1154
Anal. Chem. 1992, 6 4 , 1154-1157
Host-Guest Sensors of 6A,6B-,6A,6C-,6A ,6D-, and 6A ,6E-Bis(2-naphthylsulfenyl)-y-cyclodextrins for Detecting Organic Compounds by Fluorescence Enhancement Akihiko Ueno*
Department of Bioengineering, Faculty of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku, Yokohama 227, Japan
Shingo Minato and Tetsuo Osa* Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980,Japan y-Cyclod.xtrin derivatlves 1-4 which have two naphthyl moletks at AB, AC, AD, and AE glucose residues, respecUvdy, have km pnpcuwl as a serlw at so"for detecting organk compounds. They exhibit ahnod pure monomer fluor~encewhose intenslty is enhanced upon addition of gwst spocks. The value Im/Imo, where I m and ImO are fluore8cence intenstties in the presence and absence of a guost, was used as a sensltlvlty parameter. The data for twelve organk compounds were coiMed. Four steroidal compound8 swh as chdk acM (I), dwxychoilc acid (6), chenodwxychdlc acid (7), and unodwxychdic acid (8) were detected by 1,2, and 3 wtth the order ol the sensttlvtty 5 < 6 < 7 < 8 WMk they were detected by 4 wtth the order 8 < 5 < 7 < 6. Three alcohols such as /-borneol (9), cydohoxaol (lo), and cydodockcand (12) were detected by 1-4 wlth the order ol the wnrltlvtty 10 < 9 < 12. 1Adamantawcarboxyiic acid (11) exhlblts sensitivities comparable to those d bkycwC cOmpOund 9. Nerol (W), geranld (14), dmmthd (15), and /-menthol (16) were detected wtth much smalkr " H M t i e s than 9, and geometrlcai and chlral dhcrhhatkn for them was not appreciable. Bindlng constants of 1-4 for 5,9,11, and 12 were obtained. Among four hosts, 2 gave the largest binding constant for each of the guests. The binding constants of 2 for the guests are in the order 9 < 11 < 5 < 12 and roughly paraiiel with the sen& tlvlty parameters.
Cyclodextrins (CDs) are cyclic oligomers of D-glucose and form inclusion complexes with a variety of organic compounds in aqueous solution.' a-and @-CDhave six and seven glucose residues, respectively, and usually form 1:l host-guest complexes, while y C D has eight glucose residues and can form 1:2 complexes by including two guest molecules in ita large c a v i t ~ On . ~ the basis of this unique property, y C D has been used as a molecular flask or a vessel in which interactions or reactions between two guest species are facilitated."12 As an extension of the study, we have prepared some modified y-CDs appended by two naphthyl moieties and observed that they form intramolecular complexes in which the moieties are included in the y C D cavity and interact with each other.13-15 Most of the modified y-CDs prepared so far exhibit a strong tendency to form excimers. In this study, we have prepared a new series of modified y-CDs (1-4) which have two naphthyl moietiea but exhibit almost pure monomer fluoreacence. They show guest-induced enhancement in the monomer fluorescence intensity and can be used as sensors for detecting organic compounds. EXPERIMENTAL SECTION Synthesis. 6A,6B-, 6A,6C-, 6A,6D-, and 6A,6E-Bis(2naphthylsulfeny1)-y-cyclodextrin (1-4). A mixture of 0003-2700/92/0364-1154$03.00/0
Chart I n
@ @ 1
2
3
4
S
Bo
6A,6B-bis(2-naphthylsulfonyl)-y-cyclodextrin(150 mg, 0.09 mmol),12sodium 2-naphthalenethiolate (66 mg, 0.36 mmol), and dimethyl sulfoxide (DMSO) (1mL) was stirred at 80 "C for 5 h. The reaction mixture was injected into a HPLC column (YMC S-343,1-15,ODs, 20 X 250 mm), and a gradient elution (10% MeOH-70% MeOH) was applied. The UV absorption at 290 nm was monitored, and the fractions containing 1 were collected. After the removal of MeOH under reduced pressure, the resultant aqueous solution was lyophylized to give 1 as white powder (51 mg, 36%): FAB MS mle 1581 ([M + HI+); 'H NMR (500MHz, DMSO-d6) S 3.04-4.03 (m), 4.47-4.74 (m, 6 H, O&), 4.93-5.06 (m, 8 H, CIH), 5.46-6.08 (m, 16 H, 02H, 03H),7.40-7.55 (m, 7 H,aromatic), 7.67-7.82 (m, 7 H, aromatic); UV A, (log e) 215 (4.83),250 (4.70),283 (4.08). Anal. Calcd for CB8HWOsS2-3H20: C, 49.94;H, 6.00;S,3.92. Found 50.04;H, 6.00;S,4.18. Compound~2-4 were also prepared by the same procedure using 6A,6D-,and 6A,6E-bis(2-naphthylulfonyl)-y-cyclodextrins, respectively, in place of the 6A,6Bisomer (2,34%;3,29%; 4,23%). 2 FAB MS m / e 1581 ([M+ HI+);lH N M R (500 MHz, DMSO-dJ 6 3.03-4.02 (m), 4.54-4.75 (m, 6 H,O&), 4.91-5.02 (m, 8 H, CIH), 5.54-6.05 (m, 16 H, 02H, 03H), 7.27-7.52 (m,7 H, aromatic), 7.63-7.78 (m, 7 H,aromatic);W A- (log e) 219 (4.91),252 (4.59), 283 (4.08). Anal. Calcd for CB8H920&32-4H20: C, 49.39; H, 6.05; S,3.87. Found C,49.50;H, 5.92;S.4.15. 3 FAB MS mle 1581 ([M + HI+); 'H NMR (500 MHz, DMSO-$) S 2.90-3.99 (m), 4.60-4.80 (m, 6 H, 06H),4.93-5.04 (m, 8 H, CIH), 5.47-6.09 (m, 16 H, 02H,O,H),7.06-7.08 (m, 2 H, aromatic), 7.27-7.76 (m, 12 H, aromatic); UV &- (log e) 220 (4.881,252 (4.59),283 (4.05). Anal. Calcd for CB8Hg2OsS2.3H20:C, 49.94;H, 6.00; S,3.92. Found: C,49.56;H, 6.13;S,4.32. 4: FAB MS mle 1581 ([M + HI+); 'HNMR (500MHz,DMSO-d6)6 2.79-3.97 (m),4.67-4.74 (m, 6 H, 06H),4.90-5.00 (m, 8 H, CIH),5.45-6.07 (m, 16 H, 02H, O,H), 7.11-7.13 (m, 2 H, aromatic);7.44-7.72 (m, 12 H,aromatic);
e,&-,
0 1992 American Chemical Society
ANALYTICAL CHEMISTRY, VOL. 64, NO. 10, MAY 15, 1992
:t
-3
t
--
200
1155
L
250
200
4
250
Wavelength (nm)
Figure 1. Circular dichroism spectra of 1-4, abne (8.3 X 10" M, -) and in the presence of I-bomeol(2 mM, ---), in a 10% ethylene glycol aqueous solution.
UV A- (log c) 220 (4.91), 252 (4.58),283 (4.08). Anal. Calcd for C68H92038S2*2H20: C, 50.50; H, 5.94; S, 3.96. Found: C, 50.54; H, 5.82; S, 4.10. Measurements. Fluorescence and circular dichroism spectra were measured at 25 "C with a JASCO FP-770 spectrofluorometer and a JASCO J-4OOX spectrophotdichrometer, respectively. Due to the poor solubility of 1-4 in pure water, a 10% ethylene glycol aqueous solution was used as the solvent. The fluorescence measurements were performed by excitation at 290 nm. Determination of Binding Constants. The binding constants of 1-4 were obtained from guest-induced fluorescence variations around 375 nm by employinga Benesi-Hildebrand type equation as reported previously.16
RESULTS AND DISCUSSION Fluorescence and Circular Dichroism Spectra. Figure 1 shows circular dichroism spectra of 1-4, alone or in the presence of I-borneol (9), in a 10% ethylene glycol aqueous solution. The spectrum of 2 exhibits an exciton coupling band with a peak at 220 nm and a trough a t 232 nm in the naphthalene lBbtransition region below 240 nm. This is the pattern of S-helicity that reflects a counterclockwise twisting between the two naphthalene rings included in the chiral y-cyclodextrin cavity." Similar exciton coupling bands were observed for 3 and 4, while a positive band was observed for 1. The circular dichroism intensities were reduced upon addition of 9, and the result suggests that the two naphthalene rings included in the cavities of 1-4 undergo locational and orientational changes associated with host-guest complexation. Figure 2 shows fluorescence spectra of 1-4 in a 10% ethylene glycol aqueous solution. The fluorescence spectra of these compounds are composed of almost pure monomer emission with a peak around 375 nm, indicating that it is difficult for the two naphthyl rings to interact with each other and take any face-to-face orientation that is prerequisite for excimer formation. Previously, we reported that excimer emission is remarkable for the y-cyclodextrin derivatives that have two 2-naphthylsulfonyl moieties.14J5 The marked difference in the fluorescence behavior observed for the two series of the y-cyclodextrin derivatives should arise from the fact that 1-4 have thioether linkages while the others have sulfonyl ones to connect the naphthalene rings to the y-cyclodextrin framework. Since the naphthalene rings are more closely connected to y-cyclodextrin by the thioether linkages than by the sulfonyl ones, the rings in 1-4 may be limited in movement and likely to be more tightly oriented in the ycyclodextrin cavities. The fluorescence intensities of 1-4 increased upon addition of 9, indicating that complexation occurs between 1-4 and the guest. This fluorescence behavior of 1-4 also suggests that the naphthyl moieties undergo locational and orientational changes upon complexation. It implies that the fluorescence quantum yields of the naphthyl moieties in 1-4 are larger in
300
500 300 Wavelength (nm)
400
500
400
Flgure 2. Fluorescence spectra of 1-4, alone (0.02 mM, -) and in the presence of /-borneol (2.0 mM, ---), in a 10% ethylene glycol
$:)
aqueous solution.
1.6
1.2
1.1 1.o
5
6
7
8
9
10
11
12
Guest
Flgure 3. Guest-induced fluorescence enhancement of 1C.),2 (H), 3 (a)and 4 (0) for organic compounds. Im" and I m are fluorescence intensities of 1-4, alone and in the presence of a guest (0.1 mM), in a 10% ethylene glycol aqueous solution.
the complexes than in the cyclodextrin cavity. Cyclodextrins are known to affect the fluorescence of many chromophores by forming inclusion complexes.18-20For example, Hamai reported that the fluorescence of 2-methoxynaphthalene is enhanced by fl-cyclodextrin.20The polarity of the medium around a chromophore is obviously an important factor in determining its fluorescence quantum yield, and in many cases a hydrophobic environment results in fluorescence quantum yields higher than those in the polar medium. In the present system, fluorescence intensities of 1-4 are all enhanced upon guest addition. The result suggests that the naphthyl moieties in the complexes of 1-4 are likely to cap the entrance of the cyclodextrin cavity, interacting with the guest included in the cyclodextrin cavity, or in some cases they might sandwich a guest species in the exterior of the cavity. In any of these cases, the naphthyl moieties are not left alone in the bulk water, and the nature of the hydrophobic environment around the naphthyl moieties may be reflected in the fluorescence behavior. Sensitivity and Selectivity. Modified cyclodextrins whose fluorescence intensities are affected by the presence of guest molecules can be used as host-guest sensors for detecting organic species in solution:1z2 and we have examined the abilities of 1-4 as such sensors. The value Im/Imo was used as a sensitivity parameter, where Im" and Im are fluorescence intensities in the absence and presence of a guest, respectively. The data for twelve organic compounds are shown in Table I. Some of the data measured at the guest concentration of 0.1 mM are shown in Figure 3. Four steroidal compounds such as cholic acid (5), deoxycholic acid (6),
1156
ANALYTICAL CHEMISTRY, VOL. 64, NO. 10, MAY 15, 1992
&
Chart I1
@ HO"
W H
HO"
"OH
14
cyclohexanol (10) 1-ACA (ll)b
concn, m M
0.1 0.1 0.1 0.1 0.1 2.0 0.1 2.0 50.0 0.1 0.1 2.0 2.0 2.0 2.0
7
15
Table I. Guest-Induced Fluorescence Enhancement of 1-4 in a 10% Ethylene Glycol Aqueous Solution"
cholic acid (5)
* 'OH
6
13
deoxycholic acid (6) chenodeoxycholic acid (7) ursodeoxycholic acid (8) l-borneol (9)
HO"
H
5
guest
@ ! H
16
Table 11. Binding Constants of 1-4 at 25 O C in a Ethylene Glycol Aqueous Solution
Im/Imo 1
1.16 1.27 1.37 1.45 1.03 1.45 1.00 1.03 1.15 1.05 1.26 1.10 1.06 1.07 1.10
2
1.10 1.21 1.23 1.34 1.07 1.51 1.01 1.05 1.18 1.07 1.25 1.10 1.04 1.05 1.06
10%
K , M-'
3
4
guest
1
2
3
4
1.09 1.16 1.18 1.23 1.03 1.29 1.02 1.05 1.17 1.02 1.22 1.04 1.04 1.06 1.07
1.36 1.55 1.48 1.25 1.06 1.52 1.02 1.08 1.38 1.07 1.54 1.14 1.12 1.18 1.19
5 9 11 12
3590 1180 81 4880
20700 1640 3950 25000
9860 431 2110 21500
11000 966 1400 4850
cyclododecanol (12) nerol (13) geraniol (14) d-menthol (15) l-menthol (16) OMeasured at 25 O C . Excitation wavelength waa 290 nm. The concentration of 1-4 WBB 2.0 X M. * 1-Adamantanecarboxylic acid.
chenodeoxycholic acid (71, and ursodeoxycholic acid (8) were detected by 1-3 with the sensitivity order 5 < 6 < 7 < 8, and this order is the same as that reported for sensors of pyrene-modified cyclodextrins.21 On the other hand, they were detected by 4 with the order 8 < 5 < 7 < 6. Compounds 7 and 8 are isomers with the difference of stereochemistry of the hydroxyl at C-7, while 6 is the regioisomer of 7 and 8 with one hydroxyl at C-12 instead of the C-7 of 7 and 8. Therefore, the different sensitivities observed for 6-8 reveal that the molecular recognition abilities of 1-4 are remarkable. Although the reason why 4 exhibits the order 8 < 7 < 6 that is the opposite of the order observed for 1-3 is not yet clear, the result indicates that the feature of molecular recognition can be modulated by changing the positions to which two chromophores are attached. Three alcohols such as l-borneol(9), cyclohexanol (lo), and cyclodecanol(12)were detected by 1-4 with the sensitivity order 10 < 9 < 12, indicating that the size of 12 is more suitable to be included in the large y-cyclodextrin cavity of 1-4 than the sizes of 9 and 10. 1-Adamantanecarboxylic acid (11) is a rigid guest and exhibits sensitivities comparable to those of bicyclic compound 9. Nerol (13),
geraniol (14), d-menthol(15), and l-menthol(l6) are all monoterpenes and were detected by 1-4 at the guest concentration of 2 mM (Table I). The sensitivities of these compounds were much smaller than those of 9, and geometrical and chiral discrimination for them was not appreciable. Binding Constants. Binding constants of 1-4 for 5,9,11, and 12 are shown in Table 11. The data indicate that the binding abilities of 1-4 are different for each guest. Among the four hosts, 2 gives the largest binding constant for the guests. The binding constants of 2 are in the order 9 < 11 < 5 < 12 and roughly parallel with the sensitivity parameters. However, it should be noted that the sensitivity values of 2 are not always larger than those of the other hosta (Figure 3). Some structural features of the complexes as well as the binding strength may be reflected in the fluorescence enhancement. It is important to examine what factors govern the guest binding of the hosts. Previously, we observed that the binding constants of 6A,6B-,6A,6C-,6A,6D-,and GA,GE-bis(2-naphthylsulfonyl)-y-cyclodextrinsare in the order AC > AB > AI3 > AD for 9.15 The same order was observed in the series of 1-4. The process of the complexation of these systems involves the conversion from intramolecular complexes to intermolecular Complexes. The two naphthyl moieties may be difficult to be excluded from the cavity acting as intramolecular inhibitors if the naphthyl moieties are tightly included in the cavity in the intramolecular complexes. The inhibitory action of the moieties is seen in the fact that the binding constants of 1-4 for 9 are smaller than the binding constant of y-cyclodextrin (1700 M-l). The tight inclusion of the moieties is likely to be attained when two naphthalene rings take a parallel arrangement in the cavity. From this point of view, the intramolecular complexes of AD and AE hosta may be stable whereas the intramolecular complex of AC hosts, in which any
Anal. Chem. 1992, 64, 1157-1164
parallel arrangement between the two naphthalene rings is not allowed, may be unstable. As a result, AC hosts are expeded to easily include a guest molecule in the cavity. The binding constants of AC host 2 of the present series are actually larger than those of AB, AD, and AE hosts, and this binding behavior is consistent with the above argument.
CONCLUSION Compounds 1-4 have two naphthyl moieties, but they exhibit almost pure monomer fluorescence. They are capable of detecting organic species in aqueous solution by guest-induced fluorescence enhancement. S i n c e 1-4 are y-cyclodextrin derivatives, they exhibit high sensitivities to larger compounds such as cyclododecanoland steroids. This feature in molecular recognition is different from that of dansyl-modified @cyclodextrin which decreases fluorescence intensity upon guest addition and exhibits high sensitivities to smaller compounds.22 Another aspect of the present sensor systems is that 1-4 form a set of sensors whose sensitivities are different with each other and a response pattern is constructed for each guest. Such response patterns may be useful for differentiation of many organic compounds and provide a new approach for sensing chemical species by using plurality of the systems. REFERENCES Bender, M. L.; Komlyama, M. Cycbdextdn -by; Springer-Verlag: New York, 1977. Ueno. A.; Takahashi, K.; Osa, T. J . Chem. Soc., Chem. Commun. 1080, 921.
1157
Emert, J.; Kodali, D.; Catena, R. J . Chem. Soc..C t ” . Con”. 1081, 755. Turro, N. J.; Okubo, T.; Weed, G. C. Rwtochem. Rwtobkl. 1982, 35, 325. &ad-Yellin, R.; Eaton, D. F. J . phys. Chem. 1088, 87, 5051. Itoh, M.; Fujiwara, Y. BuU. CY”. Soc. Jpn. 1084, 57, 2261. Hkai, H.; Toshima, N.; Uenoyama, S. Bull. Chem. Soc. Jpn. 1085, 58. 1156. Hal’d, S. Bull. Chem. S0c. Jpn. 1088, 59, 2979. Chem. 1088, Kobayashl, N.; Salto, R.; Ueno, A.; Osa, T. Mk&. 184, 837. 1087, 43, 1485. Tamaki. T.; Kokubu, T.; Ichlmura, K. Tetrat” Ueno, A.; Morlwaki, F.; Osa, T.; Hamada. F.; Mural, K. J . Am. Chem. Soc. 1088, 710, 4323. Ueno. A.: Morlwakl. F.; Azuma, A.; Osa. T. J . Urg. Chem. 1080, 5 4 , 295. Ueno, A.; Moriwakl, F.; Om, T.; Hamada, F.; Mural, K. Bull. Chem. Soc. Jpn. 1088, 5 9 , 465. Mlnato, S.; Om, T.; Ueno, A. J . Chem. Soc.,Chem. Cam”.1001, 107. MlGto. S.; Osa, T.; Morita, M.; Nakamura. A.; Ikeda, H.; Toda, F.; Ueno, A. Photochem. Photobiol. 1001, 54. 593. Ueno, A.; Tomb, Y.; Osa, T. Chem. Left. 1088, 1835. Harada, N.; Nakanlshl. K. Clrcuiar Dlchrdc Spectroscopy, Exciton Chpling in Ckganic S k ” k b y ; Tokyo-Kagaku-DoJln: Tokyo, 1982. Gamer, F.; Saenger, W.; Spatz, H.Ch. J . Am. Chem. Soc. 1087, 89, 14. Harada, A.; F u w , M.; Nozakura, S. Macromdecules 1077. 10, 878. Hemal, S. Bull. Chem. Soc. Jpn. 1082, 5 5 , 2721. Ueno, A.; Suzuki, I.; Osa, T. Anal. Chem. 1000, 62, 2481. Ueno, A.; Mlnato. S.; Susukl, I.; Fukushlma, M.; Ohkubo, M.; Osa. T.; Hamada, F.; Mural, K. Chem. Left. 1000, 605.
RECEIVED for review October 25,1991. Accepted February 21, 1992.
Prediction of Carbon4 3 Nuclear Magnetic Resonance Chemical Shifts by Artificial Neural Networks Lawrence S. Anker and Peter C. Jurs*
Department of Chemistry, The Pennsylvania State University, 152 Davey Laboratory, University Park, Pennsylvania 16802
Empirical modek relatlng atom-based structural descriptors to lacNMR chemlcal rMns have been used to accurately dmulate 13CNMR spectra for compounds whose shifts are unknown. I n thb work neural networks are investigated as a supplement to regredon analysis In linking structural deaccrlptm to chemlcal shms. A recently studied data set of 431 ketoeterold carbon atoms Is reexamined using neural networks. Thk approach allows the neural network aspects of the study to be emphasized and provkkr a barb lor comparban wlth regresdon results. A Mly-comectsd threelayer ~ a i m t w o r i
