Molecular Recognition and Chirality Sensing of Epoxides in Water

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Molecular Recognition and Chirality Sensing of Epoxides in Water Using Endo-Functionalized Molecular Tubes Li-Li Wang,†,‡ Zhao Chen,† Wei-Er Liu,† Hua Ke,†,‡ Sheng-Hua Wang,† and Wei Jiang*,† †

Department of Chemistry, South University of Science and Technology of China, Xueyuan Boulevard 1088, Nanshan District, Shenzhen 518055, China ‡ School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China S Supporting Information *

Chiral epoxides, which can be converted into many functional groups, are important intermediates in chemistry14 and biology.15 The development of new synthetic methodologies for asymmetric epoxidation remains a hot topic.16 High-throughput screening will help the discovery of new asymmetric catalytic methods. However, only one optical chirality sensing method for epoxy alcohols has been reported,7c and no method for chiral epoxides without other functional groups has been published. Chiral epoxides have only one oxygen atom that can form hydrogen-bonding interactions or weak coordination. If they are not further derivatized, it will be difficult to recognize them and thus sense their absolute configurations and ee values. We reported a pair of endo-functionalized molecular tubes 1a and 1b (Figure 1a),17 which can selectively recognize highly hydrophilic molecules in water using hydrogen bonds and hydrophobic effects. We wondered if these aromatic receptors

ABSTRACT: Chiral epoxides are important intermediates in chemistry and biology. The high-throughput screening of asymmetric epoxidation conditions requires fast determination of the absolute configurations and ee values of chiral epoxides. Herein, we report molecular recognition and chiroptical sensing of epoxides in water using endo-functionalized molecular tubes. The absolute configurations and ee values were simultaneously determined by circular dichroism spectroscopy. In addition, real-time monitoring as well as the application to real asymmetric epoxidation was demonstrated. The method is simple, environmentally friendly, and amenable to highthroughput screening.

O

ptical chirality sensing1 harnesses optical signals of synthetic molecular sensors to achieve fast determination of absolute configuration and enantiomeric excess (ee) of the products of asymmetric reactions. This method is applicable to high-throughput screening, avoiding the high cost (solvent waste) and low duty cycle (ca. 20 min/sample) of common chiral chromatographic methods. Fluorescence,2 UV−vis,3 and circular dichroism (CD) spectroscopy4 are the most common optical techniques. CD spectroscopy is appealing because it is inherently sensitive to chirality and does not require molecular sensors to be chiral. It has been studied by Berova,5 Anslyn,6 Borhan,7 Canary,8 Wolf,9 Jiang,10 and others11 for the stereochemical analysis of chiral compounds. Typically, metal coordination, hydrogen bonding or dynamic covalent bonds are harnessed to bring substrates and sensors together and to achieve chirality transfer. This requires chiral substrates contain reactive functional groups, such as amines, aldehydes, ketones, carboxylic acids, and alcohols. Expanding the scope beyond these functional groups is difficult.4a Biedermann and Nau12 used cucurbit[8]uril-dye-analyte ternary complexes to circumvent this problem. However, the chiral analyte must contain an aromatic group to form a ternary complex, and the aromatic group must be in close proximity to the stereogenic centers to induce CD signals. This strategy is general in terms of functional groups but limited to aromatic compounds. It was anticipated other macrocyclic receptors can also be used for this purpose.12,4c However, rare successful cases were reported,13 presumably due to low efficiency of chirality transfer from analytes to receptors and difficulties in recognizing products of common asymmetric reactions. © 2017 American Chemical Society

Figure 1. (a) Structures of molecular tubes 1 and 2; (b) illustration of chiroptical sensing of epoxides in water using endo-functionalized molecular tubes; (c) structures of epoxides involved in this research. Received: May 19, 2017 Published: June 13, 2017 8436

DOI: 10.1021/jacs.7b05021 J. Am. Chem. Soc. 2017, 139, 8436−8439

Communication

Journal of the American Chemical Society

105 M−1, relatively high compared to other synthetic molecular recognition in water and considering the small size of the guests. Generally, the two tubes share similar binding affinities to the guests with 1b slightly in favor of 3−6 and 1a in favor of 7−12. This is presumably because 1a and 1b have different cavity sizes and arrangements. ITC results revealed both enthalpy and entropy contribute to the efficient binding, with the enthalpic contribution more prominent. This is particularly true for the aromatic epoxides, with an exception for the complex between ±10 and 1a. The large enthalpic contribution may come from two origins: nonclassic hydrophobic effects through releasing high-energy water molecules from the cavity18 and hydrogen bonding between the amide N−H protons of the host and the epoxy oxygen atom of the guest. The existence of hydrogen bonding was supported by the binding between 2 and ±11 in CDCl3 (Ka = 2.5 and 1.9 M−1 for 2a and 2b, respectively, Figures S50 and S51) and the single-crystal structure of ±11@2a (Figure 2). There was no

could recognize epoxides and sense their chirality in water (Figure 1b). Herein, we present epoxides that are well accommodated by these molecular tubes even with high binding affinities. Host−guest chemistry was used for the chirality sensing of epoxides. The absolute configurations and ee values were reliably determined, and real-time monitoring and application to screen reaction conditions were demonstrated as well. The cavities of molecular tubes 1a and 1b are hydrophobic with two hydrogen-bonding donors inside. According to our earlier study,17b we envisaged epoxides may also fit into these cavities because they contain hydrogen-bonding acceptor atoms and the rest of the molecules are hydrophobic. Indeed, all epoxides in Figure 1c were encapsulated by 1a and 1b (Figures S1−S20). Binding constants were determined by NMR titrations (Figures S21−S42), and the results are listed in Table 1. The hosts did not Table 1. Association Constants (Ka, M−1) of Molecular Tubes 1a and 1b with Various Epoxides in D2O at 25 °C As Determined by 1H NMR Titrationa

a

±4

5

6

476 524

543 621

155 283

148 292

7

8

9

±10

±11

316 304 ±12

197 135

63 58

3.53 × 104 5.70 × 103

5.25 × 104 2.44 × 104

1.47 × 105 8.97 × 104

1a 1b 1a 1b

±3

Error = ±10%. Figure 2. X-ray single-crystal structure of ±11@2a.

show obvious fluorescence responses to the epoxides with alkyl substituents but did show fluorescence responses to the aromatic epoxides. Therefore, the binding constants for the aromatic epoxides were confirmed by fluorescence titration (Figures S43− S46). The larger binding constants were also confirmed by isothermal titration calorimetry (ITC) experiments (Figures S47−S49). The binding parameters from the fluorescence and ITC titrations are listed in Table 2.

hydrophobic effect in CDCl3, where the binding should solely originate from hydrogen bonding. In the crystal structure of ±11@2a, a short hydrogen bond (2.097 Å) between the NH group and the epoxy oxygen atom was detected. Nevertheless, the addition of 1 equiv ±4 to a solution of 1a in H2O:D2O = 9:1 caused an upfield shift of the NH protons (Figure S52). This may be caused by only one hydrogen bond forming during the complex formation but destroying multiple hydrogen bonds between the NH protons and the encapsulated water molecules in the free host. Overall, the binding should be driven by hydrophobic effects with an additional contribution from hydrogen bonding. The chiral epoxides with alkyl/phenyl groups do not have electronic absorption in the >200 nm region, whereas molecular tubes, which are achiral, possess electronic absorption at long wavelengths (Figures 3a and S53). When the complexes were formed between the chiral epoxides and molecular tubes, the chirality of epoxides could be transferred to the molecular tubes and thus induce CD signals. Four pairs of chiral epoxide enantiomers (±3, ±4, ±11, and ±12) were selected for chiroptical sensing, and molecular tube 1a was used as the sensor. Two pairs of chiral epoxides with only aliphatic groups were used to test if our system could be applied beyond aromatic analytes.12 As shown in Figure 3b, the CD signals were indeed induced. Efficient recognition does not guarantee effective chirality transfer. Intimate electronic contact of the receptor chromophores with the stereocenter(s) of the substrates was required. The stereogenic center is located at the epoxy group, and thus hydrogen bonding between the epoxy oxygen and amide proton of 1a should be responsible for efficient chirality sensing. Aromatic epoxides generally induce stronger CD signals than aliphatic ones, suggesting more intimate contacts and thus better

Table 2. Association Constants (Ka, M−1) of Molecular Tubes 1a and 1b with Epoxides ±10, ±11, and ±12 in H2O at 25 °C As Determined by Fluorescence (FL) Titrations and ITC Titrationsa FL

±10 ±11 ±12

1a 1b 1a 1b 1a 1b

ITC

Ka, M−1

Ka, M−1

ΔGo, kJ/mol

−b −b 4.32 × 104 1.19 × 104 1.95 × 105 1.78 × 105

2.05 × 104 5.77 × 103 4.07 × 104 1.28 × 104 1.59 × 105 1.00 × 105

−24.6 −21.4 −26.3 −23.4 −29.7 −28.6

ΔHo, kJ/mol

−TΔSo, kJ/mol

−10.6 −13.0 −23.6 −22.0 −23.8 −23.2

−14.0 −8.4 −2.7 −1.4 −5.9 −5.4

Error = ±10%. bThe fluorescence response is too weak to determine reliably the association constants. a

1,2-Propylene oxide ±3 possessed decent binding constants considering its small size. 1,2-Butylene oxide ±4 with one additional methylene group possessed stronger binding constants. However, other epoxides (5−9) with two methyl groups, a cyclohexyl group or a cyclopentyl group, showed weaker binding than ±3. This may be due to the poor size agreement with the host cavities. In general, epoxides with larger hydrophobic groups, such as linear alkyl chains or aromatic groups, bind more strongly to molecular tubes. The largest binding constant reached 8437

DOI: 10.1021/jacs.7b05021 J. Am. Chem. Soc. 2017, 139, 8436−8439

Communication

Journal of the American Chemical Society

Table 3. Determination of the Absolute Configuration (ac) and ee Values of the Products of the Asymmetric Epoxidation of Styrene by Chiral GC and Chiroptical Sensing Methodsa

Figure 3. (a) UV−vis spectra of 1a in H2O (0.1 mM); (b) CD spectra of 1a (0.1 mM, H2O) in presence of chiral epoxides with saturated concentrations; (c) CD effects observed with 1a (0.1 mM) and nonracemic ±11 (1.0 mM); (d) calibration curves of the CD signal at 255 nm with varying ee values for the four pairs of epoxides.

entry

literature ee (%)/ac

chiral GC ee (%)/acb

optical sensing ee (%)/ac

absolute error (%)c

119a 219a 319b 420a 520b

46.0/R 59.0/R 46.0/R 24.3/R 38.0/R

45.6/R 52.8/R 40.9/R 20.7/R 35.0/R

48.4/R 56.2/R 42.2/R 21.9/R 35.8/R

+2.8 +3.4 +1.3 +1.2 +0.8

a

Catalyst I was used for entries 1−3, and catalyst II was used for entries 4 and 5. Detailed reaction conditions are available (Table S5). Assignments of the absolute configurations by chiral GC were made by comparing the retention time with that of the pure enantiomers. c Errors were calculated by comparing the ee values from chiroptical sensing with those from chiral GC (Figure S62). b

chirality transfer for aromatic epoxides. Moreover, all the enantiomers with an R configuration showed positive Cotton effects at 255 nm, whereas the S configurations provided negative Cotton effects. This can be used to determine the absolute configuration. When 1b was used as the sensor, the epoxides with alkyl groups showed different CD spectra, and even opposite Cotton effects at certain wavelengths, when compared to the aromatic epoxides (Figure S54). This may be used to distinguish alkyl epoxides from aromatic ones. Figure 3b shows CD signals induced by the R and S enantiomers are symmetric. The saturation concentrations of the guests for the CD signal at 255 nm (Figures S55−S58) were used to ensure concentration-independent spectral responses. Calibration lines with great linearity (R2 > 0.996) were obtained by plotting the CD signals at 255 nm against the ee values (Figures 3c,d and S59−S61). The absolute errors for all the four pairs of epoxides were less than ±2% (Tables S1−S4), sufficient for the preliminary screening of reaction conditions or catalysts.6g This method was applied to the asymmetric epoxidation of styrene using Jacobsen’s19 or Shi’s20 catalyst. The same conditions as reported in the literature were used. To be certain, the ee values and absolute configurations of the products were checked by chiral gas chromatography (GC, Figure S62). Chiroptical sensing was performed, and the ee values and absolute configurations were determined from the calibration line (Table 3). In general, our chiroptical method gave correct configurations and quite reliable ee values. Noncovalent interactions usually occur faster than metal coordination and dynamic covalent bonds. The complexation between R-11 and 1a completed within 30 ms, indicated by a stopped-flow experiment monitoring the CD signal (Figure 4a). The fast complexation kinetics permitted the real-time monitoring of the production or consumption of chiral epoxides in water. R-11 reacts with ammonia in water to produce (R)-2amino-1-phenylethanol as the major product.21 The latter bound strongly to 1a but induced a much weaker CD signal under the same conditions than R-11 (Ka = 6.8 × 104 M−1, Figures S63− S65). Therefore, this reaction was used to demonstrate real-time monitoring. As shown in Figure 4b, the solution only contained 1a at the beginning. Thus, no CD signal was detected. Upon addition of R-11 to this solution, the CD signal immediately appeared because the CD-active complex was formed. Afterward,

Figure 4. (a) CD signal (255 nm) of 1a (0.2 mM, H2O) monitored by stopped-flow spectrometer when mixing with one equiv R-11; (b) CD signal (255 nm) of 1a (0.1 mM, 2.0 mL, H2O) when R-11 was added (20 mM, 30 μL) and followed by NH3·H2O (15 M, 133 μL).

the addition of 1.0 M ammonia induced a decrease of the CD signal, which was due to the concentration change. With increasing time, the CD signal decreased, indicating the consumption of R-11. This showcased the present method is amenable to real-time monitoring. In summary, we reported molecular recognition and chirality sensing of epoxides in water using endo-functionalized molecular tubes. The binding is strong and driven mainly by hydrophobic effects. However, hydrogen bonding likely also contributes to binding and assists the efficient chirality transfer. Thus, the first chiroptical sensing of chiral epoxides (either aliphatic or aromatic) was achieved using CD spectroscopy. The chirality sensing system has several advantages: (a) absolute configuration and ee can be determined simultaneously; (b) the equilibrium time is rather short (30 ms), permitting the real-time monitoring of the production or consumption of chiral epoxides; (c) water is used as solvent; (d) the molecular tubes are recyclable (Figures S66 and S67); (e) the method was applied to real asymmetric reactions; (f) monitoring of the CD signals occurred at a single wavelength (255 nm) for all epoxides, allowing for manufacturing of miniaturized equipment; (g) the method is amenable to highthroughput screening of asymmetric epoxidation. We believe research along this line will expand the analyte scope of chiroptical sensing. 8438

DOI: 10.1021/jacs.7b05021 J. Am. Chem. Soc. 2017, 139, 8436−8439

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.7b05021. Experimental details (PDF) Data for C66H66N2O10, C8H8O (CIF)

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AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Wei Jiang: 0000-0001-7683-5811 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was financially supported by the National Natural Science Foundation of China (No. 21572097) and Thousand Young Talents Program. We thank Prof. Peng-Fei Li (SUSTC) for the help on chiral GC.

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DOI: 10.1021/jacs.7b05021 J. Am. Chem. Soc. 2017, 139, 8436−8439