Chiral detection at a liquid–liquid interface

www.rsc.org/chemcomm | ChemComm COMMUNICATION Chiral detection at a liquid–liquid interfacew Ritu Kataky* and Paula Lopes Received (in Cambridge, UK) 17th December 2008, Accepted 3rd February 2009 First published as an Advance Article on the web 18th February 2009 DOI: 10.1039/b822685g Chiral ion transfer and detection at a liquid–liquid interface using chiral stationary phases such as cyclodextrins; could lead to alternative methods of chiral detection and separation. Chiral separation and detection, in industry, are routinely performed using chiral chromatography as a method of choice. Interrogation of chiral ionic interactions is crucial in drug discovery and biochemical processes. We are, therefore looking at simple, appropriate methods for facilitating these studies. Some groups have reported traditional electroanalytical potentiometric sensors1–3 using chiral ionophores, for chiral detection. Interactions at a liquid–liquid interface interrogated by ion-amperometric measurement rather than potentiometric measurements, are more sensitive, allow access to the estimation of enantioselective Gibbs free energies of transfer between an aqueous and a lipophilic phase and can be adapted to enable separation and detection. In this communication we demonstrate facilitated ion-transport using ion-amperometry, at a liquid–liquid interface (interface between two immiscible electrolytes, ITIES) as a suitable method for studying chiral interactions. Very few reports exist on chiral detection at a liquid–liquid interface. Scholz, Gulaboski, Mireski and Langer4 showed that the Gibbs free energy for solvation of ions in chiral liquids could be quantified using a water/D- or L-menthol interface using decamethylferrocene as the electroactive material. The same group also reported the transfer of enantiomeric anions in three-phase electrodes consisting of a droplet of chiral 2-octanol on a graphite electrode.5 In this communication we demonstrate that size matched cyclodextrins, a common chiral stationary phase, can be used in a non-aqueous phase for facilitating chiral ion transfer. The chiral ion recognition reaction under study was: AcaCD + Eph+ - (AcaCD)Eph+ where the ligand, AcaCD, is heptakis(2,3,6-tri-O-acetyl)a-cyclodextrin (Cyclolab, Hungary) and the analyte, Eph+ is [1S,2R]-(+)-ephedrinium hydrochloride, [1R,2S]-()-2ephedrinium hydrochloride or the racemate. The experimental set up (Scheme 1), used a Ag/AgTPB as a pseudo-reference electrode in 1,2-dichloroethane (DCE), according to published procedures.6 The ITIES was formed as a hemispherical droplet at a micropipette tip (Fig. S1, ESIw). Department of Chemistry, University of Durham, Durham, UK DH1 3LE. E-mail: [email protected]; Fax: 44 191 3484737; Tel: 44 1913342091 w Electronic supplementary information (ESI) available: Fig. S1: Photographs showing pipette tip. Fig. S2: Cyclic voltammogram showing the potential window given by the interface between TBATPB solution in 1,2-DCE and aqueous solution of KCl. See DOI: 10.1039/b822685g 1490 | Chem. Commun., 2009, 1490–1492 The micropipettes were fabricated from borosilicate glass capillaries (length 10 cm, outer diameter (o.d.) 1.5 mm, inner diameter (i.d.) 0.86 mm) (World Precision Instruments, Inc.) using a micropipette puller (model P-97, Sutter Instrument). The shape of the micropipette was controlled by optimising five parameters (heat (490 1C), filament (2.5 mm  2.5 mm box filament – FB255B), velocity (75), delay (0) and pull (150). These parameters resulted in excellent reproducible tip diameter (Fig. S1, ESIw). The aqueous phase in the pipette formed hemispherical droplets with an interfacial area of 0.004  0.0002 mm2. Electrochemical measurements were performed at room temperature with iR compensation using a multichannel potentiostat (VMP, Perkin Elmert Instruments). All the chemicals used were of analytical grade and used without further purification. The chemicals were potassium chloride (99%, Sigma-Aldrich, UK), tetrabutylammonium chloride (98%, Fluka, UK), ([1S,2R]-(+)-ephedrinium hydrochloride (99%, Sigma, UK), ([1R,2S]-()-2-ephedrinium hydrochloride (99%, Sigma, UK), tetrabutylammonium tetraphenylborate (99%, Fluka, UK) and heptakis(2,3,6-tri-O-acetyl)a-cyclodextrin (99%, Cyclolab, Hungary). The aqueous solutions were made in ‘Milli-Q’ water (Watford, UK) and all organic solutions were made using 1,2-dichloroethane (99%, Sigma-Aldrich, UK). All potentials were calculated using TBA7,8 as the internal reference9 using eqn (1); (the transfer potential of the reference ion TBA+ was measured by using 10 mmol dm3 TBACl in aqueous compartment of the cell instead of Eph+). 0 1=2 w 0 Dw o fðAcaCDÞEphþ ¼ Do fðAcaCDÞEphþ   1=2 w 00  Dw o fðTBAþ Þ  Do fðTBAþ Þ ð1Þ 0 + 0 transfer Here Dw o fðTBAþ Þ is the formal potential of TBA 1=2 (230 mV)8 and Dw o fðTBAþ Þ is the measured half-wave w 1=2 00 potential; Dw o fðAcaCDÞEphþ and Do fðAcaCDÞEphþ are the equivalent potentials for the (AcaCD)Eph+ complex. The voltage window for the using this setup was 400 mV (Fig. S2, ESIw). Scheme 1 Cell schematic for facilitated chiral transport of ephedrinium ion enantiomers (Eph+) using heptakis(2,3,6-tri-O-acetyl)-a-cyclodextrin (AcaCD). This journal is  c The Royal Society of Chemistry 2009 selector, no transfer across the liquid/liquid interface was observed, within the voltage window. (Fig. 2, curve 4). TBA+ is also known to form a weak association complex with aCD. The effect of the AcaCD molecule in facilitating transport of TBA+ (Fig. 2, curve 5) indicated that the facilitated transfer occurred at approximately 265 mV. For a facilitated 1 : 1 ion-transfer, Matsue and co-workers have shown that if CEph+ o CAcaCD and the ion transfer is controlled by the diffusion of Eph+ from the aqueous phase to the liquid–liquid interface then eqn (2) applies: RT DCD ln zF DCDEphþ  RT  0 ln b1 CEphþ  zF w 0 Dw o f1=2 ¼ Do fEphþ þ Fig. 1 Cyclic voltammogram for the AcaCD facilitated transfer of Eph+ (forward scan) and TPB– reverse scan. Initial experiments using cyclic voltammetry (Fig. 1), with an excess of the AcaCD chiral ligand in DCE, in the micropipette the Eph+ racemate in the aqueous solution, showed a peak in the forward scan and a steady state wave in the reverse scan, corresponding to a transfer limited by the ligand outside the pipette on the forward scan and a steady state wave on the reverse scan corresponding to ion transfer from the pipette (TPB).10 Girault and co-workers showed that the transfer of ions out of the pipette (egress) is controlled by linear diffusion (peak shaped curve); whereas transfer into the pipette (ingress) is controlled by diffusion of a spherical type (steady state curve). This behavior, may also be indicative of transfer by interfacial complexation.11 Facilitated chiral ion transfer was monitored using differential pulse voltammetry.12 Background subtracted DPVs (Fig. 2) clearly show the facilitated chiral transfer of Eph+. The enantiomer, (1S,2R+)-Eph ((+)-Eph+) transfers at 142  0.15 mV (Fig. 2, curve 1) whereas the (1R,2S) enantiomer (()-Eph+) transfers at 117  0.15 mV (Fig. 2, curve 3). The racemate transfers at an intermediate potential of 122  0.15 mV (Fig. 2, curve 2). In the absence of the chiral ð2Þ Here, Dw o f1/2 is the half wave potential for the ion transfer 0 reaction; Dw o fEphþ is the standard ion transfer potential for + Eph ; DCD the diffusion coefficient of AcaCD; D(CD)Eph+ the diffusion coefficient of (AcaCD)Eph+ complex in the organic phase; CEph+ the concentration of Eph+ and b01 the association constant of the (AcaCD)Eph+ complex. The difference in half-wave transfer potential Dw o f1/2 between the [1S,2R]-(+)-ephedrinium hydrochloride and [1R,2S]-()-2-ephedrinium hydrochloride enantiomers reflects the difference in chiral free energy of transfer DG0,o-w of the two enantiomers in the aqueous and organic phase, which was calculated as 2.41 kJ mol1 (Table 1). The difference in the association constants of the two enantiomers with the CD derivative is small at 1.5 (Table 1). The (+)-Eph+ enantiomer showed the stronger ion-association constant. In a previous publication, Reharsky and co-workers13 using titration calorimetry to measure equilibrium constants of ephedrines with a- and b-CDs, reported K values of 18.0  0.9 and 17.0  0.9 for (+)- and ()-Eph+ with aCD at pH 6.7. The difference was 7.9 for bCD. The authors argued that the smaller equilibrium constants with aCD was due to the fact that hydrogen bonding was sterically more challenged in the smaller aCD cavity compared to the bCD cavity. Table 1 Enantioselective differentiation of (+)-Eph+, ()-Eph+ and the racemate using CD at a DCE/water ITIES 00 Dw o fðAcaCDÞEphþ /mV Db01 0,w-o 1 DG Fig. 2 Differential pulse voltammogram (DPV conditions: pulse height (mV) 2.5, pulse width (ms) 100, Step height (mV) 5, Step time (ms) 1000, depicting the facilitated chiral transfer of the ephedrinium ion at the ITIES. This journal is  c The Royal Society of Chemistry 2009 /kJ mol (+)-Eph+ ()-Eph+ Racemate 142 117 122 1.5  0.1 2.41 In conclusion, ion amperometry at an ITIES using lipophilic ligands commonly utilised in chiral stationary phases, can be used to chirally facilitate ion transfer. In this instance the method proved sensitive enough to differentiate between the enantiomers of the ephridrinium ion and its racemate, using heptakis(2,3,6-tri-O-acetyl)-a-cyclodextrin, despite the small difference in chiral association constants. Further studies with optimisation of the choice of chiral ligands and electrode geometries should lead the way to alternative methods for chiral separation and detection. We would like to thank the ACTF (EPSRC/RSC), studentship scheme for funding. Chem. Commun., 2009, 1490–1492 | 1491 Notes and references 1 P. S. Bates, R. Kataky and D. Parker, J. Chem. Soc., Perkin Trans. 2, 1994, 669–677; R. Kataky, P. Kelly and D. Parker, Scand. J. Clin. Lab. Invest., 1995, 55, 409–419; A. Gafni, Y. Cohen, R. Kataky, S. Palmer and D. Parker, J. Chem. Soc., Perkin Trans. 2, 1998, 19–23. 2 R. I. Stefan, J. F. van Staden, G. E. Baiulescu and H. Y. Aboul-Enein, Chem. Anal., 1999, 44, 417–422; R. I. Stefan, J. F. Van Staden and H. Y. Aboul-Enein, Electroanalysis, 1999, 11, 192–194; K. I. Ozoemena, R. I. Stefan, J. F. van Staden and H. Y. Aboul-Enein, Sens. Actuators, B, 2005, 105, 425–429; R. I. Stefan, J. F. Van Staden and H. Y. Aboul-Enein, Chirality, 1999, 11, 631–634; R. I. Stefan, J. F. van Staden and H. Y. Aboul Enein, Anal. Lett., 1998, 31, 1787–1794; R. I. Stefan, J. F. van Staden and H. Y. Aboul-Enein, Talanta, 1999, 48, 1139–1143; K. I. Ozoemena and R. I. Stefan, Talanta, 2005, 66, 501–504. 3 G. W. Gokel, W. M. Leevy and M. E. Weber, Chem. Rev., 2004, 104, 2723–2750; Y. Yasaka, T. Yamamoto, K. Kimura and T. Shono, Chem. Lett., 1980, 769–72; T. Shinbo, T. Yamaguchi, K. Nishimura, M. Kikkawa and M. Sugiura, Anal. Chim. Acta, 1987, 193, 367–71; M. Badis, I. Tomaszkiewicz, J. P. Joly and E. Rogalska, Langmuir, 2004, 20, 6259–6267; V. Horvath, T. Takacs, G. Horvai, P. Huszthy, J. S. Bradshaw and 1492 | Chem. Commun., 2009, 1490–1492 4 5 6 7 8 9 10 11 12 13 R. M. Izatt, Anal. Lett., 1997, 30, 1591–1609; H. Kawabata and S. Shinkai, Chem. Lett., 1994, 375–378. F. Scholz, R. Gulaboski, V. Mirceski and P. Langer, Electrochem. Commun., 2002, 4, 659–662. F. Scholz and R. Gulaboski, Faraday Discuss., 2005, 129, 169–177. D. J. Clarke, D. J. Schiffrin and M. C. Wiles, Electrochim. Acta, 1989, 34, 767–769. D. Zhan, Y. Yuan, Y. Xiao, B. Wu and Y. Shao, Electrochim. Acta, 2002, 47, 4477–4483. Y. Shao, A. A. Steward and H. H. Girault, J. Chem. Soc., Faraday Trans., 1991, 87, 2592–2597. Q. Qian, G. S. Wilson, K. Bowman-James and H. H. Girault, Anal. Chem., 2001, 73, 497–503. P. O’Dwyer and V. J. Cunnane, J. Electroanal. Chem., 2005, 581, 16–21. M. H. M. Cacote, C. M. Pereira, L. Tomaszewski, H. H. Girault and F. Silva, Electrochim. Acta, 2004, 49, 263–270. J. A. Ortuño, C. Serma, A. Molina and A. Gil, Anal. Chem., 2006, 78, 8129–8133. V. M. Rekharsky, R. N. Golberg, F. P. Schawarz, Y. B. Tewari, P. D. Roos, Y. Yamashoji and Y. Inoue, J. Am. Chem. Soc., 1995, 117, 8830–88408. This journal is  c The Royal Society of Chemistry 2009