"Unclosed cryptands": A point of departure for developing potent neutral anion receptors

Article abstract of DOI:10.1021/ol303065k

Six macrocyclic lariat-type compounds, representing a new class of anion receptors, were synthesized in a simple approach. We identified the optimal macroring size and the position of the hydrogen bond donating center in the lariat arm offering the best a

Full text of DOI:10.1021/ol303065k

ORGANIC
LETTERS
2012
Vol. 14, No. 24
6298–6301
“Unclosed Cryptands”: A Point of
Departure for Developing Potent
Neutral Anion Receptors
Kajetan Dabrowa, Marcin Pawlak, Piotr Duszewski, and Janusz Jurczak*
)
Institute of Organic Chemistry, Polish Academy of Science, Kasprzaka 44/52,
01-224 Warsaw, Poland
jurczak@icho.edu.pl
Received November 7, 2012
ABSTRACT
Six macrocyclic lariat-type compounds, representing a new class of anion receptors, were synthesized in a simple approach. We identified the
optimal macroring size and the position of the hydrogen bond donating center in the lariat arm offering the best affinities toward chloride and
carboxylate anions. The anion-binding properties of such systems were investigated by applying 1H NMR titrations in DMSO/water and methanol/
DMSO mixtures.
Both inorganic and organic anions take part in various
biological processes and are responsible for many natural
phenomena.1,2 Consequently, investigation of anion com-
plexation has attracted much attention in recent decades,
bolstering its importance among the biosciences and leading
to the discovery of its potential applications in medicine and
in industrial processes.3 For example, Gokel et al.4 recently
reported an elegant example of simple receptors based on
2,6-dipicolinic acid that facilitate the transport of large
plasmids across a lipid bilayer, which may find applications
in gene therapy. Reek et al.5 developed transition metal
catalysts, equipped with an anion binding pocket that
functions as a selectivity controlling unit, for industrially
important hydrogenation and hydroformylation reac-
tions. Nevertheless, it remains one of the great medical
challenges for anion receptor design to create an artificial
anion transport system6 that can substitute for the defec-
tive chloride channels of patients suffering from cystic
fibrosis, a common genetic disease.7 Moreover, car-
boxylic anions are also of interest due to the ubiquity of
ionized carboxylate functions in numerous important
biomolecules, ranging from simple anions, such as acetate
and benzoate, up to more complex amino acids and
proteins.8 However, to date only a few neutral, efficient
receptors for the above-mentioned anions operating in
(1) (a) Bianchi, A.; Bowman-James, K.; Garcia-Espana, E. Supra-
molecular Chemistry of Anions; Wiley-VCH: New York, 1997. (b) Sessler,
J. L.; Gale, P. A.; Cho, W. S. Anion Receptors Chemistry; The Royal Society
of Chemistry: Cambridge, 2006.
(2) Steed, J. W.; Atwood, J. L. Supramolecular Chemistry, 2nd ed.;
John Wiley & Sons, Ltd.: 2009.
(3) For selected recent reviews on anion receptors, see: (a) Caltagirone,
C.; Gale, P. A. Chem. Soc. Rev. 2009, 38, 520–563. (b) Gale, P. A. Chem.
Soc. Rev. 2010, 39, 3746–71. (c) Wenzel, M.; Hiscock, J. R.; Gale, P. A.
Chem. Soc. Rev. 2012, 41, 480–520.
(6) For recent examples of chloride anion transporters, see: (a) Davis,
A. P.; Sheppard, D. N.; Smith, B. D. Chem. Soc. Rev. 2007, 36, 348–57.
(b) Gokel, G. W.; Barkey, N. New J. Chem. 2009, 33, 947–63. (c) Davis,
J. T.; Okunola, O.; Quesada, R. Chem. Soc. Rev. 2010, 39, 3843–62.
(d) Haynes, C. J. E.; Gale, P. A. Chem. Commun. 2011, 47, 8203–09.
(e) Gale, P. A. Acc. Chem. Res. 2011, 44 (3), 216–26. (f) Haynes, C. J. E.;
Moore, S. J.; Hiscock, J. R.; Marques, I.; Costa, P. J.; Felix, V.; Gale,
P. A. Chem. Sci. 2012, 3, 1436–44.
(4) Atkins, J. L.; Patel, M. B.; Daschbach, M. M.; Meisel, J. W.;
Gokel, G. W. J. Am. Chem. Soc. 2012, 134, 13546–549.
(5) (a) Dydio, P.; Dzik, W. I.; Lutz, M.; de Bruin, B.; Reek, J. N. H.
Angew. Chem., Int. Ed. 2011, 50, 396–400. (b) Dydio, P.; Rubay, C.;
Gadzikwa, T.; Lutz, M.; Reek, J. N. H. J. Am. Chem. Soc. 2011, 133,
17176–179.
(7) (a) Chan, H. C.; Law, S. H.; Leung, P. S. J. Membrane Biol. 1997,
156, 241–49. (b) Gadsby, D. C.; Vergani, P.; Csanady, L. Nature 2006,
440, 477–83.
(8) (a) Stibor, I.; Zlatuskova, P. Top. Curr. Chem. 2005, 255, 31–63.
(b) Hembury, G. A.; Borovkov, V. V.; Inoue, Y. Chem. Rev. 2008, 108,
1–73. (c) Dieng, P. S.; Sirlin, C. Int. J. Mol. Sci. 2010, 11, 3334–48.
r
10.1021/ol303065k
Published on Web 12/10/2012
2012 American Chemical Society

demanding solvents,9 suitable for practical application,
have been identified.10 One successful strategy for devel-
oping such receptors is to use the chemistry of cryptands,
as has recently been shown by Bowman-James et al.11 In
our laboratory we obtained compounds, structurally
related to cryptands, that are in principle macrocycles
with a flexible substituentꢀlariat arm.12 In the study reported
here, we designed, obtained, and studied the properties of this
new class of putative anion receptors 1ꢀ4 (Figure 1), which
we have called “unclosed cryptands”.
Scheme 1. Synthesis of Receptors 1aꢀc and 2ꢀ4b
Figure 1. Structures of the receptors examined.
reaction developed in our laboratory.13 In this reaction
R,ω-diesters 7a,b and 14a,b react with R,ω-diamines
11aꢀc in methanol, in the presence of sodium methoxide,
affording macrocyclic receptors 1aꢀc, 2ꢀ4b in acceptable
yields of 24, 56, 60, 78, 36, and 89%, respectively, without
the necessity of employing high-dilution conditions. The
synthesis of R,ω-diesters and R,ω-diamines, substrates for
macrocyclization, is also presented in Scheme 1.
Anion Complexation Studies. The stability constants of
receptors 1aꢀc and 2b with the examined anions were
determined by a 1H NMR titration technique in a mixture
of DMSO-d6 and water (ranging from 0.5 to 10% v/v) and
additionally, in the case of receptor 2b, with acetate in a
mixture of MeOH-d3 and DMSO-d6 (20%) (Table 1). The
corresponding titration curves are consistent with a 1:1
binding model14 for all the experiments presented, except
for 1a with acetate.
We presumed that these compounds’ structural simi-
larity to that of the Bowman-James cryptand-like anion
receptors would provide a similar efficiency in anion
binding, while on the other hand their modular synthesis
would allow their selectivity to be fine-tuned toward
desired anions. In this work we also examined the influ-
ence of the type and the position of the hydrogen bond
donors (amide or thioamide group) in the lariat arm as
well as the size of the macroring on the anion recognition
process. Apart from model ligand 1a, composed of two
cooperating binding pockets and a lariat arm equipped with
additional hydrogen bonding functions that, presumably,
can strongly influence interaction with anions, we studied its
analogues: the unclosed cryptands 1b,c and 2ꢀ4b.
Synthesis. The macrocyclic receptors 1ꢀ4 were obtained
as shown in Scheme 1, utilizing the double amidation
(9) (a) Kubik, S. Chem. Soc. Rev. 2009, 38, 585–605. (b) Krause,
M. R.; Goddard, R.; Kubik, S. J. J. Org. Chem. 2011, 76, 7084–95.
(c) Dydio, P.; Lichosyt, D.; Jurczak, J. Chem. Soc. Rev. 2011, 40, 2971–
85. For selected examples, see: (d) Caltagirone, C.; Gale, P. A.; Hiscock,
J. R.; Brooks, S. M.; Hursthouse, M. B.; Light, M. E. Chem. Commun.
2008, 3007–09. (e) Caltagirone, C.; Gale, P. A.; Hiscock, J. R.; Brooks,
S. M.; Hursthouse, M. B.; Light, M. E. Chem.;Eur. J. 2008, 14, 10236–
43. (f) Fiehn, T.; Goddard, R.; Seidel, R. W.; Kubik, S. Chem.;Eur. J.
2010, 16, 7241–55. (g) Dydio, P.; Lichosyt, D.; Zielinski, T.; Jurczak, J.
Chem.;Eur. J. 2012, 18, 13686–701. (h) Basu, A.; Das, G. Dalton Trans.
2012, 41, 10792–802.
Table 1. Binding Constants [Mꢀ1] for the Formation of 1:1
(HostꢀGuest) Complexes of Ligands 1aꢀc and 2b with Various
Anions in DMSO-d6 þ 0.5% H2Oa
anions
1a
1b
1c
2b
Clꢀ
96
490
490
11
1479
ꢀ
b
CH3CO2
ꢀ
191
128
>10000c
170d
ꢀ
C6H5CO2
95
270
1202c
(10) Oshovsky, G. V.; Reinhoudt, D. N.; Verboom, W. Angew.
Chem., Int. Ed. 2007, 46, 2366–93.
a Values determined by 1H NMR titration experiments at T = 298 K
using HypNMR 2008 software,15 errors <10%, TBA salts as the source
of anions. b Complex binding interactions. c DMSO-d6 þ 10% water.
d MeOH-d3 þ 20% DMSO-d6.
(11) (a) Hossain, M. A.; Kang, S. O.; Kut, J. A.; Day, V. W.;
Bowman-James, K. Inorg. Chem. 2012, 51, 4833–40. (b) For more
examples of cryptand-like receptors, see: Kang, S. O.; Llinares, J. M.;
Day, V. W.; Bowman-James, K. Chem. Soc. Rev. 2010, 39, 3980–4003.
(12) (a) Kalisiak, J.; Piatek, P.; Jurczak, J. Synthesis 2005, 13, 2210–
2214. (b) Kalisiak, J.; Jurczak, J. Cryst. Growth Des. 2006, 6, 20–22.
(c) Kalisiak, J.; Kalisiak, E.; Jurczak, J. Tetrahedron 2006, 62, 5905–
5914. (d) Nowicka, K.; Bujacz, A.; Paluch, P.; Sobczuk, A.; Jeziorna, A.;
Ciesielski, W.; Bujacz, G. D.; Jurczak, J.; Potrzebowski, M. J. Phys.
Chem. Chem. Phys. 2011, 13, 6423–33.
Among receptors of type 1, compound 1b shows the
best affinity toward all the anions examined, showing
slight selectivity against acetate over chloride and benzoate
Org. Lett., Vol. 14, No. 24, 2012
6299

anions, a finding that is in accordance with our previous
results.15
The structures of 1b and 2b are similar to one another
and show high levels of preorganization; all four macro-
cyclic amide protons are directed into the cavity; only the
amide proton from the lariat group is faced outside the
macrocycle. The arrangement of the latter proton is un-
favorable for anion binding. Furthermore, receptor 1b
forms a dimeric structure employing two strong inter-
˚
molecular H-bonds NꢀO (2 ꢁ 2.77 A) between the amide
N(1) proton and carbonyl oxygen atoms O(2) and O(3)
from macrocyclic amide groups and one moderate NꢀO
˚
(2.98 A) intramolecular H-bonding between N(2) and
O(1). In the case of 2b the amide N(1) proton does not
participate in any intra- or intermolecular H-bonding,
which may explain the superior binding properties of 2b
in comparison to 1b. Moreover, in the latter case, before
an anion can be bound the intramolecular H-bonding
must be broken. To improve the selectivity and binding
properties of our model receptor 1b we altered the posi-
tion of heteroatoms in the lariat arm, designing and ob-
taining compounds 3b and 4b, the binding properties of
which are presented in Table 2.
Figure 2. Plot of log(Kassoc) of 1aꢀc with chloride (black
squares) and benzoate (red triangles) anions vs size of the
macroring (left). Typical 1H NMR signal shifts of amide protons
of ligand 1b (red) and 2b (black) with acetate (triangles) and
chloride (squares) anions in DMSO-d6 þ 0.5% H2O (right).
This rather unusual selectivity reveals the optimal geo-
metric complementarity of receptor 1b to the spheric
chloride anion, which is bound from 4 to over 40 times
more strongly than for receptors 1a and 1c, respectively.
In the case of carboxylate anions, 1b is about twice as effi-
cient as the other two (Figure 2). Therefore, for further
modifications we chose the 24-membered macroring (with
the three-carbon linker). Moreover, replacing the amide
(1b) with a thioamide (2b) group enhanced the acidity16a of
the hydrogen NH proton; thus one can expect the disap-
pearance of the alternatively existing intramolecular hydro-
gen bonds.16b
Table 2. Binding Constants [Mꢀ1] for the Formation of 1:1
(HostꢀGuest) Complexes of Ligands 1b vs 3b and 2b vs 4b with
Various Anions in DMSO-d6 þ 0.5% H2Oa
anions
3b
1b
4b
2b
Clꢀ
778
642
490
490
4266
1479
ꢀ
b
CH3CO2
ꢀ
>10000c
170d
ꢀ
b
C6H5CO2
162
270
ꢀ
1202c
Fortunately, receptors 1b and 2b form monocrystals
suitable for X-ray analysis, the results of which are
presented in Figure 3.16
a Values determined by 1H NMR titration experiments at T = 298K,
using HypNMR 2008 software,15 errors <10%, TBA salts as the source
of anions; b Deprotonation of the receptor; c DMSO-d6 þ 10% water;
d MeOH-d3 þ 20% DMSO-d6.
A comparison of the binding properties of these new
receptors with those of receptors 1b and 2b shows that this
simple structural isomerism results, for example, in sta-
bility constant values almost twice as high for 3b as for 1b.
Interestingly, the selectivity of 3b toward anions is more
perturbed than for 1b, the chloride anion being bound more
(13) (a) Szumna, A.; Jurczak, J. Helv. Chim. Acta 2001, 84, 3760–65.
(b) Szumna, A.; Jurczak, J. J. Org. Chem. 2001, 4031–39. (c) Szumna, A.;
Gryko, D. T.; Jurczak, J. Heterocycles 2002, 56, 361–68. (d) Piatek, P.;
Jurczak, J. Chem. Commun. 2002, 2450–51. (e) Chmielewski, M.;
Jurczak, J. Tetrahedron Lett. 2004, 45, 6007–10. (f) Chmielewski,
M. J.; Szumna, A.; Jurczak, J. Tetrahedron Lett. 2004, 45, 8699–8703.
(g) Chmielewski, M. J.; Jurczak, J. Tetrahedron Lett. 2005, 46, 3085–88.
(h) Chmielewski, M. J.; Jurczak, J. Chem.;Eur. J. 2005, 11, 6080–94.
(i) Chmielewski, M. J.; Jurczak, J. Chem.;Eur. J. 2006, 12, 7652–67.
ꢀ
(j) Chmielewski, M. J.; Zielinski, T.; Jurczak, J. Pure Appl. Chem. 2007,
79, 1087–96.
(14) (a) Job, P. Ann. Chim. Appl. 1928, 9, 113–203. (b) Connors, K. A.
Binding Constants, The Measurement of Molecular Complex Stability;
Wiley: New York, 1987; p 24.
(15) Frassineti, C.; Alderighi, L.; Gans, P.; Sabatini, A.; Ghelli, A. V.
Anal. Bioanal. Chem. 2003, 376, 1041–52.
ꢀ
(16) (a) Zielinski, T.; Jurczak, J. Tetrahedron 2005, 61, 4081–89.
Figure 3. Structures of free ligands 1b (top-left) and 2b (top-
right) and their respective dimeric forms (bottom). Nonacidic
protons and solvent molecules were omitted for clarity.
(b) Inoue, Y.; Kanbara, T.; Yamamoto, T. Tetrahedron Lett. 2003, 44,
5167–69.
(17) Both crystals were obtained by slow evaporation of DMSO
solution of receptors.
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Org. Lett., Vol. 14, No. 24, 2012

strongly than the acetate and benzoate ones. This unusual
selectivity, against the Hofmeister bias,19 is presumably a
consequence of a perfect fit of the chloride anion to the
macrocyclic cavity. This assumption is supported by DFT
calculation (Figure 4).
Figure 5. Proposed mechanism of deprotonation of 4b by car-
boxylate anions (left). Titration curves of ligands 2b (red color,
filled symbols) vs 4b (green color, unfilled symbols) with benzo-
ate in DMSO-d6 þ 10% water (right).
aromatic lariat protons next to nitro groups shift upfield,
and aromatic protons next to the thioamide group shift
downfield (Figure 5, right).
Figure 4. Top and side views of a DFT (B3LYP 6-31þG*)
optimized structure of the chloride complex of receptor 3b.
In conclusion, we obtained a new class of receptors
which present remarkable affinity and selectivity toward
important anionic guests, operating in demanding media,
i.e. DMSO-d6/water and MeOH-d3/DMSO-d6 mixtures.
Notably, the significant binding affinities of these un-
closed cryptands to chloride and carboxylates are much
higher than to some extent structurally similar neutral
cryptands.11 These properties, in connection with possi-
bilities for ready structural modifications, open up pro-
spects for constructing further receptors fulfilling the
requirements for chiral recognition of carboxylates, and
for potent chloride anion transporters.
However, the situation in the case of thioamide analog
4b is quite different; namely, the chloride anion is bound
almost three times more strongly than for 3b, while in the
case of carboxylates a deprotonation process probably
occurs. The latter observation, a common problem in anion
complexation chemistry,20 is supported by the titration
curve profiles of aromatic protons in the lariat arm and the
disappearance of the lariat NH(R) proton during titration
(Figure 5). Deprotonation of 4b is presumably enhanced by
the high stabilization of both tautomeric forms: form A by
two intramolecular H-bonds and form B by the aci- form of
the nitro group. Furthermore, titration curve profiles for
4b with carboxylate and hydroxide anions are identical
and are independent of water content in DMSO-d6 (see
Supporting Information). Additionally the titration curve
profiles for 4b are different from those for 2b, for which
Acknowledgment. We would like toacknowledge Pawez
Dydio for valuable discussions, and Dr. Łukasz Dobrzycki
and Marcin Stachowicz (Faculty of Chemistry, University
of Warsaw) for crystallographic measurements.
Supporting Information Available. Receptor synthesis,
crystallographic data (CIFs), titration experiments, Job
plots, and DFT calculated structures of the receptor com-
plexes with anions. This material is available free of charge
via the Internet at http://pubs.acs.org.
(18) Spartan’10 for Windows, Wavefunction Inc., California, USA,
2011, www.wavefun.com.
(19) Hofmeister, F. Arch. Exp. Pathol. Pharmakol. 1888, 24, 247–60.
(20) A similar observation was reported by Fabbrizzi et al.; for more
ꢀ
details, see: (a) Boiocchi, M.; Boca, L. D.; Gomez, D. E.; Fabbrizzi, L.;
Licchelli, M.; Monzani., E. J. Am. Chem. Soc. 2004, 126, 16507–14.
ꢀ
(b) Boiocchi, M.; Del Bocca, L.; Esteban-Gomez, D.; Fabbrizzi, L.;
Licchelli, M.; Monzani, E. Chem.;Eur. J. 2005, 11, 3097–3104.
The authors declare no competing financial interest.
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