Dipole-promoted and size-dependent cooperativity between pyridyl-containing triazolophanes and halides leads to persistent sandwich complexes with iodide

Full text of DOI:10.1021/ja8077329

Published on Web 12/03/2008
Dipole-Promoted and Size-Dependent Cooperativity between
Pyridyl-Containing Triazolophanes and Halides Leads to Persistent Sandwich
Complexes with Iodide
Yongjun Li,† Maren Pink, Jonathan A. Karty, and Amar H. Flood*
Department of Chemistry, Indiana UniVersity, Bloomington, 800 East Kirkwood AVenue, Bloomington, Indiana 47405
Received September 30, 2008; E-mail: aflood@indiana.edu
Encapsulation of a guest by the cooperative dimerization of a
host to form “sandwich” complexes is an effective means to increase
dimensionality1 for optimizing complex stability. Lessons provided
by crown ether binding with alkali metals2 indicate the importance
of a size difference between an ion and the cavity of the receptor
for forming sandwiches. This mismatch provides a means to
decrease the stability of the 1:1 complex (K1) relative to the 2:1
(K2). The relative magnitudes of K1 and K2 thereby provide insights
into cooperative effects.3 Only a few 2:1 sandwich complexes are
known for anionic guests. Here, the 1:1 and 2:1 complexes are
observed either depending upon the stoichiometry in solution4 or
solely as 2:1 complexes in the solid state.5 Only an “anti-crown”
Figure 2. (a) 1H NMR spectra of 1 (pyridyl region) as a function of
mercuracarborand6 shows only 2:1 sandwiches in solution with
concentration (CD2Cl2, 298 K, 400 MHz) and (b) calculated speciation
curves for self-association up to the hexamer 16 with KE ) 255 M-1
halides; however, the binding constants were not characterized.
Cooperativity has been quantified4 in two instances to result from
interactions between receptors. Here we present findings on a new
class of triazolophane7 incorporating pyridyl ring systems (Figure
1) that forms strong and persistent 2:1 complexes with the large I-
ion in solution. Quantitative binding studies with F-, Cl-, and Br-
show both 2:1 and 1:1 complexes implicating the importance of
the electronic character of the cavity in modulating cooperativity.
hypothesize that the cumulative effect of these features will
destabilize the 1:1 complex in favor of the 2:1 sandwich.
The triazolophanes were prepared following prior methods7 of
symmetric chain extension followed by macrocyclization under
conditions of high dilution and Cu(I) catalysis. The electrospray
ionization mass spectrometry (ESI-MS) and 1H NMR spectra
confirm11 the identity of the triazolophane.
Triazolophane 2 was only soluble as the tetrabutylammonium
(TBA) salt: [22•I]TBA. Crystals grown for X-ray analysis diffract
weakly. A partial solution11 shows (a) formation of the 2:1 sandwich
with the I- ion located between both triazolophanes, (b) the
triazolophanes within π stacking distance (3.4 Å), and (c) that the
angle of rotation (θ) between the two triazolophanes is ∼56°.
The triazolophane 1 was examined in dichloromethane for its
propensity to self-associate using both 1H NMR (Figure 2) and UV
studies.11 The aromatic protons shift upfield with concentration
(0.4-90 mM) indicating π-stacking and leading to the self-
association constant,11 KE ) 255 ( 70 M-1. Consistently,7b
continual changes in the diffusion coefficient11 are observed from
2 to 100 mM. Modeling12 of the equilibria shows that with
increasing concentration (Figure 2b), the amount of monomer
decreases and the dimer shows a maximum in its population at ∼3
mM, thereafter, both species are replaced by higher order species.
Figure 1. Representations of pyridyl-containing triazolophanes 1 and 2,
and the electrostatic potential surface of a model of 1 (blue sections represent
regions of positive electrostatic character).
Prior studies on tetraphenylene-based triazolophanes7,8 show size-
dependent 1:1 binding with halides (Cl- > Br- > F- . I-), using
only CH · · ·X- hydrogen bonding,9 and a propensity for self-
association. Molecular modeling indicated the I- ion was not fully
encapsulated. This tendency could lead2 to dimerization-induced
binding of iodide ions, yet the 2:1 complexes were not observed.
To elaborate on this idea, pyridyl ring systems were considered as
a replacement for the phenylenes. Pyridines have been used
previously8b,10 to alter the electronic character and size of binding
sites. Consequently, compounds 1 and 2 were designed with pyridyl
rings replacing the C-linked phenylenes in the west and east
directions. Modeling (HF/3-21G) confirms the predictions: Pyridyls
generate negative electrostatic potentials inside the cavity (Figure
1) and the cavity becomes oval (the vertical axis gets smaller by
∼0.3 Å and the horizontal axis increases by >0.2 Å). We
1
The splitting pattern in the pyridyl region of the H NMR spectra
(Figure 2a) agrees with this picture. At 0.41 mM, the pyridyl Hd
and Hf protons are observed to form an A2X spin system
corresponding to the monomer 1. This pattern transforms into an
ABC spin system at 2.5 mM, which can arise when the two Hd
protons are no longer equivalent as expected (inset, Figure 2b) from
a rotated (0°< θ < 90°), π-stacked pair of triazolophanes, 12. A
doublet of doublets (Hf) sits upfield from the partially overlapping
doublets of the inequivalent Hd and Hd′ protons. At 4.9 mM, a broad
singlet replaces the ABC pattern indicating a shift to rapidly
equilibrating higher-order aggregates. The UV spectra of 1 (2 µM-1
mM) show a decrease in the normalized intensities consistent with
self-association.7b We attribute the rotated configuration in 12 to
† Present address: CAS Key Laboratory of Organic Solids, Institute of Chemistry,
CAS, Beijing, 10080, P. R. China.
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C O M M U N I C A T I O N S
cooperativity, as observed. These cooperative effects were verified
graphically utilizing linear Scatchard plots.11,15
The 2:1 complex 12 ·I- is persistent in solution. To estimate the
stepwise binding constants, speciation curves11 were generated12
for K1 values while keeping ꢀ2 constant. The NMR concentration
of 2 mM was used to provide the greatest opportunity of observing
the 1:1 complex. This approach generates upper and lower limits:
K1 < 3200 and K2 > 32 000 000 M-1. The former concurs with
the K1 value (5000 M-1
) for the related tetraphenylene
triazolophane.7b
Solution structures of 1 with halides were characterized (Figure
4) by H NMR spectroscopy (CD2Cl2, 400 MHz). While different
1
Figure 3. (a) UV binding curves for 1 (20 µM) with halides (CH2Cl2, 298
K) and (b) the speciation curves calculated12 from K1 and K2 (Table 1) for
Cl- and Br- at 5 mM.
chemical shift behaviors are observed for the various halides, each
follows the calculated11 speciation curves ([1] ) 5 mM). Upfield
and downfield shifts are attributed to the relative importance of
π-stacking and halide binding, respectively. In the simplest case,
titration of 1 with TBAI (Figure 4a) displays shifts in all positions
up to the addition of 0.5 equiv consistent with 2:1 stiochiometry,
12 ·I-, as confirmed by a Job’s Plot.11 The stability of the sandwich
complex is maintained in the presence of 150 equiv of I-. The inner
triazole (Ha) and phenylene (Hc) CH protons both shift downfield
by ∼0.2 ppm indicating the dominance of I- binding on their
positions.7b The outer protons on the pyridyl rings (Hd and Hf) shift
modestly downfield while the phenylene He moves slightly upfield,
showing the importance of π-stacking. Diffusion NMR is consistent
with sandwich formation. Addition of 0.5 equiv of I- steps the
diffusion coefficient from 3.5 to 3.4 × 10-10 m2 cm-1 where it
stays up to 3 equiv.
electrostatic complementarity between the opposite dipoles on the
pyridines (-2.4 D) and the triazoles (+5.0 D) of the triazolophane
dimer pair.
Halide binding was investigated using UV titration (Figure 3a).
Upon addition of F-, Cl-, and Br- to 1 (20 µM) the absorbance
decreases to a minimum at 0.5 equiv as a consequence of the
π-stacked structure in the 2:1 complex. The absorbance then
increases with the addition of more halide leading to the 1:1
complex. For I-, the peak intensity decreases continuously during
the titration. When repeated at 1 µM,11 addition of F-, Cl-, and
Br- appears to proceed directly to the 1:1 complex while only I-
forms the 2:1 sandwich.
Table 1. Binding Energies (kcal mol-1, (10%) between 1 (20 µM)
and the TBA Halides in CH2Cl2 Determined by
Equilibrium-Restricted Factor Analysis of UV Titration Data
∆G1 (K1/M-1
)
∆G2 (K2/M-1
)
∆G (ꢀ2/M-2
)
F-
-7.4 (275 000)
-8.5(1 600 000)
-7.5 (315 000)
-7.6(380 000)
-7.2(190 000)
-7.9(580 000)
Cl-
Br-
I-
-14.9(8.6×1010)
Quantitative analysis of the UV titration data was conducted
using an equilibrium-restricted factor analysis13 of the entire
wavelength range11 to characterize the binding constants (Table
1). The models used the stepwise formation equilibria
1 + X- ) 1·X-
K1
K2
Figure 4. 1H NMR spectra showing the titration of 1 (5 mM, CD2Cl2, 400
MHz, 298 K) with (a) I- (inset, pyridyl region) and (b) Br- (pyridyl region).
1·X- + 1 ) 12·X-
or the direct formation of the sandwich complex
21 + X- ) 12·X-
ꢀ2 ) K1 × K2
The solution structure of 12 ·I- is consistent with dimer 12 and
the preliminary crystal structure of [22 ·I]TBA. An ABC spin system
for the pyridyl protons (inset, Figure 4a) indicates two rotated face-
to-face triazolophanes. In support of this geometry, a 1H-1H
ROSEY experiment shows through-space cross peaks from (a) the
phenylene He and (b) both the R- and ꢀ-methylene protons on the
OTg substituent to the pyridyl Hd and Hd′ protons. In the parent
triazolophane, the distances are too large (>6.4 Å) to support an
NOE. These observations indicate an average solution structure with
a centrally located halide.
The TBACl and TBABr salts behave the same as TBAI up to
∼0.5 equiv (e.g., Br-, Figure 4b). Further additions indicate the
shift from 2:1 to 1:1 complexes with the ABC spin system becoming
replaced by the A2X system. The relative intensities of these two
spin patterns signify the population ratio between the 2:1 and 1:1
species. The point where the A2X system dominates occurs at 2.0
equiv for the Cl-,11 whereas for the Br- it is as late as 15 equiv,
perfectly consistent with the differences in the speciation curves
(Figure 3b, dashed lines) between these two halides.
For the I- ion, the best fit was obtained from the direct formation
of the 2:1 dimer (ꢀ2) at both concentrations. At the higher
concentration, the titration data for F-, Cl-, and Br- are best fit
with the stepwise equilibria (K1 and K2): The data obtained from
the 20 µM titration contains reasonable proportions of all three
absorbers, 1, 12 ·X- and 1·X-, and is under moderate binding
conditions,14 therefore, it is more accurate than fitting the data at
either lower (1 µM) or higher (5 mM, NMR) concentrations. The
accuracy of these models was confirmed by inspecting the speciation
curves calculated11 from the K1, K2, and ꢀ2 values. At 1 µM, these
curves confirm that the 2:1 complex is present at <10%, consistent
with its apparent absence in the fitting.
The relative values of K1 and K2, as well as the behavior of I-,
indicate3 that positive cooperativity follows the order I- , Br-
<
F- whereas Cl- displays negative cooperativity. The halides were
defined as having two identical binding sites and the triazolophane
with one binding site. Statistical binding would occur if K2 ) K1/4
and deviations higher or lower signify positive and negative
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C O M M U N I C A T I O N S
In the case of TBAF, the titration behavior shows11 a cross over
to the A2X system beyond 22 equiv. The shifts in the proton signals,
however, are more complicated than in the Cl- and Br- cases.
Beyond 0.5 equiv all the proton signals except Hc shift steadily
upfield. The upfield shifts normally indicate increasing self-
association. Molecular modeling (HF/3-21G)11 indicates that in the
1:1 complex 1·F-, all six CH H-bond donors bind symmetrically
with the F- ion. Consequently, the proton shifts that occur upon
transformation into the 1:1 complex are attributed to the confor-
mational changes of 1 in addition to the effects of halide binding
and dedimerization.
Scheme 1. Representations of the Opposite Dipoles Participating
a
in the Formation of 12 ·X-
a NOE cross peaks are labeled in 12 ·X-.
Complex formation was confirmed by ESI-MS. The ESI-MS is
often taken to reflect the solution species present in solution.4 The
analysis11 of solutions ([1] ) 50 µM, CH2Cl2) with 2 equiv of Cl-
showed the peak for the 1:1 complex stronger than the 2:1. For the
Br-, the two peaks were equal. Under these conditions, the I-
sample retained the dominance of its 2:1 dimer peak. These
observations agree with the calculated speciation curves11 and the
change from negative (Cl-) to positive cooperativity (Br-, I-). A
competition experiment for halide binding with 1 was conducted,
in which a solution containing all four halides at 0.125 equiv was
analyzed. The peak intensities indicate the relative stabilities of
the sandwiches: I- . Br- > Cl-. The F- complexes were not
observed. In the same spectrum, the 1:1 peaks followed Cl- > Br-
≈ I-. These observations again concur with the speciation curves.
All of the titration data validate the accuracy of the K1, K2, and
ꢀ2 values and the presence of cooperativity. The propensity for 2:1
halide binding by the pyridyl triazolophanes can be best explained
by comparison to the tetraphenylene ones.7b For the Cl- and Br-
ions, the ∆G1 values for 1 are 0.5 and 0.9 kcal mol-1 lower,
respectively, than for the tetraphenylenes.7b Modeling (HF/3-21G)11
shows both 1:1 complexes are planar with the halides fitting snugly
inside the cavity. These observations confirm our hypothesis that
the lone pairs of electrons on the nitrogens are acting in a
destabilizing way. The fact that the 1:1 Br- complex is more greatly
affected is consistent with its larger size and therefore closer
proximity to the nitrogen lone pairs.
1:1 complexes. The Cl- has large 1:1 binding strength to offset
the dimer leading to slight negative cooperativity.
In conclusion, pyridyl units destabilize the 1:1 triazolophane
complexes on account of the N:· · ·:X- electron pair repulsions. In
the 2:1 sandwich complexes, the repulsions become reduced by
partial cancelation of opposite dipoles. This phenomenon can only
occur in the π-stacked dimers. These elements lower K1 and increase
K2 turning on cooperativity. The size matching between F-, Cl-,
and Br- and the central cavity leads to modest cooperative effects.
However, when these factors are coupled to a large size mismatch,
highly positive cooperativity leads to the enhanced stability and
persistent nature of the I- sandwich complex.
Acknowledgment. The authors thank D. A. Vander Griend for
discussions.
Supporting Information Available: Synthesis, characterization,
titration, modeling, ESI-MS, and X-ray analyses. This material is
available free of charge via the Internet at http://pubs.acs.org.
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In the case of F-, the 1:1 complex is more stable by 0.3 kcal
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Lastly, I- binding shows highly positive cooperativity. In contrast
to the smaller halides, modeling (HF/3-21G) of the 1:1 complex
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the tetraphenylene. This structural feature is a hallmark2 for favoring
sandwich complexes. A calculation on the 1:1 complex shows that
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the presence of the I- ion. The increase in K2, therefore, must stem
from the novel configuration of the π-stacked and rotated pair of
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The smaller halides fit snugly inside the cavity and they all have
similar 2:1 binding strengths (Table 1). Consequently, the dipole-
stabilized dimers must be primarily responsible for their sandwich
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binding strength is not significant enough to overcome the dimer’s
affinity. The F- is too small and the Br- too large for favorable
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