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2.5 Mass Spectrometry

3.2.2 Results and discussion

Previous studies focused on the complex formation between d-metal ions and amine or carboxylate complexes in aqueous–organic solvents have revealed, on the basis of the solvation-thermodynamic approach, the possibility of predicting the thermodynamic parameters of the ionic complex formation reactions in different media according to a change in the solvation state of ligands (Sharnin, 1995; Zevakin et al., 2007; Gesse et al., 2012).

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In particular, the complexation in water is considered as a set of reactions of stepwise replacement of water molecules in the first solvate shell of the central ion by a ligand molecule (Sharnin, 1995). In a binary solvent, the set of reactions is more complicated, since there is a preferential solvation of reagents with one of the solvent components (Zevakin et al., 2007;

Gesse et al., 2012). In the complexation of inorganic cations with crown ethers, cryptands and other macrocyclic structures, the central ion is completely or almost completely isolated from the solvent. For less stable complexes between macrocycle (host) and organic molecule (guest), the guest molecule and the solvent most probably compete for the formation of the complex with the HPCD.

Isothermal Titration Calorimetry and UV-Vis studies

In this work, the thermodynamic parameters of the complex formation between QCT and HPCD in water and in water/ethanol mixed solvent, at pH = 7.0 and 8.1, compared with the relevant literature data in water, are presented in Table 3.2.

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Table 3.2. Thermodynamic parameters for the association of QCT with HPCD in water and in water/ethanol mixtures

X(ETOH) molar fraction

lgK rH (kJ mol-1) rG (kJ mol-1) rS (kJ mol-1) Methods T (K) pH Refs.

0.00 3.8 ± 0.2 -4.9 ± 0.8 -21.6 ± 1.1 56.1 ± 1.4 Calorimetry 298.15 7.0 This

work

3.4 ± 0.1 - - - UV-Vis

spectra 298.15 7.0

2.7 -2.9 ± 0.1 -15.3 ± 0.2 41.6 ± 0.3 Calorimetry 298.15 8.0 (D’Aria

et al., 2017a)

2.6 - - - Phase

solubility 298.15 8.0 (D’Aria et al., 2017a)

3.5 -45.4 ± 1.74 -19.94 ± 0.03 -85.37 ± 5.69 Phase

solubility 298.15 7.4 (Liu et al., 2013)

3.6 - - -

Double-reciprocal plot

298.15 7.4 (Liu et al., 2013)

3.6 - - - Nonlinear

regression analysis

298.15 7.4 (Liu et al., 2013)

3.4 - -19.50 ± 0.02 - Phase

solubility 303.15 7.4 (Liu et al., 2013)

3.2 - -19.11 ± 0.01 - Phase

solubility 308.15 7.4 (Liu et al., 2013)

3.1 - -18.66 ± 0.02 - Phase

solubility 313.15 7.4 (Liu et al., 2013)

3.5 - - - Phase

solubility 298.15 7.4 (Liu et al., 2013)

3.2 - - - Phase

solubility 303.15 - (Jullian et al., 2007)

2.7 - - - Phase

solubility 298.15 - (Pralhad and Rajendr akumar,

2004)

4.04 - - - Phase

solubility 297.15 3.0 (Zheng et al., 2005)

0.05 3.7 ± 0.1 -7.6 ± 0.6 -20.9 ± 0.6 44.4 ± 0.8 Calorimetry 298.15 7.0 This

work

3.5 ± 0.1 - - - Uv-Vis

spectra 298.15 7.0

0.10 3.6 ± 0.1 -7.3 ± 0.5 -20.6 ± 0.6 44.8 ± 0.8 Calorimetry 298.15 7.0, 8.1 This

work

3.3 ± 0.4 - - - UV-Vis

spectra 298.15 7.0

The results of calorimetric titrations showed that the complexation occurs in water/ethanol mixtures of composition X(EtOH) = 0.00, 0.05 and 0.10 molar fraction. Conversely, no complex formation was found out when ethanol molar fraction was ≥ 0.20 at pH = 7.0 or when pH was lowered to 3.6 with a 0.10 EtOH molar fraction, according to the calorimetric titration and UV–Vis data.

The formation of the QCT-HPCD complex can be envisaged by the total heat of complexation (Qcompl) dependence on the concentration of HPCD in the cell. More in detail, when the complex formed, (Qcompl) becomes HPCD concentration independent as observed in Figure 3.5 a–c. Differently, as shown in Figure 3.5 d, e, in the presence of weak molecular

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interactions, the total heat of complexation (Qcompl) dependence on the concentration of HPCD in the cell is linear.

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Figure 3.5. Total heat effect of the interaction between QCT and HPCD in H2O–EtOH solvent, depending on the total molar concentration of HPCD in the cell, (a) in H2O at T = 298.15 K, pH = 7.0; (b) at X(EtOH)

= 0.10 molar fraction, at T = 298.15 K, pH = 7.0; (c) at X(EtOH) = 0.10 molar fraction, at T = 298.15 K, pH

= 8.1; (d) at X(EtOH) = 0.10 molar fraction, at T = 298.15 K, pH = 3.6; (e) at X(EtOH) = 0.20 molar fraction, at T = 298.15 K, pH = 7.0.

Binding constants at pH = 7.0 were also calculated by UV–Vis titration spectra (Figure 3.6 a, b), and the results are shown in Table 3.2. An inspection of Table 3.2 shows that the

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thermodynamic parameters of QCT-HPCD complex formation have been obtained in water by various methods, under different conditions (Pralhad and Rajendrakumar, 2004; Zheng et al., 2005; Jullian et al., 2007; Liu et al., 2013; D’Aria et al., 2017). In most of them, the values of the association constants are in satisfactory agreement with each other and with our values obtained by both calorimetric and UV–Vis methods.

Figure 3.6. Electronic absorption spectra of HPCD with a solution of QCT. The numbers in the legend indicate the molar concentrations of QCT and HPCD (mol L-1), (a) in H2O at pH = 7.0, (b) in X(EtOH) = 0.10 molar fraction at pH = 7.0

In the previous paper, we found the association constant in water at pH = 8.0 (D’Aria et al., 2017), and in this work we were able to obtain calorimetric data in water at pH = 7.0. At this pH, the association constant was one order of magnitude higher and the values of rH and rS showed an increase in both the exothermicity of complexation and the entropic contribution to the Gibbs energy change for the complex formation. The different rH and rS values obtained by Liu et al. can be reasonably explained, considering that they were indirectly extracted by the phase solubility analysis at a different pH of 7.4 (Liu et al., 2013). After the addition of ethanol to water, the stability of the complex was unchanged for X(EtOH) = 0.00, 0.05 and 0.10 molar fraction. However, along with this, an increase in the exothermicity of complexation and a decrease in the entropic contribution to the Gibbs energy change of the formation reaction were detected.

In a previous publication, an insignificant effect of added DMSO on the stability of molecular complexes was found in the study of the complexation of triglycine with cryptand

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[2.2.2] (Usacheva et al., 2016). This finding was discussed based on the compensation effect of the entropy/enthalpy contributions to the Gibbs energy of complexation. Furthermore, in the case of molecular complexes of crown ethers with amino acids and peptides, the addition of ethanol, DMSO and acetone resulted in an increased stability of molecular complexes and in an increase in the exothermicity of their formation reactions (Usacheva and Sharnin, 2015).

These results were explained in terms of changes in solvation of guest molecules with the replacement of waters by organic solvents. Considering previous studies, we could hypothesize that moving from water to hydroalcoholic solvent, the thermodynamics of QCT-HPCD complex formation is influenced by the change in solvation of QCT. The solubility of QCT is higher in water/ethanol mixtures than in water (Razmara et al., 2010), and this indicates that ethanol molecules displace water molecules in QCT hydration shell, affecting both the enthalpic and entropic contributions to Gibbs energy of complexation, so that the lgK for low X(EtOH) remains the same as in water. Increasing ethanol molar fraction, EtOH is able to effectively solvate QCT molecules, by subtracting them from the complexation, and competes for occupation of HPCD cavities or fills the residual empty space of the cavity of HPCD, as already found in another study (Boonyarattanakalin, 2015). The overall result is that, for X(EtOH) greater than 0.10 molar fraction, no complexation occurs.

Differential Scanning Calorimetry experiments

DSC scans have been run to provide further information on the physical and chemical processes occurring during heating. Commercial HPCD displays a broad endothermic peak, which is indicative of the release of superficial and strongly retained water from the hydrophobic core at 106 °C (Figure 3.7 a) (Oprean et al., 2016; Tang et al., 2016). After HPCD dissolution in water, the DSC peak appears at a very similar temperature (about 103.5 °C, Figure 3.7 b), therefore indicating that the same interaction occurs after immersion of HPCD in water.

The DSC peak appears at slightly lower temperatures after dissolution in 9:1 and 8:2 water/ethanol mixtures, around 100 °C (Figure 3.7 c, d). The decrease in these peak temperatures can be explained by the formation of the host–guest molecular inclusion compound that allows the replacement of the strongly retained water molecules inside the cavity by the ethanol moieties. The obtained complex mainly most probably contains superficial water molecules that are more easily released, and hence, he peak temperature decreases (Hădărugă et al., 2013). This indicates that the total water content is lower and/or weakly bound to HPCD

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after immersion in ethanolic or hydroalcoholic solvents, compared to the untreated, commercial CD. These results therefore corroborate the existence of the competition between ethanol and water for the complexation within the hydrophobic cavity of HPCD which in turn contributes in decreasing the efficacy of QCT complexation in the presence of ethanol.

Figure 3.7. Superimposed DSC data for raw HPCD (a) and dried HPCD after dissolution in water (b);

water/ethanol 9:1 v/v mixture (c); water/ethanol 8:2 v/v mixture (d); ethanol (e)

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