Mechanistic Rationalization of Unusual Sigmoidal Kinetic Profiles in the Machetti–De Sarlo Cycloaddition Reaction

Unusual sigmoidal kinetic profiles in the Machetti–De Sarlo base-catalyzed 1,3-dipolar cycloaddition of acryl­amide to <i>N</i>-methyl­nitro­acet­amide are rationalized by detailed in situ kinetic analysis. A dual role is uncovered in which a substrate acts as a precursor to catalyze its own reaction. Such kinetic studies provide a general protocol for distinguishing among different mechanistic origins of induction periods in complex organic reactions

Rationalization of Asymmetric Amplification via Autocatalysis Triggered by Isotopically Chiral Molecules

Asymmetric amplification induced in the Soai autocatalytic reaction by chiral initiators that are enantiomeric only by virtue of an isotope, e.g., −CH₃ vs CD₃–, is examined by spectroscopic, kinetic, and DFT modeling studies to help understand requirements for the emergence of biological homochirality. We find that the initiator <i>inhibit</i>s the autocatalytic pathway at the outset of the reaction but ultimately provides the imbalance required for asymmetric amplification. This work provides clues in the ongoing search for prebiotically plausible versions of asymmetric autocatalysis

In-Situ Monitoring of Enantiomeric Excess During a Catalytic Kinetic Resolution

Vibrational Circular Dichroism combined with FTIR spectroscopy (VCD-IR) is demonstrated as a viable tool for the in situ measurement of enantiomeric excess during asymmetric catalytic transformations. Employing the Jacobsen (salen)­Co-catalyzed hydrolytic kinetic resolution of racemic epoxides as a proof-of-concept case study, methodology is developed to monitor the enantiomeric excess of the epoxide substrate as a function of conversion of the limiting reactant, water. Comparison of results for monomeric and oligomeric catalysts probes the molecularity of the catalyst by investigating nonlinear effects in catalyst enantiopurity. These results are in excellent agreement with previous mechanistic investigations of this reaction based on kinetic measurements and computational studies

Curtin–Hammett Paradigm for Stereocontrol in Organocatalysis by Diarylprolinol Ether Catalysts

Detailed mechanistic study of two reactions catalyzed by diarylprolinol ether catalysts, the conjugate addition of aldehydes to nitro-olefins and the α-chlorination of aldehydes, leads to the proposal that the stereochemical outcome in these cases is not determined by the transition state of the step in which the stereogenic center is formed from enamine attack on the electrophile but instead is correlated with the relative stability and reactivity of diastereomeric intermediates downstream in the catalytic cycle. This combination of kinetic and thermodynamic factors illustrates a remarkable Curtin–Hammett scenario that can result in either an enhancement or an erosion of the selectivity that would be predicted by the transition state for enamine attack on the electrophile. Evidence is offered to suggest that this concept may represent a general phenomenon for pyrrolidine-based catalysts lacking an acidic directing proton. Implications for catalyst and reaction design are discussed

Rational Ligand Design for the Arylation of Hindered Primary Amines Guided by Reaction Progress Kinetic Analysis

We report the Pd-catalyzed arylation of very hindered α,α,α-trisubstituted primary amines. Kinetics-based mechanistic analysis and rational design have led to the development of two biarylphosphine ligands that allow the transformation to proceed with excellent efficiency. The process was effective in coupling a wide range of functionalized aryl and heteroaryl halides under mild conditions

Experimental and Theoretical Study of the Emergence of Single Chirality in Attrition-Enhanced Deracemization

Experimental studies help to deconvolute the driving forces for crystal growth during attrition-enhanced deracemization, demonstrating an interplay between crystal size and crystal number in the emergence of homochirality. A semiempirical population balance model is presented based on considerations of the solubility driving force, as outlined by the Gibbs–Thomson rule, and a frequency factor based on the total interfacial surface area between solid crystals and the solution phase

Dispersion in Compartmentalized Flow Systems: Influence of Flow Patterns on Reactivity

Rapid reaction screening in flow systems may help to reduce the time and material required to optimize, scale-up, and implement a flow process. Compartmentalization using small fluorous plugs has been implemented in several commercial reactors as a means for running a large number of isolated reactions in series within a flow reactor. Dye tracking, visual mixing, and reactivity studies are used to better understand the factors controlling dispersion within a commercial reactor. The role of dispersion on reactivity is elucidated using model reactions, and an optimized method for performing high-throughput screening is proposed

Mechanistic Rationalization of Unusual Kinetics in Pd-Catalyzed C–H Olefination

Detailed kinetic studies and novel graphical manipulations of reaction progress data in Pd­(II)-catalyzed olefinations in the presence of mono-<i>N</i>-protected amino acid ligands reveal anomalous concentration dependences (zero order in <i>o</i>-CF₃-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

Pasteur’s Tweezers Revisited: On the Mechanism of Attrition-Enhanced Deracemization and Resolution of Chiral Conglomerate Solids

Insights into the mechanism of attrition-enhanced deracemization and resolution of solid enantiomorphic chiral compounds are obtained by crystal size and solubility measurements and by isotopic labeling experiments. Together these results help to deconvolute the various chemical and physical rate processes contributing to the phenomenon. Crystal size measurements highlight a distinct correlation between the stochastic, transient growth of crystals and the emergence of a single solid enantiomorph under attrition conditions. The rapid mass transfer of molecules between the solution and solid phases under attrition is demonstrated, and the concept of a crystal-size-induced solubility driving force is exploited to overcome the stochastic nature of the crystal growth and dissolution processes. Extension to non-racemizing conditions provides a novel methodology for chiral resolution. Implications both for practical chiral separations and for the origin of biological homochirality are discussed

Mechanistic Insights into the Vanadium-Catalyzed Achmatowicz Rearrangement of Furfurol

The Achmatowicz rearrangement is a powerful method for the construction of pyranones from simple furan derivatives. Here, we describe the development of improved reaction conditions and an interrogation into the fate of the metal center during this interesting transformation. The reaction to form the synthetically important lactol, 6-hydroxy-2<i>H</i>-pyran-3­(6<i>H</i>)-one (<b>3</b>), proceeds cleanly in the presence of <i>tert</i>-butyl hydroperoxide (TBHP, <b>2</b>) using low loadings of VO­(O^<i>i</i>Pr)₃ as catalyst. The nonaqueous conditions developed herein allow for easy isolation of product <b>3</b> and synthetically important derivatives, a key advantage of this new protocol. Detailed experimental, spectroscopic, and kinetic studies along with kinetic modeling of the catalytic cycle support a positive-order dependence in both furfurol and TBHP concentrations, first-order dependence in catalyst (VO­(O^<i>i</i>Pr)₃), and a <i>negative</i> dependence on the 2-methyl-2-propanol (<b>4</b>) concentration. ⁵¹V-NMR spectroscopic studies revealed that 2-methyl-2-propanol (<b>4</b>) competes with substrates for binding to the metal center, rationalizing its inhibitory effect