Stereochemical inversion of rim-differentiated pillar[5]arene molecular swings

Article abstract of DOI:10.1021/acs.joc.0c01464

To investigate the dynamic stereochemical inversion behavior of pillar[5]arenes (P[5]s) in more detail, we synthesized a series of novel rim-differentiated P[5]s with various substituents and examined their rapid rotations by variable-temperature NMR (203

Full text of DOI:10.1021/acs.joc.0c01464

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Article
Stereochemical Inversion of Rim-Differentiated Pillar[5]arene
Molecular Swings
Ke Du,∥ Paul Demay-Drouhard,∥ Kushal Samanta, Shunshun Li, Tushar Ulhas Thikekar, Haiying Wang,
Minjie Guo, Barend van Lagen, Han Zuilhof,* and Andrew C.-H. Sue*
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ABSTRACT: To investigate the dynamic stereochemical inversion behavior of pillar[5]arenes (P[5]s) in more detail, we
synthesized a series of novel rim-differentiated P[5]s with various substituents and examined their rapid rotations by variable-
temperature NMR (203−298 K). These studies revealed for the first time the barrier of “methyl-through-the-annulus” rotation (ΔG‡
= 47.4 kJ·mol−1 in acetone) and indicated that for rim-differentiated P[5]s with two types of alkyl substituents, the smaller rim
typically determines the rate of rotation. However, substituents with terminal CC or CC bonds give rise to lower inversion
barriers, presumably as a result of attractive π−π interactions in the transition state. Finally, data on a rim-differentiated penta-
methyl-penta-propargyl P[5] exhibited the complexity of the overall inversion dynamics.
INTRODUCTION
■
Pillar[5]arene1 (P[5]s), consisting of five repeating para-
substituted hydroquinone units connected by methylene
bridges, are a class of macrocycles with intriguing dynamic
stereochemical properties.2 In the solid state, the P[5] scaffold
forms its characteristic name-giving hollow pillar-like structure,
with all five hydroquinone units aligned, as a result of both
steric hindrance and guest inclusion.1 While a near-constant
pillar shape is observed with alkoxy groups on both sides, this
conformation is not observed anymore if the alkyl substituents
are (partially) removed to expose phenolic −OH groups for
intramolecular hydrogen bonding,3 or when one of the rims
has only C−H functionalization, as shown in recently
Figure 1. Schematic representation of the stereochemical inversion
between enantiomeric conformers of pillar[5]arene and the idealized
synthesized tiara[5]arenes.4 Such structural variability reflects
the rich conformational isomerism of P[5]s,5 as the hydro-
quinone planes may rotate and adopt various angles relative to
energy curve of the inversion process. The hydroquinone units flip by
way of “R1/R2-through-the-annulus” motions: R1 moves either
through the cavity while R2 goes along the outside (top route in
the overall pentagonal scaffold in solution.
Different from calix[n]arenes,6 on which additional sub-
red) or the other way around (bottom route in blue).
stituents have to be grafted to break internal mirror planes,
P[5]s are inherently chiral7 regardless of their functionalization
patterns. The chirality of the P[5] scaffold with respect to a
Received: June 20, 2020
plane of symmetry σ arises from its nonplanar conformations,
which contain neither plane nor center of symmetry.
Enantiomeric P[5] conformers are interconvertible to each
other through a sequence of “substituent-through-the-annulus”
inside-out and outside-in rotations (Figure 1). This motion is
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complicated in nature: before the first ring has fully rotated, the
second already starts to rotate to minimize any incurred steric
hindrance between adjacent rings. Along this interconversion
path, multiple transition states and intermediates may be
observed, depending on the nature of the substituents.8 When
the inversion energy barriers are not high enough to hinder
such movements, in solution, P[5]s are stereolabile, under-
going rapid enantiomerization9 or diastereoisomerization10
when chiral substituents are attached onto the P[5] scaffold,
under thermodynamic equilibrium.
Scheme 1. (a) Syntheses of Rim-Differentiated
Pillar[5]arenes and (b) Per-Functionalized Pillar[5]arenes
under Current Study
In 2010, Ogoshi and co-workers systematically inves-
tigated11 the stereochemical inversion processes of a series of
per-functionalized P[5]s with different n-alkyl chain lengths by
dynamic NMR (DNMR). The rotation barriers derived from
the corresponding coalescence temperatures (Tc) range from
46.3 (ethyl) to 63.2 (n-dodecyl) kJ·mol−1, showing a
monotonic increase of the inversion barrier with the increase
of the n-alkyl chain length. Nonetheless, the inversion barrier
of per-methyl-P[5],1a one of the most widely used P[5]s on
account of its high-yielding facile synthesis, could not be
accurately determined, since its overall structure does not
1
contain any diastereotopic H probes for DNMR study. The
energy barrier for rotation of A1-/A2-dihydroxy-octamethyl
P[5] [A1/A23b,12 refers to both hydroxy groups being bound
to the same aryl ring, and located at different rims] was
reported13 by Stoddart et al. in 2013 to be 49.7 kJ·mol−1 in
CDCl3. The interactions provided by intramolecular hydrogen
bonds were found to significantly impact the stereochemical
inversion barriers of these difunctionalized P[5] derivatives.
When the substituents on P[5]s are bulky enough to enable
successful chiral resolution, inversion energy barriers can
apart from by DNMRalso be determined14 by monitoring
the racemization process using circular dichroism spectroscopy
or HPLC with chiral stationary phases.
recently developed.17 Per-functionalized P[5]s 2a−2c were
prepared by following the procedures reported in the
literature.11,18 We briefly describe this procedure for one of
the compounds under study, a rim-differentiated P[5] with 4-
cyanobenzyl moieties on one rim and methyl groups on the
other, (4-cyanobenzyl)5(Me)5-P[5] 1d (see also the Exper-
imental Section). Compound 1d was obtained through two
synthetic routes. The first one involved the FeCl3-catalyzed
cyclization of the corresponding asymmetrically substituted
2,5-dialkoxybenzyl alcohol according to our previously
synthesized “preoriented” procedure17a and generated the
expected product in 10% yield after careful column
chromatography. The other pathway entailed the synthesis of
generic building block (benzyl)5(Me)5-P[5] 1e16c,17bas this
can easily be obtained on a gram scale, with 25% isolated
yieldfollowed by a highly efficient two-step debenzylation/
realkylation17b with 4-cyanobenzyl bromide, affording (4-
cyanobenzyl)5(Me)5-P[5] 1d in a near-quantitative yield.
This superior yield along with a much easier purification step
(precipitation from hot EtOAc) makes this indirect route
highly preferable.
So far, only per-functionalized15 and A1/A2-disubstituted
P[5]s3b,12 have been studied by DNMR for their inversion
processes, since most other P[5] functionalization patterns
with low symmetry result in complicated NMR spectra whose
assignments remain nontrivial. Rim-differentiated P[5]s,16
whose two rims are decorated with different functionalities,
represent another type of highly symmetric P[5] species. Such
rim differentiation is desirable for a number of applications,
and we thought to make use of this platform for dynamic
stereochemical studies on account of its two nondegenerate
rotational modes, e.g., R1-through-the-annulus and R2-through-
the-annulus (Figure 1). However, progress on DNMR studies
of such rim-differentiated P[5]s was hampered by their
inefficient syntheses and difficult purification steps. In recent
years, our research group has developed17 efficient methods for
the synthesis and derivatization of C5-symmetric rim-differ-
entiated P[5]s that largely overcome these limitations.
Dynamic NMR Studies. In our molecular design for (4-
cyanobenzyl)5(Me)5-P[5] 1d, the 4-cyanobenzyl groups serve
as stoppers that are too bulky to enter the P[5] cavity, and its
1
benzylic geminal protons can be employed as the H DNMR
probe. On the other hand, the “methyl-through-the-annulus”
movement of the other rim seems hardly affected (see Figure
2a). Instead of continuous full rotations, the stereochemical
inversion of the P[5] scaffold can still happen through back-
and-forth rocking resembling that of swings on the macro-
scopic scale.
To further verify that the 4-cyanobenzyl group is an effective
stopper of the rotational motion, single-crystal samples of (4-
cyanobenzyl)5(Me)5-P[5] 1d were obtained and then
elucidated (Figure 2b) by X-ray crystallography to provide
detailed information of its molecular geometry. In the solid
state, the P[5] macrocyclic scaffold adopts the typical pillar-like
shape containing a n-hexane guest in the cavity. The distance
between the center of a hydroquinone unit and the nitrogen
Taking advantage of this unique molecular scaffold, in this
paper, we report rim-differentiated P[5]-based “molecular
pentagonal swings” with restricted rocking motions. These
specifically synthesized compounds allow for the determination
1
of unattainable inversion barriers by variable-temperature H
NMR studies (203−298 K), differentiate the roles of size and
presence of π-electrons, and indicate a far greater complexity of
the rotation behavior than anticipated.
RESULTS AND DISCUSSION
Synthesis. First, a series of rim-differentiated P[5]s 1a−1e
were synthesized (Scheme 1) using the methodology we
■
B
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appearing as two doublets in the NMR spectra recorded at
lower temperatures. The inversion processes become faster and
increasingly relevant on the NMR time scale as the
temperature increases, and the fast exchange of the chemical
environment surrounding protons Ha and Hb causes
1
coalescence of their H NMR signals at 4.69 ppm at 240 K.
Above the coalescence temperature (Tc), the −OCH2− proton
signals eventually converge into a sharp singlet. Since the
stereochemical inversion of the “molecular pentagonal swings”
is only accessible through “methyl-through-the-annulus”
motions, the value of the barrier (ΔG‡) calculated (Table 1)
from the DNMR data, 47.3 kJ·mol−1, should therefore also
serve as a reasonable estimation of the inversion barrier of per-
methyl-P[5] in acetone-d6. Owing to the poor solubility of 1d,
attempts to determine its inversion barrier in toluene-d8 were
not successful. Instead, rim-differentiated (benzyl)5(Me)5-P[5]
1e with five benzyl groups19 was subjected (Figure 2d) to
DNMR measurements in toluene-d8, and the corresponding Tc
and ΔG‡ were found (Table 1) to be 250.5 K and 49.6 kJ·
mol−1, respectively.
To further understand the dynamic stereochemical inversion
behavior of P[5]s, additional DNMR studies were carried out
in toluene-d8 on a series of rim-differentiated P[5]s with
methyl on one rim and propargyl/allyl/propyl groups on the
other (compounds 1a−1c), as well as the corresponding per-
functionalized P[5]s 2a−2c with propargyl/allyl/propyl
substituents.
Figure 2. (a) Stereochemical inversions of 1d can be completed with
predominant “methyl-through-the-annulus” rotations, while similar
movements of the other 4-cyanobenzyl side were suppressed. (b) Side
views of crystal structure of 1d, where the distance between N atom
and center of aromatic unit on the P[5] scaffold is 10.2 Å and the
cavity size is 5.5 Å. (c) Partial DNMR spectra of Ha/Hb on 1d from
298 down to 203 K in acetone-d6. (d) Partial DNMR spectra of 1e
from 298 down to 213 K in toluene-d8.
Their coalescence temperatures and inversion barriers are
summarized in Table 1, and full NMR spectra are available in
the Supporting Information. The DNMR measurement of per-
functionalized (propyl)10-P[5] 2c shows (Figure 3a) a
coalescence temperature at 258 K and a corresponding
inversion barrier of 51.8 kJ·mol−1, which is within the 1 kJ·
mol−1 error range of the DNMR method compared to the
value of 50.9 kJ·mol−1 reported11 by Ogoshi on the same
compound. Nonetheless, the −OCH2− geminal proton NMR
signals of per-functionalized (propargyl)10-P[5] 2a and
(allyl)10-P[5] 2b did not show (Figure 3b,c) any splitting
even down to 203 K, suggesting that rotations of their
hydroquinone units still occur faster than the NMR time scale,
and their ΔG‡ values are even smaller than the lower detection
limit around 40 kJ·mol−1. Given the minor difference between
propyl and propargyl/allyl groups in terms of size, this
indicates thatin addition to steric hindrance and hydrogen
bondsthe presence of π electrons might favorably interact
with the aryl π electrons during the rotation process, exerting
considerable influence on the rate of the rim inversion process.
These experimental results further substantiate our previous
theoretical investigations on P[5] rotational energy profiles,8
which indicated that “the stabilization of the intermediate
atom on the tip of the 4-cyanobenzyl group is 10.2 Å, which is
larger than the roughly 5.5 Å opening of the P[5] macrocycle
(see Figure 2b). Furthermore, a difunctionalized P[5] with two
4-cyanobenzyl moieties attached on both sides of one
particular hydroquinone unit, namely, A1/A2-bis(4-cyanoben-
zyl)-P[5] 1d′, was also synthesized (see the Experimental
1
Section) for DNMR studies. A clear AB system of H NMR
signals of the −OCH2− methylene protons was still observed
(see the Supporting Information) at an elevated temperature of
367 K, indicating that even at that temperature, the geminal
−OCH2− protons exchange only slowly on the NMR time
scale. These experiments both suggest that the size of the
oxygen-bound 4-cyanobenzyl substituent is sufficient to block
the dynamic stereochemical inversion when attached to P[5]s.
The on-average C5 symmetry of 1d renders the correspond-
ing protons on the five repeating hydroquinone units
homotopic, resulting in simple and clear NMR spectra that
are easy to interpret. Variable-temperature 400 MHz 1H NMR
spectra were collected in acetone-d6 from 203 to 298 K (Figure
2c; see the Supporting Information for full spectra). As
expected, the geminal protons Ha and Hb of the −OCH2−
methylene units are diastereotopic and anisochronous,
Table 1. Dynamic NMR Studies and Derived Kinetic Parameters for the Through-Annulus Rotation of Various Rim-
Differentiated (Compounds 1a−1e) and Per-Functionalized (2a−2c) Pillar[5]arenes
a
a
a
b
a
a
a
a
P[5]
1a
1b
1c
1d
1e
2a
2b
2c
c
d
Tc (K)
238
233
238
240
250.5
88.0
207.2
3.3
258
Δν (Hz)
65.6
159.6
4.3
26.0
87.1
8.0
80.0
182.8
3.8
90.4
211.7
3.3
65.2
150.5
4.5
kcoal (s−1
)
t1/2 (ms)
ΔG‡ (kJ/mol)
47.6
48.4
<40
47.2
47.4
49.6
<40
<40
51.8
a
b
c
d
Solvent: toluene-d8. Solvent: acetone-d6. Two datasets of 1a were obtained from the NMR signal of Ha/Hb. Two datasets of 1a were obtained
from the NMR signal of Hc/Hd.
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Figure 4. Partial DNMR spectra of (a) 1a, (b) 1b, and (c) 1c from
298 down to 203 K in toluene-d8.
Figure 3. Partial DNMR spectra of (a) 2a, (b) 2b, and (c) 2c from
298 down to 203 K in toluene-d8.
values for these two sets of protons (at the coalescence
temperature, Δυ = 26.0 Hz for the Ar−CH2−Ar protons, and
Δυ = 65.6 Hz for the −OCH2− protons; see eq 1,
Experimental Section). Although the methylene bridge protons
of rim-differentiated P[5]s are, in principle, always diaster-
eotopic to each other, so far 1a is the only compound that
shows this phenomenon, which also allows observation of this
complex dynamic behavior in our DNMR studies. Both ΔG‡
values obtained for 1a are higher than the “propargyl-through-
the-annulus” barrier (<40 kJ·mol−1), suggesting that the
enantiomerization process of 1a is more complex than that
of the other compounds under current study. This (highly
reproducible, but) counterintuitive result is in line with our
earlier theoretical findings that the mechanical movements
between different P[5] hydroquinone units are not mutually
independent,8 and it confirms that not only the transition-state
energy but also that of starting conformations and
unexpectedly stable intermediates need to be taken into
account to fully describe the complex dynamics of these
materials (see the Supporting Information for the DFT-
optimized structure of 1a). Given the relatively small size of
this effect, a thorough understanding thereof might require in-
depth theoretical investigations at a high level of theory.
structures by noncovalent van der Waals interactions, as well as
by hydrogen bonds, constitutes a major factor affecting barrier
heights.”
From the DNMR studies above, we have established the “R-
through-the-annulus” ΔG‡ values for P[5]-rims functionalized
with different short hydrocarbon chains in the following order:
propyl (51.8 kJ·mol−1 in toluene-d8) > methyl (49.6 kJ·mol−1
in toluene-d8 or 47.4 kJ·mol−1 in acetone-d6) > allyl/propargyl
(<40 kJ·mol−1 in toluene-d8). For rim-differentiated P[5]s with
two nondegenerate rotational modes, it is anticipated that the
substituent with the lower barrier height should dominate the
inversion processes. This is indeed the case for 1b and 1c (see
Table 1 and Figure 4). The energy barrier of (n-Pr)5(Me)5-
P[5] 1c is 47.2 kJ·mol−1, which is 4.6 kJ·mol−1 lower than the
“propyl-through-the-annulus” value (observed for (n-Pr)10-
P[5] 2c). Similar to the case of per-functionalized (allyl)10-
P[5] 2b, the rim-differentiated (allyl)5(Me)5-P[5] 1b also
displays rapid rotations in the temperature range studied, as a
result of the low inversion barrier of the allyl-functionalized
rim.
The rim-differentiated (propargyl)5(Me)5-P[5] 1a, nonethe-
less, displays anomalous behavior. Instead of being dominated
by the propargyl groups, which would be expected to provide a
low-energy pathway for fast rotation, the inversion slows down
significantly at lower temperatures, and coalescence of the
−OCH2− protons was observed (Figure 4a) at 238 K, which
corresponds to an energy barrier of 47.6 kJ·mol−1 (Table 1).
Moreover, it is noteworthy that the Ar−CH2−Ar protons of 1a
were also found (Figure 4a) to be anisochronous, splitting into
two sets of doublets at lower temperatures. A Tc of 233 K and a
ΔG‡ value of 48.4 kJ·mol−1 were found for the Ar−CH2−Ar
geminal protons, in which the combination of lower Tc and
higher ΔG‡ resulted from the significant difference in Δυ
CONCLUSIONS
■
Using tailor-made rim-differentiated and per-functionalized
pillar[5]arenes, we demonstrated that whereas the intercon-
version of enantiomeric pillar[5]arene conformers typically
proceeds by moving the sterically smallest substituent through
the cavity, the energy barrier for this process is in fact
dominated by the contribution of the “fastest” substituents, i.e.,
the smallest one or the one that provides most stabilization in
the transition state, e.g., by attractive π−π interactions between
the substituent and aryl rings. However, the interconversion is
a complex process, in which substituents may interact
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dissolved in H2O (1 mL), NaOH (26.5 mg, 0.662 mmol, 7.5 equiv)
was added, and the resulting mixture was stirred at 60 °C for 30 min.
A solution of 4-cyanobenzyl bromide (173 mg, 0.882 mmol, 10.0
equiv) in MeCN (1 mL) was added, and the mixture was further
stirred at 60 °C for 12 h. After being cooled down to rt, the precipitate
was filtered out, and dissolved in EtOAc (5 mL) at 60 °C. Hexane (50
mL) was added dropwise. The resulting precipitate was collected and
washed with hexane (10 mL). This procedure was repeated once to
afford 1d as a white solid (81 mg, 97%). 1H NMR (400 MHz,
CDCl3) δ 7.59 (d, J = 8.0 Hz, 10H), 7.29 (d, J = 8.0 Hz, 10H), 6.76
(s, 5H), 6.61 (s, 5H), 4.50 (s, 10H), 3.81 (s, 10H), 3.62 (s, 15H).
13C{1H} NMR (101 MHz, CDCl3) δ 151.7, 149.4, 143.1, 132.4,
129.1, 128.5, 127.6, 118.6, 115.8, 114.5, 111.9. HRMS (ESI) m/z [M
+ Na]+ calcd for C80H65O10N5Na 1278.4624, found 1278.4611.
(n-Pr)5(Me)5-P[5] 1c: To a solution of (allyl)5(Me)5-P[5] 1b17a
(285 mg, 0.323 mmol, 1.0 equiv) in EtOAc (30 mL) was added Pd/C
(10% wt, wetted with 55% H2O, 285 mg). The resulting mixture was
stirred under a H2 atmosphere at 25 °C for 24 h, then filtered over a
pad of celite, and concentrated to dryness. Column chromatography
(EtOAc/n-hexane, 5/95) afforded 1c as a white solid (256 mg, 0.287
competitively or cooperatively in many ways, yielding
inextricably intertwined motions during the inversion process
and concomitantly occasional “outliers” in the overall
activation barriers. These findings thus shed more light on
the complex nature of the dynamic process of pillar[5]arene
stereochemical inversion and may provide future design
guidance for pillararene-based chiral sensors20 and molecular
switches and machines.21
EXPERIMENTAL SECTION
■
General Procedure. Starting materials, reagents, and solvents
were purchased from commercial vendors and used as received, unless
otherwise noted. All reactions that required heating employed an oil
bath. Analytical thin-layer chromatography (TLC) was performed on
aluminum sheets, precoated with silica gel GF254. Flash column
chromatography was performed over silica gel (200−300 mesh or
300−400 mesh). The chemical shifts are listed in parts per million
(ppm) on the δ scale, and coupling constants were recorded in hertz
(Hz). Chemical shifts are calibrated relative to chloroform (CDCl3: δ
1
1
7.26 ppm for H and 77.16 ppm for 13C).
mmol, 89%). H NMR (600 MHz, CDCl3) δ 6.80 (s, 5H), 6.76 (s,
5H), 3.78 (s, 10H), 3.77 (t, J = 6.8 Hz, 10H), 3.67 (s, 15H), 1.75−
1.69 (m, 10H), 0.99 (t, J = 7.4 Hz, 15H). 13C{1H} NMR (151 MHz,
CDCl3) δ 149.6, 149.1, 127.3, 127.2, 114.0, 113.1, 68.9, 54.8, 28.6,
22.0, 9.7. HRMS (ESI) m/z [M + NH4]+ calcd for C55H74NO10
908.5307, found 908.5278.
A1/A2-bis(4-cyanobenzyl)-P[5] 1d′: In a sealed tube were
introduced A1/A2-dihydroxy-octamethyl P[5]12b (200 mg, 0.277
mmol, 1.0 equiv), 4-cyanobenzyl bromide (271 mg, 1.39 mmol, 5.0
equiv), KI (13.8 mg, 0.083 mmol, 0.3 equiv), and K2CO3 (229 mg,
1.66 mmol, 6.0 equiv). Dry MeCN (5 mL) was added, and the
resulting mixture was stirred at 115 °C for 12 h. After cooling to 25
°C, H2O was added and the crude mixture was extracted with EtOAc
(3 × 30 mL), dried over MgSO4, filtered, and concentrated to
dryness. Column chromatography (EtOAc/n-hexane, 15/85) afforded
the target compound as a white solid (152 mg, 0.159 mmol, 57%). 1H
NMR (600 MHz, CDCl3) δ 7.65 (d, J = 8.2 Hz, 4H), 7.49 (d, J = 8.2
Hz, 4H), 6.82 (s, 2H), 6.82 (s, 2H), 6.78 (s, 2H), 6.75 (s, 2H), 6.64
(s, 2H), 5.02 (d, J = 13.3 Hz, 2H), 4.94 (d, J = 13.3 Hz, 2H), 3.92 (s,
1H), 3.90 (s, 1H), 3.81 (s, 2H), 3.77 (s, 4H), 3.74 (s, 1H), 3.72 (s,
1H), 3.71 (s, 6H), 3.69 (s, 6H), 3.50 (s, 6H), 3.38 (s, 6H). 13C{1H}
NMR (151 MHz, CDCl3) δ 150.82, 150.81, 150.7, 150.6, 149.9,
143.5, 132.3, 128.7, 128.6, 128.3, 128.2, 127.43, 127.38, 118.8, 115.2,
114.1, 114.0, 113.9, 111.4, 69.4, 55.97, 55.96, 55.93, 55.92, 55.6, 55.4,
29.9, 29.6, 29.4. HRMS (ESI) m/z [M + Na]+ calcd for
C59H56O10N2Na 975.3827, found 975.3788.
Variable-Temperature NMR Measurements. All 1H NMR
spectra were recorded using a Bruker Avance III 400 MHz instrument
with 32 scans. The ΔG‡ values were calculated using the coalescence
temperature Tc and the difference in chemical shifts (Δv) measured at
203 and 273 K, respectively. To determine Tc, 1H NMR spectra were
recorded at various temperatures from 203 to 343 K in toluene-d8 or
acetone-d6. In a typical VT NMR experiment, a 1 mM solution of
P[5] was prepared by dissolving an appropriate amount in 500 μL of
toluene-d8 and thorough mixing. To accurately determine Δv, the
shimming was performed manually wherever poor shimming (i.e.,
poor resolution, broad or unsymmetrical peaks) was evidenced. To
prevent artifacts like spinning sidebands, spinning was turned off
wherever needed. The phasing of spectra and baseline were corrected
automatically. The calculation of ΔG‡ was performed using the
following equation22
Ä
É
3d: To a solution of 2-hydroxy-5-methoxybenzaldehyde (1.00 g,
6.57 mmol, 1.0 equiv) in MeCN (40 mL) was added K2CO3 (1.81 g,
13.1 mmol, 2.0 equiv) followed by 4-cyanobenzyl bromide (1.29 g,
6.57 mmol, 1.0 equiv). The resulting mixture was refluxed for 20 h,
cooled down to 25 °C, filtered, and concentrated to dryness. The
crude aldehyde was dissolved in MeOH (200 mL), to which NaBH4
(120 mg, 3.3 mmol, 0.5 equiv) was added. The resulting mixture was
stirred at room temperature for 2 h and concentrated to dryness.
Column chromatography (EtOAc/n-hexane, 20/80 to 40/60)
Å
Å
Å
Å
Å
Ñ
Ñ
Ñ
Ñ
Ñ
Ñ
T
Δν
i
j
j
j
y
z
z
z
‡
c
ΔG = 8.314T 22.96 + log
Å
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X-ray Crystallography. Single crystals suitable for X-ray
diffraction were grown by the vapor−vapor diffusion method,
EtOAc/n-hexane for 1c and CHCl3/n-hexane for 1d, then selected
and mounted in inert oil under a cold gas stream, and their X-ray
diffraction intensity data were collected on a Rigaku XtaLAB FRX
diffractometer equipped with a Hypix6000HE detector, using Cu Kα
radiation (λ = 1.54184 Å). By the use of Olex2,23 the structure was
solved either (i) with the ShelXS structure solution program using
Direct Methods or (ii) with the ShelXT structure solution program
using direct methods or intrinsic phasing,24 refined with the ShelXL
refinement package using least-squares minimization.25 The hydrogen
atoms were set in calculated positions and refined as riding atoms with
a common fixed isotropic thermal parameter. Selected details of the
data collection and structural refinement of compounds 1c and 1d can
be found in the Supporting Information, and full details are available
in the corresponding CIF files (CCDC 1989352 and 1896020).
1
afforded 3d as a white solid (1.51 g, 5.61 mmol, 85%). H NMR
(400 MHz, CDCl3): δ 7.61 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.0 Hz,
2H), 6.95 (d, J = 2.9 Hz, 1H), 6.81−6.67 (m, 2H), 5.07 (s, 2H), 4.70
(s, 2H), 3.72 (s, 3H), 2.71 (s, 1H). 13C{1H} NMR (101 MHz,
CDCl3): δ 154.2, 149.6, 142.6, 132.4, 130.8, 127.4, 118.7, 114.6,
112.8, 112.7, 111.5, 69.5, 61.0, 55.6. HRMS (ESI) m/z [M + Na]+
calcd for C16H15O3NNa 292.0944, found 292.0944.
(4-Cyanobenzyl)5(Me)5-P[5] 1d: Route A. To a solution of 3d
(700 mg, 2.60 mmol, 1.0 equiv) in Cl(CH2)2Cl2 (300 mL) was added
anhydrous FeCl3 (169 mg, 1.04 mmol, 0.4 equiv). The resulting
mixture was stirred at 25 °C for 20 h, quenched with MeOH (5 mL),
and concentrated to dryness. Column chromatography (CH2Cl2/
MeOH, 98/2 to 95/5) followed by slow evaporation from a CHCl3
solution (40 mL) afforded 1d as a white solid (60 mg, 0.05 mmol,
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c01464.
■
sı
10%). Route B. To a solution of (benzyl)5(Me)5-P[5] 1e16c 17b
(100
,
mg, 0.088 mmol, 1.0 equiv) in EtOAc (5 mL) was added Pd/C (10%
wt, wetted with 55% H2O, 100 mg). The resulting mixture was stirred
under H2 atmosphere at 25 °C for 4 h, filtered over a pad of celite,
and concentrated to dryness to afford the corresponding pentanol as a
white solid (60 mg, 0.088 mmol, quant.). This compound was
X-ray data for compound 1c (CIF)
X-ray data for compound 1d (CIF)
1H, 13C, and DNMR spectra, and X-ray data (PDF)
E
https://dx.doi.org/10.1021/acs.joc.0c01464
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Thousand Talents Program (A.C.-H.S. and H.Z.), Wageningen
University, and Tianjin University. The authors thank Prof.
Xiangyang Zhang and all staff of Instrumental Analysis Center,
School of Pharmaceutical Science and Technology, Tianjin
University, for assistance in various characterizations.
AUTHOR INFORMATION
Corresponding Authors
■
Han Zuilhof − Institute for Molecular Design and Synthesis,
School of Pharmaceutical Science & Technology, Tianjin
University, Tianjin 300072, P. R. China; Laboratory of
Organic Chemistry, Wageningen University, 6703 WE
Wageningen, The Netherlands; Department of Chemical and
Materials Engineering, King Abdulaziz University, 21589
Jeddah, Saudi Arabia; orcid.org/0000-0001-5773-8506;
Email: Han.Zuilhof@wur.nl
Andrew C.-H. Sue − Institute for Molecular Design and
Synthesis, School of Pharmaceutical Science & Technology,
Tianjin University, Tianjin 300072, P. R. China; orcid.org/
0000-0001-9557-2658; Email: andrew.sue@tju.edu.cn
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c01464
Author Contributions
∥K.D. and P.D.-D. contributed equally. The manuscript was
written through contributions of all authors. All authors have
given approval to the final version of the manuscript.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
The authors are grateful for the highly useful suggestions
obtained from reviewers of a previous version of this
manuscript. This research was supported by National Science
Foundation of China (no. 21871208; H.Z.), the Tianjin City
F
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