Binuclear complexes containing a methylnickel moiety: Relevance to organonickel intermediates in acetyl coenzyme a synthase catalysis

Article abstract of DOI:10.1021/ja803795k

A series of binuclear NiNi complexes supported by a single thiolate bridge and containing a methylnickel moiety have been prepared and fully characterized. The complexes represent structural analogues for the proposed organonickel intermediate in the acetyl coenzyme A synthase catalytic cycle. Variable temperature ³¹P NMR spectroscopy was used to examine dynamic behavior of the thiolate bridging interaction in two of the derivatives. Kinetic analyses, independent exchange and crossover experiments support an intermolecular exchange mechanism. Carbonylation results in thioester formation via a reductive elimination pathway. Copyright

Full text of DOI:10.1021/ja803795k

Published on Web 09/19/2008
Binuclear Complexes Containing a Methylnickel Moiety: Relevance to
Organonickel Intermediates in Acetyl Coenzyme A Synthase Catalysis
William G. Dougherty, Krishnan Rangan, Molly J. O’Hagan, Glenn P. A. Yap, and
Charles G. Riordan*
Department of Chemistry and Biochemistry, UniVersity of Delaware, Newark, Delaware 19716
Received May 21, 2008; E-mail: riordan@udel.edu
Scheme 1
Organonickel species have been implicated as catalytic intermedi-
ates in several enzyme reactions,1 specifically transformations that
shuttle one carbon species within the anaerobic world. Archaea and
anaerobic bacteria grow autotrophically using carbon dioxide or sulfate
as their terminal electron acceptors.2 Examples of proposed bioorga-
nometallic enzyme intermediates include the methylnickel species in
methyl coenzyme reductase (MCR) and acetyl coenzyme A synthase
(ACS), and Ni-CO adducts in carbon monoxide dehydrogenase
(COdH) and ACS. Until very recently, the evidence supporting the
involvement of such novel biological species has been indirect, that
is, direct spectroscopic or structural authentication of such species is
lacking. However, several recent reports provide the first direct
evidence for a methylnickel(III) state in MCR3 and a Ni(CO2) adduct
in COdH.4
The ACS enzyme, found in archaea and sulfate-reducing bacteria,
possessesanunprecedentedactivesiteclusterof[Fe4S4]Ni2composition.5,6
The two Ni sites are structurally distinct with consensus building toward
Nip (proximal to the Fe4S4 cluster) as the locus for methyl binding.7,8
Since the first protein structure report in 2002, a number of laboratories
including ours9,10 have modeled aspects of the binuclear NiNi site.11
Herein, we report initial efforts to prepare binuclear complexes
containing a methylnickel moiety and explore their dynamic properties
and reactivity to provide further understanding of organonickel catalysis
in biology.12
A series of binickel complexes containing a methylnickel moiety
were prepared via condensation of monomer precursors. This con-
densation strategy has been applied extensively using Ni(N2S2)
complexes leading to their apt moniker “metalloligands.” In the present
context the Ni(N2S2) species serve as monodentate donors that mimic
key aspects of the Nid site with K2[Ni(CGC)]10 replicating the exact
coordination motif. Addition of any one of three (diamidodithiola-
to)nickel complexes to (dppe)Ni(CH3)Cl13 proceeds to the thiolato-
bridged binuclear complexes, 1, Scheme 1. The red-to-orange com-
plexes have been characterized by electronic absorption, 1H, 31P NMR
and high resolution mass spectroscopies, and in one case by X-ray
diffraction.
The structure of the anion, 1a is depicted in Figure 1 (left). A single
thiolato bridge supports the binuclear core with slightly different Ni-S
distances, 2.192(1) and 2.230(1) Å. The Ni-C distance is typical for
a square planar site, 1.966(2) Å. The orientation of the two square
planes defined by the respective metal coordination spheres places the
methyl group in proximity of the other Ni. The NisNi distance,
2.952(1) Å, is most similar to the distance found in the structure of
the reduced A cluster from C. hydrogenoformans, 3.0 Å an unmethy-
lated enzyme state containing two square planar Ni sites.6
very broad signals, barely discernible above the baseline. At 265 K, a
set of resonances emerges which sharpen upon further cooling
ultimately resolving to two broad singlets, δ ) 58, 41. Upon warming
to room temperature, the 31P NMR spectrum is again void of signals,
indicating a reversible process. Warming solutions of 1b above ambient
temperatures results in significant line broadening with coalescence
reached at ca. 336 K. The variable temperature data reflect a fluxional
process in which the methyl and thiolate donors exchange positions.
Quantitative analysis of the temperature-dependent (243-278 K) 31
P
NMR spectral data of 1a using line shape analyses yields ∆G‡
)
280K
12(2) kcal/mol, ∆H‡ ) 17(2) kcal/mol and ∆S‡ ) 18(3) cal/mol-K.
At 310 K, k(1a) is 250 times larger than k(1b) indicating reduced
lability for the more electron-rich thiolates in the latter. The modest
free energy and particularly the large positive activation entropy
required suggests that the dynamic process proceeds via a dissociative
The three complexes differing in the identity of the Ni(N2S2) ligand
present disparate solution behavior as diagnosed by 31P NMR
spectroscopy (Supporting Information). At room temperature the 31
P
Figure 1. Structural diagrams of the anion, 1a (left) and 3 (right); hydrogen
atoms omitted for clarity. Ni-CH3 distances are 1.966(2) and 1.963(2) Å,
respectively.
NMR spectra of 1b and 1c display sets of sharp resonances.14 In
contrast, the room temperature 31P NMR spectrum of 1a contains two
9
13510 J. AM. CHEM. SOC. 2008, 130, 13510–13511
10.1021/ja803795k CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2
reaction, the mechanism of the model reaction remains to be deduced.
The enzyme does not acetylate the bridging Cys residues as these
thiolates are expected to be poorer nucleophiles. Given thiolate lability
it is conceivable that an incipient [(dppe)Ni(C(O)Me)]+ fragment is
subject to external attack by [Ni(phma)]2-, that is, intermolecular
thioester formation. Contemporaneous efforts have sought to prepare
methylnickel complexes via the biologically relevant transmethylation
from organocobalt reagents.17 The diversity of these molecules may
lead to differing reactivity that will allow for comprehensive model
studies of proposed intermediates along a catalytic pathway that is
still not fully understood.
Acknowledgment. We thank the NIH (GM59191) for financial
support of these studies and John Dykins and Jeffrey Spraggins
for assistance with MS experiments.
exchange involving thiolate dissociation, [Ni(dppe)Me]+ isomerization
and religation.15 Indeed, thiolate exchange is facile as demonstrated
by two experiments. First, the crossover experiment depicted in Scheme
2 proceeds within the time of mixing equimolar solutions of 1a and
1b-CD3 generating an equilibrium mixture of all four species with
Keq ) 1. Alternatively, addition of K2[Ni(phmi)] to 1a rapidly generates
an equilibrium mixture of 1a and 1b.
Supporting Information Available: Experimental details, charac-
terization data, and crystallographic information (CIF). This material
is available free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Tan, X. S.; Surovtsev, I. V.; Lindahl, P. A. J. Am. Chem. Soc. 2006,
128, 12331. (b) Ragsdale, S. W. J. Inorg. Biochem. 2007, 101, 1657. (c)
George, S. J.; Seravalli, J.; Ragsdale, S. W. J. Am. Chem. Soc. 2005, 127,
13500. (d) Ragsdale, S. W. Chem. ReV. 2006, 106, 3317.
To examine complexes in which intramolecular exchange is not
possible, selective alkylation of one thiolate donor was performed. The
target organonickel derivative, 3, was prepared via sequential benzy-
lation followed by condensation, Scheme 1. The structure of 3 is
contained in Figure 1 (right). The Bn and Ni(dppe)CH3 fragments are
found on opposite faces of the Ni(phma) unit, that is, only the anti
isomer is present in the solid state (and solution). The Ni-C distance
is 1.963(2) Å and the NisNi separation is 3.184(1) Å, the latter
parameter reflecting greater steric congestion than in 1a. The 31P NMR
spectrum of 3 at room temperature contains two signals consistent with
no/slow exchange on the NMR time scale. The stability of 3 establishes
that a single thiolate bridge is sufficient for complex formation.
The ability of these small molecules to promote stoichiometric
thioester formation was assessed. Exposure of a DMSO solution of
1a-CD3 (or 1a) to 1 atm of CO results in a rapid color change from
orange to green resulting in the formation of [Ni(phma-C(O)CD3)]-
(86%) and (dppe)Ni(CO)2, Scheme 1. The former species contains a
single thioester while maintaining the nickel ligation as deduced by
ES-MS analysis. Monitoring the fate of the CD3 group by 2H NMR
spectroscopy reveals complete loss of the Ni-CD3 (δ ) 0.48) with
concomitant growth of a resonance at δ ) 2.13. In samples of 1a
exposed to 13CO, this resonance (in the 1H NMR spectrum) is a
doublet, 2JCH ) 7 Hz consistent with acyl assignment. The products
are proposed to result from CO insertion generating a binuclear
Ni-C(O)Me followed by reductive elimination. Similar thioester
formation from monomeric nickel alkyl/thiolate complexes has been
described;16 the present results extend these studies for the first time
to a binuclear complex.
In sum, a series of NiNi binuclear complexes have been synthesized
in an effort to model the methylnickel intermediate proposed at the
A-cluster of ACS. Through facile condensation reactions employing
suitable precursors several different [Ni(N2S2)] fragments were installed
in creating the binuclear complexes. The structural differences among
these metalloligands have imparted disparate properties on the binuclear
complexes evident by their solution state dynamic behavior. Signifi-
cantly, the kinetic lability of the thiolate bridges serves to highlight a
potential role for reversible Ni-S bond rupture in opening coordination
sites at Nip that could be requisite for elementary steps in catalysis,
that is, CO and/or CoA binding, a point supported by computational
studies.8 While carbonylation results in thioester formation at the
bridging thiolate, a transformation not observed in the enzymatic
(2) Hugler, M.; Huber, H.; Stetter, K. O.; Fuchs, G. Arch. Microbiol. 2003,
179, 160.
(3) (a) Yang, N.; Reiher, M.; Wang, M.; Harmer, J.; Duin, E. C. J. Am. Chem.
Soc. 2007, 129, 11028. (b) Dey, M.; Telser, J.; Kunz, R. C.; Lees, N. S.;
Ragsdale, S. W.; Hoffman, B. M. J. Am. Chem. Soc. 2007, 129, 11030.
(4) Jeoung, J. H.; Dobbek, H. Science 2007, 318, 1461.
(5) (a) Doukov, T. I.; Iverson, T. M.; Seravalli, J.; Ragsdale, S. W.; Drennan,
C. L. Science 2002, 298, 567. (b) Darnault, C.; Volbeda, A.; Kim, E. J.;
Legrand, P.; Vernede, X.; Lindahl, P. A.; Fontecilla-Camps, J. C. Nat.
Struct. Biol. 2003, 10, 271.
(6) Svetlitchnyi, V.; Dobbek, H.; Meyer-Klaucke, W.; Meins, T.; Thiele, B.;
Romer, P.; Huber, R.; Meyer, O. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
446.
(7) (a) Schenker, R. P.; Brunold, T. C. J. Am. Chem. Soc. 2003, 125, 13962.
(b) Amara, P.; Volbeda, A.; Fontecilla-Camps, J. C.; Field, M. J. J. Am.
Chem. Soc. 2005, 127, 2776. (c) Lindahl, P. A. J. Biol. Inorg. Chem. 2004,
9, 516.
(8) Webster, C. E.; Darensbourg, M. Y.; Lindahl, P. A.; Hall, M. B. J. Am.
Chem. Soc. 2004, 126, 3410.
(9) Krishnan, R.; Voo, J. K.; Riordan, C. G.; Zakharov, L.; Rheingold, A. L.
J. Am. Chem. Soc. 2003, 125, 4422–4423.
(10) Krishnan, R.; Riordan, C. G. J. Am. Chem. Soc. 2004, 126, 4484.
(11) (a) Golden, M. L.; Rampersad, M. V.; Reibenspies, J. H.; Darensbourg,
M. Y. Chem. Commun. 2003, 1824. (b) Wang, Q.; Blake, A. J.; Davies,
E. S.; McInnes, E. J. L.; Wilson, C.; Schro¨der, M. Chem. Commun. 2003,
3012. (c) Linck, R. C.; Spahn, C. W.; Rauchfuss, T. B.; Wilson, S. R.
J. Am. Chem. Soc. 2003, 125, 8700. (d) Rao, P. V.; Bhaduri, S.; Jiang, J.;
Holm, R. H. Inorg. Chem. 2004, 43, 5833. (e) Hatlevik, Ø.; Blanksma,
M. C.; Mathrubootham, V.; Arif, A. M.; Hegg, E. L. J. Biol. Inorg. Chem.
2004, 9, 238. (f) Harrop, T. C.; Olmstead, M. M.; Mascharak, P. K. J. Am.
Chem. Soc. 2004, 126, 14714.
(12) For conceptually related transformations on a NiPd binuclear platform, see:
Rampersad, M. V.; Jeffery, S. P.; Reibenspies, J. H.; Ortiz, C. G.;
Darensbourg, D. J.; Darensbourg, M. Y. Angew. Chem. 2005, 44, 1217.
(13) Smith, M. C.; Barclay, J. E.; Davies, S. C.; Hughes, D. L.; Evans, D. J.
Dalton Trans. 2003, 4147.
(14) 1c displays two sets of equal intensity 31P NMR resonances consistent with
the presence of the two expected isomers, i.e., species in which the
Ni(dppe)Me fragment is bound either to Cys1 or Cys3.
(15) As suggested by a reviewer, the dissociated [(dppe)NiMe]+ fragment could
exist as a DMSO-bound, i.e., solvento species. Alternatively, there are
precedents for three-coordinate nickel alkyls: Conroy-Lewis, F. M.; Mole,
L.; Redhouse, A. D.; Litster, S. A.; Spencer, J. L. Chem. Commun. 1991,
1601–1603. Kitiachvili, K. D.; Mindiola, D. J.; Hillhouse, G. L. J. Am.
Chem. Soc. 2004, 126, 10554–10555.
(16) (a) Stavropoulos, P.; Muetterties, M. C.; Carrie, M.; Holm, R. H. J. Am.
Chem. Soc. 1991, 113, 8485–8492. (b) Tucci, G. C.; Holm, R. H. J. Am.
Chem. Soc. 1995, 117, 6489–6496. (c) Matsunaga, P.; Hillhouse, G. L.
Angew. Chem., Int. Ed. Engl. 1994, 1748–1749.
(17) (a) Ram, M. S.; Riordan, C. G.; Yap, G. P. A.; Liable-Sands, L.; Rheingold,
A. L.; Marchaj, A.; Norton, J. R. J. Am. Chem. Soc. 1997, 119, 1648. (b)
Eckert, N. A.; Dougherty, W. G.; Yap, G. P. A.; Riordan, C. G. J. Am.
Chem. Soc. 2007, 129, 9286.
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