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

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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)₂is highly reactive towards 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 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 reactions^5-7including biaryl,^8-11alkyl-aryl,^12-22

alkyl-alkyl,²³and aryl-alkenyl (Scheme 1).²⁴A 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).²⁵Also 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 FeCl₃in 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.³⁹The 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.^29-32These 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)₂complexes 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.³³While 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)₂and

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.²³This is a dramatic contrast to the other two existing

alkyl-alkyl cross-coupling systems with iron by Chai³⁴and

Nakamura³⁵where 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.^36-38Magnetic

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-d₈indicates μ_eff= 5.2(3) μ_b.

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 literature²³under N₂atmosphere. 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-d₈yields μ_eff= 5.1 μ_b. 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 CuSO₄standard 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.⁴⁰All 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).^41-43The 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.⁴⁴The 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-d₈indicates μ_eff= 5.0(1) μ_b. 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)₂with 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)₂or 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/N₂cryostat 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)₂with 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.²³Following 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)₂and 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)₂and

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-d₈indicates the presence of high-spin, S = 2 iron(II) for

the solution (μ_eff= 5.2(3) μ_b), consistent with the Mössbauer

presence of one major iron species in solution (1), with

Mössbauer parameters of δ = 0.57 mm/s and ΔE_Q= 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 ΔE_Q= 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)₂and 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

d_xy), 162 (LUMO+5, 80% d_xz), 167 (LUMO+7, 68% d_z2) and temperature with a 1 h reaction time generates an analogous

169 (LUMO+12, 42% d_x2-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

1

both show diffuse Fe d_yzorbital 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 d_xycontributions. 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)₂confirms 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 ΔE_Q= 2.43 mm/s, where the small change in ΔE_Qin 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 ΔE_Q= 2.33 mm/s (

blue), and δ = 0.50 mm/s and ΔE_Q= 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 ΔE_Q=

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

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.³⁶To 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-C_alkylinteractions in ). Notably, the Fe-O

o

system, isolated crystalline

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, ΔE_Q= 3.00 mm/s

evaluating in situ formed iron speciation than quantitation of (88%, green) and δ = 0.90 mm/s, ΔE_Q= 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-d₈yields μ_eff

= 5.1(3) μ_b. 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)₂and

o

2.2 equiv IMes•HCl in THF at 54 C followed by removal of

6 | J. Name., 2012, 00, 1-3

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Table 3 Mössbauer parameters of Iron(II)-NHC complexes

View Article Online

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,

ΔE_Q= 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, d_xy) and a weak

bonding interaction with the oxygen of the alkyl ligand. Fe d

character is also observed in 143 (LUMO, 43% d_yz), 148

(LUMO+5, 79% d_xz), 149(LUMO+6, 63% d_z2), and

151(LUMO+8, 52% d_x2-y2). Strong π interactions with the

carbene of the IMes ligand are observed as shown in 143,

matching the Fe d_yzorbital 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

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 ΔE_Q= 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 ΔE_Q= 2.70 mm/s (67%, purple), the latter

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)X₂complex 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^-1for 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-

8 | J. Name., 2012, 00, 1-3

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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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Journal Name

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%).²³The 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)₂and 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 ΔE_Q= 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

10 | J. Name., 2012, 00, 1-3

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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)₂confirms 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 ΔE_Q=

2.91 mm/s (see ESI), where the small change in ΔE_Qin the solid

state spectrum suggests a slight structural distortion between

solid and solution states.

Ph

X

k_obs> 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

k_obs> 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 (k_obs> 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. ⁴⁹Additionally, spin

product. This selectivity suggests that 1 is a key reactive species

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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 electrophile¹²indicating 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.²³Additionally, 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

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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Page 13 of 15

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Journal Name

ARTICLE

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.

View Article Online

9844-9845.

DOI: 10.1039/C7SC04750A

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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)₂is 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

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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.

Article Doi

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

DOI: 10.1039/c7sc04750a

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Authors:

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