Dimeric nanocapsule induces conformational change

Article abstract of DOI:10.1039/b921911k

An induced cis-trans-trans (rctt) chair to cone structural rearrangement is forced by the addition of a pentacoordinate zinc(ii) complex, overcoming thermodynamic and kinetic factors to produce the first phenyl-substituted zinc dimeric nanocapsule.

Full text of DOI:10.1039/b921911k

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Dimeric nanocapsule induces conformational changew
Andrew K. Maerz, Haunani M. Thomas, Nicholas P. Power,z Carol A. Deakyne* and
Jerry L. Atwood*
Received (in Austin, TX, USA) 21st October 2009, Accepted 20th December 2009
First published as an Advance Article on the web 15th January 2010
DOI: 10.1039/b921911k
An induced cis–trans–trans (rctt) chair to cone structural
rearrangement is forced by the addition of a pentacoordinate
zinc(II) complex, overcoming thermodynamic and kinetic factors
to produce the first phenyl-substituted zinc dimeric nanocapsule.
arenes and aryl-substituted resorcin[4]arenes is often the thermo-
dynamically preferred all-cis (rccc) isomer in the crown
conformation, due to cooperative hydrogen bonding between
the hydroxyl groups of the aromatic rings.7 The kinetically
preferred cis–trans–trans (rctt) isomer has also been isolated in
good yield, especially when the insolubility of this isomer
prevents its interconversion to the rccc configuration. Control
of the stereoselectivity is still not well understood, but on the
basis of their analysis of alkyl and aryl resorcin[4]arenes, Cram
and co-workers8 have concluded that the R group is one of the
key factors in determining the preferred stereostructure.
Due to the lack of both conformational control and easy
self-assembly associated with the rctt isomer, it has attracted
less attention in sub-unit architectural design.9 Although
Castellano et al.10 have shown conformational control of
tetraurea calix[4]arene via intermolecular hydrogen bonding,
the possibility of inducing a conformational change during
self-assembly has otherwise largely been ignored. We report
herein new dimeric metal-seamed nanocapsules formed from
phenylpyrogallol[4]areney and derivativesz (Fig. 1) in a
rctt chair arrangement converting to a kinetically-locked rccc
bowl arrangement. The analysis of the 1H NMR spectra,8
fast HMQC NMR spectra, crystallographic structures, and
ab initio electronic structure calculations also suggests that the
rctt chair structure is now favored thermodynamically.
With inherent voids or cavities that allow for encapsulation of
a variety of unique guests, molecular capsules have numerous
applications ranging from catalysis and molecular-device
design to gas storage and pharmaceutical drug delivery.1
Currently, several research groups are pushing the limits of
supramolecular chemistry in an attempt to expand our know-
ledge of the effect of factors such as size, kinetic control, and
solubility on capsule formation.2 These factors, if balanced, give
rise to a simple synthetic procedure with limitless possibilities.
In the past, research groups have implemented sub-unit
architecture to allow for easy self-assembly. ‘‘Bowl shaped’’3
and flexible linear moieties comprise the majority of these
sub-units, which yield large nanocapsules based on hydrogen
bonding or metal coordination. Hemispherical alkyl-substituted
resorcin[4]arenes have led to, for example, the Atwood
hexameric sphere,4 whereas the Rebek tennis ball5 was syn-
thesized with flexible diphenylglycoluril and durene tetra-
bromide moieties.
Acid-catalyzed condensations of a phenol and an aldehyde
produce resorcin[4]arenes and pyrogallol[4]arenes in a variety
of diastereomers, rccc, rctt, rcct and rtct, depending on the
reaction conditions.6 Although the pyrogallol[4]arenes for
which R is an aryl group are relatively unexplored (Scheme 1),
the main stereoisomeric product for the alkyl-substituted
Computational studies were performed with the use of the
Gaussian 03 suite of programs11 to compare experimental,
solid-state results with gas-phase calculations. In the absence
of solvent, the B3LYP/6-31G(d) calculations indicate that the
lowest energy arrangement of phenylpyrogallol[4]arene is the
rccc cone. Although entropically more favorable, the rctt chair
conformers with C1 or Ci symmetry are considerably enthalpi-
cally less favorable than the cone conformer at this level of
theory (Table 1). The only difference between the former two
conformers is that in the Ci system the medial hydroxyl proton
on the two pyrogallol sub-units that form the ‘‘back’’ and
Scheme 1 Preparation of compounds 1–3 was achieved through
acid-catalyzed condensation reactions of equimolar concentrations
of aldehyde and pyrogallol.
Department of Chemistry, University of Missouri-Columbia, 601 S,
College Avenue, Columbia, MO 65211, USA.
E-mail: AtwoodJ@missouri.edu; Fax: +1 573 882 2754;
Tel: +1 573 882 8374; DeakyneC@missouri.edu; +1 573 882 1347
w CCDC 752684. For crystallographic data in CIF or other electronic
format see DOI: 10.1039/b921911k
Fig. 1 Schematic representation of [Zn8(C-phenylpyrogallol[4]arene)2-
(pyridine)8C(pyridine)]. Zn: aqua, O: red, N: blue, C: grey, H: white.
z Current Address: School of Chemistry, National University of
Ireland, Galway, University Road, Galway, Ireland.
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Table 1 Calculated relative enthalpies and free energies (kJ molꢁ1
for different conformations of C-phenylpyrogallol[4]arene
)
protons. Thus, intrinsic stability, packing effects and solvent
effects13 appear to control the overall stereostructure of these
macrocycles in the solid state.
B3LYPa
MP2b
1H NMR was utilized to study the alkyl- and aryl-
substituted pyrogallol[4]arenes in solution, looking specifically
at the methine protons. For the alkyl-substituted arenes a
singlet appears around 4 ppm, indicative of a uniform chemical
environment. Observed in the spectra for the aryl-substituted
arenes are four unique singlets, caused by distortion of the
macrocycle, grouped into two distinct regions at 6 and
5.75 ppm. Fast HMQC shows a correlation between the four
singlets and the bridging carbon. The groupings can be
explained by two bridging protons up and two down out of
the equatorial plane, confirming the presence of the (distorted)
rctt chair structure in solution.
DH
DG
1.1
2.6
45.3
DH
DG
PgPh (conformation)
Cone [C4]
1,2-Chair [C1]
1,2-Chair [Ci]
0
25.1
70.9
0
12.6
68.6
11.0
0
52.8
a
b
B3LYP/6-31G(d) optimized. MP2/6-31G(d,p)//B3LYP/6-31G(d)
single-point energy + B3LYP thermal correction terms.
‘‘legs’’ of the chair is rotated out-of-plane, disrupting the
intramolecular hydrogen-bonded network and destabilizing
the molecule by, surprisingly, 40 kJ molꢁ1 with respect
to the C1 system (Table 1). At the higher MP2/6-31G(d,p)//
B3LYP/6-31G(d) level of calculation, which accounts for
stabilizing p–p interactions, there is a change in relative free
energies and the rctt chair C1 structure is now preferred
(Table 1). Interestingly enough, the chair with Ci symmetry
is destabilized relative to the C1 form. However, that trend
could be reversed in the presence of solvent (see below), and
we are currently looking at how interaction with explicit
solvent molecules affects the relative stabilities of all of the
possible isomers.
Our work in all three phases (solid, solution and gas) points
to the rctt chair arrangement as the product of the acid-
catalyzed condensation reaction. Yet, when macrocycles 1–3
are mixed with a pentacoordinated zinc(II) complex, consisting
of two nitrate and three pyridine ligands in the axial and
equatorial positions, respectively, a dimerization reaction
occurs in which molecular capsules with an estimated internal
volume of 141 A3 are formed. Displaced metal ligands and
solvent molecules are encapsulated during closure, and the
disordered nature of the guests leads to two unique chemical
environments between the upper and lower hemispheres.14
Other metal–ligand derivatives of pyridine, such as 3-methyl-
pyridine and 4-ethylpyridine, have also successfully produced
zinc-seamed dimers. However, size limitations do apply
and must be taken into account when choosing the metal
coordination complex.
That the gas-phase computations suggest rctt chair phenyl-
pyrogallol[4]arene is the thermodynamically-favored product
of the acid-condensation reactions raises the question of which
structure is preferred by this arene and its derivatives in
solution and the solid state. To examine the effect of R-group
steric bulk on the preferred stereochemistry in the solid, a
variety of ligands was used in the macrocyclic synthesis, three
of which are given in Scheme 1. Benzene, naphthalene, and
various hydroxy, methoxy and nitro derivatives of benzene
provided a wide range of symmetric and asymmetric substitution.
In each case, the phenyl derivatives of pyrogallol[4]arene show
preference toward the rctt isomer. To test the thermodynamic
stability of the rctt configuration, the isolated product was
refluxed in DMSO for a period of five days and allowed to
recrystallize. Again, only the rctt configuration was observed.
One explanation for the observed results is that the rctt chair
arrangement allows for steric decongestion in the lower rim12
of the macrocycle while increasing its stabilization via p–p
interactions (Fig. 2).
Since X-ray quality crystals have proven difficult to acquire
other methods, such as NMR and MALDI-TOF MS, were
used to confirm the formation of the desired product. The
MALDI-TOF MS analysis reveals two major peaks, one
associated with occupied dimers, the other with unoccupied.
Dimeric capsules synthesized via macrocycle 3 give peaks at
3024.02 Da and 2946.9 Da. The calculated isotopic masses are
3023.1 Da and 2941.06 Da (Fig. 3).
In conclusion, we have shown through computation and
experiment that unlike aryl-substituted resorcin[4]arenes, for
aryl-substituted pyrogallol[4]arenes the chair conformation is
thermodynamically preferred in all three phases. Moreover,
metal insertion induces a chair-to-cone conformational change
to form zinc-seamed dimeric capsules. Further studies are
needed to understand the intricacies of interconversion and
Solvent interaction also plays a crucial role in the structure
of the rctt isomer. Oxygenated aprotic solvents such as
dimethyl sulfoxide and dimethylformamide are capable of hydro-
gen bonding motifs, and the crystal structures of the aryl-
substituted pyrogallol[4]arenes indicate that O–Hꢂ ꢂ ꢂO(solvent)
H-bonding causes directional flipping of one or more hydroxyl
Fig. 3 MALDI-TOF MS spectrum of ionized [Zn8(C-(3,4,5-trimethoxy-
phenyl)pyrogallol[4]arene)2(3-methylpyridine)8C(3-methylpyridine)] using
a dithranol matrix.
Fig. 2 Crystal structure of 1 viewed along the c-axis (side view).
Hydrogens omitted for clarity.
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dimeric nanocapsule formation. However, overcoming thermo-
dynamics to induce a conformational change opens the
door to new, diverse groups of capsules that allow for easy
functionalization.
extraction, 1000–4000 Da mass range, with low mass filter gate on at
1000 Da. Laser intensity was set to 1708 at 250 shots per acquisition,
with the laser randomly positioned per acquisition. Summation of
1500 laser shots was used to acquire better resolution and signal-to-
noise ratios, resulting in two separate peaks at 2496.9 and 3204.02 Da
associated with unoccupied and occupied species, respectively.
The calculated isotopic distributions are 2941.6 and 3023.1 Da,
respectively, and coincide with the experimental values t taking
into account the loss of the 8 pyridine ligands from the ionization
process.
This research would not have been possible without the
continued support of the National Science Foundation. A
special thanks to Dr Brian Mooney for MALDI-TOF MS
analyses, performed at the Charles W. Gehrke Proteomics
Centre at UMC, and to Dr Charles Barnes for determination
of crystallographic structures.
8 NMR spectra for characterization were collected on a Bruker
AXR300 and AXR500 (300 MHz and 500 MHz). MALDI-TOF MS
was acquired on an ABI Voyager DE-PRO. Crystallographic data
were acquired with a Bruker SMART 1000 CCD diffractometer.
Notes and references
1 (a) J. L. Atwood, L. J. Barbour and A. Jerga, J. Supramol. Chem.,
2001, 1, 131; (b) J. Rebek, Jr., Acc. Chem. Res., 1999, 32, 278.
2 (a) B. Schnatwinkel, I. Stoll, A. Mix, M. V. Rekharsky,
V. V. Borokov, Y. Inoue and J. Mattay, Chem. Commun., 2008,
3873; (b) S. J. Dalgarno, N. P. Power and J. L. Atwood, Coord.
Chem. Rev., 2008, 252, 825.
y C-Phenylpyrogallol[4]arene: synthesis was readily achieved following
previous methods.15 Benzaldehyde (2.083 mL, 18.8 mmol) and
pyrogallol (2.38 g, 18.8 mmol) were simply added to a flask filled with
40 mL ethanol. The solution was allowed to stir at room temperature
for 30 min. 2 mL conc. HCl were then added. The mixture was refluxed
at 78 1C for 24 h. The solution was then filtered using a cold methanol
wash yielding a white precipitate. Recrystallization in DMSO yielded
suitable X-ray crystals. Yield: 3.27 g, 80.9%. 1H NMR (300 MHz,
DMSO-d6, shifts relative to DMSO): d = 7.70 (12H, m), 6.80
(20H, m), 6.48 (1H, s), 6.19 (1H, s), 6.02 (1H, s), 5.99 (1H, s) 5.78
(1H, s), 5.72 (1H, s), 5.66 (1H, s), 5.19 (1H, s). Crystallographic data:
C72H100O22S10, M = 1091.28 g molꢁ1, r = 0.8892 g cmꢁ3, a =
11.6125(2), b = 11.8904(2), c = 16.1797(3) A, a = 80.962(1)1, b =
74.912(1)1, g = 71.909(1)1, U = 2043.31(6) A3, triclinic, space group
3 R. M. McKinlay, G. W. V. Cave and J. L. Atwood, Proc. Natl.
Acad. Sci. U. S. A., 2005, 102, 5944.
4 L. R. MacGillivray and J. L. Atwood, Nature, 1997, 389, 469.
5 (a) R. Wyler, J. de Mendoza and J. Rebek, Jr., Angew. Chem., Int.
Ed. Engl., 1993, 32, 1699; (b) J. W. Steed and J. L. Atwood,
Supramolecular Chemistry, New York, Wiley and Sons, 2000,
pp. 497–507.
6 (a) O. Middel, W. Verboom, R. Hulst, H. Kooijman, A. L. Spek and
D. Reinhoudt, J. Org. Chem., 1998, 63, 8259; (b) A. V. Prosvirkin,
E. Kh. Kazakova, A. T. Gubaidullin, I. A. Litvinov, M. Gruner,
W. D. Habicher and A. I. Konovalov, Russ. Chem. Bull., Int. Ed.,
2005, 54, 2550; (c) S. Miao, R. D. Adams, D. Guo and Q. Zhang,
J. Mol. Struct., 2003, 659, 119.
7 O. Morikawa, E. Iyama, T. Oikawa, K. Kobayashi and
H. Konishi, J. Phys. Org. Chem., 2006, 19, 214.
8 L. M. Tunstad, J. A. Tucker, E. Dalcanale, J. Weiser, J. A. Bryant,
J. C. Sherman, R. C. Helgeson, C. B. Knobler and D. J. Cram,
J. Org. Chem., 1989, 54, 1305.
ꢀ
P1, Z = 1, l(Mo) = 71 073 A, T = 173 K, 12 549 reflections, 8205
unique R1 = 0.1109, wR2 = 0.3908 (all data), Rint = 0.0258, GOF =
1.492 CCDC 752684. Full optimization of crystallographic structures
as well as other plausible geometries was done at the B3LYP/6-31G(d)
level of theory. Cone, chair, 1,2-alternate, boat, and saddle confor-
mations of the macrocyclic ring, as well as the all-cis, cis–cis–trans,
cis–trans–trans and trans–cis–cis configurations of the R-groups, were
examined. Harmonic vibrational frequencies were also obtained at the
B3LYP/6-31G(d) level to determine whether a structure is a minimum
or transition state and to evaluate the thermal correction terms. Single-
point MP2 energies were computed with the 6-31G(d,p) basis set. The
Gaussian 03 program package11 was used for all calculations.
z [Zn8(C-Phenylpyrogallol[4]arene)2(3-methylpyridine)8C(3-methyl-
pyridine)]: C-phenylpyrogallol[4]arene (100 mg, 116 mmol) was added
to a flask with [ZnII(NO3)2pyridine3ꢂ6H2O] (200 mg, 464 mmol) and
5 mL 3 : 1 methanol–acetonitrile solution. The precipitate was then
filtered and dried under vacuum. Yield: 0.130 g, 78%. 1H NMR
(300 MHz, DMSO-d6, shifts relative to DMSO): d = 17.41 (4H, m),
16.97 (4H, m), 8.21 (16H, s), 7.45 (16H, s), 7.31 (8H, s), 7.02 (40H, m),
6.06 (2H, m, CPyr), 5.71 (2H, m, CPyr), 5.03 (1H, m, CPyr), 4.50
(8H, s), ꢁ1.91 and ꢁ1.92 ppm (2ꢂs, CMeOH). MALDI-TOF MS
analysis: spectra were collected on a Voyager DE-PRO. MALDI
sample preparation consisted of co-crystallization of product with
dithranol (10 mg mLꢁ1 in MeOH). All analyses were carried out on a
100 well gold plate. The Voyager DE-PRO was operated in positive
ion reflector mode running at 20 kV acceleration, 150 ns delayed
9 G. Rumboldt, V. Bohmer, B. Botta and E. F. Paulus, J. Org.
¨
Chem., 1998, 63, 9618.
10 R. K. Castellano, D. M. Rudkevich and J. Rebek, Jr., J. Am.
Chem. Soc., 1996, 118, 10002.
11 Gaussian reference: M. J. Frisch, et al. and J. A. Pople, GAUSSIAN
03, Revision C.02, Gaussian, Inc., Wallingford, CT, 2004.
12 Crystallographic images were produced by a combination of
mercury 2.2 as well as XSeed version 2 created by L. J. Barbour,
University of Missouri-Columbia, Columbia, MO, USA, http://
www.x-seed.net.html.
13 C. Schiel, G. A. Hembury, V. V. Borovkov, M. Klaes, C. Agena,
T. Wada, S. Grimme, Y. Inoue and J. Mattay, J. Org. Chem., 2006,
71, 976.
14 N. P. Power, S. J. Dalgarno and J. L. Atwood, Angew. Chem., Int.
Ed., 2007, 46, 8601.
15 N. P. Power, S. J. Dalgarno and J. L. Atwood, New J. Chem., 2007,
31, 17.
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