CNS and CNP Iron(II) Mono-Iron Hydrogenase (Hmd) Mimics: Role of Deprotonated Methylene(acyl) and the trans-Acyl Site in H2 Heterolysis

Article abstract of DOI:10.1021/acs.inorgchem.9b01530

We report syntheses and H₂ activation involving model complexes of mono-iron hydrogenase (Hmd) derived from acyl-containing pincer ligand precursors bearing thioether (CNS^Pre) or phosphine (CNP^Pre) donor sets. Both complexes feature pseudo-octahedral iron(II) dicarbonyl units. While the CNS pincer adopts the expected mer-CNS (pincer) geometry, the CNP ligand unexpectedly adopts the fac-CNP coordination geometry. Both complexes exhibit surprisingly acidic methylene C-H bond (reversibly de/protonated by a bulky phenolate), which affords a putative dearomatized pyridinate-bound intermediate. Such base treatment of Fe-CNS also results in deligation of the thioether sulfur donor, generating an open coordination site trans from the acyl unit. In contrast, Fe-CNP maintains a CO ligand trans from the acyl site both in the parent and dearomatized complexes (the-PPh₂ donor is cis to acyl). The dearomatized mer-Fe-CNS was competent for H₂ activation (5 atm D_2(g) plus phenolate as base), which is attributed to both the basic site on the ligand framework and the open coordination site trans to the acyl donor. In contrast, the dearomatized fac-Fe-CNP was not competent for H₂ activation, which is ascribed to the blocked coordination site trans from acyl (occupied by CO ligand). These results highlight the importance of both (i) the open coordination site trans to the organometallic acyl donor and (ii) a pendant base in the enzyme active site.

Full text of DOI:10.1021/acs.inorgchem.9b01530

Article
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Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX
CNS and CNP Iron(II) Mono-Iron Hydrogenase (Hmd) Mimics: Role of
Deprotonated Methylene(acyl) and the trans-Acyl Site in H2
Heterolysis
Yae In Cho, Gummadi Durgaprasad, and Michael J. Rose*
Department of Chemistry, The University of Texas at Austin, Austin, Texas 78712, United States
S
* Supporting Information
ABSTRACT: We report syntheses and H2 activation
involving model complexes of mono-iron hydrogenase
(Hmd) derived from acyl-containing pincer ligand precursors
bearing thioether (CNSPre) or phosphine (CNPPre) donor
sets. Both complexes feature pseudo-octahedral iron(II)
dicarbonyl units. While the CNS pincer adopts the expected
mer-CNS (pincer) geometry, the CNP ligand unexpectedly
adopts the fac-CNP coordination geometry. Both complexes
exhibit surprisingly acidic methylene C−H bond (reversibly
de/protonated by a bulky phenolate), which affords a putative
dearomatized pyridinate-bound intermediate. Such base treatment of Fe-CNS also results in deligation of the thioether sulfur
donor, generating an open coordination site trans from the acyl unit. In contrast, Fe-CNP maintains a CO ligand trans from the
acyl site both in the parent and dearomatized complexes (the −PPh2 donor is cis to acyl). The dearomatized mer-Fe-CNS was
competent for H2 activation (5 atm D2(g) plus phenolate as base), which is attributed to both the basic site on the ligand
framework and the open coordination site trans to the acyl donor. In contrast, the dearomatized fac-Fe-CNP was not competent
for H2 activation, which is ascribed to the blocked coordination site trans from acyl (occupied by CO ligand). These results
highlight the importance of both (i) the open coordination site trans to the organometallic acyl donor and (ii) a pendant base in
the enzyme active site.
(acyl) donors derived from the so-called FeGP cofactor; an S
donor from Cys176; cis carbonyl ligands; and last a labile/open
coordination site (trans to acyl-C) for solvent or substrate
binding.2,5−7 As structure dictates function, close examination
of particular coordination motifs through a biomimetic
approach can aid in clarifying the role of each ligand and its
orientation, thus providing deeper insight for understanding
the catalytic mechanism.
One of the most intriguing features of [Fe]-hydrogenase is
the presence of the Fe-acyl moiety. Indeed, this organometallic
motif is thus far unique in biological systems. Electronically,
the acyl-C donor cannot be replicated by any of the standard
amino acid residues, nor by any of the ligands found in other
hydrogenase enzymes (CO, CN−, thiolate, azadithiolate, etc.).
While it is an extremely strong σ-donor (pKa ≈ 35)stronger
than almost any other known biological ligand other than
methyl (pKa ≈ 45; e.g. methylcobalimin)it is also a good π-
acceptor due to the available resonance form of the oxyanion/
Fischer carbene (FeC−O−). It is thus presumed to play a
very specific role in the nonredox activation of H2 and hydride
transfer mechanism.
INTRODUCTION
■
In nature, dihydrogen activation has been accomplished by a
class of enzymes called hydrogenases.1 Among the three types,
mono [Fe]-hydrogenase (Hmd) catalyzes the reversible
cleavage of H2 in a nonredox, heterolytic fashion as a key
step during the methanogenic conversion of carbon dioxide
(CO2) to methane (CH4).2 In this process, the substrate
methenyltetrahydromethanopterin (methenyl-H4MPT+) is
used as a C1 “carrier” throughout the metabolic pathway. As
a result of H2 activation by Hmd, a hydride is transferred to the
H4MPT+ substrate, thus producing methylenetetrahydro-
methanopterin (methylene-H4MPT) and a proton.3,4
The active site is composed of the following moieties
(Scheme 1): a redox-inactive Fe(II) center, a bidentate acyl-
pyridine moiety presenting N (pyridone/pyridinol) and C
Scheme 1. Active site of [Fe]-hydrogenase
Regarding the geometry of the donors about the metal
center, it can be reasonably postulated that in the absence of
Received: May 23, 2019
© XXXX American Chemical Society
A
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Scheme 2. Structures of the Ligand Precursors (CNSPre and CNPPre), Our Previous Fe-carbamoyl Complex,36 and the Fe-acyl
Complexes (Fe-CNS and Fe-CNP) Used in This Work
steric (or otherwise geometrically directing) effects, the strong
σ-donating ability of the acyl-C directs the open/solvent
binding site to its trans position. Indeed, this postulate is
epitomized in the model chemistry developed by Hu, Pickett,
and otherswherein non-macrocyclic CNS donor sets (i.e.,
the thiolate is not tethered to the acylpyridine or carbamoyl-
pyridine moiety) inherently adopt a fac-CNS donor geometry
with the solvent8 or open9−11 site trans from the acyl-C donor.
However, reactivity studies with such “nontethered” model
complexes have not been forthcoming, possibly due to the
instability of hydride intermediates or lack of H2 activation due
to fluxional geometries. The strong trans influence of the acyl
group (much stronger than carbonyl)12 likely plays a major
role in the catalysis in terms of electronic effects. In this
respect, it is remarkable that nature chose to make use of a rare
type of ligand to promote catalysis.
similarly “dearomatized” intermediate, and these Ru-pincer
complexes catalyzed dehydrogenative couplings,24 transfer
hydrogenation,25 and electrocatalytic reduction of CO2.26
Among bioinorganic researchers, the Song group utilized 2-
acylmethyl-6-pyridinol (or hydroxymethyl) ligands to chelate
iron(II) and provide more structural resemblance to the [Fe]-
hydrogenase enzyme active site.27−29 Although lacking
reactivity studies, they successfully implemented all the
donor atoms in correct geometry and donor orientation as
found in the active site. The Hu group has also investigated
small-molecule mimics featuring acylmethylpyridine ligands
exhibiting a 2-hydroxy,11 2-methoxy,9,30 or 2-tertbutyl group;11
a thiolate ligand (2,6-dimethylbenzenethiolate9,11 and
others);11 and the cis-carbonyl motif. Through pioneering
studies using a hybrid protein|molecule approach,31 it was
hypothesized that the following components are crucial in the
H2 activation: (i) the presence of a protein environment and
substrate (methenyl-H4MPT+), (ii) thiolate ligand as an
internal base (in other words, a proton acceptor), and (iii)
the pyridine-2-OH moiety (or conjugate pyridone), which
positions the active site/cofactor suitable for the heterolytic
cleavage of H2. The hybrid enzyme exhibited measurable
reactivity (TOF = 2 and 1 s−1 for the heterolytic cleavage of H2
in the presence of the substrate and the production of H2,
respectively),31 which corresponded to about 1% of wild-type
activity, thus exceeding the rates of the previously reported
synthetic hydrogenation catalysts (TOF ≈ 10−3−10−1 s−1).32,33
A recent study by our group demonstrated that preservation
of the facial coordination motif of the CNS donors via an
“anthracene scaffold” approach, a synthetic model can promote
H2 activation in the absence of the protein environment.34 The
active solvato-Fe(II) species not only activates H2, but also
abstracts hydride from a model imidazolidine substrate
(hydride source via C−H activation), then produces H2 with
the aid of a bulky phenol (proton source). Furthermore, we
recently demonstrated that functional H2 activation and
hydride transfer can be performed by a thiolate-containing
model complex derived from this anthracene scaffold.35
Metal−ligand cooperativity in small molecule systems, and
even more broadly in active site chemistry,13−16 has been
recently noted. A number of related iron(II) carbonyl
complexes have been investigated by organometallic and
catalysis researchers in the past decade to better understand
the role of each donor moiety. Milstein and co-workers
adopted the use of pincer-type PCNCN and PCNCP-type
ligands, in which the central pyridine presents two phosphine
moieties at the ortho positions via methylene linkers.17−20
A
variety of Fe(II)−(PNN/PNP)−hydride complexes were
shown to serve as hydrogenation catalysts, andmechanisti-
callythese species universally proceed through a dearomat-
ized pyridinate species, wherein one of the picolinic protons in
the methylene linker is deprotonated. Subsequently, the
metal−ligand cooperativity of the Lewis acidic (metal) and
basic (ligand) sites drive the heterolytic activation of H2. In
related work, Kirchner and co-workers focused on iron(II)
complexes with PNNNP-type ligands where the pyridine ring
and the phosphine moieties are connected by amide (NH)
linkers instead.21−23 Upon activation with strong base (NH
deprotonation), the complexes catalyze the hydrogenation of
ketones and aldehydes and proceed through the same
heterolytic cleavage of H2 as supported by DFT calcula-
tions.21,23 Huang and co-workers24−26 studies a number of
ruthenium−PNN complexes that proceeded through the
More closely related to the present work, we reported the
carbamoyl-pincer model complex [(CNHNS)Fe(CO)2(Br)]36
(Scheme 2)the carbamoyl version of the methylene-acyl Fe-
B
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Scheme 3. Metalation of CNSPre and CNPPre Ligand Precursors into the Acylmethylpyridyl-Fe(II) Complexes, Fe-CNS and Fe-
CNP, Respectively
CNS complex in this report. The CNS donor set was ligated in
standard pincer (meridional) fashion, and treatment with a
hydride source (NaHBEt3) provided spectroscopic evidence
for the Fe−H species (low temp 1H NMR spectroscopy: −5.08
ppm in d8-THF). However, the complex was not competent for H2
activation, and ligand decomposition was observed upon
treatment with strong base (NH deprotonation). We were
thus interested to determine the importance of the donor
identity (acyl versus carbamoyl) in an analogous complex for
H2 activation.
In this work, we focus on the structural and reactivity effects
of the methylene-acyl donor in concert with thioether versus
Figure 1. ORTEP diagram (50% thermal ellipsoids) of Fe-CNS (left)
and Fe-CNP (right) exhibiting the mer-CNS or fac-CNP donor
orientations, respectively. Hydrogen atoms are omitted for clarity.
Color scheme: carbon (gray); nitrogen (blue); oxygen (red); sulfur
phosphine donors in a single-chelate approach by reporting the
new compounds, ligand precursor, CNSPre, and the iron(II)−
acyl complexes, Fe-CNS and Fe-CNP. (CNPPre was
synthesized previously:37 here, we report a new synthetic
(yellow); iron (orange); iodine (green); phosphorus (purple).
route and use it as a ligand precursor for synthesizing acyl
complex, Fe-CNP.). The apparent flexibility of this ligand
the position trans to the pyridine N, similar to the Hmd active
frame allows the metal center to “choose” its ideal binding
site. However, the second carbonyl in each case is differentially
mode based on steric and electronic effects. The structures and
located: trans to the iodide in Fe-CNS, and trans to the acyl-C
enzyme-like reactivities of the resulting Fe-CNS and Fe-CNP
donor in Fe-CNP. Each of the Fe−C(≡O) bond distances is
complexes are compared herein in the “forward” direction,
approximately 1.77 Å, with the notable exception for the CO
using D2 activation in the presence or absence of base.
trans to the acyl moiety in Fe-CNP, which is nearly 0.1 Å
longer (1.876(11) Å, Table 1). This is indicative of the strong
RESULTS
■
σ-donor strength of the acyl-carbanion donor. The Fe−Cacyl
bond distances for Fe-CNS and Fe-CNP are not drastically
different (1.945(5) and 1.974(10) Å, respectively). Regarding
Fe-CNP, a literature search reveals that the average distance a
Fe−Cacyl bond with a trans CO is roughly 1.976 Å,9,28,29,38,39
which is consistent with the value of Fe-CNP (1.974(10) Å).
The Fe−I distances for both complexes are nearly identical:
2.6958(7) and 2.6980(17) Å for Fe-CNS and Fe-CNP,
respectively.
In Fe-CNS, the Npy−Fe−Cacyl ferracycle angle is 85.19(17)°
(Table 1). The aryl unit coupled at the ortho position on the
pyridine ring is twisted out of plane by −41.2(7)°, primarily
due to the steric hindrance between the hydrogen atoms on
the pyridine and aryl rings ortho to the coupling site. This
“flipped up” aryl group directs the thioether S to ligate to Fe
center trans to the acyl moiety, thus affording the mer
coordination motif. In contrast, the ortho aryl unit of the CNP
ligand rotates in the opposite direction, characterized by a
+38.9(13)° torsion angle. This allows the bulkier −PPh2
moiety (versus −SMe) to occupy the site trans to iodide,
rather than cis to iodide as in Fe-CNS.
Syntheses. Metalations to prepare the Fe-CNS and Fe-
CNP complexes were performed in analogous fashion (Scheme
3). As reported previously, syntheses of the acylmethylpyr-
idyl−Fe(II) complexes typically proceed through (i) metal-
ation of ligand (or ligand precursor) with Fe(0) or Fe(2−)
carbonyls; (ii) migratory insertion of one of the carbonyls to
generate the Fe(0) intermediate with the methylene−acyl−
iron unit; finally, (iii) oxidation using X2 (X = I or Br) to afford
the desired Fe(II)−acyl complex.12,27 When using Fe(0)
carbonyls (as in this work), a harsh deprotonation of the
methylpyridine moiety of a chosen ligand precursor is required
prior to the metalation step. The crude product was collected
as a yellow−brown powder, and purification via alumina
chromatography provided analytically pure and crystallo-
graphically defined samples.
Crystal Structures: Reasons for mer versus fac
Coordination Motifs. The crystal structures of the Fe−acyl
thioether (Fe-CNS) and phosphine (Fe-CNP) complexes are
depicted in Figure 1. In each case, the Fe(II) center is
coordinated with one iodide, two carbonyls, and one ligand (C,
N, and L donors). Notably, the ligation mode of the “pincer”
ligand is different in each complex: Fe-CNS exhibits
meridional binding, whereas Fe-CNP exhibits an unexpected
facial coordination motif. In each case, one CO ligand occupies
The unexpected and spontaneous facial ligation of CNP can
be explained by closely examining and comparing both steric
and electronic effects on the Fe-acyl complexes. In both
complexes, the coordination of the acyl C, pyridine N, iodide,
C
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Table 1. Selected Bond Lengths and Bond Angle Comparison between Fe-CNS and Fe-CNP
Figure 2. Structures of Fe-CNS and Fe-CNP, respectively, showing only the six donor atoms in space-filling model. Each inset represents the
capped-sticks model of the larger structure at the same angle. Color scheme: carbon (gray); nitrogen (blue); iodine (dark magenta); sulfur
(yellow); phosphorus (orange). Hydrogen atoms are omitted for clarity.
a
Scheme 4. Deprotonation of Fe-CNS or Fe-CNP with a Bulky Phenolate Base
a
The hollow wedged bond for one carbonyl group represents the position either trans from iodide (Fe-CNS) or trans from acyl (Fe-CNP).
and COtrans‑py remains unchanged. Only two sites, those trans
to iodide and trans to acyl (represented as dotted circle and
dotted square in Figure 2, respectively) are occupied by
different donorsnamely, the second CO and either SMe or
PPh2. Also, space-filling models of both complexes reveal that
the iodide is the bulkiest donor atom (radius: 206 pm) among
the six; iodide is also larger than the combined CO ligand.
Therefore, iodide will preferentially occupy the least crowded
coordination site (complete space-filling models: Figure S2).
For Fe-CNS, the second bulkiest donor is the SMe unit, while
in Fe-CNP it is PPh2 moiety. Comparing −SMe and −PPh2,
the former has only one “short” arm (methyl), which can easily
be deflected away from the bulky iodide without changing the
coordination site of the −SMe donor. On the other hand,
−PPh2 has two bulky substituents. Therefore, the bulky
phosphine moiety cannot occupy the position cis to the
bulkiest donor atom, iodide. Incidentally, the “flexibility” of the
ortho-aryl linkage facilitates binding of the −PPh2 unit trans to
the iodide, while retaining unperturbed Fe−P bond metrics
(2.202(3) Å); the facial CNP ligation is the final result.
Deeper inspection of the donor strengths of −SMe versus
−PPh2 also provides insight into the geometric properties of
the complexes. Among the CNS and CNP donor sets, the σ-
donor strength is ordered as follows: acyl-C > −PPh2 > Npy
>
−SMe. Thus, the position trans from the acyl-C would be the
most labile site due to its strong trans influence, thus
dissuading the coordination of another strong σ-donor (such
as −PPh2). However, in case of CNS, the −SMe unit is a weak
σ-donor not unlike the weakly bound H2O molecule trans from
acyl in the active site. Indeed, all of the previously reported
D
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Figure 3. Infrared spectra of Fe-CNS (left) and Fe-CNP (right) deprotonation via bulky phenolate. Note that more than one equivalent of base is
required for a complete deprotonation to Fe-CNS′ or Fe-CNP′.
1
1
Figure 4. (A) H NMR spectrum of Fe-CNS in d8-THF. (B) H NMR spectrum of deprotonated species Fe-CNS′ and conjugate phenol +
phenolate in d8-THF.
iron-acyl-phosphine complexes38−41 exhibit non-chelating
phosphine ligand(s) at cis site(s). Similarly, all examples of
iron-carbamoyl complexes that contain non-chelating phos-
phine ligands exhibit cis-phosphine(s), except for one case of a
trans PMe3 unit.36,42 All of these data are consistent with the
strong σ-donor effect of the acyl group, thus affording the cis-
PPh2 binding motif (and consequently, fac-CNP).
Reactivity Studies. Deprotonation. In related non-
biomimetic work on iron(II) pincers, it has been established
that heterolytic cleavage of H2 occurs via metal−ligand
cooperation that utilizes the conjugate base of acidic
methylene or amide linkers in the ligand framework.16 These
conjugate bases are “dearomatized” due to the presence of a
pyridinate anion (rather than pyridine) in the central position.
E
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1
1
Figure 5. (A) H NMR spectrum of Fe-CNP in d8-THF. (B) H NMR spectrum of deprotonated species Fe-CNP′ and conjugate phenol +
phenolate in d8-THF.
In our biomimetic system, we found that the methylene linker
protons serve an analogous role (Scheme 4).
3.86 ppm for Fe-CNS in C6D6 (Ha and Hb, respectively; Figure
S4A, top) and 5.79 and 4.94 ppm for Fe-CNP (Figure S4A,
bottom). Comparing the structures of the two complexes, the
chemical environments of the “front-side” protons adjacent to
the iodide remain relatively similar, compared with distinct
chemical environments of the “back-side” protons (adjacent to
CO versus −PPh2 in Fe-CNS versus Fe-CNP). The similar
chemical shifts of 5.46 (Fe-CNS) and 5.79 (Fe-CNP) support
the assignment of the downfield diastereotopic resonance to be
Ha in both cases. The more deshielded nature of Ha indicates
more susceptibility to deprotonation, and thus Ha is likely the
acidic proton in the reactivity studies detailed below.
Up to 4 equiv of base were required for a complete
conversion of Fe-CNS to Fe-CNS′. The progress was
monitored by infrared spectroscopy, showing a clear transition
of the carbonyl stretches {2015, 1957} → {1983, 1921 cm−1}
as well as the acyl stretch (1662 → 1587 cm−1) (Figure 3, left).
Under similar conditions, deprotonation of a methylene proton
of Fe-CNP yielded the dearomatized species Fe-CNP′,
exhibiting red shift of the carbonyls {2014, 1960} → {1987,
1936 cm−1} and the acyl (1635 → 1586 cm−1) stretches in
infrared spectrum (Figure 3, right). To confirm the acid/base
nature of this transformation, attempts were made to
regenerate the parent complex, Fe-CNS, by adding a proton
source. Addition of 2,6-lutidinium bromide to Fe-CNS′ did
result in a blue shift of the carbonyl stretches {1983,1921} →
{2002,1933 cm−1} as expected (Figure S3), similar to Fe-CNS;
however, the acyl stretch near 1665 cm−1 was only partially
recovered. We also attempted to abstract iodide from Fe-CNS
and Fe-CNP using either Na[BArF] or AgBF4, in both the
presence and absence of PPh3: both reactions resulted in the
loss of all CO, indicating the decomposition of the complexes.
The methylene protons in both iron−acyl complexes are
diastereotopictheir chemical environment is quite different,
resulting in two doublets in the 1H NMR spectrum at 5.46 and
Reactivity studies required the use of THF or d8-THF versus
C6D6 as a coordinating solvent and for improved solubility of
reagents. Treatment of Fe-CNS (1H NMR spectrum, Figure
+
4A) with a bulky phenolate base (NEt4 salt of 2,6-di-tert-
butyl-4-methoxyphenolate) results in the disappearance of the
diastereotopic resonances, indicating the formation of the
dearomatized species Fe-CNS′ (Figure 4B), analogous to the
dearomatized iron-pyridinate species observed by Milstein and
Kirchner.16−21,43 As a result, the conjugate acid phenol is
observed (δ OH: 5.70 ppm), and NEt4I(s) is formed as
precipitate. It is noted that an excess of the conjugate phenol
(see assigned resonances in Figure 4B) remains observable due
to the requirement for ∼4 equiv of phenolate to drive complete
F
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deprotonation (see IR section above, Figure 3, left). Lastly, the
disappearance of the −S(CH3) resonance at 2.69 ppm suggests
deligation of the sulfur donor due to the (now) dianionic
ligand framework.
Similarly, as noted in the IR section (Figure 3, right), Fe-
CNP also requires ∼4 equiv of base to complete deprotona-
tion. After treatment of Fe-CNP with the phenolate base, the
diastereotopic protons (5.39 and 4.25 ppm in d8-THF, Figure
5A) are no longer observed, and the resonances from the
conjugate phenol emerge (Figure 5B).
For the deprotonated phosphine congener Fe-CNP′, the
2
analogous reaction with D2 (7 atm, H NMR analysis) does
not result in a phenol−OD resonance (D+); again, no Fe−D
resonance was detected (Figure S6). This phenol-OD
resonance has served as an obligate marker for D2 heterolysis
in all systems studied in our laboratory.34,35 Indeed, following
D2 exposure, both the NMR spectra (1H and 31P) as well as IR
analysis indicate that the unaltered Fe-CNP′ remains the only
detectable species; that is, no decomposition or methylene
resonance (1H or 2H) is observed. We do note the presence of
2
D2 Activation. The deprotonated species Fe-CNS′ was then
placed under 5 atm of D2, and the reaction was monitored by
2H NMR spectroscopy (Figure 6). A new resonance at 5.39
one minor peak in the H spectrum near 7.8 ppm; however,
based on the absence of 13C{2H} coupling in the 13C NMR
spectrum, we have been unable to identify this feature.
Nonetheless, we similarly attempted to detect hydride transfer
from D2 to the TolIm+ substrateunsurprisingly to no avail.
DISCUSSION
■
Fe-CNS versus Fe-CNP Reactivity. We postulate that the
reason for the lack of D2 activation in Fe-CNP′ is due to the
“blocking” of the coordination site trans to the acyl unit by the
CO ligand. We have demonstrated the requirement for an
open site trans to acyl in several other systems, including those
supported by an anthracene scaffold that uniformly enforces a
fac-CNS coordination motif with the solvent/H2 binding site
trans to the acyl unit.34,35 This generates an apparent paradox
with the Fe-CNS case, wherein the trans site is also “blocked”
by the thioether-S donor. However, recent studies have
indicated the potential hemilability of thioether-S in related
systems. It is notable that in the enzyme site, one presumed
role of the strongly σ donating, acyl carbanion is to labilize the
weakly bound water to enable H2 binding via Kubas
interaction. We did demonstrate through IR spectroscopy in
both coordinating (THF) and noncoordinating solvents
(DCE, FPh) that the Fe−S bond remains intact in the Fe-
CNS starting complex. It is likely, however, that upon
generating another negative charge in the ligand frame
(dearomatized pyridine anion), the sulfur deligates from the
iron center. Ultimately, we propose the mechanistic cycle
illustrated in Schemes 5 and 6, which is the only model
consistent with all of our observations. In the case of Fe-CNP/
Fe-CNP′, the consistent ligation of the CO ligand trans to the
acyl unit blocks H2 binding and activation, despite the
generation of a basic site on the ligand frame.
2
Figure 6. H NMR spectra of D2 activation by Fe-CNS′ with or
without the presence of substrate (TolIm+) in THF, exhibiting an
−OD signal of the conjugate phenol at 5.41 and 5.39 ppm,
respectively.
ppm was observed within 30 min, which was assigned as the
conjugate phenol−OD resonance (D+, confirmed via isolation
of the authentic phenol−OD species from CD3OD);34 no Fe−
D resonance (D−) was observed (e.g., 0 to −30 ppm).
Nonetheless, the observation of the D+ resonance indicates
activation of D2 via heterolysis by the Fe-CNS system. It is also
Relevance to Enzyme. It is evident that the indispensable
factor that dictates reactivity toward H2 is the presence of an
open coordination site trans to the organometallic acyl unit. It
is likely that the presence of a pendant base is also required
(methenyl-acyl in our work; pyridonate in enzyme). However,
due to the hemilabile thioether in the Fe-CNS system, we are
unable to unambiguously differentiate these two effects.
Regarding the pendant base postulate, the emerging
mechanism for the enzyme is that this role is fulfilled by the
pyridone moiety (rather than the Cys-S as in [NiFe], or
azadithiolate in [FeFe]). However, our system lacks the truly
biomimetic and anionic pyridonate donor and instead employs
the neutral pyridine as a substitute. We wish to highlight the
limited implication of the deprotonated methylene(acyl)
pyridine unit observed in our system, versus the methylene-
(acyl)pyridone unit in the enzyme: Due to the pre-existing
anionic charge in the enzyme’s pyridonate heterocycle, we
strongly contend that the methylene(acyl) pKa would be
biologically inaccessible; its deprotonation would require the
generation of a di-anionic pyridoneunlikely. Therefore, we
2
notable in the H NMR spectra that the ligand “basic site” is
not deuterated during successful D2 heterolysis, indicating that
the methine carbon is not directly involved in D2 activation.
A recent result from our group demonstrates that a bulky
Lewis acid substrate (putative hydride acceptor) can be
2
employed to stabilize and detect iron-hydride species in H
NMR experiments34 or serve as a hydride-accepting sub-
strate.35 Therefore, the same reaction was performed in the
presence of the model substrate TolIm[BArF], a bulky
imidazolium salt that mimics the role of methenyl-H4MPT+
in the enzyme’s H2 activation process. However, a nearly
identical 2H NMR spectrum was obtained in this case (δ −OD
= 5.41 ppm; no Fe−D resonance observed), indicating that the
TolIm+ substrate (a) does not impede H2 heterolysis, (b) does
not aid in stabilizing the implicit iron-deuteride intermediate,
and (c) does not serve as a hydride acceptor in this system.
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Scheme 5. Summary of Mechanistic Understanding of the Parameters Leading (or Blocking) H2 Activation in the Present Fe-
CNS and Fe-CNP Systems
Scheme 6. Difference in Methylene Reactivity (Acidity) between the Enzyme Active Site (Top) and Present Fe-CNS/Fe-CNP
Systems
do not claim that the methylene(acyl) → methenyl(acyl)
interconversion is an active mechanism in the enzyme. Rather,
we contend that the present system demonstrates the
important utility of a pendant base in the vicinity of the iron
center to drive H2 heterolysis.
an unexpected fac-CNP motif due to the bulkier and more
strongly σ-donating −PPh2 unit (does not prefer to bind trans
to the acyl carbanion). The reactivity studies are summarized
as follows:
(1) Both Fe-CNS and Fe-CNP undergo facile methylene-
(acyl) deprotonation that generates a dearomatized
pyridinate similar to that reported by Milstein, Kirchner,
and others.
CONCLUSION
■
In summary, we were able to directly compare the electronic
and steric effects on the binding mode of thioether versus
triphenylphosphine moiety in Fe-acyl system by designing two
pincer ligand precursors, CNSPre and CNPPre. The CNS ligand
adopted the expected mer-CNS motif, while the CNP adopted
(2) In all cases, the Fe-CNP system exhibits a “blocked”
coordination site trans to the organometallic acyl unit,
which precludes H2 binding and activation.
H
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dropwise at −78 °C. The reaction mixture was stirred for about 1.5 h
and allowed to warm to −25 °C, then recooled to −78 °C for
oxidation. Under dark conditions, the prechilled Et2O solution (7
mL) of I2 (0.212 g, 1.67 mmol) was added dropwise into the stirred
solution via cannula transfer and kept at −78 °C for 2 h. A yellow−
brown precipitate was isolated using an air-free filter tube and dried
under N2. Yield: 0.528 g (59.3%). A DCM solution of the crude
product was then filtered through neutral alumina and layered with
pentane at −25 °C to give X-ray quality crystals (red−brown
(3) In contrast, deprotonation of the Fe-CNS system
generates an open coordination site trans to acyl,
which enables H2 activation. This highlights the key
importance of the geometric location of the H2 binding
site as trans from the acyl unit to promote H2 binding
and heterolysis.
(4) However, neither a stable iron-hydride species nor
hydride transfer to a biomimetic substrate is observed in
Fe-CNS system. We suspect that the anionic nature of
the proposed Fe−H intermediates result in their
instabilities, thereby precluding spectroscopic detection.
(5) The methylene(acyl) motif occurs in both the present
systems and the enzyme. In Fe-CNS and Fe-CNP, it
serves as a convenient means to investigate the role of
“pendant base” in a model system.
1
needles). H NMR (C6D6, δ in ppm): 7.36 (s, 1H), 6.96 (s, 1H),
6.88−6.78 (m, 2H), 6.72 (t, J = 7.8 Hz,1H), 6.61 (d, J = 7.7 Hz, 1H),
6.26 (d, J = 7.8 Hz, 1H), 5.46 (d, J = 20.5 Hz, 1H), 3.86 (d, J = 20.4
Hz, 1H), 2.00 (s, 3H). 1H NMR (d8-THF, δ in ppm): 8.07 (m, 1H),
7.83 (d, J = 8.1 Hz, 1H), 7.71 (d, J = 7.5 Hz, 1H), 7.65−7.40 (m,
4H), 5.39 (d, J = 20.4 Hz, 1H), 4.24 (d, J = 20.4 Hz, 1H), 2.69 (s,
3H). IR bands (cm−1): 2032 (νC≡O vs), 1962 (νC≡O vs), 1662 (νC=O
vs), 1583, 1572, 1474 (s), 1449, 1438 (s), 760, 744 (s). Elemental
analysis for calcd (Fe-CNS with residual solvents: 0.1 equiv DCM and
0.2 equiv pentane): C 40.75, H 2.92, N 2.78; found: C 40.90, H 2.80,
N 2.41. CCDC deposition no.: 1590122.
2-(2-Bromophenyl)-6-methylpyridine (C12H10BrN). A Suzuki cou-
pling of 2-bromo-6-methylpyridine (3.27 g, 19.0 mmol) with 2-
bromophenylboronic acid (4.20 g, 20.9 mmol, 1.1 equiv) was
performed using K2CO3 (2.89 g, 20.9 mmol, 1.1 equiv) and
Pd(PPh3)4 (0.769 g, 0.66 mmol, 3.5 mol %) in a 1,4-dioxane:H2O
(3:1) mixture. The slurry was refluxed for 24 h. The organic layer was
collected by EA extractions (3 × 100 mL) and dried over Na2SO4.
Purification via column chromatography (EA:Hex = 1:8) afforded the
product as pale yellow oil. Yield: 3.89 g (83%). 1H NMR (CDCl3, δ in
ppm): 7.67−7.57 (m, 2H), 7.50 (dd, J = 7.6, 1.8 Hz, 1H), 7.40−7.33
(m, 2H), 7.20 (dddd, J = 7.5, 1.8, 0.5 Hz, 1H), 7.13 (dp, J = 7.7, 0.3
Hz, 1H), 2.62 (s, 3H). HRMS (+ESI): m/z calcd for C12H10BrN (M),
247.00, 249.00; found, (M + H)+ 248.0071, 250.0051.
(6) However, due to the already anionic pyridone in the
active site (versus neutral pyridine in this model system),
it is not claimed that the methylene(acyl) → methenyl(acyl)
conversion occurs in the enzyme. The endogenous
pyridone-O likely serves the role of “pendant base” in
the active site.
EXPERIMENTAL SECTION
■
Materials and Methods. Fe(CO)5 and Pd(PPh3)4 were
purchased from Strem Chemicals; 2-bromo-6-methylpyridine and
Pd(PPh3)2Cl2, from Oakwood Chemicals; 2-(methylthio)phenyl
boronic acid, from Boron Molecular and Matrix Scientific; 2-
bromophenylboronic acid from Combi Blocks, Inc.; I2 and ClPPh2,
from Acros Organics; 1.6 M nBuLi in hexanes and D2 (99.8%), from
Sigma-Aldrich; K2CO3, from Fisher Scientific; aluminum oxide
(neutral, Brockmann I, 50−200 μm, 60 Å), from Acros Organics;
silica (SiliaFlash Irregular Silica Gels, 40−63 μm, 40 Å), from
SiliCycle. The solvents dimethoxyethane (DME), ethyl acetate (EA),
and 1,4-dioxane were purchased from Fisher Scientific and used
without further purification. The solvents diethyl ether (Et2O),
dichloromethane (DCM), chloroform, tetrahydrofuran (THF), and
pentane were procured from Fisher Scientific and dried over alumina
columns using a Pure Process Technology solvent purification system
and stored over 3 Å molecular sieves until use. The deuterated solvent
CDCl3 was purchased from Cambridge Isotopes and used as received.
Imidazolium (Im+)44 and the bulky phenolate base were synthesized
following literature procedures.
CNPPre (2-(2-(Diphenylphosphaneyl)phenyl)-6-methylpyridine,
C24H20NP). [The synthetic conditions were modified from the work
of Speiser et al.37] Note: A rigorous air-free handling technique is
required to isolate this product as the free phosphine (avoiding
phosphine oxide). A solution of nBuLi (1.6 M in hexanes, 16 mmol)
was added dropwise into a freeze−pump−thawed solution of 2-(2-
bromophenyl)-6-methylpyridine (3.97 g, 16 mmol) in THF at −78
°C. After stirring the solution at the same temperature for 1 h, ClPPh2
(16 mmol) was added dropwise via syringe and allowed to warm to rt
overnight. Degassed H2O was added via syringe, followed by
successive air-free Et2O extractions using cannula transfers. The
organic layer was transferred to a N2-purged Schlenk flask containing
Na2SO4 via cannula and stirred for 30 min. The dried solution was
then cannula transferred to a new Schlenk flask, and the volume was
reduced under vacuum until a white powder formed. The resulting
yellow supernatant (impurities) was transferred into a separate
Schlenk flask via cannula, and the remaining white powder (product)
was washed several times with cold Et2O, then dried under N2.
Storage of the supernatant and washes at −20 °C for 2 d afforded
large colorless blocks suitable for X-ray diffraction. Yield: 2.94 g
(52%). 1H NMR (CDCl3, δ in ppm): 7.59 (ddd, J = 7.6, 4.3, 1.3 Hz,
1H), 7.49 (t, J = 7.7 Hz, 1H), 7.39 (td, J = 7.5, 1.4 Hz, 1H), 7.34−
7.18 (m, 12H), 7.04 (dddd, J = 7.7, 3.9, 1.4, 0.5 Hz, 1H), 6.97 (d, J =
7.8 Hz, 1H), 2.27 (s, 3H). 31P NMR (CDCl3, δ in ppm): −10.9 (s).
CCDC deposition no.: 1590145. HRMS (+ESI): m/z calcd for
C24H20NP (M), 353.13; found, (M + H)+ 354.1413.
Physical Methods. Infrared spectra were recorded on a Bruker
1
Alpha spectrometer equipped with a diamond ATR crystal. H and
31P NMR spectra were collected using Varian DirecDrive 400 MHz,
2
while H NMR spectra were collected using Varian DirectDrive 600
MHz. Elemental analyses were performed by Midwest Micro Lab.
Syntheses of Ligand Precursors and Complexes. CNSPre (2-
Methyl-6-(2-(methylthio)phenyl)pyridine, C13H13NS). A Suzuki cou-
pling of 2-bromo-6-methylpyridine (4.0 g, 23 mmol) with 2-
(methylthio)phenyl boronic acid (5.9 g, 35 mmol) was performed
using 1 M K2CO3 (35 mmol) and trans-Pd(PPh3)2Cl2 (0.816 g, 1.2
mmol, 5 mol %) in 100 mL of DME. The slurry was heated at 85 °C
for 24 h in a pressure vessel. The organic layer was collected by ethyl
acetate (EA) extractions (3 × 100 mL) and dried over Na2SO4.
Purification via column chromatography (EA:Hex = 1:8) afforded the
product as a pale yellow oil. Yield: 3.4 g (67%). 1H NMR (CDCl3, δ
in ppm): 7.64 (t, J = 7.7 Hz, 1H), 7.42 (ddd, J = 7.6, 1.5, 0.6 Hz, 1H),
7.38−7.30 (m, 3H), 7.22 (ddd, J = 7.5, 6.7, 1.9, 1H), 7.13 (dtd, J =
7.6, 1.0, 0.4, 1H), 2.63 (s, 3H), 2.39 (s, 3H). HRMS (+ESI): m/z
calcd for C13H13NS (M), 215.08; found, (M + H)+ 216.0845.
Fe-CNS [(CNS)Fe(CO)2(I)]. The CNSPre (0.400 g, 1.86 mmol) was
dissolved in 10 mL of Et2O and degassed by freeze−pump−thaw
method. Then it was cooled to −10 °C for the addition of nBuLi (1.6
M in hexanes, 1.86 mmol). After the addition, the reaction was stirred
at rt for 45 min. After the formation of an orange slurry, a prechilled
Et2O solution (3 mL) of Fe(CO)5 (250 μL, 1.86 mmol) was added
Fe-CNP [(CNP)Fe(CO)2(I)]. The CNPPre (0.500 g, 1.42 mmol) was
dissolved in 15 mL of Et2O and degassed by freeze−pump−thaw. The
solution was cooled to −10 °C for the addition of nBuLi (1.6 M in
hexanes, 1.42 mmol). After the addition, the reaction was stirred at rt
for 45 min. After the formation of an orange slurry, a prechilled Et2O
solution (3 mL) of Fe(CO)5 (191 μL, 1.42 mmol) was added
dropwise at −78 °C. The reaction mixture was stirred for about 1.5 h
and allowed to warm to −25 °C, then again cooled to −78 °C for
oxidation. Under dark conditions, the prechilled Et2O solution (7
mL) of I2 (0.162 g, 1.27 mmol) was added dropwise into the stirring
solution and kept at −78 °C for 2 h. A yellow−brown precipitate was
I
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Article
isolated using an air-free filter tube and, then, dried under N2. Yield:
0.615 g (77.9%). The crude product was purified by dissolving in
DCM and loaded on a short alumina (neutral) column in an N2
atmosphere glovebox; the products were eluted using a series of
solvents of increasing polarity (DCM → CHCl3 → THF). The final
elution with THF produced a yellow solution, from which the product
was collected via crystallization (vapor diffusion of pentane into the
THF solution at rt). Small orange−brown clusters of X-ray quality
Spencer Kerns and Zhu-Lin Xie for assistance in preparing D2
reactivity experiments.
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crystals were generated after ∼10 days. H NMR (C6D6, δ in ppm):
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1
1H). H NMR (d8-THF, δ in ppm): 8.0−7.0 (m, 15H), 6.77 (d, J =
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ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.inorg-
chem.9b01530.
X-ray data collection and refinement details, ORTEP
diagram, space-filling models, IR and NMR (1H, 31P, and
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Accession Codes
CCDC 1590122−1590123 and 1590145 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
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AUTHOR INFORMATION
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Corresponding Author
*Email: mrose@cm.utexas.edu.
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catalysts for the hydrogenation of ketones: Iron, the new ruthenium.
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Hydrogenation of Ketones Catalyzed by an Iron Pincer Complex.
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Michael J. Rose: 0000-0002-6960-6639
Notes
The authors declare no competing financial interest.
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catalyzed ester hydrogenation. Mild, selective, and efficient hydro-
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ACKNOWLEDGMENTS
■
This research was supported by the National Science
Foundation (NSF CHE-1808311) and the Welch Foundation
(F-1822). The authors are grateful to Dr Vince Lynch for
assistance with X-ray data collection and structure refinement,
as well as Dr Steve Sorey and Dr Garrett Blake for assistance in
acquiring and analyzing NMR spectra. The authors also thank
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