Regulating Access to Active Sites via Hydrogen Bonding and Cation-Dipole Interactions: A Dual Cofactor Approach to Switchable Catalysis.

Hydrogen bonding networks are ubiquitous in biological systems and play a key role in controlling the conformational dynamics and allosteric interactions of enzymes. Yet in small organometallic catalysts, hydrogen bonding rarely controls ligand binding to the metal center. In this work, a hydrogen bonding network within a well-defined organometallic catalyst works in concert with cation-dipole interactions to gate substrate access to the active site. An ammine ligand acts as one cofactor, templating a hydrogen bonding network within a pendent crown ether and preventing the binding of strong donor ligands, such as nitriles, to the nickel center. Sodium ions are the second cofactor, disrupting hydrogen bonding to enable switchable ligand substitution reactions. Thermodynamic analyses provide insight into the energetic requirements of the different supramolecular interactions that enable substrate gating. The dual cofactor approach enables switchable catalytic hydroamination of crotononitrile. Systematic comparisons of catalysts with varying structural features provide support for the critical role of the dual cofactors in achieving on/off catalysis with substrates containing strongly donating functional groups that might otherwise interfere with switchable catalysts.

The effect of noise on the predictive limit of QSAR models.

A key challenge in the field of Quantitative Structure Activity Relationships (QSAR) is how to effectively treat experimental error in the training and evaluation of computational models. It is often assumed in the field of QSAR that models cannot produce predictions which are more accurate than their training data. Additionally, it is implicitly assumed, by necessity, that data points in test sets or validation sets do not contain error, and that each data point is a population mean. This work proposes the hypothesis that QSAR models can make predictions which are more accurate than their training data and that the error-free test set assumption leads to a significant misevaluation of model performance. This work used 8 datasets with six different common QSAR endpoints, because different endpoints should have different amounts of experimental error associated with varying complexity of the measurements. Up to 15 levels of simulated Gaussian distributed random error was added to the datasets, and models were built on the error laden datasets using five different algorithms. The models were trained on the error laden data, evaluated on error-laden test sets, and evaluated on error-free test sets. The results show that for each level of added error, the RMSE for evaluation on the error free test sets was always better. The results support the hypothesis that, at least under the conditions of Gaussian distributed random error, QSAR models can make predictions which are more accurate than their training data, and that the evaluation of models on error laden test and validation sets may give a flawed measure of model performance. These results have implications for how QSAR models are evaluated, especially for disciplines where experimental error is very large, such as in computational toxicology.

Transition State Asymmetry in C-H Bond Cleavage by Proton-Coupled Electron Transfer.

The selective transformation of C-H bonds is a longstanding challenge in modern chemistry. A recent report details C-H oxidation via multiple-site concerted proton-electron transfer (MS-CPET), where the proton and electron in the C-H bond are transferred to separate sites. Reactivity at a specific C-H bond was achieved by appropriate positioning of an internal benzoate base. Here, we extend that report to reactions of a series of molecules with differently substituted fluorenyl-benzoates and varying outer-sphere oxidants. These results probe the fundamental rate versus driving force relationships in this MS-CPET reaction at carbon by separately modulating the driving force for the proton and electron transfer components. The rate constants depend strongly on the pKa of the internal base, but depend much less on the nature of the outer-sphere oxidant. These observations suggest that the transition states for these reactions are imbalanced. Density functional theory (DFT) was used to generate an internal reaction coordinate, which qualitatively reproduced the experimental observation of a transition state imbalance. Thus, in this system, homolytic C-H bond cleavage involves concerted but asynchronous transfer of the H+ and e-. The nature of this transfer has implications for synthetic methodology and biological systems.

Activationless Multiple-Site Concerted Proton-Electron Tunneling.

The transfer of protons and electrons is key to energy conversion and storage, from photosynthesis to fuel cells. Increased understanding and control of these processes are needed. A new anthracene-phenol-pyridine molecular triad was designed to undergo fast photoinduced multiple-site concerted proton-electron transfer (MS-CPET), with the phenol moiety transferring an electron to the photoexcited anthracene and a proton to the pyridine. Fluorescence quenching and transient absorption experiments in solutions and glasses show rapid MS-CPET (3.2 × 1010 s-1 at 298 K). From 5.5 to 90 K, the reaction rate and kinetic isotope effect (KIE) are independent of temperature, with zero Arrhenius activation energy. From 145 to 350 K, there are only slight changes with temperature. This MS-CPET reaction thus occurs by tunneling of both the proton and electron, in different directions. Since the reaction proceeds without significant thermal activation energy, the rate constant indicates the magnitude of the electron/proton double tunneling probability.

SmI2(H2O)n Reduction of Electron Rich Enamines by Proton-Coupled Electron Transfer.

Samarium diiodide in the presence of water and THF (SmI2(H2O)n) has in recent years become a versatile and useful reagent, mainly for reducing carbonyl-type substrates. This work reports the reduction of several enamines by SmI2(H2O)n. Mechanistic experiments implicate a concerted proton-coupled electron transfer (PCET) pathway, based on various pieces of evidence against initial outer-sphere electron transfer, proton transfer, or substrate coordination. A thermochemical analysis indicates that the C-H bond formed in the rate-determining step has a bond dissociation free energy (BDFE) of ∼32 kcal mol-1. The O-H BDFE of the samarium aquo ion is estimated to be 26 kcal mol-1, which is among the weakest known X-H bonds of stable reagents. Thus, SmI2(H2O)n should be able to form very weak C-H bonds. The reduction of these highly electron rich substrates by SmI2(H2O)n shows that this reagent is a very strong hydrogen atom donor as well as an outer-sphere reductant.