3-Urea-1,8-naphthalimides are good chemosensors: A highly selective dual colorimetric and fluorescent ICT based anion sensor for fluoride

Article abstract of DOI:10.1016/j.tetlet.2011.01.099

The 1,8-naphthalimide sensor 1 was developed as a colorimetric and fluorescent sensor for anions. Being the first example of such anion sensors, where the 3-position of the naphthalimide ring is used to incorporate the anion recognition moiety, in this ca

Full text of DOI:10.1016/j.tetlet.2011.01.099

Tetrahedron Letters 52 (2011) 1503–1505
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3-Urea-1,8-naphthalimides are good chemosensors: a highly selective dual
colorimetric and fluorescent ICT based anion sensor for fluoride
⇑
Rebecca M. Duke, Thorfinnur Gunnlaugsson
School of Chemistry, Centre for Synthesis and Chemical Biology, Trinity College Dublin, Dublin 2, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
The 1,8-naphthalimide sensor 1 was developed as a colorimetric and fluorescent sensor for anions. Being
the first example of such anion sensors, where the 3-position of the naphthalimide ring is used to incor-
porate the anion recognition moiety, in this case a trifluromethyl derived aryl urea moiety, the sensors
gave rise to significant changes in both the absorption and the emission spectra, which were both red
shifted upon interacting with anions. The changes were most pronounced for fluoride, and to a lesser
extent for acetate and hydrogen phosphate, in DMSO, making 1 a highly selective sensor for FÀ.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 18 October 2010
Revised 19 January 2011
Accepted 25 January 2011
Available online 1 February 2011
The development of colorimetric and fluorescent sensing of an-
ions has become a highly active area of research within the field of
supramolecular chemistry.1–5 Sensors based on the 4-amino-1,8-
naphthalimide structure have been used extensively in anion sens-
ing design,2,6–10 where various types of anion receptor moieties
have been attached or conjugated to the naphthalimide moiety,
either at the 4-amino site or via the imide moiety.2,11 We have re-
cently demonstrated that hydrogen bonding urea or thiourea
receptors can, when conjugated at the 4-position via a hydrazide
spacer, function as effective colorimetric sensorÀs for anions such
as acetate (AcOÀ) and hydrogen phosphate (HPO4 ) as well as fluo-
ride (FÀ) and chloride (ClÀ) in either organic (DMSO or CH3CN) or
aqueous solutions.11,12 Concurrently, Fabbrizzi et al. developed
urea-based di-naphthalimide sensors, where a single urea moiety
bridged two naphthalimide units at their 4-positions.13
In this Letter, we present, to the best of our knowledge, the first
example of an anion sensor based on derivatising the 3-position of
the naphthalimide moiety with an anion receptor. Our system, 1, is
based on the use of a simple urea moiety connected to the 3-posi-
tion of the naphthalimide, starting from compound 2 (Scheme 1).
As with 4-amino-naphthalimide based sensors, this new system
also takes advantage of the internal charge transfer (ICT) character
of the fluorophore, where the urea acts as an electron donor (via
the NH-moiety), and the imide as an electron acceptor. We foresaw
that this design would recognise anions through hydrogen bond-
ing, which would give rise to concomitant changes in the photo-
physical properties of the 1,8-naphthalimide, and thereby would
demonstrate the versatility of this building block in such anion
sensing. Only a few examples of 3-naphthalimide-based sensors
have been developed to date,14 and to the best of our knowledge,
none have been developed for anion sensing, while a few have
O
N
O
NCO
O
N
O
CF3
F3C
O
N
H
N
H
CH3CN
NH2
1
2
Scheme 1. Synthesis of anion sensor 1.
been synthesised as potential anticancer agents.15 Hence, there ex-
ists an unexplored opportunity to investigate the use of this fluoro-
phore in anion sensing.
The synthesis of sensor 1, was achieved in three steps from
commercially available 3-nitro-1,8-naphthalic anhydride, which
was reduced to the corresponding 3-amino-1,8-naphthalic anhy-
dride at room temperature using 10% Pd/C at 3 atm in DMF. Subse-
quent reaction, under reflux, with ethylamine in 1,4-dioxane for
16 h, giving the desired imide 2,16 as an orange solid, in 51% yield
after aqueous work-up. This product was then reacted with 1 equiv
of 4-trifluoromethylphenyl isocyanate in MeCN for 16 h under re-
flux. This resulted in precipitation of the desired urea which was
collected and dried in air, giving product 117 as an off-white solid
in 83% yield (Scheme 1). The product was characterised using ana-
lytical techniques. For example, the 1H NMR (400 MHz, DMSO-d6)
spectrum of 1 showed two broad singlets at 9.41 and 9.22 ppm
characteristic of urea protons (Fig. 1), while the 13C NMR
(100 MHz, DMSO-d6) spectrum showed the expected number of
resonances.
The absorption spectrum of 1 was recorded in DMSO. Unlike
that seen for the previously described 4-amino-1,8-naphthali-
mide-based anion sensors,2 the ICT transition of 1 was not as pro-
nounced, being shifted to shorter wavelengths, with a kmax at
394 nm and a second band at 340 nm. This is to be expected as
⇑
Corresponding author. Tel.: +353 1 896 3459; fax: +353 1 671 2826.
E-mail address: gunnlaut@tcd.ie (T. Gunnlaugsson).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.099

1504
R. M. Duke, T. Gunnlaugsson / Tetrahedron Letters 52 (2011) 1503–1505
NH6 + phenyl
NH2,4
NH5/7
CH2
NHurea
MeCN
10.0
9.0
8.0
7.0
6.0
(ppm)
5.0
4.0
3.0
2.0
1.0
Figure 1. The 1H NMR spectrum of sensor 1 (400 MHz, DMSO-d6).
the push–pull character of this isomer is not as strong as that seen,
for instance, in Farbbrizzi’s anion sensor13 discussed above, and
that of our own work and others,6,11 where the ICT band is nor-
mally red shifted by ca. 40–50 nm. This clearly demonstrates the
difference in the electronic donor ability of the 3- versus the 4-
amino moiety in such structures. Excitation at these wavelengths,
gave rise however, on both occasions, to a broad emission centred
at 453 nm, tailing into the 600 nm region.
The anion binding abilities of 1 were next investigated using
absorption and fluorescence emission spectroscopy. Interestingly,
only minor changes occurred in the absorption and the fluores-
cence emission spectra of 1 upon titration with the TBA salts of
H2POÀ4 or AcOÀ (Fig. 2A and B). We were however able to analyse
these small changes by plotting the changes as a function of added
anion, and while we were unable to determine the binding con-
stant for these changes, the analysis demonstrated a 1:1 binding
between the sensor and the anions, which would be expected to
occur through hydrogen bonding at the urea moiety.
Similar to that observed above, titration of 1 with FÀ (as a
TBAFÁ3H2O salt) gave a minor increase in the absorption spectrum
at short wavelengths (ca. 329 nm), indicating interaction of FÀ at
the phenyl based receptor, Figure 3. These changes also occurred
with a small bathochromic shift in the naphthalimide ICT transi-
tion, centred around 390 nm. However, in contrast to these
changes, after the addition of ca. 25 equiv of FÀ, significantly larger
changes were observed in the absorption spectra at both of these
wavelengths. Figure 4, demonstrates the overall changes observed
(0–100 equiv of FÀ), where the ICT band decreased in absorbance,
0.10
0.08
0.06
0.04
0.02
0.00
0.1
A
300
350
400
450
500
550
Wavelength (nm)
0.08
0.06
0.04
0.02
0
Figure 3. The changes in the absorption spectra of 1 [1.2 Â 10À5 M] upon addition
of FÀ (0–25 equiv) in DMSO, demonstrating a small red shift in the ICT transition
upon binding of the anion at low concentration.
0.45
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
300
350
400
450
500
Wavelength (nm)
410
B
360
310
260
210
160
110
60
10
400
260
310
360
410
460
510
560
450
500
550
600
Wavelength (nm)
Wavelength (nm)
Figure 2. (A) The changes in the absorption spectra of 1 [1.2 Â 10À5 M] upon
addition of AcOÀ (0–25 equiv) in DMSO. (B) The corresponding changes in the
florescence emission spectra, demonstrating that the sensor does not respond
effectively to the anion.
Figure 4. The changes in the absorption spectra of 1 [1.2 Â 10À5 M] upon addition
of FÀ (0–100 equiv) in DMSO, demonstrating that the anion can interact with the
urea moiety, giving rise to large changes in the ground state properties of the
sensor.

R. M. Duke, T. Gunnlaugsson / Tetrahedron Letters 52 (2011) 1503–1505
1505
with concomitant formation of a long wavelength absorption band,
Acknowledgements
centred at ca. 495 nm, and with the formation of a ‘pseudo’ isos-
bestic point (e.g., a small shift being observed for this isosbestic
point at higher equivalents of FÀ) at 426 nm. Large changes were
also observed at shorter wavelengths, where the absorption band
at 327 nm was enhanced dramatically, but these changes were also
accompanied with a large decrease in the absorbance band centred
at 272 nm, and previously assigned to the phenyl part of the urea
receptor moiety. As for the long wavelength changes, two ‘pseudo’
isosbestic points were observed at 370 and 397 nm, respectively.
These changes were similar to those seen upon interactions of fluo-
ride with anion receptor derivatives via the 4-amino moiety of the
naphthalimide structure,6 indicating a potential common mecha-
nism, that is, deprotonation of the urea proton adjacent to the
naphthalimide occurred at high concentrations of FÀ. Additionally,
these changes were reversed upon the addition of protic solvents
such as MeOH or H2O. The above changes in the absorption spectra
were also clearly visible to the naked eye, where the colour chan-
ged from light yellow to red, enabling the use of 1 as a colorimetric
sensor for FÀ.
We like to thank TCD (College award to R.M.D.), Science Foun-
dation Ireland for grant SFI RFP 2008, and HEA-PRTLI Cycle 3 and
Cycle 4 (CSCB) for financial support. We thank Dr. John E. O’Brien
for assisting with NMR measurements and Dr. Emma B. Veale for
helpful discussions.
References and notes
1. Gale, P. A.; Gunnlaugsson, T. Chem. Soc. Rev. 2010, 39, 3581–4008.
2. The use of naphthalimides in sensing was recently reviewed in: Duke, M. R.;
Veale, E. B.; Pfeffer, F. M.; Kruger, P. E.; Gunnlaugsson, F. Chem. Soc. Rev. 2010,
39, 3936.
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In contrast to the minor changes in the absorption spectrum at
low concentration of FÀ, large changes were seen in the fluores-
cence emission spectrum of the ICT transition within the same con-
centration range. Here, the naphthalimide emission was quenched
by ca. 75% in the presence of ca. 50 equiv of FÀ, as shown in Figure
5. Concomitantly, smaller enhancements were also seen at lower
wavelengths (e.g., ca. 410 nm as shown in Fig. 5) and at long wave-
length, ca. 650 nm, but analysis of the long wavelength changes did
not give accurate binding information. The changes in the fluores-
cence emission intensity as a function of anion equivalents for the
changes in the ICT band are shown in the insert to Figure 5, and the
results indicate that a two-step process occurred over the course of
the titrations, which was most likely due to hydrogen bonding to
the urea receptor followed by deprotonation at higher concentra-
tions of the anion.
In summary, we have developed 3-urea-1,8-naphthalimide 1 as
a fluorescent sensor for anions. We have demonstrated that the an-
ion sensing is most likely to occur via deprotonation of the urea
receptor at high concentration making this a highly selective sen-
sor for basic anions such as fluoride. This feature has both environ-
mental and biological relevance, at the same time as
demonstrating that the 3-amino moiety of the 1,8-naphthalimide
can be employed in anion sensing. We are currently working on
developing novel sensors where the 3- and 4-positions of this ver-
satile fluorophore are derivatised with a view to improving both
the sensitivity and the selectivity of the anion recognition through
synergetic action of more than one hydrogen bonding donor.
6. Gunnlaugsson, T.; Kruger, P. E.; Lee, T. C.; Parkesh, R.; Pfeffer, F. M.; Hussey, G.
M. Tetrahedron Lett. 2003, 44, 6575; Gunnlaugsson, T.; Kruger, P. E.; Jensen, P.;
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Chem. 1996, 20, 871.
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16. 2-Ethyl-5-aminobenzo[d,e]isoquinoline-1,3-dione (2). 3-Amino-1,8-naphthalic
anhydride (0.25 g, 1.18 mmol) and 70% ethylamine were refluxed in 1,4-
dioxane for 16 h. The reaction mixture was poured into H2O and the resulting
precipitate was isolated by suction filtration to give 2 as an orange solid (0.14 g,
51%). Mp 275–277 °C (Lit. mp18 276 °C); dH .(400 MHz, DMSO-d6), 8.07 (1H, d,
J = 7.0 Hz, Naph-H7), 8.02 (1H, d, J = 7.6, Naph-H5), 7.96 (1H, s, Naph-H2), 7.60
(1H, dd, J = 8.16 and 7.60 Hz, Naph-H6), 7.27 (1H, s, Naph-H4), 6.00 (2H, br s, NH2),
4.04 (2H, q, J = 7.0 Hz, NCH2), 1.18 (3H, t, J = 7.0 Hz, CH3); dc (100 MHz, DMSO-d6),
163.8 (C@O), 163.7 (C@O), 148.1 (q), 133.8 (q), 131.7 (CH), 127.3 (CH), 125.6
(CH), 122.9 (q), 122.1 (CH), 121.9 (q), 120.8 (q), 112.0 (CH), 34.9 (CH2), 13.4 (CH3).
17. 2-Ethyl-5-[(4-trifluoromethylphenyl)ureidocarbamoyl]-benzo[d,e]isoquinoline-1,3-
800
800
700
600
500
600
400
200
0
dione (1). Compound
2 (0.380 g, 1.58 mmol) and 4-trifluoromethylphenyl
isocyanate (0.296 g, 1.58 mmol) were refluxed in MeCN for 24 h. The resulting
precipitate was isolated by suction filtration to give a beige solid (0.515 g, 76%).
Mp337–339 °C; Anal. Cacld for C22H16N3O3F3: C, 61.83; H, 3.77; N, 9.83. Found: C,
61.65; H, 3.81; N, 9.65. HRMS (ES+): Calcd for C22H17N3O3F3 [M+H]+: 428.1222.
Found: 428.1242; dH (400 MHz, DMSO-d6), 9.41 (1H, s, NHurea), 9.22 (1H, s,
NHurea), 8.48 (2H, d, J = 8.2 Hz, Naph-H7,5), 8.27 (2H, d, J = 7.5 Hz, Naph-H2,4),
7.77–7.70 (3H, m, Naph-H6, Ar–H), 7.64 (2H, d, J = 7.9 Hz, Ar–H), 4.05 (2H, q,
J = 6.7 Hz, NCH2), 1.22 (3H, t, J = 6.7 Hz, CH3); dc (100 MHz, DMSO-d6) 163.4
(C@O), 163.2 (C@O), 152.6 (q), 143.4 (q), 138.5 (q), 133.6 (CH), 132.4 (q), 128.7
(CH), 127.7 (CH), 126.3 (CH), 124.9 (q, J13C–19F = 270'Hz), 123.7 (q), 123.6 (CH),
122.8 (q), 122.4 (CF3, J13C–13F = 32 Hz), 122.1 (q), 120.1 (CH), 119.8 (CH), 35.0
0 10 20 30 40 50 60 70 80 90100
Guest Equivalents
400
300
200
100
0
400
450
500
550
600
(CH2), 13.4 (CH3); dN (60 MHz, DMSO-d6), 111.0, 111.6; IR (solid) mmax (cmÀ1
)
Wavelength (nm)
3371, 3304, 1656, 1555, 1326, 1231, 1154, 1110, 1068, 1055, 1017, 843, 787, 686.
18. Pardo, A.; Martin, E.; Poyato, J. M. L.; Camacho, J. J. J. Photochem. Photobiol., A
1987, 41, 69.
Figure 5. The changes in the fluorescence emission spectra of 1 [1.2 Â 10À5 M]
upon addition of FÀ (0–100 equiv) in DMSO. Insert: The changes at 455 nm as a
function of equivalents of guest added.