Solubilization of 1,4,5,8-Naphthalenediimides and 1,8-Naphthalimides

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Solubilization of 1,4,5,8-Naphthalenediimides and 1,8-Naphthalimides through the Formation of Novel Host-Guest Complexes with r-Cyclodextrin Sergio Brochsztain and Mario J. Politi* Laborato´ rio Interdepartamental de Cine´ tica Ra´ pida, Departamento de Bioquı´mica, Instituto de Quı´mica, Universidade de Sa˜ o Paulo, Caixa Postal, 26077, Sa˜ o Paulo, SP, 05599-970, Brazil Received December 14, 1998. In Final Form: April 8, 1999 Solubility studies were performed in aqueous solutions of 1,8-naphthalimides and 1,4,5,8-naphthalenediimides (Scheme 1). A large solubility increase was found for N-butyl-1,8-naphthalimide (MBN) and N,N′-dibutyl-1,4,5,8-naphthalenediimide (DBN) in the presence of R-cyclodextrin (R-CD), indicating the formation of inclusion complexes. The presence of the N-butyl group is required for complex formation, leading to the conclusion that the butyl groups are the binding sites for R-CD. Accordingly, the analysis of solubility isotherms for the systems MBN/R-CD and DBN/R-CD showed the presence of 1:1 complexes for the former and of both 1:1 and 1:2 complexes for the latter. Association constants for the two systems were estimated, giving K ) 470 M-1 for the MBN/R-CD complex and K11 ) 1316 M-1 and K12 ) 329 M-1 for the stepwise association constants in the DBN/R-CD system. MBN undergoes hydrolysis in water, but the reaction is inhibited upon complexation with R-CD. The remarkable solubilization in water and stabilization toward hydrolysis makes these novel complexes of imides and diimides with R-CD potentially useful in the pharmaceutical applications known for these imides, as well as in the preparation of new materials, like polyimide-based polyrotaxanes.

Introduction Cyclodextrins (CDs) are cyclic oligosaccharides consisting of R-1 f 4 linked D-glucopyranosyl residues.1 They are produced by enzymatic degradation of starch, giving mainly three types of CDs: the R-, β-, and γ-CDs, containing six, seven, and eight glucose units, respectively. The circularly linked glucose units result in a molecule shaped like a truncated cone, with an internal cavity capable of hosting organic guests. The formation of hostguest complexes, with the inclusion of a great variety of organic molecules in the cavity of the cyclodextrins, has been the subject of renewed interest.2 We report here studies on the complex formation between cyclodextrins and naphthalenic imides and diimides. Naphthalenic imides are compounds of current interest in biological and medical areas as well as in supramolecular chemistry and materials science. Biological applications rely mainly on their pharmacological activity as local anesthetics,3 tumoricidals,4 and antivirals.5 In recent years, the use of naphthalenic imides in photochemoterapy has also been developed, particularly with the hydroperoxy-substituted derivatives (known as photo* Corresponding author. Fax: (55) (11) 815-5579. E-mail: [email protected]. (1) (a) Szejtli, J. Cyclodextrins and Their Inclusion Complexes; Akademiai Kiado: Budapest, 1982. (b) Szejtli, J., Osa, T., Eds. Cyclodextrins; Pergamon: Elmsford, NY, 1996. Szejtli, J. In Comprehensive Supramolecular Chemistry; Atwood, J. L., Davies, J. E. D., MacNicol, D. D., Vogtle, F., Eds.; Elsevier: Oxford, 1996; Vol. 3. (2) (a) Hoshino, M.; Imamura, M.; Ikehara, K.; Hama, Y. J. Phys. Chem. 1981, 85, 1820. (b) Yorozu, T.; Hoshino, M.; Imamura, M.; Shizuka, H. J. Phys. Chem. 1982, 86, 4422. (c) Hamai, S. Bull. Chem. Soc. Jpn 1982, 55, 2721. (d) Schuette, J. M.; Ndou, T.; Pen˜a, A. M.; Greene, K. L.; Williamson, C. K.; Warner, I. M. J. Phys. Chem. 1991, 95, 4897. (e) Soujanya, T.; Krishna, T. S. R.; Samanta, A. J. Photochem. Photobiol. A: Chem. 1992, 66, 185. (f) Fraiji, E. K., Jr.; Cregan, T. R.; Werner, T. C. Appl. Spectrosc. 1994, 48, 79. (g) Barros, T. C.; Stefaniak, K.; Holzwarth, J. F.; Bohne, C. J. Phys. Chem. A 1998, 102, 5639. (3) (a) Mattocks, A. M.; Hutchison, O. S. J. Am. Chem. Soc. 1948, 70, 3474. (b) Da Settimo, A.; Primofiore, G.; Ferrarini, P. L.; Ferretti, M.; Barili, P. L.; Tellini, N.; Bianchini, P. Eur. J. Med. Chem. 1989, 24, 263.

Fenton reagents),6 which have the ability of selectively cleaving DNA strands. Another important biological application of naphthalenic imides is as fluorescent labeling agents for biological systems.7 In addition to the biological interest, naphthalenic imides have been used for technological purposes, such as in optical brighteners8 and laser dyes.9 More recently, the potential applications of this class of compounds were further broadened with their use as building blocks in supramolecular assemblies and new molecular materials. These applications range from Langmuir-Blodgett films10 to electrically conducting materials,11 π-stacked imide anion radicals,12 nanotube-like structures,13 metallo(4) (a) Brana, M. F.; Sanz, A. M.; Castellano, J. M.; Roldan, C. M.; Roldan, C. Eur. J. Med. Chem. 1981, 16, 207. (b) Kirshenbaum, M. R.; Chen, S.-F.; Behrens, C. H.; Papp, L. M.; Stafford, M. M.; Sun, J.-H.; Behrens, D. L.; Fredericks, J. R.; Polkus, S. T.; Sipple, P.; Patten, A. D.; Dexter, D.; Seitz, S. P.; Gross, J. L. Cancer Res. 1994, 54, 2199. (5) (a) Rideout, D.; Schinazi, R.; Pauza, C. D.; Lovelace, K.; Chiang, L.-C.; Calogeropoulou, T.; McCarthy, M.; Elder, J. H. J. Cell. Biochem. 1993, 51, 446. (b) Chanh, T. C.; Lewis, D. E.; Allans, J. S.; Sogandaresbernal, F.; Judy, M. M.; Utecht, R. E.; Matthews, J. L. AIDS Res. Human Retrovir. 1993, 9, 891. (c) Hayes, B. A.; Gupta, S.; Chang, S. C.; Utecht, R. E.; Lewis, D. E. J. Labelled Compd. Radiopharm. 1996, 38, 607. (6) (a) Saito, I.; Takayama, M.; Matsuura, T. J. Am. Chem. Soc. 1990, 112, 883. (b) Matsugo, S.; Kawanishi, S.; Yamamoto, K.; Sugiyama, H.; Matsuura, T.; Saito, I. Angew. Chem., Int. Ed. Engl. 1991, 30, 1351. (c) Saito, I. Pure Appl. Chem. 1992, 64, 1305. (7) (a) Stewart, W. W. Nature 1981, 292, 17. (b) Middleton, R. W.; Parrick, J. J. Heterocycl. Chem. 1985, 22, 1567. (c) Middleton, R. W.; Parrick, J.; Clarke, E. D.; Wardman, P. J. Heterocycl. Chem. 1986, 23, 849. (d) Yasaka, Y.; Tanaka, M.; Shono, T.; Tetsumi, T.; Katakawa, J. J. Chromatogr. 1990, 508, 133. (8) Dorlars, A.; Schellhammer, C.-W.; Schroeder, J. Angew. Chem., Int. Ed. Engl. 1975, 14, 665. (9) Pardo, A.; Martin, E.; Poyato, J. M. L.; Camacho, J. J.; Guerra, J. M.; Weigand, R.; Bran˜a, M. F.; Castellano, J. M. J. Photochem. Photobiol. A: Chem. 1989, 48, 259. (10) (a) Cammarata, V.; Kolaskie, C. J.; Miller, L. L.; Stallman, B. J. J. Chem. Soc., Chem. Commun. 1990, 1290. (b) Cammarata, V.; Atanasoska, L.; Miller, L. L.; Kolaskie, C. J.; Stallman, B. J. Langmuir 1992, 8, 876. (c) Kwan, V. W. S.; Cammarata, V.; Miller, L. L.; Hill, M. G.; Mann, K. R. Langmuir 1992, 8, 3003.

10.1021/la9817157 CCC: $18.00 © 1999 American Chemical Society Published on Web 05/27/1999

Solubilization of Imides through Complex Formation Scheme 1. Structures of the 1,4,5,8-Naphthalenediimides and 1,8-Naphthalimides Employed

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development in our laboratory. Polyimides have been widely used in microelectronics and other technological applications,19 but their usefulness is limited by the low solubility. Our studies show that inclusion in cyclodextrins could lead to polyimides with improved solubility. Experimental Section

macrocycles,14 and the mimicry of the photosynthetic reaction center.15 Despite the importance acquired by the naphthalenic imides in recent years, there have been no reports in the literature concerning complexes between CDs and these compounds, except for a recent report from this laboratory16 describing the complex formation between CDs and 2,3- and 1,8-naphthalimides. In the present paper, we report on the interactions of R-, β-, and γ-cyclodextrins with the diimides N,N′-dibutyl-1,4,5,8-naphthalenediimide (DBN) and 1,4,5,8-naphthalenediimide (DHN) and with the monoimides N-butyl-1,8-naphthalimide (MBN) and 1,8-naphthalimide (MHN) (Scheme 1). The formation of novel inclusion complexes with improved water solubility between R-CD and the N-butyl-substituted imides and diimides is demonstrated. The study of CD complexes with naphthalenic imides is important from both the biological and technological points of view. It is well-known that cyclodextrins can enhance the pharmacological activity of many drugs.1 This effect is due to the solubilization of the active component, which is usually a sparingly water soluble organic molecule. A better solubilization of the active principle in water results in an increased bioavailability of the drug.1 Since naphthalenic imides are usually poorly soluble in water, the present study is a contribution to improve the pharmaceutical actions described above. In recent years, the possibility of threading cyclodextrin rings on polymer chains, leading to the formation of polyrotaxanes17 and molecular nanotubes,18 has been exploited as a new route to produce molecular materials and devices. In this regard, the study of inclusion complexes between CDs and 1,4,5,8-naphthalenediimides serves as an initial guideline for the synthesis of more elaborated structures, such as polyimide chains included in cyclodextrins, a project which is currently under (11) (a) Heywang, G.; Born, L.; Fitzky, H. G.; Hassel, T.; Hocker, J.; Muller, H. K.; Pittel, B.; Roth, S. Angew. Chem., Int. Ed. Engl. 1989, 28, 483. (b) Miller, L. L.; Zhong, C.-J.; Kasai, P. J. Am. Chem. Soc. 1993, 115, 5982. (12) (a) Penneau, J.-F.; Stallman, B. J.; Kasai, P. H.; Miller, L. L. Chem. Mater. 1991, 3, 791. (b) Miller, L. L.; Duan, R. G.; Hong, Y.; Tabakovic, I. Chem. Mater. 1995, 7, 1552. (13) Kimizuka, N.; Kawasaki, T.; Hirata, K.; Kunitake, T. J. Am. Chem. Soc. 1995, 117, 6360. (14) (a) Bilyk, A.; Harding, M. M. J. Chem. Soc., Chem. Commun. 1995, 1697. (b) Houghton, M. A.; Bilyk, A.; Harding, M. M.; Turner, P.; Hambley, T. W. J. Chem. Soc., Dalton Trans. 1997, 2725. (15) (a) Hasharoni, K.; Levanon, H.; Greenfield, S. R.; Gosztola, D. J.; Svec, W. A.; Wasielewski, M. R. J. Am. Chem. Soc. 1995, 117, 8055. (b) Hasharoni, K.; Levanon, H.; Greenfield, S. R.; Gosztola, D. J.; Svec, W. A.; Wasielewski, M. R. J. Am. Chem. Soc. 1996, 118, 10228. (16) Brochsztain, S.; Rodrigues, M. A.; Politi, M. J. J. Photochem. Photobiol. A: Chem. 1997, 107, 195. (17) (a) Ogata, N.; Sanui, K.; Wada, J. J. Polym. Sci., Polym. Lett. Ed. 1976, 14, 459. (b) Wenz, G.; Keller, B. Angew. Chem., Int. Ed. Engl. 1992, 31, 197. (c) Harada, A.; Li, J.; Kamachi, M. Nature 1994, 370, 126. (d) Harada, A. Coord. Chem. Rev. 1996, 148, 115 (e) Nepogodiev, S. A.; Stoddart, J. F. Chem. Rev. 1998, 98, 1959. (18) (a) Harada, A.; Li, J.; Kamachi, M. Nature 1993, 364, 516. (b) Li, G.; McGown, L. B. Science 1994, 264, 249.

Materials. N,N′-Dibutyl-1,4,5,8-naphthalenediimide20 (DBN) and 1,4,5,8-naphthalenediimide21 (DHN) were prepared by reaction of 1,4,5,8-naphthalenetetracarboxilic dianhydride (Aldrich) with butylamine or NH4OH, respectively, according to reported methods. N-Butyl-1,8-naphthalimide (MBN) was prepared from 1,8-naphthalic anhydride and butylamine, as previously reported.22 Characterization of the products (elemental analysis, IR, NMR, melting point) was according to literature values. 1,8-Naphthalimide (MHN) was purchased from Aldrich. R, β, and γ-cyclodextrins were obtained from Fluka. Spectral grade solvents and double-distilled Milli-Q water were employed throughout. Equipment. UV-vis absorption spectra were taken with a Hitachi U-2000 spectrophotometer, interfaced to a PC-compatible 386 computer for data handling and storage. Either 1 or 5 cm path length quartz cuvettes were employed. Fluorescence spectra (ratio mode) were registered with a SPEX-DM-3000F fluorometer, using a frontal-face arrangement. Emission spectra were taken with excitation at 320 nm. The slits were fixed at 0.5 mm (excitation) and 2.0 mm (emission). The spectra were computer corrected using the software provided with the apparatus. In the solubility measurements, a dual-action shaker (LabLine Instruments, Inc.) was employed for equilibration of the samples. For the determination of DBN solubility in water, vacuum filtration was performed using a disposable filtering unit Sterifil-B (Millipore), with HATF membrane (0.45 µm pore size). In all other cases, filtrations were performed with 0.2 µm pore size Acrodisc filters (Gelman Sciences) attached to glass syringes. Spectroscopic Measurements. Solutions of the imides for spectroscopic measurements were prepared by adding aliquots from concentrated stock solutions into cuvettes containing the solvent or solution of interest. The stock solutions were typically (1-5) × 10-3 M in DMF (DBN), DMSO (DHN), or CH3CN (MBN). The concentrations used in the measurements were usually 5 × 10-6 M for diimides and 1 × 10-5 M for monoimides. Suspensions of DBN and DHN in water were prepared similarly, i.e., by adding aliquots from stock solutions to give a formal diimide concentration of 5 × 10-6 M. Fluorescence quantum yields were calculated relative to the area of the corrected emission spectrum of N-butyl2,3-naphthalimide (φf ) 0.261 in water).23 Solubility Measurements. The solubility of the imides in water was measured by stirring mixtures of the solid imides with H2O (20 h, 23 °C) and filtering and analyzing the filtrates by absorption spectroscopy. In the case of the diimides, however, the concentration in the filtrates was too low to be determined in this way.24 The solubility of DBN was then determined as follows. Solid DBN in excess was stirred with 1 L of water (20 h, 23 °C), the mixture was filtered, and the filtrate was extracted with five portions (20 mL each) of freshly distilled chloroform.25 The chloroform extracts were joined together, the solvent was evaporated, and the residue was dissolved in CH3CN to make 1 mL of solution. The CH3CN solution was then analyzed by (19) Mittal, K. L., Ed. Polyimides; Plenum Press: New York, 1982. (20) (a) Sep, W. J.; Verhoeven, J. W.; de Boer, Th. J. Tetrahedron 1975, 32, 1065. (b) Kheifets, G. M.; Martyushina, N. V.; Mikhailova, T. A.; Khromov-Borisov, N. V. J. Org. Chem. USSR 1977, 13, 1159. (21) Nelsen, S. F. J. Am. Chem. Soc. 1967, 89, 5925. (22) Alexiou, M. S.; Tychopoulos, V.; Ghorbanian, S.; Tyman, J. H. P.; Brown, R. G.; Brittain, P. I. J. Chem. Soc., Perkin Trans. 2 1990, 837. (23) Barros, T. C.; Molinari, G. R.; Berci-Filho, P.; Toscano, V. G.; Politi, M. J. J. Photochem. Photobiol. A: Chem. 1993, 76, 55. (24) The lowest diimide concentrations detectable by absorption or fluorescence spectroscopies were in the order of 2 × 10-7 M. (25) DBN is freely soluble in chloroform so that its partition between H2O and CHCl3 can be assumed to be highly favorable towards the organic solvent.

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Brochsztain and Politi

Table 1. Absorption and Emission Data for Solutions of Naphthalenic Imidesa,b diimide

solvent

λmaxabs (nm)

max (M-1 cm-1)c

λmaxem (nm)

DBN DBN DBN DBN DHN DPNd MBNe

R-CD 0.05 M (aq) EtOH/H2O (1:1) CH3CN/H2O (1:1) CH3CN CH3CN HClO4 0.1 M H2O

348, 365, 386 344, 360, 381 343, 359, 380 340, 357, 377 338, 354, 373 345, 362, 383 343

25700

395, 416, 442 389, 410, 435 388, 408, 431 383, 404, 428 380, 398, 423 392, 412, 435 386

25500 25700 24900 21100 12800

quantum yield 0.014 0.001 0.001 < 0.001 0.016 0.364

a The lowest wavelength absorption and the highest wavelength emission maxima are shoulders in the spectra. b The values in boldface correspond to the most intense peak. c  values corresponding to the most intense peak. d Data from ref 29. e Data from ref 23.

Scheme 2. Most Likely Structures of DBN/r-CD Complexes with Either 1:1 or 1:2 Stoichiometrya

Figure 1. (A) Absorption spectra of 4.8 × 10-6 M DBN in water (dotted line), in aqueous 0.05 M R-cyclodextrin (dashed line), and in acetonitrile (solid line). (B) Emission spectra of 4.8 × 10-6 M DBN in water (dotted line), in aqueous 0.05 M R-cyclodextrin (dashed line), and in acetonitrile (solid line). Excitation ) 320 nm. absorption spectroscopy, and the [DBN] found was divided by a factor of 103 to give the solubility in water. The solubility method26 was used to study complex formation between naphthalenic imides and R-cyclodextrin. A series of screw-capped glass vials were charged with the solid imide, in considerable excess of its solubility limit (typically ca. 10 mg was weighed). Fixed volumes (usually 5 mL) of aqueous 0.01 M NaCl solutions containing increasing concentrations of R-CD were added to the vials, and the samples were brought to solubility equilibrium by shaking for 20 h in an air-conditioned room at 23 ( 1 °C (preliminary experiments showed that this time was long enough for equilibration). The samples were then filtered, and the imide concentration in the filtrates was determined by absorption spectroscopy. For low CD concentrations, the filtrates were analyzed directly in the spectrophotometer, but for high [CD], it was necessary to dilute the filtrates with H2O/EtOH mixtures (1:1 v/v) before analysis (at intermediate CD concentrations, however, the measurements could be done either with dilution or not, and the two procedures could be compared, giving equivalent results). The apparent solubility of the imide was then plotted as a function of cyclodextrin concentration, giving the solubility diagrams presented in Figures 3 and 6. The treatment of the data is given in the results section.

Results 1,4,5,8-Naphthalenediimides. Spectroscopical Studies. The absorption and emission spectra of DBN in CH3CN solutions showed well-defined vibrational structures, small Stokes shifts (λmaxab ) 377 nm, λmaxem ) 383 nm; Table 1) and mirror image relationships with each other (Figure 1). These features are typical of 1,4,5,8-naphthalenediimides in organic solvents.27 In water, on the other (26) (a) Connors, K. A.; Pendergast, D. D. J. Am. Chem. Soc. 1984, 106, 7607. (b) Connors, K. A.; Paulson, A.; Toledo-Velasquez, D. J. Org. Chem. 1988, 53, 2023. (c) Connors, K. A. Binding Constants: the Measurement of Molecular Complex Stability; Wiley-Interscience: New York, 1987; Chapter 8. (27) (a) Green, S.; Fox, M. A. J. Phys. Chem. 1995, 99, 14752. (b) Barros, T. C.; Brochsztain, S.; Toscano, V. G.; Berci-Filho, P.; Politi, M. J. J. Photochem. Photobiol. A: Chem. 1997, 111, 97. (c) Aveline, B. M.; Matsugo, S.; Redmond, R. W. J. Am. Chem. Soc. 1997, 119, 11785.

a The truncated cone structures represent the cyclodextrin rings.

hand, DBN was not soluble, but formed suspensions with interesting spectroscopical properties. The suspensions were turbid, causing intense scattering that masked the absorption spectra. The emission spectra, however, showed a characteristic broad, excimer-like band with a maximum at ca. 470 nm (Figure 1), a red shift of almost 100 nm as compared to the maximum in CH3CN (similar excimerlike bands were observed in concentrated solutions of DBN in CH3CN, λmax = 500 nm, or DMF, λmax = 550 nm). When the suspensions were filtered through 0.2 µm filters, the filtrates obtained were clear, with no detectable DBN absorbance or fluorescence, showing that all the diimide was retained in the filter. These results are consistent with the presence of a microcrystalline phase in DBN suspensions. The presence of a large excess of R-cyclodextrin (0.05 M) prevented the formation of DBN suspensions, resulting in the total solubilization of the diimide in water. The structured absorption and emission spectra of DBN in the presence of R-CD (Figure 1) were very similar to those in acetonitrile solutions, except for a red shift of ca. 10 nm (Table 1). The solutions were clear, showing no turbidity or excimer-like emission. All the diimide was recovered in the filtrate when these solutions were filtered through 0.2 µm membranes. These results show that inclusion complexes are formed between DBN and R-CD. In contrast to R-CD, the presence of β- or γ-cyclodextrins did not result in solubilization of DBN suspensions, suggesting that complexes were not formed in these cases. Taking in account that 1,4,5,8-naphthalenediimide rings are too large to fit inside the cavity of R-CD, it can be concluded that the binding sites for R-CD are the butyl groups of DBN (Scheme 2). Furthermore, the N-Hsubstituted diimide (DHN)28 was not solubilized by any

Solubilization of Imides through Complex Formation

Langmuir, Vol. 15, No. 13, 1999 4489 Table 2. Solubility of Naphthalenic Imides in Water and in Aqueous 0.1 M r-Cyclodextrina solubility (mol/L) compound DBN DHN MBN MHN a

water (S0)

aqueous 0.1 M R-CD

5 × 10-9 1 are formed, but this does not seem to be the case here, considering that MBN has only one N-butyl group for binding. It is expected that only 1:1 complexes would be formed in this case, as shown in Scheme 3. This was confirmed by the log-log plot (eq 4) in the inset of Figure 6, which was linear and gave a slope of 1.3, consistent with n ) 1. In the case of 1:1 complexes, the association equilibrium is described by eq 5. The mass balance expressions on S and L are given by eqs 13 and 14, respectively. Combining eqs 5, 13, and 14 gives eq 15, which is the solubility isotherm for the 1:1 complexation mode.

St ) S0 + [SL]

(13)

Lt ) [L] + [SL]

(14)

St ) S0 +

K11S0Lt 1 + K11S0

(15)

Equation 15 shows a linear dependence of St on Lt, and K11 can be obtained from the slope of the plot. The data in Figure 6 were then treated as a straight line, despite the slight curvature observed, giving K11 ) 470 M-1 (Table 4). Solubility experiments with the system MBN/R-CD were also performed in acidic media (1 × 10-3 M HCl + 0.1 M NaCl, pH ) 3), to make sure that hydrolysis was not influencing the results observed (MBN is stable in acidic water solutions33). The solubility diagram obtained (not shown) was quite similar to that obtained with neutral water, giving K11 ) 527 M-1 and a slope of 1.2 in the loglog plot, consistent with a small influence of the hydrolysis reaction on the solubility diagrams. Discussion Before discussing the complex formation between naphthalenic imides and cyclodextrins, it is opportune to (33) Barros, T. C. Ms.C. Thesis, Universidade de Sa˜o Paulo, 1991.

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Figure 6. Solubility diagram for the complex MBN/R-CD in aqueous 0.01 M NaCl (solid line is the corresponding linear regression assuming that eq 15 holds for this system). Inset: log-log plot of the data (eq 4), with the solid line representing the linear regression.

point out the striking differences in the physicochemical behavior of 1,8-naphthalimides and 1,4,5,8-naphthalenediimides. The monoimides are by far more water soluble than the diimides (Table 2). The diimides, on the other hand, are much more stable toward hydrolysis than the monoimides. The absorption and emission bands of the monoimides are structureless and lie at higher energies than the structured bands of the diimides (Table 1). These differences show that the presence of the extra imide group in the diimides results in a planar, rigid molecule with a large degree of stabilization by resonance. Concerning the solubility, one would expect that the introduction of two extra carbonyl groups in the 1,8naphthalimides to make the 1,4,5,8-naphthalenediimides would render the compounds more polar and hence increase the solubility in water, but the opposite behavior was observed, even with the N-H-substituted imides (compare DHN with MHN in Table 2). The low solubility of the diimides relative to the monoimides can be attributed to the high planarity of the diimide molecules, resulting in a great tendency toward stacking. Accordingly, the remarkable solubilization effect of R-CD on DBN (Table 2) must arise mainly from the presence of a bulky group around the alkyl chains preventing diimide stacking. Solubility increases have also been observed with 3,4,9,10-perylenediimides substituted with branched chains or bulky groups, which hinder molecular stacking (the socalled “swallow-tail substituent effect”).34 Since monoimides have less tendency to stack than diimides, the effect of R-CD on MBN solubility is less pronounced than that observed with DBN. The excimer-like emission band observed in DBN suspensions is analogous to that observed with crystalline aromatic hydrocarbons, like pyrene,35 and heterocycles, like acridine.36 This phenomenon is defined as a selftrapped exciton37 and is caused by the arrangement of the molecules as card-packed dimeric units within the crystals, (34) (a) Langhals, H.; Demmig, S.; Potrawa, T. J. Prakt. Chem. 1991, 333, 733. (b) Langhals, H.; Jona, W. Angew. Chem., Int. Ed. Engl. 1998, 37, 952. (35) (a) Ferguson, J. J. Chem. Phys. 1958, 28, 765. (b) Stevens, B. Spectrochim. Acta 1962, 18, 439. (36) Asahi, T.; Furube, A.; Masuhara, H. Bull. Chem. Soc. Jpn. 1998, 71, 1277. (37) Rashba, E. I. In ExcitonssSelected Chapters; Rashba, E. I., Sturge, M. D., Eds.; Elsevier: Amsterdam, 1987; Chapter 7, p 273.

Brochsztain and Politi

since the molecules cannot diffuse in the solid state to form excimers. All the evidence suggests, therefore, that DBN aqueous suspensions are formed by mycrocrystals containing stacked diimide molecules. The excimer-like bands observed in concentrated DBN organic solutions, on the other hand, can be attributed to true excimers (pyrene also forms excimers in concentrated alcoholic solutions35). The effect of R- and γ-CDs on the exciton band at low CD concentrations, shown in Figure 2, is remarkable. It could be that the presence of CDs fragmented the mycrocrystals in smaller particles. If the exciton emission was due to long-range stacking interactions, fragmentation would result in a decreased emission. An alternative explanation is that the CDs somehow perturb the crystals, causing a transition to a different crystalline, nonstacked form. In the case of γ-CD, another possible explanation for the phenomenon is the formation of insoluble complexes. The actual cause for the phenomena is not known, and new studies are being presently undertaken to clarify this point. The results of complex formation between naphthalenic imides and cyclodextrins are summarized in Table 3. The ability of the imides to form complexes with CDs was assigned based on solubility criteria so that only soluble complexes are taken into account in the table. The trends observed with R-cyclodextrin show clearly that the butyl groups are the included portion of the imides, since imides missing a N-alkyl substituent do not form complexes with R-CD. The ring system of the aromatic imides, on the other hand, is too large to fit inside the small R-CD cavity (internal diameter ) 5.7 Å).1 Let us now consider the case of β-cyclodextrin. According to Table 3, the 1,4,5,8-naphthalenediimides do not form complexes with β-CD, regardless of the N-substituent. This reflects the fact that the β-CD cavity is too large for a good fit with the butyl groups, but on the other hand, is too narrow to fit the naphthalenediimide group. The width of a 1,4,5,8-naphthalenediimide group has been estimated as 8.5 Å,10b while the cavity of β-CD has an internal diameter of 7.8 Å.1 Although formally 1,4,5,8-naphthalenediimides are naphthalene derivatives, the structure of the molecule resembles better that of pyrene. Pyrene is known to form both 1:1 and 1:2 complexes with β-CD, despite its molecular width (8.2 Å), which has been explained by inclusion of the narrow part of the molecule (the rings at positions 1,2,3 and 6,7,8).38 Comparing the behavior of pyrene with that of 1,4,5,8-naphthalenediimides, it can be concluded that the extra width provided by the imide carbonyls hinders the entrance of the imide rings in the β-CD cavity. Results from previous studies,16 displayed in Table 3, show that the 1,8-naphthalimides MBN and MHN do form inclusion complexes with β-CD. If the conclusion above is correct, the complexes formed between monoimides and β-CD must take place with the naphthalene side of the molecules, as shown in Scheme 3 (spectral changes were observed in these cases, showing that the chromophoric part is indeed included).16 Concerning the interactions of γ-cyclodextrin with the imides, the same pattern was observed as in the case of β-CD (Table 3). DBN solubility was not increased by the presence of γ-CD, indicating that complexes are not formed in this case. Furthermore, studies with the water soluble diimide DPN and with 1,4,5,8-naphthalenetetracarboxylic (38) (a) Kano, K.; Takenoshita, I.; Ogawa, T. J. Phys. Chem. 1982, 86, 1833. (b) de la Pen˜a, A. M.; Ndou, T.; Zung, J. B.; Warner, I. M. J. Phys. Chem. 1991, 95, 3330.

Solubilization of Imides through Complex Formation

dianhydride showed no evidence for complex formation between these compounds and γ-CD (Table 3).39 It should be noticed that the cavity of γ-CD (internal diameter ) 9.5 Å)1 is wide enough to include a 1,4,5,8-naphthalenediimide group. The absence of complexes can be explained if the carbonyl groups of the imides (and of the anhydride) are strongly hydrogen bonded to water molecules, increasing the molecular width, and the energy to break these hydrogen bonds is not compensated by the energetic gain of the inclusion. The formation of insoluble DBN/ γ-CD complexes, nevertheless, cannot be ruled out. The data in Table 3 shows that the monoimides MBN and MHN form complexes with γ-CD. In this case, as in the case of β-CD, it is very likely that the included part is the naphthyl group (Scheme 3), according to the conclusions above. Another point to be considered is the magnitude of the association constants obtained here (Table 4). For the system DBN/R-CD, the constant for the association of the first CD (K11) is 4 times larger than that of the second (K12). This condition was imposed when eq 11 was applied to find the values of the constants, since it was assumed that the two sites behave independently (a ) 1 in eq 11). Thus, the number 4 in eq 11 is just a statistical factor,26 meaning that the CD ring can combine with a higher possibility to free DBN (more sites available) than to the 1:1 DBN/R-CD complex. The assumption that a ) 1 is quite reasonable in the case of DBN. Cooperative binding of two ligand molecules to one substrate is usually brought about mainly by three factors.26 (a) Changes in electronic distribution at one site upon binding of L to the other site. This effect should be very small in the case of DBN, since butyl groups are not polarizable and are not conjugated to the imide ring. Furthermore, calculations reported in the literature indicate that the HOMO electronic density is zero at the imide nitrogens40 (node in the wave function), which means that substitution at that position should not disturb the ring electronic density distribution. (b) Repositioning of the first ligand molecule upon binding of the second L. This effect involves an overall conformational change of the substrate molecule, which is very unlikely in the case of DBN, since the two sites are separated by a rigid ring system. (c) Ligand-ligand interaction effects. This factor depends on a close proximity between the two CD molecules in the 1:2 complex, which is not expected in the case of DBN/R-CD complexes, since the two butyl groups are considerably far from each other. According to these considerations, the binding sites of DBN can be regarded as approximately independent, and the value a ) 1 is justified. According to the considerations above, K12 should be used to compare the affinity of R-CD for the diimide DBN to that for the monoimide MBN. The value of K12 for the system DBN/R-CD (Table 4) is of the same order of magnitude as K11 in the MBN/R-CD system. Considering the assumptions made and the errors inherent to the method, a similar affinity of R-CD toward the butyl groups of mono- and diimides is inferred. The values for the association constants in the systems DBN/R-CD and MBN/R-CD are considerable higher than (39) The absence of complexes between these compounds and γ-CD was confirmed by spectroscopic and solubility measurements in the case of DPN and by hydrolysis rate measurements in the case of 1,4,5,8naphthalenetetracarboxylic dianhydride. The dianhydride is readily hydrolyzed in water with a half-life in the order of a few minutes. The hydrolysis rate and the initial absorption spectra (at t ) 0) are both unaffected by the presence of R-, β-, or γ-CD, leading to the conclusion that no complexes are formed. (40) Adachi, M.; Murata, Y.; Nakamura, S. J. Phys. Chem. 1995, 99, 14240.

Langmuir, Vol. 15, No. 13, 1999 4493 Scheme 4. Hydrolysis of MBN in the Presence and in the Absence of r-CD

the ones reported for butylamine and analogue compounds.41 That shows an extra stabilization in the complexes with the imides, probably by means of hydrogen bonding between the imide carbonyls and cyclodextrin hydroxyls. Another important consequence of the complex formation between naphthalenic imides and R-CD is the stabilization of the imide bonds toward hydrolysis. The phenomenon is best observed in the case of N-butyl-1,8naphthalimide (Figure 5), which in pure water exists in equilibrium with the hydrolyzed naphthalamide form (eq 12). The situation in Figure 5 is conveniently described by Scheme 4. Since the experiments were carried out in the presence of excess solid imide, the whole system was in equilibrium with the solid phase. In these conditions, the [MBN] was fixed in its solubility limit (S0), and the concentration of the naphthalamide I was therefore also fixed (S′0) and determined by the equilibrium constant for the hydrolysis (Keq H2O). In the presence of increasing concentrations of R-CD, an enrichment of the imide form in solution was observed, while the concentration of the opened form I remained constant at S′0. At high CD concentrations, the spectrum became virtually that of the imide form (Figure 5), because the contribution of the amide becomes irrelevant. This suggests that the hydrolysis product I is not solubilized by R-CD, indicating that I does not form complexes with R-CD (Ka′ = 0, Scheme 4). It is also possible, however, that complexes I/R-CD are indeed formed, but I undergoes fast ring closure to the imide form (DBN) in the complexes (Keq R-CD = 0, Scheme 4). This possibility is being currently investigated in our laboratory. In any case, the net result is the stabilization of the imide form by complexation with R-CD. This stabilization probably arises from hydrogen bonding between the imide carbonyls and the hydroxyl groups on the edges of the cyclodextrin ring, as pointed out above. Conclusions N-alkyl-substituted 1,8-naphthalimides and 1,4,5,8naphthalenediimides form host-guest complexes with R-cyclodextrin, with inclusion of the alkyl chain in the CD cavity. The solubility of the imides in water is enhanced by several orders of magnitude upon complexation, and hydrolysis of the imide ring is prevented. The solubilization (41) (a) Miyajima, K.; Ikuto, M.; Nakagaki, M. Chem. Pharm. Bull. 1987, 35, 389. (b) Spencer, J. N.; Mihalick, J. E.; Paul, I. M.; Petigara, B.; Wu, Z.; Chen, S.; Yoder, C. H. J. Sol. Chem. 1996, 25, 747.

4494 Langmuir, Vol. 15, No. 13, 1999

and stabilization of the diimides in the CD complexes are highly desirable for their medical use, and we are presently trying to obtain the solid complexes in order to compare their pharmacological activities with those of the free imides. The increased solubility and stability are also promising for the preparation of new materials consisting of polyimide-based polyrotaxanes, a work that is presently being developed in our laboratories.

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Acknowledgment. This work was supported by grants from the Brazilian agencies FAPESP, CNPq, Finep, and PADCT. S.B. acknowledges FAPESP for a postdoctoral fellowship. We thank Dr. Teresa C. Barros from this department for the generous gift of N-butylnaphthalamide I. LA9817157