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A Urea-Incorporated Receptor for Aromatic Carboxylate Anion Recognition
Journal of Supramolecular Chemistry 2 (2002) 247–254
A Urea-Incorporated Receptor for Aromatic Carboxylate Anion Recognition Ailong Fan, Hon Kah Hong, Suresh Valiyaveettil* and Jagadese J. Vittal Department of Chemistry, National University of Singapore, 3 Science Drive 3, 117543 Singapore
Abstract—A neutral urea incorporated anion receptor 1 with a tripodal pseudocavity was synthesized in good yield. The influence of preorganization and rigidity of the receptors towards anion recognition was evaluated using rigid (1) and flexible (2) receptors. Binding affinities were investigated using 1H NMR and luminescence titration methods. Receptor 1 showed high binding affinities with 1:1 stoichiometry for carboxylate anions in polar solvents. No binding was observed with small anions, presumably due to the large cavity and the rigidity of the receptor. # 2003 Elsevier Ltd. All rights reserved.
Introduction Synthetic anion receptors are important in host–guest chemistry due to their significance in developing chemical sensors and membranes for selective transport and separation of anions.24 Neutral anion receptors incorporated with functional moieties such as urea or thiourea,5 amide,6 and calixpyrrole7 groups have been explored in biotic and abiotic systems. Such neutral receptors possess advantages over the charged compounds such as host molecules incorporated with cationic guanidinium,8 polyammonium9 and quaternary ammonium10 moieties. Urea or thiourea groups incorporated receptors showed selective anion recognition in nonpolar11 and polar12 solvents through hydrogen bonding. However, carboxylate anion binding in polar solvents is significant towards mimicking biological recognition processes. Recently, Anslyn and coworkers demonstrated the colorimetric detection of common additives in beverages such as citrate, tartrate and malate anions.13
with convergent binding sites (Fig. 1). It is anticipated that the receptor 1 would have a pseudocavity with C3-symmetry due to the tetrahedral structure of the tris(4-aminophenyl)methane molecule as core. There are six hydrogen bond donor sites (–NH) and three acceptor sites ( > C¼O) from three urea moieties incorporated on the three arms of the tripodal molecule (Fig. 2). Here we report the binding properties of the receptor 1 with large terephthalate and trimesylate anions using 1H NMR and luminescence titration methods. Even though the complexation properties of the flexible receptor 2 with small anions are known,15 no information is available on large di- or tricarboxylate anion binding in polar aprotic solvents. Moreover, here we compare the binding efficiency of receptors 1 and 2 and interpret the results based on rigidity and preorganization of the two receptors.
Results and discussion Synthesis of receptors 1 and 2
In order to understand the effect of preorganization of binding sites and size-shape complementarity of the carboxylate anions and the host molecules towards anion recognition,14 a neutral receptor 1 was designed
Keywords: Anion receptor; Host–guest chemistry; Preorganization; Urea; Carboxylate anion; Hydrogen bonds. *Corresponding author. Tel.: +65-6-874-4327; fax: +65-6779-1691; e-mail: [email protected] 1472-7862/02/$ - see front matter # 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S1472-7862(03)00079-0
The receptor 1 was synthesized from tris(4-aminophenyl)methane and hexylisocyanate dissolved in dichloromethane and stirred at 0 C to afford the receptor 1 in 94% yield. The tris(4-aminophenyl)methane was synthesized according to the reported procedure via nitration of the triphenylmethane followed by the reduction of nitro group to amine functionality.16 Receptor 2 was synthesized using a reported procedure from tris(2aminoethyl)amine and 1-naphthyl isocyanate.15b
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Figure 1. Molecular structure of receptors 1, 2 and terephthalate and trimesylate anions (as tetrabutylammonium salts).
Figure 2. Expected trigonal (a) or tripodal (b) arrangements of receptor 1 in anion recognition. 1
H NMR titration studies
In the 1H NMR spectrum of the unsymmetrical urea derivative (e.g., receptor 1 and 2), there were two wellresolved signals due to –NHa and –NHb protons (Fig. 2) and both were affected in a similar manner (i.e., downfield shifted) in the 1H NMR titration with anions (Fig. 3). The change in chemical shifts ( ) of the –NHa proton was used to determine the association constants (Ka) in presence of anions such as terephthalate and trimesylate anion (as tetrabutylammonium salt) at various concentrations and ambient condition (294.6 K, Fig. 3).
In a typical titration, 0.5 mL solution of the receptor 1 (2.95 mM) in DMSO-d6 was added 0.02 mL solution of terephthalate anion (concentration range from 0.01 to 0.1 M) in DMSO-d6, allowed to equilibrate and the NMR spectrum was recorded. Significant changes in the chemical shift of the –NHa proton up to 2.69 ppm (Fig. 3a–e) were found in the NMR titration of receptor 1 with terephthalate and trimesylate anions. The association constants (Ka) were calculated by plotting the changes in chemical shift ( ) as a function of the concentration of added anions (Fig. 4) using the computer program EQNMR.17 In all titrations, concentration of
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showed higher binding affinity towards linear dicarboxylate anion (Ka=22,600 M1) as compared to the tricarboxylate anion (Ka=20,800 M1). It showed no significant binding affinity for small anions such as halide ions, acetate, nitrite and nitrate anions. Receptor 2 showed low binding affinities for terephthalate (Ka= 13,000 M1) and trimesylate anions (Ka=16,000 M1) in DMSO-d6. The high binding affinity of receptor 1 towards terephthalate and trimesylate anions might be due to the higher level of preorganization of binding sites in receptor 1 due to the incorporation of rigid triphenylmethane as the core unit and the formation of bidentate hydrogen bonds19 between the urea moiety and caboxylate anions. Luminescence titration studies
Figure 3. The changes in chemical shift of the –NHa and –NHb peaks in the 1H NMR titration of receptor 1 (2.95 mM) with the terephthalate anion (as tetrabutylammonium salt) in DMSO-d6 solution at ambient conditions (294.6 K). Only five spectra were given at various concentrations of the terephthalate anion (a) 0 mM; (b) 0.8 mM; (c) 1.4 mM; (d) 2.1 mM; (e) 3.3 mM.
the receptor was kept constant. The job plot18 for the complexation of receptor 1 with terephthalate and trimesylate anions is given in Figure 5, indicating a 1:1 stoichiometry. Only the titration data for chloride and carboxylate anions are discussed in this paper due to the lack of significant changes in the chemical shift of the –NHa protons in presence of the other smaller anions. The chemical shift of the –NHa proton of receptor 1 changed with the concentration of the added acetate anion in a linear relationship and the association constant for the acetate anion was not calculated. The complexation results for receptors 1 and 2 in the 1H NMR titration are summarized in Table 1. Receptor 1
The luminescence titration studies were carried out in tetrahydrofuran (THF) solution at ambient conditions (294.6 K). The receptor 1 showed an emission maximum (lemis) at 330 nm at the excitation wavelength (lexc) of 268 nm and the receptor 2 showed a lemis at 384 nm at the lexc of 280 nm. Addition of 5 mL aliquots of each anion solution (concentration range from 5 mM to 0.1 M, as tetrabutylammonium salt) into a 3 mL solution of receptor 1 (35 mM) or 2 (45 mM) resulted in emission intensity changes from maximum (zero quenching) to minimum (maximum quenching). From each titration, relative fluorescence intensity as a function of the concentration of added anion was recorded and given in Figure 6. The emission spectra of receptors 1 and 2 showed strong fluorescence quenching in presence of terephthalate and trimesylate anions and no significant effect for other anions such as chloride, bromide, iodide, acetate, nitrate, nitrite, dihydrogenphosphate and hydrogensulfate anions. The association constants were calculated and given in Table 1 using a reported method,20 which requires the relative fluorescence intensity at various concentrations of added guests. Since the complexation studies were carried out in polar aprotic solvents (DMSO-d6 for 1H NMR titration and THF for luminescence titration), desolvation of both anions and the binding sites of the receptors is a prerequisite for observing strong binding affinities.
Figure 4. 1H NMR titration curves of the receptor 1 (2.95 mM, a) and 2 (1.7 mM, b) in DMSO-d6 for chloride, terephthalate and trimesylate anions (as tetrabutylammonium salts) done at ambient conditions (294.6 K). Small aliquots of anion solutions were added to the NMR tube without changing the overall concentration of the receptor.
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A. Fan et al. / Journal of Supramolecular Chemistry 2 (2002) 247–254 Table 1. Changes in chemical shift, association constantsa and Gibbs free energyb of receptors 1 and 2 from anion titrations Receptor+anion
max of NHac (ppm)
Ka (M1)c
G (kJ/mol)
1+chloride 1+terephthalate 1+trimesylate 2+chloride 2+terephthalate 2+trimesylate
0.50 2.69 2.30 0.47 1.12 1.19
60 22,600 20,800 780 13,000 16,000
10.0 24.5 24.3 16.3 23.2 23.7
Ka (M1)d 29,700 22,300 17,900 18,500
a
The error limits were about0.1 Ka in all cases. Gibbs free energy changes were calculated at T=294.6 K from the 1H NMR titration results. c Data from 1H NMR titration in DMSO-d6 solution, using a constant receptor concentration (2.95 mM for receptor 1 or 1.7 mM for receptor 2) and varying the anion concentration as shown in Figure 4. d Data from luminescence titration in tetrahydrofuran solution, using a receptor concentration (35 mM for receptor 1 or 45 mM for receptor 2) and varying the anion concentration as shown in Figure 6. b
Figure 5. Job plots of [complex] vs. mole fraction of anion for the complexation of receptor 1 in presence of terephthalate (a) and trimesylate (b) anions (as tetrabutylammonium salts) in DMSO-d6 at ambient conditions where [1]+[anion] was maintained at 8 mM.
Even though both receptors have three-dimensional tetrahedral geometry, it is conceivable that the receptor 1 is more rigid than the receptor 2. In other words, the binding sites in flexible receptor 2 undergo reorganization before binding to occur, which may be the reason for the8 observed low binding constants for terephthalate and trimesylate anions. The size-shape complementarity between the receptor and the anions must also be taken into consideration. The triphenylmethane segment of the receptor 1 is rigid and more hydrophobic in nature. This reduces the binding affinity of the receptor 1 for small hydrophilic anions such as chloride, bromide, iodide, acetate, nitrate and nitrite anions. On the other hand, the observed strong binding affinities of receptor 1 with the larger hydrophobic terephthalate and trimesylate anions may be due to low solvation of such anions in aprotic solvents. In the case of the receptor 2, the cavity is formed from the flexible tris(2aminoethyl)amine backbone and the observed low binding affinity for carboxylate anions indicates possible reorganization of the binding sites to achieve size-shape complementarity between the host and guest molecules. Since the receptor 2 is flexible due to the presence of a 3 -nitrogen atom at the center, it showed binding affinities for smaller anions.15
Computer modeling We anticipated that the receptor 1 would form a tripodal cavity for anion binding in solution. The energy minimized structure of the anion complexes of receptor 1 is given in Figure 7. The geometries of the complexes of receptor 1 with terephthalate anion (Figure 7a) and trimesylate anion (Figure 7b or c) are the optimized results from Spartan SGI version 5.1.3 Open GL using the AM1 21 and non-solvent model. In Figure 7a, the trigonal binding arrangement of receptor 1 is presented for the terephthalate anion involving four binding sites of two urea groups in the model with a minimized energy of 489.8 kJ/mol. Figure 7b shows the tripodal binding arrangement of receptor 1 with the trimesylate anion involving six binding sites of three urea groups with a minimized energy of 18.1 kJ/mol. The trigonal arrangement (Figure 7c) with a minimized energy of 14.6 kJ/mol is not suitable for trimesylate anion binding. The short hydrogen bond distance [N–H O with d (H O) ca. 1.76 A˚] and the angle ffN–H O ca. 142 between the binding sites of urea groups and carboxylate groups were calculated from the minimized geometry of the complex of receptor 1 with terephthalate anion (Fig. 7a). On the other hand, N–H O with d (H O) ca. 2.38
Figure 6. Luminescence titration curves of the receptor 1 (35 mM, a) and 2 (45 mM, b) for terephthalate and trimesylate anions (as tetrabutylammonium salts) in THF solution at ambient conditions (294.6 K). The value of all points along the dash-line (in the terephthalate anion case) moved 0.5 units up on the Y-axis for clarity.
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Figure 7. Geometries of the complexes of receptor 1 with terephthalate anion (a) and trimesylate anion (b or c) optimized with Spartan version 5.1.3. Hydrogen atoms are omitted for clarity.
A˚ is longer in the case of complex of receptor 1 with trimesylate anion (Fig. 7b). These values indicate that the receptor 1 shows higher affinity to terephthalate anion as compare to trimesylate anion, in consistent with the 1H NMR and fluorescence titration data.
Crystal structure of the receptor 1 Single crystals of the receptor 1 were obtained from a solution of the compound in DMSO using solvent diffusion method with water as the diffusing solvent at ambient conditions and analyzed using single crystal X-ray diffraction studies (Fig. 8). The crystal lattice belongs to P31/c space group with a crystallographic C3-symmetry. All three hexyl chains have one central bond in gauche conformation, which allows it to fill the empty space between the 1,40 -substituted benzene rings of the core triphenylmethane group. The view along the CŒH bond of the central methane carbon appears to be Table 3. Summary of crystal data and structure refinement parameters of the receptor 1 Identification code Empirical formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions
Figure 8. Single crystal structure of receptor 1 with the atomic numbering scheme.
Table 2. Intermolecular hydrogen bond parameters of the receptor 1 from single crystal X-ray analysis D–H Aa N1–H1 O1_$1I N2–H2 O1_$1I
D–H (A˚)
H A (A˚)
D A (A˚)
ffD–H A( )
0.86 0.86
2.04 2.14
2.855(4) 2.916(4)
159 151
a The intermolecular H-bonds are formed by N1–H1 and N2–H2 of the urea group (NHCONH) of one molecule interacting with oxygen atom of the urea group of another molecule. Symmetry code: (i) x, y, z+1/2. The hydrogen atoms are placed in calculated positions.
Volume Z Density (calculated) (mm1) F(000) Crystal size range ( ) h, k, l Independent reflections Completeness to theta=25.00 Absorption correction Tmax/Tmin Refinement method Data/restraints/parameters Goodness-of-fit on F2 R [I>2(I)] R (all data) Absolute structure parameter Extinction coefficient max. and min. (eA˚3) a
Triurea derivative C40H58N6O3 670.92 293(2) K 0.71073 A˚ Trigonal P31/c (No. 159) a=16.0760(4) A˚ b=16.0760(4) A˚ c=9.2201(3) A˚ 2063.6(1) A˚3 2 1.080 Mg/m3 0.069 728 0.450.250.20 mm3 2.53–25.00 . 19/18, 19/18, 10/10 2383 [Rint=0.0352] 99.8% Empirical 0.9806/0.7653 Full-matrix least-squares on F2 2383/71/149 1.129 R1=0.1065, wR2=0.2852a R1=0.1295, wR2=0.3065a 2(5) 0.008(6) 0.272,-0.265
w=1/[s2 (F2o)+(0.1600P)2+0.7185 P] where P=(F2o+2F2c )/3.
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a wheel-type structure. The calculated horizontal nonbonded distance from the nitrogen atoms (N1, N1A and N1B) attached to the benzene ring to the center of the molecule (C1) is 5.741 A˚. Since the receptor 1 has a rigid triphenylmethane core, it is expected to form a large tripodal cavity (Fig. 2) in solution to facilitate the selective binding of large anions such as terephthalate and trimesylate anions. Due to the rigidity and large distance between the binding sites of receptor 1, no binding is expected for smaller anions such as chloride, bromide, iodide, nitrite and nitrate anions. This was confirmed from both 1H NMR and luminescence titration studies. There were no intramolecular hydrogen bonds in the crystal lattice of receptor 1. However, strong intermolecular hydrogen bonds were present in the crystal lattice. Some of the hydrogen bond distances were summarized in Table 2. All crystal data and structural refinement parameters of receptor 1 are given in Table 3.
Experimental General Melting points (mp) were determined with a ReichertJung Thermo Galen Hot Stage Microscope and reported as uncorrected. The 1H and 13C NMR spectra were determined on a Bruker ACF 300 spectrometer with tetramethylsilane as an internal standard. FT-IR spectra were recorded on a Perkin–Elmer 1710 Infrared Fourier Transform spectrometer. Mass spectra (MS-ESI) were determined on a Finnigan MAT LCQ or Finnigan TSQ 7000 mass spectrometer using an ion spray volt of 4.5 kV, and heated capillary temperature was used at 270 or 350 C. The elemental analysis laboratory in the department of chemistry performed elemental analyses. Emission spectra were collected on a Shimadzu RF-5000 spectrofluorophotometer. Computer modeling has been carried out from Spartan SGI version 5.1.3 Open GL built under IRIX 6.2 using the AM121 and non-solvent model. All solvents were predistilled before use and most of the commercially available reagents were used without further purification. Synthesis of receptor 2 was achieved according to the reported method in which the tris(2-aminoethyl)amine was reacted with 1-naphthyl isocyanate.15b X-ray crystallography X-ray diffraction data on single crystals were collected on a Bruker AXS SMART CCD 3-circle diffractometer with a Mo–Ka radiation l=0.71073 A˚). The software used was: SMART22 for collecting frames of data, indexing reflections and determining lattice parameters; SAINT22 for integration of intensity of reflections and scaling; SADABS23 for absorption correction; and SHELXTL24 for space group determination, structure solution and least-squares refinements on F 2 . All the non-hydrogen atoms were refined anisotropically. The molecule has a crystallographic 3-fold symmetry. The phenyl ring (C2–C7) is disordered and the two disordered
models (occupancies 0.6 and 0.4) are related by 2-fold symmetry along the C2–C5 axis. The alkyl side chain bonded to N2 is also found to be disordered with two independent orientations having equal occupancies. Only isotropic thermal parameters were refined for all the disordered alkyl chain carbon atoms. Synthesis Tris(4-aminophenyl)methane was synthesized from the nitration of the commercially available triphenylmethane followed by the reduction of nitor groups to amines.16 Tris(4-nitrophenyl)methane. Yield: 11.6 g, 50%. mp: 211.0–212.5 C, 1H NMR (300 MHz, CDCl3, dppm): 8.20 (d, J=8.8 Hz, 6H, ArH), 7.28 (d, J=8.8 Hz, 6H, ArH), 5.85 (s, 1H,–CH). FT-IR (KBr, cm1): 3113, 1597, 1516, 1350, 1109, 835. Tris(4-aminophenyl)methane. Yield: 3.55 g, 65%. mp.: 207.0–208.5 C. 1HNMR (300 MHz, DMSO-d6, dppm): 6.69 (d, J=8.4 Hz, 6H, ArH), 6.44 (d, J=8.4 Hz, 6H, ArH), 4.96 (s, 1H,-CH), 4.80 (br, 6H,–NH2). 13CNMR (75.4 MHz, DMSO-d6, dppm): 146.2, 132.8, 129.1, 113.5 (ArC), 53.8 (CH). FT-IR (KBr, cm1): 3414, 3343, 3218, 1624, 1511, 1275, 1178, 825. MS-ESI: m/z 289 (M+). Tris{[4-(hexylaminocarbonyl)amino]phenyl}methane (1). A solution of tris(4-aminophenyl)methane (0.87 g, 3.0 mmol) in dry THF (50 mL) was stirred at 0 C under nitrogen atmosphere. Hexyl isocyanate (1.27 g, 10.0 mmol) dissolved in THF (25 mL) was added dropwise in 15 min at 0 C. Then the reaction mixture was allowed to stir for 1 h at room temperature. The excess THF was distilled under reduced pressure, the residue was poured into water to give the crude product, which was recrystallized in methanol to afford the product 1 (yield: 1.89 g, 94%). mp: 199.0–201.0 C. 1H NMR (300 MHz, DMSO-d6, d, ppm): 8.30 (s, 3H,–NHa), 7.28 (d, J=8.4 Hz, 6H, ArH), 6.92 (d, J=8.4 Hz, 6H, ArH), 6.03 (br, 3H,–NHb), 5.30 (s, 1H,–CH), 3.05 (br, 6H, N– CH2), 1.52–1.15 (m, 24H,–CH2), 0.86 (t, J=6.4 Hz, 9H,- CH3). 13C NMR (75.4 MHz, DMSO-d6, d, ppm): 155.2 (–C¼O), 138.5, 136.9, 128.9, 117.5 (ArC), 58.2 (N–CH2), 54.0 (–CH), 30.9 (–CH2), 29.7 (–CH2), 25.9 (–CH2), 22.0 (CH2), 13.8 (–CH3). FT-IR (KBr, cm1 ): 3333, 2953, 2926, 2858, 1645, 1574, 1468, 1304, 1245, 1184, 865, 771. MS-ESI: m/z 693 (M+Na)+. Anal. calcd for C40H58N6O3 (670.92): C, 71.60; H, 8.71; N, 12.53. Found: C, 71.32; H, 8.62; N, 12.42. 1
H NMR titration
Both the receptors 1 and 2 were insoluble in non-polar solvents like chloroform. Anhydrous DMSO-d6 was used in anion titration at ambient conditions (294.6 K). To 0.5 mL solution of the receptor 1 (2.95 mM) or 2 (1.7 mM) in DMSO-d6 was added 0.02 mL solution of each anion with concentration varied from 0.01 M to 0.1 M (as tetrabutylammonium salt) in DMSO-d6, allowed to equilibrate and NMR spectrum was recorded.
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The chemical shift changes of the –NHa were monitored as a function of the added anion concentration. The 1:1 binding stoichiometry was observed in all complexes and the association constants were calculated by the computer program EQNMR,18 which requires the concentration of each component and the observed chemical shift for the complex. Luminescence titration Anion binding studies of receptors 1 and 2 by the luminescence titration were carried out in THF solution at ambient conditions (294.6 K). The emission spectrum of 3 mL solution of pure receptor 1 (35 mm) or 2 (45 mm) was recorded. After addition of 5 mL aliquots of each anion solution (as tetrabutylammonium salt, concentration ranging from 5 to 0.1 M) into the above solution, the mixture was allowed to equilibrate before taking the emission spectra. The emission spectra were recorded as a function of the anion concentration up to the point where it quenched the fluorescence completely. Association constants were calculated using a reported method,20 from the fluorescence intensity and the concentration of the added guest molecules.
Conclusions Here we report the synthesis and complexation behavior of urea incorporated receptor 1 for selective complexation of carboxylate anions. The binding properties of the receptors were established using 1H NMR and luminescence titration methods. From the results presented here, the receptor 1 showed strong and selective binding for larger hydrophobic carboxylate anions in polar aprotic solvents such as DMSO and THF. Even though similar trend was observed in both DMSO and THF medium using different methods, the observed difference in the values of association constants may be due to the difference in solvation of the anions and the binding sites. No binding was observed for smaller hydrophilic anions. High association constant (Ka=22,600 M-1) was observed for terephthalate anion due to the size-shape complementarity of the host-guest complex. Flexible receptor 2 showed similar binding but a smaller affinity with terephthalate and trimesylate anions. Further synthetic modification of the structure and optimization of the binding properties are currently being explored in our laboratory.
Supplementary material 1
Details of H NMR and luminescence titration studies for receptors 1 and 2, tables of crystallographic data for the receptor 1 are available. Acknowledgements SV acknowledges National University of Singapore (NUS) for financial support. FA thanks NUS for a research scholarship award. All technical support from
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department of chemistry at National University of Singapore is appreciated.
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13. (a) Lavigne, J. J.; Anslyn, E. V. Angew. Chem., Int. Ed. 1999, 38, 3666–3669. (b) Metzger, A.; Anslyn, E. V. Angew. Chem., Int. Ed. 1998, 37, 649–652. 14. Valiyaveettil, S.; Engbersen, J. F. J.; Verboom, W.; Reinhoudt, D. N. Angew. Chem., Int. Ed. Engl. 1993, 32, 900–901. 15. (a) Werner, F.; Schneider, H.-J. Helv. Chim. Acta 2000, 83, 465–478. (b) Xie, H.; Yi, S.; Yang, X.; Wu, S. New J. Chem. 1999, 23, 1105–1110. 16. (a) Weast, R. C.; Grasselli, J. G. Handbook of Data on Organic Compounds, 2nd ed.; CRC Press: Boca Raton, Florida, 1989. (b) Touchard, F.; Fache, F.; Lemaire, M. Eur. J. Org. Chem. 2000, 3787–3792. 17. Hynes, M. J. J. Chem. Soc., Dalton Trans. 1993, 311–312.
18. Conners, K. A. Binding Constants, 1st ed.; John Wiley & Sons: New York, 1987. 19. Jorgensen, W. L.; Pranata, J. J. Am. Chem. Soc. 1990, 112, 2008–2010. 20. Sun, S.; Lees, A. J. Chem. Commun. 2000, 1687–1688. 21. Dewar, M. J. S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J. J. P. J. Am. Chem. Soc. 1985, 107, 3902–3909. 22. SMART and SAINT Software Reference Manuals, Version 6.22. Bruker AXS Analytical X-Ray Systems, Inc: Madison, WI, 2000. 23. Sheldrick, G. M. SADABS, Software for Empirical Absorption Correction; University of Go¨ttingen: Germany, 2000. 24. SHELXTL Reference Manual, Version 5.1. Bruker AXS, Analytical X-Ray Systems: Madison, WI, 1997.
A Urea-Incorporated Receptor for Aromatic Carboxylate Anion Recognition Ailong Fan, Hon Kah Hong, Suresh Valiyaveettil* and Jagadese J. Vittal Department of Chemistry, National University of Singapore, 3 Science Drive 3, 117543 Singapore
Abstract—A neutral urea incorporated anion receptor 1 with a tripodal pseudocavity was synthesized in good yield. The influence of preorganization and rigidity of the receptors towards anion recognition was evaluated using rigid (1) and flexible (2) receptors. Binding affinities were investigated using 1H NMR and luminescence titration methods. Receptor 1 showed high binding affinities with 1:1 stoichiometry for carboxylate anions in polar solvents. No binding was observed with small anions, presumably due to the large cavity and the rigidity of the receptor. # 2003 Elsevier Ltd. All rights reserved.
Introduction Synthetic anion receptors are important in host–guest chemistry due to their significance in developing chemical sensors and membranes for selective transport and separation of anions.24 Neutral anion receptors incorporated with functional moieties such as urea or thiourea,5 amide,6 and calixpyrrole7 groups have been explored in biotic and abiotic systems. Such neutral receptors possess advantages over the charged compounds such as host molecules incorporated with cationic guanidinium,8 polyammonium9 and quaternary ammonium10 moieties. Urea or thiourea groups incorporated receptors showed selective anion recognition in nonpolar11 and polar12 solvents through hydrogen bonding. However, carboxylate anion binding in polar solvents is significant towards mimicking biological recognition processes. Recently, Anslyn and coworkers demonstrated the colorimetric detection of common additives in beverages such as citrate, tartrate and malate anions.13
with convergent binding sites (Fig. 1). It is anticipated that the receptor 1 would have a pseudocavity with C3-symmetry due to the tetrahedral structure of the tris(4-aminophenyl)methane molecule as core. There are six hydrogen bond donor sites (–NH) and three acceptor sites ( > C¼O) from three urea moieties incorporated on the three arms of the tripodal molecule (Fig. 2). Here we report the binding properties of the receptor 1 with large terephthalate and trimesylate anions using 1H NMR and luminescence titration methods. Even though the complexation properties of the flexible receptor 2 with small anions are known,15 no information is available on large di- or tricarboxylate anion binding in polar aprotic solvents. Moreover, here we compare the binding efficiency of receptors 1 and 2 and interpret the results based on rigidity and preorganization of the two receptors.
Results and discussion Synthesis of receptors 1 and 2
In order to understand the effect of preorganization of binding sites and size-shape complementarity of the carboxylate anions and the host molecules towards anion recognition,14 a neutral receptor 1 was designed
Keywords: Anion receptor; Host–guest chemistry; Preorganization; Urea; Carboxylate anion; Hydrogen bonds. *Corresponding author. Tel.: +65-6-874-4327; fax: +65-6779-1691; e-mail: [email protected] 1472-7862/02/$ - see front matter # 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S1472-7862(03)00079-0
The receptor 1 was synthesized from tris(4-aminophenyl)methane and hexylisocyanate dissolved in dichloromethane and stirred at 0 C to afford the receptor 1 in 94% yield. The tris(4-aminophenyl)methane was synthesized according to the reported procedure via nitration of the triphenylmethane followed by the reduction of nitro group to amine functionality.16 Receptor 2 was synthesized using a reported procedure from tris(2aminoethyl)amine and 1-naphthyl isocyanate.15b
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Figure 1. Molecular structure of receptors 1, 2 and terephthalate and trimesylate anions (as tetrabutylammonium salts).
Figure 2. Expected trigonal (a) or tripodal (b) arrangements of receptor 1 in anion recognition. 1
H NMR titration studies
In the 1H NMR spectrum of the unsymmetrical urea derivative (e.g., receptor 1 and 2), there were two wellresolved signals due to –NHa and –NHb protons (Fig. 2) and both were affected in a similar manner (i.e., downfield shifted) in the 1H NMR titration with anions (Fig. 3). The change in chemical shifts ( ) of the –NHa proton was used to determine the association constants (Ka) in presence of anions such as terephthalate and trimesylate anion (as tetrabutylammonium salt) at various concentrations and ambient condition (294.6 K, Fig. 3).
In a typical titration, 0.5 mL solution of the receptor 1 (2.95 mM) in DMSO-d6 was added 0.02 mL solution of terephthalate anion (concentration range from 0.01 to 0.1 M) in DMSO-d6, allowed to equilibrate and the NMR spectrum was recorded. Significant changes in the chemical shift of the –NHa proton up to 2.69 ppm (Fig. 3a–e) were found in the NMR titration of receptor 1 with terephthalate and trimesylate anions. The association constants (Ka) were calculated by plotting the changes in chemical shift ( ) as a function of the concentration of added anions (Fig. 4) using the computer program EQNMR.17 In all titrations, concentration of
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showed higher binding affinity towards linear dicarboxylate anion (Ka=22,600 M1) as compared to the tricarboxylate anion (Ka=20,800 M1). It showed no significant binding affinity for small anions such as halide ions, acetate, nitrite and nitrate anions. Receptor 2 showed low binding affinities for terephthalate (Ka= 13,000 M1) and trimesylate anions (Ka=16,000 M1) in DMSO-d6. The high binding affinity of receptor 1 towards terephthalate and trimesylate anions might be due to the higher level of preorganization of binding sites in receptor 1 due to the incorporation of rigid triphenylmethane as the core unit and the formation of bidentate hydrogen bonds19 between the urea moiety and caboxylate anions. Luminescence titration studies
Figure 3. The changes in chemical shift of the –NHa and –NHb peaks in the 1H NMR titration of receptor 1 (2.95 mM) with the terephthalate anion (as tetrabutylammonium salt) in DMSO-d6 solution at ambient conditions (294.6 K). Only five spectra were given at various concentrations of the terephthalate anion (a) 0 mM; (b) 0.8 mM; (c) 1.4 mM; (d) 2.1 mM; (e) 3.3 mM.
the receptor was kept constant. The job plot18 for the complexation of receptor 1 with terephthalate and trimesylate anions is given in Figure 5, indicating a 1:1 stoichiometry. Only the titration data for chloride and carboxylate anions are discussed in this paper due to the lack of significant changes in the chemical shift of the –NHa protons in presence of the other smaller anions. The chemical shift of the –NHa proton of receptor 1 changed with the concentration of the added acetate anion in a linear relationship and the association constant for the acetate anion was not calculated. The complexation results for receptors 1 and 2 in the 1H NMR titration are summarized in Table 1. Receptor 1
The luminescence titration studies were carried out in tetrahydrofuran (THF) solution at ambient conditions (294.6 K). The receptor 1 showed an emission maximum (lemis) at 330 nm at the excitation wavelength (lexc) of 268 nm and the receptor 2 showed a lemis at 384 nm at the lexc of 280 nm. Addition of 5 mL aliquots of each anion solution (concentration range from 5 mM to 0.1 M, as tetrabutylammonium salt) into a 3 mL solution of receptor 1 (35 mM) or 2 (45 mM) resulted in emission intensity changes from maximum (zero quenching) to minimum (maximum quenching). From each titration, relative fluorescence intensity as a function of the concentration of added anion was recorded and given in Figure 6. The emission spectra of receptors 1 and 2 showed strong fluorescence quenching in presence of terephthalate and trimesylate anions and no significant effect for other anions such as chloride, bromide, iodide, acetate, nitrate, nitrite, dihydrogenphosphate and hydrogensulfate anions. The association constants were calculated and given in Table 1 using a reported method,20 which requires the relative fluorescence intensity at various concentrations of added guests. Since the complexation studies were carried out in polar aprotic solvents (DMSO-d6 for 1H NMR titration and THF for luminescence titration), desolvation of both anions and the binding sites of the receptors is a prerequisite for observing strong binding affinities.
Figure 4. 1H NMR titration curves of the receptor 1 (2.95 mM, a) and 2 (1.7 mM, b) in DMSO-d6 for chloride, terephthalate and trimesylate anions (as tetrabutylammonium salts) done at ambient conditions (294.6 K). Small aliquots of anion solutions were added to the NMR tube without changing the overall concentration of the receptor.
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A. Fan et al. / Journal of Supramolecular Chemistry 2 (2002) 247–254 Table 1. Changes in chemical shift, association constantsa and Gibbs free energyb of receptors 1 and 2 from anion titrations Receptor+anion
max of NHac (ppm)
Ka (M1)c
G (kJ/mol)
1+chloride 1+terephthalate 1+trimesylate 2+chloride 2+terephthalate 2+trimesylate
0.50 2.69 2.30 0.47 1.12 1.19
60 22,600 20,800 780 13,000 16,000
10.0 24.5 24.3 16.3 23.2 23.7
Ka (M1)d 29,700 22,300 17,900 18,500
a
The error limits were about0.1 Ka in all cases. Gibbs free energy changes were calculated at T=294.6 K from the 1H NMR titration results. c Data from 1H NMR titration in DMSO-d6 solution, using a constant receptor concentration (2.95 mM for receptor 1 or 1.7 mM for receptor 2) and varying the anion concentration as shown in Figure 4. d Data from luminescence titration in tetrahydrofuran solution, using a receptor concentration (35 mM for receptor 1 or 45 mM for receptor 2) and varying the anion concentration as shown in Figure 6. b
Figure 5. Job plots of [complex] vs. mole fraction of anion for the complexation of receptor 1 in presence of terephthalate (a) and trimesylate (b) anions (as tetrabutylammonium salts) in DMSO-d6 at ambient conditions where [1]+[anion] was maintained at 8 mM.
Even though both receptors have three-dimensional tetrahedral geometry, it is conceivable that the receptor 1 is more rigid than the receptor 2. In other words, the binding sites in flexible receptor 2 undergo reorganization before binding to occur, which may be the reason for the8 observed low binding constants for terephthalate and trimesylate anions. The size-shape complementarity between the receptor and the anions must also be taken into consideration. The triphenylmethane segment of the receptor 1 is rigid and more hydrophobic in nature. This reduces the binding affinity of the receptor 1 for small hydrophilic anions such as chloride, bromide, iodide, acetate, nitrate and nitrite anions. On the other hand, the observed strong binding affinities of receptor 1 with the larger hydrophobic terephthalate and trimesylate anions may be due to low solvation of such anions in aprotic solvents. In the case of the receptor 2, the cavity is formed from the flexible tris(2aminoethyl)amine backbone and the observed low binding affinity for carboxylate anions indicates possible reorganization of the binding sites to achieve size-shape complementarity between the host and guest molecules. Since the receptor 2 is flexible due to the presence of a 3 -nitrogen atom at the center, it showed binding affinities for smaller anions.15
Computer modeling We anticipated that the receptor 1 would form a tripodal cavity for anion binding in solution. The energy minimized structure of the anion complexes of receptor 1 is given in Figure 7. The geometries of the complexes of receptor 1 with terephthalate anion (Figure 7a) and trimesylate anion (Figure 7b or c) are the optimized results from Spartan SGI version 5.1.3 Open GL using the AM1 21 and non-solvent model. In Figure 7a, the trigonal binding arrangement of receptor 1 is presented for the terephthalate anion involving four binding sites of two urea groups in the model with a minimized energy of 489.8 kJ/mol. Figure 7b shows the tripodal binding arrangement of receptor 1 with the trimesylate anion involving six binding sites of three urea groups with a minimized energy of 18.1 kJ/mol. The trigonal arrangement (Figure 7c) with a minimized energy of 14.6 kJ/mol is not suitable for trimesylate anion binding. The short hydrogen bond distance [N–H O with d (H O) ca. 1.76 A˚] and the angle ffN–H O ca. 142 between the binding sites of urea groups and carboxylate groups were calculated from the minimized geometry of the complex of receptor 1 with terephthalate anion (Fig. 7a). On the other hand, N–H O with d (H O) ca. 2.38
Figure 6. Luminescence titration curves of the receptor 1 (35 mM, a) and 2 (45 mM, b) for terephthalate and trimesylate anions (as tetrabutylammonium salts) in THF solution at ambient conditions (294.6 K). The value of all points along the dash-line (in the terephthalate anion case) moved 0.5 units up on the Y-axis for clarity.
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Figure 7. Geometries of the complexes of receptor 1 with terephthalate anion (a) and trimesylate anion (b or c) optimized with Spartan version 5.1.3. Hydrogen atoms are omitted for clarity.
A˚ is longer in the case of complex of receptor 1 with trimesylate anion (Fig. 7b). These values indicate that the receptor 1 shows higher affinity to terephthalate anion as compare to trimesylate anion, in consistent with the 1H NMR and fluorescence titration data.
Crystal structure of the receptor 1 Single crystals of the receptor 1 were obtained from a solution of the compound in DMSO using solvent diffusion method with water as the diffusing solvent at ambient conditions and analyzed using single crystal X-ray diffraction studies (Fig. 8). The crystal lattice belongs to P31/c space group with a crystallographic C3-symmetry. All three hexyl chains have one central bond in gauche conformation, which allows it to fill the empty space between the 1,40 -substituted benzene rings of the core triphenylmethane group. The view along the CŒH bond of the central methane carbon appears to be Table 3. Summary of crystal data and structure refinement parameters of the receptor 1 Identification code Empirical formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions
Figure 8. Single crystal structure of receptor 1 with the atomic numbering scheme.
Table 2. Intermolecular hydrogen bond parameters of the receptor 1 from single crystal X-ray analysis D–H Aa N1–H1 O1_$1I N2–H2 O1_$1I
D–H (A˚)
H A (A˚)
D A (A˚)
ffD–H A( )
0.86 0.86
2.04 2.14
2.855(4) 2.916(4)
159 151
a The intermolecular H-bonds are formed by N1–H1 and N2–H2 of the urea group (NHCONH) of one molecule interacting with oxygen atom of the urea group of another molecule. Symmetry code: (i) x, y, z+1/2. The hydrogen atoms are placed in calculated positions.
Volume Z Density (calculated) (mm1) F(000) Crystal size range ( ) h, k, l Independent reflections Completeness to theta=25.00 Absorption correction Tmax/Tmin Refinement method Data/restraints/parameters Goodness-of-fit on F2 R [I>2(I)] R (all data) Absolute structure parameter Extinction coefficient max. and min. (eA˚3) a
Triurea derivative C40H58N6O3 670.92 293(2) K 0.71073 A˚ Trigonal P31/c (No. 159) a=16.0760(4) A˚ b=16.0760(4) A˚ c=9.2201(3) A˚ 2063.6(1) A˚3 2 1.080 Mg/m3 0.069 728 0.450.250.20 mm3 2.53–25.00 . 19/18, 19/18, 10/10 2383 [Rint=0.0352] 99.8% Empirical 0.9806/0.7653 Full-matrix least-squares on F2 2383/71/149 1.129 R1=0.1065, wR2=0.2852a R1=0.1295, wR2=0.3065a 2(5) 0.008(6) 0.272,-0.265
w=1/[s2 (F2o)+(0.1600P)2+0.7185 P] where P=(F2o+2F2c )/3.
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a wheel-type structure. The calculated horizontal nonbonded distance from the nitrogen atoms (N1, N1A and N1B) attached to the benzene ring to the center of the molecule (C1) is 5.741 A˚. Since the receptor 1 has a rigid triphenylmethane core, it is expected to form a large tripodal cavity (Fig. 2) in solution to facilitate the selective binding of large anions such as terephthalate and trimesylate anions. Due to the rigidity and large distance between the binding sites of receptor 1, no binding is expected for smaller anions such as chloride, bromide, iodide, nitrite and nitrate anions. This was confirmed from both 1H NMR and luminescence titration studies. There were no intramolecular hydrogen bonds in the crystal lattice of receptor 1. However, strong intermolecular hydrogen bonds were present in the crystal lattice. Some of the hydrogen bond distances were summarized in Table 2. All crystal data and structural refinement parameters of receptor 1 are given in Table 3.
Experimental General Melting points (mp) were determined with a ReichertJung Thermo Galen Hot Stage Microscope and reported as uncorrected. The 1H and 13C NMR spectra were determined on a Bruker ACF 300 spectrometer with tetramethylsilane as an internal standard. FT-IR spectra were recorded on a Perkin–Elmer 1710 Infrared Fourier Transform spectrometer. Mass spectra (MS-ESI) were determined on a Finnigan MAT LCQ or Finnigan TSQ 7000 mass spectrometer using an ion spray volt of 4.5 kV, and heated capillary temperature was used at 270 or 350 C. The elemental analysis laboratory in the department of chemistry performed elemental analyses. Emission spectra were collected on a Shimadzu RF-5000 spectrofluorophotometer. Computer modeling has been carried out from Spartan SGI version 5.1.3 Open GL built under IRIX 6.2 using the AM121 and non-solvent model. All solvents were predistilled before use and most of the commercially available reagents were used without further purification. Synthesis of receptor 2 was achieved according to the reported method in which the tris(2-aminoethyl)amine was reacted with 1-naphthyl isocyanate.15b X-ray crystallography X-ray diffraction data on single crystals were collected on a Bruker AXS SMART CCD 3-circle diffractometer with a Mo–Ka radiation l=0.71073 A˚). The software used was: SMART22 for collecting frames of data, indexing reflections and determining lattice parameters; SAINT22 for integration of intensity of reflections and scaling; SADABS23 for absorption correction; and SHELXTL24 for space group determination, structure solution and least-squares refinements on F 2 . All the non-hydrogen atoms were refined anisotropically. The molecule has a crystallographic 3-fold symmetry. The phenyl ring (C2–C7) is disordered and the two disordered
models (occupancies 0.6 and 0.4) are related by 2-fold symmetry along the C2–C5 axis. The alkyl side chain bonded to N2 is also found to be disordered with two independent orientations having equal occupancies. Only isotropic thermal parameters were refined for all the disordered alkyl chain carbon atoms. Synthesis Tris(4-aminophenyl)methane was synthesized from the nitration of the commercially available triphenylmethane followed by the reduction of nitor groups to amines.16 Tris(4-nitrophenyl)methane. Yield: 11.6 g, 50%. mp: 211.0–212.5 C, 1H NMR (300 MHz, CDCl3, dppm): 8.20 (d, J=8.8 Hz, 6H, ArH), 7.28 (d, J=8.8 Hz, 6H, ArH), 5.85 (s, 1H,–CH). FT-IR (KBr, cm1): 3113, 1597, 1516, 1350, 1109, 835. Tris(4-aminophenyl)methane. Yield: 3.55 g, 65%. mp.: 207.0–208.5 C. 1HNMR (300 MHz, DMSO-d6, dppm): 6.69 (d, J=8.4 Hz, 6H, ArH), 6.44 (d, J=8.4 Hz, 6H, ArH), 4.96 (s, 1H,-CH), 4.80 (br, 6H,–NH2). 13CNMR (75.4 MHz, DMSO-d6, dppm): 146.2, 132.8, 129.1, 113.5 (ArC), 53.8 (CH). FT-IR (KBr, cm1): 3414, 3343, 3218, 1624, 1511, 1275, 1178, 825. MS-ESI: m/z 289 (M+). Tris{[4-(hexylaminocarbonyl)amino]phenyl}methane (1). A solution of tris(4-aminophenyl)methane (0.87 g, 3.0 mmol) in dry THF (50 mL) was stirred at 0 C under nitrogen atmosphere. Hexyl isocyanate (1.27 g, 10.0 mmol) dissolved in THF (25 mL) was added dropwise in 15 min at 0 C. Then the reaction mixture was allowed to stir for 1 h at room temperature. The excess THF was distilled under reduced pressure, the residue was poured into water to give the crude product, which was recrystallized in methanol to afford the product 1 (yield: 1.89 g, 94%). mp: 199.0–201.0 C. 1H NMR (300 MHz, DMSO-d6, d, ppm): 8.30 (s, 3H,–NHa), 7.28 (d, J=8.4 Hz, 6H, ArH), 6.92 (d, J=8.4 Hz, 6H, ArH), 6.03 (br, 3H,–NHb), 5.30 (s, 1H,–CH), 3.05 (br, 6H, N– CH2), 1.52–1.15 (m, 24H,–CH2), 0.86 (t, J=6.4 Hz, 9H,- CH3). 13C NMR (75.4 MHz, DMSO-d6, d, ppm): 155.2 (–C¼O), 138.5, 136.9, 128.9, 117.5 (ArC), 58.2 (N–CH2), 54.0 (–CH), 30.9 (–CH2), 29.7 (–CH2), 25.9 (–CH2), 22.0 (CH2), 13.8 (–CH3). FT-IR (KBr, cm1 ): 3333, 2953, 2926, 2858, 1645, 1574, 1468, 1304, 1245, 1184, 865, 771. MS-ESI: m/z 693 (M+Na)+. Anal. calcd for C40H58N6O3 (670.92): C, 71.60; H, 8.71; N, 12.53. Found: C, 71.32; H, 8.62; N, 12.42. 1
H NMR titration
Both the receptors 1 and 2 were insoluble in non-polar solvents like chloroform. Anhydrous DMSO-d6 was used in anion titration at ambient conditions (294.6 K). To 0.5 mL solution of the receptor 1 (2.95 mM) or 2 (1.7 mM) in DMSO-d6 was added 0.02 mL solution of each anion with concentration varied from 0.01 M to 0.1 M (as tetrabutylammonium salt) in DMSO-d6, allowed to equilibrate and NMR spectrum was recorded.
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The chemical shift changes of the –NHa were monitored as a function of the added anion concentration. The 1:1 binding stoichiometry was observed in all complexes and the association constants were calculated by the computer program EQNMR,18 which requires the concentration of each component and the observed chemical shift for the complex. Luminescence titration Anion binding studies of receptors 1 and 2 by the luminescence titration were carried out in THF solution at ambient conditions (294.6 K). The emission spectrum of 3 mL solution of pure receptor 1 (35 mm) or 2 (45 mm) was recorded. After addition of 5 mL aliquots of each anion solution (as tetrabutylammonium salt, concentration ranging from 5 to 0.1 M) into the above solution, the mixture was allowed to equilibrate before taking the emission spectra. The emission spectra were recorded as a function of the anion concentration up to the point where it quenched the fluorescence completely. Association constants were calculated using a reported method,20 from the fluorescence intensity and the concentration of the added guest molecules.
Conclusions Here we report the synthesis and complexation behavior of urea incorporated receptor 1 for selective complexation of carboxylate anions. The binding properties of the receptors were established using 1H NMR and luminescence titration methods. From the results presented here, the receptor 1 showed strong and selective binding for larger hydrophobic carboxylate anions in polar aprotic solvents such as DMSO and THF. Even though similar trend was observed in both DMSO and THF medium using different methods, the observed difference in the values of association constants may be due to the difference in solvation of the anions and the binding sites. No binding was observed for smaller hydrophilic anions. High association constant (Ka=22,600 M-1) was observed for terephthalate anion due to the size-shape complementarity of the host-guest complex. Flexible receptor 2 showed similar binding but a smaller affinity with terephthalate and trimesylate anions. Further synthetic modification of the structure and optimization of the binding properties are currently being explored in our laboratory.
Supplementary material 1
Details of H NMR and luminescence titration studies for receptors 1 and 2, tables of crystallographic data for the receptor 1 are available. Acknowledgements SV acknowledges National University of Singapore (NUS) for financial support. FA thanks NUS for a research scholarship award. All technical support from
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department of chemistry at National University of Singapore is appreciated.
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