Thiourea derived troeger's bases as molecular cleft receptors and colorimetric sensors for anions

Article abstract of DOI:10.1021/jo4008942

Thiourea-functionalized Troeger's base receptors 1 and 2 have been synthesized and evaluated as novel for the recognition of anions. Receptor 2 gave rise to significant changes in the absorption spectrum upon titration with AcO^- and H₂

Full text of DOI:10.1021/jo4008942

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Article
Thiourea Derived Troger’s Bases as Molecular Cleft
Receptors and Colorimetric Sensors for Anions
Elaine M. Boyle, Steve Comby, Jennifer K. Molloy, and Thorfinnur Gunnlaugsson
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo4008942 • Publication Date (Web): 30 Jul 2013
Downloaded from http://pubs.acs.org on August 4, 2013
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Thiourea Derived Tröger’s Bases as Molecular Cleft
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Receptors and Colorimetric Sensors for Anions
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Elaine M. Boyle, Steve Comby, Jennifer K. Molloy and Thorfinnur Gunnlaugsson*
School of Chemistry, Centre for Synthesis and Chemical Biology and Trinity Biomedical Sciences
Institute, Trinity College Dublin, Dublin 2, Ireland.
gunnlaut@tcd.ie
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
* Corresponding author
Abstract: Thiourea functionalized Tröger’s base receptors 1 and 2 have been synthesized and
evaluated as novel receptors for the recognition of anions. Receptor 2 gave rise to significant changes in
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the absorption spectrum upon titration with AcO- and H2PO4 and acted as a colorimetric sensor for F-;
the interaction of which was also evaluated using 1H NMR spectroscopy.
Keywords: Anion sensing, thiourea, colorimetric sensing, Tröger’s base
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Introduction: The recognition of anions via non-covalent interactions is of major interest in host-guest
chemistry.1-3 In particular, molecular clefts have attracted significant attention in supramolecular
chemistry due to their ability to allow functional groups to be orientated in defined geometries.4,5
Specific geometries can also be exploited by arranging the H-bond donors around the acceptors in three-
dimensional space; either through the use of single ligands or via a self-assembly formation of more
than one such ligands.6 If the host’s preorganized binding cavity complements the guest’s geometry,
then high selectivity can be achieved, as recently demonstrated by several groups including those of
Gale,7 Steed, 8 Johnson, 9 and Pfeffer 10. The use of the urea or thiourea moiety in such anion recognition
is now well established.11-14 We have developed many examples of urea based receptors and sensors for
anions, using urea and amide functionalities, including employing them into fluorescent emissive
structures such as anthracenes15 and naphthalimides as PET sensors for anions,16,17 and as colorimetric
probes, such as for CO2 fixation,18 which was mediated by initial detection of fluoride. Recently, we
have also developed Ru(II) polypyridyl19 and lanthanide20 complexes possessing such anion recognition
systems, and we have developed molecular cleft-type structures, based on pyridyl amidothioureas,21 and
semithiocarbazides22 with the view of achieving preorganization within such anion recognition moieties.
These examples showed very promising properties as hosts for anions, particularly for oxy-anions.
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The Tröger’s base is a structural motif containing a diazocine ring conjugated to two aromatic
moieties, first described by Julius Tröger in 1887,23 that has more recently become an important
building block in supramolecular chemistry.24 The Tröger’s base is chiral, where two aromatic rings
fused to the central bicyclic framework, create a rigid, V-shaped, C2-symmetrical molecular scaffold
that places the aryl rings almost 90o to each other. This important shape has played a considerable role
in the field of molecular recognition and several receptors for the recognition of carboxylic acids have
been developed25 and we have recently shown that the Tröger’s base building unit can be employed in
structures for binding and sensing of nucleic acids, and for imaging of cancer cells.26,27 However, and to
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the best of our knowledge, their use as a preorganizing unit in the sensing of simple oxy anions has not
been explored.25 With this in mind, we set out to explore the possibility of using the Tröger’s base
platform for anion recognition and sensing. Herein we report two thiourea functionalized Tröger’s base
receptors, 1 and 2, as ‘molecular cleft-like’ hosts for the recognition of anions, but these examples were
easily formed from the Tröger’s base benzyl amine 3 in a single step with commercially available
isothiocyanates. By incorporating electron withdrawing moieties into the aryl-thiourea structures we
demonstrate that the nature of the urea moiety greatly affects the sensitivity and the selectivity of the
recognition process, which was monitored by using both UV-visible absorption and NMR
spectroscopies; were the experimental data was analyzed using non-linear regression analysis, showing
that such recognition can occur in both 1:1 and 1:2 (host:guest) stoichiometries. The results from this
investigation demonstrate that the Tröger’s base motive has a new role to play in anion recognition
chemistry; which can also potentially be mapped onto its use in organo-catalysis28.
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Results and Discussion
Synthesis of receptors 1 and 2: The synthesis of receptors 1 and 2 was achieved from 3, which was
formed by using classical organic synthesis, by first reacting potassium phthalimide with 4-
nitrobenzylbromide. Aqueous workup using EtOAC/Toluene (2:1) followed by washing with H2O gave
the desired product as white crystals in 64% yield. Reduction of the nitro group was achieved in
Scheme 1: Synthesis of receptors 1 and 2.
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quantitative yield using Pd/C under 3 atm of H2, giving the corresponding aniline derivative as yellow
crystals. Formation of the phthalimide protected Tröger’s base was achieved by using modified
synthesis of that described by Wilcox23b, by stirring overnight 4-aminobenzylphthalimide with 2 eq. of
formaldehyde and TFA, after which the aqueous workup gave the desired phthalimide based Tröger’s
base as a brown oil in 30% yield. Deprotection of the phthalimide groups was achieved by stirring with
neat hydrazine at 80°C overnight.29 The crude product was extracted into CHCl3 and then washed with
water, giving 3 as yellow oil in 61% yield. To form 1 and 2, 3 was simply reacted with the
corresponding isothiocyanates in CHCl3 in the presence of triethylamine under reflux overnight, Scheme
1. The crude products were collected by filtration, followed by trituration with CHCl3, giving
compounds 1 in 43% yield, as a white solid, and 2 as an orange solid in 40% yield. The receptors were
fully characterized by 1D and 2D NMR, 13C NMR, mass spectrometry and elemental analysis, see
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Supporting Information Figures S1-S4. For instance, H NMR (400 MHz, DMSO-d6, Figures S1 and
S3) of receptors 1 and 2 showed the presence of the two sets of thiourea N-H protons, resonating at 9.84
and 8.35 ppm for the former, while the nitro analogue displayed resonances at 10.15 and 8.58 ppm.
Anion binding studies of receptors 1 and 2: The ability of both 1 and 2 to bind to anions such as
acetate, phosphate, chloride and fluoride as well as ‘bis-anions’ such as pyrophosphate was undertaken
in organic solution. The absorption spectrum of receptor 1, Figure 1, when recorded at room temperature
in DMSO shows two main absorption bands centered at 260 nm and at 284nm ( 284 = 33752 M-1 cm-1).
In contrast, at high concentrations, the absorption spectrum of receptor 2 displayed three main bands
present in the spectrum, at 258, 355 ( 355 = 32936 M-1 cm-1, calculated after equilibration) and 484 nm,
Figure 1. However, over time, the band at 484 nm slowly decreases in absorption before completely
disappearing after ca. 1 hour standing at room temperature.30 We attribute this behavior to
intermolecular H-bonding occurring in the concentrated stock solution of the receptor as this behavior
has already been encountered for bis-thiourea receptors.31 Excitation at the
of each receptor only
max
gave rise to weak fluorescence emission. In fact, X-ray crystal structure analysis of a related structure
possessing carboxylic ester developed in our laboratory indeed showed such interactions in the solid
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state with extended
- packing and/or packing of a Tröger’s base-cleft within another cleft.30b,32
Recently, Kruger et al.32 and Giannis and co-workers. 33 have seen similar phenomenon in the solid-state
in their work on Tröger’s bases, even though in the latter case the presence of CH-π interactions was
triggering the formation of the dimeric species.
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Figure 1: Absorption spectra of receptors 1 and 2 in DMSO.
The anion binding abilities of the receptors were evaluated using UV-visible absorption and 1H NMR
spectroscopy. Solutions of H2PO4 , AcO-, F- and SO42- as their TBA salts in DMSO were titrated against
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a solution of either 1 or 2 (1 × 10-5 M) in DMSO. All titrations were repeated several times to ensure full
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reproducibility. Detailed absorption titrations were first carried out with 1 and H2PO4 , as Pfeffer et al.
had previously shown that cleft-like structures based on the use of preorganized thiourea functionalized
[3]polynorbornane receptors give excellent selectivity for phosphate and bis-carboxylate anions.10
However, to our surprise, the changes in the absorption spectra of 1, were only minor, Figure S5 in
Supporting Information. We thus investigated the binding of the more structurally simple AcO- and
2-
SO4 anions to receptor 1. The absorption spectrum of 1 was mostly unaffected upon addition of the
anions and only minor changes were observed at 284 nm, with a very weak hyperchromic and
hypochromic effect for AcO- (+3%) and SO4 (-8%), respectively, Figures S6-S7. The minor changes
2-
observed in the UV-visible spectrum of 1 upon anion addition are most likely due to the fact that both
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free and bound species have very similar UV-visible spectra as this behavior has already been observed
in other CF3-containing receptors.5a
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Conversely, the titration of 1 with F- did result in significant changes in the absorption spectrum; a
new absorption band was observed at 332 nm, while the band at 284 nm decreased in absorbance,
resulting in the concomitant formation of an isosbestic point at 300 nm, Figure S8 in Supporting
Information. Analysis of these changes showed that these could be attributed to initial hydrogen bonding
of the anion to the receptor moieties, rapidly followed by deprotonation and concomitant formation of
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the stable HF2 anion in solution, but such phenomenon has been well documented.18
Similar UV-visible titrations were next performed with receptor 2. In contrast to that observed for
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receptor 1, the absorption spectrum of 2 exhibited significant changes upon binding to H2PO4 , Figure 2.
The band centered at 355 nm experienced a gradual bathochromic shift to reach a
of 370 nm after
max
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the addition of 50 equivalents of H2PO4 . The 15 nm red shift observed for the high energy absorption
band was further accompanied by the appearance of a new absorption band at 480 nm.
0.42
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Figure 2: Evolution of the absorption spectrum of receptor 2 (ca. 10 µM) in DMSO upon titration with
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H2PO4 . Inset: Changes observed at 297, 357 and 480 nm as a function of the equivalents H2PO4 added.
Similarly, upon titration with AcO-, again the new band at ca. 480 nm appears during the course of
the titration and the band at ca. 355 nm also experiences a similar bathochromic shift to that seen for
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H2PO4 , Figure 3. There was no clear isosbestic point observed in this titration but a ‘pseudo’ isosbestic
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point at ca. 377 nm could be seen. In comparison to the titration with H2PO4 , a plateau was reached
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much earlier, at ca. 20 equivalents of the anion. It can also be seen that at higher concentrations of AcO-,
from ca. 200 eq., absorbance of the bands at 355 nm and 480 nm undergo a slight increase and decrease
respectively, indicating the changes are bi-phasic.
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Figure 3: Evolution of the absorption spectrum of receptor 2 (ca. 10 µM) in DMSO upon titration with AcO-.
Inset: Changes observed at 294, 356, 374 and 473 nm as a function of the equivalents AcO- added.
In contrast to the results obtained for H2PO4 and AcO-, SO42- resulted in no significant modulation of
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the absorption spectrum of 2, even at over 400 equivalents of the anions, Figure S9. The titration of 2
and F- resulted in significant changes of the absorption spectrum that were accompanied with a color
change from colorless to orange, Figure 4A. The absorbance maximum at ca. 355 nm experienced a
hypochromism; however no red shift of this band occurred. The presence of two ‘pseudo’ isosbestic
points at ca. 286 nm and 392 nm can be seen. Nevertheless, a plateau for this titration is not reached
until ca. 100 equivalents of F-, Figure 4B. From the observed changes in the UV-visible absorption
studies, the binding affinities of each receptor with different anions (1 vs. F- and 2 vs. F-, AcO- and
H2PO4 ) were determined using SPECFIT™. The binding constants obtained are summarized in Table 1.
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The data obtained from the titration of 2 with AcO- and H2PO4 were both best fitted to a 1:1 and 2:1
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(Guest:Host) stoichiometry, indicating identical binding modes for these two oxyanions. As expected
from the changes in the UV-visible spectra, similar binding constants were determined for these anions
with the values for H2PO4 only marginally higher than that obtained for AcO-. An excellent fit of the
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data was obtained for both of these anions, Figure 5A and Figure S10.
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(A)
(B)
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Figure 4: (A) Evolution of the absorption spectrum of receptor 2 (ca. 10 µM) in DMSO upon titration with F-
; Inset: Photographs of receptor 2 before and after the addition of F-. (B) Changes observed at 310, 356 and
483 nm as a function of the equivalents F- added.
Table 1: Binding Constants and Binding Modes between anions and receptors 1 and 2 as determined
from the analysis of the UV-visible titrations performed in DMSO.
Binding Mode
Gn:Lm
G4:L
log βn:m
Receptor
Anion
F-
AcO-
± Std. Dev.
13.48 ± 0.04
4.13 ± 0.03
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4.25 ± 0.05
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8.19 ± 0.04
14.88 ± 0.08
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2
G:L
G2:L
G:L
G2:L
G2:L
G4:L
-
H2PO4
F-
2
2
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The speciation distribution diagram demonstrates H2PO4 binds to the receptor with an initial 60%
formation of the 1:1 species, forming at lower concentrations before evolving towards the 2:1 species,
the latter becoming the most dominant species in solution (ca. 80 % formation) at higher equivalents,
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Figure 5B. At ca. 100 equivalents of H2PO4 both species are present in solution in almost equal
concentrations. The speciation of the titration with AcO- was almost identical as shown in Figure S10.
These interactions are undoubtedly H-bonding between the thiourea moiety of 2 and these anions.
The results obtained for F- are very similar to that seen for 1 and are most likely due to H-bonding
initially, but deprotonation is the main outcome which can be concluded from these titrations. As for the
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oxyanions, the titration of 2 with F- were best fitted using a model involving three colored species,
namely receptor 2, a 2:1 and 4:1 (Guest:Host) species, Figure S11. The initial formation of a 2:1
(Guest:Host) species, where each F- anion is hydrogen-bonded to the thiourea protons that are directly
conjugated to the electron-withdrawing NO2 groups is followed by the formation of a 4:1 (Guest:Host)
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species and subsequent deprotonation and release of HF2 . The binding constants obtained for 2 and F-
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reflect the higher acidity of the thiourea protons as a result of the highly electron withdrawing NO2
group compared to the CF3 derivative.
(A)
(B)
0.33
100
Data
Fit
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0.27
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G:L
G :L
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481 nm
517 nm
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Eq. H2PO4- added
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Figure 5: (A) Experimental binding isotherms for the UV-visible titration of 2 (ca. 10 M) with H2PO4
(0 471 equivalents) in DMSO and their corresponding fit by means of SPECFIT ( ). (B) Speciation
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distribution diagram obtained from the fit of the titration of 2 (L) with H2PO4 (G).
The varying response of this receptor compared to the CF3 analogue with the anions studied has
provided some very interesting results. Receptor 2 does indeed show H-bonding interactions with AcO-
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and H2PO4 with relatively strong binding constants determined for both the 1:1 species (log K1:1 = 4.13
± 0.03 and 4.25 ± 0.05, respectively) and the 2:1 complex (log K2:1 = 3.10 ± 0.05 and 3.15 ± 0.07,
respectively), while receptor 1 showed no or extremely weak interaction with these anions. Interestingly
2-
neither receptor showed any binding interaction with SO4 . The most significant changes occurred
between both receptors and F-. However, due to the presence of the nitro groups, which are more
electron withdrawing than the CF3 groups of 1, the N-H protons of 2 are highly acidic and more readily
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deprotonated. This translates into an overall binding constant log β that is more than one order of
4:1
1
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4
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magnitude larger for 2 than for the CF3 analogue 1. Interestingly, colorimetric changes have been
observed for 2 upon addition of F- while such changes were not observed for the other anions studied,
Figure 4A. Because of these interesting results, we next investigated the anion recognition further using
1H NMR spectroscopy, which will be discussed in next section.
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Given our experience in the binding of bis-anions, such as bis-carboxylates and
pyrophosphate5c,d,10b,21 using pre-organized calixarene hosts, and inspired by the work of Ghosh et al.
and Moriwaki et al.25 we also investigated the binding of 1 and 2 to pyrophosphate. We had anticipated
that possibly the bis-anion could bridge the cavity of the Tröger’s base, binding in a 1:1 stoichiometry.
However, while the changes observed in the UV-visible absorption spectra were similar to that observed
above, we were unable to obtain reliable binding constants from these changes. It is possibly that unlike
that demonstrated by Ghosh et al.25a the thiourea receptors of 1 and 2, might not facilitate the binding of
such bis-anions with the same ease, as the changes observed only occurred at higher concentrations of
pyrophosphate. We are currently carrying out modifications on 1 and 2, with the view of achieving such
bis-anion binding.
1H NMR Titration of receptors 1 and 2 with anions: Having evaluated the ability of 1 and 2 to bind
various anions using UV-Vis titrations, we next investigated the mode of binding using NMR. The
1
changes in the H NMR spectra of 1 and 2 in DMSO-d6 solutions were monitored upon the addition of
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AcO- and H2PO4 as their TBA salts, as these were the two anions that showed the most significant
2-
spectral differences between the two receptors. A titration with TBA SO4 was also carried out to
determine if any interaction between this anion and the receptors occurred at higher concentrations. The
chemical shifts of the thiourea protons were monitored after addition of the different anions to evaluate
and determine the strength of the interaction taking place with receptors 1 and 2. The data were plotted
as the cumulative changes in chemical shift ( ) against the equivalents of anion added, where NHa
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refers to the thiourea protons that are directly linked to the para-substituted phenyl of receptors 1-2 and
NHb, to the remaining thiourea protons.
1
2
3
4
5
6
Although no significant changes were observed in the absorption spectrum of 1 upon titration of
-
1
-
7
8
H2PO4 , changes were observed in the H NMR spectrum upon addition of H2PO4 , depicted by the
9
binding isotherm in Figure 6A. The anion did interact with the receptor resulting in a chemical shift of
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ca. 2.2 ppm for the NHa protons being observed after the addition of 4 equivalents of H2PO4 and a
smaller shift of ca. 1.7 ppm for the NHb ones. A plateau was reached after the addition of 2.5-3
equivalents of the anion. The doublet assigned to the protons of the phenyl ring ortho to the CF3 group
also experienced a downfield shift, but to a much lesser extent (
~ 0.4 ppm). These changes,
indicative of H-bonding, were only observed in the NMR studies as the absorption spectrum of 1
-
displayed only minor changes upon addition of H2PO4 , see Figure S5. The data obtained from the
-
titration of 1 with AcO- showed an almost identical trend than for H2PO4 , Figure 6B.
(A)
(B)
2.5
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
2.0
1.5
1.0
0.5
0.0
NHa
NHb
NHa
NHb
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
Eq. H2PO4- added
Eq. AcO- added
Figure 6: Changes in the thiourea proton resonances NHa and NHb of receptor 1 (as ) upon titration with
-
H2PO4 (A) and AcO- (B).
The binding of AcO- to receptor 1 resulted in larger downfield shifts of the thiourea protons (ca. 3 and
-
3.2 ppm for NHa and NHb, respectively) than the ones observed upon binding to H2PO4 , Figure 6. This
is indicative of a larger perturbation of the magnetic environment of 1 upon binding to AcO- compared
-
to H2PO4 . The doublet assigned to the protons of the phenyl ring ortho to the CF3 group also
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experienced a small downfield shift as shown in Figure 7. This binding interaction, most likely due to
1
2
3
H-bonding, was also not seen during the UV-visible titration of 1 with AcO-.
4
5
6
0 eq.
N-Ha
N-Hb
7
8
9
0.5 eq.
1 eq.
2 eq.
4 eq.
10
11
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59
60
[ppm]
Figure 7: Stack plot of the 1H NMR (400 MHz, DMSO-d6) spectra of receptor 1 upon addition of AcO-.
-
The successive addition of H2PO4 to 2 resulted in significant changes in the chemical shifts of the
thiourea protons. In the case of NHa, the resonance became considerably broadened after the addition of
-
ca. 0.5 equivalents and progressively disappeared once higher equivalents of H2PO4 were added.
Therefore, only the NHb proton resonance could be followed throughout the course of the titration,
Figure 8A. In contrast to the results seen for receptor 1, the phenyl protons ortho to the thiourea shifted
downfield, while the protons ortho to the NO2 group shifted upfield, simultaneously experiencing
significant broadening. Additionally, the aromatic protons adjacent to the Tröger’s base moiety and their
multiplicities were clearly resolved up until ca. 1 equivalent of the anion before also becoming
broadened. A color change from pale yellow to deep orange was observed after the addition of ca. 0.5
equivalent of H2PO4 . The titration of 2 and AcO-, a plot of
versus the equivalents of AcO- added is
-
-
shown in Figure 8B, was slightly different to that seen for H2PO4 . The two thiourea resonances were
clearly visible throughout the entire titration, showing almost identical changes in chemical shifts, both
signals experiencing a downfield shift of over ca. 3 ppm. Similarly to what was observed for receptor 1,
the extent of shift is larger than the one seen for H2PO4 , which confirms that the binding of AcO- leads
-
to a stronger difference in the magnetic environment between the free and bound states. The phenyl
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protons adjacent to the thiourea moiety merged to become one singlet at ca. 2 equivalents of the anion,
while the other aromatic resonances became more resolved. The binding profile indicates a plateau was
reached at ca. 2 equivalents of the anion. Again a drastic color change from pale yellow to deep orange
was observed almost immediately, after the addition of 0.2 equivalent of AcO-. In direct contrast, the
titration of both receptors 1 and 2 with SO42- did not result in any perturbation of the thiourea protons or
any other resonances in the spectrum, corroborating the results obtained from the UV-visible absorption
titrations, Figures S12-S13 in the Supporting Information.
1
2
3
4
5
6
7
8
9
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(A)
(B)
3.0
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
2.5
2.0
1.5
1.0
0.5
0.0
NHa
NHb
NHa
NHb
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
Eq. H2PO4- added
Eq. AcO- added
-
Figure 8: Changes in the thiourea resonances NHa and NHb of receptor 2 (as ) upon titration with H2PO4
(A) and AcO- (B).
The binding constants for the interaction of the different anions with receptors 1 and 2 were
determined using NMRTit HGG.34 The cumulative changes in chemical shift plotted against the
equivalents of anion added were best fitted following a binding model involving the presence of two
main species, namely a 1:1 and 2:1 (Guest:Host) species. An excellent fit of the NMR data was obtained
-
for 1 and 2 with H2PO4 and AcO- (Figures S14-S15) and the binding constants determined are
summarized in Table 2.
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Table 2: Binding Constants and Binding Modes between anions and receptors 1 and 2 as determined from the
analysis of the 1H NMR titrations performed in DMSO-d6.
1
2
3
4
5
6
7
8
Binding Mode
Gn:Lm
G:L
log βn:m
Receptor
Anion
± Std. Dev.
3.42 ± 0.05
5.99 ± 0.09
3.18 ± 0.05
6.25 ± 0.09
4.21 ± 0.06
7.21 ± 0.11
4.22 ± 0.06
7.40 ± 0.11
-
H2PO4
AcO-
1
1
2
2
9
G2:L
G:L
G2:L
G:L
G2:L
G:L
G2:L
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
-
H2PO4
AcO-
The values obtained for 2 were in good agreement with those determined from the UV-visible titrations.
Conversely, the binding constants of receptor 1 with the different anions were found to be lower than
those determined for 2.
The 1H NMR titrations of receptors 1 and 2 gave some interesting results. The studies performed on
receptor 1 demonstrated that interactions occurred with H2PO4 and AcO-. Indeed, contrary to the
-
absorption studies above, it can be concluded that these anions do in fact form H-bonded complexes
with the receptor. The results for receptor 2 were found to be in agreement with the UV-visible
spectroscopic titrations as the formation of H-bonded complexes with H2PO4 and AcO- was confirmed.
-
Color changes were also observed upon addition of these anions to 2. Interestingly, as before, neither
2-
receptor was found to interact with SO4 .
Conclusion
In this article, we demonstrate that the attachment of thiourea functional groups, capable of
forming H-bonds, at the extremities of the Tröger’s base skeleton can be used successfully to create
synthetic receptors for the recognition of anions. The two receptors were synthesized and fully
characterized; and a description of their photophysical properties has been described. The anion
1
recognition abilities of both receptors were investigated by absorption and H NMR spectroscopy. The
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presence of H-bonding interactions between the CF3 derivative 1 and the oxy-anions, AcO- and H2PO4 ,
were only observed in the 1H NMR studies as addition of these anions resulted in no or extremely weak
changes during the UV-visible absorption titrations. Conversely, receptor 1 underwent deprotonation
-
1
2
3
4
5
6
7
8
-
upon titration with F-. The NO2 derivative 2 was found to be selective for AcO- and H2PO4 , while
9
acting as a colorimetric sensor for F-, most likely via deprotonation. Attaching H-bond donor units to a
suitable molecular scaffold is a common method for achieving preorganisation of the binding cavity and
the use of conformationally preorganized receptors have been shown to bind anions very efficiently. The
two thiourea functionalized Tröger’s base receptors detailed herein are the first example of this unique
structural framework being incorporated into synthetic receptors for anions. The results highlight the
fact that exceptionally strong complexation can be achieved through the active cooperation of multiple,
prepositioned H-bonds in a preorganized binding cavity. We are currently investigating the use of other
Tröger’s base receptors based on this design as molecular clefts for bis-carboxylates anions and for use
in anion-driven supramolecular self-assembly formations.
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Experimental Section
Starting Materials and General Procedures All solvents and chemicals were purchased from
1
13
commercial sources and used without further purification. H- and C NMR spectra were recorded in
dimethyl-d6 sulfoxide (>99.8 atom % D). using either a 400 or 600 MHz NMR spectrometer. Chemical
shifts are reported in ppm using deuterated solvents as internal standards. Full assignments of the
1
resonances observed in the H NMR spectra of receptors 1 and 2 have been confirmed by measuring
15
13C-1H and N-1H HSQC and HMBC COSY experiments. Mid-infrared spectra were recorded using a
FT-IR spectrometer equipped with a universal attenuated total reflection (ATR) sampler. Mass
spectrometry was carried out using HPLC grade solvents. MALDI Q-Tof mass spectra were carried out
on a MALDI Q-Tof Premier and high-resolution mass spectrometry was performed using Glu-Fib as an
internal reference (peak at m/z 1570.6774).
Bis-1-Benzyl-3-(4-(trifluoromethyl)phenyl)thiourea-[1,5]diazocene, receptor 1
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2,8-Bis(methanamine)-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine (3) (0.246 g, 0.88 mmol) was
dissolved in CHCl3 with Et3N and stirred vigorously while trifluoro-p-tolyl isothiocyanate (0.358 g, 1.76
mmol) was added dropwise in CHCl3 over one hr. The solution was heated at reflux overnight, after
which the product was isolated by suction filtration to give a white solid in 43% yield (0.260 g), mp =
211-213oC. 1H-NMR (600 MHz, DMSO-d6) δH: 9.80 (s, 2H), 8.31 (s, 2H), 7.71 (d, 2H, J = 8.5 Hz), 7.62
(d, 2H, J = 8.5 Hz), 7.12 (d, 2H, J = 8.4 Hz), 7.09 (d, 2H, J = 8.4 Hz), 6.91 (s, 2H,), 4.61 (d, 2H, J =
16.8 Hz), 4.58 (bs, 4H, CH2), 4.22 (s, 2H, ), 4.09 (d, 2H, J = 16.7 Hz); 13C NMR (150 MHz, DMSO-d6)
δC: 180.3, 147.1, 143.3, 133.4, 127.8, 126.6, 126.0, 125.6, 125.2, 124.7, 123.5, 121.9, 66.3, 58.3, 46.8;
19F NMR (376 MHz, DMSO-d6) δF: -60.8; HRMS (m/z) (MALDI-ToF) Calculated for C33H29N6F6S2
m/z = 687.1799 [M+H]+. Found m/z = 687.1801; Calculated for C33H28F6N6S2·0.2H2O: C, 57.41; H,
1
2
3
4
5
6
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60
4.15; N, 12.17 %. Found C, 57.02; H, 4.03; N, 12.44 %; IR
(cm-1) 3250, 1616, 1543, 1493, 1462,
max
1422, 1321, 1266, 1209, 1166, 1121, 1066, 1016, 978, 962, 942, 888, 836, 744, 670.
Bis-1-Benzyl-3-(4-nitrophenyl)thiourea-[1,5]diazocene, receptor 2
Compound 3 (0.19 g, 0.68 mmol) was dissolved in CHCl3 with Et3N and stirred vigorously while 4-
nitrophenyl isothiocyanate (0.26 g, 1.43 mmol) was added dropwise in CHCl3 over one hr. The solution
was heated at reflux overnight at 65°C, after which the product was isolated by suction filtration to give
1
an orange solid in 40% yield (0.17 g) mp = 215-217oC. H-NMR (600 MHz, DMSO-d6) δH: 10.11 (s,
2H), 8.54 (s, 2H), 8.16 (d, 2H, J = 9.1 Hz), 7.82 (d, 2H, J = 9.2 Hz), 7.13 (d, 2H, J = 8.1 Hz), 7.09 (d,
2H, J = 8.2 Hz), 6.92 (s, 2H,), 4.61 (d, 2H, J = 17.1 Hz), 4.59 (bs, 4H, CH2), 4.22 (s, 2H), 4.09 (d, 2H, J
= 16.8 Hz); 13C NMR (150 MHz, DMSO-d6) δC: 180.0, 147.2, 146.3, 141.8, 133.1, 127.9, 126.6, 126.0,
124.7, 124.4, 120.4, 66.3, 58.3, 46.8. HRMS (m/z) (ES+) Calculated for C31H29N8O4S2 m/z = 641.1753
[M+H]+. Found m/z = 641.1740; Calculated for C31H28N8O4S2·0.2H2O·0.2CHCl3: C, 56.08; H, 4.31; N,
16.77 %. Found C, 56.27; H, 4.53; N, 17.01 %; IR
(cm-1) 3295, 3082, 2979, 1597, 1495, 1453,
max
1327, 1319, 1257, 1231, 1171, 1111, 969, 875, 849, 751, 725, 721.
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Preparation of the anion solutions The TBA salts of the various anions used in the titrations were
purchased from Sigma-Aldrich. All TBA salts were dried over P2O5 at 313 K under vacuum, except for
TBAF∙3H2O, which was dried under vacuum at room temperature. The dried salts were then used to
prepare the different anion stock solutions required on the day of the titration.
1
2
3
4
5
6
7
8
9
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UV-visible Spectrophotometry UV-visible absorption spectra were measured in 1-cm quartz cuvettes.
Baseline correction was applied for all spectra. The DMSO used for the UV-visible studies was of
spectroscopic grade (≥ 99.8 %, GC). The temperature was kept at 298 K throughout the measurements
by using a thermostatted unit block. All stock solutions were prepared freshly prior to measurement.
Solutions of 1 and 2 were prepared at a concentration of 10-3 M in DMSO before being diluted to the
desired concentration before titration (ca. 10-5 M). The exact concentration of the host solution in the
titration cell was confirmed using the molar absorption coefficient calculated for each host. The
solutions of the TBA salts were prepared in DMSO at varying concentrations of ca. 10-3, 5x10-3 and 10-2
M. Binding constants of receptors 1 and 2 with the different anions were determined using the non-
linear regression analysis software SPECFIT.
1H NMR Spectroscopy 1H NMR titrations were carried out on a 400 MHz NMR spectrometer at 298
K. Solutions of 1 and 2 were prepared freshly before titration at a concentration of 7x10-3 M in DMSO-
d6. The solutions of the TBA salts were prepared in DMSO-d6 at varying concentrations such that 2-5
µL would correspond to ca. 0.1 molar equivalents of anion. Binding constants of receptors 1 and 2 with
the different anions were determined using the program NMRTit-HGG (for 1:2 host:guest complexes).
Acknowledgments: We would like to thank TCD (Postgraduate Scholarship to JKM), Science
Foundation Ireland (SFI) for Research Frontier Programme Grant 2009 (to TG), Swiss National Science
Foundation (Grant to SC) and HEA-PRTLI Cycle IV (Postgraduate Scholarship to EMB), for financial
support. We thank the Microanalytical Laboratory of the University College Dublin for performing
elemental analyses and Dr. Emma B. Veale for her support and fruitful discussion on the use of TB in
supramolecular chemistry, and for introducing it to our research group.
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Supporting Information Available: H and 13C NMR spectra of receptors 1 and 2; UV-visible
absorption titrations and 1H NMR titrations of 1 and 2 and corresponding fits. For each Figure, see main
text for reference. This material is available free of charge via the Internet at http://pubs.acs.org.
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References and notes
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program
is
freely
available
from
Prof.
C.
Hunter’s
web
site:
http://www.shef.ac.uk/uni/projects/smc/soft.html.)
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