Fluorescent chemosensor for chloroalkanes

Article abstract of DOI:10.1021/ol8003723

Two structurally related macrocyclic amines with naphthalene groups are shown to act as fluorescent dosimeters for reactive chloroalkanes, including the common Industrial solvent dichloromethane. The macrocyclic structures contain two NH residues which greatly accelerate N-alkylation by activating the chloride leaving group. The chemical reaction increases fluorescence Intensity by promoting excimer emission and attenuating the quenching Induced by photoinduced electron transfer (PET).

Full text of DOI:10.1021/ol8003723

ORGANIC
LETTERS
2008
Vol. 10, No. 9
1735-1738
Fluorescent Chemosensor for
Chloroalkanes
Jung-Jae Lee, Bruce C. Noll, and Bradley D. Smith*
Department of Chemistry and Biochemistry, UniVersity of Notre Dame,
Notre Dame, Indiana 46556
smith.115@nd.edu
Received February 18, 2008
ABSTRACT
Two structurally related macrocyclic amines with naphthalene groups are shown to act as fluorescent dosimeters for reactive chloroalkanes,
including the common industrial solvent dichloromethane. The macrocyclic structures contain two NH residues which greatly accelerate
N-alkylation by activating the chloride leaving group. The chemical reaction increases fluorescence intensity by promoting excimer emission
and attenuating the quenching induced by photoinduced electron transfer (PET).
Although they are known to be toxic chemicals,1 chloroal-
kanes are produced in large amounts for various applications
in modern society.2 For example, dichloromethane is widely
used as a solvent for extraction and synthesis,3 and it is also
a common component in paint strippers and removers.4 The
homologue, 1,2-dichloroethane, is produced in much larger
amounts primarily for use as a precursor monomer for
poly(vinyl chloride).5 More reactive chloroalkanes are em-
ployed as pharmaceuticals,6,7 insecticides,8 and chemical
warfare agents.9 Since many of these compounds have long
residence times in the environment, there is a need to develop
methods of detecting and scavenging them from contami-
nated air and water streams.10 This report describes a
prototype fluorescent chemosensor that can detect certain
types of chloroalkanes. The design is based on our recent
discovery that amine macrocycle 1 attacks chloroalkanes with
unusually high reactivity.11 For example, it reacts with
dichloromethane solvent to form the quaternary ammonium
salt 2 with a half-life of 2 min at room temperature (Scheme
1). This is about 50000 times faster than the analogous
(1) (a) ClaysonD. B. Chemical Carcinogenesis; Little, Brown and
Company: Boston, 1962; p 176. (b) Searle, C. E. Chemical Carcinogens,
2nd ed.; ACS Monograph 182; American Chemical Society: Washington,
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1994, 33, 1920. (d) Watanabe, K.; Liberman, R. G.; Skipper, P. L.;
Tannenbaum, S. R.; Guengerich, F. P. Chem. Res. Toxicol. 2007, 20, 1594.
(e) Ahmed, A. E.; Anders, M. W. Drug. Metab. Dispos. 1976, 4, 357. (f)
Their, R.; Taylor, J. B.; Pemble, S. E.; Humphreys, W. G.; Persmark, M.;
Ketterer, B.; Guengerich, F. P. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 8576.
(2) Fishbein, L. J. Toxicol. EnViron. Health. 1980, 6, 1133.
(3) (a) Bekkevoll, S.; Svorstøl, I.; Høiland, H.; Songstand, J. Acta Chem.
Scand. B 1983, 37, 935. (b) Kost, D.; Aviram, K. J. Am. Chem. Soc. 1986,
108, 2006.
(5) (a) Hollaway, P.; Knoke, K. L.; Trevors, J. T.; Lee, H. Biotechnol.
Bioeng. 1998, 59, 520. (b) Kirk-Othmer Encyclopedia of Chemical
Technology, 4th ed.; Wiley: New York, 2003; Vol. 6, p 253.
(6) Izbicka, E.; Tolcher, A. W. Curr. Opin. InVest. Drugs. 2004, 5, 587.
(7) Sanderson, B. J. S.; Shield, A. J. Mutat. Res. 1996, 355, 41.
(8) Mathew, G.; Abdul Rahiman, M.; Vijayalaxmi, K. K. Mutagenesis
1990, 5, 147.
(9) Munro, N. B.; Talmage, S. S.; Griffin, G. D.; Waters, L. C.; Watson,
A. P.; King, J. F.; Hauschild, V. Curr. Opin. InVest. Drugs. 1999, 107,
933.
(10) Kirk-Othmer Encyclopedia of Chemical Technology, 5th ed.; Wiley:
New York, 2003; Vol. 16, p 81.
(11) Lee, J.-J.; Stanger, K.; Noll, B.; Gonzalez, C.; Marquez, M.; Smith,
B. D. J. Am. Chem. Soc. 2005, 127, 4184.
(4) Kirk-Othmer Encyclopedia of Chemical Technology, 5th ed.; Wiley:
New York, 2003; Vol. 16, p 371.
10.1021/ol8003723 CCC: $40.75
Published on Web 03/26/2008
2008 American Chemical Society

reactivity due to activation by the two NH residues in the
macrocyclic cavity, and also gain a fluorescent enhancement
effect due to loss of PET quenching upon N-alkylation. The
structural difference between 3 and 4 is the replacement of
an electron-donating methylene unit attached to each naph-
thalene with a withdrawing carbonyl. As shown below, this
leads to a significant change in the PET quenching response.
We expected that the free base forms of 3 and 4 would
exhibit low fluorescence due to PET quenching of the
naphthalenes by the centrally located tertiary amine, and that
fluorescent intensity would increase as the accelerated
N-alkylation reaction occurs to give products 5 and 6. As
discussed below, an additional sensing feature is the pro-
pensity of the ion-pair products to self-associate and form
aggregates that exhibit excimer emission spectra.
Scheme 1
alkylation reaction with control acyclic amines. Similar rate
accelerations have also been measured with other types of
primary chloroalkanes and detailed mechanistic studies
indicate that macrocycle 1 exhibits enzyme-like properties
to accelerate the bimolecular alkylation reaction.12 Most
importantly, the chloroalkane associates with the macrocycle
to form a prereaction complex, which allows the two NH
residues in the macrocyclic cavity to activate the chloride
leaving group as the adjacent electrophilic carbon is attacked
by the macrocyclic amine nitrogen. After reaction, the
chloride leaving group remains strongly associated with the
quaternary ammonium cation such that 2 is a contact ion
pair. Furthermore, ion pair 2 has a tendency to form a cofacial
aggregate in the solid state and in weakly polar solvents.11
Previous investigations of fluorescent sensors for haloal-
kanes have used fluorescent amines to react covalently and
form ammonium salts.13 The reaction leads to an increase
in fluorescence intensity because it decreases quenching by
photoinduced electron transfer (PET) from the lone pair on
the nucleophilic amine to the attached fluorophore.14 Herein,
we describe the reactivity and fluorescence sensing properties
of naphthalene containing macrocycles 3 and 4 (Scheme 2).
The synthesis of compounds 3 and 4 was achieved in
straightforward fashion using methods that are described in
the Supporting Information. Macrocycle 3 was obtained as
single crystals, which allowed analysis by X-ray diffraction.
As shown in Figure 1, the solid-state macrocyclic conforma-
Figure 1. X-ray crystal structure of the macrocycle 3; the unit cell
packs as a cofacial dimer.
Scheme 2
tion closely matches that of parent 1 with the lone pair of
the amine nitrogen pointing into the macrocyclic cavity and
poised to attack an associated chloroalkane. Also shown is
the unit cell packing of two cofacial macrocycles in a head
to tail orientation with close overlap of the naphthalene units.
The reactivity of macrocycles 3 and 4 was first evaluated
by measuring rate constants in dichloromethane solvent.
NMR studies showed that the reaction products 5 and 6 (R′
) Cl) were obtained in quantitative yield, and pseudo-first-
order rate constants were measured using a previously
described HPLC method.12 The second-order rate constant
with 3 in dichloromethane was 2.9 × 10-4 M-1 s-1 at
25 °C, which corresponds to a half-life of about 1 min. This
is approximately two times faster than the reaction of original
macrocycle 1 with dichloromethane. The reaction of analogue
4 in dichloromethane is about 50 times slower with a second-
order rate constant of 6.3 × 10-6 M-1 s-1 and a half-life of
almost 1 h. It appears that the presence of the two electron-
withdrawing carbonyl groups in 4 decreases the nucleophi-
licity of its attacking nitrogen.
The designs incorporate two identical naphthalene fluoro-
phores within the macrocyclic scaffold of parent 1 in a way
that does not change the number of atoms in the macrocyclic
cavity. Thus, we expected to maintain the high chloroalkane
(12) Stanger, K.; Lee, J,-J.; Smith, B. D J. Org. Chem. 2007, 72, 9663.
(13) (a) Tal, S.; Salman, H.; Yael, A.; Botoshansky, M.; Eichen, Y.
Chem. Eur. J. 2006, 12, 4858. (b) Dale, T. J.; Rebek, J. J. Am. Chem. Soc.
2006, 128, 4500.
(14) (a) de Silva, A. P.; Gunaratne, H. Q. N.; Gunnlaugsson, T.; Huxley,
A. J. M.; McCoy, C. P.; Rademacher, J. T.; Rice, T. E. Chem. ReV. 1997,
97, 1515. (b) Weller, A. Pure Appl. Chem. 1968, 16, 115.
1736
Org. Lett., Vol. 10, No. 9, 2008

Figure 2. Change in fluorescence emission for macrocycle 3 (10
µM) in tert-butylmethyl ether after treatment with dichloromethane
(2 mM) at 25 °C (ex: 306 nm).
Macrocycles 3 and 4 were subsequently evaluated for their
abilities to sense the presence of dichloromethane in the inert
solvent tert-butylmethyl ether. Figure 2 shows the change
in fluorescence emission of 3 (10 µM) in tert-butylmethyl
ether after addition of 2 mM of dichloromethane. Over 200
min, there was a modest enhancement of the monomer
emission at 420 nm, presumably due to reaction induced
inhibition of PET quenching, and a stronger enhancement
of the excimer emission band at 520 nm. It appears that as
the reaction progresses, the ion-pair product 5 (R′ ) Cl)
aggregates in the weakly polar solvent. A more dramatic
change in emission spectra was obtained when 3 was treated
with the more reactive chloromethyl methyl ether, a repre-
sentative carcinogenic alkylating agent. As expected, the
Figure 4. (Top) Fluorescence emission of: (a) macrocycle 3 (10
µM) in tert-butylmethyl ether, (b) after addition of TFA aliquots
(up to 100 µM), and (c) subsequent single addition of tetrabuty-
lammonium chloride (10 µM). (Bottom) Fluorescence emission of:
(d) macrocycle 3 (10 µM) in tert-butylmethyl ether before and after
addition of tetrabutylammonium chloride (100 µM) and (e)
subsequent addition of TFA aliquots (up to 100 µM). T ) 25 °C
(ex: 306 nm).
N-alkylation reaction was much faster. For example, treat-
ment of 3 (20 µM) with 1 molar equiv of chloromethyl
methyl ether in tert-butylmethyl ether solvent leads to
complete reaction after 10 min. Again, there is a modest
increase in the monomer emission band at 420 nm, but now
a much larger increase in the excimer band at 520 nm (Figure
3). Thus, compared to the previous reaction product 5 (R′
) Cl), the propensity of product 5 (R′ ) OMe) to aggregate
in weakly polar solvent is greater.
Further evidence that the excimer band at 520 nm is due
to product self-aggregation was gained from the following
titration experiments. As shown in the top of Figure 4, the
fluorescence emission of macrocycle 3 (10 µM) is slightly
enhanced upon protonation by trifluoroacetic acid (TFA) (100
µM) which inhibits PET quenching. A subsequent additon
of tetrabutylammonium chloride (10 µM) leads to aggrega-
tion of the 3·HCl ion pair and significant enhancement of
the excimer emission band at 520 nm. Reversing the addition
order produces the outcome shown in the bottom of Figure
4. As expected, adding tetrabutylammonium chloride to
macrocycle 3 induces no change in fluorescence emission,15
Figure 3. (Top) Change in fluorescence emission of macrocycle 3
(15) Even though Cl- associates with 3 in weakly polar solvent (see
citation 24 in ref 12) the data in Figure 4 indicates that it does not
induce any heavy atom quenching. Furthermore, UV spectra of 3 and the
product 5 are almost identical and show no evidence for charge-transfer
formation.
(20 µM) in tert-butylmethyl ether after addition of chloromethyl
methyl ether (20 µM) at 25 °C. (Bottom) Change in intensity ratio
for excimer (I500) divided by monomer (I425) (ex: 306 nm).
Org. Lett., Vol. 10, No. 9, 2008
1737

Figure 5. Change in fluorescence emission for macrocycle 4 (10
µM) in tert-butylmethyl ether after addition of dichloromethane
(14 mM) at 25 °C (ex: 306 nm).
Figure 6. Change in fluorescence emission for macrocycle 4 (10
µM) in tert-butylmethyl ether after addition of chloromethyl methyl
ether (10 µM) at 25 °C (ex: 306 nm).
but subsequent protonation by TFA induces ion-pair ag-
gregation and excimer formation.
In summary, we have prepared macrocycles 3 and 4 and
evaluated them as fluorescent dosimeters for chlorolkanes.
Macrocycle 3 is the more reactive sensor, whereas macro-
cycle 4 gives the larger signal enhancement. Depending on
the exact sensing application, either of these two prototype
chemosensors may be useful for optimization within analyti-
cal devices that measure the amount of chloroalkane in
polluted air. We envision a design that draws air through a
nonvolatile liquid or thin film containing the chemosensor.
The naphthalene units in macrocycle 4 have a lower
reduction potential due to the attached withdrawing carbonyl
groups which makes quenching by PET from the central
tertiary amine thermodynamically more favorable.14 Thus,
macrocycle 4 was expected to produce a stronger fluores-
cence response upon reaction with chloroalkanes. Indeed,
treatment of 4 in tert-butylmethyl ether with dichloromethane
(Figure 5) and the more reactive chloromethyl methyl ether
(Figure 6) produced large enhancements in the monomer
emission bands at 398 nm and much smaller changes in the
corresponding excimer bands. The large increase in fluores-
cent intensity observed with this macrocycle prompted us
to demonstrate fluorescent sensing by the naked eye. Shown
in the Supporting Information is a comparison of three
cuvettes, each containing macrocycle 4 in tert-butylmethyl
ether. The cuvettes treated with dichloromethane or chlo-
romethyl methyl ether are clearly brighter than the untreated
control cuvette.
Acknowledgment. Financial support for this work was
provided by the ACS-Petroleum Research Fund.
Supporting Information Available: Synthetic methods,
X-ray and spectral data, kinetic data, curve fittings, and naked
eye detection data. This material is available free of charge
via the Internet at http://pubs.acs.org.
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Org. Lett., Vol. 10, No. 9, 2008