Supporting
Information, Figures S28ꢀS31 and Table S1) to the transition
state illustrates that the reaction follows a pseudopericyclic
pathway18 (Scheme 3), and not a disrotatory electrocyclic
ring-opening reaction as previously suggested.12a,b In the ring-
closing direction, population of the C4ꢀC5 π* orbital occurs
by depletion of electron density in the original N6 lone pair
(not the C1ꢀN6 π orbital) to give the new C5ꢀN6 σ-bond.
The C1ꢀN6 π orbital evolves into the new N6 lone pair. Thus
the transformation includes eight electrons in a cyclic orbital
array and takes place in concert because it is not subject to the
WoodwardꢀHoffmann rules. Full details of this analysis are
provided in the Supporting Information.
The photophysical properties of 1 and 2 were studied in
aqueous DMSO (Figure 3a). The emission intensity of 1 is
much lower than that for the previously reported deriva-
tive that lacks the p-OMe substituent.13 As expected this
group quenches the emission of 1 by enhancing the charge
Figure 3. (a) Fluorescence intensity spectra of 1 (2.5 ꢁ 10ꢀ5 M in
DMSO/H2O (99:1)) recorded after the addition of 2 equiv of the
sodium salts of various anions (1 alone, CNꢀ, Iꢀ, N3ꢀ, AcOꢀ,
Fꢀ, NO3ꢀ, H2PO4ꢀ, Clꢀ, Brꢀ, and SCNꢀ). (b) Fluorescence
change of 1 observed upon excitation at 365 nm after the
addition of various anions (conditions identical to those de-
scribed above).
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Org. Lett., Vol. XX, No. XX, XXXX
C

2 equiv of CNꢀ occurs almost instantaneously (Figure S11).
These results attest to the reactivity of 1 and show how it can
be quickly used in the detection of low quantities of CNꢀ.
To evaluate the selectivity of sensor 1, 2 equiv of various
potentially competing anions (studied as their correspond-
selective 60-fold increase in emission is observed upon the
addition of NaCN to 1, enabling the quick detection of
0.2 ppm of the analyte. The characterization of the fluores-
cent cyano adduct 2 confirmed that the ring-opening reaction
of the bridgehead nitrogen is responsible for the observed
sensing capability of 1. This process was further elucidated
using DFT/NBO calculations, which showed that it most
likely proceeds via a pseudopericyclic pathway. We are
currently working on further optimizing the conditions of
this reaction in order to employ it in real-world applications.
ꢀ
ing sodium salts) including Iꢀ, N3ꢀ, AcOꢀ, Fꢀ, NO3
,
H2PO4ꢀ, Clꢀ, Brꢀ, and SCNꢀ were each added to DMSO/
H2O (99:1) solutions of 1. The fluorescent properties of the
resulting solutions remained unaffected for days (Figure 3a
and b and Supporting Information Figure S8) demonstrat-
ing the high selectivity of the ring-opening reaction toward
cyanide.22
Acknowledgment. This work was supported by Dart-
mouth College and the Burke Research Initiation Award.
R.P.H. thanks the National Science Foundation for an
operating grant that made possible the purchase of hard-
ware and software used for the DFT calculations.
In conclusion we have shown that the triazolopyridi-
nium salt 1 is an efficient reaction-based sensor for CNꢀ. A
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Supporting Information Available. Experimental pro-
cedures, NMR spectra, emission spectra, and computa-
tional data. This material is available free of charge via
the Internet at http://pubs.acs.org.
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(22) No reaction was observed between the competing anions and 1
by 1H NMR spectroscopy. On the other hand, the hydroxide ion reacts
with 1 leading to a nonemissive triazole derivative.
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The authors declare no competing financial interest.
D
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