N-tosylpyrrolidine calix[4]pyrrole: Synthesis and ion binding studies

Article abstract of DOI:10.1021/jo101882r

The synthesis and preliminary solution phase ion binding properties of the N-tosylpyrrolidine calix[4]pyrrole 2 are reported. This β-octaalkyl- substituted calix[4]pyrrole, the first to be prepared via a direct condensation reaction, was obtained by react

Full text of DOI:10.1021/jo101882r

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N-Tosylpyrrolidine Calix[4]pyrrole: Synthesis and Ion Binding Studies
Sung Kuk Kim,† Dustin E. Gross,† Dong-Gyu Cho,†,‡ Vincent M. Lynch,† and
Jonathan L. Sessler*,†,§
†Department of Chemistry and Biochemistry, 1 University Station-A5300, The University of Texas at Austin,
Austin, Texas 78712-0165, United States, ‡Department of Chemistry, Inha University,
253 Yonghyundong Namgu, Incheon, 402-751, Korea, and §Department of Chemistry,
Yonsei University, Seoul 120-749, Korea
sessler@mail.utexas.edu
Received September 25, 2010
The synthesis and preliminary solution phase ion binding properties of the N-tosylpyrrolidine calix-
[4]pyrrole 2 are reported. This β-octaalkyl-substituted calix[4]pyrrole, the first to be prepared via a direct
condensation reaction, was obtained by reacting the 3,4-alkyl-functionalized pyrrole 8 with acetone in the
presence of an acid catalyst. On the basis of 1H NMR spectroscopic analyses and isothermal titration
calorimetry, it was concluded that, compared with the parent, β-unsubstituted calix[4]pyrrole (1),
compound 2 possesses significantly enhanced binding ability for halide anions in chloroform. Further-
more, 2 proved capable of solubilizing in chloroform solution the otherwise insoluble salts, CsF and CsCl.
These effects are ascribed to the interactions between the four tosyl groups present in 2 and the counter
cations of the halide anion salts.
Introduction
affinity and selectivity for specific anionic guests. These efforts
have led, inter alia, to the development of calix[4]pyrrole-based
anion receptors, such as strapped calix[4]pyrroles5 and β-sub-
stituted calixpyrroles.6 In addition, calix[4]pyrrole derivatives
equipped with various chromogenic, fluorogenic, or redox-
active units have been synthesized for anion sensing.6,7 As a
general rule, calix[4]pyrrole derivatives with improved anion
recognition features have been obtained by modifying either the
A century after it was first synthesized in 1886 by Baeyer,1
meso-octamethylcalix[4]pyrrole 1, a tetrapyrrolic macrocycle,
was found in 1996 by Sessler and co-workers to act as an effi-
cient receptor for specific anions, such as halides, carboxylates,
and phosphates.2,3 Since that time, increasing attention has
been paid to calix[4]pyrrole 1 as an anion receptor,4 with con-
siderable effort having been devoted to enhancing the binding
(1) Baeyer, A. Ber. Dtsch. Chem. Ges. 1886, 19, 2184–2185.
ꢀ
(5) (a) Lee, C.-H.; Miyaji, H.; Yoon, D.-W.; Sessler, J. L. Chem. Commun.
2008, 24–34. and references cited therein. (b) Yoon, D.-W.; Gross, D. E.;
Lynch, V. M.; Sessler, J. L.; Hay, B. P.; Lee, C.-H. Angew. Chem., Int. Ed.
2008, 47, 5038–5042.
(2) (a) Gale, P. A.; Sessler, J. L.; Kral, V.; Lynch, V. J. Am. Chem. Soc.
1996, 118, 5140–5141. (b) Allen, W. E.; Gale, P. A.; Brown, C. T.; Lynch,
V. M.; Sessler, J. L. J. Am. Chem. Soc. 1996, 118, 12471–12472.
ꢀ
ꢀ
(6) (a) Sessler, J. L.; Anzenbacher, P., Jr.; Shriver, J. A.; Jursıkova, K.;
´
(3) Gale, P. A.; Sessler, J. L.; Kral, V. Chem. Commun. 1998, 1–8.
(4) (a) Sessler, J. L.; Gale, P. A.; Cho, W.-S. Anion Receptor Chemistry;
Monographs in Supramolecular Chemistry; Stoddart, J. F., Ed.; RSC Publish-
ing: Cambridge, U.K., 2006. (b) Beer, P. D.; Gale, P. A. Angew. Chem., Int. Ed.
2001, 40, 486–516. (c) Gale, P. A. Coord. Chem. Rev. 2003, 240, 191–221. (d) Gale,
P. A.; Quesada, R. Coord. Chem. Rev. 2006, 250, 3219–3244. (e) Gale, P. A.;
Lynch, V. M.; Marquez., M. J. Am. Chem. Soc. 2000, 122, 12061–12062. (b)
Sessler, J. L.; Cho, W.-S.; Gross, D. E.; Shriver, J. A.; Lynch, V. M.;
Marquez, M. J. Org. Chem. 2005, 70, 5982–5986. (c) Nielsen, K. A.;
Jeppesen, J. O.; Levillain, E.; Becher, J. Angew. Chem., Int. Ed. 2003, 42,
187–191. (d) Nielsen, K. A.; Cho, W.-S.; Lyskawa, J.; Levillain, E.; Lynch,
V. M.; Sessler, J. L.; Jeppesen, J. O. J. Am. Chem. Soc. 2006, 128, 2444–2451.
´
Garcıa-Garrido, S. E.; Garric, J. Chem. Soc. Rev. 2008, 37, 151–190.
DOI: 10.1021/jo101882r
r
Published on Web 12/09/2010
J. Org. Chem. 2011, 76, 1005–1012 1005
2010 American Chemical Society

Kim et al.
JOCFeatured Article
meso-positions or the β-pyrrolic positions with various
functional groups.5-8 However, in both cases the under-
lying syntheses are subject to limitations. For instance, the
use of asymmetric ketones leads to a mixture of configura-
tional isomers, which complicates purification efforts.8 In
contrast, functionalization of the pyrrolic β-positions leads
to unfavorable steric interactions with the methyl groups
on the meso-carbon atoms.9 Therefore, only relatively
small groups such as halogen, oxygen, and sulfur atoms,
but not methylene (-CH2-), can be introduced directly
into the β-pyrrolic positions via the standard acid-cata-
lyzed pyrrole þ ketone condensation strategy typically
used to prepare calix[4]pyrroles.6,9 In some cases, the
introduction of β-pyrrolic substituents decreases the anion
affinity, presumably as the result of destabilizing the cone
conformation that favors calix[4]pyrrole-anion interac-
tions.9,10 Nevertheless, we consider β-carbon functiona-
lized calix[4]pyrroles bearing methylene substitutents to be
worthy synthetic targets. In particular, we suggest that, if
appropriately elaborated, such species could prove useful
as ion pair receptors. Ion pair receptors, species capable of
forming simultaneously a complex with both a cation and
an anion, are interesting in that they generally display
higher selectivities and affinities than do simple ion recep-
tors.4b,11 We recently reported that calix[4]pyrrole 1 can
form a complex with cesium halide ion pairs in the solid
state where anions are bound to the pyrrolic NH protons
through hydrogen bonds and the Csþ cation is held within
the cone-like cavity of the calix[4]pyrrole via apparent
π-cation interactions.12 Here, we report that the intro-
duction of N-tosylpyrrolidine units, specifically when fused
onto the β-pyrrolic positions, gives rise to a system, 2, that
displays anion affinities that are enhanced relative to calix-
[4]pyrrole1. We also show that this new β-octaalkyl-substituted
calix[4]pyrrole acts as an effective receptor for cesium halide ion
pairs in chloroform solution.
Results and Discussion
The synthesis of 2 is outlined in Scheme 1. It starts with
diethyl pyrrole-3,4-dicarboxylate 3,13 which was subjected to
N-protection by treating with tosyl chloride. The diester groups
were then reduced with LAH to afford N-p-toluenesulfonlyl-
pyrrole-3,4-dimethanol (5). Bromination of this latter diol with
PBr3, followed by cyclization with TsNHNa, gave the bicyclic
pyrrole (7) in moderate yield. Treatment of this ditosyl pyrrole
(7) with excess sodium methoxide (30 equiv) in a mixture of
THF/methanol (3/1) served to remove only the tosyl group on
the pyrrole moiety leaving that on the pyrrolidine moiety
untouched; this gave N-p-toluenesulfonylpyrrolidinylpyrrole 8
in 91% yield. Condensation of this latter pyrrole with acetone in
the presence of 1 equiv of trifluoroacetic acid (TFA) then gave
the desired β-octaalkyl-substituted calix[4]pyrrole derivative 2
in 20% yield.
Calix[4]pyrrole 2 was characterized by standard spectro-
scopic techniques as well as by single-crystal X-ray diffraction
analysis. Two crystals of the anion-free form of 2 suitable for
such analyses were obtained. They were grown by slow
evaporation of solutions of 2 made up in chloroform/methanol
(1/1) and dichloromethane/DMF (10/1). In both cases, the
resulting structures revealed that calix[4]pyrrole 2 adopts the
so-called 1,2-alternate conformation in the solid state with
two solvent molecules bound to the pyrrolic NH protons
(7) (a) Miyaji, H.; Anzenbacher, P., Jr.; Sessler, J. L.; Bleasdale, E. R.;
Gale, P. A. Chem. Commun. 1999, 1723–1724. (b) Anzenbacher, P., Jr.;
ꢀ
´
Jursıkova, K.; Sessler, J. L. J. Am. Chem. Soc. 2000, 122, 9350–9351. (c)
Miyaji, H.; Sato, W.; Sessler, J. L. Angew. Chem., Int. Ed. 2000, 39, 1777–1780.
(d) Miyaji, H.; Sato, W.; Sessler, J. L.; Lynch, V. M. Tetrahedron Lett. 2000, 41,
1369–1373. (e) Miyaji, H.; Sato, W.; An, D.; Sessler, J. L. Collect. Czech. Chem.
Commun. 2004, 69, 1027–1049. (f) Nishiyabu, R.; Anzenbacher, P., Jr. J. Am.
Chem. Soc. 2005, 127, 8270–8271. (g) Nishiyabu, R.; Palacios, M. A.; Dehaen,
W.; Anzenbacher, P., Jr. J. Am. Chem. Soc. 2006, 128, 11496–11504. (h)
Palacios, M. A.; Nishiyabu, R.; Marquez, M.; Anzenbacher, P., Jr. J. Am.
Chem. Soc. 2007, 129, 7538–7544.
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(8) (a) Anzenbacher, P., Jr.; Jursıkova, K.; Lynch, V. M.; Sessler, J. L.
´
J. Am. Chem. Soc. 1999, 121, 11020–11021. (b) Bonomo, L.; Solari, E.; Toraman,
G.; Scopelliti, R.; Floriani, C.; Latronico, M. Chem. Commum. 1999, 2413–2414.
(Figures 1 and 2). In the single-crystal structure of 2 (MeOH)2,
3
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rez, G.; Benet-Buchholz, J.; Escudero-Adan, E. C.; Ballester, P. J.
(c) Gil-Ramı
Am. Chem. Soc. 2007, 129, 3820–3821. (d) Gil-Ramı
E. C.; Benet-Buchholz, J.; Ballester, P. Angew. Chem., Int. Ed. 2008, 47, 4114–
4118. (e) Verdejo, B.; Gil-Ramırez, G.; Ballester, P. J. Am. Chem. Soc. 2009, 131,
3178–3179. (f) Ballester, P.; Gil-Ramırez, G. Proc. Natl. Acad. Sci. 2009, 106,
10455–10459. (g) Chas, M.; Gil-Ramırez, G.; Escudero-Adan, E. C.; Ballester, P.
Org. Lett. 2010,12, 1740–1743. (h) Gil-Ramırez, G.; Chas, M.; Ballester, P. J. Am.
Chem. Soc. 2010, 132, 2520–2521.
two tosyl groups are directed in toward the inside of the
calix[4]pyrrole cavity, while the other two point toward the
outside of the macrocycle. In contrast, in the case 2 (DMF)2 all
ꢀ
rez, G.; Escudero-Adan,
´
´
3
´
of four tosyl groups point toward the outside of the cavity; such
a finding is consistent with the expected steric repulsion between
the tosyl groups and the two bound DMF molecules.
ꢀ
´
´
(9) Gale, P. A.; Sessler, J. L.; Allen, W. E.; Tvermoes, N. A.; Lynch, V.
Chem. Commun. 1997, 665–666.
(10) Sessler, J. L.; Roznyatovskiy, V. V.; Lynch, V. M. J. Porphyrins
Phthalocyanines 2009, 13, 322–355.
(11) (a) Smith, B. D. In Ion-pair Recognition by Ditopic Receptors,
Macrocyclic Chemistry: Current Trends and Future Prospectives; Gloe, K.,
Antonioli, B., Eds.; Kluwer: London, U.K., 2005; pp 137-152. (b) Kirkovits,
G. J.; Shriver, J. A.; Gale, P. A.; Sessler, J. L. J. Inclusion Phenom.
Macrocyclic Chem. 2001, 41, 69–75. (c) Kim, S. K.; Sessler, J. L. Chem.
Soc. Rev. 2010, 39, 3784–3809. and references cited therein.
(12) Custelcean, R.; Delmau, L. H.; Moyer, B. A.; Sessler, J. L.; Cho,
W.-S.; Gross, D.; Bates, G. W.; Brooks, S. J.; Light, M. E.; Gale, P. A.
Angew. Chem., Int. Ed. 2005, 44, 2537–2542.
The first evidence that compound 2 is capable of forming
a complex with an anion came from a single-crystal X-ray
diffraction analysis of the presumed chloride anion complex,
2 Cl- (Figure 3). The resulting structure confirmed that in this
3
complex calix[4]pyrrole adopts the cone conformation and that
the four pyrrolic NH protons participate in hydrogen bonding
(13) Bush, L. C.; Heath, R. B.; Feng, X. U.; Wang, P. A.; Maksimovic, L.;
Song, A. I.; Chung, W.-S.; Berinstain, A. B.; Scaiano, J. C.; Berson, J. A.
J. Am. Chem. Soc. 1997, 119, 1406–1415.
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FIGURE 1. Two different views of the single crystal structure of 2 (MeOH)2. Displacement ellipsoids are scaled to the 30% probability level.
3
Hydrogen atoms have been removed for clarity. The macrocycle lies on a crystallographic inversion center at 1/2, 1/2, 1/2.
FIGURE 2. Two different views of the single crystal structure of 2 (DMF)2. Displacement ellipsoids are scaled to the 50% probability level.
3
Hydrogen atoms have been removed for clarity. The macrocycle lies on a crystallographic inversion center at 1/2, 1/2, 1/2.
SCHEME 1. Synthesis of Compound 2
interactions with the chloride anion (Figure 3). The distance
between the chloride anion and nitrogen atoms is 3.372 A and
displays a singlet peak for the Ha and Hb protons at 4.27 ppm.
Such a finding is consistent with the rate of conformation
change being fast on the NMR time scale, as is true for most
other anion-free calix[4]pyrrole derivatives. However, upon
the addition of increasing quantities of tetrabutylammonium
fluoride (TBAF), the singlet peak of Ha and Hb first becomes
the N-H Cl- angle is ca. 155°.
3 3 3
Initial evidence that calix[4]pyrrole 2couldbindhalideanions
in solution came from 1H NMR spectroscopic analyses carried
out in CDCl3. As shown in Figure 4, the anion-free form of 2
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FIGURE 3. Two different views of the single crystal structure of 2 Cl-. Displacement ellipsoids are scaled to the 30% probability level. Compound 2 in
3
1
this complex lies around a crystallographic 4-fold rotation axis at /2, 1/2, z. Most hydrogen atoms have been removed for clarity. Dashed lines are
indicative of H-bonding interactions. The countercation, TBAþ, sitting in the cavity formed by four sulfonyl groups, is disordered and is not shown.
FIGURE 4. Partial 1H NMR spectra recorded during the titration of receptor 2 with TBAF (tetrabutylammonium fluoride) in CDCl3. The
asterisk denotes peaks due to the NMR solvent.
broadened, something that is apparent after the addition of
fewer than 0.38 equiv, and then becomes split. This splitting
gives rise to two doublets (J = 10.8 Hz) in an AB pattern, and
is consistent with the conformation of 2 becoming fixed in the
cone conformation as the result of fluoride anion binding
(Figures 4 and 5).
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FIGURE 5. Proton NMR spectra of 2 recorded in CDCl3 after adding quantities of TBAX (tetrabutylammonium halide) sufficient to induce
no further observable spectral changes. Note the position of the NH signal. An asterisk denotes peaks due to the NMR solvent and other
residual impurities.
This anion-induced conformational locking stands in
contrast to what is seen in the case of calix[4]pyrrole 1; at
room temperature in CDCl3, the conformation of this latter
system is not fixed via fluoride anion binding, as evidenced
by the fact that the meso carbons of 1 still appear as a singlet
in the 1H NMR spectrum after the addition of excess TBAF
(Figure S1, Supporting Information). This difference led us
to postulate that the new calix[4]pyrrole derivative, 2, binds
fluoride anion more strongly than does the parent system 1.
In an effort to test the above assumption, more detailed
titrations were carried out. As shown in Figures 4 and 5, these
titrations revealed that the changes in the spectrum are essen-
tially complete after receptor 2 is treated with ca. 1.0 equiv of
TBAF, whereas ca. 2.8 equiv is required to achieve saturation in
the case of calix[4]pyrrole 1. Further support for the conclusion
that 2 is a better fluoride anion receptor under these solution
phase conditions came from the observation that the NH
proton resonance of 2 is split into a doublet (JHF = 29.6 Hz)
at room temperature in the presence of the fluoride anion,
presumably as the result of coupling between the bound fluoride
anion and the NH protons.14 A significant downfield shift in the
NH proton peak (by roughly 5 ppm; final δ ≈ 12.7 ppm) was
also seen in the presence of TBAF (Figure 4).
fixing the conformation on the NMR time scale. This binding
also serves to lock the calix[4]pyrrole framework into the cone
conformation, which places protons Ha and Hb in a diaster-
eotopic environment (Figure 5, as well as Figure S2 in the
Supporting Information). Such an interpretation is fully con-
sistent with the crystal structure of the chloride anion complex
of 2 discussed above (cf. Figure 3). The observation that
the changes in the NH proton chemical shift of 2 become
saturated upon the addition of ca. 1.0 equiv of TBACl provides,
as above, further support for the notion that the chloride anion
is strongly bound by 2 (Figure S2, Supporting Information). In
contrast to what was seen with TBAF and TBACl, when 2 was
subject to the titration with the TBA salts of bromide and
iodide, the Ha and Hb signals did not split, but rather remained
in the form of a singlet at room temperature. This lack of change
is ascribed to the fact that the bromide and the iodide anions are
bound only weakly and that calix[4]pyrrole undergoes fast
conformational “flipping” in the presence of these two anions.
Support for this conclusion comes from the fact that only
relatively small downfield shifts in the NH proton resonance
are seen upon the addition of TBABr or TBAI (Figure 5 and
Figures S3 and S4 in the Supporting Information).
Unfortunately, in the case of the fluoride and chloride
anions, kinetics and difficulties associated with integrating the
signals for the separate species precluded the use of 1H NMR
spectroscopic methods to obtain quantitative measures of the
anion affinities in the case of 2. Therefore, isothermal titration
calorimetry (ITC) analyses were carried out. In contrast to
NMR spectroscopic methods, ITC analyses provide direct
access to the energetics of the binding event without the neces-
sity of a structural probe (e.g., an NMR spectroscopic signal).
In analogy to what is seen in the case of fluoride, the singlet
corresponding to the meso Ha and Hb resonances of 2 was
found to split into two doublets upon the addition of TBACl
(CDCl3 solution; room temperature). As above, this was taken
as evidence that the chloride anion binds strongly to 2 thus
(14) Sato, W.; Miyaji, H.; Sessler, J. L. Tetrahedron Lett. 2000, 41, 6731–
6736.
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TABLE 1. Selected Thermodynamic Data Derived from Isothermal Titration Calorimetry (ITC) for the Interactions of Receptors 1 and 2 with
Tetraalkylammonium Halidesa
data obtained after adjusting host concn to
obtain a value of 1 for N (stoichiometry)b
original Ka
(M-1
ΔG
ΔH
TΔS
salt (mM)
host (mM)
original N
)
(kcal mol-1
)
(kcal mol-1
)
(kcal mol-1
)
Ka (M-1
)
3
3
3
TBA-Cl
1
2
2
TEA-Cl
1
c
c
c
c
23.1
2.71
0.09
1.1
0.21
1.57
-
<102
-
-
-
<102
0.83
1.19
2.5 ꢀ 106
-8.70
-8.65
-8.27
-8.96
0.43
-0.30
2.4 ꢀ 106
1.6 ꢀ 106
7.0 ꢀ 103
1.8 ꢀ 107
2.2 ꢀ 106
7.0 ꢀ 103
1.8 ꢀ 107
21.0
4.74
1.64
0.21
0.99
0.83
-5.26
-9.89
-8.60
-8.97
-3.34
0.92
2
TBA-Br
2
TEA-Br
2
TBA-I
2
TEA-I
2
10.3
16.4
11.9
12.2
1.0
1.0
1.0
1.0
0.85
0.75
0.77
0.85
2.2 ꢀ 105
8.9 ꢀ 105
4.4 ꢀ 102
1.5 ꢀ 104
-7.29
-8.11
-3.60
-5.70
-6.38
-5.01
-5.21
-1.86
0.91
2.2 ꢀ 105
8.9 ꢀ 105
4.4 ꢀ 102
1.5 ꢀ 104
3.10
-1.61
3.84
aTitrations were performed in CHCl3 at 25 °C. bSee ref 15. cUnable to determine the energetics of the presumed interaction due to weak binding.
While these two techniques necessarily probe different aspects
of the presumed binding event, we have recently demonstrated,
in collaboration with Gale and Schmidtchen, that NMR spec-
troscopic titrations and ITC analyses give rise to concordant
results when the conditions for the measurements are com-
parable.15 Accordingly, ITC methods were explored in an effort
to quantify the anion affinities of calixpyrrole 2.
case of 2. As detailed further below, the relatively high affinities
seen in the case of 2 are ascribed in part to additional interac-
tions between the countercations and the four tosyl groups.
Such interactions are not possible in the case of the unsubsti-
tuted system 1. Additional evidence for the interactions between
the countercation and the tosyl groups came from the 1H NMR
spectroscopic titrations of receptor 2 with TEACl (tetraethyl-
ammonium chloride) (Figure S13, Supporting Information). In
the presence of less than 1.0 equiv of TEACl ([2] > [TEACl]),
the ethyl peak of the tetraethylammonium cation appears to be
significantly shifted downfield, which is attributable to the
encapsulation of the cation by the tosyl group forming an ion
pair complex. For instance, adding 0.59 equiv of TEACl to 2
gives rise to a spectrum with two sets of distinguishable reso-
nances for the Ha and Hb proton signals. This splitting, which is
not seen in the absence of TEACl, is ascribed to the presence of
both ion pair-free and TEACl-bound forms of 2 and is thus
consistent with the ion pair binding/decomplexation equilibri-
ITC experiments were carried out under conditions chosen
to given an N value (calculated stoichiometry) close to 1.
Under varying host-guest ratios, different N values between
0.5 and 2.0 could be obtained depending on the exact salt and
concentration. This variation, which in all cases remained
within a factor of less than two, is thought to reflect ion-
pairing effects. Such effects are significant in this system as
noted below. Nevertheless, the possibility of forming com-
plexes of non-1:1 stoichiometry, especially under conditions
where either the host or guest is present in great excess,
cannot be eliminated. Therefore, in order to allow intercom-
parisons between different anion binding processes the host
concentration (i.e., concentration of 2) was adjusted to
obtain an N value of 1. The uncorrected Ka values are,
however, also shown in Table 1 for purpose of reference.
Interestingly, the interactions of 2 with halide anions are
driven almost entirely by enthalpy. For example, the chloride
complex is formed with ΔH contributing >95% to the inter-
action energy. In conjunction with a modest entropic term, this
gives rise to a favorable (negative) ΔGand a Ka of 2.4 ꢀ 106 M-1
in CHCl3 (Table 1). This represents a considerable increase
in affinity relative to the parent, unsubstituted calix[4]pyrrole 1
(Ka <102 M-1 in CHCl3). This ca. 4 orders of magnitude differ-
ence can be noted qualitatively from an inspection of the
associated titration plots (Figure 6).
1
um being slow on the H NMR time scale. This splitting
becomes enhanced up to the point where 1.0 equiv of TEACl
is added. After this point, the addition of further equivalents
results in no appreciable change in these resonances. Conver-
sely, the signals corresponding the tetraethylammonium cation
continue to move downfield as the number of equivalents
increases. This is consistent with the cation being bound within
the cavity via an equilibrium process.
The ability of calix[4]pyrrole 2 to act as an ion pair receptor
was tested and compared with that of normal calix[4]pyrrole 1.
This was done via solid-liquid extraction experiments using the
chloroform-insoluble salts, CsF and CsCl, as test ion pairs.
After subjecting CDCl3 solutions of 1 and 2 to sonication for 1 h
in the presence of 5.0 equiv of CsF and CsCl, the soluble portion
of the samples was monitored by 1H NMR spectroscopy. Under
these experimental conditions, two sets of distinguishable peaks,
corresponding to the free calix[4]pyrroles and their ion pair
complexes, were seen in the 1H NMR spectra of 1 CsF, 2 CsF,
The affinities of receptor 2 for other halide anions, such as
bromide and iodide, are also substantially enhanced as com-
pared with calix[4]pyrrole 1. Whereas no appreciable interaction
with these latter anions could be discerned under the conditions
of ITC analysis, binding constants (Ka) of 8.9 ꢀ 105 for TEABr
and 1.5 ꢀ 104 for TEAI, respectively, could be derived in the
3
3
and 2 CsCl (cf. Figure 7 and in the Supporting Information
3
Figure S14). Such findings are consistent with the formation
of ion pair complexes, albeit under conditions of slow equi-
librium. Comparison of the peak integral ratios for the free form
of calix[4]pyrrole 1 and its corresponding ion pair complexes
(15) Sessler, J. L.; Gross, D. E.; Cho, W.-S.; Lynch, V. M.; Schmidtchen,
F. P.; Bates, G. W.; Light, M. E.; Gale, P. A. J. Am. Chem. Soc. 2006, 128,
12281–12288.
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FIGURE 6. ITC plots showing the titration of TBACl into chloroform solutions of calixpyrroles 1 (left, 10 mM) and 2 (right, 0.1 mM). A high
concentration was used in the former case in an attempt to obtain a discernible binding isotherm.
FIGURE 7. Proton NMR spectra of 2 recorded at room temperature in CDCl3 before and after the addition of CsF and CsCl. The asterisk and
dots denote the peaks of the NMR solvent and complexes 2 CsF and 2 CsCl, respectively. Note the position of the NH signals.
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3
(cf. Figure S14 in the Supporting Information) revealed that
<10% of the receptor was involved in ion pair recognition in the
case of CsF and essentially none in the case of CsCl. In contrast,
under these solid-to-solution extraction conditions ca. 95% and
ca. 15% of the available calix[4]pyrrole 2 in solution was tied up
in the form of CsF and CsCl ion pairs, respectively (Figure 7).
These results lead us to suggest that receptor 2 acts as an ion pair
receptor and is even more effective for this purpose than calix-
[4]pyrrole 1. This, we propose, reflects participation of the tosyl
groups of 2 in the cesium cation binding process. Support for
this supposition comes from the observation that relatively
larger downfield shifts are seen for the signals of the aromatic
protons of the tosyl groups upon complexation of CsF and CsCl
than are observed upon treatment with TBAF and TBACl.
Relatively larger splittings in the Ha and Hb proton peaks are
also seen.
In conclusion, we have shown that it is possible to obtain a
β-substituted calix[4]pyrrole, in this case one bearing fused
J. Org. Chem. Vol. 76, No. 4, 2011 1011

Kim et al.
JOCFeatured Article
N-tosyl pyrrolidine subunits (i.e., 2), via a direct condensa-
tion of an appropriately chosen pyrrolic precursor and
acetone under conditions of acid catalysis (TFA in the present
N-p-Toluenesulfonylpyrrolidinyl-N-p-toluenesulfonylpyrrole (7).
To a suspension of TsNHNa (3.35 g, 17.3 mmol) in dry CH3CN
(75 mL) was added dropwise a solution of 6 (3.00 g, 7.37 mmol) in
dry DMF (25 mL) at 80 °C. After the reaction mixture was stirred
for a further 30 min, the hot mixture was filtered through Celite and
the filter was washed with DMF. The filtrate was evaporated in
vacuo to give a white solid, which was extracted with dichloro-
methane and washed with water three times. The organic phase was
separated off and dried over anhydrous MgSO4. Crystallization
from diethyl ether, following evaporation of solvents in vacuo, gave
1
instance). Taken in concert, H NMR spectroscopic titration
experiments and isothermal titration calorimetry (ITC) analyses
provide support for the conclusion that calix[4]pyrrole 2 recog-
nizes halide anions much more effectively than normal calix-
[4]pyrrole 1. In particular, receptor 2 is a good receptor for
certain chloride salts, with a strong dependence on the counter-
cation being seen. Likewise, compound 2 appears to be a
considerably better ion pair receptor for cesium salts than 1.
For instance, the N-tosyl pyrrolidine functionalized calix-
[4]pyrrole 2 is able to extract solid cesium fluoride and cesium
chloride into chloroform solution well under conditions where
calix[4]pyrrole 1 is not particularly effective. This latter increase
in efficacy, as well as the enhancement in anion affinities, is
ascribed at least in part to ancillary interactions between the tosyl
groups present in receptor 2 and the countercations in question.
These interactions appear particularly favorable in the case of
cesium cations.
1
compound 7 (2.10 g, 68% yield) as a white solid. H NMR (300
MHz, CDCl3) δ7.71 (m, 4H, ArH (tosyl)), 7.31 (d, 2H, ArH (tosyl),
J = 4 Hz), 7.28 (d, 2H, ArH (tosyl), J = 5 Hz), 6.83 (s, 2H, ArH
(pyrrole)), 4.29 (s, 4H, pyrrole-CH2N), 2.40 (s, 6H, ArCH3); 13C
NMR (100 MHz, CDCl3) δ 145.5, 144.0, 136.0, 134.1, 130.3, 130.1,
128.2, 127.7,127.1, 112.0, 47.4, 21.9, 21.7; HRMS (CI) m/z 417.0943
(M þ H)þ calcd for C20H21N2O4S2, found 417.0941.
N-p-Toluenesulfonylpyrrolidinylpyrrole (8). To a solution of 7
(1.50 g, 1.20 mmol) in dry THF/MeOH (3:1 v/v) was added
NaOMe (30% solution in MeOH, 30 equiv) via syringe. The
resulting solution was heated at reflux for 20 min and then
cooled to room temperature. After the solvent was removed in
vacuo, the resulting crude product was extracted with dichloro-
methane and washed with water twice. The organic phase was
separated off and dried over anhydrous MgSO4. Crystallization
from hexane, following evaporation of solvents in vacuo, gave
compound 8 (0.86 g, 91% yield) as a white solid. 1H NMR (300
MHz, CDCl3) δ 8.22 (broad s, 1H, NH), 7.76 (d, 2H, ArH
(tosyl), J = 8 Hz), 7.23 (d, 2H, ArH (tosyl), J = 8 Hz), 6.45 (s,
2H, ArH (pyrrole)), 4.42 (s, 4H, pyrrole-CH2N), 2.40 (s, 3H,
ArCH3); 13C NMR (100 MHz, CDCl3) δ 143.6, 134.5, 129.9,
127.7, 122.9, 109.0, 48.3, 21.7; HRMS (CI) m/z 263.0854 (M þ
H)þ calcd for C13H15N2O2S, found 263.0854.
Experimental Section
Diethyl N-p-Toluenesulfonylpyrrole-3,4-dicarboxylate (4). To
a mixture of diethyl pyrrole-3,4-dicarboxylate (3)13 (3.00 g, 14.2
mmol) and NaOH (0.68 g, 17.0 mmol) in 1,2-dichloroethane
(250 mL) was added dropwise p-toluenesulfonyl chloride (5.51 g,
28.9 mol) dissolved in 1,2-dichloroethane (20 mL) at 0 °C.
After being stirred for 48 h at room temperature, the reaction
mixture was extracted with dichloromethane and washed with
water two times. The organic layer was separated off and then
dried over anhydrous MgSO4. The solvent was removed in
vacuo to give a colorless oily solid. The crude product was
purified by column chromatography over silica gel (eluent: ethyl
acetate/hexane (1/3)) to give 5.0 g (96.3% yield) of 4 as a white
solid. All spectroscopic data for this compound proved consis-
tent with those reported in the literature.13
N-p-Toluenesulfonylpyrrole-3,4-dimethanol (5). To a suspen-
sion of LiAlH4 (1.56 g, 41.2 mmol) in THF (30 mL) was added a
solution of 4 (5.00 g, 13.7 mmol) in THF (30 mL) at 0 °C. The
reaction mixture was stirred for 10 min at 0 °C and then a small
amount of water was added to quench the reaction. The reaction
mixture was extracted with dichloromethane (30 mL) twice. The
organic layer was collected, washed with water, and dried over
anhydrous MgSO4. The solvent was evaporated in vacuo to give
a white solid. The resulting solid was crystallized from dichloro-
methane/hexane (1/10) and filtered to give compound 5 (3.01 g,
78% yield) as a white solid. All spectroscopic data for this com-
pound proved consistent with those reported in the literature.13
N-p-Toluenesulfonyl-3,4-bis(bromomethy)pyrrole (6). A solu-
tion of 5 (4 g, 14.2 mmol) in dry CH2Cl2(40 mL) was cooled to
0 °C under an argon atmosphere. To the resulting suspension
was added phosphorus tribromide (3.21 mL, 34.1 mmol) via
syringe. The reaction mixture was warmed to room temperature
and stirred for 2 h. At this point, 30 mL of aqueous Na2CO3
solution (sat.) was added slowly to the reaction mixture to quench
the reaction. The organic phase was separated off, washed with
water three times, and dried over anhydrous MgSO4. Evaporation
of the solvent in vacuo, followed by crystallization from dichloro-
methane/hexane (1/10), afforded the desired compound 6 (5.15 g,
89% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.76 (d,
2H, ArH (tosyl), J = 8 Hz), 7.33 (d, 2H, ArH (tosyl), J = 8 Hz),
7.18 (s, 2H, ArH (pyrrole)), 4.45 (s, 4H, pyrrole-CH2Br), 2.43 (s,
3H, ArCH3); 13C NMR (100 MHz, CDCl3) δ 146.0, 135.6, 130.5,
127.4, 124.2, 121.1, 23.7, 21.9; HRMS (CI) m/z 405.9112 (M þ H)þ
calcd for C13H14NO2SBr2, found 405.9111.
N-p-Toluenesulfonylpyrrolidinecalix[4]pyrrole (2). To com-
pound 8 (1.2 g, 4.57 mmol) in acetone (150 mL) was added
TFA (0.52 g, 4.57 mmol) in one portion. The resulting solution
was stirred for 24 h at room temperature and taken to dryness in
vacuo to give a brownish solid. To the crude product were added
dichloromethane (100 mL), water (100 mL), and triethylamine
(5 mL). The organic phase was then separated off and washed three
times with water (100 mL). The organic layer was dried over
anhydrous MgSO4 and evaporated in vacuo to give a yellowish
solid. Column chromatography over silica gel (eluent: ethyl acetate/
dichloromethane (99/1)), followed by crystallization from methanol,
gave the target compound 2 (0.28 g, 20% yield) as a white solid. 1H
NMR (400 MHz, CDCl3) δ 7.73 (d, 8H, ArH (tosyl), J = 8 Hz),
7.35 (d, 8H, ArH (tosyl), J = 8 Hz), 4.27 (s, 16H, pyrrole-CH2N),
2.46 (s, 12H, ArCH3), 1.32 (s, 24H, pyrrole-C(CH3)2); 13C NMR
(100 MHz, CDCl3) δ 144.0, 134.3, 130.2, 127.7, 127.5, 118.1, 48.5,
36.4, 29.9, 21.9; HRMS (CI) m/z 1209.4434 (M þ H)þ calcd for
C64H73N8O8S4, found 1209.4435. The results of an HPLC analysis
are given in the SI. This compound was further characterized by
X-ray diffraction analysis.
Acknowledgment. This work was supported by the National
Institutes of Health (GM 58907 to J.L.S.), the Robert A. Welch
Foundation (F-1018 to J.L.S.), and the National Science Foun-
dation (grant no. 0741973 for the X-ray diffractometer). Support
under the WCU (World Class University) program (R32-2008-
000-10217-0) is also acknowledged.
Supporting Information Available: NMR spectroscopic
data, CI-HRMS, HPLC analysis of 2, ITC analyses, and
X-ray structural data and CIF files for 2 (DMF)2 (CCDC
3
794361), 2 (CH3OH)2 (CCDC 794362), and 2 TBACl (CCDC
794363). This material is available free of charge via the Internet
at http://pubs.acs.org.
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1012 J. Org. Chem. Vol. 76, No. 4, 2011