Design, preparation, and study of catalytic gated baskets

Article abstract of DOI:10.1021/jo202443j

We report a diastereoselective synthetic method to obtain a family of catalytic molecular baskets containing a spacious cavity (～570 A³). These supramolecular catalysts were envisioned, via the process of gating, to control the access of substrates to the embedded catalytic center and thereby modulate the outcome of chemical reactions. In particular, gated basket 1 comprises a porphyrin floor fused to four phthalimide side walls each carrying a revolving aromatic gate. With the assistance of ¹H NMR and UV-vis spectroscopy, we demonstrated that the small 1-methylimidazole guest (12, 94 A³) would coordinate to the interior while the larger 1,5-diadamantylimidazole guest (14, 361 A³) is relegated to the exterior of basket Zn(II)-1. Subsequently, we examined the epoxidation of differently sized and shaped alkenes 18-21 with catalytic baskets 12 _in-Mn(III)-1 and 14_out-Mn(III)-1 in the presence of the sacrificial oxidant iodosylarene. The epoxidation of cis-stilbene occurred in the cavity of 14_out-Mn(III)-1 and at the outer face of 12 _in-Mn(III)-1 with the stereoselectivity of the two transformations being somewhat different. Importantly, catalytic basket 14_out-Mn(III) -1 was capable of kinetically resolving an equimolar mixture of cis-2-octene 20 and cis-cyclooctene 21 via promotion of the transformation in its cavity.

Full text of DOI:10.1021/jo202443j

Article
pubs.acs.org/joc
Design, Preparation, and Study of Catalytic Gated Baskets
̌
Bao-Yu Wang, Teodora Zujovic, Daniel A. Turner, Christopher M. Hadad, and Jovica D. Badjic*
́
́
Department of Chemistry, The Ohio State University, Columbus, Ohio 43210, United States
S
* Supporting Information
ABSTRACT: We report a diastereoselective synthetic method to
obtain a family of catalytic molecular baskets containing a spacious
cavity (∼570 Å3). These supramolecular catalysts were envisioned,
via the process of gating, to control the access of substrates to the
embedded catalytic center and thereby modulate the outcome of
chemical reactions. In particular, gated basket 1 comprises a
porphyrin “floor” fused to four phthalimide “side walls” each
1
carrying a revolving aromatic “gate”. With the assistance of H
NMR and UV−vis spectroscopy, we demonstrated that the small 1-
methylimidazole guest (12, 94 Å3) would coordinate to the interior
while the larger 1,5-diadamantylimidazole guest (14, 361 Å3) is
relegated to the exterior of basket Zn(II)−1. Subsequently, we
examined the epoxidation of differently sized and shaped alkenes 18−21 with catalytic baskets 12in−Mn(III)−1 and 14out−
Mn(III)−1 in the presence of the sacrificial oxidant iodosylarene. The epoxidation of cis-stilbene occurred in the cavity of 14out−
Mn(III)−1 and at the outer face of 12in−Mn(III)−1 with the stereoselectivity of the two transformations being somewhat
different. Importantly, catalytic basket 14out−Mn(III)−1 was capable of kinetically resolving an equimolar mixture of cis-2-octene
20 and cis-cyclooctene 21 via promotion of the transformation in its cavity.
but investigations on the effect of the catalyst’s dynamics on the
reaction’s outcome are emerging.33−36 Accordingly, the present
work focuses on the design, synthesis, and optimization of the
catalytic behavior of a new family of gated baskets (Figure 1).
These compounds comprise a porphyrin “floor” surrounded
with four phthalimide-based “walls” for forming a semirigid
platform (Figure 1A).37 The aromatic “gates” are placed at the
top of the platform to, via CH2 “hinge” groups, revolve about
the basket’s entrance/exit and thereby regulate the access of
guests to the catalytic center (Mn(III)) embedded in the cavity
(Figure 1A).
INTRODUCTION
■
Ever since Cram’s seminal paper1 about the prospect of
molecular encapsulation, many covalent2−4 and self-as-
sembled5,6 capsules have been made7 and demonstrated to
entrap smaller compounds having complementary size, shape,
and functionality. Indeed, the isolation of a guest in the interior
of a host provides the entrapped compound with a unique
environment sometimes referred to as “a new state of matter”.8
By way of encapsulation, one can thus modulate the persistence
of reactive intermediates9,10 and even change the course/rate of
chemical reactions11−13 or conformational changes.14 The
mechanism by which the entrapment occurs15 is typically a
function of the host’s structure, and in accord with one of the
following mechanistic scenarios: slippage, dissociation, or
gating.15 In particular, gating15,16 comprises a conformational
change in the host that regulates the rate (e.g., the constrictive
binding energy ΔG⧧)17 by which guests enter or depart the
host. Enzymes use gating for controlling the selectivity of
catalytic reactions,18 while ion/molecular channels employ
gating for regulating the trafficking of ions across cell
membranes.19 This study poses a question about the relationship
between the gating of reactants and its effect on the outcome of a
chemical reaction occurring inside a gated catalyst. In particular,
we would like to understand if modulating (1) the residence
time of encapsulated reactant(s) and/or (2) its access to such a
gated catalyst20,21 has any effect on the reaction’s yield,
stereoselectivity, and/or product distribution.
On the basis of our previous study,39 we first developed a
reliable synthetic method for the preparation of catalytic
1
molecular baskets (Figure 1). Next, we used H NMR and
UV−vis spectroscopic methods for quantifying the axial
coordination of differently sized imidazoles to zinc(II)- and
manganese(III)-metalated baskets. Finally, we examined the
epoxidation of alkenes40−44 inside and outside the cavity (∼570
Å 3, Figure 1B) of Mn(III)-containing baskets. In particular, the
oxygen atom transfer (OAT) reaction was promoted with
monomeric and soluble iodosylarene (t-BuSO2PhIO).45,46
Consistent with prior work,47−49 this sacrificial terminal oxidant
converted the resting state Mn(III) supramolecular catalyst into
an elusive Mn(V)O species that further transferred the
oxygen atom to entrapped alkenes (Figure 1A). Importantly, the
results of our catalytic studies suggest that gated baskets are capable
of promoting the epoxidation of differently sized-alkenes in their
We22−26 and others27−32 have, during the past decade,
explored gated hosts and their mechanisms of operation.
Importantly, there have been no studies about gated catalysis,
Received: December 6, 2011
Published: February 3, 2012
© 2012 American Chemical Society
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Figure 1. (A) Catalytic gated baskets comprise a porphyrin “floor”, phthalimide “walls”, and aromatic “gates”. (B) Inner volume of the catalytic
basket, with four gates pointing toward the cavity, was estimated to be 570 Å3;38 note that the right-hand illustration represents a computed van der
Waals surface of the basket with the front side omitted for clarity.
Scheme 1. Synthetic Methodology for Obtaining Enantiopure Pyrromethanecarbinol 10
interior. The stereoselectivity and rates of these reactions appear
to be a function of the size/shape of various alkene substrates.
1 (Scheme 2) was based on the notion that compound 10
would undergo a diastereoselective head-to-tail tetramerization
and, upon oxidation, give rise to porphyrin derivative 11
(Scheme 2). In addition, we surmised that octaester 11 could
easily be transformed into gated basket 1 using a previously
described methodology.50
RESULTS AND DISCUSSION
■
Synthetic Hypotheses. We recently developed a diaster-
eoselective synthetic method for obtaining cup-shaped
porphyrins akin to gated molecular basket in Figure 1.39 In
particular, we showed that enantiopure pyrromethanecarbinol,
akin to 10 (Scheme 1), would undergo a stereoselective
Synthesis. Benzonorbornadiene derivative 2 was made in
multigram quantities following a published procedure.51 The
epoxidation of 2 with m-CPBA occurred with exclusive transfer
of the oxygen atom to the exo side of the norbornene; 2D-
oligomerization in the presence of a Bronsted acid, such as p-
̈
NMR NOESY investigation52 of epoxide 3 revealed H−1H
1
TsOH, to give a sole porphyrin product with four bicyclic rings
pointing to the same direction in space (Scheme 2). The acid-
catalyzed condensation was under kinetic control as longer
reaction times and higher concentrations of the acid led to the
formation of other diastereomeric porphyrins.39 In accord with
such findings, the synthetic strategy for obtaining gated basket
correlations implying the exo position of the epoxide
functionality. Compound 3 was further subjected to ring-
opening with thiophenol in the presence of Lewis acid
(CH3)3Al53 (Scheme 1). Interestingly, in this reaction the
nucleophile attacked both the exo and endo sides of 3 to give 4;
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Scheme 2. Diastereoselective Oligomerization of 10 (5.0 mM) Completed in CHCl3 with p-TsOH (0.395 mM) at Room
a
Temperature
a
For the chemical structure of 1, see Figure 2A.
note that 4 was obtained as a mixture of two diastereomers
4arac and 4brac. Complete oxidation of the sulfide functional
group in 4 was accomplished with m-CPBA to give sulfones
5arac/5brac (Scheme 1). Diastereomeric 5arac/5brac were
subsequently separated by silica column chromatography, and
their ratio was roughly 32:68. To continue the synthesis, we
used the more abundant 5brac diastereomer as compound 5arac
would not give the desired products. In an attempt to resolve
racemic 5brac, we employed (1S,4R)-camphanic chloride.54
Upon esterification of 5arac, two diastereomeric esters 6a/b
were separated by column chromatography (hexanes/EtOAc =
2:1) and then each independently reacted with sodium
methoxide in order to remove the chiral auxiliary (Scheme
1); note that compounds 7 and now enantiopure 5b were, from
6a, obtained in a 1:9 ratio. Upon mesylation of enantiopure 5b
and then elimination of the mesyl group with non-nucleophilic
DBU, we were able to isolate 8; the enantiopurity of this
compound was checked with chiral HPLC and found to have
an ee > 99% (Figure S10, Supporting Information).52 The
treatment of compound 8 with tert-butyl isocyanoacetate, in the
presence of t-BuOK (the Barton−Zard reaction), led to the
formation of pyrrole derivative 9. Hydrolysis of the tert-butyl
ester functional group in 9 was optimized (70%) to give the
corresponding carboxylic acid product; note that “deprotec-
tion” with trifluoroacetic acid (TFA) would give lower amounts
(∼40%) of the desired acid with competing decarboxylation
product. The esterification of the product with coupling reagent
PyBOP (benzotriazol-1-yloxytripyrrolidinophosphonium hexa-
fluorophosphate) followed by NaBH4 reduction gave pyrro-
methanecarbinol 10 (Scheme 1).
We used 0.395 mM p-TsOH in CHCl3 for promoting the
oligomerization of pyrromethanecarbinol 10 (5.0 mM, Scheme
2). The reaction allowed almost the exclusive formation of
desired porphyrinogen that, upon oxidation with DDQ, gave
octaester 11. The cup-shaped octaester was isolated by column
chromatography (dichloromethane/methanol = 50:1) and then
converted into gated basket 1 (Scheme 2).
Spectroscopic and Conformational Characteristics of
Gated Baskets. We incorporated metal cations, Zn(II) and
Mn(III), into gated basket 1 to form Zn(II)−1 and Mn(III)−1
(Figure 2A) and then completed the characterization of these
Figure 2. (A) Chemical structure of gated basket 1, Zn(II)−1, and
1
Mn(III)−1. (B) H NMR spectrum (400 MHz, CD2Cl2) of basket
Zn(II)−1 at 298.0 K. (C) UV−vis spectra of gated basket 1 (0.005
mM, solid line), Zn(II)−1 (0.003 mM, dashed line), and Mn(III)−1
(0.004 mM, dotted line) in CH2Cl2 at 298 K.
1
compounds. The H NMR spectrum of gated basket 1 (400
MHz, CDCl3) showed of a set of resonances corresponding to
a C4v symmetric species (Figure 2B). On the basis of our prior
study,39 we reasoned that the shuttling of the N−H protons
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was, at room temperature, fast enough for averaging the proton
1
resonances. Indeed, variable-temperature (VT) H NMR study
of 1 revealed decoalescence of all signals at ∼228 K (Figure
S40, Supporting Information),52 corresponding to the expected
change in the symmetry from C4v to C2v and the decelerated
N−H shuttling. Moreover, the revolving of four benzene gates
at the basket’s entrance/exit must be accompanied with a small
activation barrier, since the VT 1H NMR measurement did not
show any additional change up to 194.2 K (Figure S40,
Supporting Information).52
The porphyrin macrocycle has characteristics of an aromatic
compound yet is flexible enough to adopt various nonplanar
conformations.55 The position of the Soret and Q bands in the
electronic (UV−vis) spectrum of porphyrins is, in fact,
indicative of the planarity of the ring: one typically identifies
red shifts of the absorption bands originating from nonplanar
deformations in the macrocycle.56 The UV− vis spectra of free
base 1, Zn(II)−1, and Mn(III)−1 baskets are shown in Figure
2C. Importantly, the λmax bands of 1 and Zn(II)−1 are
positioned at 645 and 572 nm (Figure 2C) and close to those
measured for recently prepared free-base and Zn(II)−
metalated bicyclic porphyrins (λmax = 665 and 551 nm);57
these porphyrins were “equipped” with bicyclo[2.2.2]octene
framework for increasing the system’s rigidity and stabilizing
the planar conformation in solution.57 Moreover, the
absorption bands in 1 and Zn(II)−1 are blue-shifted with
respect to the λmax of nonplanar octaethylporphyrins (for free-
base and Zn(II)−OEP, λmax = 686 and 637 nm).57,58 Another
diagnostic feature of the distortion of the porphyrin macrocycle
is the 1H NMR chemical shift of the N−H resonance appearing
at a lower field than typically observed (δ = −2 to −5 ppm).59
The chemical shift for the N−H protons in basket 1 were found
at −4.97 ppm,52 which in line with UV−vis measurements
suggest that the base of our basket is indeed adopting a planar
conformation in solution. The absorption spectrum of
Mn(III)−1 reveals two Soret bands at 374 and 470 nm (Figure
2C) and Q-band at 565 nm (Figure 2C). Importantly, the
measured transitions are in the range of those reported for
numerous Mn(III) porphyrins48 further validating the incor-
poration of Mn(III) into basket 1.
Figure 3. (A) Axial coordination of ligands 12−1452 could occur
1
inside or outside of Zn(II)−1, and VT H NMR spectroscopy was
used to quantify the equilibrium (Kin/out). (B) Chemical structures of
energy minimized 12−14 (AM1, Spartan) and their corresponding
volumes.
corresponding to outer Hb protons (Figure 3A) should be
diagnostic for the coordination occurring on the basket’s outer
side; in principle, measuring host−guest NOEs could give
information about the position of the guest though we were
unable to assign the guest’s 1H NMR signals due to an
extensive broadening and/or rapid exchange of its resonances.
Accordingly, we titrated 12−14 (∼13 mM) to Zn(II)−1 (0.15
1
mM) in CD2Cl2 and recorded H NMR spectrum (400 MHz,
298.0 K) upon each addition of the ligand (Figures S11−S19,
Supporting Information).52 Then, we plotted the relative
change in the chemical shift (Δδ, ppm) of protons Hb (located
on the basket’s outer side, Figure 3A) and He (located on the
basket’s inner side, Figure 3A) as a function of the molar
equivalents of 12−14 (Figure 4). Evidently, the binding of
smaller 1-methylimidazole 12 to Zn(II)−1 caused a greater
perturbation of the magnetic environment of the inner He
protons (Δδ = 0.04 ppm, Figure 4A).
1H NMR Study of the Coordination of Imidazole-
Based Ligands 12−14 to Zn(II)−1. For promoting chemical
reactions (epoxidation)60 in the interior of gated baskets we
decided to first investigate the axial coordination of imidazole-
based ligands to Zn(II)−1 and Mn(III)−1 (Figure 3). The
rationale for such studies rested in the notion that the
coordination of N-heterocycles to the outer side of Mn(III)−1
would enforce the chemical transformation to occur in the
cavity of the basket.61,62
The coordination of more sizable 14 to Zn(II)−1, however,
caused a more considerable perturbation of the outer Hb
protons (Δδ = 0.06 ppm, Figure 4C). Despite rather small
perturbations (Δδ < 0.1), there still exists a trend in the relative
change of the chemical shifts (Δδ, Figure 4) of He and Hb: the
more sizable the ligand the greater the 1H NMR chemical shift
of the outer protons and vice versa! A useful way to visualize
the trend is to view the blue and red curves in Figure 4 from left
to right. It subsequently follows that at 298.0 K smaller 12 (94
Å3) prefers coordinating to the inner while bigger 14 (361 Å3)
to the outer side side of Zn(II)−1 (Figure 5).
The cavity of gated basket 1 is sizable, and we used molecular
mechanics (MM2) to estimate the volume of its inner space to
be ∼570 Å3 (Figure 1B).38 On the basis of their different size
and shape, three imidazoles 12−14 (94−361 Å3, Figure 3B)
were anticipated to coordinate to inner and/or outer sides of
For quantifying the observed in/out stereoisomerism, we
1
used variable-temperature H NMR spectroscopy (Table 1).
1
Zn(II)−1 (Figure 3A). We used H NMR spectroscopy to
The chemical exchange of ligands 12−14 to and from Zn(II)−
1 was, at low temperatures, expected to slow down with a
decoalescence of proton resonances corresponding to the
formation of in/out stereoisomers (Figure 3A). Indeed,
variable-temperature 1H NMR measurements (400 MHz,
CD2Cl2) of 13−Zn(II)−1 and 14−Zn(II)−1 (∼190−220 K)
showed two sets of resonances with the integration ratio being
a function of the external temperature (Figures S22−S25,
Supporting Information).52 The integration of the signal
study the regioselectivity of the axial coordination: zinc(II) is in
porphyrin systems diamagnetic (d10 electronic state) and prone
to form ML5 square-pyramidal complexes suitable for 1H NMR
studies.63,64 The working hypothesis was based on our earlier
work:39 if the coordination of 12−14 to Zn(II)−1 occurs on a
particular side of the basket, the magnetic environment of the
nearby proton is perturbed to a greater extent (Figure 3). For
instance, a greater change in the chemical shift of the signal
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Figure 4. Relative 1H NMR (400 MHz, 298.0 K) chemical shifts (Δδ, ppm) of He/Hb protons in Zn(II)−1 measured upon incremental addition of
variously sized ligands 12−14 to its CD2Cl2 solution.52.
He, δin = 7.95 ppm; see Figure S21, Supporting Information),
indicating the exclusive formation of 12in−Zn(II)−1 (Table 1).
Apparently, there is an enthalpic ΔH°in/out but not entropic
ΔS°in/out advantage (see Table 1) for ligands 13 and 14
coordinating to the inner side of Zn(II)−1. The situation is
different from previously examined cup-shaped baskets39
whereby the entropically favorable desolvation of ligands
would allegedly drive their coordination to the inner side. We
surmise that in the case of Zn(II)−1, the extended phthalimide
“side walls” as well as the revolving gates (absent in cup-shaped
baskets) interact with the entrapped guest, thereby affecting the
enthalpy/entropy balance in the binding.
Preliminary computational study of the in/out stereo-
Figure 5. Chemical structures of energy-minimized (AM1, Spartan)
14out−Zn(II)−1 (A) and 12in−Zn(II)−1.
isomerism (DFT, RI-BP86/SV(P), TZVP)52,65−68 furthermore
revealed a somewhat greater affinity of 12 (ΔEout/in = −3.60
kcal/mol) over 13 (ΔEout/in = −2.61 kcal/mol) or 14 (ΔEout/in
= −1.91 kcal/mol) for residing in the interior of Mn(III)−1.
The origin of the trend for the computed energy difference
(ΔE) rests in the van der Waals strain increasing in the series
12in−Mn(III)−1 < 13in−Mn(III)−1 < 14in−Mn(III)−1: the
distance between the two opposite phthalimide “side walls” is in
ligandin−Mn(III)−1 increasing with more sizable ligands51
therefore indicating adverse steric interactions. In fact, one
needs to take the solvation as well as dynamics of the host/
guest pair into an account to obtain more information on the
binding thermodynamics.
Quantitative Study of the Coordination of 12/14 to
Metalloporhyrins. With a good understanding of the in/out
stereoisomerism, we used UV−vis spectroscopy for quantifying
the binding affinity of 12 and 14 toward Zn(II)−1 and
Mn(III)−1 as well as metalloporphyrins 15−17 (Figure 6).
Since 1,5-dicyclohexylimidazole 13 would, at room temper-
ature, coordinate to both inner and outer sides of Zn(II)−1, we
refrained from quantifying the axial binding of this particular
compound. The modes of the complexation of Zn(II) and
Mn(III) porphyrins with N-heterocycles, forming five- and six-
coordinate species (Figure 6A), are described in the
literature63,69−73 and as such used in our analysis. The
coordination of 12 and 14 to Zn(II)−1 (CH2Cl2, 298.0 K)
affected both the Soret and Q absorption bands of the
porphyrin chromophore (Figure 6B); note that the red (10−15
nm) shift of the Soret band is typically observed for N-
heterocycles binding to Zn(II) porphyrins.74,75 The appearance
Table 1. Thermodynamic Parameters for Stereoisomeric In/
Out Equilibration (Kin/out = [out]/[in]) of Complexes (13/
1
14)−Zn(II)−1 Generated from VT H NMR Measurements
a
and van’t Hoff Analysis
d
ΔH°in/out
TΔS°in/out
%
Out
d
d
d
ligand Kin/out
(kcal/mol)
(kcal/mol)
% In
b
12
∼100
50
0
13
0.99
6.5
0.55 0.03
1.44 0.09
0.54 0.03
2.55 0.20
50
c
14
∼10
∼90
a
Figure S26 (Supporting Information), R2 = 0.98 for 13 and R2 = 0.97
for 14).51. VT H NMR showed no decoalescence of resonances.
b
1
c
The estimated percentage of in and out stereoisomers changes to
0:100 if one plots % (out) as a function of temperature (linear
d
dependence, R2 = 0.99). At 298.0 K.
corresponding to He protons (with the ligand coordinated on
the inner δin = 7.97 ppm and the outer side δout = 8.03 ppm)52
in both 13−Zn(II)−1 and 14−Zn(II)−1 allowed us to evaluate
the proportion of in/out stereoisomers and create the
corresponding van’t Hoff plots (Figure S26, Supporting
Information, Table 1).52
Markedly, 1,5-dicyclohexylimidazole 13 would at 298.0 K
coordinate to both inner and outer sides of Zn(II)−1, while the
larger 1,5-diadamantylimidazole 14 would preferentially reside
1
at the outer side of Zn(II)−1 (Table 1). A set of H NMR
resonances (298.0 K) corresponding to the coordination
complex 12−Zn(II)−1 was unaltered at all temperatures (for
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Figure 6. (A) Two modes of binding of imidazole-based ligands (L) to Zn(II) and Mn(III) porphyrins63,69−73 (top) and chemical structure of 15−
17 (bottom).52 (B) UV−vis spectra of Zn(II)−1 (0.0026 mM, CH2Cl2) recorded upon an incremental addition of a solution of 14 (up to 1000
molar equiv) at 298.0 K. (C) UV−vis spectra of Mn(III)−1 (0.029 mM, CH2Cl2) recorded upon an incremental addition of a solution of 14 (up to
1000 molar equiv) at 298.0 K.
Table 2. Thermodynamic Stability Constants (Ka1 and Ka2 at 298.0 K) Characterizing 12 and 14 Complexation to Zn(II) and
Mn(III) Porphyrins Obtained by Multivariate Factor Analysis of the UV−vis Titration Data52
1-methylimidazole (12)
1,5-diadamantylimidazole (14)
porphyrin
Ka1 (M−1
)
Ka2 (M−1
)
Ka1 (M−1
)
Ka2 (M−1
)
a
15
4.0 0.2 × 103
1.78 0.04 × 104
4.46 0.09 × 104
58 12
5.1 0.3 × 103
3.7 0.1 × 104
1.91 0.07 × 105
68 18
a
16
Zn(II)−1
17
45 22
<5
<10
b
Mn(III)−1
58 13
332 26
0
a
78,79 b
For a direct comparison of these data, we applied statistical correction Ka1 = 1/2 K(experimental)
.
The coordination of the second ligand was not
observed.
of isosbestic points is, in our experiments (Figure 6B),
indicative of 14 (but also 12, Figure S33, Supporting
Information)52 exclusively coordinating to one side of Zn-
(II)−1 (at 298.0 K). The UV−vis titration data were subjected
to multivariate factor analysis (Figures S27−S36, Supporting
Information, ReactLab EQUILIBRIA software)52 for obtaining
equilibrium constant Ka1 (Table 2).76,77 Interestingly, the
affinity of 12/14 toward Zn(II)−1 is somewhat greater than
toward “flat” porphyrins 15 and 16 (Table 2). Furthermore,
1,5-diadamantylimidazole 14 has a greater propensity for
coordinating zinc(II) porphyrins than 1-methylimidazole 12
(Table 2). N-Heterocycles are known to bind to Mn(III)
porphyrins forming five- and six-coordinate complexes (Figure
6A);69−73,80−85 in case of Mn(III)−1, the heterocycle should
displace the coordinated chloride anion (Figure 2A). The
literature precedents would, in addition, suggest that the
thermodynamic stability of Mn(III) complexes is (a) a function
of the porphyrin’s counterion (Figure 2A) and (b) typically
smaller than that of the corresponding zinc(II) porphyrins. An
incremental addition of 1,5−diadamantylimidazole 14 to
Mn(III)−1 led to distinct UV−vis spectroscopic changes,
resembling the results of the titration of the Collman’s picnic
basket84 (Figure 6C). Importantly, the appearance of several
isosbestic points suggested that two colored species, e.g. the
metalated basket and its 1:1 complexed form, contributed to
the recorded spectra (Figure 6C); the result bodes well with the
finding that large guest 14 prefers coordinating to one (the
outer) side of Zn(II)−1. For other titrations involving Mn(III)
porphyrins (Table 2), no isosbestic point(s) were observed,69
suggesting the formation of both 1:1 (Ka1, Figure 6A) and 1:2
(Ka2, Figure 6A) complexes.52 In these experiments,52 rather
small and insufficient UV−vis spectroscopic changes accom-
panied the complexation events (Figures S31/32 and S35/36,
Supporting Information), thus complicating the binding
analysis82 and contributing to a greater uncertainty of the
stability constants Ka1 and Ka2 (Table 2).
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Working Hypotheses about the Epoxidation of
Alkenes with Gated Baskets. The interior of concave
hosts could accommodate complementary guests and, in some
cases even alter the course of chemical reactions.5,11,86,87 In
particular, the confined environment of hosts can modulate the
energy landscape of encapsulation reactions having an effect on
the stability of reactive intermediates9 and/or transition states14
thereby affecting the rate, overall yield, product distribution and
stereoselectivity.11 One of the basic features of the
encapsulation catalysis is so-called shape selectivity:88 the
catalyst promotes a faster conversion of substrates with size/
shape complementary to its inner space.89−91 For example,
“picnic basket” (Figure 7A) was designed to comprise a
The cavity of gated basket 1 is sizable (Figure 1B, ∼570
Å3)37,95 so that numerous guests populating ∼55% of its space
may reside in the interior.38 Along with this notion, we decided
to investigate the catalytic epoxidation of alkenes with
Mn(III)−1 having a heterocyclic ligand complexed at its
outer (14out−Mn(III)−1) or inner (12in−Mn(III)−1) side
(Figure 7B). On the basis of earlier mechanistic studies,47−49
we reasoned that our Mn(III) baskets (∼570 A3) should give
rise to a reactive Mn(V)O species in the presence of
iodosylarene (t-BuSO2PhIO/236 Å3, Figure 7B). This low spin
(Mn(V) is d2 with S = 0) intermediate should, in turn, be
capable of transferring its oxygen atom to an alkene and form
the corresponding epoxide.95 In this way, basket 14out−
Mn(III)−1 would form the elusive oxo intermediate on the
interior of the cavity, while in 12in−Mn(III)−1, the oxygen
transfer moiety would be outside of the cavity; importantly, the
counter chloride anion is in these complexes noncoordinat-
ing.63,69−73 The oxygen transfer reaction should thus be
possible to occur on either face of the metalated porphyrin
(Figure 7B). Given a particular regio-, stereo-, and shape-
selectivity of such epoxidations,44,96−99 one should be able to
draw a conclusion about the transformation occurring in the
interior of 14out−Mn(III)−1 (Figure 7B). Note that the four
aromatic gates are expected to restrict the rate by which alkenes
reach the embedded catalytic center.
To test our working hypotheses, we studied the regio and
stereoselectivity of the epoxidation of four differently sized
olefins 18−21 (Figure 8A) using baskets 12in−Mn(III)−1 and
14out−Mn(III)−1 (Figure 7B), and model catalyst 17 (Figure
6).
Epoxidation of (R)-Limonene 18. (R)-Limonene 18
contains one stereocenter and two double bonds (Figure
8A). While most oxidizing reagents predominantly epoxidize
more substituted (internal) alkene functionality (pathway a,
Figure 8B),100 sterically hindered Mn(III)−porphyrins were
shown to prefer functionalizing the external double bond
(pathway b, Figure 8B).101 The sizable cavity of 14in−Mn(III)−
1 (∼570 Å3) should easily accommodate 18 (176 Å3), though
we were still curious about the regio-/diastereoselectivity of the
epoxidation.
All reactions were completed in CH2Cl2 at 298 K, at which
point ligands 12 and 14 were found to coordinate to the inner
and outer sides, respectively, of Mn(III)−1 (Table 2). Small
solvent molecules (CH2Cl2, 61 Å3) were assumed to have
negligible affinity for the interior of the basket and therefore be
poorly competitive with (R)-limonene 18 as guests. The
excessive amounts of alkene (6000 molar equiv) were used to
suppress the rapid disproportionation of iodosylarene (Figure
7B).45 The amount of imidazole-based ligands 12/14 (500−
1000 molar equiv) was chosen to saturate Mn(III)−1 (0.05
mM, Table 2) under experimental conditions. The formation of
μ-oxo dimers of Mn(III)−porphyrins has been known to
contribute to their decomposition102 although the unique
topology of our Mn(III)−1 basket improved the catalyst’s
stability as was also exemplified by Nolte’s clip-shaped
porphyrins (Figure 7A).94 The epoxidation of (R)-limonene
18 (0.3 M) with Mn(III)−1 (0.05 mM) was thus repeated,
with three consequent additions of iodosylarene (5.0 mM) to
reveal a small drop (5−10%) in the overall yield of the epoxide.
The epoxidations of (R)-limonene 18 with 12in−Mn(III)−1
and 14out−Mn(III)−1 were found to have identical outcomes
(Table 3). Accordingly, if the chemical transformation occurred
inside 14out−Mn(III)−1 then the reaction’s energetics would
Figure 7. (A) Energy-minimized forms (MMFF, Spartan) of
Collman’s picnic basket61 and Nolte’s porphyrin-capped clip.92 (B)
Epoxidation of alkenes, with the assistance of terminal iodosylarene,
had been envisioned to occur in the interior of 14out−Mn(III)−1 and
at the outer face of 12in−Mn(III)−1.
Mn(III)−porphyrin “floor” and two isophthaloyl-based “side
walls” forming a cavity whose size could be adjusted via
synthesis.61,84,93 Remarkably,44 this compound promoted
shape-selective epoxidation of alkenes in its interior. The picnic
basket and more recently developed porphyrin-capped clip82,94
(Figure 7A), however, each have a molecular framework
requiring considerable synthetic effort for installing gates and
thereby controlling the constrictive binding energy17 of guests.
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Figure 8. (A) Chemical structures of alkenes 18−21 having different size and shape (AM1). (B) Epoxidation of (R)-limonene 18 occurs at the (a)
internal or (b) external double bond.
Table 3. Epoxidation of (R)-Limonene 18 (0.3 M)
Completed in CH2Cl2 (298 K) with Iodosylarene (5.0 mM)
and Porphyrin (0.05 mM) (Alkene/ArIO/Porphyrin =
cis- but also trans-2,3-diphenyloxirane (Figure 9).81,82,94
Typically, the reaction is, in the presence of various terminal
oxidants, diastereoselective with predominant formation of the
cis product and the retention of stereochemistry.103−105 In fact,
the stepwise transfer of oxygen atom81,106 occurs at a faster rate
and with a greater stereoselectivity in the presence of strong σ-
donating ligands (L, Figure 9).82 It has, accordingly, been
proposed that the axial coordination has an effect on the
position of the manganese atom with respect to the porphyrin
ring: the stronger the coordination the closer the manganese
atom to the porphyrin ring and the greater the stereo-
selectivity.82,107 The epoxidations of cis-stilbene 19 (0.3 M)
with 12in−Mn(III)−1 and 14out−Mn(III)−1 (0.05 mM) were
completed in the presence of iodosylarene (5.0 mM) in CH2Cl2
at room temperature. The yields of the two reactions, with
respect to the terminal oxidant, were comparable (∼50%)
although the stereoselectivity was somewhat different (Table
4). The epoxidation occurring in the cavity of 14out−Mn(III)−
1 would, to a greater degree, favor the formation of the trans
product (cis/trans = 6.6:1, Table 4). On the other hand, the
reaction occurring at the outer face of 12in−Mn(III)−1 gave
less of the trans epoxide (cis/trans = 8.6: 1, Table 4).
Importantly, model porphyrin systems 12/14−17 promoted
the epoxidation of 19 with the stereoselectivity of cis/trans
∼12.5:1 (Table 4) whereby ligands 12 and 14 had no
measurable effect on the stereoisomeric product ratio!
a
6000:100:1)
porphyrin
system
epoxidation
regioselectivity
internal
external
d
e
e
diastereoselectivity diastereoselectivity
b
12−17
4.81 0.01
4.81 0.03
3.94 0.01
1.12 0.01
1.12 0.01
1.04 0.01
1.27 0.01
1.29 0.02
1.47 0.01
c
12−17
12in−
Mn(III)−
b
1
14out
−
4.04 0.01
1.11 0.01
1.40 0.01
Mn(III)−
b
1
a
The progress of the epoxidation was monitored with quantitative gas
chromatography (GC) with error bars presenting standard deviation
b
c
from two measurements. 500 molar equiv of the ligand. 1000 molar
equiv of the ligand. GC was used to determine the ratio of [internal
epoxide]/[external epoxide]. GC was used to determine the ratio of
d
e
diastereomeric epoxides.
simply be indistinguishable from the one taking place at the
outer face of 12in−Mn(III)−1. At this point, we only deduced
that the spacious cavity of the basket had no effect on the
chemical behavior of this particular reactant and decided to
consider the epoxidation of more sizable cis-stilbene 19 (214 Å3,
Figure 8A). A somewhat different outcome of the epoxidation
of 18 with “flat” porphyrin 17 (Table 3) can be accounted for
by considering distinct electronic and steric characteristics of
the two catalysts.81
On the basis of the results of the epoxidation of compounds
18 (176 Å3) and 19 (214 Å3), it follows that the conversion of
more sizable cis-stilbene 19 is indeed taking place in the interior
of 14out−Mn(III)−1. The cavity of the basket has a small, yet
measurable, effect on the thermodynamic stability of the
Epoxidation of cis-Stilbene 19. The catalytic epoxidation
of cis-stilbene 19 with manganese(III) porphyrins gives rise to
Figure 9. Epoxidation of cis-stilbene with Mn(III) porphyrins is apparently a stepwise process.81,82,105
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Table 4. Epoxidation of cis-Stilbene 19 (0.3 M) Completed
in CH2Cl2 (298 K) with Iodosylarene (5.0 mM) and
Porphyrin (0.05 mM) (Alkene/ArIO/Porphyrin =
Table 5. Epoxidation of Equimolar 20/21 (0.15 M Each)
Completed in CH2Cl2 (298 K) with Iodosylarene (5.0 mM)
and Porphyrin System (0.05 mM)
a
a
6000:100:1)
c
cis/trans
20/21 product
overall yield
(%)
c
c
d
d
porphyrin system
epoxide
ratio
porphyrin system
cis/trans epoxide
11
overall yield (%)
b
b
12−17
9.56 0.01
9.31 0.07
6.6 0.3
1.27 0.01
1.27 0.01
1.2 0.1
>90
>90
82
12−17
12−17
14−17
1
73
71
76
49
47
49
b
c
14−17
12.5 0.2
12.3 0.1
8.7 0.1
8.6 0.1
6.6 0.3
b
b
12in−Mn(III)−1
b
14out−Mn(III)−
6.4 0.2
2.0 0.1
68
12in−Mn(III)−1
12in−Mn(III)−1
b
1
c
a
The progress of the epoxidation reactions was monitored with
b
14out−Mn(III)−1
quantitative gas chromatography (GC) with error bars presenting the
a
b
The progress of the epoxidation was monitored with quantitative gas
standard deviation from two measurements. 500 molar equiv of the
c
chromatography (GC) with error bars presenting the standard
ligand. GC was used to determine the ratio of [cis]/[trans]-2-methyl-
b
deviation from two measurements. 500 molar equiv of the ligand.
3-pentyloxirane obtained from cis-2-octene 20. We used quantitative
GC for obtaining the product ratio and overall reaction yield.
c
d
1000 molar equiv of the ligand. Two GC measurements were
completed to determine the reaction’s stereoselectivity and overall
yield.
was promoted with model systems 12−17 and 14−17, we
measured the comparable selectivity of 1.27:1 (Table 5).61
The epoxidation within the interior of 14out−Mn(III)−1,
however, gave greater quantities of the linear epoxide: the ratio
of the linear to cyclic epoxide products was found to be 2.0:1
(Table 5).
The fact that the epoxidation of equimolar 20/21 had, in the
presence of catalysts 12in−Mn(III)−1 and 14out−Mn(III)−1, a
different outcome is in line with the notion that the reaction is
indeed taking place in two distinct environments. That is to say,
the epoxidation with 12in−Mn(III)−1 occurs at its outer side
while with 14out−Mn(III)−1 in the basket’s cavity. In addition,
the epoxidation of linear alkene 20 appears somewhat faster (or
cyclic 21 slower) in the interior of 14out−Mn(III)−1 (Table 5);
the observed effect is small but quantifiable from multiple
measurements. What is the origin of the observed “shape
selectivity”?61,96,99
reaction’s transition states and intermediates (Figure 9),
thereby leading to the formation of two diastereomeric
products in the observed ratio (Table 4); somewhat smaller
quantity of cis-stilbene produced inside the host is indeed
intriguing, and perhaps due to the inner space stabilizing the
transition state leading to the trans compound.
Competitive Epoxidation of cis-2-Octene 20 and cis-
Cyclooctene 21. What would be the outcome of two
concurrent epoxidations of alkenes having different shape/size
inside the basket’s cavity? Olefins 20 (cis-2-octene, 187 Å3,
Figure 8A) and 21 (cis-cyclooctene, 142 Å3, Figure 8A) could
both easily occupy the interior of gated 1 (570 Å3, Figure 10).
To evaluate the ability of the basket for kinetically resolving 20
from 21, we completed the epoxidation of their equimolar
mixture (0.15 M each) with 12in−Mn(III)−1 and 14out−
Mn(III)−1 (0.05 mM) in CH2Cl2 at room temperature; note
that the term “kinetic resolution” is more precisely used for
describing two enantiomers reacting at different rates and
giving rise to predominantly one product.108
First, we examined the host−guest interaction of (R)-
52
1
limonene 18 and basket 1 using H NMR spectroscopy.
Upon an incremental addition of (R)-limonene (2.0−30.0
molar equiv) to the basket (0.67 mM) dissolved in CH2Cl2
(298.0 K), there was no observable change in the chemical shift
of any proton resonance (Figure S37, Supporting Information).
Notably, the epoxidation of equimolar 20/21 at the outer
face of 12in−Mn(III)−1 led to the formation of linear/cyclic
epoxides in the ratio 1.2:1 (Table 5). When the same reaction
Figure 10. Molecular sufaces of energy-minimized (MMFF) structures of 20 and 21 docked in the interior of gated basket 1 (left). In reaching the
interior of 14out−Mn(III)−1, olefins 20 and 21 pass the revolving gates at the rim of the basket (right).
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One can, accordingly, estimate76 that guest 18 (176 Å3) has a
rather negligible affinity (if any, Ka < 10 M−1) for occupying the
sizable cavity of host 1 (570 Å3). As shown earlier (Table 3),
the epoxidation of (R)-limonene occurred in the interior of
14out−Mn(III)−1 with regio- as well as diastereoselectivity
identical to the reaction at the outer side of 12in−Mn(III)−1.
Altogether, the binding and the reactivity studies suggest that
alkene 18 is likely adopting various isoenergetic orientations
inside spacious 14out−Mn(III)−1. Subsequently, we completed
1H NMR titration of similarly sized cis-2-octene 20 (187 Å3)
and cis-cyclooctene 21 (142 A3) to basket 1 (Figures S38/S39,
Supporting Information), to reveal that these two alkenes have
negligible affinity (if any, Ka < 10 M−1) for occupying the cavity
of the basket (570 Å3). Given that the gated basket has no
measurable propensity for complexing alkenes 20/21, could the
observed kinetic resolution of such compounds emanate from
the catalyst’s topology and/or its dynamic nature (gating) in
which linear guest 20 has a greater access to the embedded
catalytic site in gated 14out−Mn(III)−1 than the spherical 21
(Figure 10)?109
Small energetic changes that characterize the competition
reaction make any quantitative evaluation of the mechanism a
challenging task. For instance, if one guest (20 or 21) has an
affinity of Ka = 5 M−1 and another Ka = 2 M−1 toward 14out−
Mn(III)−1, then ΔΔG° would at 298 K be 0.54 kcal/mol; on
the basis of the observed reaction’s selectivity, however, one
estimates that the rate difference for the oxidation of 20/21
amounts to ΔΔG⧧ ∼0.3 kcal/mol (Table 5). Evidently,
additional studies are needed to examine the validity of the
discussed mechanistic scenarios as well as evaluate the potential
of a dynamic control of the outcome of a chemical reaction
occurring in a gated environment.
referenced using the solvent residual signal as an internal standard.
The chemical shift values are expressed as δ values (ppm) and the
couple constants values (J) are in Hertz (Hz). The following
abbreviations were used for signal multiplicities: s, singlet; d, doublet;
t, triplet; m, multiplet; and br, broad.
Compound 3. A solution of m-CPBA (4.4 g, 70%, 18.0 mmol) in
dichloromethane (50.0 mL) was added to a solution of compound 2
(3.1 g, 12 mmol) in dichoromethane (50.0 mL) at 0 °C. The reaction
mixture was stirred for 4 h at room temperature, quenched with
aqueous Na2S2O3 (1.0 M, 30.0 mL), and washed with H2O (100.0
mL), aqueous Na2CO3, and brine. The organic layer was dried over
Na2SO4, and the solvent was removed under reduced pressure to give
a solid residue. The residue was purified with column chromatography
(SiO2, hexane/ethyl acetate = 4:1) to give compound 3 as a white solid
(2.96 g, 90%). 1H NMR (400 MHz, CDCl3, 298 K): δ = 7.55 (s, 2H),
3.88 (s, 6H), 3.49 (s, 2H), 3.39 (s, 2H), 1.99 (dd, J = 9.2, 1.2 Hz, 1H),
1.55 (d, J = 9.2 Hz, 1H). 13C NMR (100 MHz, CDCl3, 298 K): δ =
168.1, 152.0, 130.2, 122.8, 55.6, 52.6, 44.6, 39.3. HRMS (ESI): m/z
calcd for C15H14O5Na 297.0739 [M + Na]+, found 297.0725.
Compound 4. Trimethylaluminum (1.0 M solution in heptane,
1.05 mL, 1.05 mmol) was added to a solution of PhSH (108.0 μL, 1.05
mmol) in dichloromethane (1.5 mL) at 0 °C under nitrogen
atmosphere. The reaction mixture was stirred for 20 min, and then
the external temperature was lowered to −78 °C. After the
temperature stabilized, compound 3 (274 mg, 1.0 mmol) in
dichoromethane (1.5 mL) was added and the reaction mixture stirred
for another 2 h. The dry ice/acetone bath was taken away, ans the
external temperature slowly rose to 298 K. The solution was stirred for
an additional 5 h before being quenched with HCl (1.0 M), extracted
with dichloromethane (3 × 75 mL), and washed with brine (100 mL).
The organic layer was dried with Na2SO4 and dichloromethane
removed under reduced pressure. The solid residue was purified with
column chromatography (SiO2, hexane/ethyl acetate = 4:1) to give 4
(276.5 mg, 72%) as a mixture of two diastereomers 4arac and 4brac
.
The intrinsic instability of this mixture prevented us from separating
and/or fully characterizing the two diastereomers. We, however,
1
1
acquired an H NMR spectrum of the mixture. H NMR (400 MHz,
CDCl3, 298 K): δ = 7.62−7.22 (m, 14H), 4.04−4.01 (m, 2H), 3.93−
3.90 (m, 12H), 3.75 (d, J = 12.0 Hz, 1H), 3.49 (s, 2H), 3.42 (m, 2H),
3.37 (s, 1H), 3.19 (d, J = 8.0 Hz, 2H), 2.27 (d, J = 8.0 Hz, 2H), 2.00
(d, J = 8.0 Hz, 2H).
CONCLUSIONS
■
Dynamic control of substrate access to a catalytic center,
embedded in a synthetic molecular cavitand, could presumably
have an effect on the outcome of chemical reaction taking place
in such a confined space. We designed, prepared and
investigated the catalytic behavior of a new family of gated
baskets15 comprising a porphyrin “floor” fused to four
phthalimide “side walls” and each carrying a revolving aromatic
“gate”. These rather spacious supramolecular catalysts (∼570 Å3)
were hereby shown to promote the epoxidation of alkenes (142−
214 Å3) in their interior. Despite the fact that the measured
catalytic characteristics of the basket are still far from being
useful for any particular synthetic application, the unique
topology and dynamic nature of gated catalysts are certainly
worth exploring for directing the outcome of chemical
reactions. It is shown, therefore, that the results described in
this study are important for learning about the relationship
between the process of gating15 and chemical reactions
occurring in confined environments.
Compounds 5arac and 5brac. A solution of m-CPBA (3.68 g, 15.0
mmol) in dichloromethane (80.0 mL) was added to a solution of 4rac
(1.92 g, 5.0 mmol) in dichloromethane (80.0 mL) at 0 °C, and the
reaction mixture was stirred for 4 h at room temperature. The reaction
was quenched with aqueous Na2S2O3 (1.0 M, 50.0 mL), and the
organic layer was washed with H2O (100.0 mL), Na2CO3 (10%, 200.0
mL), and brine (200.0 mL). The organic solvent was dried over
Na2SO4 and removed under reduced pressure. The residue was
purified by flash column chromatography (SiO2, hexane/ethyl acetate
= 2:1) to give 5arac (Rf = 0.25, 0.64 g) and 5brac (Rf = 0.2, 1.4 g) each
as a white solid in overall 99% yield. Compound 5brac. 1H NMR (400
MHz, CDCl3, 298 K): δ = 7.97 (d, J = 8.0 Hz, 2H), 7.69 (m, 1H), 7.59
(m, 3H), 7.37 (s, 1H), 4.28 (s, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.77 (s,
1H), 3.68 (d, J = 5.2 Hz, 1H), 3.48 (s, 1H), 3.19 (d, J = 6.4 Hz, 1H),
2.75 (d, J = 10.4 Hz, 1H), 2.02 (d, J = 10.4 Hz, 1H). 13C NMR (125
MHz, CDCl3, 298 K): δ = 167.9, 167.7, 149.8, 147.9, 139.7, 134.0,
131.2, 131.0, 129.3, 128.4, 123.2, 121.3, 73.8, 67.8, 52.65, 52.64, 51.6,
45.7, 45.2. HRMS (ESI): m/z calcd for C21H20O7SNa: 439.0827 [M +
Na]+, found 439.0822. Compound 5arac. 1H NMR (400 MHz, CDCl3,
298 K): δ = 7.85−7.83 (m, 2H), 7.66−7.52 (m, 3H), 7.46 (s, 2H),
3.83 (s, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.77 (s, 1H), 3.42 (t, J = 1.6
Hz, 1H), 3.25 (s, 1H), 2.98 (dd, J = 6.8, 8.8 Hz, 1H), 2.59 (m, 1H),
1.61 (dd, J = 8.8, 12.8 Hz, 1H). 13C NMR (100 MHz, CDCl3, 298 K):
δ = 167.6 (2C), 146.4, 145.5, 137.9, 134.3, 131.3, 130.9, 129.6, 128.1,
123.1, 121.7, 83.2, 66.4, 52.59, 52.57, 49.7, 49.6, 26.8. HRMS (ESI):
m/z calcd for C21H20O7SNa 439.0827 [M + Na]+, found 439.0812.
Compounds 6a/6b. Triethylamine (544 μL, 4.0 mmol),
camphanic acid chloride (868 mg, 4.0 mmol), and DMAP (50 mg)
were added to a solution of 5 (832 mg, 2.0 mmol) in dry
EXPERIMENTAL SECTION
■
General Methods. All chemicals were purchased from commercial
sources and used as received unless stated otherwise. All solvents were
dried prior to use according to standard literature procedures.
Chromatography purifications were performed using silica gel 60
(SiO2, 40−75 μm, 200 × 400 mesh). Thin-layer chromatography
(TLC) was performed on silica gel plate w/UV254 (200 μm).
Chromatograms were visualized by UV light and stained using 20%
phosphomolybdic acid in ethanol, if needed. 1H and 13C NMR spectra
were recorded, at 400 and 100 MHz respectively. They were
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dichloromethane (44.0 mL) at 0 °C. After the solution was stirred for
2 h at room temperature, a saturated aqueous solution of citric acid
was added. The organic layer was washed with NaHCO3 and dried
over Na2SO4. The solvent was removed under reduced pressure and
the residue purified by flash column chromatography (SiO2, hexane/
ethyl acetate = 2:1) to give diastereomeric 6a and 6b, each as a white
solid (overall 1.15 g, 96%; approximate 1:1 ratio of 6a/6b). Note that
6a and 6b were assigned arbitrarily, and we do not have experimental
evidence for distinguishing the two molecules. Each compound was,
however, successfully used for completing the synthesis of gated basket
1. Compound 6a. 1H NMR (400 MHz, CDCl3, 298 K): δ = 8.00 (d, J
= 3.2 Hz, 2H), 7.74−7.61 (m, 4H), 7.20 (s, 1H), 5.51 (dd, J = 6.8, 0.8
Hz, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 3.52 (d, J = 12.8 Hz, 2H), 3.32
(dd, J = 6.8, 1.6, Hz, 1H), 2.86 (d, J = 10.0 Hz, 1H), 2.56 (m, 1H),
2.18 (m, 1H), 2.04 (d, J = 10.0 Hz, 1H), 1.93 (m, 1H), 1.70 (m, 1H),
1.16 (s, 3H), 1.12 (s, 3H), 1.07 (s, 3H). 13C NMR (100 MHz, CDCl3,
298 K): δ = 178.3, 167.9, 167.4, 166.5, 149.5, 146.3, 139.7, 134.1,
131.8, 131.0, 129.6, 128.4, 123.8, 121.2, 90.9, 74.3, 66.5, 54.7, 54.3,
52.70, 52.68, 49.7, 46.4, 45.7, 30.7, 28.8, 16.61, 16.58, 9.63. HRMS
(ESI): m/z calcd for C31H32O10SNa 619.1614 [M + Na]+, found
added to a solution of mesylate (418.9 mg, 0.847 mmol) in
dichloromethane (5.0 mL) at 0 °C, and the reaction mixture was
subsequently stirred for 30 min at room temperature. The solvent was
removed under reduced pressure and the residue purified by column
chromatography (SiO2, hexane/ethyl acetate = 2:1) to give compound
8 as a white solid (303.7 mg, 90%). 1H NMR (400 MHz, CDCl3, 298
K): δ = 7.79−7.43 (m, 7H), 6.92 (s, 1H), 4.19 (s, 1H), 4.06 (s, 1H),
3.87 (s, 3H), 3.85 (s, 3H), 2.61 (d, J = 8.0 Hz, 1H), 2.35 (d, J = 8.0
Hz, 1H). 13C NMR (100 MHz, CDCl3, 298 K): δ = 168.0, 167.7,
156.5, 152.5, 151.1, 150.8, 138.3, 133.7, 129.8, 129.44, 129.36, 128.1,
122.5, 122.1, 69.1, 52.7, 52.5, 51.2, 50.6. HRMS (ESI): m/z calcd for
C21H18O6SNa 421.0722 [M + Na]+, found 421.0707.
Compound 9. Under an atmosphere of nitrogen, tert-butyl
isocyanoacetate (184.0 μL, 1.266 mmol) was added to 1.0 M solution
of t-BuOK in THF (1.266 mL) at 0 °C. Then, 0.1 M solution of
compound 8 (420.0 mg, 1.055 mmol) in dry THF (11.0 mL) was
added and the reaction mixture stirred for 4 h at ambient temperature.
The reaction was quenched with dilute HCl (5%, 4.5 mL) and the
extracted with dichloromethane (25.0 mL). The organic layer was
washed with saturated NaHCO3 (25.0 mL) and brine (25.0 mL) and
dried over Na2SO4. The solvent was removed under reduced pressure
and the residue was purified by column chromatography (SiO2,
hexane/ethyl acetate = 2:1) to give compound 9 as a white solid
1
619.1605. Compound 6b. H NMR (400 MHz, CDCl3, 298 K): δ =
7.98 (d, J = 3.2 Hz, 2H), 7.74−7.62 (m, 4H), 7.18 (s, 1H), 5.57 (d, J =
7.0 Hz, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.48 (d, J = 5.5 Hz, 2H), 3.29
(d, J = 7.0 Hz, 1H), 2.92 (d, J = 8.0 Hz, 1H), 2.87−2.78 (m, 1H),
2.17−2.07 (m, 2H), 2.01−1.93 (m, 1H), 1−76−1.67 (m, 1H), 1.18 (s,
3H), 1.12 (s, 3H), 1.03 (s, 3H). 13C NMR (100 MHz, CDCl3, 298 K):
δ = 177.8, 167.9, 167.3, 166.3, 149.2, 146.1, 139.8, 134.2, 132.0, 131.1,
129.6, 128.2, 123.9, 121.2, 91.2, 74.3, 66.2, 54.9, 54.3, 52.74, 52.73,
49.9, 46.4, 45.6, 30.7, 29.1, 17.4, 17.0, 9.7. HRMS (ESI): m/z calcd for
C31H32O10SNa 619.1614 [M + Na]+, found 619.1605.
1
(365.5 mg, 87%). H NMR (500 MHz, CDCl3, 298 K): δ = 8.03 (br,
1H), 7.544 (s, 1H), 7.539 (s, 1H), 6.55 (d, J = 2.5 Hz, 1H), 4.50 (s,
1H), 4.27 (s, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 2.68 (s, 2H), 1.58 (s,
9H). 13C NMR (100 MHz, CDCl3, 298 K): δ = 168.5, 168.3, 160.3,
155.2, 154.5, 140.7, 136.0, 129.4, 129.2, 121.7, 121.4, 116.6, 113.3,
80.7, 68.4, 52.5, 52.4, 46.4, 45.6, 28.4. HRMS (ESI): m/z calcd for
C22H23O6NNa 420.1423 [M + Na]+, found 420.1406.
Compounds 7 and 5b. To a solution of 6a (1.1 g, 1.8 mmol) in
dry CH3OH (50.0 mL) was added a catalytic amount of NaOCH3/
CH3OH (38.5 mM, 13.0 mL) at 0 °C. The solution was stirred for 5 h
at room temperature, the solvent was removed under reduced
pressure, and the residue was purified by flash column chromatography
(SiO2, hexane/ethyl acetate = 2:1) to give 7 (Rf = 0.3, 82.5 mg, 10%)
and 5b (Rf = 0.25, 640.0 mg, 85%) each as a white solid. Compound
5b. 1H NMR (500 MHz, CDCl3, 298 K): δ = 7.97 (d, J = 8.0 Hz, 2H),
7.69 (m, 1H), 7.59 (m, 3H), 7.37 (s, 1H), 4.28 (t, J = 6.0 Hz, 1H),
3.87 (s, 3H), 3.85 (s, 3H), 3.77 (s, 1H), 3.68 (d, J = 5.2 Hz, 1H), 3.48
(s, 1H), 3.19 (d, J = 6.4 Hz, 1H), 2.75 (d, J = 10.4 Hz, 1H), 2.02 (d, J
= 10.4 Hz, 1H). 13C NMR (100 MHz, CDCl3, 298 K): δ = 167.9,
167.7, 149.8, 147.9, 139.7, 134.0, 131.2, 131.0, 129.3, 128.4, 123.2,
121.3, 73.8, 67.8, 52.65, 52.64, 51.6, 45.7, 45.2. HRMS (ESI): m/z
calcd for C21H20O7SNa 439.0827 [M + Na]+, found 439.0822.
Compound 7. 1H NMR (400 MHz, CDCl3, 298 K): δ = 7.90 (m, 2H),
7.68−7.54 (m, 5H), 3.92 (s, 3H), 3.91 (s, 3H), 3.81 (s, 1H), 3.67 (m,
2H), 3.54 (s, 1H), 3.28 (s, 3H), 2.18 (d, J = 5.2 Hz, 1H), 2.05 (d, J =
5.2 Hz, 1H). 13C NMR (100 MHz, CDCl3, 298 K): δ = 168.3, 168.0,
146.8, 146.4, 139.5, 133.7, 131.5, 130.4, 129.2, 128.2, 124.8, 122.4,
83.1, 72.7, 57.9, 52.7, 52.6, 49.0, 48.3, 45.3. MS (ESI): m/z calcd for
C22H22O7SNa 453.09 [M + Na]+, found 453.1.
Compound 8. To a stirred solution of 5b (324.5 mg, 0.78 mmol)
in anhydrous pyridine (4.0 mL) at 0 °C were added MsCl (179.4 mg,
1.56 mmol) and a catalytic amount of DMAP. The reaction mixture
was stirred for 12 h and then quenched with H2O (20.0 mL).
Following, the organic layer was extracted with dichloromethane (50.0
mL), washed with brine (50.0 mL), and dried over Na2SO4. The
organic solvent was removed under reduced pressure and the solid
residue purified by column chromatography (SiO2, hexane/ethyl
acetate = 2:1) to give mesylate (see the structure above) as a white
solid (308.6 mg, 80%). 1H NMR (400 MHz, CDCl3, 298 K): δ = 8.00
(m, 2H), 7.77−7.60 (m, 4H), 7.29 (s, 1H), 5.05 (d, J = 7.2 Hz, 1H),
3.89 (s, 3H), 3.87 (s, 3H), 3.79 (s, 1H), 3.64 (s, 1H), 3.42 (dd, J = 7.2,
1.6 Hz, 1H), 3.16 (s, 3H), 2.75 (d, J = 10.4 Hz, 1H), 2.09 (d, J = 10.4
Hz, 1H). 13C NMR (100 MHz, CDCl3, 298 K): δ = 167.8, 167.4,
149.6, 145.7, 139.5, 134.3, 132.0, 131.2, 129.6, 128.6, 124.1, 121.3,
78.8, 66.8, 52.76, 52.74, 50.9, 46.1, 45.3, 38.4. HRMS (ESI): m/z calcd
for C22H22O9S2Na 517.0603 [M + Na]+, found 517.0618. 1,8-
Diazabicycloundec-7-ene (DBU, 253.0 μL, 1.69 mmol) was slowly
Compound 10. Solid iodine (5.4 mg, 0.04 mmol) was added to a
solution of 9 (57 mg, 0.143 mmol) in acetonitrile (3.0 mL). Water
(30.0 μL) was added and the reaction mixture refluxed for 5 h. The
mixture was then diluted with aqueous Na2S2O3 (5.0 mL) and
extracted with ethyl acetate (10.0 mL) and the organic layer dried over
anhydrous Na2SO4. The solvent was removed under reduced pressure
and the residue purified by column chromatography (SiO2, hexane/
ethyl acetate = 1:4) to give carboxylic acid product (see the chemical
structure above) as a white solid (35.0 mg, 70%). 1H NMR (500 MHz,
CDCl3, 298 K): δ = 8.41 (br, 1H), 7.63 (s, 1H), 7.54 (s, 1H), 6.65 (d,
J = 2.5 Hz, 1H), 4.61 (s, 1H), 4.29 (s, 1H), 3.856 (s, 3H), 3.854 (s,
3H), 2.71 (s, 2H). 13C NMR (125 MHz, CDCl3, 298 K): δ = 168.4,
168.3, 165.4, 155.1, 154.2, 144.0, 137.1, 129.5, 129.4, 122.2, 121.5,
115.2, 114.4, 68.7, 52.52, 52.50, 46.4, 45.6. HRMS (ESI): m/z calcd for
C18H15O6NNa 364.0797 [M + Na]+, found 364.0782. To a stirred
suspension of the carboxylic acid compound (75.0 mg, 0.22 mmol)
and benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophos-
phate (PyBop) (126 mg, 0.242 mmol) in THF (1.2 mL), N,N-
Diisopropylethylamine (DIPEA) (46 μL, 0.264 mmol) was added at
room temperature. The reaction mixture was allowed to stir for 2 h,
the solvent was removed under reduced pressure and the residue was
purified by column chromatography (SiO2, hexane/ethyl acetate =
2:1) to give the desired ester (see the chemical structure above) as a
white solid (80.0 mg, 80%). 1H NMR (500 MHz, CDCl3, 298 K): δ =
8.90 (br, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.65 (s, 1H), 7.58 (s, 1H),
7.56−7.39 (m, 3H), 6.84 (d, J = 2.5 Hz, 1H), 4.70 (s, 1H), 4.36 (s,
1H), 3.86 (s, 3H), 3.85 (s, 3H), 2.71 (q, J = 8.0 Hz, 2H). 13C NMR
(125 MHz, CDCl3, 298 K): δ = 168.3, 168.2, 156.4, 154.8, 153.5,
147.0, 143.5, 138.3, 129.9, 129.6, 129.0, 128.8, 124.9, 122.4, 121.8,
120.4, 118.5, 109.2, 108.6, 69.1, 52.64, 52.63, 47.1, 45.7. HRMS (ESI):
m/z calcd for C24H18O6N4Na 481.1124 [M + Na]+, found 481.1123.
NaBH4 (5.7 mg, 0.15 mmol) was in small portions added to a stirred
solution of the Bop ester (46.0 mg, 0.1 mmol) in THF (1 mL) at 0 °C.
The reaction mixture was stirred for 2 h at room temperature and the
progress of the reduction was followed with TLC (SiO2; Rf = 0.2;
hexane/ethyl acetate = 2:1). The reaction mixture was quenched with
water (5 mL) and extracted with dichloromethane (3 × 5 mL) and the
solvent was removed to give compound 10. Note that pyrrometha-
necarbinol 10 is unstable, which prevented us from completing its full
1
characterization. H NMR (250 MHz, CDCl3, 298 K): δ = 7.52 (s,
2685
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The Journal of Organic Chemistry
Article
1H), 7.50 (s, 1H), 7.42 (br, 1H), 6.43 (d, J = 2.3 Hz, 1H), 4.59 (s,
1H), 4.57 (s, 1H), 4.25 (s, 2H), 3.857 (s, 3H), 3.852 (s, 3H), 2.62 (q, J
= 7.75 Hz, 2H).
1456.3680 [M + H]+, found 1456.3628. The UV−vis spectrum of
Mn(III)−1 is shown in Figure 6C.
1,5-Diadamantylimidazole 14. Adamantylamine (825.0 mg, 5.46
mmol) and adamantylaldehyde (700.0 mg, 4.27 mmol) were dissolved
in benzene (7.0 mL) and refluxed for 4 h with a Dean Stark distilling
trap for removing H2O and forming the Schiff base. Next, benzene was
removed under reduced pressure followed by the addition of methanol
(7.0 mL) and tosylmethyl isocyanide (819.0 mg, 4.2 mmol). The
solution was stirred for 20 h and then heated to reflux for 3 h. The
methanol was removed under reduced pressure and the residue
extracted with dichloromethane (3 × 50 mL) and brine (50 mL). The
organic layer was diluted with hexane to precipitate p-toluenesulfonic
acid, which was removed by filtration. The dichloromethane solution
was concentrated,and the crude product was boiled with an excess of
K2CO3 in 10 mL of methanol for 5 h. The organic solvent was
removed under reduced pressure, and the crude product was purified
by column chromatography (SiO2, dichloromethane/methanol =
Compound 11. Pyrromethanecarbinol 10 (19.6 mg, 0.06 mmol)
was dissolved in 12 mL of CHCl3, and p-TsOH (0.81 mg, 0.00474
mmol) was added to such a mixture at room temperature. After 6 min,
DDQ (27.0 mg, 0.12 mmol) was added, and the reaction mixture was
stirred for additional 1 h. Upon the addition of triethylamine (12.0
μL), the reaction mixture was filtered through a pad of alumina and
washed with dichloromethane until the eluent was colorless. The
solvent was removed under reduced pressure to give crude 11 as a
brown solid (5.5 mg, 30%). After an additional purification with
preparatory TLC (SiO2, dichloromethane/methanol = 20:1), we
obtained octaester 11. 1H NMR (400 MHz, CDCl3, 298 K): δ = 10.22
(s, 4H), 8.05(s, 8H), 5.81 (s, 8H), 3.77−3.76 (m, 28H), 3.64 (d, J =
7.6 Hz, 4H), −4.83 (s, 2H). 13C NMR (100 MHz, CDCl3, 27 °C): δ =
168.2, 155.8, 129.4, 122.6, 101.2, 75.7, 52.4, 49.1. HRMS ESI m/z
calcd for C72H53N4O16Na 1253.3433 [M + Na]+, found 1253.3425.
Gated Basket 1. An aqueous solution of LiOH (17 mg of LiOH in
0.7 mL of H2O) was transferred to 11 (12.3 mg, 0.01 mmol) dissolved
in THF (0.8 mL), and the reaction mixture was stirred at 80 °C for 3
h. The aqueous phase was acidified with 5% aqueous HCl solution,
and the resulting precipitate was filtered, washed with water (2 × 0.5
mL), and dried at 60 °C under high vacuum to give octaacid product
1
15:1) to give 14 as a white solid (366.9 mg, 20%). H NMR (500
MHz, CDCl3, 298 K): δ = 7.80 (s, 1H), 7.02 (s, 1H), 2.35 (d, J = 2.5
Hz, 6H), 2.29 (s, 3H), 2.16 (d, J = 2.5 Hz, 6H), 2.12 (s, 3H), 1.78 (m,
12H); 13C NMR (125 MHz, CDCl3, 298 K): δ = 143.8, 136.3, 125.6,
70.6, 61.2, 43.9, 43.4, 36.4, 35.6, 30.1, 28.7 ppm; HRMS (ESI): m/z
calcd for C23H32N2 337.2644 [M + H]+, found 337.2633.
1
(10.1 mg, 90%). H NMR (500 MHz, MeOD, 298 K): δ = 11.74 (s,
ASSOCIATED CONTENT
■
4H), 8.11 (s, 8H), 6.23 (s, 8H), 3.97 (d, J = 8.0 Hz, 4H), 3.77 (d, J =
8.0 Hz, 4H). 13C NMR (100 MHz, CDCl3, 298 K): δ = 169.5, 162.0,
154.3, 130.6, 123.1, 76.4, 49.2. A solution of octaacid (17.0 mg, 0.0152
mmol) in acetic anhydride (1.0 mL) was heated at 130 °C for 2 h. The
solvent was removed under high vacuum to give pure tetraanhydride
(the chemical structure is shown above) as a brown powder (15.6 mg,
S
* Supporting Information
1
Detailed description of H NMR and UV−vis spectroscopic
titration experiments and the epoxidation procedures. This
material is available free of charge via the Internet at http://
pubs.acs.org.
1
98%). H NMR (400 MHz, DMSO, 298 K): δ = 10.68 (s, 4H), 8.24
(s, 8H), 6.14 (s, 8H), 3.89 (d, J = 7.6 Hz, 4H), 3.62 (d, J = 7.6 Hz,
4H), −5.03 (s, 2H). We observed that the tetraanhydride compound
would undergo a fast hydrolysis in DMSO, which limited a complete
characterization of this compound. Tetraanhydride (15.6 mg, 0.015
mmol) was added to benzylamine (8.0 mg, 0.075 mmol) dissolved in
dry DMSO (1.0 mL) and the solution was stirred at room temperature
for 2 h. Following, neat pyridine (0.1 mL) was added and the
temperature raised to 125 °C. The reaction was allowed to complete
(48 h) after which the solvent was evaporated in vacuum and the
residue purified by column chromatography (SiO2, dichloromethane/
AUTHOR INFORMATION
■
Corresponding Author
*Tel: 614 247 8342. Fax: 614 292 1685. E-mail: badjic@
chemistry.ohio-state.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
1
methanol = 20:1) to yield brown solid 1 (10.5 mg, 50%). H NMR
This work was financially supported with funds obtained from
the National Science Foundation under CHE-1012146 by the
Department of the Defense, Defense Threat Reduction Agency
(HDTRA1-11-1-0042). The content of the information does
not necessarily reflect the position or the policy of the federal
government, and no official endorsement should be inferred.
We thank the Ohio Supercomputer Center for generous
computational resources.
(400 MHz, CD2Cl2, 298 K): δ = 10.23 (s, 4H), 7.98 (s, 8H), 7.12−
7.04 (m, 20H), 5.87 (s, 8H), 4.52 (s, 8H), 3.88 (d, J = 8.0 Hz, 4H),
3.69 (d, J = 8.0 Hz, 4H), −4.97 (s, 2H). 13C NMR (125 MHz, CDCl3,
298 K): δ = 168.0, 159.8, 142.2, 138.8, 136.8, 128.3, 127.9, 127.3,
117.1, 78.2, 49.3, 41.1. HRMS MALDI-TOF: m/z calcd for
C92H58N8O8 1403.4456 [M + H]+, found 1403.4467.
Compound Zn(II)−1. To a solution of basket 1 (2.5 mg, 0.00178
mmol) in CHCl3 (1.5 mL) was added Zn(OAc)2·2H2O (7.8 mg, 0.036
mmol) in CH3OH (0.3 mL), upon which the reaction mixture was
stirred for 24 h at room temperature. The solvent was removed under
reduced pressure and then the residue purified by TLC preparative
chromatography (SiO2, dichloromethane/methanol = 15:1) to yield
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