The Effect of β-Hydrogen Atoms on Iron Speciation in Cross-Couplings with Simple Iron Salts and Alkyl Grignard Reagents

Article abstract of DOI:10.1002/anie.201813578

The effects of β-hydrogen-containing alkyl Grignard reagents in simple ferric salt cross-couplings have been elucidated. The reaction of FeCl₃ with EtMgBr in THF leads to the formation of the cluster species [Fe₈Et₁₂]^2?, a rare example of a structurally characterized metal complex with bridging ethyl ligands. Analogous reactions in the presence of NMP, a key additive for effective cross-coupling with simple ferric salts and β-hydrogen-containing alkyl nucleophiles, result in the formation of [FeEt₃]^?. Reactivity studies demonstrate the effectiveness of [FeEt₃]^? in rapidly and selectively forming the cross-coupled product upon reaction with electrophiles. The identification of iron-ate species with EtMgBr analogous to those previously observed with MeMgBr is a critical insight, indicating that analogous iron species can be operative in catalysis for these two classes of alkyl nucleophiles.

Full text of DOI:10.1002/anie.201813578

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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Accepted Article
Title: Effect of β-Hydrogens on Iron Speciation in Cross-Couplings with
Simple Iron Salts and Alkyl Grignard Reagents
Authors: Jeffrey D Sears, Salvador B Munoz III, Stephanie L Daifuku,
Ari A Shaps, Stephanie H Carpenter, William W Brennessel,
and Michael Neidig
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201813578
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10.1002/anie.201813578
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b
Effect of -Hydrogens on Iron Speciation in Cross-Couplings with
Simple Iron Salts and Alkyl Grignard Reagents
Jeffrey D. Sears,† Salvador B. Muñoz III,† Stephanie L. Daifuku, Ari A. Shaps, Stephanie H. Carpenter,
William W. Brennessel and Michael L. Neidig*
Abstract: The elucidation of the effects of b-hydrogen containing alkyl
Grignard reagents in simple ferric salt cross-coupling is presented.
The reaction of FeCl3 with EtMgBr in THF leads to the formation of the
Our previous studies on the iron species formed with both
MeMgBr and PhMgBr demonstrated the generation of
organoferrate species that are effective for cross-coupling, the
cluster species [Fe8Et12]2–,
a
rare example of
a
structurally
multi-iron
clusters
[Fe8Me12]–
and
Fe4(µ-Ph)6(THF)4,
characterized metal complex with bridging ethyl ligands. Analogous
reactions in the presence of NMP, a key additive for effective cross-
coupling with simple ferric salts and b-hydrogen containing alkyl
nucleophiles, results in the formation of [FeEt3]–. Reactivity studies
demonstrate the effectiveness of [FeEt3]– to rapidly and selectively
form cross-coupled product upon reaction with electrophiles. The
identification of iron-ate species with EtMgBr analogous to those
previously observed with MeMgBr is a critical insight, indicating that
analogous iron species can be operative in catalysis for these two
classes of alkyl nucleophiles.
respectively.[5] Note that Jacobi von Wangelin and coworkers
have also found evidence for the competence of iron clusters in
catalysis for alkene hydrogenations.[6] For cross-coupling,
additional investigations have demonstrated that in the presence
of NMP co-solvent, cluster formation is avoided and an alternative
organoferrate species is formed with MeMgBr, [FeMe3]–, which is
also highly effective for cross-coupling.[4] While our previous
methyl and phenyl studies support the proposed organoferrate
manifold, herein we identify the in situ formed iron species in
reactions of simple ferric salts with alkyl nucleophiles containing
b-hydrogens to evaluate if the proposed reduced Fe(–II) species
are accessible for effective formation of cross-coupled products.
Iron-catalyzed cross-coupling reactions of simple ferric salts
and alkyl Grignard reagents have attracted significant interest
since their initial development by Kochi in the 1970s.[1] Importantly,
these reactions retain high fidelity even with the use of alkyl
Grignard reagents containing b-hydrogens (e.g. ethyl) which is
often a significant challenge in metal-catalyzed cross-couplings.
Furthermore, use of N-methylpyrrolidone (NMP) as a co-solvent
in these reactions has enabled effective, preparative scale iron-
catalyzed cross-coupling between alkyl Grignard reagents and a
wide range of electrophilic partners.[2] Despite the tremendous
advances in our understanding of the key iron-methyl species
involved in simple iron salt cross-couplings, it remains undefined
if reactions with alkyl Grignard reagents containing b-hydrogens
would yield similar or completely divergent iron species. In fact,
following some elegant studies of low-valent iron precursors for
cross-coupling, Fürstner proposed that methyl/aryl versus β-
hydrogen containing alkyl Grignard reagents would result in two
distinct iron distributions and mechanistic pathways (Scheme 1).[3]
Specifically, methyl/aryl Grignard reagents lacking β-hydrogens
would lead to an organoferrate manifold (as experimentally
observed for MeMgBr),[4] whereas b-hydrogen containing
Grignard reagents, such as ethylmagnesium bromide (EtMgBr),
would result in the formation of Fe(–II)MgX clusters (X = halide)
through β-hydride elimination following transmetalation from ethyl
and longer chain length Grignard reagents.
Initial studies focused on identifying the iron species formed
upon reactions of simple ferric salts and EtMgBr using excess
Grignard reagent previously shown to generate [Fe8Me12]– when
using MeMgBr.[5a] Reaction of FeCl3 with 20 equiv of EtMgBr in
THF at –78 °C generated a dark brown solution which, following
layering with pentane at –80 °C, rendered exceptionally air and
thermally sensitive dark brown crystalline material. Single crystal
X-ray diffraction revealed the iron species to be an octairon-ethyl
cluster analogous to that of the recently reported methyl-ligated
[Fe8Me12]– cluster,[5a] with the main difference being that the ethyl-
ligated cluster is dianionic. Based on the experiment, these highly
air-, moisture-, and temperature-sensitive brown crystals were
RMgX
"R4Fe(MgX)2"
R-X
FeX3
(R = Me, Ph)
RMgX
(R = Et or higher)
R-R
R-R
[Fe(MgX)2]
organoferrate
manifold
R-X
MgX2
low-valent redox
manifold
R
[R-Fe(MgX)2]
[*]
J. D. Sears, Dr. S. B. Muñoz III, Dr. S. L. Daifuku, A. A. Shaps, S. H.
Carpenter, Dr. W. W. Brennessel and Prof. M. L. Neidig
Department of Chemistry, University of Rochester
B31 Hutchison Hall, 120 Trustee Road
[R-Fe(MgX)]
Rochester, NY 14627 (USA)
RMgX
neidig@chem.rochester.edu
[†]
These authors contributed equally to this work.
Scheme 1. Proposed divergent reactive iron species and mechanistic
pathways for simple salt cross-coupling with alkyl Grignard reagents with and
without b-hydrogens.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201813578
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Figure 1. X-ray crystal structure of 1. Anisotropic displacement ellipsoids drawn at the 50% probability level. The bridging ethyl ligands are
common to both positions of the Fe8 core which is disordered over a crystallographic inversion center. Only one position of the Fe8 core is shown,
and hydrogen atoms and co-crystallized solvent molecules have been removed for clarity.
formulated as [MgX(THF)5]2[Fe8Et12]·18THF (1) (Figure 1, X =
0.77 Cl, 0.23 Br). Each iron center is coordinated by three iron
atoms and three carbon atoms. Like the methyl analog, the Fe8
Table 1. Comparison of metal-carbon metrics of transition metal complexes
containing bridging ethyl ligands. The two sets of values are distances and
core is composed of two interpenetrating tetrahedra of iron
centers, one with shorter (2.109(4)–2.169(3) Å; avg. 2.142(6) Å)
and one with longer (2.391(4)–2.445(4) Å; avg. 2.412(6) Å) Fe-C
distances. The dianion of 1 formally has two Fe(II) and six Fe(I)
centers, whereas [Fe8Me12]– formally contains three Fe(II) and five
Fe(I) metal centers,[5a] The average Fe-Fe bond lengths of
2.418(1) Å and 2.433(3), respectively, are consistent with the
slightly more reduced cluster having placed additional electron
density in the Fe-Fe bonds. Also, while agostic interactions are
possible, they were unable to be identified conclusively from this
X-ray diffraction. Theopold and coworkers have suggested that
the unexpected stability of species like [Cp*Cr(μ-R)]2, R = Et, n-
Bu, also containing β-hydrogen atoms, is due to strong metal-
metal bonding.[7] Thus, analogous strong Fe-Fe bonding
interactions in the cluster may significantly contribute to the
isolability of 1. Unfortunately, more detailed characterization and
reactivity experiments were not feasible due to its extreme
thermal sensitivity.
angles from the common ethyl ligand to the two-different metal centers.
Complex
1a
M-CH2 (Å)
M···CH3 (Å)
M-CH2-CH3 (o)
2.142(6), 2.412(6) 3.101(8), 3.415(7) 114.2(3), 118.3(3)
2.133(7), 2.403(7) 3.095(7), 3.412(9) 114.5(2), 118.8(3)
1a,b
Cr-Cr[7]
Cr-Cr[9]
2.204(16), 2.252(10)
3.21, 3.25
117.7(13), 117.7(13)
2.143(2), 2.299(2)
2.145(2), 2.302(2)
2.248(6), 2.248(7)
2.72, 3.60
2.77, 3.56
3.14, 3.17
93.58(15), 137.1(2)
96.13(15), 135.0(2)
111.3(5), 113.4(5)
Ag-Ag[10]
–
[Fe8Me12
]
2.147(3), 2.336(5)
-
-
aAverage values for the cluster. bDifferent independent crystal structure
containing a [Fe8Et12
2– dianion (see SI).
]
For simple ferric salt cross-couplings with alkyl Grignards, the
addition of NMP as a co-solvent leads to significantly improved
cross-coupling yields with β-hydrogen containing alkyl Grignard
reagents.[3b, 13] In fact, the combination of simple ferric salts, alkyl
Grignard reagents and NMP co-solvent has been utilized broadly
in pharmaceutical research.[14] While recent studies demonstrated
that the addition of NMP to reactions with MeMgBr lead to the
formation of a trimethyliron(II) ferrate complex with NMP ligated
to a magnesium dication, [Mg(NMP)6][FeMe3]2, it was unclear
what species might be stabilied by NMP when employing b-
hydrogen containing alkyl Grignards such as EtMgBr. Therefore,
the iron speciation generated from reactions of Fe(acac)3 and
EtMgBr in the presence of NMP was explored. Following the
While 1 is the first structurally characterized iron complex with
bridging ethyl ligands, well-defined ethyl bridged transition metal
complexes are exceedingly rare across the transition metals and
only four structurally characterized examples have been reported
to date in the Cambridge Structural Database.[8] Theopold and
coworkers presented a bridging ethyl ligand in [Cp*Cr]2(μ-Ph)(μ-
Et), a derivative of [Cp*Cr(μ-Et)]2 from its reaction with benzene
(Table 1).[7] Both the methylene and methyl carbon atoms are
slightly asymmetric with respect to the two metal centers (Table
1). A second structure with ethyl ligands bridging Cr centers,
[((tBu)NP(Ph)2N(tBu))Cr(μ-Et)]2,[9] however, shows a moderate
degree of asymmetry in the methylene carbon atoms with respect
to the metal centers, while the methyl carbon atoms are highly
asymmetric to the extent that one Cr···C(methyl) distance for
each metal is only ~ 0.5 Å greater than the sum of the covalent
radii of the individual atoms.[10] The final two reports show a cation,
{[(SIPr)Ag]2(μ-Et)}+, that has a highly symmetric ethyl bridge[11]
and an anion, {[Et2Zn]2(μ-Et)}–, whose disordered metal centers
prevented detailed discussion of bond lengths and angles.[12]
reaction
protocol
utilized
for
the
generation
of
[Mg(NMP)6][FeMe3]2, 5 equiv of EtMgBr was added dropwise to a
3 mM solution of 57Fe(acac)3 in 1:1 THF/2-MeTHF with 180 equiv
of NMP at –5 °C (consistent with Cahiez protocol ratio),[2] and the
reaction was freeze-trapped after 30 s. Note that a slightly
reduced reaction temperature is utilized for catalysis with b-
hydrogen containing nucleophiles than for MeMgBr. The 80 K
57Fe Mössbauer spectrum indicates the generation of one major
iron species (95% of total iron, blue component) with parameters
of δ = 0.19 mm/s and ΔEQ = 1.43 mm/s (Figure 2A). A minor
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in the presence of NMP. Unfortunately, no crystals suitable for
XRD could be obtained despite exhaustive crystallization efforts.
Having established that [FeEt3]– is the major iron species
formed in situ in the presence of NMP, it was critical to determine
if this species was reactive towards electrophiles to generate
cross-coupled product as previously demonstrated for
[Mg(NMP)6][FeMe3]2. Initial studies focused on reactions with β-
bromostyrene, previously shown to cross-couple with both
MeMgBr and EtMgBr in the presence of NMP.[2] [FeEt3]– was
o
generated in situ at –5 C (93 % of all iron, see SI) via the slow
addition of 20 equiv EtMgBr to Fe(acac)3 in the presence of 180
equiv of NMP, and subsequently reacted with 1 equiv of β-
bromostyrene. Chemical-quench GC analysis of the reaction
indicated that β-Et-styrene was obtained in 97% yield (with
respect to [FeEt3]–). It should be noted that the same distribution
of E- and Z-isomers are obtained in β-Et-styrene as present in the
β-bromostyrene. Lastly, note that [FeEt3]– is stable in solution at
–5 oC for > 5 min as determined by Mössbauer spectroscopy (see
SI), far exceeding its rate of reactivity with electrophile (≤ 10 s).
In contrast to reactions with β-bromostyrene, previous reports
from Fürstner and coworkers demonstrated a difference in
reactivity between methyl and ethyl Grignard reagents and less
activated aryl chloride electrophiles.[3] Therefore, we pursued
analogous reaction studies of [FeEt3]– and [FeMe3]– with Me-4-Cl-
benzoate. Generation of [FeEt3]– in situ using 4 or 20 equiv
EtMgBr/180 equiv NMP followed by reaction with 1 equiv of Me-
4-Cl-benzoate for 10 s led to the quantitative formation of cross-
coupled product with respect to [FeEt3]– as determined by
chemical quench GC analysis. Note that this reaction occurs at a
rate (kobs ≥ 6 min-1) consistent with the average turnover rate of
catalysis.[3c] By constrast, analogous reactions of in situ generated
[FeMe3]– (97 % of iron) with Me-4-Cl-benzoate did not yield
appreciable cross-coupled product by GC analysis, even at
extended reaction times (≤ 5% after 2 min). Lastly, note that
reaction of in situ generated [Fe8Et12]2– and [Fe8Me12]– with Me-4-
Cl-benzoate (–5 oC and RT, respectiviely) did not produce cross-
coupled products by GC analysis and instead yielded intractable
distributions of organic products.
Figure 2. Spectroscopic analyses of in situ formed iron speciation upon
reaction of Fe(acac)3 with EtMgBr in the presence of 180 equiv of NMP. (A)
80 K Mössbauer, (B) 5 K, 7 T near-infrared MCD spectrum and (C) 10K X-
band EPR spectrum of the freeze-trapped reaction 30 s after reaction of
Fe(acac)3 with 5 equiv EtMgBr. (D) Saturation magnetization data (dots) and
fit (lines) collected at 10020 cm-1. (*) indicates a minor spectral feature due
to decomposition (see SI).
component (5% of total iron, red component) is also present with
parameters of δ = –0.28 mm/s and ΔEQ = 0.73 mm/s, consistent
with a S = 3/2 signal observed by 10 K X-band electron
paramagnetic resonance (EPR) spectroscopy (g ~ 4.3, 2.0, ~ 5%
total iron in solution from spin quantitation) at the same time point.
Note that these parameters are analogous to those observed for
[Mg(NMP)6][FeMe3]2 generated under similar reaction conditions,
consistent with the formation of [FeEt3]–. To further support this
assignment, 5 K, 7 T near-infrared (NIR) MCD was utilized to
identify the major iron species in solution which displays two
intense ligand-field (LF) transitions at ≈ 10300 cm–1 and a
shoulder at ≈ 9200 cm–1 (Figure 2B). This result is consistent with
the presence of a high-spin, three-coordinate Fe(II)-alkyl species
analogous to [Mg(NMP)6][FeMe3]2.[4] Note that a very small
amount of decomposition occurs upon the prolonged handling
required for MCD sample preparation, as evidenced by the weak
positive feature at ≈ 10300 cm–1 (indicated by an asterisk, see SI).
Variable-temperature, variable-field MCD data collected at 10020
cm–1 is well-fit to S = 2 positive zero-field split (+ZFS) non-
Kramers doublet model (Figure 2D). The ground-state spin
Hamiltonian is described by D = 13.2 ± 2 cm–1,|E/D| = 0.04 ± 0.03,
gǁ = 8.0. Combined with the similar NIR MCD spectrum and 57Fe
Mössbauer parameters to that collected for [Mg(NMP)6][FeMe3]2,
these data unambiguously confirm that [FeEt3]– is the major iron
species formed in situ from the reaction of EtMgBr and Fe(acac)3
While these studies demonstrate the utility of [FeEt3]– in cross-
coupling, it was important to define the effects of Grignard addition
rate and temperature on the ability to favor formation of [FeEt3]–.
In terms of temperature, it is noteworthy that previously reported
catalytic protocols were performed at elevated temperatures, and
exotherms upon rapid addition of nucleophile have also been
observed.[15] As determined by Mössbauer spectroscopy (see SI),
the iron speciation in reactions involving the rapid vs. slow
addition (rate of addition: 20 equiv/s vs. 12 equiv/min) of 20 equiv
of EtMgBr to 57Fe(acac)3 with 180 equiv of NMP at –5 °C showed
similar distributions of iron species with the major species still
being [FeEt3]– (74% and 93% total iron, respectively). Even at
ambient temperature [FeEt3]– remains the major iron species in
situ for slow addition of EtMgBr. In fact, [FeEt3]– was found to be
relatively stable up to 5 min (see SI) in contrast to iron complexes
utilizing bis-phosphine ligands.[16] Overall, these observations
indicate that [FeEt3]– is accessible under a variety of reaction
conditions, implicating its potential role in cross-coupling across a
broader array of cross-coupling protocols.
Combined with prior studies of reactions of simple ferric salts
17]
and MeMgBr,[4-5,
the current study with EtMgBr enables a
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Conflicts of Interest
The authors declare no conflict of interest.
Keywords: homogeneous catalysis • iron • cross-coupling •
Grignard reagents
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S. M. Neumann, J. K. Kochi, J. Org. Chem. 1975, 40, 599-606; c) R. S.
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Goddard, C. W. Lehmann, J. Am. Chem. Soc. 2008, 130, 8773-8787.
S. B. Muñoz III, S. L. Daifuku, J. D. Sears, T. M. Baker, S. H. Carpenter,
W. W. Brennessel, M. L. Neidig, Angew. Chem. Int. Ed. 2018, 57, 6496-
6500.
[2]
[3]
[4]
[5]
a) S. B. Muñoz III, S. L. Daifuku, W. W. Brennessel, M. L. Neidig, J. Am.
Chem. Soc. 2016, 138, 7492-7495; b) S. H. Carpenter, T. M. Baker, S.
B. Muñoz III, W. W. Brennessel, M. L. Neidig, Chem. Sci. 2018, 9, 7931-
7939.
Scheme 2. Effect of b-hydrogens on the structure of iron-alkyl species in
reactions of simple ferric salts and alkyl Grignard reagents.
broader definition of the in situ species and reaction pathways for
cross-couplings with simple ferric salts and alkyl Grignards and
the effect of b-hydrogens. In both the presence and absence of
b-hydrogens, formally mixed valent iron-alkyl clusters are formed
(Scheme 2), however, the ethyl cluster is one electron more
reduced and exhibits significantly reduced thermally stability.
Importantly, the ability to access related clusters demonstrates
that similar iron species are accessbile even when b-hydrogens
are present, contrasting previous proposals of organoferrate
(MeMgBr) vs. reduced iron-magnesium clusters (EtMgBr).[3c]
Furthermore, the finding that generation of similar high-spin Fe(II)
species, [FeR3]– (R = Me or Et) in the presence of NMP which
rapidly react with electrophile to form cross-coupled products is
highly consistent with these species being competent in catalysis.
However, only [FeEt3]– was found to be reactive with less
activated substrates such as Me-4-Cl-benzoate, while
organoferrate species generated from MeMgBr have significantly
diminished reactivity with less activated substrates, such as aryl
chlorides.
[6]
a) T. N. Gieshoff, U. Chakraborty, M. Villa, A. Jacobi von Wangelin,
Angew. Chem. 2017, 129, 3639-3643; b) T. N. Gieshoff, U. Chakraborty,
M. Villa, A. Jacobi von Wangelin, Angew. Chem. Int. Ed. 2017, 56, 3585-
3589.
[7]
[8]
[9]
R. A. Heintz, R. L. Ostrander, A. L. Rheingold, K. H. Theopold, J. Am.
Chem. Soc. 1994, 116, 11387-11396.
C. R. Groom, I. J. Bruno, M. P. Lightfoot, S. C. Ward, Acta Crystallogr.
Sect. B: Struct. Sci. 2016, 72, 171-179.
K. Albahily, V. Fomitcheva, Y. Shaikh, E. Sebastiao, S. I. Gorelsky, S.
Gambarotta, I. Korobkov, R. Duchateau, Organometallics 2011, 30,
4201-4210.
[10] B. Cordero, V. Gómez, A. E. Platero-Prats, M. Revés, J. Echeverría, E.
Cremades, F. Barragán, S. Alvarez, Dalton Trans. 2008, 2832-2838.
[11] B. K. Tate, A. J. Jordan, J. Bacsa, J. P. Sadighi, Organometallics 2017,
36, 964-974.
[12] D. R. Armstrong, W. Clegg, P. García-Alvarez, M. D. McCall, L. Nuttall,
A. R. Kennedy, L. Russo, E. Hevia, Chem. Eur. J. 2011, 17, 4470-4479.
[13] G. Seidel, D. Laurich, A. Fürstner, J. Org. Chem. 2004, 69, 3950-3952.
[14] A. Piontek, E. Bisz, M. Szostak, Angew. Chem. Int. Ed. 2018, 57, 11116-
11128.
[15] a) B. Scheiper, M. Bonnekessel, H. Krause, A. Fürstner, J. Org. Chem.
2004, 69, 3943-3949; b) S. Gangula, U. K. Neelam, S. R. Baddam, V. H.
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[16] A. Casitas, H. Krause, R. Goddard, A. Fürstner, Angew. Chem. Int. Ed.
2015, 54, 1521-1526.
In summary, the current study has evaluated iron speciation
in reactions of simple ferric salts and EtMgBr. Analogous iron
species were found to be accessible both in the absence and
presence of NMP as observed in previous studies involving
[17] M. H. Al-Afyouni, K. L. Fillman, W. W. Brennessel, M. L. Neidig, J. Am.
Chem. Soc. 2014, 136, 15457-15460.
MeMgBr.[4-5]
Furthermore, [FeEt3]– is found to be highly
competent for cross-coupled product formation with alkenyl and
aryl halide electrophiles. Importantly, these studies demonstrate
that highly reduced Fe(–II) species are not required for successful
cross-coupling in the presence of NMP. However, reduced iron
species might be important in alternative reaction protocols with
b-hydrogen containing nucleophiles and will be the focus of future
studies in this area.
Acknowledgements
This work was supported by a grant from the National Institutes of
Health (R01GM111480 to M.L.N.) and a Ruth L. Kirchstein
National Research Service award (F32GM120823 to S.B.M. III).
The NSF is gratefully acknowledged for support for the acquisition
of an X-ray diffractometer (CHE-1725028).
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10.1002/anie.201813578
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COMMUNICATION
Jeffrey D. Sears,† Salvador B. Muñoz III,†
Stephanie L. Daifuku, Ari A. Shaps,
Stephanie H. Carpenter, William W.
Brennessel and Michael L. Neidig*
Page No. – Page No.
Effect of β-Hydrogens on Iron
Speciation in Cross-Couplings with
Simple Iron Salts and Alkyl Grignard
Reagents
The effects of b-hydrogen containing alkyl Grignard reagents in simple ferric salt
cross-coupling is presented. While [Fe8Et12]2– is formed upon reaction of simple ferric
salts and EtMgBr in THF, the addition of NMP leads to the formation of [FeEt3]–.
Overall, these studies demonstrate that similar iron species are accessible for alkyl
Grignard reagents containing or lacking β-hydrogens.
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