A pyrrolyl-based triazolophane: A macrocyclic receptor with CH and NH donor groups that exhibits a preference for pyrophosphate anions

Article abstract of DOI:10.1021/ja107098r

A pyrrolyl-based triazolophane, incorporating CH and NH donor groups, acts as a receptor for the pyrophosphate anion in chloroform solution. It shows selectivity for this trianion, followed by HSO₄^- > H₂PO₄^- > Cl^- > Br^- (all as the corresponding tetrabutylammonium salts), with NH-anion interactions being more important than CH-anion interactions. In the solid state, the receptor binds the pyrophosphate anion in a clip-like slot via NH and CH hydrogen bonds.

Full text of DOI:10.1021/ja107098r

Published on Web 09/20/2010
A Pyrrolyl-Based Triazolophane: A Macrocyclic Receptor With CH and NH
Donor Groups That Exhibits a Preference for Pyrophosphate Anions
Jonathan L. Sessler,*,†,§ Jiajia Cai,† Han-Yuan Gong,† Xiaoping Yang,† Jonathan F. Arambula,† and
Benjamin P. Hay‡
Department of Chemistry and Biochemistry, 1 UniVersity Station-A5300, The UniVersity of Texas,
Austin, Texas 78712-0165, Department of Chemistry, Yonsei UniVersity, Seoul 120-749, Korea, and Chemical
Sciences DiVision, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830-6119
Received August 7, 2010; E-mail: sessler@mail.utexas.edu
Scheme 1. Synthesis of Macrocycle 1a
Abstract: A pyrrolyl-based triazolophane, incorporating CH and
NH donor groups, acts as a receptor for the pyrophosphate anion
in chloroform solution. It shows selectivity for this trianion, followed
by HSO4 > H2PO4 > Cl- > Br- (all as the corresponding
tetrabutylammonium salts), with NH-anion interactions being
more important than CH-anion interactions. In the solid state,
the receptor binds the pyrophosphate anion in a clip-like slot via
NH and CH hydrogen bonds.
-
-
a (a) CuSO4, sodium ascorbate, EtOH/H2O/toluene (7:3:1); (b) NaOC-
(CH3)3, anhydrous THF; (c) acetone, TFA, Ar, RT.
Pyrophosphate detection has aroused interest in the scientific
community not only because pyrophosphate is the product of ATP
hydrolysis under cellular conditions1 but also because it could afford
a means of effecting real-time DNA sequencing.2 Pyrophosphate
monitoring may also have a role to play in cancer research since
this anion is involved in DNA replication catalyzed by DNA
polymerase.3 Pyrophosphate is also of interest as a larger, more
highly charged analogue of inorganic phosphate (H2PO4-/HPO42-),
which has physiological relevance in energy storage and signal
transduction, in addition to being a structural component in teeth
and bones.4 Not surprisingly, therefore, considerable effort has been
devoted recently to the development of synthetic receptors that allow
for the recognition, detection, or extraction of pyrophosphate and
related species, such as inorganic phosphate.5 Systems incorporating
neutral or cationic NH hydrogen bond donor groups (e.g., pyrrole,
indole, ammonium, and guanidinium) or cationic CH hydrogen bond
donor motifs (e.g., imidazolium and triazolium) have been par-
ticularly effective in this regard. However, to the best of our
knowledge, receptors with neutral CH H-bond donors have yet to
be exploited for the purpose of pyrophosphate (or phosphate) anion
recognition.
CH bonds are present in the overwhelming majority (97%) of
chemical compounds.6 Nevertheless, it is only recently that the
importance of CH H-bonds in biological and artificial anion
recognition has come to be appreciated.7 In recent pioneering work,
Flood and co-workers reported the synthesis and anion binding
properties of [34]triazolophanes. These new macrocycles have a
diameter of about 3.8 Å and display a high affinity for the chloride
ion.7c On the basis of this and previous theoretical and experimental
studies,8 it was suggested that the strength of neutral, triazole-
derived C-H· · · X- (X- ) halide) bonds can approach those of
more traditional NH donors, such as pyrrole. We thus considered
it of interest to combine both these recognition motifs within the
same macrocyclic framework. Here, we report the first such system,
namely the calix[2]1,3-bis(pyrro-2-yl)(1,4)-1,2,3-triazolo-phane (1)
and show that it acts as a highly effective receptor for the
pyrophosphate anion, both in the solid state and in organic media.9
Our findings, supported by theory, provide support for the conclu-
sion that NH-anion bonding interactions are more important than
CH-anion interactions.
The synthesis of 1 is shown in Scheme 1. Using “click” chemistry
conditions, a copper-catalyzed Huisgen 1,3-dipolar cycloaddition10
was used to couple 2 with 3. This was followed by t-BOC
deprotection11 to give 1,3-bis(pyrro-2-yl)-(1,4)-1,2,3-triazolo-
benzene (4) in 24% combined yield for two steps. Condensation
of 4 with acetone12 produced 1 in 10% yield.
NOESY spectroscopic studies provided support for the notion
that 1 has a flexible conformation at ambient temperature. This was
1
further verified by variable temperature H NMR spectroscopic
studies; specifically, signals that became broader with decreasing
temperature were observed (cf. Supporting Information (SI)).
A single crystal X-ray diffraction analysis of 1 revealed a nearly
flat structure, wherein the pyrrole NH protons on N5 and N5A point
out from the center of the core. The distance between the exocyclic
C-H or N-H and the nitrogen atoms on the neighboring triazole
ring generally proved to be less than 3 Å. This leads us to suggest
that intramolecular H-bonding interactions on the exterior of the
ring7r help stabilize the observed planar conformation in the solid
state (cf. Figure 1).
The anion properties of 1 in solution were first analyzed using
UV-vis spectroscopy. Standard titrations, associated curve fit-
tings,13 and Job plots provided support for pyrophosphate (as the
tetrabutylammonium (TBA) salt) being bound to 1 strongly in
chloroform at 300 K (Ka ) (2.30 ( 0.40) × 106 M-1) and with a
1:1 binding stoichiometry. Mass spectrometric analyses also provide
support for the formation of stable complexes (cf. SI).
The association constants (Ka) between receptor 1 and various
other test anions were also determined in chloroform Via UV-vis
absorption titrations. Among the test anions considered, receptor 1
displays selectivity for the trianionic pyrophosphate anion, followed
by HSO4- ((4.98 ( 0.40) × 105) > H2PO4- ((2.38 ( 0.25) × 105)
† The University of Texas at Austin.
§ Yonsei University.
‡ Oak Ridge National Laboratory.
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C O M M U N I C A T I O N S
Figure 3. (a) Top and (b) side views of a single-crystal X-ray diffraction
structure of 1·TBA3HP2O7 ·3H2O in which the pyrophosphate anion is in
a space filling representation. Solvent molecules and TBA cations have been
omitted for clarity.
Figure 1. (a) Top and (b) side views of the single crystal X-ray structure
of 1·4CH3OH·H2O. All solvent molecules have been omitted for clarity.
the ring and are involved in hydrogen bond interactions with the
bound pyrophosphate guest, as inferred from bond distances (pyrrole
NH · · · O ca. 1.9 Å, triazole CH · · · O ca. 2.3 Å, benzene CH · · ·O
ca. 3.7 Å). The resulting conformation thus stands in contrast to
what is seen in the case of the free host 1.
In summary, the pyrrolyl-based receptor 1 has been prepared in
a moderate yield. It binds the pyrophosphate anion in the solid state
and displays a high selectivity for this trianion relative to various
test monoanions in chloroform solution. The present results thus
serve to underscore the utility of new recognition motifs in the
design of anion binding agents, particularly those that combine both
CH- and NH-anion interactions within a single framework. The
present work also helps calibrate directly the relative importance
of these interactions. It thus provides a foundation for future receptor
design.
Figure 2. 1H NMR spectra (aromatic region) of 1 recorded upon titration
with (TBA)3HP2O7; CDCl3, 300 K.
Acknowledgment. This work was supported by the National
Institutes of Health (Grant No. GM58907 to J.L.S.) and the National
Science Foundation (Grant Nos. 0749571 to J.L.S. and 0741973
for the X-ray diffractometer). B.P.H. acknowledges support from
the Division of Chemical Sciences, Geosciences, and Biosciences,
Office of Basic Energy Sciences, U.S. DOE at Oak Ridge National
Laboratory. Support under the WCU (World Class University)
program (R32-2008-000-10217-0) is also acknowledged.
> Cl- ((1.18 ( 0.07) × 104) > Br- ((2.64 ( 0.09) × 103) (all as
TBA salts; cf. SI). Macrocycle 1 thus displays a high pyrophosphate/
dihydrogenphosphate selectivity (Ka(HP2O73-)/Ka(H2PO4-) ) 10).
The host-guest interactions between macrocycle 1 and the
1
pyrophosphate anion were further analyzed by H NMR spectros-
copy. Specifically, a solution of 1 (5 mM, CDCl3) was titrated with
up to 10 equiv of TBA3HP2O7 (Figure 2). The hydrogen signals
for the pyrrole NH, the triazole CH, and the endocyclic hydrogen
atom of the N1-linked phenyl unit were seen to shift downfield by
5.09, 1.96, and 1.22 ppm, respectively (Figure 2). These changes
followed the sequence of expected H acidity, namely pyrrole NH
> triazole CH > benzene CH.14 Thus the trends observed in the
NMR spectral studies are consistent with the intrinsic strength of
the various H-bond donor groups as inferred from electronic
structure calculations carried out with chloride anion. Binding
energies (MP2/aug-cc-pVDZ) computed for complexes of chloride
with pyrrole N-H, triazole C-H, and benzene C-H donors are
-22.50, -18.94, and -8.42 kcal mol-1, respectively (cf. SI).15 They
are also consistent with the hydrogen bond distances observed in
the solid state (see below). Nevertheless, it is important to appreciate
that all three hydrogen bond donor motifs play a role in the observed
anion recognition. In contrast, only a small downfield shift was
seen for the signals ascribed to the exocyclic hydrogen atoms on
the phenyl and pyrrole rings (∆δ ) 0.09 and 0.10 ppm, respec-
tively); apparently these C-H bonds play little role in anion
recognition.
Supporting Information Available: Details describing the synthesis
and characterization of compounds 4 and 1, details of fitting binding
curves, details of electronic structure calculations, and crystallographic
data (CIF). This material is available free of charge via the Internet at
http://pubs.acs.org.
References
(1) Mathews, C. P.; van Hold, K. E. Biochemistry; The Benjamin/Cummings
Publishing Company, Inc.: Redwood City, CA, 1990.
(2) Ronaghi, M.; Karamohamed, S.; Pettersson, B.; Uhle´n, M.; Nyre´n, P. Anal.
Biochem. 1996, 242, 84–89.
(3) Xu, S.; He, M.; Yu, H.; Cai, X.; Tan, X.; Lu, B.; Shu, B. Anal. Biochem.
2001, 299, 188–193.
(4) Saenger, W. Principles of Nucleic Acid Structure; Springer-Verlag: New
York, 1988.
(5) For review, see: (a) Sessler, J. L.; Gale, P. A.; Cho, W.-S. Anion Receptor
Chemistry; RSC Publishing: Cambridge, U.K., 2006. (b) Kim, S.-K.; Lee,
D.-H.; Hong, J.-I.; Yoon, J.-Y. Acc. Chem. Res. 2009, 42, 23–31. For recent
reports, see: (c) Kumar, A.; Pandey, P. S. Org. Lett. 2008, 10, 165–168.
(d) Chen, K.-H.; Liao, J.-H.; Chan, H.-Y.; Fang, J.-M. J. Org. Chem. 2009,
74, 895–898. (c) Xu, Z.; Singh, N. J.; Lim, J.; Pan, J.; Kim, H.-N.; Park,
S.-S.; Kim, K. S.; Yoon, J.-Y. J. Am. Chem. Soc. 2009, 131, 15528–15533.
(6) Of the 18 426 559 molecules in PubChem (March 2008), 17 947 719 (97%)
contained one or more CH units. Li, Y.; Flood, A. H. J. Am. Chem. Soc.
2008, 130, 12111–12122.
Additional support for the suggestion that both NH and neutral
CH interactions combine to effect pyrophosphate anion recognition
in the case of receptor 1 came from a single crystal X-ray diffraction
analysis of the complex formed between pyrophosphate and 1
(1·TBA3HP2O7 ·3H2O) (Figure 3). In this complex, the macrocycle
displays a folded conformation; this provides a clip-like slot into
which the pyrophosphate anion inserts. All the pyrrole NH, triazole
CH, and endocyclic benzene CH protons point into the center of
(7) (a) Bryantsev, V. S.; Hay, B. P. Org. Lett. 2005, 7, 5031–5034. (b)
Bryantsev, V. S.; Hay, B. P. J. Am. Chem. Soc. 2005, 127, 8282–8283. (c)
Li, Y.; Flood, A. H. Angew. Chem., Int. Ed. 2008, 47, 2649–2652. (d)
Yoon, D. W.; Gross, D. E.; Lynch, V. M.; Sessler, J. L.; Hay, B. P.; Lee,
C.-H. Angew. Chem., Int. Ed. 2008, 47, 5038–5042. (e) Li, Y.; Pink, M.;
Karty, J. A.; Flood, A. H. J. Am. Chem. Soc. 2008, 130, 17293–17295. (f)
Zhu, S. S.; Staats, H.; Brandhorst, K.; Grunenberg, J.; Gruppi, F.; Dalcanale,
E.; Lu¨tzen, A.; Rissanen, K.; Schalley, C. A. Angew. Chem., Int. Ed. 2008,
47, 788–792. (g) Juwarker, H.; Lenhardt, J. M.; Pham, D. M.; Craig, S. L.
Angew. Chem., Int. Ed. 2008, 47, 3740–3743. (h) Meudtner, R. M.; Hecht,
9
J. AM. CHEM. SOC. VOL. 132, NO. 40, 2010 14059

C O M M U N I C A T I O N S
S. Angew. Chem., Int. Ed. 2008, 47, 4926–4930. (i) Berryman, O. B.; Sather,
A. C.; Hay, B. P.; Meisner, J. S.; Johnson, D. W. J. Am. Chem. Soc. 2008,
130, 10895–10897. (j) Maeda, H.; Mihashi, Y.; Haketa, Y. Org. Lett. 2008,
10, 3179–3182. (k) Hay, B. P.; Bryantsev, V. S. Chem. Commun. 2008,
2417–2428. (l) Romero, T.; Caballero, A.; Ta´rraga, A.; Molina, P. Org.
Lett. 2009, 11, 3466–3469. (m) Mullen, K. M.; Mercurio, J.; Serpell, C. J.;
Beer, P. D. Angew. Chem., Int. Ed. 2009, 48, 4781–4784. (n) Juwarker,
H.; Lenhardt, J. M.; Castillo, J. C.; Craig, S. L. J. Org. Chem. 2009, 74,
8924–8934. (o) Fisher, M. G.; Gale, P. A.; Hiscock, J. R.; Hursthouse,
M. B.; Light, M. E.; Schmidtchen, F. P.; Tong, C. C. Chem. Commun.
2009, 3017–3019. (p) Pedzisa, L.; Hay, B. P. J. Org. Chem. 2009, 74,
2554–2560. (q) Schulze, B.; Friebe, C.; Hager, M. D.; Gu¨nther, W.; Ko¨hn,
U.; Jahn, B. O.; Go¨rls, H.; Schubert, U. S. Org. Lett. 2010, 12, 2710–
2713. (r) Lee, S.; Hua, Y.; Park, H.; Flood, A. H. Org. Lett. 2010, 12,
2100–2102. (s) Yano, M.; Tong, C. C.; Light, M. E.; Schmidtchen, F. P.;
Gale, P. A. Org. Biomol. Chem. 2010, 8, 4356-4363.
calixpyrrole and showed it to be effective for chloride anion recognition.
See: ref 7o and 7s.
(10) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew.
Chem., Int. Ed. 2002, 41, 2596–2599.
(11) Tom, N. J.; Simon, W. M.; Frost, H. N.; Ewing, M. Tetrahedron Lett. 2004,
45, 905–906.
(12) Kim, S. K.; Sessler, J. L.; Gross, D. E.; Lee, C.-H.; Kim, J. S.; Lynch,
V. M.; Delmau, L. H.; Hay, B. P. J. Am. Chem. Soc. 2010, 132, 5827–
5836.
(13) Bourson, J.; Pouget, J.; Valeur, B. J. Phys. Chem. 1993, 97, 4552–4557.
(14) Katritzky, A. R. Handbook of Heterocyclic Chemistry; Pergamon Press:
2000.
(15) The CH binding energies are consistent with a prior description of individual
hydrogen-bond contributions within a triazolophane*Cl- complex, which
implicated energies of-10 kcal/mol per triazole CH and-3 to-4 kcal/
mol per aryl CH: Bandyopadhyay, I.; Raghavachari, K.; Flood, A. H.
ChemPhysChem 2009, 10, 2535–2540.
(8) Hua, Y.; Flood, A. H. Chem. Soc. ReV. 2010, 39, 1262–1271.
(9) Although it does not contain triazole and pyrrole in the same macrocyclic
ring, it is to be noted that Gale recently reported a triazole strapped
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