The solution-phase structures of the monomeric forms of the cationic Pd-eta(3)-allyl and Pd-eta(3)-cyclohexenyl complexes [Pd(R,R)-1(eta(3)-C(3)H(5))](+) (7(+)) and [Pd(R,R)-1(eta(3)-C(6)H(9))](+) (8(+)) bearing the trans-cyclohexylenediamine-based Trost 'Standard Ligand' (R,R)-1 have been elucidated by NMR, isotopic labeling and computation. In both complexes, (R,R)-1 is found to adopt a C(1)-symmetric conformation, leading to a concave shape in the 13-membered chelate in which one amide group in the chiral scaffold projects its NH unit out of the concave surface in close vicinity to one allyl terminus. The adjacent amide has a reversed orientation and projects its carbonyl group out of the concave face in the vicinity of the opposite allyl terminus. Stoichiometric and catalytic asymmetric alkylations of [8(+)][X(-)] by MCHE(2) (E = ester, M = 'escort' counterion, X = Pd allyl counterion) show the same selectivities and trends as have been reported for in situ-generated catalysts, and a new model for the enantioselectivity has been explored computationally. Three factors are found to govern the regioselectivity (pro-S vs pro-R) of attack of nucleophiles on the eta(3)-C(6)H(9) ring in 8(+) and thus the ee of the alkylation product: (i) a pro-R torquoselective bias is induced by steric interaction of the eta(3)-C(6)H(9) moiety with one phenyl ring of the ligand; (ii) pro-S delivery of the nucleophile can be facilitated by hydrogen-bonding with the concave orientated amide N-H; and (iii) pro-R delivery of the nucleophile can be facilitated by escort ion (M) binding to the concave orientated amide carbonyl. The latter two opposing interactions lead to the selectivity of the alkylation being sensitive to the identities of X(-) and M(+). The generation of 8(+) from cyclohexenyl ester substrate has also been explored computationally. The concave orientated amide N-H is able to activate the leaving group of the allylic ester by hydrogen bonding to its carbonyl group. However, this interaction is only feasible for the (S)-enantiomer of substrate, leading to the prediction of a powerful kinetic resolution (k(S) >> k(R)), as is found experimentally. This new model involving two regiochemically distinct (NH) and (CO) locations for nucleofuge or nucleophile binding, may prove of broad utility for the interpretation of the selectivity in asymmetric allylic alkylation reactions catalyzed by Pd complexes of (R,R)-1 and related ligands.
Detailed kinetic studies and novel graphical manipulations of reaction progress data in Pd(II)-catalyzed olefinations in the presence of mono-N-protected amino acid ligands reveal anomalous concentration dependences (zero order in o-CF(3)-phenylacetic acid concentration, zero order in oxygen pressure, and negative orders in both olefin and product concentrations), leaving the catalyst concentration as the sole positive driving force in the reaction. NMR spectroscopic studies support the proposal that rate inhibition by the olefinic substrate and product is caused by formation of reversible off-cycle reservoirs that remove catalyst from the active cycle. NMR studies comparing the interaction between the catalyst and substrate in the presence and absence of the ligand suggest that weak coordination of the ligand to Pd prevents formation of an inactive mixed acetate species. A fuller understanding of these features may lead to the design of more efficient Pd(II) catalysts for this potentially powerful C-H functionalization reaction.
Experimental studies on the mechanism of copper-catalyzed amination of aryl halides have been undertaken for the coupling of piperidine with iodobenzene using a Cu(I) catalyst and the organic base tetrabutylphosphonium malonate (TBPM). The use of TBPM led to high reactivity and high conversion rates in the coupling reaction, as well as obviating any mass transfer effects. The often commonly employed O,O-chelating ligand 2-acetylcyclohexanone was surprisingly found to have a negligible effect on the reaction rate, and on the basis of NMR, calorimetric, and kinetic modeling studies, the malonate dianion in TBPM is instead postulated to act as an ancillary ligand in this system. Kinetic profiling using reaction progress kinetic analysis (RPKA) methods show the reaction rate to have a dependence on all of the reaction components in the concentration range studied, with first-order kinetics with respect to [amine], [aryl halide], and [Cu]total. Unexpectedly, negative first-order kinetics in [TBPM] was observed. This negative rate dependence in [TBPM] can be explained by the formation of an off-cycle copper(I) dimalonate species, which is also argued to undergo disproportionation and is thus responsible for catalyst deactivation. The key role of the amine in minimizing catalyst deactivation is also highlighted by the kinetic studies. An examination of the aryl halide activation mechanism using radical probes was undertaken, which is consistent with an oxidative addition pathway. On the basis of these findings, a more detailed mechanistic cycle for the C–N coupling is proposed, including catalyst deactivation pathways.
Over the last two decades many different auxiliary ligand systems have been utilized in the copper-catalyzed Ullmann amination reaction. However, there has been little consensus on the relative merits of the varied ligands and the exact role they might play in the catalytic process. Accordingly, in this work some of the most commonly employed auxiliary ligands have been evaluated for C–N coupling using reaction progress kinetic analysis (RPKA) methodology. The results reveal not only the relative kinetic competencies of the different auxiliary ligands but also their markedly different influences on catalyst degradation rates. For the model Ullmann reaction between piperidine and iodobenzene using the soluble organic base bis(tetra-n-butylphosphonium) malonate (TBPM) at room temperature, N-methylglycine was shown to give the best performance in terms of high catalytic rate of reaction and comparatively low catalyst deactivation rates. Further experimental and rate data indicate a common catalytic cycle for all auxiliary ligands studied, although additional off-cycle processes are observed for some of the ligands (notably phenanthroline). The ability of the auxiliary ligand, base (malonate dianion), and substrate (amine) to all act competitively as ligands for the copper center is also demonstrated. On the basis of these results an improved protocol for room-temperature copper-catalyzed C–N couplings is presented with 27 different examples reported.
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