The Pd loading was then lowered to 0.25 mol %, thereby affording an almost quantitative yield of 1 in only 30 min. Attempts to make OACs from biaryl phosphines, using tBuXPhos and tBuBrettPhos as representative examples and applying the identical successful protocol that led to OAC-1, were unsuccessful due to their instability to both air and silica gel (Scheme 4). The fast rate of reaction can presumably be attributed to OAC-1 being a pre-catalyst (i.e., bypassing an initial oxidative addition for catalyst activation; Scheme 5). Scheme 5 has the usually postulated catalytic mechanism for arylbromides, modified to show fluorosulfate salt intermediates. It also shows one possible way that the precatalyst OAC-1 could form the LPd 0 catalyst by amine coordination, followed by deprotonation and reductive elimination to produce P1, initially. Ultimately, this could form LPd 0 , which then could undergo oxidative addition to the aryl fluorosulfate, thereby starting the actual the catalytic cycle leading to the desired product. Scheme 5. Postulated Mechanism of aminations using an OAC. To gain insight into the structure of OAC-1, a single crystal X-ray structure was determined (see Figure ). A structure for OAC-1 was also calculated at the M06/6-31+G(d,p)/SDD(Pd,Br) level of theory, giving a geometry for a conformer, D, that very closely matches the X-ray crystal structure, except for a minor difference of 15° in dihedral angle for one phenyl group (Figure ), consistent with other comparisons we have made between X-ray crystal structures and calculated gas-phase structures. Surprisingly, the 1 H and 13 C NMR spectra for chloroform solutions of OAC-1 show evidence of three low-energy conformers with a ratio of 9.0:6.5:1.3. Relative free energies [M06/6-31+G(d,p)/SDD(Pd,Br)/SMD(CHCl3)] for the four lowest energy conformers A, B, C and D were 0.00, 0.13, 0.29, and 2.17 kcal/mol, respectively, with low barriers for rotation of the phenyl and t-butyl groups as observed in the NMR spectra (see SI-2 for details). This accounts nicely for the experimental NMR ratios but is unusual in that the highest energy conformer D corresponds to the observed geometry in the crystal structure. This could be the result of crystal packing forces that have a large enough effect that all three of the lowest energy conformers become less stable than conformer D. An interesting feature of the calculated structure for OAC-1 was the bonding between Pd and a pyrazole ring in BippyPhos, which was later confirmed in the X-ray crystal structure (vide supra). This appears to be a sort of pcomplexation to the heterocycle ring carbon and has some precedent in an X-ray structure of an aryl group bound to Pd in a G6 OAC pre-catalyst, (see Scheme 2A). 39a, We find evidence of the energetic consequences of this pcomplexation to Pd by comparing the free energy at 298K of conformer A of OAC-1 with that of conformer OAC-1anti in which the Pd is rotated anti to the heterocycle rings of the ligand, as shown in Scheme 6. Species OAC-1-anti is uphill by 12.1 kcal/mol in chloroform when this pcomplexation is ruptured. The reductive elimination transition state OAC-1-TS-1 would be on one of several pathways by which OAC-1 could conceivably return to a Pd(0) catalytic intermediate for the coupling reaction. As the extent of functionality in each partner increased, the loading of catalyst increased to 0.50 mol %. This was the case with several N-heterocycle-containing anilines, presumably due to their known propensity to coordinate with the catalyst Late-stage C-N cross couplings with complex, pharmaceutically relevant substrates. C-N Bond formation involving late-stage pharmaceutical derivatives bearing multiple functional groups can exhibit a high rate of failure. Nevertheless, given the large number of nitrogencontaining biologically active compounds, both discovery and process chemists place significant value in Pdcatalyzed C-N couplings. In order to extend the generality of this methodology, several pharmaceutically relevant compounds were made using OAC-1. Thus, with only 0.50-0.75 mol % of OAC-1, complex pharmaceuticals bearing multiple functional groups could be aminated to products 24-32 with a variety of aryl fluorosulfates (Scheme 8). Arylation of a pyrimidine containing polycyclic aniline, a reaction partner en route to the anti-cancer drug imatinib (Gleevec™, affording product 24) was realized in excellent yield. Furthermore, arylation of aminoglutethimide (Elip-ten™), which is used in the treatment of seizures, Cushing's syndrome, breast, and prostate cancer proceeded very smoothly to product 25 in close to quantitative isolated yield. It is noteworthy that under these mild reaction conditions, the glutarimide moiety does not fragment. Likewise, arylation of (i) Procaine (affording product 26; No-vocain™), a local anesthetic; (ii) Metoclopramide (affording product 27; Reglan™); an anti-emetic and gut motility stimulator; and (iii) Mosapride (affording product 28; Gasmotin™); a prokinetic 5-HT4 receptor agonist used to stimulate gastric motility, all proceeded very efficiently to afford excellent yields of the corresponding coupled products. Moreover, aryl fluorosulfates derived from pharmaceutically relevant phenols, such as: (i) Capsaicin, used in the treatment of neuralgia and rheumatoid arthritis (affording product 28); (ii) Estrone (Estragyn™; affording product 29), used in hormone therapy; (iii) Ezetimibe (Zetia™; affording product 31), used in the treatment of high cholesterol, and (iv) Arctigenin, a plant lignan with antioxidant, anti-inflammatory, and antiviral properties (affording product 32), all proceeded smoothly. Collectively, C-N couplings of this nature involving complex pharmaceuticals and materials used under environmentally responsible conditions further establishes the generality of these technologies as important tools in the growing toolbox that are based on chemistry in water. Noteworthy is the finding that levels of residual Pd in products from ICP-MS analyses are relatively quite low (see 30-32 in Scheme 8). This is reflective of the levels needed for these otherwise challenging aminations which, as part of any sequence, should eventually lead to products well below FDA limits. 66