Cage-catalyzed Knoevenagel condensation under neutral conditions in water

Article abstract of DOI:10.1021/ja210068f

A cationic coordination cage dramatically accelerates the Knoevenagel condensation of aromatic aldehydes in water under neutral conditions. The addition of a nucleophile to the aldehyde to generate anionic intermediates seems to be facilitated by the cationic environment of the cavity. The products are ejected from the cage as a result of the host-guest size discrepancy. As a result, the condensation is promoted by a catalytic amount of the cage.

Full text of DOI:10.1021/ja210068f

Communication
pubs.acs.org/JACS
Cage-Catalyzed Knoevenagel Condensation under Neutral
Conditions in Water
Takashi Murase, Yuki Nishijima, and Makoto Fujita*
Department of Applied Chemistry, School of Engineering, The University of Tokyo, and CREST, Japan Science and Technology
Agency (JST), 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan
S
* Supporting Information
ABSTRACT: A cationic coordination cage dramatically
accelerates the Knoevenagel condensation of aromatic
aldehydes in water under neutral conditions. The addition
of a nucleophile to the aldehyde to generate anionic
intermediates seems to be facilitated by the cationic
environment of the cavity. The products are ejected from
the cage as a result of the host−guest size discrepancy. As a
result, the condensation is promoted by a catalytic amount
of the cage.
Cage 1 (5.0 mM in D2O, 1.0 mL) was treated with 2-
eversible dehydration condensation in water is in principle
naphthaldehyde (2a, 8 equiv, suspended) for 30 min at room
R
a difficult transformation because the large excess of water
temperature (Figure 1a). After removal of the excess guest by
filtration, the quantitative formation of the inclusion complex
1·(2a)4 was observed by H NMR analysis (Figure 1b,c). The
pushes the equilibrium in favor of the hydrated compounds.1
To date, dehydration reactions in water have usually been
achieved by employing the local hydrophobic environment of
emulsion droplets2 but have not yet been established in a
homogeneous aqueous environment.3 On the contrary,
naturally elaborated enzymes easily accomplish the homoge-
neous dehydration in water even under neutral conditions at
ambient temperature. Learning the mechanism of catalysis from
enzymes is therefore an intriguing approach to shift conven-
tional dehydration reactions in organic media into environ-
mentally benign aqueous systems.1,4
1
aromatic protons of 2a were considerably upfield-shifted (e.g.,
Δδ = −3.12 ppm for Hb). Subsequently, Meldrum’s acid (3, 4
equiv) was added to the solution. After 2 h at room
temperature, the product was extracted with chloroform, and
NMR spectroscopy showed the formation of condensation
product 4a in 92% yield (Figure 1d).
Without the cage, aldehyde 2a (mostly suspended) gave only
a trace amount of the condensation product (∼2%) in an
aqueous solution of 3. Even under homogeneous conditions in
MeOH, the condensation proceeded poorly (∼8%). These
results indicate that cage 1 is not merely a dissolving reagent
but also promotes the condensation in water. The hydrophobic
cavity of the cage is crucial for the reaction because the cage
components, (en)Pd(NO3)2 or 2,4,6-tripyridyl-1,3,5-triazine,
did not promote the reaction.
There are several tricks in enzyme catalysis: (1) providing
hydrophobic pockets, (2) strong substrate binding therein, (3)
transition-state or intermediate stabilization, and (4) weak
product binding.5 Many previous synthetic hosts have fulfilled
conditions (1) and (2), but rarely have (3) and (4) been met.6,7
Regarding (3), enzymes stabilize the oxyanion intermediate
resulting from the carbonyl addition of nucleophilic species by
their positively charged surroundings.8 We thus assumed that
hydrophobic cationic cavities could fulfill conditions (1)−(3)
and examined a dehydration condensation with 12+ charged
M6L4 cage 1, which has shown remarkable molecular
recognition abilities toward organic substrates.6c We found
that cage 1 efficiently promotes the Knoevenagel condensation
of various aromatic aldehydes in water.9 The reaction
conditions are very mild (neutral, room temperature), and
more surprisingly, the reaction proceeds catalytically as
condensed products are spontaneously released from the cage
because of their poor fit to the cage, thus fulfilling condition
(4). We also note that the present reaction provides a fine
example of an electrostatic counterpart for Bergman and
Raymond’s cage-catalyzed reactions where cationic intermedi-
ates are stabilized by an anionic cage host.7
We noted that a clear, pale-yellow solution of inclusion
complex 1·(2a)4 became turbid during the reaction with 3 as a
result of the precipitation of 4a as a yellow powder (Figure 2).
NMR measurements corroborated that the condensation
product 4a was scarcely encapsulated within cage 1 (see Figure
S10 in the Supporting Information). The poor fit of 4a to cage
1 is probably due to 4a having too large a volume to be fully
encapsulated in the cage. The spontaneous release of the
product from the cavity encouraged us to predict that catalytic
turnover of the reaction would occur and thus to examine the
reaction with a catalytic amount of cage 1. Aldehyde 2a (78 mg,
0.50 mmol) and compound 3 (72 mg, 0.50 mmol) were mixed
Received: October 26, 2011
Published: December 6, 2011
© 2011 American Chemical Society
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Journal of the American Chemical Society
Communication
Table 1. Cage-Catalyzed Knoevenagel Condensation of
a
Aldehydes 2 with Meldrum’s Acid (3).
Figure 1. Knoevenagel condensation of 2-naphthaldehyde (2a) with
Meldrum’s acid (3) in cage 1. (a) Schematic representation of the
formation of inclusion complex 1·(2a)4 and the subsequent
Knoevenagel condensation with 3 leading to condensation product
4a. (b−d) 1H NMR spectra (500 MHz, 300 K) of (b) aldehyde 2a (in
CDCl3), (c) inclusion complex 1·(2a)4 (in D2O), and (d)
condensation product 4a obtained after extraction without purification
(in CDCl3).
a
Reaction conditions: aldehyde 2 (0.50 mmol), Meldrum’s acid 3
(0.50 mmol), and cage 1 (1 mol %) in H2O (5.0 mL) at room
b
c
temperature (rt) for 6 h unless otherwise noted. 1H NMR yields. 96
h. 24 h.
d
The proposed mechanism for the catalytic Knoevenagel
condensation within cage 1 is shown in Figure 3. First,
Figure 2. Photographs of the sample mixture in the Knoevenagel
condensation of inclusion complex 1·(2a)4 with 3 (a) before and (b)
after the addition of 3.
in water (5.0 mL) in the presence of cage 1 (1 mol %), and the
resulting solution was stirred at room temperature. After 6 h,
condensation product 4a was formed in 96% yield.
Encapsulation of aldehyde 2a by cage 1 is essential for the
catalytic condensation because 1-adamantanol, a strong binder
for the cage, completely inhibited the catalytic condensation.
Despite the very mild conditions, even sterically hindered
aldehydes underwent efficient condensation with the cage
catalyst (Table 1). Because of steric congestion of the aromatic
group, the Knoevenagel condensation of 9-anthraldehyde (2b)
hardly occurred (<1%) in a control experiment without the
cage (entry 2). In the presence of cage 1, however, the
condensation of 2b with 3 was effectively promoted to give 4b
in 63% yield.10 Similarly, 1-naphthaldehyde (2c) gave 4c in
67% yield (entry 3). In contrast, benzaldehyde (2d), which is
sterically nondemanding but only weakly bound to the cage,
was not a suitable substrate, and the product yield (38%) was
almost comparable to that in the control experiment (26%)
(entry 4).11 Because cationic cage 1 prefers electron-rich guests,
methoxy- and amino-substituted naphthaldehydes 2e and 2f
were good substrates, giving the corresponding adducts in
yields of 96 and 82%, respectively (entries 5 and 6).
Figure 3. Proposed mechanism for the catalytic Knoevenagel
condensation of aldehyde 2a with 3 in the presence of cage 1. For
simplicity, the encapsulation number of guest molecules is not
considered in this catalytic cycle.
aldehyde 2 is accommodated in cage 1 to form the inclusion
complex 1·(2)n (typically, n = 4) [step (i)]. Meldrum’s acid 3,
which is water-soluble and not a suitable guest for cage 1, exists
in equilibrium with its enolate form because of its low pKa value
(4.83).12,13 The enolate of 3 attacks encapsulated aldehyde 2 to
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Journal of the American Chemical Society
Communication
(3) 1,3,5-Triazine-based dehydrocondensing agents work in an
aqueous solvent. See: (a) Kunishima, M.; Kawachi, C.; Morita, J.;
Terao, K.; Iwasaki, F.; Tani, S. Tetrahedron 1999, 55, 13159.
(b) Kunishima, M.; Kawachi, C.; Hioki, K.; Terao, K.; Tani, S.
Tetrahedron 2001, 57, 1551. (c) Kunishima, M.; Yoshimura, K.;
Morigaki, H.; Kawamata, R.; Terao, K.; Tani, S. J. Am. Chem. Soc.
2001, 123, 10760. (d) Kunishima, M.; Imada, H.; Kikuchi, K.; Hioki,
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(4) (a) Organic Synthesis in Water; Grieco, P. A., Ed.; Blackie
Academic and Professional: London, 1998. (b) Lindstrom, U. M.
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(e) Koshland, D. E. Jr. Proc. Natl. Acad. Sci. U.S.A. 1958, 44, 98.
(f) Pauling, L. Nature 1948, 161, 707.
generate oxyanion intermediate 5 [step (ii)]. Presumably, this
step is facilitated by cage 1 because the cationic charge of the
cage can stabilize the anionic intermediate.14 The loss of water
via intermediate 6 should readily occur within the hydrophobic
cavity to give dehydrated product 4 [step (iii)]. The product 4
is too large for the cavity and is spontaneously released from
the cage [step (iv)] to be replaced with a new incoming
molecule of 2.
Oxyanion intermediate 5 [step (ii)] is effectively stabilized by
the Pd2+ centers located at every portal of the cage. If it is
assumed that the nucleophilic addition of 3 occurs around a
portal, the anionic intermediate 5 is most effectively stabilized
by the three Pd2+ centers sitting at the vertices of the roughly
triangular shaped portal (see the proposed geometry of 5 in
Figure 3). A control experiment was performed with bowl-
shaped cage 7 that has a 12+ net charge and the same formula
as cage 1 but does not have the closely arranged Pd2+ centers
around its open cavity. Although efficient host−guest complex-
ation was observed with cage 7 [to form the inclusion complex
7·(2a)3], even with a stoichiometric amount of 7, the
Knoevenagel condensation product 4a was obtained in only
17% yield under the same conditions (H2O, room temperature,
2 h).
̀
(6) (a) Vriezema, D. M.; Aragones, M. C.; Elemans, J. A. A. W.;
Cornelissen, J. J. L. M.; Rowan, A. E.; Nolte, R. J. M. Chem. Rev. 2005,
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In summary, we have successfully demonstrated dehydration
condensation under neutral conditions in water catalyzed by
synthetic cationic host 1. Following the efficient binding of the
substrate in the hydrophobic cavity, the condensation reaction
seems to be facilitated by the stabilization of the anionic
intermediate in the cationic environment of the cage,
reminiscent of the tricks of enzyme catalysis. Further
development of catalytic reactions by using cage 1 as a
synthetic mimic of enzymes is currently under investigation.
(9) For reactions within cage 1, see: (a) Yoshizawa, M.; Tamura, M.;
Fujita, M. Science 2006, 312, 251. (b) Nishioka, Y.; Yamaguchi, T.;
Yoshizawa, M.; Fujita, M. J. Am. Chem. Soc. 2007, 129, 7000.
(c) Horiuchi, S.; Nishioka, Y.; Murase, T.; Fujita, M. Chem. Commun.
2010, 46, 3460. (d) Murase, T.; Horiuchi, S.; Fujita, M. J. Am. Chem.
Soc. 2010, 132, 2866. (e) Horiuchi, S.; Murase, T.; Fujita, M. Chem.
Asian J. 2011, 6, 1839.
(10) Unlike naphthaldehyde 2a, two molecules of anthraldehyde 2b
are encapsulated within cage 1.
(11) Since droplets of benzaldehyde 2d dissolve compound 3, the
condensation may take place in dispersed 2d.
ASSOCIATED CONTENT
■
(12) (a) McNab, H. Chem. Soc. Rev. 1978, 7, 345. (b) Wang, X.;
Houk, K. N. J. Am. Chem. Soc. 1988, 110, 1870. (c) Wiberg, K. B.;
Laidig, K. E. J. Am. Chem. Soc. 1988, 110, 1872. (d) Nakamura, S.;
Hirao, H.; Ohwada, T. J. Org. Chem. 2004, 69, 4309.
S
* Supporting Information
Experimental procedures and physical properties. This material
is available free of charge via the Internet at http://pubs.acs.org.
(13) Interactions between the outside of cage 1 and compound 3 are
also negligible because the pH value of 3 in water did not change after
the addition of cage 1.
(14) Knoevenagel condensation is accelerated by rare-earth-
exchanged NaY zeolites, where electrostatic interactions between the
embedded cations and the encapsulated substrates play an important
role. See: Reddy, T, I.; Varma, R, S. Tetrahedron Lett. 1997, 38, 1721.
AUTHOR INFORMATION
Corresponding Author
mfujita@appchem.t.u-tokyo.ac.jp
■
ACKNOWLEDGMENTS
■
This research was supported in part by the Global COE
Program “Chemistry Innovation through Cooperation of
Science and Engineering” from MEXT, Japan.
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