Catalysis by a synthetic receptor sealed at one end and functionalized at the other

Article abstract of DOI:10.1021/ja045167x

A deep cavitand bearing a zinc (II) salen wall catalyzes the hydrolysis of para-nitrophenylcholine carbonate. The closed end of the cavitand properly positions the carbonyl function of the substrate for activation by the metal center. Substrate specificity for acetylcholine derivatives results from simultaneous cation-π interactions and a C≡O...Zn coordination bond. Copyright

Full text of DOI:10.1021/ja045167x

Published on Web 11/24/2004
Catalysis by a Synthetic Receptor Sealed at One End and Functionalized at
the Other
S e´ bastien Richeter and Julius Rebek, Jr.*
The Skaggs Institute for Chemical Biology and The Department of Chemistry, The Scripps Research Institute,
1
0550 North Torrey Pines Road, La Jolla, California 92037
Received August 10, 2004; E-mail: jrebek@scripps.edu
Cavitands derived from resorcinarenes are macrocyclic structures
1
with one open end. Deep cavitands act as hosts that can more or
less completely surround their guests while displaying high
2
selectivities. Specifically, a trimethylammonium “knob” fits snugly
within deeper cavitands, and guests bearing this feature are more
3
predictably positioned within than in other macrocyclic receptors.
Calixarenes and cavitands bearing additional functionalities on their
peripheries are able to catalyze methanolysis4 or aminolysis5
reactions of choline derivatives, respectively. We describe here a
salen functionalized cavitand (1), its zinc(II) complex (Zn-1) and
relate how the metal can accelerate reactions of choline derivatives.
The catalyst (Zn-1) is a resorcin-[4]-arene fused to a salen-type
6
ligand, and its synthesis was accomplished by the condensation
©
Figure 1. Left: energy-minimized structure (CaChe 4.9 ) of the complex
7
of the appropriate salicylaldehyde with a diamino cavitand,
followed by metalation with ZnEt
Both 1 and Zn-1 are in the vaselike shape in CH
between Zn-1 (CPK) and the PNPCC (stick); the front wall has been
removed for viewing clarity. Right: experimental kinetic curves for entries
8
2
(see Supporting Information).
Cl , as their
1
(black), 3 (red), 5 (green), and 6 (blue) of Table 1.
2
2
1
methine protons appear between 5.5 and 6 ppm in the H NMR
Table 1. Kinetic Data of the Hydrolysis of the PNPCC
9
spectra. The seam of hydrogen bonds provided by the six secondary
amides stabilizes this conformation, but the structure permits
dynamic exchange: guests enter and depart slowly on the NMR
time scale by the folding and unfolding of the cavitand.10
The guest (reactant) is para-nitrophenyl choline carbonate
entry
catalyst (mole %)
k
obsd (10- mn-1)
3
t
50% (mn)
kobsd/kuncat
(
PNPCC), and the (admittedly) easy reaction is its hydrolysis;
4
PNPCC is used as a reactive acetylcholine derivative because the
para-nitrophenolate anion released does not compete with the ester
for the metal. The Lewis acid zinc(II) was expected to activate the
well-positioned carbonyl toward reactions with an external nucleo-
phile. An energy-minimized structure of the PNPCC@Zn-1 com-
plex shows that cation-π interactions11 and a CdO- - -Zn coor-
dination bond occur simultaneously (Figure 1, left).
1
2
3
4
5
6
7
8
- (0)
1.6
10.3
19.1
43.7
84.7
3.6
>300
85
1
Zn-1 (10)
Zn-1 (20)
Zn-1 (50)
Zn-1 (100)
Zn-2 (20)
1 (20)
6.4
11.9
27.3
52.9
2.3
1
38
9
4
230
>300
173
1.6
3.9
Zn-1 (20)b
2.4
a
Conditions: 40 µM PNPCC, 20 mM H u¨ nig’s base, 0.5 mM TFA in
CH2Cl2, room temperature. b Same conditions as in footnote a + 65 µM
acetylcholine chloride.
in Figure 1.13 The reaction is found to be first-order in PNPCC,
and the observed rate constants (kobsd) are summarized in the Table.
Carbonate hydrolysis without catalyst is slow under these
conditions, and only ca. 30% of the PNPCC is decomposed after 5
h (Table 1, entry 1). The reaction rate is significantly increased by
the presence of Zn-1 (entries 2-5), and the acceleration is more
than 50-fold when 1 equiv of the cavitand is present (entry 5).
Control experiments were used to estimate the catalytic efficiency
of Zn-1.13 When the compound Zn-2 (salen wall without cavitand)
is used as catalyst (0.2 equiv, entry 6), the zinc(II) cation plays its
Lewis acid role and the reaction rate is increased, but is still five
times slower than the reaction catalyzed with Zn-1 (entry 3). No
acceleration is observed with the metal-free salen cavitand 1 (entry
7). Acetylcholine acts as a competitive inhibitor (entry 8), owing
to its structural similarity to PNPCC: the same distance exists
between the carbonyl and the trimethylammonium moieties in both.
With carbonate 3 as the substrate, hydrolysis using cavitand Zn-1
Kinetic studies of the PNPCC hydrolysis by water present in
commercial12 CH
Cl
to the quantity of PNPCC) were performed as described by de
2
2
(0.01%, i.e., more than 100 equiv compared
4
Mendoza (Table 1). The reactions were carried out in CH
2 2
Cl
buffered with CF CO H/EtN(i-Pr) at different concentrations of
3
2
2
Zn-1 and monitored by UV-vis spectroscopy (λmax ) 405 nm of
the para-nitrophenolate). Key experimental kinetic curves are shown
16280
9
J. AM. CHEM. SOC. 2004, 126, 16280-16281
10.1021/ja045167x CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
NMR data (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
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13
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15
1
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1
(
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4
-1
a
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(
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1
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6
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Acknowledgment. We are grateful to the Skaggs Foundation
and the National Institutes of Health (GM 27932) for financial
support and B. Purse for experimental assistance. S.R. is a Lavoisier
Postdoctoral Fellow of the Minist e` re des Affaires Etrang e` res de
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Supporting Information Available: Experimental details, full
synthetic procedures, characterization of new compounds, kinetic, and
JA045167X
J. AM. CHEM. SOC.
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