NMR Spectroscopic Determination of Enantiomeric Excess using

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NMR Spectroscopic Determination of Enantiomeric Excess using Small Prochiral Molecules Shinsuke Ishihara, Jan Labuta, Zdenek Futera, Shigeki Mori, Hisako Sato, Katsuhiko Ariga, and Jonathan P Hill J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.8b03684 • Publication Date (Web): 24 Apr 2018 Downloaded from http://pubs.acs.org on May 1, 2018

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The Journal of Physical Chemistry

NMR Spectroscopic Determination of Enantiomeric Excess Using Small Prochiral Molecules Shinsuke Ishihara,†,* Jan Labuta,†,* Zdeněk Futera,‡ Shigeki Mori,§ Hisako Sato,∆ Katsuhiko Ariga,†,¶ and Jonathan P. Hill†,* †

World Premier International Center for Materials Nanoarchitectonics (WPI-MANA), National Institute for Materials Science (NIMS), Tsukuba, Ibaraki 305-0044, Japan ‡ Department of Physics and Astronomy, University College London, London WC1E 6BT, U.K. § Advanced Research Support Center, and ∆Department of Chemistry, Graduate School of Science and Engineering, Ehime University, Matsuyama, Ehime 790-8577, Japan ¶ Department of Advanced Materials Science, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8561, Japan

ABSTRACT: The use of chiral auxiliaries, which derivatize enantiomers to diastereomers, is an established technique for NMR spectroscopic analysis of chirality and enantiomeric excess (ee). Here we report that some small prochiral molecules exhibit eedependent splitting of 1H-NMR signals at room temperature based on acid/base interactions with chiral analytes, especially when either chiral or prochiral acid contain a phenoxy group at the α-position of the carboxylic acid. As a representative case, the benzylamine (BA)/2-phenoxylpropionic acid (PPA) complex was comprehensively investigated by using various methods. Notably, X-ray crystallographic analysis shows that there are multi-point interactions in the BA/PPA complex, implying that ‘fixing’ of molecular conformation is critical for efficient intermolecular transfer of magnetic anisotropy. Our results suggest that a wide range of prochiral molecules are available for NMR determination of ee when intermolecular interactions between prochiral molecule and chiral analytes are adequately designed.

INTRODUCTION Enantiomeric excess (ee) is an important chiral parameter that determines, for example, pharmacological effect of drugs, folding of polymers (e.g., α-helix of peptides), and the macroscopic structure of molecular assemblies (e.g., cholesteric liquid crystals).1−7 ee is defined as ee = |[R]t−[S]t|/([R]t+[S]t), where [R]t and [S]t are the respective total concentrations of the (R)- and (S)-enantiomers. Analysis of ee is particularly important in the pharmaceutical industry since the majority of medicinal compounds are chiral, and their enantiomers may possess different pharmacological activities. 8 For the purpose of determining ee, various methodologies have been developed including optical rotation,9 circular dichroism spectroscopy,10 chiral column chromatography,11 chiral surface/interface,12,13 and nuclear magnetic resonance (NMR) spectroscopy.14 Since NMR spectroscopy provides only chemical shift information, enantiomers of a compound exhibit identical NMR spectra so that the use of chiral auxiliaries (e.g., chiral solvating agents, chiral derivatizing agents, lanthanide shift reagents which derivatize or bind to each enantiomer forming pairs of non-identical diastereomers) has become the established technique for the determination of ee of chiral analytes.15 Several recent NMR techniques offer highthroughput chiral sensing. For example, Zhao and Swager16 reported that ee and absolute configuration of 12 chiral amines can be simultaneously analysed using 19F NMR, where a partly-fluorinated chiral auxiliary (metal-

ligand complex) binds chiral amines in a ‘slow’ exchange regime. In contrast to traditional NMR chiral sensing techniques (which rely on formation of diastereomers), we have proposed a unique approach that utilizes prochiral molecules, so-called, prochiral solvating agents (proCSAs), to estimate ee of chiral analytes by solution-state 1 H-NMR spectroscopy.17−22 A prochiral molecules interacts with chiral analytes in a fast exchange regime (relative to the NMR timescale) so that its symmetry is broken while concurrently experiencing the average magnetic anisotropy originating from the chiral analyte. Consequently, 1H-NMR resonances of the prochiral molecule are split to a degree that is linearly proportional to the ee of the chiral analyte. In the reported cases of this phenomenon, saddle-shaped macrocyclic host molecules, such as porphyrin dications and oxoporphyrinogens, were used. However, although these prochiral molecules have been proved useful for NMR ee sensing (i.e., pro-CSA) they are rather elaborate molecules of high molecular weight, and the generality of the phenomenon including the essential conditions for the operation of pro-CSAs remain unclear. In fact, the splitting of NMR signals due to the presence of a chiral analyte is rather unusual behaviour since intermolecular transfer of magnetic anisotropy in isotropic media is generally thought to be too weak for NMR detection.23 Splitting of NMR signals of prochiral molecules has often been observed in chiral liquid crystal media.23 In

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such anisotropic media, the magnetic anisotropy of chiral molecules can be efficiently transferred to prochiral molecules due to ordering of the solutes (i.e., prochiral molecules). Also, some special chiral adducts, such as those involving praseodymium(III) shift reagents24 or horseshoe-shaped host molecules,25 give rare examples of NMR signal splitting for prochiral molecules in isotropic media. However, in those cases, ee-dependent NMR splitting was not investigated, and it is unclear whether or not those special chiral adducts show fast exchange leading to averaging of magnetic anisotropy acting on the prochiral molecules. Regardless of this, even if ee-dependent NMR splitting occurs due to fast exchange, those systems are less attractive for analytical procedures since the chiral counterpart (i.e., praseodymium(III) shift reagents24 or horseshoe-shaped host molecules25) are too specific. Here we report that some small prochiral molecules (among 23 combinations of acid/base pairs tested) show eedependent splitting of 1H-NMR signals in isotropic media, particularly when either chiral acid (as analyte) or prochiral acid (as probe) contains a phenoxy group at an α-position of a carboxylic acid group (Table 1). 1H-NMR signals of various prochiral amines (e.g., benzylamine (BA), 1-aminopropane, piperidine) are clearly split in proportion to the ee of 2phenoxylpropionic acid (PPA) at ambient temperature. 1HNMR signals of phenoxyacetic acid are similarly split depending on ee of 1-phenylethylamine (PEA). In the absence of an appropriately positioned phenoxy group, NMR splitting was very weak or could not be observed even at −50 ºC (where host-guest interactions should be stronger). In a typical example, the BA/PPA complex was comprehensively investigated using 1H-NMR titrations, host-guest binding models, infrared (IR) and vibrational circular dichroism (VCD) spectroscopy, density functional theory (DFT) calculation and X-ray crystal structure analysis. Notably, X-ray crystal structure analysis indicated that there are multiple points of interaction (ionic interaction, hydrogen bonding, and CH-π interactions) that fix the conformation of the BA/PPA complex, and which are crucial for efficient intermolecular transfer of magnetic anisotropy (i.e., yield clear splitting of NMR signals) in isotropic media. We believe that the appropriate design of prochiral molecules (pro-CSAs) will lead to a convenient technique for the estimation of ee of various chiral compounds using NMR spectroscopy. RESULTS AND DISCUSSION BA + chiral acids (Case 1-3). BA belongs to the Cs point group, which is one of the four allowed point groups (Cs, C2v, D2d, S4) where splitting of NMR signals may be observed for compounds dissolved in chiral liquid crystals.23 In fact, we note that all of the previously reported prochiral molecules exhibiting ee-dependent NMR splitting in isotropic media (i.e., pro-CSAs) can be classified into one of these point groups, specifically oxoporphyrinogen (S4),17 porphyrin dications (S4)19 and N,N’disubstituted oxoporphyrinogen (C2v).20 We found that the 1H-NMR resonance due to the benzylic CH2 of BA shows ee-dependent splitting when mixed with a chiral acid, PPA, in CDCl3 at room temperature (RT) (Figures 1a, 1b, Case 1 in Table 1). Enantiopure (100% ee) PPA (i.e., (R)-PPA or (S)-PPA) provides identical spectra when measurement conditions (e.g., temperature, concentration, etc.) are identical. Decreases in the ee of PPA lead to a

Note: Prochiral protons proximal to the binding site are indicated with an orange circle. All measurements were performed in CDCl3. RT is about 22 ºC. #Splitting was also observed for (rac)-PPA, indicating a slow exchange regime of binding. ##Both CH2 resonances were split. ### Only benzyl CH2 resonance was split.


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The Journal of Physical Chemistry



expected). However, only weak splitting of BA at RT or low temperature could be observed. These results indicate that PPA is a somewhat unusual chiral analyte and that the conformation of the acid/base complex is critical for efficient intermolecular transfer of magnetic anisotropy from analyte to prochiral probe. Effect of basicity of BA (Case 4-5). In order to investigate the effect of basicity of the amine moiety, secondary (Nmethylbenzylamine; Case 4 in Table 1, Figure S4) and tertiary (N,N-dimethylbenzylamine; Case 5 in Table 1, Figure S5) analogues of BA were investigated. The benzylic resonance of N-methylbenzylamine (10 mM) is split in the presence of (R)-PPA (200 mM) at RT. However, the degree of splitting is less than for the BA/(R)-PPA complex measured at the same temperature and concentration. In sharp contrast, the benzylic resonance of N,N-dimethylbenzylamine (10 mM) does not split in the presence of (R)-PPA (200 mM) at RT. Splitting could be observed for N,N-dimethylbenzylamine/(R)PPA complex at −50 ºC, although identical splitting was also observed for N,N-dimethylbenzylamine/(rac)-PPA at −50 ºC. This is indicative of a slow exchange regime of binding (on the NMR timescale). The basicities of these benzylamines are similar falling in the order N-methylbenzylamine (pKa = 9.58) > BA (pKa = 9.34) > N,N-dimethylbenzylamine (pKa = 8.93),26 thus it is likely that the basicity of amines is not an important parameter in determining the tendency of NMR resonances to split. Other prochiral amines + PPA (Case 6-15). In order to further elucidate a general rule for the NMR splitting phenomenon, different prochiral amines were tested in combination with (R)-PPA. It was found that the 1HNMR signals of a large group of prochiral amines, including primary amines, secondary amines and cyclic secondary amines, are split upon addition of (R)-PPA at RT (Case 6-11 in Table 1). The same splitting was not observed if (rac)-PPA was used, confirming that binding in these combinations is in the fast exchange regime. NMR resonances of azetidine/(R)-PPA complex (Case 8 in Table 1, Figure S8) exhibit a larger degree of splitting than those of 1-aminopropane (Case 6 in Table 1, Figure S6) or piperidine (Case 11 in Table 1, Figure S11) presumably due to the greater rigidity of azetidine ring. However, the NMR signals of azetidine did not split upon addition of (S)ibuprofen at RT (Case 15 in Table 1, Figure S15). This further supports the case that PPA is a special chiral acid showing strong intermolecular transfer of magnetic anisotropy to prochiral amines in isotropic media. 1 H-NMR signals of pyridines (C2v point group) did not undergo any splitting when mixed with (R)-PPA even at −50ºC (Case 12 and 13 in Table 1, Figure S12 and S13) presumably due to fast rotation of pyridine about its C2 axis. In contrast, 5,6,7,8-tetrahydroquinoline (Cs) showed weak splitting at RT when mixed with (R)-PPA (Case 14 in Table 1, Figure S14), so that heterocyclic amine is available as pro-CSAs. Prochiral acids + chiral amines (Case 16-22). 1HNMR signals of prochiral acids such as butyric acid (Case 16 in Table 1, Figure S16) and p-tolylacetic acid (Case 17 in Table 1, Figure S17) in the presence of chiral amine, (S)-1-pheneyethylamine ((S)-PEA), do not split at RT. Cooling the mixture of p-tolylacetic acid/(S)-PEA to −50 ºC leads to a very weak splitting of the 1H-NMR signals of p-tolylacetic acid at the benzylic CH2 position accom-

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panied by the expected side bands due to an AB-type second order spectral pattern with J-coupling. No splitting was observed at −50 ºC when (rac)-PEA was used, confirming that the exchange regime remains fast on the NMR timescale. Interestingly, the 1H-NMR signals of phenoxyacetic acid at its α-carboxyl position exhibited clear splitting when mixed with (S)-PEA even at RT (Case 18 in Table 1, Figure S18). Magnetic anisotropy due to PEA originates largely from the ring current effect (different degree of shielding) of its phenyl ring; the use of (S)-1-cyclohexylethylamine did not cause any splitting in phenoxyacetic acid resonances even at −50 ºC (Case 19 in Table 1, Figure S19). However, it should be noted that the presence of an aromatic ring in chiral analytes is not essential for operation of pro-CSAs since we have already demonstrated that ee of menthol and camphor can be determined by using pro-CSAs based on an N,N’disubstituted oxoporphyrinogen.20 If the phenoxy group in phenoxyacetic acid is replaced with either ethoxy or tertbutoxy groups, then NMR splitting of the resulting prochiral molecules could not be observed at RT (Case 20, 21 in Table 1, Figure S20 and S21). Furthermore, insertion of an additional methylene unit into phenoxyacetic acid also made NMR splitting unobservable at RT (Case 22 in Table 1, Figure S22). In the latter case, the splitting of NMR signals could only be observed on cooling below −30 ºC. Thus, as is summarized in Table 1, the experimental results indicate that ee-dependent 1H-NMR splitting at RT occurs especially when either prochiral acid or chiral acid contain a phenoxy group at an α-position to their carboxyl groups. IR studies. In order to understand the significance of having a phenoxy group attached at the α-position to the carboxyl group, various physical analyses were conducted on the BA/PPA complex. First, infrared (IR) spectroscop-

Figure 2. (a) IR spectra of (R)-PPA at various concentration in CDCl3 measured at RT. A CaF2 cell with a 0.2 mm spacer was used and the spectrum of CDCl3 has been subtracted. (b) IR spectra of (R)-PPA in CDCl3 (14 mM) upon addition of 0−2.54 molar equivalent of BA. (c) Concentration dependent molar fraction of (R)-PPA in monomer and dimer form calculated from IR data in (a). IR data was converted to ACS Paragon Plus Environment absorbance for the calculations.

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The Journal of Physical Chemistry ic measurements were performed for PPA as well as BA/PPA complex in CDCl3. As shown in Figure 2a and S24, IR spectra of (R)-PPA contain two signals due to C=O stretching at 1775 cm−1 and 1730 cm−1, which can be assigned to carboxylic acid monomer and hydrogenbonded dimer, respectively.27 As the concentration of (R)PPA in CDCl3 decreases, the intensity of the 1775 cm−1 band relative to the 1730 cm−1 band is enhanced due to dissociation of the dimer form. The molar fraction of (R)PPA existing in monomer (fG) and dimer form (fGG) can be estimated from the relative absorbances (A) of the corresponding IR signals as fG = A1775/(A1775+A1730) and fGG = A1730/(A1775+A1730), respectively. The dimerization constant KGG = 124 ± 13 M−1 can be calculated using a model based solely on the equilibrium Equation 2 (for details see Supporting Information). IR bands due to C=O stretching in PPA (i.e., 1775 cm−1 and 1730 cm−1) decrease dramatically in intensity upon addition of BA (Figure 2b, S25) with concurrent appearance of new IR signals around 1500-1700 cm−1, corresponding to deprotonated carboxylic acid.28 IR bands due to PPA monomer and dimer are then absent after a small excess (1.39 molar equiv.) of BA has been added indicating almost quantitative deprotonation of PPA by BA. We note here that since the 1H-NMR signal of BA did not fully split in the presence of a small excess of (R)PPA (Figure S1), protonation of BA by PPA by itself is not sufficient to cause the splitting of 1H-NMR peaks. Vibrational circular dichroism (VCD) spectroscopy. VCD spectra29−31 were measured in order to investigate chiral interactions between PPA and BA. As shown in Figure 3a, 3b VCD spectra of (R)-PPA and (S)-PPA in CDCl3 were of low intensity although mirror-image signals can be found at 1240 cm−1. IR spectra were identical for (R)-PPA, (S)-PPA, and (rac)-PPA. In order to assign VCD active vibrations, IR and VCD spectra of (R)-PPA were simulated by using DFT calculations (Figure S29).

Figure 3. IR (a) and VCD (b) spectra of (R)-PPA, (S)-PPA, and (rac)-PPA in CDCl3 (72 mM). Spectrum of CDCl3 has been subtracted. Baseline correction was not applied. Optical length is 0.15 mm. IR (c) and VCD (d) spectra of BA/(R)-PPA, BA/(S)-PPA, and BA/(rac)-PPA in CDCl3. [PPA]t = 72 mM, [BA]t = 436 mM. Spectrum of CDCl3 has been subtracted. Baseline correction was not applied. Enlarged versions of these figures can be found in Figure S27.

Here, Cartesian coordinates obtained from the X-ray crystal structure determination of (R)-PPA dimer (Figure 4a) were employed as the starting molecular geometry. The structure was then optimized to minimum energy level. Patterns of simulated IR/VCD spectra for (R)-PPA are consistent with the experimental results although simulated spectra were slightly (approximately by 100 cm−1) shifted to higher wavenumber, presumably due to solvent effects. Thus, based on DFT calculations, VCD active vibrations in PPA could be assigned to the C-O stretching vibration at 1240 cm−1, which is a typical vibration for carboxylic acids.27 In order to measure the VCD spectrum of BA/PPA complex, a large amount of BA (436 mM) was added to PPA solution (72 mM). Under these conditions, it is expected that PPA (i.e., chiral source) is saturated with BA, so that it can in turn be assumed that (with respect to PPA) the observed VCD spectra are due mainly to the BA/PPA complex (i.e., VCD signals from PPA monomer and dimer ought to be negligible). As shown in Figure 3c, 3d the BA/PPA complex exhibits a new intense VCD signal at 1300 cm−1 as well as moderate signals around 1600 cm−1. Our attempts to assign these new VCD vibrations using DFT calculations based on the crystal structure of BA/(S)-PPA (Figure 4b) lead to simulated IR/VCD spectra that did not fit well with the experimental data (Figure S30, S31). This is probably due to (i) the charge of the BA/PPA complex, (ii) delocalization of the acidic proton atom between BA and PAA and (iii) the existence of various stable molecular geometries in solution. Despite these features, it is evident that new VCD signals do appear for the BA/PPA complex, implying transfer of chiral information between BA and PPA. X-ray crystal structure. Molecular interactions in the solid state were investigated by X-ray crystal structure analysis. An X-ray crystal structure of (R)-PPA obtained from literature32 shows the characteristic hydrogen bonded dimer of carboxylic acid moieties (Figure 4a). The bond length of C9-O10 (1.214(2) Å) is shorter than that of C9-O11 (1.307(2) Å), so that C9-O11 and C9-O11 can be assigned to C=O bond and C−O bond, respectively. This result indicates that the carboxyl proton is localized on O11.

Figure 4. (a) X-ray crystal structure of (R)-PPA. Thermal ellipsoids are drawn at 50% probability level and H atoms are shown as small spheres of arbitrary radius. (b) X-ray crystal structure of BA/(S)-PPA. Black, red, blue, and white balls denote carbon, oxygen, nitrogen, and hydrogen atoms, respectively. Green dashed lines denote close contact. CCDC deposit number: 1555133 We have successfully obtained single crystals of the complex of BA and (S)-PPA in 1:1 molar ratio by opti-



mizing the conditions for crystal growth (Figure 4b). It should be noted that, of all the reported pro-CSAs,18 this BA/(S)-PPA complex is the first example where an actual crystal structure has been obtained. The structure clearly indicates that the two benzylic CH2 protons of BA are non-equivalent due to symmetry breaking involving (S)PPA. Bond lengths of C9-O2 (1.252(4) Å) and C9-O3 (1.259(4) Å) are quite similar both lying in between that expected for a carbonyl C=O bond and C-O bond as observed in the (R)-PPA dimer. Thus, (S)-PPA is in the form of carboxylate with partial double bonds between these carbon and oxygen atoms. Notably, not only the carboxylate oxygen atoms but also the phenoxy ether oxygen of PPA are closely interacting with the ammonium group of BA (due to hydrogen bond). Moreover, it is likely that the methyl group of PPA interacts with the phenyl group of BA through CH-π interactions (distance of C12H8B is 2.882 Å). These multiple point interactions should also apply in solution state to fix the conformation of the BA/PPA complex. In previous examples of pro-CSAs,18 saddle-shaped prochiral macrocylic compounds (porphyrin dications and oxoporphyrinogens) bind chiral guest molecules at their two (per binding site) pyrrolic NH positions through two hydrogen bonds. Thus, now it is obvious that the presence of multi-point interactions is beneficial for capturing of the chiral analyte and critical for promotion of efficient transfer of magnetic anisotropy in isotropic media. Other evidence for multi-point interactions (Case

23). The presence of muliti-point interactions between prochiral molecules and chiral analytes in the solution state is further supported by the interesting results found for benzyloxyacetic acid and (S)-PEA (Case 23 in Table 1, Figure 5a, 5b, S23). In that case, the reporting group exhibiting splitting at RT was not the α-carbonyl CH2 but the benzylic CH2 despite the benzyl CH2 being far from the carboxylic acid moiety. This indicates that the ether oxygen of benzyloxyacetic acid is coordinating to (S)-PEA, resulting in the benzylic CH2 of benzyloxyacetic acid being sterically close to (S)-PEA in the folded structure (Figure 5c).

CONCLUSION In conclusion, we demonstrate ee-dependent splitting of H-NMR signals of prochiral molecules at room temperature in some simple acid/base pairs composed of prochiral molecules and chiral analytes. The results reveal the critical importance of molecular conformation obtained through multipoint interaction for efficient intermolecular transfer of magnetic anisotropy (i.e., well-resolved NMR splitting pattern) in isotropic media, while maintaining fast exchange of binding is also necessary for averaging of magnetic anisotropy. We believe that a wide range of pro-CSAs can be created if intermolecular interactions between prochiral molecules and chiral analytes are adequately designed taking into account the appropriate symmetry restrictions. The synthetic flexibility, low cost and good availability of prochiral molecules make the pro-CSAs convenient reagents for the estimation of ee of chiral compounds using the widely available NMR spectroscopic technique. 1

ASSOCIATED CONTENT Supporting Information. The supporting information is available free of charge via the Internet at http://pubs.acs.org. Materials, general experimental procedures, additional NMR data, IR/VCD spectra, binding model study and DFT calculations.

AUTHOR INFORMATION Corresponding Author * [email protected], [email protected], [email protected]

Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENT

Figure 5. (a) Temperature dependency of 1H-NMR spectra of benzyloxyacetic acid (20 mM) in the presence of (S)PEA (200 mM) in CDCl3. (b) Temperature dependency of 1 H-NMR spectra of benzyloxyacetic acid (20 mM) in the presence of (rac)-PEA (200 mM) in CDCl3. (c) Plausible mechanism for long range transfer of magnetic anisotropy occurring in the benzyloxyacetic acid/(S)-PEA complex.

This work was partly supported by World Premier International Center for Materials Nanoarchitectonics (WPI-MANA), JSPS KAKENHI (grant numbers: 25810055, 16H00840, 25104011, 26620068, 17H03044) and Kurata Grant from the Kurata Memorial Hitachi Science and Technology Foundation. Mr. Tsubasa Uesugi (Ehime Univ.) and Ms. Kumiko Hara (NIMS) are acknowledged for assisting research.

REFERENCES (1) Bonner, W. A. The origin and amplification of biomolecular chirality. Origins Life Evol. Biospheres 1991, 21, 59−111.


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The Journal of Physical Chemistry (2) Donohue, J. Hydrogen bonded helical configurations of the polypeptide chain. Proc. Natl. Acad. Sci. U.S.A. 1953, 39, 470−478. (3) Hirschberg, J. H. K. K.; Brunsveld, L.; Ramzi, A.; Vekemans, J. A. J. M.; Sijbesma, R. P.; Meijer, E. W. Helical selfassembled polymers from cooperative stacking of hydrogenbonded pairs. Nature 2000, 407, 167−170. (4) Akagi, K. Helical polyacetylene: asymmetric polymerization in a chiral liquid-crystal field. Chem. Rev. 2009, 109, 5354−5401. (5) Hutt, A. J. In Smith and Williams’ Introduction to the Principles of Drug Design and Action; Smith, H. J., Ed.; CRC Press, Taylor & Francis: Boca Raton, FL, 2006; Chapter 5. (6) Morrow, S. M.; Bissette, A. J.; Fletcher, S. P. Transmission of chirality through space and across length scales. Nat. Nanotech. 2017, 12, 410–419. (7) Yashima, E.; Ousaka, N.; Taura, D.; Shimomura, K.; Ikai, T.; Maeda, K. Supramolecular helical systems: helical assemblies of small molecules, foldamers, and polymers with chiral amplification and their functions. Chem. Rev. 2016, 116, 13752–13990. (8) Kim, J. H.; Scialli, A. R. Thalidomide: the tragedy of birth defects and the effective treatment of disease. Toxicol. Sci. 2011, 122, 1−6. (9) Schellman, J. A. Circular dichroism and optical rotation. Chem. Rev. 1975, 75, 323–331. (10) Berova, N.; Nakanishi, K.; Woody, R. W. Circular Dichroism: Principles and Applications, 2nd Edition, John Wiley & Sons, 2000. (11) Okamoto, Y.; Ikai, T. Chiral HPLC for efficient resolution of enantiomers. Chem. Soc. Rev. 2008, 37, 2593−2608. (12) Nakanishi, T.; Matsunaga, M.; Nagasaka, M.; Asahi, T.; Osaka, T. Enantioselectivity of redox reaction of DOPA at the gold electrode modified with a self-assembled monolayer of homocysteine. J. Am. Chem. Soc. 2006, 128, 13322−13323. (13) Michinobu, T.; Shinoda, S.; Nakanishi, T.; Hill, J. P.; Fujii, K.; Player, T. N.; Tsukube, H.; Ariga, K. Mechanical control of enantioselectivity of amino acid recognition by cholesterol-armed cyclen monolayer at the air-water interface. J. Am. Chem. Soc. 2006, 128, 14478−14479. (14) Wenzel, T. J. Discrimination of Chiral Compounds using NMR Spectroscopy, John Wiley & Sons, 2007. (15) Parker, D. NMR determination of enantiomeric purity. Chem. Rev. 1991, 91, 1441−1457. (16) Zhao, Y.; Swager, T. M. Simultaneous chirality sensing of multiple amines by 19F NMR. J. Am. Chem. Soc. 2015, 137, 3221−3224. (17) Shundo, A.; Labuta, J.; Hill, J. P.; Ishihara, S.; Ariga, K. Nuclear magnetic resonance signaling of molecular chiral information using an achiral reagent. J. Am. Chem. Soc. 2009, 131, 9494−9495. (18) Labuta, J.; Hill, J. P.; Ishihara, S.; Hanyková, L.; Ariga, K. Chiral sensing by nonchiral tetrapyrroles. Acc. Chem. Res. 2015, 48, 521−529.

(19) Labuta, J.; Ishihara, S.; Shundo, A.; Arai, S.; Takeoka, S.; Ariga, K.; Hill, J. P. Chirality sensing by nonchiral porphines. Chem. Eur. J. 2011, 17, 3558−3561. (20) Labuta, J.; Ishihara, S.; Šikorský, T.; Futera, Z.; Shundo, A.; Hanyková, L.; Burda, J. V.; Ariga, K.; Hill, J. P. NMR spectroscopic detection of chirality and enantiopurity in referenced systems without formation of diastereomers. Nat. Commun. 2013, 4, 2188. (21) Labuta, J.; Ishihara, S.; Ariga, K.; Hill, J. P. Dynamic processes in prochiral solvating agents (pro-CSAs) studied by NMR spectroscopy. Symmetry 2014, 6, 345−367. (22) Labuta, J.; Futera, Z.; Ishihara, S.; Kouřilová, H.; Tateyama, Y.; Ariga, K.; Hill, J. P. Chiral guest binding as a probe of macrocycle dynamics and tautomerism in a conjugated tetrapyrrole. J. Am. Chem. Soc. 2014, 136, 2112−2118. (23) Lesot, P.; Aroulanda, C.; Zimmermann, H.; Luz, Z. Enantiotopic discrimination in the NMR spectrum of prochiral solutes in chiral liquid crystals. Chem. Soc. Rev. 2015, 44, 2330−2375. (24) Fraser, R. R.; Petit, M. A.; Miskow, M. Separation of nuclear magnetic resonance signals of internally enantiotropic protons using a chiral shift reagent. The deuterium isotope effect on geminal proton-proton coupling constants. J. Am. Chem. Soc. 1972, 94, 3253−3254. (25) Bilz, A.; Stork, T.; Helmchen, G. New chiral solvating agents for carboxylic acids: discrimination of enantiotopic nuclei and binding properties. Tetrahedron Asymmetry 1997, 8, 3999−4002. (26) Hall, H. K., Jr. Correlations of the base strengths of amines. J. Am. Chem. Soc. 1957, 79, 5441−5444. (27) Stuart, B. Infrared Spectroscopy: Fundamentals and Applications; John Wiley & Sons, 2004. (28) Smith, B. Infrared Spectral Interpretation: A Systematic Approach; CRC Press, 1999. (29) Sato, H.; Taniguchi, T.; Nakahashi, A.; Monde, K.; Yamagishi, A. Effects of central metals ions on vibrational circular dichroism spectra of tris-(β-diketonato)metal(III) complexes. Inorg. Chem. 2007, 46, 6755−6766. (30) Sasaki, T.; Hisaki, I.; Miyano, T.; Tohnai, N.; Morimoto, K.; Sato, H.; Tsuzuki, S.; Miyata, M. Linkage control between molecular and supramolecular chirality in 21-helical hydrogen-bonding networks by using achiral components. Nat. Commun. 2013, 4, 1787. (31) Sato, H.; Tamura, K.; Takimoto, K.; Yamagishi, A. Solid state vibrational circular dichroism towards molecular recognition: chiral metal complexes intercalated in a clay mineral. Phys. Chem. Chem. Phys. 2018, 20, 3141−3147. (32) Sørensen, H. O.; Larsen, S. Hydrogen bonding in enantiomeric versus racemic mono-carboxylic acids; a case study of 2-phenoxy-propionic acid. Acta Cryst. 2003, B59, 132−140.



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NMR Spectroscopic Determination of Enantiomeric Excess using

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