Oxidative Addition of Aryl and Alkyl Halides to a Reduced Iron Pincer Complex

Article abstract of DOI:10.1021/jacs.1c01486

The two-electron oxidative addition of aryl and alkyl halides to a reduced iron dinitrogen complex with a strong-field tridentate pincer ligand has been demonstrated. Addition of iodobenzene or bromobenzene to (3,5-Me2MesCNC)Fe(N2)2 (3,5-Me2MesCNC = 2,6-(2,4,6-Me-C6H2-imidazol-2-ylidene)2-3,5-Me2-pyridine) resulted in rapid oxidative addition and formation of the diamagnetic, octahedral Fe(II) products (3,5-Me2MesCNC)Fe(Ph)(N2)(X), where X = I or Br. Competition experiments established the relative rate of oxidative addition of aryl halides as I > Br > Cl. A linear free energy of relative reaction rates of electronically differentiated aryl bromides (ρ = 1.5) was consistent with a concerted-type pathway. The oxidative addition of alkyl halides such as methyl-, isobutyl-, or neopentyl halides was also rapid at room temperature, but substrates with more accessible β-hydrogen positions (e.g., 1-bromobutane) underwent subsequent β-hydride elimination. Cyclization of an alkyl halide containing a radical clock and epimerization of neohexyl iodide-d2 upon oxidative addition to (3,5-Me2MesCNC)Fe(N2)2 are consistent with radical intermediates during C(sp3)-X bond cleavage. Importantly, while C(sp2)-X and C(sp3)-X oxidative addition produces net two-electron chemistry, the preferred pathway for obtaining the products is concerted and stepwise, respectively.

Full text of DOI:10.1021/jacs.1c01486

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Oxidative Addition of Aryl and Alkyl Halides to a Reduced Iron
Pincer Complex
Stephan M. Rummelt, Paul O. Peterson, Hongyu Zhong, and Paul J. Chirik*
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ABSTRACT: The two-electron oxidative addition of aryl and alkyl
halides to a reduced iron dinitrogen complex with a strong-field
tridentate pincer ligand has been demonstrated. Addition of iodobenzene
or bromobenzene to (3,5-Me2MesCNC)Fe(N2)2 (3,5-Me2MesCNC = 2,6-
(2,4,6-Me-C6H2-imidazol-2-ylidene)2-3,5-Me2-pyridine) resulted in rapid
oxidative addition and formation of the diamagnetic, octahedral Fe(II)
products (3,5-Me2MesCNC)Fe(Ph)(N2)(X), where X = I or Br.
Competition experiments established the relative rate of oxidative
addition of aryl halides as I > Br > Cl. A linear free energy of relative
reaction rates of electronically differentiated aryl bromides (ρ = 1.5) was consistent with a concerted-type pathway. The oxidative
addition of alkyl halides such as methyl-, isobutyl-, or neopentyl halides was also rapid at room temperature, but substrates with more
accessible β-hydrogen positions (e.g., 1-bromobutane) underwent subsequent β-hydride elimination. Cyclization of an alkyl halide
containing a radical clock and epimerization of neohexyl iodide-d2 upon oxidative addition to (3,5-Me2MesCNC)Fe(N2)2 are
consistent with radical intermediates during C(sp3)−X bond cleavage. Importantly, while C(sp2)−X and C(sp3)−X oxidative
addition produces net two-electron chemistry, the preferred pathway for obtaining the products is concerted and stepwise,
respectively.
activation.19 As a consequence, the activation of the electro-
phile occurs with a more oxidized iron intermediate and likely
does not occur in a discrete two-electron fashion in analogy to
palladium or nickel examples. In addition, it remains an open
question whether a molecular iron intermediate forms that
contains iron−carbon bonds from both the nucleophilic and
electrophilic partners.
One of the seminal and most prominent iron-catalyzed
cross-coupling procedures was reported by Nakamura and co-
workers and involves combination of alkyl halides with aryl
boronates activated with Grignard reagents or alkyl lithium
reagents in the presence of an iron(II) precursor with a
bis(phosphine) ligand.20,21 Subsequent, in-depth spectroscopic
and mechanistic studies by Neidig and co-workers22,23 support
a pathway involving halide-atom abstraction from the electro-
phile by a bis(phosphine)-ligated Fe(II)−aryl complex
followed by C−C bond formation by capture of the alkyl
radical by the resulting Fe(III) aryl complex (Scheme 1a).
Similar catalytic24−27 and stoichiometric28,29 chemistry has
also been reported with N-heterocyclic carbene (NHC)
INTRODUCTION
The oxidative addition of both polar and nonpolar bonds by
reduced transition metal complexes is a fundamental organo-
■
metallic transformation and key substrate activation step in
many catalytic cycles.1−4 Among the most prominent is the net
two-electron oxidative addition of carbon−halogen bonds
invoked in palladium-5 and nickel-catalyzed cross-coupling
reactions.6−8 The impact of these reactions cannot be
overstated, as transition-metal catalyzed cross-coupling reac-
tions are among the most widely utilized carbon−carbon bond
forming reactions in synthetic chemistry. Not only are more
than half of all carbon−carbon bonds in medicinal chemistry
formed using these methods,9,10 but they are also widely
employed in large-scale reactions and in commercial
contexts.11
Due to the high terrestrial abundance, comparatively low
cost and toxicity of iron, there has been a growing interest in
developing iron-catalyzed cross coupling reactions in both
academia and industry.12−14 Building on early examples,15,16
several successful protocols for iron-catalyzed cross-coupling
have been developed in the past two decades.17,18 These
methods are mechanistically distinct from traditional palla-
dium- and nickel-catalyzed cross-coupling reactions and do not
proceed through the same types of intermediates. While iron-
catalyzed cross-coupling reactions are mechanistically diverse
and much remains to be learned, a general feature is that
transmetalation with typically strongly nucleophilic organo-
metallic reagents takes place prior to carbon−halide bond
Received: February 6, 2021
Published: April 8, 2021
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© 2021 American Chemical Society
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addition of the C−C bond, forming a metallacycle.43 The
addition of aryl or alkyl halides to reduced iron or cobalt
complexes often leads to halogen abstraction yielding the
corresponding one-electron oxidized metal complex and an
organic radical (Scheme 1c).20,44−48 An alternative possibility
is that the two-electron oxidative addition product forms
initially but is unstable toward comproportionation.49 While
there is some precedent that certain strong field ligands such as
CO enable the formal two electron oxidative addition of alkyl
iodides to iron,50−52 the only successful isolations of an iron
aryl halide complex rely on the stabilizing effect of directing
groups in the position ortho to the halide.53,54
Scheme 1. Overview of Aryl and Alkyl Halide Oxidative
Addition to Iron Complexes
The design of reduced iron complexes capable of two-
electron oxidative addition of aryl and alkyl halides has been a
long-standing challenge but, if successful, will likely open new
opportunities for iron-catalyzed reactions. As a general
strategy, two-electron oxidative addition to first-row transition
metals may be favored by introduction of a strong ligand field
around the metal center to increase d-orbital splitting and
minimize one-electron processes.2,3 Pincer ligands with
strongly σ-donating phosphines or N-heterocyclic carbenes
are a privileged ligand class for this task, enabling several iron-
and cobalt-catalyzed processes that involve two-electron
oxidative addition of nonpolar bonds.2
Reduced iron complexes supported by bis(imidazol-2-
ylidene)pyridine (CNC) ligands, originally synthesized by
Danopoulos and co-workers,55 have been reported to promote
the oxidative addition of C−H,56 H−H,57 and Si−H58 bonds
and are among the most active first row transition metal
catalysts for the hydrogenation of sterically hindered olefins59
and hydrogen isotope exchange reactions with arenes involving
C−H activation.60,61 The resulting oxidative addition products
as well as [(CNC)Fe] dialkyl compounds62 are isolable,
octahedral, low-spin, S = 0 complexes. Additionally, (CNC)-
Fe(N2)2 derivatives have two labile ligands, potentially
enabling facile generation of 14-electron complexes, which
are a prerequisite for Pd(0) complexes to engage in concerted
oxidative addition of aryl halides.63−66 These characteristics
make (CNC)Fe(N2)2 complexes attractive candidates for the
study of the oxidative addition of aryl and alkyl halides. Here
we describe successful demonstration of the net two-electron
oxidative addition of aryl and alkyl halides to a bis-
(arylimidazol-2-ylidene)pyridine iron dinitrogen complex and
study the mechanism through a combination of competition
experiments, radical clock reactions, and stereochemical probes
(Scheme 1c).
stabilized iron complexes. While reactions with bis(phosphine)
or NHC-supported iron precatalysts are typically limited to
alkyl halide electrophiles, Bedford and co-workers recently
disclosed that aryl halides with an N-pyrrole amide directing
group ortho to the C−X bond engaged in iron-catalyzed cross-
coupling.30 Details on the nature of the C−X activation step
operative during catalysis were not reported.
While early examples of polar oxidative additions featured
anionic supernucleophilic organometallic iron complexes such
as [(η5-C5H5)Fe(CO)2]− and [Fe(CO)4]2− (Scheme 1b),31
direct observation of the oxidative addition of alkyl- and aryl-
halides to reduced iron complexes has remained rare and the
mechanisms are poorly understood. In the course of
investigations of an iron-catalyzed cross-coupling reaction
between alkyl- or electron poor aryl-halides and Grignard
RESULTS AND DISCUSSION
■
Our initial studies focused on the oxidative addition of
essentially unfunctionalized aryl halides to (3,5-Me2MesCNC)-
Fe(N2)2 (1-(N2)2, 3,5-Me2MesCNC = 2,6-(2,4,6-Me3-C6H2-
imidazolin-2-ylidene)2-3,5-Me2-pyridine), a readily synthesized
variant of (CNC)Fe(N2)2 complexes62 where the 3,5-methyl
groups on the central pyridine increase the electron donation
of the pincer. Addition of 1 equiv of bromobenzene to a
toluene solution of 1-(N2)2 resulted in the precipitation of a
diamagnetic red-brown solid, isolated by filtration in 79% yield,
identified as the two-electron oxidative addition product (3,5-
Me2MesCNC)FePh(N2)Br (1-Ph(N2)Br) (Scheme 2). In a
similar manner, (3,5-Me2MesCNC)FePh(N2)I (1-Ph(N2)I)
was isolated as a brown-red and diamagnetic solid in 59%
yield following addition of iodobenzene to 1-(N2)2. The
analogous reaction with PhCl and 1-(N2)2 was sluggish, and
reagents,32−34 Fu
̈
rstner and co-workers proposed that reaction
of an iron salt with the Grignard reagent forms the active iron
alkyl or aryl intermediate which then undergoes reaction with
the carbon−halogen bond.35−38 It was also reported that
negatively charged iron ate-complexes underwent net two-
electron reactions with aryl halides in a nucleophilic displace-
ment-type reaction (Scheme 1b).38 Related studies with alkyl
halides supported a radical pathway en route to the observed
products.39,40
While iron and cobalt complexes bearing redox-active
pyridine(diimine) ligands have exhibited a rich catalytic
chemistry,2,41,42 observation of well-defined oxidative addition
reactions is rare. Addition of biphenylene to the iron
dinitrogen complex, (iPrPDI)Fe(N2)2, resulted in oxidative
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Scheme 2. Oxidative Addition of Phenyl Halides to 1-(N2)2
although (3,5-Me2MesCNC)FePh(N2)Cl was generated, other
unidentified products were detected.
The benzene-d6 1H NMR spectrum of 1-Ph(N2)Br exhibits
four signals for the methyl groups of the CNC-chelate between
1.4 and 2.9 ppm, establishing inequivalent methyl groups on
the aryl rings of the pincer and an overall Cs-symmetric iron
compound. The signals corresponding to the phenyl group
were located between 6.4 and 6.7 ppm while the carbon of the
phenyl group directly attached to the iron center appears at
165.5 ppm in the 13C NMR spectrum. The carbene carbons of
the CNC chelate were located at 219.4 ppm, comparable to
other (CNC)Fe complexes.62 The 1H and 13C NMR spectra of
1-Ph(N2)I exhibit similar features. The benzene solution IR
spectra of 1-Ph(N2)Br and 1-Ph(N2)I display bands at 2139
and 2134 cm−1 respectively, corroborating dinitrogen coordi-
nation. While attempts to obtain single crystals of 1-Ph(N2)Br
produced poorly diffracting samples, slow diffusion of pentane
into a concentrated toluene solution of 1-Ph(N2)I at −35 °C
yielded single crystals suitable for X-ray diffraction. The solid-
state structure exhibits an idealized octahedral geometry
around the iron center with the iodide (Fe−I = 2.7195(5)
Å) and phenyl ligand (Fe−C32 = 1.993(4) Å) in a trans
arrangement (C32−Fe−I = 179.08(4)°, Figure 1a). The sixth
coordination site trans to the pyridine of the CNC-chelate is
occupied by the dinitrogen ligand. The same spatial arrange-
ment of two trans X-type and one L-type ligand has been
previously observed with (CNC)Fe dialkyl and dihydride
complexes.62 The plane of the phenyl ligand is parallel to
mesityl substituents on the CNC-ligand, likely minimizing
Figure 1. (a) Solid-state molecular structure of (3,5-Me2MesCNC)-
FePh(N2)I at 30% probability ellipsoids. Hydrogen atoms and one
mesityl group of the CNC-chelate are omitted for clarity. (b and c)
Solid-state, zero-field Fe Moßbauer spectra of (3,5-Me2MesCNC)-
57
̈
FePh(N2)I and (3,5-Me2MesCNC)FePh(N2)Br, respectively at 80 K.
Simulated parameters (blue lines) are (b) δ = 0.15 mm/s, |ΔEQ| =
1.72 mm/s; (c) δ = 0.16 mm/s, |ΔEQ| = 1.77 mm/s.
Scheme 3. Oxidative Addition of 2-Halo-6-methylpyridines
to (3,5-Me2MesCNC)Fe(N2)2
steric interactions.
Zero-field Fe Moßbauer spectra of 1-Ph(N2)Br and 1-
57
̈
Ph(N2)I recorded at 80 K exhibits doublets with isomer shifts
of δ = 0.16 mm/s and δ = 0.15 mm/s respectively with
quadrupole splittings of |ΔEQ| = 1.77 mm/s and |ΔEQ| = 1.72
mm/s, consistent with the observed diamagnetism and low-
spin iron(II) complexes (Figure 1b, c).67 The weaker ligand
field imparted by the halide results only in a slightly higher
isomer shift than the value reported for (3,5-Me2MesCNC)Fe-
(CH2SiMe3)2(N2) (δ = 0.11 mm/s)62 but does not change the
overall spin state of the complex. The absence of detectable
signals corresponding to the pyridyl group were assigned to the
two doublets at 6.04 and 5.55 ppm (the third resonance is
overlapping), with the 6-methyl group located at 1.60 ppm. In
contrast to 1-Ph(N2)Br, no NN band was observed in the
57
̈
benzene-d6 infrared spectrum. The zero-field Fe Moßbauer
quantities of (CNC)FeX2 (X = Br or I)68 in the Moßbauer
spectrum of 1-(MePy)Br exhibits a doublet at δ = 0.16 mm/s
with a quadrupole splitting of |ΔEQ| = 2.26 mm/s. Although
the quadrupole splitting is slightly higher compared to 1-
Ph(N2)Br and 1-Ph(N2)I, it remains consistent with an
idealized, low-spin iron(II) center, as a potential 5-coordinate
compound is expected to have a much higher |ΔEQ| value.67
The structure of 1-(MePy)Br is therefore assigned in analogy
to 1-Ph(N2)I with the coordination site trans to the pyridine of
the CNC-chelate occupied by the N atom of the 6-
methylpyridin-2-yl ligand. Addition of 2-chloro- and 2-iodo-
̈
spectra is noteworthy, as these products are typically formed
from halogen atom abstraction pathways common with iron.48
Given the importance of heteroarenes in cross-coupling
reactions,9 2-bromo-6-methylpyridine was added to a toluene
solution of 1-(N2)2 and a green solid identified as (3,5-
Me2MesCNC)Fe(6-Me pyridin-2-yl)Br (1-(MePy)Br) was
isolated in 79% yield (Scheme 3). The benzene-d6 1H NMR
spectrum of 1-(MePy)Br is consistent with a Cs symmetric
iron compound exhibiting similar features to 1-Ph(N2)Br. The
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6-methylpyridine to benzene-d6 solutions of 1-(N2)2 generated
the corresponding two-electron oxidative addition products
(3,5-Me2MesCNC)Fe(6-Me pyridin-2-yl)Cl (1-(MePy)Cl) and
(3,5-Me2MesCNC)Fe(6-Me pyridin-2-yl)I (1-(MePy)I).
To establish the relative reactivity of different aryl halides,
competition experiments were conducted: 1 equiv of both
bromo- and iodobenzene were added to 1-(N2)2 at ambient
temperature. Because the two products, 1-Ph(N2)Br and 1-
Ph(N2)I, have different and relatively low solubility in
1
benzene-d6 and peaks in the respective H NMR spectra are
overlapping, NMR spectroscopy was not used for analysis. The
relative conversion was determined by GC analysis of the
supernatant solution following precipitation of the iron
complexes by the addition of pentane. In this manner, a
reactivity ratio of conversionPhI/conversionPhBr = 4/1 was
determined. This reactivity trend of oxidative addition on the
dependence of the identity of the halide is the same observed
with similar experiments using palladium69,70 although one-
electron pathways often show the same trend.1
Electronic effects were also evaluated for the oxidative
addition of C−X bonds with 1-(N2)2. Relatively electron-poor
1-bromo-4-(trifluoromethyl)benzene underwent clean reaction
with 1-(N2)2 to yield the two-electron oxidative addition
product, (3,5-Me2MesCNC)Fe(C6H4CF3)(N2)Br (1-
(C6H4CF3)(N2)Br), as a diamagnetic brown-red solid in
73% yield (Scheme 4). Likewise, (3,5-Me2MesCNC)Fe-
Figure 2. (a) Competition experiments between electronically
differentiated aryl halides, (b) relative conversions and rate constants,
and (c) Hammett plot showing the effect of aryl halide substitution
on rate, modeled with COPASI.
benzene at ambient temperature yielded a mixture of two (3,5-
Me2MesCNC)Fe(aryl)(N2)Br complexes that were precipitated
by the addition of pentane. The relative conversions of the aryl
bromides established by quantitative GC-analysis of the
supernatant are reported in Figure 2b. In general, electron-
poor aryl bromides reacted faster than the electron-rich,
consistent with a buildup of negative charge on the aromatic
ring during the transition state for C−X oxidative addition, a
trend generally observed for the oxidative addition of aryl
halides to group 10 transition metals.64,69−74
Scheme 4. Oxidative Addition of 4-Substituted Aryl Halides
to (3,5-Me2MesCNC)Fe(N2)2
Taking the relative conversions as an approximation for the
relative rate of reaction, a Hammett plot was generated by
correlating log(conversionR/conversionH) with the sigma
values75 of the substituents in the 4-position of the aryl
bromide. The linear regression generated from this data
produced a slope of ρ = 1.0. For a more accurate value for ρ,
which is not subject to varying concentrations of the aryl
halides during the reaction, the relative conversions were fit
against krel = kR1/kR2 using a reaction model assuming two
competing second-order reactions which are both first-order
dependent on iron and the aryl halide (Figure 2b; see
Supporting Information (SI) for details). By employing the so
obtained numbers for krel, a ρ value of ρ = 1.5 was obtained
(Figure 2c), slightly higher than ρ = 1.0 derived from the
relative conversions.
Relative reaction rates of electronically differentiated aryl
halides and the corresponding Hammett plots have been
previously used to inform on the mechanism of oxidative
addition with palladium and nickel.64,72−74 While oxidative
addition reactions with small positive ρ values of ρ = ca. 2 are
generally considered to proceed through a concerted transition
state,64,73 more charge buildup on the arene and therefore
higher ρ values of ρ = ca. 4 are observed for reactions
proceeding by SnAr70,74 or SET72 mechanisms. While certainly
not conclusive, the comparatively small positive ρ value of ρ =
1.5 for the presented oxidative addition to iron indicates a
small charge buildup on the aryl ring during the transition state
and a more concerted reaction.
(C6H4OMe)(N2)Br (1-(C6H4OMe)(N2)Br) was isolated in
67% yield from addition of the more electron-rich 1-bromo-4-
methoxybenzene to 1-(N2)2. Both complexes exhibit features
in the 1H and 13C NMR spectra similar to parent 1-Ph(N2)Br
and were therefore assigned to have the same geometry around
the iron center and spin state as 1-Ph(N2)Br. Accordingly, the
benzene solution infrared spectrum of 1-(C6H4CF3)(N2)Br
exhibited a strong NN band at 2141 cm−1. The analogous
spectrum of 1-(C6H4OMe)(N2)Br surprisingly exhibited two
NN bands at 2117 and 2136 cm−1. Because only one iron
product was observed by NMR spectroscopy, it is likely that
two different conformers or isomers rapidly interconvert on the
time scale of the experiment but are resolved by infrared
spectroscopy. Given the variance in the stretching frequencies,
the two isomers are likely differentiated by the ligand trans to
the N2 ligand.
Having established the tolerance of the iron-promoted
oxidative addition with bromobenzene with electron-donating
and -withdrawing groups, the relative rates of reaction of
electronically differentiated aryl bromides were determined by
competition experiments (Figure 2). Treatment of 1 equiv of
1-(N2)2 with 1 equiv of each of the two aryl bromides in
Oxidative Addition of Alkyl Halides. The oxidative
addition of alkyl halides to 1-(N2)2 was also explored to
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establish the generality of the iron-promoted reaction.
Treatment of a toluene solution of 1-(N2)2 with methyl
iodide resulted in an immediate color change from brown to
bright green, and following filtration, a diamagnetic, green solid
identified as the corresponding two-electron oxidative addition
product (3,5-Me2MesCNC)Fe(Me)(N2)(I) (1-Me(N2)I) was
slightly longer iron−carbon bond to the methyl group (Fe−
C32 = 2.237(10) Å). The iodine and methyl ligands are both
slightly bent toward the CNC chelate producing a C32−Fe−I
angle of 170.0(2)°. IR spectroscopy confirmed N2 coordina-
tion in solution (νN2(benzene-d6) = 2127 cm−1), and zero-field
57
̈
Fe Moßbauer parameters (δ = 0.19 mm/s, |ΔEQ| = 1.90 mm/
1
isolated in 84% yield (Scheme 5). The H NMR spectrum
s, Figure 3b) are consistent with a low-spin, octahedral iron(II)
complex.67
Scheme 5. Oxidative Addition of Alkyl Iodides to (3,5-
Me2MesCNC)Fe(N2)2
Analogous reactivity was observed with isobutyl iodide
(Scheme 5), resulting in the isolation of a green, diamagnetic
solid in 69% yield identified as (3,5-Me2MesCNC)Fe(isobutyl)-
(N2)(I) (1-iBu(N2)I) using a combination of NMR, IR
(νN2(benzene-d6) = 2130 cm−1), and zero-field 57Fe Moßbauer
̈
(δ = 0.20 mm/s, |ΔEQ| = 1.96 mm/s, Figure 3c) spectros-
copies. An iron compound with nearly identical features in the
1H NMR spectrum was detected as the sole organometallic
product when isobutyl bromide was used, which was assigned
accordingly as (3,5-Me2MesCNC)Fe(isobutyl)(N2)(Br) (1-
iBu(N2)Br). The stability of isolable 1-iBu(N2)I is noteworthy
as the alkyl ligand contains β-hydrogens potentially accessible
for elimination. Heating a sample of the compound in
benzene-d6 to 60 °C resulted in generation of isobutylene
and a new, diamagnetic iron product (Scheme 6a). A Cs
exhibits features similar to the aryl halide oxidative addition
products, again consistent with a Cs symmetric iron compound.
A diagnostic feature in the spectrum was the signal at −1.28
ppm, assigned as the methyl group bound to the iron.
The solid-state structure of 1-Me(N2)I was determined by
X-ray diffraction on single crystals obtained from a
concentrated toluene solution of 1-Me(N2)I stored at −35
°C (Figure 3a). An idealized octahedral coordination geometry
was observed about iron and is analogous to 1-Ph(N2)I with a
Scheme 6. β-Hydride Elimination from (3,5-
Me2MesCNC)Fe(alkyl)(N2)I Complexes
1
symmetric iron product was observed by H NMR spectros-
copy with a high field signal at −19.54 ppm diagnostic of an
iron hydride.59 The iron product, assigned as (3,5-
Me2MesCNC)Fe(H)(N2)(I) (1-H(N2)I), was also generated
by exposure of a benzene-d6 solution of 1-iBu(N2)I to 1 atm of
H2 with attendant formation of isobutane, and subsequently
isolated in 68% yield as a red solid.
Iron alkyl complexes with more sterically accessible
hydrogens in the β-position of the alkyl ligand proved
kinetically unstable. For example, addition of 1-bromobutane
to a benzene-d6 solution of 1-(N2)2 resulted in a 78:22 ratio of
trans to cis-2-butene, along with a Cs symmetric iron
Figure 3. (a) Solid-state molecular structure of (3,5-Me2MesCNC)-
FeMe(N2)I at 30% probability ellipsoids. Hydrogen atoms and a
1
compound with a H NMR signal at −21.71 ppm assigned
mesityl group of the CNC-chelate are omitted for clarity. (b and c)
as (3,5-Me2MesCNC)Fe(H)(N2)(Br) (1-H(N2)Br) (Scheme
6b). It is likely that this iron product arises from oxidative
addition of the alkyl halide to 1-(N2)2 to form the unobserved
n-butyl iron complex that undergoes rapid β-hydride
Solid-state, zero-field Fe Moßbauer spectra of (3,5-Me2MesCNC)-
57
̈
Fe(Me)(N2)I and (3,5-Me2MesCNC)Fe(isobutyl)(N2)I respectively at
80 K. Simulated parameters (blue lines) are (b) δ = 0.19 mm/s, |ΔEQ|
= 1.90 mm/s; (c) δ = 0.20 mm/s, |ΔEQ| = 1.96 mm/s.
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elimination to produce 1-butene and (1-H(N2)Br). Subse-
quent isomerization generates the observed internal olefins. To
determine if (1-H(N2)Br) was competent for the isomer-
ization of 1-butene to trans- and cis-2-butene, (1-H(N2)Br)
was independently prepared and 5 equiv of 1-butene were
added. The same ratio of trans- and cis-2-butene was observed
as judged by 1H NMR spectroscopy. Addition of 2-
bromobutane to a benzene-d6 solution of 1-(N2)2 also
produced 1-H(N2)Br and the same equilibrium mixture of
trans- and cis-2-butene, as judged by analysis of the volatile
Scheme 8. Oxidative Addition of an Alkyl Halide
Containing a Radical Clock to (3,5-Me2MesCNC)Fe(N2)2
1
components by H NMR spectroscopy. This type of reactivity
was consistent among secondary alkyl halides as addition of
bromocycloxane to a benzene-d6 solution of 1-(N2)2 yielded 1-
H(N2)Br in 86% yield along with cyclohexene, as judged by
1H NMR spectroscopy.
Treatment of a benzene-d6 solution of 1-(N2)2 with tert-
butyl bromide resulted in the exclusive formation of 1-
1
iBu(N2)Br by H NMR spectroscopy, through rearrangement
of the alkyl ligand (Scheme 7). Similar reactivity was observed
previously with iron46 and cobalt44 complexes arising from a
chain walking mechanism by β-hydride elimination and
reinsertion44 or radical pathways.46
a radical followed by rapid cyclization and capture by the iron
complex. An alternative pathway, however, is two-electron
oxidative addition followed by insertion to form the C−C
bond. To assess the feasibility of this latter pathway, 1-H(N2)I
was treated with 1,5-hexadiene in benzene-d6 at room
temperature, resulting in a color change from brown to
Scheme 7. Oxidative Addition of tert-Butyl Bromide to (3,5-
Me2MesCNC)Fe(N2)2
1
green. The H NMR spectrum of the iron product following
addition is consistent with formation of an olefin insertion
product in equilibrium with 1-H(N2)I (Scheme 8b; see SI for
details). Formation of 1-cyclopentylmethyl(N2)I was not
observed under these conditions as judged by 1H NMR
spectroscopy. Exposure of this mixture to 1 atm of H2 resulted
in formation of 1-H(N2)I and n-hexane as the major organic
product without any evidence for methylcyclopentane
formation. Therefore, a two-electron oxidative addition of 6-
iodo-1-hexene to 1-(N2)2 followed by migratory insertion is
unlikely to account for the observed cyclized product, and the
available data are more consistent with the intermediacy of
alkyl radicals.
The observed alkyl rearrangement from the oxidative
addition of tert-butyl bromide prompted a more thorough
investigation into the nature of the oxidative addition of alkyl
halides to 1-(N2)2 and more specifically the presence of alkyl
radical intermediates. Accordingly, oxidative addition of an
alkyl halide bearing a radical clock was conducted (Scheme
8).76 6-Iodo-1-hexene was selected, as this substrate has been
used previously in iron-catalyzed cross-coupling reactions to
support the intermediacy of alkyl radicals.22,27 Addition of 6-
iodo-1-hexene to a benzene-d6 solution of 1-(N2)2 resulted in a
color change from brown to green, and a green solid identified
as the cyclized product (3,5-Me2MesCNC)Fe(cyclopentyl-
methyl)(N2)(I) (1-cylcopentylmethyl(N2)I) was isolated in
78% yield (Scheme 8a). The benzene-d6 1H NMR spectrum of
1-cylcopentylmethyl(N2)I exhibited analogous features to the
product arising from the oxidative addition of iodomethyl-
cyclopentane with 1-(N2)2 under the same conditions. As an
additional mechanistic probe, treatment of 1-(N2)2 with
(bromomethyl)cyclopropane as a radical clock resulted in
formation of a mixture of iron-containing products as judged
The stereochemistry of alkyl halide oxidative addition to 1-
(N2)2 was also explored to provide additional mechanistic
insights. Deuterated neohexyl halide isotopologues have been
applied to determine the stereochemistry of oxidative addition,
as the H−H coupling constants are diagnostic for the presence
of the two possible diastereomers.77 Diastereomerically pure
threo-ICHDCHDC(CH3)3 was prepared by a modified
literature procedure using the hydrozirconation of neo-
hexene-d2 and subsequent treatment with iodine. The addition
of threo-ICHDCHDC(CH3)3 to a benzene-d6 solution of 1-
(N2)2 produced an immediate color change to green, and
subsequent analysis by 1H NMR spectroscopy established
formation of (3,5-Me2MesCNC)Fe(CHDCHDC(CH3)3)(N2)-
3
(I) (1-neohexyl(N2)I) (Scheme 9). However, the JH−H
1
by H NMR spectroscopy that upon treatment with H2 and
coupling of the neohexyl group was poorly resolved, likely
due to dynamic reversible N2 coordination. To eliminate the
dynamic process substitution of the labile N2 ligand with a
more substitutionally inert carbonyl group was carried out by
addition of 0.1 atm of CO to 1-neohexyl(N2)I. The resulting
iron carbonyl complex, (3,5-Me2MesCNC)Fe(CHDCHDC-
(CH3)3)(CO)(I) (1-neohexyl(CO)I), exhibited well-resolved
vacuum transfer of volatiles resulted in isolation of n-butane as
the sole detected organic product. This observation is
consistent with intermediate formation of the ring-opened
cyclopropyl product.
The observed iron product following reaction of 1-(N2)2
with 6-iodo-1-hexene is consistent with the initial generation of
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Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Despite the similarity in the iron products, radical clocks and
deuterium labeling experiments support a radical pathway for
C(sp3)−H oxidative addition and demonstrates that even
when alkyl radicals are intermediates, net two-electron
chemistry can result. Gaining a detailed understanding of
iron-mediated carbon−halogen bond activation adds impor-
tant fundamental insights for the development of iron catalysts
for cross-coupling by more traditional palladium-like pathways.
Scheme 9. Synthesis of Dideuterated threo-Neohexyl Iodide
and Oxidative Addition to (3,5-Me2MesCNC)Fe(N2)2
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c01486.
3JHH coupling in the neohexyl group and established formation
of a near-equimolar mixture of the threo and erythro
diastereomers. The observed scrambling of stereochemistry
supports a radical pathway for oxidative addition and is
inconsistent with SN2 or concerted pathways.
General considerations; preparation of transition metal
complexes; general procedures; spectroscopic and
crystallographic data (PDF)
Accession Codes
To further understand reactivity trends, the relative rates of
oxidative addition of various alkyl halides with 1-(N2)2 were
investigated. We note that measurement of absolute rate
constants and determination of overall reaction order have
been unsuccessful due to the fast rates of oxidative addition
even at cryogenic temperatures. Competition experiments
between 1.5 equiv each of isobutyl iodide and neopentyl iodide
to 1-(N2)2 resulted in a 4:1 ratio of the corresponding
oxidative addition products, 1-iBu(N2)I and (3,5-
Me2MesCNC)Fe(neopentyl)(N2)(I) (1-Np(N2)I), supporting
a possible steric effect on the rate of oxidative addition. The
relative rates of alkyl halide oxidative addition were also
sensitive to the identity of the halide. The series of neosilyl
halides, (CH3)3SiCH2X (X = I, Br, Cl), all underwent oxidative
CCDC 2061553−2061554 contain the supplementary crys-
tallographic 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 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
Paul J. Chirik − Department of Chemistry, Princeton
University, Princeton, New Jersey 08544, United States;
orcid.org/0000-0001-8473-2898; Email: pchirik@
princeton.edu
1
addition to 1-(N2)2 in benzene-d6 as judged by H NMR
Authors
spectroscopy. Related alkyl chlorides, including neopentyl
chloride, isobutyl chloride, and hexyl chloride, exhibited no
reaction even at elevated temperatures of 60 °C with 1-(N2)2.
When 1-(N2)2 was added to an equimolar mixture of neosilyl
chloride and neosilyl bromide, only the product arising from
oxidative addition of the latter, (3,5-Me2MesCNC)Fe(neosilyl)-
Stephan M. Rummelt − Department of Chemistry, Princeton
University, Princeton, New Jersey 08544, United States;
orcid.org/0000-0003-3996-0271
Paul O. Peterson − Department of Chemistry, Princeton
University, Princeton, New Jersey 08544, United States;
orcid.org/0000-0002-0602-2695
1
(N2)(Br), was observed by H NMR spectroscopy. Similarly,
Hongyu Zhong − Department of Chemistry, Princeton
University, Princeton, New Jersey 08544, United States;
orcid.org/0000-0002-6892-482X
when 1-(N2)2 was added to an equimolar mixture of neosilyl
bromide and neosilyl iodide, only the product from neosilyl
iodide oxidative addition, (3,5-Me2MesCNC)Fe(neosilyl)(N2)-
(I), was observed. These results establish the relative rates of
alkyl halide oxidative addition as I > Br > Cl.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c01486
CONCLUDING REMARKS
■
Funding
In summary, the two-electron oxidative addition of a variety of
aryl and alkyl halides to a reduced iron complex, 1-(N2)2, has
been demonstrated. Key to this reactivity is introduction of an
electron-donating pincer to generate a strong ligand field
around the iron favoring two-electron chemistry rather than
the atom abstraction pathways typically observed with iron.
Aryl iodides and bromides containing electron-donating and
-withdrawing functional groups were tolerated in these
reactions and generated two-electron oxidized, diamagnetic
Fe(II) aryl halide complexes. Linear free energy relationships
established minimal charge buildup on the arene in the
transition state, supporting a concerted pathway for C(sp2)−X
bond cleavage. Alkyl halides were also activated, again giving
rise to the two-electron oxidative addition iron products. If the
alkyl ligand contained β-hydrogens, elimination to the
corresponding Fe(II) hydride halide complexes was observed.
We thank the National Institutes of Health (R01 GM121441)
for financial support.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. István Pelczer (Princeton) for assistance with the
acquisition of H{2H} NMR data.
1
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