Elucidating the Mechanism of Tetrahydrofuran-Diol Formation through Os(VI)-Catalyzed Oxidative Cyclization of 5,6-Dihydroxyalkenes Ligated by Citric Acid.

A computational study is reported here on the mechanism of tetrahydrofuran (THF)-diol formation from the Os(VI)-catalyzed oxidative cyclization of 5,6-dihydroxyalkene ligated with citric acid and in the presence of BroÌ·nsted acid. Initiated by Os(VI) dioxo citrate formation, coordination of co-oxidant pyridine-N-oxide (PNO) and protonation of its oxo group generate the active catalyst. The catalytic cycle commences through successive steps, including dihydroxyalkene addition to the active catalyst in a concerted mechanism to form hexacoordinated alkoxy-protonated PNO-complexed Os(VI) bisglycolate as a turnover-limiting step (TLS), cyclization to Os(IV) THF-diolate, reoxidation to Os(VI) THF-diolate, and hydrolysis via a dissociative mechanism to furnish the THF-diol and regenerate the active species, sustaining the catalytic cycle through an Os(VI)/Os(IV) cycle. Despite the overall exergonic nature of catalytic cycle (ΔGrcycle = -45.0 kcal/mol), the TLS is accelerated by the formation of an open-valence 16-electron Os(VI) intermediate but decelerated by the undesired formation of a saturated/hexacoordinate 18-electron Os(VI) intermediate. BroÌ·nsted acid plays crucial roles in the formation of Os(VI) citrate and the active catalyst, impediment of the second cycle, and the cyclization step. Additionally, besides its role as a co-oxidant, and in the presence of acid, PNO is found to assist the insertion of dihydroxyalkene and, importantly, in releasing the THF-diol to regenerate the active intermediate.

Remote Steric and Electronic Effects of N-Heterocyclic Carbene Ligands on Alkene Reactivity and Regioselectivity toward Hydrocupration Reactions: The Role of Expanded-Ring N-Heterocyclic Carbenes.

The remote groups in N-heterocyclic carbene (NHC) ligands have a significant influence on metal-catalyzed reactions. We examine how remote bulkiness, electronic groups, and expanded-ring NHCs (ER-NHCs) influence alkene reactivity and regioselectivity toward hydrocupration using density functional theory calculations. The impact of remote steric bulkiness on the Cu-H insertion rate is analyzed, revealing a strong correlation between the steric substituent constant and rate ratio, where a bulky group increases the rate due to reduced steric effects in the transition state (TS). The steric properties of the examined catalysts (with a remote group R2 = CPh3, CHPh2, CH2Ph, CH3, and H) and their corresponding TSs are found to be modulated greatly by the remote steric substitution group and the ring size of the NHC ligand. Enhanced bulkiness enhances the nucleophilic Cu-H moiety. The remote electronic groups have a smaller impact on insertion barrier compared to that of steric hindrance. Furthermore, ER-NHC exploration indicates that NHCs with over five-membered rings have a significantly negative influence on the reaction rate. Finally, with a highly bulky group (R2 = CPh3), anti-Markovnikov insertion preference is attributed to high interaction energy and improved steric properties. Overall, our findings here provide valuable insights for the development of a more effective catalyst in metal-catalyzed reactions.

Impact of counteranions on N-heterocyclic carbene gold(i)-catalyzed cyclization of propargylic amide.

N-Heterocyclic carbene (NHC) Au(i)-catalyzed organic synthesis has recently been receiving increasing attention, especially with the activation of alkynes. In contrast, counteranions, being widely problematic in Au(i)-catalyzed transformations, are commonly considered as innocent partners and are not respectably included in a computational model. Herein, we report density functional theory (DFT) investigations of the Au(i)-catalyzed cyclization of propargylic amides to exploit the mechanistic effect of several counteranions to shed some light for further future developments. Among the counteranions used in this study, NTf2 -, ClO4 -, TsO-, TFA-, TfO-, MsO-, and SbF6 -, both the cyclization and protodeauration step favor the 5-exo-dig product over the 6-endo-dig product when the alkyne moiety is terminated with hydrogen. These anions reveal a crucial influence on the energy profile through lowering the barriers of the reaction. Mechanistically, the results obtained from all counteranions show that the protodeauration is slower than the cyclization. By using an energetic span model, the results clearly indicate that the rate-determining state is the protodeauration step for all counteranions, and thus protodeauration is the turnover-limiting step. The turnover frequency (TOF) results for the formation of the 5-exo-dig product show cyclization reactivity in the order of MsO- > TFA- > ClO4 - > NTf2 - > TfO- > TsO- ≫ SbF6 -, whereas an order of TFA- > MsO- > NTf2 - > TfO- ≈ ClO4 - > SbF6 - ⋙ TsO- is calculated for the protodeauration, suggesting that SbF6 - and TsO- are disfavored due to their slow protodeauration. In this regard, and for the 6-endo-dig pathway, our conclusions demonstrate an order of TfO- > TFA- > MsO- > NTf2 - > ClO4 - > TsO- ⋙ SbF6 - for the cyclization and TFA- > TsO- > MsO- > TfO- > NTf2 - > ClO4 - ⋙ SbF6 - for the protodeauration, advocating that the anions SbF6 -, NTf2 - and ClO4 - are unlikely partners for the 6-endo-dig pathway because of their slow protodeauration. Finally, the findings here advise that any engineering of the counteranion to increase the efficiency of catalytic system would be more effective on the protodeauration step rather than the cyclization step.

Partner effect in accelerating pincer-co catalyzed nitrile hydroboration reactions.

The pincer-Co catalyzed nitrile hydroboration of nitrile has been presented as an elegant strategy to afford amine synthesis; however, ligand engineering is required. We show here a strategy to tune the catalytic behavior of the organometallic catalyst, as an alternative approach to ligand engineering, by means of computational investigations to understand the effect of partners such as (18-crown-6)K+, W(CO)3 and W(PMe3)3 on the reactivity of the pincer-Co catalyzed nitrile hydroboration reaction through π-coordination to the ligand aromatic ring. The extra additives bind the central phenyl ring of the ligand by either dispersion or chemical bonding. The electron-richness of the cobalt center is tuned by the partner, and follows the order (18-crown-6)K+ > W(PMe3)3 > no partner > W(CO)3. While the influence of the covalent W-containing partners parallels the electron-richness of the W, the non-covalent partner, (18-crown-6)K+, surprisingly increases the donor ability of the pincer ligand through the polarization effect. All the elementary steps involved in the nitrile hydroboration reaction are influenced by the partner, and the overall barrier is lowered by a surprisingly large amount of 4.9 kcal mol-1 in the presence of (18-crown-6)K+, suggesting a notable partner effect to be explored by experimentalists so that the reactivity of a catalyst can be tuned without ligand modification.

The nature of metal-metal bonding in Re-, Ru- and Os-corrole dimers.

Studies of multiple bonding between transition metal complexes offer fundamental insight into the nature of bonding between metal ions and facilitate predictions of the physical properties and the reactivities of metal complexes containing metal-metal multiple bonds. Here we report a computational interrogation on the nature of the metal-metal bonding for neutral, oxidized, and reduced forms of dinuclear rhenium and osmium corrole complexes, [{Re[TpXPC]}2]0/1+/1- and [{Os[TpXPC]}2]0/1+/1-, using a complete active space self-consistent (CASSCF) methodology and density functional theory (DFT) calculations. For [{Re[TpXPC]}2]0, [{Ru[TpXPC]}2]0, and [{Os[TpXPC]}2]0, CASSCF calculations shows that the effective bond order is 3.29, 2.63, and 2.73, respectively. On their oxidized forms, [{Re[TpXPC]}2]1+, [{Ru[TpXPC]}2]1+, and [{Os[TpXPC]}2]1+ molecules, the results indicate an electron removal from a ligand-based orbital, where [{Re[TpXPC]}2]1+ gives slightly different geometry from its neutral form due to populating the δ* orbital. In this regard, the CASSCF calculations give an effective bond order of 3.25 which is slightly lower than in the [{Re[TpXPC]}2]0. On their reduced forms, the electron addition appears to be in the metal-based orbital for [{Re[TpXPC]}2]1- and [{Ru[TpXPC]}2]1- whereas in the ligand-based orbital for the Os-analogue which has no effect on the Os-Os bonding, an effective bond order of 3.18 and 2.17 is presented for the [{Re[TpXPC]}2]1- and [{Ru[TpXPC]}2]1-, respectively, within the CASSCF simulations. These results will further encourage theoreticians and experimentalists to design metalloporphyrin dimers with distinct metal-metal bonding.

Selective Synthesis of Azoloyl NH-1,2,3-Triazoles and Azolyl Diazoketones: Experimental and Computational Insights.

Here, we report that the reaction of enaminones, from a class of azole series, with sulfonyl azides leads to a difficult-to-separate mixture of two pairs of compounds: (1) 4-azoloyl-NH-1,2,3-triazoles with sulfonamides and (2) azolyl diazoketones with N-sulfonamidines, as a result of the implementation of two competing reactions. On one hand, the electron-donating methyl or methoxy group in the aryl para-position of arylsulfonyl azides favors the production of NH-1,2,3-triazoles together with sulfonamides. On the other hand, the use of highly electrophilic 4-nitrophenylsulfonyl azide promotes the formation of diazoketones and sulfonamidines. It is shown that the direction of each reaction is not only controlled by the nature of the initial enaminones and sulfonyl azides but also depends on the tested solvent. The problem of removing sulfonamides and amidines from the desired products was solved for the first time using new water-soluble enaminones. Based on the experimental and computational studies, the factors contributing to the selective course of alternative reactions were identified, and methods for the synthesis of azoloyl-NH-1,2,3-triazoles and azolyl diazoketones were developed. Density functional theory (DFT) results have shown that the 1,3-dipolar cycloaddition is totally driven toward one single regioisomer with a high asynchronous bond formation, and the introduction of an electron-deficient group in sulfonyl azides induces faster cycloaddition. Additionally, DFT calculations were used to gain further mechanistic insights on the reaction studied here.

Boosting Palladium-Catalyzed Aryl-Nitro Bond Activation Reaction by Understanding the Electronic, Electrostatic, and Polarization Effect: A Computational Study from a Basic Understanding to Ligand Design.

Although palladium-catalyzed aryl-nitro bond activation reaction has recently gained a lot of interest, it still requires rather harsh conditions. We here systematically explore the substituent effect on oxidative addition steps, known as the rate-determining step, by density functional theory simulations based on a Nakao's nitrogen heterocyclic carbene (NHC) ligand. The key aryl ring on the catalyst, ring A, acts as a π-donor and stabilizes the palladium center of the transition state, and thus an electron-rich ring A is expected to lower the barrier. However, the polarization and electrostatic effects were shown to be more important, although they were often ignored before. These effects originate from through-space interaction with a nitro group in the resting state, and the overall effect is that any polarizable or partly negative group near ortho- or meta-site of ring A is harmful for the reaction. Based on these discoveries, we proposed a list of guidelines for successful ligand developments and designed several new ligands. These ligands exhibit a significantly lower barrier than the reported Nakao's ligand by as large as ∼5 kcal/mol, in both gas phase and solvent with a moderate dipole. These candidates will promote further experimental studies and enhance the ability to improve ligands in a rational and predictive manner.

Novel Approach for Characterizing Propofol Binding Affinities to Serum Albumins from Different Species.

The interaction between the main carrier (serum albumin, SA) of endogenous and exogenous compounds in the bloodstream of different species (human, bovine, canine, rat, rabbit, and sheep) and a general anesthetic agent (propofol, PR) was investigated using an experimental technique (high-performance liquid chromatography) and computational methods (molecular docking, molecular dynamics, sequence, and phylogenetic analyses). The obtained results revealed the differences in the PR binding affinity to various homologous forms of this protein with reliable statistics (R 2 = 0.9 and p-value < 0.005), correlating with the evolutionary relationships among SAs from different species. Additionally, the protein conformational changes (root-mean-square deviation ≈ 1.0 Å) and amino acid conservation of binding sites in protein domains were detected, contributing to the SA-PR binding modes. Overall, the outcomes from this study might provide a novel methodology to assess protein-ligand interactions and to gain some interesting insights into drug pharmacokinetics and pharmacodynamics to explain its variations among different species.

Revealing the Mechanism and Origin of Reactivity of Au(I)-Catalyzed Functionalized Indenone Formation of Cyclic and Acyclic Acetals of Alkynylaldehydes.

A density functional theory study is presented here to offer mechanistic insights and explications of experimentally intriguing observations in the Au(I)-catalyzed cyclization of cyclic and acyclic acetals of alkynylaldehydes that leads to indenone formation. The reactivity of catalytic cycles with and without methoxy migration is clearly defined when the alkyne terminus is phenylated. The reaction mechanism of indenone formation proceeds first with the coordination of Au(I) to alkyne to initiate the reaction with 1,5-H shift as a rate-determining step (RDS), and the fastest 1,5-H shift is achieved when one phenyl ring carries an electron-donating group and the other one is substituted with an electron-withdrawing group. Following the 1,5-H shift, the reaction undergoes feasible steps that are cyclization and 1,2-H shift before elimination to persist the iterative cycle, but the reactivity of both steps is highly affected by the existence of the phenyl group on the alkyne terminus. The unreactivity of the alkyne terminus not bearing a phenyl ring is because the cyclization is thermodynamically disfavorable, subsequently deactivating the 1,2-H shift kinetically and thermodynamically. The absence of a tether in the acetal unit considerably outpaces any 1,5-H shift and instead activates 1,5-methoxy migration, giving methoxy-migrated indenone, with the 1,2-OMe shift being an RDS.

Visible-Light-Mediated C-H Alkylation of Pyridine Derivatives.

We report herein a visible-light-mediated C-H alkylation of pyridine derivatives that proceeds by simple combination of a large variety of N-alkoxypyridinium ions with alkanes in the presence of 2 mol % of fac-Ir(ppy)3 under blue illumination. The mild reaction conditions together with the high group functional tolerance make of this process a useful synthetic platform for the construction of structurally strained heterocycles. Detailed mechanistic investigations, including density functional theory calculations and quantum yield measurement, allowed us to understand factors controlling the reactivity and the selectivity of the reaction.

Mechanistic investigations on Pinnick oxidation: a density functional theory study.

A computational study on Pinnick oxidation of aldehydes into carboxylic acids using density functional theory (DFT) calculations has been evaluated with the (SMD)-M06-2X/aug-pVDZ level of theory, leading to an important understanding of the reaction mechanism that agrees with the experimental observations and explaining the substantial role of acid in driving the reaction. The DFT results elucidated that the first reaction step (FRS) proceeds in a manner where chlorous acid reacts with the aldehyde group through a distorted six-membered ring transition state to give a hydroxyallyl chlorite intermediate that undergoes a pericyclic fragmentation to release the carboxylic acid as a second reaction step (SRS). 1H NMR experiments and simulations showed that hydrogen bonding between carbonyl and t-butanol is unlikely to occur. Additionally, it was found that the FRS is a rate-determining and thermoneutral step, whereas SRS is highly exergonic with a low energetic barrier due to the Cl(III) → Cl(II) reduction. Frontier molecular orbital analysis, intrinsic reaction coordinate, molecular dynamics and distortion/interaction analysis further supported the proposed mechanism.

Ru-catalysed oxidative cyclisation of 1,5-dienes: an unprecedented role for the co-oxidant.

The Ru-mediated oxidative cyclisation of 1,5-dienes to furnish 2,5-dihydroxyalkyl-substituted tetrahydrofuran-diols (THF-diols) represents a practical approach for the synthesis of many bioactive natural products. In the current study, we reported profound findings obtained by density functional theory (DFT) simulations, and they were consistent with the experimental conditions. The results set out a catalytic cycle within intermediacy of NaIO4-complexed Ru(vi) species. Importantly, the co-oxidant played a critical role in the cyclisation step and subsequently the release of THF-diols. Following the formation of Ru(vi) glycolate, cyclisation and THF-diol release proceeded through NaIO4-coordinated Ru(vi) intermediates, outpacing the Ru(viii) glycolate or THF-diolate intermediates and subsequently entering "second cycle" type pathways. The results indicated a cycle involving Ru(viii)/Ru(vi)/Ru(iv)/Ru(vi) rather than Ru(viii)/Ru(vi)/Ru(viii)/Ru(vi)/Ru(viii). Additionally, the existence of an electron-withdrawing group (EWG) on one of the double bonds of 1,5-dienes revealed that the regioselectivity of the Ru-catalysed oxidative cyclisation was predominantly initiated at the electron-rich alkene. Overall, this study offers new insights, which were ignored by earlier experimentalists and theoreticians, into the Ru-catalysed functionalizations of alkenes and 1,5-dienes.

Mechanism of Os-Catalyzed Oxidative Cyclization of 1,5-Dienes.

The oxidative cyclization of 1,5-dienes by metal-oxo species is a powerful method for stereocontrolled synthesis of tetrahydrofuran diols (THF-diols), structural motifs present in many bioactive natural products. Oxidative cyclization of (2E,6E)-octa-2,6-diene catalyzed by OsO4/NMO has been studied using density functional theory (DFT) calculations (M06-2X/aug-cc-pVDZ/Hay-Wadt VDZ (n+1) ECP), highlighting the remarkable effect of acid on the fate of the first intermediate, an Os(VI) dioxoglycolate. A strong acid promotes cyclization of the Os(VI) dioxoglycolate, or its NMO complex, through protonation of an oxo ligand to give more electrophilic species. By contrast, in the absence of acid, reoxidation may occur to afford the Os(VIII) trioxoglycolate, which is shown to favor conventional "second cycle" dihydroxylation reactivity rather than cyclization. The results of the calculations are consistent with experimental results for reactions of OsO4/NMO with 1,5-dienes with acid (oxidative cyclization) and without acid (second cycle osmylation/dihydroxylation). Detailed evaluation of potential catalytic cycles supports oxidation of the cyclized Os(IV) THF-diolate intermediate to the corresponding Os(VI) species followed by slow hydrolysis and, finally, regeneration of OsO4.

Phytochemical and pharmacological attributes of piperine: A bioactive ingredient of black pepper.

Plants are vital for the wellbeing of humankind in a variety of ways. Some plant extracts contain antimicrobial properties that can treat different pathogens. Most of the world's population relies on medicinal plants and natural products for their primary health care needs. Therefore, there is a growing interest in natural products, medicinal plants, and traditional medicine along with a desire to design and develop novel plant-based pharmaceuticals. These plant-based pharmaceuticals may address the concerns of reduced efficacy of synthetic antibiotics due to the emergence of drug-resistant pathogens. In this regard, some plant extracts from black pepper (Piper nigrum) with antimicrobial properties, including piperine, have the potential to be used as natural dietary supplements together with modern therapeutic approaches. This review highlights possible applications of piperine as the active compound in the fields of rational drug design and discovery, pharmaceutical chemistry, and biomedicine. We discuss different extraction methods and pharmacological effects of the analyzed substance to pave the way for further research strategies and perspectives towards the development of novel herbal products for better healthcare solutions.

Computational assessments of diastereoselective [4+2] cycloaddition and 1,3-borotopic shift of a dearomatized tertiary boronic ester intermediate: reactivities explained through transition-state distortion energies.

Interception of a dearomatized tertiary boronic ester, formed through a kinetically and thermodynamically favorable 1,2-metalate rearrangement/anti-SN2' elimination of an activated ortho-lithiated benzyl amine, in a [4+2] cycloaddition or 1,3-borotopic shift has been investigated by density functional theory (DFT). Although superacitvated "naked" Li+ was found to greatly promote 1,3-borotopic shift, the diastereoselective [4+2] cycloaddition was favored. It was revealed that the factor that controls the diastereoselectivity was the steric bulk provided by the diene, which is in agreement with experimental diastereoselectivity. A comparison of unreactive dienophiles such as maleic anhydride, diethyl maleate, and others with 4-phenyl-3H-1,2,4-triazole-3,5(4H)-dione (PTAD) was found to be in an excellent agreement with the experiments; where their lack of reactivity is attributed to the high deformation energies of the interacting components to achieve the transition state structure which was pronounced with the high energy of LUMO orbitals.