Catalytic role of the enol ether intermediate in the intramolecular Stetter reaction: a computational perspective.

The intramolecular Stetter reaction catalyzed by a carbene is investigated by density functional theory (DFT) calculations and kinetic simulations. Catalyst 1 first reacts with aldehyde 2 to give the primary adduct (PA). The PA undergoes the intramolecular oxa-Michael reaction to irreversibly generate enol ether intermediate 9. The conversion of the enol ether to the Breslow intermediate (BI) requires the assistance of a base such as the PA. The next step involves formation of a carbon-carbon bond through the Michael addition, and expulsion of the catalyst generates the Stetter product 7. Calculations show that the catalytic cycle is composed of two irreversible processes: the first one involves the exergonic formation of the enol ether intermediate, while the second one is the conversion of the enol ether to the final product. Kinetic simulations using initial concentrations of [1]0 = 0.005 M and [2]0 = 0.025 M demonstrate that under a steady-state condition, 35% of the catalyst rests on the state of the enol ether (0.0018 M). The catalyst resting state therefore consists of the unbound form (the free catalyst) and its bound form (the enol ether species). According to variable time normalization analysis, the reaction exhibits a second-order dependence (first order in catalyst and first order in substrate), which agrees with experiments. The oxa-Michael reaction to form the enol ether is identified to be turnover limiting in the intramolecular Stetter reaction, which rationalizes the observed electronic effect of the Michael acceptor on the reactivity, as well as the measured isotope effect with respect to the aldehydic proton/deuteron. The base that participates in the BI formation has a significant effect on the build-up of the resting state 9 and the active catalyst concentration. In addition, the thermodynamic stability of the enol ether is found to depend on the tether length between the aromatic aldehyde and the Michael acceptor, as well as the chemical nature of the carbene catalyst. The favorability for the oxa-Michael reaction is therefore suggested to govern the reactivity of the intramolecular Stetter transformation.

Formation of Breslow Intermediates under Aprotic Conditions: A Computational Study.

The mechanism of formation of the Breslow intermediate (BI) under aprotic conditions is investigated with density functional theory (DFT) calculations. The zwitterionic adduct (ZA) is formed by the first addition of an imidazolinylidene to benzaldehyde. The forward reaction is found to proceed through the second addition of the ZA to another benzaldehyde, and subsequent proton migration gives a hemiacetal. The bimolecular reaction enables the conversion of the ZA to a more reactive hemiacetal, which is further decomposed to the BI with the assistance of the ZA. During the ZA-assisted process, the hemiacetal and the BI act as hydrogen bond donors to stabilize the ZA. The hydrogen bond interactions between the ZA and the BI or hemiacetal are analyzed. The DFT computations demonstrate that along the proposed route, the proton migration leading to the hemiacetal intermediate is the rate-determining step (ΔG⧧ = 21.2 kcal mol-1). The bimolecular mechanism provides an alternative pathway to explain BI formation under aprotic conditions.

Analyses on Molecular Properties of the Diamidinate CrI-CrI Complex by Multireference and DFT Approaches.

The model system of the diamidinate CrI-CrI complex is investigated by wave function theory (WFT) and Kohn-Sham density functional theory (KS-DFT). The multireference perturbation theory (RASPT2) estimates a stabilization energy of ca. 20 kcal mol-1 for the δ bonding. The multiconfiguration pair-density functional theory (MC-PDFT) with the ftPBE functional well predicts the singlet energy curve comparable to the RASPT2 level. For the KS-DFT scheme based on a single determinant, seven functionals including BP86, BLYP, PBE, B3LYP, M06-L, M06, and ωB97X-D are assessed: two types of functionals are classified according to the nature of the restricted and broken symmetry potential energy curves. The broken symmetry scheme with the type I functionals can give good results for the energy curve in agreement with the multireference calculations. In regard to the metal-metal bonding, the restricted KS-DFT calculations performed by all of the seven functionals yield inferior description due to the lack of significant multiconfigurational character. The Mayer bond order, the electron localization function, and electron density predicted by the broken symmetry formalism with the type II functionals are consistent with those obtained with the multireference theory.

Can the Radical Channel Contribute to the Catalytic Cycle of N-Heterocyclic Carbene in Benzoin Condensation?

NHC can catalyze benzoin condensation via the key Breslow intermediate. EPR spectroscopy recently confirmed the existence of the radical species, but its catalytic role is still unclear. Herein, we use density functional approaches to study the radical-associated pathway in comparison with the nonradical mechanism reported previously. Theoretical investigations show that the nonradical path (Δ G⧧ = 18.7 kcal/mol) is more kinetically favorable than the radical route (Δ G⧧ = 27.6 kcal/mol), which is initialized by the hydrogen abstraction from the Breslow intermediate by benzaldehyde, leading to a radical pair. The product formation is thus dominated by the nonradical pathway. In addition, the Breslow intermediate is less stable than its keto form, which blocks the benzoin condensation, and the radical species could play an important role in assisting the tautomerization and promoting the catalytic reaction.

Reversible Cleavage/Formation of the Chromium-Chromium Quintuple Bond in the Highly Regioselective Alkyne Cyclotrimerization.

Herein we report the employment of the quintuply bonded dichromium amidinates [Cr{κ2 -HC(N-2,6-i Pr2 C6 H3 )(N-2,6-R2 C6 H3 )}]2 (R=iPr (1), Me (7)) as catalysts to mediate the [2+2+2] cyclotrimerization of terminal alkynes giving 1,3,5-trisubstituted benzenes. During the catalysis, the ultrashort Cr-Cr quintuple bond underwent reversible cleavage/formation, corroborated by the characterization of two inverted arene sandwich dichromium complexes (µ-η6 :η6 -1,3,5-(Me3 Si)3 C6 H3 )[Cr{κ2 -HC(N-2,6-i Pr2 C6 H3 )(N-2,6-R2 C6 H3 )}]2 (R=i Pr (5), Me (8)). In the presence of σ donors, such as THF and 2,4,6-Me3 C6 H2 CN, the bridging arene 1,3,5-(Me3 Si)3 C6 H3 in 5 and 8 was extruded and 1 and 7 were regenerated. Theoretical calculations were employed to disclose the reaction pathways of these highly regioselective [2+2+2] cylcotrimerization reactions of terminal alkynes.

Enantiodivergent Steglich rearrangement of O-carboxylazlactones catalyzed by a chirality switchable helicene containing a 4-aminopyridine unit.

A pseudo-enantiomeric pair of optically switchable helicenes containing a catalytic 4-N-methylaminopyridine (MAP) bottom unit and a C2-symmetric, (10R,11R)-dimethoxymethyl-dibenzosuberane top template was synthesized. They underwent complementary photoswitching at 290 nm (P/M', <1/>99) and 340 nm (P/M', 91/9) and unidirectional thermo-rotation at 130 °C (P/M', >99/<1). They were utilized to catalyze enantiodivergent Steglich rearrangement of O- to C-carboxylazlactones, with formation of either enantiomer with up to 91% ee (R) and 94% ee (S), respectively.

Enzyme Catalysis that Paves the Way for S-Sulfhydration via Sulfur Atom Transfer.

S-sulfhydration is generally anticipated to proceed through the transfer of the SH group (Nu-SH···(-)S-R → Nu(-)···HS-S-R). The other route involves the sulfur atom (S(0)) transfer between two sulfhydryl anions (Nu-S(-)···(-)S-R → Nu(-)···(-)S-S-R) and is considered electrostatically unfavorable. Mercaptopyruvate sulfurtransferase (MST, PDB code: 4JGT ) catalyzes sulfur transfer from mercaptopyruvate to sulfur acceptors, and the first step of the reaction is the formation of cysteine (Cys248) persulfide via S-sulfhydration. Mechanistic studies on S-sulfhydration in MST using QM/MM methods show that the sulfur atom transfer initialized by the deprotonation of the Ser250/His74/Asp63 triad is kinetically preferred to the SH-promoted sulfur transfer. The calculated barrier of approximately 16 kcal mol(-1) for the S(0) transfer agrees well with experimental results. The electrostatic repulsion during the S(0) transfer can be sophisticatedly reduced by the aid of the Cys248-Gly249-Ser250-Gly251-Val252-Thr253 (CGSGVT) loop. Electrostatic potentials and frontier orbitals are also analyzed for the persulfide anion surrounded by the loop. The sulfur atom transfer which is seldom regarded possible is therefore facilitated with the assistance of the triad and the loop in the enzyme.

A computational study of the activation of allenoates by Lewis bases and the reactivity of intermediate adducts.

Several chemical properties of Lewis base-allenoate adducts (LB·allenoate), such as solvent effect, basicity, nucleophilicity and cycloaddition, are studied to provide a detailed foundation for the analysis of LB-catalyzed reactions of allenoates. The zwitterionic LB·allenoates formed between methyl allenoate and Lewis bases, such as N-heterocyclic carbenes (NHCs), phosphines, amines and aza-heterocycles, are studied at the M06-2X/6-31+G* level. The addition of the LBs to the allenoate can yield Z- or E-type adducts. The formation of the Z-type adducts is more favorable in the gas phase due to electrostatic interactions. The yield of the E-type adducts increases with the permittivity of the solvent. The lowest barriers for the addition and the most stable adducts are observed with NHCs as catalysts. It is also shown that the α-carbon atom of the allenic moiety in LB·allenoate is more nucleophilic than the γ-carbon atom. Aza-arenes, phosphines and NHCs stabilize the [3 + 2]-ylides formed by the cycloaddition of LB·allenoate to ethylene; therefore, these LBs thermodynamically support the [3 + 2] cycloadditions. The detailed analysis of [3 + 2]-, [2 + 4]-, [2 + 2]- and [2 + 2 + 2]-cycloadditions with enones/ketones shows that the amine-catalyzed reactions follow the kinetically preferred path, and that the exergonic formation of the P-ylide favors the [3 + 2] cycloaddition in the phosphine-catalyzed reaction. The thermodynamically preferred pathway is followed with NHCs whereas the high stability of NHC·allenoate adducts reduces the overall catalytic efficiency of NHCs.

A computational study: reactivity difference between phosphine- and amine-catalyzed cycloadditions of allenoates and enones.

Allenoates and enones form cyclopentenes via a phosphine-catalyzed [3 + 2] cycloaddition while the amine-catalyzed [2 + 4] cycloaddition yields dihydropyrans or pyrans. The difference between these catalysts is studied with M06-2X/6-31+G* calculations. The addition of the catalyst to the allenoate is the first step in both pathways followed by the reaction with the enone. The formation of the [3 + 2] phosphorus-ylide is exergonic, and hence, the [3 + 2] cycloaddition is kinetically favored over the [2 + 4] addition. Amines do not stabilize [3 + 2] ammonium-ylides. However, electron-withdrawing groups on the enone enable [2 + 4] cycloadditions. The strength of the electron-withdrawing group further controls the α/γ regioselectivity of the [2 + 4] cycloaddition, and the analysis of the HOMO-LUMO interactions explains why only E-dihydropyrans from the direct γ-[2 + 4] cycloaddition have been observed in experiments. The quantum calculations further reveal a new path to the α-[2 + 4] product starting with an intermediate Rauhut-Currier reaction. This new path is kinetically favored over the direct amine-catalyzed α-[2 + 4] cycloaddition.