Methyl transfer from methylcobaloxime to (triphos)Ni(PPh3): Relevance to the mechanism of acetyl coenzyme a synthase

Article abstract of DOI:10.1021/ja072063o

The zerovalent nickel complex, (triphos)Ni(PPh₃), is quantitatively alkylated by a methylcobaloxime reagent. Independent chemical synthesis confirms the nickel-containing product as the cation, [(triphos)NiMe]⁺. These studies provide small molecule precedent for a Ni(0) nucleophile during acetyl coenzyme A synthase (ACS) biocatalysis. That the corresponding (triphos)NiCO is not a substrate for the reaction provides a chemical-based rationale for ordered binding of methyl followed by CO. Copyright

Full text of DOI:10.1021/ja072063o

Published on Web 07/10/2007
Methyl Transfer from Methylcobaloxime to (Triphos)Ni(PPh3): Relevance to
the Mechanism of Acetyl Coenzyme A Synthase
Nathan A. Eckert, William G. Dougherty, Glenn P. A. Yap, and Charles G. Riordan*
Department of Chemistry and Biochemistry, UniVersity of Delaware, Newark, Delaware 19716
Received April 3, 2007; E-mail: riordan@udel.edu
Acetyl coenzyme A synthase/carbon monoxide dehydrogenase
(ACS/COdH) is a bifunctional enzyme found in certain methano-
genic, acetogenic, and sulfate-reducing organisms. The reduction
of CO2 to CO and the production of acetyl coenzyme A (acetyl-
CoA) allow these organisms to grow autotrophically via the Wood-
Ljungdahl pathway.1 The active site for acetyl CoA synthesis,
termed the A cluster, is a metallocluster containing a dinickel site
bridged to an Fe4S4 cuboidal cluster.2 The catalytic assembly of
CO, CH3-cob(III)alamin, and CoA to yield acetyl CoA and cob-
(I)alamin is proposed to proceed at one of the two nickel ions, the
“labile-nickel” site, NiP, which resides between the Fe4S4 cluster
and the diamido, dicysteinato Ni(II)d site.3
Evidence has been presented in support of an SN2-type reaction
Figure 1. Time course of the formation of [Co] in the reaction of 0.25
mM MeCo and 0.25 mM (triphos)Ni(PPh3). Spectra were recorded at 4
min intervals at 20 °C (initial scan is at t ) 4 min). The inset shows the
Job plot of the reaction of MeCo and (triphos)Ni(PPh3). The absorption
maxima were reached at 0.5 mole ratio, indicating a 1:1 stoichiometry of
reaction.
between methylcob(III)alamin and NiP with the equilibrium favoring
the products.3,4 The oxidation state of the nickel nucleophile has
yet to be established. Evidence for a Ni+p state (Ared-CO) has been
presented.5 If this species participates in an SN2 methylation, a
Ni3+-Me intermediate would result. However, the products of the
transmethylation reaction are diamagnetic, indicating that the
proposed Ni3+-Me intermediate must be rapidly reduced by one
electron, perhaps from the Fe4S4 cluster.6 Recent kinetic studies
suggest that Ared-CO is not involved in the catalytic cycle.7 An
alternative proposal by Lindahl implicates Nip0 as the nucleophile
attacking methylcob(III)alamin generating a Ni2+-Me intermedi-
ate.3 A transformation accessing the Ni2+/0 couple is more favorable
from an organometallic perspective.8
Scheme 1
Previously, the cobalt(III) complex, MeCo(dmgBF2)2py (MeCo)
was shown to react with 2 equiv of Ni+, [Ni(tmc)][OTf], via an
electron-transfer mechanism producing the Ni2+-Me species,
[Ni(tmc)Me][OTf].9,10 Here, we demonstrate that the reaction
between MeCo and a Ni0 source, (triphos)Ni(PPh3),10 yields a
Ni2+-Me complex via a different mechanism. Triphos was selected
as an appropriate ancillary ligand because (i) the electronic donor
aptitude of bridging thiolates has been likened to phosphines11 and
(ii) the flexible chelate supports both tetrahedral and square planar
stereochemistries, geometries favored for Ni0 and Ni2+, respec-
tively. To our knowledge, alkyl transfer from MeCo to Ni0 is
unprecedented.
formation of [Co] is confirmed (Figure 1). A Job plot analysis
establishes a Ni:MeCo stoichiometry of 1:1 (Figure 1, inset).
This reaction can also be followed by 1H and 31P NMR
spectroscopies. Mixing solutions of MeCo in CD3CN and (triphos)-
Ni(PPh3) in C6D6 gives immediate formation of deep-blue [Co].
The 31P NMR spectrum shows a distinct change in chemical shift
of the triphos signals, with them shifting downfield with respect to
the signals for (triphos)Ni(PPh3): δ ) 47.8 (d, 2P) and 95.8 (t,
1P) with JPP of 23 Hz. These values are consistent with a Ni2+ ion
1
bound by triphos in a square-planar environment.12 The H NMR
spectrum shows complete loss of signals attributable to MeCo (δ
) 1.2) and growth of two new dmg-containing species. These
species are assigned as [Co(dmgBF2)2py]- and [Co(dmgBF2)2-
(CD3CN)]-, on the basis of comparison to reported values.7b Indeed,
axial ligand exchange at cobalt has been established previously.13
More importantly, a new signal arises at δ ) 0.34. This resonance
integrates to three protons and couples to the phosphorus nuclei of
the triphos ligand. The coupling constants are within values
observed for phosphine-containing methylnickel(II) complexes (JHP1
) 4 Hz; JHP2 ) 8 Hz).14 Taken together, NMR and absorption
spectroscopies suggest a clean 1:1 reaction yielding [(triphos)NiMe]-
[Co(dmgBF2)2py] (Scheme 1).
Combining equimolar amounts of triphos, Ni(COD)2, and PPh3
in THF, followed by stirring for 12 h at ambient temperature and
precipitation with pentane, gave a bright orange solid. Recrystal-
lization via slow evaporation of a Et2O solution provided large
orange blocks in modest yield (50%). A diagnostic 31P NMR
spectrum is obtained in C6D6: two signals are observed in a 3:1
ratio corresponding to the PPh3/Ph2P and PhP groups of the
complex, respectively (δ ) 37.5 (m, 3P) and 46.95 (dt, 1P)).
Mixing equimolar amounts of MeCo in CH3CN and (triphos)-
Ni(PPh3) in THF under an inert atmosphere generates a deep-blue
solution, corresponding to formation of the intense Co(I) chro-
mophore, [Co(dmgBF2)2py]- ([Co]). The reaction time course can
be followed spectrophotometrically, and after ∼1 h quantitative
Addition of a CD3CN solution of the perdeuteromethyl complex,
CD3Co, to a C6D6 solution of (triphos)Ni(PPh3) gave immediate
9
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J. AM. CHEM. SOC. 2007, 129, 9286-9287
10.1021/ja072063o CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
SN2 methyl-transfer in ACS/COdH can proceed through a Ni0
intermediate. Importantly, these studies provide a chemical reactiv-
ity-based rationale for the ordered binding of Me, then CO, during
ACS catalysis. In vitro experiments and structure-based arguments
have proven contentious with regard to the order of binding during
catalysis. We are currently investigating the kinetics of this reaction
to obtain a more detailed understanding of the mechanism.
Acknowledgment. The authors acknowledge the National
Institutes of Health (Grant GM059191) for funding and Steve Bai
for interpretation of 2D 31P NMR spectra.
Supporting Information Available: Experimental details, spectral
characterization, and full crystallographic data for (triphos)Ni(PPh3)
and [(triphos)NiMe]OTf. This material is available free of charge via
the Internet at http://pubs.acs.org.
Figure 2. Thermal ellipsoid depiction of the cation of [(triphos)NiMe]-
OTf. H atoms and OTf- removed for clarity. Ellipsoids are shown at 30%
probability. Metrical parameters are provided in SI.
References
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ReV. Biochem. Mol. Biol. 2004, 39, 165.
1
formation of [Co]. The H NMR spectrum shows similar spectral
features to the reaction with protio MeCo, with the exception of
the lack of the Ni-Me signal at δ ) 0.34. The deuterium NMR
spectrum shows that quantitative transfer of the methyl group is
effected, with a single Ni2+-CD3 species produced, δ ) 0.2.
Independent synthesis of [(triphos)NiMe]OTf was achieved via
oxidative addition of MeOTf to a stoichiometric mixture of triphos
and Ni(COD)2 in toluene at -78 °C.15 The OTf salt was crystallized
by slow diffusion of Et2O into a saturated toluene solution at room
temperature (Figure 2). The spectroscopic data of [(triphos)NiMe]-
[OTf] are nearly identical to those of the product of methyl transfer
from MeCo to (triphos)Ni(PPh3). A solution of [(triphos)NiMe]-
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98.0 (t, 1P) (JPP: 23 Hz). The Ni-Me signal is observed at δ )
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scopic properties of [(triphos)NiMe][OTf] and the transmethylation
product, [(triphos)NiMe][Co], corroborate that methyl transfer has
been achieved (Scheme 1).
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P
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unsaturated Ni0P attacks methylcob(III)alamin prior to CO binding.3
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MeCo in CD3CN/C6D6. After 24 h at room temperature, there was
no evidence for formation of [(triphos)NiMe]+. Approximately 10%
of (triphos)NiCO had decomposed, along with concomitant forma-
tion of [Co] (see Supporting Information for details). In stark
contrast, (triphos)Ni(PPh3) was methylated quantitatively in ∼1 h
under similar conditions. These striking differences in reactivity
provide chemical precedent in support of the hypothesis that Me
binds before CO in ACS catalysis.
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We have shown that MeCo can quantitatively methylate a Ni0
complex, (triphos)Ni(PPh3). Electrochemical experiments suggest
that this reaction does not take place via electron transfer. The
potential of the Ni+/0 couple of (triphos)Ni(PPh3) (-100 mV vs
NHE) is too positive to reduce MeCo (-1.1 V vs NHE). Therefore,
we propose that this transformation takes place via an SN2
mechanism. This small molecule model reaction suggests that the
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