Colorimetric detection of achiral anions and chiral carboxylates by a chiral thiourea-phthalimide dyad

Article abstract of DOI:10.1039/c0pp00175a

The chiral chemosensor 1, based on a thiourea-activated phthalimide, is available by four reaction steps from 4-nitrophthalimide. 1 detects fluoride, chloride, acetate, and dihydrogen phosphate anions by changes in UV-vis absorption. Fluoride in excess induces deprotonation whereas the other anions show only complex formation in the ground state. ¹H-NMR studies confirm the formation of these H-bonded complexes and the fluoride-induced receptor deprotonation in the recognition process. Moderate chiral recognition was observed for sodium d/l-lactate with K_ass(d)/K_ass(l) = 1.93.

Full text of DOI:10.1039/c0pp00175a

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Colorimetric detection of achiral anions and chiral carboxylates by a chiral
thiourea–phthalimide dyad†
Axel G. Griesbeck,* Sebastian Hanft and Yrene D´ıaz Miara
Received 18th June 2010, Accepted 11th August 2010
DOI: 10.1039/c0pp00175a
The chiral chemosensor 1, based on a thiourea-activated phthalimide, is available by four reaction steps
from 4-nitrophthalimide. 1 detects fluoride, chloride, acetate, and dihydrogen phosphate anions by
changes in UV-vis absorption. Fluoride in excess induces deprotonation whereas the other anions show
only complex formation in the ground state. 1H-NMR studies confirm the formation of these
H-bonded complexes and the fluoride-induced receptor deprotonation in the recognition process.
Moderate chiral recognition was observed for sodium D/L-lactate with Kass(D)/Kass(L) = 1.93.
of pharmaceuticals, enantioselective sensors, catalysts, enzyme
Introduction
models, respectively, as well as other molecular devices.22,23 With
In chemical and biological processes, anions act as nucleophiles,
this premise, we became motivated in developing a new mod-
ular receptor–chromophore system (Fig. 1) based on thiourea–
and selective recognition of these species are of current interest in
phthalimide conjugates in order to observe sensing of halide
bases, redox agents, or catalysts.1 Sensors that allow the sensitive
analytic and mechanistic studies.2
A typical colorimetric sensor for anions is designed by a
ions, acetate, dihydrogen phosphate as well as the enantioselective
recognition of chiral carboxylates.
modular approach, attaching an appropriate chromophore either
covalently or non-covalently to the receptor fragment with high
affinity for the desired analyte.3 Following the receptor–anion
interaction, an appropriate signalling process must take place.
The mechanisms for anion sensing signalling processes are gen-
erally photoinduced electron transfer (PET),4–8 excited-state pro-
ton transfer.9,10 excimer/exciplex formation,11,12 metal-to-ligand
charge transfer,9 or modulation of efficiency of interchromophore
energy transfer.13 Thioureas are currently used for the design
of neutral receptors for anions and neutral donors due to their
ability to act as strong H-bond donors in sensor design and in
asymmetric organocatalysis.14,15 We have intensively investigated
the phthalimide chromophore in recent years and tuned these
Fig. 1 Chiral phthalimide–thiourea conjugate 1.
compounds from non-fluorescent to highly fluorescent by specific
Herein, we report the synthesis of 1 and the investigation
substitution.16,17 Recently, chiral photocages were developed on
the phthalimide basis, both non-fluorescent18 and fluorescent
with fluorescence up/down reporter function,19 as well as a
phthalimide-urea sensor for fluoride.20
of its absorption properties in the presence of anions F-, Cl-,
AcO-, H2PO4 , and D/L-lactate by absorption studies and by
-
confirmation of the H-bonding interaction between 1 and anions
by 1H-NMR titration experiments.
Concerning asymmetricguest–hostinteractions, itis wellknown
that chemical properties and biological activity of chiral com-
pounds are strongly dependent on their absolute configuration
in chiral environments; enantiomers have different pharmacolog-
ical properties in terms of activity, potency, toxicity, transport
mechanisms or metabolic routes.21 Thus, the development of
artificial chiral receptors, which show properties of strong chiral
recognition and chiral catalysis, attracts considerable attention
because recognition and catalysis are fundamental characteristics
of biochemical systems and could contribute to the development
Results and discussion
The synthesis of the chiral thiourea–phthalimide pair was per-
formed from phthalimide following a five-step synthetic route
shown in Scheme 1. The first step is the selective C-4 nitration
which yields 3 in 58%.24 2-Benzyl-5-nitroisoindoline-1,3-dione (4)
was obtained in the second step by nucleophilic substitution in
47%.25 Catalytic hydrogenation of 4 with Pd/C in EtOH gave 5-
amino-2-benzylisoindoline-1,3-dione (5) in 78% yield.26 2-Benzyl-
5-isothiocyanatoisoindoline-1,3-dione 6 was obtained from 5 by
reaction with thiosphosgene in 57% yield,27 and coupling with (S)-
1-phenylethylamine gave 1-(2-benzyl-1,3-dioxoisoindolin-5-yl)-3-
(phenylethyl) thiourea (1) in 81% yield.
Department of Chemistry, University of Cologne, Greinstr. 4, 50939, Ko¨ln,
Germany. E-mail: griesbeck@uni-koeln.de; Fax: +49 221 4705057
† Electronic supplementary information (ESI) available: Absorption spec-
tra changes in the presence of chloride, iodide, DBU and complexing
anions with an excess of methanol; proton NMR spectra changes of
the sensor in the presence of acetate, dihydrogenphosphate, L-lactate and
chloride. See DOI: 10.1039/c0pp00175a
The absorption spectra of sensor 1 were measured in the absence
of anions in different solvents and show two bands centered at 272
and 350 nm. These bands correspond to the two characteristic
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Scheme 1 Synthesis of the thiourea–phthalimide dyad 1.
Table 1 Absorption of sensor 1 in different solvents
Solventa
p,p*/nm
n,p*/nm
log e (n,p*)
DCM
274
271
276
270
351
347
356
348
3.87
3.73
3.82
3.88
MeCN
DMSO
MeOH
a DCM = dichloromethane; 10-5 M solutions.
electronic transitions, p,p* at higher and n,p* transition at lower
energy. Table 1 lists these absorption bands of 1 in different
solvents with the p,p* transition between 270 and 276 nm and
the n,p* transition between 347 and 356 nm. The magnitude of
the 350 nm transition also confirm the n,p* configuration. No
significant changes were observed with increasing solvent polarity
and also the protic solvent methanol does not significantly change
the absorption behavior. Sensor 1 shows zero fluorescence even
under basic conditions in protic solvents, an unusual property
when considering other compounds with the thiourea group not
directly connected to the chromophore.28
Fig. 2 Absorption spectra of 1 (3.3 ¥ 10-5 M) in the presence of increasing
amounts of fluoride (0.033 → 0.3 mM) in acetonitrile. Inset: changes in the
absorption intensity at 433 nm upon addition of fluoride (non-line-fitted
curve).
absorption data were used to calculate the association constant
as applied14 and described by Fabbrizzi and coworkers.29 These
consecutive equilibria in solution can be described involving the
neutral receptor LH and the anion X-:
The degree and selectivity of anion recognition was studied
by absorption spectra. The sensor solution was titrated with the
-
different anions F-, Cl-, Br-, I-, AcO- and H2PO4 , each applied
LH + X- ꢀ [LH ◊ ◊ ◊ X]-
(1)
as tetrabutylammonium salts (TBA+X-) in acetonitrile. The less
strongly binding anions sulfate and nitrate were not investigated.
The water content of these solution was approx. 1% which did
not disturb the association analysis. The spectra in the presence
of an additional equivalent of water (with respect to the sensor
concentration) did not lead to a change in the absorption spectra.
Consecutive titration with fluoride affects the ground state
and shifts the absorption at 347 nm bathochromic due to anion
recognition. Furthermore, two isosbestic points appeared at 286
and 367 nm and a new absorption band at 434 nm. These changes
in absorption behaviour confirm the formation of a new species
after recognition of F- by sensor 1. Fig. 2 shows the UV spectra
during titration with F- in acetonitrile solution of the sensor,
the inset shows the 433 nm absorption change / concentration
(A0 = absorbance without added anion; CA/CH = anion versus
host concentration) correlation for this specific recognition.
This curve can be interpreted as the superposition of two
processes, complex formation and subsequent deprotonation. The
[LH ◊ ◊ ◊ X]- + X- ꢀ L- + [HX2]-
(2)
The first equilibrium (eqn (1)) results in a more or less stable
hydrogen-bonded complex for all investigated anions. The second
equilibrium (eqn (2)) is related to both the intrinsic acidity of LH
and the stability of [HX2]- where LH corresponds to the sensor and
X to the anion. Our results suggest that complex formation can be
ruled out as the only recognition mechanism for fluoride. Taken
into consideration the literature results,29 the possible mechanism
for sensor system 1 could be related to a deprotonation reaction of
the NH group of the thiourea (receptor part) to F-. The potential
deprotonated species are shown in Fig. 3.
Taking into account the two extreme early and late absorption
change regions corresponding to association and deprotonation,
data evaluation resulted in two equilibrium constants: 6.7 ¥ 105
for eqn (1) and 3.0 ¥ 104 for eqn (2) (Table 2).
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Table 2 Association constants of sensor 1 with the different anions and enantioselectivites (Kass(D)/Kass(L) for lactate)a
-
F- (¥104)
Cl- (¥103)
AcO- (¥103)
H2PO4 (¥103)
D-lact. (¥103)
L-lact (¥103)
D/L
1.93
Kass (eqn (1))
Kass (eqn (2))
67.7 8.6
3.0 0.43
1.37 0.82
21.79 5.26
7.48 2.11
4.03 0.76
2.07 0.58
a 3.3 ¥ 10-5 M in 1 in CH3CN.
Fig. 3 Resonance structure of the sensor 1 after deprotonation.
1
To confirm the second deprotonation process of 1, H NMR
titration experiments were performed in DMSO-d6. The thiourea
protons appear at 8.36 (H2) and 9.35 (H1) ppm (Fig. 4). In the
presence of increasing equivalents of F-, the H1 signal disappeared
and the H2 signal was gradually shifted to higher fields with
progressively reduced intensity. The deprotonation of H1 did also
affect the proton signals Ha, Hb and Hc: urea anion formation led
to a highfield shift of all of these three aromatic proton signals.
Fig. 5 Absorption spectra of 1 (3.3 ¥ 10-5 M) in the presence of increasing
amounts of AcO- (0.033 → 0.3 mM) in acetonitrile. Inset: changes in the
absorption intensity at 380 nm upon addition of acetate.
consequence of complex formation or deprotonation process of
the thiourea protons (Fig. 6). In this case it was possible to
calculate the association constant from the absorption inten-
sity/concentration plot by a non-linear least-squares method,30
the inset in Fig. 5 shows the corresponding plot (Table 2).
Fig. 6 Association complexes between sensor 1 and the anions AcO- and
Fig. 4 Changes in 1H NMR (300 MHz) spectra of 1 in DMSO upon
-
H2PO4
.
addition of fluoride.
-
With increasing amounts of H2PO4 , in the absorption spectra
of 1 an isosbestic point appeared at 323 nm and the band at 347 nm
is weakly red-shifted by 13 nm. The absorption spectra of 1 with
large amounts of Cl- are shown in the ESI.† The spectra of 1
showed an isosbestic point at 321 nm and an increasing band at
350 nm.
The results of the titration process with acetate and dihydrogen
phosphate and the other anions are shown in Fig. 7. The
absorption spectra thus obtained allow the assumption that a
Other anions such as chloride, acetate, and dihydrogen phos-
phate were also recognized by the sensor 1. In the absorption
spectra, one isosbestic point at 353 nm appeared with increasing
concentration of acetate and the np* transition at 347 nm is weakly
red-shifted by 19 nm. Fig. 5 shows the absorption spectra following
titration with acetate.
The absorption shift indicates that the ground state of sensor
1 is affected, i.e. these changes in the absorption spectra are the
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Fig. 8 Absorption spectra of 1 (3.3 ¥ 10-5 M) in the presence of increasing
amounts of L-lactate (0.033 → 0.3 mM) in acetonitrile.
Fig. 7 Changes in the absorption of 1 at 350 nm upon titration of F-,
-
Cl-, Br-, I-, AcO- and H2PO4
.
charge transfer complex (CT) is primarily formed with each
anion. To confirm these processes, NMR titration experiments
were performed and compared with the distinct deprotonation
process induced by a non-nucleophilic base (DBU, see ESI).
The perturbation and partial reversibility of the process was
demonstrated by addition of a protic solvent like methanol or
ethanol, respectively (see ESI).
For bromide and iodide, no changes in absorption lines or
intensities of 1 were observed. The slopes corresponding to Br-
and I- addition are nearly identical. The slope for the recognition
of Cl-, AcO- and H2PO4 , respectively, increases gradually upon
-
rising concentration (Fig. 7). Fluoride, as already discussed,
displays a special behavior, in that the absorption spectra change
is highly non-linear and points to two processes that are highly
different in their equilibrium constants. These changes can be
associated with the deprotonation of H1 and the hydrogen bonding
with H2.
Fig. 9 Changes in the absorption of 1 at 373 nm upon addition of D- and
L-lactate.
A comparison of the behaviour of AcO- with F- shows that the
complex formed with AcO- is more stable than the F- complex.
The small fluoride ion interacts with H1 to release HF that in
⎡
2
⎤
⎥
⎥
⎥
presence of F- forms HF2 . The reason for this is the relatively low
-
⎛
⎜
⎞
⎢
A
lim / A −1
CA
1
CA
1
CA
CH
⎟
⎟
⎟
⎟
⎠
0
⎢
A/ A =1+
1+
+
− ⎜1+
+
−4
stability of the intermediate complex [1H ◊ ◊ ◊ F]- in comparison
0
⎜
⎜
⎝
⎢
2
CH KaCH
CH KaCH
⎢
⎣
⎥
⎦
-
to the stability of HF2 . The sensors studied by Fabbrizzi et al.
presented the same behavior as sensor 1 in the presence of F-.14
For all complexes, the association constants Kass were calculated
by using the equation published by Qing et al.30
A0 is the absorption intensity of the host in the absence of
anions, Alim is the absorption intensity reaching a limit by adding
excessive anions, CA is the concentration of anions added. CH is
the concentration of the host molecule and A is the absorption
intensity of the complex. By allowing 1/KaCH to be varied, the
Ka values can be obtained by non-linear least-squares analysis of
A/A0 vs.CA/CH.
From the two association constants for D- and L-lactate, an
enantioselectivity coefficient of 1.93 results, which corresponds to
moderate chiral differentiation between lactate enantiomers.
Chiral recognition experiments were also carried out. The
absorption spectra of sensor 1 in the presence of D- and L-lactate
did not show significant changes (see ESI). Fig. 8 shows the
absorption spectra of 1 in the presence of L-lactate. Only a weak
increase of the absorption band at 373 nm was observed. This can
be interpreted again as complex formation in the ground state.
The analogous behaviour was obtained for D-lactate.
Fig. 9 shows the plot of the absorption changes of 1 in the
presence of D- and L-lactate. The difference between both anions
can be observed in the plot especially at lower concentrations of
the chiral anions.
-
In summary, a new sensor for F-, Cl-, AcO- and H2PO4
is described. F- recognition involves two consecutive associa-
tion/deprotonation processes and the recognition of Cl-, AcO-
and H2PO4 shows formation of CT complexes. Sensor 1 exhibits
For these complexes, the association constants Kass (Table 2)
were calculated by using the following equation and coefficient
optimization:30,31
-
a moderate chiral discrimination between D- and L-lactate.
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with 40 mL portions of water, 2% sodium hydroxide solution, and
water. The dried crude product 4 was recrystallized from EtOH
(the solution was concentrated and water was added dropwise
until the turbidity ju◦st disappeared) and filtered while hot: 47%
Conclusion
In summary, the acidity of the NH protons of sensor 1 gives rise to
the different interactions between sensor and anions. The recogni-
tion of these anions through hydrogen bonding and deprotonation
were observed by absorption spectra and H NMR. The sensor
showed efficient recognition of AcO- > H2PO4 > Cl- through
hydrogen bonding and for F- as a combination of association and
deprotonation of the receptor. The sensor 1 can be used as a basic
model for a chiral absorption chemosensor for chiral carboxylic
acids.
1
yield. M.p. 164–165 C, H NMR (CDCl3, 300 MHz) d 4.89 (s,
1
2H, CH2), 7.32 (m, 3H, CHar), 7.44 (m, 2H, CHar), 8.04 (d, 1H,
J = 8.1, CHar), 8.59 (dd, 1H, J1 = 8.1, J2 = 1.8, CHar), 8.66 (d, 1H,
J = 1.7, CHar).
-
5-Amino-2-benzylisoindoline-1,3-dione (5)26.
A mixture of
2.09 mmol of 4, 5% Pd/C in 20 mL of EtOH was vigorously
stirred at room temperature under a hydrogen atmosphere for 4 h.
The reaction mixture was then filtered over celite and concentrated
in vacuo. The residue wa◦s recrystallized from EtOH to give 5 in
78% yield. m.p. 126–127 C, 1H NMR (CDCl3, 300 MHz) d 4.33
(s, 2H, NH2), 4.81 (s, 2H, CH2), 6.82 (dd, 1H, J1 = 8.1, J2 = 2.1,
CHar), 7.03 (d, 1H, J = 2.0, CHar), 7.34 (m, 5H, CHar), 7.61 (d, 1H,
J = 8.1, CHar); 13C NMR (CDCl3, 75 MHz) d 41.3 (CH2), 108.5
(CHar), 117.8 (CHar), 120.5 (Car), 125.1 (CHar), 127.6 (CHar ¥ 2),
128.4 (CHar), 128.5 (CHar ¥ 2), 134.9 (Car), 136.7 (Car), 152.2 (Car),
168.1 (C O), 168.3 (C O).
Experimental
Materials
The starting materials thiophosgene, benzlybromide and ph-
thalimide, as well as (S)-phenylethylamine were commercially
available and used without further purification. Spectroscopic
grade acetonitrile (MeCN), dimethylsulfoxide (DMSO), methanol
(MeOH) and dichloromethane (DCM) were used as solvents.
Commercial TBA salt solutions were used.
1H NMR. The spectra were recorded on Bruker AC 300 and
Bruker AV 600 spectrometers (300/600 MHz). Chemical shifts
are reported as d in ppm and the coupling constant, J, in Hz. In
all spectra solvent peaks were used as internal standard. Solvent
used are DMSO-d6 (d = 2.49 ppm) and CD3CN (d = 1.94 ppm).
Splitting patterns are designated as follows: s, singlet; d, doublet;
dd, doublet of doublets; t, triplet; q, quintet; m, multiplet. 13C
NMR. The spectra were recorded either on a Bruker AC 300
spectrometer instrument operating at 75 MHz or on a Bruker AV
600 spectrometer instrument operating at 126 MHz. Absorption
spectroscopy. Absorption spectra were recorded using Perkin-
Elmer Lambda 35 UV/vis spectrometer. The samples were placed
into quartz cells of 1 cm path length. Compound concentrations
were fixed as indicated.
2-Benzyl-5-isothiocyanatoisoindoline-1,3-dione
(6)27. To
a stirred solution of 126 mg (0.50 mmol) of 5-amino-2-
benzylisoindoline-1,3-dione (5) in 2 mL of CH2Cl2, 46.0 mL of
thiophosgene (69.0 mg, 0.60 mmol) was added in one portion via
syringe. After 10 min of stirring, 0.15 mL of Et3N was added in
one portion. The whole mixture was stirred at room temperature
for additional 4 h. Next, CH2Cl2 (2 mL) and water (5 mL) were
added to the mixture. The layers were separated, the organic
layer was washed with 1 N HCl (2 ¥ 5 mL), dried over MgSO4
and evaporated to dryness. The crude product was purified by
column chromatography, Rf 0.90 (SiO2, CH2Cl2), to give 6 in
57% yield. M.p. 155–156 ◦C, 1H NMR (CDCl3, 300 MHz) d 4.83
(s, 2H, CH2), 7.34 (m, 5H, CHar), 7.47 (dd, 1H, J1 = 7.9, J2
=
1.8, CHar), 7.63 (d; 1H, J = 1.7, CHar), 7.82 (d; 1H; J = 7.9 Hz;
CHar); 13C NMR (CDCl3, 75 MHz) d 41.9 (CH2), 120.5 (CHar),
124.7 (CHar), 127.9 (CHar ¥ 2), 128.6(Car), 128.7 (CHar ¥ 2), 129.6
(CHar), 130.8 (CHar), 133.9 (Car), 135.9 (Car), 137.4 (Car), 140.2
Synthesis of the chemosensor 1
5-Nitroisoindoline-1,3-dione (3)24. At 15 ◦C, 10 g (68.0 mmol)
of phthalimide (2) was added in ten portions over a 15 min interval
to 62.5 mL of a mixture of concentrated sulfuric acid and 100%
nitric acid (4 : 1 v / v◦) under vigorous stirring. The temperature was
raised slowly to 35 C and held for 45 min whereby the solution
turned yellow. The reaction mixture was subsequently cooled to
(S
C
N), 166.5 (C O), 166.7 (C O).
1-(2-benzyl-1,3-dioxoisoindolin-5-yl)-3-((R)-1-phenyl-ethyl) thi-
ourea (1). (S)-1-phenylethylamine (18.3 mL, 17.3 mg,
0.143 mmol) was added into an argon filled reactor containing
42.2 mg of 2-benzyl-5-isothiocyanatoisoindoline-1,3-dione (6)
(0.143 mmol) in dry dioxane (10 mL). The mixture was heated
at 100 ◦C under stirring for 24 h. The solvent was evaporated
and the crude product 1 was purified by column chromatography,
Rf 0.42 (SiO2, EtOAc / cyclohexane, 2 : 3), in 81% yield. M.p:
171–173 ◦C, 1H NMR (acetone-d6, 300 MHz) d 1.57 (d, 3H, J =
6.9, CH3), 4.80 (s, 2H, CH2), 5.71 (m, 1H, CH), 7.34 (m, 10H,
CHar), 7.75 (d; 1H, J = 8.1, CHar), 7.89 (dd, 1H, J1 = 8.1, J2 =
1.8, CHar), 7.95 (d, 1H, J = 7.7, NH), 8.36 (m, 1H, CHar), 9.35
(s, 1H, NH).13C NMR (acetone-d6, 75 MHz) d 22.9 (CH3), 42.9
(CH2), 55.0 (CH), 117.9 (CHar), 125.4 (CHar), 128.0 (CHar), 128.2
(CHar), 128.9 (CHar), 129.3 (CHar ¥ 2), 129.7 (CHar ¥ 2), 130.3
(CHar ¥ 2), 130.4 (CHar ¥ 2), 134.8 (Car ¥ 2), 139.0 (Car), 145.2
(Car), 147.5 (Car), 168.1 (C O), 168.2 (C O), 180.9 (C S). IR
n 3306(w), 2920 (w), 1769 (m), 1697 (s), 1614 (m), 1530 (s) cm-1;
0
◦C, slowly poured into 250 g of ice at such a rate that the
temperature was kept below 15 ◦C. The precipitate was collected
by vacuum filtration and washed with cold water. Product 3 was
recrystallized ◦from EtOH to give colorless crystals in 58% yield.
m.p. 194–195 C, 1H NMR (DMSO-d6, 300 MHz) d 8.07 (d, 1H,
J = 8.2, CHar), 8.44 (d, 1H, J = 1.9, CHar), 8.61 (dd, 1H, J1 = 8.2,
J2 = 2.0, CHar), 11.38 (s, 1H, NH).
2-Benzyl-5-nitroisoindoline-1,3-dione (4)25. In a 100 mL round
flask 2.00 g (10.4 mmol) of 4-nitrophthalamide (3), 0.90 g
(6.51 mmol) of anhydrous potassium carbonate and 0.20 g
potassium iodide were placed. Then 12.4 mL benzylbromide and
20 mL of dry DMF were added. The mixture was heated at 140 ◦C
for 1.5 h. The cooled reaction mixture was poured into 150 mL of
cold water. After collecting the solid, it was washed successively
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C24H21N3O2S (415.1354) HRMS: 415.136; calculated: C 69.37, H
5.09, N 10.11%; found: C 69.39, H 5.13, N 10.06%.
14 D. E. Gome´z, L. Fabbrizzi, M. Licchelli and E. Monzani, Urea vs.
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16 A. G. Griesbeck, N. Hoffmann and K.-D. Warzecha, Photoinduced
electron transfer chemistry: from studies on PET processes to applica-
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17 A. G. Griesbeck and S. Schieffer, Intra- and intermolecular fluores-
cence quenching of N-activated 4,5-dimethoxyphthalimides by sulfides,
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Acknowledgements
This work was generously supported by the German Academic
Exchange Service DAAD (Ph. D. fellowship to Y. D.).
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