Protonation activates anion binding and alters binding selectivity in new inherently fluorescent 2,6-bis(2-anilinoethynyl)pyridine bisureas

Article abstract of DOI:10.1039/b901643k

A new class of 2,6-bis(2-anilinoethynyl)pyridine-based bisureas forms 1: 1 complexes with halides; protonation enhances binding by over one order of magnitude, alters the binding selectivity, and provides a colorimetric indication of anion binding. The Ro

Full text of DOI:10.1039/b901643k

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Protonation activates anion binding and alters binding selectivity in new
inherently fluorescent 2,6-bis(2-anilinoethynyl)pyridine bisureasw
Calden N. Carroll, Orion B. Berryman, Charles A. JohnsonII, Lev N. Zakharov,
Michael M. Haley* and Darren W. Johnson*
Received (in Austin, TX, USA) 26th January 2009, Accepted 24th February 2009
First published as an Advance Article on the web 27th March 2009
DOI: 10.1039/b901643k
A new class of 2,6-bis(2-anilinoethynyl)pyridine-based bisureas
forms 1 : 1 complexes with halides; protonation enhances binding
by over one order of magnitude, alters the binding selectivity,
and provides a colorimetric indication of anion binding.
as heterodimers incorporating both a halide and a water guest,
depending upon the protonation state of the pyridine nitrogen.
Unfortunately, the complicated equilibria present in solution
prevented unambiguous determination of the host–guest
stoichiometry in solution. We reasoned that an increase in
the number of hydrogen bonding sites within a convergent
The synthesis and study of hydrogen bonding receptors
for anions is an engaging challenge because of the design
difficulties associated with targeting such relatively diffuse,
weakly basic and highly solvated analytes.1 The prevalence
of systems in both biological and supramolecular research
whose behaviour is dictated by their hydrogen bonding ability
with simple ions has also generated increased attention in this
field.2 We are developing a modular design strategy for
the preparation of ion and molecule receptors based on an
arylacetylene core, a well-known chromophore and fluorophore
which lends itself to facile synthetic modification. The adaptation
of phenylacetylene scaffolding to supramolecular chemistry
has yielded a surprising array of host–guest and coordination
complexes.3 This rigid and linear motif has provided suitable
geometric dimensions for both macrocyclic and acyclic ligands
in transition metal complexes. Among the benefits of such core
structures is the degree of preorganization resulting from use
of the rigid, conjugated components. Given the elegant metal
cation sensors that have been developed utilizing molecules
such as these,4 a modular receptor class that targets anions
based on fluorescent cores may offer new applications in anion
sensing. Ureas show well-known affinities for anions in
solution,5 and can easily be coupled to a modular synthetic
scaffold built upon the 2,6-bis(2-anilinoethynyl)pyridine core 1
(Scheme 1). Furthermore, the ethynylpyridine core has the
added feature that the protonation state of the pyridine
nitrogen can regulate binding geometries and selectivities.6
We previously reported two sulfonamide-based ethynylpyridine
receptors that showed promise as rigid receptors for anions
and/or water in a [2 + 2] binding mode.7 Both solid-state and
serial dilution experiments revealed that these receptors form
helical homodimers around two halide or water guests, as well
receptor binding pocket would likely favour [1
+ 1]
complexation. To that end, we report herein the synthesis of
the bisurea analogues 2a–d derived from 1 and the solution
and solid-state data of 2a that confirm this binding hypothesis.
Key intermediate
1 can be synthesized easily on a
multi-gram scale from known iodoaniline 3 (Scheme 1).8
Sonogashira cross-coupling with (trimethylsilyl)acetylene,
protiodesilylation in basic MeOH, and a second cross-
coupling with 2,6-dibromopyridine affords bis-aniline 1 in
470% overall yield. Treatment of 1 with a variety of
commercially available isocyanates gives bisureas 2a–d in very
good to excellent yields. Although our synthetic method
allows for the facile preparation of a variety of these
compounds, our focus for solution and solid-state studies
has thus far been on the phenylurea derivative 2a.
Slow evaporation of a MeOH solution of 2a yielded crystals
suitable for X-ray diffraction (Fig. 1).z Unlike the sulfonamide
[2 + 2] dimers,7 in which the ‘‘arms’’ wrap around the guest
Department of Chemistry and the Materials Science Institute,
1253 University of Oregon, Eugene, OR, 97403-1253, USA.
E-mail: haley@uoregon.edu, dwj@uoregon.edu;
Fax: +1 541-346-0487; Tel: +1 541-346-1695
w Electronic supplementary information (ESI) available: Experimental
details and spectral data for 1, 2a, and 2aꢀTFA, DFT calculated
energies and structures for 2aꢀTFA, titration data and binding
isotherms. CCDC 717899 (2aꢀMeOH) and 717900 (2aꢀHCl). For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/b901643k
Scheme 1 Synthesis of urea receptors 2a–d.
ꢁc
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2520 | Chem. Commun., 2009, 2520–2522

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pocket in this model is sufficiently compact that the receptor
arms must twist significantly from planarity to allow the
receptor to accommodate such a large guest. While smaller
oxoanions may fit more easily into the binding pocket of
protonated 2a, we reasoned that any competition between
the trifluoroacetate and halide guests would favour the
guest with the greater number of stabilizing hydrogen bonds,
i.e., the halide.
UV-Vis spectrophotometric titrations of protonated
2aꢀTFA with Bu4NCl, Bu4NBr and Bu4NI were carried out,
and the data individually fit with the HyperQuad 2006 suite of
programs (see ESIw).11 In comparison with the TFA salt,
titration with the tetraalkylammonium salts showed a new
absorbance band at 422 nm which increased in intensity and
shifted bathochromically. Isosbestic behaviour was observed
when sufficient time was allowed between aliquots for
the system to reach equilibrium (less than 3 min). Binding
Fig. 1 ORTEP representation (50% probability ellipsoids) of the two
conformers of 2aꢀMeOH with two solvent molecules in different
H-bonding motifs. The ‘‘W’’ conformer (orange) and the ‘‘S’’
conformer (light blue) show half of the ‘‘SWWS’’ tetrameric repeat
unit. The tert-butyl groups have been omitted for clarity. The Nꢀ ꢀ ꢀO
distances (2.889–3.291 A) are typical for H-bonds (dashed lines).
H atoms have been omitted.
1
constants for 2a were obtained via titrations using H-NMR
molecules, the solid-state structure revealed that receptor 2a
adopts two different conformations—a backwards ‘‘S’’ and a
‘‘W’’ which stack in an ‘‘SWWS’’ fashion with the bottom
‘‘SW’’ in a centrosymmetrical arrangement with respect to the
top ‘‘WS’’. In the W form, a MeOH guest donates a hydrogen
bond to the pyridine nitrogen while both urea arms are
pointed away from the MeOH. In the S form, a second MeOH
donates a hydrogen bond to the pyridine nitrogen and
accepts two hydrogen bonds from the urea N–H of one arm.
Intermolecular urea N–Hꢀ ꢀ ꢀOQC contacts make up the
remainder of the [4 + 4] ‘‘tetrameric’’ repeat unit. There are
no additional H-bonds between these ‘‘isolated’’ units.
spectroscopy since the UV-Vis spectra of the neutral receptor
did not exhibit any significant spectroscopic handle. These
latter data were fit to a [1 + 1] model using HypNMR 2006.11
As shown in Table 1, protonation of 2a activates the halide
binding ability of this receptor class. Whereas unprotonated 2a
obeys the classic Hofmeister series, protonated 2a strongly
binds all three halides in the range of 42 700–83 200 Mꢂ1. In
fact, the binding constants for bromide and iodide are two and
four orders of magnitude larger in the protonated receptor
compared to the neutral receptor. However, these are apparent
binding constants and a decrease in the observed binding
values from competition with the trifluoroacetate counter-ion
in the 2aꢀTFA receptor must be taken into account.12
As in the case of the neutral sulfonamide receptors,7 the
neutral bisurea receptors show an affinity for neutral guests
(e.g., MeOH, Fig. 1). Protonation of the central pyridine
nitrogen activates strong anion binding in this system as well.
To perform binding constant measurements, the trifluoroacetate
and tetrafluoroborate salts were prepared under the assumption
that these weakly basic, larger anions would not strongly
compete for the binding pocket in this receptor. (Preliminary
molecular models had indicated halides were appropriately
sized guests.) Fortunately, 2aꢀTFA proved easy to prepare on
large scale as an anhydrous, analytically pure crystalline solid.
While a crystal structure of the TFA-protonated urea has so
far proven elusive,9 DFT modelling of this complex indicated
that the urea backbone was flexible enough to partially
Evidence of our target [1 + 1] binding behaviour was
confirmed in the solid state. X-Ray quality crystals of
2aꢀHCl were grown by addition of HCl to a solution of
2a in hexanes–EtOAc.z In contrast to the free-base receptor,
the two urea arms of 2aꢀHCl envelop the chloride ion affording
a [1 + 1] host–guest complex with a total of five N–Hꢀ ꢀ ꢀCl
hydrogen bonds (Nꢀ ꢀ ꢀCl distances 3.03–3.66 A, Fig. 3).
The neutral receptor relies entirely upon the urea functionality
for its hydrogen bonding capabilities, and thus shows preference
for the more basic guests. The arms in the neutral receptor
seem to be too far apart to participate effectively in
cooperatively stabilizing the guest, and exhibit both the S
and W forms, while the U-shaped [1 + 1] complex is not
observed. In contrast to the neutral receptor, 2aꢀTFA has a
well-defined binding pocket. The pyridinium hydrogen
provides a third point of contact, which anchors the receptor
arms in the desired conformation upon guest binding and
converges all available hydrogen bonds to the binding pocket.
ꢂ
accommodate the CF3CO2 counter-ion, with one oxygen
stabilized by three hydrogen bonds between the central
pyridine, and one urea arm (Fig. 2).10 Nonetheless, the binding
Table 1 Calculated Ka (Mꢂ1) fit to a [1 + 1] model.11 Average values
from triplicate measurements are shown. Experimental errors are
ca. ꢃ10%
Guest
2aa
2aꢀTFAb
42 700
61 700
83 200
Clꢂ
Brꢂ
Iꢂ
2100
400
Not measurable
Fig. 2 Top (left) and side (right) views of the DFT calculated position
of the trifluoroacetate anion in protonated 2a.
b
a 1H-NMR data. UV-Vis data.
ꢁc
This journal is The Royal Society of Chemistry 2009
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rigid group model. One of the t-Bu groups in 2aꢀHCl is disordered over
two positions and refined with restrictions on its geometry. The
investigated compounds crystallized as thin plates which provided
weak reflections at high angles. The large Rint values are a result of
weak reflections at high angles. All calculations were performed by the
Bruker SHELXTL package.
Crystal data for 2aꢀMeOH: C44H45N5O3, M = 691.85, triclinic,
ꢀ
0.32 ꢄ 0.14 ꢄ 0.04 mm, P1, a = 15.977(4) A, b = 17.510(5) A,
c = 17.934(5) A, a = 115.738(6)1, b = 92.041(5)1, g = 115.933(5)1,
V = 3903.6(18) A3, Z = 4, T = 173 K, rcalcd = 1.177 g cmꢂ3
,
m(MoKa) = 0.075 mmꢂ1; 2ymax = 501, 28 502 reflection measured,
13 659 reflections independent [Rint 0.0842], 981 parameters,
Fig. 3 ORTEP representation of the protonated receptor 2aꢀHCl
with ellipsoids at the 50% probability level. On the right, the dashed
lines indicate N–Hꢀ ꢀ ꢀCl hydrogen bonds.
=
R1 = 0.0836, wR2 = 0.1940 (reflections with I 4 2s(I)), GooF =
1.006, max/min residual electron density +1.135/ꢂ0.213 e Aꢂ3
.
Crystal data for 2aꢀHCl: C43H42ClN5O2, M = 696.27, 0.25 ꢄ 0.12
ꢀ
ꢄ 0.02 mm, triclinic, P1, a = 12.237(2) A, b = 17.221(3) A,
This disrupts the intermolecular hydrogen bond network that
held the neutral tetrameric complex intact and yields the
[1 + 1] complex while disfavouring our previously observed
[2 + 2] dimeric and SWWS tetrameric complexes.7 The slight
preference for the less basic Brꢂ and Iꢂ anions over Clꢂ could
be attributed to a larger binding pocket in the U-shaped
conformation, which mitigates the traditional bias in binding
more basic anions to favour the larger halides.
c
=
20.026(3) A,
a
=
107.216(3)1,
b
=
101.613(4)1,
g
=
=
103.090(4)1, V = 3759.5(11) A3, Z = 4, T = 203 K, rcalcd
1.230 g cmꢂ3, m(MoKa) = 0.145 mmꢂ1; 2ymax = 501, 27 464 reflection
measured, 13 172 reflections independent [Rint
=
= 0.1307], 955
parameters, R1 0.0856, wR2 0.1078 (reflections with
=
I 4 2s(I)), GooF = 0.945, max/min residual electron density
+0.371/ꢂ0.275 e Aꢂ3
.
1 (a) B. Dietrich, Pure Appl. Chem., 1993, 65, 1457; (b) A. Bianchi,
K. Bowman-James and E. Garcia-Espana, Supramolecular
Chemistry of Anions, Wiley, New York, 1997; (c) P. D. Beer
and P. A. Gale, Angew. Chem., Int. Ed., 2001, 40, 486;
(d) J. L. Sessler, P. A. Gale and W.-S. Cho, Anion Receptor
Chemistry, The Royal Society of Chemistry, Cambridge, UK,
2006.
2 (a) J. Friedman, Y. T. Meharenna, A. Wilks and T. L. Poulos,
J. Biol. Chem., 2006, 282, 1066; (b) C. E. MacBeth,
A. P. Golombek, V. G. Young, Jr., C. Yang, K. Kuezera,
M. P. Hendrich and A. S. Borovik, Science, 2000, 289, 938;
(c) For a recent review of anions in supramolecular chemistry,
see: P. A. Gale, S. E. Garcia-Garrido and J. Garric, Chem. Soc.
Rev., 2008, 37, 151.
3 For representative examples, see: (a) S. Leininger, B. Olenyuk and
P. J. Stang, Chem. Rev., 2000, 100, 853; (b) F. Romero, R. Ziessel,
A. Dupont-Gervais and A. van Dorsselaer, Chem. Commun., 1996,
551.
4 (a) A. J. Zucchero, J. N. Wilson and U. H. F. Bunz, J. Am. Chem.
Soc., 2006, 128, 11872; (b) J. D. Lewis and J. N. Moore, Phys.
Chem. Chem. Phys., 2004, 6, 4595; (c) J. Tolosa, A. J. Zucchero and
U. H. F. Bunz, J. Am. Chem. Soc., 2008, 130, 6498.
In conclusion, we have synthesized and performed a
preliminary analysis on a new class of hydrogen bonding
receptors for halide anions, based on an inherently fluorescent
arylacetylene core. Bisurea receptor 2a binds chloride,
bromide and iodide and fits with good agreement to a
[1 + 1] model, which significantly simplifies the solution
studies of this receptor class relative to the previously reported
sulfonamide analogues. Protonation of the pyridyl nitrogen in
the receptor increases the association constant by more than
an order of magnitude over the free-base receptor, and alters
the selectivity between the larger halides and chloride. The
increasing discovery of anionic contaminants in the environment,
and the facile mobility of anions in natural systems, make
developing new approaches for anion sensing and binding
vitally important. These modular receptors offer potential
long-term applications in the design of new materials for
remediation and sensing and the development of new
molecular probes for anions.
5 (a) P. A. Gale, Amide and Urea Based Anion Receptors, in The
Encyclopedia of Supramolecular Chemistry, ed. J. Atwood and
J. W. Steed, Dekker, New York, 2004, pp. 31–41;
(b) V. A. Amendola, D. Esteban-Gomez, L. Fabbrizzi and
´
This work was funded by the National Science Foundation
(NSF) and the University of Oregon (UO). C.N.C. and O.B.B.
acknowledge the NSF for Integrative Graduate Education and
Research Traineeships (DGE-0549503). C.A.J. thanks UO for
a Doctoral Research Fellowship. D.W.J. is a Cottrell Scholar
of Research Corporation and gratefully acknowledges the
NSF for a CAREER award. The authors would like to thank
Dr, Cameron L. Hilton for help refining the crystallographic
data and Sean P. McClintock for performing the DFT
calculations. Kyle R. Hanson is gratefully acknowledged for
M. Licchelli, Acc. Chem. Res., 2006, 39, 343; (c) E. Quinlan,
S. E. Matthews and T. Gunnlaugsson, J. Org. Chem., 2007, 72,
7497.
6 (a) M.-V. Martinez-Diaz, N. Spencer and J. F. Stoddart, Angew.
Chem., Int. Ed. Engl., 1997, 36, 1904; (b) M. H. Al-Sayah and
N. R. Branda, Org. Lett., 2002, 4, 881; (c) S. Rashdan, M. E. Light
and J. D. Kilburn, Chem. Commun., 2006, 4578; (d) E. Cordova,
R. A. Bissell, N. Spencer, P. Ashton, J. F. Stoddart and
A. E. Kaifer, J. Org. Chem., 1993, 58, 6550.
7 O. B. Berryman, C. A. Johnson, L. N. Zakharov, M. M. Haley and
D. W. Johnson, Angew. Chem., Int. Ed., 2008, 47, 117.
8 W. B. Wan and M. M. Haley, J. Org. Chem., 2001, 66, 3893.
9 Crystals of the urea complexes suitable for X-ray diffraction have
proven exceedingly difficult to grow, often resulting in hair-like or
opaque crystals. Some recent success has been had by adding small
amounts of simple ammonium salts to the crystallization solutions.
See: N. E. Kelly, S.-O. Lee and K. D. Harris, J. Am. Chem. Soc.,
2001, 123, 12682.
1
obtaining the preliminary H-NMR titration data. Prof. Keiji
Hirose of Osaka University is duly thanked for helpful
discussions.
Notes and references
10 M. J. Frisch et al., GAUSSIAN 03 (Revision B.04), Gaussian Inc.,
Pittsburgh, PA, 2003.
z X-Ray diffraction data were collected at low temperature on a
Bruker APEX diffractometer with MoKa-radiation (l = 0.71073 A).
Absorption corrections were applied by SADABS. The structures were
solved using direct methods. All non-hydrogen atoms were refined
with anisotropic thermal parameters. H atoms involved in H-bonds
were found on the residual densities and refined with isotropic thermal
parameters. Other H atoms were treated in calculated positions in a
11 P. Ganz, A. Sabatini and A. Vacca, Talanta, 1996, 43, 1739.
12 Judicious choice of a larger counter-ion is expected to increase the
apparent binding constants. Initially the tetrafluoroborate salt was
our preferred material to perform the UV titrations, although
preparation and purification of this salt proved difficult.
ꢁc
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2522 | Chem. Commun., 2009, 2520–2522