Despite the widespread application of Suzuki-Miyaura cross-coupling to forge carbon-carbon bonds, the structure of the reactive intermediates underlying the key transmetalation step from the boron reagent to the palladium catalyst remains uncertain. Here we report the use of low-temperature rapid injection nuclear magnetic resonance spectroscopy and kinetic studies to generate, observe, and characterize these previously elusive complexes. Specifically, this work establishes the identity of three different species containing palladium-oxygen-boron linkages, a tricoordinate boronic acid complex, and two tetracoordinate boronate complexes with 2:1 and 1:1 stoichiometry with respect to palladium. All of these species transfer their boron-bearing aryl groups to a coordinatively unsaturated palladium center in the critical transmetalation event.
The existence of the oft-invoked intermediates containing the crucial Pd-O-B subunit, the "missing link", has been established in the Suzuki-Miyaura cross-coupling reaction. The use of low-temperature, rapid injection NMR spectroscopy (RI-NMR), kinetic studies, and computational analysis has enabled the generation, observation, and characterization of these highly elusive species. The ability to confirm the intermediacy of Pd-O-B-containing species provided the opportunity to clarify mechanistic aspects of the transfer of the organic moiety from boron to palladium in the key transmetalation step. Specifically, these studies establish the identity of two different intermediates containing Pd-O-B linkages, a tri-coordinate (6-B-3) boronic acid complex and a tetra-coordinate (8-B-4) boronate complex, both of which undergo transmetalation leading to the cross-coupling product. Two distinct mechanistic pathways have been elucidated for stoichiometric reactions of these complexes: (1) transmetalation via an unactivated 6-B-3 intermediate that dominates in the presence of an excess of ligand, and (2) transmetalation via an activated 8-B-4 intermediate that takes place with a deficiency of ligand.
The Suzuki–Miyaura reaction is the most practiced palladium-catalyzed, cross-coupling reaction because of its broad applicability, low toxicity of the metal (B), and the wide variety of commercially available boron substrates. A wide variety of boronic acids and esters, each with different properties, have been developed for this process. Despite the popularity of the Suzuki–Miyaura reaction, the precise manner in which the organic fragment is transferred from boron to palladium has remained elusive for these reagents. Herein, we report the observation and characterization of pretransmetalation intermediates generated from a variety of commonly employed boronic esters. The ability to confirm the intermediacy of pretransmetalation intermediates provided the opportunity to clarify mechanistic aspects of the transfer of the organic moiety from boron to palladium in the key transmetalation step. A series of structural, kinetic, and computational investigations revealed that boronic esters can transmetalate directly without prior hydrolysis. Furthermore, depending on the boronic ester employed, significant rate enhancements for the transfer of the B-aryl groups were observed. Overall, two critical features were identified that enable the transfer of the organic fragment from boron to palladium: (1) the ability to create an empty coordination site on the palladium atom and (2) the nucleophilic character of the ipso carbon bound to boron. Both of these features ultimately relate to the electron density of the oxygen atoms in the boronic ester.
Cyclophanes, especially those where pyridinium units in conjugation with each other are linked up face-to-face within platforms that are held approximately 7 Å apart by rigid linkers, are capable of forming inclusion complexes with polycyclic aromatic hydrocarbons (PAHs) with high binding affinities as a result of a combination of noncovalent bonding interactions, including face-to-face [π···π] stacking and orthogonal [C-H···π] interactions. Here, we report the template-directed, catalyst-assisted synthesis of a three-fold symmetric, extended pyridinium-based, cage-like host (ExCage(6+)) containing a total of six π-electron-deficient pyridinium units connected in a pairwise fashion by three bridging p-xylylene linkers, displayed in a trigonal (1,3,5) fashion around two opposing and parallel 1,3,5-tris(4-pyridinium)benzene platforms. The association constants (K(a)) of eight complexes have been measured by isothermal titration calorimetry (ITC) in acetonitrile and were found to span the range from 2.82 × 10(3) for naphthalene up to 5.5 × 10(6) M(-1) for perylene. The barriers to decomplexation, which were measured in DMF-d7 for phenanthrene, pyrene, triphenylene, and coronene by dynamic (1)H NMR spectroscopy undergo significant stepwise increases from 11.8 → 13.6 → 15.5 → >18.7 kcal mol(-1), respectively, while complexation experiments using rapid injection (1)H NMR spectroscopy in DMF-d7 at -55 °C revealed the barriers to complexation for pyrene and coronene to be 6.7 and >8 kcal mol(-1), respectively. The kinetic and thermodynamic data reveal that, in the case of ExCage(6+), while the smaller PAHs form complexes faster than the larger ones, the larger PAHs form stronger complexes than the smaller ones. It is also worthy of note that, as the complexes become stronger in the case of the larger and larger PAHs, the Rebek 55% solution formula for molecular recognition in the liquid state becomes less and less relevant.
Using a mechanistically guided ligand design approach, a new ligand (SEGFAST) for the CuHcatalyzed hydroamination reaction of unactivated terminal olefins has been developed, providing a 62-fold rate increase over reactions compared to DTBM-SEGPHOS, the previous optimal ligand. Combining the respective strengths of computational chemistry and experimental kinetic measurements, we were able to quickly identify potential modifications that lead to more effective ligands, thus avoiding synthesizing and testing a large library of ligands. By optimizing the combination of attractive, non-covalent ligand-substrate interactions and the stability of the catalyst under the reaction conditions, we were able to identify a finely-tuned hybrid ligand that greatly enables accelerated hydrocupration rates with unactivated alkenes. Moreover, a modular and robust synthetic sequence was devised, which allowed for practical, gram-scale synthesis of these novel hybrid ligand structures.
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