Amphidynamic crystals of a steroidal bicyclo[2.2.2]octane rotor: A high symmetry group that rotates faster than smaller methyl and methoxy groups

Article abstract of DOI:10.1021/ja4024463

The synthesis, crystallization, single crystal X-ray structure, and solid state dynamics of molecular rotor 3 provided with a high symmetry order and relatively cylindrical bicyclo[2.2.2]octane (BCO) rotator linked to mestranol fragments were investigated in this work. By use of solid state ¹³C NMR, three rotating fragments were identified within the molecule: the BCO, the C19 methoxy and the C18 methyl groups. To determine the dynamics of the BCO group in crystals of 3 by variable temperature ¹H spin-lattice relaxation (VT ¹H T₁), we determined the ¹H T₁ contributions from the methoxy group C19 by carrying out measurements with the methoxy-deuterated isotopologue rotor 3-d₆. The contributions from the quaternary methyl group C18 were estimated by considering the differences between the VT ¹H T₁ of mestranol 8 and methoxy-deuterated mestranol 8-d₃. From these studies it was determined that the BCO rotator in 3 has an activation energy of only 1.15 kcal mol^-1, with a barrier for site exchange that is smaller than those of methyl (E_a = 1.35 kcal mol^-1) and methoxy groups (E_a = 1.92 kcal mol^-1), despite their smaller moments of inertia and surface areas.

Full text of DOI:10.1021/ja4024463

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Article
Amphidynamic Crystals of a Steroidal Bicyclo[2.2.2]octane Rotor: A High
Symmetry Group that Rotates Faster than Smaller Methyl and Methoxy Groups
Braulio Rodriguez-Molina, Salvador Perez-Estrada, and Miguel A. Garcia-Garibay
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja4024463 • Publication Date (Web): 24 Jun 2013
Downloaded from http://pubs.acs.org on June 26, 2013
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Amphidynamic Crystals of a Steroidal
Bicyclo[2.2.2]octane Rotor: A High Symmetry
Group that Rotates Faster than Smaller Methyl and
Methoxy Groups
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Braulio Rodríguez-Molina, Salvador Pérez-Estrada, Miguel A. Garcia-Garibay*
Department of Chemistry and Biochemistry, University of California, Los Angeles, California
90095-1569, United States
E-mail: mgg@chem.ucla.edu
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Abstract. The synthesis, crystallization, single crystal X-ray structure, and solid state dynamics
of molecular rotor 3 provided with a high symmetry order and relatively cylindrical
bicyclo[2.2.2]octane (BCO) rotator linked to mestranol fragments were investigated in this work.
Using solid state 13C NMR, three rotating fragments were identified within the molecule: the
BCO, the C19 methoxy and the C18 methyl groups. To determine the dynamics of the BCO
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group in crystals of 3 by variable temperature H spin-lattice relaxation (VT H-T1), we
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determined the H-T1 contributions from the methoxy group C19 by carrying out measurements
with the methoxy-deuterated isotopologue rotor 3-d6. The contributions from the quaternary
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methyl group C18 were estimated by considering the differences between the VT H-T1 of
mestranol 8 and methoxy-deuterated mestranol 8-d3. From these studies it was determined that
the BCO rotator in 3 has an activation energy of only 1.15 kcal mol-1, with a barrier for site
exchange that is smaller than those of methyl (Ea = 1.35 kcal mol-1) and methoxy groups (Ea =
1.91 kcal mol-1), despite their smaller moments of inertia and surface areas.
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Introduction. Amphidynamic crystals are materials designed to display engineered
mechanical processes in the solid phase. They are built with a combination of static components
that guide crystalline order, which are generally linked to dynamic elements that display
conformational motions along well-defined directions.1 One of the most interesting challenges
in molecular structure and crystal design is the preparation of structures with components that
rotate close to the limit of their moment of inertia, as the result of barriers that are smaller than
thermal energies. While this is an unchartered territory, one may expect their physics to be
fascinating and their perspectives in materials science very exciting. Amphidynamic crystals
have the potential of exhibiting spontaneous organization guided by internal forces, and
externally addressable functions with the use of external fields. These properties may lead to
novel devices and to the construction of artificial molecular machines.2 Knowing that the
physical properties of solids depend on their molecular units, their packing interactions, and the
symmetry of the lattice,3 materials scientists and crystal engineers4 have sought the development
of structure-function relationships leading to specific crystal arrangements and desirable
functions.5 Based on this, a relatively large number of crystalline structures with internal
rotation has been studied in structures that range from close-packed molecular crystals,6 to
supramolecular complexes7 and MOFs.8 Particularly, molecular rotors with a central rotator
linked by a linear diethynyl axle to bulky triarylmethanes acting as stator have been synthesized
and used to analyze the relationship between the size of the stator and the dynamics of the
rotator. We have adopted in this paper the nomenclature proposed by Michl, where the word
“rotor” is reserved to describe entire molecular assemblies and the terms “rotator” and “stator” to
define the to rotary units and the static frames that are used to define the frame of reference.9
These studies have revealed that variations in the internal dynamics in crystals depend on the
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steric shielding provided by the stator10 and on the symmetry order of the rotator.11 While bulky
stators can generate larger cavities, highly symmetric cylindrical rotators require lower activation
energies to move within the shape-conforming environments that result from short-range van der
Waals packing forces.
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Using these design concepts, we recently reported structures based on 1,4-disubstituted
phenylenes flanked by two steroid molecules.12,13 The use of mestranol allows the molecule to
adopt an overall “U” conformation (compound 1, Figure 1) that packs in a helical array of nested
molecular rotors that at room temperature display ultrafast 180o rotations (kr >> 107 s-1) and
strongly correlated slower motions with angular displacements of ca. 85°.13 The use of
homochiral steroids is also appealing because their non-centrosymmetric crystals will enable
valuable physical properties, such as piezoelectricity, pyroelectricity, and optical activity.14 We
noticed that the dynamically disordered phenylenes in 1 occupy a significantly greater volume
than a static ring, suggesting that the formation of isomorphic structures may be possible with a
more cylindrical rotator. We hypothesized that the packing properties of chiral mestranol
combined with the C3 rotational symmetry of a 1,4-disubstituted bicyclo[2.2.2]octane (BCO)
rotator,15 may lead to smaller rotational barriers. The efficient rotational properties of the BCO
group had been recently demonstrated in other BCO crystals, including compound 2, which was
shown to have ambient temperature site exchange rates of 4.3 x 1011 s-1 and 7.7 x 1010 s-1, with
activation energies of 1.48 and 2.75 kcal/mol for two distinct crystallographic sites.15a
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Figure 1. Line diagrams of crystalline compounds with fast rotating portions in red and static
o
fragments in blue. At 25 C, the phenylene ring in compound 1 with a syn-steroid orientation
presents two distinct dynamic processes with site exchange rates of ca. 1.5 x 106 and >106 s-1.
Ordered and disorderd sites of the bicyclo[2.2.2]octane in 2 have site exchange rates of ca. and
4.3 x 1011 s-1 and 7.7 x 1010 s-1, respectively. A combination of components in molecular rotor 3
studied in this paper is expected to facilitate faster rotation.
In this paper we describe the synthesis, molecular and crystal structure, solid state
characterization, and rotational dynamics of molecular rotor 3. Although the packing of 3 turned
out to be substantially different than that previously documented for 1, it does exhibits
exceedingly fast rotation in the solid state, with an activation energy of only Ea = 1.15 kcal/mol,
as characterized by variable-temperature 1H spin-lattice relaxation experiments (T1). In order to
assign the dynamics of the BCO fragment in 3 it was essential to carry out measurements with a
methoxy-deuterated isotopologue, 3-d6, as well as crystals of mestranol 8 and its methoxy-
deuterated isotopologue 8-d3, which allowed us to identify the contributions of the methyl groups
of the steroidal backbone to the overall spin-lattice relaxation time.
Results and Discussion
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As outlined in Scheme 1, our synthetic strategy relied on the diastereoselective addition of
bicyclo[2.2.2]octane-1,4-diethynylmagnesium bromide to two molecules of mestrone 5. The
synthesis began with conversion of estrone 4 to mestrone 5 by treatment with sodium hydride
and methyl iodide. We planned to access to the bicyclo[2.2.2]octane-1,4-dilithiumdiacetylide by
a Corey-Fuchs one-carbon homologation of the corresponding aldehyde. Thus, Swern oxidation
of bicyclo[2.2.2]octane-1,4-dimethanol 616 afforded the corresponding bicyclo[2.2.2]octane-1,4-
dicarbaldehyde which proved to be highly unstable, hence the crude product was immediately
reacted with CBr4/PPh3 to produce the 1,4-bis(2,2-dibromovinyl)bicyclo[2.2.2]octane 716 in 95%
yield over two steps.
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Scheme 1
Reagents and conditions: a) MeI or CD3I, NaH, THF, r.t., 5 (94%), 5-d3 (90%); b) DMSO,
(COCl)2, Et3N, CH2Cl2, -78 - 0 °C; c) CBr4, PPh3, CH2Cl2, 0 °C - r.t., 95% over two steps; d) i.
n-BuLi, THF, -78 - 0 °C; ii. MgBr2∙OEt2, Et2O, -78 °C; iii. 5 or 5-d6, THF, CH2Cl2, -78 °C - r.t.,
3 (46%), 3-d6 (53%).
At this stage we developed a one-pot, three-step process to couple the steroid and 1,4-
diethynylbicyclo[2.2.2]octane fragments to reach the desired compound by converting bis-
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dibromoalkene 716 to its Grignard reagent by treatment with n-butyllithium followed by
transmetalation with MgBr2.OEt2. Subsequent addition of a solution of mestrone 5 delivered
molecular rotor 3 in 46% yield as a single diastereomer. Compared to the lithium acetylide
intermediate, the derived Grignard reagent provided higher yields. The remarkable
diastereoselectivity is a result of the directing effect of the angular methyl group that forces the
nucleophile to enter from the opposite alpha face of the ketone. The deuterated analogue 3-d6
was obtained in a slightly higher yield of 53% following the same synthetic route starting from
5-d3. Signals belonging to the central rotator in 3 in solution were observed at 1.76 ppm in the
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1H NMR, and at 32.1 ppm in the C NMR spectra. Both spectra were consistent with a time-
averaged C2-symmetry.
a)
b)
Figure 2. (a) Molecular structure of the molecular rotor 3 showing the disordered
bicyclo[2.2.2]octane rotator over two positions. (b) Packing arrangement of compound 3
showing a ribbon-like array found in the P43212 space group.
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Single crystals of 3 suitable for X-ray diffraction experiments were obtained from slow
evaporation of a solution in hexanes/ethyl acetate (8:2) and were analyzed at 100(2) K. The
main crystallographic parameters are included in the Supporting Information. The solvent-free
structure was solved in the space group P43212; a chiral space group (with no center of inversion)
in the tetragonal system with four molecules in the unit cell (Z = 4) and only half molecule in the
asymmetric unit (Z’ = 0.5). The steroidal fragments do not present geometric deviations when
compared to previously reported mestranol structures (Figure 2a)17 and the dialkynyl molecular
axis is slightly deviated from the idealized 180° linearity, as described by the angle C17-C21-
BCOcentroid = 172°. Perhaps the most interesting and unmistakable feature from the X-ray crystal
studies is the disorder in the bicyclo[2.2.2]octane fragment (Figure 3), which occurs over two
positions with a 50:50 occupancy. The disorder of the BCO group originates from the mismatch
that exists between the two-fold symmetries of the lattice [C2(cryst)] and the rotator [C2(BCO)].
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a)
b)
C2(cryst)
b
C2(BCO)
o
c
a
Figure 3. (a) Misalignment between the crystallographic [C2(cryst)] and bicyclo[2.2.2]octane
[C2(BCO)] two-fold symmetry axes gives rise to the two sites of the BCO fragment in 3 with the
two symmetry related positions colored purple (light) and red (dark). (b) Close up of the
resulting crystallographic disorder with 50:50 occupancy with the hydrogen atoms removed for
clarity.
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The lattice two-fold rotational symmetry [C2(cryst)] relates the two steroids of the structure by
rotation along the axis that lays on the diagonal of the ab-plane of the unit cell. Although the
BCO group has three 2-fold axes that cut each of the three bridges in the middle (average point
group D3h), none of them is coincident with the two fold axis defined by the crystal (Figure 3a).
The superposition of non-coincident two-fold symmetries generates the two sites (Figure 3b),
which produces an effective six-fold symmetric potential if rotation about the principal axis of
the molecule is considered. The disordered positions of the bicyclo[2.2.2]octane are related by
an angular displacement of 48° and 72°, suggesting that any possible rotation in the crystal must
occur by two non-equivalent, short and long jumps.15
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The packing of compound 3 presents the rather infrequent OH…π interaction reported in
crystals from similar structures; namely, 2-ethynyladamantan-2-ol, and gem-alkynols.18 We
observed close contacts between the hydroxyl groups at C17 and the triple bonds in neighboring
molecules with H…C≡Ccentroid distance of 2.533 Å and O-H…C≡Ccentroid angle of 149.6°. Through
these self-complementary interactions involving the two triple bonds, molecular rotors can
accommodate in parallel displaced layers in the crystal (Figure 2b). With the relative position of
the steroids close to an anti, or “Z-shaped” conformation (torsional angle C3-C17-C17’-C3’ =
153°), layers accommodate such that the empty spaces left by the steroidal portions in a
particular layer are filled with molecules from a second layer, giving rise to the ribbon-like
arrangement that characterizes the crystal (Figure 2b). Additionally, analysis of the packing
array revealed that the surrounding stators display some contacts with the two disordered
positions of the rotator.
Considering that the rotation of groups linked to triple bonds is essentially barrierless in
solution, we reasoned that a “U” conformation such as that previously observed in compound 1
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should be accessible for compound 3. Searching for a similar polymorph we carried out
crystallization in a large selection of pure solvents and solvent mixtures that included acetone,
benzene, o-xylene, dichloromethane, dimethylformamide, and ethyl acetate, among several
others. We used powder X-ray diffraction (PXRD) to characterize the solids resulting from the
crystallization experiments and discovered that only the P43212 is obtained, judging by the
excellent match between the calculated and experimental X-ray powder patterns in the range of
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4-50° (2θ degrees) (Please see Supporting Information).
Only the fast removal of
dichloromethane under vacuum gave an amorphous solid. Furthermore, seeding saturated
solutions of compound 3 with small crystallites of compound 1, did not affect the outcome of the
crystallization experiments.
Once the identity and crystallinity of compound 3 were established, the thermal stability of the
P43212 form was determined by differential scanning calorimetry (DSC) in the -50 °C to 350 °C
range. A melting transition was observed in the range of 251-253 °C with no indications of
phase transitions before melting. Thermogravimetric analysis (TGA) confirmed that the solid
contains no solvent and that it decomposes well after the melting point, as shown by an abrupt
weight loss at 323 °C.19 Freshly crystallized samples of compound 3 were analyzed by CPMAS
13C NMR. In agreement with the X-ray information, the solid state CPMAS 13C NMR spectrum
(see Supporting Information) showed a number of signals that correspond to one half of the
molecule, confirming that the two halves of the molecular rotor are crystallographically
equivalent. Relatively narrow signals with full width at half maximum (FWHM) between 35-45
Hz corroborated the high crystallinity of the sample. The signal corresponding to the methylenes
of the bicyclo[2.2.2]octane fragment was readily identified by the use of a dipolar-dephasing,
non-quaternary suppression sequence (NQS), which removes all the static protonated signals but
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retains those that correspond to groups undergoing rapid motion. This and other assignments
were consistent with those previously determined in solution NMR based on 2-D techniques. It
was determined that the methylene carbon atoms of the bicyclo[2.2.2]octane give rise to a very
strong single signal at δ 32.3, which is very close to the value δ 32.1 determined in CDCl3. That
the intensity of this sharp signal is unaffected even by long dephasing (60 µs) times indicates that
the bicyclo[2.2.2]octane fragment displays a rotational behavior with a frequency that is greater
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than that of the heteronuclear H-13C dipolar coupling (25-30 kHz), showing that the disorder
observed in the X-ray analysis is dynamic. In addition to the BCO signal, those corresponding to
the methyl C18 (δ 12.0) and methoxy group C19 (δ 53.8) also remained in the NQS spectrum.
Based on literature precedent20 and the CPMAS 13C NMR-NQS results, which suggest that
rotation of the BCO rotator occurs beyond the kilohertz regime, we decided to explore the
internal dynamics of molecular rotor 3 using 1H spin lattice relaxation experiments.21 It is well-
known that molecular rotation in the solid state is an important mechanism for longitudinal spin
lattice relaxation (T1). Fluctuating magnetic fields arising from motion-mediated magnetic
modulations of hydrogen nuclei with a strong dipolar coupling can lead to effective spin-lattice
relaxation. If a particular motion has a characteristic correlation time τc that follows an
Arrhenius behavior, the correlation time will vary as a function of temperature and a minimum
will be obtained when the τc matches the inverse of the Larmor frequency ( -1) of the nuclei
being observed. The activation energy (Ea, eq 1) of the corresponding dynamic process in the
solid can then be extracted by fitting the experimental T1 values to the Kubo-Tomita equation (eq
2).22
=
0 exp (Ea/RT)
(Eq. 1)
(Eq. 2)
C
T1-1 = C [ C (1+
2)-1 + 4 C (1+4
11
2)]-1
C
2
2
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C = n/N (9/40) [µo/4π]2 γ4ħ2/r6
(Eq. 3)
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It should be noted that equation 2 describes the relaxation rate for a given process, which is
simply given by the inverse of the relaxation time (i.e., 1/T1). The constant C in equation 2
characterizes the strength of the various dipole-dipole interactions modulated by the rotation of
the molecular fragments, and can its magnitude can be approximated with help of equation 3.23
The proton-proton separation in the rotating group is r, the permeability of free space is µo and
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the H magnetogyric ratio is γ.24 The value of C is further affected by a reducing factor n/N,
where n represents the number of mobile protons that are responsible for the relaxation of the
total number of protons N in the corresponding molecule.24
In the case of crystalline molecular rotor 3, experiments between 395 K and 155 K using a
saturation-recovery pulse sequence revealed 1/T1 values that were satisfactorily adjusted to the
Kubo-Tomita fit from high temperatures down to 195 K (Figure 4, triangles and Supporting
Information). Below 195 K, the 1/T1 values increase when a monotonic decrease was expected.
This deviation suggested that the relaxation recorded may be the result of overlapping dynamics
that contribute to the overall relaxation of the sample, suggesting that the rotation of the BCO
could be similar to that of the smaller methyl and methoxy groups (Figure 5a).25 The time
constant for inertial rotation in the gas phase ( IR) at a temperature T can be estimated from the
rotator moment of inertia, I, according to:
= (2 /9) (I/kBT)1/2, where kB is the Boltzmann
IR
constant.26 With moments of inertia of ca. 89 and 3.4 g•mol-1A-1 for BCO and methyl groups,
respectively, one would expect the gas phase rotation of the larger one to be about one order of
magnitude slower at ambient temperature. Furthermore, with a ca. three times greater molecular
surface area, it would be reasonable to expect that the larger BCO should have greater barriers to
rotation due to more van der Waals interactions and short contacts with the environment. Given
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this simple analysis, it became of great interest to investigate the potential similarity between the
rotational dynamic of the BCO and the methyl and methoxy groups.
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Figure 4. Comparison of the measured spin lattice relaxation rates 1/T1 of compounds studied in
this paper. In compound 3 both the BCO and MeO groups contribute with significance to the
relaxation process (triangles). In crystals of methoxy-deuterated 3-d6 the BCO group is the main
responsible of the relaxation (filled squares). Similarly, the MeO group causes the relaxation in
mestranol 8 (open circles) whereas the Me group is responsible for the relaxation in methoxy-
deuterated mestranol 8-d3 (solid circles).
For structures that have two or more fragments that contribute to the magnetic relaxation in a
coupled spin system that is at the same spin temperature, the observed relaxation rate (1/T1)Total
is given by the sum of the relaxation rates from the different contributors. In the case of
compound 3, we initially considered that the observed relaxation was realized by all the rotating
components in the molecule, (1/T1)Total = (1/T1)BCO + (1/T1)OMe + (1/T1)Me, where the subscripts
identify each of the three mobile groups. To examine the contributions of the methyl and
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methoxy groups,, and assuming that differences in crystal structures will not be dominant, we
determined the spin-lattice relaxation of mestranol 8, which has only the steroid frame and the
triple bond but not the BCO rotator. We considered that the relaxation in compound 8 would be
dictated by [(1/T1)Mestranol = (1/T1)OMe + (1/T1)Me]. Similarly, knowing that deuterium does not
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contribute to the H spin-lattice relaxation, we studied the methoxy-deuterated analog 8-d3 to
pin-down the contribution of the angular methyl groups to the relaxation of mestranol
[(1/T1)Mestranol-d3 =(1/T1)Me].
As observed in Figure 4 (open circles), a fit of the experimental 1/T1 values of 8 to Kubo-
Tomita expression revealed an activation energy of only 1.92 kcal mol-1, a pre-exponential factor
= 1.8 x 1011 s-1, and a C value of 1.42 x 108 s-2. These values are collected in Table 1.
-1
0
Regarding compound 8-d3 (Figure 4, filled circles), even though we could not reach the
maximum in 1/T1 values a linear regression of the data indicated an activation energy of Ea =
1.35 kcal mol-1. Such low activation energies are consistent with analogous measurements for –
CH3 groups reported in the literature.28 The smaller relaxation rate from the methyl group makes
a very small contribution to the relaxation of mestranol 8 in the range of temperatures explored,
as indicated by the lower position of the fitted line in Figure 4, indicating that the rotation of the
OMe group constitutes the relaxation sink for all the protons in the molecule, thus the expression
for mestranol 8 could be reduced to [(1/T1)Mestranol ≈ (1/T1)OMe]. In the absence of this group, the
angular methyl group (Me) is solely responsible of the relaxation in derivative 8-d3.
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Figure 5. (a) Components of molecular rotor 3 involved in dynamic processes. (b) Qualitative
representation of the rotational potential with angular displacements between the sites of the
BCO (green and purple). While the two sites are isoenergetic (50% occupancy each), each of the
two barriers may have different heights, such that the measured activation energy is an average.
Assuming that mestranol is a reasonable model to determine the behavior of the methyl and
methoxy groups of molecular rotor 3, we replaced the hydrogens of the methoxy group in 3 by
deuterons and studied the resulting analog, 3-d6 to determine (1/T1)Total ≈ (1/T1)BCO
.
Interestingly, even though no maximum in the 1/T1 values (Figure 4, filled squares) was
observed due to low temperature limitation of our spectrometer, a linear regression fit obtained
from 3-d6 reveals a very low activation energy of only 1.15 kcal mol-1. The activation energy for
the rotation of the BCO portion obtained in this manner should be considered an average that
reflects two distinct site exchange processes with angular displacements of 48o and 72o (Figure
5), which are isoenergetic, but may have different magnitude barriers. An average Ea value of
1.15 kcal/mol deduced in this manner is smaller than those of the methyl and methoxy groups in
the same structure, suggesting that small jumps in a six-fold potential are advantageous when
compared to the larger 120o jumps required for rotation of the smaller methyl groups. The
barrier in crystals of 3 is also smaller than the one reported for the reorientation of pure BCO
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over its 1,4 axis in its plastic crystalline state (1.84 kcal mol-1),29 and the structurally related and
also positionally disordered one in 1,4-bis(iodoethynyl)bicyclo[2.2.2]octane (1.48 kcal mol-1).15
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Table 1. Arrhenius Parameters Derived from Fits of the 1/T1 Data.
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-1 (s-1)
Compound
3
Group
causing the (kcal/mol)
relaxation
Ea
C (s-2)
0
OMe + BCO
OMeb
2.5a
3.2
1.0 x 1012* 1.0 x 108*
2.5 x 1011* 6.8 x 108*
3-d6
8
BCO
1.15c
OMe
Me
1.9
1.9 x 1011
1.4 x 108
8-d3
1.35c
3.3 x 1011* 1.7 x 108*
b
aApparent activation energy resulting from contributions of two groups. Obtained from the
c
difference between compounds 3 and 3-d6 (SI, Figure S8), Obtained from linear regression of
the data. *Resulting from 1/T1 data extrapolation using the Kubo-Tomita expression.
Based on the results obtained, we have attempted to develop a model that can predict the
dynamic behavior of the Me, OMe and BCO groups adapting the 1/T1 data and fitting the values
to the Kubo-Tomita expression. The parameters obtained using these models are compiled in
Table 1. In order to reduce the number of possible results, we used the activation energies
described above as constraints. From our simplified model, we noticed that regardless of the
residual dipolar interactions that originate the C values, their relative magnitude agrees
reasonably well when considering the reducing factor (nmobile/Ntotal): when the two OMe groups
(n/N = 6/62) are responsible of the relaxation, the C value should be smaller than that obtained
from compound 3-d6 (C = 6.8 x 108) where the BCO acts as the relaxation sink and the protons
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from the OMe groups were removed (n/N = 12/56). Similarly, in compound 8 (C = 1.42 x 108)
one OMe relaxes the molecule (n/N = 3/26), and its C value is smaller than that found for
compound 8-d3 (C = 1.65 x 108) with no protons in the OMe group (n/N = 3/23).
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This data analysis allowed us to use the temperature variation in the spin lattice relaxation rate
of natural abundance 3, (1/T1)total, and in the BCO molecular rotor deduced from 3-d6, (1/T1)BCO
to qualitatively obtain the relaxation rates of the methoxy group in the stator, (1/T1)MeO. That is
to say, the trend in the line describing the relaxation of molecular rotor 3, represented by the
filled triangles in Figure 4, results from the addition of the lines that correspond to the behavior
of the BCO (filled squares) and the MeO groups, as shown in Figure S8 in the SI section. We
noticed that there is a shift in the incipient maximum of the Kubo-Tomita fit of the model steroid
MeO (open circles) as compared to that of the molecular rotor (filled triangles), which indicates
that the MeO group in 3 has different activation parameters as compared to the one in 8. Using
the simulated curve, one can estimate a barrier of ca. 3.2 kcal/mol (Table 1) indicating that there
is more hindrance to the MeO group in crystals of rotor 3 than in crystals of the steroid 8.30
Based on this analysis, we reformulate our expression for the relaxation of compound 3 to be
(1/T1)Total = (1/T1)BCO + (1/T1)OMe
.
The low activation energy determined in compound 3-d6 implies that the BCO rotator has a
site exchange rate of 1.4 x 1010 s-1 at ambient temperature. It is worth noting that the pre-
-1
exponential factor simulated for the site exchange of the BCO group in 3 (
= 2.22 x 1011) is
0
-1
about an order of magnitude smaller than those of the same group in crystals of 2 (
= 5.21 x
0
1012 and 8.0 x 1012). Similarly, the rotational dynamics of the BCO group in two
crystallographic sites of tetrabutylammonium salt of an analogous 1,4-
a
bis(carboxyethynyl)bicyclo[2.2.2]octane were reported have barriers of 2.03 and 2.72 kcal mol-1
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-1
with pre-exponential factors, t0 = 3.6x1012 and t0 = 3.1x1012 s-1.15b It is interesting that those
compounds do not have the BCO linked to a large rigid stator, and may be considered to have
plastic crystal character. By contrast, the rotation of a BCO group linked by triple bonds to
bulky triphenylsilyl groups in a previously reported molecular gyroscope displayed a barrier of
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3.5 kcal/mol and a smaller pre-exponential factor of t0 = 3.6 x 1010 s-1.11 Taking all of these
results together, it is remarkable that BCO rotators present such a low, and relatively similar
activation energies, despite occurring in widely different molecular structures and crystalline
environments. In one exceptional case involving an organic conductor, a dialkynyl BCO rotator
was shown to have a barrier of ca. 7.3 kcal/mol, which was speculated to arise from local
interactions in the lattice of perhaps a quantum dissipation phenomenon.15b Although the
amount of data is rather limited, they suggest that structures with rotators covalently linked to
larger, rigid stators are likely to reduce the magnitude of the pre-exponential factor, a hypothesis
that will be worth testing with molecular dynamics calculations.
Conclusions. We have combined the rigidity of the steroid mestranol with the three-fold
symmetric and relatively cylindrical bicyclo[2.2.2]octane (BCO) fragment in the crystalline
molecular rotor 3 to explore its crystallization and solid state dynamics. Compound 3 and its
isotopologue 3-d6 were synthesized by a one-pot, three-step coupling reaction between mestrone
and 1,4-diethynylbicyclo[2.2.2]octane with perfect diastereoselectivity and good overall yields.
It was discovered that compound 3 does not form crystals isomorphous to those of compound 1
with a central phenylene instead of a BCO rotator. Single crystal X-ray diffraction analysis of 3
showed that substitution of the 1,4-phenylene rotator with a bicyclo[2.2.2]octane originates a
ribbon-like packing of the molecular rotors with a disordered BCO rotator. Notably, the disorder
results in two distinct sites related by angular displacements of 48o and 72o, which are equally
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occupied. Analysis of solid state CPMAS 13C NMR data indicated that the BCO group
undergoes rapid rotary motion with exchange rates well beyond the tens of 103 s-1 regime, as
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indicated by H dipolar dephasing experiments. For that reason, the exchange dynamics of the
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BCO rotator were explored by variable temperature H spin-lattice relaxation experiments. By
1
comparing H T1 values of molecular rotors 3 and methoxy-deuterated 3-d6 along with those of
mestranol 8 and methoxy-deuterated 8-d3, it was possible to assign the relative relaxation
contributions of the BCO, methyl and methoxy groups. These results indicate that the BCO
rotator has an effective average barrier of Ea = 1.15 kcal mol-1, which allows it reach an average
site exchange rate of 1.4 x 1010 s-1 at ambient temperature, which is rather remarkable
considering that the BCO group is relatively large. These results demonstrate that the relatively
cylindrical BCO and suitable analogs and derivatives will be promising building blocks for the
design of ultrafast responsive materials and molecular machines based on amphidynamic crystals
with inertial rotors.
Experimental section:
General Information. All reactions were carried out under an inert atmosphere of argon in oven
or flame-dried glassware. All chemicals were purchased from commercial suppliers and used as
received. Mestrone (4) and Ethynylestradiol (9) are commercially available and
bicyclo[2.2.2]octane-1,4-dimethanol (6) was prepared following literature procedures.16 Solvents
were dried and purified following standard literature procedures. Analytical thin-layer
chromatography (TLC) was performed using pre-coated TLC plates with silica gel and
visualized using combinations of UV, potassium permanganate (KMnO4), and cerium molybdate
(CAM) staining. Flash column chromatography was performed using silica gel as the stationary
phase. Proton magnetic resonance spectra were recorded at 500 MHz, and carbon-13 magnetic
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resonance spectra were recorded at 125 MHz, respectively. All chemical shifts are reported in
ppm on the δ-scale relative to TMS (δ 0.0) using residual solvent as reference (CDCl3 δ 7.26 and
δ 77.16 for proton and carbon, respectively). Coupling constants J are reported in Hz.
Multiplicities are reported as broad (br), singlet (s), doublet (d), triplet (t), quartet (q), quintet
(qnt), sextet (sxt), septuplet (spt) and multiplet (m). Uncorrected melting points were recorded on
a melting point apparatus using open glass capillaries. IR spectral data were obtained using an
Attenuated Total Reflectance (ATR) spectrometer as the neat compound and the units are stated
in cm-1. Optical Rotations were measured on a polarimeter with a sodium lamp and a light
wavelength of 589 nm (the sodium D line). High resolution mass spectrometric data were
collected using Electrospray Ionization technique with a Time-of-Flight detector (ESI-TOF)
mass spectrometer and a Liquid Introduction Field Desorption Ionization mass spectrometer with
a Time-of-Flight detector (LIFDI-TOF).
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Synthesis of molecular rotor 3
Step 1. Preparation of MgBr2 OEt2. Some drops of 1,2-dibromoethane were added to a mixture of
Magnesium turnings (50 mg, 2.05 mmol, 4.0 equiv) and dry diethyl ether (3.0 mL). The mixture
was heated until reflux started, then the remaining 1,2-dibromoethane (0.18 mL (total), 386 mg,
2.05 mmol, 4.0 equiv) was added dropwise. The mixture was allowed to stir at room temperature
for 1 h after completion of the addition.
Step 2. n-BuLi (1.6M in hexanes, 1.76 mL, 2.82 mmol, 5.5 equiv) was added dropwise to a
solution of bis-dibromoalkene 7 (245 mg, 0.51 mmol, 1.0 equiv) in dry THF (3.6 mL) at -78 °C,
the reaction mixture was stirred at this temperature under argon atmosphere for 1.5 h and 30 min
at 0 °C. The resulting mixture was cooled again to -78 °C and the previously prepared
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MgBr2 OEt2 mixture was added by syringe. Afterwards, mestrone 5 (292 mg, 1.03 mmol, 2.0
equiv) was added dissolved in dry diethyl ether (2.7 mL) and dry CH2Cl2 (2.7 mL). Then the dry
ice bath was replaced by a 0 °C ice bath and the reaction mixture was stirred 15 h, allowing the
mixture reach room temperature slowly. Then, the mixture was cooled to -78 °C, and aqueous
saturated solution of NH4Cl (6.0 mL) was added, the mixture was stirred at room temperature
and after separation of the layers, brine was added (6 mL). The organic phase was separated and
the aqueous phase was extracted with ethyl acetate (3 x 20 mL). The combined organic phases
were dried over Na2SO4, filtered and the solvent was evaporated in vacuo. The crude product
was purified by flash column chromatography (20% ethyl acetate-hexanes) to afford compound 3
(170 mg, 46%) as a white solid.
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Spin lattice relaxation experiments (T1, NMR). H T1, NMR relaxation was measured on
polycrystalline samples of compound 3 and 3-d3 recrystallized from hexanes/ethyl acetate and
polycrystalline samples of commercial mestranol 8 and mestranol-d3 (8-d3) recrystallized from
ethanol. The experiments were carried out with a static wideline probe using solid-state
spectrometer operating at a 1H Larmor frequency of 300 MHz. The saturation recovery sequence
used contains a saturation pulse comb followed by a time τ’ (τ’ values taken from the variable
delay list) with a π/2 pulse p1. For each measurement, an acquisition time of 2.0985 ms was
1
used. The H spin-lattice relaxation experiments were determined for T=165 - 395 K. For
compounds 3, 3-d6, 8 and 8-d3 the T1 experiments were analyzed using the TopSpin software
from Bruker and were suitably fit to a monoexponential behavior.
Acknowledgements. S. P. thanks to ICyT DF for a postdoctoral fellowship. Work was
supported by National Science Foundation grants DMR1101934 and CHE0844455. This
material is based upon work supported by the National Science Foundation under equipment
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grant no. CHE-1048804. The project described was supported by Grant Number S10RR025631
from the National Center for Research Resources. The content is solely the responsibility of the
authors and does not necessarily represent the official views of the National Center for Research
Resources or the National Institutes of Health.
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Supporting Information Available. Complete experimental details for all remaining
compounds, spectroscopic data for compounds 3, 3-d3, 5-d3, and 8-d3, X-ray powder diffraction
13
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pattern, C CPMAS, C CPMAS Non-Quaternary Suppression spectra, thermogravimetric and
differential scanning calorimetry traces of compound 3, crystallographic parameters and
crystallographic information file (cif) of 3, analysis of the distances between close neighbors in
the packing arrays in 3 and 8, plots of the Kubo-Tomita fit with experimental data for
compounds 3, 3-d3, 8 and 8-d3. This material is available free of charge via the Internet at
http://pubs.acs.org .
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19. Considering that a new solid form could also be obtained from the melt, we heated a freshly
crystallized sample up to 275 °C (before decomposition) and then returned it to room
temperature. The DSC trace showed again the melting point transition but the reverse path
presented only a very subtle exothermic transition corresponding to crystallization. The analysis
of the resulting solid by PXRD indicated that after melting, compound 3 becomes an amorphous
solid and solution 1H NMR showed decomposition products in very small amounts.
20. Hardouin Duparc, O. B. M.; Meyer, M. J. Chem. Phys. 1990, 93, 1313.
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Applications, CRC Press, Boca Raton, USA, 2011.
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22. Kubo, R.; Tomita, K. Phys. Soc. Jpn., 1954, 9, 888.
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23. Conn, K. G.; Beckmann, P. A.; Mallory, C. W., Mallory, F. B. J. Chem. Phys. 1987, 87, 20.
24. Although equation 3 is valid only in a case of a two-spin system, we employed it to extract
approximate r values from the C constants obtained from Kubo-Tomita fitting processes. Values
of r ranging between 1.79 – 2.15 Å were obtained.
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26. Kawski, A. Crit. Rev. Anal. Chem., 1993, 23, 459.
27. Mestranol 8-d3 was freshly recrystallized from ethanol. Its phase and crystallinity were
determined by powder X-ray diffraction.
28. (a) Wang, X.; Beckmann, P. A.; Mallory, C. W.; Rheingold, A. L.; DiPasquale, A. G.;
Carroll, P. J.; Mallory, F. B., J. Org. Chem. 2011, 76, 5170. (b) Wang, X.; Rotkina, L.; Su, H.;
Beckmann, P. A. Chem. Phys. Chem. 2012, 13, 2082.
29. McGuigan, S.; Strange, J. H.; Chezeau, J. M.; Nasr, M. J. Phys. (Paris) 1985, 46, 271
30. Analyzing the crystal packing, the methoxy group in compound 3 has three neighboring
molecules with distances of 2.49, 2.51 and 2.56 Å, whereas compound 8 has only two neighbors
with distances of 2.62 and 2.64 Å (Supporting Information). There are no noticeable differences
between the molecular structures of compounds 8 (296 K) and 3 (100 K), as shown by the
overlay of the two structures with a RMS of only 0.103 (Supporting Information).
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