Multiple hindered rotators in a gyroscope-inspired tribenzylamine hemicryptophane

Article abstract of DOI:10.1021/jo102480s

A gyroscope-inspired tribenzylamine hemicryptophane provides a vehicle for exploring the structure and properties of multiple p-phenylene rotators within one molecule. The hemicryptophane was synthesized in three steps in good overall yield using mild con

Full text of DOI:10.1021/jo102480s

pubs.acs.org/joc
Multiple Hindered Rotators in a Gyroscope-Inspired
Tribenzylamine Hemicryptophane
Najat S. Khan,† Jose Manuel Perez-Aguilar,† Tara Kaufmann, P. Aru Hill, Olena Taratula,
One-Sun Lee, Patrick J. Carroll, Jeffery G. Saven,* and Ivan J. Dmochowski*
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104. †These authors
contributed equally to this work.
ivandmo@sas.upenn.edu; saven@sas.upenn.edu
Received December 15, 2010
A gyroscope-inspired tribenzylamine hemicryptophane provides a vehicle for exploring the structure
and properties of multiple p-phenylene rotators within one molecule. The hemicryptophane was
synthesized in three steps in good overall yield using mild conditions. Three rotator-forming linkers
were cyclized to form a rigid cyclotriveratrylene (CTV) stator framework, which was then closed with
an amine. The gyroscope-like molecule was characterized by 1H NMR and 13C NMR spectroscopy,
and the structure was solved by X-ray crystallography. The rigidity of the two-component CTV-
1
trismethylamine stator was investigated by H variable-temperature (VT) NMR experiments and
molecular dynamics simulations. These techniques identified gyration of the three p-phenylene
rotators on the millisecond time scale at -93 °C, with more dynamic but still hindered motion at
room temperature (27 °C). The activation energy for the p-phenylene rotation was determined to be
∼10 kcal mol-1. Due to the propeller arrangement of the p-phenylenes, their rotation is hindered but
not strongly correlated. The compact size, simple synthetic route, and molecular motions of this
gyroscope-inspired tribenzylamine hemicryptophane make it an attractive starting point for con-
trolling the direction and coupling of rotators within molecular systems.
Introduction
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Published on Web 01/27/2011
DOI: 10.1021/jo102480s
r
2011 American Chemical Society

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JOCArticle
SCHEME 1. Gyroscope-Inspired Tribenzylamine Hemicrypto-
phane (5) Possessing a Rigid Stator (a and c) and Three Rotator
Groups (b)a
microporous polymers.32 In the current design, a single
CTV unit provides a rigid hemicryptophane framework for
the synthesis of a novel gyroscope-inspired molecule. Our
design incorporates a novel combination of features: (i) an
efficient, high-yielding synthetic scheme, (ii) multiple, prox-
imate rotators in one covalently bonded molecular system,
(iii) exclusion of other molecules and ions from the stator
interior that may impede rotator motion, and (iv) hindered
rotators experiencing friction through exposure to solvent.
Gyroscope-inspired molecular systems have focused
largely on approaching barrierless rotation of isolated or
sequestered rotors. One of the first examples (also referred to
as a molecular turnstile) was synthesized by Moore and
Bedard.33,34 The creative design included a rigid hexakis-
(phenylacetylene) framework that preserved the low barrier
of rotation about the 1,4-axis of the substituted p-phenylene
moiety. Garcia-Garibay and co-workers extended these ideas
in the construction of amphidynamic crystals,11,15,35-54 where
the introduction of bulky substituents creates sufficient space in
the lattice framework to allow near-barrierless rotation of the
central p-phenylene group. Furthermore, the p-phenylene moi-
ety can be functionalized to create a dipole moment that could
be used for controlling motion with an external electric fi-
eld.11,36-38,42 Following a different approach, Gladysz and
co-workers prepared a series of metal-centered molecular
gyroscopes in which the rotator is protected by three-spoke
structures as part of the stator. The rotational dynamics of these
gyroscopes were studied in solution, and their crystal structures
indicated sufficient free volume around the rotator to allow
aArrows illustrate rotation but are not intended to suggest unidi-
rectionality.
of freedom, while allowing the specific motions of targeted
molecular components.9 Although synthesis of such mole-
cules can also be challenging, criteria for the construction of
molecular gyroscopes have been identified and generally
applied: rotary elements (rotators) are attached to a static
framework (stator); steric contacts, internal rotation barriers,
and interaction with solvent should be minimized to allow
low-friction, low-barrier rotary motion; rotating groups are
isolated and/or well-separated from each other. To expand
upon these criteria, we designed a gyroscope-inspired frame-
work with cyclotriveratrylene (CTV) and trismethylamine as
the two-component stator, bridged by three p-phenylene
rotators (Scheme 1). Previously, two opposing CTV units
have been linked to generate cryptophanes with suitable
cavities for host-guest chemistry, as well as useful biosensing
and chiroptical properties.16-31 CTV has also been em-
ployed in supramolecular assemblies, gels, and organic
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SCHEME 2. Three-Step Synthesis of Gyroscope-Inspired Tri-
benzylamine Hemicryptophane 5
troscopy, high-resolution mass spectrometry (using the elec-
trospray ionization method), and X-ray crystallography. This
short synthetic scheme utilizes mild conditions and results in
high overall yields. Moreover, this route provides ample
versatility by increasing the number of methylene spacer
units or introducing new functional groups on 3 to form
rotators with different conformations, rotation barriers, and
dipole moments.
The X-ray crystal structure of 5 indicates the three rotators
adopt a propeller conformation (Figure 1). 5 crystallizes in
the monoclinic space group P21/c, and each unit cell consists
of four molecules with two of each enantiomer (Figure 1;
Figure S1, Supporting Information). In both enantiomers
the p-phenylene rotators are oriented edgewise into the
interior (angled away from the methoxy group ortho to them)
with an average dihedral angle of ∼88.1° for
O-Cbenzylic-Cphenyl-Cphenyl, ∼ -68.6° for N-Cbenzylic
-
-
Cphenyl-Cinterior-phenyl
,
and ∼107.5° for N-Cbenzylic
Cphenyl-Cexterior-phenyl (see Figure 1c). The minimal distance
from the phenylic proton on C44 (pointing into the cage) to
the plane described by the next aryl ring (C10-C15) is
˚
relatively small at 3.22 A. After the van der Waals radii for
low-barrier rotation.9,55-59 Most recently, Kitagawa et al.
designed a self-assembled supramolecular gyroscope where
the stator is a heterocapsule formed by noncovalent interac-
tions and the rotator is an encapsulated guest.60
hydrogen and carbon are included,61 the “clearance” dis-
˚
tance is approximately 0.32 A. The distance from the same
˚
proton to the nitrogen atom was even shorter at 2.97 A, with
˚
a clearance distance of 0.22 A when van der Waals radii are
Herein, we report a streamlined synthesis of a gyroscope-
inspired tribenzylamine hemicryptophane (5; Scheme 2)
involving multiple hindered rotators, where fast rotation is
included, as the nitrogen is oriented into the interior with an
average C-N-C bond angle of 114.42° (see Figure 1c). This
propeller-shaped conformation with a pyramidal nitrogen
atom where the lone pair is pointed into the cage is similar to
the crystal structure of tribenzylamine, where the rigid CTV
is not present.62 It is believed that this conformation is
primarily favored due to steric hindrance.62 Despite the
propeller conformation of the rotators and the positioning
of the nitrogen atom into the interior of the cage, rotator
motion is expected, given the observed clearance distances
(Figure 1).
1
observed by H NMR spectroscopy above a critical tem-
perature. Rotations about the 1,4-axis of the three p-pheny-
lene rotators encased in a rigid CTV-trismethylamine stator
were investigated using 1H variable-temperature (VT) NMR
spectroscopy and molecular dynamics (MD) simulations.
Results and Discussion
Synthesis and X-ray Crystal Structure of Hemicryptophane
5. In order to synthesize the gyroscope-inspired tribenzyl-
amine hemicrytophane 5, the linkers (including the rotators)
were first cyclized in the rigid CTV framework and then closed
with an amine to form the final three-dimensional structure
(Scheme 2). Reaction of commercially available vanillyl
alcohol 1 and dibromo-p-xylene 2 gave the versatile linker
3 in 65% yield. Cyclization of 3 was achieved with a catalytic
amount of Sc(OTf)3 in acetonitrile to afford the “gyroscope
scaffold intermediate” 4 in 29% yield. This reaction was
based on previous protocols where various 3,4-disubstituted
benzyl alcohols were treated with catalytic Sc(OTf)3 to
prepare CTV and cryptophane derivatives.18 Compound 4
was reacted with 7 N NH3 in MeOH to give 5 in 67% yield,
with an overall yield of 13% for the three steps. Compound 5
was characterized by solution 1H NMR and 13C NMR spec-
Unlike some previously reported porous gyroscopes,58
which encountered barriers to rotation due to the intercala-
tion of solvent molecules (or neighboring molecules in solid
state), the small internal volume in 5 should prevent guest
encapsulation. Indeed, X-ray crystallography indicated an
empty tribenzylamine hemicryptophane, lacking solvent
molecules. Small molecules such as helium, dihydrogen,
dinitrogen, and xenon were not observed to bind to 5 at
1 atm over a range of temperatures, þ47 to -93 °C (see the
Supporting Information for experimental details). Molecu-
lar dynamics simulations were also in agreement with the
experimental findings and suggest that these small molecular
species should be excluded from the interior (Figure S2,
Supporting Information). Computational modeling was
used to explore effects due to rotation of the p-phenylene
rotators. GRASP63 was employed in order to investigate
whether a potential interior cavity within 5 emerges with
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˚
rotation of the rotators. With a probe radius of 1.4 A, only in
,
improbable, high-energy structures (ΔE > 30 kcal mol-1
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Chem. 2008, 47, 3474–3476.
(58) Wang, L.; Hampel, F.; Gladysz, J. A. Angew. Chem., Int. Ed. 2006,
45, 4372–4375.
where ΔE is the energy relative to the X-ray structure) where
the angle of each p-phenylene rotator increased by 90° relative
(59) Wang, L.; Shima, T.; Hampel, F.; Gladysz, J. A. Chem. Commun.
2006, 4075–4077.
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Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 10444–10448.
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FIGURE 1. (a) ORTEP representations for 5 with atom labels. Hydrogen atoms are omitted for clarity. (b) Space-filling side and bottom view
˚
of 5. Atom color code: C is gray, O is red, N is blue, and H is white. (c) Selected bond lengths (A), angles (deg), and dihedral angles (deg) of
compound 5.
these doublets became broader and the energy barrier for p-
phenylene rotation was estimated from eqs 1 and 264 (see the
Experimental Procedures) to be 9.2 kcal mol-1 from the
coalescence temperature (ca. -70 °C; kcoalesce ∼ 2300 Hz). As
the temperature was further reduced to -93 °C, a new pair of
doublets of equal intensity (three protons each) arose for
each doublet that coalesced. This led to splitting of the
doublet for H2 and H5 and also H3 and H4, where H2 and
H3 shift upfield as they are pointed into the cavity while H4
and H5 are oriented away from the cavity. The H3-H5
splitting pattern (Figure 2b) shows that p-phenylene rotation
at -93 °C is slow on the NMR time scale, trot > 3 ms. Similar
temperature-dependent behavior was recently reported for a
2,3-dichlorophenylene rotator caged within a polysilaalkane
stator.65 In line with our design, the stator remained rigid
throughout the 1H VT-NMR data set, as indicated by the fact
that the integration and splitting pattern of all CTV-trismethyl-
amine proton peaks were constant. It is also interesting to note
FIGURE 2. (a) Schematic model of the molecular motion of 5. (b)
that protons HA1 and HA2 remained diastereotopic through-
1H VT-NMR spectra of 5 measured in CD2Cl2 with a 500 MHz
out the 1H VT-NMR series (Figure 2b). All peaks were assigned
spectrometer.
by 1H-1H NOESY experiments (Figure 3).
Molecular Dynamics Simulations. To investigate the con-
to the crystal structure was a cavity identified (Figure S3,
Supporting Information). This suggests that a cavity of suffi-
cient volume to accommodate small guest molecules is esse-
ntially nonexistent, thereby preventing the inclusion of small
molecules that may hinder p-phenylene rotation.
formational fluctuations of the rotators and stator, MD sim-
ulations were carried out on 5 (Figure 4). One of the crystal
structures was used as the initial structure, and the length of
the simulations was 50 ns. Equilibration was confirmed by
monitoring relaxation of structural parameters (Figure S4,
Supporting Information). Three dihedral angles that reflect
the conformations of the rotators were selected: (Rꢀ N1-
C16-C13-C14, β ꢀ N1-C32-C29-C30, and γ ꢀ N1-
C48-C45-C44). The symmetry of the structure yields nearly
identical average values of these angles that are in agreement
with the values observed in the crystal structure: R=-72.3 (
10°, β=-71.8 ( 10°, and γ=-72.8 ( 10°; the uncertainties
1H VT-NMR Experiments with Hemicryptophane 5. In
order to investigate the energy barrier of the rotators in
solution phase, we performed a 1H VT-NMR study of 5 in
CD2Cl2 from -93 to þ27 °C. The NMR spectra in Figure 2
indicate that the rotational rate of the p-phenylene rotators
became slow on the NMR time scale as the temperature was
decreased. At 27 °C, the four protons (labeled H2, H3, H4,
and H5 in Figure 2a) on each of the three rotators were split
into two doublets at 6.1 ppm (average signal from H2 and H4)
and 6.9 ppm (average signal from H3 and H5). Upon cooling,
(64) Sandstrom, J. Dynamic NMR Spectroscopy; Academic Press: New
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FIGURE 5. Minimized energy as a function of ΔR, which is rota-
tion of the R dihedral angle relative to the energy-minimized X-ray
structure (gray). The crystal structure of 5 was minimized, and the
angle R was varied in 10° increments, driving rotation of the R ring
(magenta). For each value of ΔR, the structure was energy mini-
mized, constraining the coordinates of all atoms but those in the two
remaining p-phenylene rotators: β ring (cyan) and γ ring (yellow).
For clarity, the CTV moiety and hydrogens are not shown; two
carbons of the R ring are rendered in black.
FIGURE 3. 1H-1H NOESY spectrum of 5 in CDCl3 at 27 °C
measured with a 500 MHz spectrometer to determine the assign-
ment of protons.
experiments (∼10 kcal mol-1). The modeling results suggest
that, although not entirely independent, the rotations of the
R and γ rings are only weakly coupled.
Conclusions
In summary, the novel gyroscope-inspired tribenzylamine
hemicryptophane 5 was synthesized in three steps in good
overall yield using mild conditions. This synthetic route
offers the possibility of preparing hemicryptophanes with
multiple, proximate rotators, where the molecular properties
of the rotators can be varied by changing the length and
composition of the linkers used to cyclize the “gyroscope
scaffold intermediate” 4. The compact size of the cavity in
this system helps to avoid the inclusion of solvent and
gaseous molecules that have the potential to inhibit rotation.
1H VT-NMR data indicate a critical temperature for the onset
of rotation on the submillisecond time scale and a hindered,
dynamic motion of these three rotators at room temperature.
The desired rigidity of the CTV stator and the rotator prop-
erties of the p-phenylenes were corroborated by 1H VT-
NMR spectroscopy and MD simulations. As a p-phenylene
ring rotates, it encounters one of the neighboring p-pheny-
lenes, leading to a steric barrier that hinders rotation. Rota-
tions of the rings appear not to be strongly correlated with
one another.
The compact size and molecular motions of 5 make it a
compelling initial motif from which to engineer unidirec-
tional, potentially coupled rotators for molecular locomo-
tion or transmission of torque. Toward this goal, it may be
possible to introduce sterically bulky substituents on the
linkers to control the temperatures at which rotation be-
comes accessible and to favor one direction of rotation.
Different substituent groups can also be introduced to create
a dipole moment on the rotators, thereby allowing the use of
electric fields to explore rapid conformational response in
these systems and to control the direction of rotation.
FIGURE 4. Orthogonal views of 30 superimposed structures from
the MD simulation of 5. The dihedral angles are indicated: R
(magenta), β (cyan), and γ (yellow).
(fluctuations) are one standard deviation (Figure S5, Sup-
porting Information). The MD simulations at 25 °C indi-
cated limited fluctuations within the structure on the nano-
second time scale (Figure 4), and the CTV unit that forms the
stator remains highly rigid, in agreement with the NMR
results noted above. The p-phenylene units are not observed
to rotate and instead librate in a manner consistent with a
hindered rotor that rotates on a time scale>100 ns. There-
fore, simulations, X-ray, and NMR structural data all agree that
the propeller-shaped conformation is highly favored in 5. High
temperatures were artificially employed to observe rotation in
the simulations: at 527 °C, rotations of the three p-phenylenes
are frequent, conformations where the rotators are directed
edgewise into the interior (similar to what is seen in the crystal
structure) are preferentially populated, and no preferred rota-
tional direction in the three p-phenylenes is observed.
To investigate further the p-phenylene rotation and inter-
actions among the rotators, the crystal structure of 5 was
minimized, and the dihedral angle R was systematically
varied (Figure 5). The structure was then relaxed via energy
minimization, constraining the coordinates of all atoms but
those in the two remaining β and γ p-phenylene rings. The β
ring is essentially invariant during the rotation. The γ ring
only rotates at most 19.7° to accommodate the 180° rotation
of the R ring. An energy barrier arises due to this interaction
between the R ring and γ ring. Interestingly, the rotational
energy barrier estimated from this simplistic and highly
constrained calculation (∼12 kcal mol-1) is consistent with
the experimental value inferred from the 1H VT-NMR
Experimental Procedures
Reagents. All reactions were carried out in oven-dried
glassware under an atmosphere of dry nitrogen. Column
1422 J. Org. Chem. Vol. 76, No. 5, 2011

Khan et al.
JOCArticle
˚
chromatography was performed using 60 A porosity, 40-75 μm
particle size silica gel from Sorbent Technologies. Thin-layer
chromatography (TLC) was performed using silica gel plates
with UV light at 254 nm for detection. 1H NMR (360 and
500 MHz) and 13C NMR (125 MHz) spectra were acquired on
Bruker DMX 360 and AMX 500 spectrometers. Electrospray
ionization (ESI) mass spectrometry was performed in high-
resolution mode on a Micromass Autospec instrument. All
reagents were commercially available and used without
further purification, unless otherwise stated.
evaporated under reduced pressure. The crude material was
purified by silica gel column chromatography (50/50 CH2Cl2/
hexanesf50/40/10 CH2Cl2/hexanes/EtOAcf 60/30/10 CH2Cl2/
hexanes/EtOAc; all with 1% TEA) to give 5 as a white powder
(0.0206 g, 67%): mp >250 °C dec; 1H NMR (360 MHz, CDCl3,
25 °C) δ 7.34 (s, 3H), 6.96-6.93 (m, 9H), 6.18 (d, 6H, J =7.9 Hz),
5.41 (d, 3H, J=12.1 Hz), 5.06 (d, 3H, J=12.2 Hz), 4.83 (d, 3H, J=
13.7 Hz), 3.60 (d, 3H, J=13.8 Hz), 3.58 (s, 9H), 3.54 (d, 3H, J=
13.2 Hz), 3.41 (d, 3H, J=13.2 Hz); 13C NMR (125 MHz, CDCl3,
25 °C) δ 147.7, 143.0, 140.3, 132.9, 131.7, 130.8, 128.4, 127.4, 117.9,
113.9, 68.8, 55.5, 55.3, 34.9; HRMS (ESI) m/z calcd for
C48H45NO6 (M þ Hþ) 732.3326, found 732.3340.
[4-((4-(Bromomethyl)benzyl)oxy)-3-methoxyphenyl]methanol
(3). A mixture of vanillyl alcohol (1; 2.5091 g, 16.276 mmol, 1.0
equiv), dibromo-p-xylene (2; 6.4033 g, 24.259 mmol, 1.5 equiv),
and K2CO3 (2.2511 g, 16.288 mmol, 1.0 equiv) dissolved in acet-
one (24.0 mL, 0.786 g/mL, 18.9 g) was heated at 70 °C overnight
with stirring. The reaction solvent was removed by rotary evapora-
tion. The resulting residue was rinsed in a separatory funnel with a
1:1 mixture of H2O (60 mL) and CH2Cl2 (60 mL). The phases
were separated, and the aqueous layer was extracted three times
with CH2Cl2 (100 mL). The combined organic layer was washed
once with 1 M NaOH (100 mL) and once with saturated NaCl
(100 mL). The organic layer was dried over MgSO4, filtered, and
evaporated under reduced pressure. The crude material was pur-
ified by silica gel column chromatography (5/95 acetone/
CH2Cl2 f 20/80 acetone/CH2Cl2) to give 3 as a white powder
Crystal Growth and X-ray Crystallography. Compound 5 was
crystallized by vapor diffusion of diethyl ether or n-pentane into
toluene. It crystallizes in the monoclinic space group P21/c
(systematic absences 0k0, k=odd and h0l, l = odd) with a =
˚
˚
˚
17.098(2) A, b=11.4592(9) A, c=21.096(2) A, β=113.539(2)°,
V = 3789.3(6) A , Z=4, and dcalcd=1.283 g/cm3. X-ray intensity
3
˚
data were collected on a Rigaku Mercury CCD area detector
employing graphite-monochromated Mo KR radiation (λ =
˚
0.71073 A) at a temperature of -130 °C. Preliminary indexing
was performed from a series of twelve 0.5° rotation images with
exposures of 30 s. A total of 336 rotation images were collected
with a crystal to detector distance of 35 mm, a 2θ swing angle
of -12°, rotation widths of 0.5°, and exposures of 10 s: scan
1 was a φ scan from 170 to 338° at ω=0° and χ=0°. Rotation
images were processed using CrystalClear,67 producing a listing
of unaveraged F2 and σ(F2) values which were then passed to the
CrystalStructure68 program package for further processing and
structure solution on a Dell Pentium III computer. A total of
15 571 reflections were measured over the ranges 5.20° e 2θ e
50.02°, -16e h e20,-13e k e12, and -23 e l e 25, yielding
6 601 unique reflections (Rint=0.0261). The intensity data were
corrected for Lorentz and polarization effects and for absorp-
tion using REQAB69 (minimum and maximum transmission
0.853, 1.000).
1
(3.5422 g, 65%): mp 86-88 °C; H NMR (500 MHz, CDCl3,
25 °C) δ 7.42-7.38 (m, 4H), 6.96 (s, 1H), 6.85-6.81 (m, 2H),
5.14 (s, 2H), 4.60 (s, 2H), 4.49 (s, 2H), 3.89 (s, 3H), 1.86 (s, 1H);
13C NMR (125 MHz, CDCl3, 25 °C) δ 149.9, 147.6, 137.6, 137.5,
134.5, 129.4, 127.7, 119.4, 114.1, 111.1, 70.8, 65.4, 56.1, 33.36;
HRMS (ESI) m/z calcd for C16H17BrO3 (MþNaþ) 359.0259,
found 359.0239.
2,7,12-Tris((4-(bromomethyl)benzyl)oxy)-3,8,13-trimethoxy-
10,15-dihydro-5H-tribenzo[a,d,g]cyclononene (4). A mixture of 3
(2.0232 g, 6.0210 mmol, 1.0 equiv) and Sc(OTf)3 (0.0295 g,
0.0599 mmol, 0.01 equiv) dissolved in MeCN (5.9 mL, 0.786 g/mL,
4.7 g) was heated at 65 °C overnight with stirring. The reac-
tion solvent was removed by rotary evaporation. The resulting
residue was extracted twice with CH2Cl2 (150 mL) and washed
three times with saturated NaCl (150 mL). The organic layer was
dried over anhydrous MgSO4, filtered, and evaporated under
reduced pressure. The crude material was purified by silica gel
column chromatography (CH2Cl2 f 2/98 THF/CH2Cl2) to give
4 as a white powder (0.5571 g, 29%): mp 91-93 °C; 1H NMR
(360 MHz, CDCl3, 25 °C) δ 7.39-7.37 (m, 12H), 6.85 (s, 3H),
6.72 (s, 3H), 5.09 (s, 6H), 4.73 (d, 3H, J=13.7 Hz), 4.50 (s, 6H),
3.76 (s, 9H), 3.50 (d, 3H, J = 13.8 Hz); 13C NMR (125 Hz,
CDCl3, 25 °C) δ 148.6, 147.2, 137.9, 137.5, 132.9, 131.9, 129.4,
127.6, 116.4, 114.0, 71.4, 56.4, 36.6, 33.3; HRMS (ESI) m/z calcd
for C48H45Br3O6 (Mþ) 954.0766, found 954.0724. The NMR
spectra matched the reported literature data.66
Tribenzylamine Hemicryptophane (5). A mixture of 4 (0.0406
g, 0.0426 mmol, 1.0 equiv) and K2CO3 (0.0869 g, 0.629 mmol,
15.0 equiv) dissolved in MeCN (58 mL, 0.786 g/mL, 46 g) was
heated at 90 °C with stirring as 7 N NH3 in MeOH (0.0711 mL of
7 N NH3, 0.5 mmol, ∼12 equiv, in 4.7 mL of MeCN) was added
by a syringe pump over 8 h. The reaction solvent was removed
by rotary evaporation. The resulting residue was extracted with
CH2Cl2 and transferred to a separatory funnel. The organic
layer was washed once with a 1/1 mixture of H2O (50 mL) and
1 M NaOH (50 mL) and then with 1 M NaOH (50 mL). The aqu-
eous layer was extracted with CH2Cl2 (50 mL), and the com-
bined organic layer was washed with saturated NaCl (50 mL). The
organic layer was dried over anhydrous MgSO4, filtered, and
The structure was solved by direct methods (SIR97).70 Re-
finement was by full-matrix least squares based on F2 using
SHELXL-97.71 All reflections were used during refinement (F2
values that were experimentally negative were replaced by F2=
0). The weighting scheme used was w=1/[σ2(Fo2)þ 0.0547P2 þ
2
2
0.9350P] where P=(Fo þ 2Fc )/3. Non-hydrogen atoms were
refined anisotropically, and hydrogen atoms were refined using
a “riding” model. Refinement converged to R1 = 0.0479 and
wR2=0.1107 for 5502 reflections for which F > 4σ(F) and R1=
0.0599, wR2 =0.1204, and GOF=1.078 for all 6 601 unique,
P
P
nonzero reflections and 500 variables (R1= ||Fo| - |Fc||/
|
-
P
P
P
2 2
2
Fo2|;2wR2={ w(Fo2 - Fc ) / w(Fo2)2}1/2 ; GOF =
{
w(Fo
Fc ) /(n - p)}1/2 where n=the number of reflections and p=the
number of parameters refined). The maximum Δ/σ in the final
cycle of least squares was 0.001, and the two most prominent
3
˚
peaks in the final difference Fourier were þ0.173 and -0.253 e/A .
Calculating from 1H VT-NMR Data the Energy Barrier for p-
Phenylene Rotation. Equation 1 was used to determine the
p-phenylene rotation rate at the coalescence temperature:
πΔv0
pffiffi
shift difference (in Hz) between the two separate signals at slow
k ¼
ð1Þ
2
where k is the rate coefficient and Δv0 = vA - vB is the chemical
(67) CrystalClear; Rigaku Corp., 1999.
(68) CrystalStructure; Rigaku Corp., 2002.
(69) Jacobsen, R. A., REQAB4 (personal communication).
(70) Altomare, A.; Burla, M.; Camalli, M.; Cascarano, G.; Giacovazzo,
C.; Guagliardi, A.; Moliterni, A.; Polidori, G.; Spagn, R. J. Appl. Crystal-
logr. 1999, 32, 115–119.
€
(66) van Strijdonck, G. P. F.; van Haare, J. A. E. H.; Honen, P. J. M.; van
den Schoor, R. C. G. M.; Feiters, M. C.; van der Linden, J. G. M.;
Steggerdab, J. J.; Nolte, R. J. M. J. Chem. Soc., Dalton Trans. 1997, 449–461.
(71) Sheldrick, G. M. Program for the Refinement of Crystal Structures;
€ €
University of Gottingen, Gottingen, Germany, 1997.
J. Org. Chem. Vol. 76, No. 5, 2011 1423

Khan et al.
JOCArticle
exchange (in this case at -93 °C or 180 K). The Arrhenius
equation (2) was used to determine the activation energy, Ea, at
the coalescence temperature, T (in K):
systematically performed in 10° increments using one of the
crystal structures of 5 as reference. A probe radius of 1.4 A was
used for all calculations.
˚
ꢀ ꢁ
Ea
R
1
Acknowledgment. I.J.D. appreciates support from the
DOD (No. W81XWH-04-1-0657), the NIH (No. CA110-
104), the NSF (No. CHE-0840438), a Camille and Henry
Dreyfus Teacher-Scholar Award, and the UPenn Chemistry
Department. J.G.S. acknowledges support from the NSF (No.
DMR08-32802). We thank George Furst for discussions and
access to NMR instrumentation, Emily Berkeley for access to
hydrogen and helium for H NMR experiments, and Laura
Spece for her early contributions to this work. Molecular
structures in Figures 1, 4, and 5 were generated using PyMOL.79
lnðk=HzÞ ¼ -
þ lnðA=HzÞ
ð2Þ
T
where A is the pre-exponential factor and R is the universal gas
constant.64
Computational Methods. All-atom MD simulations were
carried out using NAMD2.72 The internal bonded parameters
were obtained from AMBER-94,73 and the nonbonded para-
meters were proposed in previous studies.74-78 Simulations were
performed in the absence of solvent at 25 °C, and the tempera-
ture was controlled using Langevin dynamics with a damping
coefficient of 5 ps-1. The time step of the simulations was 0.5 fs.
Relaxation calculations using energy minimization consist of up
to 10 000 steps of the conjugate gradient algorithm as imple-
mented in NAMD2; the energy was monitored to confirm
minimization.72
1
Supporting Information Available: A CIF file giving crystal-
lographic data for 5 and figures giving 1H NMR and 13C NMR
spectra, NMR experiments investigating guest binding, analysis
of molecular dynamics simulations, and computational model-
ing. This material is available free of charge via the Internet at
http://pubs.acs.org.
GRASP63 was employed to investigate a potential interior
cavity within 5. Different conformations were generated by
manual rotations of the three p-phenylenes. The rotations were
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1424 J. Org. Chem. Vol. 76, No. 5, 2011