Fluorescent anion sensors based on 4-amino-1,8-naphthalimide that employ the 4-amino N-H

Article abstract of DOI:10.1016/j.tetlet.2006.05.161

The new charge neutral 4-amino-1,8-naphthalimide based anion sensors 2 and 3 bind to both acetate and dihydrogenphosphate with 1:1 stoichiometry through hydrogen bonding to both thiourea N-H atoms and in the case of dihydrogenphosphate, the naphthalimide

Full text of DOI:10.1016/j.tetlet.2006.05.161

Tetrahedron Letters 47 (2006) 5241–5245
Fluorescent anion sensors based on 4-amino-1,8-naphthalimide
that employ the 4-amino N–H
Frederick M. Pfeffer,* Marianne Seter, Naomi Lewcenko and Neil W. Barnett
School of Life and Environmental Sciences, Deakin University, Waurn Ponds, 3217, Australia
Received 4 May 2006; revised 15 May 2006; accepted 24 May 2006
Available online 13 June 2006
Abstract—The new charge neutral 4-amino-1,8-naphthalimide based anion sensors 2 and 3 bind to both acetate and dihydrogen-
phosphate with 1:1 stoichiometry through hydrogen bonding to both thiourea N–H atoms and in the case of dihydrogenphosphate,
1
ꢀ
the naphthalimide 4 amino N–H group as well. This was clearly established from H NMR titration experiments with H2PO4 in
DMSO-d6 where a substantial shift in the resonance for the naphthalimide N–H was observed concomitant with the expected migra-
tion of the thiourea N–H chemical shifts. The binding constants determined from the titration studies indicate that the new sensors
ꢀ
ꢀ
bind H2PO4 more strongly than AcO . Fluorescence titrations with sensor 3 indicate quenching of 59% and 36% upon addition of
acetate and dihydrogenphosphate, respectively.
Ó 2006 Elsevier Ltd. All rights reserved.
In the field of supramolecular chemistry charge neutral
O
N
O
O
N
O
anion receptors rely on hydrogen bonding as the domi-
nant interactive force with anions.1 A number of well
placed hydrogen bond donors maximise the binding
strength to a specific anionic species.1,2 A naturally
occurring example, the sulphate binding protein, con-
tains a total of seven dedicated hydrogen bonds to en-
sure that binding of the target is both strong and
selective.3
2 R=H
3 R=F
3
1
3
4
5
4
5
NH
NH
anion
anion
H
H
H
H
N
N
N
N
S
S
R
Figure 1. Structure of 1 and the new naphthalimide hosts 2 and 3.
The rapid detection of anionic species is of great signif-
icance given the roles they play in the environment and
in physiological systems.1 Our interest in this field has
led us to develop luminescent chemosensors for anions
using both cationic and charge neutral receptors.4,5 Re-
cently we synthesised and evaluated the combined thio-
urea/naphthalimide host 1 as a photo-induced electron
transfer (PET) chemosensor for anions6 (Fig. 1). Recep-
tor 1 was purposely constructed such that the acidic
‘pseudo amide’ N–H at position 4 of the naphthalimide
ring could be employed as an additional H-bond donor
(Fig. 1).6 Whilst definite evidence of this H-bond donor
participating in the binding of the tetrahedral dihydro-
genphosphate anion was obtained using NMR titration
ꢀ
studies, to give strong binding (for 1: H2PO4 logb =
3.4), no quenching of the fluorescence of 1 was observed
upon addition of any anion. The lack of any modulation
in fluorescence was attributed to either, the purely ali-
phatic nature of the urea and its associated reduction
potential, or that a nonconjugated two-carbon ethyl
spacer was employed. It is known that ET requires the
donor and acceptor to be in close proximity.7
In order to elicit PET quenching in the presence of an-
ions whilst preserving the co-operative binding observed
for 1 (with multiple H-bond donors) the new sensors
2 and 3 were designed. As can be seen (Fig. 1), the
new design incorporates an ortho substituted amino-
benzylamine spacer, with only one nonconjugated CH2,
and hence an element of conformational preorgani-
sation has also been introduced.
*
Corresponding author. Tel.: +61 3 5227 1439; fax: +61 3 5227
1040; e-mail: thefef@deakin.edu.au
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.161

5242
F. M. Pfeffer et al. / Tetrahedron Letters 47 (2006) 5241–5245
Fꢀ mediated deprotonation of the naphthalic amine of
2 and 3 had occurred.7,11
O
N
O
O
N
O
O
N
O
The successive addition of the trigonal planar AcOꢀ an-
ion to DMSO-d6 solutions of both 2 and 3 resulted in
significant changes in the chemical shifts of the protons
of interest (Fig. 2). As anticipated, the largest shifts were
seen for the two thiourea proton resonances, which
experienced significant downfield shifts (ca. 3.5 ppm)
for both 2 and 3, indicative of strong hydrogen bonding
between the thiourea anion receptor and the geometri-
cally complementary acetate anion. Unfortunately, only
a small shift (<0.5 ppm) in the naphthalimide amino N–
H resonances of 2 and 3 (along with negligible shifts for
the remaining naphthalimide ring protons) was observed
and it was concluded that this N–H was not involved to
any great extent in the binding of acetate. Both binding
isotherms are consistent with a 1:1 host:guest stoichio-
metry and from this data binding constants, of logb =
2.8( 0.1) for 2 and logb = 3.4( 0.2) for 3, were deter-
mined when fitting the data using WinEQNMR.12 Such
binding constants are slightly less than that of 1 against
acetate (logb = 3.6)6 and it is possible that for the new
sensors the introduced element of conformational preor-
ganisation may slightly hinder the binding of anions
such as acetate and the N–H at position 4 of the naph-
thalimide ring actually interacts unfavourably with the
CH3 of the bound acetate anion.
i
ii
R
2 R=H
3 R=F
S
C
N
NH
NH2
4
5
Br
NH
H
H
N
N
S
R
Scheme 1. Synthesis of hosts 2 and 3 from N-ethyl-4-bromonaphthal-
imide. Reagents and conditions: (i) o-aminobenzylamine, sealed tube,
130 °C, 12 h, 86%; (ii) DMF, rt, 12 h, 2 33%, 3 40%.
Herein, the synthesis of the new 4-amino-1,8-naphthal-
imide based hosts, 2 and 3, is presented along with an
evaluation of their anion binding ability using 1H
NMR and fluorescence titration techniques.
The synthesis of 2 and 3 was achieved in three steps
(Scheme 1) by first reacting 1 equiv of ethylamine in
refluxing 1,4-dioxane with 4-bromo-1,8-naphthalic
anhydride, which after aqueous work-up gave the imide
4 in ca. 90% yield as an off-white powder.5,8 Nucleo-
philic aromatic substitution was accomplished by heat-
ing an excess of neat o-aminobenzylamine with 4 in a
sealed tube to afford amine 5 as a yellow powder in
86% yield after recrystallisation. The final step involved
stirring the requisite isothiocyanate with amine 5 in
DMF to provide the desired compounds 2 and 3 in
33% and 40% yield after chromatographic purification.
Both new compounds were highly fluorescent (UF =
0.62 for 2 and 0.70 for 3) and they were fully character-
ised by 1H and 13C NMR and elemental analysis and/or
HRMS.9
The successive addition of the tetrahedral dihydrogen-
phosphate anion to a DMSO-d6 solutions of 2 and 3
also produced significant changes in the chemical shifts
of several protons. Unfortunately, in this instance, after
3 equiv of the anion had been added the resonances
4.0
3.5
3.0
2.5
The binding of the new hosts to a series of anions was
first investigated by monitoring the changes in the H
1
NMR spectra of DMSO-d6 solutions of 2 and 3 upon
addition of AcOꢀ, H2PO ꢀ, Fꢀ and Brꢀ as their tetrabut-
4
Thiourea NH
Thiourea NH
Naphthalimide NH
Aromatic H
2.0
ylammonium (TBA) salts.
1.5
1.0
The spherical halides were investigated first, however,
the addition of Brꢀ afforded only minor changes in the
1H NMR spectrum (after 6.0 equiv Dd = 0.16 ppm for
the thiourea protons of 3) and it was concluded that
very weak, if any, binding of the bromide anion
occurred.
0.5
0.0
0.0
1.0
2.0
3.0
4.0
5.0
6.0
Anion equivalent
4.0
In the case of Fꢀ, however, the naphthalimide N–H sig-
nal became significantly broadened after the addition of
only small quantities of the anion and completely disap-
peared after the addition of only 0.6 equiv. Concomitant
with this disappearance was a distinct, visible colour
change from fluorescent yellow/green to deep red/
purple. This observation was in close agreement with
previous experience with 4-aminonaphthalimide deriva-
tives, as was the appearance of a new triplet at ca.
16.00 ppm—assigned to the formation of the bifluoride
[FHF]ꢀ anion10—after 2.5 equiv of Fꢀ had been added.
These observations are consistent with our previous
studies with 4-amino-naphthalimides and indicate that
3.5
3.0
2.5
2.0
Thiourea NH
Thiourea NH
1.5
1.0
Naphthalimide NH
Aromatic H
0.5
0.0
0.0
1.0
2.0
3.0
4.0
5.0
6.0
Anion equivalent
Figure 2. Changes in the chemical shift of relevant protons within 2
(top) and 3 (bottom) upon addition of AcOꢀ in DMSO-d6.

F. M. Pfeffer et al. / Tetrahedron Letters 47 (2006) 5241–5245
5243
2.00
1.50
1.00
0.50
0.00
ther experiments are in progress to elucidate this
unusual behaviour.
ꢀ
To confirm that the new receptors bind H2PO4 more
strongly than AcOꢀ, receptor 3 was investigated using
low temperature titration studies (conducted in 50:50
CDCl3–DMSO-d6 at ꢀ10 °C). At this temperature the
N–H resonance was clearly visible during theꢀaddition
Thiourea NH
Thiourea NH
Naphthalimide NH
Aromatic H
of up to 6 equiv of both AcOꢀ and H2PO anions.
4
From these titration curves a binding constant of
logb =ꢀ3.2( 0.2) for AcOꢀ and logb = 3.9( 0.3) for
H2PO4 was determined. The binding constants for
both acetate and dihydrogenphosphate are comparable
to those determined and estimated in neat DMSO-d6.
Most importantly both results support the earlier con-
0.0
1.0
2.0
3.0
4.0
5.0
6.0
Anion equivalent
2.00
1.50
1.00
0.50
0.00
ꢀ
clusion that the new host 3 actually binds to H2PO4
Thiourea NH
Thiourea NH
Naphthalimide NH
Aromatic H
more strongly than AcOꢀ.
When changes in the UV/vis absorption spectra were
monitored upon successive addition of anions to sensors
ꢀ
2 and 3 (Fig. 4), only when H2PO4 was added to either
2 or 3 was a very weak hypsochromic shift observed. All
other sensor and anion combinations afforded subtle
bathochromic shifts. These results alsoꢀsuggest a unique
0.0
1.0
2.0
3.0
4.0
5.0
6.0
Anion equivalent
Figure 3. Changes in the chemical shift of relꢀevant protons within 2
(top) and 3 (bottom) upon addition of H2PO4 in DMSO-d6.
mode of binding of 2 and 3 to H2PO4
.
When DMSO solutions of anions were added to 2 and 3
and the fluorescence spectrum monitored (kex
440 nm), the fluorescence was quenched to varying de-
grees (Fig. 5 for compound 3 and Table 1 for both 2
and 3). The best results were observed for additions of
acetate to 3 where 59% quenching was observed after
5 equiv of anion had been added.
=
assigned to the thiourea protons became too broad to
track. A plot of DdH for several resonances as a function
of anion equivalents is presented in Figure 3 for sensors
2 and 3. The thiourea N–H proton resonances experi-
enced a significant downfield shift of ꢁ1.9 ppm for 2
and ꢁ2.0 ppm for 3, indicative of strong hydrogen
ꢀ
bonding of the receptor to the H2PO4 anion. The resul-
0.16
0.14
tant isotherms were consistent with a 1:1 host:guest stoi-
chiometry but unfortunately the N–H resonances
completelyꢀdisappeared after the addition of 3 equiv of
the H2PO4 anion. As the titration curves were ‘incom-
plete’ the binding constants calculated from these titra-
tion curves had a high degree of uncertainty and are
thus only estimates. Nevertheless the values of
logb ꢁ 3.7 for 2 and logb ꢁ 4.1 for 3 are impressive
and actually indicate that the new receptors 2 and 3 bind
0.12
0.1
0
0.1
0.2
0.3
0.4
0.6
0.8
1
0.08
0.06
0.04
0.02
0
2
3
5
H2PO4 more strongly than AcOꢀ. This is the first 4-
ꢀ
amino-naphthalimide based sensor where this ‘reversal’
of binding preference has been observed.
350
370
390
410
430
450
470
490
510
530
550
Wavelength (nm)
0.18
0.16
0.14
0.12
0.1
Significantly, and in contrast to the results obtained
upon addition of acetate to either 2 or 3, a large down-
field shift of ca. 1.4 ppm was observed for the 4-amino
N–H proton. This change in chemical shift is only of a
slightly smaller magnitude than that experienced by
the thiourea N–H protons. Furthermore, of the remain-
ing protons only that at position 5 of the naphthalimide
ring experienced an appreciable shift (ca. 0.5 ppm, see
Figure 3, green triangles). These results clearly indicate
that the binding event involves the naphthalimide amino
N–H—as was observed for compound 1.6 Of particular
interest was the apparent 1:2 host:guest binding of this
proton—the titration curves fit this model almost per-
fectly. The authors are unaware of any instances where
a single H-bond donor binds to two acceptors and fur-
0
0.1
0.2
0.3
0.4
0.6
0.8
1
0.08
0.06
0.04
0.02
0
2
3
5
350
370
390
410
430
450
470
490
510
530
550
Wavelength (nm)
Figure 4. Changes in UV/vis absorbtion spectra upon addition of
AcOꢀ (top) and H2PO (bottom) to a DMSO solution of 3.
ꢀ
4

5244
F. M. Pfeffer et al. / Tetrahedron Letters 47 (2006) 5241–5245
2000
anions. A ꢀsignificant enhancement in binding affinity
1800
1600
1400
1200
for H2PO4 was observed with the additional H-bond
donor and indeed this anion is bound more strongly
than AcOꢀ. The most significant result was that, unlike
the previous compound 1, the new sensors successfully
combined this co-operative binding with fluorescence
quenching. Further developments in the field of naph-
thalimide based sensor technology will be reported in
due course.
1000
800
600
400
200
0
400
450
500
550
600
650
700
Wavelength (nm)
1600
1400
1200
1000
Acknowledgements
We thank Deakin University (School of Biological and
Chemical Science) for financial support in the form of
a start up grant and Ms. Gail Dyson for assistance with
NMR studies.
800
600
400
200
0
400
450
500
550
600
650
700
References and notes
Wavelength (nm)
1. Supramolecular Chemistry of Anions; Bianchi, A., Bow-
Figure 5. Quenching of fluorescence after addition of 0–5 equiv of
AcOꢀ (top) and H2PO (bottom) to a DMSO solution of 3.
ꢀ
man-James, K., Garcia Espana, E., Eds.; Wiley-VCH:
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Table 1. Bindiꢀng constants and fluorescence quenching for 2 and 3
against H2PO and AcOꢀ
4
Compound logb for Quenching for logb for Quenching for
AcOꢀ
AcOꢀ (%)
H2PO4
H2PO4 (%)
ꢀ
ꢀ
2
3
2.8
3.4
3.2b
31
59
3.7a
4.1a
3.9b
6.5
36
Binding constants determined or estimated from 1H NMR titration
data using WinEQNMR software.12
a Values are estimates.
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J.; Martin, N. M. Chem. Commun. 2002, 2192–2193;
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b Values determined at ꢀ10 °C in 50:50 CDCl3–DMSO-d6.
For the previously constructed sensor 1, binding con-
stants of logb = 3.8( 0.1) and 3.4( 0.1) were deter-
mined for AcOꢀ and H2PO ꢀ, respectively. The results
4
for the new compounds indicate weaker binding of ace-
tate (possibly based on steric reasons) and stronger
binding for dihydrogenphosphate (as a result of both
co-operation of the 4-amino N–H with the thiourea
and the preorganised receptor site). Undoubtedly the
more electron withdrawn thiourea receptor of 2 and 3
as compared to 1 also contributed to the increased bind-
ing strength. This factor also explains the results from
the fluorescence quenching experiments which are in line
with our previous findings where more electron deficient
thiourea groups induce the greatest decrease in fluores-
cence intensity upon anion binding. Whilst the 4-amino
N–H assists in overall binding strength it appears to
play no part in fluorescence quenching and it is the more
electron deficient thiourea for which the most effective
quenching is observed.
3. Jacobson, B. L.; Quiocho, F. A. J. Mol. Biol. 1988, 204,
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thalimide N–H at position 4 in conjunction with thꢀe
thiourea can cooperatively bind tetrahedral H2PO4
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N-Ethyl-4-[20-(N-p-fluorophenylthioureido)-benzylamino]-
1,8-naphthalimide 3
Yield 67 mg, (40%) of fine yellow crystals; mp 193–195 °C.
Found: C, 67.32; H, 4.53; N, 11.25. C28H23FN4O2S
requires C, 67.45; H, 4.65; N, 11.24; dH (399.78 MHz;
DMSO-d6): 1.17 (3H, t, J 7.0 Hz, NCH2CH3), 4.03 (2H, q,
J 7.0 Hz, NCH2CH3), 4.68 (2H, d, J 5.1 Hz, ArCH2NH),
6.65 (1H, d, J 8.4 Hz, H3), 7.15 (1H, d, J 8.8 Hz, H19),
7.18 (1H, d, J 8.8 Hz, H17), 7.22 (1H, t, J 4.4 Hz, H13),
7.26 (1H, t, J 7.3 Hz, H12), 7.31 (1H, d, J 3.3 Hz, H14),
7.31 (1H, d, J 3.3 Hz, H11), 7.47 (1H, d, J 8.8 Hz, H16),
7.48 (1H, d, J 8.8 Hz, H20), 7.73 (1H, t, J 8.1 Hz, H6),
8.14 (1H, d, J 8.4 Hz, H2), 8.31 (1H, t, J 5.1 Hz,
ArNHCH2), 8.46 (1H, d, J 7.3 Hz, H5), 8.76 (1H, d, J
8.4 Hz, H7), 9.50 (1H, s, ArNHCS), 9.87 (1H, s,
CSNHAr); dC (100.54 MHz; DMSO-d6): 13.28, 34.26,
42.99, 104.83, 108.32, 115.07, 115.30, 120.23, 122.01,
124.53, 126.42, 126.51, 126.60, 126.90, 127.48, 128.51,
128.93, 129.27, 130.65, 133.77, 135.08, 135.54, 137.53,
150.42, 159.31(d), 162.68, 163.50, 181.16; LRMS m/z (ES)
533.4 [M+Cl]ꢀ C28H23FN4O2S + Cl requires 533.1.
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9. N-Ethyl-4-[20-(N-phenylthioureido)-benzylamino]-1,8-naph-
thalimide 2
Yield 49 mg (33%) of fine yellow/orange crystals; mp 199–
201 °C; dH (399.78 MHz; DMSO-d6): 1.17 (3H, t, J 7.0 Hz,
NCH2CH3), 4.04 (2H, q, J 7.0 Hz, NCH2CH3), 4.69
(2H, d, J 5.2 Hz, ArCH2NH), 6.66 (1H, d, J 8.8 Hz, H3),
7.14 (1H, t, J 7.3 Hz, H18), 7.21 (1H, d, J 5.1 Hz, H14),
7.22 (1H, d, J 4.8 Hz, H11), 7.26 (1H, d, J 7.7 Hz, H19),
7.26 (1H, d, J 7.7 Hz, H20), 7.33 (1H, t, J 7.3 Hz, H17),
7.49 (1H, d, J 7.7 Hz, H16), 7.73 (1H, t, J 7.7 Hz, H6),
8.14 (1H, d, J 8.4 Hz, H2), 8.31 (1H, t, J 5.5 Hz,
ArNHCH2), 8.47 (1H, d, J 7.0 Hz, H5), 8.77 (1H, d, J
8.4 Hz, H7), 9.51 (1H, s, ArNHCS), 9.93 (1H, s,
CSNHAr); dC (100.54 MHz; DMSO-d6): 13.28, 34.25,
43.00, 104.84, 108.31, 120.23, 122.01, 123.85, 124.52,
124.67, 126.55, 126.93, 127.44, 128.52, 128.58, 128.95,
129.27, 130.65, 133.77, 135.10, 137.64, 139.21, 150.44,
162.67, 163.50, 180.81; LRMS m/z (ES) 515.4 [M+Cl]ꢀ
C28H24N4O2S + Cl requires 515.1; HRMS: calcd for
[C28H24N4O2S + Na]+ = 503.1518, found 503.1515.
11. Gunnlaugsson, T.; Kruger, P. E.; Jensen, P.; Pfeffer, F.
M.; Hussey, G. M. Tetrahedron Lett. 2003, 43, 8909–8913;
for other examples of Fꢀ mediated deprotonation see:
Camiolo, S.; Gale, P.; Hursthouse, M. B.; Light, M. E.
´
Org. Biomol. Chem. 2003, 1, 741–744; Gomez, D. E.;
Fabbrizzi, L.; Licchelli, M.; Monzani, E. Org. Biomol.
Chem. 2005, 3, 1495–1500.
12. Hynes, M. J. J. Chem. Soc., Dalton Trans. 1993, 311–312.