Deprotonation-electrophile trapping of terminal epoxides

Organolithium-induced deprotonation of terminal epoxides in the presence of appropriate diamine ligands allows trapping with a range of electrophiles, yielding functionalised di- and tri-substituted epoxides in good yields and with control of stereochemistry at the epoxide.     

Suicide inactivation of dioldehydratase by glycolaldehyde and chloroacetaldehyde: an examination of the reaction mechanism

High-level ab initio calculations have been used to study the mechanism for the inactivation of diol dehydratase (DDH) by glycolaldehyde or 2-chloroacetaldehyde. As in the case of the catalytic substrates of DDH, e.g., ethane-1,2-diol, the 5'-deoxyadenosyl radical (Ado*) is able to abstract a hydrogen atom from both substrate analogues in the initial step on the reaction pathway, as evidenced by comparable energy barriers. However, in subsequent step(s), each substrate analogue produces the highly stable glycolaldehyde radical. The barrier for hydrogen atom reabstraction by the glycolaldehyde radical is calculated to be too high ( approximately 110 kJ mol-1) to allow Ado* to be regenerated and recombine with the cob(II)alamin radical, the latter therefore remaining tightly bound to DDH. As a consequence, the catalytic pathway is disrupted, and DDH becomes an impotent enzyme. Interconversion of equivalent structures of the glycolaldehyde radical via the symmetrical cis-ethanesemidione radical is calculated to require 38 kJ mol-1. EPR indications of a symmetrical cis-ethanesemidione structure are likely to be the result of formation of an equilibrium mixture of glycolaldehyde radical structures, this equilibration being facilitated by partial deprotonation of the glycolaldehyde radical by the carboxylate of an amino acid residue within the active site of DDH.     

Should dithiophosphinate esters function as RAFT agents?

[graph: see text] High-level ab initio calculations indicate that *CH3 addition to the sulfur center of S=P(Z)(Z')SCH3 (Z,Z' = CH3, CN, OCH3, Ph) is considerably less exothermic than addition to the corresponding RAFT agents, S=C(Z)SCH3. This suggests that dithiophosphinate esters may have only limited use in controlling free-radical polymerization, but should make excellent radical chain carriers in organic synthesis. The results cast doubt on the notion that phosphoranyl radicals are more "intrinsically" stabilized than carbon-centered radicals.     

The effects of substrate orientation on the mechanism of a phosphotriesterase

While the underlying chemistry of enzyme-catalyzed reactions may be almost identical, the actual turnover rates of different substrates can vary significantly. This is seen in the turnover rates for the catalyzed hydrolysis of organophosphates by the bacterial phosphotriesterase OpdA. We investigate the variation in turnover rates by examining the hydrolysis of three classes of substrates: phosphotriesters, phosphothionates, and phosphorothiolates. Theoretical calculations were used to analyze the reactivity of these substrates and the energy barriers to their hydrolysis. This information was then compared to information derived from enzyme kinetics and crystallographic studies, providing new insights into the mechanism of this enzyme. We demonstrate that the enzyme catalyzes the hydrolysis of organophosphates through steric constraint of the reactants, and that the equilibrium between productively and unproductively bound substrates makes a significant contribution to the turnover rate of highly reactive substrates. These results highlight the importance of correct orientation of reactants within the active sites of enzymes to enable efficient catalysis.     

Efficient protocol for quantum Monte Carlo calculations of hydrogen abstraction barriers: Application to methanol

Accurate calculation of hydrogen abstraction reaction barriers is a challenging problem, often requiring high level quantum chemistry methods that scale poorly with system size. Quantum Monte Carlo (QMC) methods provide an alternative approach that exhibit much better scaling, but these methods are still computationally expensive. We describe approaches that can significantly reduce the cost of QMC calculations of barrier heights, using the hydrogen abstraction of methanol by a hydrogen atom as an illustrative example. By analysing the combined influence of trial wavefunctions and pseudopotential quadrature settings on the barrier heights, variance, and time‐step errors, we devise a simple protocol that minimizes the cost of the QMC calculations while retaining accuracy comparable to large‐basis coupled cluster theory. We demonstrate that this protocol is transferable to other hydrogen abstraction reactions.     

A universal approach for continuum solvent pK a calculations: are we there yet?

This paper reviews several pK _a calculation strategies that are commonly used in aqueous acidity predictions. Among those investigated were the direct or absolute method, the proton exchange scheme, and the hybrid cluster–continuum (Pliego and Riveros) and implicit–explicit (Kelly, Cramer and Truhlar) models. Additionally, these protocols are applied in the pK _a calculation of 55 neutral organic and inorganic acids in conjunction with various solvent models, including the CPCM-UAKS/UAHF, IPCM, SM6 and COSMO-RS, with a view to identifying a universal approach for accurate pK _a predictions. The results indicate that the direct method is unsuitable for general pK _a calculations, although moderately accurate results (MAD <3 units) are possible for certain classes of acids, depending on the choice of solvent model. The proton exchange scheme generally delivers good results (MAD <2 units), with CPCM-UAKS giving the best performance. Furthermore, the sensitivity of this approach to the choice of reference acid can be substantially lessened if the solvation energies for ionic species are calculated via the IPCM cluster–continuum approach. Reference-independent hybrid approaches that include explicit water molecules can potentially give reasonably accurate values (MAD generally ~2 units) depending on the solvent model and the number of explicit water molecules added.     

First-principles prediction of the pK(a)s of anti-inflammatory oxicams

The gas- and aqueous-phase acidities of a series of oxicams have been computed by combining M05-2X/6-311+G(3df,2p) gas-phase free energies with solvation free energies from the CPCM-UAKS, COSMO-RS, and SMD solvent models. To facilitate accurate gas-phase calculations, a benchmarking study was further carried out to assess the performance of various density functional theory methods against the high-level composite method G3MP2(+). Oxicams are typically diprotic acids, and several tautomers are possible in each protonation state. The direct thermodynamic cycle and the proton exchange scheme have been employed to compute the microscopic pK(a)s on both solution- and gas-phase equilibrium conformers, and these were combined to yield the macroscopic pK(a) values. Using the direct cycle of pK(a) calculation, the CPCM-UAKS model delivered reasonably accurate results with MAD ~ 1, whereas the SMD and COSMO-RS models' performance was less satisfactory with MAD ~ 3. Comparison with experiment also indicates that direct cycle calculations based on solution conformers generally deliver better accuracy. The proton exchange cycle affords further improvement for all solvent models through systematic error cancellation and therefore provides better reliability for the pK(a) prediction of compounds of these types. The latter approach has been applied to predict the pK(a)s of several recently synthesized oxicam derivatives.     

Effect of temperature and solvent on polymer tacticity in the free‐radical polymerization of styrene and methyl methacrylate

The effect of temperature and solvent on polymer tacticity in free‐radical polymerization of styrene and methyl methacrylate was studied by ¹³C and ¹H NMR, respectively. Polystyrene shows a mild syndiotactic tendency (P_m = 0.36 ± 0.02) that is independent of temperature over a wide range (?10 to 120 °C), while poly(methyl methacrylate) shows a stronger syndiotactic tendency (P_m = 0.17 ± 0.01 at 30 °C) that decreases as temperature is increased (P_m = 0.22 ± 0.02 at 80 °C). None of the polymerization solvents studied (bulk, THF, DMF, DMSO, acetonitrile, and acetone) had a significant effect on polymer tacticity in either system. The triad fractions of both polymers showed deviations from the Bernoulli model, implying that the antepenultimate unit affects the propagation reaction. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013 , 51, 3351–3358