NHC and nucleophile chelation effects on reactive iron(II) species in alkyl-alkyl cross-coupling

Article abstract of DOI:10.1039/c7sc04750a

While iron-NHC catalysed cross-couplings have been shown to be effective for a wide variety of reactions (e.g. aryl-aryl, aryl-alkyl, alkyl-alkyl), the nature of the in situ formed and reactive iron species in effective catalytic systems remains largely undefined. In the current study, freeze-trapped M?ssbauer spectroscopy, and EPR studies combined with inorganic synthesis and reaction studies are utilised to define the key in situ formed and reactive iron-NHC species in the Kumada alkyl-alkyl cross-coupling of (2-(1,3-dioxan-2-yl)ethyl)magnesium bromide and 1-iodo-3-phenylpropane. The key reactive iron species formed in situ is identified as (IMes)Fe((1,3-dioxan-2-yl)ethyl)₂, whereas the S = 1/2 iron species previously identified in this chemistry is found to be only a very minor off-cycle species (<0.5% of all iron). Reaction and kinetic studies demonstrate that (IMes)Fe((1,3-dioxan-2-yl)ethyl)₂ is highly reactive towards the electrophile resulting in two turnovers with respect to iron (k_obs > 24 min^-1) to generate cross-coupled product with overall selectivity analogous to catalysis. The high resistance of this catalytic system to β-hydride elimination of the alkyl nucleophile is attributed to its chelation to iron through ligation of carbon and one oxygen of the acetal moiety of the nucleophile. In fact, alternative NHC ligands such as SIPr are less effective in catalysis due to their increased steric bulk inhibiting the ability of the alkyl ligands to chelate. Overall, this study identifies a novel alkyl chelation method to achieve effective alkyl-alkyl cross-coupling with iron(ii)-NHCs, provides direct structural insight into NHC effects on catalytic performance and extends the importance of iron(ii) reactive species in iron-catalysed cross-coupling.

Full text of DOI:10.1039/c7sc04750a

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NHC and nucleophile chelation effects on reactive iron(II) species
in alkyl-alkyl cross-coupling
Valerie E. Fleischauer,‡ Salvador B. Muñoz III,‡ Peter G. N. Neate, William W. Brennessel and
Michael L. Neidig*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
While iron-NHC catalysed cross-couplings have been shown to be effective for a wide variety of reactions (e.g. aryl-aryl, aryl-
alkyl, alkyl-alkyl), the nature of the in situ formed and reactive iron species in effective catalytic systems remains largely
undefined. In the current study, freeze-trapped Mössbauer spectroscopy, and EPR studies combined with inorganic
synthesis and reaction studies are utilised to define the key in situ formed and reactive iron-NHC species in the Kumada
alkyl-alkyl cross-coupling of (2-(1,3-dioxan-2-yl)ethyl)magnesium bromide and 1-iodo-3-phenylpropane. The key reactive
iron species formed in situ is identified as (IMes)Fe((1,3-dioxan-2-yl)ethyl)2, whereas the S = 1/2 iron species previously
identified in this chemistry is found to be only a very minor off-cycle species (< 0.5% of all iron). Reaction and kinetic studies
demonstrate that (IMes)Fe((1,3-dioxan-2-yl)ethyl)2 is highly reactive towards electrophile resulting in two turnovers with
respect to iron (kobs > 24 min-1) to generate cross-coupled product with overall selectivity analogous to catalysis. The high
resistance of this catalytic system to b-hydride elimination of the alkyl nucleophile is attributed to its chelation to iron
through ligation of carbon and one oxygen of the acetal moiety of the nucleophile. In fact, alternative NHC ligands such as
SIPr are less effective in catalysis due to their increased steric bulk inhibiting the ability of the alkyl ligands to chelate. Overall,
this study identifies a novel alkyl chelation method to achieve effective alkyl-alkyl cross-coupling with iron(II)-NHCs, provides
direct structural insight into NHC effects on catalytic performance and extends the importance of iron(II) reactive species in
iron-catalysed cross-coupling.
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Scheme 1 Examples of Iron-NHC Catalysed Cross-Coupling Reactions.
Introduction
Transition-metal-catalysed cross-coupling chemistry has solved
countless problems in total synthesis, pharmaceutical
chemistry, and the production of fine chemicals. Traditionally
these reactions have been carried out with precious metals, but
lower cost, low toxicity, and rich redox chemistry make iron-
catalysed C-C cross-coupling an attractive alternative.1-4
Towards this goal, systems using iron and N-heterocyclic
carbenes (NHCs) have been shown to facilitate a wide variety of
cross-coupling reactions5-7 including biaryl,8-11 alkyl-aryl,12-22
alkyl-alkyl,23 and aryl-alkenyl (Scheme 1).24 A key example is
early work by Bedford and co-workers which demonstrated the
use of monodentate NHCs in the catalytic cross coupling of aryl
Grignard reagents and alkyl halides in high yield using well-
defined iron-NHC complexes (Scheme 1d).25 Also of note is the
selective biaryl cross-coupling system using SIPr•HCl and
FeF3•3H2O developed by Nakamura and co-workers (Scheme
1b).8, 26 In this case, other NHC complexes and iron starting
materials resulted in poor yields of cross-coupled product with
the exception of FeCl3 in the presence of KF.
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Despite these recent advances in the development of spectroscopy allow for the quantification of iron species during
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effective iron-NHC systems for cross-coupling and isolation of catalysis.39 The combination of these techniques with inorganic
DOI: 10.1039/C7SC04750A
transmetalated iron-NHC’s,27, 28 active catalyst structure and synthesis, GC analysis, and density functional theory (DFT)
mechanism in these reactions remain poorly defined. In fact, investigations is a powerful method for identifying the active
the most detailed insight available to date on iron-NHCs for iron species in catalysis, providing insight into the mechanism of
cross-coupling has focused on stoichiometric reactions of well- catalysis and defining the role of reaction protocols in
defined iron-NHC complexes. For example, Deng and co- promoting high cross-coupling yields.
workers reported some of the first mechanistic investigations of
In the current study, this physical-inorganic approach has
iron catalysed cross-coupling reactions with NHCs.29-32 These identified the key in situ formed reactive iron(II)-NHC species in
studies included the synthesis of well-defined (NHC)2FeR2 (R = this alkyl-alkyl cross-coupling as (IMes)Fe((1,3-dioxan-2-
alkyl or aryl) complexes and reactivity of well-defined yl)ethyl)2. While a S = 1/2 iron species was previously proposed
(NHC)2Fe(aryl)2 complexes with alkyl halides, resulting in a as the reactive species in this chemistry, spin quantitated EPR
proposed iron(II/III) cycle with
a bis-arylated iron-NHC has shown that it is only present as < 0.5 % of all iron in solution
intermediate as the likely reactive species towards and represents an off-cycle species. In (IMes)Fe((1,3-dioxan-2-
electrophile.33 While these stoichiometric reactions provide yl)ethyl)2, the acetal moieties of the alkyls create two weakly
initial insight into the cross-coupling reactivity of well-defined coordinating metallacycles, protecting against
iron-NHCs, it is unclear if similar reactive species are formed in elimination. In turn, further studies provided direct structural
situ in effective catalytic reactions. insight into NHC effects on cross-coupling performance and
b-hydride
While studies across the breadth of iron-NHC catalysed explore alternative nucleophiles with potential chelating
cross-couplings are required to define the variation in iron-NHC substituents in order to broaden the accessible alkyl
active species that might exist, an important system for initial nucleophiles for effective cross-coupling.
investigation is the iron-NHC catalysed alkyl-alkyl cross-coupling
reaction reported by Cárdenas and co-workers due to the
challenges that exist for effective alkyl-alkyl cross-couplings.23
In this reaction, 1-iodo-3-phenylpropane iscoupled to an alkyl
Grignard reagent containing an acetal group using Fe(OAc)2 and
IMes•HCl with 75% product yield. In contrast to the use of NHC
ligands, Xantphos as a ligand system only results in 27% product
yield.23 This is a dramatic contrast to the other two existing
alkyl-alkyl cross-coupling systems with iron by Chai34 and
Nakamura35 where Xantphos is uniquely effective as a ligand
additive for the production of cross coupled product. . Based
upon GC monitoring of homocoupled nucleophile upon pre-
catalyst quenching, radical clock substrate experiments, and
electron paramagnetic resonance spectroscopy (EPR), Cárdenas
proposed an iron(I/III) catalytic cycle with an iron(I) active
species. While these initial mechanistic studies by Cárdenas
represent the most detailed study of a catalytic iron-NHC cross-
coupling system to date, several issues remain. For example, no
spin quantification of the EPR studies was reported, and it is
therefore unclear what amount of S = 1/2 iron is formed in situ.
Additionally, no direct structural evidence was provided in
support of the proposed catalytic cycle, nor was any direct
reactivity of a S = 1/2 species with electrophile evaluated to
determine if it reacts selectively or at a catalytically competent
rate. More studies are required to unambiguously determine
the nature of the key iron species in iron-NHC catalysed alkyl-
alkyl cross-coupling.
Experimental
General Considerations
All general experimental methods, NMR, characterisation
including collection and refinement of X-ray data, and synthesis
of alternative nucleophiles may be found in the ESI.
Preparation of (IMes)Fe((1,3-dioxan-2-yl)ethyl)2 (1)
To a 20 mL scintillation vial was added Fe(OAc)2 (75 mg, 0.43
mmol) and 1,3-dimesitylimidazolium chloride (150 mg, 0.44
mmol) along with a stir bar. To the solid mass was added (2-
(1,3-dioxan-2-yl)ethyl)magnesium bromide in THF (0.5 M, 0.86
mL, 0.43 mmol) dropwise while stirring at room temperature.
After 10 min an additional equivalent of the Grignard in THF (0.5
M, 0.86 mL, 0.43 mmol) was added to the tan slurry. A third
equivalent of Grignard in THF (0.5 M, 0.86 mL, 0.43 mmol) was
added to the yellow solution 10 minutes later. The final
equivalent of Grignard was added after 3 more minutes and the
yellow reaction mixture stirred at room temperature for 2 min
followed by cooling to -78 °C with continued stirring. The yellow
slurry was then warmed on a room temperature stir plate for
five min after which room temperature pentane (ca. 14 mL) was
added to the mixture and the vial cooled back to -78 °C. The
resulting solution was filtered through Celite (precooled to -78
°C) and the collected filtrate was stored at -80 °C for one week
rendering yellow crystals. Yellow crystals were carefully
selected at low temperature in batches from several reactions
with varying crystallisation yields. Evans method analysis of
Recently, our group has applied a series of inorganic
spectroscopic techniques to study the mechanism of iron-
bisphosphine catalysed cross coupling reactions involving the
coupling of alkyl electrophiles with aryl and alkynyl Grignard
reagents using FeCl2(SciOPP) as a pre-catalyst.36-38 Magnetic
circular dichroism (MCD), EPR, and Mössbauer spectroscopic
studies of freeze-trapped solutions of in situ generated iron
species were able to identify the catalytically active iron
complexes in these reactions. Importantly, EPR and Mössbauer
crystalline
1 redissolved in THF-d8 indicates μeff= 5.2(3) μb.
Elemental Anal. Calcd: C, 67.11; H, 7.85; N, 4.74. Found: C,
67.09; H, 8.023; N, 4.692.
Preparation of (IMes)FeBr((1,3-dioxan-2-yl)ethyl) (2) and
(IMes)FeBr2(THF) (3)
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To a solution of Fe(OAc)2 (80 mg, 0.46 mmol) and IMesHCl (346 Catalytic reaction solution samples for EPR spectroscopy were
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DOI: 10.1039/C7SC04750A
mg, 1.02 mmol) in THF was added (2-(1,3-dioxan-2- prepared directly from the reaction mixture as reported in the
yl)ethyl)magnesium bromide (0.5 M in THF, 0.39 mL, 1.94 literature23 under N2 atmosphere. In situ reaction samples were
mmol) at 55 ⁰C in THF and stirred 20 min. The yellow solution prepared directly from the reactions as described. All samples
was cooled to room temperature and solvent removed in vacuo. for EPR spectroscopy were prepared in an inert atmosphere
A 2:1 mixture of diethyl ether and pentane was added to the glove box equipped with a liquid nitrogen fill port to enable
pale yellow solid residue and stirred for 3 min. The solution was sample freezing to 77 K within the glove box. EPR samples were
filtered through celite resulting in a yellow clear solution and prepared in 4 mm OD suprasil quartz EPR tubes from Wilmad
was stored at -30 ⁰C for one week after which yellow crystals Labglass. Samples for spin integration utilised high precision
were isolated. Yellow crystals were carefully selected at low suprasil quartz tubes to allow for direct comparison of
temperature in batches from several reactions with varying intensities between different samples. X-band EPR spectra were
crystallisation yields. Evans method analysis of the crystalline recorded on a Bruker EMXplus spectrometer equipped with a
mixture redissolved in THF-d8 yields μeff = 5.1 μb. Elemental Anal. 4119HS cavity and an Oxford ESR-900 helium flow cryostat. The
Calcd (for 86:14 mixture of 2-Br and
3 with co-crystallised ether instrumental parameters employed for all samples were as
and pentane): C, 57.96; H, 6.96; N, 4.48. Found: C, 57.84; H, follows: 1 mW power; time constant 41 ms; modulation
6.52; N, 4.60.
amplitude 8 G; 9.38 GHz; modulation frequency 100 kHz.
Samples exhibiting S = 1/2 EPR spectra were spin integrated
using a 3 mM CuSO4 standard under non-saturating conditions.
Identical instrumentation parameters were used for both the
iron and standard samples.
Preparation of (SIPr)Fe((1,3-dioxan-2-yl)ethyl)2 (4)
To a scintillation vial was added Fe(OAc)2 (33 mg, 0.19 mmol)
and (1,3-Bis(2,6-diisopropylphenyl)imidazolinium chloride (81
mg, 0.19 mmol) along with a stir bar. To the solid mass was
added (2-(1,3-dioxan-2-yl)ethyl)magnesium bromide in THF (0.5
Electronic Structure Calculations
M, 2.28 mL, 1.14 mmol) over the course of two minutes while Spin unrestricted density functional theory (DFT) calculations
stirring at room temperature. The yellow reaction mixture was were performed with the Gaussian 09 package.40 All geometry
stirred at room temperature for an additional 10 minutes optimization calculations were performed with the PBEPBE
followed by cooling to -78 °C. The yellow slurry was then functional with the TZVP basis set on all atoms and inclusion of
warmed on a room temperature stir plate for five minutes while solvation effects using the polarised continuum model (PCM)
stirring after which room temperature pentane (ca. 18 mL) was with THF as the solvent).41-43 The dispersion correction of
added to the mixture and the vial cooled back to -78 °C. The Grimme (GD2) was used in geometry optimizations of all
resulting solution was filtered through Celite (precooled to -78 complexes.44 The geometries of all complexes were fully
°C) and the yellow filtrate stored at -80 °C for one week optimised starting from X-ray crystal structures. All optimised
rendering yellow crystals. Yellow crystals were carefully geometries had frequencies found to be positive. Energies are
selected at low temperature in batches from several reactions given in the ESI and include zero-point and thermal corrections.
with varying crystallisation yields. Evans method analysis of Further calculations of molecular orbitals (MOs) and TD-DFT
crystalline
4 redissolved in THF-d8 indicates μeff= 5.0(1) μb. used the B3LYP functional with the TZVP basis set on all atoms.
Elemental Anal. Calcd. for C39H60FeN2O4·0.1MgBr2: C 67.38, H The analysis of MO compositions and Mayer bond orders were
8.70, N 4.03. Found: C 67.39, H 8.97, N 3.98
performed using the AOMix program.45, 46 Orbitals from the
Gaussian calculations were plotted with the ChemCraft
program.
Mössbauer Spectroscopy
Solid samples for 57Fe Mössbauer spectroscopy were made with
isolated complexes based on natural abundance of 57Fe or from
57Fe-enriched samples of isolated complexes. Frozen solution
Reactions of Fe(OAc)2 with IMesHCl, Grignard, and
Electrophile for Pre-catalyst and in situ Reaction Studies
samples for 57Fe Mössbauer spectroscopy were prepared from As an example of the general procedure performed; 57Fe(OAc)2
57Fe(OAc)2 or isolated 57Fe-enriched complexes. All samples (0.010 mmol) was reacted with IMes•HCl (0.021 mmol) in THF
were prepared in an inert atmosphere glovebox with a liquid at 55 ⁰C in 2 mL of THF and alkyl Grignard was added quickly
nitrogen fill port to freeze each sample at 77 K within the (0.122 mmol, 12 equiv to iron), dropwise, to form the pre-
glovebox. Each sample was loaded in to a Delrin Mössbauer catalyst. The reaction was cooled to 23 ⁰C after 20 min and 1-
sample cup for measurements and loaded under liquid iodo-3-phenylpropane was added (0.400 mmol). Mössbauer or
nitrogen. Low temperature 57Fe Mössbauer measurements EPR samples were then prepared at various time points (1 min,
were performed using a See Co. MS4 Mössbauer spectrometer 20 min, etc.) and frozen in liquid nitrogen to freeze quench the
integrated with
a Janis SVT-400T He/N2 cryostat for reaction at the desired time. When GC studies were performed,
measurements at 80 K or 5 K. Isomer shifts were determined dodecane was added to the reaction to match the molarity of
relative to α-Fe at 298 K. All Mössbauer spectra were fit using electrophile after it was cooled to room temperature.
the program WMoss (SeeCo).
Reactions were quenched using 0.1 mM HCl in THF and filtered
Electron Paramagnetic Resonance
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through a Florisil pad. Cross-coupled product yields were
determined from quantitative GC analysis.
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DOI: 10.1039/C7SC04750A
Reactions of (IMes)57Fe((1,3-dioxan-2-yl)ethyl)2 with alkyl
iodide
(IMes)57Fe((1,3-dioxan-2-yl)ethyl)2•2(THF) (7.3 mg, 0.01 mmol)
was reacted with x equiv of 1-iodo-3-phenylpropane in 2 mL THF
at 23 ⁰C (x = 0.7, 20). Time points for GC were quenched using
0.5M HCl in THF using dodecane as an internal standard. Freeze
trapped Mössbauer samples were prepared as previously
described.
Reactions of (IMes)57FeBr((1,3-dioxan-2-yl)ethyl) with
Grignard and alkyl iodide for in situ spectroscopic studies
(IMes)57FeBr((1,3-dioxan-2-yl)ethyl) (2.80 mg, 0.005 mmol) was
reacted with 1.0 equiv of (2-(1,3-dioxan-2-yl)ethyl)magnesium
bromide (0.5 M in THF) and 20 equiv of 1-iodo-3-phenylpropane
in 1 mL THF at 23 ⁰C. After stirring at room temperature the
reaction was freeze quenched in liquid nitrogen in inert
atmosphere as previously described at various time points for
Mössbauer spectroscopy. GC studies were also performed with
addition of dodecane and workup as previously described.
Results and analysis
Pre-catalyst formation and characterization.
The iron-NHC catalysed Kumada alkyl-alkyl cross-coupling
reaction is composed of three major steps: (1) in situ formation
of a pre-catalyst at elevated temperature, (2) addition of
electrophile at room temperature, and (3) slow addition of
Grignard reagent at room temperature. To complete a rigorous
mechanistic investigation of this reaction each step was
evaluated using in situ freeze-trapped EPR and 57Fe Mössbauer
spectroscopy. Initial investigations focused on the identification
of the iron species formed in the pre-catalyst formation step,
where Cárdenas and co-workers previously reported that a S =
1/2 iron(I) active species is generated.23 Following the reported
Fig. 1 Iron-NHC pre-catalyst formation. (A) 5 K Mössbauer spectrum of the pre-catalyst
reaction iron products in frozen THF solution. The data is shown as black dots and
individual fit components are given by blue (1) and orange (1-THF) lines. (B) Single crystal
X-ray crystal structure of (IMes)Fe(1,3-dioxan-2-ylethyl)2 (1) with thermal ellipsoids
shown at the 50% probability level and select bond distances and angles given, H-atoms
were omitted for clarity.
addition of 4 equiv of (2-(1,3-dioxan-2-yl)ethyl)magnesium
bromide to a mixture of Fe(OAc)2 and IMes•HCl (1 equiv of
each) in THF at room temperature yielded yellow crystals
suitable for single crystal X-ray diffraction. The single crystal X-
procedure,
12
equivalents
of
(2-(1,3-dioxan-2-
yl)ethyl)magnesium bromide were added to Fe(OAc)2 and
o
IMes•HCl in THF (1.0 and 2.1 equiv respectively) at 54 C and
stirred for 20 min, forming a bright yellow solution. The 5 K
Mössbauer spectrum of the reaction mixture freeze-trapped at
the end of the 20 min pre-catalyst reaction indicated the
ray structure of
1 corresponds to (IMes)Fe((1,3-dioxan-2-
yl)ethyl)2 (Fig. 1B). The structure can be described as trigonal
bipyramidal iron(II) complex with an Fe-IMes bond length of
2.1222(12) Å. The iron-carbon bond lengths to the alkyl groups
are 2.0994(13) and 2.1062(12) Å. Additional iron-oxygen
interactions from the acetal on the alkyl group are at a distance
of 2.4632(9) and 2.4428(9) Å, forming a set of five membered
rings with iron. Evans method analysis of crystalline 1 dissolved
in THF-d8 indicates the presence of high-spin, S = 2 iron(II) for
the solution (μeff= 5.2(3) μb), consistent with the Mössbauer
presence of one major iron species in solution (1), with
Mössbauer parameters of δ = 0.57 mm/s and ΔEQ = 2.33 mm/s
(78%, blue, Fig. 1A) that is stable at this elevated temperature
for over an hour before any significant decomposition occurs. A
minor species is also present in the pre-catalyst Mössbauer
spectrum with parameters of δ = 0.50 mm/s and ΔEQ = 2.70
mm/s (22%, orange, Fig. 1A). Spin quantitated X-band EPR
indicates that the same S = 1/2 species reported by Cárdenas
also forms in the pre-catalyst reaction (see ESI) but represents
< 0.5% of all iron in solution and, hence, is not observable by
Mössbauer spectroscopy.
parameters of
Spin unrestricted DFT calculations were utilised to further
analyse the bonding in Geometry optimizations with the
1 (vide infra).
1
.
PBEPBE functional and TZVP basis set yielded calculated
structures in good agreement with crystallographic data in gas
phase and THF solvent model cases (see ESI). Additionally,
Single crystal X-ray crystallographic studies were pursued in
order to unambiguously assign the structure of the major iron
species
1 formed in the pre-catalyst reaction. Slow
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Table 1 Comparison of calculated and experimental Fe-O bonding parameters for IMes-Iron(II)-Alkyl complexes
molecular orbitals were evaluated using B3LYP/TZVP in the gas also important to consider whether
1
and 1-THF could be
phase (see ESI), placing emphasis on the occupied and formed in situ at room temperature or at shorter time points. In
unoccupied frontier molecular orbitals (FMOs) of the manifold fact, the addition of 12 equiv of (2-(1,3-dioxan-2-
to describe the major contributions to bonding. Complex yl)ethyl)magnesium bromide to Fe(OAc)2 and IMes•HCl in THF
exhibits dominant Fe d orbital character in 156 (HOMO, 84 % (1.0 and 2.1 equiv respectively) at 54 C for 1 min or room
dxy), 162 (LUMO+5, 80% dxz), 167 (LUMO+7, 68% dz2) and temperature with a 1 h reaction time generates an analogous
169 (LUMO+12, 42% dx2-y2). 157 (LUMO) and 161 (LUMO+4) mixture of and 1-THF (Fig. 2) and < 0.5% of S = 1/2 iron by spin
b
1
o
b
b
b
b
b
b
1
both show diffuse Fe dyz orbital character (16 and 12% quantitated EPR (see ESI) demonstrating that elevated
respectively) with a strong π-bonding interaction to the temperature is not required to form the key iron(II) species.
carbene carbon of the IMes ligand. The highest occupied ligand Even after 2 h of reaction at room temperature, the distribution
based FMO is
b155 (HOMO-1), exhibiting s bonding of iron species remains constant with no additional S = 1/2
interactions between the alkyl carbons and dxy contributions. demonstrating the stability of these complexes.
Mayer bond order analysis was carried out from optimised gas
This result indicated that effective cross-coupling might be
phase, solvent model, and crystal structure coordinates to achieved by performing all reaction steps at room temperature.
quantify the interaction between iron and oxygen of the acetal Pre-catalyst reaction at room temperature for 1 h followed by
alkyl substrate. In each of the three cases, very small bond the addition of electrophile and subsequent slow addition of
orders between iron and the coordinating oxygen of the alkyl Grignard reagent was found to give 81% cross-coupled product.
ligand (e.g. 0.071 and 0.099 for the gas phase model, Table 1) This yield is analogous to those achieved when pre-catalyst
were found. This indicates the presence of very weak Fe-O treatment was carried out at 54 oC for either 1 or 20 min (~ 79
interactions, consistent with the elongated Fe-O distances %, Table 2). Thus, the elevated temperature pre-catalyst
observed crystallographically.
treatment in the original method is clearly not required. It
Mössbauer spectroscopy of crystalline (IMes)Fe((1,3- should also be noted that further evaluation of the original
dioxan-2-yl)ethyl)2 confirms that this complex represents the catalytic protocol determined slow addition of 1.23 equiv of
major iron species
1 observed to form in situ in the pre-catalyst Grignard reagent (with respect to electrophile) over 6.25 h, as
reaction. The 5 K Mössbauer spectrum of solid
1
is represented opposed to 3.7 equiv over 18 h, gave analogous cross-coupled
by a single quadrupole doublet with parameters δ = 0.57 mm/s product yields to the originally reported protocol.23
and ΔEQ = 2.43 mm/s, where the small change in ΔEQ in the solid
state spectrum suggests a slight structural distortion between
solid and solution states (see ESI). Consistent with this
hypothesis, dissolution of 57Fe-enriched
1 in THF solution results
in a Mössbauer spectrum (see ESI) analogous to that previously
observed for the pre-catalyst reaction mixture containing two
major iron species: δ = 0.57 mm/s and ΔEQ = 2.33 mm/s (
blue), and δ = 0.50 mm/s and ΔEQ = 2.70 mm/s (19%, green).
Dissolution of 57Fe-enriched
in 2-MeTHF results in only a single
major iron species in frozen solution by Mössbauer
spectroscopy with parameters corresponding to (see ESI),
enabling the assignment of the minor δ = 0.50 mm/s and ΔEQ =
2.70 mm/s component as the THF adduct of 1-THF). Thus, the
pre-catalyst reaction results in the formation of and 1-THF
1, 81%,
1
1
1
(
1
Fig. 2 5 K Mössbauer spectrum of the pre-catalyst reaction iron products in frozen THF
solution following formation at RT. The data is shown as black dots and individual fit
components are given by blue (1, 76 % of total iron) and orange (1-THF, 24 % of total
iron) lines.
with only a trace amount of S = 1/2 iron also present.
Due to the elevated temperature utilised in the reported
pre-catalyst reaction step by Cárdenas and co-workers, it was
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Table 2 Pre-catalyst reaction condition and NHC additive effects on alkyl-alkyl cross-coupling reactions
While
1 and 1-THF represent nearly all iron species formed solvent in vacuo. The residues were extracted with 1:1
in the pre-catalyst reaction (>99.5 % at either RT or 54 oC) and ether:pentane, filtered and stored at -30 ⁰C yielding yellow
spin quantitated EPR indicated a very minor S = 1/2 component crystals suitable for X-ray analysis. X-ray crystallography
(< 0.5 %), Cárdenas and co-workers also reported that a large confirmed the formation of (IMes)FeBr((1,3-dioxan-2-yl)ethyl)
amount of homocoupled nucleophile was also formed in the
pre-catalyst reaction. Previous studies from our group on iron- 86:14 ratio (Fig. 3B). For both species, the bromide ligand
SciOPP catalysed phenyl-alkyl cross-coupling have derives from the magnesium salt formed upon transmetalation
(2-Br) (Fig. 3A) co-crystallised with (IMes)FeBr2(THF) (3) in an ~
demonstrated that homocoupled nucleophile can form as a with the Grignard reagent via anion exchange. The solid state
result of the chemical quench of transmetalated iron(II)-SciOPP structure of 2-Br is described as having an Fe-IMes bond length
species with the sample preparation used for GC analysis.36 To of 2.096(4) Å, slightly decreased compared to the Fe-IMes bond
test whether a similar issue might be present in the current length observed for
1
(2.1222(12) Å). The Fe-C bond to the alkyl
was re-dissolved in THF at 54 C in 2-Br has a length of 2.016(12) Å (compared to 2.0994(13) and
and quickly quenched for GC analysis using the same procedure 2.1062(12) Å for Fe-Calkyl interactions in ). Notably, the Fe-O
o
system, isolated crystalline
1
1
reported by Cárdenas in his homocoupling experiment. Large bond length to the oxygen on the acetal for 2-Br is 2.181(4) Å,
amounts of homocoupled alkyl nucleophile were observed by approximately 0.25 Å shorter than that of the Fe-O interactions
GC analysis following the chemical quenching procedure (~ 0.7 in the same five-membered metallacycle of
1. The bis-halide
equiv homocoupled nucleophile with respect to ). Consistent complex is also well-described as a distorted tetrahedron with
1
3
with previous iron-SciOPP studies, these results demonstrate Fe-Br bond lengths of 2.4184(8) and 2.329(6), which are slightly
that correlation of homocoupled nucleophile to iron oxidation elongated compared to other isolated bishalide iron(II)-NHC
states in solution can be unreliable as the chemical quenching complexes (e.g. 2.310 and 2.992 Å in (IMes)2FeCl2).29, 47, 48
of alkylated iron(II) species can result in the formation of
The 5 K frozen solution Mössbauer spectrum of 57Fe-
homocoupled nucleophile. As expected, quantitated enriched crystals used for X-ray crystallography reflected the
spectroscopic methods that directly assess iron speciation and co-crystallised iron complexes when re-dissolved in THF (Fig. 3C)
electronic structure are much more reliable means for with Mössbauer parameters of δ = 0.67 mm/s, ΔEQ = 3.00 mm/s
evaluating in situ formed iron speciation than quantitation of (88%, green) and δ = 0.90 mm/s, ΔEQ = 3.18 mm/s (12% red).
organic products that can artificially form because of the These are similar to the ratios observed in the X-ray data and,
quenching procedures used for GC analysis.
hence, are assigned to 2-Br and 3, respectively (see Table 2 for
comparison to previously reported bishalide and mono- and bis-
transmetalated iron-NHCs). Importantly, 2-Br is stable in
Formation and characterization of undertransmetalated iron-
NHCs.
solution and does not disproportionate in solution to form
1
and
3
. Solid state Mössbauer spectroscopy of a sample of crystalline
Following the identification of the bis-transmetalated iron(II)-
material also shows a mixture of 2-Br and
method analysis of the crystals redissolved in THF-d8 yields μeff
= 5.1(3) μb. Thus, both and are high-spin, S = 2 iron(II)
complexes, consistent with their Mössbauer parameters and
distorted tetrahedral structures.
3 (see ESI). Evans
IMes complex
catalyst reaction, it was clear that
1
as the major iron species formed in the pre-
related mono-
a
2
3
transmetalated iron(II)-IMes complex could also be accessible.
In order to form this type of species, a minimal amount of alkyl
Grignard reagent was utilised. Following the addition of 4.2
equiv alkyl nucleophile to a mixture of 1 equiv 57Fe(OAc)2 and
o
2.2 equiv IMes•HCl in THF at 54 C followed by removal of
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Table 3 Mössbauer parameters of Iron(II)-NHC complexes
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DOI: 10.1039/C7SC04750A
(see Table 1 for other models), more than twice that observed
in for all models calculated, demonstrating a much stronger
1
Fe-O interaction is present in the mono-alkyl complex (Table 1)
consistent with the shorter Fe-O distance observed
crystallographically in 2-Br
.
Reactivity of (IMes)Fe((1,3-dioxan-2-yl)ethyl)2 (1) with
electrophile.
Since the bis-alkylated iron(II)-IMes complex
1 is the major iron
species formed in the pre-catalyst step, it was important to
evaluate its reactivity with electrophile. Following the reported
catalytic protocol, after pre-catalyst formation the second
reaction step involves the addition of excess electrophile (40
equiv 1-iodo-3-phenylpropane) at 23 ⁰C directly to the in situ
formed pre-catalyst reaction mixture. The freeze trapped 57Fe
Mössbauer spectrum of the reaction 1 min after electrophile
Fig. 3 X-ray structural and Mössbauer analysis of 2-Br and 3. X-ray crystal structures of
(A) (IMes)FeBr(1,3-dioxan-2-ylethyl) (2-Br) and (B) (IMes)FeBr2(THF) (3). For both
structures, thermal ellipsoids shown at the 50% probability level and select bond
distances and angles given, H atoms are omitted for clarity. Note that these species co-
crystallize in an ~ 86:14 ratio of 2-Br:3. (C) 5 K Mössbauer spectrum of 57Fe-enriched
crystals containing 2-Br and 3 redissolved in THF. The data is shown as black dots and
individual fit components are given by green (2-Br) and red (3) lines.
addition shows that in situ formed
1 has completely reacted to
form one major iron species with parameters of δ = 0.90 mm/s,
ΔEQ = 3.18 mm/s (100%, red) (see ESI), similar to those for the
The resulting gas phase and solvent model calculations of 2-
Br produced structures with bond lengths and angles in good
agreement with crystallographic data (see ESI). FMO analysis
iron bis-halide complex
3 (vide supra). GC analysis of the
reaction mixture at the same time point after electrophile
addition indicates the formation of 9% cross-coupled product
and 8% allylbenzene with respect to electrophile,
corresponding to a total of 8 turnovers with respect to iron. This
is consistent with complete consumption of the excess Grignard
reagent used in the formation step. Notably, spin quantitated
EPR analysis indicates no consumption of the trace S = 1/2
reveals a ground state consisting of one occupied FMO,
with 84% Fe d orbital character (HOMO, dxy) and a weak
bonding interaction with the oxygen of the alkyl ligand. Fe d
character is also observed in 143 (LUMO, 43% dyz), 148
(LUMO+5, 79% dxz), 149(LUMO+6, 63% dz2), and
151(LUMO+8, 52% dx2-y2). Strong π interactions with the
carbene of the IMes ligand are observed as shown in 143,
matching the Fe dyz orbital observed in the LUMO of . Similar
to , the highest occupied ligand based orbital in 2-Br is
composed of a Fe d bonding interaction with the alkyl carbon.
b142,
p
*
b
b
b
b
b
1
1
s
Lastly, Mayer bond order analysis of the Fe-O interaction in 2-
Br yields a MBO of 0.224 in the gas phase model
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Table 4 Reactivity of 1 with 1-iodo-3-phenylpropane in THF at 23 oC
species during this electrophile reaction (see ESI). Thus, the S = coupled product (A), 15 % propylbenzene (D), and 24%
1/2 iron presentfollowing the pre-catalyst reaction is either phenylpropene (C) (with respect to electrophile) as determined
unreactive or significantly less reactive than
represents an off-cycle iron species in catalysis.
1
and, hence, by GC analysis, a lower product selectivity than observed at the
end of both turnovers (~80 %, vide supra). In the same reaction,
Reactivity studies of isolated
1 with excess alkyl iodide (20 freeze-trapped in situ Mössbauer spectroscopy shows a
o
equiv) in THF at 23 C were also performed to determine the distribution of two iron species in solution (Fig. 4B) with
inherent reaction rate and selectivity in the absence of excess parameters of δ = 0.57 mm/s and ΔEQ = 2.33 mm/s (33%, blue,
Grignard reagent in pseudo first order reaction conditions. Two
turnovers are observed with respect to , resulting in a product consistent with the iodine analogue of 2-Br due to halide
distribution of 160 cross-coupled product (2-(5- exchange (denoted 2-I; note that when 0.7 equiv of 1-bromo-3-
phenylpentyl)-1,3-dioxane) (A), 20% allylbenzene (B) and 20% phenylpropane are added to 2-Br is observed to form by
propylbenzene (D) (yields are with respect to iron, see Table 4). Mössbauer spectroscopy though at reduced rate, see ESI).
The observed product distribution for the direct reaction of Thus, the two turnovers of proceed through an intermediate
1), δ = 0.67 mm/s and ΔEQ = 2.70 mm/s (67%, purple), the latter
1
%
1
,
1
1
with excess electrophile (80 % cross-coupled product with mono-alkylated iron(II)-IMes species. Furthermore, the
respect to electrophile) is consistent with that observed in substoichiometric reaction with electrophile indicates that the
catalysis (75
allylbenzene, 9 % propylbenzene, along with trace amounts of product. Since reaction of
1,6-diphenylhexane and1-phenyl-1-propene). Both alkyl groups selective to cross-coupled product following two total turnovers
of are ultimately consumed in this reaction, consistent with (vide infra), the second turnover is highly selective.
%
2-(5-phenylpentyl)-1,3-dioxane, 12
%
first turnover of
1
is only ~ 60% selective towards cross-coupled
1
with excess electrophile is ~ 80 %
1
the formation of an Fe(IMes)X2 complex by Mössbauer
spectroscopy with an isomer shift of 0.88 mm/s and quadrupole
Reactivity of (IMes)FeBr((1,3-dioxan-2-yl)ethyl) (2-Br) with alkyl
splitting of 3.32 mm/s (Fig. 4A). These parameters are similar to iodide.
those observed for , consistent with a variation in halide from
3
After substoichiometric reactions of
1 with electrophile
Br to I due to reaction in the absence of excess Br. The reaction
is complete within five seconds, setting the lower limit of rate
of reaction at 24 min-1 for each turnover. In the reported
catalytic reaction, electrophile addition is followed by slow
addition of the remaining Grignard reagent at a rate of only 8
equivalents to iron per hour, much slower than the rate of
indicated the formation and reactivity of a mono-alkylated
intermediate, the direct reactivity of 2-Br with 1-iodo-3-
phenylpropane was evaluated. Following the addition of 20
equiv of 1-iodo-3-phenylpropane in THF at 23 ⁰C, no reactivity
was observed by GC analysis over the course of 5 min.
Consistent with this lack of reactivity, both in situ formed 2-Br
during catalysis and redissolved crystalline mixtures of 2-Br and
reaction of
catalysis.
1
with electrophile and, hence, rate limiting for
3
show no ligand redistribution to form 1 and 3 from freeze-
Since the reaction of
1
with electrophile results in two total
trapped solution Mössbauer. While 2-X species (X = Br, I) can be
turnovers, it was important to evaluate whether a mono-
alkylated iron species might form after an initial turnover as well
freeze-trapped as intermediates in the two observed turnovers
of
1 to yield product, they are not the higher selectivity
as the relative selectivity of the first and second turnovers of
1
intermediate mono- alkylated species. It is likely that there is a
different form of the mono-alkylated iron species that is
reactive in solution but is transformed to 2-X upon freezing.
to generate product. Reaction of isolated with 0.7 equiv 1-
1
iodo-3-phenylpropane for 1 min results in the complete
consumption of electrophile and production of 60% cross-
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Fig. 5 5 K Mössbauer spectrum of in situ iron species present in solution 2 h into the slow
Grignard addition step. The individual components of the fit are shown which include 3
(red, 82 %) and 2-Br (green, 18 %).
nucleophile addition is also observed for catalysis performed
using room temperature pre-catalyst formation, see ESI). GC
results indicate that upon completion of slow addition of
Grignard reagent, 75% cross-coupled product, 9 % allylbenzene,
9% 1-phenylpropene, and 7% n-propylbenzene are produced.
Fig. 4 In situ freeze trapped Mössbauer spectra of reactions of isolated 1 with excess and
substoichiometric alkyl iodide. 5 K Mössbauer spectra of the iron speciation in solution
following addition of (A) 20 equiv of 1-iodo-3-phenylpropane to isolated 1 and (B) 0.7
equiv of 1-iodo-3-phenylpropane to 1 at room temperature.
Catalytic reactions with alternative nucleophiles.
The catalytic reaction reported by Cárdenas utilizes (2-(1,3-
dioxan-2-yl)ethyl)magnesium bromide. After the isolation of
1
and 2-Br, which both contain oxygen interactions from this
substrate to form chelating interactions to iron, it was
important to evaluate whether the presence of the acetal
moitiey (and resulting Fe metallacycle) was essential for
effective catalysis. Therefore, the reported catalytic reaction
was performed using (2-cyclohexylethyl)magnesium bromide
(i.e. the cyclohexyl analogue of the acetal moiety) and 1-iodo-3-
phenylpropane (Scheme 2). For this reaction, only 9 % of cross-
coupled product was observed along with 1-phenylpropene and
propylbenzene as the major side products. Thus, the inability
to achieve effective cross-coupling upon substitution of the
acetal moiety for the cyclohexyl analogue demonstrates that
the acetal moiety (and likely the ability to form an iron
metallacycle through Fe-O interactions) is essential for
obtaining high yields of cross-coupled product.
One possibility would be an open form of 2-X resulting from
reaction of
1 with electrophile, where the alkyl group from the
Grignard reagent is not chelated to iron through oxygen on the
acetal. However, all attempts to isolate this mono-alkylated
species (by freeze-trapped analysis or crystallisation) have only
resulted in the isolation of 2-Br
.
Despite the lack of reactivity of 2-Br towards electrophile, 2-
Br can react with additional Grignard reagent to generate the
highly reactive bis-alkyl complex 1. Addition of 1 equiv of (2-
(1,3-dioxan-2-yl)ethyl)magnesium bromide in THF at 23 ⁰C to 2-
Br results in an immediate colour change of the solution from
pale to bright yellow, and Mössbauer spectroscopy indicates
the formation of the pre-catalyst mixture of
(15 %) (see ESI).
1 (85 %) and 1-THF
In situ Iron speciation with slow Grignard reagent addition.
Scheme
2 Iron-IMes Catalyzed Cross-Coupling Reactions with Alkyl Nucleophiles
After identifying the key reactive species in the pre-catalyst
reaction as the bis-alkylated iron(II)-IMes complex, the catalytic
distribution of iron species present during catalysis was
evaluated in order to determine the degree of transmetalation
during catalysis and to probe for the potential formation of
Containing Alternative Terminal Moieties.
additional off cycle iron species. After formation of
addition of electrophile, 0.5 (2-(1,3-dioxan-2-
yl)ethyl)magnesium bromide is slowly added at a rate of 0.16
mL/hr. Consistent with slow addition of nucleophile, is not
observed to reform during the catalytic reaction; Fig. 5 shows
the presence of only 2-Br and (18 % and 82 %, respectively)
1 in situ, and
M
1
3
after the first 2 h of Grignard reagent addition. Spin quantified
EPR shows the persistence of < 0.5 % S = 1/2 iron in solution
during catalysis (see ESI). Analogous iron speciation during slow
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Due to the importance of the acetal moiety of the alkyl
nucleophile in coordinating to iron(II) to disfavour -H
View Article Online
DOI: 10.1039/C7SC04750A
b
elimination from the alkyl nucleophile and promote cross-
coupled product formation, we hypothesized that the
introduction of alternative moieties on the alkyl nucleophile
with the potential to coordinate to iron (e.g. ether, pyridine)
might also be effective for achieving alkyl-alkyl cross-coupling.
The ether based nucleophiles (2-methoxypropyl)magnesium
bromide and (3,3-dimethoxypropyl)magnesium bromide were
ineffective in the formation of cross-coupled product in
reactions with 1-iodo-3-phenylpropane (Scheme 2), instead
side-products arising from β-hydride elimination were
observed. This indicates the sensitivity of nucleophile chelation
to the rigidity and possibly steric encumbrance of the chelating
motif. In contrast, (2-(pyridine-2-yl)ethyl)magnesium bromide
was found to successfully yield cross-coupled product without
optimizing reaction conditions and with a yield comparable to
those obtained using more functionalized electrophiles in the
original study (~ 50%).23 The ability to utilise alternative ligating
moieties in the alkyl nucleophile not only reinforces the critical
importance of alkyl chelation in forming cross-coupled product,
but also provides initial insight into how nucleophile scope for
iron-NHC alkyl-alkyl cross-couplings might be further
broadened through the use of different chelating groups on the
nucleophile. Based on these results, future studies will focus on
optimising the use of varied directing groups to maximise the
yield and scope of such cross-coupling reactions.
Molecular level insight into the poor selectivity of other NHC
additives.
Fig. 6 Iron-SIPr pre-catalyst formation. (A) 5 K Mössbauer spectrum of the pre-catalyst
reaction iron products using SIPr•HCl as the ligand additive in frozen THF solution. The
data is shown as black dots and the fit as a solid line. (B) Single crystal X-ray crystal
structure of (SIPr)Fe(1,3-dioxan-2-ylethyl)2 (4) with thermal ellipsoids shown at the 50%
probability level and select bond distances and angles given, H atoms are omitted for
clarity.
While (IMes)Fe((1,3-dioxan-2-yl)ethyl)2 (1) was identified as the
key reactive iron species for alkyl-alkyl cross-coupling,
interesting NHC dependences exist for this reaction. For
example, while IMes is a highly effective NHC ligand additive for
catalysis (80 % product yield), the use of SIPr as the ligand
additive results in a significant reduction in cross-coupled
product formation (23 %) with increased amounts of
allylbenzene and n-propylbenzene side product formation
compared to reactions with IMes as the ligand additive (see ESI).
Thus, molecular-level insight into the effects of SIPr versus IMes
on iron speciation and reactivity could provide critical insight
into ligand design for catalysis. Since the key reactive iron
quantitated EPR indicated the additional presence of a very
minor S = 1/2 component (< 0.5%, see ESI).
Single crystal X-ray crystallographic studies were pursued in
order to unambiguously assign the structure of the major iron
species
4 formed in the pre-catalyst reaction with SIPr. Slow
addition of 6 equiv of (2-(1,3-dioxan-2-yl)ethyl)magnesium
bromide to a mixture of Fe(OAc)2 and SIPr•HCl (1 equiv of each)
in THF at room temperature followed by cooling to -78 ⁰C
yielded yellow crystals suitable for single crystal X-ray
species
1 forms in the pre-catalyst formation step in the
diffraction. The single crystal X-ray structure of
4 corresponds
presence of IMes, an analogous pre-catalyst reaction was
performed using SIPr as the ligand additive. Addition of 12 equiv
of (2-(1,3-dioxan-2-yl)ethyl)magnesium bromide to Fe(OAc)2
and SIPr•HCl in THF (1.0 and 2.1 equiv respectively) at 54 ⁰C
followed by stirring for 20 min led to formation of a yellow
solution. The 5 K Mössbauer spectrum of the reaction mixture
freeze-trapped at the end of the 20 min pre-catalyst reaction
to (SIPr)Fe((1,3-dioxan-2-yl)ethyl)2 (Fig. 6B). The structure of
this iron(II) complex has an Fe-SIPr bond length of 2.0920(10) Å
as well as iron-carbon bond lengths to the alkyl groups of
2.0885(12) and 2.0707(12) Å. In contrast to 1, only one iron-
oxygen interaction from the acetal on one of the alkyl groups is
present at a distance of 2.3130(9) Å, over 0.1 Å shorter than the
corresponding Fe-O interactions in 1. The other alkyl group in 4
indicated the presence of one major iron species in solution (4),
is in an open confirmation, likely the result of the increased
steric bulk of the 2,6-diisopropyl substituents present in SIPr.
DFT studies further support steric bulk as a key mode for
decrease in reactivity with use of the SIPr ligand as analogous d-
orbital configurations to those of the IMes structure are found
(see ESI for further orbital descriptions). In addition, Mayer
with Mössbauer parameters of δ = 0.45 mm/s and ΔEQ = 2.87
mm/s (Fig. 6A). The significant reduction in the isomer shift and
increase in the quadrupole splitting of
4 compared to 1 is
consistent with a significant structural difference in the pre-
catalyst formed as a function of the NHC ligand employed.
Analogous to the pre-catalyst reaction with IMes, spin
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Scheme 3 Summary of Observed Iron(II) Species and their Reactive Transformations in
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bond order analysis revealed that the coordinated Fe-O bond
has a bond order of 0.074. This is on the same order of
the Cardenas Iron-NHC Catalysed Alkyl-Alkyl Cross-Coupling System (Note: X= Br or I).
DOI: 10.1039/C7SC04750A
interaction as found in
1 despite the shortened bond length.
Mössbauer spectroscopy of crystalline (SIPr)Fe((1,3-dioxan-
2-yl)ethyl)2 confirms that this complex represents the major iron
Fe(OAc)2 + IMes HCl + RMgBr
species
4
observed to form in situ in the pre-catalyst reaction.
is represented by a single
Pre-catalyst
Formation
The 5 K Mössbauer spectrum of solid
4
R
quadrupole doublet with parameters δ = 0.44 mm/s and ΔEQ =
2.91 mm/s (see ESI), where the small change in ΔEQ in the solid
state spectrum suggests a slight structural distortion between
solid and solution states.
Ph
X
kobs > 24 min-1
Ph
(IMes)Fe
(1)
R
RMgBr
+
R
Ph
+
Ph
The significant structural differences between the iron-NHC
pre-catalysts formed with IMes and SIPr provide direct insight
in to their differences in catalytic performance. The IMes
R
X
Freeze
Intermediate
Mono-Alkyl
(2-X)
(IMes)Fe
(2-X)
Quench
derivative,
which protects each alkyl group from β-hydride elimination
reactions. In the case of SIPr, , only a single chelating alkyl
ligand is observed with the second being in an open
configuration. This leaves more susceptible to β-hydride
1, contains two alkyl ligands with oxygen chelation
Ph
X
4
N.R.
Ph
X
4
kobs > 24 min-1
X
elimination reactions, shown through its significantly decreased
catalytic performance (see Table 2).
(IMes)Fe
X
THF
RMgBr
Ph
R
(3-X)
quantified EPR studies show that this reported S = 1/2 iron
species represents < 0.5 % of all the iron formed in situ even
after addition of electrophile and throughout the subsequent
slow addition of Grignard reagent.
Reaction studies combining GC analysis and freeze-trapped
Mössbauer spectroscopy enable identification of the key
reactive iron-NHC species for the generation of cross-coupled
product. While 2-Br exhibits no reactivity towards 1-iodo-3-
Discussion
The determination of the reactive iron species and mechanism
of iron-catalysed cross-coupling reactions provides
a
fundamental framework for the development of novel iron
cross-coupling methods. In the present study, the use of
rigorous physical inorganic methodology combining 57Fe
Mössbauer spectroscopy, EPR, and inorganic synthesis with GC
analysis defines the in situ formed and reactive iron species in
iron-NHC catalysed alkyl-alkyl cross-coupling. These studies are
the first determination of the key reactive species in an iron-
catalysed alkyl-alkyl cross-coupling system.
Detailed spectroscopic and synthetic studies enable
identification of the key alkylated iron-NHC species formed in
situ during the pre-catalyst generation reaction with Fe(OAc)2,
IMesHCl and excess (2-(1,3-dioxan-2-yl)ethyl)magnesium
bromide. The bis-alkylated iron(II)-IMes complex (IMes)Fe((1,3-
phenylpropane,
product and an overall product distribution analogous to that
observed in catalysis. Specifically, is observed to react with
1 reacts rapidly to generate cross-coupled
1
excess electrophile to undergo two rapid turnovers at rates that
are catalytically relevant (kobs > 24 min-1), resulting in the
formation of bishalide iron(II)-IMes species. When
1 is formed
in situ the previously reported S = 1/2 species is also present,
but the consumption of the S = 1/2 species is not observed by
spin quantitated EPR analysis. This is consistent with the S = 1/2
species being either non-reactive or much less reactive towards
dioxan-2-yl)ethyl)2 (1) and its THF adduct are the major iron
species formed in situ during the pre-catalyst reaction,
representing > 99% of all iron in solution. Independent synthetic
studies also demonstrate that the mono-alkylated complex
(IMes)FeBr((1,3-dioxan-2-yl)ethyl) (2-Br) is also accessible in
this chemistry, which can readily be converted to
reaction with additional Grignard reagent.
Previously, a S = 1/2 iron(I) active species was proposed to
form in the pre-catalyst reaction based upon EPR spectroscopy
and GC monitoring of homocoupled Grignard reagent.
However, this study shows that upon oxidation of iron during
electrophile than
catalysis.
1 and, therefore, an off-cycle species in
Combined with radical clock substrate experiments
previously reported12, the observed reactivity of
is consistent
with an Fe(II)/Fe(III) mechanistic cycle involving radical
formation from the alkyl iodide. Two total turnovers of are
1
1 upon
1
observed, suggesting the formation of an intermediate mono-
alkyl iron(II)-IMes intermediate as summarized in Scheme 3. In
fact, substoichiometric reaction studies of
1 with electrophile
result in the formation of a mono-alkylated iron(II)-IMes
complex and ~ 60% selectivity towards cross-coupled product
by GC analysis. When this reaction mixture is subsequently
exposed to excess electrophile, overall selectivity increases to
that observed in catalysis (~ 80% cross-coupled product) and
the second turnover is highly selective for cross-coupled
acid quench of isolated 1, homocoupled product is formed,
demonstrating that GC counting of electrophile can be an
unreliable way to identify metal oxidation state. This
observation is consistent with previous work by Kochi and co-
workers where reductive elimination of two alkyl groups on iron
to form homocoupled product can be promoted by formation
of more highly oxidized iron species. 49 Additionally, spin
product. This selectivity suggests that 1 is a key reactive species
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J. Name., 2013, 00, 1-3 | 11
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in catalysis rather than reactivity deriving solely from a transient
mono-alkylated iron-NHC which would have a much higher derived from the nucleophile is another key aspect of the
overall selectivity, like that of the second turnover described Cárdenas iron-NHC alkyl-alkyl cross-coupling system, a common
above. Lastly, while reactivity of this intermediate mono- problem for reactions with alkyl nucleophiles. The ability to
Journal Name
The relatively low amount of
b
-hydride elimination product
View Article Online
DOI: 10.1039/C7SC04750A
alkylated iron with alkyl radical generated by
envisioned, no organic radical is observed in in situ freeze IMes species formed in situ provides direct insight into the
trapped EPR. origins of minimized -hydride eliminated product derived from
1 could be isolate and structurally characterize the key alkylated iron(II)-
b
The isolated mono-alkylated species observed by the alkyl nucleophile. Both the bis-alkylated and mono-
Mössbauer spectroscopy in these studies corresponds to 2-X (X alkylated iron(II)-IMes complexes exhibit chelation of the
= Br, I), however, the lower oxidizing ability of 2-Br compared ligated alkyl via coordination to carbon and interaction with one
with
1 may be responsible for its lack of reactivity with oxygen atom of the acetal moiety of the nucleophile to generate
electrophile. Even after heating at 60 oC for 5 min to encourage a 5-membered ring chelate to iron(II). This chelation appears to
dissociation of the acetal chelate in the presence of excess 1- lock the alkyl substrate into a configuration that is less prone to
iodo-3-phenylpropane, 100% of the alkyl iodide is recovered by
b-hydride elimination, orienting the b-hydrogens away from
GC analysis. Notably, catalysis remains effective with the use of iron while also increasing the barrier to geometric
an alkyl bromide electrophile12 indicating that a halide effect is rearrangement to achieve the required orientation for
not present. Instead, these studies suggest that the elimination. As a result, even at elevated temperature (T > 50
intermediate mono-alkylated iron(II)-IMes species likely oC) these alkylated iron(II)-IMes complexes exhibit significant
represents a perturbed form of 2-X, perhaps one in which the stability over the course of many tens of minutes. Consistent
hemi-labile acetal is not coordinated to iron. However, all with this hypothesis, the use of an analogous alkyl Grignard
attempts at freeze-trapping or isolation of this intermediate reagent where the acetal moiety is replaced by a cyclohexyl
mono-alkyl species only result in the isolation of unreactive 2- group leads to substantially reduced cross-coupling activity,
Br. Importantly, the observed product yields and selectivity in likely the result of the instability of IMes-iron(II)-alkyl species
catalysis is consistent with the 80:20 (C-C product:side product) formed with the cyclohexyl substituted nucleophile as indicated
distribution resulting from reaction of
electrophile. Therefore, catalysis most likely proceeds through nucleophile (see ESI). Thus, the current system is highly
two total turnovers of rather than the proposed mono- dependent on coordination of the acetal moiety in order to
alkylated iron(II)-IMes intermediate which would produce a achieve high alkyl-alkyl cross-coupling yields.
1 with excess by the complex iron speciation observed to form in-situ with this
1
much higher overall selectivity. This is further supported by the
The isolation and reactivity of these iron(II) chelate
observation of mono-alkylated 2-Br during steady state intermediates suggests that the development of future cross-
catalysis.
The requirement for slow addition of Grignard reagent after capable of chelate formation to increase selectivity with alkyl
electrophile addition to achieve high cross-coupling yields nucleophiles. Specifically, the use of alternative alkyl
coupling systems could benefit from the use of reagents
results from the low selectivity observed during the first nucleophiles such as (2-(pyridine-2-yl)ethyl)magnesium
turnover of 1. First of all, simply doubling the Grignard reagent bromide as an effective alkyl nucleophile for alkyl-alkyl cross-
addition rate results in product distributions containing only ~ coupling, demonstrates how the insight into alkyl chelation can
50 % cross-coupled product.23 Additionally, the reported be leveraged to broaden the scope of nucleophile partners for
reaction of in situ generated
presence of excess Grignard reagent. As a direct result, product
1
with electrophile occurs in the alkyl-alkyl cross-coupling.
The specific NHC used in this catalytic system also has an
yields are only ~ 50 % selective towards cross-coupled product effect on the productivity of catalysis. Specifically, SIPr is less
with excess Grignard reagent present in solution prior to the effective as a ligand additive in this system compared to IMes.
subsequent slow addition of the remaining Grignard reagent. This could be directly correlated to structural effects of the NHC
Together, these observations show that high product selectivity ligand on the ability of the alkyl nucleophiles to chelate.
requires that
1 react twice with 1-iodo-3-phenylpropane prior Additionally, the added steric bulk of the SIPr compared with
to re-transmetalation with Grignard reagent. In cases where IMes could lead to a slower or less efficient rebound of the
excess Grignard is present in solution (i.e. from rapid addition substrate radical, leading to decreased cross-coupling
of Grignard to form
intermediate from the first turnover of
be re-transmetalated to faster than its reaction with the importance of steric effects of NHC ligands over electronic
electrophile to form product. In turn, cross-coupled product structure changes.
yields consistent with only the first turnover of with The observation of a highly reactive iron(II)-IMes species in
1
), the resulting mono-alkylated performance. In fact, the d-orbital configuration and energies of
1
with electrophile could and are remarkably similar (see ESI), further demonstrating
1
4
1
1
electrophile would be generated, consistent with our iron-NHC alkyl-alkyl cross-coupling further expands the catalytic
observations in the current study. Thus, slow Grignard reagent relevance of iron(II) from previously reported iron-SciOPP cross-
addition is required in order to enable two turnovers of
1 prior coupling to both alkyl nucleophiles and NHC supporting ligands.
to any transmetalation event, ensuring that the more highly While it remains unlikely that a conserved overall mechanism
selective second turnover reaction can occur.
exists for all iron-catalysed cross-coupling reactions, the current
studies demonstrate that iron(II) complexes must be considered
12 | J. Name., 2012, 00, 1-3
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8. T. Hatakeyama and M. Nakamura, J. Am. Chem. Soc., 2007, 129,
as potential reactive species across the breadth of iron cross-
couplings. Potential iron(I) active species have been proposed
in other cross-couplings, notably in Negishi cross-coupling using
dppe and dpbz ligands,50, 51 and it will be exciting to determine
the role of iron(I) versus iron(II) in those systems in order to
more broadly define the role of these oxidation states in iron-
catalysed cross-coupling.
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Conclusions
In this study, inorganic spectroscopic methods (i.e. Mössbauer,
EPR) combined with inorganic synthesis and reaction studies
have been utilized to determine the in situ formed and reactive
iron species in iron-NHC catalysed alkyl-alkyl cross-coupling.
(IMes)Fe((1,3-dioxan-2-yl)ethyl)2 is identified as the key
reactive iron species formed in situ, while the S = 1/2 iron
species previously identified in this chemistry is found to be only
a minor (< 0.5 % of all iron) off-cycle species. The high resistance
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chelation of the alkyl nucleophile through carbon and one
oxygen of the nucleophile, which could be disrupted by the use
of more bulkily NHC ligands such as SIPr resulting in reduced
cross-coupling yields. These studies extend the importance of
iron(II) active species to systems utilizing NHC ligands and alkyl
nucleophiles, demonstrating the broader importance of this
oxidation state of iron for generating highly reactive species for
effective cross-coupling catalysis, and identifying a novel alkyl
chelation method to achieve effective alkyl-alkyl cross-coupling
with iron-NHCs.
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Conflicts of interest
There are no conflicts to declare.
29. L. Xiang, J. Xiao and L. Deng, Organometallics, 2011, 30, 2018-
Acknowledgements
This work was supported by a grant from the National Institutes
of Health (R01GM111480 to M.L.N.) and by a Sloan Research
Fellowship (M.L.N.).
2025.
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DOI: 10.1039/C7SC04750A
Isolation and reactivity of iron-NHCs observed during catalysis demonstrate ligand effects on nucleophile
chelation, suppressing β-hydride elimination within alkyl-alkyl cross-coupling.