Anal. Chem. 2002, 74, 4002-4006
Electrochemical Recognition of Chiral Species Using Quaternary Ammonium Binaphthyl Salts Andrew P. Abbott,*,† George W. Barker,† David L. Davies,† Gerald A. Griffiths,† Andrew J. Walter,† and Pavel Kocˇovsky´‡
Department of Chemistry, University of Leicester, Leicester LE1 7RH, U.K., and Department of Chemistry, Joseph Black Building, University of Glasgow, Glasgow G12 8QQ, U.K.
The use of ephedrine-substituted quaternary ammonium binaphthyl salts as molecular receptors is demonstrated. The electrochemical oxidation of the receptor is affected by the binding of an analyte in solution. The binding site on the binaphthyl salt has been determined using computer modeling and confirmed using 1D and 2D NMR studies. It is shown that the sensitivity of the receptor is related to the size of the analyte. Axially chiral binaphthyl salts are shown to bind chiral analytes in a different manner and this is demonstrated using lactic and mandelic acid. The presence of a polar functional group on the analyte is also shown to have an effect on the guesthost interaction. Over the last two decades, 2,2′-disubstituted 1,1′-binaphthyls have played a pivotal role in the development of chiral catalysts for asymmetric synthesis.1 In particular, BINAP and its analogues have been shown to exhibit excellent enantioselectivities and turnovers in several types of asymmetric reactions,1 often matching the enantioselectivities traditionally regarded as being reserved for the enzyme realm. Owing to their architecture, 1,1′-binaphthyls also became a popular chiral scaffold for the construction of a variety of supramolecular structures2 to be employed in molecular recognition studies.3,4 While the binaphthyl skeleton itself is normally viewed as an inert, robust block, whose activity is confined to rare examples of racemization, there have been occasional reports of its reactions under special conditions. Thus, * Corresponding author. E-mail:
[email protected]. † University of Leicester. ‡ University of Glascow. (1) (a) Rosini, C.; Franzini, L.; Raffaelli, A.; Salvadori, P. Synthesis 1992, 503. (b) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley & Sons: New York, 1994. (c) Putala, M. Enantiomer 1999, 4, 243. (d) Ojima, I. Catalytic Asymmetric Synthesis, 2nd ed.; J. Wiley and Sons: New York, 2000. (2) For selected recent applications of 1, 1′-binaphthyls in optoelectronics, see, e.g.: (a) Burnham, K. S.; Schuster, G. B. J. Am. Chem. Soc. 1998, 120, 12619. (b) Lee, I. S.; Chung, Y. K. Organometallics 1999, 18, 5080. (c) Deussen, H.-J.; Boutton, C.; Thorup, N.; Geisler, T.; Hendrickx, E.; Bechgaard, K.; Persoon, A.; Bjørnholm, T. Chem. Eur. J. 1998, 4, 240. (d) Go´mez, R.; Segura, J. L.; Martı´n, N. J. Org. Chem. 2000, 65, 7501. (e) Go´mez, R.; Segura, J. L.; Martı´n, N. J. Org. Chem. 2000, 65, 7566. (f) Go´mez, R.; Segura, J. L.; Martı´n, N. Org. Lett. 2000, 2, 1585. (g) Feringa, B. L.; van Delden, R. A.; Koumura, N.; Geertsema, E. M. Chem. Rev. 2000, 100, 1789. (h) Gong, L.-Z.; Hu, Q.-S.; Pu, L. J. Org. Chem. 2001, 66, 2367. For examples of glass-forming chromophores, see: (i) Ostrowski, J. C.; Hudack, R. A., Jr.; Robinson, M. R.; Wang, S.; Bazan, G. Chem. Eur. J. 2001, 7, 4500. For other recently reported binaphthyl-based supramolecular structures, see: (j) Aspinall, H. C.; Bickley, J. F.; Dwyer, J. L. M.; Greeves, N.; Steiner, A. Angew. Chem., Int. Ed. 2000, 39, 2858.
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for instance, Shoute recently studied its redox chemistry upon radiolysis.5 Using time-resolved absorption spectroscopy, it was shown that the initially generated radical anion either undergoes an acid-catalyzed protonation or transfers an electron to organic molecules present in the solution.5 In recent work, we have shown6 that quaternary ammonium binaphthyl salts (QABS) can be electrochemically reduced to yield a relatively stable cation radical. This ammonium salt can be easily modified to act as a receptor for species in solution. It has been demonstrated that azacrown ether derivatives can act as receptors for Li+ and Na+, and a quantitative response between ionic concentration and reduction current has been observed.6 The ability of the binaphthyl cation to act as a receptor was controlled by the conformation around the quaternary ammonium center and the strain imparted on the dihedral angle between the two naphthyl rings. The binaphthyl salts were also shown to give a qualitative response to anions in solution, although the decrease in current was interfered with by the adsorption of the cation on the electrode surface and the reaction of the cation radical with traces of oxygen in solution. We have also recently shown that the quaternary ammonium binaphthyl salts form a cation radical when oxidized,7 which is more stable in solution than the neutral radical, hence, gives a more reversible electrochemical response. The cation radical is also less likely to adsorb on the electrode surface decreasing possible artifacts in the electrochemical response. It was, however, shown that because of the charge distribution close to the azacrown ether it was less likely that an alkali metal cation would bind to the receptor making it less sensitive to the analyte than previously reported for the radical produced upon electrochemical reduction. In contrast, it was shown that the radical formed by oxidation was more sensitive (3) For the original work and selected examples, see: (a) Chao, J.; Cram, D. J. J. Am. Chem. Soc. 1976, 98, 1015. (b) Judice, J. K.; Cram, D. J. J. Am. Chem. Soc. 1991, 113, 2791, (c) Lehn, J.-M. Supramolecular Chemistry; Verlag Chemie: Weinheim, 1995. (4) For the chiral, binaphthyl-derived sensors for carbohydrates, see: (a) Rusin, O.; Kra´l, V. Chem. Commun. 1999, 2367. (b) Rusin, O.; Lang K.; Kra´l, V. Chem. Eur. J. 2002, 8, 655. (c) Takeuchi, M.; Mizuno, T.; Shinkai, S.; Shirakami, S.; Itoh, T. Tetrahedron: Asymmetry 2000, 11, 3311. (d) Droz, A. S.; Neidlein, U.; Anderson, S.; Seiler, P.; Diederich, F. Helv. Chim. Acta 2001, 84, 2243. (5) Shoute, L. C. T. J. Phys. Chem. A 1997, 101, 5535. (6) (a) Abbott, P. A.; Cheung, C. S. M.; Lonergan, G. R.; Stara´, I. G.; Stary´, I.; Kocˇovsky´, P. Chem. Commun. 1999, 641. (b) Abbott, A. P.; Barker, G. W.; Lonergan, G. R.; Walter A. J.; and Kocˇovsky´, P. Analyst 2001, 126, 1892. (7) Abbott, A. P.; Barker, G. W.; Walter A. J.; Kocˇovsky´, P., submitted for publication. 10.1021/ac025635q CCC: $22.00
© 2002 American Chemical Society Published on Web 07/18/2002
Chart 1
to anionic species in solution than the corresponding neutral radical. In the present work, we show how the stereochemical architecture of the binding site affects the specificity of the receptor to a variety of carboxylic acid analytes and how the use of a chiral receptor can differentiate the absolute configuration of the analyte. EXPERIMENTAL SECTION The binaphthyl salt receptors 1 and 2 (Chart 1) were prepared according to the literature procedures.8 The concentration of the quaternary ammonium binaphthyl salt was 1 × 10-3 mol dm-3 in all experiments. Electrochemical experiments were carried out using a PGSTAT 12 potentiostat (Ecochemie). The working electrode was a 10-µm-diameter gold disk sealed in glass. The counter electrode was a Pt wire, and the potentials were quoted versus a Ag/AgBF4 reference electrode. The working electrode was polished with 1- and 0.3-µm alumina between each measurement. Tetrabutylammonium tetrafluoroborate (TBABF4) (Fluka, Electrochemical grade) was used as the electrolyte at a concentration of 0.1 mol dm-3. Acetonitrile (Fisher, >99.98%), p-toluenesulfonic acid (Fluka), mandelic acid (Aldrich), and lactic acid (Aldrich) were all used as received. Cyclic voltammograms were all measured at a sweep rate of 10 mV s-1. Molecular modeling calculations were carried out using PC Spartan Pro.9 The equilibrium geometry and surface charge density of the binaphthyl receptors and analytes were calculated by a Hartree-Fock method utilizing an STO-3G model. While the method may not produce exact minimum energy conformations, the “3-D cartoons” are useful for comparative analysis. 1H NMR spectra were recorded on a Bruker DRX 400 spectrometer (400.13 MHz) using a 5-mmbore inverse probehead (TXI). Samples were dissolved in CD3CN (Goss Scientific) and internally referenced to TMS (0 ppm). 1D spectra were recorded with 32K data points over a 5995-Hz (14.9 ppm) window using a 30° acquisition pulse (90° pulse 9.6 µs). Sixteen transients were collected using a 1.5-s recycle delay added to the 2.73-s acquisition time. Data were processed using exponential multiplication (line-broadening factor of 0.2 Hz). 2D phase-sensitive NOESY spectra were recorded using the standard Bruker pulse program (noesytp). A total of 256 blocks of 1K data points covering a 4401 Hz (11 ppm) range in F2 were recorded with a recycle delay of 5 s, a mixing time of 850 ms, and 16 transients per block. Data in F1 was zero-filled to 1K, and both dimensions were processed using sine-bell squared window function shifted by π/2. (8) For the original synthesis of 1 and 2, see: (a) Marigot, N.; Mazaleyrat, J. P. Synthesis 1985, 317. For a closely related work, see: (b) Stara´, I. G.; Stary´, I.; Za´vada, J. J. Org. Chem. 1992, 57, 6966. (9) Spartan Pro, Wavefunction Inc., Irvine, CA.
Figure 1. Surface potential of 1. Binding site A highlights Ha and Hb, and binding site B highlights Ha′ and Hb′.
RESULTS AND DISCUSSION In previous work,6b it was suggested that the ability of quaternary ammonium binaphthyl salts to act as receptors and sense the presence of analytes in solution was due to the hindered geometry around the quaternary ammonium nitrogen and the effect this had upon the dihedral angle between the naphthyl moiety. The proximity of the receptor and analyte will affect the stability of the oxidized intermediate and hence the electrochemical response of the receptor. The analyte-receptor interaction will be effected by the size of the analyte and the geometry of the binding site. We have previously shown using NMR spectroscopy6b that the binding of carboxylic acids to the binaphthyl cations shifts the NMR signal for benzylic protons. To gain further insight into the position and geometry of the binding site, molecular modeling was used to determine the charge distribution around the binaphthyl cation. Figure 1 shows the surface charge density of 1, calculated by Spartan Pro. The blue areas correspond to the most electropositive regions of the surface, which are located around the benzylic protons on either side of the molecule. Since it was previously shown6b that the 1H NMR signal for the benzylic protons shifted when the analyte was added to the solution, it can be assumed that there is significant interaction with the analyte in this region. Since sites A and B are diastereotopic, it is important to determine where the analyte is binding and which site is dominant in controlling the electrochemical response of the receptor. This information will help in designing future receptors since blocking the less sensitive site should increase the specificity of the analyte recognition. Figure 2 shows the cyclic voltammogram of 1 in acetonitrile and the effect of adding different amounts of p-toluenesulfonic acid (pTos). The current decreases with increasing analyte concentration, showing that 1 can act as a receptor for sensing the presence of anions. The voltammograms did not change significantly with Analytical Chemistry, Vol. 74, No. 16, August 15, 2002
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Figure 2. Cyclic voltammogram of 1 at a gold electrode following the addition of 0, 0.9, 3.3, and 5 mol equiv of pTos (in order of decreasing current).
Figure 3. Normalized limiting current for 1 and 2 with various mole equivalents of propionic, benzoic, and p-toluenesulfonic acids.
repetitive cycling, showing the absence of adsorption artifacts that were previously observed for the reduction of the QABS.6b Use of chiral receptors allows the effect of the binding site geometry for a given analyte to be determined. The current has been normalized to the current without the addition of analyte to eliminate any fluctuations caused by changes in concentration and for ease of comparison. Figure 3 shows a similar response was observed for pTos with 2 but the response was not identical, which shows that the geometry of the binding site has an effect upon the analyte-receptor interaction. The same experiment was repeated using benzoic acid (benz) and propionic acid (prop) as the analytes, and the results are also presented in Figure 3. All analytes showed an approximately linear decrease in current with analyte concentration, although each receptor showed a different succeptibility to each analyte.10 As before,6b a decrease in the limiting current for the oxidation of the receptor was observed although there was negligible change for the half-wave potential, (10) Linear relationships are generally observed between I/Io and analyte concentration although deviations from linearity could be expected since the concentration of free anions may not necessarily change linearly with analyte concentration due to the large concentration of supporting electrolyte, which could act as a buffer.
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Figure 4. Effect of the addition of mandelic acid on the limiting current (normalized to the current in the absence of analyte) for the oxidation of 1 and 2.
suggesting that the binding of the receptor prevents electron transfer rather than making it thermodynamically more difficult. It is also evident that the effect of the analytes on the two enantiomers of the ephedrine-substituted binaphthyl salts is different. The largest change in electrochemical signal is observed with pTos as the analyte; although there are no clear trends with size or receptor geometry, the difference may result from the significantly larger pKa of sulfonic acids compared to carboxylic acids. This may suggest that the analyte binds through chargecharge interactions and the difference is caused by the higher concentration of dissociated anions in the pTos solutions. Analyte binding and the effect that this has upon the electrochemical response of the receptor is understandably complex. It is, however, evident from the results in Figure 3 that the geometry of the binding site and the size of the analyte affect the recognition of the analyte by the receptor. It seems logical therefore that the receptors should discriminate between the enantiomers of a chiral analyte. To test this idea, the effect on the electrochemical response of 1 and 2 to adding enantiomers of mandelic acid [C6H5CH(OH)COOH] and lactic acid [CH3CH(OH)COOH] to the solution was determined. Figure 4 shows how the limiting current for 1 and 2 (normalized to the voltammogram of the solution without analyte) varies with the amount of D- and L-mandelic acid added to the solution (the original voltammograms can be seen in Supporting Information). As in Figure 3, there is a decrease in current with increasing analyte concentration, suggesting the basis for an analytical discrimination. The greatest change observed is for 1 with the L-enantiomer of mandelic acid while the smallest effect is with 2 and the D-enantiomer. It is interesting to note that the other two combinations give similar, but mirror image-type responses. This suggests that the interaction of the bound analyte with the axially chiral binaphthyl moiety is constant and the bound analyte has the same effect upon the stability of the oxidized binaphthyl radical. It can therefore be concluded that the molecular recognition is stereoselective.11 (11) On the data presented here, it would be difficult to estimate enantioselectivity.
Figure 5. NMR spectra of 1 and 2 in CD3CN and the effect of adding 1 mol equiv of D- and L-mandelic acid.
The interactions between the receptor and the analyte were also investigated using 1H NMR spectroscopy. Figure 5 shows the 1H NMR spectra of 1 and 2 with the addition of 1 mol equiv
of L- and D-mandelic acid. The signals for the four benzylic protons (occurring between 3.7 and 5.5 ppm) are shown for clarity (their assignment was confirmed using 2D NMR). It is clear that the addition of mandelic acid to the solution caused negligible change to the position of the signals for protons a, a′, b, and b′ (see Chart 1). What is noticeable, however, is the appearance of a set of weaker signals for the benzylic protons of 1 (and to a much lesser extent 2), which are deshielded, suggesting interaction with a strongly electron-withdrawing moiety. These signals were absent from the spectra of the pure receptor and analyte and must therefore be due to the binding of the analyte to the receptor. It is suggested that these are due to the binding of the anion of the dissociated acid. For 2, a weak signal appears at ∼6.0 ppm, whereas for 1 it is slightly more intense and occurs at 6.5 ppm, suggesting a stronger interaction of the analyte with 1. A similar set of weak signals is also associated with proton b occurring at 4.3 ppm. The set of signals associated with proton b′ (4.7 ppm) is less strongly deshielded and only observed for receptor 1. No such signal is observed for proton a′ with either receptor. This shows that the binding is enantioselective and suggests that the main binding site is associated with the a and b protons, i.e., binding site A in Figure 1. Similar results were found using D- and L-lactic acid as the analyte. This analyte was chosen since it replaces the phenyl by a methyl moiety and can be used to probe the effect of analyte size on the receptor response while keeping the stereochemistry around the binding site of the analyte constant. These two acids also have similar pKa values in water, suggesting that anion activity should be similar. It can also be used as a direct comparator to propionic acid as it shows the effect of a polar substituent on the analyte. The OH group of the analyte could have two effects; it could either act as the binding position of the guest, or it could hydrogen bond to some other moiety on the ephedrine side chain. Lactic acid displays the same trend as mandelic acid; i.e., the greatest change in oxidation current was caused by the addition of the L-enantiomer to 1. The decrease in the limiting current is less than that observed for the corresponding experiment using mandelic acid, which shows that the sensitivity of the receptor to
Figure 6. Effect of the addition of lactic, mandelic, and propionic acids on the limiting current for the oxidation of 1 and 2.
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the analyte is governed not only by the stereochemical architecture of the binding moiety relative to the analyte’s chiral center but also by the overall size of the analyte. This may be due to steric factors; e.g., in the case of mandelic acid, the phenyl group restricts movement in the binaphthyl moiety to stabilize the radical formed upon oxidation, which would account for the stereospecific response of the receptor, although the stacking of the phenyl group with the binaphthyl moiety could also restrict the motion. The same trends were also obtained for the 1H NMR spectra of 1 and 2 with the addition of L- and D-lactic acid, confirming that the analytes bind in a similar manner. Mandelic acid may also interact with the receptor via π-π interactions, although no strong evidence was observed for this using NOESY spectroscopy. Figure 6 compares the limiting current of D-mandelic, D-lactic, and propionic acids, which shows the effect of size, polar functional group, and binding site conformation more clearly. The largest change is associated with D-mandelic acid, confirming that analyte size is the most important factor in deciding analyte sensitivity. Comparison of the effect of mandelic acid with lactic acid shows that the same trends are observed for the two receptors; i.e., there is a pronounced curvature to response of 1 whereas 2 is more linear. At low analyte concentrations, the response for 2 with lactic acid is similar to that with propionic acid, but both are less pronounced than the effect of 1 with lactic acid. This suggests that the polar functional group does have some effect but it depends on the conformation of the binding site. It may involve (12) For visual enantiomeric recognition of amino acids via the phenolphthalein sensor, with appended crown ethers units, see: Tsubaki, K.; Nuruzzaman, M.; Kusumoto, T.; Hayashi, N.; Bin-Gui, W.; Fuji, K. Org. Lett. 2001, 3, 4071. (13) For a recent application of related quaternary ammonium salts as chiral phase-transfer catalysts utilized in asymmetric alkylation reactions, see: Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 1999, 121, 6519. (14) Bates, P. S.; Kataky, R.; Parker, D. J. Chem. Soc., Perkin Trans. 2 1994, 669. (b) Kataky, R.; Parker, D. Analyst 1996, 121, 1829 (c) Gafni, R.; Cohen, Y.; Kataky, R.; Palmer, S.; Parker, D. J. Chem. Soc., Perkin Trans. 2 1998, 19.
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an interaction with the OH group in the ephedrine moiety, and the effect of the various polar substituents on ephedrine-like side chains is currently under investigation. CONCLUSIONS This work has shown that axially chiral binaphthyl quaternary ammonium salts can be used for the enantioselective recognition of chiral carboxylic acids. A combination of the 1H NMR spectroscopy and computer modeling has shown that the most probable binding site on the binaphthyl surface is in the vicinity of the benzylic Ha proton. Electrochemical investigations have shown that the current for the oxidation of the receptor decreases with increasing concentration for a variety of carboxylic acids. The relative decrease in current is dependent upon the shape and size of the analyte and the stereoconformation of the receptor’s binding site. Qualitatively, it has been shown that the receptors are more sensitive to larger analytes. It has also been shown that the presence of a polar functional group on the analyte has a significant effect on the sensitivity of the receptor, which may be due to hydrogen bond interactions. The electrochemical recognition of chiral carboxylic acids presented here complements the recently reported visual recognition12,13 and reinforces earlier work on chiral electrochemical receptors.14 ACKNOWLEDGMENT The authors thank the EPSRC (GR/M 68145) for funding this work. SUPPORTING INFORMATION AVAILABLE Voltammograms for 1 and 2. This material is available free of charge via the Internet at http://pubs.acs.org. Received for review March 20, 2002. Revised manuscript received May 10, 2002. Accepted June 7, 2002. AC025635Q
