Influence of intramolecular hydrogen bonds on the binding potential of methylated β-cyclodextrin derivatives

Article abstract of DOI:10.3762/bjoc.8.218

Various heptasubstituted derivatives of β-cyclodextrin (β-CD) bearing 1, 2 and 3 methyl substituents per glucose unit were synthesized by regioselective methods. Binding free energies and binding enthalpies of these hosts towards 4-tert-butylbenzoate and adamantane-1-carboxylate were determined by isothermal titration microcalorimetry (ITC). It was found that methyl substituents at the secondary positions of β-CD lead to a tremendous reduction of the binding potential, while methylation at the primary positions significantly improved binding. Stabilizing intramolecular hydrogen bonds between the glucose units were made responsible for the high binding potentials of those β-CD derivatives that possess secondary hydroxy groups.

Full text of DOI:10.3762/bjoc.8.218

Influence of intramolecular hydrogen bonds
on the binding potential of methylated
β-cyclodextrin derivatives
Gerhard Wenz
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 1890–1895.
Organic Macromolecular Chemistry, Saarland University, Campus
Saarbrücken C4.2, 66123 Saarbrücken, Germany
doi:10.3762/bjoc.8.218
Received: 21 June 2012
Email:
Accepted: 16 October 2012
Published: 06 November 2012
Gerhard Wenz - g.wenz@mx.uni-saarland.de
This article is part of the Thematic Series "Superstructures with
cyclodextrins: Chemistry and applications".
Keywords:
binding constant; cyclodextrin; hydrogen bond; methylation;
regioselective
Guest Editor: H. Ritter
© 2012 Wenz; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Various heptasubstituted derivatives of β-cyclodextrin (β-CD) bearing 1, 2 and 3 methyl substituents per glucose unit were synthe-
sized by regioselective methods. Binding free energies and binding enthalpies of these hosts towards 4-tert-butylbenzoate and
adamantane-1-carboxylate were determined by isothermal titration microcalorimetry (ITC). It was found that methyl substituents at
the secondary positions of β-CD lead to a tremendous reduction of the binding potential, while methylation at the primary positions
significantly improved binding. Stabilizing intramolecular hydrogen bonds between the glucose units were made responsible for the
high binding potentials of those β-CD derivatives that possess secondary hydroxy groups.
Introduction
Cyclodextrins (CDs) are a well-known class of organic hosts enantiomers [2,7,8]. Application of β-CD 1 is hampered by its
able to include various guests, preferably in aqueous solution low solubility of 18.8 g L−1 at 25 °C [9]. Solubility of β-CD and
[1-3]. Inclusion is mainly driven by hydrophobic and van der its inclusion compounds can be significantly increased by the
Waals interactions [4-6]. The host–guest complexes, so-called covalent attachment of neutral or ionic substituents [10].
cyclodextrin inclusion compounds, find many applications such Methylated β-CDs, such as heptakis(2,6-di-O-methyl)-β-CD 2
as solubilization of pharmaceutical drugs, dispersion of and heptakis (2,3,6-tri-O-methyl)-β-CD 3, are well known for
cosmetics, catalysis, or chromatographic separation of their high solubilities in water (2: > 300 g L−1) and their
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Beilstein J. Org. Chem. 2012, 8, 1890–1895.
interesting inclusion behavior [11-13]. Because of the tedious
synthesis of the disubstituted derivative 2 [11,14], the readily
available randomly substituted derivative RAMEB with a
degree of substitution DS = 1.7–1.8 is preferred nowadays and
produced on an industrial scale [15].
Methylated CDs have already found several applications in drug
delivery [10] and polymer chemistry [16]. They allow radical
polymerizations of hydrophobic vinyl monomers in homo-
genous aqueous solution [17-20] and living RAFT polymeriza-
tions as well [21]. Methylated CDs are already applied industri-
ally on a large scale, e.g., for switching the viscosity of poly-
meric thickeners [22], for decontamination of soil [23,24], or
for cosmetic formulations [25]. High binding potentials of the
methylated CDs are essential for their specific functions in
these applications. Therefore, a quantitative understanding of
the binding potential as a function of the degree and pattern of
methylation is highly desirable.
The attachment of methyl groups to β-CD improves its solu-
bility in water because it reduces formation of intermolecular
hydrogen bonds. Methylation should also extend the
hydrophobic cavity of β-CD and therefore improve the binding
potential for hydrophobic guest molecules. Up to now, only
little is known about the influence of methyl substituents on the
inclusion potential of β-CD [26,27]. The dimethyl derivative 2
binds adamantane derivatives with a similar binding constants K
Figure 1: Structures of the methylated β-CD derivatives investigated.
to those of native β-CD, while the trimethyl derivative 3 binds dynamic data obtained for the guests 4-tert-butylbenzoate and
much more weakly [28]. Similar differences in binding affini- adamantane-1-carboxylate are listed in Table 1 and Table 2, res-
ties between native 1 and permethylated β-CD 3 were observed pectively.
for the inclusion of anti-inflammatory drugs [29].
Remarkable differences in the binding constants for 4-tert-
For the systematic investigation of the influence of the pattern butylbenzoate were found for the β-CD derivatives 2–7. The
of methylation on the complexation of amphiphilic guests, we completely methylated β-CD 3 and the 2,3-dimethylated deriva-
synthesized well-defined model compounds 2–6 (Figure 1) of tive 6 showed the lowest binding constants K, less than one
methylated β-CD, using regioselective procedures already tenth of the one of native β-CD 1. These very low binding
published [30]. 4-tert-Butylbenzoate and adamantane-1- constants are accompanied by positive values of the entropy
carboxylate were chosen as representative guests. Complexa- term −TΔS° weakening the binding free enthalpy ΔG°. On the
tion of these guests should sensitively respond to changes in the other hand, binding constants of the 2,6-di-O-methyl derivative
methylation pattern, because they fit tightly into the cavity of 2 as well as the 6-O-methyl derivative were higher than the one
β-CD giving rise to high binding constants [26,27]. Binding of β-CD. Apparently, methylations of secondary hydroxy
data were measured by isothermal titration calorimetry (ITC) groups lead to a decrease of the binding constant, while
because it is known to be the most accurate method, and methylation at primary hydroxy groups leads to an increase. For
because it additionally yields binding enthalpies and entropies the 2,6-di-O-methyl derivative both effects seem to compensate
[31,32].
each other giving rise to a binding constant K similar to the one
of native β-CD. The randomly methylated β-CD 7 also showed
an inclusion potential very similar to β-CD for the same reason.
Results
Since methylated β-CD derivatives 2–6 are highly water-soluble
they are well suited for ITC. The ITC titration curves for all the The thermodynamic data (Table 2) measured for the inclusion
β-CD derivatives 1–6 were exothermic and were in accordance of adamantane-1-carboxylate in β-CD and β-CD derivatives
with a 1:1 stoichiometry of the host–guest complexes. Thermo- 2–6, showed a similar trend to that observed before. This guest,
1891

Beilstein J. Org. Chem. 2012, 8, 1890–1895.
Table 1: Thermodynamics of the inclusion of 4-tert-butyl-benzoate in β-cyclodextrin 1 and its methyl derivatives 2–6.
Host
No.
K (M−1)
ΔG° (kJ mol−1)
ΔH° (kJ mol−1)
−TΔS° (kJ mol−1)
unsubstituted β-CD
2,6-di-O-methyl-β-CD
2,3,6-tri-O-methyl-β-CD
6-O-methyl-β-CD
2-O-methyl-β-CD
2,3-di-O-methyl-β-CD
RAMEBa
1
2
3
4
5
6
7
16400 ± 4
−24.34
−24.13
−17.54
−25.60
−23.33
−16.77
−23.77
−19.00 ± 0.08
−19.98 ± 0.14
−30.54 ± 0.37
−20.14 ± 0.12
−14.30 ± 0.11
−19.24 ± 0.84
−14.60 ± 0.09
−3.82
−4.18
12.98
−5.49
−9.05
+2.45
−9.20
17000 ± 485
1190 ± 21
30700 ± 898
12300 ± 428
869 ± 28
14700 ± 363
arandomly methylated β-CDs.
Table 2: Thermodynamics of the inclusion of adamantane-1-carboxylate in β-cyclodextrin 1 and its methyl derivatives 2–6.
Host
No.
K (M−1)
ΔG° (kJ mol−1)
ΔH° (kJ mol−1)
−TΔS° (kJ mol−1)
unsubstituted β-CD
2,6-di-O-methyl-β-CD
2,3,6-tri-O-methyl-β-CD
6-O-methyl-β-CD
2-O-methyl-β-CD
2,3-di-O-methyl-β-CD
RAMEBa
1
2
3
4
5
6
7
38100 ± 1150
20400 ± 975
606 ± 43
−26.13
−24.58
−15.87
−27.10
−24.37
−15.79
−23.87
−22.38 ± 0.09
−20.75 ± 0.22
−19.94 ± 0.82
−19.11 ± 0.15
−20.85 ± 0.05
−12.72 ± 0.70
−15.48 ± 0.09
−3.78
−3.87
+4.04
−8.02
−3.57
−3.09
−8.41
56400 ± 2400
18700 ± 275
586 ± 65
15300 ± 341
arandomly methylated β-CDs.
which is known as one of the most suitable guests for the β-CD
cavity, was bound even more weakly by the 2,6-di-O-methyl
derivative 2 than by native β-CD 1. Again, all β-CD derivatives
methylated at the secondary positions showed much lower
affinities towards this guest than 1 did. Again, a positive value
of the entropy term −TΔS° was found for 2,3,5-tri-O-methyl-β-
CD. As shown in Figure 2, this entropy term further grew with
increasing temperature, compensating most of the strongly
negative binding enthalpy ΔH°. Taking into account these data
and previous results from literature, the observed reduction of
the binding potential by substitutions at the secondary positions
appeared to be a general feature of β-CD.
In addition, the differential heat capacity, ΔCp = −510 ±
30 J mol−1 K−1, was calculated from the slope of the tempera-
ture dependence of ΔH°. Negative ΔCp are generally inter-
preted as the liberation of “hot” water molecules during com-
plexation of the guest [33-35]. The liberation of water mole-
cules of high energy from a cavity is regarded as a major
driving force for the complexation of neutral guests by concave
hosts in water, because it can lead both to entropy gains and
enthalpic advantages [36]. The observed value for 2,3,5-tri-O-
methyl-β-CD is even higher than that for native β-CD, ΔCp =
−320 ± 20 J mol−1 K−1 [37]. This difference was attributed to
the larger internal hydrophobic surface of 2,3,5-tri-O-methyl-β-
Figure 2: Temperature dependence of −TΔS°, ΔH° and ΔG° for the
inclusion of 1-adamantane carboxylate in heptakis-2,3,6-tri-O-methyl-
β-CD (3) measured by ITC.
1892

Beilstein J. Org. Chem. 2012, 8, 1890–1895.
CD compared to native β-CD leading to the liberation of more
bound water molecules during complexation. Nevertheless, the
effect of the negative heat capacity on binding adamantane
carboxylate by 2,3,5-tri-O-methyl-β-CD is overcompensated by
a strong increase of binding entropy leading in total to a reduc-
tion of the complex stability with increasing temperature.
Discussion
Only methylations at the primary positions lead to the antici-
pated increase of the binding potential of β-CD due to an
elongation of the hydrophobic cavity of β-CD. The negative
effect of methylations at the secondary positions was initially
surprising. The discussion of the entropy term −TΔS° appeared
most appropriate to us to understand this behavior.
The entropy term −TΔS° was negative (−3 to −9 kJ mol−1) for
those β-CD derivatives (1,2,4,5 and 7) equipped with free sec-
ondary hydroxy groups. This negative value is quite normal and
attributed to the liberation of bound water molecules from the
cavity, while the entropy of the host remains more or less
unchanged [5,6]. Neutron scattering studies revealed that native
Figure 3: Structural drawing of β-CD [43], according to structural data
(CSD-ID BUVSEQ03) from Zabel et al. [38], generated by VMD 1.8.4
showing the intramolecular hydrogen bonds between OH-3 and O-2.
β-CD is strongly rigidified by intermolecular hydrogen bonds significantly diminish the rigidity of the CD torus. This explains
(flip-flop bonds) between the secondary hydroxy groups of why methylation at the primary position leads to the expected
adjacent anhydroglucose units, as depicted in Figure 3 [38]. improvement of the binding potential. Also the substitution of
This finding was confirmed by MD calculations of CDs in the the primary hydroxy groups with other hydrophobic groups,
crystalline state and in aqueous environment [39,40]. A stabi- such as thioether moieties, is known to furnish host molecules
lization energy due to all O3H∙∙∙∙O2’ hydrogen bonds of 14 to with much higher binding potentials than native β-CD [46,47].
23 kJ mol−1 was calculated by using density functional theory
(basis set B3LYP) [41]. In addition, recent density-functional Conclusion
calculations also took into account strong intermolecular The binding potential of β-CD can be improved significantly if
hydrogen bonds of these hydroxy groups with water molecules hydrophobic substituents are exclusively attached at the prima-
in aqueous solution [42].
ry positions. Intramolecular hydrogen bonds between second-
ary hydroxy groups of β-CD are crucial for achieving high
The conformational stabilization of β-CD by these hydrogen binding constants. This result provides an example of a host,
bonds between the secondary hydroxy groups is lost upon where intramolecular hydrogen bonds control the binding
methylation. Furthermore, methylated β-CDs are less hydrated potential [48]. It will help to better understand binding mecha-
than the native ones [44]. The lack of stabilizing hydrogen nisms in supramolecular systems [48] and in the future help to
bonds leads to much higher ring flexibilities for derivatives 3 design improved hosts based on β-CD for specific applications
and 6, which explains the low or even positive entropy contri- such as drug delivery [49], removal of pollutants [50-53],
butions −TΔS° to the binding free enthalpy ΔG°. Especially for catalysis [54] or smart materials [55].
a guest such as adamantane-1-carboxylate, which fits well into
the CD cavity, its inclusion will significantly reduce the con- Experimental
formational degrees of freedom of a flexible host, such as 3 or 4-tert-Butylbenzoic acid and adamantane-1-carboxylic acid and
6, leading to an unfavorable decrease in entropy.
β-CD derivative 3 were purchased from Aldrich, β-CD 1 and
RAMEB 7 from Wacker Chemie, β-CD derivative 2 from
In contrast, primary hydroxy groups in β-CD are too far apart Cyclolab. β-CD derivatives 4–6 were synthesized from β-CD 1
from each other to allow intramolecular hydrogen-bond forma- following published procedures (Table 3) [30].
tion. Hydrogen bonds between primary hydroxy groups were
only found for α-CD, leading to a conical host conformation, Binding data were measured with isothermal microcalorimetric
which is unfavorable for the accommodation of a guest [45]. titration at a temperature of 25.0 °C with an AutoITC
Therefore, methylation at the primary positions should not isothermal titration calorimeter (MicroCal Inc., Northampton,
1893

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