Xuebo Zhangab,
Jing Xuab,
Zhaofeng Sunb,
Guangling Bian*b and
Ling Song
*b
aCollege of Chemistry and Materials Science, Fujian Normal University, Fuzhou, China
bThe Key Laboratory of Coal to Ethylene Glycol and Its Related Technology, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian, China. E-mail: glb@fjirsm.ac.cn; songling@fjirsm.ac.cn
First published on 8th February 2022
A new boric agent with bridged structure, boric acid D, was first synthesized and used as an excellent chiral derivative agent for highly efficient enantiodiscrimination of various diols. The derivatization reaction is fast and complete, easy to operate and has high accuracy in measurement of ee values. The characteristic split NMR signals are well-distinguishable with a large chemical shift nonequivalence (up to 0.39 ppm).
Chiral diols are very important chiral inducers and organic synthons.13 So far, only a few NMR methods,14 including chiral solvating agents (CSAs)15–18 and chiral derivatizing agents (CDAs),19,20 have been reported for the chiral recognition of diols, but the obtained chemical shift nonequivalent (ΔΔδ) values are small in general. Among, chiral boric acids are potential excellent chiral recognition agents for diols, because diols are very easy to be derivatized by boric acids to generate stable cyclic ester compounds, resulting in a relatively large ΔΔδ values.21 In 1988, Snyder et al. developed camphanylboronic acid as a simple, effective CDA for the optical purity determination of 1,2-diols by 13C NMR spectroscopy.22 In 2003, Prati Fabio et al. developed (S)-(+)-N-acetylphenylglycineboronic acid as a CDA for enantiomeric excess (ee) determination of 1,2-diols by 1H NMR (Fig. 1, boric acid A). The derivatized cyclic boric acid ester shows high diastereomeric proton NMR signal.20 In 2006, Tony D. James group reported a three-component recognition system for measuring excess enantiomers of chiral diols (Fig. 1, boric acid B).23 Chiral diols were mixed with 2-formylphenylboronic acid and alpha-methylbenzylamine to form phenylborate ester imines, and then the split signals of the imines were observed for determination of ee of diols. In 2009, they developed another three-component chiral derivatization scheme to accurately determine ee of chiral diols by 19F NMR spectroscopy (Fig. 1, boric acid C).24 1,2-Diphenylethylenediamine is a very important chiral skeleton. In the past, we have developed several agents based on 1,2-diphenylethylenediamine to recognize chiral carboxylic acids, amino acids, amines, alcohols and other compounds with great success.25–28 Based on our experience and inspired by the above chiral boric acid agents, herein, a new boric acid derived from chiral 1,2-diphenylethylenediamine was developed for measuring ee of chiral diols (Fig. 1, boric acid D). This boric acid is simple in synthesis and highly effective and practical for enantiodiscrimination of 1,2- and 1,3-diols.
With boric acid D in hand, we tested its capability as an NMR derivatization agent for chiral discrimination of diols. We first dissolved 10 mmol racemic hydrobenzoin (1) and 30 mmol of boric acid D in 0.6 mL of CDCl3 in an NMR tube. The mixture was mixed for 15 min at 25 °C by ultrasound and then 1H NMR data were collected on a Bruker Avance 400 MHz spectrometer (Fig. 3A). To our delight, the HA signals of boric acid D in the formed two diastereomeric derivatives had a very clear baseline separation with a large ΔΔδ value (0.39 ppm) (Fig. 3B). Moreover, the signal of HA is in the middle of the field, and it is hardly overlapped with other signals and easy to be distinguished, so it is a very practical characteristic peak for chiral analysis. Another, the development of CDAs requires that CDA should be stable enough, and the substrate and derivative cannot be racemized during the derivatization process. To verify whether boric acid D is suitable as a CDA for the determination of the diol's ee, the following experiment was carried out: the reaction of optically pure (R,R)-1 and boric acid D at room temperature in a ratio of 1:
3 was continuously monitored by 1H NMR for 12 hours. It was found that the derivatization was completed within 15 min (the benzyl hydrogen or hydroxyl hydrogen NMR signal of free (R,R)-1 disappeared) and no racemization was observed during the whole process (Fig. S5, ESI†). Therefore, boric acid D can be used as a CDA. Subsequently, we explored the effects of other factors on the chiral discrimination ability of boric acid D (Table 1). Decreasing the molar ratio of boric acid D/1 slowed down the reaction (Table 1, entries 1–3). While the molar ratio was 1
:
1, diol 1 could not react completely. When the reaction temperature was increased to 35 °C, the reaction time was slightly shortened to 12 min. However, lowering the reaction temperature, the reaction rate decreased dramatically, and the reaction time increased to 30 min when the reaction temperature dropped to 0 °C (Table 1, entries 1, 4 and 5). In addition, the reaction solvent was optimized. CD3CN and toluene-d8 showed poor solubility for boric acid D. Although DMSO had good solubility for boric acid D, but the derivatization reaction could not proceed. Compared with them, CDCl3 is the most suitable solvent (Table 1, entries 1 and 6–8). Therefore, in order to complete the derivatization reaction quickly and conveniently, the following best derivatization conditions were adopted: 3
:
1 molar ratio of boric acid D/substrates, CDCl3 as solvent, reaction at 25 °C.
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Fig. 3 (A) The structures of rac-1,2-diphenylethane-1,2-diols (1) and boric acid D/rac-1. (B) 1H NMR spectra of 1, boric acid D, boric acid D/R-1, boric acid D/S-1 and boric acid D/rac-1 in CDCl3. |
Entry | Solvent | Molar ratio (boric acid D/1) | T (°C) | t b(min) |
---|---|---|---|---|
a Boric acid D and 1 (10 mM) were mixed in the specified solvent (0.6 mL) and 1H NMR data were collected on a Bruker Advance 400 MHz spectrometer.b Time from the beginning of the reaction to the disappearance of the benzyl hydrogen or hydroxyl hydrogen NMR signal of free 1.c Diol 1 cannot react completely after 12 hours. | ||||
1 | CDCl3 | 3/1 | 25 | 15 |
2 | CDCl3 | 2/1 | 25 | 25 |
3 | CDCl3 | 1/1 | 25 | —c |
4 | CDCl3 | 3/1 | 35 | 12 |
5 | CDCl3 | 3/1 | 0 | 30 |
6 | CD3CN | 3/1 | 25 | — |
7 | Toluene-d8 | 3/1 | 25 | — |
8 | DMSO | 3/1 | 25 | — |
In order to study the scope and limitations of boric acid D, we investigated the derivatization reactions of 12 racemic chiral diols with different structural types including alkyl, aryl, large sterically hindered and cyclic alkanes (Table 2). All the substrates were measured under the optimal conditions, and clear baseline separations were obtained (ΔΔδ = 0.06–0.39 ppm). In entries 1–5 and 7–8, the configurations were determined by comparing with spectra of nonracemic samples of known configurations. The other five diols have no chiral samples for comparison, so the corresponding configuration was not determined. Diol 6 exists in the form of three stereoisomers, including a pair of chiral enantiomers and meso isomers. They could be well separated after derivatization with boric acid D (entry 6, the peak of 6.6 ppm represents meso isomers). The results showed that diols containing large hindered groups or aromatic groups could produce the larger ΔΔδ values. Derivatives of diols containing primary alcohols had relatively small ΔΔδ values, and ΔΔδ values of 1,3-diol derivatives were smaller than those of 1,2-diol derivatives. The proposed reason is that the substrates with large steric hindrance and aromatic groups generate more rigidity difference between the epimers (a pair of derivatives), which makes the chemical environments of HA more different resulting in larger ΔΔδ values of HA.
Entry | Chiral diols | Spectrab | ΔΔδc (ppm) |
---|---|---|---|
a All samples were prepared by mixing boric acid D and chiral diols in NMR tubes (10 mM of the chiral diols and 30 mM of boric acid D in 0.6 mL of CDCl3). 1H NMR were collected on a Bruker Avance 400 MHz. Spectrometer at 25 °C.b The configurations were determined by comparing with spectra of nonracemic sample of known configurations; the red and blue lines represent the S and R enantiomers of analytes, respectively (entry 1 red is (S,S) and blue is (R,R), entry 8 red is (−) and blue is (+)).c ΔΔδ values of the proton HA of the derivatives. | |||
1 | ![]() |
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0.39 |
2 | ![]() |
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0.18 |
3 | ![]() |
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0.10 |
4 | ![]() |
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0.11 |
5 | ![]() |
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0.11 |
6 | ![]() |
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0.23 |
7 | ![]() |
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0.27 |
8 | ![]() |
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0.18 |
9 | ![]() |
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0.11 |
10 | ![]() |
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0.17 |
11 | ![]() |
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0.08 |
12 | ![]() |
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0.06 |
In order to further prove the practicality of boric acid D as a CDA for determination of ee, the substrate 1 with different ee values was determined by integration of HA signal of derivative. Fig. 4 shows that boric acid D maintains analytic resolution of 1 over a wide range of ee values. The linear relationship between gravimetry determined values and those NMR-determined values is good with R2 = 0.9999. The absolute errors are within 2% in the ee measurements between NMR integrations and the gravity calibration.
Footnote |
† Electronic supplementary information (ESI) available. CCDC 2061749. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d2ra00428c |
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