Acta Crystallographica Section C research papers

Acta Crystallographica Section C research papers

Inclusion complex of -cyclodextrin with coffee chlorogenic acid: New insights from a combined crystallographic and theoretical study

Thammarat Areea*

aDepartment of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand

Correspondence email: thammarat.aree@gmail.com

Funding informationThe Ratchadapisek Sompoch Endowment Fund, Chulalongkorn University (grant No. CU-GR_61_022_23_008).

The [4]pseudorotaxane of -cyclodextrin (-CD) with coffee chlorogenic acid (CGA) has been reported for the first time in CD inclusion complexes. The atomistic and thermodynamic insights of the trimodal and dimeric -CDCGA inclusion complexes are gained through single-crystal X-ray diffraction combined with DFT calculation.

This work reports the elusive structural evidence for [4]pseudorotaxane of -cyclodextrin (-CD) with coffee chlorogenic acid (CGA), a conjugate of caffeic acid (CFA) and quinic acid (QNA). A single-crystal X-ray analysis reveals that CGA threading through -CD and assembling via OHO hydrogen bonds and parallel-displaced interactions in the twofold symmetry-related dimer yield a [4]pseudorotaxanecrystallographically observed for the first time in CD inclusion complexes. The encapsulation of the aromatic ring and C=CC(=O)O chain in the -CD dimeric cavity indicates that the CFA moiety plays a determinant role in complexation. This is in agreement with the DFT-derived relative thermodynamic stabilities of the trimodal -CDCGA inclusion complexes, that is, -CD in complex with different CGA components: C=CC(=O)O chain > cyclohexane ring > aromatic ring. The complexation stability is further enhanced in the dimeric -CDCGA complex with the CFA moiety totally enclosed in the -CD dimeric cavity.

1. -Cyclodextrin; Chlorogenic acid; Pseudorotaxane

Introduction

Coffee is the most favorite beverage in the world and has high economic value worldwide due to its unique aroma, excellent flavor and wide-spectrum health benefits. Polyphenol chlorogenic acid [CGA; IUPAC name, 5-caffeoylquinic acid (5-CQA)], an ester of caffeic acid (CFA) and quinic acid (QNA), is most prevalent in green coffee beans (Clifford, & Willson, 1985; Clarke, & Vitzthum, 2001; Ludwig et al., 2014). CGA has diverse bioactivities including potent antioxidant, antibacterial, anticarcinogenic and anti-inflammatory activities (Chu, 2012; Ludwig et al., 2014; Preedy, 2015; Bagchi et al., 2017; Tajik et al., 2017; Naveed et al., 2018), but it is labile to heat, light and air. Together with the variety of CGA constituents (aromatic and glucose rings linked by the C=CC(=O)O group) and the extent of structural flexibility, CGA is difficult to crystallize, and its crystal structure in the free acid form has not been reported thus far (Groom, Bruno, Lightfoot, & Ward, 2016).

Cyclodextrins (CDs) are a family of macrocyclic oligosaccharides comprising 68 glucose units for -, - and -CDs, respectively. They have the prominent ability to form inclusion complexes with a variety of guest molecules (Saenger, 1980; Dodziuk, 2006). The encapsulation of CGA in -CD cavity helps not only to maintain and improve the antioxidant capacity of CGA (Budryn et al., 2014; Shao et al., 2014; Chao et al., 2012), but also to mask the bitter taste in coffee (Szejtli, & Szente, 2005). The inclusion complex of -CD with CGA has been studied quite well, mostly in aqueous solutions. The unimolar -CDCGA complex is relatively stable with binding constants ranging from 3501470 M1 and the CFA moiety is mostly found to be included in the -CD cavity, as revealed by NMR (Irwin et al., 1994; Rodrigues et al., 2002; Zhao et al., 2010), UV (Irwin et al., 1995), fluorescence (lvarez-Parrilla et al., 2005; Grnas et al., 2009) and isothermal titration calorimetry (Irwin et al., 1999). However, the inclusion geometries of the -CDCGA complex are still ambiguous as the combined fluorescence, calorimetric, voltammetric and NMR data indicate that the bimodal complexes with the CFA and QNA moieties are bound competitively within the -CD cavity with comparable affinity constants (lvarez-Parrilla et al., 2010). Aiming at resolving this structural problem and deepening atomistic and thermodynamic insights, single-crystal X-ray diffraction combined with the DFT calculation of the -CDCGA inclusion complex have therefore been carried out.

Materials and methods

Materials

-CD was purchased from Cyclolab, Budapest, Hungary. CGA hemihydrate was obtained from SRL, Mumbai, India. All AR grade chemicals were used as received.

Single-crystal X-ray diffraction

Colorless plate-like single crystals of the -CDCGA complex were harvested from a saturated 50% aqueous EtOH solution of -CD 50 mg (0.044 mmol) and CGA 16 mg (0.044 mmol), after two weeks of slow solvent evaporation in an air-conditioned room (25C). Crystal data, data collection and structure-refinement details are summarized in Table 1. All H-atom positions (excluding those of OH groups) were calculated geometrically and treated using a riding model. The H atoms of hydroxyl groups and some water sites were initially located from difference Fourier electron density maps. Then the hydroxyl H-atoms were refined using AFIX 147 or AFIX 83 and the water H-atoms were treated with AFIX 3. 8.5 water molecules are distributed over 14 sites, of which 3 are well ordered.

Experimental details.

Crystal data

Chemical formula

2[(C6H10O5)7C16H18O98.5H2O]

Mr

3267.51

Crystal system, space group

Orthorhombic, C2221

Temperature (K)

100

a, b, c ()

19.0698(3), 24.1017(5), 31.0577(4)

V (3)

14274.6(4)

Z

4

Radiation type

Mo K

(mm1)

0.136

Crystal size (mm)

0.06 0.14 0.26

Data collection

Diffractometer

Bruker APEXII CCD

Absorption correction

Multi-scan (SADABS; Bruker, 2014b)

Tmin, Tmax

0.977, 0.992

No. of measured, independent and

observed [I > 2(I)] reflections

67302, 21982, 13217

Rint

0.076

(sin )max 1)

0.720

Refinement

R [F2 > 2(F2)], wR(F2), S

0.069, 0.162, 1.01

No. of reflections

21982

No. of parameters

1049

H-atom treatment

H atoms treated by a mixture of independent

and constrained refinement

max, min (e 3)

0.83, 0.75

Computer programs: APEX2 (Bruker, 2014a), SAINT (Bruker, 2008a), XPREP (Bruker, 2008b), SHELXTL XT (Bruker, 2014c), SHELXTL XLMP (Bruker, 2014d) and Mercury (Macrae et al., 2008).

DFT full-geometry optimization

The crystal structure of the -CDCGA complex reveals that the bridging C=CC(=O)O group of CGA is embedded in the -CD cavity, contrary to what is proposed by lvarez-Parrilla et al. (2010) in solution. Hence, the DFT calculation was carried out for insight into the occurrence and relative thermodynamic stabilities of the trimodal and dimeric -CDCGA inclusion complexes. The asymmetric unit from the final crystal structure refinement of -CDCGA complex, excluding water molecules of hydration was used as a starting model for plausible trimodal inclusion complexes of -CD with different CGA components: mode 1, bridging C=CC(=O)O group; mode 2, CFA moiety; and mode 3, QNA moiety. Initial atomic coordinates for each inclusion mode were obtained by shifting the center-of-mass of each CGA component to about the -CD O4-center. Before the calculation, the relevant CH and OH bond distances were normalized to the neutron diffraction distances of 1.083 and 0.983 . The normalized structures were fully optimized with the semiempirical PM3 method and were then fully re-optimized using DFT/B3LYP with mixed basis sets 4-31G for C atoms and 6-31+G* for H and O atoms. DFT calculations were solely performed in the gas phase because they reproduced accurate X-ray structures at a more reasonable computational cost, compared to the calculations in implicit water. This calculation protocol has been used to successfully model the largest CD with 546 atoms of cyclomaltohexaicosaose (CA-26) (Schnupf & Momany, 2011) and the inclusion complexes of -CD with tea catechins (Aree & Jongrungruangchok, 2016, 2018a) and olive polyphenols (Aree & Jongrungruangchok, 2018b). All calculations were carried out using GAUSSIAN09 (Frisch et al., 2009) on a DELL PowerEdge T430 server and they converged quite well without negative vibrational frequency. The stabilization energy of inclusion complexation (Estb) was calculated by subtracting the molecular energies of -CD and CGA from the energy of -CDCGA complex from the full geometry optimization. Similarly, the dimeric complex was also thermodynamically evaluated. The DFT-derived molecular structures of trimodal and dimeric -CDCGA complexes are displayed in Figs. S1S4; the OHO hydrogen bonds and the -CD geometrical parameters together with stabilization energies are given in Tables S2S5.

Results and discussion

Elusive supramolecular [4]pseudorotaxane

Single-crystal X-ray analysis indicates that in the 2:2 -CDCGA complex the host molecule macrocycle adopts a round conformation due to the formation of inter- and intra-molecular H-bonds between the secondary hydroxyl groups (the intermolecular H-bonds are given in Table S1). This is commonly observed in the crystal structures of -CD dimeric inclusion complexes. X-ray analysis also reveals a distinct inclusion scenario of the -CDCGA complex. The hydrophobic C=CC(=O)O chain of CGA is almost entirely embedded in the hydrophobic -CD cavity. Consequently, the linked cyclohexane ring of the QNA moiety protrudes from the O6H side and the connected aromatic ring of the CFA moiety protrudes from the O2H/O3H side; this is a monomeric complex the asymmetric unit. Assembling with other twofold symmetry related monomer yields an elusive [4]pseudorotaxane with two CGAs (the axle) threading through the head-to-head -CD dimer (the rotor) and the hydrophilic QNA moieties acting as slippages at both termini (Fig. 1).

[4]pseudorotaxane of the 2:2 -CDCGA inclusion complex related by twofold symmetry (indicated by ); all water molecules outside the -CD cavity are omitted for clarity. The chemical structures of -CD and CGA comprising the caffeic acid (CFA; red) and quinic acid (QNA; blue) moieties are shown nearby.

The [4]pseudorotaxane is stabilized by intermolecular O3H(QNA)O66(CD), O2'H(CFA)O3(QNA) hydrogen bonds and the off-centered parallel stacking of twofold symmetry-related CFA moieties (Fig. 2 and Table 2). Relevant geometrical parameters of the off-centered parallel stacking of the symmetry-related CFA moieties are the following: i) the distance between the centroids of rings C1'C6' and C1'C6'(1 x, y, 0.5 z): 3.815(4) ; ii) the distance of the centroid shift: 3.581(3) ; and iii) interplanar angle: 16.5(3). This is contrary to the inclusion structure of the bimodal -CDCGA complex of which the CFA and QNA moieties are competitively bound to the -CD cavity, as indicated by NMR and fluorescence spectroscopies (lvarez-Parrilla et al., 2010). To the best of our knowledge, this is the first crystal structure of [4]pseudorotaxane for the CD inclusion complexes. There have been long attempts to synthesize and characterize spectroscopically and crystallographically the [n]pseudorotaxanes and [n]rotaxanes, particularly the larger n with more structural complexity. In the solid state, one [2]pseudorotaxane (without stopper groups) of the -CDbisimidazolyl complex (Baleizao et al., 2004) and several [3]pseudorotaxanes of - and -CDs have been reported (Wenz et al., 2006). Moreover, the [2]rotaxane type has been observed for the -CD inclusion complexes with different stilbenes (Stanier et al., 2001; Cieslinski et al., 2006; Maniam et al., 2008), poly(p-phenylenevinylene) (Terao et al., 2004), and diphenylacetylene (Nishimura et al., 2008), and the [3]rotaxane type for -CD with alkylene (Akae et al., 2016). Recently, spectroscopic evidences for [4]rotaxanes of permethyl--CD with alkylene (Akae et al., 2016) and -CD with alkynylpyrenes (Inouye et al., 2014) have been reported.

OHO hydrogen bonds and parallel-displaced interactions stabilizing the [4]pseudorotaxane of -CDCGA inclusion complex; hostguest interactions are shown with magenta lines, and interactions within and between guests with cyan lines. Names in italics represent atoms/groups of the adjacent asymmetric units; see also Fig. 1 and Table 2, including Supporting information, Table S1.

Selected OHO hydrogen bonds in -CDCGA inclusion complex deduced from X-ray analysis (, o).

DHA

DH

DA

DHA

DHA

DH

DA

DHA

O1'AHO43 i

0.84

2.822(9)

127.2

O61HO2 ii

0.84

2.724(5)

171.3

O1'BHO45 i

0.84

2.728(8)

162.8

O2HO1W

0.84

2.93(2)

124.0

O2'HO3 i

0.84

2.790(6)

142.2

O3HO66

0.84

2.984(5)

166.6

O1HO64 ii

0.84

2.671(5)

167.5

O6HO62 iii

0.84

2.602(6)

137.1

O2HO1

0.84

2.732(5)

142.1

O37HO3'

0.98

2.89

157.9

Symmetry codes: (i) 1 x, y, 0.5 z; (ii) x 0.5, y + 0.5, z + 1; (iii) x, y + 1, z + 1, see also Table S1.

The crystal packing types of -CD dimeric inclusion complexes are described based on their different crystal symmetries and packing modes: i) triclinic, P1 in channel and intermediate; ii) monoclinic, P21 in screw-channel and chessboard; iii) monoclinic, C2 in channel and tetrad; and iv) orthorhombic, C2221 in chessboard and screw-channel, according to the classifications of Mentzafos et al. (1999) and Brett et al. (2000). In the crystal of -CDCGA complex, the head-to-head dimeric motifs of adjacent unit cells form a layer. Together with the twofold screw symmetry-related upper and lower layers (i.e., lateral layers are shifted by a half unit cell length along the a-axis), they yield a chessboard packing fashion (Fig. 3). A Cambridge Crystallographic Database (CSD) search reveals that there are 19 -CD dimeric inclusion complexes that are isostructural to the -CDCGA and all are categorized into a chessboard packing mode. Note that 8.5 water molecules are disordered over 14 sites in the intermolecular interstices between the protruding parts (QNA moieties) of two successive dimers along the c-axis, and they act as hydrogen bonding mediators to stabilize the entire crystal lattice; see the H-bonding networks in Table S1.

Chessboard-type 3D arrangement of the -CDCGA inclusion complex in orthorhombic, C2221, viewed down the b-axis. -CD macrocycles, CFA, QNA moieties and water sites are displayed with cyan wireframes, red, blue space-filling and yellow ball models, respectively; H-atoms are not shown.

DFT-derived trimodal and dimeric -CDCGA inclusion complexes

CDs are not rigid, but flexible, to an extent, to attain the optimal real-space fit to guests of different sizes and shapes; this is a well-known induced-fit process (Koshland, 1958). Therefore, CDs tend to be distorted upon inclusion complex formation. In the full-geometry DFT optimization starting from the X-ray-derived structure of the -CDCGA complex with a round -CD macrocycle, the DFT-derived -CD structure of mode 3 becomes elliptical while those of modes 1 and 2 mostly retain their annular shapes (Figs. S1 and S3). This is indicated by the -CD geometrical parameters of mode 3 that have greater spans than those of modes 1 and 2: i) O4(n 1)O4(n)O4(n + 1) angles, 117.1140.1 vs. 124.9132.4; ii) O4 deviations from their mean plane, |0.0470.368| vs. |0.0340.200| ; and iii) ranges of the O4(n)O4(n 1), O4(n)centroid distances, 0.427, 1.005 vs. 0.0790.150, 0.2080.323 (Table S4). Moreover, the existences of intramolecular, interglucose O3(n)O2(n + 1) and intradimer O2(n)/O3(n)O2(m)/O3(m) hydrogen bonds are necessary for maintaining the round -CD conformation in the solid state (Table S1) and in the gas phase (Tables S2 and S3). The molecular structures of trimodal and dimeric -CDCGA inclusion complexes from DFT full-geometry optimization and the starting structures from the X-ray analysis are globally compared by estimation of the root mean square deviations (RMSD) of two overlaying structures. Only -CD skeletons are considered for the calculation; O6, H atoms and guest molecules are omitted. The corresponding RMS fits are 0.410 (mode 1), 0.348 (mode 2), 0.763 (mode 3) and 0.515 (dimer), as shown in Figs. S1 and S2, suggesting that the -CD macrocycles adapt the most upon the inclusion of the QNA moiety. Selected hostguest OHO hydrogen bonds stabilizing the -CDCGA complex deduced from DFT full-geometry optimization are given in Table 3.

Selected OHO hydrogen bonds in the -CDCGA inclusion complex deduced from DFT full-geometry optimization (, o).

DHA

DH

DA

DHA

DHA

DH

DA

DHA

Trimodal complex a

Dimeric complex a

Mode 1: Bridge

Monomer 1

O3HO66

0.98

2.89

144.6

O1'HO43 i b

0.98

2.76

140.9

O66HO3'

0.98

2.82

174.1

O66HO3' i

0.97

2.91

159.3

Mode 2: CFA

O2'HO3 i

0.98

2.80

154.1

O66HO3'

0.98

2.86

148.2

Monomer 2

Mode 3: QNA

O1'HO43 i

0.98

2.85

125.9

O1HO47

0.99

2.92

155.0

O66HO3' i

0.97

2.78

163.4

O6HO42

0.98

2.68

162.0

O3HO66

0.99

2.80

153.7

O34HO3

0.98

3.00

172.4

O2'HO3 i

0.98

2.75

149.3

O37HO3'

0.98

2.89

157.9

a Trimodal and dimeric -CDCGA inclusion complexes derived from DFT energy minimization in vacuum

at the B3LYP/6-31+G*/4-31G level, see also Tables S2S4.

b Atoms belong to the pseudo-twofold symmetry related monomer (i).

The DFT-derived stabilization energies Estb (9.42 to 17.26 kcal mol1) in the gas phase and the experimentally-derived Hbind (2.73 to 6.53 kcal mol1) in solution indicate the necessity of weak intermolecular OHO hydrogen bonding interactions in stabilizing the -CDCGA inclusion complex (Table S5). The relative stabilities are mode 1 (bridge) > mode 3 (cyclohexane ring) > mode 2 (aromatic ring), suggesting that although the two rings on both ends of CGA can enter and bind competitively to the -CD cavity, the more energetically favorable binding mode is the one with the bridging C=CC(=O)O group of the guest embedded in the hydrophobic CD cavity (Fig. 4). Considering the dimeric -CDCGA complex (Fig. S2), the composite of i) hosthost O2H/O3HO2H/O3H hydrogen bonds, ii) guestguest O2'HO3 hydrogen bonds and paralleldisplaced interactions, and iii) hostguest O1'HO43, O3HO66HO3' hydrogen bonds amplifies the complexation stability to 19.47 kcal mol1 (Tables S3 and S5). In solution, mode 2 (aromatic ring) tends to be more thermodynamically favorable than mode 3 (cyclohexane ring) as indicated by larger K and lower H deduced from UV, fluorescence, NMR and calorimetry (Table S5). Hence, the CFA moiety plays a key role in the complexation of -CDCGA. Note that in Section 3.1, X-ray crystallography sheds light on the true binding mode in which the two symmetry-related CGA molecules are enclosed in a formed dimeric -CD cavity. So, in solution the 2:2 complex is predominant in a mixture with the 1:1 complex.

Thermodynamic stability profiles of trimodal -CDCGA complexes. (Left axis) Relative stabilization energies (Estb) with the most energetically stable inclusion mode 1 as a reference structure (green areas). (Right axis) Stabilization energy (Estb) of dimeric complex in comparison with trimodal complexes (yellow areas). For the atom legends, see Fig. 3.

Implication for improving antioxidant capacity of CGA by -CD encapsulation

The X-ray analysis combined with the DFT calculation provide an understanding regarding the structureantioxidant property relationship of -CD inclusion complexes with some functional foods as recently demonstrated for tea catechins (Aree & Jongrungruangchok, 2016, 2018a) and olive polyphenols (Aree & Jongrungruangchok, 2018b). For the -CDCGA complex, the CGA OH groups are stabilized through hydrogen bonding interactions with -CD and the o-dihydroxybenzene (catechol) in conjugation with the double bond (ethylene moiety) having a great effect in stabilizing the antioxidant-derived radical (Bors et al., 1990; Rice-Evans et al., 1996) is well shielded in the -CD cavity. Hence the CGA antioxidant capacity is maintained and enhanced upon inclusion complexation (Budryn et al., 2014; Chao et al., 2012; Shao et al., 2014; Zhao et al., 2010).

Conclusion

Single-crystal X-ray diffraction combined with DFT calculations have been undertaken for new insights into -cyclodextrin (-CD) inclusion complexes with coffee chlorogenic acid (CGA), an ester of caffeic acid (CFA) and quinic acid (QNA). The -CDCGA complex with the C=CC(=O)O moiety embedded in the -CD cavity is stabilized through off-centered parallel stacking interactions and OHO hydrogen bonds in the twofold symmetry-related head-to-head dimer, which is the elusive X-ray structure of [4]pseudorotaxane. For the 3D arrangement, the dimeric motifs form a chessboard-type packing style. Among the three plausible inclusion modes, the conjugated C=CC(=O)O group plays a pivotal role in inclusion complexation of -CD with CGA, as further conveyed by DFT full-geometry optimization. The energetically favorable trimodal -CDCGA inclusion complexes with relative thermodynamic stabilities: mode 1 (bridging C=CC(=O)O group) > mode 3 (QNA cyclohexane ring) > mode 2 (CFA aromatic ring) and the most stable dimeric complex with the CFA moiety totally enclosed in the -CD cavity suggest the potential implications in the enrichment of the antioxidant capacity via -CD encapsulation (Pinho et al., 2014).

1. This work was financially supported by the Ratchadapisek Sompoch Endowment Fund, Chulalongkorn University (CU-GR_61_022_23_008).

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Supporting information

Inclusion complex of -cyclodextrin with coffee chlorogenic acid:

New insights from a combined crystallographic and theoretical study

Thammarat Aree

Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand

Correspondence email: thammarat.aree@gmail.com

List of Tables and Figures

Table S1 OHO hydrogen bonds in the -CDCGA complex from X-ray analysis

Table S2 OHO hydrogen bonds in the trimodal -CDCGA inclusion complexes from DFT full-geometry optimization

Table S3 OHO hydrogen bonds in the dimeric -CDCGA inclusion complex from DFT full-geometry optimization

Table S4 Selected geometrical parameters of the four -CD macrocycles in the -CDCGA complexes from X-ray analysis and DFT calculation

Table S5 Stabilization energies of the trimodal and dimeric -CDCGA inclusion complexes from DFT full-geometry optimization

Figure S1 Molecular structures of the trimodal -CDCGA inclusion complexes from DFT full-geometry optimization in comparison with the starting structures from X-ray analysis

Figure S2 Molecular structure of the dimeric -CDCGA inclusion complex from DFT full-geometry optimization in comparison with the starting structure from X-ray analysis

Figure S3 Molecular structures of the trimodal -CDCGA inclusion complexes from DFT full-geometry optimization

Figure S4 Molecular structure of the dimeric -CDCGA inclusion complex from DFT full-geometry optimization

OHO hydrogen bonds in the -CDCGA complex from X-ray analysis.

DHA

DH

DA

DHA

DHA

DH

DA

DHA

-CD-CD

O12WH1O34 ii

0.96

2.96(1)

154.5

O21HO37

0.84

2.795(5)

159.3

O12WH2O21 xiii

0.95

2.922(9)

147.1

O31HO22

0.84

2.864(5)

152.9

O13WH1O66

0.96

2.707(6)

148.9

O22HO27 iv c

0.84

3.001(5)

145.7

O13WH2O56 xiv

0.96

2.797(5)

156.1

O33HO32 i

0.84

2.760(5)

168.4

O5WO23

2.85(3)

O24HO10WB vi b

0.84

2.85(3)

171.6

CGAa-CD/CGA/H2O

O34HO31 i

0.84

2.756(5)

167.4

O1'AHO43 i

0.84

2.822(9)

127.2

O35HO26

0.84

2.900(5)

173.6

O1'BHO45 i

0.84

2.728(8)

162.8

O65HO62 ix

0.84

2.706(6)

146.7

O2'HO3 i

0.84

2.790(6)

142.2

O27HO36

0.84

2.880(6)

127.6

O1HO64 ii

0.84

2.671(5)

167.5

O67HO63 x

0.84

2.989(5)

174.4

O2HO1

0.84

2.732(5)

142.1

-CDH2O

O61HO2 ii

0.84

2.724(5)

171.3

O32HO7W i

0.84

2.91(2)

139.0

O2HO1W

0.84

2.93(2)

124.0

O23HO6W

0.84

2.52(1)

157.9

O3HO66

0.84

2.984(5)

166.6

O23HO7W

0.84

3.11(2)

167.5

O6HO62 v

0.84

2.602(6)

137.1

O63HO8W

0.84

2.718(6)

150.3

O3WO1

2.90(1)

O64HO9W

0.84

2.658(7)

160.9

O3WO5

2.76(1)

O25HO7W viii

0.84

2.64(2)

170.4

H2O2O

O66HO9W ii

0.84

2.709(6)

156.1

O9WH1O1W vii

0.96

3.08(2)

145.5

O26HO10WA

0.84

2.665(8)

167.0

O9WH1O2W vii

0.96

2.59(1)

154.2

O26HO10WB

0.84

2.99(3)

162.6

O9WH2O8W

0.96

2.80(1)

131.7

O36HO10WB i

0.84

2.66(2)

124.4

O11WH2O10WA xii

0.96

2.90(1)

129.5

O37HO6W x

0.84

2.90(1)

136.3

O11WH2O10WB xii

0.96

2.38(3)

130.6

O37HO7W x

0.84

2.67(2)

127.6

O1WO3W

3.05(2)

O8WH1O57 xi

0.96

3.121(6)

151.5

O4WO6W v

2.93(2)

O9WH2O54

0.96

2.974(6)

133.5

a Twofold disordered O1'H group of CGA with occupancy factor 0.5 for both sites A and B.

b Water sites with occupancy factors: 1.0 (O8W, O9W, O13W); 0.8 (O10WA); 0.7 (O2W, O12W), 0.6 (O3W),

0.5 (O6W, O7W, O11W), 0.4 (O4W), 0.3 (O1W, O5W) and 0.2 (O10WB).

c Symmetry codes: (i) 1 x, y, 0.5 z; (ii) x 0.5, y + 0.5, z + 1; (iii) x 0.5, y + 0.5, z;

(iv) x + 0.5, y + 0.5, z + 0.5; (v) x, y + 1, z + 1; (vi) x + 1.5, y + 0.5, z + 0.5;

(vii) x + 0.5, y + 0.5, z + 1; (viii) x + 1.5, y 0.5, z + 0.5; (ix) x + 0.5, y 0.5, z; (x) x 0.5, y 0.5, z;

(xi) x + 0.5, y + 0.5, z; (xii) x + 1, y, z + 0.5; (xiii) x + 0.5, y + 0.5, z + 0.5; (xiv) x, y, z + 1.

OHO hydrogen bonds in the trimodal -CDCGA inclusion complexes from DFT full-geometry optimization [, o]. a

DHA

DH

DA

DHA

DHA

DH

DA

DHA

Mode 1: Bridge

-CD

conformation

-CD-CD

Round

CGA-CD

O21HO37

0.98

3.00

158.9

O3HO66

0.98

2.89

144.6

O31HO22

0.98

2.95

166.1

O66HO3

0.98

2.82

174.1

O32HO23

0.98

2.89

164.4

O33HO24

0.98

2.93

163.1

O34HO25

0.98

2.88

166.7

O35HO26

0.98

2.93

166.5

O27HO36

0.98

2.93

152.2

Mode 2: CFA

-CD-CD

Round

CGA-CD

O21HO37

0.98

2.99

155.3

O66HO3

0.98

2.86

148.2

O31HO22

0.98

2.92

165.9

O32HO23

0.98

2.87

165.1

O33HO24

0.98

2.89

165.6

O25HO34

0.98

2.94

144.7

O35HO26

0.98

3.09

167.2

O27HO36

0.98

2.94

151.9

Mode 3: QNA

-CD-CD

Elliptical

CGA-CD

O21HO37

0.98

2.85

160.5

O1HO47

0.99

2.92

155.0

O31HO22

0.98

2.94

167.6

O6HO42

0.98

2.68

162.0

O32HO23

0.98

2.82

168.5

O34HO3

0.98

3.00

172.4

O33HO24

0.98

2.85

166.1

O37HO3

0.98

2.89

157.9

O25HO34

0.98

2.97

168.4

O35HO26

0.98

2.95

172.2

O27HO36

0.98

2.90

144.8

a DFT calculation in vacuum at the B3LYP/6-31+G*/4-31G level, see also Tables S4 and S5.

OHO hydrogen bonds in the dimeric -CDCGA inclusion complex from DFT full-geometry optimization [, o]. a

DHA

DH

DA

DHA

DHA

DH

DA

DHA

Monomer 1

-CD

conformation

Monomer 2

-CD-CD

Round

-CD-CD

O21HO37

0.99

2.87

170.3

O21HO37

0.98

2.92

170.2

O31HO22

0.99

2.76

164.0

O31HO22

0.99

2.75

167.1

O32HO23

0.98

2.85

157.5

O32HO23

0.98

2.86

160.6

O25HO34

0.98

2.89

164.8

O25HO34

0.98

2.97

164.1

O35HO26

0.99

2.75

168.9

O35HO26

0.98

2.89

169.4

O27HO36

0.98

2.99

152.8

O27HO36

0.98

3.28

134.7

O22HO33 i b

0.98

3.10

156.3

O22HO33 i

0.98

3.23

147.7

O33HO32 i

0.98

2.77

178.6

O33HO32 i

0.99

2.74

175.0

O24HO31 i

0.97

3.05

120.6

O24HO31 i

0.97

3.03

120.5

O34HO31 i

0.99

2.80

162.0

O34HO21 i

0.99

3.13

121.6

O26HO27 i

0.99

2.71

162.3

O34HO31 i

0.99

2.82

159.1

O37HO35 i

0.99

2.72

166.8

O26HO27 i

0.98

2.84

156.4

O37HO35 i

0.99

2.75

165.0

CGA-CD/CGA

CGA-CD/CGA

O1'HO43 i

0.98

2.76

140.9

O1'HO43 i

0.98

2.85

125.9

O66HO3' i

0.97

2.91

159.3

O66HO3' i

0.97

2.78

163.4

O2'HO3 i

0.98

2.80

154.1

O3HO66

0.99

2.80

153.7

O2'HO3 i

0.98

2.75

149.3

a DFT calculation in vacuum at the B3LYP/6-31+G*/4-31G level, see also Tables S4 and S5.

b Atoms belong to the pseudo-twofold symmetry related monomer (i).

Acta Crystallographica Section C research papers

1

Selected geometrical parameters of the four -CD macrocycles in the -CDCGA complexes from X-ray analysis and DFT calculation.

Residue

Tilt angle [o] a

O4 angle [o] b

O4 deviation [] c

O4(n)O4(n 1), O4(n)centroid []

n

X-ray

Mode 1 d

Mode 2 d

Mode 3 d

X-ray

Mode 1

Mode 2

Mode 3

X-ray

Mode 1

Mode 2

Mode 3

X-ray

Mode 1

Mode 2

Mode 3

1

13.2(1)

7.5

9.9

12.8

128.6(1)

126.6

127.2

118.3

0.119(2)

0.034

0.048

0.138

4.372(5)

5.042

4.447

5.197

4.433

5.212

4.530

5.497

2

5.2(1)

15.1

10.0

11.2

129.2(1)

128.2

127.0

124.7

0.066(2)

0.263

0.200

0.123

4.333(5)

4.929

4.412

5.081

4.394

5.137

4.144

5.314

3

10.6(1)

20.2

16.7

6.6

131.8(1)

131.5

132.4

134.9

0.009(3)

0.107

0.094

0.368

4.345(5)

4.917

4.467

4.989

4.449

4.940

4.567

4.621

4

11.0(1)

1.1

0.1

21.7

123.1(1)

125.8

127.8

131.8

0.009(2)

0.190

0.099

0.205

4.416(5)

5.224

4.391

5.188

4.458

5.160

4.539

4.952

5

9.8(1)

6.6

13.8

16.4

130.9(1)

128.8

124.9

117.1

0.020(3)

0.169

0.079

0.148

4.182(5)

4.955

4.398 5

112

4.363

5.263

4.243

5.573

6

18.4(1)

23.2

25.8

10.7

130.6(1)

129.0

131.7

130.1

0.024(3)

0.130

0.107

0.199

4.594(5)

4.911

4.462

5.056

4.513

4.995

4.346

4.960

7

9.5(1)

12.4

12.4

1.9

125.3(1)

128.6

128.2

140.1

0.096(3)

0.231

0.145

0.047

4.257(5)

5.149

4.470

5.104

4.488

5.096

4.572

4.568

0.412 e

0.313 e

0.079

0.208

0.150

0.323

0.427

1.005

0.869 e

0.869

0.869

0.878

a Interplanar angle of the plane through C1(n), C4(n), O4(n) and O4(n 1) against the O4 plane.

b O4(n 1)O4(n)O4(n + 1) angle.

c Deviation of glycosidic O4 atoms from the least-squares plane through the seven O4 atoms.

d Trimodal -CDCGA inclusion complexes derived from DFT energy minimization in vacuum at the B3LYP/6-31+G*/4-31G level.

Three inclusion modes: mode 1, bridging C=CC(=O)O group; mode 2, CFA moiety; and mode 3, QNA moiety.

e Ranges of the O4(n)O4(n 1), O4(n)centroid distances and the average of their ratios are in italics.

17

Stabilization energies of the trimodal and dimeric -CDCGA inclusion complexes from DFT full-geometry optimization. a

Dimer

Trimodal

Mode 1: Bridge

Mode 2: CFA

Mode 3: QNA

DFT calculation

Ecpx b

11139.50994

5569.72645

5569.70310

5569.70652

E-CD_opt

8545.98608

4272.96989

4272.95905

4272.95905

ECGA_opt

2593.49283

1296.72905

1296.72905

1296.72905

Estb [Hartree] c

0.03103

0.02751

0.01500

0.01842

Estb [kcal mol1]

19.47

17.26

9.42

11.56

No. of host-guest

OHO H-bonds

5

2

1

4

Experiments

Method

HUV [337C, pH 6.5] d

UV

2.73

KUV [25C, pH 6.5] d

UV

59727

HUV [525C, pH 6.7] e

UV

6.530.93

KUV [20C, pH 6.7] e

UV

103254

HITC [1055C, pH 6.7] f

Calorimetry

3.020.06

KITC [25C, pH 6.7] f

Calorimetry

146789

KFluor [25C, pH 7] g

Fluorometry

[42050] h

HFluor [525C, pH 5] i

Fluorometry

[6.10] h

KFluor [25C, pH 5] i

Fluorometry

[35169] h

220

93

HITC [525C, pH 5] i

Calorimetry

[3.09] h

KITC [25C, pH 5] i

Calorimetry

[442] h

207

235

HFluor [560C, pH 7] j

Fluorometry

3.04

KFluor [20C, pH 7] j

Fluorometry

424

KNMR [25C, pH 7] k

NMR

504

a DFT/B3LYP calculation using mixed basis sets 4-31G for C atoms and 6-31+G* for H and O atoms.

X-ray-derived structure was used as a starting model, see also Tables S2 and S3.

Bimodal -CDCGA inclusion complex (modes 2 and 3) stems from fluorescence and colorimetric data

(lvarez-Parrilla et al., 2010).

b Original unit of E is Hartree (1 H = 627.5 kcal mol1).

c Stabilization energy, Estb = Ecpx (E-CD_opt + ECGA_opt), where Ecpx, E-CD_opt and ECGA_opt are the energies

from full optimization of complex, -CD and CGA, respectively.

d Multiple-temperature UV studies (337C) in aqueous solution. Inclusion structure is predicted using NMR

(Irwin et al., 1994). Units: H, kcal mol1 and K, M1.

e Multiple-temperature UV studies (525C) in MeOH aqueous solution.

Inclusion structure is predicted using NMR (Irwin et al., 1995).

f Variable-temperature isothermal titration calorimetry (ITC) (1055C) in aqueous solution.

Inclusion structure is predicted using NMR (Irwin et al., 1999).

g Fluorescence data at 25C, pH 7 (lvarez-Parrilla et al., 2005).

h [Macroscopic value] is deduced from two microscopic contributions of the two main structural components of

CGA, i.e., CFA and QNA moieties.

i Variable-temperature fluorescence and isothermal titration calorimetry (ITC) (525C, pH 5) in aqueous solution.

Inclusion structures are predicted using ROESY NMR (lvarez-Parrilla et al., 2010).

j Multiple-temperature fluorescence studies (560C) in aqueous solution.

Inclusion structures are predicted using molecular dynamics (Grnas et al., 2009).

k NMR data at 25C, pH 7 (Rodrigues et al., 2002).

Molecular structures of the trimodal -CDCGA inclusion complexes from DFT full-geometry optimization in comparison with the starting structures from X-ray analysis; top view (left) and side view (right). RMS fit is calculated for the host -CD (cyan wireframes), excluding O6, H atoms and guest molecules.

Molecular structure of the dimeric -CDCGA inclusion complex from DFT full-geometry optimization in comparison with the starting structure from X-ray analysis; top view (left) and side view (right). RMS fit is calculated for the dimeric -CD (cyan wireframes), excluding O6, H atoms and guest molecules.

Molecular structures of the trimodal -CDCGA inclusion complexes from DFT full-geometry optimization; top view (left) and side view (right). OHO hydrogen bonds are indicated by dotted lines with HO distances in .

Molecular structure of the dimeric -CDCGA inclusion complex from DFT full-geometry optimization. OHO hydrogen bonds are indicated by dotted lines with HO distances in .

18

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