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Review

Cyclodextrins’ Internal Cavity Hydration: Insights from Theory and Experiment

by
Silvia Angelova
1,2,
Stiliyana Pereva
3,
Todor Dudev
3,* and
Tony Spassov
3
1
Institute of Optical Materials and Technologies “Acad. J. Malinowski”, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria
2
University of Chemical Technology and Metallurgy, 1756 Sofia, Bulgaria
3
Faculty of Chemistry and Pharmacy, Sofia University “St. Kliment Ohridski”, 1164 Sofia, Bulgaria
*
Author to whom correspondence should be addressed.
Inorganics 2025, 13(1), 28; https://doi.org/10.3390/inorganics13010028
Submission received: 21 December 2024 / Revised: 15 January 2025 / Accepted: 16 January 2025 / Published: 20 January 2025
Browse Figures
Figure 1
<p>(<b>A</b>) Molecular structure of CDs; (<b>B</b>) Schematic representation of the shape of CDs; (<b>C</b>) M062X/6-31G(d,p) fully optimized non-hydrated CDs (top view from the narrow rim): “closed” configuration—structures 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 counterclockwise, while the orientation of the narrow rim hydrogen bonds is counterclockwise; “open” configuration—the orientation of the wide rim hydrogen bonds is clockwise.</p> "> Figure 2
<p>Electron density of α-CD (isovalue: MO = 0.02, density = 0.0004), mapped with electrostatic potential (color scheme: red/yellow for negative surface map values and blue for positive ones).</p> "> Figure 3
<p>Schematic representation of CD–H<sub>2</sub>O complexes with water molecules/clusters located at three different positions, and M062X/6-311++G(d,p)//M062X/6-31G(d,p) calculated relative enthalpies of the respective complexes.</p> "> Figure 4
<p>Schematic representation of the energetically preferred α-CD–nH<sub>2</sub>O complexes (where n = 1–6).</p> "> Figure 5
<p>Structures of the most densely populated CD hydrates (α-CD—6H<sub>2</sub>O, β-CD—10H<sub>2</sub>O, and γ-CD—7H<sub>2</sub>O).</p> "> Figure 6
<p>Fully optimized geometries of selected β-CD assemblies with water and N<sub>2</sub>O (β-CD—nH2O—N<sub>2</sub>O denotes a complex between β-CD, n water molecules, and N<sub>2</sub>O), and the respective Gibbs free energies of complex formation (in kcal/mol). The hydrogen bond network is visualized in the β-CD—9H<sub>2</sub>O—N<sub>2</sub>O construct (in yellow).</p> "> Figure 7
<p>Thermogravimetric/TG (<b>a</b>) and DSC (<b>b</b>) analysis of as-received α-CD, β-CD, and γ-CD.</p> "> Figure 8
<p>Schematic representation of the possible crystal structure packs of CDs.</p> ">
Versions Notes

Abstract

:
In this short review, recent findings from both theory and experiment regarding the process of hydration of α-, β-, and γ-cyclodextrins are summarized and critically assessed. Key important questions are addressed, including: What factors govern the number of water molecules entrapped in the internal cavity of the host macrocycle? What is the driving force behind this process? What are the “hot spots” for water entrapment inside the host cavity? What is the underlying mechanism of water hydration and dehydration of cyclodextrins? What is the role of the confined water cluster in determining the outcome of the host–guest complexation between cyclodextrins and molecules of inorganic/organic nature? To what extent does water hydration affect the crystalline structure of the cavitand?

1. Introduction

Water is all around us, water is inside us. It is one of the simplest existing molecules but possesses extraordinary properties. Its versatility and adaptability help conduct chemical reactions, and most importantly, its properties as a fantastic solvent also affect all life forms on Earth. Water is a polar molecule (μ = 1.85 D) [1] owed to its polar covalent bonds and bent shape. It can dissolve many different molecules (ions and polar entities) and more substances than any other liquid, so it is considered a universal solvent. Water not only acts as a solvent but it can also serve as a building block in shaping the structure of various formations. Substances that contain water molecule(s) within their structures are called hydrates. Three types of hydrates exist: inorganic, organic, and gas (or clathrate) hydrates; the first type being the most common. Water molecules in inorganic hydrates are weakly bound to the compound and no chemical reactions take place. The water molecule(s) can be removed from the hydrate easily; for example, by heating. In organic hydrates, water molecules chemically react with the compound and bond to it. In the third type of hydrates, gas hydrates, water molecules form a crystal lattice structure, based on hydrogen bonding. The gas molecules are located in the interstitial vacancies of the lattice without occupying a position in the water lattice.
The multifaceted nature of water shows one of its most interesting features in a confined space: so-called confined water. Confined water is generally liquid water held within nanometer and sub-nanometer pores or vessels. It can be found in many technologically and biologically relevant systems [2]. Examples of structures with confined water include membrane water/ion channels, carbon nanotubes, pores of zeolites, clay mineral interlayers, voids in concrete, and nano-scale pores and channels of sedimentary rocks and soils, etc. [2,3].
Water molecules can also be entrapped inside the hydrophobic cavities of molecular cages and containers such as cyclodextrins (CDs). These (mostly natural) cavitands are made of several glucose fragments, linked with 1–4 α-glycosidic bonds [4,5,6,7]. The most frequently found/used CDs are those comprising six, seven, and eight glucopyranose units, designated as α-, β- and γ-CDs, respectively. CDs are toroid-like (truncated cone) structures with one aperture (lower rim) wider than the other (upper rim). These garlands of hydrogen-bonded -OH groups (primary ones for the narrow rim and secondary units for the wider rim; Figure 1A) are hydrophilic and can participate in binding polar or cationic species. Structures lacking a hydrogen bond network between hydroxyl groups, resulting in a cylindrical shape of the molecule (Figure 1B), are also possible, although they are energetically less stable than their respective toroid-like counterparts [8,9,10]. The CDs’ internal cavity, unlike the -OH decorated rims, is hydrophobic and can encapsulate non-polar guest molecules by employing van der Waals and hydrophobic forces [11,12,13]. Electrostatic interactions and hydrogen bonding can also contribute favorably (although to a lesser extent) to the energetics of the host–guest complex [14]. Being strange at first glance, the hydrophobic cavity of CDs can accommodate polar water molecules (in stoichiometric amounts) and form a special type of hydrate–organic compound with weakly bound water molecules. The internal cavity of the host CDs is populated by water molecules at ambient temperature (it is never empty), which can be displaced, fully or partially, by increasing the external temperature/pressure or by the attack of other guest molecule(s). Notably, the confined water molecules play a substantial role in forming CDs host–guest complexes with organic/inorganic substances, where the incoming species competes with the entrapped waters for the host’s interior [15]. The number of water molecules immersed in the CDs internal cavity varies widely: 2, 3, 6, 9 for α-CD [8,16,17,18,19]; from 9–12 for β-CD [9,20,21,22,23,24,25,26,27,28] and from 5–17 for γ-CD [10,21], depending on the theoretical/experimental methods/approaches used. However, no consensus exists on the subject. No agreement has been reached on the mechanism of water hydration, the binding position of the encapsulated water molecules, and the driving forces governing the process, either. In this review, we endeavor to shed light on the mechanism of CD hydration by summarizing and critically assessing the recent findings in the field (without claiming to be exhaustive) by covering both theoretical and experimental studies on the most popular representatives of the series, such as α-, β- and γ-CDs. For each system/approach, we will present the major findings/conclusions, relying on the original references to provide details of the experimental/computational methodology.

2. Quantum–Chemical Evaluations

2.1. Mechanism of Hydration—Number of Confined Water Molecules

The process of the internal cavity hydration of CDs has been studied by employing well-calibrated density functional theory (DFT) calculations in both the gas-phase and implicit aqueous medium (at M062X/6-311++G(d,p)//M062X/6-31G(d,p) level). The “closed” configuration (truncated cone) of the host molecule has been considered. Note that this construct is energetically more favorable than the alternative “open” (cylinder-like) configuration by about 11 kcal/mol (α-CD) [8], 13 kcal/mol (β-CD) [9] and 22 kcal/mol (γ-CD) [10]. In addition, these intramolecular hydrogen bonds stabilize the molecule, which, in this configuration, is less prone to twisting/distortion of the original structure.
Calculations reveal the crucial role of the narrow belt in the process of cyclodextrins hydration: it provides high electron density concentrated in a narrow space (Figure 2) and, not surprisingly, appears to be the strongest attractor (“hot spot”) for the incoming water molecule, thus securing the most energetically favorable CD-(H2O)1 construct.
Indeed, as seen in Figure 3, other localities of water coordination (middle of the cavity or lower rim) are less attractive for the guest molecule. Furthermore, the first resident water molecule, tightly bound at the center of the narrow rim opening, serves as an anchor for subsequent water coordination which, on its side, promotes the creation of an elaborate hydrogen bond network with the other arriving water molecules (Figure 4). Calculations, in agreement with experimental observations (see below), imply that α-CD can accommodate up to 6 water molecules in its internal cavity [8], β-CD can accommodate 10 water molecules [9], and γ-CD can accommodate 7 water molecules [10].
Structures of the most densely populated CD hydrates are shown in Figure 5. These results suggest that the stability of water clusters inside the host cavity stems mostly from the favorable hydrogen bond interactions between water molecules, whereas the water–CD wall interactions play a lesser role.
The described mechanism postulates sequential (stepwise) binding of water molecules. Another mechanism—bulk binding of water clusters (droplets)—is also possible. Water clusters (H2O)n (n ≥ 2) of various sizes and shapes can also exist at ambient conditions [29,30,31,32,33,34,35,36,37,38] and can be rightful players in the process of CD hydration. Several water oligomers comprising two, three, four, five, and six water molecules have been optimized, and their binding, as droplets, to α-CD has been modeled [8]. The calculations imply that bulk binding of water clusters is also favorable (negative enthalpies of formation) yielding stable inclusion complexes. However, compared to the respective sequential water-binding mechanism (above), this process appears less energetically efficient as it is characterized by less favorable enthalpies of hydration. Apparently, a penalty has been imposed on the system for distorting/destroying the preformed water oligomer structures upon coordinating with the host CD cavern.
The “open” configuration of the host molecule (Figure 1) has been considered in studying the hydration mechanism of α-CD [39]. Semiempirical PM3 and DFT calculations (at the BLYP/6-31G(d,p) level) have been employed in evaluating the structure and properties of the inclusion complex between α-CD and a cluster of six water molecules. The authors found that only two water molecules (as a water dimer) are entrapped inside the α-CD cavity, whereas the rest of the water content is coordinated externally near the edges of the cavitand (in the form of water tetramer). The low hydration number of 2 detected for this configuration is not surprising since most of the primary -OH groups (the major attractor for the incoming water molecules) point away from the cavity’s aperture, and thus, do not secure optimal (concentrated) electrostatic potential for stabilizing larger water droplets inside the host’s interior (see above).

2.2. Competition Between Confined Water Molecules and Other Guest Entities for the Host’s Interior

Entrapped water molecules play a substantial role in forming inclusion complexes between the host CDs and guest molecules of inorganic or organic origin. The thermodynamic characteristics of the process have been evaluated by employing DFT computations on host–guest complex formation between β-CD and a number of gaseous substances such as N2O, CO2, NO2, SO2, HCN, methane, and propane [15]. An intriguing question has been addressed: Which process of gas incorporation by β-CD is more energetically advantageous—insertion inside the central cavern without ejecting an entrapped water molecule or guest coordination associated with a dislodgment of one or more H2O?
Various different scenarios for the interaction between hydrated β-CD and attacking gas molecules have been considered: host–guest complex formation without ejecting hydration water molecule(s) or gas entrapment with releasing 1, 2, 3, 4, and 10 water molecules. DFT-optimized structures of the β-CD–nH2O–N2O complexes, and the corresponding Gibbs energy of complex formation, are presented in Figure 6.
The optimally hydrated host structure, β-CD—10H2O, has been considered (see above). The data obtained imply that a reaction without exchanging water for a N2O molecule is thermodynamically unlikely (positive ΔG value, Figure 6) due to the overpopulation of the cavitand’s interior (the number of internally entrapped species goes beyond 10), which imposes additional strain on the complex. In contrast, the dislocation of one, two, or three water molecules by the incoming gas is thermodynamically advantageous (negative ΔG values; Figure 6). Indeed, the size of N2O is not so dissimilar from that of H2O, and thus, exchanging water molecule(s) for N2O is not expected to elevate additionally the strain of the complex. Additional ejection of confined waters (4 or 10) by the incoming N2O is no longer favorable (positive ΔGs). Note that the number of water molecules occupying the cavity seems to be correlated to the effectiveness of complex formation: the more water remaining in the cavern, the more efficient the N2O coordination is. As can be seen, the first N2O → H2O replacement is the most favorable event, while lowering the number of confined waters reduces the effectiveness of gas incorporation: ΔG equals −11 kcal/mol for the first water ejection but rises to about −6, −2, 3, and 10 kcal/mol for displacing 2, 3, 4, and 10 H2O, respectively. The stability of the inclusion complex is an outcome of the competition between two opposite effects. On one side, elevated entropy of the system with lowering the water content inside the CD interior is likely to favor the complex formation; i.e., the more water molecules liberated, the more effective (entropically) the gas coordination would be. On the other side, however, the greater water cloud immersing N2O (i.e., more water molecules stay inside the cavity) would enlarge the hydrogen bond network, and thus, stabilize the complex. As an example, the elaborate web of hydrogen bonds surrounding N2O for the β-CD—9H2O—N2O construct is presented in Figure 6. Therefore, the larger the hydration cloud, the firmer the inclusion formation will be. Seemingly, this latter effect is dominant since, as already demonstrated, the β-CD—9H2O—N2O complex is the most stable in the series. Similar trends of changes have been detected for β-CD inclusion complexes with other gaseous substances, such as CO2, NO2, SO2, and HCN [15]. The calculations reveal that, although the internal cavity of β-CD is predominantly hydrophobic, it binds preferably polar species (N2O, NO2, SO2, HCN), or such, with strong electronegative centers (CO2) over non-polar entities (methane and propane). The role of the internal water cloud in the process has been emphasized: when a polar gas molecule coordinates to the β-CD central cavity, it barely interacts with the hydrophobic walls of CD but is wrapped up by an aquatic pool (and -OH dipoles), which provides a “welcoming” hydrophilic environment for the incoming gaseous entity (Figure 6). As the calculations imply, the richer/larger the water shell around the guest substance and the more intricate the resultant hydrogen bond network inside the host aperture, the more efficient the encapsulation process is.

3. Monte Carlo (MC) and Molecular Dynamics (MD) Simulations

A common feature of all MC/MD simulations is the assumption that the CD molecule is in “open” configuration with primary hydroxyl groups pointing away from the central aperture of the internal pore. While this is justifiable for constructs subjected to an explicit water emersion, thus engaging the cavitand’s -CH2OH groups in intermolecular hydrogen bond formation, it is hardly relevant for computations in vacuo, solid-state, or low-dielectric environments where “closed” configuration (Figure 1) is predicted to be dominant. Expectedly, since the “open” structures have limited abilities to attract and stabilize internal water molecules/clusters, the calculated MC/MD number of confined water molecules for α- and β-CD is smaller than that established by considering the “closed” CD–water constructs. For the γ-CD, the trend is the opposite—MD simulations predict a greater number of hydration water molecules than the respective DFT calculations. This is probably due to the much larger aperture of the “open” configuration of γ-CD than its “closed” form (Figure 1). Thus, the former can accommodate and stabilize larger water droplets than the narrower “closed” form. Allegedly, this factor dominates the water hydration energetics in γ-CD over the alternative “anchoring” mechanism, which, in this case, is relatively less efficient. The results of theoretical evaluations regarding the maximum number of confined water molecules in α-, β- and γ-CD are presented in Table 1.

4. Experimental Evaluations

4.1. Measured Water Content

Both the calculated and experimentally determined number of water molecules in CDs vary within certain limits. Table 2 provides information about the measured water content in CDs along with the experimental methods used, the enthalpies of dehydration, and other relevant details. The primary reason for the differences in the experimentally determined water content is the varying storage conditions of the powdered substances—some are measured as-received [9,21], while others are stored in desiccators with controlled humidity levels [21]. Studies have shown that under well-controlled humidity conditions, CDs stored at 90% humidity can contain two to five times more water molecules than those stored at 3% humidity [21]. Additionally, discrepancies in the experimentally determined water content may arise from the use of different analytical techniques (see Table 2).
The thermal stability and X-ray diffraction studies performed by us were primarily focused on as-received commercial α-, β-, and γ-CD. In these studies, we also determined the number of included water molecules in samples exposed to air at room temperature for extended periods [8,9,10]. Figure 7 presents the TG (Figure 7a) and DSC (Figure 7b) curves for the three main CDs measured in their as-received state. It is important to note that the reproducibility of the analyses was excellent and was not significantly influenced by the duration for which the samples were exposed to air, despite minor variations (±3 °C) in room temperature and humidity (~50%). From the TG curve in Figure 7, it is evident that the decomposition of α-CD occurs in two stages. The first process, beginning at approximately 45 °C, is likely associated with the release of weakly bound water (“surface water”). The second stage, starting around 74 °C, involves the release of more strongly bound water molecules (often referred to as “strongly retained water”). The total number of water molecules released during the annealing of α-CD was found to be six in our study, a value also reported by Manakov [46] and Bettinetti [47]. The temperature ranges in which these reactions occur are similar across studies. Overall, the number of water molecules in α-CD, as determined in various studies, ranged from five to seven water molecules per α-CD molecule. The clear two-step release of water observed in both our studies and those of others supports the idea that some water molecules are less strongly bound (located near the rings of the CD cavity, referred to as “surface water”), while others are situated deeper within the cavity (“strongly retained water”), requiring a higher temperature for their release. It has also been noted in the literature that depending on the production method, α-CD hydrates crystallize with a different structure. Two crystalline forms contain 6 water molecules per CD molecule, while the third form contains 7.5 hydration molecules [46,51,52].
In contrast, the desorption of internally bound water in β-CD occurs in a single step (Figure 7a), displaying the most distinct relief among the three CDs, indicating the highest amount of included water molecules. Consistent with other studies [9,20,21,22,24,45], β-CD exhibits thermal behavior similar to that of α-CD, with the key difference being that its dehydration occurs in a single thermogravimetric step (TG) and a single large endothermic peak (DTA/DSC), corresponding to water dissociation and evaporation at around 100 °C. The mass loss of the as-received commercial β-CD hydrate is 11.5%, corresponding to the release of 10 water molecules. The thermal analyses of as-received commercial γ-CD also indicate a different water content, although it is generally lower than that of β-CD and α-CD (Table 2). The thermogravimetric curve for γ-CD shows the onset of water release at approximately 50 °C, continuing until about 130 °C, with two strongly overlapped TG steps. Our thermogravimetric analysis of commercial γ-CD reveals a mass loss of 7.5% in the temperature range of 50–150 °C. The lower onset temperature for water release, compared to the other two CDs, may be linked to the higher mobility of water molecules within the γ-CD cavity. Indeed, water molecules in γ-CD exhibit the highest mobility compared to those in α-CD and β-CD.
Evidence for the two-stage desorption of water in α-CD is also provided by the DSC analysis of the CDs studied (Figure 7b). The endothermic peaks associated with water release in α-CD overlap but exhibit distinct maxima, making them clearly identifiable. In contrast, the thermal peak for water release from β-CD is single, corresponding to the single step observed in the TG curve, consistent with other literature results [9,20,22,24]. In the case of β-CD, distinguishing between differently bound water molecules—“surface” and “strongly retained”—is impossible. However, by combining the two analyses (TG and DSC/DTA), it is possible to determine the overall enthalpy of dehydration for the CDs. Additionally, by deconvoluting the thermal peaks for α-CD, we can obtain the enthalpies of binding for the “surface” and “volume-bound” water molecules. For α-CD, the enthalpy of dehydration we determined (310 J/g) is comparable to values reported by Manakov [46] and Giordano [49]. The enthalpy of dehydration for γ-CD, determined by us (300 J/g), is in good agreement with values reported by other researchers [21] and is not significantly different from that of α-CD. The shape of the calorimetric effect and the TG curve for γ-CD are more similar to those of α-CD than β-CD, suggesting the presence of differently bound water molecules—some located closer to the rings of the molecular cavity, and others more tightly bound within its volume.

4.2. Cyclodextrins Structure—Water Relationship

The crystal structure of CDs is crucial for understanding the mechanisms underlying their complexation with guest molecules, significantly influencing their physicochemical properties, including spatial and localization preferences for both the CDs and their guests.
In the solid state, CDs can form various crystalline hydrates and structures. The primary crystal structures of CDs include channel-like configurations, characterized by linearly aligned cavities that create extended channels within the lattice [28], and cage-like structures, where CDs block adjacent cavities, isolating guest molecules. Among the cage structures, the herringbone and brick arrangements are the most common (Figure 8) [53,54,55,56]. Channel-like structures are stabilized by hydrogen bonds between CD molecules and typically form complexes with small organic molecules, larger compounds, ions, or gases [57]. Conversely, cage structures are often observed when α-, β-, or γ-CDs co-crystallize with water or other molecules. To date, no crystalline forms of CDs devoid of guest molecules, such as water, have been reported [28], likely due to the instability of the cage structure. Water molecules stabilize the CD cages, and during the inclusion formation, can also stabilize the guest molecules; however, some guests could lead to thermodynamic instability [9,28,57].
Several single-crystal structures of α-, β-, and γ-cyclodextrins have been reported, showing slight variations in water content [27]. For α-CD, these include α-CD·6H2O [16,55] and α-CD·11H2O [58]. In particular, one study on the hexahydrate form describes four water molecules located outside the CD stabilized through extensive hydrogen bonding, and two water molecules positioned inside the cavity, and hydrogen-bonded to each other and the CD [16]. For β-CD, several crystal structures with varying water content have also been reported, including β-CD·11H2O [26], β-CD·12H2O [56], β-CD·10.5–12.0H2O [59], and β-CD·9.4–12.3H2O [60]. Additionally, β-CD·8H2O and β-CD·12H2O have been characterized, with the latter showing 6.5 water molecules statistically distributed across 8 sites within the cavity and 5.5 water molecules statistically distributed across 8 external sites around the torus. This distribution is non-stoichiometric, as steric hindrance prevents all sites from being occupied simultaneously [56]. Betzel et al. reported a similar structure, identifying 8 water sites within the cavity and 8 external sites, with an average of 6.13 water molecules occupying the internal sites and 4.88 molecules occupying the external ones [26]. These variations highlight the significant influence of methodology and other factors on the reported hydration states.
The reported γ-CD structures include γ-CD·13.3H2O [50], γ-CD·14.1H2O [50], and γ-CD·17H2O [61], illustrating that some structures have been investigated multiple times with slight variations in results. Similar to β-CD, the 14 water-binding sites within the γ-CD cavity and the 9 external sites cannot be fully occupied simultaneously due to steric hindrance. For the tetradecahydrate γ-CD·14.1H2O, 7.1 water molecules occupy the internal sites, while 7.0 water molecules are distributed externally [62].
CDs crystallize as hydrates from aqueous solutions. Saenger reports that α-CD crystallizes from water as a hexahydrate in two distinct forms (Form I and Form II), both with the same space group but differing cell constants, with Form I being the preferred structure [27]. In Form I, four water molecules are located externally, and the α-CD molecule exhibits a distorted conformation due to the disruption of the O(2)…O(3) hydrogen-bonding ring at one glucose unit. This unit rotates out of alignment with the rest of the glucose residues, resulting in distorted torsion angles. Form II, while nearly identical in conformation, includes one water molecule and the O(6) hydroxyl group of a symmetry-related α-CD molecule within its structure, with five water molecules located externally. The distorted α-CD is intrinsically associated with the “empty” water complex. Upon complexation with guest molecules, α-CD undergoes a conformational change to adopt a “round, undistorted” structure, restoring the complete O(2)…O(3) hydrogen-bonding ring. This transformation exemplifies an “induced-fit” model of complexation [27].
The two crystal forms (I and II) of α-CD·6H2O differ primarily in two aspects:
  • In Form I, the orientation of adjacent α-CD rings positions the O(2)…O(3) rim of one α-CD molecule over the cavity of the neighboring molecule. In contrast, in Form II, the O(6) rim is closer to the cavity of the adjacent molecule.
  • This packing arrangement in Form II allows one of the O(6) hydroxyl groups to protrude into the neighboring cavity, resulting in the formation of a self-inclusion complex.
The inclusion stoichiometry of Form I crystals can be represented as α-CD·2H2O·4H2O, with two water molecules included within the cavity and four water molecules located in the interstices between α-CD rings. In Form II crystals, the stoichiometry is α-CD·H2O·O(6)·5H2O, where the α-CD accommodates one water molecule and one O(6) hydroxyl group, with five water molecules positioned outside the ring. The distinct packing schemes of the two forms of α-CD·6H2O are so fundamentally different that they cannot be attributed to crystal-packing artifacts. Instead, these differences appear to be intrinsically linked to the inclusion of water molecules. The “empty” α-CD in aqueous solution adopts a conformation that differs from the conformation observed when a guest other than water occupies the cavity.
In a study, Manor and Saenger [16] investigated α-CD hydrates, particularly the structure of α-CD·6H2O with water dimers, which may represent the native “empty” α-CD molecule observed in aqueous solution. Their findings provide insights into why α-CD forms inclusion complexes: (1) In aqueous solution, α-CD adopts a conformation similar to its solid-state hexahydrate structure. (2) In this conformation, the α-CD molecule exists in a “strained”, high-energy state, stabilized by hydrogen bonding with the incorporated water molecules and by reducing the otherwise “empty” volume in the CD cavity. (3) Under thermal influence, or in the presence of a potential guest molecule, the α-CD undergoes a conformational change, where the gauche-trans O(6) hydroxyl groups rotate to the gauche form required for the final complex. (4) The guest molecule displaces the two included water molecules, adopting various orientations depending on the available thermal energy and the specific interactions between the guest and the CD, including potential hydrogen bond formation. This mechanism expands upon previously proposed models of α-CD inclusion complex formation based on kinetic and thermodynamic data. By involving a conformational change, the process aligns with the “induced fit” mechanism proposed for enzyme-substrate interactions, suggesting that α-CD may serve as an even better enzyme model than previously recognized [14,16].
Additionally, neutron diffraction studies on the three native CDs (α-, β-, and γ-CD) were performed to better understand hydrogen bond formation. Key findings include: α-CD exhibits two distinct conformations with well-defined hydrogen bonds: (1) A “tense” structure and a “relaxed” structure, supporting an “induced-fit” mechanism for complex formation. Circular hydrogen-bonding networks were also observed, attributed to an energetically favorable cooperative effect. (2) β-CD, with a disordered water structure, displays an unusual “flip-flop” hydrogen bonding system of the type O-H···H-O, representing equilibrium between two states: O-H···O ↔ O···H-O. (3) γ-CD, like β-CD, has a disordered water structure and also features the “flip-flop” hydrogen bond. These findings provide deeper insights into the structural and dynamic aspects of CD hydration and inclusion complex formation.
As previously mentioned, the crystal structure of CDs significantly influences their thermal properties. Manakov et al. [46] conducted an experimental study of the temperature (T)–composition (x) phase diagrams of the CD–water binary system under isochoric conditions using differential thermal analysis (DTA) and differential scanning calorimetry (DSC). They also employed powder X-ray diffraction to identify the structures of various α-CD hydrates and monitor their phase transformations. Their findings reveal significant differences between the dehydration processes under isochoric (sealed) and isobaric (open-air) conditions (Table 3). In the temperature range of approximately 77.85–85.85 °C (351–359 K), the α-CD hexahydrate with the known Form I structure transforms to α-CD·5.3H2O, whose structural type remains unidentified. Furthermore, they observed that a solid solution based on the α-CD hexahydrate Form I structure forms within the compositional range of α-CD·6.1H2O to α-CD·2.1H2O, providing new insights into dehydration processes in the α-CD–water binary system. Manakov et al. [46] also derived thermodynamic parameters for the dehydration process using DSC data and tensimetric vapor pressure measurements over α-CD·6.1H2O using a static method. Their results offer valuable information for optimizing gas-phase synthesis conditions for α-CD complexes. In their study, they also reported that dehydration of α-CD hydrates differs significantly between closed and open systems. In open systems, the calculated decomposition enthalpy was 258.0 J/g or 274.2 kJ/mol. Using the DSC method at p = 0.1 MPa, they determined the dehydration enthalpy of hydrated α-CD·nH2O (where n is the number of water molecules per α-CD molecule). These results are summarized in Table 3.
While studying the water sorption isotherm at temperatures around 20 °C, they found that with increasing relative humidity, the hydrate number (n) grows to n = 6.6, having α-CD·6.6H2O hydrate at P/P0 = 1 and the anhydrous α-CD absorbs water quickly to the composition of α-CD·2H2O.
As mentioned earlier (page 1), the storage conditions of native CDs significantly influence their water content and thermal properties. Specogna’s research [21] on the dehydration, dissolution, and melting of CD crystals demonstrates that water content varies with relative humidity (RH), as illustrated in Table 4. The initial water content in the as-received CD powders was determined to be 9.68% for α-CD, 13.59% for β-CD, and 9.03% for γ-CD. Under high humidity (RH = 90%), these values increased to 10.15%, 15.21%, and 18.18%, respectively. Conversely, under low humidity (RH = 3%), water content dropped to 5.26%, 2.95%, and 4.55%, respectively, for α-CD, β-CD, and γ-CD. Differential thermogravimetric analysis (TGA) in Specogna’s study [21] revealed that water loss occurs in a stepwise manner, with three distinct dehydration steps observed depending on the initial humidity levels (e.g., RH = 44%, 90%, or the initial state). For α-CD, the first dehydration step occurs between 27 °C and 48–50 °C, with the maximum rate of mass loss observed at 40 °C, corresponding to a loss of 2.2 H2O molecules per α-CD molecule. Linert’s findings corroborate this, showing that up to 2 H2O molecules occupy the internal cavity of α-CD [63]. These cavity-bound water molecules are less energetically stabilized than those bound outside due to the molecular environment within the cavity. To summarize Specogna’s DTA results [21] for α-CD: (1) The cavity-bound water molecules (two H2O per α-CD) exhibit similar thermal stability in both cage and columnar crystal structures. This suggests that the binding energy of these water molecules is largely independent of the overall crystal structure. (2) In the cage structure, the four water molecules located outside the cavity desorb in two distinct steps: primarily between 50 °C and 73 °C, and then between 73 °C and 95 °C. Full dehydration occurs above 95 °C (at a low heating rate). These external water molecules stabilize the crystal structure through two different binding energies. (3) In the columnar structure, approximately 2.5 H2O molecules (including cavity and some external water) desorb collectively below 70 °C. A highly stable water fraction, representing 0.5 H2O per α-CD, remains bound and desorbs between 85 °C and 110 °C, with full dehydration completed at approximately 110 °C. These findings highlight the role of water in stabilizing cyclodextrin crystals and the influence of hydration on their thermal properties.
For β-CD, water content varies significantly with relative humidity (RH), ranging from 11.3 H2O/β-CD to 1.9 H2O/β-CD as RH decreases [21]. The highest water content values reported in the literature are from Sabadini [20] (9.6 H2O/β-CD) and Nakai [23] (12 H2O/β-CD). Most of the water in hydrated β-CD crystals releases upon heating between 40 °C and 80 °C, with 10.5–11.3 H2O/β-CD being lost during this temperature range, exhibiting similar thermal curves and stability (Specogna). Approximately six to seven water molecules remain within the β-CD structure after initial dehydration. Manor and Saenger demonstrated that these remaining water molecules, along with those in the crystal interstices, are disordered [16]. This disorder indicates that the water molecules are mobile and that the OH groups of β-CD can rotate freely. Complete dehydration of β-CD occurs before 70 °C, with stabilization at RH = 3%, resulting in minimal water content (1.9 H2O/β-CD), as observed by both Specogna [21] and Nakai [23]. In this dehydrated state, X-ray diffraction (XRD) analyses show reduced crystallinity, potentially leading to the heterogeneous distribution of residual water. This heterogeneity may cause mechanical tensions that result in structural cracks and an irreversible collapse of the crystal lattice.
The water content in γ-CD ranges from 16 to 4.75 H2O/γ-CD, as reported by Specogna [21]. Nakai documented that γ-CD recrystallized from water and stored at RH = 93.66% can contain up to 17 H2O/γ-CD [23]. Specogna’s study [21] of the most hydrated γ-CD sample (16 H2O/γ-CD at RH = 90%) identified a three-step dehydration process. The first step, occurring between room temperature and approximately 46 °C, involves the desorption of ~10 H2O/γ-CD. Literature data by Sabadini [20] indicates that in hydrated forms of γ-CD, 8.8 water molecules are located within the γ-CD cavities. The initial dehydration peak observed by Specogna may correspond to the release of cavity-bound water in the “cage” crystal structure. The second dehydration peak, which overlaps the first, likely corresponds to interstitial water in the “cage” structure, involving a 4.7 H2O/γ-CD fraction. The third, most stable fraction (1.3 H2O/γ-CD) desorbs between 80 °C and 108 °C at RH = 90%. For γ-CD samples stabilized at RH = 44%, the water content decreases to 7.6 H2O/γ-CD, and the dehydration process occurs in two steps: a primary peak between 42 °C and 49 °C, releasing 6.8 H2O/γ-CD, followed by a smaller peak between 80 °C and 108 °C, corresponding to the loss of 0.8 H2O/γ-CD. Bilal’s study on β-CD hydration demonstrates that the enthalpy of dissolution is influenced by water content, ranging from 0 to 12 H2O molecules [22]. For example, with 5 H2O molecules, the dissolution enthalpy per β-CD is −26.3 J/g, whereas for 10.4 H2O, it is −11.9 J/g. The enthalpy of the endothermic effect during dehydration, measured by DSC in the temperature range of 20–150 °C, was 302 J/g for 10.4 H2O/β-CD. Bilal’s findings suggest that the driving force for complex formation is the removal of high-energy water molecules from the β-CD cavity [22]. They concluded that approximately 10 kJ/mol (555 J/g) is required to remove one mole of water from one mole of β-CD.

5. Concluding Remarks

This review summarizes recent findings from both experiments and theory about the degree of hydration in CDs and the mechanism of water encapsulation by the host macrocycle. The data provided demonstrate that the number of trapped water molecules inside the CD internal cavity depends, apart from the cavity size of different CDs, on the varying storage conditions of the powdered substances (as-received vs. stored in desiccators with controlled humidity) and on the configuration of the host CD molecule (“open” vs. “closed” form). The role of hydrogen-bond formation between the water molecules themselves and with CD walls in stabilizing the “water cloud” inside the cavity has been emphasized. Note that, as experiments reveal, the mechanism of dehydration of different CDs may vary—sequential vs. bulk water release. The properties of the confined water cluster appear to be of crucial importance in determining the outcome of the process of the host–guest complexation between CDs and inorganic/organic substances, as well as shaping the crystalline form of the host cavitand.

Author Contributions

Conceptualization, T.D. and T.S.; writing—original draft preparation, S.A., S.P., T.D. and T.S.; writing—review and editing, T.D. and T.S.; visualization, S.A. and S.P.; supervision, T.D.; funding acquisition, T.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the European Union-NextGenerationEU, through the National Recovery and Resilience Plan of the Republic of Bulgaria, project No. BG-RRP-2.004-0008.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflicts of interest.

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Figure 1. (A) Molecular structure of CDs; (B) Schematic representation of the shape of CDs; (C) M062X/6-31G(d,p) fully optimized non-hydrated CDs (top view from the narrow rim): “closed” configuration—structures 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 counterclockwise, while the orientation of the narrow rim hydrogen bonds is counterclockwise; “open” configuration—the orientation of the wide rim hydrogen bonds is clockwise.
Figure 1. (A) Molecular structure of CDs; (B) Schematic representation of the shape of CDs; (C) M062X/6-31G(d,p) fully optimized non-hydrated CDs (top view from the narrow rim): “closed” configuration—structures 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 counterclockwise, while the orientation of the narrow rim hydrogen bonds is counterclockwise; “open” configuration—the orientation of the wide rim hydrogen bonds is clockwise.
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Figure 2. Electron density of α-CD (isovalue: MO = 0.02, density = 0.0004), mapped with electrostatic potential (color scheme: red/yellow for negative surface map values and blue for positive ones).
Figure 2. Electron density of α-CD (isovalue: MO = 0.02, density = 0.0004), mapped with electrostatic potential (color scheme: red/yellow for negative surface map values and blue for positive ones).
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Figure 3. Schematic representation of CD–H2O complexes with water molecules/clusters located at three different positions, and M062X/6-311++G(d,p)//M062X/6-31G(d,p) calculated relative enthalpies of the respective complexes.
Figure 3. Schematic representation of CD–H2O complexes with water molecules/clusters located at three different positions, and M062X/6-311++G(d,p)//M062X/6-31G(d,p) calculated relative enthalpies of the respective complexes.
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Figure 4. Schematic representation of the energetically preferred α-CD–nH2O complexes (where n = 1–6).
Figure 4. Schematic representation of the energetically preferred α-CD–nH2O complexes (where n = 1–6).
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Figure 5. Structures of the most densely populated CD hydrates (α-CD—6H2O, β-CD—10H2O, and γ-CD—7H2O).
Figure 5. Structures of the most densely populated CD hydrates (α-CD—6H2O, β-CD—10H2O, and γ-CD—7H2O).
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Figure 6. Fully optimized geometries of selected β-CD assemblies with water and N2O (β-CD—nH2O—N2O denotes a complex between β-CD, n water molecules, and N2O), and the respective Gibbs free energies of complex formation (in kcal/mol). The hydrogen bond network is visualized in the β-CD—9H2O—N2O construct (in yellow).
Figure 6. Fully optimized geometries of selected β-CD assemblies with water and N2O (β-CD—nH2O—N2O denotes a complex between β-CD, n water molecules, and N2O), and the respective Gibbs free energies of complex formation (in kcal/mol). The hydrogen bond network is visualized in the β-CD—9H2O—N2O construct (in yellow).
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Figure 7. Thermogravimetric/TG (a) and DSC (b) analysis of as-received α-CD, β-CD, and γ-CD.
Figure 7. Thermogravimetric/TG (a) and DSC (b) analysis of as-received α-CD, β-CD, and γ-CD.
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Figure 8. Schematic representation of the possible crystal structure packs of CDs.
Figure 8. Schematic representation of the possible crystal structure packs of CDs.
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Table 1. Theoretically evaluated maximum number of confined water molecules for α-, β- and γ-CD.
Table 1. Theoretically evaluated maximum number of confined water molecules for α-, β- and γ-CD.
MoleculeMaximum Number of Water MoleculesMethod UsedReferences
α-CD5MCGeorg et al. [18]
2.3–3.1MDSandilya et al. [14]
3.6MDRaffaini et al. [40,41]
2MDKoehler et al. [42]
4 MDJana et al. [43]
2DFTNascimento et al. [39]
6DFTAngelova et al. [8]
β-CD4.6–7.5 MDSandilya et al. [14]
6.5MDWinkler et al. [44]
6.3MDRaffaini et al. [40]
8–4 MDJana et al. [43]
10DFTPereva et al. [9]
γ-CD8.6–15.5MDSandilya et al. [14]
8.9MDRaffaini et al. [40]
11MDJana et al. [43]
7DFTPereva et al. [10]
Table 2. Experimentally measured water content in CDs, methods used, enthalpies of dehydration, and references details *.
Table 2. Experimentally measured water content in CDs, methods used, enthalpies of dehydration, and references details *.
MoleculeWater Content ΔHMethodsReferences
α-CD6–7.5338 J/gDSC, TG, DTAHădărugă et al. [45]
6–9 (44% HD)
3 (3% HD)		 μDSC, TGA, XRDSpecogna et al. [21]
6 overall:
2 H2O in
4 out of the cavity forming HB		 Powder XRDManor et al. [16]
Lindner et al. [27]
6 DTA, DSC, TG, EGA, STAAngelova et al. [8]
Manakov et al. [46]
Bettinetti et al. [47]
5.1304 °C: 258 J/g
341 °C: 27 J/g		DTAManakov et al. [46]
β-CD10 μDSC, TGA, XRDSpecogna et al. [21]
9.6 DSC, TG, XRDSabadini et al. [20]
10–12302 J/gTG, DSC, Bilal et al. [22]
Nakai et al. [23]
10 DSC, TGPereva et al. [9]
10.41 XRDSeidel and Koleva [24]
9.4–12 XRDBetzel et al. [48]
γ-CD7 DSC, TGPereva et al. [10]
7.6 μDSC, TGA, XRDSpecogna et al. [21]
5–17 DTA, DSC, TGGiordano et al. [49]
13.3
5.3 in 13 sites		 XRDHarata [50]
* Abbreviations: HB—hydrogen bonds, HD—humidity, DTA—differential thermal analysis, DSC/TG/TGA—differential scanning calorimetry/thermal gravimetry analysis, XRD—X-ray diffraction, EGA—evolved gas analyses, STA—sorption thermal analyses.
Table 3. The influence of ambient conditions on the thermal experiment *.
Table 3. The influence of ambient conditions on the thermal experiment *.
α-CD HydrateT Peak Max, °CΔH J/g
α-CD·5.1H2O as-received, open pan≈66°, 101°, 110°Total = 258.0
α-CD·5.1H2O as-received, sealed pan86°27.4
α-CD·5.1H2O as-received, sealed pan upon heating to T ≈ 100°76–77°27.7
* From Manakov et al. [44].
Table 4. Water content compared to RH and storage conditions *.
Table 4. Water content compared to RH and storage conditions *.
RH %α-CDβ-CDγ-CD
initial9.713.69
9010.1515.218.2
35.32.9–34.5
* From Specogna et al. [21].
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Angelova, S.; Pereva, S.; Dudev, T.; Spassov, T. Cyclodextrins’ Internal Cavity Hydration: Insights from Theory and Experiment. Inorganics 2025, 13, 28. https://doi.org/10.3390/inorganics13010028

AMA Style

Angelova S, Pereva S, Dudev T, Spassov T. Cyclodextrins’ Internal Cavity Hydration: Insights from Theory and Experiment. Inorganics. 2025; 13(1):28. https://doi.org/10.3390/inorganics13010028

Chicago/Turabian Style

Angelova, Silvia, Stiliyana Pereva, Todor Dudev, and Tony Spassov. 2025. "Cyclodextrins’ Internal Cavity Hydration: Insights from Theory and Experiment" Inorganics 13, no. 1: 28. https://doi.org/10.3390/inorganics13010028

APA Style

Angelova, S., Pereva, S., Dudev, T., & Spassov, T. (2025). Cyclodextrins’ Internal Cavity Hydration: Insights from Theory and Experiment. Inorganics, 13(1), 28. https://doi.org/10.3390/inorganics13010028

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