Reversibly addressing an allosteric catalyst in situ: Catalytic molecular tweezers

Article abstract of DOI:10.1002/anie.200460932

Abiotic allosteric regulation: The design, synthesis, and application of novel, reversible allosteric catalytic molecular tweezers that contain a structural metal, addressable in situ, and two functional catalytic metals are reported (see picture). Kinetic and selectivity data reflect a significant decrease in cooperativity upon opening of the "arms" of the catalyst caused by reactions occurring at the hinge.

Full text of DOI:10.1002/anie.200460932

Angewandte
Chemie
Asymmetric Catalysis
Reversibly Addressing an Allosteric Catalyst
In Situ: Catalytic Molecular Tweezers**
Nathan C. Gianneschi, So-Hye Cho,
SonBinh T. Nguyen, and Chad A. Mirkin*
In biology, allosteric regulation is the control of enzyme
activity by the fast, reversible binding of molecules or ions to
structural sites that are remote from, but control conforma-
tional changes that occur at, the active site.[1] If one considers
that reversibility in a biological sense implies in situ control
over activity, then there are no known abiotic systems that are
truly allosteric catalysts. Recently, the first efforts towards the
development of artificial allosteric catalysts have been
described.[2,3] Thus far, there have been two distinct
approaches to realizing systems that mimic biological allos-
teric regulation of catalysis. One approach consists of organic
[*] N. C. Gianneschi, S.-H. Cho, Prof. S. T. Nguyen, Prof. C. A. Mirkin
Department of Chemistry and
the Institute for Nanotechnology
2145 Sheridan Road, Evanston, IL, 60208-3113 (USA)
Fax: (+1)847-467-5123
E-mail: camirkin@chem.northwestern.edu
[**] CAM acknowledges the NSF and AFOSR for support of this work.
SHC acknowledges the DOE for funding through the Institute for
Environmental Catlysis (Grant no. DE-FG02-03ER15457)
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200460932
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frameworks in which structural metal ions induce conforma-
We present the synthesis and catalytic activity of tweezer
complexes that contain a RhI hinge and two CrIII–salen
catalytic arms (Scheme 2). The RhI–thioether bonds can be
broken by reaction with CO and ClÀ, while leaving the RhI–
phosphine bonds intact. The result of the selective breaking of
these bonds is a significant topological change coupled with a
change in the selectivity and rate of the reaction occurring at
the CrIII metal center. Essentially, the catalysis is controlled
using changes in coordination chemistry at a structural site
distal to a catalytic site. This is a rare example of a tweezer
complex capable of undergoing an actual modulation of the
distance between the arms of the complex in situ by the
introduction and removal of small molecules and ions capable
of addressing the hinge.[6] In this manner we have a unique,
biologically inspired, reversible switch for catalyst activity and
selectivity.
tional changes that affect the ability of catalytic metals, within
the same complex, to function.[2] Essentially, structural metal
coordination prepares a suitable ligand for the catalytically
active metal centers.[4] However, in a biological context, this
strategy is more reminiscent of the way various enzymes,
notably Zn-finger proteins,[1] use structural metals to define
their tertiary structure in a static fashion rather than behaving
dynamically and reversibly (Scheme 1a).
The asymmetric ring opening of cyclohexene oxide by
TMSN3 (TMSN = azidotrimethylsilane) was used to demon-
strate the utility of this approach to catalytic control. This
reaction was selected because of its demonstrated bimetallic
mechanism that requires two metal–salen monomeric cata-
lysts to activate both the epoxide and the nucleophile.[7] We
hypothesized that the incorporation of a bimetallic catalyst
into a tweezer complex that can be opened and closed would
provide control over catalyst activity and selectivity by virtue
of the ability to address the relative orientation of the two
catalytic sites involved in the bimetallic reaction. We were
encouraged to move towards a tweezer-type catalyst because
of our earlier experience with the related, macrocyclic salen-
based system.[3] Notably, the tweezer complex (Scheme 2)
Scheme 1. Ms =Structural transition-metal center. Mc =Catalytic transi-
tion-metal center. Ms and Mc may be the same or different depending
on the system. a) The metal-ion directed arrangement of an active site.
b) The allosteric effector mediated shape change of a catalytic hetero-
bimetallic macrocycle.
The second approach is based upon hetero-
bimetallic supramolecular complexes in which
one metal center acts as a structure control site
and the other acts as a catalytic site (Sche-
me 1b).[3] These large macrocyclic complexes are
assembled in high yield by the weak-link
approach.[5] This strategy provides
a close
mimic of a biological allosteric catalyst in the
sense that it contains structural and catalytic sites
that are independently addressable. The struc-
tural metal centers hold the catalyst in different
conformations depending on the presence or
absence of the allosteric effectors. However,
these effectors prove difficult to remove from
this system, making the reversibility slow and
difficult to achieve.
Herein, we describe the synthesis and char-
acterization of a new allosteric catalyst based
upon a novel class of tweezer complex with
catalytic rates and selectivities that can be
increased and decreased reversibly in situ by
selectively opening and closing the catalytic cleft
through reactions that occur at the allosteric
hinge. By using supramolecular coordination
chemistry as a synthetic tool, we are beginning
to understand how to construct addressable,
conformationally flexible entities capable of
catalyzing reactions with allosteric enzyme-like
control.
Scheme 2. Synthesis of the allosteric tweezer complexes. Counterions are BF4À. All cy-
clohexyl salen backbones have (R,R) stereochemistry. Reagents and solvents;
a) [Rh(NBD)2]BF4, CH2Cl2; b) PPNCl/CO (PPNCl=bis(triphenylphosphoranylidene)am-
monium chloride); 3 and 4 may be synthesized from 5 and 6, respectively, by the
removal of CO in vacuo or by purging with N2.
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Table 1: Selectivity data for the ring opening of cyclohexene oxide by
TMSN3 catalyzed by 3, 5, and the monomeric CrIII–salen complex 7.[a]
offers an increase in the solubility in comparison with the
macrocycle, thus allowing the epoxide ring-opening reactions
to be performed over greater ranges of catalyst concentration
in THF. In addition, upon RhI–thioether bond breakage the
catalyst changes from the compact tweezers-shaped molecule
into a flexible, linear molecule. This dramatic change in shape
was expected to generate a larger allosteric effect than the
related macrocyclic analogue.
Entry
Catalyst
[Catalyst] m 1”10À3
% ee of product[b]
The novel enantiomerically pure hemilabile ligands 1 and
2 were synthesized in eight steps (see Supporting Informa-
tion) and incorporate a binding site for a RhI metal center
(Scheme 2). Compounds 3 and 4 were synthesized in almost
quantitative yield by treating 1 and 2 respectively with
[Rh(NBD)2]BF4 in CH2Cl2 (NBD is norbornadiene). Com-
pound 3 has been characterized by elemental analysis,
31P NMR spectroscopy (compounds 3 and 5 are paramagnetic,
due to the incorporation of CrIII metal centers, which results in
broad NMR signals), and electrospray mass spectrometry,
and all data are consistent with its proposed structure. In
addition, 4 has been fully characterized in solution. Com-
pounds 3 and 4 can be converted to 5 and 6, respectively, by
treating with 1 equivalent of PPNCl and CO (1 atm) in
benzonitrile, CH2Cl2, or THF at room temperature. Com-
pounds 5 and 6 exhibit diagnostic nCO bands at 1976 cmÀ1 and
1978 cmÀ1, respectively.[5c] The 31P{1H} NMR spectra of 5 and
6 also support the proposed structures with each exhibiting a
single resonance at 25 ppm (JP-Rh = 123 Hz) diagnostic of
square-planar trans-phosphine, Cl/CO complexes of RhI.[5c,8]
Significantly, the tweezer complexes 5 and 6 undergo
reversible conversion to 3 and 4 upon vacuum removal of
the solvent or by purging N2 through the solution. The
conversion can be monitored easily by 31P{1H} NMR and
infrared spectroscopies.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
3
5
7
3
5
3
5
7
3
5
3
5
3
5
3
5
3
5
7.2
7.2
7.2
4.7
4.7
3.6
3.6
3.6
2.5
2.5
1.8
1.8
0.72
0.72
0.36
0.36
0.14
0.14
80
74
26
80
73
79
68
12
77
60
72
54
65
44
63
32
49
21
[a] All reactions were performed at room temperature in THF. [b] %ee of
1-azido-2-(trimethylsiloxy)cyclohexane was determined by chiral GC.
The differences in catalytic reactivity between the open,
closed, and monomeric forms of the catalyst were evaluated
using the asymmetric ring opening of cyclohexene oxide by
TMSN3 to yield 1-azido-2-(trimethylsiloxy)cyclohexane
[Eq. (1); Table 1]. The incorporation of two catalysts into
the tweezer complex results in competing intramolecular and
intermolecular mechanisms. This is further complicated by
the observation that linked, dimeric CrIII–salen catalysts
display increased intermolecular reaction rates, with respect
to their monomeric analogues, in which highly reactive
multimetallic assemblies have been implicated.[7b,c] Theoret-
ically, if only one molecule of either 3 or 5 were present in
solution the catalytic reaction would be entirely intramolec-
ular and as the catalyst concentration is increased the reaction
would become more intermolecular. If this theory is true, we
expect that the catalytic activity of 3 and 5 will be affected
differently by dilution and we can optimize the allosteric
effect by varying the concentration of the catalyst. We were
able to demonstrate this effect by monitoring the enantio-
meric excess of product formed by 3 and 5 at various catalyst
concentrations (Table 1) and plotting the resulting data as a
function of catalyst concentration (Figure 1).
Figure 1. The allosteric effect expressed in terms of selectivity. R is the
allosteric selectivity ratio=(%ee of the product formed by using
3):(%ee of the product formed by using 5).
decreases until they both reach a maximum of approximately
80% ee (Table 1). A similar trend is seen for the monomeric
version of the catalyst (7) in which the selectivity of the
catalyst increases with concentration (Table 1, entries 3 and
8). We hypothesize that the predefined cavity of complex 3 is
able to maintain a selective environment for catalysis over a
broad range of concentrations. Complex 5 is comparatively
more adversely affected by solvent and reagent molecules
that contribute to a reduction in the selectivity of the catalyst.
The allosteric effect is enhanced as we move to lower
concentrations of catalyst and the system becomes more
dependent on the intramolecular reaction (Figure 1).
The difference in the selectivity of the open and closed
tweezer complexes is enhanced at low concentrations
(Figure 1). As the concentration of 3 and 5 increases, the
difference between the selectivity of the two catalysts
Open and closed tweezer complexes, 3 and 5, are more
selective and active than the monomeric version of the
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catalyst, which suggests that
cooperativity is present for both
of the dimers. However, for 5 that
cooperativity is reduced, thus
rendering the catalyst less selec-
tive. The selectivity depends
greatly on the nature of the
alignment of the two catalytic
centers in each tweezer complex.
By monitoring the catalysis over
a range of concentrations, we
were able to map out and opti-
mize the allosteric effect with
respect to selectivity.
Figure 2. In situ reversibility of the catalysis. a) The catalyst being taken through an open/closed/open
&
cycle. b) The switch point ( ) indicates CO saturation or CO desaturation (N2 purge) points at which
As mentioned earlier, a key
requirement of a system that
the catalyst is opened (complex 5 from complex 3) or closed (complex 3 from complex 5) respectively.
Reaction conditions: Cyclohexene oxide (6.1 mmol), TMSN3 (2.3 mmol), 3.6 mm catalyst in benzonitrile
seeks to mimic biological-like at room temperature (see Supporting Information for details).
allosteric control over catalysis,
is its reversibility. The ease by
Keywords: asymmetric catalysis · coordination chemistry ·
ligand design · ligand effect· supramolecular chemistry
.
which the allosteric initiator molecules and ions can be
introduced and removed from the system dictates the
plausibility of this approach to catalytic control. Hence, the
use of a gas as an allosteric protagonist is ideal if one wishes to
develop a system that can easily be addressed during the
course of the reaction. Both members of the CO/ClÀ pair are
required to break the RhI–thioether bonds, as confirmed by
31P{1H} NMR and FTIR spectroscopies. A catalytic reaction
occurring in a solution containing ClÀ ions and lacking CO
will have only one of the necessary allosteric elements and
vice versa. Subsequently, the ability to reversibly convert from
3 to 5 in situ by CO saturation and CO desaturation of a
solution containing ClÀ ions allows us to conveniently cycle
the catalyst through two modes. With the introduction and
removal of CO (1 atm) as our switch, we were able to
demonstrate this allosteric effect with respect to the rate of
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To the best of our knowledge, this data represents the only
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control over catalytic activity and selectivity and can be
addressed in a reversible fashion, in situ. In view of the
growing number of reactions that are catalyzed in a bimetallic
fashion,[7,10] this could become
approach to catalyst preparation and modulation.
a reliable and general
Received: June 10, 2004
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[9] There is a linear relationship between product formation and
time, which indicates the catalyst is intact over the time course of
the reaction. However, the rate of reaction observed following
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