Synthesis of novel chiral fluorescent sensors and their application in enantioselective discrimination of chiral carboxylic acids

Article abstract of DOI:10.1177/1747519819867619

Novel chiral fluorescent sensors are synthesized from a dibromide containing a tetraphenylethylene moiety and enantiomerically pure amino alcohols and an amine. The sensors are applied for the chiral recognition of a wide range of chiral carboxylic acids and related derivatives.

Full text of DOI:10.1177/1747519819867619

867619CHL0010.1177/1747519819867619Journal of Chemical ResearchY
u
et al.
review-article2019
Research Paper
Journal of Chemical Research
1–7
© The Author(s) 2019
Article reuse guidelines:
sagepub.com/journals-permissions
Synthesis of novel chiral fluorescent sensors
and their application in enantioselective
discrimination of chiral carboxylic acids
https://doi.org/10.1177/1747519819867619
DOI: 10.1177/1747519819867619
journals.sagepub.com/home/chl
Qiuhan Yu1, Weiwen Lu1, Zhiqiang Ding1,
Min Wei2 and Zhenya Dai1
Abstract
Novel chiral fluorescent sensors are synthesized from a dibromide containing a tetraphenylethylene moiety and
enantiomerically pure amino alcohols and an amine. The sensors are applied for the chiral recognition of a wide range of
chiral carboxylic acids and related derivatives.
Keywords
aggregation-induced emission, carboxylic acids, chiral recognition, chiral sensors, fluorescent
Date received: 17 February 2019; accepted: 10 July 2019
The synthesis of several novel aggregation-induced emission sensors and their application in chiral recognition are
reported. The results suggest that sensors R-6 and S-6 are capable of recognizing various chiral carboxylic acids and
their derivatives at a low concentration.
Introduction
1Department of Medicinal Chemistry, School of Pharmacy, China
Chiral recognition is an important process in the natural
Pharmaceutical University, Nanjing, P.R. China
2Institute of Botany, Jiangsu Province and Chinese Academy of Sciences,
Nanjing, P.R. China
world and plays a vital role in asymmetric synthesis, chiral
drug discovery, catalyst screening, and many other aspects.1–6
However, conventional enantiomeric analyses not only usu-
ally need expensive instruments or complex chiral reagents,
but they are also time-consuming in practice. Therefore, it
Corresponding authors:
Min Wei, Institute of Botany, Jiangsu Province and Chinese Academy of
Sciences, Nanjing 210000, Jiangsu, P.R. China.
is still important to develop simple, highly efficient, and Email: wm96403@sina.com
low-cost methods for chiral recognition, such as chiral flu-
orescent sensors for the enantioselective discrimination of
enantiomers.
Zhenya Dai, Department of Medicinal Chemistry, School of Pharmacy,
China Pharmaceutical University, Nanjing 210024, Jiangsu, P.R. China.
Email: daizhenya@hotmail.com

2
Journal of Chemical Research 00(0)
Scheme 1. Synthesis of sensors.
In 2001, Tang and co-workers observed an uncommon are widely used as excellent fluorophores due to their facile
and unconventional phenomenon in which some compounds synthesis and easy modification. We combined a known
with unique structures are almost non-fluorescent when dis- TPE derivative with two nitrogen-containing chiral auxilia-
solved in an organic solvent, but which become highly ries in order to provide novel chiral sensors. Treatment of
emissive in the aggregate state, a process known as aggrega- TPE derivative 3,14,16,32–34 and optically pure compounds 4
tion-induced emission (AIE) or aggregation-induced emis- and 5 resulted in the formation of chiral sensors 6 and 7
sion enhancement (AIEE).7 It is promising that AIE (Scheme 1).26 Details of the synthesis and characterization
compounds not only solve the aggregation-induced quench- are provided in the “Experimental” section.
ing (ACQ) problem without causing any adverse effects,8,9
but are also stable and highly selective fluorescent sensors
for proteins,10,11 DNA,12 sugars,13 metal ions,14,15 biological
Photophysical studies
anions,16 cyanide detection,17 drug carriers,18 cell imaging,19,20 These chiral products were soluble in most organic solvents
and explosive detection.21,22 According to recent research such as chloroform, tetrahydrofuran (THF), dimethyl sul-
achievements related to chiral recognition, the conclusion is foxide (DMSO), and 1,2-dichloroethane, but were insoluble
that there is a simple and effective method to obtain excel- in petroleum ether and water. As expected, after S-6 was
lent chiral sensors via the combination of one molecule hav- dissolved in THF, the solution (1.0×10−5 M) was not fluo-
ing AIE character with another molecule having a chiral rescent. When an 80% fraction of water (volume ratio of
center.23–28 Unfortunately, for chiral carboxylic acids, very water vs THF) was added to the solution, the fluorescence
few sensors have been reported, and they are required to be intensity of S-6 started to increase. Next, when a 90% frac-
tested at a large concentration.4,24,26
tion of water was added and turbidity emerged, the solution
Herein, in continuation of our work on enantioselective started to emit fluorescent light. A suspension appeared
discrimination,29–31 several new chiral sensors were de- when a 99% fraction of water was added, and the fluores-
signed, synthesized, and fully characterized. Their fluorescent cence intensity of the suspension increased 28.6-fold at
response behaviors to various chiral substrates were analyzed
λmax =469nm (Figure 1). Therefore, sensor S-6 was an AIE
by fluorescence spectroscopic methods. In addition, morphol- compound. With the same method, compounds R-6 and R-7
ogy studies for sensors were analyzed with various micro- in a mixed solvent were also tested and were found to be
scopic techniques, including transmission electron microscopy AIE compounds as well (Supplemental Figure S3).
(TEM) and fluorescent inverted microscope analysis.
Studies of chiral recognition
Results and discussion
The chiral recognition properties of S-6 were initially tested
with the interaction of S-6 and several different substrates
with the concentration ratio between sensor S-6 and the chiral
Synthesis of the sensors
Phenylglycinol and α-methylbenzylamine are cheap and substrate being kept as 1:1 in all tests. As shown in Table 1
common quenchers that reduce the fluorescence intensity of and Supplemental Figure S4, it was clear that S-6 was capable
fluorophores.1 Tetraphenylethylene (TPE) and its derivatives of recognizing chiral acids and related derivatives.

Yu et al.
3
Figure 1. (a) Fluorescence emission spectra of S-6 (1.0×10−5 M) in THF–water mixtures with different water fractions (fw) at
a fixed concentration (conditions: λex =320nm, ex/em slits=10/10nm). (b) Curve of fluorescence intensity for S-6 versus the
compositions of the aqueous mixtures (λmax =469nm). Inset: photographs taken under UV illumination (365nm).
Table 1. Fluorescence intensity ratios of mixtures of enantiomers of analytes with S-6, R-6, and R-7.
Entry
Analyte
S-6
R-6
R-7
I1/I2a,b
I1/I2a,b
I1/I2a,b
1
5.68 (L/D)
6.01 (D/L)
1.34 (L/D)
2
2.36 (L/D)
2.71 (D/L)
1.04 (L/D)
3
4
2.83 (L/D)
2.63 (S/R)
2.49 (D/L)
2.16 (R/S)
2.14 (L/D)
1.01 (S/R)
5
6
2.79 (S/R)
2.12 (R/S)
2.41 (R/S)
1.78 (S/R)
1.12 (S/R)
1.04 (R/S)
aEnantiomer 1/enantiomer 2.
bVolume ratio of solvents, [sensor]=[analyte].

4
Journal of Chemical Research 00(0)
Figure 2. (a) Fluorescence spectra of a mixture of compound 8 and sensor S-6 in solvent (2×10−4 M in 1,2-dichloroethane).
(b) Fluorescence spectra of a mixture of compound 8 and sensor R-7 in solvent (2×10−4 M in 1,2-dichloroethane). The ratio of
chiral guests/chiral sensor is 1:1; conditions: λex =320nm, ex/em slits=10/10nm.
When S-6 and L-8 were mixed and the mixture left to intensity with different contents of L-8 in the two enanti-
stand for 1h at room temperature, a suspension appeared. omers of 8 was measured. As shown in Figure 4, two stand-
ard curves were drawn, and any enantiomeric composition
of 8 could be obtained. Besides, the mixture of compound
8 (65%e.e. for L-8) with S-6 or R-6 was also tested, and the
fluorescence ratio of R-6 and S-6 to compound 8 (65%e.e.
for L-8) was IS-6/IR-6 =3.11. Under the same conditions,
when compound 8 (65%e.e. for D-8) was added, the fluo-
rescence ratio of R-6 and S-6 to compound 8 (65%e.e. for
D-8) was IR-6/IS-6 =3.18. The results were similar to those
listed in Figure 4. These results provided a promising entry
to the high-throughput screening of chiral drugs and the
rapid construction of various chiral molecules.
The mixture of S-6 and L-8 had a fluorescence intensity of
742.4, while that of the mixture of S-6 and D-8 was only
130 at λmax = 456 nm, showing that the fluorescence ratio
of the two enantiomers was IL-8/ID-8 = 5.68 (Table 1 and
Figure 2(a)). Under the same conditions, a mixture of L-9
or D-9 with S-6 was also tested, and the fluorescence ratio
of these two enantiomers was IL-9/ID-9 =2.36 (Table 1 and
Supplemental Figure S4(a)). For simple structure and low-
molecular-weight chiral diacids such as malic acid (10), the
fluorescenceratioofthetwoenantiomerswasIL-10/ID-10 =2.83
(Table 1 and Supplemental Figure S4(b)). In addition, a
chiral monocarboxylic acid (12) and its esterification
product (11) were also tested. The fluorescence ratio was
2.63 (IR-11/IS-11) and 2.79 (IS-12/IR-12) for methyl mande-
late (11) and mandelic acid (12), respectively (Table 1 and
Supplemental Figure S4(c) and (d)). Furthermore, for
BINOL (13), S-6 also showed a good enantioselective abil-
ity, and the fluorescence ratio was 2.12 (IR-13/IS-13) (Table
1 and Supplemental Figure S4(e)).
The analytes in Table 1 were also tested with sensors R-6
and R-7 in different solvent systems. The interactions of the
enantiomers with R-6 were tested and gave opposite results
in comparison with S-6 under the same conditions (Table 1).
However, the test of enantioselectivity indicated that R-7
was not a useful enantioselective sensor (Table 1, Figure
2(b), and Supplemental Figure S5). Structurally, the biggest
difference between sensors 6 and R-7 is the reduction in the
number of hydrogen bonds. As there are no hydroxy groups
in R-7 compared with sensor 6, it would probably be more
Microscopic studies
To understand the morphology of aggregates in mixed sol-
vents, TEM images were examined and the formation of
aggregates of S-6 and S-6 with 8 was revealed (Figures 5
and 6). In comparison with a solution of S-6 in THF–water
mixture (water fraction was 10%), numerous spherical aggre-
gates could be observed when the water fraction was 95%. As
shown in Figure 6, the morphology of aggregates of S-6 with
L-8 was observed as spherical, but slightly different from that
in the mixture of S-6 and D–8. We speculate that the distinc-
tion in aggregation probably causes the differences in fluores-
cence intensity and mixture solubility at a macro level.
Experimental
Materials and measurements
difficult for the chiral guests to interact with the sensor R-7 All reagents and solvents were chemically pure (CP) or
due to the change in the chiral environment. analytical reagent (AR) grade and were used as received
In addition, the chiral response for racemic acids was without further purification. 1H NMR and 13C NMR spectra
also investigated. For example, when racemate 8 was were measured on a Bruker AV 500 spectrometer at 303K
added, the fluorescence ratio of R-6 and S-6 to the racemate from sample solutions in CDCl3. Mass spectra were meas-
was IR-6/IS-6 =1.03 (Figure 3). In order to ascertain whether ured on a Waters Q-TOF microspectrometer. Optical rota-
the fluorescence difference resulting from the enantiose- tions were measured at 25°C on an Anton Paar MCP 500
lective aggregation could be applied to determination of the polarimeter with a sodium lamp as the light source (589nm).
enantiomeric composition, the change of fluorescence Fluorescence emission spectra were collected on a Perkin

Yu et al.
5
Figure 3. Fluorescence spectra of mixtures in 1,2-dichloroethane (5×10−4 M). Mixtures: (a) compound 8 and sensors,
(b) compound 8 (65%e.e. for L-8) and sensors, and (c) compound 8 (65%e.e. for D-8) and sensors.
Synthesis of ((S)-2-((2-(4-(1-(4-
(2-(((R)-2-hydroxy-1-phenylethyl)amino)
ethoxy)phenyl)-2,2-diphenylvinyl)phenoxy)
ethyl)amino)-2-phenylethan-1-ol (S-6)
Compound 3 was synthesized according to the reported
procedure.14,16,32–34 To a flask was added 3(460mg,0.80mmol),
S-4 (440mg, 3.20mmol), K2CO3 (220mg, 1.60mmol),
and dry acetonitrile (20mL). The mixture was refluxed
overnight until 3 had disappeared (monitored by thin layer
chromatography (TLC), ethyl acetate/petroleum ether, 1:5).
The acetonitrile was removed by evaporation under reduced
pressure, and the residue was dissolved in dichloromethane
(DCM). The organic phase was washed with water twice,
dried over anhydrous Na2SO4, filtered, and evaporated to
dryness under reduced pressure. The crude residue was
purified by flash column chromatography (silica gel,
DCM/methanol, 50:1) to give S-6 as a light yellow solid
(282mg, 51%); m.p. 206−208°C; [α]20D +26.3 (c 1.1, DCM);
1H NMR (300 MHz, CDCl3): δ 7.36–7.34 (m, 10H),
7.12–7.10 (m, 6H), 7.05–7.03 (m, 4H), 6.94 (d, J=8.5Hz, 4H),
6.64 (d, J = 8.5 Hz, 4H), 3.99–3.98 (m, 4H), 3.85
(dd, J = 8.3, 4.2 Hz, 2H), 3.78–3.76 (m, 2H), 3.62–3.58
(m, 2H), 2.94–2.89 (m, 4H), 2.37 (s, 4H); 13C NMR
(75MHz, CDCl3): δ 159.9, 146.9, 143.1, 142.6, 141.9,
139.2, 135.2, 134.0, 131.3, 130.3, 129.8, 128.7, 116.2, 80.1,
Figure 4. Change in fluorescence intensity of S-6 or R-6 with
the enantiomeric content of compound 8 in 1,2-dichloroethane
([S-6]=[R-6]=[L-8]+[D-8]=5×10−4 M).
Elmer LS 55 Fluorescence Spectrometer. The fluorescence
spectra for the AIE effect were measured after preparation
and leaving the mixture to stand for 2h at 298K. To meas-
ure changes in the fluorescence intensity in the presence of
chiral guests, all mixtures of sensors S-6, R-6, and R-7 and
chiral guests 8–13 were left to stand for 2h at 298K before
measuring their fluorescence spectra.

6
Journal of Chemical Research 00(0)
Figure 5. TEM images of a suspension of S-6 in water/THF (9.5:0.5) ([S-6]=1.0×10−5 M). (a) Scale bar: 1.0nm and (b) scale bar:
200μm.
Figure 6. (a) TEM image of a suspension of S-6 and L-8 in 1,2-dichloroethane, scale bar: 500μm. (b) TEM image of a solution of
S-6 and D-8 in 1,2-dichloroethane, scale bar: 200μm ([S-6]=[L-8]=[D-8]=5.0×10−4 M).
79.6, 79.2, 70.0, 69.4, 67.2, 49.0; ESI-MS: m/z calcd for (20mL). The mixture was refluxed overnight until 3 disap-
C46H46N2O4: 690 [M]+; found: 691 [(M+v1)]+.
peared (monitored by TLC, ethyl acetate/petroleum ether,
1:5). After the acetonitrile had been removed by evapora-
tion under reduced pressure, the residue was dissolved in
DCM. The organic phase was washed with water twice,
dried over anhydrous Na2SO4, filtered, and evaporated to
dryness under reduced pressure. The crude residue was
purified by flash column chromatography (silica gel,
Synthesis of ((R)-2-((2-(4-(1-(4-
(2-(((S)-2-hydroxy-1-phenylethyl)amino)
ethoxy)phenyl)-2,2-diphenylvinyl)phenoxy)
ethyl)amino)-2-phenylethan-1-ol (R-6)
The method was the same as that described for S-6. Yellow DCM/methanol, 50:1) to give R-7 as a light yellow solid
solid, 272mg, 49%; m.p. 205−207°C; [α]20D –25.9 (c 1.0, (299mg,45%); m.p. 211–213°C; [α]20D +21.7 (c 1.0, DCM);
DCM); 1H NMR (300MHz, CDCl3): δ 7.35–7.33 (m, 10H), 1H NMR (300MHz, CDCl3): δ 7.37–7.36 (m, 8H), 7.29–7.28
7.13–7.10 (m, 6H), 7.05–7.03 (m, 4H), 6.97 (d, J=8.5Hz, (m, 2H), 7.12–7.10 (m, 6H), 7.05–7.03 (m, 4H), 6.93
4H), 6.67 (d, J = 8.5 Hz, 4H), 3.99–3.98 (m, 4H), 3.87 (d, J=8.5Hz, 4H), 6.64 (d, J=8.6Hz, 4H), 3.98 (m, 4H),
(dd, J = 8.2, 4.3 Hz, 2H), 3.78–3.73 (m, 2H), 3.62–3.59 3.92–3.86 (m, 2H), 2.88–2.83 (m, 4H), 2.66 (s, 2H), 1.42 (d,
(m, 2H), 2.92–2.87 (m, 4H), 2.39 (s, 4H); 13C NMR (75MHz, J=6.5, 6H); 13C NMR (75MHz, CDCl3): δ 159.9, 147.4,
CDCl3): δ 157.3, 144.2, 140.4, 139.9, 139.4, 136.6, 132.6, 146.9, 142.7, 141.9, 139.1, 135.1, 133.9, 132.3, 131.9, 131.1,
131.3, 128.7, 127.7, 127.2, 126.1, 113.6, 77.3, 77.0, 76.8, 130.7, 130.3, 129.7, 129.3, 128.7, 128.4, 117.2, 116.8, 116.2,
67.4, 66.8, 64.5, 46.4; ESI-MS: m/z calcd for C46H46N2O4: 80.1, 79.6, 79.2, 69.7, 60.9, 56.0, 49.2, 26.8; ESI-MS:
690 [M]+; found: 691 [(M+1)]+.
m/z calcd for C46H46N2O2: 658 [M]+; found: 659 [(M+1)]+.
Synthesis of 2-(4-(2,2-diphenyl-1-(4-
(2-(((R)-1-phenylethyl)amino)ethoxy)phenyl)
vinyl)phenoxy)-N-((S)-1-phenylethyl)
ethan-1-amine (R-7)
Conclusion
In summary, the combination of a TPE moiety and several
optically pure molecules has provided several excellent
novel chiral sensors. Sensors R-6 and S-6 were proven to be
To a flask was added 3 (460mg, 0.80mmol), R-5 (440mg, good chiral sensors for the chiral recognition of various car-
3.20mmol), K2CO3 (220mg, 1.60mmol), and dry acetonitrile boxylic acids and their derivatives. This work has provided

Yu et al.
7
11. Yu Y, Huang YY, Hu F, et al. Anal Chem 2016; 88: 6374.
12. Tong H, Hong Y, Dong YQ, et al. Chem Commun 2006; 35:
an efficient methodology to synthesize new chiral fluores-
cent sensors and is expected to be of great value in high-
throughput assays of chiral products.
3705.
13. Liu Y, Deng CM, Tang L, et al. J Am Chem Soc 2011; 133:
660.
Declaration of conflicting interests
14. Liu L, Zhang GX, Xiang JF, et al. Org Lett 2008; 10: 4581.
15. Feng HT, Song S, Chen YC, et al. J Mater Chem C 2014; 2:
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
2353.
16. Park C and Hong JI. Tetrahedron Lett 2010; 51: 1960.
Funding
17. Duan YL and Zheng YS. Talanta 2013; 107: 332.
18. Wang ZY, Wang C, Fang YY, et al. Polym Chem 2018; 9:
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article: We
were thankful to the National Natural Science Foundation of
China for financial support (no.: 21102180).
23.
19. Xu DZ, Zou H, Liu MY, et al. J Colloid Interf Sci 2017; 508:
248.
20. Chen SX, Qiu RM, Yu QH, et al. Tetrahedron Lett 2018; 59:
2671.
ORCID iD
21. Wang J, Mei J, Qin AJ, et al. Sci China Chem 2010; 53:
Zhenya Dai
https://orcid.org/0000-0003-4383-709X
2409.
22. Wang M, Zhang G, Zhang D, et al. J Mater Chem 2010; 20:
1858.
Supplemental material
23. Zheng YS and Hu YJ. J Org Chem 2009; 74: 5660.
24. Zheng YS and Hu YJ. Talanta 2010; 80: 1470.
Supplemental material for this article is available online.
25. Li DM and Zhen YS. Chem Commun 2011; 47: 10139.
26. Liu NN, Song S, Li DM, et al. Chem Commun 2012; 48:
References
1. Pu L. Chem Rev 2004; 35: 1687.
4908.
2. Zehnacker A and Suhm MA. Angew Chem Int Ed Engl 2008;
47: 6970.
27. Feng HT, Zhang X and Zheng YS. J Org Chem 2015; 80:
8096.
3. Zhang X, Yin J and Yoon JY. Chem Rev 2014; 114: 4918.
4. You L, Zha DJ and Anslyn EV. Chem Rev 2015; 115: 7840.
5. Zhang XX, Bradshaw JS and Izatt RM. Chem Rev 1997; 97:
3313.
28. Xiong JB, Xie WZ, Sun JP, et al. J Org Chem 2016; 81:
3720.
29. Zhang XY, Yu QH, Chen SX, et al. New J Chem 2018; 42:
4045.
6. Pirkle WH and Pochapsky TC. Chem Rev 1989; 20: 347.
7. Tang BZ, Xie ZL, Lam JWY, et al. Chem Commun 2001; 18:
1740.
8. Hong YN, Lam JWY and Tang BZ. Chem Commun 2009;
29: 4332.
9. HongYN,LamJWYandTangBZ.ChemSocRev2011;40:5361.
10. Tong H, Hong YN, Dong YQ, et al. J Phys Chem B 2007;
111: 11817.
30. Zhang XY, Chen SX, Xu P, et al. Tetrahedron Lett 2017; 58:
2850.
31. Zhang XY, Yu QH, Lu WW, et al. Tetrahedron Lett 2017;
58: 3924.
32. Hubbard SC and Jones PB. Tetrahedron 2005; 61: 7425.
33. Duan XF, Zeng J, Lu JW, et al. J Org Chem 2006; 71:
9873.
34. Lv W, Liu JZ, Skaar TC, et al. J Med Chem 2015; 58: 2623.