Metal organic frameworks as nitric oxide catalysts

Article abstract of DOI:10.1021/ja210771m

The use of metal organic frameworks (MOFs) for the catalytic production of nitric oxide (NO) is reported. In this account we demonstrate the use of Cu ₃(BTC)₂ as a catalyst for the generation of NO from the biologically occurring substrate, S-nitrosocysteine (CysNO). The MOF catalyst was evaluated as an NO generator by monitoring the evolution of NO in real time via chemiluminescence. The addition of 2, 10, and 15-fold excess CysNO to MOF-Cu^II sites and cysteine (CysH) resulted in catalytic turnover of the active sites and nearly 100% theoretical yield of the NO product. Control experiments without the MOF present did not yield appreciable NO generation. In separate studies the MOF was found to be reusable over successive iterations of CysNO additions without loss of activity. Subsequently, the MOF catalyst was confirmed to remain structurally intact by pXRD and ATR-IR following reaction with CysNO and CysH.

Full text of DOI:10.1021/ja210771m

Communication
pubs.acs.org/JACS
Metal Organic Frameworks as Nitric Oxide Catalysts
Jacqueline L. Harding† and Melissa M. Reynolds*,†,‡
‡
†Department of Chemistry and School of Biomedical Engineering, Colorado State University, Fort Collins, Colorado, 80523
S
* Supporting Information
and MOFs offer the potential to be either NO donors or
ABSTRACT: The use of metal organic frameworks
(MOFs) for the catalytic production of nitric oxide
(NO) is reported. In this account we demonstrate the
use of Cu3(BTC)2 as a catalyst for the generation of NO
from the biologically occurring substrate, S-nitrosocysteine
(CysNO). The MOF catalyst was evaluated as an NO
generator by monitoring the evolution of NO in real time
via chemiluminescence. The addition of 2, 10, and 15-fold
excess CysNO to MOF-CuII sites and cysteine (CysH)
resulted in catalytic turnover of the active sites and nearly
100% theoretical yield of the NO product. Control
experiments without the MOF present did not yield
appreciable NO generation. In separate studies the MOF
was found to be reusable over successive iterations of
CysNO additions without loss of activity. Subsequently,
the MOF catalyst was confirmed to remain structurally
intact by pXRD and ATR-IR following reaction with
CysNO and CysH.
catalysts for the generation of NO directly from bioavailable
sources. Recently, the Morris group has demonstrated that Cu-
based zeolites can be used to catalytically produce NO from
nitrite and to store NO. Thus, MOFs and zeolites offer a single
therapeutic substrate that can be designed as either an NO
donor or an NO generator.
While there are numerous bioavailable sources of NO,
including nitrite (176 nM) and S-nitrosothiols (RSNOs) (10
μM), the most abundant and structurally varied species in the
blood are RSNOs. As such, RSNO decomposition has been the
most heavily investigated. RSNOs have been reported to
decompose via several different mechanisms.7 One well-
established mechanism of RSNO decomposition involves a
copper-mediated pathway with thiol reducing equivalents
resulting in the generation of 1 mol of NO and the
corresponding disulfide.7 MOFs have been previously demon-
strated to catalyze a variety of reactions. Thus, we propose that
MOFs can be utilized as catalysts for long-term NO generation
by selectively permitting the diffusion of RSNO substrates to
the active CuII sites.
The general requirements for a MOF−NO catalyst are that
the material is resistant to degradation under the reaction
conditions and has accessible catalytic sites. To this end, three
MOFs were investigated: Cu3(BTC)2 (BTC:1,3,5-benzenetri-
carboxylate), Cu-triazolate, and Fe(BDC) (BDC-benzenedicar-
boxylate). Of these, only Cu3(BTC)2 met the specified
requirements. Cu3(BTC)2 features unsaturated metal sites
and pore sizes up to 18 Å that allow for the accessibility of
the RSNO species to the metal center.8 In addition, previous
reports have demonstrated that Cu3(BTC)2 remains structur-
ally stable after being utilized as a catalyst for other reactions.9
Thus, this well-studied MOF presents an ideal starting point for
studying the catalytic production of NO via the copper-
mediated decomposition of RSNOs. In this work, we report the
first example of using a MOF to catalyze the decomposition of
RSNOs to generate NO.
itric oxide (NO) has been identified as a crucial biological
N
signaling molecule in the cardiovascular,1−3 nervous, and
immune systems.1,4−6 As a result, NO storage and delivery
vehicles have been extensively developed to target a range of
diseases and to control material−cell interactions.2 Current
approaches for NO storage and delivery have primarily focused
on incorporating NO donor moieties such as diazeniumdiolates
(R-N2O2) and S-nitrosothiols (RSNO) onto both organic3 and
inorganic4 substrates. However, the relatively small NO
reservoir that can be stored on such donor substrates ultimately
limits their potential use.
In order to increase the NO loading capacity and expand the
potential use of NO donor materials to more diverse
biomedical applications, porous inorganic materials such as
metal organic frameworks (MOFs) and zeolites have been
investigated as NO storage materials. MOF materials provide
an NO therapeutic substrate with tunable physical and chemical
properties.5 Recently, the Morris, Rosseinsky, and Cohen
groups have postsynthetically modified MOFs with various NO
donor moieties.6 Their work shows that MOF substrates are7
indeed viable NO donor materials. These NO donor MOF
materials have increased storage capacity over previous NO
donors.
Yet, even the use of a MOF substrate does not eliminate the
capacity and NO-release duration limitations that are inherent
in NO donor materials. Long-term biomedical applications
require a therapeutic substrate that is stable and capable of
producing NO for lengthy and sustained periods of time.
Advantageously, structured inorganic materials such as zeolites
As depicted in Figure 1, RSNOs can interact with the CuII
metal sites of Cu3(BTC)2 to decompose RSNO and
subsequently produce NO. The RSNO decomposition reaction
to generate NO via the Cu3(BTC)2 catalyst is shown in Scheme
1. S-Nitrosocysteine (CysNO) was selected as a model RSNO
species because of its reported bioavailability in the micromolar
range.10 In addition, these RSNOs do not decompose
prematurely with reducing equivalents of cysteine (CysH) to
a significant extent (see Table 1). Both reactions were
monitored by measuring the formation of the product, NO.
Received: November 15, 2011
Published: January 20, 2012
© 2012 American Chemical Society
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Table 2. Catalytic Production of NO via Turnover of the
MOF−CuII Sites
a
conditions
catalyst turnover
CysNO:CysH:MOF−CuII (2:1:1)
CysNO:CysH:MOF−CuII (10:1:1)
CysNO:CysH:MOF−CuII (15:1:1)
CysNO:CysH:MOF−CuII Recycling
1.9 0.1
9.8 0.3
15.0 0.1
8.0 0.3
a
Nearly 100% NO recovered; see SI.
Figure 1. Schematic illustration of RSNO decomposition to produce
NO via a MOF catalyst: Cu3(BTC)2; copper sites are shown in blue,
the oxygen sites in red, and the BTC ligand in black.
Scheme 1. Decomposition of CysNO To Produce NO via
Cu3(BTC)2
Table 1. Summary of the Decomposition of CysNO via CuII
Catalysts
conditions
catalyst turnover
time (h)
b
CysNO:CysH (2:1)
n/a
n/a
10.2
b
CysNO:CysH:BTC (2:1:0.66)
CysNO:CysH:MOF−CuII (2:1:1)
CysNO:CysH:CuCl2 (2:1:1)
10.2
a
1.9 0.1
10.2 0.2
0.2 0.1
a
2
0.1
b
CysNO:CysH:CuCl2 (2:1:0.0005)
n/a
10.2
Figure 2. (A) NO release profile of CysNO catalyzed with and
without Cu3(BTC)2. The inset shows an enlargement of the 4−11 h
time period for CysNO decomposition by Cu3(BTC)2. (B) NO
release profile of CysNO (black) catalyzed by Cu(CH3COO)2 and
(red) CuCl2.
a
b
Nearly 100% NO recovered. Experiment stopped to match the time
interval of experiment 3.
The structural rigidity of the framework and the reaction media
postreaction were evaluated to further support that the
generation of NO was not due to framework instability.
Nitric oxide production was measured directly by chem-
iluminescence to determine the catalytic turnover of the MOF.
Briefly, the MOF was suspended in ethanol containing 1
reducing equivalent of cysteine (CysH). Subsequently, CysNO
was added and the real-time production of NO monitored. The
addition of 2, 10, and 15-fold excess CysNO to CuII resulted in
the spontaneous generation of NO and nearly 100% theoretical
yield of the NO product (see Table 2). In each case
Cu3(BTC)2 had the anticipated turnover with respect to
available CuII centers. In contrast, the absence of the MOF
failed to produce a significant amount of NO from a
CysNO:CysH solution. These experiments clearly show the
ability of the MOF to catalyze the generation of NO from the
decomposition of CysNO.
slower rate of decomposition (Figure 2A). The initial bolus of
NO release can be attributed to equilibration of CysNO in the
reaction medium. The slight increase in the NO release profile
after 2 h may be attributed to an increased availability of the
MOF−CuII sites as a result of the formation of disulfide
products. This behavior was found reproducibly after a total of
50% of the CysNO had decomposed. However, in the absence
of a catalyst there were no deviations in the NO release profiles
over the course of the experiment. In contrast, the addition of
GSNO to the MOF did not produce appreciable NO as
compared to the CysNO which quantitatively decomposed to
produce NO (see SI). The lack of NO production from GSNO
may be attributed to the size of the GSNO compared to the
size of the pore cavity in Cu3(BTC)2. The overall size of the
cavity is 18 Å. Since the size of GSNO is 19 Å, the access of the
GSNO to an active CuII site is limited.
The time release profiles demonstrating the generation of
NO are shown in Figure 2. The CysNO decomposition of the
MOF-catalyzed reaction was initially more rapid followed by a
To demonstrate if the MOF could function as a catalyst for
continued use, recycling experiments were performed. After the
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CysNO had completely decomposed, the MOF catalyst was
removed from the reaction flask, rinsed, and subsequently
reacted with 2 additional equivalents of CysNO for three
iterations. After each successive addition of CysNO/CysH, the
catalyst remained active. This was evident by the consistent
turnover of the MOF−CuII sites as a function of reusing the
MOF material (Table 2).
As a comparison to verify that the observed NO generation
was due to the MOF and not Cu2+ ions in solution, similar NO
generation experiments were performed using CuCl2 and
Cu(CH3COO)2 as catalysts. The decomposition of CysNO in
the presence of CuCl2 was 50 times faster than that of the
MOF-catalyzed system, shown in Figure 2B. When Cu-
(CH3COO)2 was evaluated as a catalyst for the decomposition
of CysNO, the immediate release of NO was observed. NO
release was sustained for a 1 h period resulting in 80 5% of
the theoretical NO accounted for. In comparison to
Cu3(BTC)2 the resulting profiles were markedly different,
indicating that the conversion of CysNO to NO is occurring as
a function of the MOF structure and not the solvated Cu2+ ion
species in solution. The slowed rate of reaction by the
Cu3(BTC)2 is attributed to the accessibility of the active sites
within the MOF network. Given the small interior pore space
(18 Å), occupation of a pore is restricted to only one CysNO at
a time. This accounts for the slowed rate of reaction in
comparison to solvated copper salts which are freely accessible
to CysNO. Since the ratio and concentrations of CysNO to Cys
to CuII were held constant, the slower reaction rate of the CuII−
MOF system compared to that of CuCl2 strongly suggests that
decomposition of the CysNO is mediated by the MOF instead
of any nonframework Cu2+ complexes that may be present in
the solution.
To further substantiate that the CysNO decomposition was
not mediated by nonframework Cu2+ complexes, the MOF
particles were filtered from the solution. Both the filtrate and
the recovered MOF particles were then extensively charac-
terized. The filtrate was evaluated for copper content using
ICP-OES via EPA method 200.8.11 The residual copper in the
solution was found to be 0.1 0.08% of the total MOF copper
content. Previous work by Poppl has shown that Cu3(BTC)2
contains nonframework Cu2+ complexes within the MOF pore
space which may account for the solution copper content.12
The contribution of the solution Cu2+ content toward the
overall NO generation was determined by adding an
appropriate aliquot of CuCl2 to a solution of CysNO/CysH.
The resulting NO generation was similar to that of the control
CysNO/Cys experiments and is shown in the Supporting
Information [SI] as Figure S8. This result indicates that the
nonframework Cu2+ in solution does not contribute to the
overall decomposition of CysNO.
Figure 3. Powder diffraction patterns of Cu3(BTC)2 after reaction of
CysNO/CysH (top) and Cu3(BTC)2 before reaction with CysNO/
CysH (bottom).
observed between the fresh and reacted particles (see Figure S3
in the SI). Taken together, these data indicate that the MOF
catalyst remains structurally robust during and after the
reaction.
In summary, the use of a MOF as an NO catalyst is a
significant step toward developing advanced NO materials for
longer delivery times. In contrast to NO donors, these materials
have the potential to overcome the inherent loading capacities
of NO donors. This work clearly demonstrates that MOFs can
be used as catalysts in the decomposition of RSNOs. This is the
first time that a MOF has been used to catalytically decompose
RSNO to produce the therapeutic NO species. Although these
materials have a high copper content per unit mass, the amount
of MOF needed to produce NO at physiologically relevant
levels is below the recommended daily dose of copper. Thus,
MOFs present an ideal candidate material to ultimately
produce NO in vivo from biologically available sources without
resulting in toxicity issues. Future studies aim to take advantage
of this catalytic activity by developing catalysts that are
hydrolytically robust in aqueous solution and that can be
formulated for the site-specific generation of NO to control a
range of cellular responses.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, NO release profiles of RSNOs by
various catalysts, and the IR spectra of Cu3(BTC)2 after
reaction with RSNOs and the disulfide product. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
The filtered MOF particles were examined via pXRD and
ATR-IR to provide insights into the structural robustness of the
MOF following reaction with CysNO/CysH. Upon desolva-
tion, the MOF particles underwent the expected characteristic
color change from turquoise to dark purple. Furthermore, the
reacted particles were evaluated for changes in crystallinity by
powder X-ray diffraction (pXRD). A direct comparison of the
powder patterns of the fresh catalyst and the reacted material
suggest that the crystallinty of the framework remained
unaltered as shown in Figure 3. This is evident by the identical
reflexions and the anticipated 2d line spacings. Further support
that the original structure was maintained was evidenced in the
ATR-IR spectra. No deviations in the IR resonances were
■
Corresponding Author
melissa.reynolds@colostate.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was funded in part by the State of Colorado
House Bill (HB10-01) and Colorado State University. We also
acknowledge the National Science Foundation’s Bridge to the
Doctorate fellowship program for financial support for J.L.H.
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