The entrapment of chiral guests with gated baskets: Can a kinetic discrimination of enantiomers be governed through gating-

Article abstract of DOI:10.1002/chem.201204344

The capacity of gated hosts for controlling a kinetic discrimination between stereoisomers is yet to be understood. To conduct corresponding studies, however, one needs to develop chiral, but modular and gated hosts. Accordingly, we used computational (RI-BP86/TZVP//RI-BP86/SV(P)) and experimental (NMR/CD/UV/Vis spectroscopy) methods to examine the transfer of chirality in gated baskets. We found that placing stereocenters of the same kind at the rim (R¹=CH₃, so-called bottom) and/or top amide positions (R²=sec-butyl) would direct the helical arrangement of the gates into a P or M propeller-like orientation. With the assistance of ¹H NMR spectroscopy, we quantified the intrinsic (thermodynamic) and constrictive (kinetic) binding affinities of (R)- and (S)-1,2-dibromopropane 5 toward baskets (S_3b/P)-2, (S_3t/M)-3, and (S_3bt/P)-4. Interestingly, each basket has a low (≤1.3 kcal mol^-1), but comparable (de<10 %) affinity for entrapping enantiomeric (R/S)-5. In terms of the kinetics, basket (S_3b/P)-2, with a set of S stereocenters at the bottom and P arrangement of the gates, would capture (R)-5 at a faster rate (k_in^R/k_in^S=2.0±0.2). Basket (S_3t/M)-3, with a set of S centers at the top and M arrangement of the gates, however, trapped (S)-5 at a faster rate (k_in ^R/k_in^S=0.30±0.05). In light of these findings, basket (S_3bt/P)-4, with a set of S stereocenters installed at both top and bottom sites along with a P disposition of the gates, was found to have a lower ability to differentiate between enantiomeric (R/S)-5 (k _in^R/k_in^S=0.8). Evidently, the two sets of stereocenters in this "hybrid" host acted concurrently, each with the opposite effect on the entrapment kinetics. Gated baskets are hereby established to be a prototype for quantifying the kinetic discrimination of enantiomers through gating and elucidating the electronic/steric effects on the process. Falling into a trap: Controlling the rate at which two stereoisomeric compounds enter a host presents a challenge. Gated molecular baskets (see figure) are shown to be excellent prototypes for implementing a kinetic differentiation of guests. Copyright

Full text of DOI:10.1002/chem.201204344

FULL PAPER
DOI: 10.1002/chem.201204344
The Entrapment of Chiral Guests with Gated Baskets: Can a Kinetic
Discrimination of Enantiomers Be Governed through Gating?
Bao-Yu Wang, Sandra Stojanovic´, Daniel A. Turner, Tanya L. Young,
Christopher M. Hadad, and Jovica D. Badjic´*[a]
Abstract: The capacity of gated hosts
for controlling a kinetic discrimination
between stereoisomers is yet to be un-
derstood. To conduct corresponding
studies, however, one needs to develop
chiral, but modular and gated hosts.
Accordingly, we used computational
(RI-BP86/TZVP//RI-BP86/SV(P)) and
experimental (NMR/CD/UV/Vis spec-
troscopy) methods to examine the
transfer of chirality in gated baskets.
We found that placing stereocenters of
the same kind at the rim (R1 =CH3, so-
called bottom) and/or top amide posi-
tions (R2 =sec-butyl) would direct the
helical arrangement of the gates into a
P or M propeller-like orientation. With
the assistance of 1H NMR spectrosco-
py, we quantified the intrinsic (thermo-
dynamic) and constrictive (kinetic)
binding affinities of (R)- and (S)-1,2-di-
bromopropane 5 toward baskets (S3b/
P)-2, (S3t/M)-3, and (S3bt/P)-4. Interest-
ingly, each basket has a low (|DG8|ꢀ
1.3 kcalmolÀ1), but comparable (de<
10%) affinity for entrapping enantio-
meric (R/S)-5. In terms of the kinetics,
basket (S3b/P)-2, with a set of S stereo-
centers at the bottom and P arrange-
ment of the gates, would capture (R)-5
at a faster rate (kinR/kinS =2.0Æ0.2).
Basket (S3t/M)-3, with a set of S centers
at the top and M arrangement of the
gates, however, trapped (S)-5 at
a
faster rate (kinR/kinS =0.30Æ0.05). In
light of these findings, basket (S3bt/P)-4,
with a set of S stereocenters installed
at both top and bottom sites along with
a P disposition of the gates, was found
to have a lower ability to differentiate
R
between enantiomeric (R/S)-5 (kin
/
kinS =0.8). Evidently, the two sets of
stereocenters in this “hybrid” host
acted concurrently, each with the oppo-
site effect on the entrapment kinetics.
Gated baskets are hereby established
to be a prototype for quantifying the
kinetic discrimination of enantiomers
through gating and elucidating the
electronic/steric effects on the process.
Keywords: chirality transfer · en-
capsulation · equilibrium · kinetics ·
NMR spectroscopy · stereoselective
recognition
Introduction
namic processes.[9] Indeed, the inner space of such concave
hosts could serve as a medium for promoting enantioselec-
tive reactions[10] or detection of important analytes,[11] al-
though little is known about the principles that guide the
chirality transfer or the kinetics/thermodynamics[11b,12] of
stereoselective encapsulation in such asymmetric environ-
ments. In fact, self-assembled and covalent capsules could
differentiate enantiomers, although with poor diastereose-
lectivity[11b,11f,11 g,11k,13] relative to modern standards of asym-
metric catalysis. The symmetric characteristics[12a,14] of hosts
have been suggested to play a role in the recognition by re-
ducing the number of diastereomeric substrate–host interac-
tions and thereby improving the selectivity. Accordingly,
two-[15] and threefold[15c,16] receptors have been employed for
differentiating enantiomers. In terms of the stereoselective
encapsulation kinetics, however, the characteristics of the
hostꢀs aperture were claimed to have an effect on the
energy of the process.[11b,12b,17] Despite these advances, there
is a need to elucidate the details of the stereoselective en-
capsulation and, in particular, learn about controlling the
constrictive (kinetic)[18] and intrinsic (thermodynamic)[19]
binding energies that characterize the process.
There has been growing interest in understanding the ampli-
fication of chirality within supramolecular systems[1] for ap-
plications in separation and materials science,[2] as well as
asymmetric catalysis.[3] To transfer chirality, one typically
relies on steric and electronic communication[4] between
groups in close proximity to a stereocenter, with stereo-
chemical information propagating throughout the entire
molecule,[5] and/or dynamic assembly;[2,6] an example of the
effective transmission of chiral information in synthetic sys-
tems is given by the “sergeants and soldier” principle.[1c]
Cavitands with or without a symmetry axis possess so-called
inherent chirality[7] (Figure 1A) that may be changed
through reversal of their curved surface[8] and/or other dy-
´
[a] Dr. B.-Y. Wang, S. Stojanovic, D. A. Turner, T. L. Young,
´
Prof. C. M. Hadad, Prof. J. D. Badjic
Department of Chemistry and Biochemistry
The Ohio State University
100 West 18th Avenue, Columbus, OH (USA)
Fax: (+1)614-292-1685
Our gated baskets regulate the movement of molecules to
and from their interior with a set of hydrogen-bonded gates
revolving from a P to an M orientation, and vice versa
E-mail: badjic@chemistry.ohio-state.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201204344.
Chem. Eur. J. 2013, 19, 4767 – 4775
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4767

Figure 1. A) Gated molecular baskets are, at the top, lined with three intramolecular hydrogen bonds (dotted arrow) for holding pyridine-based gates.
The C3-symmetric baskets possess inherent chirality, which is switched upon 1808 rotation of each gate at the rim (solid arrows). B) Top view of energy
minimized (M)-1 and (P)-1 (RI-BP86/SV(P)) forms of basket 1.
(Figure 1).[20] We have shown that the P/M racemization is,
in this C3-symmetric system (Figure 1), somewhat synchron-
ized with the in/out transfer of the guest, that is, the gates
must assume the “open” state, without internal hydrogen
bonding, before the departure/entrance of a guest molecule
takes place.[21] The conformational changes in the host, that
is, the revolving of the gates, controlling the encapsulation
kinetics are referred to as gating.[20a,22] In this vein, we reas-
dynamic equilibrium,[20b] each assuming a left- or right-
handed helical orientation of the gates (Figure 1B). On the
basis of our earlier studies of metal-containing baskets,[23]
we hypothesized that the placement of an alkyl group at the
hinge position (R1 =CH3, Figure 2) could bias the helicity of
this system. That is to say, the stereogenic CH3CH center (R
or S) may force the pyridine gates to adopt either a P or M
orientation. In addition, the placement of stereogenic cen-
ters at the amide positions (R2 =sec-butyl, Figure 2) could
also have an effect on the orientation of the gates. With this
in mind, we synthesized baskets 1–4 by following established
protocols (Figure 2 and Scheme S1 in the Supporting Infor-
mation). Basket 1 has no stereogenic centers, whereas (S3b)-
2 has three S stereogenic groups at the hinge (bottom) posi-
tions, compound (S3t)-3 has an S stereogenic center at each
amide group (top), and basket (S3bt)-4 has three S stereocen-
ters at both the bottom and top sites (Figure 2).
ACHTUNGTRENNUNGoned that by restricting the orientation of the gates to either
a P or M propeller-like form[23] (Figure 1B), the capsule
would develop a chiral inner space. Given the modular
nature of such a chiral cavitand,[24] an opportunity for inves-
tigating the enantioselective encapsulation of guests would
arise and, in particular, their kinetic discrimination (the
rates by which molecules become entrapped) through
gating. Indeed, cryptophans were recently shown[17] to en-
capsulate one enantiomeric guest at a faster rate than anoth-
er (kinfast/kinslow <2) with, perhaps, steric strain directing the
difference in the measured activation energies, although no
Compound (S3b)-2: The computed structure of basket (P)-1
(RI-BP86/SV(P), Figure 1B) shows three pyridine gates
somewhat shifted to the right, driving one of the “hinge” hy-
drogen atoms (HI, Figure 3A) away from the adjacent car-
bonyl oxygen atom. We surmised that a more sizeable group
(CH3, Figure 3B) would create less van der Waals strain if
placed at this particular position (S stereocenter), thereby
stabilizing the P helical stereoisomer. In contrast, through
this same mechanism, the substitution of HII in (M)-1 with a
CH3 group (Figure 3A) should give rise to an M helical
structure (Figure 3B). Indeed, we computed (RI-BP86/
TZVP//RI-BP86/SV(P), Figure 3C) that the (S3b/P)-2 dia-
stereomer is 2.19 kcalmolÀ1 (DG at 298.0 K) more stable
than (S3b/M)-2, with CH3 groups pivoting the three pyridine
gates into a right-handed helix (Table 1).
form of “gating” was part of the proACHTUNGTRNEUNG
cess.[12b,25]
In this study, we utilized computational and experimental
methods to investigate the transfer of chirality in baskets 1–
4 (Figure 2). Next, we measured binding constants (K) and
rate coefficients (kin/out) that characterize the entrapment
and release of the enantiomers of 1,2-dibromopropane by a
number of chiral baskets. The utility of the gating process
for a kinetic discrimination of enantiomers is yet to be un-
derstood, and this study will quantify the phenomenon and
then set the stage for elucidating the fine details of the pro-
ACHTUNGTRENNUNGcess.
Results and Discussion
1
The H NMR spectrum of (S3b)-2 in CD2Cl2 showed one
Transfer of chirality:
set of signals corresponding to a C3-symmetric species
À
(Figure 2). The N H resonance at approximately 12.15 ppm
À
Research hypothesis and nomenclature: Gated basket 1 is, in
CD2Cl2, a racemic mixture of two C3-symmetric species in a
was shifted downfield, denoting the formation of N H···N
intramolecular hydrogen bonds.[20b] Evidently, there was no
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Entrapment of Chiral Guests with Gated Baskets
FULL PAPER
Figure 2. Chemical structure of the four baskets used in this study. Chiral baskets 2–4 contain “bottom” (R1) and/or “top” (R2) sites, each comprising a
stereogenic center. A 1H NMR spectroscopic study of (S3b)-2 (500 MHz, CD2Cl2) suggests the exclusive formation of diastereomer (S3b/P)-2 in solution
(see also Figure S1 in the Supporting Information); the * corresponds to the residual signal from methanol used in the preceding chromatographic sepa-
ration.
Table 1. Computed thermodynamic parameters (RI-BP86/TZVP//RI-
BP86/SV(P)) for the interconversion of the M and P stereoisomers for
each basket and the Boltzmann-weighted population [%] of such states
at 298 K (DGM/P).
ure 3C). To further verify the formation of (S3b/P)-2, we
measured the electronic (UV/Vis) and circular dichroism
(CD) spectra of this compound in CH2Cl2 at 273.0 K
(Figure 4). Three prominent Cotton effects were observed at
280 (I), 257 (II), and 237 nm (III).[23b] On the basis of an ear-
lier study,[23b] we formally ascribe band I to the pyridine, and
transitions II and III are assigned to the phthalimide chro-
mophores. Importantly, the CD spectrum of (S3b)-2 is akin
to the one corresponding to the previously studied AgI
folded basket containing the S stereogenic CH3CH center at
Basket
(S3b)-2
(S3t)-3
(S3bt)-4
DHM/P [kcalmolÀ1
]
DGM/P [kcalmolÀ1
]
M [%]
P [%]
N
À2.72
0.15
À2.53
À2.19
À0.40
À4.06
2
34
0
98
66
100
ACHTUNGTRENNUNG
E
1
decoalescence of the H NMR signals at lower temperatures
(210.0–300.0 K, Figure S3 in the Supporting Information),
suggesting the exclusive formation of either the (P)- or (M)-
diastereomer of (S3b)-2; note that the racemization of basket
1 has previously been found to occur with a free energy of
activation barrier of 10.6 kcalmolÀ1 at 250.0 K.[26] Further-
more, the 2D 1H NMR NOESY spectrum of (S3b)-2 exhibit-
ed cross-peaks corresponding to the saturation transfer be-
the hinge and the P sense of twist of unsubstituted pyr
ACHTUNGTRENNUNGi-
AHCTUNGTRENNUNG
greater quantity of the P basket in the mixture (Figure 3B),
and variable-temperature 1H NMR spectroscopy experi-
ments (Figure S3 in the Supporting Information) revealed a
de>95% for (S3b/P)-2.
À
tween N H/Ha and Hb (from the adjacent ring), CH3/Hc and
Compounds (S3t)-3 and (S3bt)-4: As stated earlier, we were
also interested to find whether a set of stereogenic centers
at the top of basket (S3t)-3 (Figure 2) would have an effect
on the helicity of its pyridine-based stereogenic unit. One
Hd/Hb protons (Figure 2 and Figure S1 in the Supporting In-
formation). These protons were computed to reside within
2.70 ꢂ of each other in the (S3b/P)-2 diastereomer (Fig-
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4769

´
J. D. Badjic et al.
the chirality amplification oc-
curred in this system and the S
stereogenic centers at the top
drove the formation of the (S3t/
M)-3 basket. The computation-
al results were not in complete
agreement with the experi-
ments as the calculated enthal-
py at 298 K indicated only a
slight preference for the ob-
served M-isomer (0.15 kcal
molÀ1), whereas the calculated
free energy indicated a prefer-
ence
for
the
P-isomer
(0.40 kcalmolÀ1). This discrep-
ancy could be due to a greater
degree of freedom of sec-butyl
moieties and/or a differential
solvation effect.
Nevertheless, we examined
the chiral characteristics of
(S3bt)-4, having S chiral centers
at both bottom and top sites
(Figure 2). Variable-tempera-
ture 1H NMR spectroscopic
measurements of (S3bt)-4 in
CDCl3
(400 MHz,
210.0–
300.0 K) showed the presence
of one C3-symmetric diaster-
eomer at all temperatures (Fig-
ure S5 in the Supporting Infor-
mation), with CD spectroscop-
ic results indicating the forma-
tion of the P helix (Figure 4).
That is to say, diastereomer
AHCTNUGTER(GNNUN S3bt/P)-4 is now dominating
the P/M equilibrium! Note
that the 1H–1H NOESY spec-
trum of (S3bt)-4 (see Figure S2
in the Supporting Information)
was also in line with the forma-
tion of (S3bt/P)-4. In this case,
the computational results sug-
gested an effective transfer of
Figure 3. A) Newman projections of P (left) and M (right) stereoisomeric forms of basket 1. B) Newman pro-
jections of (S3b/P)-2 and (S3t/M)-2 stereoisomeric forms of basket 2. C) Energy-minimized (DFT: RI-BP86/
SV(P)) structures of more-stable (S3b/P)-2 and less-stable (S3b/M)-2 (Table 1).
reason to place sec-butyl groups (R2 =sec-butyl, Figure 2) at
the amide positions is related to the availability of the
proper synthetic precursor ((S)-2-methylbutanoic anhydride,
see Scheme S1 in the Supporting Information). With the as-
sistance of density functional theory (DFT: RI-BP86/
TZVP//RI-BP86/SV(P)), we first computed that diastereo-
meric baskets (S3t/P)-3 and (S3t/M)-3 are comparable in
energy (DGM/P =À0.4 kcalmolÀ1 at 298.0 K, Table 1). Varia-
chirality with (S3bt/P)-4 being 4.1 kcalmolÀ1 (DDG at 298 K,
Table 1) more stable than (S3bt/M)-4. It appears that the
hinge group (R1 =CH3, Figure 2) takes precedence over the
amide unit (R2 =sec-butyl, Figure 2) in setting up the chirali-
ty of gated baskets.
Intrinsic binding of 1,2-dibromopropane ((R/S)-5): Previous-
ly, we have shown that numerous haloalkanes or small hy-
drocarbons (V<130 ꢂ3) would occupy the inner space of
gated baskets (V=221Æ9 ꢂ3).[27] With the goal of investi-
gating the stereoselectivity of such encapsulations, it seemed
reasonable to begin our studies with small, but also chiral
1,2-dibromopropane ((R/S)-5, Figure 5A). This compound
1
ble temperature H NMR spectra (400 MHz, 300.0–210.0 K)
of (S3t)-3, however, showed no decoalecence of proton reso-
nances (see Figure S4 in the Supporting Information),
whereas the CD spectrum of this compound (Figure 4) sug-
gested an M orientation of the pyridine moieties! Evidently,
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Entrapment of Chiral Guests with Gated Baskets
FULL PAPER
the racemic guest (Figure 5B):
the doublet corresponding to
the CH3 group in (S3b/P)-
2ꢁ(R)-5 at a higher field (d=
À2.41 ppm, Figure 5C) is thus
analogous to the CH3 reso-
nance in (P)-1ꢁ(R)-5 (d=
À2.39 ppm, Figure 5B). Thus,
we conclude that the P basket
has a somewhat greater ther-
modynamic affinity for the R
stereoisomer of 1,2-dibromo-
propane (Table 2). The poor
stereoselectivity of the recog-
nition (deꢂ10%), however, is
not unexpected since the over-
all affinity of (R/S)-5 for occu-
pying the cavity of the basket
is small (|DG8|ꢀ0.9 kcalmolÀ1,
Table 2).[9b,29] In another ex-
periment, 1H NMR chemical
shifts of the same R guest
Figure 4. UV/Vis (top) and CD (bottom) spectra of A) (S3b/P)-2, B) (S3t/M)-3, and C) (S3bt/P)-4 in CH2Cl2 at
273.0 K.
has previously been found[28] to exist in three conformation-
al states, of which the one with the bromine atoms in an an-
tiperiplanar orientation (Figure 5A) is the most stable (pop-
ulation>65%). Furthermore, the size (V=107 A3) and
shape of (R/S)-5 are complementary to the basketꢀs interior
(Figure 5A), and each stereoisomeric form of this guest
could be prepared from commercially available (R)- or (S)-
2-bromopropanoic acid (see Scheme S2 in the Supporting
Information).
Table 2. Thermodynamic parameters for the encapsulation of (R)- and
(S)-5 with chiral baskets (CD2Cl2) were obtained from variable tempera-
ture H NMR measurements and the corresponding vanꢀt Hoff plots (see
Figures S7–S12 in the Supporting Information). The superscript (R) or
(S) in the first column corresponds to the entrapment of (R)- or (S)-5.
1
Basket
(S3b/P)-2(R)
(S3b/P)-2(S)
(S3t/M)-3(R)
(S3t/M)-3(S)
(S3bt/P)-4(R)
(S3bt/P)-4(S)
DH8 [kcalmolÀ1
]
DS8 [calmolÀ1 K]
DG8 [kcalmolÀ1
]
N
À1.72Æ0.06
À1.88Æ0.06
À3.5Æ0.2
À3.5Æ0.3
À3.7Æ0.3
À4.0Æ0.3
À4.0Æ0.3
À5.1Æ0.3
À16.7Æ0.9
À15.9Æ1.4
À14Æ1
À0.92Æ0.08[a]
À0.86Æ0.06[a]
À0.3Æ0.2[b]
À0.5Æ0.4[b]
À1.0Æ0.3[b]
À1.3Æ0.5[b]
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
When racemic (R/S)-5 (244.5 mm) was added to a solution
G
À14Æ2
1
of (P/M)-1 (1.63 mm) in CD2Cl2, two sets of H NMR signals
[a] At 200 K. [b] At 189 K.
appeared at 200.0 K, corresponding to the guest residing in
two different environments (Figure 5B and Figure S6 in the
Supporting Information). Since basket 1 is a racemic mix-
ture of P and M stereoisomers (Figure 3A), we reasoned
inside the M basket ((S3t/M)-3, Figure 5E) were as expected,
with the CH3 signal appearing at a lower field. Interestingly,
1H NMR signals of (R)-5 inside the (S3bt/P)-4 were broad-
ened and difficult to discern (Figure 5F). We surmise that
the hybrid nature of this basket, with two stereocenters
having an opposite effect on the P/M propellerꢀs chirality,
could contribute to the formation of a “less-defined” encap-
sulation environment. The propensity of (R/S)-5 for residing
in (S3t/M)-3 and (S3bt/P)-4 was also small (|DG8|<1.3 kcal
molÀ1, Table 2), with the encapsulation driven by enthalpy
(DH8<0, Table 2). Interestingly, adverse entropy (DS8ꢂ
À14 to À17 calmolÀ1 K) characterized such entrapments
with perhaps restricted rotational mobility of the sec-butyl
moieties and/or solvation effects preventing the complexꢀs
formation.
1
that two sets of H NMR signals concur with the formation
of two pairs of diastereomeric complexes: (P)-1ꢁ(R)-5/(M)-
1ꢁ(S)-5 as the first and (P)-1ꢁ(S)-5/(M)-1ꢁ(R)-5 as the
second pair (Figure 5B); in this analysis, we assumed rapid
rotation of the guest within the host, which CPK models
also support. When enantioenriched (R)-5 (ee>85%) was
1
added to (S3b/P)-2, only a single set of H NMR resonances
emerged at d<0 ppm (Figure 5C), corresponding to this
guest situated within the (S3b/P)-2 complex ((S3b/P)-2ꢁ(R)-
5; see also Figure S7 in the Supporting Information). Finally,
the addition of enantioenriched (S)-5 (ee>85%) to the
same basket, (S3b/P)-2, led to the formation of (S3b/P)-
2ꢁ(S)-5 with a single set of 1H NMR resonances (Fig-
ure 5D).
1
Notably, a distinct set of H NMR signals for either (R)-5
Constrictive binding of 1,2-dibromopropane ((R/S)-5): The
or (S)-5 within (S3b/P)-2 (Figure 5 C/D) denotes two diaster-
eomeric complexes. In fact, these 1H NMR signals can be
further correlated with those found in the experiments with
encapsulation of guests with gated baskets was shown[21] to
be first order in both basket and guest (vin =k
inACHTUNGTRENNUNG[basket]-
AHCTUNGTRENNUNG
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4771

´
J. D. Badjic et al.
pound.[21] For chiral baskets,
however, the orientation of the
gates is predominantly P or M.
Presumably, the opening of
such a basket is best described
with the unidirectional motion
of the gates starting from the
most dominant stereoisomeric
form as it is populated most of
the time (Figure 6). That is to
say, guests are expected to
enter/exit the basket as the
gates progress from the princi-
pal
P or M stereoisomeric
state. With two enantiomeric
guests, this should lead to the
formation of diastereomeric
transition states, each with dif-
ferent free energies of activa-
tion (DG°in/out, Figure 6) char-
acterizing the process. Will
chiral baskets (S3b/P)-2, (S3t/
M)-3, and (S3bt/P)-4 have the
capacity to kinetically discrimi-
nate between (R/S)-5 despite a
comparable thermodynamic af-
finity of the two enantiomers
for occupying their interior?
Since the thermodynamic sta-
bility of all host–guest com-
plexes was low (DG8, Table 2),
we had to use an excess of
guests to observe the encapsu-
lation with 1H NMR spectro-
scopy. This, in turn, required
selective-inversion-transfer
1H NMR methodology[31] to
determine rate coefficients
R/S
R/S
kin and kout characterizing
(R/S)-5 entering/exiting the
(S3b/P)-2, (S3t/M)-3, and (S3bt
/
Figure 5. A) Energy-minimized structures of (R)-5 and (S3b/P)-2ꢁ(R)-5 complexes (MMFFs, Spartan). B) A
region of the 1H NMR spectrum (400 MHz, 200.0 K) of a mixture of (M/P)-1 (244.5 mm) and (R/S)-5
(1.63 mm), revealing the presence of two diastereomeric complexes. C) A region of the 1H NMR spectrum
(400 MHz, 200.0 K) of a mixture of (S3b/P)-2 (3.92 mm) and (R)-5 (62.7 mm), with signals corresponding to the
(S3b/P)-2ꢁ(R)-5 complex. D) A region of the 1H NMR spectrum (400 MHz, 200.0 K) of a mixture of (S3b/P)-2
(3.92 mm) and (S)-5 (74.5 mm), with signals corresponding to the (S3b/P)-2ꢁ(S)-5 complex. E) A region of the
1H NMR spectrum (400 MHz, 189.0 K) of a mixture of (S3t/M)-3 (3.34 mm) and (S)-5 (734.8 mm), with signals
P)-4 baskets (Table 3, for more
details see the Supporting In-
formation). Importantly, at
such high concentrations of (R/
S)-5, there was an intense T1
noise signal in the 1H NMR
EXSY spectrum of the mix-
ture, thereby preventing an ac-
curate determination of the
rates with this methodology.[21]
1
corresponding to the (S3t/M)-3ꢁ(S)-5 complex. F) A region of the H NMR spectrum (400 MHz, 189.0 K) of a
mixture of (S3bt/P)-4 (5.04 mm) and (R)-5 (302.4 mm), with signals corresponding to the (S3bt/P)-4ꢁ(S)-5 com-
plex. For spectra in C, D, and E one can observe the presence of a small quantity of another diastereomeric
complex as the guests were not enantiomerically pure (ee>85%).
was zeroth order in the guest (vout =kout[basketꢁguest]). In
accord with this rate law, the basket “opens” its three aro-
matic gates, upon disruption of the internal hydrogen bond-
ing, for guests to enter/exit its inner space.[30] The P/M re-
volving of the gates (Figure 3) could, to some extent, also
occur without the in/out exchange of the entrapped com-
Hence, in this study, we can only compare the rates of
guests entering baskets (kinR/S, Table 3) because the starting
ground states are equivalent in energy (Figure 6). In fact,
the constrictive decomplexation energies (DG°out) comprise
a contribution from the intrinsic binding (DG8) making any
comparison ambiguous and therefore difficult to analyze.
4772
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Chem. Eur. J. 2013, 19, 4767 – 4775

Entrapment of Chiral Guests with Gated Baskets
FULL PAPER
Figure 6. Energy-minimized structure of (S3b/P)-2 (RI-BP86/SV(P)) containing a molecule of CH2Cl2. The unidirectional opening of the basket will lead
to the entrapment of enantiomeric (R)-5 and (S)-5; the corresponding transition states are thus expected to be diastereomeric, and with different barriers
of activation.
Table 3. Kinetic parameters for the entrapment/release of (R)-5 (kinR, koutR) and (S)-5
governing the stereoselectivity of the transfer, with
the P basket favoring (S)-5, and the M basket fa-
voring the (R)-5 enantiomer. This is reasonable be-
(kinS, koutS) with chiral baskets were obtained from 1H NMR selective-inversion-trans-
fer measurements (see Figure S13–S18 in the Supporting Information).[a]
R
R
S
S
S
S
Basket
kin
[mÀ1 sÀ1
kout
A
kin
[mÀ1 sÀ1
kout
A
kinR/kin
koutR/kout
cause the two transition states for the encapsula-
tion can, perhaps, be described as nearly “enantio-
meric” in character. Basket (S3bt/P)-4 encompasses
two stereocenters and is, in a way, a hybrid of the
first two hosts, although with the P arrangement of
the gates. On the basis of such a P disposition, we
expected a greater kinetic/thermodynamic affinity
for the (R)-5 guest. However, the rate coefficients
G
]
[sÀ1
]
G
]
[sÀ1
]
A
46Æ1
8.3Æ0.5
17Æ1
23Æ2
7.7Æ0.4
19.7Æ0.3
29.5Æ0.5
2.0Æ0.2
1.1Æ0.1
R
4.6Æ0.6
56Æ3
15.5Æ1.3
81Æ4
0.30Æ0.05
0.70Æ0.04
0.86Æ0.05
0.95Æ0.02
A
28Æ3
[a] Spectral data for (S3b/P)-2 were collected at 200.0 K, whereas for (S3t/M)-3 and
(S3bt/P)-4, 189.0 K was used.
On the basis of our earlier studies, there should be a
for the entrapment of enantiomeric guests turned out to be
linear relationship between DG8 and DG° describing the
comparable (kinR/kinS =0.70Æ0.04, Table 3), with the propor-
in
S
encapsulation of isosteric guests;[30] thus the greater the in-
trinsic binding energy (DG8) the faster the encapsulation
(DG°in). Interestingly, we found that compound (R)-5
(DG8=À0.92Æ0.08) enters basket (S3b/P)-2 twice as fast as
(S)-5 (DG8=À0.86Æ0.06; kinR/kinS =2.0Æ0.2, Table 3). That
is, the P basket has a greater kinetic affinity toward the R
stereoisomer of 1,2-dibromopropane. With (S3t/M)-3, howev-
er, we found that the (S)-5 guest enters the host at a faster
rate (kinR/kinS =0.30Æ0.05, Table 3). In this case, the M
basket has a greater kinetic affinity toward the S stereo-
isomer of 1,2-dibromopropane.
tion kinR/kin falling in comparison to those characterizing
the other two hosts (kinR/kinS =0.30Æ0.05 to 2.0Æ0.2,
Table 3). Thus, the “hybrid basket” acts as a composite host
with two sets of spatially separated stereocenters operating
simultaneously and having an opposite effect on the recogni-
tion event. In other words, the bottom (S)-CH*CH3 center
promotes the formation of the P basket and the encapsula-
tion of the R guest, whereas the top (S)-CHACTHNUGTRNEUNG(CH3)CH2CH3
unit acts in the opposite way by assisting the entrapment of
the S guest. Working together, the two centers imposed a
modest kinetic/thermodynamic preference toward the S
guest. Clearly, stereocenters at the amide functionality, in
addition to the gates, are important for tuning the kinetics
(Table 2) and thermodynamics (Table 3) of gated encapsula-
tion. The results are encouraging because additional modifi-
Evidently, chiral and gated baskets discriminate between
the enantiomers of 5 (DDG° (R/S) =0.3 to 0.5 kcalmolÀ1) re-
in
gardless of their similar thermodynamic propensity (DG8(R/
S) =0.06 to 0.20 kcalmolÀ1) for occupying the cavity of such
dynamic hosts. The effect is noteworthy because basket 1
has a much poorer ability to differentiate between isosteric
bromoalkanes; for five guests with a range of thermodynam-
ic affinities (DDG8) of 2.83 kcalmolÀ1, we found a relatively
cations of the steric characteristics[11b,17] of the amide moi
ACHTUNGTRENNUNGe-
AHCTUNGTRENNUNG
ties or even alterations to the bulk solvent[32] should lead to
a greater kinetic selectivity kinR/kinS, which could be quanti-
fied with linear free energy relationships.
small difference in the encapsulation rates DDG°in =0.3 kcal
[26]
molÀ1
!
Furthermore, the unidirectional orientation of the
aromatic gates at the basketꢀs rim must be playing a role in
Chem. Eur. J. 2013, 19, 4767 – 4775
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4773

´
J. D. Badjic et al.
2008, 3069–3078; e) R. G. Chapman, J. C. Sherman, J. Am. Chem.
Soc. 1999, 121, 1962–1963.
Conclusion
[10] C. J. Brown, R. G. Bergman, K. N. Raymond, J. Am. Chem. Soc.
2009, 131, 17530–17531.
Gated molecular baskets can be transformed into chiral
hosts by incorporating stereogenic[25] centers at the hinge
(bottom) or amide (top) positions. Both stereocenters are
important for directing the P or M helical disposition of the
pyridine gates, and the bottom site seemingly dominates the
process. Chiral baskets encapsulate enantiomeric 1,2-dibro-
mopropane such that the orientation of the gates and the
nature of the top amide functionality have an effect on the
kinetic stereoselectivity. Notably, the stereodifferentiation of
[11] a) C. J. Hastings, M. D. Pluth, S. M. Biros, R. G. Bergman, K. N.
Raymond, Tetrahedron 2008, 64, 8362–8367; b) J. Yoon, D. J. Cram,
J. Am. Chem. Soc. 1997, 119, 11796–11806; c) T. Amaya, J. Re-
bek, Jr., J. Am. Chem. Soc. 2004, 126, 6216–6217; d) A. Bouchet, T.
Brotin, M. Linares, H. Aagren, D. Cavagnat, T. Buffeteau, J. Org.
Chem. 2011, 76, 4178–4181; e) U. Darbost, X. Zeng, M. Giorgi, I.
Jabin, J. Org. Chem. 2005, 70, 10552–10560; f) D. Fiedler, D. H.
Leung, R. G. Bergman, K. N. Raymond, J. Am. Chem. Soc. 2004,
126, 3674–3675; g) J. M. Rivera, T. Martin, J. Rebek, Jr., Science
1998, 279, 1021–1023; h) J. M. Rivera, J. Rebek, Jr., J. Am. Chem.
Soc. 2000, 122, 7811–7812; i) A. Scarso, A. Shivanyuk, O. Hayashi-
da, J. Rebek, Jr., J. Am. Chem. Soc. 2003, 125, 6239–6243; j) A.
Scarso, A. Shivanyuk, O. Hayashida, J. Rebek, Jr., Prog. Biol. Chir-
ality 2004, 261–270; k) H. Singh, R. Warmuth, Tetrahedron 2002, 58,
1257–1264; l) T. J. Wenzel, N. H. Pham, Artif. Recept. Chem. Sens.
2011, 191–248.
slow
enantiomers is small (kinfast/kin ꢂ3.3), but manageable.
That is to say, governing a kinetic differentiation of stereo-
isomers with gated hosts should, in this environment, be
possible by varying the steric and electronic characteristics
of the top amide functionalities.
[12] a) C. Moberg, Angew. Chem. 2006, 118, 4838–4840; Angew. Chem.
Int. Ed. 2006, 45, 4721–4723; b) J. K. Judice, D. J. Cram, J. Am.
Chem. Soc. 1991, 113, 2790–2791.
Acknowledgements
[13] a) H. J. Schneider, Angew. Chem. 1993, 105, 890–892; Angew.
Chem. Int. Ed. Engl. 1993, 32, 848–850; b) M. C. Schopohl, C. Sier-
ing, O. Kataeva, S. R. Waldvogel, Angew. Chem. 2003, 115, 2724–
2727; Angew. Chem. Int. Ed. 2003, 42, 2620–2623.
[14] C. Moberg, Angew. Chem. 1998, 110, 260–281; Angew. Chem. Int.
Ed. 1998, 37, 248–268.
[15] a) G. Dotsevi, Y. Sogah, D. J. Cram, J. Am. Chem. Soc. 1975, 97,
1259–1261; b) B. Escuder, A. E. Rowan, M. C. Feiters, R. J. M.
Nolte, Tetrahedron 2004, 60, 291–300; c) Y. Kubo, S. y. Maeda, S.
Tokita, M. Kubo, Nature 1996, 382, 522–524.
This work was financially supported with funds obtained from the Na-
tional Science Foundation under CHE-1012146 (to J.D.B.) and the De-
partment of the Defense, through the Defense Threat Reduction Agency
(HDTRA1-11-1-0042, to J.D.B. and C.M.H.). The content of the informa-
tion 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.
[1] a) A. L. Hofacker, J. R. Parquette, Proc. R. Soc. A 2010, 466, 1469–
1487; b) K. S. Cheon, J. V. Selinger, M. M. Green, J. Phys. Org.
Chem. 2004, 17, 719–723; c) L. J. Prins, P. Timmerman, D. N. Rein-
houdt, J. Am. Chem. Soc. 2001, 123, 10153–10163; d) M. A. Mateos-
Timoneda, M. Crego-Calama, D. N. Reinhoudt, Chem. Soc. Rev.
2004, 33, 363–372; e) N. Micali, H. Engelkamp, P. G. van Rhee,
P. C. M. Christianen, L. M. Scolaro, J. C. Maan, Nat. Chem. 2012, 4,
201–207.
[2] M. M. J. Smulders, I. A. W. Filot, J. M. A. Leenders, P. van der
Schoot, A. R. A. Palmans, A. P. H. J. Schenning, E. W. Meijer, J.
Am. Chem. Soc. 2010, 132, 611–619.
[3] B. Wu, J. R. Parquette, T. V. RajanBabu, Science 2009, 326, 1662.
[4] K. C. Harper, E. N. Bess, M. S. Sigman, Nat. Chem. 2012, 4, 366–
374.
[5] a) M. Alajarꢃn, C. Lopez-Leonardo, A. Vidal, J. Berna, J. W. Steed,
Angew. Chem. 2002, 114, 1253–1256; Angew. Chem. Int. Ed. 2002,
41, 1205–1208; b) P. Axe, S. D. Bull, M. G. Davidson, C. J. Gilfillan,
M. D. Jones, D. E. J. E. Robinson, L. E. Turner, W. L. Mitchell, Org.
Lett. 2007, 9, 223–226; c) S. D. Bull, S. G. Davies, D. J. Fox, A. C.
Garner, T. G. R. Sellers, Pure Appl. Chem. 1998, 70, 1501–1506;
d) J. W. Canary, Chem. Soc. Rev. 2009, 38, 747–756.
[16] a) S.-G. Kim, K.-H. Kim, J. Jung, S. K. Shin, K. H. Ahn, J. Am.
Chem. Soc. 2002, 124, 591–596; b) M. Schnopp, G. Haberhauer,
Eur. J. Org. Chem. 2009, 4458–4467; c) S. Sambasivan, S.-G. Kim,
S. M. Choi, Y. M. Rhee, K. H. Ahn, Org. Lett. 2010, 12, 4228–4231;
d) F. Fabris, L. Pellizzaro, C. Zonta, O. De Lucchi, Eur. J. Org.
Chem. 2007, 283–291; e) R. J. Pieters, F. Diederich, Chem.
Commun. 1996, 2255–2256.
[17] C. Givelet, J. Sun, D. Xu, T. J. Emge, A. Dhokte, R. Warmuth,
Chem. Commun. 2011, 47, 4511–4513.
[18] M. L. C. Quan, D. J. Cram, J. Am. Chem. Soc. 1991, 113, 2754–2755.
[19] D. J. Cram, J. M. Cram, Container Molecules and Their Guests,
Royal Society of Chemistry, Cambridge, 1997.
[20] a) S. Rieth, K. Hermann, B.-Y. Wang, J. D. Badjic, Chem. Soc. Rev.
2011, 40, 1609–1622; b) B.-Y. Wang, X. Bao, Z. Yan, V. Maslak,
C. M. Hadad, J. D. Badjic, J. Am. Chem. Soc. 2008, 130, 15127–
15133.
[21] K. Hermann, S. Rieth, H. A. Taha, B.-Y. Wang, C. M. Hadad, J. D.
Badjic, Beilstein J. Org. Chem. 2012, 8, 90–99.
[22] K. N. Houk, K. Nakamura, C. Sheu, A. E. Keating, Science 1996,
273, 627–629.
[23] a) S. Stojanovic, D. A. Turner, A. I. Share, A. H. Flood, C. M.
Hadad, J. D. Badjic, Chem. Commun. 2012, 48, 4429–4431; b) S. Sto-
janovic, D. A. Turner, C. M. Hadad, J. D. Badjic, Chem. Sci. 2011, 2,
752–759.
[6] T. W. Anderson, G. D. Pantos, J. K. M. Sanders, Org. Biomol. Chem.
2011, 9, 7547–7553.
[7] a) A. Szumna, Chem. Soc. Rev. 2010, 39, 4274–4285; b) O. Trapp, S.
Caccamese, C. Schmidt, V. Bohmer, V. Schurig, Tetrahedron: Asym-
metry 2001, 12, 1395–1398; c) A. Dalla Cort, L. Mandolini, C. Pas-
quini, L. Schiaffino, New J. Chem. 2004, 28, 1198–1199; d) J.
Vachon, S. Harthong, E. Jeanneau, C. Aronica, N. Vanthuyne, C.
Roussel, J.-P. Dutasta, Org. Biomol. Chem. 2011, 9, 5086–5091.
[8] A. Collet, J. Gabard, J. Jacques, M. Cesario, J. Guilhem, C. Pascard,
J. Chem. Soc. Perkin Trans. 1 1981, 1630–1638.
[9] a) J. Sun, J. L. Bennett, T. J. Emge, R. Warmuth, J. Am. Chem. Soc.
2011, 133, 3268–3271; b) R. K. Castellano, B. H. Kim, J. Rebek, Jr.,
J. Am. Chem. Soc. 1997, 119, 12671–12672; c) D. M. Rudkevich, G.
Hilmersson, J. Rebek, Jr., J. Am. Chem. Soc. 1998, 120, 12216–
12225; d) B. Kuberski, M. Pecul, A. Szumna, Eur. J. Org. Chem.
[24] B.-Y. Wang, S. Rieth, J. D. Badjic, J. Am. Chem. Soc. 2009, 131,
7250–7252.
[25] B. Botta, M. Botta, A. Filippi, A. Tafi, G. Delle Monache, M. Sper-
anza, J. Am. Chem. Soc. 2002, 124, 7658–7659.
[26] S. Rieth, J. D. Badjic, Chem. Eur. J. 2011, 17, 2562–2565.
[27] B.-Y. Wang, X. Bao, S. Stojanovic, C. M. Hadad, J. D. Badjic, Org.
Lett. 2008, 10, 5361–5364.
[28] A. J. LaPlante, H. D. Stidham, Spectrochim. Acta Part A 2009, 74,
808–818.
[29] J. Canceill, L. Lacombe, A. Collet, J. Am. Chem. Soc. 1985, 107,
6993–6996.
4774
www.chemeurj.org
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Entrapment of Chiral Guests with Gated Baskets
FULL PAPER
[30] S. Rieth, X. Bao, B.-Y. Wang, C. M. Hadad, J. D. Badjic, J. Am.
Chem. Soc. 2010, 132, 773–776.
182; c) J. J. Led, H. Gesmar, F. Abildgaard, Methods Enzymol. 1989,
176, 311–329.
[32] J. Yoon, D. J. Cram, Chem. Commun. 1997, 1505–1506.
[31] a) D. Flemming Hansen, J. J. Led, J. Magn. Reson. 2003, 163, 215–
227; b) L.-Y. Lian, G. C. K. Roberts, NMR of Macromolecules (Ed.:
G. C. K. Roberts), Oxford University Press, Oxford, 1993, pp. 153–
Received: December 5, 2012
Published online: February 21, 2013
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4775