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. 2023 May 2;3(5):1348–1357. doi: 10.1021/jacsau.2c00661

Chirality Sensing of N-Heterocycles via 19F NMR

Guangxing Gu †, Zhenchuang Xu †, Lixian Wen †, Jinhua Liang †, Chenyang Wang †, Xiaolong Wan ‡, Yanchuan Zhao †,§,*
PMCID: PMC10206601  PMID: 37234104

Abstract

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Methods to rapidly detect and differentiate chiral N-heterocyclic compounds become increasingly important owing to the widespread application of N-heterocycles in drug discovery and materials science. We herein report a 19F NMR-based chemosensing approach for the prompt enantioanalysis of various N-heterocycles, where the dynamic binding between the analytes and a chiral 19F-labeled palladium probe create characteristic 19F NMR signals assignable to each enantiomer. The open binding site of the probe allows the effective recognition of bulky analytes that are otherwise difficult to detect. The chirality center distal to the binding site is found sufficient for the probe to discriminate the stereoconfiguration of the analyte. The utility of the method in the screening of reaction conditions for the asymmetric synthesis of lansoprazole is demonstrated.

Keywords: chirality sensing, 19F NMR, molecular recognition, palladium, N-heterocycles

Introduction

Chiral molecules play an increasingly important role in the fields of pharmaceuticals, pesticides, and liquid crystal materials.1−4 Synthetic methods that allow rapid access to various chiral molecules are being vigorously investigated, which greatly promotes the exploration of the unique properties of chiral substances. With the emergence of automated and high-throughput techniques, chiral molecules are now created at an unprecedented rate,5−8 which demands innovations to solve the bottleneck in the speed of enantioanalysis. In addition to improving the pump pressure and column efficiency of chiral liquid chromatography,9,10 in situ optical and spectroscopic methods have shown great potential in accelerating chiral analysis.11−17 During the past decade, chemosensing systems based on fluorescence and circular dichroism have been well documented, wherein the covalent derivatization or dynamic interactions between the optical probes and analytes alter the intensity of the optical signal.18−21 To perform the chiral analysis, these methods usually require a calibration curve constructed using enantioenriched samples with known enantiomeric excess (ee) values. Under the scenario of the development of new asymmetric reactions, access to enantiopure analytes can be challenging.

Nuclear magnetic resonance (NMR) spectroscopy is a classic method for determining optical purity, which utilizes chiral reagents to generate diastereomeric complexes of distinct spectroscopic signatures through covalent modification or transient intermolecular interactions.22−30 In practice, its widespread adoption in chiral analysis is hampered by the complicated derivatization/purification step, the tedious signal assignments, and the overlap of NMR resonances. These challenges are partially addressed by strategies using chiral oriented solvents, which allow NMR to probe the stereochemical information of a molecule with anisotropic NMR data.31−34 Recently, 19F NMR-based chemosensing has emerged as a burgeoning subfield in chiral analysis, where the reversible bindings between the 19F-labeled probe and the target chiral analytes are transduced into simplified 19F NMR signals of discrete chemical shifts.35−39 As such, enantiomers of different configurations are simultaneously identified, allowing reliable ee determination by ratiometric analysis. This approach has been successfully applied to the chiral differentiation of diverse analytes, including primary amines, alcohols, amides, etc.36−39 N-Heterocyclic compounds are ubiquitously found in natural products and drug molecules, exhibiting a wide spectrum of biological activities.36 Chiral N-heterocycles are also considered privileged structural components for the exploration of transition-metal ligands and luminescent materials.40−43 However, rapid and reliable enantioanalysis of N-heterocycles via chemosensing remains challenging. Compared to primary amines (Scheme 1a), the microenvironment around the nitrogen atom of N-heterocycles becomes more congested, which is detrimental to their affinity toward probes. Furthermore, chiral derivatization of aromatic N-heterocycles, such as pyridine, is not straightforward. Herein, we report a 19F-labeled cyclopalladium probe for the prompt chiral analysis of both aliphatic and aromatic N-heterocycles (Scheme 1b). The open binding site allows the probe to effectively recognize various sterically hindered analytes that were difficult to detect by chemosensing. A chirality center distal to the binding site is found sufficient for the probe to discern the stereoconfiguration of the analyte (Scheme 1b). The chiral information transduction strategy paves new avenues for the design of robust sensors targeting biologically relevant chiral analytes.

Scheme 1. Strategies for Chirality Sensing via 19F NMR.

Scheme 1

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(a) Enantiodifferentiation using spatially proximal chirality centers. (b) Enantiodifferentiation enabled by a distal chirality center.

Results and Discussion

We set out our investigation by examining the performance of previously reported 19F probes in the enantiodifferentiation of N-heterocycles. Among various probes, the 19F-labeled palladium pincer complexes were known to be robust for the enantioanalysis of amines (Scheme 1a).36 Upon recognition, the analytes encapsulated in the chiral binding pocket are distinguished by the proximal 19F atoms. To test whether these probes are amenable to the differentiation of N-heterocycles, we selected 1-phenyl-1,2,3,4-tetrahydroisoquinoline (A1) as a model analyte, which is a common synthetic target for a number of asymmetric reactions.44−47 To our surprise, no new 19F NMR signal was generated when the analyte was mixed with the probe (1) depicted in Scheme 1a, suggesting that the chiral pocket of the pincer ligand is too confined to accommodate bulky analytes (Figure S1a–c in the Supporting Information). This observation revealed that the probe design based on spatially proximal chiral scaffolds, though powerful in promoting intimated analyte–probe interactions, is only amenable for sterically less hindered analytes. We envision that the probe with a helical-typed chirality may bind bulky analytes more effectively because the chirality can be introduced by an asymmetric twist of the probe scaffold without the need for the proximal central chirality required in previous designs (Scheme 1a). We see the monomeric cyclopalladium complexes as a promising platform to test the feasibility of our idea because they possess relatively open binding sites and are readily accessible via C–H palladation.48−50 The robustness of these complexes toward chromatographic purification implies high stability,51 which is a desirable feature for analytical applications. By design, the central chirality at the benzylic position is envisioned to induce twisting of the square planar palladium complex (a fused 6–5–5–6 ring system, Scheme 1b), resulting in differential bindings of the chiral analytes. This intriguing signal transduction mechanism would allow the chirality of the analyte to be sensed by the trifluoromethyl moiety on the pyridine (Scheme 1b). As the chirality center is placed distal to the binding site, this probe design allows facile accommodation of bulky analytes that are otherwise difficult to enantiodifferentiate. It is noteworthy that the bridged dimers of palladium complexes were used for the chiral analysis and resolution of various amino acids; however, the complexation of monodentate N-heterocycles by these complexes is difficult.52

The designed probe can be readily prepared from commercially available chemicals. The condensation between 6-(trifluoromethyl)picolinic acid and (R)-1-phenylethan-1-amine (2-R) in the presence of EDCI·HCl produced the chiral ligand 3-R. A subsequent C–H palladation using Pd(OAc)2 in acetonitrile at 80 °C affords the desired probe 4-R in 92% yield (Scheme 2). With probe 4-R in hand, we next evaluated its performance in the enantioanalysis of N-heterocycles by selecting a series of biologically relevant analytes. As shown in Figure 1, analyte A1 that displays diminished affinity to the previously reported pincer-typed probe produces two well-separated 19F NMR signals upon mixing with probe 4-R in chloroform (Figure 1a), suggesting a superior recognition property of 4-R to bind sterically bulky analytes. The 19F signal appeared upfield corresponds to A1 of the R configuration as confirmed by the experiments using the enantiopure analyte (Figure 1b,c). The method is amenable to the enantiodifferentiation of various 2-substituted piperidine (A2–A5), morpholine (A6), and piperazine (A10, A11), leading to sharp and discrete 19F signals. Piperidines with a substituent at 3-position are also resolvable (A8, A9). For these analytes, the chemical shift difference between newly generated 19F signals becomes smaller as the chirality center of the analyte is too distal from that of probe 4-R. Five-membered N-heterocycles, such as 2-substituted pyrrolidines (A12–A16), are easily differentiated, as evidenced by the well-separated 19F signals. The linewidths of 19F NMR signals produced by enantiomeric analytes are sometimes different (A3, A11), indicating that the stereoconfiguration of the analyte has an influence on the chemical exchange rate of the system. Interestingly, the splitting of the 19F NMR signals is observed in the analysis of certain saturated five- and six-membered N-heterocycles (A8, A12, A13, A15). As 1H-decoupled 19F NMR experiments afford sharp singlet 19F signals, the splitting is attributed to the through-space 1H-19F J coupling (Figure 2a,b). This assumption is supported by the deuteration experiments, where a set of new singlet 19F NMR signals attributed to the deuterated A15 was observed (Figure 2c). This observation indicates that the current sensing scheme may also apply to the identification of the small differences between the deuterated and nondeuterated species (for more examples, see Figure S2 in the Supporting Information). We next extended our method to the enantioanalysis of aromatic N-heterocycles. Upon mixing the racemic 1-(pyridin-2-yl)ethan-1-ol (A17) with probe 4-R, four new 19F NMR signals were observed, suggesting that the binding of each enantiomer may produce two 19F signals. This assumption is unambiguously confirmed by the experiment using the enantiopure analyte, where the recognition of A17R produced two 19F NMR signals with chemical shifts of −65.95 and −66.26 ppm, respectively (Figure 2e). We attributed these observations to the restricted rotation of the bound analyte around the Pd–N coordination bond, which impedes the conversion between different binding models (Figure 2f). According to the density functional theory (DFT) calculation (Figures S6–S8 in Supporting Information), the energy barrier for the conversion between the complex model-A and model-B is higher than 17.4 kcal/mol, which is consistent with the slow exchange behavior on the NMR time scale. The calculation also revealed that the twisting of the planar scaffold of the probe is influenced both by the methyl-substituted chiral center and the bound analyte. Twisting angles vary between −0.11 and 15.83°, indicating that the planar scaffold of the probe is partially flexible (Figure S9 in Supporting Information). The twisting is thus adaptive to the size, shape, and stereoconfiguration of the bound analyte, promoting the production of 19F NMR signals of distinct chemical shifts. 1H–1H nuclear Overhauser effect spectroscopy (NOSEY) experiments confirmed the spatial proximity between the probe and the bound analyte, supporting that the two 19F NMR signals produced by each enantiomer correspond to different conformers of the complex (Figure S10a–c in Supporting Information). In addition to pyridines, other classes of N-heterocyclic analytes, such as quinoline (A22), benzo[d]oxazole (A23), and oxazol-5(4H)-one (A24), are also resolvable by probe 4-R, indicating a wide analyte scope. As confirmed by the experiments using enantioenriched analytes, each enantiomer of the aromatic N-heterocycles (A17–A24) corresponds to a pair of nonadjacent 19F NMR signals (Figure S3 in Supporting Information). This empirical rule may be helpful to guide the assignment of 19F signals obtained in the analysis of aromatic N-heterocycles. The method is also applicable to the resolution of various heterocyclic medications, as exemplified by the analysis of flecainide (A25) and lansoprazole (A26). Given the extraordinary resolving ability of probe 4-R, we next examine the feasibility to simultaneously detect and identify multiple chiral analytes. A series of structurally similar five- and six-membered N-heterocycles were selected to form a mixture that is difficult to resolve by traditional analytical methods. As demonstrated in Figure 1ac, the resolution of all six chiral analytes is easily achievable via our sensing scheme, highlighting the potential of this approach for the multicomponent analysis of complex real-world samples.

Scheme 2. Synthetic Route for 19F-Labeled Cyclopalladium Probe 4-R.

Scheme 2

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Figure 1.

Figure 1

Figure 1

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(a–ac) Enantiodifferentiation of racemic N-heterocycles using probe 4-R. (a–j, l–ac) 19F NMR spectra of mixtures of 4-R (0.9 mg) and various racemic analytes (0.5–2.0 mg) in CDCl3. (k) 1H-decoupled 19F NMR spectra of a mixture of 4-R (0.9 mg) and racemic A(9) (1.5 mg) in CDCl3. (ac) 19F NMR spectrum of the probe 4-R (ca. 3.0 mg) and 3 pairs of enantiomeric chiral N-heterocycles (each 0.5–2.0 mg) in CDCl3. Note: for (a–ab), the signals in blue are produced by one enantiomer; the signals in red are produced by the other enantiomer. The absolute configuration of the analyte was assigned when the enantioenriched sample is available.

Figure 2.

Figure 2

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Investigation of binding models. (a) 19F NMR spectrum of a mixture of probe 4-R (0.9 mg) and enantiopure A15 (1.2 mg) in CDCl3. (b) 1H-decoupled 19F NMR spectrum of a mixture of probe 4-R (0.9 mg) and A15 (1.2 mg) in CDCl3. (c) 19F NMR spectrum of a mixture of probe 4-R and partially deuterated A15 in CDCl3. (d) Proposed binding models between probe 4-R (0.9 mg) and A15 (1.2 mg). (e) 19F NMR spectrum of a mixture of probe 4-R (0.5 mg) and enantiopure (R)-1-(pyridin-2-yl)ethan-1-ol (0.4 mg) in CDCl3. (f) Proposed binding models between probe 4-R and (R)-1-(pyridin-2-yl)ethan-1-ol.

In chiral HPLC analysis, racemic analytes are needed in the optimization of chromatographic conditions. Without racemic standards, it is often difficult to tell whether a given sample is enantiopure. This scenario is common when analyzing natural products and certain chiral ligands, where only one enantiomer is accessible. Our sensing scheme provides a viable solution to this unmet challenge by using a pair of enantiomeric 19F probes. As depicted in Figure 3, the 19F NMR signal for probe 4-R with a bound (R)-3-methylmorpholine is the same as that for probe 4-S with a bound (S)-3-methylmorpholine (Figure 3a,c). As such, the 19F NMR spectra for the analysis of a racemic sample would be identical to that obtained by using an enantiopure analyte and both enantiomers of the 19F probe (Figure 3e). To test the scope of the strategy, we next selected a series of enantiopure analytes, the enantiomers of which are either costly or inaccessible. From the comparison between the 19F NMR spectra obtained using probe 4-R and the racemic mixture of probe 4, it is evidenced that the enantioresolution of these chiral analytes is successfully achieved (Figure 3f,g). As the binding strengths of enantiomeric analytes toward probe 4-R are usually similar, the circumstance that only one of the enantiomers binds to the probe is unlikely.

Figure 3.

Figure 3

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Enantioanalysis using only one enantiomer of the chiral analyte. (a, b) 19F NMR spectra of mixtures of probe 4-R (0.9 mg) and enantiopure (R)- or (S)-3-methylmorpholine (0.5 mg) in CDCl3. (c, d) 19F NMR spectra of mixtures of probe 4-S (0.9 mg) and enantiopure (R)- or (S)-3-methylmorpholine (0.5 mg) in CDCl3. (e) 19F NMR spectra of mixtures of racemic probe 4 (0.9 mg) and (S)-3-methylmorpholine (0.5 mg) in CDCl3. (f–h) 19F NMR spectra of mixtures of racemic probe 4 (0.9 mg) and enantiopure analytes (0.4–1.2 mg) in CDCl3. Note: (e–h) signals in blue–green and dark red are produced by probes 4-R and 4-S, respectively.

We next tested the feasibility to use probe 4-R to determine the ee value of enantioenriched samples. Owing to the open binding site, the affinities of probe 4-R to enantiomeric analytes are usually similar. When the two 19F NMR signals generated in the analysis of the racemic sample are of equal intensity, the enanoticomposition of the sample can be directly determined by the 19F NMR integration. If there is a preference for 4-R to bind one of the enantiomers, a correction coefficient is introduced. The use of the coefficient has been demonstrated to offset the deviation induced by the unequal affinities of enantiomeric analytes toward the chiral probe.38,39 We next selected methylpyrrolidine (A12) and 2-(1-hydroxyethyl)pyridine (A17) as model analytes to test the performance of probe 4-R in the enantiocomposition determination of aliphatic and aromatic N-heterocycles. As shown in Table 1, the ee values determined by our methods are all in good agreement with the actual enantiocomposition of the sample (Figures S11 and S12 in Supporting Information), with an average deviation lower than 2% (for an example in which the binding strengths of the enantiomeric analytes vary significantly, see Table S1 in Supporting Information). To further increase the accuracy of the ee assessments, quantitative NMR experiments may be applied. Our preliminary investigations indicate that the NMR experiments with short relaxation delay (1s) give the same results as those using quantitative NMR experiments, probably due to the comparable T1 values of 19F NMR signals corresponding to the enantiomeric analytes (Figure S14 in Supporting Information). It is noteworthy that high-throughput ee value evaluation via 19F NMR has been previously demonstrated, which allows the analysis of more than 1000 samples in a day using an NMR spectrometer equipped with a regular autosampler.38

Table 1. Evaluation of the Enantiomeric Excess Valuesa.

(R)-2-methylpyrrolidine (A12)
 (R)-2-(1-hydroxyethyl)pyridine (A17)
actual ee (%) calculated ee (%)b corrected ee (%)c deviation (%) actual ee (%) calculated ee (%)b corrected ee (%)c deviation (%)
0.00 5.7 0.0 0.0 0.0 0.0 0.0 0.0
9.6 15.3 9.7 0.1 10.5 11.9 11.9 1.4
20.1 24.0 18.5 –1.6 20.0 20.0 20.0 0.0
30.0 34.4 29.3 –0.7 29.9 30.8 30.8 0.9
39.5 43.8 39.2 –0.3 39.9 42.0 42.0 2.1
50.1 53.2 50.0 –0.1 50.2 51.0 51.0 0.8
59.5 61.8 58.1 –1.4 59.9 60.2 60.2 0.3
69.8 70.5 67.5 –2.3 69.8 68.7 68.7 –1.1
79.8 79.8 77.6 –2.2 80.0 79.1 79.1 –0.9
90.0 88.8 87.6 –2.4 89.7 87.9 87.9 –1.6
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a

NMR measurements were taken in CDCl3 using probe 4-R (ca. 0.9 mg), 2-methylpyrrolidine (ca. 1.0 mg), and 2-(1-hydroxyethyl)pyridine (ca. 0.3 mg).

b

Calculation is based on the 19F NMR integrations associated with probe 4-R bound with R and S analytes.

c

The values are corrected based on the relative binding strength observed in the analysis of racemic samples.

Lansoprazole is a proton pump inhibitor, which is often used to treat ulcers and other stomach problems.53 The enantioselective synthesis of lansoprazole is of great interest because the R and S enantiomers of lansoprazole display distinct pharmacokinetics.54 We next took the asymmetric synthesis of lansoprazole as an example to demonstrate the utility of our approach in rapid ee value assessments. In these reactions, the chiral ligand for Fe(acac)3 is in situ formed through the condensation between (S)-2-amino-3,3-dimethylbutan-1-ol and various salicylaldehydes, wherein enantioenriched lansoprazole is produced through the oxidation of the sulfide precursor 5 with hydrogen peroxide (Figure 4).55 To perform the analysis, part of the reaction solution was taken and concentrated. The crude products obtained under different reaction conditions were directly mixed with the probe for 19F NMR analysis. As revealed by 19F NMR analysis (Figure 4b,c), the substituent on the salicylaldehyde has a profound influence on the enantioselectivity of the reaction, with 3,5-dichlorosalicylaldehyde giving a much high ee (50.3%) compared to the pristine salicylaldehyde (9.4%). Lowering the reaction temperature to −10 °C significantly increases the stereoselectivity of the reaction, affording lansoprazole with an ee value of 94.6%. It is noteworthy that the remaining starting material is also observable by our method, which allows both the conversion and the enantioselectivity of the reaction to be simultaneously monitored. Furthermore, the chromatogram-like output is easily interpreted without the need for advanced spectroscopic knowledge. This appealing feature would promise the easy adoption of the 19F NMR sensing strategy in various enantioanalysis. The spectral deconvolution may further increase the accuracy of the ee evaluation when the 19F NMR signals are overlapped. A preliminary comparison revealed that the deviations between the ee values determined by the point-to-point integration and the spectral deconvolution method are between 0.5 and 1.7% (Figure S15 in Supporting Information).

Figure 4.

Figure 4

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Evaluation of the ee values of lansoprazole produced in asymmetric oxidation using probe 4-S. (a) 19F NMR spectrum of probe 4-S (1.0 mg) and lansoprazole (ca. 1.0 mg) in acetone-d6. (b–d) 19F NMR spectra of mixtures of probe 4-S (2.0 mg) and the crude products (ca. 2.0 mg) obtained under different conditions.

Conclusions

In summary, we have developed a new 19F-labeled probe for the enantioanalysis of chiral N-heterocyclic compounds. The open binding site of the probe allows the recognition of structurally bulky analytes that are previously difficult to detect. The probe design strategy of using a distal chirality center to promote unequal twisting of the probe upon binding with a pair of enantiomeric analytes is the key to chiral discrimination. The sensing system is amenable to the screening of conditions for asymmetric reactions, visualizing both the chiral product and the prochiral substrate simultaneously. We expect that the scope of described sensing scheme can be easily extended to a wide range of analytes, providing a powerful solution to rapid and unambiguous chiral analysis.

Methods

General Procedure for the Synthesis of Pincer Ligands

A solution of 6-trifluoromethyl-2-pyridinecarboxylic acid (500 mg, 2.62 mmol) in CH2Cl2 (5 mL) was added to a solution of (R)-1-phenethylamine (380 mg, 3.14 mmol), 4-dimethylaminopyridine (16 mg, 0.13 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (598 mg, 3.14 mmol) in CH2Cl2 (30 mL). The reaction mixture was stirred at room temperature overnight before being quenched with water. The mixture was then extracted with EtOAc, and the organic layer was separated and washed with brine. The solution was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography (AcOEt/hexane = 1:4) to give ligand 3-R.

Procedure for the Preparation of 19F-Labeled Probes

Ligand 3-R (200 mg, 0.68 mmol, 1.0 equiv) was added to a solution of Pd(OAc)2 (167 mg, 0.75 mmol, 1.10 equiv) in acetonitrile (10 mL). The mixture was stirred at 80 °C for 12 h before cooling to room temperature. The solution was filtered through a 0.22 μm syringe filter. The filtrate was concentrated to give the crude product, which was transferred to a filter funnel and washed with water and hexane. After drying under vacuum, probe 4-R was obtained as a yellow powder.

NMR Measurements

Certain amounts of analytes were dissolved in CDCl3 to obtain solutions of analytes with the required concentrations (40–100 mM). A stock solution of probe 4-R (6.8 mM, 6.0 mg in 2.0 mL of CDCl3) was also prepared. Then, 300 μL of the probe solution (containing 0.9 mg of probe) and 100 μL of the analyte solution (containing 0.5–2 mg of analyte) were mixed and transferred into an NMR tube for 19F NMR measurements. For Figures 1a–j,l–ac, 2e, and 3a–h, 19F NMR spectra were recorded on a Bruker Avance-II 400 NMR spectrometer (376 MHz for 19F nucleus) with a BBO probe at 298 K, using a default relaxation delay (D1) of 1 s and a scan number of 32. For Figures 1k, 2a–c, and 4a–d, 19F NMR spectra were recorded on a Bruker Avance neo 600 NMR spectrometer (565 MHz for 19F nucleus) with a BBFO probe at 298 K, using a default relaxation delay (D1) of 1 s and a scan number of 32.

Acknowledgments

This work was supported by the National Key Research and Development Program (2021YFF0701700), the National Natural Science Foundation of China (Nos. 91956120, 21871291), and the Shanghai Science and Technology Committee (21142201400).

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacsau.2c00661.

  • General information about materials and instruments, synthetic procedures, characterization data of products, procedures for NMR experiments, NMR spectra, DFT calculations, and HPLC traces (PDF)

The authors declare the following competing financial interest(s): A patent has been filed on the described technique.

Supplementary Material

au2c00661_si_001.pdf (4.9MB, pdf)

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