Enhanced catalytic decomposition of a phosphate triester by modularly accessible bimetallic porphyrin dyads and dimers

Article abstract of DOI:10.1039/c2cc17568a

A series of metalloporphyrin dimers were modularly prepared and shown to catalyze the methanolysis of a phosphate triester, yielding rates that are large compared to the rate of the uncatalyzed reaction. Up to 1300-fold rate acceleration can be achieved v

Full text of DOI:10.1039/c2cc17568a

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COMMUNICATION
Enhanced catalytic decomposition of a phosphate triester by modularly
accessible bimetallic porphyrin dyads and dimersw
a
Ryan K. Totten,a Patrick Ryan,b Byungman Kang,a Suk Joong Lee,z Linda J. Broadbelt,b
Randall Q. Snurr,b Joseph T. Hupp*a and SonBinh T. Nguyen*a
Received 4th December 2011, Accepted 27th January 2012
DOI: 10.1039/c2cc17568a
A series of metalloporphyrin dimers were modularly prepared
and shown to catalyze the methanolysis of a phosphate triester,
yielding rates that are large compared to the rate of the
uncatalyzed reaction. Up to 1300-fold rate acceleration can be
achieved via a combination of cavity-localized Lewis-acid acti-
vation and methoxide-induced methanolysis.
of porphyrins, the periphery of assemblies can readily be tuned
to provide attractive environments for both hydrophobic and
hydrophilic reactants. Thus, we set out to explore the use of
these non-covalent interactions for the solvolysis of phosphate
triesters, a process that has important implications in the
decomposition of biologically relevant phosphate diesters9 as
well as the degradation of toxic organophosphate-based nerve
agents.10 As a model, we selected a cyclic cofacial porphyrin
dimer that would allow us to approximate the action of
phosphotriesterases (PTEs), whose active sites comprise two
zinc ions: one coordinates the substrate and the other delivers
a coordinated hydroxide to induce hydrolysis (Fig. 1, left).11
We reasoned that related bis-porphyrin assemblies could, in
principle, bind and activate an organophosphate substrate at
one metal site, while simultaneously delivering a methoxide
nucleophile from the second in a cooperative fashion (Fig. 1,
right). In polar media, a hydrophobic organophosphate sub-
strate could also be driven to interact favorably with the highly
hydrophobic porphyrinic cavity, further enhancing substrate
binding. Together, these interactions could serve to bring an
organophosphate sufficiently close to a nucleophilic methoxide
ion to catalyze substrate solvolysis within the cavity.
Cofacial porphyrin assemblies1 have attracted great attention
over the past several decades due to their unusual photo-
physical properties,2 a coordination environment that can
accommodate two or more metal centers,3 and structural
rigidity.4 Of particular interest to us is the design of assemblies
suitable for applications involving molecular recognition5 and
catalysis.1 In such cases, manipulating the distance between
two or more porphyrin entities can afford cavities with differing
shapes and sizes that are capable of recognizing and trans-
forming small-molecule substrates.6 In deploying cofacial multi-
porphyrin architectures, two metal centers can be exploited
in a cooperative fashion to increase the rate of bimolecular
reaction,1,6 as is often observed in biological systems. Additionally,
careful cavity design can yield bio-inspired structures with
catalytic behavior and potency reminiscent of enzymes, without
being constrained by biological operating conditions.
In designing cyclic porphyrin dyads and dimers, we wanted
to explore, via the incorporation of different bimetallic
arrangements into the hydrophobic porphyrinic cavity, how
the local reaction environment—and especially its propensity
for catalysis—could be tuned. While phosphotriesterases
II
employ Zn ions to deliver a nucleophilic hydroxide to the
substrate,11 the dianionic environment of the porphyrin ligand
Many porphyrin-based supramolecular catalysts have taken
advantage of the axial ligation ability of metalloporphyrins to
position reactive moieties in close proximity within a cavity,
thereby reducing the entropic barrier for the ensuing reaction.7
Surprisingly, non-directive interactions such as van der Waals
forces and solvophobic effects, which are highly prevalent in
biological systems, have rarely been explored.8 Given the
broad range of substituents available in the synthetic chemistry
does not permit such a feature in our design. As such, we
III
incorporated Al , which can accommodate an anionic methoxide
ligand as the nucleophile. By manipulating the porphyrin
a Department of Chemistry, Northwestern University,
2145 Sheridan Road, Evanston, IL 60208, USA.
E-mail: j-hupp@northwestern.edu, stn@northwestern.edu;
Fax: +1 847-467-1425, +1 847 491-7713;
Tel: +1 847-491-3504, +1 847-467-3347
b Department of Chemical and Biological Engineering, Northwestern
University, 2145 Sheridan Road, Evanston, IL 60208, USA
w Electronic supplementary information (ESI) available: Complete
experimental details of syntheses; compound characterization data
and spectra; NMR/titration experimental methods, spectra, and data
analysis; as well as detailed description of catalytic conditions and
results of the methanolysis. See DOI: 10.1039/c2cc17568a
z Department of Chemistry, Korea University, 5 Anam-dong, Sungbuk-gu,
Seoul 136-701, Republic of Korea.
Fig. 1 Degradation of a phosphate triester in the active site of a
phosphotriesterase enzyme11 (left) and proposed catalytic methanolysis
of a phosphate triester in an Al porphyrin dimer.
c
4178 Chem. Commun., 2012, 48, 4178–4180
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Scheme 1 Modular synthesis of catalytic porphyrin dimers starting from the same starting porphyrin monomer, Zn1.
substituents, the electronic environment can be further adjusted
to simultaneously enhance the nucleophilicity of this methoxide
for catalysis as well as the Lewis acidity of the metal center.
To accommodate the aforementioned criteria, we designed a
series of porphyrin dyads and dimers that we envisioned would
be readily attainable from a single zinc–porphyrin monomer,
Zn1, in a highly modular fashion. After quantitative olefin
functionalization, Zn1 can be converted to the unsaturated
dimer unsat-Zn1–Zn1 in good yield (84%) through a one-step
templated ring-closing metathesis reaction (tRCM), a strategy
previously employed by our group12 and others13 (Scheme 1,
left path). Demetallation of unsat-Zn1–Zn1 with trifluoro-
acetic acid (TFA) gives the free-base dimer, which is readily
remetallated with AlMe3 to provide unsat-Al1–Al1 in quanti-
tative yield.
and degrees of rigidity that can be employed for the catalytic
solvolysis of phosphate triesters.
The methanolysis of p-nitrophenyl diphenyl phosphate
(PNPDPP), a common simulant for toxic nerve agents,14 is
enhanced by all of the bimetallic porphyrin assemblies
(Table 1). As expected, significantly enhanced rates were
observed when the porphyrin catalysts contained Al–OMe
centers as compared to the Zn-containing catalysts. The most
active catalyst, diyne–Al1–Al1, enhances the rate of methano-
lysis by B225-fold rate relative to the uncatalyzed process,
and by B14-fold relative to sat-Zn1–Zn1, the least potent of
the six bimetallic catalysts. The rigidity of the linker has a
moderate, but noticeable, effect on the catalysis rate, with the
most rigid dimer, diyne–Al1–Al1, showing a 2.2-fold enhance-
ment over the flexible sat-Al1–Al1 dimer. That the Zn dimers
show B3-fold enhanced catalysis rates compared to the Zn
The fully saturated monozincated porphyrin dyad sat-Zn1–H21
can also be readily obtained from Zn1 in good yield in 3 steps
(Scheme 1, middle path). This mixed porphyrin synthetic
strategy allows ready access to heterobimetallic porphyrin
dyads containing various Zn1–M1 combinations. As above,
the free-base porphyrin component can be metallated with
AlMe3 to afford sat-Zn1–Al1 in quantitative yield without
transmetallation. Alternatively, sat-Zn1–H21 can be demetal-
lated with TFA and remetallated to give the homobimetallic
sat-Zn1–Zn1 or sat-Al1–Al1 species. Finally, the more rigid
diacetylene-linked dimer, diyne–Zn1–Zn1, can be obtained
from Zn1 through a templated Glaser–Hay coupling and can
be readily modified to provide diyne–Al1–Al1. Our design
allows for the modular synthesis of eight distinct robust cyclic
multiporphyrin assemblies from a single porphyrin in five or
fewer steps. The result is a series of hollow supramolecular
metalloporphyrin assemblies with tunable metal environments
Table 1 Observed initial rates (through 10% conversion) for the
methanolysis of PNPDPP (25 mM) with 3 mol% porphyrin catalyst
Relative rate vs.
uncat. reaction
Entry
Catalyst
Observed rate/M sꢀ1
1
2
3
4
5
6
sat-Zn1–Zn1
unsat-Zn1–Zn1
sat-Zn1–Al1
sat-Al1–Al1
unsat-Al1–Al1
diyne–Al1–Al1
1.47 ꢁ 10ꢀ8
1.53 ꢁ 10ꢀ8
6.03 ꢁ 10ꢀ8
9.51 ꢁ 10ꢀ8
1.69 ꢁ 10ꢀ7
2.05 ꢁ 10ꢀ7
16
17
66
104
184
224
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Chem. Commun., 2012, 48, 4178–4180 4179

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methanolysis of the nerve agent simulant PNPDPP. While
the absolute turnover numbers are still quite modest when
directly compared to the kcat’s reported for PTEs,11 the
advantage of our highly modular synthetic approach is its
facile scope for tuning the many design parameters available,
thus influencing the catalytic rate in a single synthetic enzyme
cavity. For our small dimers, where a 1 : 1 substrate/cavity
binding stoichiometry was observed (Section XII in ESIw),16
the most critical factors for enhanced catalysis are Lewis acid
activation and the presence of Al–OMe centers (Sections IX
and XII in ESIw). This combination of supramolecular
encapsulation and activation resembles the molecular organi-
zation features in some enzymes and points to the vast
potential that mimicking biological designs can bring to
supramolecular catalysis, without being limited by the narrow
activity range defined by biological pHs.10
Fig. 2 Reaction profiles for the methanolysis of PNPDPP carried
out in the absence or presence of 3 mol% of unsat-Al2–Al2 or
unsat-Zn2–Zn2.
monomer, which in turn is 5 times faster than the uncatalyzed
reaction, points to the advantage of having Lewis acid activa-
tion and cavity encapsulation operating in concert. Lewis acid
activation is clearly essential for catalysis, as the free base
dimer, unsat-H21–H21, only elicits a reaction rate similar to
that for the uncatalyzed reaction.
This material is based upon research sponsored by the
AFOSR under agreement FA-9550-07-1-0534. We acknowledge
DTRA (grant HDTRA1-10-1-0023) and the DoE (grant
DE-FG02-03ER15457) for additional financial support.
Notes and references
The importance of having cavity-localized methoxide
nucleophiles is clearly demonstrated by the increased reaction
rates observed when the Zn centers in sat-Zn1–Zn1 are
successively replaced with Al–OMe groups (Table 1, cf. entries
1, 3, and 4). Thus, we were intrigued about the possibility of
tuning the electronic properties of the metalloporphyrin to
further enhance the nucleophilicity of the methoxide ions and
catalysis. To accomplish this, we replaced the 3,5-di-tbutyl aryl
substituents on unsat-Al1–Al1 with Si(hex)3-protected alkynyl
groups (Fig. 2). We reasoned that the delocalization of the
porphyrin electron density into a silyl-protected acetylene
would better stabilize partial positive charge on the Al center,
making it more Lewis acidic and the ꢀOMe anion more
nucleophilic,15 both of which would enhance catalysis. Indeed,
CHELPG calculations show that the partial charge separation
between Al and OMe is greater for a porphyrin bearing 10,20-
(CRCSi(hex)3) groups (ꢀOMe: ꢀ0.653 e, Al: 1.248 e)
compared to an analogous porphyrin with 3,5-di-tbutyl aryl
substituents (ꢀOMe: ꢀ0.645 e, Al: 1.189 e).
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As shown in Fig. 2, unsat-Al2–Al2 is highly active for the
methanolysis of PNPDPP, engendering a rate that is over
1300 times the uncatalyzed rate and B7 times faster than
unsat-Al1–Al1. Along with a stronger ꢀOMe nucleophile, the
highly Lewis acidic Al–OMe centers in unsat-Al2–Al2 bind
PNPDPP more effectively, as observed from the 2-fold binding
constant increase of PNPDPP in unsat-Al2–Al2 (49 Mꢀ1) over
unsat-Al1–Al1 (25 Mꢀ1). Moreover, the presence of a solvo-
phobic encapsulation effect for PNPDPP is clearly demon-
strated by both Zn and Al dimers, which bind PNPDPP in
1 : 1 v/v CHCl3/MeOH at concentrations 15–50 times higher
than expected statistically (Section XII in ESIw).
16 A larger tetramer assembly can bind more than one substrate in its
cavity. See: B. Kang, J. W. Kurutz, K.-T. Youm, R. K. Totten,
J. T. Hupp and S. T. Nguyen, Chem. Sci., 2012, 3, DOI: 10.1039/
c2sc00950a.
In summary, we have demonstrated that covalently linked
hollow metalloporphyrin dimers possessing tunable Lewis
acidic metal sites can significantly increase the rate of
c
4180 Chem. Commun., 2012, 48, 4178–4180
This journal is The Royal Society of Chemistry 2012