Condensation Oligomers with Sequence Control but without Coupling Reagents and Protecting Groups via Asymmetric Hydroformylation and Hydroacyloxylation

A novel strategy, free of coupling reagents and protection/deprotection steps, for the synthesis of oligo­(2-hydroxyacid)­s containing up to four monomer units with atom economy, sequence specificity, and control of stereocenter configuration is described. The strategy comprises an iterative application of the sequence asymmetric hydroformylation/oxidation/alkyne hydroacyloxylation that features catalytic, atom-economical C–C and C–O bond forming reactions. Asymmetric hydroformylation with Rh-bisdiazaphospholane catalyst introduces each stereocenter with high enantio- (ca. 93% e.e.), diastereo- (up to 25:1 d.r.), and regioselectivity (>50:1) at low catalyst loadings and mild pressures. The side chain in each monomer is tailored by choosing from a variety of readily available alkynes

Unexpected CO Dependencies, Catalyst Speciation, and Single Turnover Hydrogenolysis Studies of Hydroformylation via High Pressure NMR Spectroscopy

Rhodium bis­(diazaphospholane) (BDP) catalyzed hydroformylation of styrene is sensitive to CO concentration, and drastically different kinetic regimes are affected by modest changes in gas pressure. The Wisconsin High Pressure NMR Reactor (WiHP-NMRR) has enabled the observation of changes in catalyst speciation in these different regimes. The apparent discrepancy between catalyst speciation and product distribution led us to report the first direct, noncatalytic quantitative observation of hydrogenolysis of acyl dicarbonyls. Analysis and modeling of these experiments show that not all catalyst is shunted through the off-cycle intermediates and this contributes to the drastic mismatch in selectivities. The data herein highlight the complex kinetics of Rh­(BDP) catalyzed hydroformylation. In this case, the complexity arises from competing kinetic and thermodynamic preferences involving formation and isomerization of the acyl mono- and dicarbonyl intermediates and their hydrogenolysis to give aldehydes

Interception and Characterization of Alkyl and Acyl Complexes in Rhodium-Catalyzed Hydroformylation of Styrene

Reaction of [Rh­(H)­(CO)₂(BDP)] (BDP = bis­(diazaphospholane)) with styrene at low temperatures enables detailed NMR characterization of four- and five-coordinate rhodium alkyl complexes [Rh­(styrenyl)­(CO)_<i>n</i>(BDP)] presumed to be intermediates in rhodium-catalyzed hydroformylation. The five-coordinate acyl complexes [Rh­(C­(O)­styrenyl)­(CO)₂(BDP)] are also observed and characterized. The equilibrium distribution of these species suggests an inversion of thermodynamic preference for branched vs linear species from the alkyl to the acyl stage

Stopped-Flow NMR and Quantitative GPC Reveal Unexpected Complexities for the Mechanism of NHC-Catalyzed Lactide Polymerization

Stopped-flow NMR spectroscopy provides the first direct, <i>in situ</i> observation of lactide epimerization during polymerization with the <i>N</i>-heterocyclic carbene organocatalyst 1,3-dimesityl­imidazol-2-ylidene (IMes). Hexad analysis of the polymer microstructure using ¹³C NMR spectroscopy supports a chain-end-controlled mechanism for stereocontrol of the lactide polymerization. Data for both monomer consumption and molecular weight distribution (MWD) as a function of time have been examined using more than one dozen kinetic models. The most successful models feature reversible, unimolecular termination, first-order propagation in monomer, no backbiting term, and include a first-order catalyst death term. The developed modeling method allows insight into a challenging mechanistic problem by successfully modeling MWD evolution and monomer concentration with time

Immobilized Bisdiazaphospholane Catalysts for Asymmetric Hydroformylation

Condensation reactions of enantiopure bis-3,4-diazaphospholanes (BDPs) that are functionalized with carboxylic acids enable covalent attachment to bead and silica supports. Exposure of tethered BDPs to the hydroformylation catalyst precursor, Rh­(acac)­(CO)₂, yields catalysts for immobilized asymmetric hydroformylation (iAHF) of prochiral alkenes. Compared with homogeneous catalysts, catalysts immobilized on Tentagel resins exhibit similarly high regioselectivity and enantioselectivity. When corrected for apparent catalyst loading, the activity of the immobilized catalysts approaches that of the homogeneous analogues. Excellent recyclability with trace levels of rhodium leaching are observed in batch and flow reactor conditions. Silica-bound catalysts exhibit poorer enantioselectivities

Regioselective Rh-Catalyzed Hydroformylation of 1,1,3-Trisubstituted Allenes Using BisDiazaPhos Ligand

The efficient hydroformylation of 1,1,3-trisubstituted allenes is accomplished with low loadings of a Rh catalyst supported by a BisDiazaPhos (BDP) ligand. The ligand identity is key to achieving high regioselectivity, while the mild reaction conditions minimize competing isomerization and hydrogenation to produce β,γ-unsaturated aldehydes and their derivatives in excellent yields

Bonding Analysis of TM(cAAC)₂ (TM = Cu, Ag, and Au) and the Importance of Reference State

A recent analysis of the bonding in transition metal (TM) complexes with cyclic aminoalkyl carbene (cAAC) ligands, TM­(cAAC)₂ (TM = Cu, Ag, and Au), purports to show that metal–ligand bonding involves the TM in the excited ²P state and that TM­(pπ) → (cAAC)₂ backdonation is not properly recognized in NBO analysis because of biases against participation of n<i>p</i> functions in transition metal bonding. The questions of TM n<i>p</i> orbital involvement in bonding and the possible biases in the NBO occupancy-weighted symmetric orthogonalization procedure have been examined by performing NBO analyses in two ways: (1) single Lewis structure (loc) analysis with TM n<i>p</i> orbitals treated as valence (NBO_s) or nonvalence (NBO_<i>x</i>) and (2) direct comparison of a two-configuration resonance model (res/NBO_s) treatment with a single configuration model using the expanded valency (loc/NBO_<i>x</i>) treatment. The principal bonding picture that emerges from NBO analysis features a TM cation with two “non-innocent” cAAC ligands that are each reduced by 0.5 electrons. The unpaired spin delocalizes over a π network spanning the two ligands, whether or not a TM cation is present. In the localized NBO framework, the unpaired spin primarily occupies a 1<i>e</i> π-type “long-bond” between the carbonic carbon centers, with secondary resonance delocalization over the TM n<i>p</i>π and the two N<i>p</i>π orbitals. This description is consistent with all experimental data. Energy decomposition analysis–natural orbitals for chemical valence (EDA-NOCV) analysis of the Cu complex with different reference states reveals that the inferred nature of the bonding depends wholly on the choice of reference state. We show that the earlier selection of a neutral, excited ²P Cu reference state virtually dictates the bonding description to feature an unphysical degree of TM­(pπ) → (cAAC)₂ backdonation

Asymmetric Hydroformylation of <i>Z</i>‑Enamides and Enol Esters with Rhodium-Bisdiazaphos Catalysts

Asymmetric hydroformylation (AHF) of <i>Z</i>-enamides and <i>Z</i>-enol esters provides chiral, alpha-functionalized aldehydes with high selectivity and atom economy. Rh-bisdiazaphospholane catalysts enable hydroformylation of these challenging disubstituted substrates under mild reaction conditions and low catalyst loadings. The synthesis of a protected analog of l-DOPA demonstrates the utility of AHF for enantioselective, atom-efficient synthesis of peptide precursors

Are Phosphines Viable Ligands for Pd-Catalyzed Aerobic Oxidation Reactions? Contrasting Insights from a Survey of Six Reactions

Phosphines are the broadest and most important class of ligands in homogeneous catalysis, but they are typically avoided in Pd-catalyzed aerobic oxidation reactions because of their susceptibility to oxidative degradation. Recent empirical reaction-development efforts have led to a growing number of Pd/phosphine catalyst systems for aerobic oxidative coupling reactions, but few of these studies have assessed the fate of the phosphine ligand. Here, we assess six different oxidative coupling reactions, including the homocoupling of boronic acids, amino- and alkoxycarbonylation reactions, intramolecular C–H annulation, and enantioselective Fujiwara–Moritani C–C coupling. The fate and role of the phosphine, analyzed by ³¹P NMR spectroscopy throughout the reaction time course in each case, varies in different reactions. In one case, the phosphine has an inhibitory effect and leads to lower selectivity relative to ligand-free conditions. In other cases, the phosphine ligands have a beneficial effect on the reaction but undergo oxidative decomposition in parallel with productive catalytic turnover. Inclusion of MnO₂ in one of the reactions slows phosphine oxidation by catalyzing disproportionation of H₂O₂ and thereby supports productive catalytic turnover. Negligible oxidation of the chiral phosphine (<i>S</i>,<i>S</i>)-chiraphos is observed during the enantioselective C–C coupling reaction, due to strong chelation of the ligand to Pd^II. The results of this study suggest that phosphines warrant broader attention as ligands for Pd-catalyzed aerobic oxidation reactions, particularly by implementing strategies identified for ligand stabilization

Backbone-Modified Bisdiazaphospholanes for Regioselective Rhodium-Catalyzed Hydroformylation of Alkenes

A series of tetraaryl bisdiazaphospholane (BDP) ligands were prepared varying the phosphine bridge, backbone, and substituents in the 2- and 5-positions of the diazaphospholane ring. The parent acylhydrazine backbone was transformed to an alkylhydrazine via a borane reduction procedure. These reduced ligands contained an all sp³ hybridized ring mimicking the all sp³ phospholane of (<i>R,R</i>)-Ph-BPE, a highly selective ligand in asymmetric hydroformylation. The reduced bisdiazaphospholane (red-BDP) ligands were shown crystallographically to have an increased C–N–N–C torsion anglethis puckering resembles the structure of (<i>R,R</i>)-Ph-BPE and has a dramatic influence on regioselectivity in rhodium catalyzed hydroformylation. The red-BDPs demonstrated up to a 5-fold increase in selectivity for the branched aldehyde compared to the acylhydrazine parent ligands. This work demonstrates a facile procedure for increased branched selectivity from the highly active and accessible class of BDP ligands in hydroformylation