Cubane Arrives on the Cucurbituril Scene

Article abstract of DOI:10.1021/acs.orglett.7b01029

Cubane, an intriguing chemical curiosity first studied in the early 1960s, has become a valuable structural motif and has recently been involved in the structures of a great number of prospective compounds. The first dicationic supramolecular guest 5 is prepared and derived from a 1,4-disubstituted cubane moiety, and its binding behavior toward cucurbit[n]urils (CBn) and cyclodextrins (CD) is studied. The bisimidazolium salt 5 forms 1:1 inclusion complexes with CB7, CB8, and β-CD with the respective association constants (6.7 ± 0.5) × 10¹¹ M^-1, (1.5 ± 0.2) × 10⁹ M^-1, and <10² M^-1 in water. The solid-state structures of the 5@CB7 and 5@CB8 complexes are also reported.

Full text of DOI:10.1021/acs.orglett.7b01029

Letter
pubs.acs.org/OrgLett
Cubane Arrives on the Cucurbituril Scene
Kristyna Jelínkova,† Heda Surmova,† Alena Matelova,† Michal Rouchal,† Zdenka Pruckova,†
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́
́
̌
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Lenka Dastychova,† Marek Necas,‡ and Robert Vícha*,†
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†Department of Chemistry, Faculty of Technology, Tomas Bata University in Zlín, Vavreck
̌
ova 275, 760 01 Zlín, Czech Republic
‡Department of Chemistry, Faculty of Science, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic
S
* Supporting Information
ABSTRACT: Cubane, an intriguing chemical curiosity first studied in the
early 1960s, has become a valuable structural motif and has recently been
involved in the structures of a great number of prospective compounds. The
first dicationic supramolecular guest 5 is prepared and derived from a 1,4-
disubstituted cubane moiety, and its binding behavior toward cucurbit[n]urils
(CBn) and cyclodextrins (CD) is studied. The bisimidazolium salt 5 forms 1:1
inclusion complexes with CB7, CB8, and β-CD with the respective association
constants (6.7 0.5) × 1011 M−1, (1.5 0.2) × 109 M−1, and <102 M−1 in
water. The solid-state structures of the 5@CB7 and 5@CB8 complexes are
also reported.
age hydrocarbons have recently been recognized as
bindinding with cucurbit[7/8]uril (CB7/8) and β-cyclodextrin
C
outstanding scaffolds for preparing cationic guests in
(β-CD). The structures of the studied guests and hosts are
depicted in Figure 1.
supramolecular chemistry. Particularly, ammonio derivatives of
diamantane,1 adamantane,2 and bicyclo[2.2.2]octane,2 along
with similar ferrocene3 derivatives, have displayed extraordi-
narily high association constants toward cucurbit[7]uril which
surpass, in some cases, the tightest natural avidin−biotin
complex. Simultaneously, to obtain the strongest binding by
using structural modifications, high-affinity binding motifs were
employed in various more complex, self-assembled supra-
molecular systems in an effort to create molecular tools.4 In this
light, it is slightly surprising that derivatives of another highly
symmetric, synthetically feasible cage hydrocarbon, cubane, has
not attracted the interest of supramolecular chemists so far. To
the best of our knowledge, there is only one report describing
cubane binding sites, published by Lincoln and co-workers,
who studied noncharged adamantane/cubane-cyclodextrin
conjugates.5 Since the initial preparation of cubane by Eaton
and Cole in 1964, its derivatives have been investigated in
several branches of chemistry. Apart from nitrocubanes, which
are well-known high-energy materials,6 a number of intriguing
polymers,7 sulfides,8 peptides,9 and chiral ligands10 have been
studied. Biegasiewitz et al. has published a comprehensive
review of recent cubane chemistry.11 In addition, Eaton
suggested in 1992 that the cubane scaffold can act as a benzene
bioisostere (both 1,4-disubstituted), and thus cubane can
replace the potentially toxic benzene ring in drug molecules.12
This hypothesis inspired the preparation of various bioactive
compounds in which the cubane skeleton was incorporated in
place of benzene.13 The above-mentioned examples demon-
strate the recent increased interest in cubane chemistry, and
extensive supramolecular studies can be expected as the next
logical step. As a part of our ongoing research on cage-
hydrocarbon binding motifs, we report here the first
preparation of a dicationic cubane-derived guest and its
Figure 1. Structures of hosts and guests used in this study.
We employed the Chapman modification14 of the original
Eaton and Cole’s synthesis15 to prepare cubane-1,4-dicarboxylic
acid (1), which is a key intermediate in the wide spectrum of
1,4-disubstituted cubanes. Subsequently, the acid 1 was
transformed to the dibromide 3 using the sequence of Fisher
esterification with MeOH, reduction, and Appel bromination,
as depicted in Scheme 1. Dibromide 3 was reacted with sodium
imidazolide within 4 h at 5 °C to produce intermediate 4 in
satisfactory yield. Finally, the desired guest 5 was readily
obtained via quaternization with MeI. The sample of the
dicarboxylic acid 1, which was pure enough for binding studies,
was obtained by hydrolysis of the sublimated dimethyl ester of
acid 1.16
1
We examined the supramolecular properties of 5 using H
NMR spectroscopy. First, we tested the ability of 5 to form
Received: April 5, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01029
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Organic Letters
Letter
corresponding stacking plots, see the Supporting Information
(SI), Figures S9 and S11).
Scheme 1. Synthesis of Cubane-Based Dicationic Guest 5
To obtain comprehensive insight into the complexation
ability of cubane guests, we performed 1H NMR titrations with
β-CD. The noncationic guests 1 and 2 displayed an
unambiguous downfield shift of the cubane signals, indicating
the formation of inclusion complexes in fast exchange mode
with the cubane moiety inside the CD cavity (for the spectra,
see SI, Figures S8 and S10). In contrast, the signals of the guest
5 displayed an order of magnitude smaller chemical shifts upon
titration with β-CD.
Continuing our study, we determined the thermodynamic
binding parameters by means of titration calorimetry (ITC).
Because there is no serious need for buffering, we performed
titrations of the permanently dicationic guest 5 and noncharged
diol 2 in pure water to avoid competition between guest and
buffer components. Nevertheless, we also provide data, which
were obtained using 50 mM AcONa buffer, to allow
comparison with results from other laboratories. All these
titration data indicated a 1:1 binding mode. The acid 1 was
titrated in 1 mM HCl (pH = 2.88) to maintain its protonated
1
inclusion complexes with CB7/8. The H NMR spectrum of
guest 5 shows three signals corresponding to aliphatic H atoms.
All of these signals appear within the range 3.7−4.4 ppm due to
the electron-withdrawing effects of the adjacent imidazolium
cation or strained structure (Figure 2, line (iii). It should be
form (the dissociation constants of 1, pKa,1 = 3.83 and pKa,2
=
5.13, were determined by acidimetric titration). The ITC
showed no interaction of 1 with CB8, and only a relatively weak
interaction (millimolar dissociation constants) with β-CD and
CB7 (the K values are summarized in Table 1, and full ITC
data are given in Table S4). In pure water, no complexation was
detected for 1. The diol 2 can be considered as a model
compound, in which binding with CBn’s is not affected by ion−
dipole interactions between the guest and the portals of CBn.
As seen in Table 1, 2 binds CB7 and CB8 significantly more
strongly than 1; the approximate log K values in water are 8 and
4, respectively. In agreement with the well-known competition
of ionic guests and metal ions for the portals of CBn, 10 times
lower binding strengths were observed in AcONa buffer.
Finally, as the cationic moieties of 5 can be attracted to the
portals of CBn via ion−dipole interactions, the guest 5
displayed 104−5 times stronger binding toward CB7/8 than 2.
Note that the relative increase in the binding strength is
significantly higher for CB8 than that for CB7 (6.7× in water
Figure 2. Stacking plot of a region of the 1H NMR (500 MHz) spectra
of guest 5 (iii) titrated with CB8 (i, ii) and CB7 (iv, v) in D2O at 303
K. For signal assignment, see Figure 1.
noted that signal of H(c) was not observed due to rapid H/D
exchange. Upon the addition of 0.5 equiv of CB7 or CB8, new
sets of guest signals appeared, and the original signals of the
free guest completely vanished in equimolar solutions. The
strong upfield shift of the cubane CH and CH2 signals and the
simultaneous downfield shift of the CH3 signals imply that the
cubane moiety was included inside the CBn cavity, whereas
terminal methyls are positioned outside near the CB’s portals.
Broadening of the guest signals during the titration of 5 with
CB8 (Figure 2, line ii) can be attributed to the faster exchange
compared to CB7. Similarly, the inclusion complexes of
cubane-1,4-dicarboxylic acid (1) and diol 2 with CB7 in slow
and 3.4× in AcONa buffer; the K5@CB7/K2@CB7 and K5@CB8
/
K2@CB8 ratios were compared). We speculate that this increase
in binding strength can be attributed to the more effective
involvement of imidazolium moieties through C−H···O
interactions within the portals or the better accommodation
of guests by the wider CB8 cavity. As seen below, the X-ray
data support the latter conclusion.
All the three complexes of 5, whose formation in solution
was indicated by either NMR or ITC, were detected using the
ESI MS technique. The structures of the complexes with the
1
exchange mode were detected via H NMR titrations (for
Table 1. ITC-Determined Values of K for the Interactions of 1, 2, and 5 with CB7, CB8, and β-CD at 303 K, Reported in dm3·
a
mol−1
CB7
CB8
β-CD
b
c
h
1
2
2
5
5
(3.5 0.3) × 103
(5.6 0.2) × 107
nb
(3.7 0.8) × 103
(1.62 0.04) × 103
(1.66 0.02) × 103
e
(2.08 0.07) × 104
(1.2 0.4) × 103
d
c
(2.19 0.02) × 106
f
g
h
(6.0 0.6) × 1011
(6.4 0.6) × 1010
(1.5 0.2) × 109
nb
d
f
g
h
(1.2 0.5) × 108
nb
a
b
c
d
e
f
The titration experiments were performed in triplicate. In 1 mM HCl. In water. In 50 mM AcONa. Cyclopentanone used as competitor. 1,6-
g
h
Hexamethylene diamine·2HCl used as competitor. Methylviologen used as a competitor. nb = no binding detected by ITC.
B
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CBn hosts were determined by tandem mass spectrometry. For
the corresponding spectra, see SI, Figures S15−S17.
As Figure 3 shows, there are some remarkable differences in
the binding of the guest 5 inside CB7 and CB8. As mentioned
above, the imidazolium moieties do not match the symmetry of
either the 1,4-disubstituted cubane moiety or cucurbituril.
Therefore, the cubane moiety is tilted by 22.4° in the 5@CB7
complex to allow positioning the adjacent N atoms of
imidazolium essentially on the virtual c7 axis of CB7 (i.e., in
the portal center). In fact, 5−7 contacts were found in which
the O···H distance is lower than the sum of the van der Waals
radii in each portal (full list of contacts is given in Table S2 in
SI). Surprisingly, the cubane moiety is much more tilted
(57.4°) in the 5@CB8 complex. The two most important
consequences are that imidazolium cations are moved far from
the centers of the portals and methylene bridges are buried into
the cavity. Accordingly, only four short contacts (Figure 3)
were found in the portal, and CB8 adopts an elliptical
geometry. We infer that the 5@CB8 geometry highlights
CB8’s inability to bind cations in the centers of its portals.
In addition to ion−dipole interactions, which occur in the
CBn portals, the dispersion forces play a significant role in
complex stabilization. Although this stabilization force arises
everywhere the molecular surfaces are close, the theoretical
calculations suggest that short side chains that protrude from
the cavity into the external environment contribute to the
overall dispersive force by approximately 10−15%.17 In other
words, the most significant contribution to the dispersive force
is related to the stiffness of the guest inside the CBn cavity,
which can be qualitatively estimated by means of Hirshfeld
surface (HS) analysis. The Hirshfeld surface can be
straightforwardly computed from crystallographic data and,
simply said, reflects the intermolecular interactions in a very
subtle way.18 Although HS is usually used for the analysis of
intermolecular interactions in crystal lattices, it can also provide
insight into intermolecular contacts inside macrocycle cavities.
We calculated the HS for the hydrocarbon skeleton of 5
(including methylene bridges) and compared it with the HS of
the diamantane moiety in the BTAD@CB7 complex, which
was published by Isaacs and co-workers.1 The side and front
views of the complexes with the HS, on which the distances
from the adjacent inside atoms are encoded from red (close) to
blue (far), are depicted in Figure 4 (top). The fingerprints
display the distance from each point on the HS toward the
closest atom inside and outside the surface, which is indicative
Since we succeeded in growing single crystals of 5@CB7 and
5@CB8, we can provide direct insight into their solid-state
geometries (side and front views are depicted in Figure 3). It is
Figure 3. Solid-state structure of 5@CB7 (top) and 5@CB8 (bottom)
determined by X-ray diffraction. Iodide counterions are not shown for
clarity. Hydrogen short contacts within the portals are drawn with
dotted lines. Gray lines are virtual axes of 1,4-disubstituted cubane
moiety, blue lines go through the N atoms adjacent to the cubane
moiety, and green lines go through the centers of gravity of O atoms in
opposite portals.
well-known that ion−dipole interactions are one of the most
important attractive forces that hold the CBn inclusion
complexes together. Since the CBn’s have two identical,
opposite-facing carbonyl-rimmed portals, the cage moieties,
which can be disubstituted along the axis, are the most
promising candidates for construction of high-affinity guests.
Because of the strong rigidity of the CBn macrocycle, the
distance between the two centers of positive charge in the guest
molecule plays a very important role. Considering the 4,9-
disubstituted diamantane to be at this point the best suited for
CB7 (the N+···N+ distance in 4,9-bis(trimethylammonio)-
diamantane (BTAD) is 7.78 Å, and the bridgehead-to-
bridgehead distance is dBB = 4.64 Å),1 it is clear that much
more compact bicyclo[2.2.2]octane (dBB = 2.60 Å) or cubane
(dBB = 2.70 Å) moieties must be extended by suiatable linkers
between the hydrocarbon cage and cationic moieties to prevent
the nonpreferred burying of cations deep into the portals.
Unfortunately, prolongation by sp3 or sp2 carbons breaks the
symmetry of the axially disubstituted central hydrocarbon cage,
and interactions in the portals cannot be fully established.
However, this disadvantage can be partially compensated for by
tilting of the hydrocarbon cage inside the CB cavity. With the
above-mentioned circumstances considered, it is clear that the
cubane-based bisimidazolium salts cannot overcome the
superior BTAD, with its K(CB7) = 7.2 × 1017 M−1; however,
cubane derivatives complement the family of high-affinity
guests and are important from both a theoretical and practical
point of view.
Figure 4. Hirshfeld surfaces (top and side views) and corresponding
fingerprints for 5@CB7 (left) and BTAD@CB71 (right). Gray dots are
related to the CiNe intramolecular covalent bonds.
C
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(3) Rekharsky, M. V.; Mori, T.; Yang, C.; Ko, H. K.; Selvapalam, N.;
Kim, H.; Sobransingh, D.; Kaifer, A. E.; Liu, S.; Isaacs, L.; Chen, W.;
Moghaddam, S.; Gilson, M. K.; Kim, K.; Inoue, Y. Proc. Natl. Acad. Sci.
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of guest stiffness inside the cavity. As can be clearly seen in
Figure 4 (bottom), on the HS, the distances of inner atoms in
the diamantane complex do not exceed 1.8 Å. In contrast, a
significant number of surface points for 5@CB7 have di
coordinates within the range of 1.80−2.35 Å. This clearly
indicates that the cubane moiety does not fill the inner space of
the CB7 cavity as nicely as diamantane. Therefore, it is
reasonable to suppose that the contribution of dispersive forces
inside the CB7 cavity is significantly lower for our cubane guest
than that for the diamantane derivatives.
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molecular guest 5 based on a highly symmetric hydrocarbon
cubane cage and investigated its ability to form host−guest
complexes with CB7, CB8, and β-CD. The association
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0.6) × 1011
M−1 and (1.5 0.2) × 109 M−1 in water, are lower than those
for the strongest complex, as known to date, BTAD@CB7,1
which is likely due to the imperfect symmetry of the
imidazolium cationic moieties and lower degree of dispersive
interactions of the much smaller cubane inside the CB7 cavity.
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design of multitopic guests in which binding sites with diverse
properties are desired.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01029.
Experimental procedures and analytical data for all new
compounds; NMR, ITC, and MS data for the complexes
(PDF)
X-ray data for inclusion complex 5@CB7 (CIF)
X-ray data for inclusion complex 5@CB8 (CIF)
X-ray data for intermediate 4 (CIF)
(14) Chapman, N. B.; Key, J. M.; Toyne, K. J. J. Org. Chem. 1970, 35,
3860−3867.
(15) Eaton, P. E.; Cole, T. W. J. Am. Chem. Soc. 1964, 86, 962−964.
(16) Griffiths, J. R.; Tsanaktsidis, J.; Savage, G. P.; Priefer, R.
Thermochim. Acta 2010, 499, 15−20.
̌
̌
́
(17) Hostas, J.; Sigwalt, D.; Sekutor, M.; Ajani, H.; Dubecky, M.;
̌
́ ̌ ́
Rezac, J.; Zavalij, P. Y.; Cao, L.; Wohlschlager, C.; Mlinaric-Majerski,
AUTHOR INFORMATION
K.; Isaacs, L.; Glaser, R.; Hobza, P. Chem. - Eur. J. 2016, 22, 17226−
■
17238.
Corresponding Author
*E-mail: rvicha@ft.utb.cz.
ORCID
(18) Spackman, M. A.; Jayatilaka, D. CrystEngComm 2009, 11, 19−
32.
Robert Vícha: 0000-0002-5229-9863
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was financially supported by the Internal Founding
Agency of Tomas Bata University in Zlın, Project No. IGA/
■
́
FT/2017/001. The CIISB Research Infrastructure Project
LM2015043 funded by MEYS CR is gratefully acknowledged
for the financial support of the measurements at the CEITEC
X-ray Diffraction and Bio-SAXS Core Facility. The authors
thank Lukas Maier from Masaryk University (Brno, Czech
́ ̌
Republic) for assistance with the NMR measurements.
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■
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Majerski, K.; Glaser,
D
DOI: 10.1021/acs.orglett.7b01029
Org. Lett. XXXX, XXX, XXX−XXX