Intramolecular hydrogen bonds preorganize an aryl-triazole receptor into a crescent for chloride binding

Article abstract of DOI:10.1021/ol1005856

Figure presented Aryl-triazole pentads have been preorganized with intramolecular hydrogen bonds to enhance chloride binding. This outcome highlights the dual hydrogen bond donor and acceptor properties of 1,2,3-triazoles.

Full text of DOI:10.1021/ol1005856

ORGANIC
LETTERS
2010
Vol. 12, No. 9
2100-2102
Intramolecular Hydrogen Bonds
Preorganize an Aryl-triazole Receptor
into a Crescent for Chloride Binding
Semin Lee, Yuran Hua, Hyunsoo Park, and Amar H. Flood*
Department of Chemistry, Indiana UniVersity, 800 East Kirkwood AVenue,
Bloomington, Indiana 47405
aflood@indiana.edu
Received March 10, 2010
ABSTRACT
Aryl-triazole pentads have been preorganized with intramolecular hydrogen bonds to enhance chloride binding. This outcome highlights the
dual hydrogen bond donor and acceptor properties of 1,2,3-triazoles.
Recent studies on macrocyclic triazolophanes,1aryl-triazole
foldamers,1b,2 and other triazole-containing molecules3 have
shown that C-H· · ·X- hydrogen bonds are strong enough
to play a major role in the field of anion supramolecular
chemistry.4 Triazolophanes have unexpectedly large halide
binding constants, which take advantage of macrocyclic
preorganization5 to direct four triazole C-H donors and
four phenylene C-H donors into the central cavity. On
the other hand, flexible aryl-triazole oligomers containing
the same number or more of C-H donors have binding
constants that are weaker by orders of magnitude com-
pared to rigid triazolophanes.1b,2 Such effects were also
observed between indole-based macrocycles and foldamers.6
Thus, preorganizing the conformation of receptors is crucial
for obtaining high binding affinities. Herein, we demonstrate
a strategy to preorganize the conformations of aryl-triazole
pentads using intramolecular hydrogen bonds to increase the
Cl- affinity without forming macrocycles.
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10.1021/ol1005856  2010 American Chemical Society
Published on Web 04/07/2010

Intramolecular hydrogen bonds have been used in various
types of foldamers7 to preorganize their conformations and
assist folding. For instance, aromatic oligo-amide,8 -urea,9
and -hydrazide10 foldamers have been synthesized. Hydrogen
bonds have also been used to achieve high yield macrocy-
clizations.11 Isophthalamides with intramolecular hydrogen
bonds12 and oligoindoles with metal binding13 showed an
increase in the anion binding constant. Recently, triazole
C-H· · ·O hydrogen bonds have been investigated with the
aid of X-ray crystallography.14 Therein, it was also observed
that the triazole C-H group forms intermolecular hydrogen
bonds with triazole N2/N3 atoms in the crystal. It is
noteworthy that the N3 of a triazole could serve as a hydrogen
bond acceptor. We envisioned, therefore, that the triazole’s
N3 nitrogen could be used as an intramolecular hydrogen
bonding site to preorganize aryl-triazole pentads.
phenyls for the purpose of solubility. Pentad 2, which does
not have hydroxyl groups, was prepared as a control.
Synthetic routes for pentads 1 and 2 are shown in Scheme
1. Diiodoresorcinol (3) was protected with tetrahydropyran
(THP) groups using dihydropyran (DHP) with a catalytic
amount of pyridinium p-toluenesulfonate (PPTS) to give 4.
Sonogashira coupling of 4 with trimethylsilylacetylene
followed by desilylation provided diacetylene 5 in 95% yield.
5 was “clicked”16 with aryl azide 6, and then the THP groups
were removed to afford pentad 1 in a moderate yield. Aryl
triazole pentad 2 was prepared by click reaction between 6
and 7. All compounds were fully characterized.17 2D NOESY
studies on 1 (strong Ha,b and Hb,c cross peaks) and 2 (medium
Ha,b, Hb,c, and Hb,f cross peaks) are consistent with greater
preorganization of 1.17
The 1H NMR titration (Figure 1) of 1 and 2 with
tetrabutylammonium chloride (TBACl) in CD2Cl2 provides
insight into the structures of the resulting complexes in
solution. The downfield position of the -OH 1H NMR signal
in pentad 1 (10.9 ppm), compared to 3 (5.4 ppm), indicates
that it is deshielded by hydrogen bonding. Upon addition of
TBACl, pentads 1 and 2 both showed large downfield shifts
of the triazoles’ Hb and central phenylene’s Ha protons. The
R-CH2 proton of the TBA+ cation peak also shifted in both
titrations indicating that TBA+ is involved in the solution-
phase equilibria. Additionally, the -OH signal of 1 did not
have a large peak shift, which implies that it does not have
a direct interaction with Cl-.
Pentad 1 (Scheme 1) was designed to have two hydroxyl
groups on the central phenylene that could form hydrogen
Scheme 1. Syntheses of Pentads 1 and 2
1
Quantitative analysis of the H NMR titration data was
achieved using combinations of the following equilibria
P + Cl- ) P · Cl- Ka
(1)
TBA+ + Cl- ) TBA+ · Cl-
(2)
(3)
Kion
P + TBA+ · Cl- ) P · Cl- · TBA+
Kipc
P · Cl- + TBA+ ) P · Cl- · TBA+
(P: Pentad 1 or 2)
ꢀ
Kipc
(4)
bonds with the triazoles on either side. Although electron-
donating groups on phenylene have been shown15 to decrease
the binding affinity in previous studies on triazolophanes,1b
we assumed that preorganization would be the dominant
factor in this case. t-Butyl groups were used on the terminal
In addition to formation of the 1:1 complex (P·Cl-, Ka),
we included the ion pairing,18 both competitive with TBACl
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Org. Lett., Vol. 12, No. 9, 2010
2101

kJ mol-1)12 and indole (∆∆G ) 9.1 kJ mol-1)13 receptors.
All three systems are consistent with the entropy content of
rotation about sp2-sp2 single bonds.21 While the C-H
hydrogen bond of 1 will also be enhanced by polarization,17
preorganization seems to dominate.
The intramolecular hydrogen bond is observed in the X-ray
crystal structure of pentad 8 (Figure 2)17 where the backbone
Figure 2. Crystal structure of pentad 8. Non-hydrogen atoms are
drawn with 50% probability ellipsoids.
is preorganized into a crescent. Two OH· · ·N3 hydrogen
bonds are formed, and the triazole C-H forms a hydrogen
bond with the benzylether’s oxygen atom.14
In conclusion, intramolecular hydrogen bonds between
hydroxyl groups and triazole N3 preorganize the pentad
backbone for Cl- binding to enhance the binding constant.
Such intramolecular hydrogen bonds could be further
extended to preorganize foldamers and receptors.
Figure 1.
1H NMR titration (5 mM CD2Cl2, 298 K) of 1 and 2
with increasing equivalents of TBACl.
(Kion)19 and as the ion-paired complex (P·Cl-·TBA+, Kipc or
Kipc′). The latter was inferred from peak shifts of the TBA+
signal.17 Data fittings (Table 1)17 were conducted using
HypNMR.20 Fitting of the data for 2 is based on the
Acknowledgment. We acknowledge support from the
NSF (CHE-0844441) and the Chemical Sciences, Geo-
sciences, and Biosciences Division, Office of Basic Energy
Sciences, Office of Science, US DOE.
Note Added after ASAP Publication. Scheme 1 con-
tained errors in the version published ASAP April 7, 2010;
the correct version reposted April 12, 2010.
Table 1. Equilibrium Constants (M-1) and Free Energies
1
(kJ·mol-1) Obtained from Fitting the H NMR Data
Supporting Information Available: Syntheses, experi-
mental procedures, tables of X-ray crystallography, and
titration data. This material is available free of charge via
the Internet at http://pubs.acs.org.
Ka
Kion
Kipc
Kipc′
(∆G)
(∆G)
(∆G)
(∆G)
46800 ( 2500
(-26.6)
1000 ( 250
(-17.1)
72000 ( 5000
(-27.7)
72000 ( 5000
(-27.7)
360 ( 10
(-14.6)
8 ( 1
550 ( 80
(-15.6)
550 ( 80
(-15.6)
1
2
OL1005856
(18) (a) Huang, F.; Jones, J. W.; Slebodnick, C.; Gibson, H. W. J. Am.
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2 1998, 1747–1750.
(-5.2)
assumption that Kipc′ (1) is equal to Kipc′ (2), i.e., complexes
1·Cl- and 2·Cl- have similar structures.
The anion binding strength (Table 1) of preorganized
pentad 1 is ∼50 times greater than 2 (∆∆G ) 9.5 kJ mol-1).
This enhancement is similar to isophthalamide (∆∆G ) 8.2
(20) Frassineti, C.; Ghelli, S.; Gans, P.; Sabatini, A.; Moruzzi, M. S.;
Vacca, A. Anal. Biochem. 1995, 231, 374–382.
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