Arylpyrrole oligomers as tunable anion receptors

Article abstract of DOI:10.1039/c4ob00357h

A novel type of arylpyrrole oligomer possessing an appropriate electropositive cavity has been designed, prepared and analysed for use as readily accessible receptors for negatively charged guests. Affinities of the receptors for various anions were determined by UV/Vis titration experiments and in depth insights into the host-guest interactions were gained by performing ¹H NMR titration experiments and X-ray crystallographic structure analyses. Experimentally determined association constants were correlated with the calculated maximum electrostatic potentials of the electropositive cavities of the receptors, allowing estimation of the strengths of host-guest associations in similar compounds. The joint contribution of aryl C-H and pyrrole N-H hydrogens was shown to be key to a strong guest association, resulting in the arylpyrrole oligomers being efficient anion receptors. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00357h

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Arylpyrrole oligomers as tunable anion receptors†
Wim Van Rossom,* Tatyana G. Terentyeva, Keitaro Sodeyama, Yoshitaka Matsushita,
Yoshitaka Tateyama, Katsuhiko Ariga and Jonathan P. Hill*
Cite this: Org. Biomol. Chem., 2014,
12, 5492
A novel type of arylpyrrole oligomer possessing an appropriate electropositive cavity has been designed,
prepared and analysed for use as readily accessible receptors for negatively charged guests. Affinities of
the receptors for various anions were determined by UV/Vis titration experiments and in depth insights
into the host–guest interactions were gained by performing 1H NMR titration experiments and X-ray
crystallographic structure analyses. Experimentally determined association constants were correlated with
the calculated maximum electrostatic potentials of the electropositive cavities of the receptors, allowing
estimation of the strengths of host–guest associations in similar compounds. The joint contribution of
aryl C–H and pyrrole N–H hydrogens was shown to be key to a strong guest association, resulting in the
arylpyrrole oligomers being efficient anion receptors.
Received 16th February 2014,
Accepted 29th May 2014
DOI: 10.1039/c4ob00357h
www.rsc.org/obc
Introduction
Structurally simple anion receptors, tuned for their binding
strength and lipophilicity, have shown to mediate transmem-
brane transport of anions and may find use in biological appli-
cations.1 Much effort has been invested in developing hosts
with various anion-responsive moieties including amides,2
(thio)ureas,3 squaramides,4 etc.5 The pyrrole unit is also useful
for this purpose due to its potentially strong hydrogen-
bonding interactions with negatively charged species and, in
particular, due to its high affinities for naturally abundant
chloride and bicarbonate ions.6 Therefore, the pyrrole ring has
been used extensively as a building block for anion receptors
and transmembrane transporting agents including synthetic
prodigiosins and tambjamines (Fig. 1), which are related to
secondary metabolites produced by a number of micro-
organisms. They have a wide variety of important therapeutic
properties leading to their excellent potential use as anti-
malarials, immunosuppressants and chemotherapy agents.7
Synthetic prodiginines have been intensively studied
despite the preparation of these compounds being labour
intensive and, unfortunately, these derivatives have failed to
yield improvements in properties over those obtained from
natural sources.8 Therefore, further development of novel and
Fig. 1 Naturally-occurring and oligomeric aryltriazole anion receptors.
potent anion receptors and transporters containing pyrrole as
a fundamental component is required, although an alternative
molecular configuration may be considered to optimize any
potentially important properties.
The recent discovery that polarized C–H bonds can form
hydrogen bonds strong enough to bind anions has played a
crucial role in the development of a new class of neutral anion
receptors.9,10 The most widely explored of these are the macro-
cyclic and acyclic aryltriazole oligomers, which have been
studied mostly due to their high affinity for chloride anions
(Fig. 1).10 Polarized C–H bonds, in conjunction with an
alternating arrangement of hexagonal and pentagonal com-
ponents, have been shown to form a binding pocket with
dimensions ideal for encapsulation of chloride ions, resulting
in strong and selective interactions.
World Premier International (WPI), Research Center for Materials Nanoarchitectonics
(MANA), National Institute for Materials Science (NIMS), 1-1 Namiki, Tsukuba, 305-
0044 Ibaraki, Japan. E-mail: wimvanrossom@gmail.com, jonathan.hill@nims.go.jp
†Electronic supplementary information (ESI) available: Detailed synthetic pro-
cedures, 1H and 13C NMR spectra, additional information regarding UV/Vis and
1H NMR titrations, crystallographic data and CIF files for 5a and [5a : AcO−], and
electrostatic potential data. CCDC 975509 and 975510. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/c4ob00357h
At the outset of this work we envisioned a novel type of
oligomeric arylpyrrole receptor that unites the features of
prodiginines, which offer the strong N–H hydrogen donating
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character of pyrrole units, with those of oligomeric aryltriazole p-toluenesulfonamide (BF3·Et2O, toluene, reflux, 3 h) gave,
receptors, which provide the appropriate dimensions and pre- after simple filtration, sulfonimine 2 in good yield (81%).
organization required to form a well-defined binding pocket. Barbier reaction of 2 with propargyl bromide (Zn, THF, 0 °C to
The preparation of molecules combining pyrrole and aryl rt, 5 h) resulted quantitatively in homopropargyl sulfonamide
moieties is expected to increase the binding strength of any 3, which required no further purification. Sonogashira reac-
host–guest interactions over the corresponding aryltriazole tions (Pd(PPh3)2Cl2, CuI, DMF, piperidine, 40 or 80 °C, 24 h) of
oligomers. Moreover, oligomeric or macrocyclic molecules 3 with various substituted aryl halides gave compounds
composed of pyrrole/aryl groups may offer advantages over the 4a–d.12 These compounds were subjected to 5-endo-dig cyclisa-
prodiginines, which consist exclusively of pyrrole or indole tion with in situ deprotection and tautomerisation to the
rings, since it is possible to readily tune association and respective pyrrole using TBAF as a base and deprotecting agent
lipophilicity characteristics through facile introduction of (DMF, 80 °C, 48 h) affording receptors 5a–d.
particular substituents.
The pyridine analogue 9 was also prepared since it contains
Our novel methodology for synthesis of unsymmetrical 2,5- a central nitrogen atom which directs both pyrrole N–H hydro-
diarylpyrroles from readily available homopropargyl sulfon- gens to the central cavity due to intramolecular hydrogen
amides by a tetra-n-butylammonium fluoride (TBAF) mediated bonding. This should render conformations of the oligomeric
one-pot 5-endo-dig cyclisation–deprotection–tautomerisation arylpyrrole backbone appropriate for optimum binding of an
reaction11 has proven to be extremely valuable and applicable anionic guest and removes any requirement for reorganization
in the preparation of oligomeric arylpyrrole anion receptors, of the host molecule. The receptor 9 was synthesized according
and is used here to prepare several arylpyrrole receptors.
to a similar synthetic route to that for 5a–d but working in
from the molecular periphery (Scheme 1). DOWEX-assisted
condensation reaction of p-trifluoromethylbenzaldehyde with
p-toluenesulfonamide (81% yield) and the subsequent Barbier
reaction (95% yield) gave homopropargyl sulfonamide 7.
Compound 8 was obtained by the Sonogashira reaction
(Pd(PPh3)2Cl2, CuI, DMF, piperidine, 40 °C, 24 h) of 7 with 2,6-
dibromopyridine in good yield (84%).12 As described in our
Results and discussion
Synthesis of oligomeric arylpyrrole receptors
A series of oligomeric arylpyrrole receptors was prepared from
isophthalaldehyde 1 (Scheme 1). Condensation reaction with
Scheme 1 Synthesis of oligomeric arylpyrrole receptors 5a–d, 9.
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previous work,8 an alternative method for the cyclisation of
pyridine substituted alkynes was required consisting of a palla-
dium catalysed 5-endo-dig cyclisation with a consecutive depro-
tection step. The pyridine analogue 9 was obtained using
Pd(PPh3)2Cl2 as a catalyst and K2CO3 as a base in dry DMF at
80 °C for 5 h, followed by the addition of NaOH (40 equiv.)
and a few drops of water (14% over 2 steps).
Anion binding studies
UV/Vis titration experiments. The host–guest chemistry
between the receptor molecules and a variety of anions (Cl−,
−
HCO3−, AcO−, H2PO4−, NO3 or Br− as their tetrabutyl-
ammonium or tetraethylammonium salts) was analysed by
means of UV/Vis titration experiments. Titration curves were
fitted to a 1 : 1 stoichiometry, as determined by Job plot analy-
sis and supported by single-crystal X-ray analysis (see ESI†),
using the HypSpec software (Table 1).13
Fig. 2 UV/Vis titration of 5a with tetra-n-butylammonium chloride in
MeCN. Inset: variation of absorbance at λ = 350 nm vs. equiv. Cl− added.
The receptor 5a, substituted with two electron-withdrawing
trifluoromethyl groups in meta-positions at each end of the
highest affinity for AcO−, except for H2PO4−, which in this case
is bound more strongly than Cl− (most probably due to the
lower steric hindrance of the smaller F substituent relative to
the large CF3 group). Receptors 5c and 5d, having respectively
CN or CF3 groups at their para-positions, exhibit further
molecule, exhibits
a broad absorption band centred at
345 nm. Slow addition of Cl− resulted in a hypochromic shift
of the initial band at 345 nm and a concurrent hyperchromic
shift around 400 nm (Fig. 2). There is a clear isosbestic point
at λ = 366 nm. Titration curves for the changes in absorbance
were fitted and an association constant Kass = 9.3 × 103 M−1
was obtained.
−
elevation of the association constant of H2PO4 over that of
−
Cl− and HCO3 most likely due to their lack of meta-substitu-
ents and the resulting loss of steric hindrance. Furthermore, a
reduction in the number of electron-withdrawing groups from
four CF3 groups to two CF3 (similarly for CN groups) did not
significantly affect their association with anionic guests.
−
Titration of 5a with the more basic HCO3 resulted in only
a slight increase in the host–guest interaction (Kass = 1.9 × 104
M
−1), whereas for AcO− a notably stronger association (Kass
=
2.4 × 105 M−1) was observed (see ESI†). Interestingly, the recep-
tor 5a binds Cl− more effectively than the much more basic
For the pyridine analogue 9, which is expected to possess a
greater degree of preorganization compared to the benzene
derivatives, titration with HCO3− resulted in only a small hypo-
chromic shift of the spectrum from which a modest associ-
ation constant of Kass = 1.2 × 102 M−1 could be determined.
H2PO4 (Kass = 7.9 × 103 M−1). In general, the H2PO4 anion is
bound stronger than Cl− and only in rare cases has this
affinity order been reversed, usually in sterically congested
binding sites.14 This suggests that the large CF3 groups and
the well-defined dimensions of the cavity prevent strong inter-
action of H2PO4− with the electropositive cavity of the receptor.
−
−
−
−
Additionally, slow addition of Cl−, H2PO4 or NO3 did not
induce any spectral change while for AcO− no proper fitting
could be obtained. Overall, the pyridine derivative 9 appeared
to be a much poorer anion receptor compared to the benzene
derivatives 5a–d. Most probably the lower affinity is caused by
a greater loss in binding energy, due to repulsion between the
electron pair of the pyridyl nitrogen atom and the negatively
charged guest, over the binding energy gained by preorganiz-
ing the oligomeric arylpyrrole backbone. In addition, the intra-
molecular hydrogen bonds cause a contraction of the central
cavity (see ESI†) shielding the electropositive pocket and allow-
ing only the strongest hydrogen-accepting guests, able to
disrupt these hydrogen bonds, to associate with the receptor 9.
Variation of the solvent used for binding studies offers a
clear insight into its effect (Table 2). Performing the titration
experiments for 5a in a competitive solvent such as DMSO/
0.5% H2O resulted in a strong decrease in association to the
extent that only a small interaction with AcO− was observed
(Kass = 1.2 × 102 M−1). When a less competitive solvent such as
acetone was used generally much stronger association con-
stants were obtained, as expected due to weaker solvation of
−
Slow addition of trigonal NO3 did not induce any discernable
spectral changes in the UV/Vis profile.
For the receptor 5b, fluorinated in both meta and para-posi-
tions, an overall improved interaction was found for all the
studied anions with an affinity pattern similar to 5a with the
Table 1 Association constants Kass (M−1) for 1 : 1 complexation between
hosts 5a–d, 9 (1 × 10−5 M, 298 K) and anionic guests in dry MeCNa
−
−
−
Receptor
Cl−
HCO3
AcO−
H2PO4
NO3
5a
5b
5c
5d
9
9.3 × 103
2.5 × 104
1.3 × 104
8.5 × 103
<10c
1.9 × 104
4.4 × 104
1.8 × 104
1.4 × 104
1.2 × 102
2.4 × 105
3.0 × 105
9.1 × 104
4.8 × 104
7.9 × 103
4.0 × 104
2.3 × 104
1.9 × 104
<10c
<10c
<10c
11
<10c
<10c
b
—
a Calculated on the basis of UV/Vis titration data using HypSpec.13
Values are the average of at least three separate wavelengths and are
considered reproducible to 15%. b Proper fitting could not be
obtained. c No notable spectral changes.
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Table 2 Association constants Kass (M−1) for 1 : 1 complexation between the host 5a (1 × 10−5 M, 298 K) and anionic guests in different solventsa
−
−
−
Solvent
Cl−
HCO3
<10b
AcO−
H2PO4
NO3
Br−
c
c
c
DMSO
MeCN
Acetone
<10b
28
—
—
—
9.3 × 103
1.8 × 105
1.9 × 104
2.4 × 105
1.4 × 107
7.9 × 103
1.5 × 106
<10b
26
51
c
—
3.9 × 102
a Calculated on the basis of UV/Vis titration data using HypSpec.13 Values are the average of at least three separate wavelengths and are
considered reproducible to 15%. b No notable spectral changes. c Not determined.
the anions. For Cl− anions, an association constant of 1.8 ×
105 M−1 was obtained while for AcO− a large value of 1.4 × 107
M−1 was derived. In comparison with Cl−, a much weaker
association was observed with Br− as a guest (Kass = 3.9 × 102
M−1 in acetone and Kass = 51 M−1 in MeCN), emphasizing the
preference of the receptor 5a for smaller and more basic
anions.
Compounds 5a–d all demonstrate a higher affinity for AcO−
over Cl−; however, placing this with respect to the anion basi-
city according to the pKa of the conjugated acid (pKa(AcO−) =
4.76; pKa(Cl−) = −8.00) it should be noted that a remarkably
strong interaction for Cl− was found.15 This high affinity for
Cl− can be attributed to the well preorganized cavity formed
upon association with the ion. Overall these arylpyrrole oligo-
mers show greatly improved anion association activity over
their triazole analogues and a wide scope of linear pyrrolic
systems.10,16 Moreover, the aryl groups allow for facile intro-
duction of different substituents that can alter the anion
selectivity of the receptors, a characteristic that prodiginines
lack. These arylpyrrole oligomers are thus a promising new
class of anion receptors.
1H NMR titration experiments. For a better understanding
of the binding interactions between the oligomeric arylpyrrole
1
receptor and the anionic guests a series of H NMR titrations
in CD3CN (5 × 10−5 M, 298 K) was performed. During titration
of 5a with Cl− resonances due to the pyrrole N–H protons and
the central aryl proton Ha shift downfield considerably (from
8.1 and 10.1 ppm to 9.7 and 12.7 ppm, respectively), with the
more acidic N–H contributing slightly more to the interaction
than Ha (Δδ = 2.6 versus 1.6 ppm, respectively). In addition, the
outer aryl protons Hb apparently associate less strongly with a
less significant downfield shift (from 8.3 ppm to 8.8 ppm)
being observed. Peaks due to the remaining aromatic protons
shift slightly upfield consistent with a general conformational
reorganization (Fig. 3).
Fig. 3 1H NMR titration of 5a with increasing equivalents of tetra-n-
butylammonium chloride in CD3CN.
corresponds to deprotonation of the host by the anion
although at least 2 equiv. would be required for full deproto-
nation of both N–H hydrogens (slow proton exchange cannot
really be excluded).17 Nevertheless, a clear interaction between
the host and the guest was observed as both Ha and Hb
undergo downfield shifts (see ESI†).
A very similar pattern was found upon slow addition of
AcO− with downfield shifts of peaks from 10.0 and 8.0 ppm to
14.0 and 9.0 ppm for the N–H and Ha protons, respectively,
and from 8.2 to 8.7 ppm for the Hb proton resonance. Here,
the largest perturbation is clearly experienced by the N–H
protons (Δδ = 4.0 ppm) while Ha and Hb interact only modestly
(Δδ = 1.0 and 0.5 ppm, respectively).
Calculations of electrostatic potential
To obtain further information regarding the interaction
between the studied receptors and anions, electronic struc-
tures of the arylpyrrole oligomers were evaluated. Compu-
tational ab initio calculations of electrostatic potential and
geometry optimizations were carried out using density func-
tional theory (DFT) in the Gaussian 09 software18 at B3LYP/
cc-pVDZ (C, H, N, and O) and aug-cc-pVDZ (F, Cl) levels. A con-
ductor-like polarized continuum model (CPCM) was used to
take into account the effect of the MeCN solvent.
Upon addition of 0.5 equivalents of HCO3−, the peak due to
N–H protons disappeared while the peaks due to Ha and Hb
protons shift downfield (from 8.2 and 8.4 ppm to 8.8 and
8.6 ppm, respectively). In general, the disappearance of peaks
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Fig. 4 Graphical representation of the correlation between the associ-
ation constant (Log Kass
) of the receptors with chloride and the
maximum electrostatic potential mapped on the molecular electron
density surface (pink dot corresponds to the location of the VS,max).
A substantially lower value was found for the maximum
electrostatic potential mapped on the molecular electron
density surface (VS,max, see ESI†) of the pyridine derivative 9
compared to the benzene-based hosts. This is in agreement
with the higher repulsion of the anion by the free electron pair
of the pyridyl nitrogen, which results in lower association
constants.
Fig. 5 Crystal structure of (a) receptor 5a and (b) complex [5a : AcO−]
(TBA+ counter ion omitted for clarity).
groups on opposite sides rather than forming a potential
binding pocket with NH groups on the same side. Each NH
group interacts with an individual DMSO molecule (see ESI†).
Single-crystals of the complex [5a : AcO−] could also be
obtained by slow evaporation of an MeCN solution (Fig. 5b).‡
The structure shows that binding of a guest causes rotation of
a pyrrole group (relative to the conformation for the structure
of the anion free 5a) to form a central binding pocket in which
a single AcO− is bound. This is in good correlation with the
1 : 1 stoichiometry observed in solution. The host 5a was found
to form hydrogen bonds with one oxygen atom of the AcO−
through one N–H and two C–H hydrogens while interacting
with the second oxygen atom through one N–H and one C–H
hydrogen.
Plotting the association constants (Log Kass) found for
receptors (5a–d) with Cl−, HCO3 or AcO− against the calcu-
−
lated VS,max values indicates a good correlation (Fig. 4). There-
fore, the VS,max value serves as a good indicator from which the
association constants for oligomeric arylpyrrole receptors may
be estimated and against which new receptor designs in future
work may be evaluated in advance of synthesis. Setting out the
−
association constants for the hosts with H2PO4 against VS,max
presented 5a as an outlier in accordance with the diminished
association constant due to steric hindrance by the meta-CF3
substituents (see ESI, Fig. S38†). Moreover, the outlier denotes
a change in selectivity from the general pattern highlighting a
lead compound in any search for anion selective receptors.
Important distances between the oxygen atom of the
acetate guest and the host found for the [5a : AcO−] complex
are 2.2–2.3 Å from pyrrole N–H nitrogen and 3.3–3.4 Å from
the phenyl C–H. Hydrogen bonds have been categorized
according to their donor–acceptor distances of 2.2–2.5 Å as
“strong, mostly covalent”, 2.5–3.2 Å as “moderate, mostly elec-
trostatic”, and 3.2–4.0 Å as “weak, electrostatic”.19 Therefore,
the AcO− is bound to the host 5a by a combination of strong,
mostly covalent interactions through the N–H hydrogens and
moderate, mostly electrostatic interactions with the C–H hydro-
gens. The joint interaction of N–H and C–H hydrogens results
in a strong binding of the anionic guest, demonstrating that
arylpyrrole oligomers are a promising novel class of anion
receptors.
X-ray crystallographic analysis
Single-crystals of 5a suitable for X-ray analysis were grown by
slow evaporation of a DMSO solution at 50 °C (Fig. 5a).‡ The
molecule possesses a nearly planar form with pyrrole NH
‡X-ray crystallographic data 5a: Rigaku Varimax Saturn; T = 110(2) K. Monoclinic
space group P21/a, a = 9.4849(8) Å, b = 18.4276(16) Å, c = 19.2588(17) Å, α = 90°,
β = 92.1781(15)°, γ = 90°, V = 3363.7(5) Å3, Z = 4, ρcalc = 1.557 g cm−3, μ =
0.261 mm−1. 7632 reflections, 6010 independent. Final wR2 = 0.1182, R1
0.0435. GOOF = 1.088. X-ray crystallographic data [5a : AcO−]: Rigaku Varimax
Saturn; T = 110(2) K. Monoclinic space group P21/n, a = 17.1963(19) Å, b = 22.354
(3) Å, c = 24.519(3) Å, α = 90°, β = 97.389(2)°, γ = 90°, V = 9347(2) Å3, Z = 8, ρcalc
1.327 g cm−3, μ = 0.114 mm−1. 20 016 reflections, 8961 independent. Final wR2
0.2581, R1 = 0.1229. GOOF = 1.071.
=
=
=
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for these new compounds as neutral fluorophores and
sensors.
Conclusions
A new class of anion receptors was developed consisting of an
oligomeric arylpyrrole framework, which benefits from the
presence of both acidic pyrrole N–H protons and the ideal
dimensions of the alternating aryl-pyrrole backbone. Both
1
UV/Vis and H NMR titration experiments confirm that strong
guest association occurs due to contributions from aryl C–H
and pyrrole N–H hydrogens. This is further supported by X-ray
crystal structure analyses. The correlations found between the
calculated electrostatic potentials and the experimentally
determined association constants provide a tool for prelimi-
nary evaluation of the binding affinity in the search for anion
selective receptors. The strong fluorescence character of the
non-halogenated compounds also suggests that these com-
pounds might be suitable as fluorophoric sensors. Further
improvements and preorganization of the oligomeric arylpyr-
role receptors will allow for continued exploration of the poten-
tial of these receptors in various applications.
Acknowledgements
The authors gratefully acknowledge the Japan Society for the
Promotion of Science (JSPS) for financial support and a post-
doctoral fellowship for W.VR. The World Premier International
(WPI) Research Center for Materials Nanoarchitectonics
(MANA) is also thanked for financial support.
Fig. 6 (a) Absorbance and fluorescence emission spectra for 5a and 5c
(in MeCN). Inset: visual representation of the fluorescence. (b) Fluo-
rescence quenching for 5c upon addition of anionic guests (in MeCN).
Inset: visual representation of the fluorescence after addition of an
excess of anion.
Notes and references
Fluorescence analysis
An interesting additional feature of these oligomeric aryl-
pyrroles is their fluorescence character. The spectra and inten-
sity of emitted light proved to be highly dependent on the
substitution pattern. Trifluoromethyl and fluoride substituents
yield arylpyrrole oligomers emitting weak fluorescence. Upon
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excitation of 5a at 350 nm (εabs346 = 57 000 M−1 cm−1, Φ350
=
5% in MeCN) only 5% of absorbed photons are emitted with
a maximum intensity around 455 nm and an additional
shoulder around 520 nm giving a typical blue fluorescence
(Fig. 6a).
Excitation of 5c, decorated with nitrile groups, at 350 nm
resulted in an intense emission around 425 nm with a high
fluorescence quantum yield of 69%. The absorbance of this
receptor is, in general, greater with its maximum shifted to
370 nm (εabs370 = 72 000 M−1 cm−1, MeCN). Adding an excess
of Cl− as a guest to a solution of 5c caused only a slight
decrease in the fluorescence intensity (Fig. 6b). However, on
addition of an equal amount of HCO3−, AcO− or H2PO4 the
−
fluorescence emission was completely quenched. Thus,
further variation of the substituents may offer great potential
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