Extended cavitands of nanoscale dimensions

Article abstract of DOI:10.1002/ejoc.200500342

New tetrabenzimidazole cavitands with upper rims extended by aromatic groups have been prepared and their X-ray structures were analyzed. The reversible encapsulation of a series of n-alkylammonium guests was studied by NMR spectroscopy and mass spectrometry. These guests showed different binding modes and unique interactions with the hydrophobic cavity. The trimethylammonium guests bearing n-butyl to n-hexyl substituents stabilize the C_4v conformation of the cavitand by additional CH...π interactions with the aromatic upper part. The longest n-hexylammonium salt adopts a minimal gauche conformation to fit in the cavity. Wiley-VCH Verlag GmbH & Co. KGaA, 2005.

Full text of DOI:10.1002/ejoc.200500342

SHORT COMMUNICATION
Extended Cavitands of Nanoscale Dimensions
Edoardo Menozzi,[a] Hideki Onagi,[a] Arnold L. Rheingold,[b] and Julius Rebek, Jr.*[a]
Keywords: Supramolecular chemistry / Cavitands / Host-guest systems
New tetrabenzimidazole cavitands with upper rims extended
by aromatic groups have been prepared and their X-ray
structures were analyzed. The reversible encapsulation of a
series of n-alkylammonium guests was studied by NMR
spectroscopy and mass spectrometry. These guests showed
different binding modes and unique interactions with the
hydrophobic cavity. The trimethylammonium guests bearing
n-butyl to n-hexyl substituents stabilize the C4v conformation
of the cavitand by additional CH···π interactions with the aro-
matic upper part. The longest n-hexylammonium salt adopts
a minimal gauche conformation to fit in the cavity.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Cavitands are open-ended host molecules possessing en- described by Singh et al.[6] Accordingly, the very upper rim
forced cavities in which complementary guest molecules can of the cavitands can be basic (4a,b), neutral (5) or func-
be accommodated.[1] Most are derived from shallow resor- tional (6). Cavitands 4–6 were obtained in 20–30% yield
cinarenes that are deepened through synthesis, but such and were characterized by NMR spectroscopy and mass
changes can also result in conformations that no longer spectrometry. A crystal of the cavitand 5 was obtained by
possess well-defined cavities.[2] Additional features such as slow diffusion of EtOH into its solution in CH2Cl2. The
a cyclic array of intramolecular hydrogen bonds,[3] and even crystal structure shows that the cavitand has a deep vase-
covalent bonds can stabilize a vase-like structure. These al- like conformation (Figure 1, Table 1), stabilized by four
low the formation of kinetically stable complexes with size- EtOH molecules that form a network of hydrogen bonds
able guests like adamantane derivatives[4] and ammonium with the benzimidazole rings. The cavity is filled with two
cations.[5] We report here the synthesis and characterization additional molecules of EtOH, one deep inside the cavity
of three new tetrabenzimizadole cavitands with upper rims while the second one is located between the phenyl and
extended by aromatic groups. The binding of a series of imidazole region. The distance between the methine carbon
alkylammonium salts is analyzed by NMR methods that atom and the para position of the corresponding phenyl
show idiosyncratic behavior of the cations in filling the group is 12.1 Å; the width is 7–8 Å, and the approximate
space of the hosts.
volume of 300 Å3 makes this one of the largest cavitands
The synthesis (Scheme 1) proceeds from the known res- known that can be used for the inclusion of long alkyl am-
orcinarenes 1a,b and follows well-trodden paths. Two dif- monium salts. The X-ray structure of 4a was also obtained
ferent alkyl chains were deployed at the lower rim of resor- and showed nearly identical features (for Supporting infor-
cinarene: To improve the solubility in organic media we mation see footnote on the first page of this article).
used R = C11H23; to favor the formation of crystals for X-
ray determination we used R = C2H5. The octanitro deriva-
tives 2a,b were prepared by alkylation of 1a,b with 4 equiv.
of 4,5-difluoro-1,2-dinitrobenzene, then reduction using
SnCl2 in EtOH/HCl, and subsequent base workup gave
3a,b. The extended walls were installed by the treatment of
the octamines 3a or 3b with an excess of the appropriate
aldehyde using the benzimidazole ring formation protocol
Trimethylammonium salts from n-C2H5 to n-C6H13 and
cavitand 5 form kinetically stable 1:1 inclusion complexes
on the NMR time scale in [D6]DMSO (Table 1). The elec-
tron-rich aromatic surfaces of the hosts provide cation–π
attractions[7] with the partially positive hydrogen atoms on
the surface of the guests. ESI-MS clearly shows that only
one guest molecule is contained in the gas phase as well
(prominent peaks at [(Guest@5)-Br]+ and [(Guest@5)+Na]+;
Guest refers to compounds 7–11).
The NMR spectra of the included guests are shown in
Figure 2. The shorter guests 7 and 8 show signals broad-
ened by exchange with their free counterparts with a rate
that, at the temperature employed for the experiments, is
still slower but not very different than the 1H NMR chemi-
cal shift time scale (600 MHz). Relatively sharp signals are
seen for complexes with guests n-C4H9 to n-C6H13 (9–11)
[a] The Skaggs Institute for Chemical Biology and Department of
Chemistry, The Scripps Research Institute, MB-26,
10550 North Torrey Pines Road, La Jolla, California 92037,
USA
E-mail: jrebek@scripps.edu
[b] Department of Chemistry and Biochemistry, University of Cali-
fornia at San Diego,
La Jolla, California 92093, USA
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2005, 3633–3636
DOI: 10.1002/ejoc.200500342
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3633

E. Menozzi, H. Onagi, A. L. Rheingold, J. Rebek, Jr.
SHORT COMMUNICATION
Scheme 1. Synthesis of the tetraimidazole-modified cavitands 4–6. i) 4,5-difluoro-1,2-dinitrobenzene, DMF, 70 °C, 16 h; ii) SnCl2, EtOH/
HCl, 70 °C, 16 h followed by base workup; iii) DMF, 80 °C, 2 h, under N2; iv) FeCl3·6H2O, DMF, 110 °C, 16 h.
Table 1. Crystal data and structure refinement for 5. High values
of R and wR are due to disordered solvent molecules present in the
unit cell.
Empirical formula
Formula mass
Temperature
Wavelength
Crystal system
Space group
C100H96N8O14
1633.85
120(2) K
0.71073 Å
triclinic
¯
P1
Unit cell dimensions
a = 15.394(3) Å; α = 110.556(3)°
b = 15.540(3) Å; β = 92.603(3)°
c = 19.781(4) Å; γ = 92.784(3)°
4415.6(14) Å3
Volume
Z
2
Figure 1. X-ray structure of cavitand 5 crystallized from CH2Cl2/
EtOH.
Density (calculated)
Absorption coefficient
F(000)
1.229 g/cm3
0.083 mm–1
1728
Crystal size
θ range for data collection
Index ranges
0.40×0.05×0.03 mm
1.40–27.53°
–19 Յ h Յ 20, –20 Յ k Յ 20,
–24 Յ l Յ 25
and separate signals are observed for each methylene and
for the terminal methyl group. The longer guests 9–11 stabi-
1
lize the C4v conformation of the cavitand: The H NMR
Reflections collected
Independent reflections
Completeness to θ
Absorption correction
Max./min. transmission
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I Ͼ 2σ(I)]
R indices (all data)
37008
spectra of the complexes are sharper than the free host’s
spectrum. The chemical shifts of each methylene and
methyl group were assigned by 2D-COSY experiments (see
Supporting information). These exposed some unusual fea-
tures. For example, the trimethylammonium groups (NMe3)
of 9–11 are deeply buried in the cavity and are subjected to
maximal upfield shifts with ∆δ up to –5.0 ppm. Not so with
the shortest compound 7. Here the methyl group of the
ethyl group is directed at the tapered end and shows the
furthest upfield shift. Also, the signal of the terminal CH3
group of the n-hexyl group of 11 appears at δ = –1.21 ppm,
19098 [R(int) = 0.0857]
θ = 27.53°; 93.9%
none
0.9975/0.9677
full-matrix least-squares on F2
19098/0/1099
1.134
R1 = 0.1552, wR2 = 0.2981
R1 = 0.2598, wR2 = 0.3345
0.709/–0.373 e·Å–3
Largest difference peak/hole
while the signals of the terminal methyl groups of the butyl guests is summarized as follows. The n-butyl compound 9
and pentyl compounds are found at δ = –2.26 ppm. This is the most straightforward to interpret and will be used as
difference in the chemical shift in the case of 11 places it a reference. The magnetic shielding provided by the aro-
almost out of the cavity, but where? The behavior of these matic rings of the hosts is greatest near the tapered bottom
3634
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 3633–3636

Extended Cavitands of Nanoscale Dimensions
SHORT COMMUNICATION
of the cavitand; it gradually decreases near the imidazole 11 are not quite as deep in the cavity as the shorter one 9.
region of the cavitand then increases at the top near the The signal for the terminal methyl group of 9 at δ =
four phenyl groups. This trend gives some predictability; the –2.2 ppm is also shifted (∆δ = –2.8 ppm) and places it in the
chemical shifts report the positions of the hydrogen atoms center of the deshielding regions of the four phenyl groups.
in the cavity (Figure 3). The trimethylammonium group, t Accordingly, the butyl group of 9 is in a maximally ex-
(∆δ = –5.0 ppm) is deepest, then the proximal methylene tended conformation.
group a [signal at δ = –1.2 ppm (∆δ = –4.5 ppm)]. Next
deepest is the b methylene group [signal found at δ =
–2.2 ppm (∆δ = –3.8 ppm)]. The sheer, tert-butyl-like bulk
of the trimethylammonium group insures that the confor-
mation around the a–b bond is trans-antiperiplanar; in this
extended conformation the signal of the hydrogen atoms at
the c position appears at δ = –1.5 ppm (∆δ = –2.7 ppm).
Modeling (Figure 3) places the c methylene group at about
the midpoint of the single bond that connects the phenyl
groups to the benzimidazole groups, i.e. in a magnetic envi-
ronment less shielded than positions below and, as we shall
soon see, above. The a, b, c and t signals of 9–11 are fairly
constant but a slight downfield drift is apparent with in-
creasing size. This indicates that the longer guests 10 and
Figure 3. Energy-minimized structures of the inclusion complex be-
tween cavitand 5 and n-alkylammonium guests 9–11 (MMFF force
field); one wall of the receptor has been removed for viewing clarity.
Gradient of the shielding effect inside cavitand 5 is shown.
We already mentioned that the very short compound 7
presents its ethyl group toward the bottom of the cavity
(note the positions of the trimethylammonium and terminal
methyl signals). The broadened spectrum of 8 speaks for
another dynamic process of intermediate rate on the NMR
timescale and that appears to be tumbling. For 8, it was not
possible to detect separate signals for each methylene group
and for the terminal methyl group, even though the 1H
NMR was recorded at 293 K. This is supported by the posi-
tion of the signals for b and c at δ Ϸ –2.1 ppm. The c signal
of 8 is considerably upfield of its counterparts, fixed in
space in complexes of 9, 10 and 11. Tumbling of these
longer alkyl salts is improbable, but they are expected to
rotate freely about the longitudinal axis of the cavitand. The
case of n-C5H11 (10) also appears fully extended although
its terminal methyl signal e appears at the same chemical
shift as that of the shorter but fully extended compound 9.
The downfield shift of signal d (∆δ = 0.6 ppm) is compar-
able to what happens outside the capsules for methyl vs.
methylene group. For the n-C6H13 group of 11 the terminal
methyl group f is in a minimally shielding environment. At
first glance, this would place it beyond the upper rim of
the cavitand, a position it could achieve in a fully extended
conformation. The signal for e has also moved downfield
(∆δ = 0.5 ppm) as before. A gauche interaction about the
d–e bond reconciles the chemical shifts and places the ter-
1
Figure 2. Up-field regions of the H NMR spectra at 600 MHz in
[D6]DMSO of encapsulated alkylammonium bromide salts at [5] =
2 m, [guest] = 10–15 m. Broad peaks close to signals t arise from
different arrangements of hydrogen bonds in cavitand 5, which
cause a slight modification of the shielding effect in the cavity.
Table 2. Data of the trimethylammonium salts included in cavitand 5.
Length
[Å]
Volume
PC[a]
Kass
ESI-TOF
[m/z]
[Å3]
[–1]
n-C2H5N(CH3)3Br (7)
n-C3H7N(CH3)3Br (8)
n-C4H9N(CH3)3Br (9)
n-C5H11N(CH3)3Br (10)
n-C6H13N(CH3)3Br (11)
5.6
6.8
8.1
9.4
10.6
106
122
140
153
172
0.35
0.41
0.46
0.51
0.57
90 30
110 50
370 50
550 50
230 80
[7@5-Br]+ = 1449.6 [7@5+H]+ = 1526.5
[8@5-Br]+ = 1463.6 [8@5+Na]+ = 1564.7
[9@5-Br]+ = 1477.6 [9@5+Na]+ = 1578.5
[10@5-Br]+ = 1491.6 [10@5+Na]+ = 1592.5
[11@5-Br]+ = 1505.6 [11@5+Na]+ = 1606.5
[a] PC: Packing coefficient.
Eur. J. Org. Chem. 2005, 3633–3636
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3635

E. Menozzi, H. Onagi, A. L. Rheingold, J. Rebek, Jr.
SHORT COMMUNICATION
minal methyl group between two adjacent phenyl groups
Supporting Information (see footnote on the first page of
rather than near the center of the cavitand. This is shown this article): Synthetic procedures and spectroscopic data of
on the right in Figure 3. cavitands 4–6; 2D NMR spectra of inclusion complexes;
The relative affinities of the guests were obtained from X-ray crystallographic data of the cavitand 4a (CCDC-
NMR titrations (Table 2) and a direct competition experi- 277575 contains the supplementary crystallographic data
ment between n-C5H11 (10) and n-C6H13 (11) shows the for- for this paper. These data can be obtained free of charge
mer to be the better guest (Figure 4). The difference in from The Cambridge Crystallographic Data Centre via
binding free energies is calculated to be ca. 0.5 kcal/mol, a www.ccdc.cam.ac.uk/data_request/cif).
value near the energetic cost of a single gauche interaction
(0.5–0.6 kcal/mol in the liquid phase).[8] As the C–H···π in-
Acknowledgments
teractions, the surface areas of 10 and 11, their packing
coefficients (PC)[9] and positioning also differ, this differ-
We are grateful to the Skaggs Institute and the National Institutes
of Health for financial support. E. M. and H. O. are Skaggs Post-
doctoral Fellows.
ence in energies is likely a coincidence.
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[2] D. J. Cram, H.-J. Choi, J. A. Bryant, C. B. Knobler, J. Am.
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[4] L. D. Corinne, C. L. D. Gibb, E. D. Stevens, B. C. Gibb, J. Am.
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[5] a) A. F. Far, A. Shivanyuk, J. Rebek, Jr., J. Am. Chem. Soc.
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Received: May 11, 2005
Figure 4. Competition experiment between guests n-pentyl/n-hexyl-
trimethylammonium bromide, 1H NMR ([D6]DMSO) and ESI-
TOF data are reported.
Extensive conformational changes involving coiling of
long alkyl chains in cavitands and capsules has been pre-
viously encountered.[10] In the cases at hand the gauche con-
formation is supported by 2D-NOESY experiment (see
Supporting information) that is consistent with the conclu-
sions regarding the positions of the guests in the cavitand.
What is unexpected concerns the variation of binding
modes in a seemingly simple homologous series: almost ev-
ery guest shows a unique interaction with the host. These
deeper, functionalizable cavitands promise increasing ca-
pacities for reactions between host and guest or even be-
tween two guests.
Published Online: July 20, 2005
3636
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 3633–3636