Synthesis and Recognition Properties of Enantiomerically Pure Acyclic Cucurbit[n]uril-Type Molecular Containers

Article abstract of DOI:10.1021/acs.orglett.5b01948

Enantiomerically pure acyclic cucurbit[n]uril containers 1 and 2 were synthesized by the condensation of enantiomerically pure aromatic sidewalls 3b and 4b with glycoluril tetramer 5. Containers 1 and 2 are C₂-symmetric, feature four arms of th

Full text of DOI:10.1021/acs.orglett.5b01948

Letter
pubs.acs.org/OrgLett
Synthesis and Recognition Properties of Enantiomerically Pure
Acyclic Cucurbit[n]uril-Type Molecular Containers
Xiaoyong Lu and Lyle Isaacs*
Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742, United States
S
* Supporting Information
ABSTRACT: Enantiomerically pure acyclic cucurbit[n]uril
containers 1 and 2 were synthesized by the condensation of
enantiomerically pure aromatic sidewalls 3b and 4b with
glycoluril tetramer 5. Containers 1 and 2 are C2-symmetric,
feature four arms of the same handedness, and bind to a
variety of guests (6−15) in aqueous solution including
aliphatic and aromatic ammonium ions, amino acids, dyes,
and viologens. The binding constants of hosts 1Ac and 1OH toward selected chiral ammonium ions were measured by 1H NMR
and UV/vis spectroscopy.
ucurbit[n]urils (CB[n], Figure 1) are a family1 of highly
symmetric (Dnh) molecular container compounds that
receptors including CB[n] derivatives,6 hemicucurbit[n]urils,7
bambus[n]urils,8 biotin[n]urils,9 nor-seco-CB[n],10 and acyclic
CB[n].11 Macrocyclic CB[n] derivatives are poorly suited for
chiral recognition since any substituents are by necessity
remote from the binding site. As anion binders, enantiomeri-
cally pure hemicucurbit[n]urils, bambus[n]urils, and biotin[n]-
urils show potential for the recognition of chiral organic acids.
Specifically, enantiomerically pure cyclohexylhemicucurbit[6]-
uril has already been shown to bind more strongly to (R)-
methoxyphenyl acetic acid (27 M−1 versus 20 M−1 for S) in
CDCl3.7b Previously, we have shown that ( )-bis-ns-CB[6]
forms complexes with amino acids in water with up to 7:1
diastereoselectivity and affinity up to 105 M−1.10b In recent
years, we have been investigating the preparation of acyclic
CB[n] (e.g., M1 and derivatives, Figure 1), their molecular
recognition properties in water, and their use as solubilizing
agents for insoluble drugs and as agents to reverse neuro-
muscular block in vivo.11c,d,g Container M1 and its derivatives
consist of a central glycoluril tetramer to impart a C-shape,
aromatic sidewalls to allow it to engage in π−π interactions
with guests, and sulfonate-terminated arms to enhance aqueous
solubility. In this paper, we explore the synthesis and molecular
recognition properties of enantiomerically pure acyclic CB[n]
containers 1 and 2.
C
Figure 1. Cucurbit[n]uril and acyclic CB[n]-type containers.
feature a hydrodrophobic cavity that is guarded by two
symmetry equivalent ureidyl carbonyl portals of highly negative
electrostatic potential.2 CB[n] compounds exhibit remarkable
recognition properties toward hydrophobic cations (e.g., alkyl
ammonium ions) in water with Ka values readily exceeding 109
M−1 and also exhibit high levels of selectivity toward
structurally similar guests.3 CB[n] complexes are chemically,
electrochemically, and photochemically responsive and have
been used therefore as the basis of advanced supramolecular
systems including molecular machines, supramolecular materi-
als, chemical sensors, drug delivery, gas purification, and
(affinity) separations materials.4 However, because unfunction-
alized CB[n] compounds are achiral they are incapable of
performing chiral recognition of guest compounds on their
own.5 This is unfortunate, because the high levels of affinity and
selectivity exhibited by CB[n] compounds would be expected
to translate into high levels of enantioselectivity which could be
used to create enantioselective catalysts, sensors, and
separations materials. This current limitation of CB[n]
synthetic and supramolecular chemistry lead us to ponder
how CB[n]-type receptors could be augmented to create
enantioselective analogues.
For the preparation of enantiomerically pure acyclic CB[n]-
type containers, we decided to utilize aromatic sidewalls
containing enantiomerically pure arms. Scheme 1 shows the
synthesis of 3b and 4b. Alkylation of hydroquinone or 1,4-
dihydroxynaphthalene with enantiomerically pure epichlorohy-
drin yields 3a and 4a in moderate yields, respectively.
Subsequently, reduction of 3a and 4a with LiAlH4 delivers
sidewalls 3b and 4b in high yield.
Beyond unfunctionalized macrocyclic CB[n], researchers in
the field have been synthesizing a variety of CB[n]-type
Received: July 7, 2015
© XXXX American Chemical Society
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Letter
a
and k′) located at the chiral center (Figure 2). The chirality of
(R,R,R,R)-2OH is also seen in the resonances for the aromatic
Scheme 1. Synthesis of Sidewalls 3 and 4
1
Figure 2. H NMR spectra (DMSO-d6, 600 MHz) of chiral acyclic
CB[n]-type molecular container (R,R,R,R)-2OH.
a
Conditions: (a) K2CO3, CH3CN, reflux, 48 h; (b) LiAlH4, THF, 1 h,
0−25 °C.
naphthalene sidewalls where two sets of multiplets appear at
8.15−8.06 and 7.55 ppm which correspond to the non-
equivalent protons m, m′ and h, h′. Similarly, the C2-symmetric
structure of compound 1Ac and 2Ac was evident on the basis of
the four different ureidyl CO 13C NMR resonances (155.5,
155.4, 154.0, 153.8 ppm) of the central glycoluril tetramer unit
(only two signals were observed for achiral C2v-symmetric M1
previously).
Next, we reacted enantiomerically pure sidewalls 3b and 4b
with glycoluril tetramer 5 by double-electrophilic aromatic
substitution reactions in TFA/Ac2O as solvent to deliver
enantiomerically pure tetraacetate acyclic CB[n]-type contain-
ers (S,S,S,S)-1Ac and (R,R,R,R)-2Ac in high yields (Scheme 2).
Scheme 2. Synthesis of Enantiomerically Pure Acyclic CB[n]
a
After having firmly established the structures of enantiomeri-
cally pure hosts (S,S,S,S)-1 and (R,R,R,R)-2, we decided to
explore their molecular recognition properties toward guests
Containers 1 and 2
1
6−15 (Figure 3). Initially, we measured the H NMR spectra
Figure 3. Structures of guests 6−15 used in this study.
a
for the complexes of hosts (S,S,S,S)-1Ac and (S,S,S,S)-1OH
,
Conditions: (a) 2 M LiOH, MeOH, 50 °C (70% for 1OH, 61% for
2OH).
which are slightly soluble in water (∼1 mM), toward p-
xylylenediammonium ion 6 as shown in Figure 4. Parts b and d
of Figure 4 display distinct resonances for free 6 and the
(S,S,S,S)-1Ac·6 and (S,S,S,S)-1OH·6 complexes, which estab-
Containers (S,S,S,S)-1Ac and (R,R,R,R)-2Ac could be hydrolyzed
to the corresponding tetra-alcohols (S,S,S,S)-1OH and
(R,R,R,R)-2OH by treatment with 2 M LiOH in MeOH at 50
°C in good yields. The structures of compounds 1 and 2 were
1
lishes that guest 6 undergoes slow exchange on the H NMR
time scale. Slow guest exchange on the NMR time scale would
be advantageous for determination of the degree of chiral
recognition of (S,S,S,S)-1Ac, for example, because when a chiral
but racemic guest is used the ratio of the two competing
diastereomeric complexes can be measured quite accurately by
integration of the 1H NMR spectrum. Accordingly, we
fully characterized by FTIR, H NMR, 13C NMR, and mass
1
spectroscopy (Supporting Information). Compounds (S,S,S,S)-
1 and (R,R,R,R)-2 do not possess mirror planes or inversion
centers and are chiral and C2-symmetric. The C2-symmetry of
1
1
(S,S,S,S)-1OH and (R,R,R,R)-2OH are reflected in their H and
proceeded to measure the H NMR spectrum for the host·
13C NMR spectra. For example, (R,R,R,R)-2OH shows two
doublets at 1.25 and 1.21 ppm (coupling constant J = 6.4 and
6.2 Hz, respectively) for the two nonequivalent CH3-groups (k
guest complexes formed between hosts (S,S,S,S)-1Ac and
(S,S,S,S)-1OH and guests (R,R)-8 and (S,S)-8 (Supporting
Information). Unfortunately, these 1H NMR spectra are
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urements were performed in 50 mM NaOAc buffered H2O at
pH 5.5 to maximize the change in UV/vis absorbance upon
complex formation. Subsequently, we performed the UV/vis
indicator displacement assays. Figure 5 shows the UV/vis
Figure 4. 1H NMR spectra recorded (D2O, 400 MHz, rt) for (a) host
(S,S,S,S)-1OH (0.5 mM); (b) a mixture of (S,S,S,S)-1OH (0.5 mM) and
guest 6 (1 mM); (c) host (S,S,S,S)-1Ac (0.5 mM); (d) a mixture of
(S,S,S,S)-1Ac (0.5 mM) and guest 6 (1 mM); (e) guest 6 (1 mM).
Figure 5. Representative UV/vis spectra for the titration of guest (S)-7
toward host (S,S,S,S)-1OH containing dye 15. Conditions: 50 mM
NaOAc buffered H2O (pH = 5.5), 25 °C. [(S,S,S,S)-1OH] = 0.2 mM;
[15] = 0.2 mM.
broadened and do not exhibit slow exchange in the NMR time
scale, which precludes the planned chiral recognition
determination by 1H NMR integration. Broadened spectra
were also observed for the complexes formed between
(S,S,S,S)-1OH and guest 7 and amino acids 10−12. In addition,
we could not perform 1H NMR competition experiments
involving (S,S,S,S)-1Ac or (S,S,S,S)-1OH, 6, and chiral guests
spectra recorded when a solution containing (S,S,S,S)-1OH (0.2
mM), and 15 (0.2 mM) was titrated with a solution containing
(S)-7. The inset to Figure 5 shows a plot of UV/vis absorbance
versus [15]. We fitted this plot of absorbance at 370 nm versus
[15] using a competitive binding model implemented in
Scientist (Supporting Information) to determine Ka for the
(S,S,S,S)-1OH·(S)-7 complex (Ka = 9.3 ( 1.0) × 103 M−1).
Binding constants for chiral guests (R)-7, (S)-7, (R,R)-8, and
(S,S)-8 toward host (S,S,S,S)-1Ac (or (S,S,S,S)-1OH) were
determined in an analogous manner and are given in Table 1.
1
because the broadness of the H NMR resonances for Ho and
Ho′ for (S,S,S,S)-1Ac·6 or (S,S,S,S)-1OH·6 preclude accurate
integration.
From our previous work, we know that acyclic CB[n]
compounds with naphthalene sidewalls display higher affinity
toward their guests and do so more frequently with slow
Table 1. Binding Constants Measured from the UV/vis
Titration for Host (S,S,S,S)-1Ac and (S,S,S,S)-1OH toward
Selected Chiral Guests
11c,d,g
1
exchange on the H NMR time scale.
Accordingly, we
synthesized (R,R,R,R)-2Ac and (R,R,R,R)-2OH as described
above in hopes of achieving the slow exchange kinetics needed
for accurate relative binding constant measurement by 1H
NMR spectroscopic integration. Unfortunately, compounds
(R,R,R,R)-2Ac and (R,R,R,R)-2OH, which have larger and more
hydrophobic naphthalene sidewalls, are nearly insoluble in
water. Treatment of solid (R,R,R,R)-2Ac and (R,R,R,R)-2OH
with solutions of guest 6 result in the formation of soluble
(R,R,R,R)-2Ac·6 and (R,R,R,R)-2OH·6 complexes, with slow
exchange on the 1H NMR time scale (Supporting Information).
Unfortunately, complexes between (R,R,R,R)-2OH and chiral
guests (R,R)-8 and (S,S)-8 once again display sufficiently
Ka (M−1
)
guest
(S,S,S,S)-1Ac
(S,S,S,S)-1OH
(R)-7
(S)-7
(R,R)-8
(S,S)-8
15
2.9 ( 0.2) × 105
3.9 ( 0.5) × 105
1.3 ( 0.2) × 106
1.1 ( 0.3) × 106
6.6 ( 0.8) × 104
1.3 ( 0.3) × 104
9.3 ( 1.0) × 103
1.9 ( 0.4) × 105
1.7 ( 0.2) × 105
2.4 ( 0.1) × 103
Quite disappointingly, the ratio of the binding constants for
(R)-7 and (S)-7 toward hosts (S,S,S,S)-1Ac and (S,S,S,S)-1OH is
only 0.74 and 1.4, respectively. In the case of (R,R)-8 and (S,S)-
8, the ratio is about 1.2 and 1.1 toward host (S,S,S,S)-1Ac and
(S,S,S,S)-1OH, respectively. We conclude that hosts (S,S,S,S)-1Ac
and (S,S,S,S)-1OH do not display useful levels of chiral
recognition toward guests 7 and 8.
We were fortunate to obtain the X-ray crystal structure of
(S,S,S,S)-1OH as its acetone solvate (Figure 6). Compound
(S,S,S,S)-1OH packs in the crystal in dimeric units linked
together by bridging K+ ions via the CO portals, which then
further pack into tapes along the c-axis by π−π interactions
between the substituted o-xylylene sidewalls. The individual
molecules of (S,S,S,S)-1OH exhibit a small helical twist, but both
senses of helicity are observed in the crystal. In the design of
(S,S,S,S)-1OH, we hoped that the OH groups would H-bond to
1
broadened H NMR spectra that determination of the degree
1
of chiral recognition by H NMR was not possible.
As described above, it was not possible to determine the
1
degree of chiral recognition exhibited by 1 and 2 by H NMR
because the exchange rates were not appropriate. Accordingly,
we decided to measure the binding constants of (S,S,S,S)-1Ac
and (S,S,S,S)-1OH toward chiral guests 7 and 810a by UV/vis
spectroscopy. Because guests 7 and 8 do not possess a
chromophore that undergoes substantial UV/vis changes upon
formation of the host·guest complexes, we decided to employ
an indicator displacement assay. We selected 15 as indicator
and measured the Ka values for the (S,S,S,S)-1Ac·15 complex
(Ka = 6.6 ( 0.8) × 104 M−1) and (S,S,S,S)-1OH·15 complex (Ka
1
= 2.4 ( 0.1) × 103 M−1) by direct UV/vis and H NMR
titration, respectively (Supporting Information). These meas-
C
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ACKNOWLEDGMENTS
We thank the National Science Foundation (CHE-1404911 to
L.I.) for financial support of this work.
■
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the ureidyl CO portals to rigidify the arms and therefore
sculpt a chiral cavity. Figure 6 shows that the chiral arms are
remote from and do not H-bond to the CO portals. The lack
of these structural features provides a rationale for the observed
low levels of chiral recognition of hosts (S,S,S,S)-1Ac and
(S,S,S,S)-1OH
.
In summary, we presented the synthesis of a series of
enantiomerically pure CB[n]-type containers (S,S,S,S)-1Ac,
(S,S,S,S)-1OH, (R,R,R,R)-2Ac, and (R,R,R,R)-2OH that are C2-
symmetric, chiral, and enantiomerically pure by virtue of the
arms attached to their aromatic sidewalls. Compounds
(S,S,S,S)-1Ac, (S,S,S,S)-1OH, (R,R,R,R)-2Ac, and (R,R,R,R)-2OH
bind to a variety of cationic species in water but exhibit
1
intermediate kinetics of exchange on the H NMR time scale.
The binding affinities of (S,S,S,S)-1Ac and (S,S,S,S)-1OH toward
two pairs of enantiomers ((R)-7 and (S)-7; (R,R)-8 and (S,S)-
8)) were therefore determined by UV/vis competition
experiments and were found to be comparable. We conclude
that (S,S,S,S)-1Ac and (S,S,S,S)-1OH display poor levels of
enantioselectivity in their complexation behavior. We speculate
that the remote location of the chiral centers on the side arm
does not render the cavity itself, where binding occurs,
significantly asymmetric. In ongoing work, we aim to introduce
inherently chiral aromatic sidewall surfaces to enhance cavity
asymmetry and enantioselectivity and enable the use of acyclic
CB[n]-type containers in a variety of applications including
chiral separations, enantioselective catalysis, and chiral recog-
nition and sensing.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01948.
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■
S
1
Experimental procedures, characterization data, H and
13C NMR spectra for new compounds; 1H NMR spectra
for host·guest complexes; data from UV/vis and NMR
titration experiments (PDF)
Crystallographic data for (S,S,S,S)-1OH (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: lisaacs@umd.edu.
Notes
The authors declare no competing financial interest.
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DOI: 10.1021/acs.orglett.5b01948
Org. Lett. XXXX, XXX, XXX−XXX