Functional Hydride Transfer by a Thiolate-Containing Model of Mono-Iron Hydrogenase featuring an Anthracene Scaffold

Article abstract of DOI:10.1002/anie.201712948

We report the synthesis, X-ray structure and functional biomimetic activity of a model complex of mono-iron hydrogenase (Hmd). To achieve the desired biomimetic fac-CNS(thiolate) ligation motif, an anthracene framework is used to provide the requisite donors in a single chelate. A bulky aryl thiolate (ortho dimethylphenyl) is included to achieve mononuclearity. In addition to exhibiting structural (X-ray) and spectroscopic (NMR, IR) similarity to the enzyme, the complex is competent for H₂ activation (heterolysis) and hydride transfer to a model substrate—mimicking the functional behavior of the enzyme in a biomimetic CNS coordination sphere for the first time.

Full text of DOI:10.1002/anie.201712948

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Accepted Article
Title: Functional Hydride Transfer by a Thiolate-containing Model of
Mono-Iron Hydrogenase featuring an Anthracene-Scaffold
Authors: Spencer Kerns, Anne-Clarisse Magtaan, Pisey Vong, and
Michael Rose
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201712948
Angew. Chem. 10.1002/ange.201712948
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http://dx.doi.org/10.1002/ange.201712948

10.1002/anie.201712948
Angewandte Chemie International Edition
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Functional HydrideTransfer by a Thiolate-containing Model of
Mono-Iron Hydrogenasefeaturing an AnthraceneScaffold
Spencer A. Kerns, Anne-Clarisse Magtaan, Pisey Vong and Michael J. Rose*
structure was supported by spectroscopy and theoretical
calculation,[9] but direct structural evidence (X-ray) for the fac-
CNS chelating motif remained elusive. Herein, we report the
structural characterization of a synthetic model derived from the
anthracene scaffold that exhibits H2 activation and hydride
transfer activity.
Abstract: Herein we report the synthesis, X-ray structure and
functional biomimetic activity of a model complex of mono-iron
hydrogenase (Hmd). To achieve the desired biomimetic fac-
CNS(thiolate) ligation motif, an anthracene framework is used to
provide the requisite donors in a single chelate. A bulky aryl thiolate
(ortho dimethylphenyl) is included to achieve mononuclearity. In
addition to exhibiting structural (X-ray) and spectroscopic (NMR, IR)
similarity to the enzyme, the complex is competent for H2 activation
(heterolysis) and hydride transfer to a model substrate – mimicking
The target asymmetric ligand [Anth·pyNH3·SH]Cl was
synthesized via two tandem borylation/Suzuki couplings to 1,8-
dichloroanthracene (Scheme 1). The asymmetric aminopyridine
synthon Anth·pyNH2·Clwas obtained utilizing Pd2(dba)3/SPhos as
catalyst.[9-10] The key breakthrough herein is the inclusion of the
aryl thiolate with a bulky dimethylphenyl unit at the ortho position
to maintain mononuclearity. The bulky synthon was prepared by
base-catalyzed ring-opening of 2-amino-6-bromobenzothiazole
followed by treatment with MeI. Nucleophilic substitution of the
aromatic amine functionality was achieved by a Sandmeyer
reaction using NaI, enabling the selective Suzuki coupling of 2,6–
dimethylphenylboronic acid. A tandem borylation/Suzuki reaction
using the bulky thioether moiety with Anth·pyNH2·Cl using
Pd2(dba)3/XPhos provided Anth·pyNH2·SMe in very good yield.
Finally, deprotection with NaH and tert-nonyl mercaptan in DMF
(160 °C) and subsequent protonation with excess HCl afforded
the target ligand Anth·py NH2·SH as the HCl salt (46%, 0.292 mg).
the functional behavior of the enzyme in
coordination sphere for the first time.
a biomimetic CNS
The metabolism of dihydrogen (H2) performed by the family of
hydrogenase enzymes is an important energy utilization process
in methanogens and anaerobic bacteria.[1] The dinuclear [Fe-Fe]
and [Ni-Fe] hydrogenases catalyze the reversible reduction and
oxidation of dihydrogen, respectively, via redox mechanisms
involving iron-sulfur clusters. Mono-iron hydrogenase, on the
other hand, exhibits non-redox reactivity with H2, catalyzing the
heterolysis of dihydrogen and subsequent hydride transfer to
methenyltetrahydromethanopterin (methenyl-H4MPT+,
a
C1
carrier derived from CO2). The enzyme garners its alternate
namesake from the reverse reaction, namely H2-forming
methylenetetrahydromethanopterin dehydrogenase (Hmd).
The elucidation of the crystal structure in 2009[2] (Figure 1, left)
galvanized the development of synthetic model complexes of
Hmd inspired by its distinct organometallic binding motifs –
especially the fac arrangement of the Cacyl, Npyridone, and SCys176
donors. Structural analogues reported by Hu[3], Pickett[4], and
Song[5] replicate the biomimetic coordination, including an Fe–C
organometallic bond, with some containing an exogenous thiolate
ligand. However, despite their structural similarity, none of the
complexes have exhibited both functionality and stability, possibly
due to the absence of a single chelating ligand.
Scheme 1.Synthesis ofthe ligand [Anth·pyNH2·SH]·HCl:A (i) KOH(aq) reflux,MeI
(89%); (ii) HCl, NaNO2(aq), NaI(aq), acetone (79%); (iii) Ba(OH)2·8H2O, 2,6-
dimethylphenylboronic acid,Pd(PPh3)4,dioxane/H2O(3:1) (88%).B (iv) KOAc,
B2pin2, Pd2(dba)3/SPhos, K3PO4, 1,8-dichloroanthracene, dioxane/H2O (38%);
(v) KOAc, B2pin2,Pd2(dba)3/XPhos,K3PO4,bulkythioether,dioxane/H2O(81%);
(vi) NaH,tnonyl-SH,HCl(aq),DMF(46%).
Metallation of Anth·py NH2·SH was performed in the presence of
i
9]
2 equiv of NPr2Et and Fe(CO)4(Br)2 in DCM at –80 °C.[4,
Removal of the DCM in vacuo, followed by treatment with THF
afforded a vibrant orange powder. Vapor diffusion of Et2O in to a
1:1 DCM/PhCN mixture resultedin orangecrystalline platesof the
PhCN adduct [(Anth·py NH2·SH)Fe(CO)2(PhCN)] (1) in 38% yield.
The X-ray structure of 1 is displayed in Figure 2. As designed and
predicted computationally in 2014,[11] the Anth·CNS chelate
adopts a facial coordination motif that accommodates two CO
ligands. The solvent binding site (the putative H2 binding site) is
thermodynamically arranged trans to the carbamoyl-C donor,
similar to the arrangement found in the enzyme. All of the above
features re-create the first coordination sphere of the enzyme.
The similar coordination environments of 1 and the complex
[(CNH·py)(SDMPh)Fe(CO)2(MeCN)] (fac-CNS, but with an
exogenous thiolate) reported by Pickett[4] provide context to
understand the structural influences of the anthracene scaffold.
The N1–Fe1–C1 bite angle of the ‘ferracyclic’ carbamoyl ring is
relatively unperturbed by the use of the anthracene scaffold:
82.30(9)° in 1 versus 82.54(8)° reported by Pickett. The N1–Fe1–
Figure 1.A truncated image (left) ofthe Hmd active site crystal structure (PDB:
3F47),and graphic representations ofthe active site (center) and the synthetic
analogue(1,right) reported in this work.
Molecular scaffolding has proven a useful tool to overcome
stability issues and to enforce desired structural arrangements in
bioinorganic chemistry. For example, Holm[6] synthesized [Fe4S3]
clusters using a trisubstituted benzene scaffold, and more
recently Lippard[7] utilized an elegant triptycene scaffold in
modeling the bimetallic core of methane mono-oxygenase.
Relatedly, there are several reports of anthracene as a scaffold in
coordination chemistry for the construction of trans-spanning
diphosphine ligands for catalysis.[8] We reasoned that an
asymmetric anthracene-based ligand could support a facial set of
biomimetic donors (Figure 1, right). We previously reported using
a 1,8–anthracene scaffold bearing a thioether moiety in a
functional modeling study (H2 activation, H-D scrambling, and C–
H hydride abstraction – but no hydride transfer).[9] The proposed
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S1 angle in 1 (94.34(6)°) is larger than the Pickett model
(90.33(5)°), consistent with the increased span between the N
and S donors (3.213 Å vs. 3.121 Å). Complex 1 exhibits Fe1–S1
(2.3719(7) Å) and Fe1–N1 (1.9957(19) Å) bond distances
characteristic of closely related iron(II) dicarbonyl complexes.[3a, 4-
the endogenous H4MPT+ substrate was included. Thus, the same
reaction (1,7 atm D2, base) was performed in the presence of 2,6-
difluoro(phenyl)-2-(4-methyl)imidazolium as the BArF salt,
denoted hereon as CH3Im+. A new feature was observed at 5.39
ppm (Figure 3c), corresponding to the hydride transfer product
CH3Im-D (Scheme 2). Notably, the resonances corresponding to
CH3Im-D (5.39 ppm) and MeOtBu2PhOD (4.79 ppm) grew
proportionately over the course of the reaction (~2 days). The
authenticity of the methine resonance at 5.38 ppm was
independently confirmed by reduction of CH3Im+ with both NaBD4
Lastly, 1 and [(CNH·py)(SDMPh)Fe(CO)2(MeCN)] exhibit very
5]
similar Fe–CNH bond distances (1.945(2) Å in 1 vs 1.9390(19) Å),
though each is significantly longer than the bond distance
observed in the enzyme crystal structure (1.914 Å).
2
(Figure 3d) and NaBH4 (Figure 3e), which resulted in H singlet
(5.39 ppm, CH2Cl2) and a 1H quartet (5.38 ppm, CD2Cl2)
respectively. IR analysis of the resulting solution indicated that 1
persists in solution, exhibiting ν(C≡O) features at 2018 and 1951
cm–1. Two smaller features and 2007 and 1974 cm–1 were
observed, but remain unidentified (SI, Figure S4).
Scheme 2.Reactivity scheme for 1 catalyzing hydride transfer to CH3Im+ under
D2 to form the hydride transfer product, CH3ImD.
Figure 2. ORTEP diagram (30% thermal ellipsoids) for 1 (one of the two
molecules in the asymmetric partofthe unitcell). Hydrogen atoms are omitted
for clarity. Selected bond distances (Å): Fe1–C1 = 1.945(2), Fe1–N1 =
1.9957(19),Fe1–S1=2.3719(7),Fe1–C2 =1.802(3),Fe1–C3=1.787(2), Fe1–
N2 = 2.029(2).Selecteddihedral angles (°): donor arm offsetfrom parallel, ∠C7–
C9–C22–C23 = 15.53(±2.28); anthracene framework twist, ∠C10–C11–C20–
C21) = 9.98(±3.07)°.
Regardingthe bond angles in the ligand framework, thepyridine
moieties exhibit an average torsion angle of 46.05(±5.33)° (there
are 2 molecules in the asymmetric part of the unit cell) with
respect to the anthracene plane, while the aryl(thiolato-S) units
display an average torsion of 54.05(±14.16)°; these values are
similar to those seen in manganese tricarbonyl complexes
synthesized with related symmetric anthracene ligands.[10]
Notably, the two aryl donor moieties are ‘vertically’ skewed (up-
and-down with respect to the anthracene plane) as evident in the
∠C7–C9–C22–C23 torsion angle of 15.53(±2.28)°. Indeed, the
offset between the two donor moieties propagates through the
structure of the ‘rigid’ anthracene unit, resulting in a 9.98(±3.07)°
‘twist’ in the plane of the aromatic framework (∠C10–C11–C20–
C21).
Complex 1 exhibits ν(C≡O) stretches at 2016 and 1956 cm–1
and a ν(C=O) feature at 1632 cm–1 (carbamoyl) (Figure S1). The
ν(C≡N) stretch of PhCN is observed at 2221 cm–1. The ν(C≡O)
features are red–shifted compared with the analogous thioether
1
[9]
Figure 3. Stacked 2H NMR (a, b, c, d,e) and H NMR (f) spectra from the
complex (2031, 1981 cm–1) due to the presence of the more
reactions of(a) D2 + [MeOtBu2PhO]NEt4 + CH3Im+ (b) 1 + D2 + CH3Im+;(c)1 + D2
+ [MeOtBu2PhO]NEt4; (d) 1 + D2 + [MeOtBu2PhO]NEt4 + CH3Im+; (e) CH3Im+ +
NaBD4;and (f) CH3Im+ + NaBH4. Additional peaks in (e) correspond to methylene
-CH2 peaks in CH3Im-H.
strongly donating, anionic thiolate ligand. These features are
slightly red–shifted in comparison with those reported by Pickett
(2026 and 1958 cm–1).[4] Most importantly, the C≡O stretching
frequencies closely resemble that of the enzyme measured in
water (2011 and 1944 cm–1)[2b], but are slightly blue–shifted, likely
due to the lack of the pyridone moiety as in the Hmd active site.
Provided the structural similarity of 1 to the enzyme, we
investigated reactions with H2/D2 and model substrates to
determine its enzyme-like function. Reaction of 1 with 7 atm (100
The implications of this reactivity are as follows. First, as D2
activation is not observed in the absence of base, this suggests
that the iron-bound sulfur is insufficiently basic to drive the
heterolysis of D2;[12] a moderately basic proton acceptor must be
included to drive the reaction. Second, in two previous reports we
spectroscopically observed iron-hydride species derived from
thioether-based ligands, thus formulated as neutral complexes;
such species, as formed, were not competent hydride transfer
agents.[9, 13] However, the putative iron-hydride in this system is
an anion (Scheme 3) due to the thiolato-S donor, and evidently is
a competent hydride transfer agent.
2
psi) D2 gas in DCM did not result in any color change, new H
NMR resonances (Figure 3a), or change in the IR spectrum.
However, the same reaction in the presence of a proton acceptor
–
namely, the bulky, non-coordinating phenolate base
NEt4[OMetBu2PhO]
–
resulted in the appearance of
OMetBu2PhOD (i.e. D+, δ 4.78 ppm), indicative of D2 activation
(Figure 3b); however, no resonance for the corresponding
deuteride (D–) could be located in the H spectrum (+50 to –50
2
ppm), suggesting that the complementary iron-deuteride was
insufficiently stable for NMR detection.
Based on the apparent high reactivity of the iron-hydride
intermediate, a hydride-accepting model substrate analogous to
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10.1002/anie.201712948
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COMMUNICATION
[11] J. Seo, A. K. Ali, M. J. Rose, Comments Inorg.Chem. 2014, 34,103-
113.
[12] Y. Misumi,H.Seino,Y. Mizobe, J. Am . Chem.Soc.2009, 131,14636-
14637.
[13] G. Durgaprasad,Z.-L.Xie, M. J. Rose,Inorg.Chem.2016, 55,386-
389.
Scheme 3. Proposed reactivity scheme indicating the observed stoichiometric
hydride transfer to form CH3Im-Hand return to compound1.
In summary, a synthetic analogue (1) of the Hmd active site
derived from an anthracene scaffold was structurally
characterized (X-ray) and exhibited H2 activation and hydride
transferto a model substrate – a first for a CNS-ligated biomimetic
of Hmd. Complex
1 also represents the first structurally
characterized example with all three donors of the fac-CNS
coordination motif derived from a single chelate. Functionally, 1 is
biased towards hydride transfer (versus hydride abstraction), as
the in situ formed iron-hydridespecies is anionic (Scheme 3).This
provides a rationale for the presence of the anionic thiolato-S and
acyl-C (and perhaps pyridone-N) donors in the active site, i.e. to
promote hydride transfer.
Acknowledgements
This research was supported by the Robert A. Welch Foundation
(F-1822) and the ACS Petroleum Research Fund (53542-DN13).
The authors also thank Dr. Vince Lynch and Taylor Manes for
assistance with X-ray data collection and the refinement of
structures.
Keywords: mono-iron hydrogenase • scaffold chelate • hydride
transfer • hydrogen activation • biomimetic
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A synthetic model of the enzyme
mono-iron hydrogenase is built
upon an ‘anthracene scaffold’, and
can catalyze biomimetic H2
activation and hydride transfer to a
model substrate
Author(s), Corresponding Author(s)*
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Title
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[1]
[2]
C. Tard, C. J. Pickett, Chemical Reviews 2009, 109, 2245-2274.
a) S. Shima, O. Pilak, S. Vogt, M. Schick, M. S. Stagni, W. Meyer-Klaucke, E. Warkentin, R. K.
Thauer, U. Ermler, Science (Washington, DC, U. S.) 2008, 321, 572-575; b) T. Hiromoto, K.
Ataka, O. Pilak, S. Vogt, M. S. Stagni, W. Meyer-Klaucke, E. Warkentin, R. K. Thauer, S.
Shima, U. Ermler, FEBS Lett. 2009, 583, 585-590.
[3]
[4]
[5]
a) D. Chen, R. Scopelliti, X. Hu, Angew. Chem. Int. Ed. Engl. 2010, 49, 7512-7515; b) D. Chen,
R. Scopelliti, X. Hu, Angew. Chem. Int. Ed. Engl. 2011, 50, 5671-5673.
P. J. Turrell, J. A. Wright, J. N. T. Peck, V. S. Oganesyan, C. J. Pickett, Angew. Chem., Int. Ed.
2010, 49, 7508-7511, S7508/7501-S7508/7532.
a) L.-C. Song, Z.-J. Xie, M.-M. Wang, G.-Y. Zhao, H.-B. Song, Inorg. Chem. 2012, 51, 7466-
7468; b) L.-C. Song, G.-Y. Zhao, Z.-J. Xie, J.-W. Zhang, Organometallics 2013, 32, 2509-2512;
c) L.-C. Song, F.-Q. Hu, G.-Y. Zhao, J.-W. Zhang, W.-W. Zhang, Organometallics 2014, 33,
6614-6622; d) L.-C. Song, F.-Q. Hu, M.-M. Wang, Z.-J. Xie, K.-K. Xu, H.-B. Song, Dalton
Trans. 2014, 43, 8062-8071; e) L.-C. Song, K.-K. Xu, X.-F. Han, J.-W. Zhang, Inorg. Chem.
2016, 55, 1258-1269.
[6]
[7]
[8]
J. Zhou, Z. Hu, E. Münck, R. H. Holm, J. Am. Chem. Soc. 1996, 118, 1966-1980.
Y. Li, R. Cao, S. J. Lippard, Org. Lett. 2011, 13, 5052-5055.
a) L. Kaganovsky, K.-B. Cho, D. Gelman, Organometallics 2008, 27, 5139-5145; b) L.
Kaganovsky, D. Gelman, K. Rueck-Braun, J. Organomet. Chem. 2010, 695, 260-266.
J. Seo, T. A. Manes, M. J. Rose, Nature Chemistry 2017, 9, 552.
[9]
[10] T. A. Manes, M. J. Rose, Inorg. Chem. 2016, 55, 5127-5138.
[11] J. Seo, A. K. Ali, M. J. Rose, Comments Inorg. Chem. 2014, 34, 103-113.
[12] Y. Misumi, H. Seino, Y. Mizobe, Journal of the American Chemical Society 2009, 131, 14636-
14637.
[13] G. Durgaprasad, Z.-L. Xie, M. J. Rose, Inorganic Chemistry 2016, 55, 386-389.
This article is protected by copyright. All rights reserved.