A pyridinium cation-π interaction sensor for the fluorescent detection of alkyl halides

Article abstract of DOI:10.1039/c0cc01420f

N-Alkylation of a novel pyridine sensor results in pyridinium salts whose conformations are stabilised by pyridinium cation-π interactions resulting in a fluorescent response that can be used to sense the presence of alkylating agents in solution at low c

Full text of DOI:10.1039/c0cc01420f

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A pyridinium cation–p interaction sensor for the fluorescent detection of
alkyl halideswz
a
a
ab
Wenbo Chen, Souad A. Elfeky, Yse Nonne, Louise Male,a Kabir Ahmed,a
Claire Amiable,bc Philip Axe,c Shinji Yamada,d Tony D. James,c Steven D. Bull*c and
John S. Fossey*ae
´
Received 15th May 2010, Accepted 10th June 2010
DOI: 10.1039/c0cc01420f
N-Alkylation of a novel pyridine sensor results in pyridinium
salts whose conformations are stabilised by pyridinium cation–p
interactions resulting in a fluorescent response that can be used
to sense the presence of alkylating agents in solution at low
concentration.
fluorescence spectroscopy to show that conversion of
conformationally flexible 4-(phenylpropyl)-pyridine 1 into its
corresponding N-methyl-pyridinium iodide 2a (Scheme 1)
results in a large change in fluorescence response, due to the
presence of intramolecular cation–p interactions in 2a.16
Consequently, we now report that the increased fluorescent
response of pyridinium salts 2 may be exploited to enable
pyridine 1 to be used to sense the presence of low concen-
trations of alkylating agents in solution (Scheme 2).17,18
We reasoned that the contrasting fluorescent properties of
pyridine 1 and its corresponding N-alkyl-pyridinium salts 2
might enable it to be used as a sensor to detect the presence of
alkylating agents in solution. In order to test this hypothesis,
aliquots of methyl iodide (0–0.6 mM) were sequentially added
to a solution of pyridine 1 in CH2Cl2 (1.0 mM) and the
fluorescent spectra of the solution recorded 5 minutes after
each addition. This revealed an eleven fold fluorescence
enhancement (F/Fo) over the concentration range (0–0.6 mM)
of methyl iodide assayed (see Fig. 1).19 In order to determine
the detection limits of this sensor we reduced the concentration
of pyridine 1 to 0.01 mM in CH2Cl2 and assayed its fluorescent
response to the presence of low concentrations of methyl
iodide (0–400 nM). This resulted in a three fold increase in
fluorescence over a concentration range of 0–400 nM, with a
lower detection limit for methyl iodide of 1 nM (see Fig. 2 and
ESIw).
Potent alkylating agents such as methyl iodide or benzyl
bromide are extremely useful reagents for organic synthesis
that have been used widely for the synthesis of many drug
molecules. However, their inherent reactivity means they are
potentially toxic/mutagenic due to their ability to react with
numerous biological nucleophiles present within the human
body.1 Consequently, their use requires rigorous detection
regimes to ensure that no alkylating agent is present in any
pharmaceutical agent that is used for human consumption.2
Alkylating agents are also present in trace amounts in the
environment due to their use as soil sterilizers,3 cancer drugs,4
chemical reagents and chemical weapon agents.5 Therefore,
there is significant demand for the development of reliable
assays that allow the presence of alkylating agents to be
detected in a wide range of scenarios.6
Cation–p interactions have been widely exploited in
supramolecular chemistry, where they play pivotal roles in
the design of host–guest assemblies7 and synthetic receptors.8
These type of interactions have also proven useful for
synthesis,9 where their presence has been invoked to explain
the selectivity of nucleophilic catalysts,10 cyclopropanations,11
cycloadditions12 and various nucleophilic additions.13 In the
biological arena cation–p interactions have been implicated in
many biomolecular recognition events,14 whilst they also play
an important role in stabilising the secondary and tertiary
structures of proteins.15 We have previously used NOEsy and
In order to demonstrate the potential of this cation–p
stacking sensor towards other types of alkylating agent, we
then treated pyridine 1 (1.0 mM, CH2Cl2) with a range of
commonly used electrophiles 3a–k (0.6 mM) under reflux
for 3 h to ensure complete consumption of electrophile, and
determined the maximum fluorescence of each solution. In
each case a fluorescence enhancement was observed (29–114 fold
increase), indicating that pyridine 1 has the potential to be
used as a sensor for a wide range of alkylating agents. It is
a School of Chemistry, University of Birmingham, Edgbaston,
Birmingham, West Midlands, B15 2TT, UK.
E-mail: j.s.fossey@bham.ac.uk; Web: www.johnfossey.com
b
´
´
ESCOM (Ecole Superieur de Chimie Organique et Minerale), 1,
´
´
`
Allee du reseau Jean-Marie Buckmaster, 60200 Compiegne, France
c Department of Chemistry, University of Bath, Claverton Down,
Bath, BA2 7AY, UK. E-mail: s.d.bull@bath.ac.uk
d Department of Chemistry, Ochanomizu University, 2-1-1 Otsuka,
Bunkyo-ku, Tokyo 112-8610, Japan
e Department of Chemistry, Ochanomizu University, 2-1-1 Otsuka,
Bunkyo-ku, Tokyo 112-8610, Japan
w Electronic supplementary information (ESI) available: A representative
synthetic procedure, corresponding analysis and X-ray crystallographic
data. CCDC 775629. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c0cc01420f
Scheme 1 Alkylation of pyridine 1 with methyl iodide forms pyridi-
nium 2 which exhibits characteristic cation–p fluorescence.
z This article is part of the ‘Emerging Investigators’ themed issue for
ChemComm.
ꢀc
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Scheme 2 Screening of fluorescent response of N-alkyl-pyridinium
salts 2a–k derived from different alkylating agents.
Fig.
3
ORTEP plot of 2i with ellipsoids drawn at the 50%
probability level. Atoms N(1) and C(10) lie on the same site at 50%
occupancy each. Selected bond lengths (A) and angles (1): C(9)–C(10)/
N(1) = 1.490 (9), C(10)/N(1)–C(11) = 1.371 (8), C(10)/N(1)–C(12) =
1.379 (8), C(4)–C(7)–C(8) = 111.9 (5), C(7)–C(8)–C(9) = 112.5 (5),
C(8)–C(9)–C(10)/N(1) = 111.5 (5), C(11)–C(10)/N(1)–C(12) = 118.9
(6), C(4)–C(7)–C(8)–C(9) = ꢁ171.0 (5), and C(7)–C(8)–C(9)–C(10) =
62.2 (7).
heavy atom quenching effect of the iodide counter ion.19
Whilst alkylation of pyridine 1 with the potent triflate/iodide
alkylating agents 3a–c gave an almost instantaneous increase
in fluorescence (seconds), use of alkyl bromides 3d–k required
a longer time (hours) to react before solutions with stable
fluorescence maxima were obtained. The corresponding
control experiments where pyridine and benzene with and
without added methyl iodide had previously confirmed an
intramolecular interaction is responsible for the observed
fluorescence.16a
Fig.
1 Fluorescence increase on addition of aliquots of MeI
(0 to 0.6 mM) to a solution of pyridine 1 (1.0 mM) in CH2Cl2
(lex = 260 nm); F/F0 versus wavelength (nm) for increasing [MeI].
A range of N-alkyl-pyridinium salts 2a–k were then
prepared in order to confirm that these species were responsible
for the fluorescent response observed in these assays. Isolated
yields of each fluorescent salt were generally high (>90%).20 The
structure of compound 2i was determined by X-ray crystallo-
graphy (see Fig. 3),21 which revealed that electrostatic
cation–anion interactions dominate in the solid state, with no
intramolecular cation–p stacking interactions being observed.16b
In conclusion, we have reported an operationally simple,
robust and cheap pyridine sensor 1 for the fluorescent
detection of a range of commonly employed alkylating agents.
We are currently working on the design of new pyridine
architectures with higher fluorescent output and improved
response time that we envisage will enable even lower
concentrations of alkylating agent to be detected.
The Leverhulme Trust, Royal Society, Universities of
Birmingham and Bath, EPSRC, Birmingham AWM II and
the JSPS are thanked for support. SAE acknowledges
Cairo University (NILES-LAMPA). The EPSRC National
Crystallography Service is thanked for the collection of
X-ray diffraction data on 2i.
Fig. 2 Fluorescence F/F0 at 400 nm for addition of MeI (0–400 nM)
to pyridine 1 (0.01 mM) in CH2Cl2 (lex = 260 nm).
Notes and references
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pyridinium triflate salt 2b was 2.3 fold greater than the
corresponding iodide salt 2a, which we ascribed to the known
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20 Pyridinium salt 2j was not isolated as a single compound, rather as
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21 X-Ray crystal structure data for 2i: single crystals of 2i were
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group Pbca (no. 61),
Z = 4, 22 489 reflections measured,
2183 unique (Rint = 0.0468) which were used in all calculations.
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