60th Annual Report on Research 2015

     Reactions mediated by the noble metals ruthenium, rhodium and palladium have, without a question, been instrumental to the advancement of organometallic catalysis as practical methods for laboratory organic synthesis.¹ Applications of those reactions to large-scale or industrial syntheses, however, have been limited due to the cost and toxicity of these metals.  First-row transition metals, however, are far more common and are often more biocompatible than their second-row congeners.¹ As a result, metals such as iron, cobalt and nickel have become attractive candidates for small molecule synthesis as sustainable catalysts.² Unfortunately, due to their electronic structure, these metals generally undergo single electron or radical chemistry that often precludes the two-electron chemistry characteristic of the noble metals.³

     We have developed cobalt catalysts capable of the formation of sterically encumbered C-N bonds.  Prior to our work, only two examples of C-N bond coupling by a cobalt catalyst was known and both of these examples have limited substrate scope. Excitingly, reaction of iodobenzene with 2.6 equivalents of LiN(SiMe₃)₂ in the presence of 7.5 mol% (PPh₃)₃CoCl refluxing in toluene for 12 h, cleanly resulted in the formation of the N,N-bis(trimethylsilyl)aniline in 77% yield, which readily hydrolyzes with acid to aniline (Table 1).  In the absence of (PPh₃)₃CoCl, no coupling product was observed, suggesting that this is a cobalt-mediated process. We evaluated the relative importance of solvents, temperature, equivalents of silylamide and ligands on the reaction using iodobenzene as a model substrate.  The choice of solvent was critical for success as only non-coordinating solvents (toluene (77%), benzene (53%) and hexanes (46%)) gave rise to the expected product.  Lower temperatures (< 100 ^oC) did not result in formation of the coupled product. Since other nucleophiles (e.g., lithium amide, lithium diisopropylamide, and lithium ditertbutylamide) were not tolerated, the number of equivalents of LiN(SiMe₃)­₂  necessary for the transformation was investigated.  When only one equivalent of LiN(SiMe₃)­₂ was utilized, both aminated product and the formation of C-C coupled regioisomers of methylbiphenyl was observed, from the reaction of an aryl radical with toluene.  Fortunately, the formation of the biaryl product is completely suppressed by the addition of 2.6 equivalents of nucleophile.

     We hypothesized that using various bidentate phosphine ligands may prevent the loss of the strong-field phosphine ligand and improve overall catalytic reactivity.  Screening of various chelating phosphine ligands (15 mol%) generated aniline in higher yields.  DPPE gave lower yield (68%) than any of the other phosphines (DPPF (diphenylphosphine ferrocen)e (97%), BINAP (99%) and DPEPhos (95%)). DPEPhos (Bis(2-diphenylphosphinophenyl)ether) was chosen as the added phosphine because of improved yield and overall cost effectiveness. Based on the summarized results the reaction conditions were optimized to include only 2.6 equivalents of nucleophile and 15 mol% of DPEPhos (Figure 3).  The overall effectiveness of the addition of DPEPhos was greater than that of the addition of more nucleophile in the reaction. Lowering the overall catalyst loading (from 7.5 mol%) reduced product yield significantly.

     A detailed investigation into the mechanism through both stoichiometric studies and kinetic analyses revealed that reaction proceeds via a two-electron pathway whereby the active catalyst is (PPh₃)₂CoN(SiMe₃)₂ and (PPh₃)₃CoCl serves as the pre-catalyst.⁴  These studies prompted a more detailed investigation into understanding the active catalyst and its ability to promote this transformation especially given the steric constraints placed on the metal center when very large sterically encumbered functional groups are utilized. Reactions of (PPh₃)₃CoCl readily dissociate triphenylphosphine at room temperature, as observed by ³¹P NMR spectroscopy.   Therefore a variety of new cobalt catalysts were prepared from the reaction of, (PPh₃)₃CoCl with various bidentate phosphine ligands and then subsequent addition of LiN(SiMe₃)­₂ (Figure 1).    Of the various bidentate phosphines reacted, the dppf and DPEPhos (Bis[(2-diphenylphosphino)phenyl] ether) produced the best catalyst and both were studied further.  Initial rate analysis revealed that althougth the dppf catalyst is much slower than the others it is long-lasting and can be reused at least 6 times. 

     A ¹H nuclear Overhauser effect (nOe) NMR experiment at variable temperatures was conducted on (PPh₃)₂CoN(SiMe₃)₂, (DPEPhos)CoN(SiMe₃)₂,  and (dppf)CoN(SiMe₃)₂  to determine if a coordination site is opening up upon heating closer to those at which catalysis occurs. In doing so, we would expect to see an enhancement effect when ligand movement around the metal center is greatest. While nOe spectra are not commonly collected with paramagnetic compounds, work on metalloproteins and metalloprotein model complexes offers insight into how to carry out such an experiment. ⁵  Although, none of the cobalt complexes studied displayed an nOe enhancement at room temperature, enhancement was observed at 80 ^oC (the temperature catalysis turns on) and enhancement is maximized at 100 ^oC (Figure 1). This implies that the ligands are fluxional at elevated temperatures and is consistent with our observed catalytic reactivity. 

     Based on the data described herein we hypothesize that the N(SiMe₃)₂ ligand plays an important role in the two-electron reactivity by simultaneously acting  as a strong-field ligand while enabling access to the low-coordinate geometry. Based on kinetics and structural data, it would appear that stabilization of the intermediate leads to more effective catalysis. Thus, we can assign the resting state of the catalytic cycle as the trigonal planar Co(I) complex, but ligand distortion opens a coordination site allowing reactivity to ensue. Understanding this structural rearrangement may allow us to target stronger donor nuclei that still provide access to this metal center geometry which will allow for a more effective and diverse chemistry.

      Future studies involved the investigation of a variety of sterically encumbered coupling partners featuring the formation of new C-N and C-C bonds catalyzed by the newly synthesized (dppf)CoN(SiMe₃)₂ catalyst.  A variety of sterically encumbered substrates are being targeted for this reactivity.