Two levels of conformational pre-organization consolidate strong CH hydrogen bonds in chloride-triazolophane complexes

Article abstract of DOI:10.1039/c1cc10428d

Structural rigidity is verified as a pre-organizational factor that acts together with the macrocyclic effect such that synthesis helps in paying the cost of bringing together electropositive CH donors ready for H-bonding with chloride.

Full text of DOI:10.1039/c1cc10428d

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COMMUNICATION
Two levels of conformational pre-organization consolidate strong
CH hydrogen bonds in chloride–triazolophane complexeswz
Yuran Hua, Raghunath O. Ramabhadran, Jonathan A. Karty, Krishnan Raghavachari and
Amar H. Flood*
Received 21st January 2011, Accepted 3rd April 2011
DOI: 10.1039/c1cc10428d
Structural rigidity is verified as a pre-organizational factor that
acts together with the macrocyclic effect such that synthesis
helps in paying the cost of bringing together electropositive CH
donors ready for H-bonding with chloride.
Based on this description, the key question emerges: Does
rigidity afford additional benefits for the macrocycle? This idea
has never before been tested experimentally with shape-
persistent macrocycles.2,10–12 We recognized that the idea
could be investigated in a straightforward manner because it
is easier to remove rigidity from 1 than to add it, which is the
task undertaken in most other cases.1,14 Triazolophane 2
(Fig. 1) was designed to make use of propylene linkers (blue)
to reduce the rigidity generating a ‘‘partially’’1 pre-organized
macrocycle while retaining a similar size (24-membered) and
the semi-planar east–west wings as in 1. Furthermore,
replacing phenylene with methylene CH donors is believed
to reduce the H-bond strength by half.7b,15 Our estimates for
the sum of the individual CHꢂ ꢂ ꢂClꢀ strengths16,17 provide ideal
Clꢀ-binding free energies in the optimal configuration for
eight H-bonds in 1 and 2 of DGideal = ꢀ48 and ꢀ44 kJ molꢀ1
(Table 1), respectively. Calculations on the conformations of
18 and 2 (vide infra)16 show them to have similarly-small
configurational (entropy) changes2c,4,18 upon Clꢀ binding.
However, these conformations are differently organized such
that we expect there will be a drop in Clꢀ binding for 2 in order
to prepare the correct conformation when electropositive
hydrogens are brought together for binding. To provide a
measure of this effect, we calculate electrostatic potentials
Pre-organization is a foundational concept in supramolecular
chemistry where enhanced binding arises from optimal
conformational preparation and low solvation of the host.1
The importance of a host’s conformational pre-organization
was exemplified by comparing rigid spherands to less organized
acyclic ether hosts for cation binding.1 Demonstrations of
increasing pre-organization in the field of anion binding are
rare. On the basis of their structure, triazolophanes2 are a class
of anion-binding macrocycles that enable such an examination.
While the specific enthalpy and entropy factors resist
generalization,3 they can be described for each specific system.
We do this here, and in response to a recent proposal by
Craig,4 we focus on the enthalpic benefit of pre-organizing
electropositive H-bond donors.
Triazolophanes display large Clꢀ binding strengths from
non-classical5 CH H-bond donors: the affinity is as high as
Ka = 5 ꢁ 106 Mꢀ1 (CH2Cl2) with tetraphenylene triazolophane,
1 (Fig. 1). The origins of this affinity are still being verified.
Chloride stabilization is provided by CH H-bonds6,7 from
the 1,2,3-triazole units2,4,8,9 and the weaker phenylene CH
donors.8 Yet this is only half the story. Unlike most neutral
receptors, these macrocycles, as well as those of Hamilton,10
Jeong11a and Maeda,12 are rigid. Consequently, these are all
thought to be ‘‘highly’’1 pre-organized such that the H-bond
donors are already directed into the center of the cavity.
Achieving this structure, however, forces the electropositive
triazole hydrogens into contact13 with each other—an enthalpic
cost that is largely paid during the synthesis of the rigid
macrocycle 1.
Department of Chemistry, Indiana University, 800 East Kirkwood
Avenue, Bloomington, IN 47405, USA. E-mail: aflood@indiana.edu;
Fax: +1 (812)855-8300; Tel: +1 (812)856-3642
w This article is part of a ChemComm ‘Supramolecular Chemistry’
web-based themed issue marking the International Year of Chemistry
2011.
z Electronic supplementary information (ESI) available: Syntheses,
spectra, titration data, and data modeling. See DOI: 10.1039/
c1cc10428d
Fig. 1 Different levels of pre-organization in rigid macrocycle 1,
flexible macrocycle 2 and oligomeric receptor 3.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 5979–5981 5979

Table 1 Observed, ideal17 and computed25 energy values (kJ molꢀ1 a
)
R =
1
2
3
DGa R + Clꢀ = RꢂClꢀ
DGideal R* + Clꢀ = RꢂClꢀ
DEprep R# = R#*
ꢀ38 ꢃ 2
ꢀ48
ꢀ23 ꢃ 2
ꢀ44
ꢀ11 ꢃ 1
ꢀ52
+10
+24
+33
a *
#
= prepared structure, = model of receptor.
(ESP, HF/3-21G, SPARTAN)16 as a function of different
conformations and correlate higher positive ESP values to
the build-up of repulsion.
The idea of pre-organization has been visited with other
shape-persistent receptors10,11b,12 as the macrocyclic effect.19
Triazolophanes are no exception, as was shown using the
‘‘poorly’’ pre-organized oligomer 3 (Fig. 1), which folds
around Clꢀ with much reduced affinity2b even though its
ideal16 binding energy using nine H-bond donors17 is
DGideal = ꢀ52 kJ molꢀ1. Consequently, we expect its low-
energy conformations to have smaller ESPs than 2, which
would generate a larger electrostatic penalty upon preparation
of the folded form, explaining some of the drop in Clꢀ
binding. Additional entropy adjustments will also arise from
freezing out the conformations18 and rotations.
Solvation is also known to play a role.4 Small differences in
solvation upon Clꢀ binding across the complexes is expected.20
There will also be a small favorable effect of pre-organization
in 1 for excluding some but not all solvent, however, this effect
is assumed to be small for the uncharged receptors.
Fig. 2 1H NMR titration of 2 (500 mM) upon addition of 0–20 eq. of
TBA+ꢂClꢀ in CD2Cl2 (298 K).
the strong competition between semi-rigid triazolophane 2 and
the TBA+ cation for Clꢀ. Consistent with Fuoss’ Law,23 the
ion-pairing of 2ꢂClꢀ with the TBA+ countercation (eqn (3),
DGipc = ꢀ21 ꢃ 3 kJ molꢀ1) was weaker than between Clꢀ and
TBA+ (ꢀ28 kJ molꢀ1).
The prior titration data on oligomer 32b was re-evaluated to
accommodate ion pairing. A reliable simulation of the NMR
peak positions16 was generated when considering the direct
formation of ion-pair complex 3ꢂClꢀꢂTBA+ (eqn (4)). Based
on reasonable assumptions,16 the binding affinity for 3ꢂClꢀ
was estimated as DGa = 11 ꢃ 1 kJ molꢀ1
.
3 + TBA+ + Clꢀ = 3ꢂClꢀꢂTBA+ bipc = Ka ꢁ Kipc (4)
This datum completes the series (Table 1). Differences between
17
DGa and DGideal define the preparation free energies.24
By examining differences between oligomeric 3 and flexible
2, we will focus on identifying any benefit arising from
directing the electropositive triazole hydrogens toward the
center region of the cavity (macrocyclic effect) and when
comparing 2 with 1, to identify the benefit of rigidly forcing
them close together (conformational pre-organization).
The synthesis of 2 is described in the supporting informa-
tion. Titration of tetrabutylammonium chloride (TBA+ꢂClꢀ)
into a solution of 2 (CH2Cl2) generated signals for the anion-
complex (2ꢂClꢀ) using electrospray ionization mass
spectrometry2c,16 and for the complexed ion-pair (2ꢂClꢀꢂTBA+)
using diffusion NMR.2c The following three equilibria co-exist
together in solution:
Calculations on 1–3 and their complexes provide insights
into the nature of the pre-organization by considering their
conformations, computed preparation energies (DEprep, Table 1)25
and electropositive character. The results on an analog of 1
(1#, Fig. 3)8 can be compared to the computational results on
an analog of 2 (2#, Fig. 3) and of 3 (3#),16 where all t-butyls are
replaced with hydrogens. In 1#, the empty triazolophane
shows8 (Fig. 3) the electropositive hydrogens (blue) barely
directed out of the receptor’s plane with average nonbonded
Hꢂ ꢂ ꢂH distances of 2.30 A and an ESP maximum situated on
the triazole hydrogens of 287 kJ molꢀ1 (= 287 ev for ‘‘ESP
value’’). Upon Clꢀ binding, the structure planarizes with
dHꢂ ꢂ ꢂH decreasing by 0.14 A to 2.16 A. By examining the
structure with the Clꢀ removed, 1#*, an increase in the ESP
to 327 ev (more blue) was observed. Presumably this increase
is reflected in the computed energy penalty to prepare the
2 + Clꢀ = 2ꢂClꢀ DGa
(1)
(2)
(3)
TBA+ + Clꢀ = TBA+ꢂClꢀ DGip
TBA+ + 2ꢂClꢀ = 2ꢂClꢀꢂTBA+ DGipc
perfectly planar structure 1#* of DEprep = 10 kJ molꢀ1 25
.
NMR titration of 2 with TBA+ꢂClꢀ (Fig. 2) suggests weak
binding on account of the poor saturation after 20 equivalents.
All the inward facing protons shift downfield with large
peak migrations from the triazole Ha (Dd = 2.3 ppm) and
phenylene Hb (Dd = 1.0 ppm). The peak position of propylene
Hd was barely affected. These shifts indicate the dominance of
C–Hꢂ ꢂ ꢂClꢀ H-bonds on the peak positions.21 The positions of
protons a–c, and the a-CH2 proton on TBA+ were included in
the estimation of the binding constants.16
Using the complete set of binding equilibria, the 1 : 1
binding energy for 2ꢂClꢀ was determined16 to be DGa
Fig. 3 Optimized structures (B3LYP/6-31+G(d,p)) of 1#, 2# and 2#ꢂ
Clꢀ and the prepared structures 1#* and 2#*; ESP (isovalence = 0.002:
ꢀ230 (red) to 330 (blue) ev.
=
ꢀ23 ꢃ 2 kJ molꢀ1. This value is smaller than the ion pairing
between Clꢀ and TBA+ (DGip = ꢀ28 kJ molꢀ1),22 indicating
c
5980 Chem. Commun., 2011, 47, 5979–5981
This journal is The Royal Society of Chemistry 2011

Geometry optimization (B3LYP/6-31+G(d,p)) shows that
the lowest energy conformation of the empty macrocycle 2#
(Fig. 3) is different from the one minimized for the complex
2#ꢂClꢀ. The key difference is the two semi-planar east–west
Notes and references
1 D. J. Cram, Angew. Chem., Int. Ed. Engl., 1986, 25, 1039–1057.
2 (a) Y. Li and A. H. Flood, Angew. Chem., Int. Ed., 2008, 47,
2649–2652; (b) Y. Li and A. H. Flood, J. Am. Chem. Soc., 2008,
130, 12111–12122; (c) Y. Hua, R. O. Ramabhadran, E. O. Uduehi,
J. A. Karty, K. Raghavachari and A. H. Flood, Chem.–Eur. J.,
2011, 17, 312–321.
3 R. M. Izatt, J. S. Bradshaw, S. A. Neilsen, J. D. Lamb and
J. J. Christensen, Chem. Rev., 1985, 85, 271–339.
4 H. Juwarker, J. M. Lenhardt, J. C. Castillo, E. Zhao,
S. Krishnamurthy, R. Jamiolkowski, K.-H. Kim and S. L. Craig,
J. Org. Chem., 2009, 74, 8924–8934.
5 G. R. Desiraju and T. Steiner, The weak hydrogen bond in structural
chemistry and biology, Oxford University Press, Oxford, 1999.
6 (a) D. W. Yoon, D. E. Gross, V. M. Lynch, J. L. Sessler, B. P. Hay
and C. H. Lee, Angew. Chem., Int. Ed., 2008, 47, 5038–5042;
(b) O. B. Berryman, A. C. Sather, B. P. Hay, J. S. Meisner and
D. W. Johnson, J. Am. Chem. Soc., 2008, 130, 10895–10897.
7 (a) V. S. Bryantsev and B. P. Hay, J. Am. Chem. Soc., 2005, 127,
8282–8283; (b) L. Pedzisa and B. P. Hay, J. Org. Chem., 2009, 74,
2554–2560.
wings in 2# are arranged in a divergent manner (average dHꢂꢂꢂH
=
2.53 A, ESP = 253 ev), whereas in 2#ꢂClꢀ, they re-arrange to
converge the CH H-bonds onto the Clꢀ ion. The average
dHꢂ ꢂ ꢂH = 2.27 A reduces by 0.26 A, twice as much as 1#*
,
indicative of differences in rigidity. When the Clꢀ is removed
from the structure of the complex, the ESP (296 ev)
has increased and the preparation energy of 2#* (DEprep
=
24 kJ molꢀ1) comes close to the difference between DGa and
DGideal (Table 1) of 21 kJ molꢀ1. Consistent with predictions,
the ESP of 2# starts out smaller than 1#—the empty flexible
macrocycle relaxes its structure to diverge the electropositive
hydrogens. However, once 2#* is prepared, its ESP increases
(more blue than 2#) because the penalty of bringing its
electropositive hydrogens together is paid by Clꢀ binding.
In the case of oligomer 3#, 44 conformations were found
within a span of 18 kJ molꢀ1 (AM1).16 In the six lowest-energy
ones (o1.5 kT), and just as for 1# and 2#, the triazole protons
are directed away from each other. The average ESP for the six
conformations of 3# (236 ev) is even smaller than 2# (253 ev),
which is consistent with expectations. However, the ESP of the
prepared receptor 3#* (302 ev) is very close to 2#* (296 ev).
Correspondingly, the computed preparation energy16
DEprep = 33 kJ molꢀ1 is larger than that of 2#* (24 kJ molꢀ1).
8 I. Bandyopadhyay, K. Raghavachari and A. H. Flood,
ChemPhysChem, 2009, 10, 2535–2540.
9 (a) H. Juwarker, J. M. Lenhardt, D. M. Pham and S. L. Craig,
Angew. Chem., Int. Ed., 2008, 47, 3740–3743; (b) S. Hecht and
R. M. Meudtner, Angew. Chem., Int. Ed., 2008, 47, 4926–4930;
(c) Y. Wang, F. Li, Y. M. Han, F. Y. Wang and H. Jiang,
Chem.–Eur. J., 2009, 37, 9424–9433.
10 K. Choi and A. D. Hamilton, J. Am. Chem. Soc., 2003, 125,
10241–10249.
11 (a) K.-J. Chang, D. Moon, M. S. Lah and K.-S. Jeong, Angew. Chem.,
Int. Ed., 2005, 44, 7926–7929; (b) K.-J. Chang, B.-N. Kang, M.-H. Lee
and K.-S. Jeong, J. Am. Chem. Soc., 2005, 127, 12214–12215.
12 Y. Haketa and H. Maeda, Chem.–Eur. J., 2011, 17, 1485–1492.
13 The steric repulsions between hydrogens in all the structures and
complexes considered here are believed to be negligible.
14 E. Ghidini, F. Ugozzoli, R. Ungaro, S. Harkema, A. Abu El-Fadl
and D. N. Reinhoudt, J. Am. Chem. Soc., 1990, 112, 6979–6985.
15 A similar macrocycle to 1 with one propylene replaced by a
phenylene was used2c to study this difference in H-bonding.
16 See Supporting Information.
However, it falls short of the amount needed (DGa ꢀ DGideal
=
41 kJ molꢀ1) to take full advantage of the H-bond donors,17
suggesting that factors (solvation and entropy) other than
pre-organization of the electropositive hydrogens are playing
a role in weakening the stability of 3ꢂClꢀ.
The structures of 1#, 2# and 3# show that the receptors try to
achieve relaxed conformations by diverging the electropositive
hydrogens, as suggested by Craig.4 Forming a macrocycle
confers a benefit24 of B20 kJ molꢀ1 for which some of this
will arise from bringing the hydrogens together. The rigid
constraints in 1# prevent it from relaxing as much electro-
positive character as 2# resulting in a benefit of B11 kJ molꢀ1
to the preparation energy.25 This line of reasoning suggests
that rigidity can allow a jump in the stability of the Clꢀ
complexes that a partially pre-organized macrocycle alone
cannot furnish. It is also the feature that confers the halide
selectivity for Clꢀ and Brꢀ over Fꢀ and Iꢀ.2b
17 Triazole, N-linked phenylene, C-linked phenylene and propylene
CHꢂ ꢂ ꢂClꢀ H-bonds strengths (B8.9, 3.6, 2.6 and 1.3 kJ molꢀ1
,
respectively)16 as estimated from within the structure of 1# (Fig. 3).
18 Limits to the entropy adjustment; e.g., 2 and 20 degenerate
conformations freezing into one cost between 2 and 8 kJ molꢀ1
.
19 D. K. Cabbines and D. W. Margerum, J. Am. Chem. Soc., 1969,
91, 6540–6541.
20 Assuming Clꢀ has a coordination number of six, the enthalpic
penalty of removing Bfour solvent molecules prior to binding is
paid by greater translational entropy. This model assumes Btwo
solvents will bind with the Clꢀ above and below the complex. The
largest benefit from solvation is expected from 1. Structures of
the complexes16 suggest there are small increases in solvent-
accessibility going from 1 to 3: opening solvent-accessibility on
one side of 2ꢂClꢀ is offset by reduction on the other; in 3ꢂClꢀ,
receptor wrapping has a similar opening–closing compensation.
21 Any peak shifts reflect changes in conformations as well as the Clꢀ.
22 S. Alunni, A. Pero and G. Reichenbach, J. Chem. Soc., Perkin
Trans. 2, 1998, 1747–1750.
Rigidity is identified as a pre-organizational factor in tetra-
phenylene triazolophanes that acts with the macrocyclic effect
to prevent the relaxation of electropositive hydrogens such
that they remain pre-organized in a complementary manner
for forming CHꢂ ꢂ ꢂClꢀ H-bonds. While the analysis presented
here gives credence to electrostatics, a full deconvolution will
require evaluations of solvation and an estimate of the relative
weights of each contributing factor.
23 R. M. Fuoss, J. Am. Chem. Soc., 1958, 80, 5059–5061.
24 Differences between preparation free energies16 indicate that the
benefit of the macrocyclic effect when generating partially pre-
organized 2 from 3 is 20 kJ molꢀ1, and rigidifying the macrocycle
to be highly pre-organized in 1 provides another 11 kJ molꢀ1
.
25 DEprep is defined as the computed energy difference between the
structure of the complex with the Clꢀ removed and the optimized
structure of the free receptor.
We thank the NSF (CHE-0844441 and CHE-0911454) for
funding and the referees for input.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 5979–5981 5981