Complexation of adamantyl derivatives by a β – cyclodextrin dimer

The binding constants, standard molar enthalpy, Gibbs free energy, and entropy changes were determined for the formation of complexes between adamantyl derivatives and a β-cyclodextrin dimer. It is concluded that, within experimental error, the two cyclodextrin residues in the dimer behave independent to each other when complexing the adamantyl derivatives.


Introduction
Supramolecular chemistry is mainly focused in designing new molecules which, after processes as recognition and assembling, form new identities denoted complexes, supramolecular assemblies, etc. 1 One well known example of a supramolecular entity is the formation of an host/guest complex between a cyclodextrin (the host) and an organic molecule (the guest) in which the organic molecule is located inside the cavity of the cyclodextrin. 2In designing new systems which improve the efficiency or selectivity of the natural ones (for instance, the catalysis by enzymes), the first step is the knowledge of the energetic (as well as geometric) features among the interacting species.For that purpose, techniques as rotating-frame Overhauser enhancement spectroscopy (ROESY), which provides information on the complex structure, and Isothermal Titration Calorimetry (ITC), which allows the determination of basic thermodynamic parameters (ΔH, ΔS, ΔG and K eq ) and the stoichiometry of the complex in a single experiment, are nowadays routinely used in chemical laboratories.

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The analysis of ITC experiments is straightforward when both guest and host are monotopic entities (i.e., both having one single site of interaction) since only one data analysis is possible. 3However, several possibilities appear when (at least) one of the interacting species, is ditopic or polytopic in nature, since the sites can cooperatively interact or not.The knowledge of the microscopic equilibrium constants involved in the different equilibria will allow the determination of the existence of cooperativity (positive, negative or zero) between the different sites.Examples of the determination of microscopic binding contants in cyclodextrin systems have been given by Connors and Pendergast 4 when studying the complexation of sym-1,4-disubstituted benzenes, by Connors et al 5 for sym-4,4´-dibsubtituted biphenyls, and by Sur and Bryant 6 for porphyrins.In all these cases, the determination of the microscopic binding constants was possible since the two binding sites were identical and the relationships between microscopic and macroscopic binding constants is greatly simplified.
The complexation of adamantane derivatives with cyclodextrins has been the subject of numerous studies during the last twenty years.  Thiis due to several reasons.First, adamantane derivatives form strong complexes with β-cyclodextrin and the equlibrium constants are the strongest which can be found for the formation of this kind of inclusion complexes.This is because of the adamantyl residue perfectly fits inside the βcyclodextrin cavity since the radius of this residue is slightly larger than the radius inside the cavity available for guest in this cyclodextrin.Second, unimers simultaneously having guest (adamantyl residue) and host (β-cyclodextrin residue) moieties in their structure have been obtained and by self-association formed linear supramolecular structure. 26Third, adamantyl dimers have been synthesized and complexed with β-cyclodextrin dimers to form the so called "chelate complexes". 189][30] Finally, polytopic hosts and polytopic guests can be used to form other macromolecular assemblies. 31,32In such cases, high viscosity enhancements have been observed, which are maximum for a composition in which the stoichiometry is one host (βCD residue):one guest (adamantyl residue). 33he aim of this paper is to study the complexation of several adamantyl derivatives by the β-cyclodextrin dimer shown in Figure 1, in order to check the existence or not of cooperative effects during the complexation process.

Results and Discussion
Figure 2 shows typical experimental enthalpograms for the complexation of guests of Figure 1 with the βCD 2 EDTA dimer.The fitting of the experimental results to the "single set of identical sites" model 34 leads to the fitting parameter values given in Table 1.
It must be remembered that according to this model the equilibrium constant corresponds to the equilibrium and n is the number of sites.It can be noticed that n values are close to the expected stoichiometry for a complex formed by a ditopic host and a monotopic guest.On the other hand, equilibrium constants and ΔHº values are in agreement with those obtained for similar systems. 7Because of the n value, the experimental results were also fitted to a "two sets of independent sites" model.The obtained values for the thermodynamic parameters are given in Table 2.
-0,5 0,0 0, 5  Experiments were carried out at; T = 30,01ºC; pH= 7,55 phosphate buffer (50mM) to ensure ionization of any functional group, amine or carboxylate.Lines correspond to fit experimental results to stepwise (macroscopic) model for biding of two guests to the host.The fitting parameters are given in Table 1.
Guest n Table 2.-Thermodynamic parameters from ITC data fitted with a "two sets of independent sites model" for biding of two guests to the host.The complexation process is shown in Figure 3.Although four microscopic equilibrium constants are involved only three equilibrium constants are independent since the obvious relationship K 1x ·K 12 = K 2x ·K 22 applies.The relationships between the equilibrium constants are given by For the present dimer, both sites are identical and, consequently, The site-specific interaction parameter is defined as α= K 12 /K 2x = K 22 /K 1x . 35Under the condition of two independent binding sites, K 1x = K 22 and α=1.Therefore,  2 shows that except for the negatively charged guest 1-AdCOONa (although it is possible that in this case the value is affected by some undetected bias), the 2 1 / K K values are close to the expected ones.Therefore, it can be concluded that, within experimental error, the two cyclodextrin residues in the dimer behave independent to each other when complexing adamantyl derivatives.

ITC measurements.
The description of the thermodynamic background for ITC experiments can be found elsewhere 3 and experimental procedure in the MicroCalc calorimeter instructions.ITC experiments were carried out at 30.00 (0.01 °C).Experimental titration curves were analyzed with the MCS Origin ITC 5.0 program delivered with the instrument.Average values of the thermodynamic parameters and their standard deviations were calculated from 2-3 experimental runs.
The synthesis of the β-cyclodextrin dimer can be found elsewhere. 36

Figure 3 .
Figure 3.-Schematic microscopic description of the complexation process.
self-consistency of the analysis of the experimental results, this should be the value obtained for the 2 1 / K K relationship.Table