Macrocyclic and acyclic molecules synthesized from dipyrrolylmethanes: Receptors for anions

Article abstract of DOI:10.1021/ol101598e

A new class of macrocyclic and acyclic molecules was synthesized by the Mannich reactions of dipyrrolylmethanes to investigate anion recognition. The X-ray structures of the macrocycle and sulfate complexes are reported.

Full text of DOI:10.1021/ol101598e

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3910-3913
Macrocyclic and Acyclic Molecules
Synthesized from Dipyrrolylmethanes:
Receptors for Anions
Ganesan Mani,* Tapas Guchhait, Rajnish Kumar, and Shanish Kumar
Department of Chemistry, Indian Institute of Technology, Kharagpur, India 721 302
gmani@chem.iitkgp.ernet.in
Received July 12, 2010
ABSTRACT
A new class of macrocyclic and acyclic molecules was synthesized by the Mannich reactions of dipyrrolylmethanes to investigate anion
recognition. The X-ray structures of the macrocycle and sulfate complexes are reported.
Developing synthetic receptors that bind anions with high
affinity and selectivity is an active area of research in
supramolecular chemistry, as selective binding of an anion
can lead to an effective remedy for problems caused by
anions, which contaminate the environment and play im-
portant roles in biological systems.1,2 For example, the sulfate
anion is present in nuclear fuel waste along with other
oxoanions,3 which eventually get into the environment. Given
that the sulfate anion has a large standard Gibbs energy of
hydration (-1080 kJ mol-1), the separation of the sulfate
anion from an aqueous solution is a challenging task.4
However, in nature, the sulfate anion is recognized and
transported by the sulfate-binding protein through hydrogen
bonds.5 In an effort to mimic this natural phenomenon,
several synthetic sulfate-binding receptors have been reported
which can be broadly classified as receptors containing metal
centers6 and receptors without metal centers.7 While many
receptors of the former type have been reported and showed
high affinity and selectivity for the sulfate anion by a
(1) (a) Sessler, J. L.; Gale, P. A.; Cho, W.-S. Anion Receptor Chemistry;
Royal Society of Chemistry: Cambridge, 2006. (b) Bianchi, A.; Bowman-
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Lassahn, P. G. Chem. Commun. 2003, 902–903. (d) Custelcean, R.; Bosano,
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J. L. Coord. Chem. ReV. 2001, 222, 57–102. (c) Beer, P. D.; Gale, P. A.
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Nishiyabu, R.; Palacios, M. A. Coord. Chem. ReV. 2006, 250, 2929–2938.
(e) Zhang, Z.; Schreiner, P. R. Chem. Soc. ReV. 2009, 38, 1187–1198. (f)
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Sessler, J. L.; Katayev, E.; Pantos, G. D.; Llinares, J. M.; Hossain, M. A.;
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10.1021/ol101598e  2010 American Chemical Society
Published on Web 08/12/2010

Scheme 1. Synthesis of Receptors, 2·2H2O and 4·H2O, and Their Sulfate Complexes, 3 and 5·2H2O·MeOH
competition crystallization experiment, very few receptors
of the latter type with high affinity and selectivity for the
sulfate anion in aqueous medium are known.8
To develop receptors containing pyrrole rings, we used
Mannich reactions giving macrocycles9 in contrast to the
traditionally used condensation reactions. Applying the same
strategy on dipyrrolylmethanes, herein we report yet another
new class of receptors 2a-c and 4a-d, their sulfate
complexes 3a,b and 5, selective crystallization of 3a, and
anion recognition studies.
The new macrocycles 2a-c·2H2O were synthesized in
40-75% yields by the Mannich reactions of dipyrrolyl-
methanes10 in the presence of primary amine hydrochloride and
formaldehyde in a 1:1:2 molar ratio, respectively. In analogy
to azacalixarenes,11 2 can be named tetrahomodiazacalix[2]-
dipyrrolylmethane or diazacalix[2]dipyrrolylmethane. When the
reaction was carried out with secondary amine hydrochloride
and formaldehyde in a 1:2:2 molar ratio, respectively, acyclic
molecules 4a-d·H2O containing two R2NCH2 groups in the
1,9-positions were obtained in good yields (Scheme 1). Lind-
sey’s group reported similar types of acyclic Mannich bases of
dipyrrolylmethanes by using Eschenmoser’s reagent.12
1
The H NMR spectra of 2a-c·2H2O showed a broad
singlet at δ 8.55, 8.52, and 8.76, respectively, for their NH
protons, which are downfield shifted as compared to the
corresponding dipyrrolylmethane. The structures of the
macrocycles 2a-c are confirmed by the X-ray structure of
2a·2H2O and (+)ESI-MS spectra of 2a-c, which showed
the molecular ion peaks m/z at 515.3862, 539.3867, and
707.3858, respectively, corresponding to the mass of their
[M + H+] ions.
The structure of 2a·2H2O (Figure 1, a) reveals that the
molecule consists of two dipyrrolylmethane moieties con-
nected by two CH2N(Me)CH2 segments at 1,9-positions of
the dipyrrolylmethane molecule to form a tub-shape con-
formation, resembling the conformation of the cot molecule,
and two water molecules situated below the tub shape. While
two of the alternative pyrrole NH protons (N2 and N5) are
facing each other, the remaining two NH protons (N3 and
N6) and both the N-Me groups are pointing downward, the
direction in which the water molecules are attached. The
tertiary amine nitrogen atoms, N1 and N4, as H-bond
acceptor and the pyrrole N6H proton as H-bond donor are
involved in trapping a water molecule, which in turn is
H-bonded to another water molecule lying below the first
one.
(7) (a) Mateus, P.; Delgado, R.; Branda˜o, P.; Fe´lix, V. J. Org. Chem.
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K. J. Am. Chem. Soc. 2008, 130, 14386–14387. (b) Eller, L. R.; Stepien˜,
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Kubik, S. Org. Lett. 2007, 9, 5271–5274.
To investigate anion coordination chemistry of 2, the
sulfate anion complexes 3a and 3b·MeOH were synthesized
in 72% and 77% yields by the reaction between 2a·2H2O or
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Org. Lett., Vol. 12, No. 17, 2010
3911

Figure 1. ORTEP diagram of 2a·2H2O (a), 3a (b), and 5·2H2O·MeOH (c) with 30% probability ellipsoids. Most H atoms and one water
molecule of 5·2H2O·MeOH are omitted for clarity. Selected bond lengths (Å) and angles (deg): For 2a·2H2O: O1···N1 2.803(3), H1···N1
2.042(19), O1-H1···N1 147(3); O1···N4 2.823(3), H2···N4 2.010(18), O1-H2···N4 157(3); O2···O1 2.736(4), H3···O1 1.824(17), O2-H3···O1
174(3). For 3a: N1···O1 2.740(5), H1···O1 1.82, N1-H1···O1 172.4; N1···S1 3.493(4), H1···S1 2.63, N1-H1···S1 154.2; N2···O2 3.076(6),
H2A···O2 2.20, N2-H2A···O2 173.6; N2···S1 3.680(3), H2A···S1 2.91, N2-H2A···S1 147.7; N3···O2 2.992(6), H3A···O2 2.14, N3-H3A···O2
162.3; N4···O1 2.833(4), H4···O1 1.92, N4-H4···O1 167.8; N4···S1 3.530(4), H4···S1 2.65, N4-H4···S1 158.4. For 5·2H2O·MeOH: N2···O1
2.800(2), H2···O1 1.94, N2-H2···O1 178.2; N3···O1 2.821(2), H3···O1 1.97, N3-H3···O1 171.2; N4···O2 2.773(2), H4···O2 2.02, N4-H4···O2
139.3; O5···O3, 2.832(3), H2o···O3, 1.93(2), O5-H2o···O3 165(3); O5···S1 3.700(2), H2o···S1 2.93(2), O5-H2o···S1 142(2).
2b·2H2O and 2 equiv of Bu4NHSO4 in an EtOAc/MeOH
mixture, respectively. The analogous reaction between the
acyclic molecule 4c·H2O and Bu4NHSO4 afforded the sulfate
complex 5·2H2O·MeOH in 87% yield. As a result of the
a flat shape to 2a, and the sulfur atom lies at ∼1.5 Å from
this plane. Besides, 3a has a mirror plane passing through
N1, N4, C1, C17, S1, and O1 atoms; SO42- sits on the mirror
plane, and its O2, O3, and O4 atoms are disordered over
two positions.
1
sulfate anion coordination, the H NMR spectra of 3a and
3b showed, in contrast to the sulfate free macrocycles, two
different sets of resonances for the methylene groups of the
CH2N+H(Me)CH2 segment and their coupling with the N+H
proton.
The X-ray structure of 5·2H2O·MeOH (Figure 1, c) reveals
that one sulfate anion is bound to one molecule of 4c by
both electrostatic interactions from the ammonium cations
and hydrogen bonds. The two pyrrole NH protons, in a
chelated fashion, and one of the ammonium hydrogen atoms
(N4H), whose methyl groups are in gauche and trans
positions to the pyrrole carbon atom (C24) that is supported
by the dihedral angles (C26-N4-C25-C24 ) 48.9° and
C27-N4-C25-C24 ) 172.8°), are hydrogen bonded to O1
and O2, respectively. Conversely, the hydrogen atom of the
ammonium cation (N1H), whose two methyl groups are in
gauche positions to the pyrrole carbon atom (C1-N1-C3-C4
) -59.4° and C2-N1-C3-C4 ) 68.8°), is not hydrogen
bonded to the sulfate anion, but the methyl and methylene
groups of this segment (N1) are involved in C-H···O type
hydrogen bonds. Although the cation [4c·2H]2+ has four NH
protons for H-bonds, the sulfate anion utilizes only three of
them and prefers H-bonds with the solvent molecules.
The anion binding study of 2a·2H2O was carried out by
1H NMR titrations. The binding constants Ka of the com-
plexes formed between the receptor 2a·2H2O and the halide
anions were determined from the changes in the NH or
pyrrole ꢀ-CH resonance observed upon addition of aliquots
of anions as their tetra-n-butylammonium salts in acetone-
d6 at room temperature by the EQNMR program with a 1:1
receptor:anion model complex, which are verified by another
nonlinear least-squares method.13 As an interesting example,
upon addition of aliquots of fluoride anion to a solution of
2a·2H2O in acetone-d6, the NH resonance initially appeared
very broad and then appeared as a doublet with JHF ) 27
Hz, indicating a strong interaction with the receptor. Similar
coupling between pyrrole NH and F- has been reported
The sulfate complex 3a was also synthesized in 77%
crystalline yield from the reaction between 2a·2H2O and
sodium sulfate in the presence of 2 equiv of HCl. However,
the same reaction in the absence of HCl has not yielded 3a,
suggesting geometric and electrostatic complementarities
2-
between SO4 and [2a·2H]2+ that prefers the formation of
a sulfate complex rather than a chloride complex. This
observation led us to investigate the affinity of 2a·2H2O
toward the sulfate anion by a competition crystallization
experiment. Interestingly, only the sulfate complex 3a was
crystallized in more than 85% yield from a solution contain-
ing a mixture of 2 equiv of each competing anion such as
-
-
-
HSO4 (or SO42-/2HCl), H2PO4 , F-, Cl-, Br-, and NO3
(10 equiv) in the THF/H2O/MeOH (5:1:1, v/v) mixture and
was confirmed by 1H NMR and IR spectra (see the
Supporting Information). Treatment of 3a with aq NaOH
gave back the receptor 2a·2H2O. Thus, the selective crystal-
lization of 3a from an aqueous-organic solvent and the
recovery of the receptor form a process for separating sulfate
anions present in nuclear waste.
The structure of the sulfate complex 3a (Figure 1, b) is
confirmed by X-ray and reveals that the sulfate anion is
coordinated to 2a through NH···O, NH···S, and C-H···O
types of H-bonds and is further stabilized by the electrostatic
interactions from the two ammonium cations formed in situ
by the transfer of protons from Bu4NHSO4. While all the
pyrrole NH and the ammonium hydrogen atoms are pointing
toward the sulfate anion and hydrogen bonded, the NMe
groups are facing the opposite side. All of the pyrrole N
atoms, both of the meso-carbons of the dipyrrolylmethane
moieties, and the sulfate O1 atom are in a plane, rendering
(13) (a) Hynes, M. J. J. Chem. Soc., Dalton Trans. 1993, 311–312. (b)
Hirose, K. J. Inclusion Phenom. Macrocyclic Chem. 2001, 39, 193–209.
3912
Org. Lett., Vol. 12, No. 17, 2010

earlier.14 Conversely, the resonance due to the pyrrole ꢀ-CH
protons smoothly shifted to the upfield region for which the
titration curve could be fitted rather well in comparison to
the NH resonance. The fluoride anion induced change in the
chemical shift of the NH proton is the largest (∆δ ) 5.34)
among the halide anions.
A similar range of log Ka has also been observed with other
receptors.15 This binding stoichiometry was confirmed by
the Job’s plot in CDCl3 that showed a maximum at 0.33
mol fraction of 4c·H2O. This 1:2 complex formation in CDCl3
is in constrast to the solid state structure of 5·2H2O·MeOH.
Probably, the structure of the 1:2 complex is cleaved to form
most stable (Bu4N)2SO4 and a 1:1 complex when it crystal-
lizes from a MeOH-EtOAc mixture. The slow exchange
process and the large Ka indicate the preference of the
receptors, 2·2H2O and 4·H2O, for the sulfate anion over other
anions and is supported by the readily forming crystals of 3
and 5·2H2O·MeOH and the selective crystallization of 3a.
In conclusion, novel macrocycles 2a-c·2H2O, representing
a new class of expanded calix[4]pyrrole molecule, and
acyclic molecules 4a-d·H2O are synthesized and act as
receptors for anions. 2a-c·2H2O and 4a-d·H2O have both
hydrogen bond donors (NH) and acceptors (tertiary amine
groups) in the cleft, which make them suitable to act as an
ion-pair receptor for which 3 and 5·2H2O·MeOH are the
examples. The flexibility of the macrocycle in changing its
conformation to accommodate a guest species is demon-
strated through the crystal structure of 3a. Work on other
pyrrole-based receptors is under progress.
Figure 2.
1H NMR titration curve fittings for 2a·2H2O.
The titration curve fittings are given in Figure 2. The
binding constants Ka of 2a·2H2O for F-, Cl-, and Br- are
>104, 4763 (<10% error), and 317 (13% error) M-1,
respectively, and the binding stoichiometry 1:1 for each
complex is confirmed by Job’s plots, showing maxima at
0.5 mol fraction of 2a·2H2O (see the Supporting Information).
No change in the NH resonance was observed upon addition
of iodide anion. This trend of Ka, F- > Cl- > Br- > I-, is
the same as the strength of the hydrogen bonds formed by
these anions.
Acknowledgment. We thank the CSIR and DST for
support and for the X-ray and NMR facilities. We thank Dr.
G. P. A. Yap, Department of Chemistry and Biochemistry,
University of Delaware, for his help with the X-ray structures
and Dr. Carola Schulzke, Trinity College, Dublin, for HRMS.
Supporting Information Available: Synthetic procedures;
NMR, IR, crystallographic data (CIF); structure refinement
data;16 X-ray structures; and details of binding constant
calculations. This material is available free of charge via the
Internet at http://pubs.acs.org.
As 1H NMR titration spectra of 2a·2H2O and Bu4NHSO4
showed a slow exchange process in CDCl3 or in acetone-d6,
its Ka could not be determined. Conversely, log Ka for the
sulfate complex of 4a·H2O or 4c·H2O in CDCl3 was estimated
to be >4 by EQNMR with a 1:2 model complex (host:guest).
OL101598E
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