X‐ray Spectroscopic Verification of the Active Species in Iron‐Catalyzed Cross‐Coupling Reactions

Abstract

X-ray absorption: The activation of the pre-catalyst as well as the catalytically active species and reaction mechanism of Fe-catalyzed cross-couplings were investigated by X-ray absorption spectroscopy. The active catalytic components are small iron clusters with three to four FeI centers. The reaction seems to proceed by an FeI/FeIII mechanism (see figure). Over the past two decades iron catalysis has become a powerful tool in organic synthesis.1 Cross-coupling reactions doubtless rank among the most important of these reactions, because they allow effective formation of carbon scaffolds.1f,1h–1, 2 Nowadays, these transformations are a standard tool for the preparation of fine chemicals and biologically active compounds on both laboratory and industrial scales.1d Although cross-coupling reactions are dominated by palladium complexes, iron complex catalysts offer an alternative of increasing importance due to their easy accessibility, short reaction times and broad functional group tolerance.1b,1g Under established conditions alkyl or aryl Grignard reagents are coupled with aryl chlorides, triflates and tosylates.1e,1g,1n, 2a, 3a Despite the importance of iron-catalyzed cross-coupling reactions and intensive investigations, the mechanism of this reaction is still subject to ongoing discussion.1m, 3 Spectroscopic studies are very limited due to the paramagnetic character of the species formed.3a Hence, mechanistic findings are mainly based on investigations of potential intermediates.3a In contrast to palladium-catalyzed cross-couplings, for which detailed mechanistic knowledge exists,4 this gap prevents the directed development of improved iron catalysts for cross-coupling reactions. X-ray absorption spectroscopy represents a method to bridge this gap.5 It provides element specific clarification of local structure and oxidation state of metal centers through EXAFS (extended X-ray absorption fine structure) and XANES (X-ray absorption near edge structure) spectroscopy.6 Employing these methods, the type and number of ligands as well as their distance from the catalytically active metal center can be determined in situ.7 Despite these advantages, which were already used for investigations of different cross-coupling and Grignard reactions,5, 8 to the best of our knowledge no XAS investigations on iron-catalyzed cross-coupling reactions have been reported to date. This is even more surprising, because this type of investigation would enable a comparison of the five suggested mechanisms proposed to date for this type of cross-coupling:3a Kochi et al.9 postulate a “soluble iron species” of unspecified oxidation state, which exists as an aggregate complexed by Grignard compounds. In this case, FeFe pairs characteristic of a metal cluster would be expected in the EXAFS analysis. Bogdanovic et al.10 suggest a heterobimetallic inorganic Grignard complex [Fe−II(MgCl)2]n, which would show FeMg pairs in the EXAFS spectrum. Fürstner et al.11 describe the formation of FeII organoferrates [RnFe+II]2−n. This type of compound would exhibit only Fe–C contributions to the radial distribution function. Noda et al.12 propose diaryl FeII compounds stabilized by TMEDA, which would show similar EXAFS characteristics to the organoferrates described in point 3). Norrby et al.3b suppose a catalytically active FeI-species, which is not further structurally specified. Herein, these proposals will be discussed on the basis of X-ray-spectroscopic investigations. According to the literature,10 a maximum amount of four equivalents Grignard compound are required to form the active iron species. Analogously, the reaction products of iron(III)-acetylacetonate Fe(acac)3 and one to four equivalents phenylmagnesiumchloride PhMgCl in THF/NMP were examined to identify the species formed through activation of the pre-catalyst Fe(acac)3.13 Figure 1 shows the energy-calibrated XANES spectra during addition of 1–4 equivalents of PhMgCl to Fe(acac)3 in THF/NMP. To emphasize small changes, the first derivatives14 of the spectra are displayed as well. Two spectral regions can be distinguished: The pre-edge signal (prepeak)15 at an energy of 7.10–7.11 keV (signal A) and the absorptions edge at a range of 7.11–7.12 keV (signals B and C). The prepeak position of the pre-catalyst Fe(acac)3 is located at 7.106 keV and shifts after addition of one equivalent PhMgCl to a smaller value of 7.104 keV. Whereas this prepeak is caused by a 1s→3d transition, the decreased resonance energy reflects the transition from an s0d5 to an s0d6 electron configuration, which corresponds to a reduction from FeIII to FeII. This energy does not change with addition of further equivalents, but the prepeak intensity and the shape and energy of the absorption edge (signals B and C) changes in a systematic way. The first derivative of the pre-catalyst spectra shows only one signal (B), which shifts significantly in energy after addition of one equivalent of PhMgCl and then exhibits an FeII characteristic doublet structure.14 With addition of the second equivalent, the higher-energetic signal of the doublet disappears. A related spectrum to the resulting first derivative is not known in the literature so far. With addition of three equivalents, another signal appears in the derivative, which can also be found in the spectrum of an iron foil (Fe0). The addition of the fourth equivalent causes no further changes in the spectrum, indicating that the activation of the catalyst is finished after the addition of three equivalents PhMgCl. XANES spectra (right) and their derivatives (left) of the pre-catalyst Fe(acac)3 (1) and after addition of one to four equivalents (2–5) PhMgCl in comparison to Fe0 (6) and under reaction conditions (7). Although the XANES spectra of the active species might lead to speculation about a metalloide species due to the presence of the signals A, B and C, the shape and position of the signals deviate from that of an Fe0 species. Even size-effects do not cause considerable changes in spectra of Fe0 nanoparticles compared with spectra of a bulk Fe foil.16 Hence the broadened shape of the prepeak signal is not the result of Fe0 nanoparticle formation.17 The rather distinct separation of the prepeak from the main-edge indicates a certain ionic character. Because the Fe0 and FeII oxidation states can be excluded due to the XANES shape, the spectra of three and four equivalents of PhMgCl are thus assigned to an oxidation state of FeI, in keeping with the findings of Adams et al. in iron-catalyzed Negishi reactions.18 This argument is supported by quantification of the organic redox product biphenyl (PhPh). It is formed by an oxidative coupling of two Ph− during the reduction of FeIII. Because β-hydride elimination can be excluded as side path, the number of electrons transferred to iron can be determined by quantification of the PhPh formed by means of gas chromatography.19 Because no organo-halide is present as potential coupling reagent at this stage, reversible redox-pairs can be excluded.18 Fe(acac)3 was treated with 1–10 equiv PhMgCl and the resulting reaction mixtures were analyzed by quantitative GC.20 In presence of one equivalent of PhMgCl, full conversion to biphenyl was observed. It is likely, that the phenyl-anion reduced FeIII to FeII under formation of a phenyl-radical, two of which can couple forming the biphenyl observed. Analogous homo-couplings of Grignard compounds in presence of FeIII-complexes have already observed.18, 20 With the addition of two equivalents of PhMgCl, only 65 % of the theoretical amount of biphenyl is formed through reduction of FeIII to FeI (Table 1, entry 2). This suggests a formal alteration of the oxidation state from +3 to +1.7. In contrast, the addition of three equivalents of Grignard reagent leads to a formal change in oxidation state from +3 to +1. If one equivalent of Fe(acac)3 is converted with an excess of four or ten equivalents PhMgCl, only small differences in the formed oxidation states are visible compared to addition of three equivalents. Entry Sample AbsBs[a] N(Bs)[b] R(Bs)[c] [Å] σ[d] [Å] R[e] [%] Transferred e− oxidation state of Fe 1 Fe(acac)3 FeO(acac) FeC 6 6 1.99±0.02 2.93±0.03 0.067±0.007 0.084±0.008 24.10 – 2 +1 equiv PhMgCl FeO(acac) FeO(THF/NMP) FeFe 3.9±0.2 2.0±0.2 0.7±0.3 2.04±0.02 2.20±0.02 2.55±0.03 0.081±0.004 0.039±0.004 0.100±0.040 19.85 1.0 equiv +2.0 3 +2 equiv PhMgCl FeC(Ph) FeO(THF/NMP) FeFe FeMg 1.4±0.1 0.4±0.1 5.1±0.5 1.6±0.3 1.94±0.02 2.19±0.02 2.42±0.02 2.74±0.03 0.112±0.011 0.032±0.003 0.102±0.010 0.097±0.040 7.97 1.3 equiv +1.7 4 +3 equiv PhMgCl FeC(Ph) FeO(THF/NMP) FeFe FeMg 1.1±0.1 1.5±0.1 2.0±0.4 0.5±0.3 1.97±0.02 2.07±0.02 2.55±0.03 2.62±0.03 0.032±0.003 0.039±0.004 0.112±0.011 0.032±0.015 23.32 2.0 equiv +1.0 5 +4 equiv PhMgCl FeC(Ph) FeO(THF/NMP) FeFe FeMg 0.8±0.1 1.4±0.1 2.6±0.4 1.0±0.3 1.95±0.02 2.10±0.02 2.52±0.02 2.59±0.03 0.059±0.006 0.032±0.003 0.112±0.011 0.050±0.015 19.03 2.3 equiv +0.7 7 Reaction cond. (+4 equiv PhMgCl+10 equiv 1 b) FeC(Ph) FeO(THF/NMP) FeFe FeMg 1.5±0.1 0.4±0.1 6.7±0.4 1.8±0.3 1.93±0.02 2.14±0.02 2.44±0.02 2.80±0.03 0.112±0.011 0.045±0.004 0.100±0.040 0.097±0.040 10.29 – The trends observed in the XANES spectra and the results of the GC investigations are reflected in the EXAFS spectra as shown in Figure 2. The nuclearity of the iron compound formed during the activation process and the nature of the ligands coordinated to the metal core can both be extracted from the EXAFS spectra. In course of the activation, the EXAFS signal is dominated by iron–iron contributions because of the high backscattering amplitude of iron. The coordination number of iron follows no regular behavior, as can be seen in Table 1. Based on the FeFe coordination number of 0.7 obtained after reaction with one equivalent of PhMgCl the formation of dimers can be deduced. The iron–iron distance of 2.55 Å is consistent with the partial reduction of the iron centers deduced from the XANES spectra and literature values (2.46–2.69 Å) for FeII dimers with direct FeFe contact and bridging C- or N-containing ligands (e.g., [Fe(mes)2]2 or [Fe(tim)]2).22 With two equivalents PhMgCl the number of iron–iron contacts increases to 5.1. Thereby the presence of iron-clusters with a size of 13±2 atoms can reasonably be assumed.23 GC quantification of the biphenyl formed, suggests a formal oxidation number of +1.7.23 A fractional oxidation number, such as 1.7, cannot be realized in a molecular compound and supports the cluster formation hypothesis. The iron–iron distance of 2.42 Å extracted, on the other hand, is in the lower range of documented values for multinuclear FeII compounds24 and supports the ascertained number electrons transferred. Surprisingly, the addition of three and four equivalents PhMgCl causes a decrease in aggregation from Fe13 to Fe3–4. The oxidation state determined from GC analysis is FeI, which is verified by the FeFe distance of 2.53 Å.25 In general the error in the determination of the iron core size by EXAFS spectroscopy is small, because the FeFe coordination number excludes the presence of larger clusters. Fourier-transformed EXAFS spectra of the pre-catalyst Fe(acac)3 (1) after addition of one to four equivalents PhMgCl (2–5) and under reaction conditions (7) with 2-chloropyridine as coupling reagent. The constitutive shells are indicated as bars.21 Besides FeFe pairs, contributions of the lighter atoms present (Table 1) also provide information about the ligands stabilizing the iron core. After addition of one equivalent of PhMgCl, FeO contributions are found, which can be assigned to the pre-catalyst Fe(acac)3.26 Because all PhMgCl was consumed by the formation of Ph-Ph, the coordination of phenyl residues can be excluded. The coordination number of four determined agrees well with UV/Vis measurements, which indicated that 65 % FeO(acac) signal signal remained.27 In addition to the first FeO shell, a second contribution of a lighter backscatterer at a distance of 2.2 Å could be detected, which is attributed to bridging, neutral ligands like THF or NMP.28 NMP is known to stabilize small nanoparticles.29 Further contributions, which could indicate coordinating MgX groups, were not found after addition of one equivalent of PhMgCl. This changes with addition of the second equivalent PhMgCl. Raman and UV/Vis-measurements detect only marginal FeO(acac) contributions.30 An FeC bond with a length of 1.94 Å can be deduced, which suggest an average of 1.4 coordinating phenyl residues.31 The sterically demanding aryl groups coordinate to FeI at a distance of 2.0 Å.18, 32 Because 1.3 equivalents of phenyl anion were consumed forming PhPh, 0.7 equivalents remain formally available. To obtain an EXAFS coordination number of 1.4, the phenyl groups must act as bridging ligands. Furthermore, every iron center is stabilized by 1.6 Mg atoms at a distance of 2.74 Å, which can be attributed to FeMg(Cl) according to literature.10 The coordination is complemented through coordination of 0.5 THF/NMP ligands at a distance of 2.2 Å.28b Although addition of a third equivalent PhMgCl causes significant alterations in the FeFe core, the coordination numbers in the ligand shells change only slightly. The number of coordinating Ph− residues decrease to one because two equivalents of Ph− are consumed in reduction process the FeC coordination number obtained by EXAFS coincides exactly with the quantitative GC analysis results. In contrast, the number of THF/NMP ligands increases slightly, whereas their distance from the FeFe core decreases by 0.12 to 2.07 Å. These FeO distances are known for ether compounds coordinating on low-valent iron-centers.8a,8b The FeMg coordination number decreases to 0.5 when three equivalents of PhMgCl are used, accompanied by a shorter bond length of 2.62 Å. This relatively short distance is characteristic for a strong covalent interaction between magnesium ligands and an Fe3 core.8a, 33 Through addition of a fourth equivalent of PhMgCl, no further structural changes were observed. The results of the EXAFS analysis correspond to the XANES evaluation. Both methods together with GC analysis, Raman and UV/Vis spectroscopy demonstrate that only three equivalents of reduction reagent PhMgCl are necessary to form the catalytically active species. Furthermore the data show that in contrast to iron-catalyzed Negishi couplings, the active species is not characterized by FeX (X=Cl−, Br−) bonds, but by FeR (R=Ph−) bonds.18 Finally, after structural determination of the species formed in the activation process, the catalytic activity of these species was demonstrated. Hereto 5 mol % Fe(acac)3 were converted with 15 mol % PhMgCl (Scheme 1). In presence of the in situ formed catalyst a cross-coupling reaction between aryl halide 1 a and nHexMgCl to form product 2 a with a yield of 89 % could be conducted. The yield of an analogous reaction with nHexMgBr is documented with 91 % yield in ref. 2a. In general, cross-coupling of heterocyclic compounds with nHexMgCl is possible under similar reaction conditions. The conversion of the pyridine derivate 1 b leads to product 2 b in moderate yield of 59 % (Scheme 1). However, with nHexMgBr a 91 % yield could be achieved.34 Test reactions and yields. The XANES spectrum of the spectroscopic “resting state” under reaction conditions as applied in the first example is shown in Figure 1. It displays the same spectral signatures as the spectrum of an FeII species with two equivalents PhMgCl. Nevertheless, EXAFS data imply the formation of larger nanoparticles as indicated by a higher FeFe coordination number. Although XAS only gathers the average spectra of all species present in the reaction mixture, the mechanism displayed in Scheme 2 can be deduced based on the spectroscopic and catalytic data presented. In the first step the pre-catalyst Fe(acac)3 is reduced to the catalytically active FeI species with an oxidation state. Subsequently an oxidative addition of the organohalide occurs, associated with a change of the oxidation state from FeI to FeIII. The spectroscopic observation of FeII substantiates the presence of Fe nanoparticles in this case. In their core, FeI centers persist. Averaged with the FeIII centers from the oxidative addition on the particle surface this yields a mean oxidation state of FeII. The averaged FeFe coordination number corresponds to a cluster diameter of approximately 10 Å.23c Clusters of that size exhibit a surface atom (FeIII) to bulk atom (FeI) ratio of 1:1,35 which would result in an observed FeII. Proposed mechanism of Fe-catalyzed cross-coupling reactions. Subsequent transmetallation and ensuing reductive elimination with release of the product and regeneration of the active catalyst has not been experimentally demonstrated so far, but is certainly plausible. Based on XAS results, a composition of Fe3(MgCl)3L3 is possible. The oxidation state obtained from XANES spectra and GC analysis is FeI, which is in agreement with the recent study of Norrby et al. who also found that the Grignard reagent alone can only reduce the iron pre-catalyst to FeI.36 The XAS results presented allow the assessment of the non-spectroscopic mechanistic studies of iron cross-coupling reactions reported to date. Based on the oxidation state of FeI for the active species determined by XANES and GC analysis, it is possible to preclude hypotheses 2,10 311 and 4,12 because these species have oxidation states of −II and +II. Nevertheless the suggestion of Bogdanovic et al.10 postulates a structure element with an FeMg bond, which was also advanced by Kochi.9 The proposal assumes an agglomeration, the extent of which could only be demonstrated to be very small by the EXAFS results described herein. The oxidation state found agrees with that established by Norrby.3b Comparisons with related studies37 suggest that the oxidation state of the active species depends on the nature of the Grignard reagent, which is based on coordination of the organic Grignard reagent. Further systematic studies to this point are planned for the near future. X-ray absorption measurements were carried out at beamlines XAS and X1 at the synchrotrons ANKA (Karlsruhe) and HASYLAB (Hamburg). All measurements at the Fe K edge (7.112 keV) were performed in transmission under application of a Si(111) double crystal monochromator and N2-filled ionization chambers in a cell, which allows for work under inert conditions. Details of the experimental procedure and treatment of the date are found in the Supporting Information, as well as details of the GC analysis and sample preparation. M.B. gratefully acknowledges financial support of the Carl-Zeiss foundation and the Landesforschungsschwerpunkt Rheinland-Pfalz Nanokat. Additionally, beamtime provision by HASYLAB (Hamburg) and ANKA (Karlsruhe) is acknowledged as well as support by Dr. E. Welter and Dr. S. Mangold. As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.