Î±-Cyclodextrin: How Effectively Can Its Hydrophobic Cavity Be

Subscriber access provided by UNIVERSITY OF ADELAIDE LIBRARIES

Article

#-Cyclodextrin: How Effectively Can Its Hydrophobic Cavity Be Hydrated? Silvia E. Angelova, Valia Nikolova, Stiliyana Pereva, Tony Spassov, and Todor Dudev J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.7b04501 • Publication Date (Web): 08 Sep 2017 Downloaded from http://pubs.acs.org on September 9, 2017

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

The Journal of Physical Chemistry B is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 37

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Physical Chemistry

α-Cyclodextrin: How Effectively Can Its Hydrophobic Cavity Be Hydrated? Silvia Angelova†, Valya Nikolova‡, Stiliyana Pereva‡, Tony Spassov*‡, Todor Dudev*‡ †

Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria

‡

Faculty of Chemistry and Pharmacy, Sofia University “St. Kl. Ohridski”, 1164 Sofia, Bulgaria

ACS Paragon Plus Environment

1


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 37

ABSTRACT

Cyclodextrins (CDs) are among the most widely used native host systems with ability to form inclusion complexes with various molecular objects. This ability is so strong that the “hydrophobic” CD cavity never remains empty – even in the guest-free state it is filled with water molecules. However, no consensus has been reached concerning both the total number of hydrating water molecules and their preferred binding location in the CDs. Several outstanding questions regarding the CD hydration still wait to be answered: (1) Which spots of the CD cavity (“hot spots”) have the highest affinity for the guest water molecules? (2) How stable are water clusters inside the cavity? (3) Which mode of water binding - sequential or bulk - is thermodynamically more favored? (4) What is the upper limit of the number of water molecules bound inside the host cavity? (5) What factors do control the CD hydration process? Here, using αCD as a typical representative of the cyclodextrin family, we endeavor to answer these questions by combining experimental measurements (differential scanning calorimetry and thermogravimetry) with theoretical (DFT) calculations. Enthalpies of the αCD hydrate formation are evaluated and the role of different factors, such as the number and mode of binding (sequential vs. bulk) of water molecules, type of hydrogen bonds established (water-water vs. water-αCD), and the dielectric properties of the medium, on the complexation process is assessed. The results obtained shed light on the intimate mechanism of water binding to αCD and disclose the key factors governing the process.


2

Page 3 of 37

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1. INTRODUCTION Cyclodextrins (CDs) are well-known macrocyclic molecules with distinctive “doughnut” shape and ability to form inclusion complexes with various molecular objects of interest to pharmacology, food industry, cosmetics, catalysis and environmental protection.1-4 The CD walls are hydrophobic while the two rims, decorated with OH groups (upper/narrow and lower/wide rim), are hydrophilic. As a result, the exterior of CDs is hydrophilic whereas the cavity is hydrophobic, which gives cyclodextrins the capability to accommodate mostly hydrophobic substances inside their cavity.5-9 Supramolecular structures with CDs as host molecules exist in both the solid state and in solution. However, the internal cavity can bind hydrophilic objects as well, though with lower affinity than the respective hydrophobic moieties. In fact, the cavity of guest-free cyclodextrins is never empty - it hosts water molecules. In the solid state, the CDs are usually described as non-defined hydrates with some water molecules in the host cavity, others forming hydrogen bonding networks between macrocycles.10-12 Even for the smallest representative of the cyclodextrin family, αCD, there are conflicting reports concerning both the total number of water molecules and their binding position in the αCD (into the inner cavity, outside it, partly inside the cavity).13-17 The data on the binding energy of the water molecules to αCD are dispersed as well.15,16 For crystalline αCD, X-ray diffraction analysis has detected only two water molecules located in the center of the αCD ring.13,14 On the other side, in Monte Carlo simulations of hydrated αCD an average of five water molecules have been found inside the cavity where 2.4 of them formed hydrogen bonds with the host molecule.15 There exists also a report for about 6 water molecules per αCD.16 Molecular dynamics simulations have been used to study the conformations and the hydration of CDs containing from six (αCD) to nine (δCD) sugar rings in vacuo and in water medium. The average number of water molecules found inside


3


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 4 of 37

the αCD cavity, 3.6, exceeding the experimental value of two obtained in the solid state,13,14 has been explained by the larger flexibility of the molecule in solution at room temperature.18 Several studies have tried to shed light on the intimate mechanism of the hydration-dehydration processes of CDs and the role of water molecules in the inclusion complex formation.7,19-22 It has been argued that the exclusion of water molecules, so called “high-energy water molecules” from the host cavity upon guest binding is not contributive to the CD complex formation.23 Furthermore, the release of water molecules from the CD cavity has been found to be enthalpically unfavourable (but entropically favorable) and the number of water molecules released depends on the geometry and size of the incoming guest molecule.24 Several outstanding questions regarding the αCD hydration still wait to be answered: (1) Which spots of the αCD cavity (“hot spots”) have the highest affinity for the guest water molecules? (2) How stable are water clusters inside the cavity - should the water molecules be hydrogen bonded to each other or separate binding to the cavity "hot spots" will suffice? (3) Which mode of water binding - sequential (by individual water molecules) or bulk (by preformed water clusters) - is thermodynamically more favored? (4) What is the upper limit of the number of water molecules bound inside the host cavity? (5) What factors do control the αCD hydration process? Here, we endeavor to answer these questions (which have not been addressed before, to the best of our knowledge) by combining experimental measurements (differential scanning calorimetry and thermogravimetry) with theoretical calculations (density functional theory, DFT, computations). Enthalpies of the αCD hydrates formation are evaluated and the role of different factors, such as the number and mode of binding (sequential vs. bulk) of water molecules, type of hydrogen bonds established (water-water vs. water-αCD), and the dielectric properties of the


4

Page 5 of 37

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


medium, on the complexation process is assessed. Note that reliable experimental evidence for the distribution of water molecules between the αCD cavity and outside it is missing. Therefore in this study we attempt to determine theoretically how many water molecules can be retained inside the αCD cavity and compare this number and the respective binding energies with the experimentally determined by us (by precise thermal analyses) quantities. The results obtained shed light on the intimate mechanism of water binding to αCD and disclose the key factors governing the process. 2. MATERIALS AND METHODS 2.1.

Materials The αCD was produced by Wacker Chemie AG (CAVAMAX W6 FOOD) with purity of

≥ 98% and was used for the thermal analyses in the as-received form (without any further purification). 2.2.

Experimental measurements The thermal behavior of αCD cyclodextrin was characterized by Differential scanning

calorimetry (DSC) using Perkin-Elmer DSC-7 and Thermogravimetry (TG) using Perkin-Elmer TG-2. Samples were heated from room temperature (25°C) to 160°C with different scanning rates – from 5 to 20 K min-1 in pure nitrogen atmosphere. Temperature and heat flow calibration of the DSC was made by evaluating the melting peak of pure In and Zn. Dry nitrogen was used as purge gas at a fixed flow rate of 20 ml min-1. All DSC and TG measurements were repeated at least three times to ensure the reproducibility and precision of the determined quantities. 2.3.

Computational details


5


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 6 of 37

The M062X functional in combination with 6-31G(d,p) basis set was used to optimize the geometry of αCD, water clusters and hydrated complexes and evaluate the electronic energy, Eel, of each structure using the Gaussian 09 program.25 Recent calculations on αCD-metal complexes have proven the M062X/6-31G(d,p) level of theory suitable for evaluating the properties of cyclodextrin complexes as it reliably reproduces the geometry of model systems of similar structure/composition.26 The method/basis set combination was further tested here with respect to experimentally determined structure of the host αCD and demonstrated, again, to be appropriate for structural modeling of the systems under study (Supporting Information; Table S1). In order to assess the effect of the increased sophistication of the employed basis set on the calculated energies, we performed single point calculations (using the optimized M062X/631G(d,p) structures) and evaluated Eel at M062X/6-311++G(d,p) level of theory. Electronic energies obtained at both levels of theory (M062X/6-31G(d,p)//M062X/6-31G(d,p) and M062X/6-31G(d,p)//M062X/6-311++G(d,p)) were used alongside in the subsequent evaluations. Furthermore, the calculations at the two theoretical levels were successfully validated against experimental data on water dimer (see below). The frequency calculations for each M062X/631G(d,p) optimized construct were performed at the same level of theory. No imaginary frequency was found for the lowest energy configurations of any of the optimized structures. The frequencies were used to compute the respective thermal energy correction, Eth, including zero point energy, to the electronic energy yielding the enthalpy of the molecule/complex at T= 298.15 K. H = Eel + Eth

(1)

Solvation effects were accounted for by employing the Solvation Model based on Density (SMD) scheme27 as implemented in the Gaussian 09 suite of programs.25 The fully optimized


6

Page 7 of 37

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


structure of each molecule/complex in the gas phase was subjected to single point calculations in water (with dielectric constant ε ≈ 78) at both M062X/6-31G(d,p)//M062X/6-31G(d,p) and M062X/6-31G(d,p)//M062X/6-311++G(d,p). The difference between the gas-phase and SMD energies was used to calculate the solvation energy, ∆Esolvε, of the respective entity: ∆Esolvε ≈ Eelε - Eel1. Note that the gas-phase geometry of αCD and its complexes was shown here to match very closely that optimized in aqueous solution (Supporting Information; Figure S2) thus employing gas-phase geometry in evaluating the respective solvation energies is not expected to affect the reliability of the calculations. Following the standard thermodynamic cycle approach, the solvation energies of the reactants and products were employed to calculate the enthalpy of complex formation, ∆Hε, in condensed medium (water): ∆Hε =∆H1 + ∆Еsolvε (Products) − ∆Еsolvε (Reactants)

(2)

Basis set superposition errors (BSSE) were accounted for by employing the counterpoise procedure of Boys and Bernardi28 as coded in Gaussian 09 package. PyMOL molecular graphics system was used for generation of the molecular graphics images.29

3. RESULTS AND DISCUSSION 3.1. Thermal dehydration of αCD The thermal dehydration of αCD was studied by thermogravimetry (TG) and differential scanning calorimetry (DSC). Figure 1 shows the thermogravimetric curve for αCD, obtained with 5 K min-1 heating rate in nitrogen atmosphere. Two distinguishable stepwise weight


7


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 8 of 37

reductions can be observed in the temperature interval 40-100oC with an additional slope between 100-130oC. Decomposition of the αCD takes place at temperatures above 250oC and, since it was not a subject of the present study, was not followed further. The derivative thermogravimetric curve (DTG in Figure 1) reveals more clearly the temperature intervals of the volatile components release. Since water is the only volatile component released in this temperature range (40-130oC) our analysis of the full αCD weight reduction revealed 6 water molecules liberated per αCD molecule.

Figure 1. Termogravimetric (TG) and derivative termogravimetric (DTG) curves for αCD. This result is fully reproducible as the same number was obtained after several repetitions of the experiment and regardless of the αCD storage conditions (time and small variations of the room temperature in open air holder). This indicates that a certain number of water molecules (for the αCD used in this study it is 6) are inherently involved in stabilizing the cyclodextrin molecule at room temperature. It was also proved by DSC in this study that, in partial or full


8

Page 9 of 37

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


elimination of water molecules from the cyclodextrin host, the structure of the latter changes, but in a subsequent hydration the initial structure recovers. Although the TG steps observed in Figure 1 blend into one another, the number of water molecules corresponding to the different stages of release could be determined with satisfactorily precision. The first about two water molecules (exactly 2.1) dehydrate in the low temperature range of 40-70oC meaning a very weak interaction with the αCD. In the temperature range of 70100oC another 3 (exactly 3.0) molecules water desorb and, finally, at about 120oC the weight decrease corresponds to about 0.6 water molecules per αCD molecule. To answer the question regarding the water stability inside the αCD cavity a DSC analysis was also applied (Figure 2). At certain annealing conditions (heating rate, open sample pan, nitrogen flux rate) the endothermic peaks corresponding to the release of water molecules bound with different energy in the CD cavity are distinctly separated and allow correct assessment of the respective dehydration enthalpies. As expected, the observed DSC peaks match well the steps from the TG analysis (DTG peaks, Figure 1). Combining the results from both thermal methods (TG and DSC), the enthalpies of the first and second water release from the αCD were determined: 5.3±0.9 and 7.2±0.6 kcal mol-1 H2O, respectively, corresponding to the first and second thermal peak in Figure 2. To increase the precision of the analysis, the dehydration enthalpies were averaged from 3 independent measurements.


9


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 10 of 37

Figure 2. Differential scanning calorimetry (DSC) plot for αCD. The thermal analyses performed showed small but noticeable difference in the thermal stability of the water molecules inside the αCD cavity, reflected by the different enthalpies of dehydration. The results show that the water molecules releasing in several subsequent stages during heating are more differently bonded to the αCD than facing different diffusion difficulties in their transition from the solid αCD to the gas phase. 3.2.

Validation of calculations

The experimentally determined dissociation energy, D0, of water dimer in the gas-phase was used to validate our calculations. The calculated D0 of 3.71 kcal mol-1 at M062X/631G(d,p)//M062X/6-31G(d,p)

and

3.00

kcal

mol-1

at

M062X/6-31G(d,p)//M062X/6-

311++G(d,p) are in very good agreement with the experimental value ranging between 3.59 ± 0.5 kcal mol-1 and 3.16 ± 0.03 kcal mol-1.30,31 3.3.

Nonhydrated αCD

αCD is highly symmetric, possessing nearly sixfold symmetry. The primary OH groups from the narrow rim can be arranged in two different ways: (i) pointing inward and forming a hydrogen bond belt (“head-tail” configuration) that greatly reduces the size of the aperture from


10

Page 11 of 37

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


the narrow rim side (Figure 3A), and (ii) pointing outward thus opening the pore (“open” configuration, Figure 3B). In the latter case, the primary OH groups do not participate in intramolecular hydrogen-bond formation. Weaker (than its narrow-rim “head-tail” counterpart) hydrogen bonds are formed between the secondary hydroxyl groups in the wide rim. The calculations imply that the “head-tail” configuration is energetically preferred over the “open” configuration (by 11.2 kcal mol-1) thus the former was employed in further evaluations.

Figure 3. Molecular structure of M062X/6-31G(d,p) fully optimized nonhydrated αCD in two projections (side view and top view from the narrow rim): A) structure with intramolecular hydrogen bonds at both rims with opposite mutual orientation: looking from the narrow rim side the orientation of the wide rim hydrogen bonds is clockwise, while the orientation of the narrow rim hydrogen bonds is counter-clockwise; and B) structure with “open” narrow rim. 3.4. Hydrated αCD


11


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 12 of 37

3.4.1. Successive water binding to the central cavity Coordination of one to six guest water molecules at different positions and orientations inside the cavity of αCD has been considered (Figure 4). The αCD cavity has been scanned for spots with high affinity to the guest water molecules. The first resident water molecule can be positioned at either rim (n = 1; Figure 4, structures a, c) or buried inside the αCD cavity (n = 1; Figure 4, structure b). The calculated relative enthalpies of the three resulting complexes are given in Table 1. The structure with a water molecule positioned at the narrow rim (n = 1; Figure 4, structure a) appeared to be the most stable one, so the narrow belt with the “head-tail” arrangement of the primary OH groups can be indicated as a “hot” spot for water coordination/attraction. This finding is not surprising in view of the higher electron density concentrated in the narrow belt compared to other αCD localities26 (Figure 5) thus securing more favorable interactions with the guest water molecule. Interestingly, the positioning inside the cavity is preferred (∆∆H1 = 2.8 kcal mol-1) over the wide rim coordination (∆∆H1 = 4.5 kcal mol1

) probably due to the proximity of the narrow rim “hot” spot to the bound water in the former

structure compared to the latter construct. The calculations indicate that water coordination to the narrow and wide rim results in creating two new hydrogen bonds between αCD and the guest water molecules at the expense of destroying one hydrogen bond from the initial αCD structure.


12

Page 13 of 37

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 4. Graphical representation of αCD-nH2O complexes (n=1÷6) with different positioning of the water molecules/clusters, and relative enthalpies of the respective hydrates evaluated at M062X/6-31G(d,p)//M062X/6-311++G(d,p) level of theory. A second water molecule can be added to form a dimer with the first one or, alternatively, float away from it and bind to a distant location in the αCD cavity. The latter case appeared, however, unfavorable, as the two water molecules, though separated in the starting structure, approached each other and formed hydrogen bonded dimer during the geometry optimization. The results obtained demonstrate that the αCD-2H2O complexes with the first water bound to the narrow rim and the second one located inside the cavity and hydrogen bonded to its water partner are the most stable (n = 2; Figure 4, structures a, d). Simultaneous binding of two water


13


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 14 of 37

molecules to the narrow rim is not possible – the second water molecule was shifted/displaced outside the cavity upon optimization (n = 2; Figure 4, structure b). In modeling water clusters containing larger number of water molecules, each additional water molecule was added to the aCD-(n-1)H2O complex at a position appropriate to maximize its interactions with the existing water molecules or cavity OH-groups. When studying the coordination of three to six water molecules to the host cyclodextrin it was found that, similarly to the mono- and dehydrated structures, the hydrogen bonded cluster of water molecules with a single water ligand bound to the narrow belt is preferred over the other isomeric structures (a structures for n = 3÷6 in Figure 4). Note that the first water molecule engaged in interactions with the narrow rim OH groups plays a pivotal role in formation and stabilization of the αCD polyhydrates as it acts as an anchor for the subsequently formed hydrogen-bonded water clusters inside the host cavity.

Figure 5. Electron density (isovalue=0.002), mapped with electrostatic potential (color scheme: red/yellow for negative surface map values and blue for the positive ones). The enthalpies evaluated for the process of subsequent water binding to the host cyclodextrin in both the gas phase and water environment at both levels of theory are given in Table 1. The two sets of calculations employing different basis sets follow the same trend of changes. All the interactions in the gas phase are favorable, characterized with negative ∆H1. Generally, increasing the number of hydrogen bonds (water-water and water-cyclodextrin wall


14

Page 15 of 37

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


interactions) created upon water addition increases the efficiency of the hydration process: For example, placing 3 and more water molecules inside the cavity increases the number of hydrogen bonds resulting in lower (i.e. more favorable) formation enthalpies (compare ∆H1 for reactions 1 and 2 with those of reactions 3÷10 in Table 1). However, straightforward correlation between the number of hydrogen bonds and formation enthalpies is not observed. Note that the calculated gas-phase enthalpies at M062X/6-31G(d,p)//M062X/6-31G(d,p) level for the release of the sixth (8.8 kcal mol-1) and fifth water molecule (9.5 kcal mol-1) from the host cyclodextrin (reverse of equations 6 and 5 in Table 1) are in good agreement with the experimental data obtained by TG and DSC techniques (5.3±0.9 and 7.2±0.6 kcal mol-1, respectively; see above). Solvation effects (high dielectric water environment) attenuate the energy gains in the gas-phase and render the complex formation less favorable in condensed media. This is mainly due to the fact that the desolvation penalty for the two interacting entities (on the left-hand side of the equation) exceeds the energy gain for the product solvation (on the right-hand side of the equation) thus increasing the resultant energy. Table 1. Calculated enthalpies in the gas phase (∆H1) and water environment (∆H78) (in kcal mol-1) for the most stable αCD-nH2O complex formation (n=1÷10). ∆H1

Reaction

∆H78

∆H1

∆H78

(M062X/6- (M062X/6- (M062X/6- (M062X/631G**)

31G**)

311++G**)

311++G**)

1. αCD + H2O→αCD-H2O

-6.9

-2.6

-7.1

-2.2

2. αCD-H2O + H2O→αCD-2H2O

-6.1

-2.0

-5.7

1.0

3. αCD-2H2O + H2O → αCD-3H2O

-16.7

-9.5

-13.7

-6.5


-14.3

-6.7

-8.4

0.4


15


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 16 of 37


-9.5

-3.0

-11.8

-5.7

6. αCD-5H2O + H2O→αCD-6H2O

-8.8

-4.6

-8.0

-4.2


-17.5

-11.2

-12.1

-5.4


-11.1

-2.5

-7.3

3.1


-11.0

-4.0

-9.8

-2.5


-13.2

-7.0

-14.0

-6.4

How many water molecules could be accommodated inside the host cavity, i.e. what is the saturation point of the αCD internal hydration? The calculations in the gas phase demonstrate that subsequent insertion of water molecules (up to 10) in the cavity is favorable with no sign of reaching a saturation limit of the binding energy. However, scrutinizing the optimized structures of the αCD hydrates (Figure 6) it becomes evident that the additional water molecules in the heavier αCD-nH2O complexes (n ≥ 7) are not strictly placed inside the host cavity. Rather, they float slightly out of the vicinity of the wide rim in the “no man’s” zone between inner and outer space of the host cyclodextrin. Note that they do not interact with the cavity walls and secure their position only by forming hydrogen bonds with adjacent water partners. Thus, our results imply that the number of “true” hydrating water molecules inside the αCD pore does not exceed 6.


16

Page 17 of 37

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 6. M062X/6-31G(d,p) fully optimized structures of αCD-nH2O complexes (n=1÷10); a structures for n = 1÷6 (from Figure 2) are presented.


17


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 18 of 37

Figure 7. M062X/6-31G(d,p) fully optimized structures of complexes between αCD and externally bound water molecule. Energies (M062X/6-31G(d,p)//M062X/6-311++G(d,p)) are relative to the energy of the most stable complex with internally bound water guest. The absolute energy values are given in Table S3 of the Supporting Information.

3.4.2. Internal vs. external water binding It is of particular interest to juxtapose the water binding efficiency of internal and external localities of the host cyclodextrin. Thus, in addition to the structures with water molecules accommodated inside the cavity (see above), we modeled several other structures where the incoming water molecule was bound to some external spots of the host macrocycle. The optimized structures of these hydrates are shown in Figure 7 and their energy is compared with that of the most stable “internal” aqua complex (Figure 4, n=1, structure a and αCD-1H2O structure in Figure 6). As the calculations reveal, external binding to any of the spots comprising −OH or C-O-C attractors is less favorable (by 1.2÷5.4 kcal mol-1) than the binding inside the αCD cavity. 3.4.3. Effect of the addition of water clusters (bulk binding)


18

Page 19 of 37

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


So far, we have studied the effect of stepwise binding of individual water molecules to the host cyclodextrin. However, in both the gas phase and solution, water clusters (H2O)n (n ≥ 2) of different size and shape can also exist32 and can be active players in the process of αCD hydration.

Figure 8. M062X/6-31G(d,p) fully optimized water clusters (the less stable clusters for the higher members of the series are in blue circle shape). Therefore, it is of particular interest to study the mechanism of the water cluster binding (bulk binding) to the host cyclodextrin and compare its efficiency with that of the individual water hydration. For this purpose we have modeled and optimized several water oligomers comprising 2, 3, 4, 5 and 6 water molecules starting from the stable isomers of small water clusters reported in the literature.32-41 The energetically more stable structures of the constructed tetramers (with almost square symmetric structure), pentamers (with planar pentagon shape) and hexamers (prism-type cluster) are shown in red circles in Figure 8. These, along with the modeled dimers and trimers (nonsymmetric triangular cluster) were used for subsequent evaluations. The pre-optimized water clusters were inserted into the host cyclodextrin cavity and the resulting αCD-(H2O)n complex was subjected to full geometry optimization.


19


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 20 of 37

The energies of bulk hydration in both the gas phase and water environment are given in Table 2 (left-hand side). Table 2. Formation energies (in kcal mol-1) of αCD – aqua complexes with pre-formed water clusters (left-hand side) and with individual non-hydrogen bonded water ligands (right-hand side).a ∆H1

a

∆H78

∆H1

∆H78

αCD + (H2O)2 → αCD-2H2O

αCD + 2H2O → αCD-2H2O

-10.5 (-10.7)

-13.0 (-13.1)

-5.5 (-2.7)

-4.6 (-1.5)



-16.1 (-15.1)

-29.6 (-26.8)

-11.9 (-8.4)

-14.1 (-8.0)



-15.2 (-13.8)

-43.9 (-35.0)

-9.9 (-5.3)

-20.8 (-7.4)



-20.0 (-19.2)

-53.4 (-46.9)

-13.0 (-10.6)

-23.8 (-13.3)



-18.3 (-17.3)

-62.2 (-54.9)

-17.5 (-15.1)

-28.4 (-17.5)

Numbers outside parentheses refer to M062X/6-31G(d,p)//M062X/6-31G(d,p) enthalpies

whereas

those inside parentheses

refer to

M062X/6-31G(d,p)//M062X/6-311++G(d,p)

enthalpies.

The results imply that the process is energetically favorable in both media. However, there is no straight correlation between the size and shape of the attacking cluster and the


20

Page 21 of 37

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


resultant energy of complex formation. This is mainly due to the non-uniform distortion of the initial structure of different water clusters upon binding yielding varying degree of energy penalty for the respective structural alterations of the incoming oligomer. As compared to the respective hydration mechanism involving individual, non-hydrogen bonded water molecules (Table 2, right-hand side), the bulk binding generally appears less favorable than the single-water mechanism (more negative energies for the latter than the former). Again, a price has to be paid for distorting/destroying the pre-formed water oligomer structure upon binding to the host cyclodextrin cavity.

4. CONCLUSIONS Both experimental and theoretical results reveal that although the α-cyclodextrin internal cavity is predominantly hydrophobic, it can favorably bind polar substances as well, water molecules in particular. Water binding to the exterior of the host molecule seems enthalpically less favorable. Up to six water molecules can be accommodated internally by the host. The water clusters inside the αCD cavern are stabilized by elaborate network of hydrogen bonds between water molecules themselves and favorable interactions between water entities and cyclodextrin walls. We identify two key players which appear to be of crucial importance for the hydration process: (1) the narrow belt organized into closed “head-tail” formation, providing concentrated high electron density medium for favorable binding of the first water guest; (2) the first water molecule which, firmly bound at the center of the narrow rim aperture, serves as an anchor for subsequent water binding. Our results imply that the stability of water clusters inside the host cavity stems mainly from the favorable hydrogen-bond interactions between water molecules, whereas the water-αCD wall interactions play a lesser role.


21


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 22 of 37

The stepwise individual water binding as opposed to the bulk hydration by pre-formed water clusters appears to be the preferred mode of internal hydration of αCD. Furthermore, increasing the dielectric constant of the medium attenuates the energy gains from the αCD hydration and reduces the effectiveness of the process.

AUTHOR INFORMATION Corresponding Authors [email protected] [email protected] Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes The authors declare no competing financial interest. SUPPORTING INFORMATION The Supporting Information is available free of charge on the ACS Publications website at DOI:… Information on the performance of the M062X/6-31G(d,p) method/basis set combination in predicting experimental structural data of αCD; comparison between the gas phase and water optimized geometries of αCD and selected water-αCD complexes; energies of formation of water-αCD complexes.


22

Page 23 of 37

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


ACKNOWLEDGMENT This work was supported by the Materials Networking Project H2020-TWINN-2015 and the Bulgarian Scientific Fund under Project “MADARA” at IOCCP-BAS (RNF01/0110, Contract No. DO02-52/2008). REFERENCES (1)

Wenz, G. Cyclodextrins as building blocks for supramolecular structures and functional units. Angew. Chem. Int. Ed. Engl. 1994, 33, 803-822.

(2)

Saenger, W. Inclusion compounds; Atwood, J. L., Davies, J. E. D. , MacNicol, D. D., Eds.; Academic Press, London, 1984, pp 231-259.

(3)

Szejtli, J. Cyclodextrins and their inclusion compounds; Akademiai Kiado, Budapest, 1982.

(4)

Kurkov, S.; Loftsson, T. Cyclodextrins. Int. J. Pharm. 2013, 453, 167-180.

(5)

Szejtli, J. Introduction and general overview of cyclodextrin chemistry. Chem. Rev. 1998, 98, 1743-1754.

(6)

Chen, G.; Jiang, M. Cyclodextrin-based inclusion complexation bridging supramolecular chemistry and macromolecular self-assembly. Chem. Soc. Rev. 2011, 40, 2254-2266.

(7)

Connors, K. A. The stability of cyclodextrin complexes in solution. Chem. Rev. 1997, 97, 1325-1358.

(8)

Sifaoui H.; Modarressi, A.; Magri, P.; Stachowicz-Kuśnierz, A.; Korchowiec, J.; Rogalski M. Formation of β-cyclodextrin complexes in an anhydrous environment. J. Mol. Model. 2016, 22, 207-219.


23


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

(9)

Page 24 of 37

Hansen, P. E.; Dettman, H. D.; Sykes, B. D. Solvent-induced deuterium isotope effects on

19

F chemical shifts of some substituted fluorobenzenes. Formation of inclusion

complexes. J. Magn. Reson. 1985, 62, 487-496. (10)

Bilal, M.; de Brauer, C.; Claudy, P.; Germain, P.; Letoffé, J. M. β-Cyclodextrin hydration: a calorimetric and gravimetric study. Thermochim. Acta 1995, 249, 63-73.

(11)

Wiedenhoff, N.; Lammers, J. N. J. J. Properties of cyclodextrins: Part I. Solubility measurements. Carbohydr. Res. 1967, 4, 318-325.

(12)

Granero-Garcia, R.; Lahoz, F. J.; Paulmann, C.; Saouanea, S.; Fabbiani, F. P. A. A novel hydrate of a-cyclodextrin crystallised under high-pressure conditions. Cryst. Eng. Comm. 2012, 14, 8664-8670.

(13)

Manor, P. C.; Saenger, W. Topography of cyclodextrin inclusion complexes. III. Crystal and molecular structure of cyclohexaamylose hexahydrate, the water dimer inclusion complex. J. Am. Chem. Soc. 1974, 96, 3630-3639.

(14)

Lindner, K.; Saenger, W. Topography of cyclodextrin inclusion complexes. XVI. Cyclic system of hydrogen bonds: structure of α-cyclodextrin hexahydrate, form (II): comparison with form (I). Acta Crystallogr. B 1982, 38, 203-210.

(15)

Georg, H. C.; Coutinho, K.; Canuto, S. A look inside the cavity of hydrated αcyclodextrin: A computer simulation study. Chem. Phys. Lett. 2005, 413, 16-21.

(16)

Tanada, S.; Nakamura, T.; Kawasaki, N.; Kurihara, T.; Umemoto, Y. Adsorption behavior of water molecules onto α-, β-, and γ-cyclodextrins and branched αcyclodextrins. J. Colloid Interface Sci. 1996, 181, 326-330.

(17)

Linert, W.; Margl, P.; Renz, F. Solute-solvent interactions between cyclodextrin and water: a molecular mechanical study. Chem. Phys. 1992, 161, 327-338.


24

Page 25 of 37

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(18)

Raffaini, G.; Fabio Ganazzoli, F. Hydration and flexibility of α-, β-, γ- and δcyclodextrin: A molecular dynamics study. Chem. Phys. 2007, 333, 128-134.

(19)

Germain, P.; de Brauer, C.; Diot, M.; Letoffé, J. M. Influence of the water content on the thermal behaviour of β-cyclodextrin at low and very low temperature. J. Incl. Phenom. Mol. Recogn. Chem. 1998, 31, 205-212.

(20)

Diot, M.; de Brauer, C.; Germain, P. Calorimetric behaviour of anhydrous β-cyclodextrin at very low temperature. J. Incl. Phenom. Mol. Recogn. Chem. 1998, 30, 143-150.

(21)

de Brauer, C.; Merlin, M. P.; Germain, P.; Guerandel, T. Thermal behaviour of anhydrous α-, β- and γ-cyclodextrin at low temperature, J. Incl. Phenom. Macrocycl. Chem. 2000, 37, 75-82.

(22)

de Brauer, C.; Germain, P.; Diot, M.; Merlin, M. P. Energetics of water/cyclodextrins interactions. J. Incl. Phenom. Macrocycl. Chem. 2002, 44, 197-201.

(23)

Liu, L.; Guo, Q.-X. The driving forces in the inclusion complexation of cyclodextrins. J. Incl. Phenom. Macrocycl. Chem. 2002, 42, 1-14.

(24)

García-Río, L.; Mejuto, J. C.; Rodríguez-Dafonte, P.; Hall, R. W. The role of water release from the cyclodextrin cavity in the complexation of benzoyl chlorides by dimethyl-β-cyclodextrin. Tetrahedron 2010, 66, 2529-2537.

(25)

Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A., et al. Gaussian 09, Revision D.01; Gaussian, Inc, Wallingford CT, 2009.

(26)

Angelova, S.; Nikolova, V.; Molla, N.; Dudev, T. Factors governing the host-guest interactions between IIA/IIB group metal cations and α-cyclodextrin: a DFT/CDM study. Inorg. Chem. 2017, 65, 1981 – 1987.


25


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

(27)

Page 26 of 37

Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. Universal solvation model based on solute electron density and on a continuum model of the solvent defined by the bulk dielectric constant and atomic surface tensions. J. Phys. Chem. B 2009, 113, 6378-6396.

(28)

Boys, S. F.; Bernardi, F. The calculation of small molecular interactions by the differences of separate total energies. Some procedures with reduced errors. Mol. Phys. 1970, 19, 553-566.

(29)

PyMOL, Version 1.7.6.6; Molecular Graphics System; Schrödinger, LLC.

(30)

Curtiss, L. A.; Frurip, D. J.; Blander, M. J. Studies of molecular association in H2O and D2O vapors by measurement of thermal conductivity J. Chem. Phys. 1979, 71, 27032711.

(31)

Rocher-Casterline, B. E.; Ch'ng, L. C.; Mollner, A. K.; Reisler, H. Communication: Determination of the bond dissociation energy (D0) of the water dimer, (H2O)2, by velocity map imaging. J. Chem. Phys. 2011, 115, 6903-6909.

(32)

Keutsch, F. N. ; Saykally, R. J. Water clusters: Untangling the mysteries of the liquid, one molecule at a time. Proc. Natl. Acad. Sci. U. S. A.2001, 98, 10533-10540.

(33)

Pérez, C.; Muckle, M. T.; Zaleski, D. P.; Seifert, N.A.; Temelso, B.; Shields, G. C.; Kisiel, Z.; Pate, B. H. Structures of cage, prism, and book isomers of water hexamer from broadband rotational spectroscopy. Science 2012, 336, 897-901.

(34)

Wang, Y.; Babin, V.; Bowman, J. M.; Paesani, F. The water hexamer: cage, prism, or both. Full dimensional quantum simulations say both. J. Am. Chem. Soc. 2012, 134, 11116-11119.

(35)

Foley IV, J. J.; Mazziotti, D. A. Cage versus rrism: Electronic energies of the water hexamer. J. Phys. Chem. A 2013, 117, 6712-6716.


26

Page 27 of 37

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(36)

Mrázek, J.; Burda, J. V. Can the pH value of water solutions be estimated by quantum chemical calculations of small water clusters? J. Chem. Phys. 2006, 125, 194518.

(37)

Chesnut, D. B. Structures, energies, and NMR shieldings of some small water clusters on the counterpoise corrected potential energy surface. J. Phys. Chem. A 2002, 106, 68766879.

(38)

Lee, C. T.; Chen, H.; Fitzgerald, G. Structures ot water hexamer using density functional methods. J. Chem. Phys. 1994, 101, 4472.

(39)

Lee, C. T.; Chen, H.; Fitzgerald, G. Chemical bonding in water clusters. J. Chem. Phys. 1995, 102, 1266.

(40)

Kim, J.; Kim, K. S. Structures, binding energies, and spectra of isoenergetic water hexamer clusters: Extensive ab initio studies. J. Chem. Phys. 1998, 109, 5886-5895.

(41)

Losada, M.; Leutwyler, S. Water hexamer clusters: Structures, energies, and predicted mid-infrared spectra. J. Chem. Phys. 2002, 117, 2003-2016.


27


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 28 of 37

TOC Graphic


28

Page 29 of 37

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 1 54x47mm (300 x 300 DPI)



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60



Page 30 of 37

Page 31 of 37

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60





1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

87x89mm (300 x 300 DPI)


Page 32 of 37

Page 33 of 37

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60





1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60



Page 34 of 37

Page 35 of 37

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


122x42mm (300 x 300 DPI)



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Figure 8 123x87mm (300 x 300 DPI)


Page 36 of 37

Page 37 of 37

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


TOC image 104x35mm (300 x 300 DPI)


Î±-Cyclodextrin: How Effectively Can Its Hydrophobic Cavity Be

Recommend Documents