DOI: 10.1002/chem.201100052 Chirality Sensing by Nonchiral Porphines Jan Labuta, [a] Shinsuke Ishihara, [a] Atsuomi Shundo, [a, b] Satoshi Arai, [c] Shinji Takeoka, [d] Katsuhiko Ariga, [a, e] and Jonathan P. Hill* [a, e] The enantiomeric excess (ee) is a critical parameter both as determinant of the efficacy of a chiral therapeutic agen- t, [1] and as an indicator of success of an organic asymmetric reaction. [2] Methods based on nuclear magnetic resonance (NMR) spectroscopy exist for evaluating the ee [3] and in- volve three main protocols: a) chiral derivatization of the analyte, [4–6] b) chiral lanthanide NMR shift reagents, [5] or c) chiral solvating agents (CSAs), [5, 6] which can be used to discriminate chirality through the formation of diastereo- meric complexes with each enantiomer of the analyte. Be- cause NMR spectroscopy is not itself sensitive to the identi- ty of one enantiomer, analysis of the ee in the absence of a substance that works as an intrinsically chiral analytical probe is a challenging issue. Our research group has previously reported on the deter- mination of the ee using an ostensibly achiral tetrapyrrolic oxoporphyrinogen (OxP) macrocyclic reagent. [7] However, in that case several complicating factors, including tautomer- ic processes, nonsymmetrical substitution, and ambiguous peak assignments, made the development of an unequivocal description of the mechanism for the determination of the ee inconvenient. Moreover, electrospray ionization mass spectrometry (ESI-MS) on solutions of OxP and a mixture of the (R)- and (S)-enantiomers of two different chiral car- boxylic acids (see the Supporting Information) has revealed the lack of any cooperativity in the complexation of chiral acids with OxP, which in turn indicates that chiral sensing in this case does not rely on the formation of the diastereomer. For this reason, we chose to study a system, in which tau- tomeric processes and symmetry do not interfere with any potential mechanism of stereochemical discrimination. Con- sequently, we can now present a technique for the determi- nation of the ee in chiral carboxylic acids by using achiral porphine macrocycles as nonchiral–chiral solvating agents (nc–CSAs). This system is unique in that chiral sensing is due to the fast exchange of analyte molecules at a protonat- ed meso-substituted porphyrin dication (Figure 1 a) rather than the formation of diastereomeric complexes with a chiral solvating reagent. Porphines and their metal com- plexes have been extensively used as chiral probes for circu- lar dichroism (CD) spectroscopy. [8] Actually, given that por- phine macrocycles have been available in large quantities for nearly 50 years [9] and have been known to chemists for nearly a century, [10] it is rather surprising that this unusual property of simple achiral tetrapyrrole macrocycles has not been noted until now. In solutions of tetraphenylporphine (TPP) with (R)-1 (i.e., (R)-2-phenoxypropionic acid) at 32.5 8C, the resonan- ces corresponding to the ortho-phenyl protons and the pyr- role protons (b-H) are split into two sets of symmetrical sig- nals (Figure 1c). The separation of the respective signals (Dd) depends on the enantiomeric excess of the chiral car- boxylic acid. [7] A plot of Dd against the ee (red dots in Fig- ure 1 b) reveals a linear relationship, Dd = Dd max  ee (Dd max is characteristic of a particular nc–CSA/analyte pair) and can be considered a calibration curve for determining the ee of an unknown mixture based on observed Dd. For a high accuracy of the ee determination ( 3% ee), fitting [11] of the NMR spectra is recommended as illustrated in Figure 1 c and d. In solutions of TPP and a molar excess of a chiral carbox- ylic acid 1 at room temperature there is no apparent interac- tion between the two solutes. Upon cooling to 32.5 8C, however, variation of the 1 H NMR spectrum of TPP and 1 can be observed (Figure 2 a) as a result of double protona- tion confirmed by characteristic changes in the electronic absorption spectrum of TPP (Figure 2 b). Solutions contain- ing TPP and 1 exhibit a minimal mono-signated Cotton effect in circular dichroism (CD) spectra upon cooling (Fig- ure 2 c), thus suggesting a small distortion of the macrocycle in response to the chiral-guest binding. However, the Cotton [a] Dr. J. Labuta, Dr. S. Ishihara, Dr. A. Shundo, Dr. K. Ariga, Dr. J.P. Hill World Premier International (WPI) Research Center for Materials Nanoarchitectonics (MANA) National Institute for Materials Science (NIMS) 1–1 Namiki, Tsukuba, Ibaraki 305-0044 (Japan) Fax: (+ 81) 29-860-4832 E-mail: Jonathan.Hill@nims.go.jp [b] Dr. A. Shundo Department of Applied Chemistry, Faculty of Engineering Kyushu University, 744 Motooka, Nishi-ku Fukuoka 819-0395 (Japan) [c] Dr. S. Arai Comprehensive Research Organization, Waseda University 513 Tsurumakicho, Shinjuku-ku, Tokyo 162-0041 (Japan) [d] Prof. Dr. S. Takeoka Department of Life Science and Medical Bioscience Graduate School of Advanced Science and Engineering Waseda University, Tokyo 162-8480 (Japan) [e] Dr. K. Ariga, Dr. J.P. Hill JST, CREST, 1–1 Namiki, Tsukuba, Ibaraki 305-0044 (Japan) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201000052.  2011 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim Chem. Eur. J. 2011, 17, 3558 – 3561 3558