The (salen)Mn(III)-catalyzed epoxidation reaction mechanism has been investigated using density functional theory (DFT). There is considerable interest in and controversy over the mechanism of this reaction. The results of experimental studies have offered some support for three different reaction mechanisms: concerted, stepwise radical, and metallooxetane mediated. In this paper, a theoretical examination of the reaction suggests a novel mechanism that describes the reaction as a multichannel process combining both concerted and stepwise radical pathways. The competing channels have different spin states: the singlet, the triplet, and the quintet. The singlet reaction pathway corresponds to a concerted mechanism and leads exclusively to a cis epoxide product. In contrast, the triplet and quintet reactions follow a stepwise mechanism and lead to a product mixture of cis and trans epoxides. We show that the experimentally observed dependence of isomer product ratios on electronic effects connected with the substitution of the catalyst ligands is due to changing the relative position and, hence, the relative activities of the channels with different cis-trans yields. Because the results and conclusions of the present work dramatically differ from the results and conclusion of the recent DFT theoretical investigation (Linde, C.; Akermark, B; Norrby, P.-O.; Svensson, M. J. Am. Chem. Soc. 1999, 121, 5083.), we studied possible sources for the deep contradictions between the two works. The choice of the DFT functional and a model has been shown to be crucial for accurate results. Using high level ab initio calculations (coupled cluster-CCSD(T)), we show that the computational procedure employed in this study generates significantly more reliable numerical results. It is also shown that the smaller cationic model without a chlorine ligand that was used by Linde et al. is too oversimplified with respect to our larger neutral model. For this reason, using the cationic model led to a qualitatively wrong quintet reaction profile that played a key role in theoretical postulates in the earlier work.

Recent experimental observations support the assumption that all families of polynucleotide polymerases have a universal "two-metal-ion" mechanism of nucleotide addition. This mechanism provides a general picture of the nucleotidyl transfer reaction. However, the detailed reaction pathway is still a matter of debate. We investigated two potential reaction pathways for DNA polymerase β using density-functional theory. Our model consists of 67 atoms of the polymerase active site and includes all major features thought to be important for catalysis. The first mechanism we investigated involves the formation of a PO 3 intermediate. This intermediate is thought to be involved in phosphate reactions in solution and could be accommodated in the polymerase β active site. However, the barrier to formation of this intermediate is 37.0 kcal/mol, and we do not expect that this mechanism is the one that occurs in the enzyme. The second mechanism that leads to a pentacoordinated intermediate appears to be feasible. This stepwise mechanism has relatively low barriers and, after the nucleophilic attack, every step of the reaction is exothermic. The rate-limiting step of the reaction is the nucleophilic attack, which needs 13 kcal/mol of activation energy. We predict that the barrier of the corresponding transition state, which is ionic, can be further lowered by taking into account electrostatic stabilization coming from the rest of the protein.

A method for finding the transition structures (TS) based on constrained optimization techniques is proposed. The algorithm can be considered as a step-by-step walking uphill process along the minimum energy path, followed by a refining procedure of TS parameters in the saddle point vicinity. By accounting for the constraint conditions in a straightforward manner, it is possible to use efficient quasi-Newton algorithms at every geometry reoptimization step and to manage the moving direction in a reaction valley. This approach may be suitable in the framework of density functional theory. Tests including a potential energy surface model, HNC→HCN and N2H2 trans–cis isomerizations and LiBH4 rearrangements are given. The possible future development of the approach is discussed.

[structure: see text] A novel (two-zone process with different spin-state channels) mechanistic picture for the Jacobsen-Katsuki reaction is presented that provides insight into the still elusive understanding of the epoxidation mechanism. For the first time, we show that the salen moiety of the catalyst can be explicitly involved in the epoxidation process.