Cd(II) Sensing in Water Using Novel Aromatic Iminodiacetate Based Fluorescent Chemosensors

Article abstract of DOI:10.1021/ol035484t

(Equation presented) Compounds 1 and 2 were designed as fluorescent chemosensors for Cd(II). For both, a selective determination of Cd(II) over Zn(II) was achieved. The fluorescence emission of both was pH-independent and switched off between pH 3-11 in 1

Full text of DOI:10.1021/ol035484t

ORGANIC
LETTERS
2003
Vol. 5, No. 22
4065-4068
Cd(II) Sensing in Water Using Novel
Aromatic Iminodiacetate Based
Fluorescent Chemosensors
,†
Thorfinnur Gunnlaugsson,* T. Clive Lee,‡ and Raman Parkesh†
Department of Chemistry, Trinity College Dublin, Dublin 2, Ireland, and
Department of Anatomy, Royal College of Surgeons in Ireland,
St. Stephen’s Green, Dublin 2, Ireland
gunnlaut@tcd.ie
Received August 6, 2003
ABSTRACT
Compounds 1 and 2 were designed as fluorescent chemosensors for Cd(II). For both, a selective determination of Cd(II) over Zn(II) was
achieved. The fluorescence emission of both was pH-independent and switched off between pH 3−11 in 100% water. Whereas the recognition
of Cd(II) at pH 7.4 gave rise to the formation of charge-transfer complexes (exciplexes) for both (λmax ca. 500 and 506 nm, respectively), the
recognition of Zn(II) only switched on the (monomeric) anthracene emission of 2, while for 1 it was red-shifted (λmax ) 468 nm).
The developments of luminescent chemical devices is an
active field of research in supramolecular chemistry.1,2 An
important area within this field is the development of
luminescent chemosensors.2 Such sensors have the advantage
of possessing high sensitivity and selectivity, as well as
providing on-line and real-time analysis that has revolution-
ized the field of chemical analysis, particularly in critical
care analysis of blood and serum samples.3,4 Of the many
literature cases reported, only a few examples of fluorescent
chemosensors for Cd(II) have been described.5 Cadmium is
currently used in many processes such as the production of
nickel-cadmium rechargeable batteries for cellular phones6
and is also found in phosphate fertilizers. Because of the
(3) Spichiger-Keller, U. S. Chemical Sensors and Biosensors for Medical
and Biological Applications; Wiley-VCH: Weinheim, Germany, 1998.
(4) He, H.; Mortellaro, M. A.; Leiner, M. J. P.; Fraatz, R. J.; Tusa, J. K.
J. Am. Chem. Soc. 2003, 125, 1468. Tusa, J. K.; Leiner, M. J. P. Ann. Biol.
Clin. 2003, 61, 183.
(5) (a) Costero, A. M.; Andreu, R.; Monrabal, E.; Martinez-Manez, R.;
Sancenon, F.; Soto, J. J. Chem. Soc., Dalton Trans. 2002, 1769. (b) Prodi,
L.; Montalti, M.; Zaccheroni, N.; Bradshaw, J. S.; Izatt, R. M.; Savage, P.
B. Tetrahedron Lett. 2001, 42, 2941. (c) Choi, M.; Kim, M.; Lee, K. D.;
Han, K. N.; Yoon, I. A.; Chung, H. J.; Yoon, J. Org. Lett. 2001, 3, 3455.
(d) Charles, S.; Yunus, S.; Dubois, F.; Vander Donckt, E. Anal. Chim. Acta
2001, 440, 37. (e) Ertas, N.; Akkaya, E. U.; Ataman, O. Y. Talanta 2000,
51, 693. (f) Prodi, L.; Bolletta, F.; Montalti, M.; Zaccheroni, N. Eur. J.
Inorg. Chem. 1999, 3, 455. (g) Lu, J. Z.; Zhang, Z. J. Analyst 1995, 120,
453. (h) Huston, M. E.; Engleman; Czarnik, A. W. J. Am. Chem. Soc. 1990,
112, 7054.
† Trinity College Dublin.
‡ Royal College of Surgeons in Ireland.
(1) de Silva, A. P.; McCaughan, B.; McKinney, B. O. F.; Querol, M.
Dalton Trans. 2003, 1902. Balzani, V. Photochem. Photobiol. Sci. 2003,
2, 459. Balzani, V.; Credi, A.; Venturi, M. Pure Appl. Chem. 2003, 75,
541. Raymo, F. M. AdV. Mater. 2002, 14, 401. Raymo, F. M.; Giordani, S.
J. Am. Chem. Soc. 2002, 124, 2004. Brown, G. J.; de Silva, A. P.; Pagliari,
S. Chem. Commun. 2002, 2461. Ballardini, R.; Balzani, V.; Credi, A.;
Gandolf, M. T.; Venturi, M. Acc. Chem. Res. 2001, 36, 445. deSilva, A.
P.; Gunaratne, H. Q. N.; McCoy, C. P. Nature 1993, 364, 42.
(2) Rurack, K.; Resch-Genger, U. Chem. Soc. ReV. 2002, 116. Lavigne,
J. J.; Anslyn, E. V. Angew. Chem. Int. Ed. 2001, 40, 3119. Beer, P. D.;
Gale, P. A. Angew. Chem., Int. Ed. 2001, 40, 486. de Silva, A. P.; Fox, D.
B.; Huxley, A. J. M.; Moody, T. S. Coord. Chem. ReV. 2000, 205, 41.
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10.1021/ol035484t CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/01/2003

toxicity of the metal, the use of cadmium has several
environmental impacts,7 and as lithium-based batteries
become common, this gives rise to an increased level of
disused cadmium batteries, with an increased environmental
effect.6 Consequently the uptake of Cd(II) has increased in
humans in recent times,8 where it can have several physio-
logical effects as it can accumulate in organs such as the
kidney, thyroid gland, and spleen.8 It is thus important to be
able to monitor such uptake in humans as well as in the
environment by employing simple responsive chemosensors.
We are interested in the development of luminescent
devices such as switches,9 chemosensors,10 and logic-gates.11
Herein we describe the design, synthesis, and photophysical
properties of two new fluorescent chemosensors for Cd(II),
1 and 2. Several researchers have recently developed
potential chemosensors for Cd(II).5 However, the drawback
to all of these was the use of receptors consisting of aliphatic
amines that are easily protonated under physiological condi-
tions. Moreover, the Cd(II) selectivity in water was not fully
demonstrated for many of these examples. Our sensors 1
and 2 are based upon the fluorophore-spacer-receptor and
receptor-spacer-fluorophore-spacer-receptor models devel-
oped by de Silva for PET (photoinduced electron transfer)
sensors.12 Here we have selected anthracene12 as a fluoro-
phore, and a simple aromatic iminodiacetate (shown in its
ester form in 3) as the receptor.13 As the receptor is aniline-
based, we foresaw that it could be used either under
physiological conditions or for detection of soil samples, as
the protonation of the receptor nitrogen moiety would only
occur under high acidic conditions.14 Moreover, the use of
this simple design would overcome interferences from other
physiologically important cations such as Mg(II) and Ca(II),13
and the use of potassium salts of the carboxylates impart
high water solubility to 1 and 2.
Scheme 1. Syntheses of the Two Chemosensors 1 and 2a
a Reagents: (i) AlCl3, CHCl3; (ii) Koh, H2O, MeOH.
3 in good yield. The phenyl iminodiester 3 was made in a
single step by reacting aniline with ethyl bromoacetate using
potassium dihydrogen phosphate as a base in acetonitrile in
89% yield. This was followed by Friedel-Craft alkylation
of 3 with 9-chloro-methylanthracene,14b 4, giving the diethyl
ester 6 in 60% yield. Similarly, 2 was made by reacting 3
with 9,10-bischloromethylanthracne,16 5, under identical
conditions, yielding the desired product 7 in 58% yield after
flash column chromatography. The final products were
obtained by alkaline ester hydrolysis of 6 and 7 using
aqueous KOH in refluxing MeOH solution, yielding 1 and
2 in 92% and 90% yields, respectively, after precipitation
from the cold solution.
The ground and the excited-state properties of 1 and 2
were investigated in water and at pH 7.4 in buffered HEPES
solution in the presence of 0.135 M of NaCl to maintain
constant ionic strength. First, the response of 1 and 2 toward
pH was investigated. The changes in the fluorescence
emission spectra of 2 as a function of pH are shown in the
Supporting Information (λex ) 370 nm). Here the emission
was completely switched off upon treating an acidic solution
of 2 (pH ∼1) with diluted NaOH solution. This switching
was fully reversible. The concomitant changes in the
absorption spectra of 2 were, however, only minor. This is
a typical PET effect,12 where the excited state of the
The synthesis of 1 and 2 is shown in Scheme 1.15 Both
sensors utilize the same receptor and fluorophore moieties,
and 1 and 2 were obtained easily in two-step syntheses from
(7) Rydh, C. J.; Sva¨rd, B. Sci. Total EnViron. 2003, 302, 167.
(8) Dobson, S. Cadmium-EnVironmental Aspects; World Health Or-
ganization: Geneva, 1992. Friberg, L.; Elinger, C. G.; Kjelstro¨m, T.
Cadmium; World Health Organization: Geneva, 1992.
(9) Gunnlaugsson, T.; Leonard, J. P. Chem. Commun. 2003, in press.
Gunnlaugsson, T.; Harte, A. J.; Leonard, J. P.; Senechal, K. J. Am. Chem.
Soc. 2003, 125, in press. Gunnlaugsson, T. Tetrahedron Lett. 2001, 42,
8901. Gunnlaugsson, T.; Nieuwenhuyzen, M.; Richard, L.; Thoss, V.
Tetrahedron Lett. 2001, 42, 4725.
(10) Gunnlaugsson, T.; Kruger, P. E.; Lee, T. C.; Parkesh, R.; Pfeffer,
F. M.; Hussey, M. G. Tetrhedron Lett. 2003, 44, 6575. Gunnlaugsson, T.;
Harte, A. J.; Leonard, J. P.; Nieuwenhuyzen, M. Chem. Commun. 2002,
2134. Gunnlaugsson, T.; Davis, A. P.; Glynn, M. Org. Lett. 2002, 4, 2449.
Gunnlaugsson, T.; Bichell, B.; Nolan, C. Tetrahedron Lett. 2002, 43, 4989.
Gunnlaugsson, T.; Davis, A. P.; Glynn, M. Chem. Commun. 2001, 2556.
(11) Gunnlaugsson, T.; Mac Do´naill, D. A.; Parker, D. J. Am. Chem.
Soc. 2001, 123, 12866; Gunnlaugsson, T.; Mac Do´naill, D. A.; Parker, D.
Chem. Commun. 2000, 93.
(12) 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. Fluorescent Chemosensors for Ion and Molecular Recognition;
Czarnik, A. W., Ed.; American Chemical Society: Washington, 1993.
(13) Structurally similar receptors have been used for the detection of
Mg2+: de Silva, A. P.; Gunaratne, H. Q. N.; Maguire, G. E. M. J. Chem.
Soc., Chem. Commun. 1994, 1213. And for Zn(II): Reany, O.; Gunnlaug-
sson, T.; Parker, D. J. Chem. Soc., Perkin Trans. 2 2000, 1819.
(14) (a) Gunnlaugsson, T.; Leonard, J. P. J. Chem. Soc., Perkin Trans.
2 2002, 1980. (b) Gunnlaugsson, T.; Nieuwenhuyzen, M.; Richard, L.;
Thoss, V. J. Chem. Soc., Perkin Trans. 2 2002, 141.
(15) Calculated for 1 (C25H19K2NO4‚2H2O): C, 58.69; H, 4.53, N, 2.74.
Found: 57.80; H, 4.33; N, 2.56. Calculated for 2 (C36H28K4N2O8‚3H2O):
C, 52.28; H, 4.14; N, 3.39. Found: C, 52.46; H, 4.02; N, 3.23. See
Supporting Information for more details.
(16) de Silva, A. P.; Sandanayake, K. R. A. S. Angew. Chem., Int. Ed.
Engl. 1990, 29, 1173.
4066
Org. Lett., Vol. 5, No. 22, 2003

anthracene is quenched by electron transfer from the receptor
unit causing the switching off.12 Similar results were observed
for 1. For 2 a pKa of ca. 2.4 ( 0.1 was determined from
these changes, whereas for 1, a pKa of 2.0 ( 0.1 was
determined.17 From these results it is clear that the emission
is pH-independent in a physiological pH range.
The ability of 1 and 2 to recognize group II and various
transition metal ions was investigated at pH 7.4. Using Mg(II)
and Ca(II), no changes were observed in the fluorescence
emission spectra, indicating that the simple receptor was not
coordinating to the ions to prevent PET quenching.13,17 When
using transition metal ions such as Co(II), Ni(II), Cu(II),
Zn(II), Cd(II), and Hg(II) (as their Cl-, NO3-, or ClO4- salts),
only Zn(II) and Cd(II) gave rise to any significant changes
in the fluorescence emission spectra. Consequently the ability
of 1 and 2 to recognize these ions was further investigated.
Upon titrating 2 at pH 7.4 (I ) 0.135 M NaCl) using Zn(II),
the fluorescence was switched on, Figure 1, with large
Figure 2. Uncorrected changes in the florescence emission spectra
of 1 as a function of [Zn(II)] at pH 7.4, λex ) 360 nm.
was only slightly enhanced upon ion recognition, with the
formation of a new structureless band centered at 468 nm.
We suggest that these changes are due to the formation of a
bound receptor charge transfer complex, or an exciplex,
between the Zn(II) moiety and the anthracene that is highly
luminescence at long wavelengths.19 From the changes at
468 nm, as a function of pZn, we obtained a sigmoidal curve,
which changed over 2 pZn units. From these changes we
determined log â of 3.8 ( 0.15, for the binding of Zn(II) to
1. Unlike that seen for 2, the concomitant changes in the
absorption spectra (though only minor) showed that the
anthracene vibrational bands were bathochromically shifted
with isosbestic points at 370, 385, and 410 nm for 2.
However, the most interesting results were observed when
1 and 2 were titrated with Cd(II), as the emission spectra of
both were reminiscent of that seen for 1 when titrated with
Zn(II), as is evident from Figure 3, for 2. For 2, only minor
Figure 1. Changes in the fluorescence emission spectra of 2 at
pH 7.4, as a function of added Zn(II) concentration, upon excitation
at 370 nm. Insert: relative fluorescence changes at 415 nm as a
function of pZn (pZn ) -log[Zn(II)]).
fluorescence enhancements in a similar manner as seen for
the above pH titration. Minor bathochromic changes were
observed in the absorption spectra. Hence, only the emission
intensity changed as a function of Zn(II), indicating that the
Zn(II) ion was able to coordinate to the carboxylates as well
as the aniline nitrogen and increase the oxidation potential
of the receptors in 2, in a usual PET fashion.12,13,17,18 From
the relative fluorescence changes at 415 nm as a function of
pZn (pZn ) -log[Zn(II)]), a sigmoidal curve was observed,
which switched on over two logarithmic units between pZn
≈ 5-3 (Figure 1 insert). From these changes a binding
constant log â of 3.8 ( 0.1 was determined. When these
titrations were repeated using 1, the emission spectra were,
however, very different from that observed for 2, as is evident
from Figure 2. Here, the (monomeric) anthracene emission
Figure 3. Changes in the fluorescence emission spectra of 2 upon
titration with Cd(II) at pH 7.4. λex ) 370 nm. Insert: changes in
the relative intensity at 500 nm as a function of pCd.
changes were seen in the monomeric emission, which was
reduced, with large concomitant changes at long wavelengths,
where again a rather structureless band was observed
(17) 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.
(18) Huston, M. E.; Haider, K. W.; Czarnik, A. W. J. Am. Chem. Soc.
1988, 110, 4460.
(19) Bhattacharyya, K.; Chowdhury, M. Chem. ReV. 1993, 93, 507.
Org. Lett., Vol. 5, No. 22, 2003
4067

centered at ca. 500 nm. Similar results were seen for 1, with
a narrower band centered on 506 nm, Figure 4. Furthermore,
formation of the long emitting emission bands for both 1
and 2 suggests strong π-complex interactions.
As can be seen from the above results, both sensors display
moderate selectivity for Cd(II) over Zn(II). To investigate
the ability of these sensors to recognize Cd(II) in the presence
of Zn(II), we carried out Cd(II) titrations on 1 and 2 in the
presence of high concentrations of Zn(II). On both occasion
a selective detection of Cd(II) was possible. This was
particularly noticeable for 2, which only showed a mono-
meric emission in the presence of Zn(II). However, upon
Cd(II) addition the fluorescence emission spectra was found
to be shifted to longer wavelengths, Figure 5.
Figure 4. Changes in the fluorescence emission spectra of 1 upon
titration with Cd(II) at pH 7.4, λex ) 360 nm. Insert: changes in
the relative intensity at 506 nm as a function of pCd.
whereas the absorption spectra of 2 was slightly bathochro-
mically shifted, the absorption spectra of 1 was reduced in
intensity by ca. 10% upon addition of 6 µM f 2 mM of
CdCl2. When these measurements were repeated using the
esters 6 or 7, no fluorescent enhancements were observed,
signifying that neither were binding to either Zn(II) or Cd(II).
Figure 5. Changes in the florescence emission spectra of 2 at pH
7.4, in the presence of Zn(II) upon titration with Cd(II), [Cd(II)] )
0 M f 2 mM: (A) free sensor 2; (B) after addition of Zn(II)
[Zn(II)] ) 3 mM; (C) in the presence of of Cd(II).
Plotting the relative changes in the 500 nm band for 2, as
a function of pCd (pCd ) -log[Cd(II)]), gave a sigmoadal
curve that changed over 2 pCd units. From these changes a
binding constant log â of 3.9 ( 0.1 was determined. For 1,
similar results were observed, with log â of 4.2 ( 0.1. Once
more, we suggest that these changes are due to the formation
of charge-transfer complexes between the anthracene moiety
and the bound receptors. Both Yoon et al. and Czarnik et al.
have reported that they observed red shifts in the fluorescence
emission spectra of anthracene-based sensors upon interac-
tions of aliphatic receptors with Cd(II).5c,h They concluded
that indeed this was due to the formation of a π-complex,
which subsequently gives rise to the formation of a σ-com-
plex. In both cases the emission was centered around 446
nm, which is a substantially smaller shift than seen for both
1 and 2 upon Cd(II) recognition. Even though we do not
envisage that such direct σ-complex interaction is occurring
for our sensors, purely as a result of steric effects, the
In summary, we have developed two new fluorescent
chemosensors 1 and 2, which have good water solubility,
are pH-independent in the physiological pH range, and show
sufficient selectivity and photophysical changes upon ion
recognition to allow for the selective sensing of Cd(II) over
Zn(II) at pH 7.4.
Acknowledgment. We like to thank TCD, RCSI, and
HRB for financial support. We also thank Dr. Hazel M.
Moncrieff and Dr. John E. O’Brien.
1
Supporting Information Available: Synthesis and H
and 13C NMR of 1 and 2, pH fluorescence, and Zn(II) and
Cd(II) absorption titrations of 1 and 2. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL035484T
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Org. Lett., Vol. 5, No. 22, 2003