Intermediates and Reactivity in Iron-Catalyzed Cross-Couplings of

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Intermediates and Reactivity in Iron-Catalyzed CrossCouplings of Alkynyl Grignards with Alkyl Halides Jared L. Kneebone, William W. Brennessel, and Michael L. Neidig J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 26 Apr 2017 Downloaded from http://pubs.acs.org on April 26, 2017

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Journal of the American Chemical Society

Intermediates and Reactivity in Iron-Catalyzed Cross-Couplings of Alkynyl Grignards with Alkyl Halides Jared L. Kneebone, William W. Brennessel, and Michael L. Neidig* Department of Chemistry, University of Rochester, Rochester, New York 14627, United States ABSTRACT: Iron-catalyzed cross-coupling reactions using alkynyl nucleophiles represent an attractive approach for the incorporation of alkynyl moieties into organic molecules. In the present study, a multi-technique approach combining inorganic spectroscopic methods, inorganic synthesis, and reaction studies is applied to iron-SciOPP catalyzed alkynyl-alkyl cross-couplings, providing the first detailed insight into the effects of variation from sp2 to sp nucleophiles on iron speciation and reactivity. Reaction studies demonstrate that reaction of FeBr2(SciOPP) with 1 equiv (triisopropylsilyl)ethynylmagnesium bromide (TIPS-CC-MgBr) leads to a distribution of mono-, bis-, and tris-alkynylated iron(II)-SciOPP species due to rapid alkynyl ligand redistribution. While coordinating solvents such as THF promote these complex redistribution pathways, non-polar solvents such as toluene enable increased stabilization of these iron species and further enabled assessment of their reactivity with electrophile. While the tris-alkynylated iron(II)-SciOPP species was found to be unreactive with cycloheptyl bromide electrophile over the average turnover time of catalysis, the in-situ formed neutral mono- and bis-alkynylated iron(II)-SciOPP complexes are consumed upon reaction with electrophile with concurrent generation of cross-coupled product at catalytically relevant rates, indicating the ability of one or both of these species to react selectively with electrophile. The nature of reaction solvent and Grignard reagent addition rate were found to have broader implications in overall reaction selectivity, reaction rate, and accessibility of off-cycle iron(I)-SciOPP species. Additionally, effects of steric substitution of the alkynyl Grignard reagent on catalytic performance were investigated. The fundamental insight into iron speciation and reactivity with alkynyl nucleophiles reported herein provides an essential foundation for the continued development of this important class of reactions.

1. INTRODUCTION Iron catalyzed carbon-carbon (C-C) cross-coupling methods have become promising alternatives to traditional precious metal catalytic systems in terms of cost and accessibility of novel reactivity.1-9 Following the pioneering work of Kochi and co-workers,10-13 the last two decades have witnessed a significant increase in reports of iron-based Kumada,14-31 Negishi,32-37 and Suzuki-Miyaura38-43 systems that promote effective arylations, alkylations, and alkenylations of a range of electrophilic substrates. Such methods have demonstrated the applicability of ‘ligandless’ catalytic protocols as well as the effectiveness of a number of reaction additives and supporting ligands on optimizing reaction yields and selectivity. In contrast, the development of iron catalyzed cross-coupling methods utilizing alkynyl nucleophiles has received relatively little attention despite the importance of sp-hybridized carbon centers within a wide range of organic products. Currently, iron catalyzed cross-coupling methods using alkynyl nucleophilic coupling partners are limited to couplings with alkyl or alkenyl electrophiles and facilitated by bisphosphine-supported precatalysts44-45 or simple iron salts.46-47 Scheme 1 highlights progress made in the development of iron catalyzed Csp-Csp3 cross-coupling methods to date.

A particularly versatile example of such methods was highlighted by Nakamura and co-workers using alkynyl Grignard reagents (Scheme 1, top).44 In this reaction, the combination of FeCl2(SciOPP) precatalyst and bulky alkynyl Grignard reagents results in high yields of ethynylated cyclic and primary alkanes deriving from alkyl bromides, chlorides, and pseudohalides over relatively short reaction times (2 h). Notably, elevated reaction temperature and the use of slow nucleophile addition rates are key to successful catalysis in THF solvent. Based on radical clock experiments, Nakamura and coworkers proposed a radical-based mechanism for this catalysis in which a doubly alkynylated iron(II)-SciOPP species serves as the active catalyst resting state (Scheme 2), similar to previous proposals for aryl-alkyl coupling systems using the FeCl2(SciOPP) precatalyst.26, 39, 43, 45 The proposed cycle proceeds via homolytic cleavage of the C-X bond of the electrophile by the alkynylated iron(II)-SciOPP active species to generate a transient iron(III) intermediate from which crosscoupled product is ultimately formed. The resulting monoalkynylated iron(II)-SciOPP species could then undergo transmetalation by additional equivalents of Grignard reagent to regenerate the active catalyst. Furthermore, alkynylated

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Scheme 1. Examples of Iron Catalyzed Csp-Csp3 Cross-Coupling Reactions.

Scheme 2. Catalytic Cycle Proposed by Nakamura and Coworkers for the Cross-Coupling of Alkynyl Grignards with Alkyl Halides Catalyzed by FeCl2(SciOPP). P

Cl FeII Cl

P

2 equiv R

excess highly alkynylated ferrate species

R

MgBr

R

P

MgBr

R' X

FeII P

R

R

MgBr

P X P

R

FeIII

X

P

FeII P

R'

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characterization of in situ generated iron speciation with assessment of their reactivity to form cross-coupled product.4851 In particular, freeze-trapped 57Fe Mössbauer spectroscopy has been demonstrated to serve as a powerful complement to traditional analyses of organic product distributions to correlate formation and consumption of iron intermediates with product generation. Use of this approach has generated unprecendented insight into the principles governing reactivity within iron catalyzed cross-coupling methods using aryl nucleophiles, enabling the identification of iron(II) active species in ironSciOPP catalyzed cross-couplings of alkyl halides with mesitylmagnesium bromide (MesMgBr)48 and phenyl nucleophiles (PhMgBr and activated phenyl borates).49 Such findings support Fe(II)/Fe(III) mechanistic cycles in these cross-coupling reactions and have enabled elucidation of how aspects of reaction protocol (i.e. excess ligand addition, slow nucleophile addition rate) correlate to effective catalysis. While such insight has proven valuable in understanding the origins of reactivity within aryl-alkyl cross-coupling reactions, extension of these studies to systems using non-aryl nucleophiles has not yet been undertaken. The promising scope and growing versatility of cross-coupling methods using alkynyl nucleophiles necessitates a more fundamental understanding of the effects of variation of nucleophile on origins of reactivity, formation of reactive intermediates, and active catalyst oxidation state within iron catalyzed cross-coupling catalysis. Herein, we employ a multi-technique inorganic spectroscopic approach to complement synthetic and reaction studies in order to achieve the first fundamental insight into iron speciation and reactivity in cross-couplings using alkynyl nucleophiles, focusing on iron-SciOPP catalyzed alkynyl-alkyl cross-couplings using alkynyl Grignards reagents. Variation of the nature of the nucleophilic coupling partner from aryl to alkynyl was found to impart considerable effects on accessible iron speciation, stability of reactive intermediates, and off-cycle species accessible during catalysis. Importantly, while iron(I) is accessible in this system during catalytic turnover, it represents unproductive, off-cycle species. In contrast, neutral alkynylated iron(II)-SciOPP species are identified as key reactive intermediates that promote selective formation of cross-coupled product upon reaction with electrophile. The findings presented in this study further illuminate the intricacies of iron catalyzed cross-coupling and provide the first insight into the broader relevance of iron(II)-bisphosphine active species in cross-coupling systems beyond those employing aryl nucleophiles.

R

R

R'

R

ferrate species formed via over-alkynylation of iron(II)-SciOPP centers were proposed to be responsible for the generation of side products. To date, none of the proposed iron intermediates have been directly observed or characterized and the nature of potential off-cycle species has not been assessed. Recent studies in our group have overcome inherent challenges associated with the characterization of iron intermediates and mechanism within iron catalyzed crosscoupling reactions through the application of a multi-technique experimental approach, combining direct spectroscopic

2. RESULTS AND ANALYSIS 2.1. Stoichiometric Reactions of FeBr2(SciOPP) with TIPSCC-MgBr: Observation of Alkynyl Ligand Redistribution. The slow rate of Grignard addition reported by Nakamura and co-workers for the iron-SciOPP catalyzed cross-coupling of alkynyl Grignard reagents with alkyl halides (~ 0.4 equiv per minute with respect to iron)44 is comparable to the average turnover time of catalysis (~ 0.4 min-1)52 and thus fundamentally limits the amount of nucleophile present in solution with respect to iron during turnover. This low ratio of Grignard to iron in solution during catalysis suggests that mono- and/or bisalkynylated iron-SciOPP species may be candidates for reactive and selective catalytic intermediates. Having previously identified neutral arylated iron(II)-SciOPP species as reactive


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intermediates in the cross-coupling of aryl nucleophiles with alkyl halides,48-49 we sought to access analogous alkynylated iron(II)-SciOPP species and ultimately examine their potential role as active species in the catalytic alkynylation of alkyl halides. Therefore, initial studies focused on the identification of iron species formed in situ upon reaction of iron(II)-SciOPP precatalyst with stoichiometric TIPS-CC-MgBr. Reaction of FeBr2(SciOPP) with 1 equiv TIPS-CC-MgBr in 1:1 (v:v) THF/2-MeTHF solvent at room temperature resulted in the rapid formation of an orange-brown solution and aliquots of the reaction mixture were freeze-trapped for frozen solution Mössbauer analysis as a function of reaction time.53 5 K Mössbauer spectra of this reaction timepoints revealed formation of a four-component iron distribution by 1 min following Grignard reagent addition and further evolution of the iron speciation through 30 min (Figure 1). The multicomponent fit analysis in Figure 1A (1 min after Grignard addition) indicates the presence of untransmetalated FeBr2(SciOPP) as the major iron component in solution (green doublet, 45% of all iron) along with three additional quadrupole doublet components all with reduced isomer shifts relative to the dihalide complex, consistent with transmetalation of SciOPP-supported iron centers. The two major transmetalated species are characterized by Mössbauer parameters ! = 0.57 mm/s and "EQ = 2.41 mm/s (21%, blue doublet, 1) and ! = 0.31 mm/s and "EQ = 3.18 mm/s (26%, purple doublet, 2), similar to those of mono- and bis-arylated iron(II)-SciOPP complexes studied previously by our group.48-49 By comparison, the third minor doublet species present in Figure 1A is characterized by a reduced isomer shift and quadrupole splitting relative to 1 and 2 (! = 0.14 mm/s and "EQ = 0.76 mm/s; 8%, orange doublet, 3), suggestive of a more highly transmetalated iron-SciOPP species. Over the course of 30 min (Figure 1B-C) the amount of FeBr2(SciOPP) (53% at 5 min, 61% at 30 min) and 3 (16% at 5 min, 22% at 30 min) present in solution increases with concomitant consumption of both 1 (13% at 5 min, fully consumed by 30min) and 2 (18% at 5 min, 17% at 30 min). 5 K frozen solution EPR analysis of reaction aliquots sampled at the same reaction time points indicated the absence of halfinteger spin iron species, confirming that neither 1, 2, nor 3 are mononuclear iron(I) complexes. Iron distributions similar to those in Figure 1 can also be achieved at 70 oC over shorter time periods (< 30 s), demonstrating the accessibility of 1, 2, and 3 at temperatures required for effective iron-SciOPP catalyzed alkynyl-alkyl cross-couplings (see Section 2.6). Lastly, reaction of FeBr2(SciOPP) with 1 equiv TIPS-CC-MgBr at 70 o C in the absence of THF (in toluene solvent using TIPS-CCMgBr prepared in Et2O) also results in a mixture of FeBr2(SciOPP), 1, 2, and 3 (see section 2.6). The dynamic nature of the in situ generated iron distribution in Figure 1 is consistent with the redistribution of alkynyl ligands between iron centers over time and supplies further evidence that the Mössbauer parameters of 3 characterize a more highly alkynylated iron center than 1 and 2. Stabilization of 3 as the majority component in 1:1 THF/2-MeTHF was unsuccessful even when 3 equiv TIPS-CC-MgBr was added to FeBr2(SciOPP) (see SI Figure S1). However, formation of complex iron distributions was inhibited upon rigorous exclusion of THF. Using alternative reaction solvents such as 1:1 (v:v) Et2O/isopentane in conjunction with TIPS-CC-MgBr prepared in Et2O results in the quantitative generation of a

Figure 1. 5 K frozen solution Mössbauer spectra of the in situ generated iron distribution formed upon reaction of 57 FeBr2(SciOPP) with 1 equiv TIPS-CC-MgBr in 1:1 THF/2MeTHF at room temperature after (A) 1 min, (B) 5 min, and (C) 30 min of reaction time. Assignments of individual doublets and their relative percentages in each spectrum are as follows: (A) 57 FeBr2(SciOPP), 45% (green); 1, 21% (blue); 2, 26% (purple); 3, 8% (orange). (B) 57FeBr2(SciOPP), 53% (green); 1, 13% (blue); 2, 18% (purple); 3, 16% (orange). (C) 57FeBr2(SciOPP), 61% (green); 2, 17% (purple); 3, 22% (orange).

single iron species following treatment of 57FeBr2(SciOPP) with 3 equiv TIPS-CC-MgBr, characterized by Mössbauer parameters matching those of 3 measured in 1:1 THF/2-MeTHF frozen solutions (! = 0.14 mm/s and "EQ = 0.76 mm/s in 1:1 Et2O/isopentane, see SI Figure S2). Solutions of in situ generated 3 in 1:1 Et2O/isopentane, neat Et2O, or neat hydrocarbon solvents including pentane and toluene are green at room temperature, and slow evaporation of 1:1 Et2O/isopentane or neat Et2O solutions of 3 resulted in the formation of green crystalline solid identified as the fivecoordinate ferrate complex [Fe(CC-TIPS)3(SciOPP)][MgBr] by single-crystal X-ray diffraction (Figure 2A). Mössbauer spectroscopic analysis of ground crystals of 3 at 5 K demonstrated a distinct increase in the quadrupole splitting ("EQ = 2.61 mm/s) compared to the frozen solution spectrum of 3, while the isomer shift remains essentially unchanged (! = 0.10 mm/s) (Figure 2B). This square-pyramidal iron(II) complex was determined to be intermediate spin (S = 1) in solution at room temperature by solution magnetic susceptibility measurements.



Figure 2. Solid state characterization of 3. (A) X-ray crystal structure of 3 with thermal ellipsoids drawn at the 50% probability level. Hydrogen atoms as well as the terminal methyl groups of the (triisopropylsilyl)ethynyl ligands have been removed for clarity. (B) 5 K Mössbauer spectrum of solid 3 isolated from the reaction of 57FeBr2(SciOPP) with 3 equiv TIPS-CC-MgBr (Grignard reagent prepared in Et2O) at room temperature in 1:1 (v:v) Et2O/isopentane. Assignments of the doublets and their relative percentages in Figure 2B are as follows: ! = 0.10 mm/s, "EQ = 2.61 mm/s (red, 90%) and ! = 0.14 mm/s and "EQ = 0.76 mm/s (orange, 10%).

The minor component present in the 5 K solid Mössbauer spectrum of 3 (! = 0.14 mm/s and "EQ = 0.76 mm/s, orange doublet, 10% of all iron) is characterized by Mössbauer parameters matching those observed in the frozen solution Mössbauer spectra of in situ generated 3. Also noteworthy is the change in solution color from green to yellow upon cooling solutions of in situ generated 3 to low temperatures as well as in the process of freezing spectroscopy samples, indicative of a structural and/or spin state change under such conditions. Consistent with these observations, storage of Et2O solutions of 3 at -30 oC induced the precipitation of yellow block crystals from the corresponding yellow solution, the solid state molecular structure of which was characterized by single crystal X-ray diffraction as the coordinatively saturated dinitrogen adduct of 3, [Fe(CC-TIPS)3(!1-N2)(SciOPP)][MgBr] (3-N2, Figure 3A). 5 K Mössbauer analysis of the ground crystalline

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Figure 3. Solid state characterization of 3-N2. (A) X-ray crystal structure of 3-N2 with thermal ellipsoids drawn at the 50% probability level. Hydrogen atoms as well as the terminal methyl groups of the (triisopropylsilyl)ethynyl ligands have been removed for clarity. (B) 5 K Mössbauer spectrum of solid 3-N2, characterized by a doublet with ! = 0.14 mm/s and "EQ = 0.76 mm/s.

solid yielded parameters matching those of 3 in 1:1 Et2O/isopentane frozen solutions (Figure 3B). Dinitrogen coordination to the iron center was unexpected as such behavior has not yet been observed in iron-SciOPP chemistry. The magnitude of both the isomer shift and quadrupole splitting of 3-N2 are consistent with a coordinatively saturated low-spin (S = 0) iron(II) center, and the presence of a minor amount of 3-N2 in the solid Mössbauer spectrum of isolated 3 is consistent with finite dinitrogen uptake in the solid state upon cooling. While dinitrogen coordination to form 3-N2 is quantitative in solution at low temperatures, 3 represents the dominant species in solution during reactions at room temperature or above and thus the observation of 3-N2 in frozen solution Mössbauer spectra reflects 3 being present in solution. Therefore, throughout the remainder of this report the observation of 3-N2 in freeze-trapped solutions is correlated with the presence of 3 in solution. 2.2. Stability and Reactivity of [Fe(CCTIPS)3)(SciOPP)][MgBr] (3). As discussed in section 2.1, the


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Journal of the American Chemical Society dissolved in toluene or 1:1 THF/2-MeTHF. The Mössbauer spectra in Figure 4 indicate that the (triisopropylsilyl)ethynyl ligands of 3 dissociate and alkynylate 57FeBr2(SciOPP) to form 1 (6%, blue doublet) and 2 (12%, purple doublet) when toluene solutions of 3 are mixed with equimolar 57FeBr2(SciOPP) in 1:1 THF/2-MeTHF. By contrast, no alkynyl ligand redistribution was observed using a toluene solution of 57FeBr2(SciOPP), indicating that the spontaneous generation of additional ironSciOPP species via alkynyl ligand redistribution between 3 and FeBr2(SciOPP) is solvent dependent. The stability of 3 toward decomposition and alkynyl ligand redistribution at elevated temperatures in higher-boiling nonpolar solvents such as toluene enabled the assessment of its reactivity with electrophile at catalytically relevant temperature (70 oC, reported by Nakamura and co-workers). Simultaneous freeze-trapped Mössbauer spectroscopic and GC analysis of the reaction of 3 with 20 equiv cycloheptyl bromide at 70 oC over 5 min indicated no consumption of 3 and no conversion of cycloheptyl bromide (see SI Figure S5). Thus, 3 is unreactive toward cycloheptyl bromide in toluene within a timeframe relevant to the average turnover time of catalysis. Moreover, the ability to achieve effective catalysis at elevated temperature in toluene further supports 3 as an off-cycle iron species (see below, section 2.4). Importantly, GC analysis of the unproductive reaction of 3 with cycloheptyl bromide resulted in the observation of homocoupled nucleophile 1,4bis(triisopropylsilyl)buta-1,3-diyne (TIPS-CC-CC-TIPS) as well as (triisopropylsilyl)acetylene (TIPS-CC-H), indicating that such products can result from hydrolysis quenching of alkynylated iron-SciOPP species (see also SI Figure S5).

Figure 4. 5 K frozen solution Mössbauer spectra demonstrating the solvent dependence of alkynyl ligand redistribution between 3 and 57 FeBr2(SciOPP). (A) In situ generated 3 at room temperature in toluene, characterized by a single doublet with ! = 0.14 mm/s and "EQ = 0.76 mm/s. (B) The in situ generated iron distribution resulting from addition of 57FeBr2(SciOPP) in 1:1 THF/2-MeTHF to an equimolar amount of in situ generated 3 in toluene at room temperature and (C) resulting from addition of 57FeBr2(SciOPP) in neat toluene to an equimolar amount of in situ generated 3 in toluene at room temperature. Assignments of individual doublets and their relative percentages in spectra (B) and (C) are as follows: (B) 57FeBr2(SciOPP), 40% (green); 1, 7% (blue); 2, 12% (purple); 3, 41% (orange). (C) FeBr2(SciOPP), 50% (green); 3, 50% (orange).

stability of 3 towards alkynyl ligand redistribution was observed to be solvent dependent, and even solutions of 3 generated in toluene at 70 oC using TIPS-CC-MgBr prepared in Et2O were found to be stable over the course of hours (see SI Figure S3). However, exposure of these solutions of 3 to THF resulted in a color change from green to dark brown over the course of minutes even at room temperature, and freeze-trapped Mössbauer spectroscopic analysis of the resulting mixture indicated alkynyl ligand redistribution and potential decomposition (see also SI Figure S3). Notably, exposure of solutions of in situ generated 3 to additional equivalents of TIPS-CC-MgBr prepared in Et2O demonstrated lack of further alkynylation of the iron center, likely due to the terminal steric bulk of the (triisopropylsilyl)ethynyl ligands of 3 (see SI Figure S4). Furthermore, exposure of toluene solutions of 3 to equimolar solutions of FeBr2(SciOPP) resulted in different iron distributions depending on whether the dihalide complex was

2.3. Identification and Characterization of Neutral Alkynylated Iron(II)-SciOPP Species. The identification of 3 as a SciOPP-coordinated iron(II) ferrate combined with the observation of facile alkynyl ligand redistribution between alkynylated iron-SciOPP species in situ further suggests that 1 and 2 are singly and doubly alkynylated iron(II)-SciOPP species, respectively. The exceptional solubility of both 1 and 2 in hydrocarbon and ethereal solvents combined with their propensity toward alkynyl ligand redistribution in THF necessitated more stringent conditions to pursue structural and solution characterization. Treatment of a room temperature hexane suspension of FeBr2(SciOPP) with 1 equiv TIPS-CCMgBr (Grignard reagent prepared in Et2O) was found to result in yellow-orange reaction mixtures that, following the separation of magnesium salts, yielded orange crystals during slow evaporation of the mother liquor at room temperature. Despite the use of only 1 equiv TIPS-CC-MgBr in the reaction, the crystals formed were confirmed by single crystal X-ray diffraction to be the neutral bis-alkynylated iron(II) species Fe(CC-TIPS)2(SciOPP)•MgBr2 (Figure 5A). Such a result is consistent with the facile akynyl ligand redistributions observed in 1:1 THF/2-MeTHF described above, demonstrating that such processes are not completely inhibited in non-polar media. The 5 K Mössbauer spectrum of the solid bis-alkynylated complex is characterized by ! = 0.36 mm/s and "EQ = 3.32 mm/s, similar to those previously reported for the bis-phenylated iron(II)SciOPP species Fe(Ph)2(THF)(SciOPP) (see Figure 5B and Table 2).49 The solid state Mössbauer parameters of the complex are quite similar to those of 2 in 1:1 THF/2-MeTHF frozen solution. Furthermore, dissolution of solid 57Fe(CCTIPS)2(SciOPP)•MgBr2 in 1:1 THF/2-MeTHF at -70 oC is accompanied by the following observations: 1) the presence of



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Table 1. Summary of Mössbauer parameters of alkynylated and phenylated iron(II)-SciOPP species a complex

sample

b

! (mm/s)

"E Q (mm/s)

Alkynylated iron(II)-SciOPP (this work) Fe(CC-TIPS)Br(SciOPP) (1)

frozen soln

0.57

2.41

Fe(CC-TIPS)2(SciOPP) (2)

frozen soln solid

0.31 0.36

3.18 3.32

[Fe(CC-TIPS)3(SciOPP)][MgBr] (3)

solid

0.10

2.61

frozen soln solid

0.14 0.14

0.76 0.76

Fe(Ph)Br(SciOPP)

frozen soln

0.50

2.37

Fe(Ph)2(THF)(SciOPP)

frozen soln

0.32

3.13

Fe(Ph)2(SciOPP)

frozen soln

0.33

1.50

1

[Fe(CC-TIPS)3(! N 2)(SciOPP)][MgBr] (3-N 2) Phenylated iron(II)-SciOPP (ref. 49)

a

All spectra were collected at 5 K.

b

All frozen solution spectra were acquired on 1:1 THF/2-MeTHF frozen solution samples.

Figure 5. Solid state characterization of 2. (A) X-ray crystal structure of 2 with thermal ellipsoids drawn at the 50% probability level. Hydrogen atoms as well as the terminal methyl groups of the (triisopropylsilyl)ethynyl ligands have been removed for clarity. (B) 5 K Mössbauer spectrum of solid 2, characterized by a doublet with ! = 0.36 mm/s and "EQ = 3.32 mm/s.

solution Mössbauer parameters that are closer to those observed for in situ generated 2 in 1:1 THF/2-MeTHF frozen solutions, and 2) alkynyl ligand redistribution from 2 to form 1, 3, and 57 FeBr2(SciOPP) (see SI Figure S6). Combined, the structural and solution characterization data enabled the assignment of 2 in solution as a bis-alkynylated iron(II)-SciOPP species. The inherent instability of 2 in solution precluded a detailed in situ spectroscopic analysis of spin state and thus DFT calculations were performed to gain further insight into the electronic structure of this species. Spin-unrestricted calculations on optimized structures of Fe(CC-TIPS)2(SciOPP)•MgBr2 as a function of spin state resulted in a description of the structure as intermediate spin iron(II) (S = 1) (see SI Tables S5 and S6). Notably, the distorted square planar complex iron(II) complex Fe(Mes)2(SciOPP) reported previously by our group is also intermediate spin.48 In contrast, the neutral bis-alkynylated iron(II)-NHC complex (IPr2Me2)2Fe(CC-tBu)2 reported by Deng and co-workers is characterized by a distorted tetrahedral geometry at iron and is high spin (S = 2).54

The lack of complete inhibition of alkynyl ligand redistribution even at low temperatures in non-polar solvents resulted in unsuccessful attempts to isolate a mono-alkynylated iron(II)-SciOPP species. However, treatment of 57 FeBr2(SciOPP) in 1:1 Et2O/isopentane with 1 equiv TIPS-CCMgBr prepared in Et2O at -30 oC provided conditions conducive to stabilizing 1 as the major species in solution on a timeframe that and enabled its solution characterization. Freeze-trapped solution Mössbauer analysis after 1 min of this reaction provided a glimpse into the iron distribution prior to ligand redistribution where 1 is the major iron species (Figure 6A, blue doublet, 83%). In this spectrum 1 is characterized by a quadrupole doublet with ! = 0.57 mm/s and "EQ = 2.41 mm/s, matching its frozen solution parameters in 1:1 THF/2-MeTHF. Furthermore, these Mössbauer parameters are consistent with mono-arylated iron(II)-SciOPP species studied previously by our group (see Table 1 for co mparison to phenylated iron(II)SciOPP species). The minor components in the mixture are untransmetalated FeBr2(SciOPP) (green doublet, 16%) and 2 (purple doublet, 3%). The relative cleanliness of this distribution enabled ligand field and ground-state analyses of 1 using MCD spectroscopy. The 5 K, 7 T near-infrared magnetic circular dichroism (NIR MCD) spectrum of 1 in 1:1 Et2O/isopentane frozen solution is dominated by two low energy d-d transitions at ~6410 cm-1 (positive MCD intensity) and ~7550 cm-1 (negative MCD intensity) (Figure 6B). The pseudo-A term profile of the ligand field transitions in the NIR MCD spectrum is a feature that is commonly observed in highspin iron(II) species with distorted tetrahedral geometries at iron and supported by chelating phosphine ligands, examples of which include mono-mesitylated and mono-phenylated iron(II)-SciOPP species Fe(Mes)X(SciOPP)48 and Fe(Ph)X(SciOPP) (X = Cl or Br).49 The dominance of the d-d transitions of 1 in the NIR MCD spectrum of this mixture is consistent with large magnitudes of "# observed for monoarylated iron(II)-SciOPP complexes compared to their dihalide and bis-arylated analogues.55 Saturation magnetization data collected at 6060 cm-1 are well-fit by a negative zero-field split (-ZFS) S = 2 ground state doublet model with ! = 1.4 ± 0.2 cm-


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Figure 7. Solution spectroscopic analysis of the iron species generated during catalysis in the 57FeBr2(SciOPP) catalyzed crosscoupling of TIPS-CC-MgBr with cycloheptyl bromide in toluene using TIPS-CC-MgBr prepared in Et2O. (A) 5 K frozen solution Mössbauer spectrum of the reaction mixture 2.5 h into the catalytic reaction. Assignments of individual doublets and their relative percentages in Figure 7A are as follows: 57FeBr2(SciOPP), 92% (green); 3, 8% (orange). (B) 5 K frozen solution EPR spectrum of the reaction mixture 2.5 h into the catalytic reaction, displaying a rhombic S = 3/2 feature with effective g values of 1.81, 2.87, and 5.31.

1:1 THF/2-MeTHF did not result in a further increase of yield of cross-coupled product (Table 2 entry 4). Importantly, most of the iron in solution during catalytic turnover was observed to be untransmetalated 57FeBr2(SciOPP) (92%, green doublet, Figure 7A) and species 1 and 2 are not detected. The predominance of untransmetalated 57 FeBr2(SciOPP) during catalysis in consistent with the catalytic iron distribution observed during the cross-couplings of PhMgBr with cycloheptyl bromide.49 Additionally, 31P{1H} NMR analysis of the catalytic reaction mixture confirmed the absence of free SciOPP ligand, indicating the lack of formation of SciOPP-dissociated iron centers (see SI Figure S20). It is notable that frozen solution EPR analysis of this same catalytic reaction mixture indicated the formation of a rhombic S = 3/2 signal during turnover, characterized by effective g values of 1.81, 2.87, and 5.31 (Figure 7B).57 Spin integration of this EPR feature resulted in a quantitated value of ~1% of the total iron in solution, and thus the species was not detectable in Mössbauer samples of the catalytic reaction. Such a S = 3/2 iron species has not previously been observed under any conditions in iron-SciOPP chemistry and, notably, its formation is observed to a larger extent during catalysis in the presence of THF (see section 2.6 and SI Figure S16). Furthermore, formation of the S = 3/2 iron species in catalysis was determined to be dependent on the presence of electrophile, as EPR analysis

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of the in situ generated iron speciation during slow addition of Grignard reagent to 57FeBr2(SciOPP) at 70 oC in the absence of electrophile indicated a lack of formation of the same S = 3/2 feature (see SI Figure S17). 2.5 Structure and Reactivity of S = 3/2 Iron Species Formed In Situ During Catalysis. Despite the fact that S = 3/2 species were observed to form only in minor amounts during the catalytic cross-coupling of TIPS-CC-MgBr with cycloheptyl bromide, it was important to attempt identification of the type of species that could be characterized by such a spectroscopic feature and their inherent reactivity with electrophile. Such knowledge would in turn aid in evaluation of these species as on- or off-cycle. The reducing environment present under catalytic conditions guided the hypothesis that a mononuclear iron(I) site may be responsible for the EPR activity observed. Since attempts to isolate any new iron species from the catalytic mixtures for further structural characterization were unsuccessful, independent syntheses of iron(I) species that might be accessed during catalysis were pursued. While homocoupled nucleophile TIPS-CC-CC-TIPS and free TIPSCC-H were observed to form upon hydrolysis quenching of in situ generated 3, both products could potentially form as unselective byproducts via undesired reductive processes during catalysis. Additionally, upon formation these organic by-products could potentially support otherwise coordinatively unsaturated iron(I) centers. We reasoned that such stability may derive from %-coordination of an alkynyl unit, similar to the aryl binding mode in the iron(0) species Fe(6-biphenyl)(SciOPP) easily accessible upon reaction of FeCl2(SciOPP) with phenyl nucleophiles.49 Reduction of FeBr2(SciOPP) with potassium graphite and subsequent exposure to TIPS-CC-H or independently prepared TIPS-CC-CC-TIPS resulted in both cases in the formation of green solutions from which single crystals could be isolated, characterized via X-ray diffraction to be the SciOPP-supported iron(I) complexes Fe(!2-[TIPS-CC-H])Br(SciOPP) (4) and Fe(!2-[TIPS-CC-CC-TIPS])Br(SciOPP) (5), respectively (Figure 8A-B). Both structures are monomeric and incorporate one stoichiometric equivalent of supporting alkynyl unit in a %bound fashion. Both 4 and 5 are characterized by rhombic S = 3/2 EPR signals at 5 K in frozen 1:1 THF/2-MeTHF solutions, analogous to those that characterize the S = 3/2 EPR signal observed to form during catalysis in both the presence and absence of THF (see Figure 8C-D). The temperature dependence of the EPR intensity from 4 - 40 K resulted in determination of an axial zero-field splitting (ZFS) parameter D of (8.5 ± 0.5) cm-1 and (8.0 ± 0.5) cm-1 for 4 and 5, respectively. These high-spin complexes represent the first examples of mononuclear iron(I)-SciOPP species and, importantly, their spectroscopic characterization provides evidence of the formation of species of this type during catalysis. Complexes 4 and 5 were found to display a lack of reactivity with electrophile in the absence of Grignard reagent. Diynebound complex 5 demonstrated no reactivity toward cycloheptyl bromide at 70 oC over a period of 30 min in 1:1 THF/2-MeTHF, a time frame well exceeding the average turnover time of catalysis (reactivity studies were performed in 1:1 THF/2-MeTHF based on the greater formation of S = 3/2 iron in catalysis performed in the presence of THF; see section 2.6). Over the same time period, acetylene-bound 4 was found


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Page 11 of 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


precatalysts in Nakamura’s published catalytic protocol, however, resulted in low conversion of starting material, achieving < 20% cross-coupled product by the end of the reaction in both cases (SI Table S4). These results demonstrate the lack of effectiveness of each species in promoting catalysis or in entering a productive catalytic cycle under these reaction conditions. In the end, while neutral alkynylated iron-SciOPP species 1 and/or 2 react with electrophile in both the presence and absence of THF, it is clear that the nature of the solvent plays an important role in governing rates and selectivity of product formation as well as in the formation of off-cycle reduced iron species. 2.7 Effect of Steric Substitution of Alkynyl Grignards on Catalytic Reactivity. Decreasing the degree of steric substitution of alkynyl nucleophiles has previously been reported to result in decreased yields of alkynyl-alkyl crosscoupled products in iron-SciOPP catalysis.44-45 Thus, we became interested in investigating the origins of disparities in reactivity that result from variation of the steric nature of the alkynyl Grignard reagent in the iron-SciOPP system. The reaction of 1-propynylmagnesium bromide (Me-CC-MgBr) with cycloheptyl bromide in 1:1 THF/2-MeTHF in the presence of 3 mol % FeBr2(SciOPP) was found to result in lack of conversion of electrophile using the same reaction conditions employed in Table 2 entry 1. Reactivity only slightly improved upon further reduction of the addition rate of Me-CC-MgBr (see SI Table S3). Mössbauer spectroscopic analysis of frozen solutions of these catalytic mixtures demonstrated the formation of a major iron species with Mössbauer parameters very similar to those of 3 in 1:1 THF/2-MeTHF frozen solution and 3-N2 in the solid state (see SI figure S13). Additionally, freeze-trapped EPR analysis of these catalytic reaction mixtures demonstrated a lack of formation of half-integer spin iron species (see SI Figure S19). The major iron species observed via Mössbauer spectroscopy could be isolated cleanly from reaction of FeBr2(SciOPP) with 4 equiv Me-CC-MgBr and is characterized as the tetrapropynylated ferrate [Fe(CCMe)4(SciOPP)][MgBr(THF)]2 (6, Figure 10). Frozen solution Mössbauer spectroscopic analysis of 57Fe-enriched 6 in 1:1 THF/2-MeTHF yielded parameters matching those of the major species formed during catalysis using Me-CC-MgBr and, consistent with its buildup in solution during catalysis, complex 6 was found to be unreactive toward cycloheptyl bromide at 70 o C (see Figure S14). While five-coordinate 3 was found to be unreactive with additional TIPS-CC-MgBr, the coordinatively saturated structure of 6 demonstrates that tetra-alkynylated iron(II)-SciOPP centers can be accessed using alkynyl Grignard reagents bearing less sterically demanding substitution. The ease of formation of such a species under the catalytic conditions reported by Nakamura and co-workers combined with its lack of reactivity with electrophile provide insight into origins of decreased reactivity in the iron-SciOPP catalyzed alkynyl-alkyl cross-coupling system when using less sterically encumbered alkynyl Grignard reagents. 3. DISCUSSION While iron-catalyzed cross-coupling reactions employing alkynyl nucleophiles represent attractive methods for the synthesis of organic molecules incorporating alkynyl moieties, there currently exists a lack of fundamental understanding of the nature of the reactive iron intermediates and mechanism in

Figure 10. X-ray crystal structure of 6 with thermal ellipsoids are drawn at the 50% probability level. Hydrogen atoms and the 3,5di-tert-butyl substituents of the SciOPP ligand have been removed for clarity.

these transformations. Knowledge of the similarities and differences in reactive iron intermediates between crosscoupling systems using sp2- and sp-hybridized nucleophilic coupling partners is essential to assessing the generality of reactive iron oxidation states, inherent stability of in situ generated intermediates, and accessible off-cycle species within catalytic systems using these unsaturated nucleophiles. In the present study, investigations of iron-SciOPP catalyzed alkynylalkyl cross-coupling have provided the first detailed insight into iron speciation and reactivity in cross-coupling systems using alkynyl nucleophiles, providing an important framework for the continued development of these important synthetic systems. Key to interpreting the identity of catalytically relevant iron intermediates in this catalytic system was the observation that mono-, bis-, and tris-alkynylated iron(II)-SciOPP species are directly accessible upon reaction of the bulky alkynyl Grignard reagent TIPS-CC-MgBr with FeBr2(SciOPP) precatalyst. Neutral mono- and bis-alkynylated iron(II)-SciOPP species 1 and 2 were observed to form following the reaction of 1 equiv Grignard reagent with FeBr2(SciOPP), indicating the ease of alkynyl ligand redistribution between iron centers in 1:1 THF/2MeTHF. It is notable that while previous studies confirmed the spontaneity of similar ligand redistribution effects accompanying the reaction of FeBr2(SciOPP) with 1 equiv PhMgBr, the redistribution pathways observed in the current system are 1) more rapid than those observed to convert monophenylated iron(II)-SciOPP species to bis-phenylated centers, and 2) do not ultimately terminate at double transmetalated iron(II)-SciOPP species that are readily capable of converting to reduced iron centers (i.e. iron(0) via reductive elimination).49 Instead, the SciOPP-coordinated tris-alkynylated ferrate 3 accompanies the generation of 1 and 2 upon treatment of FeBr2(SciOPP) with stoichiometric TIPS-CC-MgBr, demonstrating the accessibility of iron(II) ferrates in solution under conditions lacking excess Grignard reagent. The formation of a SciOPP-coordinated ferrate species represents a



feature that is thus far distinct to systems using alkynyl Grignard reagents, since such species were not observed to be accessible using phenyl and mesityl nucleophiles. In fact, the only ferrate species documented to date to be accessible in cross-coupling systems catalyzed by iron-bisphosphines is [Fe(Mes)3]-, generation of which required the presence of excess nucleophile (MesMgBr) and loss of SciOPP ligation.48 Solvent was found to play an important role in the stabilities of 1, 2, and 3 in solution, with increased stability of these species observed in non-polar solvents. In particular, 3 displayed exceptional stability in the absence of THF, with quantitative conversions of FeBr2(SciOPP) to 3 upon reaction with 3 equiv TIPS-CC-MgBr prepared in Et2O in reaction solvents such as 1:1 Et2O/isopentane and neat toluene. Under these conditions 3 is stable towards alkynyl ligand redistribution as well as further alkynylation by excess Grignard reagent. Despite the increased stability of 1, 2, and 3 in non-polar solvents using TIPS-CC-MgBr prepared in Et2O, effective catalysis could still be achieved in the absence of THF. While the original reaction conditions reported by Nakamura and coworkers capitalized on the efficacy of THF to promote effective catalysis using slow Grignard reagent addition rates, it was found herein that by slowing the addition rate of the Grignard reagent further (five times slower than the originally reported conditions) that high yields of cross-coupled product could be achieved at the same reaction temperature in toluene. Notably, the cross-coupling reaction in toluene also suppressed the formation of cycloheptane side-product compared to catalysis in 1:1 THF/2-MeTHF. Such improvements in catalytic efficiency are attributed to inhibited formation of offcycle/unselective iron species in toluene relative to THF. Formation of S = 3/2 iron species during catalytic turnover in both toluene and 1:1 THF/2-MeTHF represents a process thus far distinct to iron-SciOPP systems using alkynyl Grignard reagents, as such species were not accessible using aryl nucleophilic coupling partners. While the S = 3/2 species could not be isolated directly from catalytic reaction mixtures, independent synthetic efforts provided evidence that such EPR features most likely result from mononuclear iron(I)-SciOPP centers supported by %-bound alkynyl ligands. Not only do such species represent minor components of the total iron in solution (~1 % during catalysis conducted in toluene and ~8 % during catalysis in 1:1THF/2-MeTHF as determined by EPR spin integration) but they also demonstrate a lack of reactivity with electrophile to form cross-coupled product. Furthermore, %-supported iron(I) SciOPP complexes 4 and 5 do not function as effective precatalysts under the catalytic conditions reported for the iron-SciOPP catalyzed cross-coupling of TIPS-CCMgBr with cycloheptyl bromide reported by Nakamura and coworkers. Thus, while such S = 3/2 iron(I) species can form during catalysis, they represent off-cycle species. Furthermore, SciOPP ligand dissociation is also avoided in toluene relative to catalysis in THF, as evidenced by the formation of free SciOPP in solution in the latter case. The presence of such SciOPP-free iron species was found to correlate with less selective catalytic product distributions, in line with previous proposals by Nakamura and co-workers.44-45 Further reaction studies in toluene enabled the elucidation of the key iron species responsible for cross-coupled product formation. Species 3 was found to be unreactive with electrophile in toluene at 70 oC and thus represents an off-cycle intermediate. This lack of reactivity of 3 is consistent with the observed build-up of 3 during catalysis in toluene and

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concurrent lack of electrophile conversion using the nucleophile addition rate reported by Nakamura and co-workers to be effective for THF-based catalysis. By contrast, both 1 and 2 are consumed upon reaction with excess electrophile at 70 oC to yield cross-coupled product at a rate that is kinetically relevant to catalysis, consistent with one or both of these neutral iron(II)-SciOPP species being responsible for effective catalysis. The direct observation of reactivity of such species combined with results of radical clock experiments performed by Nakamura and co-workers further supports the existence of an iron(II)/iron(III) redox cycle in this catalytic system. While the accessibility of alkynyl ligand redistribution pathways in both toluene and in the presence of THF prevents the unambiguous determination of preferential reaction/selectivity of 1 or 2 with electrophile, it should be noted that in ironSciOPP catalyzed phenyl-alkyl cross-coupling both mono- and bis-phenylated iron(II)-SciOPP were found to be reactive towards electrophile at catalytically relevant rates. Lastly, the untransmetalated nature of the majority of iron under steadystate catalytic conditions indicates that the rate of reaction with electrophile during catalysis is likely limited by the rate of Grignard addition. Importantly, the current study has documented the first insight into the direct implications of solvent on formation of reactive intermediates and off-cycle iron species within ironbisphosphine catalyzed cross-coupling reactions. While reactivity was found to be more rapid in 1:1 THF/2-MeTHF than in toluene for the current system, catalysis in the presence of THF promotes accessibility of off-cycle and/or unselective iron intermediates such as unreactive iron(I)-SciOPP species and SciOPP-dissociated ferrates relative to catalysis in toluene, representing a disadvantage when considering selective conversion of electrophile. Such implications, together with insight into the origins of solvent effects, will be critical for further guided development of iron catalyzed alkynyl-alkyl cross-coupling reactions, particularly when considering the applicability of coordinating versus non-coordinating solvents to such transformations. Furthermore, effects of the steric substitution of the alkynyl Grignard reagent on catalytic productivity have become more clear. Previous studies by Nakamura and co-workers highlighted a decrease in effectiveness of iron-SciOPP catalyzed alkynyl-alkyl couplings upon use of less bulky alkynyl nucleophiles.44-45 Reactions using Me-CC-MgBr in the current study demonstrate that the lack of catalytic reactivity in this system arises from the ease of accessibility of alkynylated ferrate 6 upon exposure of FeBr2(SciOPP) to excess Me-CCMgBr, even in the presence of electrophile. The ease of formation of unreactive, high-coordinate iron(II)-SciOPP species and subsequent lack of catalytic effectiveness contrasts with observations by Hu and co-workers of effective propynylation of secondary alkyl halides in the presence of FeBr2 salt.46 Knowledge of the origins of such disparities in reactivity, defined in part in the current study, should prove valuable in guiding further rational design of catalyst systems in cases where the steric nature of the alkynyl nucleophile is an important factor. The observation of neutral alkynylated iron(II)-SciOPP active species in the current system serves to further generalize the importance of iron(II) species as key reactive intermediates in cross-coupling systems using nucleophiles lacking !hydrogens (ie, both sp2- and sp-hybridized groups). A key


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question to address moving forward will be whether iron(II) active species remain pervasive beyond iron-SciOPP catalyzed cross-coupling systems, where the potential for lower valent iron species including iron(I) remains an open question. Proposals as to the formation of iron(I) within iron catalyzed cross-coupling reactions and their potential role as active species have been advanced for cross-coupling systems using alternative supporting bisphosphine ligands6, 36, 41-42, 58 such as 1,2-bis(diphenylphosphino)benzene (dpbz) and 1,2bis(diphenylphosphino)ethane (dppe) as well as NHC additives.59 Further investigations are required to definitively assess the applicability of such proposals. Furthermore, studies of ‘ligandless’ iron cross-coupling systems using alkynyl nucleophiles as well as additional iron catalyzed cross-coupling methods using alternative supporting ligands and nucleophilic coupling partners will serve to further understanding of the diversity of iron intermediates involved in cross-coupling. 4. CONCLUSIONS The present study has highlighted important consequences deriving from variation of the nucleophilic coupling partner from aryl to alkynyl groups in iron-SciOPP catalyzed crosscoupling systems and provided direct insight into the nature and reactivity of in situ generated iron species. In contrast to ironSciOPP catalyzed aryl-alkyl cross-coupling systems, neutral mono- and bis-alkynylated iron(II)-SciOPP species demonstrate inherent instability toward alkynyl ligand redisribution in solution, aiding the accessibility of a SciOPPcoordinated ferrate species. The effects of reaction solvent on overall rate and selectivity of cross-coupling reactivity, combined with the stabilization of unproductive off-cycle iron intermediates, enabled observation of lack of reactivity of this ferrate species toward electrophile. In contrast, neutral alkynylated iron(II)-SciOPP species were identified as the reactive iron intermediates responsible for selective crosscoupling reactivity. While novel iron(I)-SciOPP species are accessed during catalytic turnover and their formation aided in the presence of THF relative to toluene, such species were found to be off-cycle and lack selective reactivity with electrophile. Furthermore, the role of steric bulk of the alkynyl Grignard reagent in governing origins of reactivity was more concretely defined. The knowledge gained from the studies presented herein provides critical insight that can be used to aid further development of iron catalyzed cross-coupling reactions using alkynyl nucleophiles and offers further evidence for the broader applicability of iron(II) active species within the field of iron-based cross-coupling catalysis. 5. EXPERIMENTAL SECTION 5.1. General Considerations. All air- and moisture-sensitive manipulations were carried out using standard Schlenk techniques on a high vacuum line or in an MBraun glovebox under dinitrogen atmosphere and moisture-free conditions. Tetrahydrofuran, 2methyltetrahydrofuran (2-MeTHF), toluene, hexane, pentane, 2methylbutane (isopentane), 2-propanol, and dimethylacetamide were all purchased as anhydrous reagents from Aldrich and filtered through activated alumina and stored over 3 Å molecular sieves prior to use. Anhydrous diethyl ether (Et2O) was purchased from EMD or J. T. Baker and further dried by the same method. Fluorobenzene, purchased non-anhydrous from Aldrich, was deoxygenated, filtered through activated alumina, and stored over 3 Å molecular sieves prior to use. SciOPP ligand was prepared according to the method reported by Nakamura and co-workers39 using starting materials purchased from

Strem (1,2-bis(dichlorophosphino)benzene, min. 97%; magnesium powder, 99.8%) and Accela (1-bromo-3,5-di-tert-butylbenzene, 97%). FeBr2(SciOPP) and FeCl2(SciOPP) were also prepared according to the procedures of Nakamura and co-workers39 in anhydrous 2-propanol using anhydrous FeBr2 (99.999%, Aldrich) or anhydrous FeCl2 (98%, Strem). 57Fe-enriched complex 57FeBr2(SciOPP) was prepared by the same method using 57FeBr2, the 57Fe-enriched salt prepared from 57Fe metal (95% enriched, Isoflex) and HBr as described in the literature.60 (Triisopropylsilyl)acetylene (TIPS-CC-H, 97%), ethylmagnesium bromide (1 M in THF and 3 M in Et2O), and 1-propynylmagnesium bromide (Me-CC-MgBr, 0.5 M in THF) were purchased from Aldrich. 1,4-Bis(triisopropylsilyl)buta-1,3-diyne (TIPS-CC-CC-TIPS) was prepared via the method of Hoheisel and Frauenrath61 using triisopropylsilyl chloride as the source of the silyl group, with all starting materials purchased from Aldrich and used without further purification. GC analysis was performed using a Shimadzu GC-2010 Plus gas chromatograph equipped with a flame ionization detector (FID). Slow, consistent Grignard reagent addition rates used during catalytic reactions were achieved using a model NE 300 or NE 1000 syringe pump from New Era Pump Systems. 1H and 31P{1H} NMR spectra were recorded on a Bruker Avance 400 MHz (400 MHz, 1H; 162 MHz, 31P{1H}) or 500 MHz (500 MHz, 1H; 202 MHz, 31P{1H}) spectrometer. 31P chemical shifts were assigned relative to 85% H3PO4(aq) external standard. 5.2. 57Fe Mössbauer Spectroscopy. Frozen solution samples for Mossbauer spectroscopic analysis were prepared from reaction mixtures in 1:1 (v:v) THF/2-MeTHF, 1:1 (v:v) Et2O/isopentane, or neat toluene. Frozen solutions of these mixtures form optical glasses at low temperatures, thus enabling the simultaneous preparation of Mössbauer and MCD samples for analysis of the same reaction mixtures by both methods. Frozen solution and solid samples for Mössbauer analysis were prepared in Delrin Mössbauer sample cups in an inert atmosphere glovebox (N2) equipped with a liquid nitrogen fill port to enable sample freezing to 77 K within the glovebox. Solid samples were sealed using a fitted inner cup prior to freezing. Analysis of solid samples was performed on either natural abundance or 57Feenriched samples. In the case of enriched solid samples, boron nitride was used as diluent to achieve an appropriate absorber thickness. Mössbauer measurements were performed using a See Co. MS4 Mössbauer spectrometer integrated with a Janis SVT-400T He/N2 cryostat for zero-field measurements at both 5 K and 80 K. Isomer shifts were determined relative to &-Fe at 298 K. All Mössbauer spectra were fit using the WMoss program (See Co.). All Mössbauer spectra provided in the main text and the SI display the raw folded data (black dots) and, where applicable, the total fit (black line) and individual component fits (colored doublets) are shown. Errors of the fit analyses were the following: ! ± 0.02 mm/s and "EQ ± 3%. For multicomponent fits, the quantitation errors of individual components were ± 3%. 5.3. Magnetic Circular Dichroism Spectroscopy. MCD samples were prepared in an inert atmosphere glovebox (N2) equipped with a liquid nitrogen fill port to enable sample freezing to 77 K within the glovebox. Frozen solution samples were prepared in 1:1 (v:v) Et2O/isopentane in copper cells fitted with quartz discs and a 3 mm butyl rubber gasket. Cryogenic near-infrared (NIR) MCD experiments were conducted using a Jasco J-730 spectropolarimeter and a liquid nitrogen cooled InSb detector. The instrument utilized a modified sample compartment incorporating focusing optics and an Oxford Instruments SM4000-7T superconducting magnet/cryostat. This set-up permits measurements from 1.6 K to 290 K with magnetic fields up to 7 T. A calibrated Cernox sensor directly inserted in the copper sample holder is used to measure the temperature at the sample to 0.001 K. All MCD spectra were baseline-corrected against zero-field scans. Saturation magnetization data were analyzed using previously reported fitting procedures.62 5.4. Electron Paramagnetic Resonance Spectroscopy. Samples for EPR analysis were prepared in an inert atmosphere glovebox (N2) equipped with a liquid nitrogen fill port to enable sample freezing to 77 K within the glovebox. EPR samples were prepared in 4 mm OD



Suprasil quartz EPR tubes (Wilmad Labglass). Samples for spinintegration were prepared in high precision Suprasil quartz tubes to allow for direct comparison of intensities between different samples. X-band EPR spectra were recorded at 5 K on a Bruker EMXplus spectrometer equipped with a 4119HS cavity and an Oxford ESR-900 helium flow cryostat. The instrumental parameters employed for all samples were as follows: 1 mW power; 0.01 ms time constant; 8 G modulation amplitude; 9.38 GHz frequency; and 100 kHz modulation frequency. Spin integration was performed using a 3 mM CuSO4!5H2O standard in 9:1 (v:v) MeOH/EtOH under non-saturating conditions (0.001262 mW power). Identical instrument parameters were used for both reaction and standard samples when spin integrating. Amounts of S = 3/2 iron determined to be present in solution by EPR spin integration were corrected for the Boltzmann distribution in the ground state spin manifold using the experimentally determined axial ZFS parameter D (see SI for further details).63 5.5. Electronic Structure Calculations. Density functional theory (DFT) calculations were performed using the Gaussian 09 package.64 Geometry optimizations of 2 as a function of spin state were performed using the PBEPBE exchange-correlation functional65 as spinunrestricted (for S = 1 and S = 2) and spin-restricted (for S = 0) calculations with the TZVP basis set66 used for all atoms. All geometries were fully optimized from the crystal structure of 2 with initial optimizations performed using the cep-31g basis set before optimizing at the TZVP level. The inclusion of solvation employed a polarized continuum model (PCM) with tetrahydrofuran as solvent.67 Each optimized geometry was found to have positive harmonic frequencies, but the ‘Stable’ keyword was required for confirming the presence or absence of internal instabilities of the wavefunctions. Relative energies of optimized structures as a function of spin state given in the SI include zero-point and thermal corrections. 5.6 Single Crystal X-Ray Diffraction Sample Preparation. Due to the air- and moisture-sensitivity of species 2-6, crystals for X-ray diffraction analysis were examined under dinitrogen at room temperature and affixed to the tip of a glass optical fiber using STP® Oil Treatment. This viscous oil protected the crystals during transfer to the cold stream. Instrument details, data acquisition parameters, and refinement details for data collections on 2-6 are provided in individual data reports in the SI. 5.6. Preparation of Grignard reagent triisopropylsilyl)ethynylmagnesium bromide (TIPS-CC-MgBr). THF solutions of TIPS-CC-MgBr were routinely prepared at concentrations between 0.3 and 0.5M via addition of a THF solution of ethylmagnesium bromide to a stirring THF solution of (triisopropylsilyl)acetylene (TIPS-CC-H) at room temperature. Following initial gas evolution, the mixture was heated to 60 oC for 36 h to drive complete deprotonation of TIPS-CC-H, confirmed by 1H NMR analysis of the reaction mixture. 1:1 THF/2-MeTHF solutions used for catalytic reactions were prepared by diluting THF solutions of the Grignard with an equal volume of 2-MeTHF. Preparation of TIPSCC-MgBr in Et2O involved addition of a Et2O solution of ethylmagnesium bromide to a stirring Et2O solution of TIPS-CC-H at room temperature followed by reaction at elevated temperature (~ 45 o C) for 12-24 h to consume all free acetylene. Et2O solutions of TIPSCC-MgBr were routinely prepared at concentrations between 0.2 and 0.3 M. Concentration of solutions of TIPS-CC-MgBr were determined via titration using salicylaldehyde phenylhydrazone as indicator.68 5.7. Isolation of 57Fe(CC-TIPS)2(SciOPP)•MgBr2 (2). A 20 mL scintillation vial was charged with 49 mg 57FeBr2(SciOPP) (0.044 mmol) and the complex suspended in 10 mL hexane with stirring at room temperature. 0.175 mL of TIPS-CC-MgBr in Et2O (0.26 M, 0.0455 mmol) was then added to the stirring suspension in a single portion, accompanied by an instantaneous generation of a yelloworange reaction mixture. The turbid mixture was allowed to stir for 10 s following addition of Grignard, followed by filtration at room temperature through a Celite plug to remove precipitated magnesium salts. The orange filtrate was divided into ~ 2 mL portions and placed

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into separate 20 mL vials to allow for slow evaporation of the solvent to facilitate crystallization. Over the course of 8-24 h solid was observed to precipitate as single orange block crystals, identified as 2 via X-ray diffraction analysis, and as colorless crystalline solid confirmed as 57FeBr2(SciOPP) via unit cell confirmation. The total yield of crystalline 2 routinely amounted to < 5 mg per reaction ( 7 % total yield as a hexane monosolvate) even upon increasing the scale of the reaction to 0.10 mmol. Attempts to crystallize 2 via precipitation from non-polar solvents at low temperatures (' -30oC) were unsuccessful due to exceptional solubility of 2 in hydrocarbon solvents even at these temperatures. Separation of precipitated solid 2 for Mössbauer analysis: The mixture of 57Fe-enriched 2 and 57FeBr2(SciOPP) obtained from the crystallization method described above proved exceptionally challenging to separate via solution phase extractions, and thus crystalline 2 was separated from the dihalide component mechanically under a microscope enclosed in a dinitrogen-filled glovebag. The identity of individual single crystals of 2 was determined via unit cell confirmations. Batches crystalline 2 isolated in this way were used for subsequent solid and frozen solution (1:1 THF/2-MeTHF) Mössbauer analysis. 5.8. Synthesis of [Fe(CC-TIPS)3(SciOPP)][MgBr] (3) 48 mg FeBr2(SciOPP) (0.043 mmol) was slurried in 5 mL pentane with stirring in a 20 mL scintillation at room temperature. To the resulting suspension was added 0.525 mL of TIPS-CC-MgBr in Et2O (0.25 M, 0.131 mmol) at room temperature, resulting in the instantaneous generation of a turbid green mixture. The reaction was allowed to stir at room temperature for 20 min following addition of Grignard and subsequently filtered through a celite plug to remove precipitated magnesium salts. The green filtrate was reduced to dryness under reduced pressure yielding a peppermint colored solid. This solid was extracted into pentane (~ 15 mL) at room temperature, refiltered through celite, and again taken to dryness. The resulting solid was dissolved in ~ 3 mL Et2O and the solution allowed to slowly evaporate at room temperature, resulting in green block crystals suitable for single crystal X-ray diffraction analysis. Crystalline yield: 36 mg (50 %). An additional 10 mg of analytically pure amorphous solid accompanied the crystals, combining for a total isolated yield of 67%. 1H NMR (400 MHz, C6D6): " 7.6, 7.5, 7.3, 7.2, 7.0, 3.4, 1.2–1.0 ppm. 31P NMR (162 MHz, C6D6) " 72.4 ppm (br s). Calcd for C95H151P2Si3FeMgBr: 71.34 C, 9.52 H. Found: 71.43 C, 9.61 H. µeff (C6D6, 25 oC) = 3.1(2) µB. The same procedure was used for isolating 57Fe-enriched 3 from 57 FeBr2(SciOPP). While, the crystal structure report for 3 provided in the SI resulted from a data collection on crystals grown from slowevaporation of a 1:1 Et2O/isopentane solution of in situ generated 3, the crystallization method described in this section was found to result reproducibly in the formation of larger crystals. 5.9. Synthesis of [Fe(CC-TIPS)3("1-N2)(SciOPP)][MgBr] (3-N2). The dinitrogen adduct of 3 could be prepared by the same reaction as used for 3 with the following variation. After initial removal of magnesium salts via filtration through celite, the green pentane filtrate was stored at -30 oC, resulting in a change of the solution color to golden yellow and precipitation of yellow block crystals suitable for single crystal X-ray diffraction. At a 0.025 mmol reaction scale using 57 FeBr2(SciOPP), 10 mg crystalline solid (24% total yield) was isolated. Calcd for C95H151P2Si3FeMgBrN2: 70.11 C, 9.35 H, 1.72 N. Found: 70.20 C, 9.34 H, 1.51 N. 5.10. Synthesis of Fe("2-[TIPS-CC-H])Br(SciOPP) (4). 99 mg FeBr2(SciOPP) (0.089 mmol) was dissolved in 5 mL Et2O in a 20 mL scintillation vial and the stirring solution cooled to -70 oC in a glovebox coldwell. Potassium graphite was added to the cold stirring solution (42 mg, 0.31 mmol, ~3.5 equiv) as a slurry in cold (-70 oC) Et2O in three portions over 30-45 s, requiring a total of ~ 5 mL for quantitative transfer of the reductant. An opaque yellow-brown mixture was produced during the addition of the reductant and the reaction was stirred for 3 h at -70 oC. After 3 h of reaction, the cold reaction mixture was filtered through celite to remove unreacted reductant/graphite. Note 1: rigorous efforts were taken to avoid warming during the 57


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filtration procedure. Pre-chilling the pipet used for transfer of the reaction mixture to the filtration vessel, the filtration vessel itself, and the collection vial/flask and stir bar to -70 oC or below was found to be imperative measures to minimize warming and the consequential access of iron species that react unproductively with TIPS-CC-H upon its addition. After stirring for 3 h, to the cold, stirring filtrate (still opaque yellow-brown in color) was added an aliquot of a cold (-70 oC) solution of TIPS-CC-H in Et2O (0.300 mL of a 0.35 M solution, 0.105 mmol, ~1.2 equiv) was added to the reaction, and the resulting mixture stirred for an additional 15 min at -70 oC. After this time, the mixture was brought to ambient temperature (25 oC) and allowed to warm while stirring and without addition of heat. Over the course of approximately 10 min of stirring toward room temperature the reaction began to turn noticeably green, and stirring at room temperature was continued for another 1.5 h to yield a green solution with colorless precipitate. Note 2: warming the reaction directly after filtration of unreacted reductant but before addition of TIPS-CC-H was observed to result in the formation of a deep red mixture upon reaching room temperature. Addition of TIPS-CC-H to this mixture was found to not reproducibly access the desired green solution. Rather, formation of intractable orange-brown mixtures were more common. The mixture was then filtered through celite and the filtrate reduced to dryness. Redissolution of the green residue in minimal (~ 1 mL) Et2O followed by cooling the sealed vessel to -30 oC resulted in the precipitation of green block crystals suitable for single crystal X-ray diffraction (24 mg, 21% total yield as Et2O monosolvate) over less than one week. Calcd for C77H120P2SiFeOBr: 71.83 C, 9.39 H. Found: 71.62 C, 9.34 H. 1H NMR (400 MHz, C6D6): " 5.1, 3.0, 2.5, -4.0 ppm. 31P NMR (162 MHz, C6D6) no resonances. µeff (C6D6, 25 oC) = 4.0(2) µB. Note 3: the use of excess potassium graphite described herein was found to increase the rate of reduction of the FeBr2(SciOPP) to the point of approximate completion over 3 h at -70 oC without any apparent over-reduction. The low reaction temperature was found to be essential to avoid forming species that would react unproductively (or, perhaps, not at all) with TIPS-CCH), even when using nearer to a single stoichiometric equivalent of reductant. 5.11 Synthesis of Fe("2-[TIPS-CC-CC-TIPS])Br(SciOPP) (5). Notes 1 – 3 within section 5.10 (synthesis of complex 4) are also imperative to the synthetic procedure for complex 5 and should be taken into account during its preparation. 153 mg 57FeBr2(SciOPP) (0.138 mmol) was dissolved in 10 mL Et2O in a 20 mL scintillation vial and the resulting solution cooled with stirring to – 70 oC in a glovebox coldwell. To the cold stirring solution was added 28 mg potassium graphite (0.201 mmol, 1.5 equiv) as a slurry in cold (-70 oC) Et2O (~ 2 mL solvent required for quantitative transfer) over the course of 30 -45 s. An opaque yellow-brown mixture was produced during addition of the reductant and the reaction was stirred for an additional 2 h at -70 o C. After 3 h of reaction, the cold reaction mixture was filtered using a pre-chilled transfer pipet through a pre-chilled celite plug into a prechilled collection vial containing a cold stir bar (-70 oC). To the cold yellow-brown filtrate was added 63 mg TIPS-CC-CC-TIPS (0.174 mmol) dissolved in 5 mL Et2O and the resulting mixture allowed to stir at -70 oC for an additional 20 min before removing the vial from the coldwell to stir at ambient temperature. After 20 min at room temperature the reaction solution had turned green and a fine colorless precipitate was observed. The mixture was filtered through celite at room temperature and the green filtrate reduced to dryness. The resulting solid was dissolved in ~ 2 mL fluorobenzene and divided evenly between two 4 mL vials and each aliquot layered with ~2.5 mL dimethylacetamide. Diffusion of the layers in the sealed vials at room temperature afforded crystalline 5 in a total combined yield of 52 mg (27 %), with maximum precipitation achieved between 72 and 84 h. 1H NMR (400 MHz, C6D6): " 4.4, 2.7, 2.5, 2.1, -4.9 ppm. 31P NMR (162 MHz, C6D6) no resonances. Calcd for C84H130P2Si2FeBr: 72.38 C, 9.40 H. Found: 71.90 C, 9.35 H. µeff (C6D6, 25 oC) = 4.0(2) µB. 5.12. Synthesis of [Fe(CC-Me)4(SciOPP)][MgBr(THF)]2 (6). A 20 mL scintillation vial was charged with 51 mg 57FeBr2(SciOPP) (0.046 mmol) and the complex stirred in 3 mL pentane at room temperature to form a fine suspension. To the stirring suspension was

added 0.365 mL of a 0.51 M THF solution of Me-CC-MgBr (0.186 mmol, ~ 4.1 equiv) resulting in the immediate formation of an orange brown solution and a clumpy colorless precipitate. The reaction was stirred for an additional 5 min at room temperature before filtering the mixture through a celite plug into a 20 mL collection vial. The celite plug was rinsed with an additional 0.5 mL pentane and the orangebrown filtrate was placed in a coldwell cooled to –60 oC. Within 30 min yellow crystalline solid had precipitated, single crystals of which were determined by X-ray diffraction to be 6. Following initial precipitation the mother liquor was decanted off of the solid and the solid (still cold, -60 oC) was washed with an additional 1 mL cold pentane with swirling. After decanting the washings, the crystals were dried in vacuo to obtain 35 mg of an analytically pure mustard yellow amorphous solid (52% total yield as tetrahydrofuran disolvate). 1H NMR (500 MHz, C6D6, 57Fe-enriched sample): " 7.9, 7.5, 7.1, 3.6, 2.5, 1.4, 1.2 ppm. 31P NMR (202 MHz, C6D6, 57Fe-enriched sample) " 97.8 ppm (d, J31P-57Fe = 33.7 Hz). Calcd for C82H116P2FeMg2O2Br2: 67.46 C, 8.01 H. Found: 67.30 C, 7.98 H. The cold temperature used above to precipitate 6 from solution was used to simply speed precipitation; the complex itself was not observed to exhibit any thermal instability at any point in during its preparation. 5.13. In Situ Spectroscopic Analysis of Reactivity of in situ generated iron species with Cycloheptyl Bromide. Assessment of the reactivity of 1, 2, and 3 with electrophile by frozen solution Mössbauer spectroscopy was performed following initial generation of these species in situ. The general procedure used for these studies involved reaction of a toluene solution of 57FeBr2(SciOPP) (13 mg, 0.012 mmol) with 1 equiv (for assessing reactivity of 1 and 2) or 3 equiv (for assessing reactivity of 3) TIPS-CC-MgBr (0.25 M in Et2O) at 70 oC following single portion addition of the Grignard to the stirring iron solution. After 10 s of stirring, 20 equiv cycloheptyl bromide (480 µL, 0.5 M in toluene) was added in a single portion and aliquots of the resulting reaction were frozen in liquid nitrogen for Mössbauer spectroscopy at the desired timepoint. Reactions conducted in 1:1 THF/2-MeTHF were performed analogously using TIPS-CC-MgBr prepared in THF (0.42 M) and solutions of cycloheptyl bromide in 1:1 THF/2-MeTHF (0.5 M). 5.14. Analysis of Reactivity of in situ generated iron species with Cycloheptyl Bromide by GC-FID. Reaction of 20 equiv cycloheptyl bromide with the in situ iron distribution generated from reaction of FeBr2(SciOPP) with 1 equiv Et2O-based TIPS-CC-MgBr in toluene is given as a representative procedure. A vial was charged with 1.2 mL of a 0.01 M toluene solution of FeBr2(SciOPP) (0.012 mmol), dodecane (120 µL of a 0.1 M toluene solution, 0.012 mmol), and 2.08 mL toluene and stirred at 70 oC before adding 1 equiv TIPS-CC-MgBr (120 µL of a 0.1 M Et2O solution, 0.012 mmol) in a single portion. Aliquots of the reaction mixture were quenched with 1.0 M NH4Cl(aq), diluted with THF, and filtered through a pad of Florisil (< 200 mesh, Aldrich). Product yields and recovery of electrophile were determined by quantitative GC analysis using dodecane as an internal standard.

ASSOCIATED CONTENT Supporting Information Supplementary figures and data including Mössbauer, EPR, NMR, and GC data as well as DFT calculations and X-ray crystal structure data. The Supporting Information is available free of charge on the ACS Publications website.

AUTHOR INFORMATION Corresponding Author [email protected].

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENTS



This work was supported by a grant from the National Institutes of Health (R01GM111480 to M.L.N.) and a Sloan Research Fellowship. The authors acknowledge the Bluehive computing cluster and the University of Rochester Center for Integrated Research Computing for providing the resources necessary to perform the computations reported in this work. J.L.K thanks Dr. Naohisa Nakagawa for insightful discussions on iron catalyzed alkynyl-alkyl cross-coupling methods, Dr. Peter Neate for helpful comments during revisions of the manuscript, and Jeffrey Sears for providing several batches of 57FeBr2.

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Intermediates and Reactivity in Iron-Catalyzed Cross-Couplings of

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