Strong, size-selective, and electronically tunable C-H...halide binding with steric control over aggregation from synthetically modular, shape-persistent [34]triazolophanes

Article abstract of DOI:10.1021/ja803341y

A series of shape-persistent [3₄]triazolophanes bearing t-butyl or triethylene glycol (OTg) substituents on the phenylene linkers have been prepared in a modular manner from simple building blocks. Triazolophane-halide binding affinities were determined using UV titrations in order to help in understanding the driving forces behind the large receptor-anion binding strengths supported solely by CH hydrogen-bond donors. The fixed size of the central cavity provides a means for selective recognition of Cl^- and Br^- anions with large binding strengths (K_a > 1 000 000 M^-1; ΔG > -8.5 kcal mol^-1). The smaller F ^- and larger I^- anions are bound less tightly by ～1 and ～3 orders of magnitude, respectively. The four triazole-based H-bond donors are believed to be of primary importance, while the four phenylene CH H-bond donors take on a secondary role. Consistent with this idea, the binding affinity can be tuned by as much as 1 kcal mol^-1 by changing the character of the four phenylene-based substituents from more (OTg) to less (t-butyl) electron-donating. Preorganization was also found to play a central role, on the basis of comparisons with a foldamer analogue that shows much-reduced binding. Aggregation was facilitated as the substituents were changed from t-butyl to OTg, increasing the degree of self-association from K_E ≈ 0 to 230 M^-1 in CD₂Cl₂. Diffusion NMR experiments established aggregation as opposed to dimerization. These findings indicate the importance of the cavity size for selective anion recognition as well as the role of the phenylene linkers in tuning the binding strengths and modulating the aggregation of the [3₄]triazolophanes.

Full text of DOI:10.1021/ja803341y

Published on Web 08/14/2008
Strong, Size-Selective, and Electronically Tunable
C-H· · ·Halide Binding with Steric Control over Aggregation
from Synthetically Modular, Shape-Persistent
[34]Triazolophanes
Yongjun Li and Amar H. Flood*
Chemistry Department, Indiana UniVersity, 800 East Kirkwood AVenue,
Bloomington, Indiana 47405
Received May 5, 2008; E-mail: aflood@indiana.edu
Abstract: A series of shape-persistent [34]triazolophanes bearing t-butyl or triethylene glycol (OTg)
substituents on the phenylene linkers have been prepared in a modular manner from simple building blocks.
Triazolophane-halide binding affinities were determined using UV titrations in order to help in understanding
the driving forces behind the large receptor-anion binding strengths supported solely by CH hydrogen-
bond donors. The fixed size of the central cavity provides a means for selective recognition of Cl- and Br-
anions with large binding strengths (Ka > 1 000 000 M-1; ∆G > -8.5 kcal mol-1). The smaller F- and
larger I- anions are bound less tightly by ∼1 and ∼3 orders of magnitude, respectively. The four triazole-
based H-bond donors are believed to be of primary importance, while the four phenylene CH H-bond donors
take on a secondary role. Consistent with this idea, the binding affinity can be tuned by as much as 1 kcal
mol-1 by changing the character of the four phenylene-based substituents from more (OTg) to less (t-
butyl) electron-donating. Preorganization was also found to play a central role, on the basis of comparisons
with a foldamer analogue that shows much-reduced binding. Aggregation was facilitated as the substituents
were changed from t-butyl to OTg, increasing the degree of self-association from KE ≈ 0 to 230 M-1 in
CD2Cl2. Diffusion NMR experiments established aggregation as opposed to dimerization. These findings
indicate the importance of the cavity size for selective anion recognition as well as the role of the phenylene
linkers in tuning the binding strengths and modulating the aggregation of the [34]triazolophanes.
use of ammonium groups,2 and more recently, bioinspired
ureas,3 amides,4 and guanidiniums5 as well as synthetically
Introduction
Effective anion receptors are often constructed from a
combination of strong hydrogen-bond donors, positively charged
moieties, and Lewis acid metal ions.1 The associated H-bonding
building blocks are classified according to their functional
groups; for example, the first recognized anion receptor made
derived polypyrroles6 have been widely employed. Each of these
moieties incorporates strong NH H-bond donors. Far fewer
receptors make use of CH H-bond donors,2e,7 with the exception
of the positively charged imidazolium ions.8 More generally,
however, neutral CH H-bonds are less commonly recognized9
in molecular systems on account of their weakness,10 even
though the CH unit is present in the majority (97%) of chemical
(1) (a) Supramolecular Chemistry of Anions; Bianchi, A., Bowman-James,
K., Garc´ıa-Espan˜a, E., Eds.; Wiley-VCH: Weinheim, Germany, 1997.
(b) Beer, P. D.; Gale, P. A. Angew. Chem., Int. Ed. 2001, 40, 486–
516. (c) Sessler, J. L.; Gale, P. A.; Cho, W.-S. Anion Receptor
Chemistry; RSC Publishing: Cambridge, U.K., 2006.
(2) (a) Park, C. H.; Simmons, H. E. J. Am. Chem. Soc. 1968, 90, 2431–
2432. (b) Yatsunami, T.; Sakonaka, A.; Kimura, E. Anal. Chem. 1981,
53, 477–480. (c) Motekaitis, R. J.; Martell, A. E.; Lehn, J. M.;
Watanabe, E. I. Inorg. Chem. 1982, 21, 4253–4257. (d) Hossain, A.;
Liljegren, J. A.; Powell, D.; Bowman-James, K. Inorg. Chem. 2004,
43, 3751–3755. (e) Ilioudis, C. A.; Tocher, D. A.; Steed, J. W. J. Am.
Chem. Soc. 2004, 126, 12395–12402.
(4) (a) Valiyayeettil, S.; Engbersen, J. F. J.; Verboom, W.; Reinhoudt,
D. N. Angew. Chem., Int. Ed. Engl. 1993, 32, 900–901. (b) Bisson,
A. P.; Lynch, V. M.; Monahan, M. K. C.; Anslyn, E. V. Angew. Chem.,
Int. Ed. 1997, 36, 2340–2342. (c) Hughes, M. P.; Smith, B. D. J. Org.
Chem. 1997, 62, 4492–4499. (d) Kavallieratos, K.; deGala, S. R.;
Austin, D. J.; Crabtree, R. H. J. Am. Chem. Soc. 1997, 119, 2325–
2326. (e) Kavallieratos, K.; Danby, A.; Van Berkel, G. J.; Kelly, M. A.;
Sachleben, R. A.; Moyer, B. A.; Bowman-James, K. Anal. Chem. 2000,
72, 5258–5264. (f) Choi, K. H.; Hamilton, A. D. J. Am. Chem. Soc.
2001, 123, 2456–2457. (g) Szumna, A.; Jurczak, J. Eur. J. Org. Chem.
2001, 4031–4039. (h) Liao, J. H.; Chen, C. T.; Fang, J. M. Org. Lett.
2002, 4, 561–564. (i) Camiolo, S.; Gale, P. A.; Hursthouse, M. B.;
Light, M. E.; Warriner, C. N. Tetrahedron Lett. 2003, 44, 1367–1369.
(5) (a) Kurzmeier, H.; Schmidtchen, F. P. J. Org. Chem. 1990, 55, 3749–
3755. (b) Best, M. D.; Tobey, S. L.; Anslyn, E. V. Coord. Chem.
ReV. 2003, 240, 3–15.
(3) (a) Fan, E.; Vanarman, S. A.; Kincaid, S.; Hamilton, A. D. J. Am.
Chem. Soc. 1993, 115, 369–370. (b) Hamann, B. C.; Branda, N. R.;
Rebek, J. Tetrahedron Lett. 1993, 34, 6837–6840. (c) Kelly, T. R.;
Kim, M. H. J. Am. Chem. Soc. 1994, 116, 7072–7080. (d) Hughes,
M. P.; Shang, M. Y.; Smith, B. D. J. Org. Chem. 1996, 61, 4510–
4511. (e) Lee, K. H.; Hong, J. I. Tetrahedron Lett. 2000, 41, 6083–
6087. (f) Snellink-Ruel, B. H. M.; Antonisse, M. M. G.; Engbersen,
J. F. J.; Timmerman, P.; Reinhoudt, D. N. Eur. J. Org. Chem. 2000,
165–170. (g) Boiocchi, M.; Del Boca, L.; Gomez, D. E.; Fabbrizzi,
L.; Licchelli, M.; Monzani, E. J. Am. Chem. Soc. 2004, 126, 16507–
16514. (h) Brooks, S. J.; Gale, P. A.; Light, M. E. Chem. Commun.
2005, 4696–4698.
(6) (a) Sessler, J. L.; Camiolo, S.; Gale, P. A. Coord. Chem. ReV. 2003,
240, 17–55. (b) Nielsen, K. A.; Cho, W. S.; Lyskawa, J.; Levillain,
E.; Lynch, V. M.; Sessler, J. L.; Jeppesen, J. O. J. Am. Chem. Soc.
2006, 128, 2444–2451. (c) Lee, C. H.; Miyaji, H.; Yoon, D. W.;
Sessler, J. L. Chem. Commun. 2008, 24–34.
9
10.1021/ja803341y CCC: $40.75
2008 American Chemical Society
J. AM. CHEM. SOC. 2008, 130, 12111–12122 12111

A R T I C L E S
Li and Flood
Scheme 1. [34]Triazolophanes Tightly Encapsulate Cl- Ions in
The triazolophane allows us to investigate the relative
importance of two classes of H-bond donors, one involving the
CH of the 1,4-disubstitued 1,2,3-triazoles and the other based
on the phenylene CH. Although the 1,2,3-triazole has only
recently been prepared17 using Cu-catalyzed 1,3-dipolar cy-
cloadditions,18 this synthesis has been carried out on a wide
scale,19 leading to functional molecules20 of increasing com-
plexity. Recent communications making use of a 1,2,3-triazo-
lium cation for phosphate anion recognition,21 a flexible
triazolophane,14e and a triazole-based cyclic peptide22 showing
self-assembly as well as the anion-binding properties of fol-
damers23 all demonstrate 1,2,3-triazoles participating in non-
covalent interactions. In particular, a crystal structure of the
triazole-based foldamer23a that contains five of the eight rings
of the [34]triazolophane core clearly shows C-H· · ·Cl- contacts.
All of these cases provide cause for examining the triazole
subunits more closely when they are employed in artificial anion
receptors.
CH2Cl2
compounds.11 Their relative importance in biological10 and
artificial1 anion recognition is the topic of ongoing studies, with
efforts focusing on experimental7 and computational9b,12 evalu-
ation. The investigation of weak noncovalent interactions can
be facilitated by studying a closely related series as well as by
employing a receptor with an unambiguous structure. Our
discovery13 of the tight binding between a Cl- anion and a
[34]triazolophane14 attributable entirely to aromatic CH H-bonds
(Scheme 1) presented a means of participating in the reexamina-
tion of the hierarchy of H-bond donors. In addition, the shape-
persistent15 character of the macrocyclic structure provided a
basis for evaluating how a well-defined cavity16 can dictate
anion-size selectivity.
In the first reported example24,25 where nonaromatic CH units
were solely responsible for F- binding, proximal CF2 units were
believed to aid in polarizing the CH bond of an adjacent
methylene group. More recently,26 polarization of methylene
CH H-bonds was found to play a major role in facilitating anion
recognition by resorcinarene cavitands. Anion binding has also
been observed by taking advantage of non-H-bonding dipoles
preorganized into a bowl-shaped receptor.27 On the basis of these
observations, we believe that there are two sources of anion
affinity that emerge from the 1,2,3-triazole structure. First, the
electronegativities of the three nitrogens combine to polarize
the CH bond.14d,22,23 Second, the lone pairs of electrons on the
nitrogen atoms act to establish and orient along the CH bond a
(7) (a) Lee, C. H.; Na, H. K.; Yoon, D. W.; Won, D. H.; Cho, W. S.;
Lynch, V. M.; Shevchuk, S. V.; Sessler, J. L. J. Am. Chem. Soc. 2003,
125, 7301–7306. (b) Chen, Q. Y.; Chen, C. F. Tetrahedron Lett. 2004,
45, 6493–6496. (c) Chmielewski, M. J.; Charon, M.; Jurczak, J. Org.
Lett. 2004, 6, 3501–3504. (d) Kang, S. O.; VanderVelde, D.; Powell,
D.; Bowman-James, K. J. Am. Chem. Soc. 2004, 126, 12272–12273.
(e) Kwon, J. Y.; Jang, Y. J.; Kim, S. K.; Lee, K. H.; Kim, J. S.; Yoon,
J. Y. J. Org. Chem. 2004, 69, 5155–5157. (f) Maeda, H.; Kusunose,
Y. Chem.sEur. J. 2005, 11, 5661–5666. (g) Vega, I. E.; Gale, P. A.;
Light, M. E.; Loeb, S. J. Chem. Commun. 2005, 4913–4915. (h)
Fujimoto, C.; Kusunose, Y.; Maeda, H. J. Org. Chem. 2006, 71, 2389–
2394. (i) Nishiyabu, R.; Palacios, M. A.; Dehaen, W.; Anzenbacher,
P. J. Am. Chem. Soc. 2006, 128, 11496–11504. (j) Zielinski, T.;
Kedziorek, M.; Jurczak, J. Chem.sEur. J. 2008, 14, 838–846. (k)
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.
(17) See the following special issue on click chemistry: QSAR Comb. Sci.
2007, 26, 1110-1323.
(18) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596–2599. (b) Tornoe, C. W.;
Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057–3064.
(19) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed.
2001, 40, 2004–2021.
(8) (a) Alcalde, E.; Alvarez-Rua, C.; Garcia-Granda, S.; Garcia-Rodriguez,
E.; Mesquida, N.; Perez-Garcia, L. Chem. Commun. 1999, 295–296.
(b) Chellappan, K.; Singh, N. J.; Hwang, I. C.; Lee, J. W.; Kim, K. S.
Angew. Chem., Int. Ed. 2005, 44, 2899–2903.
(20) (a) Collman, J. P.; Devaraj, N. K.; Chidsey, C. E. D. Langmuir 2004,
20, 1051–1053. (b) Joralemon, M. J.; O’Reilly, R. K.; Matson, J. B.;
Nugent, A. K.; Hawker, C. J.; Wooley, K. L. Macromolecules 2005,
38, 5436–5443. (c) Parent, M.; Mongin, O.; Kamada, K.; Katan, C.;
Blanchard-Desce, M. Chem. Commun. 2005, 2029–2031. (d) Mobian,
P.; Collin, J. P.; Sauvage, J. P. Tetrahedron Lett. 2006, 47, 4907–
4909. (e) Braunschweig, A. B.; Dichtel, W. R.; Miljanic, O. S.; Olson,
M. A.; Spruell, J. M.; Khan, S. I.; Heath, J. R.; Stoddart, J. F.
Chem.sAsian J. 2007, 2, 634–647. (f) Aucagne, V.; Berna, J.;
Crowley, J. D.; Goldup, S. M.; Haenni, K. D.; Leigh, D. A.; Lusby,
P. J.; Ronaldson, V. E.; Slawin, A. M. Z.; Viterisi, A.; Walker, D. B.
J. Am. Chem. Soc. 2007, 129, 11950–11963. (g) Liu, Y.; Klivansky,
L. M.; Khan, S. I.; Zhang, X. Y. Org. Lett. 2007, 9, 2577–2580. (h)
Angelos, S.; Yang, Y. W.; Patel, K.; Stoddart, J. F.; Zink, J. I. Angew.
Chem., Int. Ed. 2008, 47, 2222–2226. (i) Scrafton, D. K.; Taylor, J. E.;
Mahon, M. F.; Fossey, J. S.; James, T. D. J. Org. Chem. 2008, 73,
2871–2874.
(9) (a) Brammer, L.; Bruton, E. A.; Sherwood, P. Cryst. Growth Des.
2001, 1, 277–290. (b) Hay, B. P.; Bryantsev, V. S. Chem. Commun.
2008, 2417–2428.
(10) Desiraju, G. R.; Steiner, T., The Weak Hydrogen Bond in Structural
Chemistry and Biology; Oxford University Press: Oxford, U.K., 1999.
(11) Of the 18 426 559 molecules in PubChem (March 2008), 17 947 719
(97%) contained one or more CH units.
(12) (a) Bryantsev, V. S.; Hay, B. P. J. Am. Chem. Soc. 2005, 127, 8282–
8283. (b) Bryantsev, V. S.; Hay, B. P. Org. Lett. 2005, 7, 5031–5034.
(c) Zuo, C. S.; Quan, J. M.; Wu, Y. D. Org. Lett. 2007, 9, 4219–
4222.
(13) Li, Y.; Flood, A. H. Angew. Chem., Int. Ed. 2008, 47, 2649–2652.
(14) (a) Chande, M. S.; Athalye, S. S. Synth. Commun. 1999, 29, 1711–
1717. (b) Chande, M. S.; Athalye, S. S. Synth. Commun. 2000, 30,
1667–1674. (c) Ray, A.; Manoj, K.; Bhadbhade, M. M.; Mukho-
padhyay, R.; Bhattacharjya, A. Tetrahedron Lett. 2006, 47, 2775–
2778. (d) Chande, M. S.; Barve, P. A.; Khanwelkar, R. R.; Athalye,
S. S.; Venkataraman, D. S. Can. J. Chem. 2007, 85, 21–28. (e) Haridas,
V.; Lal, K.; Sharma, Y. K.; Upreti, S. Org. Lett. 2008, 10, 1645–
1647.
(21) Kumar, A.; Pandey, P. S. Org. Lett. 2008, 10, 165–168.
(22) Horne, W. S.; Yadav, M. K.; Stout, C. D.; Ghadiri, M. R. J. Am.
Chem. Soc. 2004, 126, 15366–15367.
(23) (a) Juwarker, H.; Lenhardt, J. M.; Pham, D. M.; Craig, S. L. Angew.
Chem., Int. Ed. 2008, 47, 3740–3743. (b) Meudtner, R. M.; Hecht, S.
Angew. Chem., Int. Ed. 2008, 47, 4926–4930.
(15) (a) Zhang, J.; Moore, J. S. J. Am. Chem. Soc. 1992, 114, 9701–9702.
(b) Shetty, A. S.; Zhang, J.; Moore, J. S. J. Am. Chem. Soc. 1996,
118, 1019–1027. (c) Lahiri, S. L.; Thompson, J. L.; Moore, J. S. J. Am.
Chem. Soc. 2000, 122, 11315–11319. (d) Tobe, Y.; Utsumi, N.;
Kawabata, K.; Nagano, A.; Adachi, K.; Araki, S.; Sonoda, M.; Hirose,
K.; Naemura, K. J. Am. Chem. Soc. 2002, 124, 5350–5364.
(16) (a) Chang, K. J.; Moon, D.; Lah, M. S.; Jeong, K. S. Angew. Chem.,
Int. Ed. 2005, 44, 7926–7929. (b) Kim, N. K.; Chang, K. J.; Moon,
D.; Lah, M. S.; Jeong, K. S. Chem. Commun. 2007, 3401–3403.
(24) Farnham, W. B.; Roe, D. C.; Dixon, D. A.; Calabrese, J. C.; Harlow,
R. L. J. Am. Chem. Soc. 1990, 112, 7707–7718.
(25) Siswanta, D.; Tanenaka, J.; Sasakura, H.; Hisamoto, H.; Suzuki, K.
Chem. Lett. 1997, 195–196.
(26) Zhu, S. S.; Staats, H.; Brandhorst, K.; Grunenberg, J.; Gruppi, F.;
Dalcanale, E.; Luetzen, A.; Rissanen, K.; Schalley, C. A. Angew.
Chem., Int. Ed. 2008, 47, 788–792.
(27) Savage, P. B.; Holmgren, S. K.; Gellman, S. H. J. Am. Chem. Soc.
1994, 116, 4069–4070.
9
12112 J. AM. CHEM. SOC. VOL. 130, NO. 36, 2008

Size-Selective, Electronically Tunable C-H· · ·X Binding
A R T I C L E S
Scheme 2. Structural Formulas of [34]Triazolophanes Bearing a Variety of Substituents
large (5 D) dipole28 whose positive end points toward the H
atom. These multiple effects contribute to the triazole’s unex-
pectedly strong H-bonding capabilities. This dipolar character
is consistent with an increasing number of reports14e,22 of the
H-bond acceptor and Lewis base29 properties of the triazole
nitrogens as well as of the 1,2,3-triazole unit serving as a
surrogate for amide bonds.22,30
The phenylene groups are believed to be less intrinsically
polarized than triazoles, but they are expected to aid in both
stabilizing and encapsulating the anion.12 The H-bond donor
properties of phenyl CH have been the topic of a greater number
of studies,12 on the basis of which the binding contributions
are believed to be half those of an NH H-bond donor. In addition
to their donor abilities, however, they also provide indispensable
structural features in triazolophanes. First, they contribute to
structural rigidity, reinforcing the preorganization31 of pairwise
interactions between host and guest. Second, they help to define
the size of the cavity (internal diameter ∼3.8 Å) by virtue of
the space they occupy. To investigate the role of size, we
employed the series of halides F-, Cl-, Br- and I-, which have
a variety of ionic radii (1.30, 1.81, 1.96, and 2.20 Å, respec-
tively32), and made use of molecular models to predict that the
halides with the best match to the cavity size will display the
strongest binding.
structure-property investigation was to vary the electronic
character of the substituents on the phenylene linkers. This
approach allowed us to examine how much the phenyl CH
H-bond donors can be used to tune the anion binding and also
to establish a baseline for how much the polarized and dipole-
stabilized triazole CH group contributes to the anion affinity.
Furthermore, the differently sized halides provide a means of
determining how effective the two classes of H-bond donors
are in accommodating alternative binding modes that are
expected with poorly encapsulated anions.
The [34]triazolophanes belong to the D2h point group. This
molecular symmetry defines two different phenylenes and gives
rise to two different types of phenyl CH H-bond donors for
evaluation in this study. The phenylenes that connect to the
1-positions of the triazoles are called N-linked phenylenes, while
C-linked phenylenes connect to the 4-positions. Our convention
is to orient the triazolophane structures such that the N-linked
phenylenes point along the “north” and “south” directions and
the C-linked phenylenes lie along the “west” to “east” axis. The
modularity of the synthesis13 allows us to easily change the
substituents and therefore to independently evaluate the impacts
of the N- and C-linked phenylenes on halide binding, thereby
answering the question of which phenylene binds most strongly
to the encapsulated anion. For this purpose, we selected the
solubility-enhancing methoxy-terminated triethylene glycol
(OTg) chain to use in conjunction with the sterically bulky
t-butyl substituent as a means of designing a series of four
[34]triazolophanes (Scheme 2) with complementary substitution
patterns. Our expectation was that the phenylenes with the
t-butyl substituents would be less electron-donating than the OTg
chains and therefore would enhance the polarization of the CH
bonds, resulting in larger anion-receptor binding strengths. In
addition, the F- anion appeared to be small enough (see above)
to be situated inside the cavity in one of the four directions.
Characterization of F- binding, therefore, provided a means of
probing which of the three H-bond donor groups located around
the inner surface of the cavity contributes the most to binding.
In addition, the ether link of the OTg substituent has a smaller
steric size than t-butyl group. This size difference effectively
extends the planarity of the triazolophane out to the oxygen
atoms. Moreover, the long ethylene glycol chains are known to
facilitate self-association through solvophobic interactions.33 As
a consequence, we also considered the propensity for the OTg
On the basis of the preexisting stepwise synthetic methodol-
ogy,13 the most straightforward means of conducting a
(28) Palmer, M. H.; Findlay, R. H.; Gaskell, A. J. J. Chem. Soc., Perkin
Trans. 2 1974, 420–428.
(29) (a) Chan, T. R.; Hilgraf, R.; Sharpless, K. B.; Fokin, V. V. Org. Lett.
2004, 6, 2853–2855. (b) Suijkerbuijk, B.; Aerts, B. N. H.; Dijkstra,
H. P.; Lutz, M.; Spek, A. L.; van Koten, G.; Gebbink, R. Dalton Trans.
2007, 1273–1276. (c) Li, Y. J.; Huffman, J. C.; Flood, A. H. Chem.
Commun. 2007, 2692–2694. (d) Colasson, B.; Save, M.; Milko, P.;
Roithova, J.; Schroder, D.; Reinaud, O. Org. Lett. 2007, 9, 4987–
4990. (e) Meudtner, R. M.; Ostermeier, M.; Goddard, R.; Limberg,
C.; Hecht, S. Chem.sEur. J. 2007, 13, 9834–9840. (f) Meudtner,
R. M.; Hecht, S. Macromol. Rapid Commun. 2008, 29, 347–351. (g)
Ziegler, T.; Hermann, C. Tetrahedron Lett. 2008, 49, 2166–2169.
(30) (a) Kolb, H. C.; Sharpless, K. B. Drug DiscoVery Today 2003, 8, 1128–
1137. (b) Bourne, Y.; Kolb, H. C.; Radic, Z.; Sharpless, K. B.; Taylor,
P.; Marchot, P. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 1449–1454.
(c) Brik, A.; Alexandratos, J.; Lin, Y. C.; Elder, J. H.; Olson, A. J.;
Wlodawer, A.; Goodsell, D. S.; Wong, C. H. ChemBioChem 2005, 6,
1167–1169. (d) Bock, V. D.; Speijer, D.; Hiemstra, H.; van Maarse-
veen, J. H. Org. Biomol. Chem. 2007, 5, 971–975. (e) Pokorski, J. K.;
Jenkins, L. M. M.; Feng, H. Q.; Durell, S. R.; Bai, Y. W.; Appella,
D. H. Org. Lett. 2007, 9, 2381–2383.
(31) Cram, D. J. Angew. Chem., Int. Ed. Engl. 1988, 27, 1009–1020.
(32) Moyer, B. A.; Bonnesen, P. V. In Supramolecular Chemistry of Anions;
Bianchi, A., Bowman-James, K., Garc´ıa-Espan˜a, E., Eds.; Wiley-VCH:
Weinheim, Germany, 1997.
(33) Nelson, J. C.; Saven, J. G.; Moore, J. S.; Wolynes, P. G. Science 1997,
277, 1793–1796.
9
J. AM. CHEM. SOC. VOL. 130, NO. 36, 2008 12113

A R T I C L E S
Li and Flood
substituents to drive aggregation, which is a common feature
of shape-persistent macrocycles.15
Herein we present the synthesis and characterization of the
four [34]triazolophanes T-tBu4,13 T-tBu2OTg2, T-OTg2tBu2
and T-OTg4 (Scheme 2). Aggregation behavior was found to
be present at higher solution concentrations, as verified using
diffusion NMR and quantified in terms of the isodesmic binding
1
model by performing H NMR spectroscopy as a function of
dilution. The propensity to aggregate increased with OTg
substitution. On account of the strong halide binding, the anion
association constants could be quantified using UV spectroscopy
and titrations between the triazolophanes and tetrabutylammo-
nium (TBA) halide salts at concentrations low enough to exclude
any interference from aggregation. In all cases, the too-small
F- and too-large I- anions were bound less tightly than the
snugly fitting Cl- and Br- anions. The electronic effects of the
substituents were capable of fine-tuning the anion-binding
strengths resulting from phenyl-based C-H· · ·anion interactions
by ∼10-20%. This modest effect is considered to be indicative
of the primary role that the triazoles play in the receptor-halide
binding. The structures of the resulting anion-receptor com-
plexes were examined in solution using 1H NMR spectroscopy
at modest concentrations. Analyses of the binding strengths for
the various halides across the series of triazolophanes as well
1
as of the H NMR spectra of the F- complexes in solution
indicated that the N-linked phenylene CH H-bond donors are
more important for anion binding than those of the C-linked
phenylenes. In the case of the [34]triazolophanes, we also
demonstrated the importance of preorganization in fortifying
these aromatic CH H-bonds by utilizing an oligomeric analogue
that folds23,34 around the halide. Taken together, these findings
indicate that a cross section of effects come together in the
triazolophanes to bind halides size-selectively and with large
strengths.
Figure 1. (a) Representation of a hypothetical 7/8-oligomer intermediate
expected to exist in a dynamic equilibrium of conformers and (b) a Monte
Carlo search (MM2) of its conformer distribution. Arrows indicate
conformations that are one bond rotation away from the preorganized
conformer (#50, red arrow). Torsion barriers were computed at the HF/3-
21G* level for the (c) N-linked and (d) C-linked bis(triazole)benzene model
compounds.
Results and Discussion
Naming and Nomenclature. We have followed the conven-
tions35 for naming cyclophanes wherever possible. The four
triazoles are the persistent feature of the macrocycle, dictating
the use of the term “triazolophane” for this class of compound
in order to be consistent with other naming schemes incorporat-
ing both 1,2,4-14a,b and 1,2,3-triazoles.14c,d There are three
intervening atoms between each triazole and a total of four
phenylene linkers, determining the use of the “3” and the
italicized subscript “4”, respectively, in the prefix [34]. The core
structure should therefore be named [34](1,4)-1,2,3-triazolo-
phane, which we have shortened to [34]triazolophane. Descrip-
tive names have been used for the various intertriazole phenylene
linkers.
Computer-Aided Design and Synthesis. Previously we re-
ported on the computer-aided design and convergent synthesis13
of [34]triazolophane T-tBu4, and here we have extended this
approach to the preparation of the compounds T-tBu2OTg2,
T-OTg2tBu2, and T-OTg4. The abbreviated names for the
compounds containing both t-butyl and OTg substituents first
give the substituents in the north and south phenylene directions
and then those in the west and east directions. Briefly, a 1,3-
diiodophenylene served as the primary starting material from
which 1,3-diazidophenylene and monoethynylphenylene build-
ing blocks were prepared. These two components were reacted
together in a 1:2 molar ratio, respectively, using click chemistry
conditions, generating a “5/8” oligomer (bearing five of the
necessary eight ring systems), which was converted into a
diethynyl-based 5/8 premacrocycle. This last oligomer was
utilized together with a 1,3-diazidophenylene in the final
macrocyclization, which was conducted under pseudo-high-
dilution conditions to produce T-tBu4 in good yield (70%).
Molecular modeling of the conformations of a key 7/8-oligomer
intermediate expected to be present during the final step (Figure
1) was used to verify that the preorganized rotamer (red arrow,
Figure 1b) was sufficiently low in energy to allow the final ring-
closing reaction to proceed through a Boltzmann-weighted
fraction of the reaction mixture. The barriers to rotation were
characterized by molecular modeling (HF/3-21G*) to be low
(∼4.5 kcal mol-1). Taken together, these semiquantitative
models provided a basic evaluation of the reasonably flat
potential energy surface for macrocyclization. For the other three
triazolophanes studied in this work, further modeling was
unnecessary since both the t-butyl and OTg substituents on the
phenylene linkers were expected to impart similarly small steric
factors. A few variations in the synthetic schemes were
investigated in order to evaluate alternative pathways for the
different building blocks as well as to demonstrate the modular-
ity of the approach.
(34) Chang, K. J.; Kang, B. N.; Lee, M. H.; Jeong, K. S. J. Am. Chem.
Soc. 2005, 127, 12214–12215.
(35) Vogtle, F. Cyclophane Chemistry; Wiley: New York, 1993.
9
12114 J. AM. CHEM. SOC. VOL. 130, NO. 36, 2008

Size-Selective, Electronically Tunable C-H· · ·X Binding
A R T I C L E S
Scheme 3. Synthesis of Monoethynylbenzene 4, Singly Protected
Diethynylbenzene 8, and Diazides 3 and 6a
T-OTg4 showed slight coloration to a faint red-purple after
storage for some time under ambient conditions. MALDI-TOF
mass spectrometry of T-tBu4 showed one peak at m/z 797.6.
High-resolution ESI analysis of triazolophanes T-tBu2OTg2,
T-OTg2tBu2, and T-OTg4 gave observed (calculated) signals
at m/z 1009.5054 (1009.5048), 1009.5017 (1009.5048), and
1221.5623 (1221.5581), respectively, corresponding to the
molecular ions [M + H+] as the major peaks.
1
The H NMR spectra of the triazolophanes in CD2Cl2 each
displayed five well-separated singlets in the aromatic region
(Figure 2). The peaks were assigned with the aid of various 2D
NMR spectroscopies in order to distinguish between N- and
C-linked phenylene resonances, as exemplified for T-tBu4. The
single downfield peak at 9.59 ppm corresponds to the four
triazole protons (Ha), which reside in identical chemical
environments. This peak position is significantly shifted down-
field by 1.27 ppm compared to the corresponding peak in the
5/8 oligomeric precursor 10a.13 This shift is believed to arise
because the triazole protons are located within the greater
deshielding environment generated by the ring currents of all
four coplanar phenyl rings. The aromatic singlets at 7.93 ppm
(Hb) and 7.78 ppm (Hc), each integrating to two protons, were
attributed to the inner CH protons of the C-linked and N-linked
phenylenes, respectively. The two four-proton singlets resonating
at 7.98 ppm (He) and 7.87 ppm (Hd) were assigned to the outer
protons of the N-linked and C-linked phenylenes, respectively.
a a: NaN3/CuI/N,N′-dimethylethane-1,2-diamine (DMEA)/sodium ascor-
bate/7:3:1 EtOH:H2O:PhMe/reflux/Ar. b: (1) trimethylsilylacetylene/
PdCl2(PPh3)2/CuI/iPr2NH/THF/Ar; (2) KF/MeOH/THF. c: K2CO3/DMF. d:
NaN3/CuI/DMEA/sodium ascorbate/5:1 DMSO:H2O/50°C/Ar. e: 2-methyl-
3-butyn-2-ol/PdCl2(PPh3)2/CuI/iPr2NH/THF/Ar.
The four building blocks 3, 4, 6, and 8 (Scheme 3) were
prepared from the two primary diiodo starting materials 2 and
5. The 5-tert-butyl-substituted 1,3-diiodophenylene 2 was used
to prepare the diazido (3) and monoethynyl (4) building blocks,
as previously described.13 The primary OTg-substituted starting
material, 1-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)-3,5-diiodo-
benzene (5), was obtained from the coupling of 3,5-diiodophenol
and 2-(2-(2-methoxyethoxy)ethoxy)ethyl-4-methylbenzene-
sulfonate.36 Compound 5 was used to obtain the diazide 6 as
well as building block 8 as a monoprotected 1,3-diethynylphe-
nylene using sequential Sonogashira reactions. The singly
protected diethynylbenzene 4-(3-(2-(2-(2-methoxyethoxy)ethox-
y)ethoxy)-5-ethynylphenyl)-2-methylbut-3-yn-2-ol (8) was pre-
pared in 59% yield (three steps) by the successive coupling of
5 with 2-methyl-3-butyn-2-ol and (trimethylsilyl)acetylene fol-
lowed by desilylation of the diethynylation products using KF
in a 1:1 methanol:THF mixture.
All of the [34]triazolophanes were prepared using the 3,5-
diazidobenzene compounds 3 and 6 and the unprotected
ethynylbenzenes 4 and 8 as building blocks. Mixing and
matching the diazides with the ethynylbenzenes yielded the
series of 5/8 oligomers 9a-d via copper-catalyzed cycloaddi-
tions. These oligomers were converted into the corresponding
diethynyl 5/8 premacrocycles 10a-d either through another
Sonogashira reaction followed by deprotection (10a, 10c) or
directly by deprotection (10b, 10d). Compounds 10a-d were
coupled with diazide 3 or 6 and cyclized using click chemistry
under pseudo-high-dilution conditions to generate the corre-
sponding triazolophanes (Scheme 4). Consistent with the
reported yield of T-tBu4 (70%),13 good yields were obtained
for the other three triazolophanes T-tBu2OTg2 (55%),
T-OTg2tBu2 (60%), and T-OTg4 (62%).
The assignments of the proton resonances were verified using
2D NMR experiments. The 1H-1H COSY spectrum of T-tBu4
in CD2Cl2 (Figure S1 in the Supporting Information) showed
correlations between the singlet at 7.93 ppm assigned to the
inner proton Hb and the peak for the outer proton Hd at 7.87
ppm, tying them into the same phenylene unit. A similar link
was observed between the other pair of inner (7.78 ppm, Hc)
and outer (7.98 ppm, He) proton resonances. Correlations
1
between H and 13C peaks were employed to distinguish the
N-linked phenylene from the C-linked one. On the basis of a
gHMQC experiment in 6:1 CD2Cl2:CD3OD at 298 K (Figure
S2 in the Supporting Information), five of the 10 carbon
resonances in the 115-125 ppm region were assigned to the
corresponding tertiary carbons. The peak at 120.7 ppm was
connected to the triazole proton Ha at 9.59 ppm, and the
following heteronuclear correlations between (1H, 13C) pairs
(ppm) were also found: (7.98, 116.1), (7.93, 122.7), (7.87,
1
122.0), and (7.78, 107.6). Lastly, a H-13C CIGAR map of
T-tBu4 in 6:1 CD2Cl2:CD3OD at 298 K (Figure S3 in the
Supporting Information) was recorded in order to identify the
connections that occur through multiple bonds, thereby provid-
ing a means to make the final assignments. The t-butyl protons
at 1.63 and 1.58 ppm corresponding to the N- and C-linked
phenylene substituents, respectively, showed correlations to the
13C peaks at 155.9 and 152.7 ppm. These assignments left just
three remaining unassigned carbon resonances in the aromatic
region. A diagnostic connection between the triazole proton Ha
at 9.59 ppm and one of the three quaternary carbons at 148.7
ppm was observed in the CIGAR map. This resonance was
assigned to the triazole carbon directly bonded with the
phenylene ring (C4) on the basis of its strong correlation with
the singlets at 7.93 ppm (Hb) and 7.87 ppm (Hd) previously
assigned to the C-linked phenylene. The four- and two-proton
singlets at 7.98 and 7.78 ppm (He and Hc, respectively) assigned
to the N-linked phenylene protons did not show any cross peaks
with either of the triazole carbons under these experimental
conditions. The remaining assignments of the 1H and 13C
Structural Characterization of Triazolophanes by Mass
1
Spectrometry and H NMR Spectroscopy. All of the triazolo-
phanes were isolated as white solids, but T-OTg2tBu2 and
(36) Heathcote, R.; Howell, J. A. S.; Jennings, N.; Cartlidge, D.; Cobden,
L.; Coles, S.; Hursthouse, M. Dalton Trans. 2007, 1309–1315.
9
J. AM. CHEM. SOC. VOL. 130, NO. 36, 2008 12115

A R T I C L E S
Li and Flood
Scheme 4. Synthesis of Diethynyl 5/8 Premacrocycles 9a-d and 10a-d and the Corresponding [34]Triazolophanesa
a a: CuSO4/sodium ascorbate/7:3:1 EtOH:H2O:PhMe. b: CuI/1,8-diaza[5.4.0]bicycloundec-7-ene (DBU)/PhMe/70°C/Ar. c: (1) trimethylsilylacetylene/
PdCl2(PPh3)2/CuI/iPr2NH/THF/Ar; (2) KF/MeOH/THF. d: KOH/PhMe/reflux. e: dropwise addition of 10 and either 3 or 6 into CuI/DBU/PhMe/Ar over 10 h
followed by stirring for another 4 h.
1
The H NMR spectra of the remaining macrocycles were
assigned on the basis of the NMR assignments for T-tBu4, their
2D COSY spectra (Figures S6-S8 in the Supporting Informa-
tion), and the substitution patterns of each triazolophane.
Principally, the spectrum of T-tBu2OTg2 showed through-space-
coupled inner and outer pairs of singlets that were shifted upfield
and thus assigned to the protons at the site of OTg substitution
in the C-linked phenylene, while the other pair of singlets were
relatively unaffected by this substitution. Conversely, the
spectrum of T-OTg2tBu2 showed that the N-linked phenylene
protons were shifted more dramatically upfield compared with
those in T-tBu4. Consistent with these trends, both sets of
resonances were shifted upfield in the spectrum of T-OTg4
triazolophane.
The NMR data supports the assignment of D2h symmetry,
and the 2D NMR (ROESY) spectrum of T-tBu4 (Figure S4 in
the Supporting Information) was found to be consistent with a
planar structure. In the case of T-tBu4, strong through-space
Figure 2. Aromatic region of the 1H NMR spectra (400 MHz, CD2Cl2) of
(a) T-tBu4, (b)T-tBu2OTg2, (c) T-OTg2tBu2, and (d)T-OTg4. All of the
spectra were recorded at ∼1 mM.
resonances were made utilizing the CIGAR map and were
fortuitously simplified by the fact that the C-linked phenylenes
were not strongly coupled with the N-linked ones.
9
12116 J. AM. CHEM. SOC. VOL. 130, NO. 36, 2008

Size-Selective, Electronically Tunable C-H· · ·X Binding
A R T I C L E S
Table 1. Experimental NMR Diffusion Coefficients (D)a of
Triazolophanes Recorded as a Function of Concentration (C)
Table 2. Association Constants (KE)a for Self-Aggregation of the
Triazolophanes in Organic Solvents at 298 K As Determined Using
1H NMR Spectroscopy Based on Proton Hd
C (mmol L-1
)
D (10-10 m2 s-1
)
solvent
KE (M-1
)
∆GE (kcal mol-1
)
T-tBu4
T-tBu2OTg2
1.0
1.6
36
72
1.6
34
4.12 ( 0.02
3.16 ( 0.04
2.96 ( 0.01
2.47 ( 0.01
2.83 ( 0.02
2.20 ( 0.02
1.95 ( 0.02
T-tBu4
CD2Cl2
CD2Cl2
CD2Cl2
CD2Cl2
CD3COCD3
CD3CN
-
31 ( 4
12 ( 2
230 ( 30
450 ( 50
1600 ( 500
-
T-tBu2OTg2
T-OTg2tBu2
T-OTg4
-2.0
-1.5
-3.2
-3.6
-4.4
T-OTg4
68
a Determined on the basis of the infinite-association model by the
NMR method.
a Measured in CD2Cl2 at 300.3 K.
cross peaks were seen between each of the inner protons: triazole
proton Ha (9.59 ppm), N-linked phenylene CH proton Hc (7.78
ppm) and C-linked phenylene CH proton Hb (7.93 ppm). Strong
cross peaks were also observed between the protons of the
t-butyl groups and the outer phenylene protons: Hf with He from
the N-linked phenylenes and Hg with Hd from the C-linked
phenylenes. If a nonplanar structure were present to any major
extent, other cross peaks would be expected to be evident. For
instance, inspection of molecular models that were generated
to represent calix[4]pyrrole-like cone structures showed that
nonplanarity would have afforded through-space interactions
from the triazole protons (Ha) to those on the t-butyl groups
(Hf and Hg). Moreover, on the basis of molecular modeling,
these nonplanar structures were found to be significantly higher
in energy (>30 kcal mol-1) than planar ones. Finally, while
deviations from complete planarity, such as those evident in
the case of porphyrins,37 cannot be excluded at this stage, these
NMR studies strongly support the conclusion that an overall
planar structure is present in CD2Cl2 solution. These NMR
assignments and the planar structures are critical for the
interpretation of anion complexation.
Aggregation Investigation using Variable-Concentration
1H NMR Spectroscopy. The presence of aggregation in samples
of the triazolophanes in CD2Cl2 was evident from the concentra-
tion-dependent chemical shifts in the 1H NMR spectra (Figures
S9-S12 in the Supporting Information) and verified from
diffusion NMR experiments. The largest effect was seen for
T-OTg4, wherein the triazole Ha proton peak moved upfield
from 9.54 to 9.06 ppm and that for the inner Hb protons of the
C-linked phenylene rings from 7.36 to 6.88 ppm as the
concentration was increased from 0.082 to 71 mM (CD2Cl2, 25
°C). The upfield shifts indicate that the aggregates adopt a
structure in which the macrocyclic frameworks stack in a face-
to-face geometry, as reported frequently in self-association
phenomena arising from π-π stacking interactions.15,38-40
In order to distinguish between the monomer-dimer equi-
librium and equilibria involving more highly aggregated spe-
cies41 in the solution phase, diffusion NMR experiments were
performed.42 The diffusion coefficient D of a spherical molecule
in solution can be described by the Stokes-Einstein equation:
can be compared on the basis of their diffusion coefficients. If
only a monomer-dimer equilibrium exists, the D values for
the monomer and dimer species should be nearly identical.44
On the other hand, for highly aggregated species, which have
much larger rs values than monomers, a change in D values
should be observable as a function of concentration. Triazolo-
phane T-tBu4, which does not aggregate because of its bulky
substituents, has a diffusion coefficient of 4.12 × 10-10 m2 s-1
at 1 mM. As shown in Table 1, for T-OTg4 and T-tBu2OTg2,
diffusion coefficients of 2.83 × 10-10 and 3.16 × 10-10 m2
s-1, respectively, were observed at a concentration of 1.6 mM.
The large difference between the D values of T-OTg4 or
T-tBu2OTg2 and monomeric T-tBu4 indicates that the hydro-
dynamic radius of the species present in solution for T-OTg4
or T-tBu2OTg2 is much larger than that of the reference
compound. These data evidently show formation of extended
aggregates in CD2Cl2. A gradual decrease in the D value was
observed when the concentration of the solution was increased,
indicating an increase of the hydrodynamic radius of the
aggregates. Triazolophane T-OTg4 showed a greater decrease
in the diffusion constant than T-tBu2OTg2, which agrees with
the association constants obtained by 1H NMR fitting (see
below). These concentration- and structure-dependent properties
are consistent with the formation of higher-order aggregates.
The self-association behavior of these triazolophanes is
sensitive to the polarity of the solvent, akin to that of
phenylacetylene15b and other related macrocycles.38 In more-
polar solvents, such as CD3CN, the chemical shifts of the outer
protons on the C-linked phenylenes of T-OTg4 (Figure 3a)
moved upfield from 6.99 to 6.15 ppm as the concentration was
increased from 0.17 to 75 mM at 25 °C. More evidently, the
seven resonances of the protons in the OTg chain moved upfield,
became broadened, and eventually merged together. The as-
sociation constants (KE) for the formation of higher-order
aggregate species45 (Table 2) were obtained by analyzing the
1
concentration-dependent H NMR data (Figure 3b). The ag-
gregation was quantified using the outer protons from the
C-linked phenylenes (Hd). Only T-tBu4 showed a negligible
propensity to aggregate in CD2Cl2; the other triazolophanes
showed increasing aggregation strengths as the number of OTg
kBT
D )
6πηrs
(41) (a) Wu, J.; Fechtenkotter, A.; Gauss, J.; Watson, M. D.; Kastler, M.;
Fechtenkotter, C.; Wagner, M.; Mu¨llen, K. J. Am. Chem. Soc. 2004,
126, 11311–11321. (b) Chen, Z.; Stepanenko, V.; Dehm, V.; Prins,
P.; Siebbeles, L. D. A.; Seibt, J.; Marquetand, P.; Engel, V.; Wu¨rthner,
F. Chem.sEur. J. 2007, 13, 436–449.
where η is the viscosity and rs is the molecular dimension.43
Thus, the average sizes of the aggregated species in solution
(37) Shelnutt, J. A.; Song, X. Z.; Ma, J. G.; Jia, S. L.; Jentzen, W.; Medforth,
C. J. Chem. Soc. ReV. 1998, 27, 31–41.
(42) Cohen, Y.; Avram, L.; Frish, L. Angew. Chem., Int. Ed. 2005, 44,
520–554.
(38) Ho¨ger, S.; Bonrad, K.; Mourran, A.; Beginn, U.; Mo¨ller, M. J. Am.
Chem. Soc. 2001, 123, 5651–5659.
(43) Tyrrell, H. J. V.; Harris, K. R. Diffusion in Liquids: A Theoretical
and Experimental Study; Butterworths: London, 1984.
(44) Dobrawa, R.; Lysetska, M.; Ballester, P.; Gru¨ne, M.; Wu¨rthner, F.
Macromolecules 2005, 38, 1315–1325.
(39) Nakamura, K.; Okubo, H.; Yamaguchi, M. Org. Lett. 2001, 3, 1097–
1099.
(40) Martin, R. B. Chem. ReV. 1996, 96, 3043–3064.
(45) Saunders, M.; Hyne, J. B. J. Chem. Phys. 1958, 29, 1319.
9
J. AM. CHEM. SOC. VOL. 130, NO. 36, 2008 12117

A R T I C L E S
Li and Flood
Figure 3. (a) Selected region of the 1H NMR spectra (400 MHz) of T-OTg4 in CD3CN at 25 °C, in which the peaks show concentration-dependent
1
chemical shifts. (b) Concentration dependence of H NMR chemical shifts for the outer protons Hd of T-tBu4, T-tBu2OTg2, T-OTg2tBu2, and T-OTg4 in
CD2Cl2 and of T-OTg4 in CD3COCD3 and CD3CN at 25 °C.
substitutions increased. On the basis of the free energy changes,
the self-association affinity almost doubled with each addition
of a pair of OTg chains, reaching ∆GE ) -3.2 kcal mol-1 (KE
) 230 ( 30 M-1) for T-OTg4. We attribute the aggregation to
an increase in the π-π interactions between macrocyclic faces
that is facilitated by the reduction of steric bulk, leading to the
proposed stacking arrangement. Additionally, increased numbers
of OTg chains on adjacent stacked pairs of triazolophanes are
expected to enhance stacking.33 The extent of aggregation of
T-OTg4 was seen to increase in more polar solvents, consistent
with a solvophobic triazolophane-based core.
coplanar with the triazolophane structure; however, the F-
ion is small enough to sit in one corner of the central cavity,
and the I- anion is too large to penetrate inside the cavity.
On the basis of these models, we expected size-selective
binding between the halides and the triazolophane’s central
cavity to be displayed.
Accurate values of the association constants (Ka) were
determined using standard UV-titration methods at concentra-
tions below 10 µM. The binding isotherms were generated by
recording the modest changes in the UV absorption as a function
of halide concentration (shown for T-tBu2OTg2 in Figure 5a).
On the basis of the confirmation (via Job’s plot) of 1:1 binding
stoichiometry determined previously13 for the T-tBu4 ·Cl-
complex in solution, the data were fitted to a 1:1 binding
isotherm (Figure 5b), providing the calculated Ka values (Table
3). The binding constants are the results of duplicate determina-
tions that were conducted at sufficiently low concentrations to
ensure that the degree of binding was less than 80% at 1:1 molar
ratios of host and guest.46
Halide-Binding Investigations. The spherical F-, Cl-, Br-,
and I- anions were tested for binding to the triazolophanes using
UV titrations, and the structures of the anion complexes were
characterized with the aid of changes in the chemical shifts in
the 1H NMR spectra. To take advantage of their good solubilities
in organic solvents and to minimize possible effects of ion-pair
formation,1 TBA salts were used in the titration experiments.
Ab initio modeling (HF/3-21G*) of the host-guest complexes
formed between T-tBu4 and the halides (Figure 4) revealed three
different binding modes. Both the Cl- and Br- ions lie
An extremely strong binding affinity (Ka ) 1.1 × 107 M-1
)
was observed for Cl- with T-tBu4,47 while the affinity of Br-
for the same receptor (Ka ) 7.5 × 106 M-1) placed a close
second. In line with the molecular modeling results, the too-
small F- and too-large I- anions (Ka ) 2.8 × 105 and 1.7 ×
104 M-1, respectively) did not bind as tightly as the ideally
sized Cl- and Br- anions. As predicted, sequential replacement
of t-butyl by the more strongly electron-donating OTg group
reduced the binding affinity across the series of triazolophanes.
On the basis of the substitution patterns, it was observed that
substitution of OTg onto the N-linked phenylenes as opposed
to the C-linked ones had a larger effect in weakening the binding
affinities toward all of the halides.
1
The H NMR spectra of the halide titrations are consistent
with the picture generated from the binding affinities. All of
1
the H NMR titrations were conducted at ∼1 mM in order to
help suppress the effect of aggregation on chemical-shift
positions while maintaining good signal intensity. Titrations with
(46) Hirose, K. In Analytical Methods in Supramolecular Chemistry;
Schalley, C. A., Ed.; Wiley-VCH: Weinheim, Germany, 2007.
(47) This value is more accurate than the one reported previously in ref
13.
Figure 4. Models (HF/3-21G*) of the structures for halide complexation
with T-tBu4.
9
12118 J. AM. CHEM. SOC. VOL. 130, NO. 36, 2008

Size-Selective, Electronically Tunable C-H· · ·X Binding
A R T I C L E S
Figure 5. (a) Representative UV changes upon titration of triazolophane T-tBu2OTg2 (1.5 µM, CH2Cl2) with TBACl and (b) the fit of the absorption
changes at 265 nm to a 1:1 isotherm.
Table 3. Association Constants (Ka) for Halide Binding with the Triazolophanes (Determined Using UV Spectroscopy) and with Oligomer 11
(Determined Using 1H NMR Spectroscopy) in CH2Cl2 at Room Temperature
Ka(UV) (M-1 a
)
Ka(NMR) (M-1 b
)
halide
T-tBu4
T-tBu2OTg2
T-OTg2tBu2
T-OTg4
11
F-
280 000 ( 30 0000
11 000 000 ( 2 000 000
7 500 000 ( 900 000
17 000 ( 1000
230 000 ( 20 000
5 100 000 ( 400 000
4 200 000 ( 300 000
19 000 ( 2000
150 000 ( 5000
3 700 000 ( 700 000
1 900 000 ( 200 000
5000 ( 200
200 000 ( 20 000
2 900 000 ( 300 000
1 700 000 ( 200 000
4000 ( 400
42 ( 4
6.9 ( 0.3
268 ( 6
210 ( 10
Cl-
Br-
I-
a Errors were obtained from the fits to the isotherms. b Obtained from 1H NMR titrations of 11 with TBA halide salts in CD2Cl2 and based on the
shift of triazole proton Ha. Errors were obtained from the fits to the isotherms.
1
T-OTg2tBu2 (Figure 6) are representative of the features
observed for all of the triazolophanes. The F- anion was seen
to engage almost exclusively with the N-linked phenylenes (Hc)
and the triazoles (Ha) and seemed to ignore the C-linked
phenylenes (Hb). This positional selectivity persisted even in
the case of T-OTg2tBu2, where the F- anion could have become
bound with the C-linked phenylene bearing the less-electron-
donating t-butyl groups, which were found to strengthen overall
anion binding. For this small halide, the triazole and inner
N-linked phenylene resonances retained their singlet splitting
patterns, and both were observed to shift during the titration,
indicating that the F- oscillates between the north and south
time scale as the H NMR experiment, consistent with strong
anion binding.48
In the case of I-, the chemical shifts indicated a different
mode of binding than for the other two sets of halides. Contrary
to the encapsulation behavior observed for both Cl- and Br-,
the triazole protons were shifted to a greater extent than the
phenylene protons, and the N- and C-linked phenylene protons
were all shifted by the same amount. Taken together, these
features suggest that the I- anion is symmetrically docked with
the triazolophanes, that the triazoles are mostly responsible for
binding I-, and that the phenylene protons contribute to
enhancing the complexation efficiency in a manner similar to
that for Cl- and Br-.
1
poles within the cavity faster than the H NMR time scale at
The different association strengths can be rationalized from
the three binding modes. The strengths of ion-dipole interac-
tions are governed by the following relationship:
298 K. These observations are in agreement with the picture
generated by modeling (Figure 4), which shows that the F- ion
is always engaged with two triazole units and just one
phenylene. This picture is consistent with the primary role that
the triazoles serve in binding the F- anion.
q1µ2 cos θ
E )
4πε0εr2
In the case of the Cl- and Br- anions, all of the proton
resonances were shifted upfield by greater (∼1 ppm) and lesser
(∼0.5 ppm) amounts for the inner and outer protons, respec-
tively. These peak shifts and the concerted impact of substitution
on Ka (Table 2) are consistent with halide encapsulation inside
the triazolophane cavity (Figure 4). The chemical shifts upon
complexation of Br- were all greater by ∼20% than those for
Cl-, even though the association constant is less than that for
Cl-. This difference is attributed to the larger size of the halide,
which exerts a steric pressure on the CH hydrogens, rather than
to larger binding strength. In addition, the peaks were observed
to broaden during the addition of 0.2-1.0 equiv of Cl- and
Br-, indicating that the kinetics of complexation are on the same
where q1 is the charge on the anion, µ2 is the dipole moment,
θ is the angle specifying the relative orientation of the anion to
the dipole, r is the distance between the centers of the anion
and the dipole, and ε is the dielectric constant. In an analysis
of the binding modes, the dipoles from all sources are valid for
interpretation. In the context of this relationship and the
measured binding affinities, the magnitudes of these interactions
are consistent with encapsulation for Cl- and Br- ions. For these
two halides, optimal close contacts (small r) and orientations
(θ ≈ 180°) can be achieved with both types of phenylene
(48) Piatek, P.; Lynch, V. M.; Sessler, J. L. J. Am. Chem. Soc. 2004, 126,
16073–16076.
9
J. AM. CHEM. SOC. VOL. 130, NO. 36, 2008 12119

A R T I C L E S
Li and Flood
Figure 6. 1H NMR spectra (aromatic region) of T-tBu2OTg2 in CD2Cl2 at 298 K upon titrational addition of (a) TBAF, (b) TBACl, (c) TBABr, and (d)
TBAI (Ha, triazole; Hb, C-linked phenylene; Hc, N-linked phenylene).
H-bond donors and the triazole-based dipoles. It is possible that
the slightly larger size of the Br- anion (ionic radii: 1.96 Å for
Br- and 1.80 Å for Cl-) accounts for the modest differences in
binding free energy (e0.4 kcal mol-1) indicated by the Ka values
in Table 3. For the two poorly fitting halides, F- appears to
have an advantage over I- by being partially encapsulated
(Figure 4). The smaller F- anion can (i) engage with two triazole
and one N-linked phenylene H-bond donor with close contacts
(it has the smallest possible r of any halide, given its ionic radius
of 1.30 Å) and at ideal geometries (θ ≈ 180°) and (ii) interact
with the five other H-bond donors with less-ideal geometries.
In contrast, while I- can form close van der Waals contacts
with all eight H-bond donors, it is forced to do so over longer
distances (I- ionic radius ) 2.20 Å) and at nonideal geometries
(θ * 180°).
the proton signals could be assigned using the same 2D NMR
techniques employed for the assignment of the triazolophane
spectra. Each proton was then assigned specifically utilizing the
through-space cross peaks seen with the aid of 2D NOESY
experiments.
NMR titration experiments involving 11 and the halides
(shown for TBABr in Figure 7) were performed under the same
conditions used for the triazolophanes. The chemical shifts were
sensitive to the size and shape of the anion. In the case of Cl-,
Br-, and I-, the chemical-shift patterns of the protons expected
to engage in H bonding were shifted downfield by the largest
amounts. The central triazole protons Ha were shifted the most,
although not to the extent shown by any of the triazolophanes.
Interestingly, both the central N-linked phenylene proton (Hc)
and the spacer C-linked phenylene protons (He) were shifted
into the same peak position. For the 11·F- complex, the halide
binding appears to engage with the three rings in the core. This
interpretation is based upon the greater downfield shift of the
“inner” proton Hc on the central phenylene than of the “inner”
protons He on the spacer phenylenes. This selective binding is
consistent with the picture generated for binding of F- to the
triazolophanes. For all of the halide complexes, the protons Hh
and Hi on the phenyl endgroups were shifted upfield. These
facts indicate that the acyclic molecule 11 binds halides in a
manner similar to that of the triazolophanes and that the final
complex results in a folded structure consistent with that found
Convergent and Preorganized Hydrogen Bonding: Control
Experiments. An acyclic analogue of T-tBu4 was synthesized
and tested for anion binding in order to study the importance
of binding-site preorganization. Oligomer 11 (Figure 7), pre-
pared from 10a and azidobenzene (see the Supporting Informa-
tion), has four triazole units, three t-butyl-substituted phenylene
groups, and two terminal phenyl rings. This oligomer can be
considered as a ring-opened foldamer23 form of macrocycle
T-tBu4 having the same types and almost the same number of
H-bond donors. Even though the molecule produced a more
1
complex H NMR spectrum because of its lower symmetry,
9
12120 J. AM. CHEM. SOC. VOL. 130, NO. 36, 2008

Size-Selective, Electronically Tunable C-H· · ·X Binding
A R T I C L E S
well. Consequently, the induced hydrogen bonds of the phe-
nylene units (Hc/He · · ·anion), which prefer to shift downfield
and merge together, suggest that they are in very similar
chemical environments upon anion complexation. The upfield
shifts of the Hh and Hi protons can be ascribed to the π-π
stacking interaction between the two terminal phenyl rings that
takes place as 11 wraps around the anion. As a result of this
conformational change, the triazole protons (Ha and Hb) and
the protons para to the t-butyl groups are projected inward, with
the two terminal phenyl rings overlapping to generate a folded
structure that resembles the conformation of the triazolophanes.
The binding constants of 11 with these halides (Table 3) were
1
obtained from an analysis of the H NMR titration data using
a 1:1 binding model (see the Supporting Information). This
acyclic reference compound showed much weaker binding to
all of the anions tested than did the triazolophanes. The weaker
affinities for 11 confirm that the rigid display of functional
groups in the preorganized triazolophane receptors makes a
significant contribution to the binding energy. Compared to that
for the macrocyclic forms, however, the size selectivity in 11
shifted in favor of the larger Br- and I- halides over Cl-.
Consequently, where the macrocyclic structure enforces close
H· · ·anion contacts, the helical oligomer 11 likely folds up to
define a slightly expanded cavity. The related work by Craig
and co-workers23a revealed that larger binding strengths [Ka(Cl-)
) 1.7 × 104 M-1] are obtained with the ester-substituted
phenylenes. The ester functionality is likely to exert a stronger
polarizing effect on the CH H-bonds by virtue of its electron-
withdrawing character. Moreover, given the propensity for the
OTg groups to facilitate aggregation in the triazolophanes, the
ester-linked tetraethylene glycol chains might favor a folded
structure, particularly in the more-polar solvent in which the
Ka values were determined (CD3COCD3). On the basis of the
much-reduced binding affinities for the t-butyl-substituted
oligomer 11 [Ka(Cl-) ) 7 M-1 in CD2Cl2], NMR experiments
were conducted to corroborate that the folded structure is present
upon anion complexation.
Figure 7. 1H NMR spectra (aromatic region) of 11 in CD2Cl2 at 298 K
upon titrational addition of TBABr .
in studies23 conducted on a similar oligomeric structure bearing
ester-linked tetraethylene glycol substituents on the central and
terminal phenyl units.
We therefore concur23 that the halides form primary hydrogen
bonds with the triazole protons, facilitating the formation of
the weaker hydrogen bonds with inner phenylene protons Hc
and He and ultimately driving a folded structure upon halide
binding. The small F- anion binds with only part of the
molecule, while for Cl- and particularly for the larger Br- and
I- anions, the oligomer 11 can wrap around the anion reasonably
Figure 8. 2D 1H-1H NOESY spectra of 11 in CD2Cl2 at 298 K (a) before and (b) after addition of TBACl.
J. AM. CHEM. SOC. VOL. 130, NO. 36, 2008 12121
9

A R T I C L E S
Li and Flood
The folded conformation of 11·Cl- was verified on the basis
of cross peaks observed in 2D NOESY experiments. The
NOESY spectrum of the uncomplexed oligomer 11 (Figure 8a)
shows connectivities from both sets of triazole protons to the
phenylene-ring protons that can be grouped into two sets, the
first linking triazole proton Ha to phenylene protons Hc, Hd,
He, and Hf and the second connecting triazole proton Hb to
phenylene protons He, Hf ′, and Hg. When TBACl was added
(Figure 8b), the NOE cross peaks connecting Ha to Hf and Hb
to Hf ′ originally seen in the spectrum of uncomplexed 11
disappeared. The associated changes in through-space proximity
arise from the conformation changes in 11 upon halide binding
and indicate that the interproton distances Ha · · ·Hf and Hb · · ·Hf ′
have become larger on average. These data are similar to those
observed for the ester-substituted foldamer23 and in this case
support the change in conformation into a folded structure upon
anion complexation.
∼10-20% of the receptor’s underlying anion affinity (>7 kcal
mol-1). Each electron-donating group weakens the anion-
binding affinity, but this effect was greatest when the substituent
was on the phenylene group linked to the triazoles through the
nitrogens. These results suggest the following order of CH
H-bond donor strengths: triazole > N-linked phenylene >
C-linked phenylene. Consistent with this ranking, the F- anion
was found to bind in a tridentate manner with two flanking
triazoles and a central N-linked phenylene. The Cl- and Br-
anions were encapsulated inside the cavity, allowing ideal
geometries for ion-dipole stabilization. The I- ion, however,
is proposed to dock with an open face of the central cavity with
much-reduced affinity. An analogous open-chain form folds up
around the anion templates with much-reduced binding strengths,
emphasizing the extreme importance of preorganization. The
triazolophanes were also found to aggregate together with
moderate strengths, and the propensity increased with an
increase in the number of triethylene glycol chains present and
with increasing solvent polarity. Finally, the triazolophanes
appear to be well-suited for fundamental studies of CH
H-bonding, with the present study clearly showing the impor-
tance of aromatic CH H-bond donors in binding anions when
these donors are preorganized into a shape-persistent macro-
cyclic structure.
Conclusions
A series of substituted [34]triazolophanes have been prepared
in good yields from simple building blocks, demonstrating the
facile modularity of the synthetic approach. Size-selective halide
recognition was observed to distinguish Cl- or Br- anions from
the too-small F- anion by 1.5 orders of magnitude and the too-
large I- anion by almost 3 orders of magnitude. A remarkably
large binding strength with Cl- ion [Ka ) (1.1 ( 0.2) × 107
M-1, equivalent to ∆Ga ) -9.6 kcal mol-1] was observed with
the use of four t-butyl substituents on the triazolophane in
nonpolar solvents. The majority of the binding arises from the
preorganized structure, in which the four triazoles are respon-
sible for focusing their polarized CH H-bonds and the positive
ends of their 5 D dipoles into the central cavity. Consistent with
this idea, the CH H-bond donor strength of the intervening
phenylene linkers can be utilized to tune the receptor’s binding
strength by an amount (1 kcal mol-1) that accounts for
Acknowledgment. We thank David J. Wild and Rajashi Guha
for help with PubChem and John Tomaszewski and Frank Gao for
help with NMR spectroscopy.
Supporting Information Available: Synthetic procedures,
compound characterization, NMR spectroscopy, UV titrations,
binding isotherms, NMR titrations, and aggregation isotherms.
This material is available free of charge via the Internet at http://
pubs.acs.org.
JA803341Y
9
12122 J. AM. CHEM. SOC. VOL. 130, NO. 36, 2008