Spectroscopic and Thermal Characterization of the Host-Guest Interactions between α-, β-, and γ-cyclodextrins and vanadocene dichloride

Abstract

Host-guest interactions between α-, β-, and γ-cyclodextrins and vanadocene dichloride (Cp₂VCl₂) have been investigated by a combination of thermogravimetric analysis, differential scanning calorimeters, PXRD and solid state and solution EPR spectroscopy. The solid state results demonstrated that only β- and γ-cyclodextrins form 1:1 inclusion complexes, while α-cyclodextrin does not form an inclusion complex with Cp₂VCl₂. The β- and γ-CD-Cp₂VCl₂ inclusion complexes exhibited anisotropic electron-⁵¹V (I = 7/2) hyperfine coupling constants whereas the α-CD- Cp₂VCl₂ system showed only an asymmetric peak with no anisotropic hyperfine constant. On the other hand, solution EPR spectroscopy showed that α-CD may be involved in weak host-guest interactions in equilibrium with free vanadocene species.

1. Introduction

Cyclodextrins (CDs) are cyclic oligosaccharides that have α-1,4 linked D-glucose units. CDs are named according the number of the glucose units, α (six),β (seven) and γ (eight). They act as molecular hosts to a variety of guests: ions, metal complexes, polar and non-polar organic molecules [1]. These inclusion complexes have found pharmaceutical applications due to the increased aqueous solubility of the drugs, better oral absorption and their improved stability towards heat, light, oxidizing reagents and acidic conditions. CDs are known to form stable inclusion compounds with a variety of organometallic species including ferrocene and its derivatives [2–5], and sandwich complexes of molybdenum [6–8].

Metallocene dihalides and pseudo halides of general formula Cp₂MX₂ (M = Ti, V, Nb, Mo; X= Cl, Br, CN, SCN) have shown activity on a wide variety of murine and human tumors [9–25]. Although they belong to the same class of complexes, they have different chemical and biochemical behaviors. One of the major complications of these metallocene complexes is the low hydrolytic stability at physiological pH [26,27]. This has hindered the study of these complexes mechanistically and as a result limited their pharmacological use. One way to protect these species from extensive hydrolysis is to encapsulate them into macromolecules such as cyclodextrins.

There are few reports on the encapsulation of metallocene dichlorides in cyclodextrins. For instance, the encapsulation of Cp₂TiCl₂ in cyclodextrins was reported in 1999 by Turel and coworkers [28]. This group has shown that the inclusion complexes are formed by the interaction of the metallocenes in the CD cavity and their penetration depends of the length of the cyclic oligosaccharides. According to this report, titanocene dichloride can be encapsulated in the larger β- and γ-cyclodextrins, and not in the smaller α-cyclodextrin. In another report, the β-CD-molybdenocene dichloride inclusion complex was characterized by physical methods and ab initio calculations [29]. The predicted geometry of β-CD-molybdenocene dichloride inclusion complex is that only one of the Cp ligands inside the cavity of the cyclodextrin D-glucopyranose units.

More recently, the CD-Cp₂VCl₂ inclusion complexes have been studied by EPR spectroscopic methods [30]. The g-tensor and the anisotropic hyperfine coupling constants (A_x, A_y, A_z) demonstrated that vanadocene dichloride and 1,1′-dimethylvanadocene dichloride were encapsulated in the β- and β-cyclodextrins and the rhombic symmetry was distorted as expected for encapsulated vanadium species, while the α-cyclodextrin can not encapsulate vanadocene complexes. In this regard, the anisotropic EPR spectral data demonstrated that only in the β- and γ-cyclodextrins, the hyperfine interactions with the vanadium nucleus can be observed as a result of the vanadocene inclusion. However, no thermal analysis, powder X-ray diffraction (PXRD) and solution EPR spectroscopies were presented. Herein we report a more detailed thermal and spectroscopic characterization of the CD-Cp₂VCl₂ inclusion complexes. While in the previous report the α-cyclodextrin-Cp₂VCl₂ was completely ruled out as inclusion complex, we obtained different results in solution, using EPR spectroscopy. Herein we report our findings on the CD-Cp₂VCl₂ host-guest interactions.

2. Experimental

2.1 MATERIAL AND METHODS

α-CD (Sigma-Aldrich), β-CD (Aldrich) and γ-CD (Fluka) were obtained commercially. The water contents of cyclodextrins were determined by thermal gravimetric analysis (TGA), α-CD (9.3 %), β-CD (13.95 %) and γ-CD (8.5 %). Cp₂VCl₂ was purchased from Aldrich and used as received. The inclusion complexes were prepared using CDs (α-, β-, and γ corrected for water content) and vanadocene dichloride.

Elemental analyses were performed by Atlantic Microlab. The thermal analysis experiments were performed using a TAQ100 (DSC) and TAQ500 (TGA) instrument. The heating rate was 3 °C/min for DSC analysis and 10°C/min for TGA analysis. A differential scanning calorimetry interfaced to a PC was used to measure the thermal properties of the inclusion compounds. The calorimetry operated with a nitrogen flow of 50 mL/min. The temperature of the calorimeter was calibrated from the observed melting points of indium. Powder x-ray diffraction (PXRD) data were collected on a Siemens D5000 diffractometer using Cu Kα radiation = 1.5418 Å. The diffractograms were acquired between 2θ angles of 2° and 60° with a step of 0.020°and step time of 2 s at 25°C.

FTIR data were collected on a Nexus 670 spectrometer using Thunderdome ATR. EPR spectra were recorded with an Elexsys E 500 spectrometer with an ER 4122SHQE resonator. Magnetic fields were measured with an E036 TM Teslameter. Solid sample spectra were acquired with 3 mm ID sample tubes. Solution samples were acquired with ER 106FC-Q flat cells. Simulations were optimized with XSophe version 1.114.

2.2 SYNTHESIS OF CD-Cp₂VCl₂ INCLUSION COMPLEXES

0.2 mmol of CD (corrected for water content) was dissolved in 30 mL of deionized water and 0.2 mmol of solid Cp₂VCl₂ was added. After stirring for 30 minutes, the green solution was filtered in a fritted funnel of fine porosity and the resulting solution was lyophilized to obtain an amorphous voluminous solid product.

Anal. Calc. for “α-CD-Cp₂VCl₂·13H₂O” [(C₃₆H₆₀O₃₀)-(C₁₀H₁₀VCl₂)·13H₂O]: C, 37.86; H, 6.63; Cl, 4.86. Found: C, 37.41; H, 5.98; Cl, 4.28. IR(KBr) cm⁻¹: 3272(bm), 2928(w), 1685(vw), 1330(w), 1151(m), 1076(m), 1024(s), 950(w), 937(w), 825(w).

Anal. Calc. for β-CD-Cp₂VCl₂·14H₂O [(C₄₂H₇₀O₃₅)-( C₁₀H₁₀VCl₂)·14H₂O]: C, 38.10; H, 6.64; Cl, 4.33. Found: C, 37.90; H, 6.24; Cl, 3.90. IR(KBr) cm⁻¹: 3278(bm), 2929(w), 1686(w), 1331(w), 1151(m), 1076(s), 1024(s), 950(w), 938(w), 826(w).

Anal. Calc. for γ-CD-Cp₂VCl₂·10H₂O [(C₄₈H₈₀O₄₀)-( C₁₀H₁₀VCl₂)·10H₂O]: C, 40.29; H, 6.41; Cl, 4.10. Found: C, 40.65; H, 5.94; Cl, 3.92. IR(KBr) cm⁻¹: 3279(bm), 2930(w), 1331(w), 1151(m), 1076(m), 1024(s), 950(w), 938(w), 826(w).

Physical mixtures were prepared by mixing equimolar amounts of cylodextrin and Cp₂VCl₂ in a bench top tumbler blender.

3. Results and Discussion

Vanadocene dichloride slowly hydrolyzes in water, at low pH, to form [Cp₂V(OH₂)₂]²⁺ [31]. However, the inclusion complexes in solution and solid states have shown that Cp₂VCl₂ is the predominant species, as corroborated by a series of spectroscopic and analytical techniques. First, we will discuss the solid state results. The inclusion complexes were characterized by elemental analysis, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and, IR, powder X-ray diffraction (PXRD) and EPR spectroscopies.

Table I summarizes the thermal properties (TGA and DSC) of the drug, cyclodextrins and the inclusion complexes and Figures 1 and 1S (Supplementary Material) show representative TGA and DSC thermograms for α-, β- and γ-cyclodextrin complexes. In general, pure α-, β- and γ-cyclodextrins loose 8–11 % of mass in the range of 25–108° C (see Supplementary Material), indicating loss of hydrated water in the cyclodextrins. The TGA and DSC thermograms of the inclusion complexes demonstrated mass loss of 7–12 % between 25–100° C, also indicating loss of water from the cyclodextrin inclusion complexes. Although we are aware that elemental analysis of lyophilized samples could be meaningless at some point, we compared the water calculated with elemental analysis and TGA for the new complexes. It can be observed that there is a discrepancy between the water content calculated by elemental analysis and the water content determined by thermal analysis. This suggests that in the thermal analysis, at low temperature (25–100° C) only the weakly bound water molecules are released. The more tightly bound water molecules are lost at higher temperatures and this process could be overlapped by other thermal events such as the melting/decomposition of the inclusion complexes. Similar results were obtained in the CD-Cp₂TiX₂ inclusion complexes reported by Turel and co- workers [28] and in CD-Cp₂NbCl₂ inclusion complexes by our group [32].

Table I.

Thermoanalytical data of the inclusion complexes (FD = freeze dried), physical mixture (PM) and precursors. Note: D= Dehydration and M = Melting.

	Dehydration		Melting		DSC Endothermic max (°C)
	Temperature range (°C)	Mass loss (%)	Temperature range (°C)	Mass loss (%)
α-CD	25–100	9	245–496	88	76(D), 108(D), 136(D/glass transition), 289(M), 325(Decomposition/exothermic)
β-CD	25–80	11	271–496	88	129(D/glass transition), 288(M), 325(Decomposition/exothermic)
γ-CD	25–98	8	276–496	93	104(D/glass transition), 284 (M), 330(Decomposition/exothermic)
Cp2VCl2	25–100	1	220–496	63	291(M/Decomposition/exothermic)
αCD- Cp2VCl2 FD	25–100	12	140–496	80	115 (D/glass transition), 170 (M) 243(Decomposition/exothermic)
αCD- Cp2VCl2 PM	25–100	8	139–496	83	83(D), 154 (D/glass transition), 186 (M), 239 (Decomposition/exothermic)
β-CD- Cp2VCl2 FD	25–80	7	162–496	72	110(D/glass transition), 175(M), 215(Decomposition/exothermic)
β-CD- Cp2VCl2 PM	25–100	12	130–496	81	144(D/glass transition), 206(M), 245 (Decomposition/exothermic)
γ-CD- Cp2VCl2 FD	25–100	11	140–496	82	167(D/glass transition), 174(M), 230(Decomposition/exothermic)
γ-CD- Cp2VCl2 PM	25–100	8	117–496	84	141(D/glass transition), 193(M), 274(Decomposition/exothermic)

Figure 1.

TGA and MDSC curves of a) α-CD-Cp₂VCl₂ FD; (b) α-CD-Cp₂VCl₂ PM. TGA (red),; c) β-CD-Cp₂VCl₂ FD; (d) β-CD-Cp₂VCl₂ PM. TGA (red), MDSC (blue). FD=freeze dried (EM=enclosed mixture), PM=physical mixture.

According to the DSC analysis, the melting points of the cyclodextrins (284–289° C), Cp₂VCl₂ (291° C) and the physical mixtures (186–206° C) are substantially higher than those of the inclusion complexes (lyophilized samples, 170–175° C). Similarly, the decomposition temperatures of the free cyclodextrins, the physical mixtures and Cp₂VCl₂ are higher than those of the inclusion complexes. These thermal behaviors initially suggest that the lyophilized samples are inclusion complexes due to their distinct thermal behaviors.

The TGA and DSC curves of the α-CD-Cp₂VCl₂ freeze dried sample (α-CD-Cp₂VCl₂ FD, Figure 1a, top trace) showed some features different from the free α-cyclodextrin and vanadocene dichloride as well as from the α-CD-Cp₂VCl₂ physical mixture (α-CD-Cp₂VCl₂ PM). This suggests that α-CD might be able to encapsulate Cp₂VCl₂. However, this is not a conclusive analysis to determine if the inclusion complex exists, as this thermal behavior could be the result of a fine dispersion rather than an inclusion complex or a mixture of inclusion complex and free vanadocene dichloride, as will be shown below with EPR spectroscopy. Likewise, the β-CD- Cp₂VCl₂ FD (Figure 1, bottom traces) and the γ-CD-Cp₂VCl₂ FD (supplementary material) exhibited thermal behaviors different to the free CD, Cp₂VCl₂ or CD- Cp₂VCl₂ physical mixtures. In this regard, for β-CD-Cp₂VCl₂ (β-CD- Cp₂VCl₂·14H₂O) to be a 1:1 inclusion compound, 69.3% of the mass must belong to β-CD, while 15.4% must be Cp₂VCl₂. Upon analysis of Figure 1d, there is a major mass loss of 72% above 215°C, which we believe belongs to the β-CD. There is a mass loss of 7.5% between 165–230°C which could involve more tightly bound water molecules and 19.6% residue that must belong to some sort of vanadium compound. For a 2:1 β-CD-Cp₂VCl₂ inclusion compound, about 90% of the total must belong to β-CD. Such evidence is not observed into the TGA and DSC curves. In any event, for the β- and γ-CDs cases, EPR spectroscopy demonstrated unambiguously that they can indeed form inclusion complexes with Cp₂VCl₂.

In the infrared spectral data of the inclusion complexes, the weak shoulder about 3100 cm⁻¹ attributed to Cp ν(C–H) vibration is most likely overlapped by the broad peak of OH vibrations and cannot be observed. Only a new peak at 825 cm⁻¹ is observed in the inclusion compounds which belong to the Cp₂VCl₂ ν(C–H) out of plane vibration [33]. The KBr IR spectrum of Cp₂VCl₂ shows a peak at 820 cm⁻¹. In any event, all the α-, β-, γ-CD- Cp₂VCl₂ samples exhibited this ν(C–H) vibration. Therefore, we explored other analytical techniques to determine inclusion compounds.

Powder x-ray powder diffraction (PXRD) analysis was undertaken on the investigated compounds. This is an importance technique to characterize inclusion complexes of cyclodextrins in the solid state. Table II shows the PXRD peaks of the hosts, guests, physical mixtures and inclusion complexes. Figures 2, 3 and Figure 2S (Supplementary Material) depict PXRD spectra of CD-vanadocene complexes.

Table II.

Powder x-ray diffraction spectral analysis of inclusion complexes (FD), physical mixtures (PM) and precursors. FD = freeze dried, PM = physical mixtures.

Compound	Major characteristic peaks at 2θ
α-CD	14.4 (strongest), 12.3, 21.8 (secondly), 5.4, 13.7, 15.8, 19.4, 22.9, 56.6
β-CD	4.5 (strongest), 12.6, 12.8 (second), 9.1, 10.7, 12.8, 17.2, 22.9, 27.3
γ-CD	5.1 (strongest), 16.5 (second), 4.5, 6.2, 9.2, 11.3, 12.3, 15.4, 15.9, 17.1, 17.8, 18.7, 22.5
Cp2VCl2	14.2 (strongest), 13.8, 15.5 (secondly), 20.2
αCD- Cp2VCl2 FD	14.2 (strongest), 13.8, 15.5 (secondly), 20.2
αCD- Cp2VCl2 PM	21.8 (strongest), 14.2, 15.5 (secondly), 12.3, 13.7
β-CD- Cp2VCl2 FD	12.3 (strongest), 6.0, 11.9, 17.8, 18.9, (secondly), 7.3, 15.8, 23.9
β-CD- Cp2VCl2 PM	12.7 (strongest), 15.5, 21.2, (secondly), 4.7, 9.2, 17.9, 19.0, 19.7, 25.9
γ-CD- Cp2VCl2 FD	12.1 (strongest), 16.6 (secondly), 7.4, 11.5, 14.2, 15.7, 20.4, 21.7, 22.4, 23.5
γ-CD- Cp2VCl2 PM	13.7 (strongest), 15.5 (secondly), 5.3, 16.5, 18.9

Figure 2.

PXRD of: (a) Cp₂VCl₂; (b) α-CD; (c) α-CD-Cp₂VCl₂ FD; (d) α-CD-Cp₂VCl₂ PM. FD = freeze dried and PM = physical mixture.

Figure 3.

PXRD of: (a) Cp₂VCl₂; (b) β-CD; (c) β-CD-Cp₂VCl₂ FD; (d) β-CD-Cp₂VCl₂ PM. FD = freeze dried and PM = physical mixture.

Upon analysis of Figure 2 and Table II, it is evident that the PXRD of the free α-CD, Cp₂VCl₂, physical mixture and freeze dried samples have some common features. In particular, the lyophilized sample has features corresponding mainly to free Cp₂VCl₂. This is supported by the fact that α-CD-Cp₂VCl₂ freeze dried sample has x- ray diffraction peaks at 2θ (13.8, 14.2, 15.5 and 20.2) corresponding to free Cp₂VCl₂. This evidence suggests that α-CD-Cp₂VCl₂, freeze dried sample is not an inclusion complex. For β- and γ-CD-Cp₂VCl₂ freeze dried samples, diffraction peaks corresponding to the free Cp₂VCl₂ and CDs are not observed. In this regard, the PXRD spectra of the β- and γ-CD- Cp₂VCl₂ freeze dried samples have diffraction patterns (see Figure 3 and Figure 2S Supplementary Material) completely different from their initial components and the physical mixtures. These new diffraction patterns observed in the PXRD spectra can only be explained as new, more amorphous solid materials containing the Cp₂VCl₂ encapsulated into their CD hydrophobic cavities.

To explore the possibility of other types of inclusion compounds with α-CD, we studied the diffraction patterns of 1:2 and 2:1 α-CD-Cp₂VCl₂ systems (Supplementary Material). None of these systems exhibited diffraction patterns that can be attributed to an inclusion compound.

Electron Paramagnetic Resonance (EPR) spectroscopy in the solid state has been used to elucidate the electronic and magnetic environments around the vanadium (d¹) metal center and determine if Cp₂VCl₂ is encapsulated into the CD cavity [30]. We have pursued solution and solid state EPR experiments to determine the inclusion complexes in both states (see Tables III and IV).

Table III.

Anisotropic hyperfine coupling constants and g factors of the inclusion complexes.

Complex	A⊥	A||	g⊥	g||
Cp2VCl2	Single	asymmetric	Peak
α–CD- Cp2VCl2	Single	asymmetric	peak
β-CD- Cp2VCl2	74.7 G	197.1 G	1.980	1.937
γ-CD- Cp2VCl2	74.0 G	198.8 G	1.980	1.936

Table IV.

Isotropic hyperfine coupling constants and g factors inclusion complexes.

Complex	Aiso	giso
Cp2VCl2	78.4 G	1.978
α–CD- Cp2VCl2	79.6 G (62%), 115.7 G (35%), 68 G (3%)	1.967, 1.979, 1.980
β-CD- Cp2VCl2	114.4 G	1.967
γ-CD- Cp2VCl2	115.1 G	1.966

The solid state EPR spectra of the α- and β-CD-Cp₂VCl₂ host-guest interactions are depicted in Figures 4 and 5. Figure 4 presents the EPR spectra of the α-CD- Cp₂VCl₂ physical mixture, α-CD-Cp₂VCl₂ freeze dried sample and the subtraction of both spectra. It is evident that in the α-CD-Cp₂VCl₂ freeze dried sample, the major species present is free Cp₂VCl₂ since only a single asymmetric peak with no electron- ⁵¹ V (I = 7/2) anisotropic hyperfine coupling is observed. This spectrum has identical features to the solid state EPR spectrum of Cp₂VCl₂. There is a second species but its concentration is too low to determine the anisotropic hyperfine coupling accurately. Thus, this is evidence that the major component in the α-CD-Cp₂VCl₂ is mainly free vanadocene and the EPR spectrum (Figure 4) is mainly a dispersion mixture rather than an inclusion complex. On the hand, the β- and γ-CD- Cp₂VCl₂ freeze dried samples exhibited anisotropic hyperfine coupling on their EPR spectra (Table III). Similar results were obtained by Vinklarek and co-workers [30]. These results can be rationalized in terms of dilution of the paramagnetic d¹ center. In this regard, magnetically diluted samples arise from the inclusion of Cp₂VCl₂ into the β- and γ-CD cavities. In other words, the d¹ (Cp₂VCl₂) center has been diluted into the diamagnetic matrix, β-CD or γ-CD.

Figure 4.

Solid state EPR spectra of α-CD-Cp₂VCl₂. Physical mixture (top trace, green), freeze dried sample (middle trace, red) and subtraction of the top spectrum to the middle spectrum (bottom, blue).

Figure 5.

Solid state EPR spectra of β-CD-Cp₂VCl₂ FD (top) and γ-CD-Cp₂VCl₂ FD (bottom). FD = freeze dried sample.

Solution EPR spectra were recorded on the α-, β- and γ-CD-Cp₂VCl₂ host-guest interactions to further investigate the possible species that may exist, in solution and not in the solid state, between vanadocene species and cyclodextrins (Table IV). In aqueous solution, the EPR spectrum of the α-CD-Cp₂VCl₂ host-guest interaction (Figure 6) is a superposition of three paramagnetic species. The major component (62%) has an isotropic hyperfine coupling constant of 79.6 G. Based on previous report, the isotropic hyperfine coupling constant of Cp₂VCl₂ in aqueous solution is 75 G (there is a slight pH dependence) [31]. Our EPR spectrum of Cp₂VCl₂ in aqueous solution showed an isotropic hyperfine coupling constant (A_iso) of 78.4 G. Since it is known that Cp₂VCl₂ dissolved in water, at low pH, forms [Cp₂V(H₂O)₂]²⁺ [27,31], we believe that the major species present in the α-CD-Cp₂VCl₂ system is free [Cp₂V(H₂O)₂]²⁺. The second component (35%), has an A_iso of 115.7 G. Upon comparison with the solution EPR spectra of the β- and γ-CD-Cp₂VCl₂ host-guest interactions we found that these inclusion complexes have A_iso values of 114.4 G and 115.1 G respectively. Since these CDs form host-guest inclusion complexes with Cp₂VCl₂, we believe that some sort of host-guest interactions exist between the α-CD and Cp₂VCl₂, albeit weak. However, to pinpoint what type of interaction is present, we analyze the EPR spectrum of [Cp₂V(MeOH)]₂Cl₂ in water. Surprisingly the A_iso of this complex which involves V-O (V-MeOH) coordination is 114 G. Therefore, it seems that in solution, vanadocene is being coordinated weakly by the secondary alcohols ((C-2 and C-3 OHs) on the wider edge of the cavity and that this interaction also exists in the β- and γ-CD-Cp₂VCl₂ host-guest interactions when the inclusion complexes are dissolved in water and the cyclodextrin releases the vanadocene species into the aqueous media. On the other hand once the water is removed from the medium (lyophilized sample), the vanadocene is enclosed into the β-CD and γ-CD but not into the smaller α-CD cavity. There is a third species (in the Cp₂VCl₂- α-CD solution) in about 3% with isotropic hyperfine coupling constant of 68 G. It is not clear what species is present but based on the A_iso it is possible that sort of vanadocene complex (perhaps [Cp₂VCl(H₂O)]⁺]) is present in the solution as a free species.

Figure 6.

EPR spectra of α-CD-Cp₂VCl₂ mixture (top) and Cp₂VCl₂ in water (bottom).

4. Conclusion

The host-guest interactions between α-, β-, and γ-CDs and Cp₂VCl₂ have been characterized by a combination of solid-state physical methods and solid and solution EPR spectroscopy. The formation of a true inclusion complex in a 1:1 ratio has been detected unequivocally for β– and γ– cyclodextrins. In the solid state, α-CD does not form stable 1:1 inclusion complex. For the α-CD, solution EPR spectral data showed to have three species. Two of them should be free vanadocene species (A_iso = 68–79 G), while the third one has an A_iso = 115.7 G which suggest that some type of weak coordination between secondary alcohols of cyclodextrin and vanadocene. On the other hand, solution EPR spectroscopy showed that the vanadocene species involved in the β- and γ-CDs have only one species with high isotropic hyperfine coupling constants (A_iso 114–115 G). This should involve, must likely, some sort of intermediate species between free and encapsulated vanadocene, coordinated by the secondary alcohols analogous to α-CD. But upon removal of water, only β- and γ- CDs are able to enclose vanadocene.

Two possible geometries for these inclusion complexes can be envisioned, A and B. According to the ¹³C CP MAS NMR spectral data on CD-niobocene [32] and CD-molybdenocene host-guest interactions [29], geometry A is the most likely conformation. On a recent study, Goncalves and co-workers found, using ab initio calculations, that geometry A and B as well as a third geometry where the chloride is inserted into the cavity with a shallow penetration of the Cp rings could exist at room temperature [34]. The most likely geometry of the CD-Cp₂VCl₂ host-guest complex will be investigated by molecular mechanics calculation.