Aromatic and aliphatic CH hydrogen bonds fight for chloride while competing alongside ion pairing within triazolophanes

Article abstract of DOI:10.1002/chem.201002340

Triazolophanes are used as the venue to compete an aliphatic propylene CH hydrogen-bond donor against an aromatic phenylene one. Longer aliphatic C-H...Cl^- hydrogen bonds were calculated from the location of the chloride within the propylene-ba

Full text of DOI:10.1002/chem.201002340

DOI: 10.1002/chem.201002340
Aromatic and Aliphatic CH Hydrogen Bonds Fight for Chloride while
Competing Alongside Ion Pairing within Triazolophanes
Yuran Hua, Raghunath O. Ramabhadran, Esther O. Uduehi, Jonathan A. Karty,
Krishnan Raghavachari, and Amar H. Flood*[a]
Abstract: Triazolophanes are used as
the venue to compete an aliphatic pro-
pylene CH hydrogen-bond donor
ed experimentally. An 1H NMR spec-
troscopy study on the structure of the
propylene triazolophaneꢀs 1:1 chloride
complex is consistent with a weaker
propylene CH hydrogen bond. To
quantify the affinity differences be-
tween the two triazolophanes in di-
chloromethane, it was critical to obtain
an accurate binding model. Four equili-
bria were identified. In addition to 1:1
complexation and 2:1 sandwich forma-
tion, ion pairing of the tetrabutylam-
monium chloride salt (TBA+·Clꢀ) and
cation pairing of TBA+ with the 1:1 tri-
azolophane–chloride complex were ob-
served and quantified. Each complex
was independently verified by ESI-MS
or diffusion NMR spectroscopy. With
ion pairing deconvoluted from the
chloride–receptor binding, equilibrium
constants were determined by using
1H NMR (500 mm) and UV/Vis (50 mm)
spectroscopy titrations. The stabilities
of the 1:1 complexes for the phenylene
and propylene triazolophanes did not
differ within experimental error, DG=
(ꢀ38ꢁ2) and (ꢀ39ꢁ1) kJmolꢀ1, re-
spectively, as verified by an NMR spec-
troscopy competition experiment. Thus,
the aliphatic CH donor only revealed
its weaker character when competing
with aromatic CH donors within the
propylene-based triazolophane.
against an aromatic phenylene one.
ꢀ
ꢀ
Longer aliphatic C H···Cl hydrogen
bonds were calculated from the loca-
tion of the chloride within the propyl-
ene-based triazolophane. The gas-
phase energetics of chloride binding
(DGbind, DHbind, DSbind) and the configu-
rational entropy (DSconfig) were comput-
ed by taking all low-energy conforma-
tions into account. Comparison be-
tween the phenylene- and propylene-
based triazolophanes shows the com-
puted gas-phase free energy of binding
decreased from DGbind =ꢀ194 to
Keywords: anions · macrocycles ·
molecular modeling · receptors ·
supramolecular chemistry
ꢀ182 kJmolꢀ1, respectively, with
a
modest enthalpy–entropy compensa-
tion. These differences were investigat-
Introduction
hance stabilizing forces (e.g., enthalpic gains of a hydrogen
bond) and to moderate any destabilizing factors (e.g., com-
petitive binding from countercations). The present work is
designed to test the recent prediction by Hay and Pedzisa
that aliphatic CH hydrogen-bond donors[7] form weaker hy-
drogen bonds than aromatic ones[8–16] by using triazolo-
phane-based anion receptors[8] as the venue in which to host
two types of competitions. The first contest involved identi-
fying whether the chloride prefers to sit closer to the aro-
matic CH donor than to the aliphatic one. The second fo-
cused on comparing the chloride binding constants between
triazolophanes that differ only in the replacement of a phen-
ylene CH for a propylene one. To get an accurate evaluation
of the affinities, it was determined that ion pairing[17] has to
be deconvoluted from the receptorꢀs actual anion binding af-
finity. To the best of our knowledge, this is the first time
that such ion-pairing effects have been quantified in the
supramolecular chemistry of anions. While the data favor
Designing receptors that bind ions[1,2] is the cornerstone of
supramolecular chemistry. While the field grew up around
cations, the recognition of anions carries these early lessons
forward.[3] Motivations for these investigations include sens-
ing[4] in biological milieu and the extraction[5] of environ-
mentally deleterious anions. These applications have a long
history and they remain active endeavors. The designs begin
by employing principles of host–guest chemistry[6] to en-
[a] Y. Hua, R. O. Ramabhadran, E. O. Uduehi, J. A. Karty,
Prof. K. Raghavachari, Prof. A. H. Flood
Department of Chemistry, Indiana University
800 E. Kirkwood Ave., Bloomington, IN 47405 (USA)
Fax : (+1)812-855-8300
E-mail: aflood@indiana.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002340.
312
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Chem. Eur. J. 2011, 17, 312 – 321

FULL PAPER
M þ Clꢀ ¼ M ꢂ Clꢀ
M ꢂ Clꢀ þ M ¼ M2 ꢂ Clꢀ
TBAþ þ Clꢀ ¼ TBAþ ꢂ Clꢀ
1 : 1 complex
2 : 1 sandwich
salt ion pairing
ð1Þ
ð2Þ
ð3Þ
the prediction by Hay and Pedzisa, the fight for chloride by
the two triazolophanes is not without debate.
Triazolophanes 1[8a] and 2 (Scheme 1) were designed to
compare a phenylene hydrogen bond (CH···Clꢀ) with a
ꢀ
ꢀ
methylene-based ( CH2 ) one. Propylene substitution in 2
maintains the 24-membered macrocycle and the similarly
sized cavity present in 1. The rigidity, and therefore the con-
formational degrees of freedom, of 1 are expected to be sim-
ilar in 2. Gas-phase calculations on the binding of chloride
to ethane,[7] benzene,[11] and triazolophane 1[18] suggest that
the Clꢀ binding energy with 2 will decrease by about 4%
M ꢂ Clꢀ þ TBAþ ¼ M ꢂ Clꢀ ꢂ TBAþ complex ion pairing ð4Þ
Previously, we have shown that 2:1 sandwiches[8c] [Eq. (2)]
need to be accounted for in addition to 1:1 complexes
[Eq. (1)]. Furthermore, the model needs to include ion pair-
ing[21] [Eq. (3)] in which the chloride resides more with its
tetrabutylammonium (TBA+) countercation than the recep-
tor. The Fuoss law[21] tells us that the larger chloride–triazo-
lophane complex, M·Clꢀ, can also pair with the TBA+
cation [Eq. (4)]. Quantitative analyses of ion pairing en-
joyed a lot of attention in the binding of alkali metals by
crown ethers with the aid of the colored picrate counteran-
ion.[22] In anion–receptor chemistry, however, only qualita-
tive treatments of ion pairing have prevailed.[17,23] While
these approaches have yielded insights into ion pairs,[24]
anion transport,[25] ion-pair receptors,[26] and opportunities
for template-directed syntheses,[27] the effect of the counter-
cation on anion recognition has never been quantified.
The ion-pairing problem, so well laid out by Roelens
et al.,[28] is the absence of an accepted and general way to
handle multiple equilibria at the same time, such as com-
plexation [Eqs. (1) and (2)] and ion pairing [Eqs. (3) and
(4)]. Pioneering work by the group of Roelens on tripodal
ureidic receptors focused on the fitting of NMR spectrosco-
py titration data (chemical shifts versus equivalents of
guest) using the software HypNMR.[29] The key challenge is
to verify the existence of each solution species in an inde-
pendent measurement. Otherwise, there is a risk of adding
equilibria that may improve the fitted outcome, but are not
actually occurring in solution. We follow this approach by
using ESI-MS[30] to identify the
after propylene substitution.[19] These calculations also indi-
ꢀ
ꢀ
cate that one linear C H···Cl hydrogen bond will form
(rather than bifurcation) such that triazolophanes 1 and 2
will both display eight near-linear C H···Cl hydrogen
bonds. These ideas suggest two hypotheses: I) Within triazo-
ꢀ
ꢀ
ꢀ
lophane 2, the phenylene C H opposite the propylene will
have a greater attraction for the chloride than the propy-
ꢀ
ꢀ
leneꢀs CH2 group. II) In a competition between the two
triazolophanes, compound 1 will have a stronger affinity for
chloride than 2. Computational studies on the gas-phase
structures, the computed thermochemistry of binding
(DGbind, DHbind, DSbind), including a correction for configura-
tional entropy (DSconfig),[20] and experimental signal shifts in
1
the H NMR spectra of 2·Clꢀ were used to validate both of
these hypotheses: Phenylene CH···Clꢀ hydrogen bonds are
stronger than propylene within 2 and 1·Clꢀ is more stable
than 2·Clꢀ.
To experimentally distinguish a small change in receptor–
chloride affinity, the existing methods of analysis needed to
be improved as a means to obtain accurate binding con-
stants. To this end, it was critical to gain a true representa-
tion of all of the binding equilibria occurring in solution,
which are shown herein to be characterized by Equa-
tions (1)–(4), in which M=1 or 2.
anionic products 1·Clꢀ, 12·Clꢀ,
2·Clꢀ, and 22·Clꢀ. Diffusion
NMR spectroscopy is a power-
ful technique to identify ion
pairs,[31] and we use it here in a
titration to verify the neutral
species, 2·Clꢀ·TBA+. Ultimate-
ly, this expanded model al-
lowed us to obtain accurate af-
finities for the 1:1 binding of
triazolophanes 1 and 2 with
chloride by fitting the UV
(50 mm) and NMR (500 mm)[29]
spectroscopy titration data.
Surprisingly, the binding free
energies are the same to
within experimental error, that
is, we are unable to ascertain
the winner. In an attempt to
Scheme 1. Phenylene (1) and propylene (2) triazolophanes and hypotheses I and II.
reconcile this outcome, the
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313

A. H. Flood et al.
two receptors were placed in direct competition for chloride
by means of an NMR spectroscopy titration: This time a
draw was observed. Thus, quantitative confirmation of hypo-
ACHTUNGTRENNUNGthesis II was not attainable even with the use of a high-fidel-
ity model that improves greatly the accuracy (if not the
level of uncertainty) of the binding constants obtained from
titration analyses. Taken together, these studies support the
proposition that propylene CH donors are weaker than
phenylene ones based on hypothesis I.
Results and Discussion
Synthesis: The propylene triazolophane 2 was synthesized
(Scheme 2) through a combination of cross-coupling reac-
tions[32] and CuI-catalyzed 1,3-dipolar cycloadditions (click
chemistry)[33] from 1-tert-butyl-3,5-diiodobenzene (3). An
excess (>6 equiv) of the diacetylene 5, prepared via protect-
ed intermediate 4, was allowed to react with diazide 6 to
favor the formation of the 5/8 oligomer 7. Subsequent mac-
rocyclization with diazide 8 under high dilution conditions
resulted in triazolophane 2 with a yield of 54%.
Figure 1. Optimized geometries (B3LYP/6-31+GACTHNUTRGNEUG(N d,p)) and relative ener-
gies for the low-energy conformations of the triazolophanes a) 1 and b) 2
and their chloride complexes (symmetries and Boltzmann weight per-
cents are annotated).
Optimized gas-phase structures from DFT: Computational
studies on the triazolophanes and their 1:1 complexes in the
gas phase corroborate the prior theoretical work by Hay
and Pedzisa that aliphatic CH donors are weaker than aro-
matic ones.[7] The geometries of the low-energy conforma-
tions (Figure 1) of 1 and 2 and their complexes 1·Clꢀ and
ꢀ
ꢀ
tion, with its near-linear C H···Cl hydrogen bond (1768),
becomes the most favored. Triazolophane 1 has a similar
distribution of conformations (Figure 1b), within a smaller
range, 3 kJmolꢀ1, but upon formation of the complex 1·Clꢀ
they collapse down to a single D2h-symmetric conformation.
To account for these thermally accessible conformations, the
enthalpy and entropy can be calculated from a Boltzmann
weighted average of all of the low-energy conformers using
Equation (5), in which E=H or S, and f denotes the weight-
ed mole fraction of each con-
2·Clꢀ were fully optimized at the B3LYP/6-31+G
ACTHUNRTGNE(GNU d,p) level
of theory. For triazolophane 2 (Figure 1a), there are four
low-energy conformations within 9 kJmolꢀ1 of the lowest-
energy conformation. Upon formation of 2·Clꢀ, these con-
formations reorder such that the Cs-symmetric conforma-
former.
n
X
E ¼
ðfiEiÞ
ð5Þ
i¼1
The average structure of
2·Clꢀ is dominated by the Cs
(59%) and C1 (40%) confor-
mations. The average geometry
of 2·Clꢀ shows the chloride is
shifted away from the center
and that the strongest interac-
tions are again through the tri-
ꢀ
azole, where the C H···Cl
bonds in one half of the mac-
rocycle (2.62 ꢂ) are slightly
shorter on average than the
two in the other half (2.69 ꢂ).
In the Cs conformation, the ali-
phatic CH shows a contact dis-
tance with Clꢀ (3.02 ꢂ), which
Scheme 2. Synthesis of propylene triazolophane 2. TMS=trimethylsilyl, DMEA=N,N’-dimethylethylenedi-
ACHTUNGTRENNUNGamine, DBU=1,8-diazabicycloACHTUGNTREN[NUNG 5.4.0]undec-7-ene.
314
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Aromatic and Aliphatic CH Hydrogen Bonds
FULL PAPER
is slightly longer than to the phenylene opposite (2.96 ꢂ).
For the C1 conformation the propylene is barely involved in
hydrogen bonding to the Clꢀ ion with both contacts longer
than 3.4 ꢂ. Regarding the entire structure, the presence of
the chloride leads to a slight decrease in the puckering of
each of the conformations of 2·Clꢀ to maximize the strength
al entropy was negligible for the propylene triazolophane 2
in which the conformational space before and after binding
is largely unchanged (Figure 1a). With triazolophane 1, an
entropy cost of +0.8 kcalmolꢀ1 results from the freezing-out
of four conformations for the empty receptor into one in the
complex 1·Clꢀ (Figure 1b). Overall, the conformation-
weighted gas-phase affinities (DGbind) are consistent with tri-
azolophane 2 having weaker Clꢀ binding than 1. Thus, the
structural and thermochemical data are both consistent with
hypotheses I and II.
ꢀ
of the C H···Cl hydrogen bonds. However, significant resid-
ual puckering of the macrocycle remains. Overall, these ob-
servations support the argument that within 2, the phenyl-
ꢀ
ꢀ
ene C H is a stronger donor than the propylene C H,
which either forms longer hydrogen bonds (Cs) or almost
none at all (C1).
Solution-phase characterization of the complexes with 2 by
using 1H NMR spectroscopy: The structures of triazolo-
phane 2 and its Clꢀ complexes were characterized in
CD2Cl2, utilizing 1H NMR spectroscopy to experimentally
evaluate hypothesis I. With different donor arrangements in
the molecule, two sets of triazole resonances, Ha and Hb,
were observed in the 1H NMR spectrum of 2 (Figure 2).
Computational thermochemistry and enthalpy–entropy com-
pensation: Thermochemical calculations (B3LYP/6-31+G-
ACHTUNGTRENNUNG(d,p)) for 1:1 complexation were performed to evaluate if
stronger binding (enthalpy) exists with 1·Clꢀ and to identify
any entropy compensation[34] in the more flexible receptor
(2). The presence of low-energy conformations predicates
the use of weighted averages [Eq. (5)]. The enthalpy
(DHbind) and entropy (DSbind) of binding are therefore de-
fined as the change in the weighted average energy. For
DSbind, these include changes to translations, rotations, and
vibrations. The configurational entropy,[20] DSconfig, arising
from any changes in the number of conformations was cal-
culated by using Equation (6).
n
X
S ¼ ꢀR
ðfi ln fiÞ
ð6Þ
i¼1
In the gas phase, chloride binding is enthalpy driven
(Table 1) with the aliphatic substitution leading to a smaller
value by about 6%, as expected.[19] Both triazolophanes re-
Figure 2. Partial 1H NMR spectra of triazolophane 2 (500 mm, CD2Cl2,
298 K) recorded upon titration with the TBA+·Clꢀ (0–5 equiv).
Table 1. Calculated chloride binding energies [kJmolꢀ1] for 1 and 2 in the gas
phase (298 K).
[b]
[c]
DE[a] DHbind ꢀTDSbind =(ꢀTDStrans ꢀTDSrot ꢀTDSvib) ꢀTDSconfig DGbind
1 ꢀ229 ꢀ230 32
45.6
45.6
1.7
ꢀ0.08
ꢀ15
3.3
0.2
ꢀ194
Upon addition of TBA+·Clꢀ, these triazole signals, together
2 ꢀ215 ꢀ216 34
ꢀ11
ꢀ182
c
ꢀ
with the interior phenylene C H signals, H (see Scheme 2
[a] DE at B3LYP/6-31++G
A
for proton labeling) and Hd, migrated steadily downfield
until 1.2 equivalents of TBA+·Clꢀ were added, which was
consistent with the ultimate formation of a 1:1 complex
[Eq. (1)]. All of the other triazolophane protons stopped
moving at the same point in the titration, however, they
showed one additional signal movement: Both propylene
protons (Hh, Hi) and all the outer aromatic protons (He, Hf,
Hg) displayed an upfield-then-downfield migration pattern
with an inflection point at about 0.5 equivalents. This behav-
ior corresponds to the formation of the sandwich complex
22·Clꢀ [Eq. (2)]. The upfield shift arises from a greater sensi-
tivity to the shielding that occurs from ring currents of the
neighboring p-stacked triazolophane.[8c]
31+G
N
.
[c] DGbind =DHbindꢀTDSbindꢀ
TDSconfigure
ceive entropy penalties, with the more rigid triazolophane 1
paying
slightly larger penalty, (ꢀTDSbindꢀTDSconfig)=
+36 kJmolꢀ1,
than propylene triazolophane 2,
a
(ꢀTDSbindꢀTDSconfig)=+34.8 kJmolꢀ1. This enthalpy–entro-
py compensation,[34] while consistent with expectations, is
only modest. This observation is consistent with the high
degree of rigid preorganization in these two classes of tri-
ACHTUNGTRENNUNGazolophanes. The translational entropy is by far the largest
entropy factor and is equivalent, as expected, for 1 and 2.
While the change in vibrational entropy favors chloride
binding, it primarily corresponds to translational degrees of
freedom being converted into vibrations. The configuration-
ꢀ
The weaker hydrogen bond with the aliphatic C H
donors in triazolophane 2 can be inferred by comparing the
relative NMR signal migrations.[8b] The interior propylene
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315

A. H. Flood et al.
h
(2.95ꢁ0.05) ppm).[37] On the basis of the known ion-pair as-
sociation constant for TBA+·Clꢀ in dichloromethane,
72000mꢀ1 (DG=ꢀ28 kJmolꢀ1, 298 K),[38] this observation in-
dicates that chloride is bound more tightly by 2 than by the
TBA+ cation. Ion pairing between TBA+ and Clꢀ [Eq. (3)],
which only occurs after the receptor is saturated with Clꢀ, is
subsequently observed in the downfield movement of the a-
TBA+ signal towards the chemical shift position of
TBA+·Clꢀ (d=(3.32ꢁ0.02) ppm, see the Supporting Infor-
mation). Consequently, ion pairing of the salt [Eq. (3)] has
to be included in the binding model.
ꢀ
C H signal moved downfield from about d=2.8 to~
3.0 ppm for 0 and 1.2 equivalents, respectively, consistent
with hydrogen bonding. The presence of a single Hh signal is
attributed, with the aid of the computations (Figure 1a), to
an averaged signal position arising from rapidly equilibrat-
ing low-energy conformations. These conformations show
ꢀ
ꢀ
both hydrogen-bonded C H and non-hydrogen-bonded C
H protons. Taking this average effect into account,[35] the
signal migration of the inward facing propylene protons is
still estimated[35] to be smaller than that observed for the
c
d
ꢀ
phenylene C H protons of 2 (H : Dd=1.2 ppm, H : Dd=
1.1 ppm) and those in compound 1 (Dd=0.9 ppm).[8a,36]
Thus, the propyleneꢀs protons are believed to have less con-
tact with the Clꢀ ion than the phenylene CH. This finding
and the fact that the triazole protons Ha (Dd=2.1 ppm) dis-
played a greater shift than those of Hb (Dd=1.8 ppm) indi-
cate that Clꢀ is bound more tightly in one half of the mole-
cule compared with the other.[36] Collectively, these NMR
spectroscopy observations and the average calculated gas-
phase structures support hypothesis I.
A third look (Figure 3) at the TBA+ signal indicates for-
mation of the ion-pair complex 2·Clꢀ·TBA+ [Eq. (4)].
During the addition of the first equivalent of TBA+·Clꢀ, the
TBA+ signal does not actually remain motionless, but mi-
grates slowly upfield from d=3.06 to 3.01 ppm towards a
position beyond both the free TBA+ and the ion-paired
TBA+·Clꢀ species. The upfield shift is consistent with partial
shielding of the a-TBA+ protons by the p ring currents of
2·Clꢀ in an assumed facial approach to form 2·Clꢀ·TBA+.
Such shielding was also seen when the TBA+ cation forms
an ion pair with the aromatic-based anion tetraphenylborate
(d=(2.65ꢁ0.05) ppm, see the Supporting Information).[39]
The stability of the contact ion pair 2·Clꢀ·TBA+ is expected
from Fuossꢀ law[21] to be smaller than TBA+·Clꢀ on account
of the larger size of the 2·Clꢀ anion. By the same logic, the
sandwich complex 22·Clꢀ is also expected to ion pair with
TBA+, albeit with an even lower binding strength. No evi-
dence for such a species was obtained at the concentrations
examined herein. Consequently, three species involving
TBA+ will contribute to the average chemical shift positions
observed throughout the entire titration (0–5 equiv).
Ultimately, a series of four equilibria [Eqs. (1)–(4)] with a
total of seven possible solution-phase species are present at
different stages throughout the entire titration (Figure 4). To
the best of our knowledge, such a fine-grained picture that
incorporates ion pairing has not previously been described
in the study of anion recognition. Of the seven species, com-
pound 2 and TBA+·Clꢀ are
Ion pairing and the solution-phase binding model: To quan-
tify the effect of the weaker propylene CH donor on the Clꢀ
binding strengths of triazolophanes as a means to confirm or
refute hypothesis II, it is imperative to use a model that ac-
curately reflects reality. Thus, the next sections outline ex-
periments that are used to identify and confirm the correct
binding model. Herein, we started by employing the ap-
proach reported by Roelens et al.[28] to analyze the NMR
spectra for some insights into additional equilibria. At first
glance, a simple 1:1 and 2:1 binding model [Eqs. (1) and (2)]
might appear to be consistent with all of the shifts in the tri-
azolophaneꢀs protons (Figure 2). However, a second and
even a third look reveals details that are a direct result of
ion pairing involving the TBA+ countercation. For instance,
the a proton of the TBA+ cation barely moves (Figure 3a)
during addition of the first 1.2 equivalents (dꢃ3.05 ppm)
and its position is strikingly similar to the free TBA+ (d=
added into solution, and both
TBA+ and Clꢀ ions are known
from Equation (3) to be pres-
ent in solution. Therefore, and
in an extension to the work by
Roelens et al.,[28] we present
independent evidence of the
charged complexes 2·Clꢀ and
22·Clꢀ, and of the neutral
2·Clꢀ·TBA+ ion-pair complex.
After this expanded model is
corroborated, only then can it
be used with confidence to an-
alyze the titration data as a
means to accurately compare
the chloride affinities of 1 and
2.
1
Figure 3. a) Partial H NMR spectra showing the signal movement of a-methylene protons of the TBA+ cation
and the Hh propylene protons of 2 during titration with TBA+·Clꢀ. b) Signal positions (dots) for Hh and H
ACTHNUTRGNE(UNG a-
TBA+) and global fitting using the partial binding model [Eqs. (1)–(3), dashed black line] or the complete
binding model [Eqs. (1)–(4), solid line]. Global fit includes the triazole (Ha, Hb), phenylene (He), propylene
(Hi, Hh), and the TBA+ protons.
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Aromatic and Aliphatic CH Hydrogen Bonds
FULL PAPER
D ¼ ðkTÞ=ð6phrHÞ
ð7Þ
were h is the viscosity. The diffusion coefficients of the indi-
vidual constituent species were determined (see the Sup-
porting Information) to facilitate the analysis of the average
self-diffusion coefficients observed during the titration.
The diffusion coefficients (ꢃ10ꢀ10 m2 sꢀ1, Table 2) observed
from the TBA+ protons follow the expected trends for the
Table 2. Observed diffusion coefficients (ꢁ0.1ꢃ10ꢀ10 m2 sꢀ1) generated
from control and titration NMR spectroscopy experiments.
Triazolophane 2[a]
TBA+[b]
TBA+·Clꢀ
10.6
10.6
TBA+
2[c]
6.9
6.2
6.2
2+0.5 equiv TBA+·Clꢀ[d]
2+1.0 equiv TBA+·Clꢀ[d]
9.9
9.0
[a] Average of Hf, Hg, and Hi signals. [b] Average of a-CH2 and terminal
CH3 signals. [c] [2]=0.5 mm. [d] [2]=1 mm.
Figure 4. Representation of the solution-phase equilibria involved in tria-
zolophane–chloride binding in dichloromethane. Conformations are not
optimized.
four equilibria [Eqs. (1)–(4) and Figure 4] and convincingly
reflect the formation of 2·Clꢀ·TBA+.[42] On account of its
smaller size and its involvement in only three species, the
average diffusion coefficient of TBA+ is more sensitive than
those from the protons on 2. The speciation curves calculat-
ed by using the binding constants (see Table 2 and Fig-
ure 6a) reflect this simplicity. Starting at D=10.6 for
TBA+·Clꢀ, the average self-diffusion coefficient of TBA+
reaches its smallest value (9.0) at 1.0 equivalent where the
fraction of 2·Clꢀ·TBA+ is at its maximum (Figure 6a) with
respect to all other TBA+-based species. Up to and beyond
this point, the average self-diffusion coefficient of TBA+ is
ESI-MS of charged species: The negatively charged 1:1 and
2:1 complexes for triazolophane 2 were confirmed by ESI-
MS analysis of a solution of TBA+·Clꢀ (0.5 equiv) in di-
chloromethane at 25 mm (Figure 5). The solution-phase equi-
libria involving triazolophane 1 are expected to be similar to
2[40] and the ESI-MS analysis shows the same 1:1 and 2:1
anionic species are present.
Figure 5. ESI-MS of solutions (CH2Cl2) with a) triazolophane 1 (25 mm)+
TBA+·Clꢀ (12.5 mm) and b) triazolophane
(12.5 mm). *Impurity peak from ESI-MS.[41]
2
(25 mm)+TBA+·Clꢀ
Diffusion NMR spectroscopy evidence for the contact ion-
pair complex: Diffusion NMR spectroscopy titrations unam-
biguously verified the presence of the neutral ion-pair com-
plex 2·Clꢀ·TBA+. By considering the inverse relationship
[Eq. (7)][31a] between the average self-diffusion coefficients
(D) and the hydrodynamic radii (rH) of each species present
at different stages in the titration (Figure 4), it is possible to
distinguish the formation of the large supramolecular com-
plex, 2·Clꢀ·TBA+, from the constituent smaller species,
TBA+ and 2.
Figure 6. Simulated speciation curves using HySS ([2]=1 mm) with re-
spect to a) TBA+ and b) triazolophane 2 using equilibrium constants ob-
tained from NMR spectroscopic data fitting.
Chem. Eur. J. 2011, 17, 312 – 321
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317

A. H. Flood et al.
larger because the percentage of the smaller species TBA+
or TBA+·Clꢀ is greater than 2·Clꢀ·TBA+. The average self-
diffusion coefficients for 2, while less straightforward to ana-
lyze (see the Supporting Information), also follow the calcu-
lated speciation curves (Figure 6b).
Binding constant determination from NMR spectroscopy
and UV titrations: With all of the solution species unambig-
uously verified, the equilibrium constants (Table 3) of the
Table 3. Free energies [kJmolꢀ1] and equilibrium constants [mꢀ1] for tri-
ACHTUNGTRENNUNGazolophanes 1 and 2 in dichloromethane generated from data fitting.
DG(1)[a] (UV)
DG(2)[a] (UV)
DG(2)[b] (NMR)
ꢀ38ꢁ2
ꢀ39ꢁ1
ꢀ38ꢁ1
Eq. (1)
Eq. (2)
Eq. (3)
Eq. (4)
4.7ꢁ2.1ꢃ106
ꢀ32ꢁ2
5.6ꢁ1.9ꢃ106
ꢀ22ꢁ3
4.0ꢁ0.8ꢃ106
ꢀ21ꢁ1
4.9ꢁ2.7ꢃ105
ꢀ28ꢁ3c
7.2ꢁ5.0ꢃ103
ꢀ28ꢁ3c
4.0ꢁ0.8ꢃ103
ꢀ28ꢁ3c
7.2ꢁ5.0ꢃ104
ꢀ22ꢁ2
7.2ꢁ5.0ꢃ104
ꢀ23ꢁ3
7.2ꢁ5.0ꢃ104
ꢀ19ꢁ1
7.2ꢁ3.2ꢃ103
1.4ꢁ0.8ꢃ104
2.5ꢁ0.5ꢃ103
[a] UV titration data, 50 mm. [b] NMR spectroscopy titration data,
[38]
500 mm. [c] Fixed at ꢀ28 kJmolꢀ1
.
four equilibria for both triazolophanes 1 and 2 were quanti-
fied by utilizing equilibrium-restricted factor analyses.
Global fitting of the NMR spectroscopy titration with tria-
zolophane 2 using HypNMR[29] was based on the chemical
shifts of the triazole protons (Ha, Hb), the outer proton on
phenylene (He), the two propylene protons (Hh and Hi), and
the a-CH2 protons of TBA+. The literature value of the
TBA+·Clꢀ ion-pair association constant[38] was used as a
fixed value in the fitting. The agreement between the mea-
sured and modeled chemical shift positions obtained from
the fitting improved with the addition of each equilibrium
into the model (see the Supporting Information). For exam-
ple, the aforementioned upfield-then-downfield movements
in the a-TBA+ proton were only reproduced (Figure 3b)
upon addition of the equilibrium for the 2·Clꢀ·TBA+ ion-
pair complex [Eq. (4)]. As a means to corroborate the equi-
librium constants generated for 2 from the HypNMR analy-
sis, a UV titration was conducted at a lower concentration
(50 mm, CH2Cl2). The UV titration data (275–340 nm) of
both triazolophanes 1 and 2[43] were then fitted according to
the same set of four equilibria by using the software
Sivvu.[8d,44] The equilibrium constants generated from both
NMR spectroscopy (500 mm) and UV (50 mm) titrations for
triazolophane 2 agree with each other to within experimen-
tal error (Table 3). The fact that reproducible values were
obtained from different titrations conducted at different
concentrations and with different techniques attests to the
accuracy of the model Equations (1)–(4).
Figure 7. a) Partial 1H NMR spectroscopy titration data of triazolophane
1 (2 mm, CD2Cl2) with TBA+·Clꢀ, as published in reference [8a]. b) Si-
mulated speciation curve at the corresponding NMR spectroscopy titra-
tion concentration with equilibrium constants obtained from UV data fit-
ting ([1]=2 mm).
tration (Figure 7a).[8a] All of the triazole and phenylene sig-
nals sharpened and stopped shifting upon the addition of
four equivalents of TBA+·Clꢀ. By contrast, triazolophane 2
(0.5 mm), which has a similarly strong 1:1 Clꢀ affinity,
stopped changing at 1.2 equivalents of TBA+·Clꢀ. These ob-
servations are consistent with the greater propensity of tri-
AHCTUNGTREGaNNNU zolophane 1 to form 2:1 sandwich complexes, as observed
in the speciation curves (Figure 7b). Therefore, complex
12·Clꢀ persisted beyond two equivalents, whereas nearly all
of the 22·Clꢀ sandwich was driven to its 1:1 complex 2·Clꢀ
with only a small excess of TBA+·Clꢀ (Figure 6a).
The 2:1 sandwich complex with 1 displayed a much higher
stability than 2 (ꢀ32 vs. ꢀ22 kJmolꢀ1). Both triazolophanes
display negative cooperativity. Presumably, the greater pla-
narity of the complexes with 1 retains more effective p
stacking to facilitate formation of sandwiches.[8c]
The stability of the ion-pair complexes (M·Clꢀ·TBA+, K
ꢃ10000mꢀ1) for both triazolophanes are lower than the
parent TBA+·Clꢀ ion pair. This observation is fully consis-
tent with the expectations from Fuossꢀ law[21] on account of
the significant size difference between the Clꢀ anion and the
anionic M·Clꢀ complexes. Speciation curves were calculated
for some typical concentrations used in NMR and UV/Vis
The NMR spectroscopy titration data for 1 (Figure 7) was
unsuitable for fitting on account of signal broadening. How-
ever, the binding constants obtained from fitting the UV ti-
tration data on triazolophane 1 helped to interpret, for the
first time, some of the features in the NMR spectroscopy ti-
318
www.chemeurj.org
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 312 – 321

Aromatic and Aliphatic CH Hydrogen Bonds
FULL PAPER
spectroscopy titrations (see the Supporting Information) to
identify when each species becomes an important compo-
nent of the solution. For both 1 and 2, the ion-pair com-
plexes, M·Clꢀ·TBA+ [Eq. (4), Kꢃ10000mꢀ1], are negligible
at 10 mm, but become increasingly significant at the typical
concentrations used for UV (50 mm) and NMR (>500 mm)
spectroscopy titrations. From these speciation curves, we
infer that the concentration used for quantifying multiple
equilibria is just as important as the right technique[45] to
guarantee that a reasonable amount of the constituent spe-
cies can contribute to the titration data being analyzed. As
noted by others,[17] higher dielectric solvents can be selected
to minimize ion pairing and simplify the solution-phase
equilibria, but this assumption itself has to be independently
verified.
determined for the first time to quantify the stabilities of
the chloride–triazolophane complexes. The model equilibria
included the frequently overlooked contribution of ion-pair
formation between the 1:1 complex and the countercation
as well as ion-pair competition. The precision of the result-
ing association constants was larger than that required to
distinguish between the hydrogen-bond strengths revealed
in the structural analyses (calculations and NMR spectra).
The greater accuracy provided by such models will be criti-
cal for quantitatively examining the design of new receptors.
Experimental Section
Details of the general methods; syntheses; and compound characteriza-
tion, computations, titration and data fittings; and simulated speciation
curves can be found in the Supporting Information.
Chloride binding in 1 and 2 and hypotheses I and II: Look-
ing first at the 1:1 complexes, replacing the phenylene in 1
with a propylene CH donor in 2 was found, within experi-
mental error, to have no effect on the receptorꢀs affinity for
chloride. To corroborate this unexpected finding, an NMR
spectroscopy competition experiment was conducted (see
the Supporting Information). The protons from 1 and 2
were observed to start and stop moving at the same stage
during the titration consistent with the similar binding affini-
ties.
Acknowledgements
The authors thank Indiana University (Collaborative Research and Crea-
tive Activity), the National Science Foundation (CHE-0844441 and
CHE-0911454) and the Chemical Sciences, Geosciences and Biosciences
Division, Office of Basic Energy Sciences, Office of Science, US Depart-
ment of Energy for funding.
Consistent with hypothesis I, the calculated structure
(Figure 1) of 2·Clꢀ indicates that the propylene CH forms a
longer, and therefore, weaker hydrogen bond with Clꢀ than
the phenylene one.[18] The computed gas-phase thermochem-
istry (Table 1) is consistent with hypothesis II, such that 2
forms a less stable 1:1 complex with chloride than 1. All of
the relative signal shifts in the NMR spectra of 1 and 2 sup-
port hypothesis I. However, the use of an accurate and self-
consistent binding model [Eqs. (1)–(4)] to quantify the 1:1
binding affinity showed that this weaker hydrogen bond did
not lead to a demonstrable change in the free energy of
binding, that is, evaluation of hypothesis II could not be pre-
cisely determined. The competition NMR spectroscopy ex-
periment provided the same result: no difference. An alter-
native interpretation is that the stability of the complexes
1·Clꢀ and 2·Clꢀ are actually the same. To support this posi-
tion, solvation would have to have a more influential role
on the entropy–enthalpy compensation than was established
in the gas-phase calculations. Ultimately, the sum of all the
observations concurs with Hayꢀs prediction that the propyl-
[1] C. J. Pedersen, J. Am. Chem. Soc. 1967, 89, 7017–7036.
[2] C. H. Park, H. E. Simmons, J. Am. Chem. Soc. 1968, 90, 2431–2432.
[3] a) A. Bianchi, K. Bowman-James, E. Garcꢄa-EspaÇa, Supramolec-
ular Chemistry of Anions, Wiley-VCH, Weinheim, 1997; b) J. L.
Sessler, P. A. Gale, W. S. Cho, Anion Receptor Chemistry, RSC,
London, 2006.
[4] See volume on anion sensing in: Top. Curr. Chem. 2005, 255.
[5] a) L. R. Eller, M. Stepien, C. J. Fowler, J. T. Lee, J. L. Sessler, B. A.
Moyer, J. Am. Chem. Soc. 2007, 129, 11020–11021; b) M. P. Winter-
gerst, T. G. Levitskaia, B. A. Moyer, J. L. Sessler, L. H. Delmau, J.
Am. Chem. Soc. 2008, 130, 4129–4139; c) C. J. Fowler, T. J. Haver-
lock, B. A. Moyer, J. A. Shriver, D. E. Gross, M. Marquez, J. L. Sess-
ler, M. A. Hossain, K. Bowman-James, J. Am. Chem. Soc. 2008, 130,
14386–14387; d) K. L. Bell, A. N. Westra, R. J. Warr, J. Chartes, R.
Ellis, C. C. Tong, A. J. Blake, P. A. Tasker, M. Schroder, Angew.
Chem. 2008, 120, 1769–1772; Angew. Chem. Int. Ed. 2008, 47, 1745–
1748; e) R. J. Warr, A. N. Westra, K. J. Bell, J. Chartes, R. Ellis,
C. C. Tong, T. G. Simmance, A. Gadzhieva, A. J. Blake, P. A. Tasker,
M. Schroder, Chem. Eur. J. 2009, 15, 4836–4850, and references
therein.
[6] J. W. Steed, J. L. Atwood, Supramolecular Chemistry, 2nd ed., Wiley,
New York, 2009.
[7] L. Pedzisa, B. P. Hay, J. Org. Chem. 2009, 74, 2554–2560.
[8] a) Y. Li, A. H. Flood, Angew. Chem. 2008, 120, 2689–2692; Angew.
Chem. Int. Ed. 2008, 47, 2649–2652; b) Y. Li, A. H. Flood, J. Am.
Chem. Soc. 2008, 130, 12111–12122; c) Y. Li, M. Pink, J. A. Karty,
A. H. Flood, J. Am. Chem. Soc. 2008, 130, 17293–17295; d) Y. Li,
D. A. Vander Griend, A. H. Flood, Supramol. Chem. 2009, 21, 111–
117; e) E. M. Zahran, Y. Hua, Y. Li, A. H. Flood, L. G. Bachas,
Anal. Chem. 2010, 82, 368–375; f) Y. Hua, A. H. Flood, Chem. Soc.
Rev. 2010, 39, 1262–1271; g) S. Lee, Y. Hua, H. Park, A. H. Flood,
Org. Lett. 2010, 12, 2100–2102; h) Y. Hua, A. H. Flood, J. Am.
Chem. Soc. 2010, 132, 12838–12840.
ene CH is a weaker donor than the phenyACTHNUTRGNEUGlN ene.
Conclusion
In a series of competition experiments, aromatic phenylene
donors were shown to be stronger than aliphatic propylene
1
ꢀ
C H groups. Gas-phase calculations and H NMR spectros-
copy on the triazolophane–chloride complexes were consis-
tent with this conclusion. The generation of a self-consistent
model of all the binding equilibria occurring in solution was
[9] a) H. Juwarker, J. M. Lenhardt, D. M. Pham, S. L. Craig, Angew.
Chem. 2008, 120, 3800; Angew. Chem. Int. Ed. 2008, 47, 3740–3743;
b) H. Juwarker, J. M. Lenhardt, J. C. Castillo, E. Zhao, S. Krishna-
Chem. Eur. J. 2011, 17, 312 – 321
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
319

A. H. Flood et al.
murthy, R. Jamiolkowski, K. H. Kim, S. L. Craig, J. Org. Chem.
2009, 74, 8924–8934.
[10] S. Hecht, R. M. Meudtner, Angew. Chem. 2008, 120, 5004; Angew.
Chem. Int. Ed. 2008, 47, 4926–4930.
Kim, B. Y. Chang, E. Park, S. M. Park, K. H. Ahn, Chem. Commun.
2008, 753–755; g) M. D. Lankshear, I. M. Dudley, K. M. Chan, A. R.
Cowley, S. M. Santos, V. Felix, P. D. Beer, Chem. Eur. J. 2008, 14,
2248–2263; h) K. Zhu, S. Li, F. Wang, F. Huang, J. Org. Chem. 2009,
74, 1322–1328; i) T. van der Wijst, C. F. Guerra, M. Swart, F. M.
Bickelhaupt, B. Lippert, Angew. Chem. 2009, 121, 3335–3337;
Angew. Chem. Int. Ed. 2009, 48, 3285–3287; j) N. Qureshi, D. S.
Yufit, J. A. K. Howard, J. W. Steed, Dalton Trans. 2009, 5708–5714;
k) X. He, V. W. W. Yam, Inorg. Chem. 2010, 49, 2273–2279.
[27] a) M. D. Lankshear, P. D. Beer, Acc. Chem. Res. 2007, 40, 657–668;
b) K. M. Mullen, P. D. Beer, Chem. Soc. Rev. 2009, 38, 1701–1713;
c) K. M. Mullen, J. Mercurio, C. J. Serpell, P. D. Beer, Angew. Chem.
2009, 121, 4875–4878; Angew. Chem. Int. Ed. 2009, 48, 4781–4784.
[28] a) S. Roelens, A. Vacca, C. Venturi, Chem. Eur. J. 2009, 15, 2635–
2644; b) S. Roelens, A. Vacca, O. Francesconi, C. Venturi, Chem.
Eur. J. 2009, 15, 8296–8302.
[11] a) V. S. Bryantsev, B. P. Hay, J. Am. Chem. Soc. 2005, 127, 8282–
8283; b) V. S. Bryantsev, B. P. Hay, Org. Lett. 2005, 7, 5031–5034;
c) B. P. Hay, V. S. Bryantsev, Chem. Commun. 2008, 2417–2428.
[12] a) O. B. Berryman, A. C. Sather, B. P. Hay, J. S. Meisner, D. W. John-
son, J. Am. Chem. Soc. 2008, 130, 10895–10897; b) D. W. Yoon,
D. E. Gross, V. M. Lynch, J. L. Sessler, B. P. Hay, C. H. Lee, Angew.
Chem. 2008, 120, 5116; Angew. Chem. Int. Ed. 2008, 47, 5038–5042.
[13] M. G. Fisher, P. A. Gale, J. R. Hiscock, M. B. Hursthouse, M. E.
Light, F. P. Schmidtchen, C. C. Tong, Chem. Commun. 2009, 3017–
3019.
[14] Y. Y. Zhu, G. T. Wang, R. X. Wang, Z. T. Li, Cryst. Growth Des.
2009, 9, 4778–4783.
[15] a) T. Romero, A. Caballero, A. Tꢅrraga, P. Molina, Org. Lett. 2009,
11, 3466–3469; b) H. Zheng, W. Zhou, J. Lv, X. Yin, Y. Li, H. Liu,
Y. Li, Chem. Eur. J. 2009, 15, 13253–13262; c) Y. Zhao, Y. Li, Y. Li,
H. Zheng, X. Yin, H. Liu, Chem. Commun. 2010, 46, 5698–5700;
d) J. J. Gassensmith, S. Matthys, J. J. Lee, A. Wojcik, P. V. Kamat,
B. D. Smith, Chem. Eur. J. 2010, 16, 2916–2921.
[16] a) H. Maeda, Y. Kusunose, Chem. Eur. J. 2005, 11, 5661–5666; b) H.
Maeda, Y. Ito, Inorg. Chem. 2006, 45, 8205–8210; c) C. Fujimoto, Y.
Kusunose, H. Maeda, J. Org. Chem. 2006, 71, 2389–2394; d) H.
Maeda, Y. Fujii, Y. Mihashi, Chem. Commun. 2008, 4285–4287;
e) H. Maeda, M. Terasaki, Y. Haketa, Y. Mihashi, Y. Kusunose, Org.
Biomol. Chem. 2008, 6, 433–436.
[17] J. L. Sessler, D. E. Gross, W. S. Cho, V. M. Lynch, F. P. Schmidtchen,
G. W. Bates, M. E. Light, P. A. Gale, J. Am. Chem. Soc. 2006, 128,
12281–12288.
[18] I. Bandyopadhyay, K. Raghavachari, A. H. Flood, ChemPhysChem
2009, 10, 2535–2540.
[29] C. Frassineti, S. Ghelli, P. Gans, A. Sabatini, M. S. Moruzzi, A.
Vacca, Anal. Biochem. 1995, 231, 374–382.
[30] C. A. Schalley in Analytical Methods in Supramolecular Chemistry,
(Eds: C. A. Schalley), Wiley-VCH, Weinheim, 2007.
[31] a) Y. Cohen, L. Avram, L. Frish, Angew. Chem. 2005, 117, 524–560;
Angew. Chem. Int. Ed. 2005, 44, 520–544; b) A. Macchioni, G. Cian-
caleoni, C. Zuccaccia, D. Zuccaccia, Chem. Soc. Rev. 2008, 37, 479–
489; c) M. D. Pluth, B. E. F. Tiedemann, H. van Halbeek, R. Nunlist,
K. N. Raymond, Inorg. Chem. 2008, 47, 1411–1413; d) P. S. Pregosin,
Pure. Appl. Chem. 2009, 81, 615–633.
[32] a) K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett. 1975,
16, 4467–4470; b) K. Sonogashira, J. Organomet. Chem. 2002, 653,
46–49; c) W. Zhu, D. Ma, Chem. Commun. 2004, 888–889.
[33] a) V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless,
Angew. Chem. 2002, 114, 2708–2711; Angew. Chem. Int. Ed. 2002,
41, 2596–2599; b) C. W. Tornoe, C. Christensen, M. Meldal, J. Org.
Chem. 2002, 67, 3057–3064.
[19] One phenylene unit contributes about 8% of the overall Cl–triazo-
[34] a) J. D. Dunitz, Chem. Biol. 1995, 2, 709–712; b) K. Sharp, Protein
Sci. 2001, 10, 661–667; c) M. Haj-Zaroubi, N. W. Mitzel, F. P.
Schmidtchen, Angew. Chem. 2002, 114, 111–114; Angew. Chem. Int.
Ed. 2002, 41, 104–107; d) M. V. Rekharsky, T. Mori, C. Yang, Y. H.
Ko, N. Selvapalam, H. Kim, D. Sobransingh, A. E. Kaifer, S. Liu, L.
Isaacs, W. Chen, S. Moghaddam, M. K. Gilson, K. Kim, Y. Inoue,
Proc. Natl. Acad. Sci. USA 2007, 104, 20737–20742.
ꢀ
lophane binding energy and the binding energy with ethaneꢀs C
H···Clꢀ bond[7] is half that of benzene.[11]
[20] a) W. Chen, C. E. Chang, M. K. Gilson, Biophys. J. 2004, 87, 3035–
3049; b) M. Haj-Zaroubi, F. P. Schmidtchen, ChemPhysChem 2005,
6, 1181–1186; c) F. P. Schmidtchen, Coord. Chem. Rev. 2006, 250,
2918–2928; d) V. D. Jadhav, E. Herdtweck, F. P. Schmidtchen,
Chem. Eur. J. 2008, 14, 6098–6107; e) V. D. Jadhav, F. P. Schmidtch-
en, J. Org. Chem. 2008, 73, 1077–1087.
[21] a) R. M. Fuoss, C. A. Kraus, J. Am. Chem. Soc. 1933, 55, 476–488;
b) R. M. Fuoss, C. A. Kraus, J. Am. Chem. Soc. 1933, 55, 1019—
1028; c) R. M. Fuoss, J. Am. Chem. Soc. 1958, 80, 5059–5061.
[22] a) K. H. Wong, M. Bourgoin, J. Smid, J. Chem. Soc. Chem.
Commun. 1974, 715–716; b) M. Bourgoin, K. H. Wong, J. H. Hui, J.
Smid, J. Am. Chem. Soc. 1975, 97, 3462–3467.
[23] Some nongeneral ways have been used to quantify ion pairs, see:
a) F. Huang, J. W. Jones, S. Slebodnick, H. W. Gibson, J. Am. Chem.
Soc. 2003, 125, 14458–14464; b) F. Huang, J. W. Jones, H. W.
Gibson, J. Org. Chem. 2007, 72, 6573–6576; c) D. E. Gross, F. P.
Schmidtchen, W. Antonius, P. A. Gale, V. M. Lynch, J. L. Sessler,
Chem. Eur. J. 2008, 14, 7822–7827.
[35] For example, for the Cs-symmetric conformation of 2·Clꢀ with one
of the two CH groups engaged in a 1768 CH···Clꢀ contact is weight-
ed by 59%, whereas the C1-symmetric conformation with no
CH···Clꢀ contacts is weighted by 40%. Consequently, the 0.2 ppm
shift represents only 29.5% of the methylene protons engaged in
the hydrogen bonding. Therefore, this 0.2 ppm can be scaled by 1/
29.5%=0.7 ppm.
[36] The magnitude of complexation-induced signal migrations (Dd/ppm)
for both triazole protons and internal phenylene protons qualitative-
ly correlate to the calculated average H···Clꢀ distances (d/ꢂ). Order
of contact distance: Ha <Hb <Hc <Hd <Hh; order of signal migra-
tion: Ha >Hb >Hc >Hd >Hh. However, it is worthwhile to point out
that the magnitude of signal migrations might not be solely depen-
dent on the contact distance.
[24] K. A. Dill, J. Biol. Chem. 1997, 272, 701–704.
[37] This position was established from studies on the tetraphenylborate
[25] a) C. C. Tong, R. Quesada, J. L. Sessler, P. A. Gale, Chem. Commun.
2008, 6321–6323; b) P. A. Gale, C. C. Tong, C. J. E. Haynes, O.
Adeosun, D. E. Gross, E. Karnas, E. M. Sedenberg, R. Quesada,
J. L. Sessler, J. Am. Chem. Soc. 2010, 132, 3240–3241.
(TPBꢀ) salt of TBA+ (see the Supporting Information).
[38] S. Alunni, A. Pero, G. Reichenbach, J. Chem. Soc. Perkin Trans. 2
1998, 1747–1750.
[39] Such types of shielding is also evidenced from the crystal structure
[26] a) J. M. Mahoney, J. P. Davis, A. M. Beatty, B. D. Smith, J. Org.
Chem. 2003, 68, 9819–9820; b) J. M. Mahoney, K. A. Stucker, H.
Jiang, I. Carmichael, N. R. Brinkmann, A. M. Beatty, B. C. Noll,
B. D. Smith, J. Am. Chem. Soc. 2005, 127, 2922–2928; c) R. Custel-
cean, L. H. Delmau, B. A. Moyer, J. L. Sessler, W. S. Cho, D. E.
Gross, G. W. Bates, S. J. Brooks, M. E. Light, P. A. Gale, Angew.
Chem. 2005, 117, 2593–2598; Angew. Chem. Int. Ed. 2005, 44, 2537–
2542; d) J. L. Sessler, S. K. Kim, D. E. Gross, C. H. Lee, J. S. Kim,
V. M. Lynch, J. Am. Chem. Soc. 2008, 130, 13162–13166; e) S. L.
Gac, I. Jabin, Chem. Eur. J. 2008, 14, 548–557; f) H. Miyaji, D. S.
of a similar salt, see Cambridge Structure Database, refcode:
ERAPIW.
[40] The NMR spectroscopy titration for 1 with TBA+·Clꢀ is less insight-
ful on account of significant signal broadening.
[41] An additional signal for triazolophane 1 was observed correspond-
ing to the iodide sandwich 12·Iꢀ, but not with triazolophane 2 under
the same conditions. The iodide sandwich was believed to result
from scavenging in the ESI-MS experiment, as seen previously. A
competition experiment using ESI-MS (see the Supporting Informa-
tion), in which 25 mm of 1 and 2 are analyzed in the presence of
320
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Chem. Eur. J. 2011, 17, 312 – 321

Aromatic and Aliphatic CH Hydrogen Bonds
FULL PAPER
TBA+·Clꢀ, showed the 12·Iꢀ complex but not 22·Iꢀ. Formation of
iodide sandwich with triazolophanes has been seen before, see refer-
ence [8c].
formation) shows that addition of the fifth equilibrium for the for-
mation of 22·Clꢀ·TBA+ had no effect on the outcome of the fitting.
[43] The NMR spectroscopy titration data for triazolophane 1 (Fig-
ure 7a)[8a] was not applicable for HypNMR fitting on account of sig-
nificant signal broadening.
[44] D. A. Vander Griend, D. K. Bediako, M. J. DeVries, N. A. DeJoing,
L. P. Heeringa, Inorg. Chem. 2008, 47, 656–662.
[45] K. Hirose in Analytical Methods in Supramolecular Chemistry (Eds.:
C. A. Schalley), Wiley-VCH, Weinheim, 2007.
[42] Evidence for 22·Clꢀ·TBA+ from diffusion NMR spectroscopy is
weak. On the basis of Fuossꢀ law,[21] the ion pairing is expected to be
too weak in a titration experiment at 1 mm. When titration experi-
ments are conducted at even lower concentrations, the population
of 22·Clꢀ·TBA+ will be smaller still. Therefore, the quantitative
NMR (500 mm) and UV (50 mm) spectroscopy titrations have been
modeled with the four primary equilibria [Eq. (1)–(4)]. Consistently,
global fitting of the NMR spectroscopy data (see the Supporting In-
Received: August 15, 2010
Published online: November 24, 2010
Chem. Eur. J. 2011, 17, 312 – 321
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