Synthesis, characterization, and solid state dynamic studies of a hydrogen bond-hindered steroidal molecular rotor with a flexible axis

Article abstract of DOI:10.1021/acs.joc.8b00134

A novel steroid molecular rotor was obtained in four steps from the naturally occurring spirostane sapogenin diosgenin. The structural and dynamic characterization was carried out by solution NMR, VT X-ray diffraction, solid state ¹³C CPMAS, and solid state ²H NMR experiments. They allowed the identification of a fast dynamic process with a frequency of 14 MHz at room temperature, featuring a barrier to rotation Ea = 7.87 kcal mol^-1. The gathered experimental evidence indicated the presence of a hydrogen bond that becomes stronger as the temperature lowers. This interaction was characterized using theoretical calculations, based on topological analyses of the electronic density and energies. In addition, combining theoretical calculations with experimental measurements, it was possible to propose a partition to Ea (～8 kcal/mol) into three contributions, that are the cost of the intrinsic rotation (～2 kcal/mol), the hydrogen bond interaction (～2 kcal/mol), and the packing effects (～2-3 kcal/mol). The findings from the present work highlight the relevance of the individual components in the function of molecular machines in the solid state.

Full text of DOI:10.1021/acs.joc.8b00134

Article
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Synthesis, Characterization, and Solid State Dynamic Studies of a
Hydrogen Bond-Hindered Steroidal Molecular Rotor with a Flexible
Axis
Martha C. Mayorquín-Torres,† Abraham Colin-Molina,‡ Salvador Perez-Estrada,§ Annia Galano,*,∥
́
Braulio Rodríguez-Molina,*,‡ and Martín A. Iglesias-Arteaga*,†
†Facultad de Química, Universidad Nacional Auton
‡Instituto de Química, Universidad Nacional Auton
oma de Mex
Mexico
§Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States
∥Departamento de Química, Division
de Ciencias Basicas e Ingeniería, Universidad Autonoma Metropolitana-Iztapalapa, Av. San
Rafael Atlixco No.186, C.P.09340 Ciudad de Mexico, Mexico
́
́ ́ ́
oma de Mexico, Ciudad Universitaria, 04510 Ciudad de Mexico, Mexico
́
́
ico, Circuito Exterior, Ciudad Universitaria, 04510 Ciudad de Mexico,
́
́
́
́
́
́
́
S
* Supporting Information
ABSTRACT: A novel steroid molecular rotor was obtained in
four steps from the naturally occurring spirostane sapogenin
diosgenin. The structural and dynamic characterization was
carried out by solution NMR, VT X-ray diffraction, solid state
13C CPMAS, and solid state 2H NMR experiments. They
allowed the identification of a fast dynamic process with a
frequency of 14 MHz at room temperature, featuring a barrier to
rotation Ea = 7.87 kcal mol−1. The gathered experimental
evidence indicated the presence of a hydrogen bond that
becomes stronger as the temperature lowers. This interaction
was characterized using theoretical calculations, based on
topological analyses of the electronic density and energies. In
addition, combining theoretical calculations with experimental
measurements, it was possible to propose a partition to Ea (∼8 kcal/mol) into three contributions, that are the cost of the
intrinsic rotation (∼2 kcal/mol), the hydrogen bond interaction (∼2 kcal/mol), and the packing effects (∼2−3 kcal/mol). The
findings from the present work highlight the relevance of the individual components in the function of molecular machines in the
solid state.
The SMR so far reported consist of two steroid frameworks
that together constitute the stator (fragment with less degrees
of freedom), linked to substituted or nonsubstituted 1,4-
diethynylphenylenes, that act as the rotators (rotating frag-
ments). Most of these compounds have been obtained
following procedures that involve the addition of an ethynyl
moiety to carbonyl functions, a group that can reside in
different positions of the steroid framework, and the
subsequent coupling of the free alkyne with 1,4-diiodobenzene
derivatives, leading to the desired SMR. In those rotors, the 1,4-
diethynylphenylene moiety is attached to the surrounding rigid
steroids. Additional structural transformations have led to
macrocyclic dimers of increased rigidity, minimizing the
steroidal degrees of freedom upon crystallization (Figure 1).
As a part of our ongoing program for the development of
steroid-based crystalline systems,5,6 we have become interested
INTRODUCTION
■
Steroid dimers constitute a developing field in which an
increasing number of linear or cyclic dimers has been either
isolated from different living organisms or designed and
synthesized to develop tailored physical, biological, or chemical
properties.1 Some of these dimers are formed through spacer-
connected monomers that, to the best of our knowledge,
contain an intact steroid skeleton.2
The design of molecular scaffolds is particularly attractive for
the synthesis of molecular machines3,4 and in particular for
crystalline Steroid Molecular Rotors (SMR), in which the
rigidity of the steroidal framework can be used to induce the
crystallization of the molecules, while the spacer between the
monomers can be appropriately modified to accommodate
small rotating groups. The resulting SMR follow a wheel-and-
axle design and have been the focus of recent reports.5 This
class of rotors have shown exciting internal motion in the solid
state, prompting us to explore new structural modifications that
can change the behavior so far observed.
Received: January 16, 2018
Published: March 5, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.8b00134
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Figure 1. Some previously described SMR (a−c)5 and (d) the herein studied compound.
Scheme 1. Synthesis of SMR 5a and 5b
in SMR with more flexible structures, which in turn may show
interesting physical properties. Herein we report the synthesis,
characterization, and solid state dynamic studies of the novel
SMR 5, featuring a 1,4-phenylene rotator in which the
surrounding ethynyl groups are attached to the secosteroid
stator through aliphatic CH2−CH2 fragments, endowing
additional flexibility to the axis. This is an apparently small
but significant structural change of the steroidal skeleton. It acts
synergistically, with the embedded carbonyl group, to modulate
the thermally activated rotational process. Such a process is
very fast at room temperature, as detailed by the variable
temperature X-ray single crystal experiments, 13C NMR
CPMAS and VT solid state H NMR studies herein discussed.
2
RESULTS AND DISCUSSION
■
The alkynone 4 was obtained through a three-step sequence
that included (i) Oppenauer oxidation of diosgenin (1), (ii)
H2O2/NaOH epoxidation of the α,β-unsaturated ketone 2 to
produce a 1/3.02 mixture of the known epimeric epoxides (3a)
and (3b)7 that resisted all attempts at separation and (iii)
B
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Figure 2. (a) Molecular structure (ellipsoids drawn at 30% probability) and (b) crystal packing of compound 5a.
Eschenmoser-Tanabe fragmentation of the mixture of the
epoxides 3α and 3β. Sonogashira coupling of 4 with 1,4-
diiodobenzene or 1,4-diiodobenzene-D4 afforded the dimers 5a
or 5b, respectively (Scheme 1).
Solid State Characterization. Single Crystal X-ray
Studies. At all explored temperatures [293(2) K − 100(2)
K] the structure of compound 5a was solved in the monoclinic
system with space group C2. The significant crystallographic
parameters are compiled in Table S1.
Given the chirality of the steroidal stator, the asymmetric unit
comprises one entire molecule (Z′ = 1); that is, all the atoms in
the structure are crystallographically nonequivalent. The
molecular structure revealed that the two stator halves show
an anti conformation, leading the molecule to adopt the shape
of a distorted “S”, most likely due to the flexible methylene
linkages (Figure 2a). The crystal packing of 5a resembles the
array of a lipid bilayer, with neighboring molecules stacking
together forming a stepladder, leaving the 1,4-diethynylpheny-
lene component relatively isolated in the middle. While the
ethynyl fragments in all molecules lie in almost parallel planes
slightly displaced one from each other, each phenylene group in
neighboring molecules are almost perpendicular to each other
(Figure 2b).
Figure 3. Lateral view and comparison between the structures of 5a
obtained at room (top) and lower temperatures, highlighting the
elongation of the ellipsoids (drawn at 30% probability).
Since no crystallographic disorder was observed at any of the
studied temperatures, it was not possible to extract conclusive
evidence of rotational motion in the central benzene ring.
Nevertheless, the thermal ellipsoids of the 1,4-diethynylpheny-
lene moiety at 293(2) K, when compared to that of the
experiment at 100(2) K, showed significant elongations in the
orthogonal direction to the 1,4-diethynyl axis (Figure 3). This
evidences an oscillation and/or vibration of the aromatic ring at
room temperature in a preferred direction, that is minimized at
lower temperatures.
A detailed inspection of the crystal array, revealed a close
contact between the central aromatic ring of a rotor and a
neighboring carbonyl group. This interaction has been
recognized as an archetype of the weak hydrogen bond.8 In
this bond, the CAr-H fragment should be considered as the
donor and the CO group as the acceptor (Figure 4). The
distance between the hydrogen and the oxygen atoms at room
temperature is 2.50 Å, which is substantially shorter than the
sum of their van der Waals radii (2.61 Å).9 Moreover, the
observed C−H---O angle of 151.6° is consistent with the mean
value of this interaction (152°), as described in a detailed
manner by Taylor.10
More importantly, the X-ray data of a single crystal collected
between 293 and 100 K made possible to determine that the
distance between the aromatic hydrogen and the oxygen atoms
is shortened at lower temperatures, while the angle of the
interaction changes marginally (Table 1). The shortened
distances suggests that the weak interaction becomes stronger
at lower temperatures and might play an important role in the
solid-state dynamics.
Phase Purity (PXRD) and Thermal Stability (DSC and
TGA). Bearing in mind the structure of compound 5a, it seemed
possible that during the crystallization process the two steroids
of the stator could adopt numerous conformations one
respective to the other, possibly yielding multiple crystal arrays.
To rule out the presence of other crystal phases within a larger
sample, powder X-ray diffraction analysis was carried out. This
C
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Figure 4. Weak CH···OC hydrogen bond between the central aromatic ring and a neighboring carbonyl group of an adjacent rotor in compound
5a.
Table 1. Distances and Angles the CH···OC Interaction in 5a at Different Temperatures
temperature (K)
distance CH···O donor−acceptor (Å)
distance CH···OC hydrogen-acceptor (Å)
C−H···O angle donor-hydrogen-acceptor (deg)
293 K
273 K
223 K
173 K
100 K
3.342
3.344
3.313
3.306
3.283
2.50
2.51
2.46
2.44
2.41
151.6
149.28
150.71
151.38
152.18
Table 2. Selected 13C NMR Signals of the SMR 5a and 5b
analysis yielded an excellent match between the experimental
diffraction pattern, collected between 4 and 70 (2θ°), and the
calculated one obtained from the single crystal diffraction
studies, corroborating the sample homogeneity (Figure S1).
Complementarily, the thermal stability of this crystal array at
high temperatures was evaluated using differential scanning
calorimetry (DSC) and thermogravimetric analysis (TGA).
The calorimetry studies indicated that the solid does not
contain solvent molecules in the crystal lattice and is highly
stable because no phase transitions were observed upon heating
from room temperature up to 227.3 °C, where the onset of a
large endothermic transition was observed, reaching a peak at
232.0 °C. This endotherm was assigned to the melting point of
compound 5a. The thermogravimetric analysis did not show
any loss of weight from room temperature to 300 °C. Above
this temperature, the sample steadily loses weight that was
attributed to sample decomposition, in agreement with a
noticeable exothermic transition in the DSC trace (Figure S2).
Spectroscopic Characterization: 13C NMR in Solution
and 13C NMR CPMAS. To gain more information for the 13C
CPMAS experiments, the assignment of all the 13C NMR
signals from the experiment in CDCl3 solutions of 5a and 5b
was carried out (vide infra experimental part). The most salient
13C chemical shifts of the SMR are collected in Table 2. In
addition to the signals associated with the steroid cores and the
methyl groups, those that characterize the spirostanic side
chains of both stators (C-16 C-16′, C-22 C-22′, and C-26 C-
26′), and the downfield signals of the 1,4-diethynylphenylene
moiety (C-3 C-3′, C-4 C-4′, 2xC-ipso and CAr), can be easily
recognized. As expected, a small triplet associated with the CAr-
D coupling was observed in the deuterated compound 5b.
Subsequently, the crystalline sample of compound 5a was
submitted to 1H → 13C cross-polarization magic-angle spinning
experiments (CPMAS) at 293 K (Figure 5). The sharp signals
in the 13C CPMAS experiment at room temperature are in
excellent agreement with the data provided by solution NMR
and X-ray studies; that is, most of the crystallographically
13C NMR (CDCl3)
13C NMR CPMAS
signals
5a
5b
5a
C-3 C-3′
C-4 C-4′
C-5 C-5′
92.1
80.4
92.1
91.9, 90.3
81.0, 79.6
213.6, 212.6
50.3, 49.9
21.2
80.3
214.3
50.5
214.3
C-10 C10′
C-11 C-11′
C-13 C-13′
C-14 C-14′
C-16 C-16′
C-17 C-17′
C-22 C-22′
C-26 C-26′
50.7
21.4
21.3
40.5
40.5
40.9, 40.5
54.7, 54.4
80.1
55.6
55.6
80.4
80.4
62.0
62.0
62.9, 61.8
107.9
109.3
66.8
109.2
66.8
64.5
Cipso C‑ipso
′
123.1
131.2
122.9
123.0, 122.6
131.1
CAr
130.8 (t, JC‑D = 25 Hz)
nonequivalent carbon atom of the structure (Z′ = 1) were
observable in the spectrum, and the chemical shifts showed a
good agreement. For instance, two signals at 213.6 (C-5) ppm
and 212.6 ppm (C-5′) were observed in the carbonyl region, in
stark contrast to solution 13C NMR, where only one signal at
214.3 ppm represents the two carbonyl atoms (C-5 and C-5′)
that become equivalent due to the rapid tumbling of the
molecule (Table 2). The fact that some nonequivalent atom
pairs were observed as single signals in the 13C CPMAS
spectrum (i.e., C-16 and C-16′ at 80.1 ppm or C-22 and C-22′
at 107.9 ppm) could be explained by the moderate resolution
obtained in the 7.05 T magnet, which despite the high
crystallinity of the sample is not high enough to distinguish
between some atom pairs.
Even considering the modest resolution, four signals were
expected in the aromatic region but only one intense peak was
observed at 131.1 ppm. The presence of only one signal could
be the result of two options: (1) the chemical shifts of the four
aromatic CH carbon atoms are coincidentally isochronous
which is improbable or (2) a fast, dynamic process takes place,
D
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Figure 5. 13C NMR spectra of compound 5a at 295 K.
Figure 6. Variable temperature 13C CPMAS spectra of 5a.
and thus the carbon atoms become equivalent. If the first
option is true, CPMAS could not shed more light upon the
matter, unless access to a stronger magnetic field could be
secured.
aromatic carbons, suggesting that the phenylene is indeed
experiencing fast intramolecular motion, as postulated above.
After the initial results, it became evident that additional
experiments were needed to gather more information about the
dynamic process. Typically, dynamic processes with frequencies
occurring within 101 to 104 Hz can be characterized by 13C
CPMAS coalescence experiments and subsequent line shape
analysis. Considering that the chemical exchange of the
compound 5a was fast at room temperature, it seemed possible
that low temperature experiments could cause the splitting of
the signals. An additional advantage for these experiments is
that due to the aliphatic architecture of this SMR, the NMR
spectrum only contains signals of the central 1,4-phenylene in
the aromatic region. When 13C CPMAS experiments between
295 and 155 K were carried out, only a significantly broadened
line shape of the aromatic signals was observed. Such change
indicates that the frequency of the motion has been lowered,
The second option was explored using the dipolar-dephasing
version of the 13C CPMAS-NQS. This strategy has been used
before to discriminate between protonated and quaternary
carbon atoms, making easier the assignment of complex
spectra.14 This experiment removes the signals of the
protonated carbon atoms, mainly −CH and −CH2, but highly
mobile groups (i.e., methyl groups) are not drastically affected
by the pulse sequence, so their signals remain unchanged in the
spectrum. In the case of compound 5a, if the central phenylene
is rotating, the signal at ca. 131 ppm should not be affected by
this experiment. Gratifyingly, the NQS spectrum (Figure 5)
showed not only the chemical shifts assigned to the quaternary
carbons and the methyl groups but also those assigned to the
E
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Figure 7. (a) Experimental (solid line) and calculated (dashed line) deuterium line shapes of compound 5b, with the corresponding temperatures
and rotational frequencies. (b) The resulting Arrhenius plot, activation energy to rotation Ea, the pre-exponential factor A and the corresponding
linear regression formulas.
but unfortunately, the lowest temperature achievable in the
spectrometer was not enough to split the signals (Figure 6).
This suggested that the chemical exchange is beyond the time
scale of this technique; a fact that was confirmed by using solid
and characterized as done for 5a. Notably, the line shape
obtained at room temperature clearly reflects that the
deuterated phenylene experiences 180° jumps in the fast
exchange range (Figure 7, panels a and b). Such high rotational
frequency is indeed surprising, and it was considered unusual in
steroidal rotors. Only a couple of SMR have reached the MHz
frequency, considered as the result of privileged crystalline
arrays.5a Consequently, a set of VT experiments was carried out
to verify if the rotational process can be slowed and unveil the
nature of this motion.
2
state H NMR, as described in the following section.
Solid State Deuterium NMR Dynamics Using Spin
Echo. Deuterium produces very wide NMR signals in the solid-
state due to its quadrupolar coupling. Despite this, the 2H spin
echo is an excellent technique to explore solid state dynamics
because it can accurately describe molecular motions in the
range of 104 − 108 Hz.11 Deuterated crystalline samples that do
not undergo motion or are in the slow exchange (<104 Hz),
show a line shape known as Pake pattern, which is characterized
by two singularities separated by 132 kHz, resulting from the
two allowed spin transitions (−1, 0, 1).12
On the other hand, if the fragment is involved in any motion
between 104 Hz and 108 Hz (intermediate exchange), the
resulting spectrum at any given temperature would be
represented by a line shape that can be fitted to a characteristic
rotational frequency (krot). Such fitting would allow the
extraction of the rotational activation energy of the process
using an Arrhenius plot of ln (krot) versus 1/T (K).
2
When a set of VT H experiments was carried out, a change
in the line shape was observed, as expected when dealing with a
thermally activated rotational process. The line shapes between
295 and 230 K could be reasonably fitted using a single
rotational process undergoing a 180° rotation. At even lower
temperatures, some small features in the line shapes were
observed, suggesting an additional dynamic process (Figure
S3).
It may be considered that those singularities at the lower
temperatures could come from additional trajectories that
overlap with the phenylene rotation. These additional vibra-
tional components might be attributed to the oscillation and/or
additional bending modes of the flexible moiety, which includes
the phenylene rotator, the alkyne axes, together with the C-1
C-2 and C-1′C-2′ fragments of the steroidal stator. This
possible vibrational mode could also be present at higher
temperatures, but it was not detectable because it is probably
masked by the fast and prevailing 180° rotation of the 1,4-
diethynylphenylene moiety.
Lastly, if the intramolecular motion reaches rotational
frequencies faster than 108 Hz (fast exchange), such a dynamic
process is beyond the detection limit of this technique and
shows a characteristic line shape that does not change any
further. In addition, the C−D bond is very sensitive to the
surroundings of the mobile fragment; therefore, it can be used
to determine the geometry of the possible motion [i.e.,
distinction of the rotation of phenylene groups (C2, 180°
jumps), methyl groups (C3, 120° jumps), or other mobile
fragments with higher point-group symmetry (C4 or C6)].
As reported in the synthesis section, the rotor with the
deuterated benzene ring 5b was readily obtained starting from
From an Arrhenius plot of ln(Krot) against 1/T, it was
possible to extract an activation energy of 7.87 kcal mol−1 for
the rotation of the phenylene in 5a and a pre-exponential factor
A = 8.76 × 1012 s−1 (Figure 7). The value of A agrees well with
that expected for the inertial rotation of a phenylene.13 Given
that the rotation frequency of 5a at room temperature lays in
the MHz regime, it was surprising that the calculated Ea was
2
1,4-diiobenzene-d4. To obtain the corresponding H spectra, a
crystalline sample of the deuterated derivative 5b was prepared
F
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Figure 8. (A) Main interactions, (B) density contour map, and bond critical points (BCP).
higher than the 7.19 kcal mol−1 reported in a previous SMR,
with rotations in the kHz regime at room temperature.5b
Therefore, it was considered that the relatively high barrier to
rotation in 5a could be due to the restricting effect of the CH···
OC hydrogen bond,14 given that this interaction has been
previously estimated to have a strength of 3 kcal mol−1.15 In
other words, the attractive nature of this interaction could raise
the activation barrier to rotation in this molecule, even though
the rotation at room temperature is 14 MHz.
bondlike interaction between the CAr−H fragment and the
CO group.
A linear correlation was also found between the ρ(r) values
and the temperature (Figure 9), which clearly shows that the
These experimental data prompted us to estimate the nature
and the contribution of this intermolecular interaction by
means of theoretical calculations.
Theoretical Characterization of the Hydrogen Bond.
According to IUPAC recommendations, “The hydrogen bond
is an attractive interaction between a hydrogen atom from a
molecule or a molecular fragment X−H in which X is more
electronegative than H, and an atom or a group of atoms in the
same or a different molecule, in which there is evidence of bond
formation”.16 In the same work, it was mentioned that one of
the characteristics of hydrogen bonds is the presence of a bond
critical point between H and Y. Thus, topological analyses of
the electronic charge density, ρ(r), were performed to
characterize the hydrogen bondlike interaction between the
CAr−H fragment and the CO group. The associated bond
critical point (BCP) was found (BCP1, Figure 8), which
confirms the proposed interaction.
In addition, another BCP was also found (BCP2, Figure 8),
which corresponds to an H-π interaction. The values of ρ(r)
and its Laplacian, ∇2ρ(r), for the geometries experimentally
identified at each investigated temperature, are reported in
Table 3. The values of ∇2ρ(r) are negative at both BCPs,
indicating that the electronic charge density is concentrated in
the space region between the interacting molecules. In addition,
the values of ρ(r) and ∇2ρ(r) at the BCPs clearly show that the
H-π interaction is significantly weaker than the hydrogen
Figure 9. Electronic charge density, ρ(r), at the bond critical points
(BCP) vs temperature. Each linear correlation includes the
corresponding linear regression formulas.
interactions get stronger as the temperature decreases. Since
the values of ρ(r) quantitatively measure the electronic charge
concentration in the internuclear region, the values of ρ(r) are a
direct indicator of the interaction strength.17 Interestingly, the
linear regression coefficient (R2) is larger for the ρ(r) of BCP1
than for BCP2 (0.96 and 0.89, respectively). Moreover, when
considering these two BCP together, the R2 value becomes
even higher (0.98). This might be taken as evidence that the
importance of BCP1 on the interactions between adjacent
molecular rotors is larger than that of BCP2, albeit the role of
the H-π interaction is not negligible. In the three cases
(considering BCP1, BCP2, and BCP1+BCP2), the value of
ρ(r) increases 15−16% as the temperatures goes from 293 to
100 K, which is significant.
A different approach was also explored to characterize the
attractive interactions between adjacent rotors. It consisted of
estimating the electronic stabilization energy (ΔE) associated
with such interaction. To that purpose, the ΔE values were
calculated as the difference between the energy of the molecular
complex (EAB) and that of the separated fragments (EA and
EB):
Table 3. Values of the Electronic Charge Density, ρ(r), and
its Laplacian, ∇2ρ(r), at Different Temperatures
BCP1
BCP2
T (K)
ρ
L
ρ
L
293
273
223
173
100
0.00773
0.00759
0.00833
0.00867
0.00915
−0.00688
−0.00671
−0.00748
−0.00779
−0.00834
0.00260
0.00280
0.00283
0.00298
0.00308
−0.00175
−0.00187
−0.00189
−0.00197
−0.00203
ΔE = (EA + EB) − EAB
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The obtained results, when considering both the reduced and
the complete models are shown in Figure 10.
proposed by Afonin et al.: EHB = 0.27−0.45 V.25 (c) The NMR
approach, based on the relationship between EHB and the
chemical shift (Δδ) of the H-bonded proton. EHB = Δδ + 0.4.25
The values obtained for EHB were 1.4, 1.2, and 1.7 kcal/mol
for approaches (a−c, respectively). The latter being in excellent
agreement with the CBS extrapolated value, which is assumed
to be the most accurate one. It was recently proposed that
CH···OC HB interactions are expected to have EHB values in
the −3 to −1 kcal/mol range.25 The EHB corresponding to the
case studied here is within that range, regardless of the
approach used to estimate it. Moreover, considering the data
obtained for EHB with the different used approaches, it can be
proposed that the energy of the HB interaction, in this case, is
around 2 kcal/mol.
Theoretical Calculations of the Activation Energy to
Rotation Ea. On the basis of the results presented in the
previous section, among other intermolecular interactions, the
hydrogen bond involving the CO group has a significant
effect over the rotating fragment. In other words, the dispersion
interactions between side chains are not expected to hinder the
rotation of the phenylene fragment, and the effect of the
surrounding H-π interaction on this is expected to be very
small.
Furthermore, to evaluate the different contributions to the
rotation barrier, the associated electronic energy surface was
explored. To that purpose, the dihedral angle in the reduced
model was scanned, using 10° steps, starting from the X-ray
molecular structure as the minimum energy conformation. It
was found that the angle at which the maximum energy is
reached is about 100°, which is in good agreement with the 2-
fold model, where the maximum energy is expected to be near
90° (Figure 11). With the use of the maximum energy value,
Figure 10. Interaction energy (ΔE) vs temperature. Each linear
correlation includes the corresponding linear regression formulas.
In the case of ΔE, the linear relationship with the
temperature is also clear (the R2 value is 0.99, regardless of
the used model). In addition, the trends shown in Figure 10 are
consistent with those from the topological analyses (i.e., the
interaction between adjacent fragments become stronger as the
temperature decreases).
The finding that the stabilization energy is larger for the
complete model can be explained by the likely dispersion
interactions between the side chains in both rotors. Therefore,
albeit the hydrogen bondlike interaction between the CAr−H
fragment and the CO group is predicted to be the strongest
one, other weaker but still significant interactions also
contribute to the packed arrangements of the molecular rotors.
To validate the proposed contribution of the HB,
calculations at M06-2X/6-311+G(d,p) level of theory were
performed for a model system that is a fragment of the rotor
investigated here, but only with the CH···OC interaction
(see Figure S9B). From this calculation, the energy associated
with the HB is 2.3 kcal/mol. This is in good agreement with
that proposed by Scheiner;15 the difference (0.7 kcal/mol) is
below the chemical accuracy (1 kcal/mol) and also below the
uncertainties inherent to both theoretical calculations. The
structural differences between the Scheiner model and ours
seem to be only of minor importance based on the fact that the
investigated HB is essentially local in nature. However, to
obtain a more reliable value for the system under investigation
here, the HB interaction energy (EHB) was recalculated to
eliminate basis sets superposition errors (BSSE). Although the
most common way to do so is to use counterpoise (CP)
corrections, there are numerous reports suggesting that CP
overcorrects the BSSE.18−22 Therefore, extrapolations to
complete basis sets (ECBS) have been performed instead. To
that purpose, correlated consisting Duning’s basis sets (cc-
pVDZ, cc-pVTZ, cc-pVQZ, and cc-pV5Z) were used, and the
extrapolations were performed using the Koppler-type23
expression. The extrapolated value was found to be 1.7 kcal/
mol.
Figure 11. Schematic representation of the energy partition of the 2-
fold (180° jumps) rotational potential of compound 5a: intrinsic
barrier to rotation (2 kcal mol−1), CH···OC hydrogen bond (2 kcal
mol−1) and packing effects (2−3 kcal mol−1). The colored bars
indicate the uncertainty inherent to the theoretical calculations and
represent approximately 1 kcal mol−1.
the electronic barrier was estimated for a single rotor and for
the complete model (Figure S9). In the isolated rotor, it is only
1.95 kcal/mol, while in the complete model the calculated
barrier is 7.06 kcal/mol. The latter value is in complete
agreement with the Ea value obtained from the solid-state NMR
data (7.87 kcal/mol).
Accordingly, an energy partition can be proposed, where at
least three contributions can be identified (Figure 11): (i) The
intrinsic component, which according to the calculations
performed for the isolated rotor is about 2 kcal/mol. (ii) The
In addition, other approaches were also used to estimate HB
interaction energies. It was estimated according to (a)
Espinosa’s approach, which is based on QTAIM, specifically
on the dependence of EHB on the local potential energy (V):
EHB = 0.5 V.24 (b) Another approach based on V recently
H
DOI: 10.1021/acs.joc.8b00134
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
processed employing the MestreNova NMR processing program
(see http://mestrelab.com/). Mass spectra were registered in a Jeol,
AccuTOF JMS-T100LC spectrometer using the electron spray
ionization with time-of-flight technique and in the MStation JMS-
700 spectrometer using the fast atom bombardment with quadrupole
mass analyzer.
energy cost of breaking the hydrogen bond (HB) interaction,
about 2 kcal/mol. (iii) Additional packing effects, responsible
for the difference between (i) + (ii) and the barrier of the
complete model [i.e., 7 kcal/mol − (2 + 2) kcal/mol ≈ 3 kcal/
mol].
However, (iii) could be higher considering that the
experimental activation energy is about 1 kcal/mol higher
than the calculated one. Thus, in the studied SMR, the
contributions from the packing effects are expected to be about
3 to 4 kcal/mol.
(25R)-Spirost-4-en-3-one (2). Diosgenin (1) (9.95 g, 24 mmol
mmol) and cyclohexanone (20 mL) were dissolved in toluene (160
mL), and 10 mL of the solvent were distilled off. Aluminum
isopropoxide (1.47 g) was added, and the mixture was refluxed for 3 h,
poured into a solution of sodium tartrate (10 g in 200 mL of water),
stirred for 20 min, and filtered. The organic layer was washed with
water (3 × 50 mL), dried (anh. Na2SO4), and evaporated.
Chromatographic purification afforded the desired α,β-unsaturated
ketone 2 (8.63 g, 20.95 mmol, 87.3%). Mp: 189.1−190.6 °C (from
CONCLUSIONS
■
The design, synthesis, and spectroscopic characterization of the
crystalline SMR 5 was carried out. X-ray diffraction studies ran
between 293 and 100 K corroborated that the crystal array is
ethyl acetate/hexane). Lit.:26 186−188 °C. H NMR (CDCl3, 400
1
MHz): δ 5.70 (d, J = 1.8 Hz, 1H), 4.38 (ddd, J = 8.8, 7.5, 6.3 Hz, 1H),
3.45 (ddd, J = 11.4, 4.9, 2.0 Hz, 1H), 3.34 (t, J = 10.9 Hz, 1H), 1.18 (s,
3H), 0.95 (d, J = 7.0 Hz, 3H), 0.80 (s, 3H), 0.77 (d, J = 6.3 Hz, 3H).
13C NMR (100.52 MHz): δ 33.6 C-1, 33.9 C-2, 199.4 C-3, 123.9, C-4,
171.1 C-5, 32.7 C-6, 32.1 C-7, 34.1 C-8, 53.7 C-9, 38.6 C-10, 20.7 C-
11, 39.6 C-12, 40.3 C-13, 55.6 C-14, 31.6 C-15, 80.7 C-16, 61.9 C-17,
16.3 C-18, 17.33 C-19, 41.6 C-20, 14.5 C-21, 109.2 C-22, 31.3 C-23,
28.7 C-24, 30.2 C-25, 67.0 C-26, 17.1 C-27.
2
stable at low temperatures. Additional solid state H NMR
experiments revealed that, at room temperature, the deuterated
analog of compound 5 (5b) undergoes very fast 180° rotations
at 14 MHz frequency. This unusually high frequency was
attributed to the flexibility of the alkyne axis, which is linked to
the secosteroid stator through an −CH2−CH2− moiety.
The activation energy of Ea = 7.87 kcal mol−1 found for this
rotational process is significantly influenced by a nonconven-
tional intermolecular hydrogen bond, which hinders the motion
of the rotating fragment. The observed hydrogen bond
interaction between adjacent rotors was characterized using
theoretical calculations. The relationship with the temperature
was confirmed using topological analyses.
(25R)-4,5-Epoxy-5α-spirostan-3-one (3a) and (25R)-4,5-epoxy-5β-
spirostan-3-one (3b) methanol (100 mL) 10% p/v NaOH solution
(5.6 mL) and 30% H2O2 (11.2 mL) were added in this order to a
solution of the α,β-unsaturated ketone 2 (8.2522 g, 20.0 mmol) in
CH2Cl2 (100 mL), and the resulting mixture was stirred for 72 h at
room temperature. Water was added, and the solvent was evaporated
until a copious precipitate was produced. The solid was filtered,
washed with water, and dried in the filter. Crystallization from hexane
ethyl acetate afforded 6.46 g (75.4%) of a 1/3.02 mixture of the known
epimeric epoxides (3a) and (3b)7 that resisted all attempts at
separation and was used in the next step without further purification or
separation. DR was calculated by relative integration of the signals of
H-4 in each epimer). Assignment of the NMR signals for each epimer
in the mixture was based on our previously reported data for a series of
spirostan sapogenins27a and epimeric 4,5-epoxy-steroids.27b
Combining theoretical calculations with experimental meas-
urements, it was possible to propose a partition of Ea into three
contributions. They are the cost of the intrinsic rotation (∼2
kcal/mol), the hydrogen bond interaction (∼3 kcal/mol), and
the packing effects (∼2−3 kcal/mol).
2
Additional features of the H line shapes noticed below 230
K could be attributed to vibrational components or further
angular trajectories of the flexible moiety that includes the
phenylene rotator, the alkyne axes, together with the C-1C-2
and C-1′C-2′ fragments of the steroidal stator. This small
oscillation mode could not be fully described, and it might be
present at higher temperatures but is not measurable because it
is masked by the fast and dominant 2-fold rotation of the 1,4-
diethynylphenylene moiety.
In summary, the amalgamation of the structural flexibility and
the effect of a CH···OC hydrogen bond modulates the
rotational motion of this novel SMR. The inclusion of
structural modifications to this SMR that might shed light on
the dynamic behavior of this kind of rotor are currently
underway.
(25R)-4,5-Epoxy-5α-spirostan-3-one (3a) and (25R)-4,5-epoxy-5β-
1
spirostan-3-one (3b) H NMR (CDCl3, 400 MHz) δ (ppm): 4.38
(ddd, J = 8.6, 7.5, 6.3 Hz, H-16 3a and 3b), 3.46 (ddd, J = 11.0, 4.5, 2.1
Hz, H-26 eq. 3a and 3b), 3.35 (m, 1H, H-26 ax. 3a and 3b), 3.02 (s,
H-4β, 3a), 2.96 (s, H4α, 3b), 1.15 (s, H-19 3b), 1.06 (s, H-19 3a),
0.96 (d, J = 6.5 Hz, H-27 3a), 0.95 (d, J = 7.0 Hz, H-27 3b), 0.78 (m
H-18 3a and 3b, H-21 3a and 3b)
(25R)-4,5-Epoxy-5α-spirostan-3-one (3a) 13C NMR (CDCl3,
100.53 MHz): δ 29.1 C-1, 33.1 C-2, 206.9 C-3, 62.8 C-4, 70.0 C-5,
29.6 C-6, 29.1 C-7, 35.0 C-8, 50.7 C-9, 36.8 C-10, 21.2 C-11, 39.4 C-
12, 40.4 C-13, 55.4 C-14, 31.7 C-15, 80.6 C-16, 62.1 C-17, 16.3 C-18,
16.5 C-19, 41.6 C-20, 14.4 C-21, 109.2 C-22, 31.3 C-23, 28.8 C-24,
30.2 C-25, 66.8 C-26, 17.1 C-27.
(25R)-4,5-Epoxy-5β-spirostan-3-one (3b) 13C NMR (CDCl3,
100.53 MHz): δ 26.1 C-1, 32.5 C-2, 206.7 C-3, 62.6 C-4, 70.2 C-5,
29.7 C-6, 30.5 C-7, 34.7 C-8, 46.5 C-9, 37.2 C-10, 21.3 C-11, 39.7 C-
12, 40.6 C-13, 55.6 C-14, 31.7 C-15, 80.5 C-16, 62.0 C-17, 16.4 C-18,
19.0 C-19, 41.6 C-20, 14.4 C-21, 109.2 C-22, 31.3 C-23, 28.8 C-24,
30.2 C-25, 66.8 C-26, 17.1 C-27.
EXPERIMENTAL SECTION
■
Synthesis and Characterization. General Conditions. Reactions
were monitored by TLC on Alugram SIL G/UV254 plates from
Macherey-Nagel. Chromatographic plates were sprayed with a 1%
solution of vanillin in 50% HClO4 and heated until color developed.
Melting points were measured on a Melt-Temp II apparatus and are
uncorrected. NMR spectra were recorded in CDCl3 solutions in a
Varian INOVA 400 MHz spectrometer using the solvent signal as
references. NMR signal assignments were carried out with the aid of a
(25R)-4,5-Secospirost-3-yn-5-one (4). p-Toluenesulfonyl hydrazide
(1.024 g, 5.5 mmol, 1.1 equiv) was slowly added during 20 min to a
solution of a mixture of the diastereomeric epoxides 3a and 3b (2.14 g,
5.0 mmol) in CH2Cl2/AcOH 1/1 (80 mL), and the mixture was
stirred for 2.5 h before pouring into saturated NaCl solution (150
mL). The organic layer was separated and the aqueous phase was
extracted with ethyl acetate (3 × 50 mL). The combined organic layers
were washed with water (4 × 50 mL), 10% aqueous NaHCO3 (6 × 50
mL), water (2 × 20 mL), brine (20 mL); dried (anh. Na2SO4) and
evaporated. The obtained syrup was purified in a column packed with
silica gel (80 g) employing hexane/ethyl acetate 12/1 as eluent, to
afford the alkynone 4 (1.55 g, 75.2%). Mp: 148.1−149.6 °C (from
combination of 1D and 2D NMR techniques that included H, 13C,
1
1H−1H correlated spectroscopy (COSY), nuclear overhauser effect
spectroscopy (NOESY), heteronuclear single quantum correlation
(HSQC), and heteronuclear multiple bond correlation (HMBC). All
2D NMR spectra were recorded using the standard pulse sequences
and parameters recommended by the manufacturer and were
I
DOI: 10.1021/acs.joc.8b00134
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The Journal of Organic Chemistry
Article
1
ethyl acetate/hexane). H NMR (CDCl3, 400 MHz): δ 4.40 (ddd, J =
specimen was fully collected at 293(2) K and at 100(2) K, and short
collections (connectivity only) were verified at 273(2) K, at 223(2) K
and at 223(2) K. The X-ray refinement of all the structures was carried
out using direct methods using SHELXL.28 All the non-hydrogen
atoms were refined anisotropically, and the hydrogens were placed
geometrically (Table S1, Figures S4 to S8).
8.6, 7.5, 6.3 Hz, 1H, H-16β), 3.46 (ddd, J = 11.0, 4.6, 2.0 Hz, 1H, H-26
equiv), 3.35 (dd, J = 10.9, 10.9 Hz, 1H, H-26 ax.), 2.53 (td, J = 14.4,
6.1 Hz, 1H, H-6 ax.), 2.27 (ddd, J = 14.7, 4.5, 2.1 Hz, 1H, H-6 equiv),
2.10 (m, 2H, H-2), 1.92 (m, 1H, H-4), 1.09 (s, 3H, H-19), 0.97 (d, J =
7.0 Hz, 3H, H-21), 0.83 (s, 3H, H-18), 0.78 (d, J = 6.4 Hz, 3H, H-27).
13C NMR (100.52 MHz): δ 33.5 C-1, 13.7 C-2, 85.0 C-3, 68.0, C-4,
214.2 C-5, 38.0 C-6, 31.2 C-7, 34.5 C-8, 47.3 C-9, 50.7 C-10, 21.3 C-
11, 39.3 C-12, 40.5 C-13, 55.6 C-14, 31.8 C-15, 80.4 C-16, 62.0 C-17,
16.4 C-18, 20.6 C-19, 41.6 C-20, 14.5 C-21, 109.2 C-22, 31.6 C-23,
28.8 C-24, 30.2 C-25, 66.8 C-26, 17.1 C-27. HRMS (ESI): calculated
for C27H41O3 [M + H]+, 413.3056; found, 413.3064.
General Procedure for Sonogashira Coupling. 1,4-Diiodobenzene
(165.0 mg, 0.5 mmol) or 1,4-diiodobenzene-D4 (166.9 mg, 0.5 mmol),
(25R)-4,5-secospirost-3-yn-5-one (4) (453.9 mg, 1.1 mmol), and
triethylamine (2.5 mL)* were placed in a dry flask under sonication.
After the addition of Pd[P(C6H5)3]4 (9.6 mg, 0.0083 mmol) and CuI
(3.2 mg, 0.0166 mmol), the flask was purged three times with Ar
under sonication and the mixture was stirred at room temperature for
1 h. Finally, the reaction mixture was filtered through a plug of silica
gel employing ethyl acetate as eluent, and the solvent was removed in
vacuo to produce the crude adduct that was purified in a
chromatographic column packed with silica gel (30 g) employing
hexane/ethyl acetate, 15/1 as eluent to afford the product 5a or 5b.
*The reaction with the deuterated analog (1,4-diiodobenzene-D4) was
carried out in 4.5 mL of triethylamine
Powder X-ray Diffraction Experiments. Powder X-ray dif-
fraction data was taken from the same crystalline material before the
solid-state NMR experiments and compared with the calculated data
from the single crystal X-ray structure. The analyses of compound 5b
was carried out in a Panalytical XPERT-PRO using Cu Kα1 = 1.5406 Å
radiation at room temperature. Data were collected at room
temperature in the range of 2Θ = 5−55° (step of 0.016°, step time
133−163 s).
Solid State NMR Samples. All solid state NMR spectra were
recorded in a Bruker Avance 300 spectrometer.
Solid State 13C CPMAS. The crystalline compound 5a was packed
in a 4 mm wide ZrO2 rotor with a ceramic cap for variable temperature
measurements. All the experiments were carried out under N2
atmosphere. The solid-state NMR 13C CPMAS spectra of 5a were
recorded at variable temperatures using a 13C frequency of 75.47 MHz,
1
with a H broadband decoupler in a 4 mm broadband probe. The
dipolar dephasing experiments used a spinning frequency of 10 kHz
for the removal of spinning sidebands, and an optimized cross-
polarization contact time of 5 ms was used.
Solid State 2H NMR Experiments. The deuterated derivative 5b was
crystallized in the same conditions and solvent (ethyl acetate/hexane)
described for 5a and packed inside a glass rod surrounded by Teflon
caps. Static wide-line deuterium NMR was carried out at variable
temperatures in a spectrometer operating at 46 MHz.
1′,4′-Di((25R)-4,5-secospirost-3-yn-5-one-4-yl)-benzene (5a).
Yield 316.0 mg, 0.35 mmol, 70%. Mp: 223.9−225.0 °C (from ethyl
1
acetate/hexane). H NMR (CDCl3, 400 MHz): δ 7.25 (s, 4H, H-
phenylene), 4.40 (ddd, J = 8.4, 7.4, 6.3 Hz, 2H, H-16 and H-16′), 3.47
(ddd, J = 10.6, 4.5, 2.0 Hz, 2H, H-26 ax. H-26′ ax.), 3.36 (dd, J = 10.9,
10.9 Hz, 2H, H-26 eq. H-26′ eq ), 2.54 (td, J = 14.5, 6.1 Hz, 2H, H-6
ax. H-6′ ax), 2.37 (ddd, J = 15.5, 10.0, 5.4 Hz, 2H, H-2a H-2a′), 2.29
(m, 1H, H-6 eq. H-6′ eq), 2.24 (m, 2H, H-2b H-2b′), 1.11 (s, 6H, H-
19 H-19′), 0.96 (d, J = 6.9 Hz, 6H, H-21 H-21′), 0.84 (s, 6H, H-18 H-
18′), 0.78 (d, J = 6.3 Hz, 6H, H-27 H-27′). 13C NMR (100.53 mHz):
δ 33.7 C-1 C-1′, 14.8 C-2 C-2′, 92.1 C-3 C-3′, 80.4 C-4 C-4′, 214.3 C-
5 C-5′, 38.0 C-6 C-6′, 31.2 C-7 C-7′, 34.5 C-8 C-8′, 47.3 C-9 C-9′,
50.7 C-10 C-10′, 21.4 C-11 C-11′, 39.4 C-12 C-12′, 40.5 C-13 C-13′,
55.6 C-14 C-14′, 31.8 C-15 C-15′ 80.4 C-16 C-16′ 62.0 C-17 C-17′,
16.4 C-18 C-18′, 20.7 C-19 C-19′, 41.6 C-20 C-20′, 14.5 C-21 C-21′,
109.2 C-22 C-22′, 31.4 C-23 C-23′, 28.8 C-24 C-24′, 30.2 C-25 C-25′,
66.8 C-26 C-26′, 17.1 C-27 C-27′, 123.1 2× ipso phenylene, 131.2 4×
CH phenylene. HRMS (FAB): calculated for C60H83O6 [M + H]+,
899.6190; found, 899.6190.
Thermal Analysis (TGA) and Differential Scanning Calorimetry
(DSC). Calorimetry and thermogravimetric analysis were performed in
a Netzsch instrument under nitrogen atmosphere. The crystalline
sample of 5a (3.354 mg) crystallized in hexane/ethyl acetate was
analyzed using a heating ramp of 10 °C/min.
Line Shape Simulations. NMR spectra were simulated with the
NMRWeblab program,29 using the following parameters: QCC = 176
kHz, cone angle θ = 60°, and recycle delay = 50 μs. A line broadening
of 4.0 and 2.5 MHz was applied for the simulated and experimental
traces, respectively.
Theoretical Calculations. All the electronic calculations were
performed with the Gaussian 09 package of programs.30 For the
analyses based on the Quantum Theory of Atoms in Molecules
(QTAIM),17 a reduced model was used (see Figure S9A) and the
calculations were carried out with the M06-2X functional31 combined
with the 6-311+G(d,p) basis set. Only single point calculations were
performed in this case, and the wave functions were obtained for each
structure at their experimental geometries. The M06-2X functional has
been chosen because it performs well for thermochemistry, kinetics,
and noncovalent interactions.31 For the estimation of the interaction
energies, the two-layer ONIOM method32 was used for the complete
model including two adjacent rotors (see Figure S9). The high level
layer was treated at the same level of theory mentioned above, while
the low level layer was computed using the semiempirical method
PM6, which has been proven to be more accurate than other
semiempirical methods, particularly in the prediction of the energies
and geometries of hydrogen bonding (HB) interactions.33
1′,4′-Di-((25R)-4,5-secospirost-3-yn-5-one-4-yl)-benzene-D4 (5b).
Yield 346.2 mg, (0.38 mmol, 76%). Mp: 226.6−227.4 °C (from ethyl
1
acetate/hexane). H NMR (CDCl3, 400 MHz): δ 4.40 (ddd, J = 8.5,
7.4, 6.3 Hz, 2H, H-16 H-16′), 3.46 (ddd, J = 11.1, 4.6, 2.0 Hz, 2H, H-
26 eq. H-26′ eq.), 3.35 (dd, J = 10.9, 10.9 Hz, 2H, H-26 ax. H-26′ ax.),
2.54 (td, J = 14.5, 6.1 Hz, 2H, H-6 ax. H-6′ ax.), 2.36 (ddd, J = 15.5,
10.0, 5.4 Hz, 2H, H-2a, and H-2a′), 2.30 (m, 2H, H-6 eq. and H-6′
eq.), 2.27 (m, 2H, H-2b, and H-2′b), 1.11 (s, 6H, H-19 H-19′), 0.96
(d, J = 7.0 Hz, 6H, H-21 H-21′), 0.83 (s, 6H, H-18 H-18′), 0.78 (d, J =
6.3 Hz, 6H, H-27 H-27′). 13C NMR (100.53 MHz): δ 33.6 C-1 C-1′,
14.8 C-2 C-2′, 92.1 C-3 C-3′, 80.3 C-4 C-4′, 214.3 C-5 C-5′, 38.0 C-6
C-6′, 31.1 C-7 C-7′, 34.5 C-8 C-8′, 47.3 C-9 C-9′, 50.7 C-10 C-10′,
21.4 C-11 C-11′, 39.3 C-12 C-12′, 40.5 C-13 C-13′, 55.6 C-14 C-14′,
31.8 C-15 C-15′, 80.4 C-16 C-16′, 62.0 C-17 C-17′, 16.3 C-18 C-18′,
20.7 C-19 C-19′, 41.6 C-20 C-20′, 14.4 C-21 C-21′, 109.2 C-22 C-22′,
31.3 C-23 C-23′, 28.8 C-24 C-24′, 30.2 C-25 C-25′, 66.8 C-26 C-26′,
17.1 C-27 C-27′, 123.0 2× ipso phenylene, 131.1, 130.8. 130.6, 4 ×
CH phenylene. HRMS (FAB) calculated for C60H79D4O6 [M + H]+,
903.6441; found, 903.6438.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.8b00134.
Solid State Studies. Crystal Growth and X-ray Diffraction.
Single crystals of 5a suitable for X-ray studies were grown by slow
evaporation of ethyl acetate/hexane solutions in open vials. The
resulting prisms were collected in a Bruker Apex-Duo with a D8
goniometer and APEX II detector using Mo Kα radiation. To rule out
crystallographic phase transitions at low temperature, a single crystal
NMR spectra of all obtained compounds. Crystallo-
graphic data, thermogravimetric analysis and differential
scanning calorimetry for compound 5a, variable temper-
ature 2H spin echo experiments for compound 5b,
ORTEP plots of the 5a crystal structure at various
J
DOI: 10.1021/acs.joc.8b00134
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
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temperatures, models used for theoretical calculations
(PDF)
5a at 100 K (CIF)
5a at 293 K (CIF)
Reduced model data (TXT)
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Echeverri, F. Molecules 2013, 18, 3356−3378.
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AUTHOR INFORMATION
■
(11) Duer, M. J. Introduction to Solid-State NMR Spectroscopy;
Blackwell: Oxford, 2004.
(12) Wasylishen, R. E.; Ashbrook, S. E.; Wimperis, S. NMR of
Quadrupolar Nuclei in Solid Materials; Wiley: Chichester, United
Kingdom, 2012.
(13) Kawski, A. Crit. Rev. Anal. Chem. 1993, 23, 459−529.
(14) Zhang, Q.-C.; Wu, F.-T.; Hao, H.-M.; Xu, H.; Zhao, H.-X.;
Long, L.-S.; Huang, R.-B.; Zheng, L.-S. Angew. Chem., Int. Ed. 2013, 52,
12602−12605.
Corresponding Authors
*E-mail: martin.iglesias@unam.mx. Tel: 52(55) 56223899, ext
44417. Fax: 52(55) 56223899.
*E-mail: brodriguez@iquimica.unam.mx. Tel: 52(55)
56224405.
*E-mail: agal@xanum.uam.mx. Tel: 52(55) 58044600, ext
4372.
ORCID
(15) Scheiner, S. J. Phys. Chem. B 2005, 109, 16132−16141.
(16) Arunan, E.; Desiraju, G. R.; Klein, R. A.; Sadlej, J.; Scheiner, S.;
Alkorta, I.; Clary, D. C.; Crabtree, R. H.; Dannenberg, J. J.; Hobza, P.;
Kjaergaard, H. G.; Legon, A. C.; Mennucci, B.; Nesbitt, D. J. Pure Appl.
Chem. 2011, 83, 1637−1641.
Annia Galano: 0000-0002-1470-3060
Braulio Rodríguez-Molina: 0000-0002-1851-9957
Martín A. Iglesias-Arteaga: 0000-0003-4764-7664
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(18) Schwenke, D. W.; Truhlar, D. G. J. Chem. Phys. 1985, 82, 2418−
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The authors acknowledge the financial support provided by
The Faculty of Chemistry-UNAM (Grant PAIP-5000-9063),
DGAPA-UNAM (Grant PAPIIT-IN212417), and CONACyT
(Grant 238913). M.C.M.T. and A.C.M. thank CONACYT
(Scholarships 294665 and 576483). Thanks are due to the
UCLA Department of Chemistry and Biochemistry for solid
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