3site Multisubstrate-Bound State of Cytochrome P450cam.

We identified a multisubstrate-bound state, hereby referred as a 3site state, in cytochrome P450cam via integrating molecular dynamics simulation with nuclear magnetic resonance (NMR) pseudocontact shift measurements. The 3site state is a result of simultaneous binding of three camphor molecules in three locations around P450cam: (a) in a well-established "catalytic" site near heme, (b) in a kink-separated "waiting" site along channel-1, and (c) in a previously reported "allosteric" site at E, F, G, and H helical junctions. These three spatially distinct binding modes in the 3site state mutually communicate with each other via homotropic allostery and act cooperatively to render P450cam functional. The 3site state shows a significantly superior fit with NMR pseudo contact shift (PCS) data with a Q-score of 0.045 than previously known bound states and consists of D251 free of salt-bridges with K178 and R186, rendering the enzyme functionally primed. To date, none of the reported cocomplex of P450cam with its redox partner putidaredoxin (pdx) has been able to match solution NMR data and controversial pdx-induced opening of P450cam's channel-1 remains a matter of recurrent discourse. In this regard, inclusion of pdx to the 3site state is able to perfectly fit the NMR PCS measurement with a Q-score of 0.08 and disfavors the pdx-induced opening of channel-1, reconciling previously unexplained remarkably fast hydroxylation kinetics with a koff of 10.2 s-1. Together, our findings hint that previous experimental observations may have inadvertently captured the 3site state as an in vitro solution state, instead of the catalytic state alone, and provided a distinct departure from the conventional understanding of cytochrome P450.

A N-Heterocyclic Carbene-Supported Zinc Catalyst for the 1,2-Regioselective Hydroboration of N-Heteroarenes.

A fluorenyl-tethered N-heterocyclic carbene LH (LH=[(Flu)H-(CH2 )2 -NHCDipp ]) and its monoanionic version L- are explored in complexation with zinc towards the hydroboration of N-heteroarenes, carbonyl, ester, amide, and nitrile under ambient condition. The N-heteroarenes exhibit high 1,2-regioselectivity which is justified by computational analyses. The relative hydroboration rates of differently p-substituted (electron donating vs. withdrawing) pyridines are also addressed. The monodentate LH offers a better catalytic activity than the chelating L- for steric reasons despite both giving three-coordinate zinc complexes. The mechanism involves a Zn-H species at the heart of these catalytic processes which is trapped by Ph2 CO. Computational studies suggest that the barrier to form the hydride complex is comparable to the barrier required for the following hydride transfer to pyridine.

Carbodicarbenes and Striking Redox Transitions of their Conjugate Acids: Influence of NHC versus CAAC as Donor Substituents.

Herein, a new type of carbodicarbene (CDC) comprising two different classes of carbenes is reported; NHC and CAAC as donor substituents and compare the molecular structure and coordination to Au(I)Cl to those of NHC-only and CAAC-only analogues. The conjugate acids of these three CDCs exhibit notable redox properties. Their reactions with [NO][SbF6 ] were investigated. The reduction of the conjugate acid of CAAC-only based CDC with KC8 results in the formation of hydrogen abstracted/eliminated products, which proceed through a neutral radical intermediate, detected by EPR spectroscopy. In contrast, the reduction of conjugate acids of NHC-only and NHC/CAAC based CDCs led to intermolecular reductive (reversible) carbon-carbon sigma bond formation. The resulting relatively elongated carbon-carbon sigma bonds were found to be readily oxidized. They were, thus, demonstrated to be potent reducing agents, underlining their potential utility as organic electron donors and n-dopants in organic semiconductor molecules.

The importance of four-membered NHCs in stabilizing Breslow intermediates on benzoin condensation pathway.

N-heterocyclic carbenes (NHCs) have been established to be effective organocatalysts for facilitating the benzoin condensation and many other reactions. These reactions involve the formation of a Breslow intermediate (BI), which exhibits umpolung chemistry. To facilitate organocatalysis, several new cyclic carbenes are being introduced, four-membered NHCs are of special interest. Whether these NHCs can exhibit catalytic influence or not, can be evaluated by exploring the potential energy surface (PES) of the benzoin condensation reaction. Quantum chemical analysis has been carried out to compare the PES of these four-membered NHCs with that of standard five-membered NHCs to explore their catalytic ability. The barrier for the first step of the reaction for the formation of BI is comparable in all the cases. But the barrier for the second step of the reaction leading to the benzoin formation from BI is estimated to be very high for the four membered NHCs. These results indicate that the probability of identifying and isolating the BI is very high in comparison to the completion of benzoin condensation reaction in the case of the four-membered NHCs.

Thiazetidin-2-ylidenes as four membered N-heterocyclic carbenes: theoretical studies and the generation of complexes with N+ center.

Thiazetidin-2-ylidenes have been designed as four membered N-heterocyclic carbenes (NHCs) using quantum chemical studies. These species are smaller analogs of thiazol-2-ylidenes, possess high singlet stability (57 kcal mol-1) and large nucleophilicity (3.4 eV). The possible existence of these carbenes has been established by synthesizing and crystalizing compounds with NHC→N+←(thiazetidin-2-ylidene) coordination bonds.

Mesoionic and N-Heterocyclic Carbenes Coordinated N+ Center: Experimental and Computational Analysis.

N-Heterocyclic carbenes, carbocyclic carbenes, remote N-heterocyclic carbenes and N-heterocyclic silylenes are known to form L→N+ coordination bonds. However, mesoionic carbenes (MICs) are not reported to form coordination bonds with cationic nitrogen. Herein, synthesis and quantum chemical studies were performed on 1,2,3-triazol-5-ylidene stabilized N+ center. Six compounds with MIC→N+ ←NHC were synthesized. Density functional theory calculations and energy decomposition analysis were carried out to explore the bonding situation between MIC and N+ center. The C→N+ bond lengths were in the range of 1.295-1.342 Šand bond dissociation energies were <400 kcal/mol. Natural bond orbital analysis supported the presence of excess electron density (>3 electrons) at the N+ center. The computational and X-ray diffraction analysis results confirmed the presence of divalent NI character of center nitrogen and MIC→N+ ←NHC coordination interactions.

Quantum chemical study in exploring the role of donor→acceptor interactions in 1,3-bis carbene-stabilized guanidinium cations.

Guanidinium species are highly basic and hence mostly exist in cationic state. Because these cations carry electron-deficient centers, they can be stabilized with the help of electron-donating ligands like N-heterocyclic carbenes. A few novel guanidinium cationic species stabilized by electron-donating ligands were designed and quantum chemically evaluated. It was shown that strong hydrogen bonds and tautomerism are the important characteristics of these species. Further, the possibility of donor→acceptor coordination interactions in these species have been explored between the electron-donating carbenes and the central guanidinium unit. The results suggest that the title compounds can be considered as ligand-stabilized guanidinium cations similar to the ligand-stabilized N+ and N3+ centers.

Divalent NI Compounds: Identifying new Carbocyclic Carbenes to Design Nitreones using Quantum Chemical Methods.

Nitreones are compounds with oxidation state 1 at the nitrogen, these compounds carry formal positive charge as well as two lone pairs of electrons at nitrogen center. These compounds are also known as divalent NI compounds and can be represented with the general formula L → N+ ← L, where L is an electron donating ligand. In the recent past, several divalent NI compounds have been reported with L = N-heterocyclic carbene (NHC), remote N-heterocyclic carbene (rNHC), carbocyclic carbene (CCC) and diaminocarbene. Recently, our group reported that a novel six-membered CCC (cyclohexa-2,5-diene-4-[diaminomethynyl]-1-ylidene) can stabilize N+ center in nitreones. As an independent carbene, this species is very unstable. In this work, modulation of this CCC using (a) annulation, (b) heterocyclic ring modification, (c) substitutions adjacent to the carbenic carbon, (d) exocyclic double bond insertion and (e) ring contraction, has been reported. These modulations and quantum chemical analyses helped in the identification of five new six-membered CCCs which carry improved donation and stability properties. Further, these CCCs were employed in the design of new divalent NI compounds (nitreones) which carry coordination bonds between ligands and N+ center. The molecular and electronic structure properties, and the donor→acceptor coordination interactions present in the resultant low oxidation state divalent NI compounds have been explored.

Donor→acceptor coordination interactions in 1,3-bis(NHC)triazenyl Cations: An electronic structure analysis.

Donor→acceptor coordination interactions (L → N) between ligands and nitrogen center as in L → N⊕ ← L were reported in the recent past. This article describes the possibility of L → N coordination interactions in triazenyl cation species L → N3 ⊕ ← L. A few 1,3-bis(NHC)triazenyl cation species were experimentally known, the electronic structure analysis reported in this work reveals the presence of L → N (donor→acceptor) interactions in these species. Molecular orbital analysis, NBO charge analysis, energy decomposition analysis, and so forth, confirm the possibility of L → N coordination bond character. Ten molecules with the general formula L → N3 ⊕ ← L have been designed carrying L → N3 ⊕ ← L interactions. © 2019 Wiley Periodicals, Inc.

The emerging role for robotics in cholecystectomy: the dawn of a new era?

Though laparoscopic cholecystectomy (LC) was highly criticized in its early stages, it quickly grew to become a new standard of care and has revolutionized the field of general surgery. Now emerging robotic technology is making its way into the minimally invasive arena. Robotic cholecystectomy (RC) is often disparaged as a costly technology that can lead to increased operative times with outcomes that are quite similar to LC. However, this perspective is skewed as many existing studies were performed in the early phase of learning for this procedure. RC can be performed in a cost-effective manner as the volume of robotic procedures increases. In addition, improved visualization and capability to perform fluorescence cholangiography can improve the safety profile of cholecystectomy to a level that has not yet been achieved with conventional laparoscopy. Advanced simulation technology for robotic surgery, and newer single-site robotic platforms have the potential to further revolutionize this technology and lead to improved patient satisfaction. In this review, we will present current data, trends, and controversies in robotic-assisted cholecystectomy.