pH-Responsive Pillar[6]arene-based Water-Soluble Supramolecular Hexagonal Boxes

Article abstract of DOI:10.1002/anie.201900217

We describe the preparation of the first water-soluble pH-responsive supramolecular hexagonal boxes (SHBs) based on multiple charge-assisted hydrogen bonds between peramino-pillar[6]arenes 2 with the molecular “lid” mellitic acid (1 a). The interaction be

Full text of DOI:10.1002/anie.201900217

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Accepted Article
Title: pH-Responsive Pillar[6]arene-based Water-Soluble
Supramolecular Hexagonal Boxes
Authors: Dana Kaizerman-kane, Maya Hadar, Noam Tal, Roman
Dobtovetsky, Yossi Zafrani, and Yoram Cohen
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201900217
Angew. Chem. 10.1002/ange.201900217
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10.1002/anie.201900217
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pH-Responsive Pillar[6]arene-based Water-Soluble
Supramolecular Hexagonal Boxes
Dana Kaizerman-Kane,[a] Maya Hadar,[a] Noam Tal,[a] Roman Dobrovetsky,*[a] Yossi Zafrani,*[a],[b] and
Yoram Cohen*[a]
Abstract: We describe the preparation of the first water-soluble
pH-responsive supramolecular hexagonal boxes (SHBs) based
on multiple charge-assisted hydrogen bonds between peramino-
pillar[6]arenes 2 with the molecular "lid" mellitic acid (1a). The
interaction between 2 and 1a, as well as the other "lids"
pyromellitic and trimesic acids (1b and 1c, respecively) were
studied by a combination of experimental and computational
methods. Interestingly, the addition of 1a to the complexes of the
protonated form of pillar[6]arene 2, i.e. 3, with bis-sulfonate 4a or
4b, immediately led to guest escape along with the formation of
closed 1a22 supramolecular boxes. Moreover, the process of the
openning and closing of the supramolecular boxes along with
threading and escaping of the guests, respectively, was found to
be reversible and pH-responsive. This study paves the way for
the easy and modular preparation of different supramolecular
HBs that may have myriad applications.
molecular manipulations at both sides of these easy-to-prepare
symmetric macrocycles is straightforward.[14] However, contrary
to the concave macrocycles such as calix[n]arenes, deep
cavitands, resorcin[4]arenes and more, that can self-assemble
into closed molecular containers,[4-6] their symmetric cylindrical-
shaped counterparts, pillar[n]arenes, tend to form nano-tubular
structures in their rim-to-rim self-assembly.[15] Therefore, not
surprisingly, in spite of the wealthy and varied chemistry of these
symmetric double entranced macrocycles, pillararene-based
supramolecular cages, capsules or boxes have not been
reported yet. Given our ongoing interest in the synthesis and
applications of pillar[n]arenes derivatives as anti-biofilm agents
and 129Xe-NMR biosensors,[16,17] and our recent findings that
per-amino- and per-caboxylato-pillararenes can serve as low
molecular weight organic gelators,[18] we became interested in
the potential of forming supramolecular hexagonal boxes (SHBs)
with these species (Figure 1). Based on their structural
characteristics we hypothesized that one can cover the
hexagonal-body of per-diethyl-amino-pillar[6]arenes (PAP[6]A,
2) with hexagonal "lids" such as mellitic (1a), pyromellitic (1b)
and trimesic (1c) acids via multiple charge-assisted hydrogen
bonds which in turn may provide SHBs. Herein we disclose the
first pillar[6]arene-based water-soluble SHBs obtained by simple
mixing, in water, of 2 or 3 with 1a-c according to equations 1 and
2 (Scheme 1). Spectroscopic (NMR, diffusion NMR, DOSY and
ESI-HRMS) and computational methods as well as host-guest
interactions with di-sulfonates (4a and 4b) reveal the existence
and the structural features of these intriguing SHBs. Compounds
4a and 4b were also used to demonstrate that the 1a22 HBs are,
in fact, pH-responsive supramolecular boxes. These findings
pave the way for easy and modular access to a myriad of
tunable pillararene-based supramolecular boxes and capsules
that may have many different applications.
Supramolecular chemistry in confined spaces has attracted
much interest in recent decades because it provides new
opportunities in basic and applied sciences that may have
implications on daily life.[1] In this context self-assembled
molecular containers such as cages[2,3] and capsules[4-6] play a
pivotal role since they can be regarded as nano-reactors or
nano-flasks where new phenomena may occur and new
chemistry may be realized.[7-11] For example, Rebek dimeric
capsules have been used to affect the course of reactions and to
probe different mode of isomerism[9] while the Raymond and
Fujita cages[2,3] were used for catalysis in water.[7,8] The deep
cavitands have been mostly used to affect the course of
photochemical reactions,[10] while the hydrogen bond-based
hexameric capsules of Atwood, which structures, in solution,
have been known for nearly twenty years now,[5] have been
utilized to catalyze reactions in organic solvents mainly in the
last five years.[11] However, the synthesis of hydrogen-bond-
based supramolecular containers in competitive solvent like
water remains challenging[12] but the importance of the
preparation of such systems cannot be overstated.
In the last decade, the cylindrical-shaped macrocycles,
pillar[n]arenes,[13] have emerged as an attractive building block
in supramolecular chemistry.[14] This occurred, inter alia, since
[a]
[b]
Dana Kaizerman-Kane,[a] Maya Hadar,[a] Dr. Noam Tal,[a] Dr.
Roman Dobrovetsky[a] Dr. Yossi Zafrani,*[a],[b] and Prof. Dr. Yoram
Cohen*[a]
.
School of Chemistry, Sackler Faculty of Exact sciences
Tel Aviv University, Ramat Aviv 69978
Tel Aviv, Israel
E-mail:ycohen@post.tau.ac.il
Dr. Yossi Zafrani,
Department of Organic Chemistry,
Israel Institute for Biological Research, Ness-Ziona 740000, Israel
E-mail: yossiz@iibr.gov.il
Supporting information for this article is given via a link at the end
of the document
Figure 1. Rational design of pillar[6]arene-based supramolecular HBs and
structures of the compounds involved in the study.
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10.1002/anie.201900217
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Table 1. Diffusion coefficients of the species involved.
PAP[6]A 2, which was prepared as previously described (see
Figures S1-S4 in the supporting information (SI)),[18] is poorly
soluble in water in contrast to 1a-c. Therefore, 2 was reacted
with acetic acid (12 equiv.), to form its water-soluble derivative
PAP[6]A-HOAc (3), before mixing with 1a-c (Eq.1, Scheme 1). In
the case of mellitic acid (1a) that has high solubility in water the
solution of this “lid” was also simply added to neat PAP[6]A 2
until complete dissolution (Eq. 2, Scheme 1). We assumed that
in line with the multivalency concept,[19] on the one hand, and the
relatively high acidity[20] of 1a-c, on the other, these "lids" would
immediately replace the acetate ions along with acetic acid
release. Indeed, when 3 was mixed with two equivalents of 1a,
1b or 1c significant changes in the 1H and 13C-NMR spectra
were observed (Figures S7-S12). As seen in Figures S7 and
[a]
[a]
D"lid" x 10-5
DAcOH x 10-5
System
DPAP[6]A x 10-5 [a]
mix.
free
mix.
free
0.16
±0.01
0.75
±0.01
3
-
-
0.16
±0.01
0.14c
0.98
±0.01
1a22b
0.14c
0.42c
1.02
±0.01
0.17
±0.01
0.17
±0.01
0.48
±0.01
0.92
±0.04
1b22b
1c22b
1
S10, the H NMR peaks and some of the 13C-NMR peaks of 3
0.17
±0.01
0.17
±0.01
0.48
±0.01
0.92
±0.04
and 1a broadened upon addition with 1a. This broadening was
accompanied by chemical shifts changes of all components. In
addition, the chemical shift change ( 0.14 ppm) of the narrow
peak at 2.03 ppm, attributed to the acetate ion also suggests the
release of acetic acid due to the addition of 1a. Similar behavior
was also observed for the mixtures of 3 with 1b or 1c (see
Figures S8-9 and S11-12) although there the line broadening
was much less pronounced.
[a]
[b]
in cm2s-1 units, obtained from 1H diffusion NMR unless stated otherwise;
In the presence of 12 eq. of CH3COOH; obtained from 13C diffusion NMR,
concentrations were double the ones used in 1H diffusion NMR, only one
experiment.
[c]
From the tabulated data in all three cases one can conclude that
the "lids" (1a-c) and the hexagonal body 2 are strongly bound
and diffuse together as a single entity.[22a] The attachment of 1a-
c to 3 is accompanied by a near complete release of AcOH all in
line with the expectations from the formation of SHBs. For
further corroboration, ESI-TOF mass spectra for all three
complexes were also measured. As shown in Figure 3 and
Figures S13-S15, the compositions of all three types of
supramolecular systems revealed the expected mass spectra,
showing intense peaks at m/z of 2605.4, 2429.5 and 2341.5
which correspond with the mass of the 1a22, 1b22 and 1c22,
respectively. Also the experimental isotopic patterns of these
peaks were found to be in accordance with the calculated ones
(Figures S13-S15). Note also that the obtained mass spectra
revels low intensity m/z peaks that correspond to 1a32 (Figure 3),
1b32 and 1b42 (Figure S13) and 1c32 (Figure S15) along with
peaks corresponding to 1a-c2.
Scheme 1. Reaction schemes for the preparation of the supramolecular HBs.
Taking into account the geometry and symmetry of 2 and 1a-c,
the above results appear to indicate the formation of the first
SHBs based on multiple charge-assisted hydrogen bond
interactions between these components in water. However
diffusion NMR and mass spectrometry provide the much needed
further evidence for the formation of these HBs.
Diffusion NMR and diffusion-ordered spectroscopy (DOSY)
which are powerful non-invasive techniques for characterizing
supramolecular systems in solution[21] have been used
extensively to study supramolecular cages and capsules.[5c,22]
Indeed, diffusion NMR and DOSY measurements confirmed the
formation of 1a.2.1a, 1b.2.1b and 1c.2.1c systems as clearly
demonstrated in Figures 2 and the data presented in Table 1.
Figure 3. MS spectrum of the supramolecular HB 1a22
.
Figure 2. DOSY of (left) PAP[6]A.HOAc (3), (right) 1b and (middle) the SHB
1b.2.1b.
All these results are consistent with the formation of (1a-c)22-
type complexes but does not probe necessarily that the formed
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10.1002/anie.201900217
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complexes are indeed SHBs. Although this is in fact a plausible
option due to the geometry, the multivalency, and the relative
acidities of the different species involved in the reactions, we still
need to eliminate the possibility that these electron poor
aromatic compounds reside inside the cavity of pillararene 2 or
even are attached to 2 externally. Unfortunately the ultimate
SHB 1a22 cannot be followed by 1H-NMR so we focused our
NOE studies on the solution of 1b22. Since conventional NOESY
and ROESY (mixing times, tM, of 400 and 800ms) were
uninformative we turned to 1D NOE which showed, after
screening a wide range of tMs, that at shorter mixing times the
NOEs between the aromatic protons of 1b and the aromatic and
bridge protons of 2, which are at the center of the molecules, are
not observable while that with other peaks are (Figure S17),
implying that indeed 1b resides in the proximity of the portals of
2 (see Figures S16-S17 and the short discussion in the SI)
2 (top view)
2 (side view)
To corroborate our findings even further we turned to
computational methods. Due to the large size of
2
1a•2•1a (side view)
1a•2•1a (top view)
(C114H192N12O12, Mw = 1923), we chose PM6 semi-empirical
Hamiltonian to calculate these species.[23] The accuracy of semi-
empirical methods is certainly lower than that of the density
functional theory ones. PM6, however, was shown to reproduce
the heats of formation and geometries of small organic
molecules with a decent accuracy.[23] This method was also
recently used by Rescifina and coworkers to calculate large
supramolecular capsules.[11e,f] In addition, we used conductor-
like polarizable continuum model (CPCM) to calculate these
capsules in water.[24] This model of course ignores the solvation
effects, which have significant influence on both structure and
energy of the molecule. However, estimates and trends can still
be made based on this level of calculations. Thus the structures
of 2,1a-c and their 1:2 complexes, i.e. 1a22, 1b22 and 1c22, were
optimized, and Gibbs free energies for the formation of 1a22,
1b22 and 1c22 were extracted from frequency calculations. The
optimized structure of 2 reveal the hexagonal shape of this
macrocyce (Figure 4). Interestingly, it was found that eight out of
12 diethylaminoethyl groups lie in the same plane of the
aromatic rings, but the four remaining groups adopt an endo
position toward the hexagonal plane of the macrocycle (Figure 4,
see top view of 2). The reaction of 2 with two equivalents of 1a
was found to be highly favoured having G value of -583
kcal/mole, probably, due to the formation of multiple multivalent
Figure 4. The calculated structures of 2 and its 1a22 complex.
With these fascinating structures in hands we next asked the
question of whether these compounds can host appropriate
guests and act as molecular capsules. Since others and we,
found that 3 is a good host mainly for sulfonates compared to
other guests, we focused our attention on the hexane- and the
decane-disulfonates (4a and 4b, respectively).[26] Figure S20
1
shows the H-NMR spectra of 4a and 4b in the presence of 3.
The significant up-field shifts of more than 2 ppm observed for
4a and 4b clearly imply that these aliphatic di-sulfonates are
threaded in the cavity of 3, thus forming pseudo rotaxanes.
[27]
Therefore 4a and 4b should, in principle, be suitable guests for
examining if the most effective "lid" i.e. 1a indeed forms with 3
pH-responsive SHBs. Figure S20 also shows that the formation
of the complexes of 4a and 4b with 3 increase the complexity of
1
their H NMR spectra, probably by preventing aromatic ring flip
and thus fast interconversion of the different isomers of the
pillararenes.[28] Interestingly, despite the fact that ITC showed
that the association constants (Kas) of 3 with 4a and 4b, are
2.16±0.1x104 M-1 and 3.16±0.04x104 M-1, respectively (Figure
S21), we found, in both cases, that addition of 1a to these
complexes resulted in the release of the guest trapped in 3 as
shown in Figure 5 and in Figures S22 and S23. This guest
escape actually provides an additional indirect proof for the
formation of SHBs in the case of 1a and 2. In addition, when 4
equivalent of 4a or 4b were added to the aqueous solution of the
pre-prepared (1a)22 SHBs no guest penetration was observed
even for days. This was true even when an excess of 10
equivalents of 4a or 4b were added to the closed box 1a22.
Giving the pKa values of all components involved in the above-
mentioned supramolecular process, we hypothesized that
opening and closing of the box along with threading and
escaping of the guest, respectively, will be sensitive to pH
changes of the system. The pKa values of all six carboxylate
groups in 1a are in the range of 1.40 to 6.96, because of the fact
that all carboxylic groups are attached to the same aromatic
charge-assisted
hydrogen
bonds,
i.e.
carboxyl-amine
interactions.25 Moreover, the resulting structures show tightly
closed complexes of the 1a22-type having a hexagonal shape
where almost all the diethylamine groups are now in exo position
to the plane of the macrocycle. Expectedly, the reaction between
2 and two equivalents of 1b or 1c (four or three carboxylic
groups each) was found to be less exergonic than the above-
mentioned reaction, but yet high, with a G values of -352 and -
240kcal/mole, respectively (see Figure S18-S19, SI). Importantly,
when we tried to calculate the optimized structure of 2 with 1b,
the narrowest "lid", nested in the cavity of 2, calculations did not
converge. These results clearly corroborate the notion that the
planar compounds 1a-c indeed act as “covering moieties“ for the
hexagonal body of pillar[6]arene 2, thus forming in fact SHBs.
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10.1002/anie.201900217
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COMMUNICATION
ring.[20] The pH value of the 1a22 solution in the presence or
absence of the disulfonate guests was found to be ~6. Therefore,
we assumed that acidifying the solutions will cause an opening
of the box along with threading of the guest into the cavity of 2.
Figure 6. Schematic representations of a) guest release from 3 by 1a (x =
OAc-), and b) the pH-response of the water-soluble 1a22 box along with guest
release and encapsulation upon addition of NaOH or HCl, respectively.
Compound 6 is PAP[6]A•HCl.
In conclusion, by closing the per-alkylamino portals of the
hexagonal-shaped pillar[6]arene 2 with 1a, we have created the
first,
pH-responsive,
water-soluble
pillar[6]arene-based
supramolecular hexagonal boxes based on multiple charge-
assisted hydrogen bonds. The formation and elucidation of the
structure of these SHBs was performed by a combination of
spectroscopic and computational methods. Interestingly, the
addition of the "lid" 1a, to per-amino-pillar[6]arene that host 4a or
4b, immediately led to guest escape along with formation of
closed boxes. This process was found to be reversible and pH-
dependent thus paving the way for easy and modular
preparation of many such pH-responsive supramolecular HBs
that may have different applications. Inverted and larger SHBs
are currently under investigation in our group and will be
reported in due course.
Figure 5. The pH-responsiveness of box 1a22 in the presence of guest 4a;
Partial 1H-NMR spectra (400 MHz, 298K, D2O) of a) Box 1a22, pH = 6; b) The
sample in (a) after addition of 4 equivalents of 4a, pH = 6; c) Sample (b) after
addition of DCl in D2O, pH = 1; d) Sample (c) after addition of NaOH, pH = 7.
The concentration of 2 was 3.8 mM in all the samples.
Keywords: molecular box • pillar[6]arene • supramolecular
chemistry • mellitic acid • multivalency
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10.1002/anie.201900217
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
The first water soluble, pH-
Dana Kaizerman-Kane, Maya
responsive, supramolecular
Hadar, Noam Tal, Roman
Dobrovetsky,* Yossi Zafrani,*and
Yoram Cohen*
hexagonal boxes (HBs) based on
multiple charge-assisted hydrogen
bonds were prepared by simple
addition of “lids” to the per-diethyl-
amino-pillar[6]arene 2. These
supramolecular HBs can be
Page No. – Page No.
obtained from simple components
and in a modular way thus paving
the way for the preparation of
different pH-responsive HBs that
may have myriad applications.
pH-Responsive Pillar[6]arene-
based Water-Soluble
Supramolecular Hexagonal
Boxes
This article is protected by copyright. All rights reserved.