1,2,3-Triazole CH...Cl- contacts guide anion binding and concomitant folding in 1,4-diaryl triazole oligomers

Article abstract of DOI:10.1002/anie.200800548

(Chemical Equation Presented) A new folder: The electropositive CH groups of diaryltriazol es interact favourably with chloride, leading to anioninduced helical folding in aryl triazole oligomers. Triazoles thus provide an alternative to conventional prot

Full text of DOI:10.1002/anie.200800548

Communications
DOI: 10.1002/anie.200800548
Molecular Recognition
1,2,3-Triazole CH···ClÀ Contacts Guide Anion Binding and
Concomitant Folding in 1,4-Diaryl Triazole Oligomers**
Hemraj Juwarker, Jeremy M. Lenhardt, David M. Pham, and Stephen L. Craig*
In memory of Dmitry Rudkevich
Manipulation of weak intermolecular interactions guides the
rational design[1] of sensors, drugs, and foldamers-synthetic,[2]
nonnatural backbones that fold into an ordered, biomimetic
array. 1,4-Substituted 1,2,3-triazoles, which are readily acces-
sible through the CuI-catalyzed Huisgen 1,3-dipolar cyclo-
addition of azides and alkynes,[3] are seemingly universal
ligation tools[4] whose capacity for independent function has
received far less attention. Recent reports, however, indicate
that the size and dipole moment ( ꢀ 5 D) of triazoles make
them interesting candidates for amide bond surrogates,[5] and
Arora and co-workers have reported the contributions of
triazoles to the conformational preferences of peptido-
triazole oligomers.[6]
We hypothesized that oligomer 1 would fold in a manner
similar to other linear, flexible oligomers[7] to provide a model
cavity by which to explore the intermolecular interactions
between the electropositive CH side of 1,4-triazoles and
electron-rich guests such as anions (Figure 1). Our expect-
ations were buoyed by previous reports of anion-induced
folding,[8,9] in particular by a recent demonstration by Jeong
and co-workers[8] that the folding of oligoindoles can be
directed through a helical arrangement of NH···anion hydro-
gen bonds. Herein, we report 1) that 1:1 interactions between
diaryl triazoles and chloride ions in acetone are directional
and sufficiently strong as to be observable by 1H NMR
spectroscopy, 2) that the strength of the interaction increases
with the generation of triazole-containing oligomer, and
3) that CH···anion contacts guide the folding of aryl triazole
oligomers in solution and in the solid state.
While the “click” coupling of alkyl azides with alkynes is
Figure 1. 1,4-Diaryl-1,2,3-triazole oligomers 1, 2, and 3 depicted in
highly efficient,[10] the formation of diaryl triazoles has, until
recently, been relatively more difficult and less efficient.[11]
Nonetheless, under modified conditions, the CuI-catalyzed
cycloaddition produces acceptable yields of the desired 1,4-
diaryl-1,2,3-triazole-containing compounds 1–3. A tetraethy-
lene glycol unit was introduced outside of the cavity for
solubility.
their inferred chloride binding conformations. Top right: Lowest energy
minimization structure (Macromodel 7.0, Amber* force field, CHCl3)
of 1·ClÀ. Side chains are replaced with OCH3 groups.
Oligomer 1 has appreciable conformational freedom only
around the arene–triazole single bonds. Molecular model-
ing[12] suggested no significant preference for a particular
rotamer, a prediction that is supported by NOESY spectra of
1 in [D6]acetone (Figure 2a). Modeling studies also show that
complexation of 1 with ClÀ aligns the electropositive triazole
CH units toward the interior of a helix, within which the ClÀ is
bound.
[*] H. Juwarker, J. M. Lenhardt, Dr. D. M. Pham, Prof. S. L. Craig
Department of Chemistry, French Family Science Center
Duke University, Durham, NC 27708-0346 (USA)
Fax: (+1)919-660-1605
The computer modeling holds true in solution, where the
chloride-induced folding of 1 is revealed by 1H NMR
E-mail: stephen.craig@duke.edu
1
spectroscopy. The H NMR spectrum of 1 changes consid-
[**] This work was supported by Duke University. We thank T. Ribeiro for
assistance with2D NMR experiments.
erably upon the addition of tetrabutylammonium chloride
(Bu4N+ClÀ). At 1 mm in [D6]acetone, triazole protons Hc and
Hh shift downfield (from d = 9.5 and 9.3ppm to 10.9 and
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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corresponding protons in 2 and 3 (vide infra), showing that
these shifts are due to tight, directional binding of ClÀ rather
than a bulk dielectric effect. Similar, but less dramatic,
downfield shifts are observed in the aryl protons Ha and Hd,
which are expected constituents of the cavity interior.
Importantly, the putative peripheral protons of the helix
(Hb, He, Hf, and Hg) feature upfield shifts, indicating increased
shielding as the electron density of 1 is polarized away from
the helix interior.
The chloride-induced folding is confirmed by 2D NOESY
experiments.[8,13] While the various rotamers of 1 are equally
populated, NOESY contacts in the presence of Bu4N+ClÀ
indicate that the folding depicted in Figure 1 is operative.
Specifically, upon ClÀ binding, Hc has a strong contact with Ha
rather than Hb, as well as a stronger contact with Hd than He.
Similarly, triazole proton Hh has a stronger contact with Hd
than Hg (Figure 2b).
We expected that individual triazole–anion interactions
would be too weak to be observed in polar solvents outside of
multivalent hosts such as 1. On the contrary, titration of 2 with
Bu4N+ClÀ in [D6]acetone leads to a gradual downfield
1H NMR shift in the triazole proton He. A Jobꢀs plot[14]
confirms a 1:1 binding stoichiometry, and a fit to the chemical
shift titration data gives a binding constant of 12 Æ 0.3mÀ1 and
an endpoint for the completely complexed proton of d =
10.8 ppm (Table 1). The binding is a factor of ca. 10 smaller
than that of the conventional NH hydrogen bond donor 1,4-
diphenylpyrrole (140mÀ1).[15]
Table 1: Bu4N+ halide binding constants and changes in chemical shift of
Hc (for 1 and 3a) or He (for 2) upon binding, as determined from 1:1
Benesi–Hildebrand fits to 1H NMR titration data in [D6]acetone.
Aryl
Anion[a]
K [mÀ1
]
Ddmax [ppm][b]
triazole
1
1
1
2
ClÀ
BrÀ
IÀ
1.7”104
1.2”104
1.3”102
1.2”101
1.3”103
1.60
1.52
1.20
1.61
2.03
ClÀ
ClÀ
3a
[a] Accurate fluoride binding constants could not be obtained due to
apparent aggregation withexcess fluoride. [b] Difference in chemical
shift of triazole proton for free vs. complexed triazole.
Similar downfield shifts, although of smaller magnitude,
are observed for Ha and Hf, protons that would also contact
ClÀ in the binding mode shown in Figure 1. The chemical
shifts of protons that are not involved in the expected anion
complexation are observed to move either very little or
upfield. Binding constants determined from the Ha and Hf
titration data agree within experimental error with that from
He (Supporting Information). That the Dd of Ha is threefold
greater than that of Hd suggests an orientation preference of
the ester group away from the bound chloride ion. This
preference is also observed in the NOESY spectrum of 2·ClÀ;
the Ha–He contacts are greater than Hd–He. Importantly, the
conformational preference is a consequence of ClÀ binding, as
2 alone in [D6]acetone exhibits stronger Hd–He contacts
(Supporting Information).
Figure 2. Partial 1H-1H NOESY spectra (500 MHz, [D6]acetone, 298 K,
0.45 ms mixing time) of a) 1 (7.0”10À3 m), b) 1 (7.0”10À3 m) and
Bu4N+ClÀ (7.3”10À3 m), and c) 1 (7.0”10À3 m) and Bu4N+FÀ
(7.3”10À3 m). Strong (solid arrows) and weak or absent contacts
(dashed lines) indicate a preference for a helical conformation in the
presence of the ions.
10.2 ppm, respectively) upon addition of 1 equivalent
Bu4N+ClÀ, indicative of a polarizing, hydrogen-bonding-like
interaction. The ClÀ concentration dependence of the chem-
ical shift of Hc in 1 is substantially different from that of the
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Increasing the number of triazoles results in the formation
of a more positive cavity, and stronger interactions are
components in anion receptors.[17] Potential advantages are
likely to be situational rather than general, for example,
synthetic accessibility and chemical compatibility. Ongoing
work in our lab suggests that similar interactions with
triazoles may be important for a variety of electron-rich
guests, particularly when presented in a multivalent fashion.
We expect that the intrinsic electronic properties of triazoles
(e.g., large dipole moment, electropositive CH) will lead to
their increasing use as functional units, including but extend-
ing beyond their utility as amide surrogates,[18] the basis for
new classes of foldamers,[2] or components of polymers with
new properties.[19] On the basis of strong anion binding, one
can also imagine triazoles as potential aprotic, organic Lewis
acid catalysts.[20,21]
observed with trimer 3a. A Jobꢀs plot again confirms a 1:1
1
interaction, and the best fit to the H NMR titration of 3a
with Bu4N+ClÀ gives an association constant of 1.3” 10 3 mÀ1
(Table 1). Similarly to 1 and 2, upon chloride binding the
triazole proton Hc exhibits the strongest NOESY contacts
with aryl protons Ha and Hd, consistent with the expected
orientation shown in Figure 1. Solid state data provide further
support for a pro-helical conformation in 3a·ClÀ; the mode of
binding deduced from the NMR spectra is observed in
crystallography data obtained for the Bu4N+ salt of acid 3b
complexed with ClÀ (Figure 3).[22]
Received: February 1, 2008
Published online: April 8, 2008
Keywords: anion binding · click chemistry · dipole moment ·
.
foldamers · hydrogen bonds
[1] J. M. Lehn, Chem. Soc. Rev. 2007, 36, 151 – 160.
[2] For reviews, see: a) J. M. Davis, L. K. Tsou, A. D. Hamilton,
Chem. Soc. Rev. 2007, 36, 326 – 334; b) Foldamers: Structure,
Properties and Applications (Eds.: S. Hecht, I. Huc), Wiley-
VCH, Weinheim, 2007; c) D. J. Hill, M. J. Mio, R. B. Prince, T. S.
Hughes, J. S. Moore, Chem. Rev. 2001, 101, 3893 – 4011; d) R. P.
Cheng, S. H. Gellman, W. F. DeGrado, Chem. Rev. 2001, 101,
3219 – 3232; e) S. H. Gellman, Acc. Chem. Res. 1998, 31, 173–
180; f) C. M. Goodman, S. Choi, S. Shandler, W. F. DeGrado,
Nat. Chem. Biol. 2007, 3, 252 – 262.
[3] a) V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless,
Angew. Chem. 2002, 114, 2708 – 2711; Angew. Chem. Int. Ed.
2002, 41, 2596 – 2599.
[4] V. D. Bock, H. Hiemstra, J. H. van Maarseveen, Eur. J. Org.
Chem. 2006, 51 – 68.
[5] a) H. C. Kolb, K. B. Sharpless, Drug Discovery Today 2003, 8,
1128 – 1137; b) Y. Bourne, H. C. Kolb, Z. Radic, K. B. Sharpless,
P. Taylor, P. Marchot, Proc. Natl. Acad. Sci. USA 2004, 101,
1449 – 1454; c) A. Brik, J. Alexandratos, Y. C. Lin, J. H. Elder,
A. J. Olson, A. Wlodawer, D. S. Goodsell, C. H. Wong, Chem-
BioChem 2005, 6, 1167 – 1169; d) V. D. Bock, D. Speijer, H.
Hiemstra, J. H. van Maarseveen, Org. Biomol. Chem. 2007, 5,
971 – 975; e) J. K. Pokorski, L. M. M. Jenkins, H. Q. Feng, S. R.
Durell, Y. W. Bai, D. H. Appella, Org. Lett. 2007, 9, 2381 – 2383.
[6] a) N. G. Angelo, P. S. Arora, J. Org. Chem. 2007, 72, 7963– 7967;
b) N. G. Angelo, P. S. Arora, J. Am. Chem. Soc. 2005, 127,
17134 – 17135.
[7] a) K. Oh, K.-S. Jeong, J. S. Moore, J. Org. Chem. 2003, 68, 8397 –
8403; b) H. Abe, N. Masuda, M. Waki, M. Inouye, J. Am. Chem.
Soc. 2005, 127, 16189 – 16196; c) H. P. Li, C. Li, J. L. Hou, X. K.
Jiang, Z. T. Li, Tetrahedron 2005, 61, 7974 – 7980; d) H. Jiang, J.-
M. Leger, C. Dolain, P. Guionneau, I. Huc, Tetrahedron 2003, 59,
8365 – 8374.
Figure 3. The crystal structure of 3b·ClÀ shows a crescent-shaped
conformation in which the triazole protons face inward to form a half-
ring withfive CH···Cl À contacts. Crystal structure (a) shows inter-
atomic distances withCl À while (b) depicts the position of Bu4N+
counter ions. Note the presence of water molecules hydrogen-bonding
to the anion.
As expected, the four triazoles of 1 result in stronger
chloride binding than for 2 or 3. A Jobꢀs plot confirms 1:1
binding in this case as well, and fits to titration data give a
binding constant of 1.7 ” 104 mÀ1. While the chloride ion is a
good guest and an effective inducer of folding, however, it is
not unique. Similar folding (Figure 2c) and binding (Table 1)
are observed with other Bu4N+ halides.
[8] K. J. Chang, B. N. Kang, M. H. Lee, K. S. Jeong, J. Am. Chem.
Soc. 2005, 127, 12214 – 12215.
[9] J. SanchØz-Ques¼da, C. Seel, P. Prados, J. deMendoza, I. Dalcol,
E. Giralt, J. Am. Chem. Soc. 1996, 118, 277 – 278.
[10] H. C. Kolb, M. G. Finn, K. B. Sharpless, Angew. Chem. 2001, 113,
2056 – 2075; Angew. Chem. Int. Ed. 2001, 40, 2004 – 2021.
[11] a) J. Andersen, S. Bolvig, X. F. Liang, Synlett 2005, 2941 – 2947;
b) K. Barral, A. D. Moorhouse, J. E. Moses, Org. Lett. 2007, 9,
Taken together, these results demonstrate that triazoles
have potentially important interactions with ions, and that
these interactions guide the folding of aryl triazole-based
oligomers. The potency of these interactions places them in
good company relative to other CH sources,[16] and triazoles
therefore provide an alternative to conventional protic
hydrogen bonds and coordination complexes as functional
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Chemie
1809 – 1811; c) A. K. Feldman, B. Colasson, V. V. Fokin, Org.
Lett. 2004, 6, 3897 – 3899.
Chem. Rev. 2003, 240, 17 – 55; d) V. Amendola, D. Esteban-
Gomez, L. Fabbrizzi, M. Licchelli, Acc. Chem. Res. 2006, 39,
343 – 353; e) K. Bowman-James, Acc. Chem. Res. 2005, 38, 671 –
678; f) F. P. Schmidtchen, Top. Curr. Chem. 2005, 255, 1 – 29.
[18] Y. L. Angell, K. Burgess, Chem. Soc. Rev. 2007, 36, 1674 – 1689.
[19] a) C. J. Hawker, V. V. Fokin, M. G. Finn, K. B. Sharpless, Aust. J.
Chem. 2007, 60, 381 – 383; b) J. E. Moses, A. D. Moorhouse,
Chem. Soc. Rev. 2007, 36, 1249 – 1262; c) D. Fournier, R.
Hoogenboom, U. S. Schubert, Chem. Soc. Rev. 2007, 36, 1369 –
1380; d) C. J. Hawker, K. L. Wooley, Science 2005, 309, 1200 –
1205; e) R. J. Thibault, K. Takizawa, P. Lowenheilm, B. Helms,
J. L. Mynar, J. M. J. FrØchet, C. J. Hawker, J. Am. Chem. Soc.
2006, 128, 12084 – 12085.
[20] a) P. R. Schreiner, Chem. Soc. Rev. 2003, 32, 289 – 296; b) M. S.
Taylor, E. N. Jacobsen, Angew. Chem. 2006, 118, 1550 – 1573;
Angew. Chem. Int. Ed. 2006, 45, 1520 – 1543; c) J. Scheele, P.
Timmerman, D. N. Reinhoudt, Chem. Commun. 1998, 2613–
2614; d) E. K. Fan, C. Vincent, A. D. Hamilton, New J. Chem.
1997, 21, 81 – 85.
[12] For selected computational studies of foldamers see: a) G. N.
Tew, D. Liu, B. Chen, R. J. Doerksen, J. Kaplan, P. J. Carroll,
M. L. Klein, W. F. DeGrado, Proc. Natl. Acad. Sci. USA 2002, 99,
5110 – 5114; b) L. A. Christianson, M. J. Lucero, D. H. Appella,
D. A. Klein, S. H. Gellman, J. Comput. Chem. 2000, 21, 763– 773.
[13] For an extensive NMR study of foldamers see: T. V. Jones, M. M.
Slutsky, R. Laos, T. F. A. de Greef, G. N. Tew, J. Am. Chem. Soc.
2005, 127, 17235 – 17240.
[14] K. A. Connors, Binding Constants: The Measurements of Molec-
ular Complex Stability, Wiley, New York, 1987.
[15] a) J. L. Sessler, N. M. Barkey, G. D. Pantos, V. M. Lynch, New J.
Chem. 2007, 31, 646 – 654; b) J. L. Sessler, D. E. Gross, W. S. Cho,
V. M. Lynch, F. P. Schmidtchen, G. W. Bates, M. E. Light, P. A.
Gale, J. Am. Chem. Soc. 2006, 128, 12281 – 12288.
[16] a) C. Fujimoto, Y. Kusunose, H. Maeda, J. Org. Chem. 2006, 71,
2389 – 2394; b) H. Maeda, Y. Kusunose, Chem. Eur. J. 2005, 11,
5661 – 5666; c) J. Y. Kwon, Y. J. Jang, S. K. Kim, K. H. Lee, J. S.
Kim, J. Y. Yoon, J. Org. Chem. 2004, 69, 5155 – 5157; d) C. A.
Ilioudis, D. A. Tocher, J. W. Steed, J. Am. Chem. Soc. 2004, 126,
12395 – 12402; e) I. E. Vega, P. A. Gale, M. E. Light, S. J. Loeb,
Chem. Commun. 2005, 4913– 4915.
[17] a) The Supramolecular Chemistry of Anions (Eds.: A. Bianchi,
K. Bowman-James, E. García-Espaæa), Wiley-VCH, Weiheim,
1997; b) K. H. Choi, A. D. Hamilton, Coord. Chem. Rev. 2003,
240, 101 – 110; c) J. L. Sessler, S. Camiolo, P. A. Gale, Coord.
[21] A related macrocycle was reported after this manuscript was
submitted: Y. Li, A. H. Flood, Angew. Chem. 2008, 120, 2689 –
2692; Angew. Chem. Int. Ed. 2008, 47, 2649 – 2652.
[22] CCDC-663329 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
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