Mechanistic Studies

3.3.3.1. H/D-Exchange Experiments

Given the unique features of the asymmetric aluminium-free nickel-catalyzed C–H alkylation, an understanding of its mode of action was desired. To study the mechanism of the C–H activation elementary step, an H/D-exchange experiment with CD₃OD as the co-solvent was conducted (Scheme 3.3.2a). Importantly, a significant H/D-exchange in the C2-position of the reisolated starting material 188a was detected. Further, a reaction performed with deuterated substrate [D]1-188a revealed H/D scrambling at the methyl group and positions of the former olefin (Scheme 3.3.2b). A possible explanation could be the formation of a nickel-hydride and/or a π-allyl-nickel intermediate that initiates isomerization.^[277] Nevertheless, both observations support a facile and reversible C–H activation step^[278] and are strikingly different from the previous report on nickel-catalyzed exo-cyclization.^[109d]

Scheme 3.3.2. H/D-exchange studies.

3.3.3.2. KIE Studies

3.3. Asymmetric Nickel-Catalyzed Hydroarylations by C–H Activation The kinetic isotope effect (KIE) of the asymmetric aluminium-free nickel-catalyzed C–H hydroarylation was measured by the comparison of independent reaction rates for substrate 188a and the isotopically labeled analogue [D]₁-188a, showing a minor value of k_H/k_D ~1.1 (Figure 3.3.2). The observed KIE is in good agreement with the results obtained from the H/D-exchange experiments, suggesting the C–H scission step not to be turnover limiting.^[279]

Figure 3.3.2. KIE study of the asymmetric aluminium-free nickel-catalyzed C–H hydroarylation.

3.3.3.3. Kinetic reaction orders

3.3.3.3.1. Reaction order of N-homoallylimidazoles 188a

Scheme 3.3.4. Kinetic order in N-homoallylimidazoles 188a.

The kinetic order of the reaction with respect to the concentration of N-homoallylimidazoles 188a equals n = 1.06 ± 0.04, which likely corresponds to a reaction

order of one (Figure 3.3.3). This result can be interpreted as a clear hint for the participation of substrate 188a in the turnover-limiting step of the reaction.

-0,60 -0,55 -0,50 -0,45 -0,40 -0,35 -0,30 -0,25 -0,20 -0,15 -7,9

Figure 3.3.3. Kinetic order in [188a] in the asymmetric aluminium-free nickel-catalyzed C–H hydroarylation conditions.

3.3.3.3.2. Reaction order of JoSPOphos (208)

Scheme 3.3.5. Kinetic order in JoSPOphos (208).

The reaction order with respect to the concentration of JoSPOphos (208) is roughly one, with n = 0.96 ± 0.09 (Figure 3.3.4), showing that the ligand coordinates during the turnover-limiting step of the catalytic cycle to the metal.

3.3. Asymmetric Nickel-Catalyzed Hydroarylations by C–H Activation

Figure 3.3.4. Kinetic order in [208] in the asymmetric aluminium-free nickel-catalyzed C–H hydroarylation conditions.

3.3.3.3.3. Reaction order of Ni(cod)₂

Scheme 3.3.6. Kinetic order in Ni(cod)₂.

Interestingly, an initial first-order rate dependence in the nickel precursor of n = 1.06 ± 0.03 was observed, followed by an inhibition at higher nickel concentrations (Figure 3.3.5). A possible interpretation to this rather unusual finding could be the existence of a critical nickel concentration, beyond which an autocatalytic deactivation of the catalyst occurs due to aggregation of nickel, as it was proposed for palladium catalysis.^[280] Another explanation to the detrimental effect of higher concentrations of Ni(cod)2 could be the competitive coordination of free cod to the nickel center, resulting in off-cycle intermediates decelerating the catalysis, as previously reported by Zimmerman and Montgomery.^[281]

-2,1 -2,0 -1,9 -1,8 -1,7 -1,6 -1,5 -1,4 -1,3

Figure 3.3.5. Kinetic order in [Ni(cod)₂] in the asymmetric aluminium-free nickel-catalyzed C–H hydroarylation conditions.

3.3.3.4. Effect of the concentration of 1,5-cyclooctadiene on the reaction rate

Scheme 3.3.7. Reaction rate dependence on the concentration of 1,5-cyclooctadiene.

Studies towards high concentrations of 1,5-cyclooctadiene (cod) showed that, in the presence of additional cod, the transformation was found to proceed with a lower rate (Figure 3.3.6). This finding provided support for the hypothesis that an inhibition of the active nickel catalyst is caused by free cod originating from the consumption or degradation of Ni(cod)₂.

3.3. Asymmetric Nickel-Catalyzed Hydroarylations by C–H Activation

Figure 3.3.6. Effect of the concentration of 1,5-cyclooctadiene in the asymmetric aluminium-free nickel-catalyzed C–H hydroarylation.

3.3.4. Proposed Catalytic Cycle

Based on our detailed mechanistic studies and previous literature reports,[105, 235b, 282]

the catalytic reaction is proposed to be initiated by the formation of the organometallic nickel(II) complex 196 (Scheme 3.3.8). Complex 196 was synthesized by Dr. Debasish Ghorai and found to be active in both stoichiometric and catalytic reactions. A plausible pathway for the generation of nickel(II) complex 196 could be the oxidative addition of nickel(0) into the P(O)–H bond, as it has been previously reported in the literature,^[283] followed by hydride migration to the bond 1,5-cyclooctadiene and chain walking.^[281b] Complex 196 is then coordinated by substrate 188a to form intermediate 209. Due to the close proximity an initial C–H activation can occur after loss of a cyclooctene molecule, yielding the proposed active catalyst 210. Intermediate 210 then undergoes the stereo-determining and C–C bond forming migratory insertion to deliver the cyclized intermediate 211. Derived from the kinetic reaction order analysis a kinetically relevant coordination of a second substrate 188a occurs, yielding intermediate 212. Finally, the facile C–H cleavage was proposed to occur via a LLHT manifold 213,[277d, 282a, 284]

yielding the desired product 189a and the reformed active catalyst 210. Taking into account that the formation of the active catalyst is an off-cycle reaction the observed H/D scrambling can be explained since during the oxidative addition of the

involved. Furthermore, the isolated complex 196 is a plausible off-cycle intermediate, or a resting state, whose reversible formation is favored by higher concentrations of cod. This can explain the negative order in Ni(cod)2 above a certain concentration and rationalizing the detrimental effect of adding an excess of free 1,5-cyclooctadiene to the catalytic reaction.

Indeed, such cod-incorporating π-allyl complexes are documented to be stable off-cycle intermediates whose formation diminishes the catalytic efficiency.^[281]

Scheme 3.3.8. Proposed catalytic cycle. Complex 196 was prepared and crystallized by Dr. Debasish Ghorai. The crystal structure was measured and resolved by Dr. Christopher Golz.

3.3. Asymmetric Nickel-Catalyzed Hydroarylations by C–H Activation In this context, detailed DFT studies by Chen and Ackermann revealed in addition to the LLHT and reductive elimination pathway, an unexpected potentially favorable nickel(0)/nickel(II) catalytic cycle compromising P–H oxidative addition, migratory insertion and C(sp²)–H activation via σ-CAM (σ-complex-assisted metathesis) and C–C reductive elimination.^[285] Similar to the experimental results the DFT calculations emphasized that complex 196 is probably an off-cycle intermediate, which can be converted to the catalytical active nickel(0) complex by sequential β-hydride elimination and reductive elimination.