Models of Pesticides inside Cavities of Molecular Dimensions. A Role

J. Heyrovský Institute of Physical Chemistry, Academy of Sciences of the Czech Republic, Dolejskova 3, 18223 Prague, Czech Republic, and Istituto per...
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Langmuir 2005, 21, 1923-1930

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Models of Pesticides inside Cavities of Molecular Dimensions. A Role of the Guest Inclusion in the Dechlorination Process Magdale´na Hromadova´,† Lubomı´r Pospı´sˇil,*,† Nicolangelo Fanelli,‡ and Stefania Giannarelli§ J. Heyrovsky´ Institute of Physical Chemistry, Academy of Sciences of the Czech Republic, Dolejskova 3, 18223 Prague, Czech Republic, and Istituto per i Processi Chimico-Fisici, via Moruzzi 1, 56124 Pisa, and Dipartimento di Chimica e Chimica Industriale, Universita` degli Studi, via Risorgimento 35, 56126 Pisa, Italy Received August 5, 2004. In Final Form: November 18, 2004 The reduction mechanism of the pesticide vinclozoline (3-(3,5-dichlorophenyl)-5-methyl-5-vinyl-1,3oxazolidine-2,4-dione) was studied in nonaqueous solvents in the confined environment of a cyclodextrin (CD) cavity. The effect of the cavity dimensions on the mechanism of the redox process was evaluated using glucose as a reference and using three cyclodextrin molecules of different cavity sizes, namely, RCD, βCD, and γCD. In the absence of CD the main reduction product of vinclozoline in the first reduction step is dichloroaniline. An addition of glucose leads to a quantitative change of mechanism with 10 products in total. Addition of CD, however, leads exclusively to dechlorination of the phenyl ring. The degree of dechlorination depends strongly on the choice of cyclodextrin molecule. The importance of the complex formation equilibria in the change of the mechanism is supported by a series of semiempirical AM1 quantummechanical calculations. Very good correlation (correlation coefficient 0.995) was obtained between the complex stabilization energy of the inclusion complex and the degree of pesticide dechlorination. Additionally, we were able to show that the complexes are stabilized by the formation of intermolecular hydrogen bonds between the host and guest species. CD molecules do not simply act as proton donors in a nonaqueous environment, but also protect parts of the molecule included within the cavity and steer the degradation process toward fewer products.

Introduction Dicarboximide types of pesticides are widely used as preventive, curative, and persistent fungicides particularly effective against Botrytis, Monilia, and Sclerotinia spp. on field crops, in vineyards, and in greenhouses. They are effective for treatment of tree fruits, strawberries, hops, and various types of vegetables.1 All these compounds contain a dichlorophenyl group attached to a nitrogen atom of a dicarboximide fragment of the heterocyclic ring. Trace amounts of the dicarboximide type of pesticides can be determined in foods, soil, and human urine by methods based on their alkaline degradation to 3,5-dichloroaniline.2 The decision to study the effect of “nanovessel-like” cyclodextrin molecules on the redox properties of dicarboximide-type pesticides was twofold: cyclodextrin molecules are in some countries used for retardation of seed germination and therefore can be present in soil together with applied pesticides, and such a system represents a good model for investigation of the influence of a confined environment of a cavity of molecular dimensions on the redox properties of the electroactive pesticides. Such pesticides can effectively encounter an entire range of media in soil and biological matrixes ranging from highly polar to nonpolar. Even though cyclodextrin (CD) molecules are well soluble in water, DMSO was selected as a solvent to separate the electron-transfer process of the * To whom correspondence should be addressed. E-mail: [email protected]. † Academy of Sciences of the Czech Republic. ‡ Istituto per i Processi Chimico-Fisici. § Universita ` degli Studi. (1) Wothing, C. R.; Walker, S. B. The Pesticide Manual, 8th ed.; British Crop Protection Council, 1987. (2) Will, W., Hoffmann, G. Occup. Health Ind. Med. 1997, 37, 121.

organic substrate of interest from proton reduction processes present in the aqueous solutions. We will show that the cyclodextrin molecules can influence not only release of the applied pesticides, but also their degradation mechanism. Studies of changes of the electrochemical reduction mechanism of organic compounds in the presence of cyclodextrin cavities appear in the literature sporadically.3-8 Smith and Utley5 observed profound changes in the reduction mechanism of ethyl cinnamate-, benzaldehyde-, and acetophenone-βCD complexes in N,N-dimethylformamide (DMF). βCD acts here as an efficient proton donor, and the presence of βCD influences profoundly the stereochemistry of the products. We have been involved in systematic studies of the mechanistic changes of the reduction processes of electroactive organic compounds in the presence of cyclodextrin cavities as well.9-11 (3) Takahashi, K. Chem. Rev. 1998, 98, 2013. (4) Martre, A. M.; Mousset, G.; Pouillen, P.; Prime, R. Electrochim. Acta 1991, 36, 1911. (5) Smith, C. Z.; Utley, J. H. J. Chem. Soc., Chem. Commun. 1981, 492. (6) Farnia, G.; Sandona, G.; Fornasier, R.; Marcuzzi, F. Electrochim. Acta 1990, 35, 1149. (7) Prime, R.; Martre, A. M.; Mousset, G.; Pouillen, P. Bull. Soc. Chim. Fr. 1991, 127, 18. (8) Gonzales-Romero, E., Malvido-Hermelo, B.; Bravo-Diaz, C. Langmuir 2002, 18, 46. (9) Pospı´sˇil, L.; Trskova´, R.; Colombini, M. P.; Fuoco, R. J. Inclusion Phenom. 1998, 31, 57. (10) Pospı´sˇil, L.; Hromadova´, M.; Fiedler, J.; Amatore, Ch.; Verpeaux, J.-N. J. Organomet. Chem. 2003, 668, 9. (11) Pospı´sˇil, L.; Sokolova´, R.; Hromadova´, M.; Giannarelli, S.; Fuoco, R.; Colombini, M. P. J. Electroanal. Chem. 2001, 517, 28. (12) Pospı´sˇil, L.; Sokolova´, R.; Colombini, M. P.; Giannarelli, S.; Fuoco, R. J. Electroanal. Chem. 1999, 472, 33. (13) Pospı´sˇil, L.; Sokolova´, R.; Colombini, M. P.; Giannarelli, S.; Fuoco, R. Microchem. J. 2000, 67, 305.

10.1021/la048021k CCC: $30.25 © 2005 American Chemical Society Published on Web 02/04/2005

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Figure 1. DC polarograms of 1 × 10-3 M vinclozoline in a dimethyl sulfoxide solution of 0.1 M tetrabutylammonium hexafluorophosphate electrolyte in the absence (line) and presence of proton donors: 5 × 10-3 M D-glucose (b), RCD (0), βCD (O), and γCD (4). Data were baseline-corrected, the drop time was 1 s, and the sweep rate was 5 mV/s.

In the case of atrazine pesticide the reduction of an uncomplexed form proceeds only after a protonation step (at low pH), whereas the hydrogen bonding in the inclusion complex with CD is sufficient to render the electron transfer possible even in neutral aqueous solutions. Marked changes in the reduction mechanism were observed for the group of dicarboximide-type pesticides, where it was shown that the electrochemical reduction proceeds through a release of the chloride ions (dechlorination) in the presence of CD, whereas reduction of free pesticides yields products due to the ring opening (chlorinated anilines). An interesting effect of the cyclodextrin cavity was demonstrated on the catalytic insertion of carbon monoxide into the organometallic iron-methyl bond with the purpose to prolong an alkyl chain at ambient temperature and pressure. When the reaction proceeds within the βCD cavity, the undesirable side reactions are suppressed as well as an undesirable loss of CO from the vicinity of the reactant.10 In previous reports11-15 we have characterized the reduction mechanism of three dicarboximide-type fungicides in their free form and as complexes with cyclodextrin molecules in nonaqueous solvents. The reduction of vinclozoline, procymidone, and iprodione in the presence of CDs leads to increased dechlorination of these compounds, whereas formation of the dechlorinated products correlates with the ability of pesticides to form inclusiontype complexes with CDs.15 In this paper we report on the systematic theoretical and experimental evaluation of the mutual interactions of the pesticide vinclozoline with three cyclodextrin molecules of different cavity sizes, namely, R-cyclodextrin (RCD), β-cyclodextrin (βCD), and γ-cyclodextrin (γCD) to assess the role of the guest inclusion in the dechlorination process. The internal diameter of their cavities is in the range of 0.42-0.53 nm for RCD, 0.560.65 nm for βCD, and 0.68-0.83 nm for γCD.16 Experimental Methods and Materials The electrochemical measurements were made using a laboratory-built electrochemical system consisting of a fast-rise-time potentiostat interfaced to a personal computer via the IEEE (14) Hromadova´, M.; Pospı´sˇil, L.; Giannarelli, S.; Fuoco, R.; Colombini, M. P. Microchem. J. 2002, 73, 213. (15) Hromadova´, M.; Pospı´sˇil, L.; Za´lisˇ, S.; Fanelli, N. J. Inclusion Phenom. 2002, 44, 373. (16) Saenger, W.; Jacob, J.; Gessler, K.; Steiner, T.; Hoffmann, D.; Sanbe, H.; Koizumi, K.; Smith, S. M.; Takaha, T. Chem. Rev. 1998, 98, 1787.

Hromadova´ et al. interface card PcLab model 748 (AdvanTech Co.). The voltage source was a 12-bit D/A card, PcLab model 818. A three-electrode electrochemical cell was used. A Ag|AgCl|1 M aqueous LiCl reference electrode was separated from the test solution by a nonaqueous salt bridge. The absence of any leakage of water within the time of an experiment was tested. The redox potential of 5 × 10-3 M ferrocene in 0.1 M TBAPF6 and DMSO solvent against this reference electrode was 0.505 V. Two types of working electrodes were used: a valve-operated static mercury electrode, SMDE2 (Laboratornı´ Prˇ´ıstroje, Prague), with an area of 1.42 × 10-2 cm2 and a dropping mercury electrode (DME) with a mechanical drop-time regulator, operating at a reservoir height of 45 cm and a mercury flow rate of 1.015 × 10-3 g s-1. A platinum net was used as the auxiliary electrode. Oxygen was removed from the solution by a stream of argon. A protecting argon layer blanketed the solution surface during the entire experiment. Vinclozoline with a purity certificate of pesticide standards was purchased in crystalline form from Ehrenstorfer, Augsburg, Germany, and was used as received both for preparation and as a GC/MS standard. Dimethyl sulfoxide (DMSO), tetrabutylammonium hexafluorophosphate of “analysis grade”, all three cyclodextrin compounds, and D-glucose were obtained from Fluka. Supporting electrolytes, glucose, and cyclodextrins were dried before use. DMSO was dried over the molecular sieves, and its water content was estimated to be 62 ppm by Karl Fischer titration. The reduction products were prepared by exhaustive electrolysis of a 1 × 10-3 mol L-1 solution of vinclozoline and a 5 × 10-3 mol L-1 solution of CD in DMSO. Electrolysis was performed at a mercury pool cathode at a potential of -2.15 V corresponding to the diffusion-limited current. The supporting electrolyte was precipitated from the sample by addition of 80% water. This ratio of DMSO and water forms an immiscible phase with diethyl ether, which was used for the extraction of the reduction products. After separation of the diethyl ether phase a mixture of dichloromethane and hexane was added, and diethyl ether was allowed to evaporate from the mixture. A 1 µL sample of the mixture was injected into the GC/MS instrument. The chromatographic separation was performed on a 5% phenyl-95% methylpolysiloxane HP-5MS chemical-bonded fused silica capillary column (Hewlett-Packard) of 30 m length, 0.25 mm internal diameter, and 0.25 µm film thickness. A 6890 gas chromatograph (Agilent Technologies) equipped with a quadrupole mass spectrometric detector, model 5973N (electron impact 70 eV, ion source 180 °C, interface temperature 280 °C), was used for GC/MS analysis of the reduction products. Helium of 99.995% purity was used as a carrier gas. The temperature profile consisted of an isothermal period of 1 min, at an initial temperature of 50 °C, a temperature increase of 20 °C min-1 up to 280 °C, followed by an isothermal period of 18 min. The split-splitless injector was kept at 250 °C. Molecular modeling was carried out on a 2.8 GHz Pentium 4 personal computer employing AM1 quantum-mechanical methods included in the Titan and Spartan software packages.17

Results and Discussion The reduction of vinclozoline in the absence and presence of three cyclodextrins (RCD, βCD, and γCD) of different cavity sizes has been studied. The reduction of vinclozoline in the presence of D-glucose completes the series to gain a better understanding of the role of a CD cavity in the overall reduction process. We know from our previous work12 that reduction of free vinclozoline yields two irreversible reduction waves in nonaqueous solvents. The first wave is an irreversible two-electron transfer coupled to subsequent chemical reactions, yielding two final products at -2.35 V, namely, 3,5-dichloroaniline and 3-(3-chlorophenyl)-5-methyl-5vinyl-1,3-oxazolidine-2,4-dione (dechloro product). The main decomposition pathways include opening of the heteroring and a much slower process of the chlorine atom (17) Titan (version 1.0) and Spartan ’02 programs from Wavefunction, Inc.

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Figure 2. Part of the cyclic voltammogram of 3 × 10-3 M vinclozoline in a dimethyl sulfoxide solution of 0.1 M tetrabutylammonium hexafluorophosphate electrolyte in the absence (dotted line) and presence (full line) of 3 × 10-3 M D-glucose, RCD, βCD, and γCD showing the redox behavior of the cathodically generated intermediates at scan rate 0.5 V s-1. Arrows indicate the scan direction. The initial potential was -1.3 V. The scan proceeded toward more negative values (data not shown), where the potential was switched at -2.6 V, continued in the positive direction (data shown from -1.3 V) up to +0.2 V, and turned back again.

Figure 3. Gas chromatograms obtained after exhaustive preparative electrolysis of 1 × 10-3 M vinclozoline in a dimethyl sulfoxide solution of 0.1 M tetrabutylammonium hexafluorophosphate electrolyte at -2.15 V containing a 5 × 10-3 M concentration of four different additives: D-glucose, RCD, βCD, and γCD.

cleavage from the aromatic ring.13 In present paper we compare these processes with those in the presence of cyclodextrins of different cavity sizes. Previously, the redox mechanism changes were postulated for three dicarboximide-type pesticides in the presence of βCD alone.14,15 Figure 1 compares the DC polarogram of free vinclozoline with those in the presence of D-glucose and cyclodextrins of different cavity sizes. The current of the first reduction wave does not change significantly in the presence of D-glucose and increases slightly upon addition of cyclodextrin molecules. The second reduction wave increases in the presence of all additives. A current increase in the first reduction wave was discussed previously in terms of a change of the reduction mechanism.15 Figure 2 shows a part of the cyclic voltammogram measured for vinclozoline in the absence (dotted line) and

presence (full line) of the additives. The scan regime of all voltammograms started at the initial potential of -1.3 V. The scan continued in the negative direction until the first switching potential of -2.6 V was reached, and the potential scan continued in the opposite direction toward more positive values until it reached the second switching potential of +0.2 V. Then the scan direction was changed again up to the final potential of -1.3 V. At potentials more negative than -1.3 V vinclozoline is reduced in two irreversible reduction steps. Since the reduction process is summarized in Figure 1, this part of the voltammogram is not shown in Figure 2, and only the potential range between -1.3 and +0.2 V is used from the entire voltammogram. Effectively, Figure 2 shows the comparison of electrochemical properties of the reductively generated reaction intermediates and/or products in the absence

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Figure 4. Mass spectra of the dichloro products obtained from the GC/MS analysis of electrolyzed vinclozoline solutions. Labels identify the chromatographic peaks shown in Figure 3.

and presence of different additives. These peaks are observed only when the vinclozoline molecule is reduced

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first at negative potentials; no redox process is otherwise observed between -1.3 and +0.2 V. Addition of cyclodextrins of different cavity sizes leads to a considerably different anodic pattern. A very sharp and distinct peak observed on the subsequent scan in the cathodic direction indicates the reduction of an adsorbed host-guest complex of one of the intermediates/products. Therefore, the complex formation process must play an important role in determination of the final products and individual steps of the reduction mechanism. Due to the complexity of the overall reaction scheme we focused our attention on the analysis of the reduction products after exhaustive electrolysis at the potential of the first reduction wave. Exhaustive controlled-potential electrolysis of vinclozoline was performed in the 5-fold excess of CDs at -2.15 V in dimethyl sulfoxide. Glucose was used as a simple proton donor for comparison.5 Figure 3 shows the gas chromatograms for reduction of 1 mM vinclozoline. In the presence of D-glucose 10 main chromatographic peaks were detected, contrary to cyclodextrins, where only four main products were obtained. No peak of vinclozoline was present. The product yield is different for RCD, βCD, and γCD. Products corresponding to individual peaks in the gas chromatograms were searched for the presence of one or two chlorine atoms on the basis of their mass spectra shown in Figures 4-6. Mass spectra are separated into three groups on the basis of the number of chlorine substituents on the aromatic ring. Compounds corresponding to peaks A, I, and J clearly contain a dichlorophenyl group, and we call this group dichloro products. Compounds E, F, G, and H contain a chlorophenyl group, and we call them chloro products. Finally, compounds B, C, and D contain a phenyl group, and we call this group dechloro products. Compound A is dichloroaniline; the rest of the compounds are various species retaining the C-N bond between the heteroring and phenyl ring. Chemical structures of the main compounds C, D, F, and

Figure 5. Mass spectra of the monochloro products obtained from the GC/MS analysis of electrolyzed vinclozoline solutions. Labels identify the chromatographic peaks shown in Figure 3.

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Figure 7. Product yields for exhaustive electrolysis of vinclozoline at -2.15 V in the absence (a) and presence of D-glucose (b), RCD (c), βCD (d), and γCD (e). Products were divided into three groups: dichloro, monochloro, and dechloro products. Figure 6. Mass spectra of the dechloro products obtained from the GC/MS analysis of electrolyzed vinclozoline solutions. Labels identify the chromatographic peaks shown in Figure 3. Chart 1

H are summarized in Chart 1, whereas the other structures nonimportant for the forthcoming discussion are omitted. Some of the products have already been characterized for reduction of the vinclozoline-βCD complex in our previous work.11 The fragmentation pattern of the MS spectra is shown in support of the structures presented in Chart 1. Elucidation of the number of chlorine

Table 1. Heats of Formation ∆Hf and Stabilization Energies ∆∆Hf for AM1-Optimized Geometries of Vinclozoline and Its Inclusion Complexes with Cyclodextrin compd

∆Hf, kcal/mol

∆∆Hf, kcal/mol

RCD βCD γCD vinclozoline RCD-vinclozoline (chlorine in) RCD-vinclozoline (chlorine out) βCD-vinclozoline (chlorine in) βCD-vinclozoline (chlorine out) γCD-vinclozoline (chlorine in) γCD-vinclozoline (chlorine out)

-1420.98 -1652.80 -1898.05 -57.89 -1479.24 -1487.85 -1710.99 -1718.57 -1958.88 -1965.23

-0.37 -8.98 -0.30 -7.88 -2.94 -9.29

atoms in the molecule is easy from the characteristic isotope patterns of the molecular ion peaks, and further analysis will rely on this aspect of product determination. Since many works deal with the effect of cyclodextrins on the enantiomeric selectivity, we have also measured optical activity changes in two systems, vinclozoline-RCD and vinclozoline-D-glucose. In the first case the optical activity stayed almost the same (changed from +0.236 to +0.225), whereas glucose samples did show a change in optical activity from +0.216 to +0.097 after electrolysis. This is indirect evidence that D-glucose serves as a donor of protons.

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The differences are also demonstrated in the number of electrons consumed during exhaustive electrolysis of 1 mM vinclozoline in the presence of additives (2.3 e- for D-glucose, 3.4 e- for βCD, 4.2 e- for RCD, and 4.8 e- for γCD). This trend does not follow the number of accessible protons brought into the system by additives; rather it is quite specific for each additive and suggests that other structural factors may play a role. The number of electrons was calculated from the total amount of charge consumed during the electrolytic process. The exhaustive reduction of uncomplexed vinclozoline at the same potential requires the consumption of two electrons as determined by the total charge consumption during the exhaustive electrolysis and comparison of the DC polarographic limiting current value with methyl viologen reduction. A summary of the yields of electrolytic products with different degrees of dechlorination is given in Figure 7. The determination of the number of chlorine atoms on the aromatic ring of the individual products was based on the analysis of mass spectroscopic data and their fragmentation patterns. Free vinclozoline is transformed mainly into the dichloroaniline, whereas the addition of D-glucose gives all three types of products in similar quantities. Addition of cyclodextrins suppresses the formation of dichloro products, and dechlorination is a preferred reaction pathway. Addition of βCD drives the reaction to the formation of monochloro products mainly, and addition of RCD and γCD leads to further dechlorination of the original pesticide. Product distribution in Figure 7 is consistent with the observed number of electrons consumed during the electrolytic process in the presence of various cyclodextrins. In this respect we can build on our previous hypothesis that the carbonyl groups are the primary electron-accepting sites with a subsequent ET through the aromatic ring and chlorine atom cleavage. Any changes of the reaction environment in the vicinity of the carbonyl groups or of the heteroring as such may lead to the observed changes in the reaction mechanism. It seems reasonable that in the aprotic environment the proton-donating capability of the additives cannot be neglected. However, comparison of the vinclozoline reduction in the presence of glucose and cyclodextrin molecules clearly shows that only in the presence of cyclodextrins, i.e., molecules that can form inclusion-type complexes with vinclozoline, dechlorination occurs exclusively. The dechlorination degree is different for each cyclodextrin used. For this reason and for better understanding of the effect of individual CD molecules, we performed a series of semiempirical quantum-mechanical studies of the hostguest complex formation of R-, β-, and γ-cyclodextrin with a vinclozoline molecule. Several authors18-22 used either molecular mechanics or quantum-mechanical methods to obtain the most probable geometries of the cyclodextrin host-guest inclusion complexes. Lipkowitz23 recently published an overview of the applicable computational methods. The initial coordinates of the hosts (R-, β-, and γ-cyclodextrin) were taken from the published X-ray data.24-26 The equilibrium geometries of individual CD molecules (18) Jaime, C.; Redondo, J.; Sa´nchez-Ferrando, F.; Virgili, A. J. Org. Chem. 1990, 55, 4772. (19) Oana, M.; Tintaru, A.; Gavriliu, D.; Maior, O.; Hillebrand, M. J. Phys. Chem. B 2002, 106, 257. (20) Balabai, N.; Linton, B.; Napper, A.; Priyadarshy, S.; Sukharevsky, A. P.; Waldeck, D. H. J. Phys. Chem. B 1998, 102, 9617. (21) Ohashi, M.; Kasatani, K.; Shinohara, H.; Sato, H. J. Am. Chem. Soc. 1990, 112, 5824. (22) Estrada, E.; Perdomo-Lo´pez, I.; Torres-Labandeira, J. J. J. Org. Chem. 2000, 65, 8510. (23) Lipkowitz, K. B. Chem. Rev. 1998, 98, 1829. (24) Manor, P. C.; Saenger, W. J. Am. Chem. Soc. 1974, 96, 3630.

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Figure 8. Heat of formation ∆Hf for the vinclozoline-βCD complex as a function of the guest displacement along the principal z-axis of βCD. The displacement is plotted as the distance between the nitrogen atom of vinclozoline and the plane inside βCD defined by three bridging glycosidic oxygen atoms of the first, third, and fifth glucose units. Nitrogen, C1, and C4 atoms of the dichlorophenyl ring of vinclozoline are on the z-axis.

and of vinclozoline were obtained using semiempirical AM1 molecular orbital calculations based on the method of Dewar et al.27 Heats of formation ∆Hf corresponding to these fully optimized (minimum energy) geometries are summarized in Table 1. Their values are consistent with the data available from the literature.28-30 The heats of formation of R- and βCD differ from published values by 0.35% and 0.37%, respectively. The fully optimized geometries of CD and vinclozoline were used as the initial inclusion complex geometries. The CD molecule was oriented to have almost all glycosidic oxygens in the xy plane (in effect the plane connecting bridging glycosidic oxygens of the first, third, and fifth glucose units, O1, O3, and O5) and the primary OH groups on the negative side of the z-axis (the symmetry axis of CD). The starting position of the carbon atoms of the carbonyl groups of vinclozoline was on the xy plane, with N and aromatic C1 and C4 atoms of vinclozoline lying on the z-axis. The inclusion was simulated by moving the guest molecule along the z-axis in and out of the CD cavity. Two possible orientations of vinclozoline were considered depending on whether the chlorine atoms on the aromatic ring enter the wider rim of the CD cavity first “chlorine in” or last “chlorine out” configuration. Calculations were performed in the gas phase, and solvation effects were not considered. However, the obtained results are qualitatively useful. Table 1 lists also the complex stabilization energies defined as ∆∆Hf ) ∆Hf(complex) - (∆Hf(CD) + ∆Hf(vinclozoline)). The more negative the stabilization energy, the more thermodynamically favorable the inclusion complex. In all the cases the arrangement of vinclozoline with chlorine atoms out of the cavity is favored. (25) Betzel, C.; Saenger, W.; Hingerty, B. E.; Brown, G. M. J. Am. Chem. Soc. 1984, 106, 7545. (26) Harata, K. Bull. Chem. Soc. Jpn. 1987, 60, 2763. (27) Dewar, M. J. S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J. J. P. J. Am. Chem. Soc. 1985, 107, 3902. (28) Huang, M. J.; Watts, J. D.; Bodor, N. Int. J. Quantum Chem. 1997, 64, 711. (29) Huang, M. J.; Watts, J. D.; Bodor, N. Int. J. Quantum Chem. 1997, 65, 1135. (30) Bodor, N.; Buchwald, P. J. Inclusion Phenom. 2002, 44, 9.

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Figure 9. Geometry of the host-guest complex corresponding to the minimum value of the heat of formation ∆Hf. For clarity the vinclozoline conformation and its molecular dimensions based on the electron isodensity surface (0.002 e- au-3) are shown above the RCD (a), βCD (b), and γCD (c) complexes.

A series of geometry optimization calculations were performed first to assess the most probable position of vinclozoline within the CD cavity. Figure 8 shows the AM1 calculated heats of formation for the vinclozoline-βCD complex (chlorine out position) as a function of the distance between the N atom of vinclozoline and the xy plane inside the CD cavity. The distance of nitrogen from the xy plane was fixed during the optimization by keeping the O1-N, O3-N, O5-N, O1-O3, O3-O5, and O5-O1 distances constant. For the vinclozoline-βCD complex the optimal N-xy plane distance using the above constraints is around 3 Å. Later these constraints were relieved, and full optimization provided the minimum-energy geometry of the complexes for all three cyclodextrins. The most probable geometries of the vinclozoline complexes with all three CDs are shown in Figure 9. In all the cases the dichlorophenyl ring is tilted with respect to the z-axis of CD. The distance of nitrogen from the O1-O3-O5 plane inside the cyclodextrin molecule is 4.32, 3.75, and 2.06 Å for fully optimized RCD, βCD, and γCD complexes. One important aspect of these simulations is the fact that the inclusion complexes are stabilized by the formation of intramolecular hydrogen bonds between the carbonyl groups of vinclozoline and the OH groups of CDs. A hydrogen bond was defined as an O-H‚‚‚O distance shorter than 3 Å, with the angle at H bigger than 90°. Possible hydrogen bonding is shown in Figure 9a,c as a dotted line. For RCD complexes the structure is stabilized by three such interactions and for γCD by one. The complex of βCD does not seem to be stabilized by such an interaction. Even though we work in the theoretical treatment in a vacuum, it is known from the literature that secondary OH groups form intramolecular hydrogen bonds and the rate of exchange of protons for βCD is much lower (stronger bonding) than that of RCD and γCD. In DMSO the intramolecular H-bonding interaction was

Figure 10. Dependence of the complex stabilization energy ∆∆Hf on the total dechlorination degree. The empty circle represents ∆∆Hf for the glucose-vinclozoline “complex” with a fixed distance between the carbonyl of vinclozoline and a hydrogen of glucose set at 3 Å.

shown to be stronger compared to that in a water environment.31 Finally, the complex stabilization energies ∆∆Hf obtained from quantum mechanical studies were correlated with the total dechlorination degree of vinclozoline in the first reduction wave in the presence of the additives. A good correlation was observed for a series of cyclodextrins used (see Figure 10). Since our computational studies indicate the importance of interactions between vinclozoline and protons of the additives (CDs and glucose), we included in Figure 10 (an empty circle) also the stabilization energy calculated for an artificial “glucose-vinclo(31) Bekiroglu, S.; Kenne, L.; Sandstro¨m, C. J. Org. Chem. 2003, 68, 1671.

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zoline” complex stabilized by one hydrogen bond between the carbonyl of vinclozoline and the secondary OH group of the glucose molecule. The stabilization energy of such an artificial complex fits very well within the presented correlation as judged by the value of the correlation coefficient, which is still 0.995 with or without the glucosevinclozoline complex. Figure 10 demonstrates that the inclusion of vinclozoline with its heterocyclic ring in the cavity and the importance of hydrogen-bond-type interactions play a decisive role in the overall change of the reduction mechanism. The stabilization of such a supramolecular structure is achieved by interactions of one or both carbonyl groups of vinclozoline with hydrogen atoms of the secondary hydroxyl groups at the rim of the cavity. Conclusions In this paper we address studies of the possible modes of interaction between vinclozoline and RCD, βCD, and γCD. Electronic structure and stabilization energy calculations were performed using a semiempirical Austin model (AM1) method within the Titan and/or Spartan program packages. A substantial change of the reaction

Hromadova´ et al.

environment in the vicinity of the electron-accepting groups is consistent with our interpretation of the reduction mechanism changes. We found that cyclodextrin in the first place acts as a protecting environment of one electroactive part of the molecule. As a result, the heteroring is protected against the ring opening reactions and vinclozoline undergoes preferably the chlorine cleavage processes that were minor reaction pathways for the reduction of free pesticide. Semiempirical molecular modeling calculations support these findings. Acknowledgment. This work was supported by the Ministry of Education, Youth and Sports of the Czech Republic (Grant COST D15/001/98, OC-D15.10) and by the Grant Agency of the Czech Republic (Grants 203/02/ P082 and 203/03/0821). The CNR (Italy) and the Academy of Sciences of the Czech Republic are gratefully acknowledged for supporting the project with exchange grants. We thank Dr. Stefan Immel for his kind help in providing us with the structure file of γCD. LA048021K