17449
J. Phys. Chem. 1995,99, 17449-17455
Calorimetric Studies on the Complexation of Several Ferrocene Derivatives by a- and B-Cyclodextrin. Effects of Urea on the Thermodynamic Parameters Luis A. Godinez, S o d Patel, Cecil M. Criss,* and Angel E. Kaifer* Chemistry Department, University of Miami, Coral Gables, Florida 33124-0413 Received: June 20, 1995; In Final Fonn: August 23, 1 9 9 9
The complexation of several alkyldimethyl(ferrocenylmethy1)ammonium cations, where the alkyl group is -CH3 (l'), -(CH2)&H3 (29,or -(CH2)7COOH (3+), by the hosts a- and p-cyclodextrin (a- and p-CD) was investigated in aqueous media using calorimetric and 'H NMR spectroscopic measurements. The calorimetric results indicate that the complexation of all the ferrocene-containing guests is enthalpically driven. p-Cyclodextrin binds all the guests primarily by including the ferrocenyl groups into its cavity. By contrast, a-cyclodextrin binds guests 2+ and 3+ by threading the aliphatic chains of these guests through its cavity. The zwitterionic, deprotonated form (3) of the latter guest is bound by partial inclusion of the fenocenyl group, a mechanism similar to that prevalent in the complexation of 1+. The complexation processes of 1+by P-CD and 2' by a-CD were also investigated in water-urea mixtures. Our calorimetric data reveal that large concentrations of urea cause a substantial decrease in the binding constant for the complexation process. The presence of urea considerably diminishes the enthalpic stabilization of both complexes.
Introduction Cyclodextrins (CDs) are a well-known class of watersoluble hosts that form stable inclusion complexes with a variety of substrates, particularly those possessing hydrophobic subunits of appropriate size to fit in the corresponding CD cavity. Unmodified (a-, p-, and y-CD) and modified CDs have received substantial attention for several decades, and their complexation properties are well documented.' In those cases in which the guest fits tightly inside the CD cavity, the complexation process is enthalpically driven, typically exhibiting large and negative enthalpic changes and small and also negative entropic changes.2 It is now clear that these thermodynamic values follow the observed pattern for most bimolecular association phenomena in aqueous media, regardless of the nature of the associating partner^.^ This thermodynamic pattern has been recently attributed to the predominance of solvent reorganization forces in aqueous bimolecular associati~n.~ We have previously reported the binding constants-obtained from electrochemical data-for the complexation in aqueous media of several cationic ferrocene derivatives by unmodified CDs.4 The ferrocene derivatives selected for these studies are interesting as CD guests because they possess two distinct hydrophobic regions, both of which may serve as binding sites for the CDs. The expectation is that different CDs will show varying binding affinities for different sites in the same guest molecule, in such a way that these ferrocene-containing substrates may act as templates for the organized assembly of CD receptors! As an example of this approach, we have described the preparation of novel a-CD-based rotaxanes5 relying on the use of this family of ferrocene-containing guests. In this work, we report on calorimetric studies of a- and B-CD complexation processes with the following series of ferrocene derivatives: @
Abstract published in Advance ACS Abstracts, November 1, 1995.
0022-365419512099- 17449$09.0010
1+
2+
3+
Urea is a well-known protein-denaturing agent? although the detailed mechanism of its denaturing action is still a matter of debate. Classically, urea was considered to be a water structure breaker7q8that diminishes the hydrophobic interactions which are largely responsible for protein folding. More recently, numerous experimental finding^^,'^ and computational studies' suggest that specific interactions between urea molecules and protein functional groups may be responsible for its denaturing ability. As a part of their extensive studies on hydrophobic effects on simple organic reactions, Breslow and co-workers measured the binding constant of 6-(4-tert-butylanilino)naphthalene-2-sulfonateto B-CD in 8 M urea and found a value of 1.6 x 10" M-I, which is substantially lower than the corresponding binding constant in pure water (3.8 x lo4 M-').'Ob This suggests that the presence of urea decreases the strength of cyclodextrin-substrate binding interactions. This finding led us to perform a detailed calorimetric study of the effects of urea on the binding of ferrocene-containing guest I+ by B-CD in an attempt to better understand how the presence of urea affects hydrophobic interactions.
','*
Experimental Section Materials. a-CD and B-CD were donated by AMAIZO and used without further purification. The hydrated molecular 0 1995 American Chemical Society
17450 J. Phys. Chem., Vol. 99, No. 48, 1995
Godinez et al.
K= 2500
o.oo\
-.lo
AH= -5.7 + 0.1 KcrVmol
'
0.000
I ,002
I ,004
I ,008
I ,008
Concentrationof2+, moln
Figure 1. Signal measured in the flow calorimeter us concentration of guest 2+ in the mixing chamber. The concentration of the host (/3CD) was fixed at 2.0 mM. The curve was calculated using the K and AH values given in the figure.
weights of both cyclodextrins (1081 g mol-' for a-CD and 1297.1 g mol-' for P-CD) were used throughout this work. The ferrocene derivatives were synthesized as their iodide (1+) or bromide (2+ and 3 9 salts according to the reported procedures? The chloride salt of 1+ was prepared by passing a solution of the iodide through an ion exchange column. The purity of the final product was verified by absorption spectroscopy. All other reagents were of the best grade commercially available. All solutions were freshly prepared using distilled water further purified by passage through a four-cartridge Barnstead Nanopure system ( p > 18 MQ cm). Calorimetry. The thermochemical measurements were performed on an LKB 2107 flow microreaction calorimeter immersed in a temperature-controlled water bath. The temperature of the bath was maintained at 298 K with a &0.001 K by means of a coupled cooling system and a Tronac Model PTC40 temperature controller. The reactant solutions were fed into the calorimeter using a Harvard Instruments multiple syringe pump operating with two syringes at a fixed flow rate of 0.21 1 mUmin. One syringe was connected directly to the calorimeter. The second syringe was connected to the calorimeter through a liquid chromatographic injection valve fitted with a 7 cm3 sample loop. All connections were made via '/16 in. Teflon tubing. Both syringes contained identical solutions (CD solution), which upon mixing gave the base line. Once the base line was established, the reacting solution (guest solution) in the sample loop was introduced into the calorimeter by displacing it from the sample loop by the incoming solution from the second syringe. After the sample had run its course, the injected solutions became identical again and the signal returned to the base line level. The heat released in the calorimeter cell was detected with a thermopile, whose voltage signal was amplified by a factor of lo5 (Keithley Model 140 Nanovoltmeter) and fed simultaenously into a strip-chart recorder and a microcomputer for data analysis. The calorimeter constant ( E ) was determined electrically using a constant current source (Hewlett-Packard Model 6177C) and a calibration heater in the calorimeter cell. The constant current through the calibration heater was determined by measuring the voltage across a standard 10 S2 resistor in series with the heater circuit. The accuracy of the system was tested by measuring the heat of neutralization of HCI with NaOH. The value found was within 1% of the literature accepted value.
In a typical run, a 2 mM solution of cyclodextrin (also containing 50 mM NaCl to maintain a constant ionic strength) was prepared and fed continuously into the calorimeter cell. Solutions containing variable guest concentrations in the range 0.7-6 mM (plus 50 mM NaC1) were pumped successively into the calorimetric cell from the sample loop, which could be refilled without interrupting the flow of solutions through the calorimeter. In the case of guest 3+, phosphate buffers (pH = 2.6 and 6.5) of similar ionic strength were used. These pH values were chosen to ensure full protonation (pH = 2.6) or deprotonation (pH = 6.5) of the carboxylic acid group of 3+ as the pKa of this compound is 4.4. In order to ascertain that the pH dependence of the enthalpy of complexation of guest 3+ was the result of protonation of the carboxylic acid group rather than some other effect, the enthalpy of complexation of guest 2+ was also measured in the same phosphate buffer solutions. No significant pH dependence was observed. For measurements involving urea, the solvents from which the cyclodextrin and guest solutions were prepared were the aqueous urea solutions (plus 50 mM NaC1). In no case was it possible to detect an enthalpy of dilution of either the ferrocene guest or the cyclodextrin solutions when mixed with equal amounts of the solvents. Assuming that the reaction is fast, the voltage signal (AV) produced by the calorimeter is related to the power generated by the host-guest complexation reaction ( Q ) . The enthalpy change of complexation per mole is then given by the equation
where 9 is the concentration of the complex formed by the reaction and o is the flow rate of solution at the exit of the calorimeter cell. Assuming that the complexation reaction exhibits 1:1 stoichiometry, the concentration of the complex is related to the equilibrium binding constant ( K ) by
where c and co are the concentrations before mixing of the guest and cyclodextrin solutions, respectively. A set of AV values corresponding to varying guest concentrations (c) is obtained experimentally for a constant concentration of cyclodextrin (co). A minimum of seven different guest concentrations was used in our experiments. Fitting of these (AV, c) data points to eqs 1 and 2 by standard regression analysis provides the corresponding binding constant along with the enthalpy change of complexation. Figure 1 shows a typical set of experimental data points and the curve calculated from the K and AH values obtained from the fitting process (at the 95% confidence level). N M R experiments. In some cases, the complexation processes were also studied using 400 MHz 'H NMR spectroscopy. These experiments were performed in a Varian VXR400 spectrometer, using 5 mm 0.d. tubes and D20 (Aldrich) as the solvent. The protons of tetramethylphosphonium chloride [(CH3)afC1-] were used as an internal reference for chemical shift measurements in experiments with P C D . The tetramethylphosphonium cation constitutes a convenient reference for these experiments as the (trimethylsilyl)alkylsulfonium salts commonly utilized as reference compounds for chemical shifts measurements in D20 are complexed by /3-CD receptors. Acetone was used as the reference for experiments involving a-CD.
J. Phys. Chem., Vol. 99, No. 48, 1995 17451
Complexation of Ferrocene Derivatives
TABLE 1: Thermodynamic Parameters for the Complexation of Ferrocene Derivatives by a-CD in Aqueous 0.050 M NaCl at 298 K TAS (kcaYmol) K (M-') AG (kcaVmo1) AH (kcal/mol)
-+i -/
3+
CCQH
210
-3.220.1
-3.8tO.l
-0.620.2
1,200
-4.220.1
4.5+0.2
-0.3t0.3
1,200
-4.220.1
-7.920.2
-3 720.3
450
-3.6+0.1
-3.520.4
0.1+0.5
& Results and Discussion Complexation Studies in Aqueous Media. The positively charged guests 1+ and 2+ contain a ferrocenyl group attached to a quaternary nitrogen center. The heptyl chain in guest 2+ also constitutes a hydrophobic site to which cyclodextrins can bind. Guest 3' is also a cation in its protonated (acidic) form, but deprotonation yields a zwitterion, 3, with positive and negative charges flanking its aliphatic chain. We investigated CD binding to this compound in both its protonated and deprotonated forms by adjusting the pH of the medium at values below and above its pKa, respectively, as described in the Experimental Section. Our previous electrochemical and NMR spectroscopic results obtained with guests 1+ and 2+ indicate that a-CD binds preferentially to the aliphatic chain while B-CD interacts predominantly with the ferrocenyl The calorimetric results obtained for the complexation of these guests by a-CD are given in Table 1. The formation of all the a-CD complexes is enthalpically driven, exhibiting large and negative AH values and smaller and also negative entropic changes. This is the typical pattern found for bimolecular association in aqueous media.3 From the AG values obtained, it could be concluded that the surveyed guests present two different types of interaction with a-CD. The strongest interaction is exhibited by guests 2+ and 3+, while I+ and 3 give rise to substantially weaker interactions with this host. However, examination of the enthalpic and entropic contributions to the binding of 2+ and 3+ reveals considerable differences in spite of the similarity of the corresponding AG values. The enthalpic contribution to complexation is clearly larger in the case of guest 3+, although this is compensated by a more unfavorable entropic term, resulting in a free energy change of complexation similar to that measured with guest 2+. This indicates that the a-CD3+ complex is held together by stronger intermolecular forces than those stabilizing the a-CD-2+ complex, with a concomitant increased rigidity in the former complex. Although the enthalpy-entropy compensation observed in this case is far from surprising, we performed 'H NMR spectroscopic experiments to understand the origin of the additional enthalpic release upon formation of the a-CD-3+ complex. Figure 2 shows the aliphatic region of the 400 MHz 'H NMR spectra of 3+ under acidic conditions in the absence and in the presence of 7 equiv of a-CD. The CD-induced shifts and broadening effects observed on the resonances corresponding to the methylene protons of the aliphatic chain are similar to those observed previously with guest This finding suggests that in 3+, as in 2+, the main interaction site for a-CD is the aliphatic chain. Therefore, complex formation proceeds in both cases by insertion of the aliphatic chain through the CD cavity. Since the aliphatic chain of 3+ terminates with a carboxylic group,
3
- 7
5
30
25
20
PPU
15
I O
2
JUUUL 35
30
IS
I O
20
PPM
1'5
0
Figure 2. Aliphatic region of the 400 MHz IH NMR spectrum of 3+ (1 mM) in D20 (pD = 2.6): (a) no CD added and (b) 7 mM a-CD added. The arrows indicate the positions of the methylene resonances in the absence of CD. we can speculate that this group may hydrogen bond to the hydroxyl groups on the cyclodextrin receptor, accounting for the additional enthalpic stabilization of the a-CD-3+ complex as compared to the a-CD-2' complex. Guest 2+ lacks the terminal carboxylic acid group and cannot establish any hydrogen bonds with the hydroxyl groups of the CD. Examination of CPK models supports this hypothesis and reveals that the a-CD-3+ complex is a very compact and rigid species. At pH values well above the pKa value, the complexation of 3 (zwitterionic form) by a-CD is strikingly different. First, the calorimetric data reveal substantially less favorable AG and AH terms as compared to those of the complexation of the protonated form 3+. Second, the aliphatic region of the IH NMR spectrum of 3 (see Figure 3) is much less affected by the presence of a-CD (as compared to the case of 3'). The resonances corresponding to the methylenes of the aliphatic chain are only slightly broadened upon addition of a-CD. Therefore, we conclude that the negatively charged carboxylate
Godinez et al.
17452 J. Phys. Chem., Vol. 99, No. 48, 1995 SCHEME 1: Binding of 3+ and 3 to a-CD
-H+
35
35
30
10
2.5
25
20
20
PPM
PPM
15
7s
IO
t'0
/I
+H+
0
0
Figure 3. Aliphatic region of the 400 MHz 'H NMR spectrum of 3 (1 mh4) in DzO (pD = 6.5): (a) no CD added and (b) 7 mh4 a-CD added. The arrows indicate the positions of the methylene resonances in the absence of CD.
group at the end of the alkyl chain largely prevents the threading of the CD cavity. The interaction of 3 with a-CD is mostly diverted to the other hydrophobic residue of the guest molecule, Le., the ferrocenyl group. This is suported by the similar thermodynamic parameters observed for a-CD complexation of 3 and 1+. The structure of 1+, which contains only one hydrophobic site (the ferrocenyl group), leads to the conclusion that the complexation of these two guests takes place through the partial inclusion of the ferrocene residue in the cavity of the a-CD host. These results constitute an interesting example of pH control on the binding interactions between a guest and a-CD. At pH values clearly below the pKa of 3+, its protonated form binds to a-CD by inserting its aliphatic chain through the cavity of the receptor. At pH values substantially over the pK,, the zwitterionic form 3 is predominantly complexed by partial inclusion of its ferrocenyl group into the CD cavity. Thus, the main interaction site with a-CD depends on the pH of the medium. Moreover, the overall stability of the resulting complex is also pH dependent, as the threaded complex (at pH = 2.6) exhibits a binding constant greater than that found for the complex at pH = 6.5. The pH dependence of the binding of this guest to a-CD is pictorially represented in Scheme 1. The calorimetric data corresponding to the complexation of the same guests by p-CD are listed in Table 2. Again, the formation of all the complexes is enthalpically driven, with large and negative AH values and smaller and also negative entropic terms. Due to the larger average diameter of the cavity of j3-CD compared to that of a-CD, we anticipated that the main complexation site for all the guests would be the ferrocenyl residue. In fact, the large affinity and excellent fit of the ferrocenyl residue into 6-CD is well This
expectation is in excellent agreement with the rather narrow ranges of AG (-4.6 to -5.0 kcdmol) and AH (-5.5 to -6.8 kcdmol) values observed for the p-CD complexes, which are substantially smaller than those observed for the complexes between the same guests and a-CD (see Table 1). Thus, the complexation by j3-CD of all the surveyed guests is characterized by the inclusion of the ferrocenyl group into the receptor's cavity regardless of the length and terminal functionalities of the aliphatic chain present on the other side of the guest. The observed differences in the thermodynamic complexation parameters arise basically from the interactions of the alkyl chain with the partially filled CD cavity and with the solvent molecules. The most favorable enthalpic change corresponds to the formation of the B-CD-l+ complex. However, the entropic term is also the most unfavorable, a finding which suggests the formation of a tight inclusion complex. The AG stabilization for the j3-CD-3 complex is smaller than that of the j3-CD-3+ complex but almost identical to those measured for the complexes between this host and guests I+ and 2+. By contrast, guest 3+(protonated form) gives rise to the most stable complex with j3-CD, a fact which has an entropic origin, as the corresponding TAS value is the least negative in the table. The comparison between the thermodynamic parameters for complexation of 3+ and 3 is again interesting. The complex formed by guest 3 is enthalpically more favorable than that formed by guest 3+, but the entropic term of the latter is favorable enough to overcome the enthalpic difference. We have performed 'H N M R experiments to address in some microscopic detail the differences between these two complexes. Figure 4 shows the aliphatic region of the 'HNMR spectra of 3+ in the absence and in the presence of 3 equiv of /3-CD. Notice that all the resonances corresponding to the methylene protons undergo appreciable CD-induced shifts. The aromatic protons corresponding to the ferrocenyl nucleus also undergo considerable CD-induced shifts (data not shown) as expected. Similar experiments performed with the zwitterionic form of this guest 3 reveal a striking difference (see Figure 5). In this case, the resonance (at 0.32 ppm) corresponding to the methylene protons adjacent to the carboxylate group does not shift at all upon addition of P-CD. All the resonances corresponding to the remaining methylene protons undergo CD-induced shifts. The fact that the methylene protons next to the -COO- terminus in 3 are insensitive to the presence of p-CD reveals that they are kept outside the CD cavity. The NMR data suggests that the ferrocenyl group is included into the /3-CD cavity, but the whole aliphatic chain of 3+ sustains some interaction with the CD cavity. By contrast, in the zwitterionic form of the guest,
J. Phys. Chem., Vol. 99, No. 48, 1995 17453
Complexation of Ferrocene Derivatives
TABLE 2: Thermodynamic Parameters for the Complexation of Ferrocene Derivatives by p-CD in Aqueous 0.050 M NaCl at 298 K K (M-I) AG (kcdmol) AH (kcaYmo1) TAS (kcdmol) ~~
2,900
-4.720.1
-6,820.2
-2.120.3
2+
2,500
-4.69.1
-5.720.1
-1 120.2
3+
4,800
-5.0+0.1
-5.520.1
-0.520.2
2.500
-4.6+0.1
-6.120.1
-1.520.2
I
-
~
,
1:4
3.2
3.0
2.1
28
2.4PPM2.2
2.0
1.8
18
14
I2
10
I:2
30
2:8
20
2iPPM22
20
1.8
1.8
11
1.2
1.0
,
34
'
I
.
,
.
/
.
,
I
I
.
,
.
,
.
,
.
I
.
32
30
28
28
24
22 PRI 20
18
18
14
1
12
10
Figure 4. Aliphatic region of the 400 MHz 'H NMR spectrum of 3+ (1 mM) in D20 (pD = 2.6): (a): no CD added and (b) 3 mM p-CD added. The arrows indicate the positions of the methylene resonances in the absence of CD.
Figure 5. Aliphatic region of the 400 MHz 'H NMR spectrum of 3 (1 mM) in DzO (pD = 6.5): (a) no CD added and (b) 3 mM p-CD added. The arrows indicate the positions of the methylene resonances in the absence of CD.
the carboxylate end of the aliphatic chain is maintained outside of the CD cavity due to the excellent solvation provided by the water molecules. Pictorial representations of these complexes are shown in Scheme 2. The binding constants of some of the complexes reported in this work had been previously measured by our group using voltammetric method^.^ The experimental values follow similar trends in both studies. However, the calorimetric determinations of the binding constants are more direct and require less manipulation of the data than the voltammetric determinations. Therefore, we believe that the values reported here are probably more accurate. Effects of Urea on the Binding of Guest 1+ to P-CD. The presence of large concentrations of urea in aqueous media has a general weakening effect on hydrophobic interactions. As a result, urea is a widely used denaturing agent in protein chemistry.6 We have investigated the effect of urea in the cyclodextrin-substrate interactions that are the subject of this paper and selected the complexation of guest 1+ by B-CD as
the most representative host-guest binding equilibrium for the study.. This selection relies on the fact that the ferrocene subunit of 1+ fits very well in the cavity of P-CD, and this guest has the simplest structure among all the guests surveyed in this work. For this portion of the study, we tried to avoid additional structural features in the guest that may substantially complicate the host-guest or guest-solvent interactions in the presence of varying concentrations of urea. The corresponding calorimetric data obtained at several concentration levels of urea are given in Table 3. The data clearly show that increasing concentrations of urea in the medium have the following effects on the thermodynamic parameters: (i) to decrease the overall stability of the complex as measured by the AG or K values, (ii) to decrease the enthalpic stabilization of the complex, and (iii) to decrease the entropic term opposing complex formation. However, the absolute value of the urea-induced enthalpic destabilization of the complex is slightly larger than the entropic stabilization effect, and, therefore, the binding constant for the l+-P-CD complex
Godinez et al.
17454 J. Phys. Chem., Vol. 99, No. 48, 1995
SCHEME 2: Proposed Changes Resulting from Deprotonation in the Structure of the Complex between 3+ and /I-CD improved solvation
p J j Eo 0 0
'7+..*, - H+ + H+
A
TABLE 3: Thermodynamic Parameters at 298 K for the Complexation of Guest 1+by /3-CD in Aqueous 0.10 M NaCl Containing Variable Concentrations of Urea [urea] AG AH TAS (moVL) K (M-') (kcaUmo1) (kcal/mol) (kcdmol) 0
2 4 6 8
2,900f330 1,580&280 1,38O=t200 1,010f170 715 f 110
-4.7i0.1 -4.4f0.1 -4.3k0.1 -4.1k0.1 -3.9 f 0.1
-6.8iz0.3 -6.1f0.6 -5.8i0.5 -5.1&0.6 -4.9 iz 0.7
-2.1f0.4 -1.7iz0.7 -1.5f0.6 -1.Oi0.7 -1.0 0.8
*
decreases monotonically as the urea concentration increases. Interestingly, all three thermodynamic parameters (AG, AH, and AS) are linearly related to the concentration of urea in the reaction medium (see Figure 6 ) . Large concentrations of urea are known to increase the solubility of hydrophobic molecules in aqueous media.Iob Therefore, the presence of urea improves the solvation of hydrophobic surfaces. Furthermore, Jorgensen and co-workers have reported computational results indicating that urea molecules bind to aromatic surfaces." In good agreement with these reports, our data can be rationalized as the result of improved solvation of the aromatic surfaces of guest I+ with increasing concentration of urea in the medium. Breslow and Halfon reported data indicating that the solvation of the p-CD receptor is essentially unaffected by the presence of urea. 'Ob Thus, the additional guest stabilization provided by the urea molecules in the solution results in the relative destabilization of the complex. This interpretation is consistent with the observed urea-induced effects on the enthalpic and entropic changes accompanying the formation of the If$CD complex. These results led us to a quick investigation of the effects of urea on the complexation of 2+ by a-CD because of the different type of binding site (aliphatic heptyl chain) prevalent in this guest-CD pair. In spite of the nonaromatic nature of the binding site, the binding constant decreases to 177 f 22 M-I in the presence of 8 M urea while the corresponding A H value was found to be -2.2 & 0.2 kcal/mol (compare with the data in Table 1 obtained in the absence of urea). Therefore, the presence of urea also causes a substantial decrease in the absolute magnitude of both thermodynamic parameters, but the magnitude of the effects is clearly larger in the case of the 2+-a-CD complex than that of the l+-p-CD complex. Direct comparisons between the data are hampered by the differences in size between the two CD hosts and their modes of interaction with solvent molecules. However, as a result of these observations, we have started a comprehensive study of urea effects on guest-CD interactions which may provide some insight into the interactions of proteins with denaturing agents.
0
2
4
6
a
Urea Concentration, moVL Figure 6. Thermodynamic parameters at 25 "C in 0.1 M NaCl for the complexation of guest 1+ by /3-CD in the presence of variable concentrations of urea.
Conclusions The complexation processes of all the ferrocene derivatives surveyed in this work by the hosts a- and p-CD exhibit thermodynamic parameters in line with those measured for other cyclodextrin complexes as well as for other bimolecular complexes that are formed in aqueous solution. The complexes with p-CD are essentially formed by the inclusion of the guest's ferrocenyl center into the receptor cavity. The remaining molecular regions of the guest interact to varying degrees with the cyclodextrin cavity. Complexation by a-CD takes place by two different mechanisms. For guests 2+ and 3+, the complex is formed by the insertion of their aliphatic chains through the receptor's cavity. For guests 1+ and 3, our data indicates that the main interaction is the partial inclusion of the ferrocenyl residue into the a-CD cavity. Urea molecules exert an effect on the binding equilibrium between 1+ and /?-CD similar to that exerted on proteins which ultimately leads to their denaturation. Large concentrations of urea decrease the stabilization of the complex. The thermodynamic parameters obtained can be rationalized as the result of improved solvation of the aromatic surfaces of guest If in the presence of urea. As is typically the case, the detailed interpretation of the thermodynamic data is quite difficult. In this study, we obtained additional information on the complexation processes by using 'HNMR spectroscopy. However, the determination of enthalpic and entropic changes of complexation affords valuable insight into these processes which could not be gained from equilibrium constant measurements.
Acknowledgment. This work was supported by the NSF (CHE-9304262). The authors are grateful to the American Maize-Products Company for the gift of substantial amounts of cyclodextrins. LAG acknowledges support in the form of a doctoral fellowship from the Universidad Nacional Aut6noma de MBxico. References and Notes (1) For a recent review, see: Wenz, G. Angew. Chem., Int. Ed. Engl. 1994, 33, 803. (2) (a) Inoue, Y.; Hakushi, T.; Liu, Y . ;Tong, L.-H.; Shen, B.-J.; Jin, D.-S. J . Am. Chem. SOC. 1993, 115, 475. (b) Inoue, Y.; Liu, Y.; Tong, L.-H.; Shen, B.-J.; Jin, D . 4 . J. Am. Chem. Soc. 1993,115, 10637. (c) Eftink, M. R; Andy, M. L.; Bystrom, K.; Perlmutter, H. D.; Kristol, D. S. J. Am. Chem. SOC. 1989, 111, 6765-6772.
Complexation of Ferrocene Derivatives (3) Chervenak, M. C.; Toone, E. J. J. Am. Chem. SOC.1994,116,10533. (4) Isnin, R.; Salam, C.; Kaifer, A. E. J. Org. Chem. 1991, 56, 35. (5) (a) Isnin, R.; Kaifer, A. E. J. Am. Chem. SOC.1991, 113, 8188. (b) Isnin, R.; Kaifer, A. E. Pure Appl. Chem. 1993, 65, 495. (6) Creighton, T. E. Proteins: Structures and Molecular Principles; Freeman: New York, 1993; Chapter 7. (7) Finer, E. G.;Franks, F.;Tait, M. J. J. Am. Chem. SOC.1972, 94, 4424. (8) Barone, G.;Vitagliano, V. J. Phys. Chem. 1970, 74, 2230. (9) Hibbard, L. S.; Tulinsky, A. Biochemistry 1978, 17, 5460. (10) (a) Breslow, R.; Guo, T. Proc. Natl. Acad. Sci. U.S.A. 1990, 87, 167. (b) Breslow, R.; Halfon, S. Proc. Natl. Acad. Sei. U.S.A. 1992, 89, 6916. (11) Duffy, E. M.; Kowalczyk, P. J.; Jorgensen, W. L. J. Am. Chem. SOC. 1993, 115, 9271.
J. Phys. Chem., Vol. 99, No. 48, 1995 17455 (12) Pranata, J. J. Phys. Chem. 1995, 99, 4855. (13) B ~ s l o w R.; , Trainor, G.;Ueno, A. J. Am. Chem. SOC. 1983, 105, 2739. (14) Harada, A.; Takahashi, S. J. Chem. SOC., Chem. Commun. 1984, 645. (15) Matsue, T.; Evans, D. H.; Osa, T.; Kobayashi, N. J. Am. Chem. SOC.1985, 107, 3411. (16) Kobayashi, N.; Opallo, M. J. Chem. SOC., Chem. Commun. 1990, 477. (17) Menger, F. M.; Sherrod, M. J. J. Am. Chem. SOC.1988,110,8606. (18) Thiem, H.-J.; Brandl, M.; Breslow, R. J. Am. Chem. SOC. 1988, 110, 8612.
JP95 1732U
