A cyclodextrin host/guest approach to a hydrogenase active site biomimetic cavity

Article abstract of DOI:10.1021/ja103774j

The hydrophobic cavity of the active site of [FeFe]-Hydrogenase is mimicked by two cyclodextrin molecules which surround a 2Fe2S synthetic analogue of the active site, outfitted with an aryl sulfonate to promote inclusion into β-cyclodextrin. The X-ray cr

Full text of DOI:10.1021/ja103774j

Published on Web 06/10/2010
A Cyclodextrin Host/Guest Approach to a Hydrogenase Active Site
Biomimetic Cavity
Michael L. Singleton, Joseph H. Reibenspies, and Marcetta Y. Darensbourg*
Department of Chemistry, Texas A & M UniVersity, College Station, Texas 77845
Received May 3, 2010; E-mail: marcetta@mail.chem.tamu.edu
The naturally engineered pockets that bind the catalytic centers
provide a degree of stability to the inclusion complex.13 For the
diiron guest in our system, an aryl sulfonate group was incorporated
into the S-to-S linker, as shown in Scheme 1. On addition of ꢀ-CyD
to an aqueous slurry of Na+1, the latter completely dissolved. ESI
mass spectral data indicated a peak bundle at m/z ) 1671
representative of a 1:1 adduct in this solution. Infrared spectral
monitoring also found a shift in the ν(CO) bands of 1 to higher
wave numbers, as the ꢀ-CyD ratio was increased, Figure S1.
of metalloenzymes impart stability to unusual molecular structures
that are poised to facilitate molecular transformations. This is readily
seen in the protein environment that surrounds the active site of
diiron hydrogenase, [FeFe]-H2ase, Figure 1, an enzyme that
produces H2 at an efficiency comparable to that of the noble metal
platinum in fuel cells.1-3
Scheme 1. Syntheses of Complex 1 and 1-CyD
Figure 1. Structure of the hydrogen producing H-cluster of [FeFe]-H2ase
in the protein environment4 (left) and as a Chemdraw figure (right) showing
selected first and second coordination sphere interactions.
While strong donation into the [FeFe] unit by the CN- and
thiolate ligands contributes to the reactivity of the active site, a
number of secondary interactions4 stabilize a unique geometry in
the organoiron motif that allows formation of a reactive terminal
hydride.5 In addition to an appropriately sized, largely hydrophobic
cavity, dipole/hydrogen bonding interactions between nearby pep-
tide residues and the cyanides and semibridging carbonyl result in
the conservation of an open site in both the FeIFeII and FeIFeI states.6
This important feature has been obtained in mixed valent FeIFeII
synthetic analogues of the oxidized enzyme active site; however,
reduction back to FeIFeI results in rearrangement to the all terminal
CO conformation and loss of the open site.7
Thus a major goal for modeling the active site should be to
identify and evaluate supramolecular constructs that might enforce
constraints mimicing the natural binding cavity of the [FeFe]-H2ase
active site. While this has been explored both computationally and
synthetically,8-10 inclusion of a diiron model system inside of a
discrete supramolecular host has not yet been reported.
Cyclodextrins (CyD) have properties long recognized as
potential scaffolds for biomimetics.11 Their hydrophobic cavities
have in fact been demonstrated to serve as hosts for organome-
tallics,12 and the hydrophilic hydroxyl rims provide hydrogen
bonding sites. In this report we describe an approach to the
inclusion of a small molecule model of the [FeFe]-H2ase active
site, (µ-SCH2NH(C6H4SO3-)CH2S)[FeI(CO)3]2 (1), within ꢀ-CyD
and the X-ray crystal structure of the sodium salt of the 1 · 2
ꢀ-CyD · 28 H2O clathrate.
Crystals of X-ray diffraction quality were obtained by carefully
layering a concentrated aqueous solution of 1-CyD with a dilute
aqueous solution of [Ph3PdNdPPh3]+Cl-. While the latter was
necessary for crystal growth, the red needles that resulted on
standing for two weeks were of the Na+ salt only.14a The structure
of 1-CyD shows two ꢀ-CyD molecules serve as hosts to one [FeFe]-
model complex guest, Figure 2. As anticipated, the aryl group of
1 is entirely encapsulated and the sulfonate projects through
the primary hydroxyl rim of the ꢀ-CyD. The apical CO ligand of
the Fe(CO)3 unit on the same side is also enclosed within the
cyclodextrin cavity while the basal CO’s are close to the secondary
hydroxyl rim. The Fe(CO)3 group distal to the aryl sulfonate is
encapsulated by the second ꢀ-CyD. The two ꢀ-CyD units interact
with one another through hydrogen bonds that form between the
secondary hydroxyl groups on the rim and also through ion-dipole
interactions with the Na+ counterion. This Na+ links the two
ꢀ-CyD’s together and also interacts with neighboring units in the
extended two-dimensional crystalline array, Figure 2. A total of
28 water molecules per Na+ 1·2 ꢀ-CyD unit are also in the crystal
lattice, with four located near, or closing off, the end of the
cyclodextrin nanocapsule opposite the sulfonate, Figure S5. No
water molecules are located in the inner part of the cyclodextrin
construct. The hydrophobic character of the 2 ꢀ-CyD cavity is
emphasized by comparison of the electrostatic potential plots of
1-CyD and that of the FeFe-H2ase active site cavity which includes
an ∼22 Å amino acid sphere, Figure S9.
The incorporation of charged functional groups into the guest
molecules of cyclodextrin host/guest systems has been reported to
9
8870 J. AM. CHEM. SOC. 2010, 132, 8870–8871
10.1021/ja103774j  2010 American Chemical Society

C O M M U N I C A T I O N S
While the Fe-Fe bond distance of the included complex is not
significantly altered from that of the free complex, 2.502(2) vs
2.499(1) Å, respectively, there are some minor structural differences
between the structures of 114b and of 1 as found in 1-CyD. Most
important is a ca. 20° increase in the torsion angle between the
apical CO groups of the Fe(CO)3 subunits in 1 vs 1-CyD indicating
destabilization of the more eclipsed conformation.
feature, the FeIFeI f FeIFe0 couple at -1.2 V vs the Ag/AgCl (sat’d
KCl) couple. In the presence of cyclodextrin however, the FeIFeI/FeIFe0
reduction is shifted ∼80 mV more negative and two reductive events
are observed upon addition of HOAc. The first, based on control
experiments without catalyst, is attributed to the reduction of HOAc
by glassy carbon while the second event, assigned to proton reduction
by 1-CyD, occurs more negative (-1.4 V) reflecting the hydrophobic
environment of the cavity, Figures S21 and S22.
In summary, we have used ꢀ-CyD to provide a first generation
artificial protein environment for a small molecule model of the
[FeFe]-hydrogenase enzyme active site. Inclusion in the cyclodextrin
not only produces structural distortions in the diiron motif, as
observed in the X-ray structure of 1-CyD, but also affects change
in the redox and electrocatalytic properties of 1. Through synthetic
modification of the host and guest components of the system, a
model with intermolecular interactions that facilitate H+ reduction
or H2 oxidation could be realized.
Acknowledgment. We thank Prof. Gyula Vigh for many helpful
discussions. We also acknowledge financial support from the
National Science Foundation (CHE-0910679 to M.Y.D., and CHE-
0541587) and the R. A. Welch Foundation (A-0924).
Supporting Information Available: Full structure files; complete
description of experiments; cyclic voltammograms and spectral data.
This material is available free of charge via the Internet at http://
pubs.acs.org.
Figure 2. Extended structure (left) and unit cell (right) of 1 -CyD. Protons
and water molecules have been removed for clarity.
Evidence for inclusion complex formation in solution comes from
1
the H NMR studies in D2O. As the mole fraction of ꢀ-CyD is
References
increased, there is a significant upfield shift in the aromatic protons
of 1, with a concomitant downfield shift for the methylene protons
in the S to S linker. Similarly, 13C NMR spectra show a 1.0 ppm
shift in the CO resonance at 206.9 ppm. For the cyclodextrin, the
1H NMR spectra exhibit only minor shifts with variation in [1]
(∆δ of (0.02) for most of the 1H resonances. However the C3 and
C5 protons shift by 0.10 and 0.19 ppm respectively. The large
change for these intracavity protons is reported to be indicative of
inclusion within the ꢀ-CyD cavity.15 Averaged Job plots based on
these changes have maxima near 0.5 indicating a 1:1 ꢀ-CyD/[1]
ratio in solution, Figure S15.16 However the accuracy of Job plots
is highly dependent on the nature of the binding constant of the
first and second ꢀ-CyD units, making this assignment tentative.
While the changes in the chemical shift provide good evidence
that the inclusion complex is forming in solution, at no point were
separate signals observed for the free and encapsulated 1 indicating
that the rate of exchange in and out of the cyclodextrin cavity is
faster than can be observed by NMR. Even upon cooling to 5 °C
in the presence of 10 equiv of cyclodextrin only a single broad
signal in the 13C NMR spectrum is observed for all six CO ligands.
These results are consistent with not only the fact that the complex
is exchanging rapidly in and out of the cyclodextrin but also, and
likely due to this exchange, that the cyclodextrin architecture does
not prevent the well studied intramolecular dynamic processes
observed in similar diiron systems.17 Despite the apparent instability
of 1-CyD, the formation of the inclusion complex still produces
interesting changes in the electrochemical properties of 1.
(1) Nicolet, Y.; Lemon, B. J.; Fontecilla-Camps, J. C.; Peters, J. W. Trends
Biochem. Sci. 2000, 25, 138–143.
(2) Fontecilla-Camps, J. C.; Volbeda, A.; Cavazza, C.; Nicolet, Y. Chem. ReV.
2007, 107 (10), 4273–4303.
(3) Hambourger, M.; Gervaldo, M.; Svedruzic, D.; King, P. W.; Gust, D.;
Ghirardi, M.; Moore, A. L.; Moore, T. A. J. Am. Chem. Soc. 2008, 130,
2015–2022.
(4) Pandey, A. S.; Harris, T. V.; Giles, L. J.; Peters, J. W.; Szilagyi, R. K.
J. Am. Chem. Soc. 2008, 130, 4533–4540.
(5) (a) Barton, B. E.; Rauchfuss, T. B. Inorg. Chem. 2008, 47 (7), 2261–2263.
(b) Jablonskyte, A.; Wright, J. A.; Pickett, C. J. Dalton Trans. 2010, 39
(12), 3026–3034.
(6) Nicolet, Y.; de Lacey, A. L.; Verne`de, X.; Fernandez, V. M.; Hatchikian,
E. C.; Fontecilla-Camps, J. C. J. Am. Chem. Soc. 2001, 123, 1596–1601.
(7) (a) Liu, T.; Darensbourg, M. Y. J. Am. Chem. Soc. 2007, 129, 7008–7009.
(b) Justice, A. K.; Rauchfuss, T. B.; Wilson, S. R. Angew. Chem., Int. Ed.
2007, 46, 6152–6154. (c) Singleton, M. L.; Bhuvanesh, N.; Reibenspies,
J. H.; Darensbourg, M. Y. Angew. Chem., Int. Ed. 2008, 47, 9492–9495.
(d) Justice, A. K.; De Gioia, L.; Nilges, M. J.; Rauchfuss, T. B.; Wilson,
S. R.; Zampella, G. Inorg. Chem. 2008, 47 (16), 7405–7414.
(8) Dy, E. S.; Kasai, H.; Redshaw, C.; Pickett, C. J. Surf. Interface Anal. 2008,
40, 1092–1097.
(9) Jones, A. K.; Lichtenstein, B. R.; Dutta, A.; Gordon, G.; Dutton, P. L.
J. Am. Chem. Soc. 2007, 129, 14844–14845.
(10) Song, L.-C.; Liu, X.-F.; Ming, J.-B.; Ge, J.-H.; Xie, Z.-J.; Hu, Q.-M.
Organometallics. 2010, 29, 610–617.
(11) Breslow, R.; Dong, S. D. Chem. ReV. 1998, 98, 1997–2011.
(12) (a) Harwani, S.; Telford, J. R. Chemtracts 2005, 18 (8), 437–448. (b) Hapiot,
F.; Tilloy, S.; Monflier, E. Chem. ReV. 2006, 106, 767–778.
(13) Kano, K. Colloid Polym. Sci. 2008, 286, 79–84.
(14) (a) Crystal data for 1-CyD: C98H204Fe2NNaO107S3, M ) 3339.49, triclinic,
P1 (No. 1), a ) 15.346(4), b ) 15.422(4), c ) 17.595(4) Å, R )
113.517(3), ꢀ ) 98.507(3), γ ) 103.154(3)°, V ) 3582.9(15) Å3, Z ) 1,
Dc ) 1.548 g/cm3, F000 ) 1766, Final GooF ) 0.999, R1 ) 0.0832, wR2
) 0.1797. (b) Crystal data for TEA+1: C22H24Fe2N2O9S3, M ) 668.31,
monoclinic, P2(1)/c, a ) 22.1279(2), b ) 7.6853(5), c ) 16.7425(10) Å,
R ) 90, ꢀ ) 99.752(2), γ ) 90°, V ) 2806.1(2) Å3, Z ) 4, Dc ) 1.582
g/cm3, F000 ) 1368, Final GooF ) 1.064, R1 ) 0.0408 wR2 ) 0.0888.
(15) Schneider, H.-J.; Hacket, F.; Ru¨diger, V.; Ikeda, H. Chem. ReV. 1998, 98,
1755–1785.
(16) Connors, K. Binding Constants. The measurement of Molecular Complex
Stability; Wiley: New York, 1987.
(17) Lyon, E. J.; Georgakaki, I. P.; Reibenspies, J. H.; Darensbourg, M. Y. J. Am.
Chem. Soc. 2001, 123, 3268–3278.
(18) Felton, G. A. N.; Mebi, C. A.; Petro, B. J.; Vannucci, A. K.; Evans, D. H.;
Glass, R. S.; Lichtenberger, D. L. J. Organomet. Chem. 2009, 694 (17),
2681–2699.
Similar to most (µ-SRS)[Fe(CO)3]2 models, 1 acts as an electro-
catalyst for H2 production from weak acid. In CH3CN solution, 1 has
very similar redox properties to (µ-S(CH2)3S)[Fe(CO)3]2,18 showing
a response (increase in current) to added increments of HOAc at a
more negative potential than the initial FeIFeI/FeIFe0 reduction. In 10
mM aqueous NaCl solution the electrochemical behavior is quite
different. For free 1 the response is observed at the first reductive
JA103774J
9
J. AM. CHEM. SOC. VOL. 132, NO. 26, 2010 8871