Just add tetrazole: 5-(2-Pyrrolo)tetrazoles are simple, highly potent anion recognition elements

Article abstract of DOI:10.1039/c1cc15875a

We report a novel pyrrolo-tetrazole motif that encodes anion binding orders of magnitude stronger than closely related systems and suggests the general utility of amide-tetrazole exchanges for creating simple, high-affinity anion binders. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1cc15875a

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COMMUNICATION
Just add tetrazole: 5-(2-Pyrrolo)tetrazoles are simple, highly potent
anion recognition elementsw
Rebecca J. M. Courtemanche, Thomas Pinter and Fraser Hof*
Received 21st September 2011, Accepted 14th October 2011
DOI: 10.1039/c1cc15875a
We report a novel pyrrolo-tetrazole motif that encodes anion
binding orders of magnitude stronger than closely related
systems and suggests the general utility of amide-tetrazole
exchanges for creating simple, high-affinity anion binders.
differences between the anion-binding potency of 1 and the
control compounds (Fig. 1 and 2). We explain the difference
between tetrazole-functionalized 1 (3300 Mꢀ1) and carboxylic
acid-functionalized 3 (125 Mꢀ1; 26-fold weaker) on the basis
of the stereoelectronic effects that favor the syn conformation
of the carboxylic acid OH.8,16 In a host like 3, a syn carboxylic
acid OH diverges from the binding pocket and can’t cooperate
with the pyrrole NH to bind a single Clꢀ anion. The pyrrolyl
amide 4 does not suffer from this particular conformational
problem, but its Clꢀ affinity is low nevertheless. Our determined
value for 4ꢁClꢀ (Kassoc 75 Mꢀ1) is similar to that reported for
related host (5) published by Gale (Kassoc 28 Mꢀ1, determined in
CD3CN containing 0.03% H2O),14 and both are >40-fold
weaker than 1 (DDG = 2.2 kcal molꢀ1). These hosts differ
from 1 in both conformation and acidity; calculations suggest
that both factors play a role in driving stronger binding by 1
(see ESI). We examined acidity in particular by comparing 1 to
its nearly isosteric, but far less acidic, analog 2,20-bipyrrole 6.
Again, the 5-(2-pyrroyl)tetrazole 1 wins out by a significant
margin, binding Clꢀ more strongly than does 6 by an order of
magnitude (DDG = 1.4 kcal molꢀ1).
In order to examine the scope of anion binding by this new
motif, we carried out NMR studies of 1 with a variety of
halides and oxyanions, both in anhydrous CD3CN and in
CD3CN containing 1% (v/v) H2O. Addition of BzOꢀ to
tetrazole-containing 1 gave rise to curves that could not be fit
to 1 : 1, 2 : 1, or 1 : 2 binding isotherms, along with disappearance
of the tetrazole NH when B2 equivalents of BzOꢀ had been
added. Job plots were complex (i.e. had multiple extrema) and
not supportive of any n : m binding stoichiometry (Fig. S23w).
These data are in line with those reported by other groups for
other combinations of acidic hosts and carboxylate anions, in
which initial (strong) binding is followed by proton transfer from
Anion-binding molecules are increasingly being pursued for
applications in waste remediation, sensing, and the treatment
of disease. In spite of the introduction of anion-pi1 and halogen
bonding2,3 interactions, hydrogen bonds remain the dominant
type of weak interaction used for anion recognition. A variety
of different neutral N–H hydrogen-bonding functional groups
have been used for binding anions, and pyrroles are prominent
examples.4 The diversity of structures made available by
combining simple N–H hydrogen-bonding elements in different
ways is impressive, but the number of different groups that have
been used is small. Increasing acidities by introducing multiple
electron-withdrawing groups is one established route to increased
potencies.5–7 We have been seeking new, highly acidic anion-
binding functional groups that might open up access to new
families of inherently more potent receptors.8,9 We report here on
the invention of 5-(2-pyrrolyl)tetrazole as a simple, two-point
hydrogen bonding functional group that encodes superb anion
affinities and a propensity for sulfonate recognition.
Our recent identification of tetrazoles as highly acidic recognition
elements8–10 suggested to us that their combination with pyrroles
might be profitable. 5-(2-pyrrolyl)tetrazole (1) is a nearly isosteric
analog of 2,20-bipyrrole that is readily prepared from commercially
available 2-cyanopyrrole in one step by treatment with Et3NHCl/
NaN3 (Scheme 1).11 We synthesized pyrrole bis(tetrazole) 2 using a
literature route to 2,5-dicyanopyrrole12,13 followed by conversion
to the bis(tetrazole) 2. Control compounds pyrrole-2-carboxylic
acid (3), simple pyrrolyl amide 4, and 2,20-bipyrrole (6)14 were
either commercially available or prepared by established routes.
Solutions of hosts 1, 3, 4, and 6 in CD3CN were titrated
with Bu4N+ Clꢀ in order to take a preliminary look at the
success of this design. Chemical shift data were fit to 1 : 1 binding
isotherms15 to determine Kassoc values that revealed striking
University of Victoria, Department of Chemistry, Victoria, V8W 3V6,
Canada. E-mail: fhof@uvic.ca; Fax: +1 250 721 7147;
Tel: +1 250 721 7193
w Electronic supplementary information (ESI) available: synthesis and
characterization data, experimental details, computational results. See
DOI: 10.1039/c1cc15875a
Scheme 1
c
12688 Chem. Commun., 2011, 47, 12688–12690
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Table 1 Affinities of 5-(2-pyrrolo)tetrazole (1) and 2,20-bipyrrole (6)
for various anionsa
Kassoc for 1
Kassoc for 1 in Kassoc for 6 in in 1% H2O/
Kassoc for 6 in
1% H2O/
Guest CD3CN (Mꢀ1) CD3CN (Mꢀ1) CD3CN (Mꢀ1) CD3CN (Mꢀ1
)
Clꢀ 3300 ꢂ 1200 310 ꢂ 10
890 ꢂ 100
110 ꢂ 15
o3
71 ꢂ 5
21 ꢂ 2
o3
Brꢀ 450 ꢂ 50
50 ꢂ 3
Iꢀ
17 ꢂ 3
3 ꢂ 1
TsOꢀꢀ 900 ꢂ 50
NO3 160 ꢂ 20
BzOꢀ p.t.b
37 ꢂ 4
420 ꢂ 120
60 ꢂ 9
p.t.b
16 ꢂ 1
7 ꢂ 1
19 ꢂ 1
1500 ꢂ 200
260 ꢂ 30
a
Guests were titrated as their Bu4N+ salts into solutions of hosts in the
stated solvent system. Chemical shift data for all nuclei that displayed
significant chemical shifts were fit to 1 : 1 binding isotherms to arrive at
Kassoc values. Experiments were done in duplicate or triplicate. Values
reported are averages of all nuclei from all experiments. Errors reported
Fig. 1 Pyrrole-based hosts and their Kassoc values for Clꢀ determined
in CD3CN. Inset: calculated structure of 1ꢁClꢀ (HF/6-311+G**).
Data for 5 taken from ref. 14.
b
are standard deviations. p.t. = evidence of proton transfer between
host and guest; see text.
Table 2 Affinities of bis(tetrazole) 2 for various anionsa
Kassoc for 2 in
CD3CN (Mꢀ1
Kassoc for 2 in 1%
H2O/CD3CN (Mꢀ1
)
Guest
Clꢀ
)
K11 26 300 ꢂ 2300
K12 780 ꢂ 120
1500 ꢂ 430
1100 ꢂ 130
34 000 ꢂ 3500
1600 ꢂ 300
p.t.b
6500 ꢂ 500
Brꢀ
1100 ꢂ 50
650 ꢂ 50
3000 ꢂ 1000
900 ꢂ 300
p.t.b
Iꢀ
TsOꢀꢀ
NO3
BzOꢀ
a
All values are for K11 unless otherwise indicated. See also footnotes for
Table 1.
In pure CD3CN, titrations with Clꢀ gave rise to data that
indicated mixed 1 : 1 and 1 : 2 (H: G) complex formation. The
simple titration data was best fit to binding isotherms including
both the formation of 1 : 1 and 1 : 2 complexes, with the
Fig. 2 Chemical shift data (points) and fitted 1 : 1 binding isotherms
(lines) that arise upon titration of Bu4N+ Clꢀ into CD3CN solutions
of hosts 1 (’), 3 (K), 4 (m), and 6 (E). See ESI for experimental
details.w
expected strong 1 : 1 complex formation (K11 = 26 300 Mꢀ1
)
host to guest that is partially driven by the formation of a strong
RCOOꢀꢁ ꢁ ꢁHOOCR complex.5,17–20 All other (less basic) anions
studied produced NMR titration data that fit well to 1 : 1
binding isotherms to give Kassoc values (Table 1). To evaluate
better the potency of 1, we also studied 2,20-bipyrrole (6) with
the complete set of anions because it has a nearly identical
hydrogen bonding geometry to 1. Chemical shift data for
bipyrrole 6 fit well to 1 : 1 binding isotherms to give Kassoc
values for all anions tested (Table 1), with no evidence of
proton transfer to BzOꢀ (as expected). A 1 : 1 stoichiometry of
complexation was confirmed by Job plots for Clꢀ and BzOꢀ
(see ESIw). Comparison of these two hosts’ Kassoc values
reveals that the increased acidity of the tetrazole in 1 gives
rise to significantly higher affinities for all anions than 6, with a
maximum difference of B25-fold observed for TsOꢀ in both
solvent systems.
Finally, we carried out NMR studies of pyrrole bis(tetrazole) 2.
NMR studies in 1% H2O/CD3CN and in pure CD3CN show
the formation of 1 : 1 complexes with significantly increased
association constants relative to host 1 for all anions (Table 2),
demonstrating that both tetrazole NH’s and the central pyrrole
NH can cooperate to bind complementary anions as suggested
by models (Fig. 3). Titration with BzOꢀ again gave rise to
data suggesting binding followed by proton transfer (Fig. S15).
Fig. 3 Calculated structures and stepwise binding constants for
complexes of 2 with Clꢀ and TsOꢀ (truncated as methanesulfonate
for calculations). Inset: structure and K11 value for reference host 7.21
c
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Chem. Commun., 2011, 47, 12688–12690 12689

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followed by a much weaker binding of a second equivalent of Clꢀ
(K12 = 780 Mꢀ1). Job plot analysis also indicated mixed complex
formation, but in an unconventional way: the Job plot tracking
the chemical shift of the pyrrolic NH had its maximum at 0.5,
indicating 1 : 1 binding, while the plot tracking the pyrrolic CH
had a maximum at 0.3, indicating 1 : 2 binding (Fig. S24w). Mixed
Job plot results of this type must be interpreted with caution. In
this case, our hypothesis is that the pyrrolic NH reports largely on
the formation of the 1 : 1 complex while the chemical shift of the
CH arises largely due to the binding of the second equivalent of
Clꢀ. This theory is consistent with the calculated structures for
2ꢁClꢀ and 2ꢁ(Clꢀ)2 (Fig. 3), as are the relative magnitudes of
the experimentally determined values of K11 and K12.
as a general and synthetically simple improvement that will
provide orders-of-magnitude affinity enhancements for a large
number of other amide and urea-based anion-binding hosts.
Notes and references
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Host 2 also displays an altered guest-binding preference
relative to 1 in pure CD3CN, showing its highest affinity for
the oxyanion TsOꢀ (Kassoc = 34 000 Mꢀ1) instead of Clꢀ.
Molecular models (HF/6-311+G**) suggest that Clꢀ can’t
hydrogen bond to the peripheral tetrazole NH’s of 2 as
effectively as does the larger TsOꢀ anion (Fig. 3). In 2ꢁClꢀ
the distance between the tetrazole NH donor and Clꢀ acceptor
is dN–Cl = 3.41 A, or 0.11 A longer than the sum of van der
Waals radii;22 in 2ꢁTsOꢀ the equivalent hydrogen bonding
distances are dN–O = 2.813 and 2.815 A, which are 0.25 A
shorter than the sum of van der Waals radii. With that said, the
‘‘normal’’ selectivity of Clꢀ over TsOꢀ is observed in 1% H2O/
CD3CN, making it incautious to interpret these selectivities
exclusively in terms of host–guest contacts observed in
gas-phase calculations.23 Whatever the details of host–guest
complexation, stoichiometries, and geometries, it is clear that
the addition of tetrazoles has a consistently strong and favorable
influence on the anion binding properties of the pyrrole scaffold.
The potency of the 5-(2-pyrrolyl)tetrazole motif in this setting is
most clearly demonstrated by a simple comparison of the K11
of 2 for Clꢀ in CD3CN (26 300 Mꢀ1) to the reported value for
the closely related pyrrole bis(amide) 7 (138 Mꢀ1),21 a nearly
200-fold increase in affinity that arises from a simple tetrazole-
for-amide swap.
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Pyrroles offer a richness of photochemical and electro-
chemical properties, as well as diverse possibilities for synthetic
derivatization, that have driven researchers to incorporate them into
myriad anion hosts and sensors.4,24,25 Yet the potencies of simple,
acyclic pyrrole-based anion receptors can be orders of magnitude
weaker than their urea, squaramide, and indolocarbazole
counterparts.26–28 Tetrazoles are prized as metabolically stable
carboxylic acid bioisosteres in medicinal chemistry29 and have
shown promise as organocatalysts,30 but their favorable recogni-
tion properties have been ignored with few exceptions.8–10,31–34
Like other acidic recognition elements, tetrazoles are inherently
limited to moderately basic anions. But the tradeoff for this
limited scope is the ability to create potent receptors quickly and
easily without complex synthetic steps like macrocyclizations
and strapping reactions. Host 1 is derived from host 5 via a
tetrazole-for-amide swap, as host 2 is derived from host 7. We
envision that this conservative modification could be applied
c
12690 Chem. Commun., 2011, 47, 12688–12690
This journal is The Royal Society of Chemistry 2011