Macrotricycles featuring a π-basic tetrahedral cavity: Preference for NH4+ detected by electrospray ionization mass spectrometry

Article abstract of DOI:10.1021/ol070498a

Cation-π interactions play an important role in biology. The title compounds are C₃-symmetric macrotricycles built from resorcinol, a π electronrich arene. They were prepared in up to 18% yield by intramolecular cyclization of 1,3,5-trisubstitu

Full text of DOI:10.1021/ol070498a

ORGANIC
LETTERS
2007
Vol. 9, No. 16
2961-2964
Macrotricycles Featuring a
π-Basic
+
Tetrahedral Cavity: Preference for NH4
Detected by Electrospray Ionization
Mass Spectrometry
Anne Le´lias-Vanderperre,† Jean-Claude Chambron,*,† Enrique Espinosa,‡
Peran Terrier,§ and Emmanuelle Leize-Wagner§
UniVersite´ de Bourgogne, Laboratoire d’Inge´nierie Mole´culaire pour la
Reconnaissance et la Se´paration des Me´taux et des Mole´cules (ICMUB,
UMR CNRS n° 5260), 9 aVenue Alain SaVary, BP 47870, 21078 Dijon, France,
UniVersite´ Henri Poincare´ - Nancy 1, Laboratoire de Cristallographie et Mode´lisation
des Mate´riaux Mine´raux et Biologiques (LCM3B, UMR CNRS n° 7036), Faculte´ des
Sciences et Techniques, BouleVard des Aiguillettes, BP 239, 54506
VandoeuVre-le`s-Nancy, France, and UniVersite´ Louis Pasteur, Laboratoire de
Dynamique et Structure Mole´culaire par Spectrome´trie de Masse (LDSM2, UMR
CNRS n° 7177), ISIS, 8 alle´e Gaspard Monge, BP 70028, 67083 Strasbourg, France
jean-claude.chambron@u-bourgogne.fr
Received February 27, 2007
ABSTRACT
Cation-π interactions play an important role in biology. The title compounds are C3-symmetric macrotricycles built from resorcinol, a π electron-
rich arene. They were prepared in up to 18% yield by intramolecular cyclization of 1,3,5-trisubstituted benzene tripods bearing pendant resorcinol
+
+
groups, with methylene acetal bridges. Positive ESI-MS showed that these receptors recognize NH4 over K , and poorly respond to the large
+
+
t-BuNH3 cation, suggesting that they bind NH4 intramolecularly, presumably via cation-
π interactions.
Since their discovery and characterization in the gas phase,1
systems has been amply demonstrated,3 and synthetic recep-
tors for alkali metal4 and quaternary ammonium5 cations
relying on these interactions have been reported. Cation-π
interactions, complementing highly directed hydrogen bonds,
the occurrence of cation-π interactions2 in several biological
† Universite´ de Bourgogne.
are involved in a few NH4 -specific receptors,6 but were
+
‡ Universite´ Henri Poincare´ - Nancy 1.
§ Universite´ Louis Pasteur.
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10.1021/ol070498a CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/03/2007

shown to operate marginally7 in the uptake of the ammonium
cation by the ammonium transporters (Amts) found in
bacteria and archae.8-10
Recently, cylindrical cage-type molecules with π cavities
were described, which bind NH4+ and Li+ preferably to other
alkali metal cations, via a gate-selective process, as shown
by ESI-MS measurements.11
sized by capping of the functionalized hexahomotrioxacalix-
[3]arene macrocycle with 1,3,5-trisubstituted benzene. The
alternative synthetic strategy was chosen for the present
study, that is, intramolecular cyclization of functionalized
tripod precursors.5f,12a,15
Resorcinol-based tripods 10 and 11 were synthesized in
four steps from known 3,5-bis(methoxymethyloxy)benzyl
alcohol 3.16 At first (Scheme 1), treatment of 3 with
In this letter, we present a class of conformationally rigid
macrotricycles featuring a potentially tetrahedral π cavity,
that are reminiscent of the spheriphanes12 and use the same
+
technique to probe the selective binding of NH4 over the
Scheme 1. Preparation of Benzyl Thiol 5
+
alkali metal cations and the large t-BuNH3 primary am-
monium, possibly by intramolecular cation-π interactions.
As carcerands and cavitands,13 cages 1 and 2 are derived
from resorcinol: this π electron-rich arene is incorporated
as its methylene acetal and forms a C3 symmetric macro-
cyclic substructure that is capped by 1,3,5-trisubstituted
benzene at the upper rim via benzylic thioether links. They
thiolacetic acid in Mitsunobu reaction conditions (PPh3,
DIAD, THF, 0 °C)17 afforded the benzylthiolacetate deriva-
tive 4 in 77% yield after chromatography. Subsequent
reduction of thiolacetate 4 (LiAlH4, THF, reflux) followed
by acidification (5% HCl) released the corresponding thiol
(5) quantitatively. Next (Scheme 2), 5 was deprotonated
complement the cages derived from hexahomotrioxacalix-
[3]arene, which feature CH2OCH2 benzylic ether instead of
the present OCH2O acetal bridges.14 The latter were synthe-
(5) (a) Dougherty, D. A.; Stauffer, D. A. Science 1990, 250, 1558-
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(c) Garel, L.; Lozach, B.; Dutasta, J.-P.; Collet, A. J. Am. Chem. Soc. 1993,
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Scheme 2. Synthesis of the Tripod Precursors 8-11
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5379.
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(NaH, THF, 0 °C) and condensed at room temperature with
stoichiometric amounts of 1,3,5-tribromomethylbenzene 6
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(17) Mitsunobu, O. Synthesis 1981, 1-28.
2962
Org. Lett., Vol. 9, No. 16, 2007

and 1,3,5-triethyl-2,4,6-tribromomethylbenzene 7, respec-
tively. The resulting protected (MOM) tripods 8 and 9 were
obtained in 95 and 75% yields after crystallization (Et2O).
Standard cleavage conditions of the MOM protections (6 N
HCl) led to decomposition of the polybenzylic framework.
However, nonaqueous conditions (excess p-TsOH, 1:1
CH2Cl2/MeOH, room temperature)18 successfully afforded
the target resorcinol-based tripods 10 and 11 as beige solids
in quantitative yields.
The intramolecular cyclization (Scheme 3) was accom-
plished by slow addition of a mixture of 10 or 11 and
dibromomethane (3 equiv) in DMF to a suspension of
Cs2CO3 (7.5 equiv) in DMF at 60 °C in high dilution
conditions (1 mM). The resulting cages 1 and 2 were isolated
in 18 and 1.4% yields, respectively, after chromatography.
Figure 1. (a) Top and (b) side views (ORTEP) of the X-ray crystal
structure of 2.
hedron: the separation between the resorcinol-derived groups
ranges from 4.31 to 5.11 Å, while their average distance to
the aryl cap is approximately 6.15 Å.
Scheme 3. Synthesis of Macrotricycles 1 and 2
The complexation properties of cages 1 and 2 toward the
ammonium and alkali cations in solution (MeOH) were
investigated by positive electrospray ionization mass spec-
trometry (+ESI-MS) in the 0-3000 m/z range.21 Both cages
(10-4 M in MeOH) show very intense signals in the presence
+
of equimolar amounts of NH4 (Figures S9 and S10). In a
first series of experiments, a mixture of 1, LiCl, NaCl, KCl,
and CsCl all at 10-4 M in MeOH was examined (Figure 2).
Cage 1 was formed in acceptable yield, as compared to
related systems.12,15 The 1,3,5-triethyl substitution of tripod
11, by forcing the three resorcinol moieties to be on the same
side of the benzene cap,19 was expected to direct its closure
to the cage 2. However, the low yield of formation of the
latter could be ascribed to strain effects arising from steric
interactions between the ethyl substituents and the benzyl
thioethers upon bridging the pendant resorcinols with the
1
short methylene connectors. As shown by H NMR, the
macrotricycles have C3V symmetry in solution. Proof of the
closed structures rests in the characteristic pairs of doublets
of the diastereotopic methylene acetal protons (e.g., for 2:
2J ) 7.2 Hz and ∆ν ) 46 Hz in CDCl3), as previously
observed for methylene groups of calixarenes fixed in the
cone conformation.20 Noteworthy, these protons show up as
a sharp singlet in d6-dmso.
In the crystal, the structure of cage 2 deviates from C3
symmetry, because one of the methylene acetal bridges
differs from the others (Figure 1). In addition, the aryl cap
is only slightly helically twisted. As a consequence, the
centroids of the four aryl groups form an elongated tetra-
Figure 2. ESI-MS of 1 and a mixture of Li+, Na+, K+, and Cs+.
An enlarged view is shown in Figure S11.
(18) Kumagai, N.; Matsunaga, S.; Kinoshita, T.; Harada, S.; Okada, S.;
Sakamoto, S.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125,
2169-2178.
Only signals corresponding to the 1:1 complexes were
observed. The absolute signal intensities of [1 + M]+
followed the order K+ > Cs+ > Li+, [1 + Na]+ being hardly
detected. The signals were left unchanged upon variation of
the voltage at the capillary exit between 70 and 300 V. In a
(19) Hennrich, G.; Lynch, V. M.; Anslyn, E. V. Chem.sEur. J. 2002,
8, 2274-2278.
(20) (a) Gutsche, C. D.; Bauer, L. J. J. Am. Chem. Soc. 1985, 107, 6052-
6059. (b) Araki, K.; Hashimoto, N.; Otsuka, H.; Shinkai, S. J. Org. Chem.
1993, 58, 5958-5963.
Org. Lett., Vol. 9, No. 16, 2007
2963

positioning in the absence of any other constraint.1b,23 In
either case the N‚‚‚aryl distance is ca. 3 Å.1b,6c
As shown by the X-ray crystal structure of 2, the
dimensions of the cages are large enough to accommodate
NH4+ in a cation-π bonding mode similar to what has been
observed in earlier studies,6 but external binding by the acetal
oxygens cannot be ruled out. Indirect indications for inclusion
of NH4+ into macrotricycle 1 come from comparative +ESI-
+
MS experiments with t-BuNH3 , a large primary ammonium
cation which, according to CPK models, cannot enter the
cavities of either 1 or 2.22a As shown in Figure S16, a 1:1
mixture of t-BuNH3Cl and 1 is hard to detect cleanly,
+
t-BuNH3 competing with trace amounts of K+. This
+
suggests that t-BuNH3 interacts only weakly with the
macrotricycle. Expectedly, addition of one equivalent of
NH4PF6 to the mixture gave rise to the strong signal of [1 +
NH4]+ (Figure S17). By contrast, the 1H NMR spectrum of
a solution of 1 (≈5 mM in d6-dmso)24 in the presence of a
large excess (>50 equiv) of 15NH4Cl did not differ signifi-
cantly from that obtained with t-BuNH3Cl (Figures S18 and
S19).25 In particular, the signal of the ammonium proton was
left unchanged in both cases, and no additional high field
Figure 3. ESI-MS of 1 and a mixture of Li+, Na+, K+, Cs+, and
NH4+. An enlarged view is shown in Figure S12.
1
resonance could be found either in the H or 15N NMR
second series of experiments (Figure 3), an equal amount of
NH4PF6 in MeOH was added to the mixture. The most
intense signal was then due to the ammonium cation and
the intensities of [1 + K]+ and [1 + Cs]+ were similar: NH4+
> K+ ≈ Cs+ > Li+. Finally, when NH4PF6 and KPF6 were
opposed, the intensity of [1 + NH4]+ was nearly three times
as much as that of [1 + K]+ (Figure S13). Similar
observations could be made for cage 2: examination of a
mixture of 2, LiCl, NaCl, KCl, CsCl, and NH4PF6 did not
show any trace of Li+ or Na+ adduct, and the K+ and Cs+
complexes appeared as minor species by comparison with
the ammonium complex (Figures S14 and S15).
spectrum of the former mixture (Figure S19). This indicates
that encapsulation of NH4 by 1 is not effective in these
latter experimental conditions.
+
In conclusion, +ESI-MS shows that macrotricycle 1 has
a clear preference for binding NH4+ over isosteric K+ or the
+
larger t-BuNH3 cation. Definitive proof of inclusion of
NH4+ in the cavity of the macrotricycles reported here awaits
X-ray crystal structure studies.
Acknowledgment. The CNRS and the Conseil Re´gional
de Bourgogne are thanked for a doctoral fellowship to ALV.
We are grateful to Emmanuel Wenger for assistance at the
Service Commun de Diffraction X (LCM3B) and Dr. Jean-
Michel Barbe (ICMUB) for helpful discussions. We also
thank the referees for pertinent suggestions.
Selective complexation of NH4+ over K+ has always been
challenging,22a as these monovalent cations have similar ionic
radii (1.43 and 1.33 Å, respectively),1b and several synthetic
receptors that fulfill this function have been described.6,22
The most efficient ones (selectivity >400) also form among
+
the most stable complexes with NH4 (Ka ≈ 106 M-1), and
Supporting Information Available: Experimental pro-
all take into account the preference of NH4+ for tetrahedral
coordination, while K+ favors coordination numbers of 6 and
cedures and spectroscopic data for all new compounds, copies
1
of the H NMR and ESI-MS spectra, and X-ray data. This
+
material is available free of charge via the Internet at
http://pubs.acs.org.
more. The orientation of NH4 within the cavities of the
receptors is imposed by highly directing hydrogen bonds.
As a result, in the few examples of complexes involving also
cation-π interactions, which have all been characterized
OL070498A
+
crystallographically,6 NH4 assumes a C3-symmetrical ori-
entation with respect to the aromatic platforms of the
receptors, whereas theoretical studies of the benzene NH4 -π
complex agree on the preference of a C2-symmetrical
(23) (a) Kim, K. S.; Lee, J. Y.; Lee, S. J.; Ha, T.-K.; Kim, D. H. J. Am.
Chem. Soc. 1994, 116, 7399-7400. (b) Malone, J. F.; Murray, C. M.;
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Tan, X.-J.; Puah, C. M.; Gu, J.-D.; Jiang, H.-L.; Chen, K.-X.; Felder, C.
E.; Silman, I.; Sussman, J. L. J. Phys. Chem. A 2000, 104, 9573-9580. (e)
Kim, D.; Hu, S.; Tarakeshwar, P.; Kim, K. S.; Lisy, J. M. J. Phys. Chem.
A 2003, 107, 1228-1238.
(24) The choice of this solvent was dictated by solubility reasons.
(25) Interestingly, NH4PF6 changed the singlet observed for the OCH2O
protons in this solvent to the expected AB system (2J ) 7.2 Hz, ∆ν ) 8.0
Hz at ≈ 120 equiv), whereas NH4Cl and t-BuNH3Cl did not.
+
(21) In several studies, ESI-MS has been already shown to reflect
solution-state rather than gas-phase interactions. See: Leize, E.; Jaffrezic,
A.; Van Dorsselaer, A. J. Mass Spectrom. 1996, 31, 537-544.
(22) (a) Graf, E.; Kintzinger, J.-P.; Lehn, J.-M.; LeMoigne, J. J. Am.
Chem. Soc. 1982, 104, 1672-1678. (b) Sasaki, S.-I.; Amano, T.; Monma,
G.; Otsuka, T.; Iwasawa, N.; Citterio, D.; Hisamoto, H.; Suzuki, K. Anal.
Chem. 2002, 74, 4845-4848. (c) Rahman, M. A.; Kwon, N.-H.; Won, M.-
S.; Hyun, M.-H.; Shim, Y.-B. Anal. Chem. 2004, 76, 3660-3665.
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Org. Lett., Vol. 9, No. 16, 2007