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Highly enantioselective fluorescent recognition of mandelic acid derivatives by chiral salen macrocycles
Tetrahedron: Asymmetry 23 (2012) 205–208
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy
Highly enantioselective fluorescent recognition of mandelic acid derivatives by chiral salen macrocycles Koichi Tanaka ⇑, Takeshi Tsuchitani, Noriaki Fukuda, Asuka Masumoto, Ryuichi Arakawa Department of Chemistry and Materials Engineering, Faculty of Chemistry, Materials and Bioengineering, Kansai University, Suita, Osaka 564-8680, Japan
a r t i c l e
i n f o
Article history: Received 9 December 2011 Accepted 31 January 2012 Available online 9 March 2012
a b s t r a c t Calixarene-like chiral salen macrocycles can be used for the enantioselective fluorescent recognition of mandelic acid derivatives. It was observed that one enantiomer of mandelic acid causes a 28-fold increase in the fluorescence intensity of a chiral salen macrocycle, whereas the other enantiomer causes only a 14fold fluorescence enhancement. This highly enantioselective fluorescent response makes chiral salen macrocycles useful for the enantioselective fluorescent recognition of some mandelic acid derivatives. Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction Fluorescence-based enantioselective sensors have attracted considerable attention because of their potential applications in the real-time analysis of chiral organic compounds.1 Rapid determination of enantiomeric composition is useful for the highthroughput combinatorial analysis of chiral molecules in catalytic reactions. 1,10 -Bi-2-naphthol (BINOL) derivatives have been widely used as enantioselective fluorescent sensors for chiral organic compounds.2 For example, BINOL–amine molecules can be used for the highly enantioselective fluorescent recognition of a-hydroxy-carboxylic acids.2h Recently, we have reported that the calixarene-like chiral salen macrocycle (S,S,S,S,S,S)-2 acts as a chiral-shift reagent for the determination of enantiomeric excess and the absolute configuration of several types of carboxylic acid derivatives by 1H NMR spectroscopy.3 We also tested the ability of (S,S,S,S,S,S)-2 toward the enantioselective fluorescent recognition of mandelic acid; however, compound 2 did not work as a fluorescent sensor. The secondary nitrogen atoms adjacent to the phenol rings of the chiral salen macrocycle (S,S,S,S,S,S)-1 may interact with the acids and can turn on the fluorescence of the phenol by inhibiting fluorescence quenching of the photoinduced-electron-transfer (PET) of the nitrogen lone pair electrons.1f Since the interaction of (S,S,S,S,S,S)1 with the two enantiomers of mandelic acid should generate diastereomers, enantioselective fluorescence enhancements may occur. Considering this, we attempted to explore the ability of (S,S,S,S,S,S)-1 toward the enantioselective fluorescent recognition of several a-hydroxy-carboxylic acids. Herein, we report the synthesis of several types of calixarene-like chiral salen macrocycles
⇑ Corresponding author. E-mail addresses: [email protected], [email protected] (K. Tanaka). 0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2012.01.024
(S,S,S,S,S,S)-1 and their application in the enantioselective fluorescent recognition of mandelic acid derivatives. R
N
R
N
OH
N
N HO
OH
R
N
N
R
NH a: R = H b: R = Me c: R = i-Pr d: R = t-Bu e: R = OMe f: R = Br
OH
HO
OH
R
H N
H N
R
(S,S,S,S,S,S)-2
H R
HN
NH
(S,S,S,S,S,S)-1 H CO2H
HN
OH
a: R = H b: R = o-Cl c: R = p-Cl
3
H CO2H
OMe 4
Me
CO2H Cl 5
2. Results and discussion Chiral salen macrocycles (S,S,S,S,S,S)-1 were prepared by the [3+3] condensation reaction of 4-substituted 2,6-diformyl phenols and trans-(1S,2S)-cyclohexanediamine in MeOH according to a previously reported method.3,4 In the UV–vis spectrum, (S,S,S,S,S,S)-1d in chloroform displays absorptions at 244, 350, and 457 nm. It emits at 527 nm on excitation at 460 nm. First, we studied the interaction of (S,S,S,S,S,S)-1d with (R)- and (S)-mandelic acid 3a. Figure 1 shows the fluorescence spectra of (S,S,S,S,S,S)-1d in the presence of (R)- and (S)-3a. As shown in the spectra, when
206
K. Tanaka et al. / Tetrahedron: Asymmetry 23 (2012) 205–208 Table 1 Results for the enantioselective fluorescent responses of (S,S,S,S,S,S)-1 (1.0 104 M in CHCl3, kex = 460 nm) to (R)- and (S)-mandelic acid 3a
a b
Figure 1. Fluorescence spectra of (S,S,S,S,S,S)-1d (1.0 104 M in CHCl3, kex = 460 nm) with or without (R)- and (S)-mandelic acid 3a (3.0 103 M).
(S,S,S,S,S,S)-1d was treated with (R)- or (S)-3a, a significant fluorescence enhancement was observed at 527 nm. The (S)-3a enantiomer enhanced the emission twice as much as (R)-3a; that is, Ef = 2.0. [Ef: enantiomeric fluorescence difference ratio = (ISI0)/ (IRI0). I0 is the fluorescence intensity of (S,S,S,S,S,S)-1d. IR and IS are the fluorescence intensities of (S,S,S,S,S,S)-1d in the presence of (R)- and (S)-3a, respectively, monitored at 527 nm.] The influence of mandelic acid concentration on the enantioselective fluorescent responses of (S,S,S,S,S,S)-1d was studied (Fig. 2). Figure 2 shows that as the concentration of 3a increases the enantioselectivity increases gradually.
Figure 2. Fluorescence enhancement (I/I0) at 527 nm of (S,S,S,S,S,S)-1d (1.0 104 M in CHCl3, kex = 460 nm) versus the concentration of (R)- and (S)mandelic acid 3a.
We also studied the substituent effect of (S,S,S,S,S,S)-1 on the enantioselective fluorescent responses for mandelic acid. Table 2 summarizes the Ef values observed for the interaction of (S,S,S,S,S,S)-1a–f with the two enantiomers of mandelic acid 3a. All of these compounds enhanced the fluorescence, and various degrees of enantioselectivity were observed. As shown in Table 1, the sterically bulky alkyl group of 1 greatly enhanced the enantioselectivity of (S)-3a (entries 1–4). The methoxy derivative 1e showed the opposite enantioselectivity (entry 5). The inversion of stereoselectivity may be due to the intermolecular interaction between the methoxy oxygen of 1e and mandelic acid. The electron withdrawing group of 1f gave almost no fluorescent response [I0 = 22.5, IS = 23.7, IR = 23.4, IS/I0 = 1.1, thus Ef = (23.722.5)/ (23.422.5) = 1.3] owing to the electronic effect of Br substituent (entry 6). Next, we studied the fluorescence of (S,S,S,S,S,S)-1d in the presence of other chiral acids 3b, c, 4, and 5. Table 2 summarizes the highest Ef values observed for the interaction of (S,S,S,S,S,S)-1d with the two enantiomers of these acid derivatives. The (S)-enantiomers of compounds 3b and 3c enhanced the fluorescence of
Entry
Macrocycle
kem (nm)
I/I0
Ef
1 2 3 4 5 6
1a 1b 1c 1d 1e 1f
524 534 532 527 595 547
7 (S) 17 (S) 25 (S) 28 (S) 11 (R) 1.1 (S)
1.2a 1.3a 1.6a 2.0a 1.2b 1.3a
S/R. R/S.
Table 2 Results for the enantioselective fluorescent responses of (S,S,S,S,S,S)-1d (1.0 104 M in CHCl3, kex = 460 nm) to chiral acids 3a–c, 4, and 5 Entry
Acid
kem (nm)
I/I0
1 2 3 4 5
3a 3b 3c 4 5
527 523 532 536 533
28 52 24 3 7
Ef (S) (S) (S) (S) (S)
2.0 2.4 2.0 1.1 1.4
Ef: enantiomeric fluorescence difference ratio = (ISI0)/(IRI0). I0 is the fluorescence intensity of (S,S,S,S,S,S)-1d. IR and IS are the fluorescence intensities of (S,S,S,S,S,S)-1d in the presence of (R)- and (S)-acids, respectively.
1d (Ef values are 2.4 and 2.0, respectively) (entries 2, 3). When the OH group of 3a was replaced with the MeO group of 4, both the enantioselectivity and fluorescence intensity decreased dramatically (Ef value is 1.1) (entry 4). Thus, the hydroxyl groups of 3a–c are essential for enantioselective fluorescent responses. 2Chloropropionic acid 5 showed a relatively low enantioselectivity (Ef value is 1.4) as compared with those of 3a–c (entry 5). In order to confirm the type of molecular recognition, the 1H NMR spectra using various ratios of (S,S,S,S,S,S)-1d and 3a in CDCl3 were recorded (Fig. 3). It was found that the methine proton signal of 3a at d 5.25 ppm shifted upfield when treated with (S,S,S,S,S,S)1d. When the ratio of (S,S,S,S,S,S)-1d to 3a was 1:2, a methine proton signal appeared and split into two singlets at d 4.84 and 4.88 ppm for the (R)- and (S)-enantiomers, respectively. This suggests that in the host-mandelic acid complex, (S)-mandelic acid is probably located much deeper inside the cavity of (S,S,S,S,S,S)1d than (R)-mandelic acid, which significantly shields the methine proton of (S)-3a. This could be the origin of the dramatic difference in the fluorescence response of (S,S,S,S,S,S)-1d toward the two enantiomers of mandelic acid. Finally, we attempted to determine the enantiomeric excess (%ee) of mandelic acid by using the fluorescence intensity (I/I0) of (S,S,S,S,S,S)-1d. Samples containing different ee values of (S)-3a
Figure 3. Partial 1H NMR spectra showing the CaH signal for various H:G ratio mixtures of (S,S,S,S,S,S)-1d (8 mmol) and rac-mandelic acid 3a (4–32 mmol) in CDCl3 (1 ml) at room temperature.
K. Tanaka et al. / Tetrahedron: Asymmetry 23 (2012) 205–208
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myl-4-isopropylphenol (0.64 g, 3.3 mmol) in MeOH (60 ml). The mixture was stirred at room temperature for 24 h. The Schiff-base macrocycle separated as a yellow solid, was filtered, and recrystallized from CH2Cl2–CH3CN. (S,S,S,S,S,S)-1c: yellow prisms, mp 228– 232 °C. Yield 0.75 g (84%). [a]D = +225 (c 0.1, CH2Cl2). IR: 3180 cm1 (OH), 1637 cm1 (C@N). 1H NMR (CDCl3) d 13.91 (s, OH), 8.67 (s, HC@N), 8.24 (s, HC@N), 7.65 (s, Ar), 6.99 (s, Ar), 3.30–3.42 (m, @N–CH), 2.72–2.79 (m, CH), 1.46–1.83 (m, –CH2–), 1.11(d, J = 8 Hz, CH3). 13C NMR (CDCl3) d 23.9, 24.1, 24.3, 24.4, 73.1, 75.5, 118.9, 123.1, 127.5, 131.1, 138.0, 156.3, 159.7, 163.7. MS (ESI) m/z: found 811.74[M+H]+, calcd 811.53. 4.2.2. Synthesis of (S,S,S,S,S,S)-1d 4
Figure 4. Fluoresence enhancement (I/I0) at 527 nm of (S,S,S,S,S,S)-1d (1.0 10 M in CHCl3, kex = 460 nm) versus the enantiomeric composition of mandelic acid 3a (3.0 103 M).
were prepared and their fluorescence spectra in the presence of (S,S,S,S,S,S)-1d were measured. The results show a linear relationship between the fluorescence intensity (I/I0) of (S,S,S,S,S,S)-1d and the percentage of (S)-3a (Fig. 4). Thus, the chiral salen macrocycle (S,S,S,S,S,S)-1d can be used as a fluorescent sensor to rapidly determine the enantiomeric composition of mandelic acid 3a. 3. Conclusions In conclusion, we have found that the calixarene-like chiral salen macrocycle (S,S,S,S,S,S)-1 is a highly enantioselective fluorescent sensor for the recognition of mandelic acid derivatives. When (S,S,S,S,S,S)-1 was treated with a chiral acid, one enantiomer of the acid greatly enhances its fluorescent emission over the opposite enantiomer. This effect leads to high enantioselectivities in the recognition of a variety of mandelic acid derivatives. Further work in this area is underway. 4. Experimental 4.1. General method 1
H NMR spectra were recorded on JEOL JNM-GSX 400 spectrometer, with tetramethylsilane (TMS) as the internal standard. IR spectra were recorded on a JASCO FT/IR 4100 spectrometer in KBr pellets. The fluorescent and UV–vis spectra were recorded with JASCO FP-6500 and JASCO V-550 spectrometers, respectively. Optical rotations were measured on an ATAGO AP-100 automatic polarimeter. ESI mass spectra were obtained by a triple quadrupole mass spectrometer TSQ (ThermoFisher) in a positive ion mode. The capillary temperature was 150 °C, spray voltage 4.5 kV, auxiliary gas pressure 20 psi, and sheath gas pressure 60 psi. 4.2. Synthesis of chiral salen macrocyles Several 4-substituted 2,6-diformyl-phenol derivatives were prepared according to the literature method.4 The chiral salen macrocyles (S,S,S,S,S,S)-1a5 and 1b6 were prepared by [3+3] cyclo-condensation reactions of the corresponding 2,6-diformyl-phenol derivatives with (S,S)-(+)-1,2-diaminocyclohexane using the literature method.5,6
To a solution of (S,S)-(+)-1,2-diaminocyclohexane (0.39 g, 3.4 mmol) in CH3CN (160 ml) was added a solution of 2,6-diformyl-4-tert-butylphenol (0.64 g, 3.1 mmol) in MeOH (60 ml). The mixture was stirred at room temperature for 24 h. The Schiff-base macrocycle separated as a yellow solid, was filtered, and recrystallized from CH2Cl2–CH3CN. (S,S,S,S,S,S)-1d: yellow prisms, mp >300 °C. Yield 0.52 g (59%). [a]D = +193 (c 0.1, CH2Cl2). IR: 3255, 3182 cm1 (OH), 1637 cm1 (C@N). 1H NMR (CDCl3) d 13.92 (s, OH), 8.67 (s, HC@N), 8.24 (s, HC@N), 7.83 (s, Ar), 7.12 (s, Ar), 3.31–3.41 (m, @N–CH), 1.46–1.83 (m, –CH2–), 1.19(s, t-Bu). 13C NMR (CDCl3) d 24.4, 31.3, 33.2, 33.8, 73.0, 75.7, 118.5, 122.9, 126.2, 130.6, 140.1, 156.1, 159.6, 164.1. MS (ESI) m/z: 853.74[M+H]+, found 859.84[M+Li]+, calcd 859.58. 4.2.3. Synthesis of (S,S,S,S,S,S)-1e To a solution of (S,S)-(+)-1,2-diaminocyclohexane (0.45 g, 3.9 mmol) in CH3CN (160 ml) was added a solution of 2,6-diformyl-4-methoxyphenol (0.64 g, 3.6 mmol) in MeOH (60 ml). The mixture was stirred at room temperature for 24 h. The Schiff-base macrocycle separated as a yellow solid, was filtered, and recrystallized from CH2Cl2–CH3CN. (S,S,S,S,S,S)-1e: yellow prisms, mp 228– 232 °C. Yield 0.85 g (91%). [a]D = +250 (c 0.1, CH2Cl2). IR: 3167 cm1 (OH), 1637 cm1 (C@N). 1H NMR (CDCl3) d 13.52 (s, OH), 8.65 (s, HC@N), 8.19 (s, HC@N), 7.40 (s, Ar), 6.70 (s, Ar), 3.69 (s, OMe), 3.32–3.69 (m, @N–CH), 1.46–1.84 (m, –CH2–). 13C NMR (CDCl3) d 24.4, 33.2, 33.5, 56.0, 73.6, 75.4, 114.9, 118.7, 119.2, 123.8, 151.2, 155.6, 163.5. MS (ESI) m/z: found 775.43[M+H]+, calcd 775.42. 4.2.4. Synthesis of (S,S,S,S,S,S)-1f To a solution of (S,S)-(+)-1,2-diaminocyclohexane (0.38 g, 3.3 mmol) in CH3CN (160 ml) was added a solution of 2,6-diformyl-4-bromophenol (0.69 g, 3.0 mmol) in MeOH (60 ml). The mixture was stirred at room temperature for 24 h. The Schiff-base macrocycle separated as a yellow solid, was filtered, and recrystallized from CH2Cl2–CH3CN. (S,S,S,S,S,S)-1f: yellow prisms, mp 228– 232 °C. Yield 0.79 g (86%). [a]D = +192 (c 0.1, CH2Cl2). IR: 3411 cm1 (OH), 1637 cm1 (C@N). 1H NMR (CDCl3) d 14.14 (s, OH), 8.58 (s, HC@N), 8.18 (s, HC@N), 7.88 (s, Ar), 7.24 (s, Ar), 3.27–3.49 (m, @N–CH), 1.46–2.01 (m, –CH2–), 1.11(d, J = 8 Hz, CH3). 13C NMR (CDCl3) d 24.4, 31.1, 33.7, 73.0, 75.7, 118.5, 122.8, 126.1, 130.6, 140.1, 156.1, 159.3, 164.0. MS (ESI) m/z: found 923.33[M+H]+, calcd 923.11. 4.3. Fluorescent measurement
4.2.1. Synthesis of (S,S,S,S,S,S)-1c To a solution of (S,S)-(+)-1,2-diaminocyclohexane (0.41 g, 3.6 mmol) in CH3CN (160 ml) was added a solution of 2,6-difor-
The general preparation procedure for the fluorescent measurement is described below: a chloroform solution of a mixture of chiral Schiff-base macrocycle and mandelic acid was freshly prepared
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K. Tanaka et al. / Tetrahedron: Asymmetry 23 (2012) 205–208
and diluted to the desired concentration. The resulting solution was allowed to stand at room temperature and the fluorescence was measured on a JASCO FP-6500 spectrometer. References 1. (a) Lin, J.; Hu, Q.; Xu, M.; Pu, L. J. Am. Chem. Soc. 2002, 124, 2088; (b) Wolf, C.; Liu, S.; Reinhardt, C. Chem. Comm. 2006, 40, 4242; (c) Qing, G.; He, Y.; Chen, Z.; Wu, X.; Meng, L. Tetrahedron: Asymmetry 2006, 17, 3144; (d) Qin, H.; He, Y.; Hu, C.; Chen, Z.; Hu, L. Tetrahedron: Asymmetry 2007, 18, 1769; (e) Qing, G.; He, Y.; Wang, F.; Qin, H.; Hu, C.; Yang, X. Eur. J. Org. Chem. 2007, 1768; (f) Dhara, K.; Sarkar, K.; Roy; Partha; Nandi, M.; Bhaumik, A.; Banerjee, P. Tetrahedron 2008, 64, 3153; (g) Chi, L.; Zhao, J.; James, D. J. Org. Chem. 2008, 73, 4684; (h) Liu, H.; Hou, X.; Pu, L. Angew. Chem., Int. Ed. 2009, 48, 382; (i) Wang, T.; Hou, Q.; Teng, Q.; Yao, X.; Niu, W.; Cao, X.; Kuck, D. Chem. Eur. J. 2010, 16, 12412; (j) Wu, Y.; Guo, H.; James, D.; Zhao, J. J. Org. Chem. 2011, 76, 5685; (k) He, X.; Zhang, Q.; Wang, W.; Lin, L.; Liu, X.; Feng, X. Org. Lett. 2011, 13, 804; (l) Accetta, A.; Corradini, R.; Marchelli, R. Top. Curr. Chem. 2011, 300, 175.
2. (a) Pu, L. Chem. Rev. 2004, 104, 1687; (b) Li, Z.; Lin, J.; Zhang, H.; Sabat, M.; Hyacinth, M.; Pu, L. J. Org. Chem. 2004, 69, 6284; (c) Li, Z.; Lin, J.; Sabat, M.; Hyacinth, M.; Pu, L. J. Org. Chem. 2007, 72, 4905; (d) Costero, M.; Llaosa, U.; Gil, S.; Parra, M.; Colera, M. Tetrahedron: Asymmetry 2009, 20, 1468; (e) Xu, K.; Qiu, Z.; Zhao, J.; Zhao, J.; Wang, C. Tetrahedron: Asymmetry 2009, 20, 1690; (f) He, X.; Cui, X.; Li, M.; Lin, L.; Liu, X.; Feng, X. Tetrahedron Lett. 2009, 50, 5853; (g) Liu, H.; Peng, Q.; Wu, Y.; Chen, D.; Hou, X.; Sabat, M.; Pu, L. Angew. Chem., Int. Ed. 2010, 49, 602; (h) Yu, S.; DeBerardinis, A. M.; Turlington, M.; Pu, L. J. Org. Chem. 2011, 76, 2814; (i) Yang, X.; Liu, X.; Shen, K.; Fu, Y.; Zhang, M.; Zhu, C.; Cheng, Y. Org. Biom. Chem. 2011, 9, 6011. 3. Tanaka, K.; Fukuoka, N. Tetrahedron: Asymmetry 2009, 20, 111. 4. Lindoy, L. F.; Meehan, G. V.; Svenstrup, N. Synthesis 1998, 1029. 5. Tanaka, K.; Shimoura, R.; Caira, M. R. Tetrahedron Lett. 2010, 51, 449. 6. (a) Korupoju, S.; Zacharias, P. S. Chem. Commun. 1998, 1267; (b) Korupoju, S. R.; Mangayarkarasi, N.; Ameerunisha, S.; Valente, E. J.; Zacharias, P. S. J. Chem. Soc., Dalton Trans. 2000, 2845; (c) Kwit, M.; Gawronski, J. Tetrahedron: Asymmetry 2003, 14, 1303.
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy
Highly enantioselective fluorescent recognition of mandelic acid derivatives by chiral salen macrocycles Koichi Tanaka ⇑, Takeshi Tsuchitani, Noriaki Fukuda, Asuka Masumoto, Ryuichi Arakawa Department of Chemistry and Materials Engineering, Faculty of Chemistry, Materials and Bioengineering, Kansai University, Suita, Osaka 564-8680, Japan
a r t i c l e
i n f o
Article history: Received 9 December 2011 Accepted 31 January 2012 Available online 9 March 2012
a b s t r a c t Calixarene-like chiral salen macrocycles can be used for the enantioselective fluorescent recognition of mandelic acid derivatives. It was observed that one enantiomer of mandelic acid causes a 28-fold increase in the fluorescence intensity of a chiral salen macrocycle, whereas the other enantiomer causes only a 14fold fluorescence enhancement. This highly enantioselective fluorescent response makes chiral salen macrocycles useful for the enantioselective fluorescent recognition of some mandelic acid derivatives. Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction Fluorescence-based enantioselective sensors have attracted considerable attention because of their potential applications in the real-time analysis of chiral organic compounds.1 Rapid determination of enantiomeric composition is useful for the highthroughput combinatorial analysis of chiral molecules in catalytic reactions. 1,10 -Bi-2-naphthol (BINOL) derivatives have been widely used as enantioselective fluorescent sensors for chiral organic compounds.2 For example, BINOL–amine molecules can be used for the highly enantioselective fluorescent recognition of a-hydroxy-carboxylic acids.2h Recently, we have reported that the calixarene-like chiral salen macrocycle (S,S,S,S,S,S)-2 acts as a chiral-shift reagent for the determination of enantiomeric excess and the absolute configuration of several types of carboxylic acid derivatives by 1H NMR spectroscopy.3 We also tested the ability of (S,S,S,S,S,S)-2 toward the enantioselective fluorescent recognition of mandelic acid; however, compound 2 did not work as a fluorescent sensor. The secondary nitrogen atoms adjacent to the phenol rings of the chiral salen macrocycle (S,S,S,S,S,S)-1 may interact with the acids and can turn on the fluorescence of the phenol by inhibiting fluorescence quenching of the photoinduced-electron-transfer (PET) of the nitrogen lone pair electrons.1f Since the interaction of (S,S,S,S,S,S)1 with the two enantiomers of mandelic acid should generate diastereomers, enantioselective fluorescence enhancements may occur. Considering this, we attempted to explore the ability of (S,S,S,S,S,S)-1 toward the enantioselective fluorescent recognition of several a-hydroxy-carboxylic acids. Herein, we report the synthesis of several types of calixarene-like chiral salen macrocycles
⇑ Corresponding author. E-mail addresses: [email protected], [email protected] (K. Tanaka). 0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2012.01.024
(S,S,S,S,S,S)-1 and their application in the enantioselective fluorescent recognition of mandelic acid derivatives. R
N
R
N
OH
N
N HO
OH
R
N
N
R
NH a: R = H b: R = Me c: R = i-Pr d: R = t-Bu e: R = OMe f: R = Br
OH
HO
OH
R
H N
H N
R
(S,S,S,S,S,S)-2
H R
HN
NH
(S,S,S,S,S,S)-1 H CO2H
HN
OH
a: R = H b: R = o-Cl c: R = p-Cl
3
H CO2H
OMe 4
Me
CO2H Cl 5
2. Results and discussion Chiral salen macrocycles (S,S,S,S,S,S)-1 were prepared by the [3+3] condensation reaction of 4-substituted 2,6-diformyl phenols and trans-(1S,2S)-cyclohexanediamine in MeOH according to a previously reported method.3,4 In the UV–vis spectrum, (S,S,S,S,S,S)-1d in chloroform displays absorptions at 244, 350, and 457 nm. It emits at 527 nm on excitation at 460 nm. First, we studied the interaction of (S,S,S,S,S,S)-1d with (R)- and (S)-mandelic acid 3a. Figure 1 shows the fluorescence spectra of (S,S,S,S,S,S)-1d in the presence of (R)- and (S)-3a. As shown in the spectra, when
206
K. Tanaka et al. / Tetrahedron: Asymmetry 23 (2012) 205–208 Table 1 Results for the enantioselective fluorescent responses of (S,S,S,S,S,S)-1 (1.0 104 M in CHCl3, kex = 460 nm) to (R)- and (S)-mandelic acid 3a
a b
Figure 1. Fluorescence spectra of (S,S,S,S,S,S)-1d (1.0 104 M in CHCl3, kex = 460 nm) with or without (R)- and (S)-mandelic acid 3a (3.0 103 M).
(S,S,S,S,S,S)-1d was treated with (R)- or (S)-3a, a significant fluorescence enhancement was observed at 527 nm. The (S)-3a enantiomer enhanced the emission twice as much as (R)-3a; that is, Ef = 2.0. [Ef: enantiomeric fluorescence difference ratio = (ISI0)/ (IRI0). I0 is the fluorescence intensity of (S,S,S,S,S,S)-1d. IR and IS are the fluorescence intensities of (S,S,S,S,S,S)-1d in the presence of (R)- and (S)-3a, respectively, monitored at 527 nm.] The influence of mandelic acid concentration on the enantioselective fluorescent responses of (S,S,S,S,S,S)-1d was studied (Fig. 2). Figure 2 shows that as the concentration of 3a increases the enantioselectivity increases gradually.
Figure 2. Fluorescence enhancement (I/I0) at 527 nm of (S,S,S,S,S,S)-1d (1.0 104 M in CHCl3, kex = 460 nm) versus the concentration of (R)- and (S)mandelic acid 3a.
We also studied the substituent effect of (S,S,S,S,S,S)-1 on the enantioselective fluorescent responses for mandelic acid. Table 2 summarizes the Ef values observed for the interaction of (S,S,S,S,S,S)-1a–f with the two enantiomers of mandelic acid 3a. All of these compounds enhanced the fluorescence, and various degrees of enantioselectivity were observed. As shown in Table 1, the sterically bulky alkyl group of 1 greatly enhanced the enantioselectivity of (S)-3a (entries 1–4). The methoxy derivative 1e showed the opposite enantioselectivity (entry 5). The inversion of stereoselectivity may be due to the intermolecular interaction between the methoxy oxygen of 1e and mandelic acid. The electron withdrawing group of 1f gave almost no fluorescent response [I0 = 22.5, IS = 23.7, IR = 23.4, IS/I0 = 1.1, thus Ef = (23.722.5)/ (23.422.5) = 1.3] owing to the electronic effect of Br substituent (entry 6). Next, we studied the fluorescence of (S,S,S,S,S,S)-1d in the presence of other chiral acids 3b, c, 4, and 5. Table 2 summarizes the highest Ef values observed for the interaction of (S,S,S,S,S,S)-1d with the two enantiomers of these acid derivatives. The (S)-enantiomers of compounds 3b and 3c enhanced the fluorescence of
Entry
Macrocycle
kem (nm)
I/I0
Ef
1 2 3 4 5 6
1a 1b 1c 1d 1e 1f
524 534 532 527 595 547
7 (S) 17 (S) 25 (S) 28 (S) 11 (R) 1.1 (S)
1.2a 1.3a 1.6a 2.0a 1.2b 1.3a
S/R. R/S.
Table 2 Results for the enantioselective fluorescent responses of (S,S,S,S,S,S)-1d (1.0 104 M in CHCl3, kex = 460 nm) to chiral acids 3a–c, 4, and 5 Entry
Acid
kem (nm)
I/I0
1 2 3 4 5
3a 3b 3c 4 5
527 523 532 536 533
28 52 24 3 7
Ef (S) (S) (S) (S) (S)
2.0 2.4 2.0 1.1 1.4
Ef: enantiomeric fluorescence difference ratio = (ISI0)/(IRI0). I0 is the fluorescence intensity of (S,S,S,S,S,S)-1d. IR and IS are the fluorescence intensities of (S,S,S,S,S,S)-1d in the presence of (R)- and (S)-acids, respectively.
1d (Ef values are 2.4 and 2.0, respectively) (entries 2, 3). When the OH group of 3a was replaced with the MeO group of 4, both the enantioselectivity and fluorescence intensity decreased dramatically (Ef value is 1.1) (entry 4). Thus, the hydroxyl groups of 3a–c are essential for enantioselective fluorescent responses. 2Chloropropionic acid 5 showed a relatively low enantioselectivity (Ef value is 1.4) as compared with those of 3a–c (entry 5). In order to confirm the type of molecular recognition, the 1H NMR spectra using various ratios of (S,S,S,S,S,S)-1d and 3a in CDCl3 were recorded (Fig. 3). It was found that the methine proton signal of 3a at d 5.25 ppm shifted upfield when treated with (S,S,S,S,S,S)1d. When the ratio of (S,S,S,S,S,S)-1d to 3a was 1:2, a methine proton signal appeared and split into two singlets at d 4.84 and 4.88 ppm for the (R)- and (S)-enantiomers, respectively. This suggests that in the host-mandelic acid complex, (S)-mandelic acid is probably located much deeper inside the cavity of (S,S,S,S,S,S)1d than (R)-mandelic acid, which significantly shields the methine proton of (S)-3a. This could be the origin of the dramatic difference in the fluorescence response of (S,S,S,S,S,S)-1d toward the two enantiomers of mandelic acid. Finally, we attempted to determine the enantiomeric excess (%ee) of mandelic acid by using the fluorescence intensity (I/I0) of (S,S,S,S,S,S)-1d. Samples containing different ee values of (S)-3a
Figure 3. Partial 1H NMR spectra showing the CaH signal for various H:G ratio mixtures of (S,S,S,S,S,S)-1d (8 mmol) and rac-mandelic acid 3a (4–32 mmol) in CDCl3 (1 ml) at room temperature.
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myl-4-isopropylphenol (0.64 g, 3.3 mmol) in MeOH (60 ml). The mixture was stirred at room temperature for 24 h. The Schiff-base macrocycle separated as a yellow solid, was filtered, and recrystallized from CH2Cl2–CH3CN. (S,S,S,S,S,S)-1c: yellow prisms, mp 228– 232 °C. Yield 0.75 g (84%). [a]D = +225 (c 0.1, CH2Cl2). IR: 3180 cm1 (OH), 1637 cm1 (C@N). 1H NMR (CDCl3) d 13.91 (s, OH), 8.67 (s, HC@N), 8.24 (s, HC@N), 7.65 (s, Ar), 6.99 (s, Ar), 3.30–3.42 (m, @N–CH), 2.72–2.79 (m, CH), 1.46–1.83 (m, –CH2–), 1.11(d, J = 8 Hz, CH3). 13C NMR (CDCl3) d 23.9, 24.1, 24.3, 24.4, 73.1, 75.5, 118.9, 123.1, 127.5, 131.1, 138.0, 156.3, 159.7, 163.7. MS (ESI) m/z: found 811.74[M+H]+, calcd 811.53. 4.2.2. Synthesis of (S,S,S,S,S,S)-1d 4
Figure 4. Fluoresence enhancement (I/I0) at 527 nm of (S,S,S,S,S,S)-1d (1.0 10 M in CHCl3, kex = 460 nm) versus the enantiomeric composition of mandelic acid 3a (3.0 103 M).
were prepared and their fluorescence spectra in the presence of (S,S,S,S,S,S)-1d were measured. The results show a linear relationship between the fluorescence intensity (I/I0) of (S,S,S,S,S,S)-1d and the percentage of (S)-3a (Fig. 4). Thus, the chiral salen macrocycle (S,S,S,S,S,S)-1d can be used as a fluorescent sensor to rapidly determine the enantiomeric composition of mandelic acid 3a. 3. Conclusions In conclusion, we have found that the calixarene-like chiral salen macrocycle (S,S,S,S,S,S)-1 is a highly enantioselective fluorescent sensor for the recognition of mandelic acid derivatives. When (S,S,S,S,S,S)-1 was treated with a chiral acid, one enantiomer of the acid greatly enhances its fluorescent emission over the opposite enantiomer. This effect leads to high enantioselectivities in the recognition of a variety of mandelic acid derivatives. Further work in this area is underway. 4. Experimental 4.1. General method 1
H NMR spectra were recorded on JEOL JNM-GSX 400 spectrometer, with tetramethylsilane (TMS) as the internal standard. IR spectra were recorded on a JASCO FT/IR 4100 spectrometer in KBr pellets. The fluorescent and UV–vis spectra were recorded with JASCO FP-6500 and JASCO V-550 spectrometers, respectively. Optical rotations were measured on an ATAGO AP-100 automatic polarimeter. ESI mass spectra were obtained by a triple quadrupole mass spectrometer TSQ (ThermoFisher) in a positive ion mode. The capillary temperature was 150 °C, spray voltage 4.5 kV, auxiliary gas pressure 20 psi, and sheath gas pressure 60 psi. 4.2. Synthesis of chiral salen macrocyles Several 4-substituted 2,6-diformyl-phenol derivatives were prepared according to the literature method.4 The chiral salen macrocyles (S,S,S,S,S,S)-1a5 and 1b6 were prepared by [3+3] cyclo-condensation reactions of the corresponding 2,6-diformyl-phenol derivatives with (S,S)-(+)-1,2-diaminocyclohexane using the literature method.5,6
To a solution of (S,S)-(+)-1,2-diaminocyclohexane (0.39 g, 3.4 mmol) in CH3CN (160 ml) was added a solution of 2,6-diformyl-4-tert-butylphenol (0.64 g, 3.1 mmol) in MeOH (60 ml). The mixture was stirred at room temperature for 24 h. The Schiff-base macrocycle separated as a yellow solid, was filtered, and recrystallized from CH2Cl2–CH3CN. (S,S,S,S,S,S)-1d: yellow prisms, mp >300 °C. Yield 0.52 g (59%). [a]D = +193 (c 0.1, CH2Cl2). IR: 3255, 3182 cm1 (OH), 1637 cm1 (C@N). 1H NMR (CDCl3) d 13.92 (s, OH), 8.67 (s, HC@N), 8.24 (s, HC@N), 7.83 (s, Ar), 7.12 (s, Ar), 3.31–3.41 (m, @N–CH), 1.46–1.83 (m, –CH2–), 1.19(s, t-Bu). 13C NMR (CDCl3) d 24.4, 31.3, 33.2, 33.8, 73.0, 75.7, 118.5, 122.9, 126.2, 130.6, 140.1, 156.1, 159.6, 164.1. MS (ESI) m/z: 853.74[M+H]+, found 859.84[M+Li]+, calcd 859.58. 4.2.3. Synthesis of (S,S,S,S,S,S)-1e To a solution of (S,S)-(+)-1,2-diaminocyclohexane (0.45 g, 3.9 mmol) in CH3CN (160 ml) was added a solution of 2,6-diformyl-4-methoxyphenol (0.64 g, 3.6 mmol) in MeOH (60 ml). The mixture was stirred at room temperature for 24 h. The Schiff-base macrocycle separated as a yellow solid, was filtered, and recrystallized from CH2Cl2–CH3CN. (S,S,S,S,S,S)-1e: yellow prisms, mp 228– 232 °C. Yield 0.85 g (91%). [a]D = +250 (c 0.1, CH2Cl2). IR: 3167 cm1 (OH), 1637 cm1 (C@N). 1H NMR (CDCl3) d 13.52 (s, OH), 8.65 (s, HC@N), 8.19 (s, HC@N), 7.40 (s, Ar), 6.70 (s, Ar), 3.69 (s, OMe), 3.32–3.69 (m, @N–CH), 1.46–1.84 (m, –CH2–). 13C NMR (CDCl3) d 24.4, 33.2, 33.5, 56.0, 73.6, 75.4, 114.9, 118.7, 119.2, 123.8, 151.2, 155.6, 163.5. MS (ESI) m/z: found 775.43[M+H]+, calcd 775.42. 4.2.4. Synthesis of (S,S,S,S,S,S)-1f To a solution of (S,S)-(+)-1,2-diaminocyclohexane (0.38 g, 3.3 mmol) in CH3CN (160 ml) was added a solution of 2,6-diformyl-4-bromophenol (0.69 g, 3.0 mmol) in MeOH (60 ml). The mixture was stirred at room temperature for 24 h. The Schiff-base macrocycle separated as a yellow solid, was filtered, and recrystallized from CH2Cl2–CH3CN. (S,S,S,S,S,S)-1f: yellow prisms, mp 228– 232 °C. Yield 0.79 g (86%). [a]D = +192 (c 0.1, CH2Cl2). IR: 3411 cm1 (OH), 1637 cm1 (C@N). 1H NMR (CDCl3) d 14.14 (s, OH), 8.58 (s, HC@N), 8.18 (s, HC@N), 7.88 (s, Ar), 7.24 (s, Ar), 3.27–3.49 (m, @N–CH), 1.46–2.01 (m, –CH2–), 1.11(d, J = 8 Hz, CH3). 13C NMR (CDCl3) d 24.4, 31.1, 33.7, 73.0, 75.7, 118.5, 122.8, 126.1, 130.6, 140.1, 156.1, 159.3, 164.0. MS (ESI) m/z: found 923.33[M+H]+, calcd 923.11. 4.3. Fluorescent measurement
4.2.1. Synthesis of (S,S,S,S,S,S)-1c To a solution of (S,S)-(+)-1,2-diaminocyclohexane (0.41 g, 3.6 mmol) in CH3CN (160 ml) was added a solution of 2,6-difor-
The general preparation procedure for the fluorescent measurement is described below: a chloroform solution of a mixture of chiral Schiff-base macrocycle and mandelic acid was freshly prepared
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