Correction: Hydrogen-activation mechanism of [Fe] hydrogenase revealed by multi-scale modeling.

[This corrects the article DOI: 10.1039/C4SC01605J.].

Synthesis of Functionalized Indolines and Dihydrobenzofurans by Iron and Copper Catalyzed Aryl C-N and C-O Bond Formation.

A simple and effective one-pot, two-step intramolecular aryl C-N and C-O bond forming process for the preparation of a wide range of benzo-fused heterocyclic scaffolds using iron and copper catalysis is described. Activated aryl rings were subjected to a highly regioselective, iron(III) triflimide-catalyzed iodination, followed by a copper(I)-catalyzed intramolecular N- or O-arylation step leading to indolines, dihydrobenzofurans, and six-membered analogues. The general applicability and functional group tolerance of this method were exemplified by the total synthesis of the neolignan natural product, (+)-obtusafuran. DFT calculations using Fukui functions were also performed, providing a molecular orbital rationale for the highly regioselective arene iodination process.

Electron density, disorder and polymorphism: high-resolution diffraction studies of the highly polymorphic neuralgic drug carbamazepine.

Analysis of neutron and high-resolution X-ray diffraction data on form (III) of carbamazepine at 100 K using the atoms in molecules (AIM) topological approach afforded excellent agreement between the experimental results and theoretical densities from the optimized gas-phase structure and from multipole modelling of static theoretical structure factors. The charge density analysis provides experimental confirmation of the partially localized π-bonding suggested by the conventional structural formula, but the evidence for any significant C-N π bonding is not strong. Hirshfeld atom refinement (HAR) gives H atom positional and anisotropic displacement parameters that agree very well with the neutron parameters. X-ray and neutron diffraction data on the dihydrate of carbemazepine strongly indicate a disordered orthorhombic crystal structure in the space group Cmca, rather than a monoclinic crystal structure in space group P2(1)/c. This disorder in the dihydrate structure has implications for both experimental and theoretical studies of polymorphism.

Terahertz underdamped vibrational motion governs protein-ligand binding in solution.

Low-frequency collective vibrational modes in proteins have been proposed as being responsible for efficiently directing biochemical reactions and biological energy transport. However, evidence of the existence of delocalized vibrational modes is scarce and proof of their involvement in biological function absent. Here we apply extremely sensitive femtosecond optical Kerr-effect spectroscopy to study the depolarized Raman spectra of lysozyme and its complex with the inhibitor triacetylchitotriose in solution. Underdamped delocalized vibrational modes in the terahertz frequency domain are identified and shown to blue-shift and strengthen upon inhibitor binding. This demonstrates that the ligand-binding coordinate in proteins is underdamped and not simply solvent-controlled as previously assumed. The presence of such underdamped delocalized modes in proteins may have significant implications for the understanding of the efficiency of ligand binding and protein-molecule interactions, and has wider implications for biochemical reactivity and biological function.

Experimental Electron Density and Neutron Diffraction Studies on the Polymorphs of Sulfathiazole.

High resolution X-ray diffraction data on forms I-IV of sulfathiazole and neutron diffraction data on forms II-IV have been collected at 100 K and analyzed using the Atoms in Molecules topological approach. The molecular thermal motion as judged by the anisotropic displacement parameters (adp's) is very similar in all four forms. The adp of the thiazole sulfur atom had the greatest amplitude perpendicular to the five-membered ring, and analysis of the temperature dependence of the adps indicates that this is due to genuine thermal motion rather than a concealed disorder. A minor disorder (∼1-2%) is evident for forms I and II, but a statistical analysis reveals no deleterious effect on the derived multipole populations. The topological analysis reveals an intramolecular S-O···S interaction, which is consistently present in all experimental topologies. Analysis of the gas-phase conformation of the molecule indicates two low-energy theoretical conformers, one of which possesses the same intramolecular S-O···S interaction observed in the experimental studies and the other an S-O···H-N intermolecular interaction. These two interactions appear responsible for "locking" the molecular conformation. The lattice energies of the various polymorphs computed from the experimental multipole populations are highly dependent on the exact refinement model. They are similar in magnitude to theoretically derived lattice energies, but the relatively high estimated errors mean that this method is insufficiently accurate to allow a definitive stability order for the sulfathiazole polymorphs at 0 K to be determined.

Expanding the palette of phenanthridinium cations.

5,6-Disubstituted phenanthridinium cations have a range of redox, fluorescence and biological properties. Some properties rely on phenanthridiniums intercalating into DNA, but the use of these cations as exomarkers for the reactive oxygen species (ROS), superoxide, and as inhibitors of acetylcholine esterase (AChE) do not require intercalation. A versatile modular synthesis of 5,6-disubstituted phenanthridiniums that introduces diversity by Suzuki­Miyaura coupling, imine formation and microwave-assisted cyclisation is presented. Computational modelling at the density functional theory (DFT) level reveals that the novel displacement of the aryl halide by an acyclic N-alkylimine proceeds by an S(N)Ar mechanism rather than electrocyclisation. It is found that the displacement of halide is concerted and there is no stable Meisenheimer intermediate, provided the calculations consistently use a polarisable solvent model and a diffuse basis set.

Total syntheses of multiple cladiellin natural products by use of a completely general strategy.

The enantioselective total syntheses of 10 cladiellin natural products have been completed, starting from the known allylic alcohol (+)-14, which can be prepared in large quantities. The bridged tricyclic core of the cladiellins has been constructed via three ring-forming reactions: (i) an intramolecular reductive cyclization between an aldehyde and an unsaturated ester, mediated by samarium(II) iodide, to form a tetrahydropyranol; (ii) reaction of a metal carbenoid, generated from a diazo ketone, with an ether to produce an ylide-like intermediate that rearranges to produce E- or Z-oxabicyclo[6.2.1]-5-undecen-9-one; and (iii) a Diels-Alder cycloaddition reaction to construct the third ring found in the core structure of the cladiellins. The key ring-forming reaction, in which a diazo ketone is converted into a bridged bicyclic ether, can be tuned to give either of the isomeric oxabicyclo[6.2.1]-5-undecen-9-ones as the major product by switching from a copper to a rhodium catalyst and selecting the appropriate reaction conditions. The tricyclic products obtained from the three-step sequence involving the Diels-Alder cycloaddition reaction can be employed as advanced intermediates to prepare a wide range of cladiellin natural products.

Switching the stereochemical outcome of 6-endo-trig cyclizations; synthesis of 2,6-cis-6-substituted 4-oxopipecolic acids.

A base-mediated 6-endo-trig cyclization of readily accessible enone-derived α-amino acids has been developed for the direct synthesis of novel 2,6-cis-6-substituted-4-oxo-L-pipecolic acids. A range of aliphatic and aryl side chains were tolerated by this mild procedure to give the target compounds in good overall yields. Molecular modeling of the 6-endo-trig cyclization allowed some insight as to how these compounds were formed, with the enolate intermediate generated via an equilibrium process, followed by irreversible tautomerization/neutralization providing the driving force for product formation. Stereoselective reduction and deprotection of the resulting 2,6-cis-6-substituted 4-oxo-l-pipecolic acids to the corresponding 4-hydroxy-L-pipecolic acids was also performed.

Discovery of a multi-bond forming, four-step tandem process: construction of drug-like polycyclic scaffolds.

A one-pot tandem process involving an Overman rearrangement, ring closing enyne metathesis and a hydrogen bonding directed Diels-Alder reaction has been developed for the efficient diastereoselective synthesis of functionalised amino substituted tetralin and indene ring systems.

Stereoselective synthesis of functionalised carbocyclic amides: construction of the syn-(4aS,10bS)-phenanthridone skeleton.

A new synthetic approach has been developed for the preparation of 7-deoxypancratistatin analogues bearing a syn-(4aS,10bS)-phenanthridone ring junction. A one-pot tandem process involving a substrate-directed Overman rearrangement and ring closing metathesis reaction was developed for the stereoselective synthesis of a carbocyclic allylic trichloroacetamide. Conversion to a 6-bromopiperonyl amide, followed by a Heck reaction generated a homoallylic alcohol and completed the syn-(4aS,10bS)-phenanthridone carbon skeleton. Stereoselective epoxidation and dihydroxylation of the syn-(4aS,10bS)-phenanthridone framework was then investigated leading to the preparation of new analogues of 7-deoxypancratistatin.

On the unusual weak intramolecular C...C interactions in Ru3(CO)12: a case of bond path artifacts introduced by the multipole model?

In a recent publication in this journal, an experimental charge density analysis on the triruthenium cluster Ru(3)(CO)(12) showed unusual C...C bond paths linking the axial carbonyl ligands [Gervasio, G.; Marabello, D.; Bianchi, R.; Forni, A. J. Phys. Chem. A 2010, 114, 9368, hereafter GMBF]. These were also observed in one theoretical DFT calculation, and are associated with very low values of ρ(r(b)) and ∇(2)ρ(r(b)). Our independent experimental charge density analysis on Ru(3)(CO)(12) is entirely consistent with GMBF and confirms the presence of these apparent weak interactions in the multipole model density. However, we conclusively demonstrate that these unusual C...C bond paths between the axial carbonyl ligands are in fact artifacts arising from the Hansen-Coppens multipole model, which is used to analyze the experimental data. Numerous relativistic and nonrelativistic gas-phase DFT calculations, using very extensive basis sets and with corrections for dispersion effects, uniformly fail to reproduce these intramolecular features in the QTAIM topology of the electron density. Moreover, multipole fitting of theoretical static structure factors computed from these quantum electron densities results in the reappearance of the C...C bond paths between the axial carbonyl ligands in the derived molecular graphs. On the other hand, using the experimental structure factors to generate "experimental" X-ray constrained DFT wave functions once again yields molecular graphs which do not show these secondary C...C bond paths. The evidence therefore strongly implicates the multipole model as the source of these spurious features and in turn suggests that great caution should be applied in the interpretation of bond paths where the values of ρ(r(b)) and ∇(2)ρ(r(b)) are very low.

Theoretical and X-ray crystallographic evidence of a fluorine-imine gauche effect: an addendum to Dunathan's stereoelectronic hypothesis.

The preference of ß-fluoroimines to adopt a gauche conformation has been studied by single-crystal X-ray diffraction analysis and DFT methods. Empirical and theoretical evidence for a preferential gauche arrangement around the NCCF torsion angle (φ) is presented ((E)-2-fluoro-N-(4-nitrobenzylidene)ethanamine: φ(NCCF) =70.0°). In the context of this study, the analysis of a pyridoxal-derived ß-fluoroaldimine was performed, a species that is implicated in the inhibition of pyridoxal phosphate (PLP)-dependent enzymes by ß-fluoroamine derivatives. The gauche preference of the internal aldimine (=NCH(2)CH(2)F) that can be rationalized by stereoelectronic arguments does not hold for the corresponding external system (N=CHCH(2)F) (E(min) when φ(NCCF) =120°). Moreover, the C-F bond is lengthened by more than 0.02 Å at φ(NCCF) =±90°, when it is exactly antiperiplanar to the conjugated imine. This activation of the C-F σ bond by an adjacent π system constitutes an addendum to Dunathan's stereoelectronic hypothesis.

Metal-metal and metal-ligand bonding at a QTAIM catastrophe: a combined experimental and theoretical charge density study on the alkylidyne cluster Fe3(µ-H)(µ-COMe)(CO)10.

The charge density in the tri-iron methoxymethylidyne cluster Fe(3)(µ-H)(µ-COMe)(CO)(10) (1) has been studied experimentally at 100 K and by DFT calculations on the isolated molecule using the Quantum Theory of Atoms in Molecules (QTAIM). The COMe ligand acts as a nearly symmetric bridge toward two of the Fe atoms (Fe-C = 1.8554(4), 1.8608(4) Å) but with a much longer interaction to the third Fe atom, Fe-C = 2.6762(4) Å. Complex 1 provides a classic example where topological QTAIM catastrophes render an exact structure description ambiguous. While all experimental and theoretical studies agree in finding no direct metal-metal interaction for the doubly bridged Fe-Fe vector, the chemical bonding between the Fe(CO)(4) unit and the Fe(2)(µ-H)(µ-COMe)(CO)(6) moiety in terms of conventional QTAIM descriptors is much less clear. Bond paths implying direct Fe-Fe interactions and a weak interaction between the COMe ligand and the Fe(CO)(4) center are observed, depending on the experimental or theoretical density model examined. Theoretical studies using the Electron Localizability Indicator (ELI-D) suggest the metal-metal bonding is more significant, while the delocalization indices imply that both Fe-Fe bonding and Fe···C(alkylidyne) bonding are equally important. The source functions at various interfragment reference points are similar and highly delocalized. The potential-energy surface (PES) for the migration of the alkylidyne group from a µ(2) to a semi-µ(3) coordination mode has been explored by DFT calculations on 1 and the model complexes M(3)(µ-H)(µ-CH)(CO)(10) (M = Fe, 2; Ru, 3; and Os, 4). These calculations confirm a semi-µ(3) bridging mode for the alkylidyne ligand as the minimum-energy geometry for compounds 2-4 and demonstrate that, for 1, both Fe-Fe and Fe···C(alkylidyne) interactions are important in the cluster bonding. The PES between µ(2) and semi-µ(3) alkylidyne coordination for 1 is extremely soft, and the interconversion between several topological isomers is predicted to occur with almost no energy cost. Analysis of the density ρ(r) and the Laplacian of the density ▽(2)ρ(r(b)) in the methoxymethylidyne ligand is consistent with a partial π-bond character of the C-O bond, associated with an sp(2) hybridization for these atoms.

Weak intra- and intermolecular interactions in a binaphthol imine: an experimental charge-density study on (+/-)-8'-benzhydrylideneamino-1,1'-binaphthyl-2-ol.

The charge density in (+/-)-8'-benzhydrylideneamino-1,1'-binaphthyl-2-ol (1) has been studied experimentally using Mo Kalpha X-ray diffraction at 100 K, and by theory using density-functional thoery (DFT) calculations at the B3LYP/6-311++G** level. The nature of the weak intramolecular peri-C...N, CH...pi, H...H and C(pi)...C(pi) interactions has been examined by topological analysis using the Quantum Theory of Atoms in Molecules (QTAIM) approach. An analysis of the density rho(r), the Laplacian of the density inverted Delta(2)rho(r(b)) and other topological properties at the bond-critical points were used to classify these interactions. The study confirms the presence of the intramolecular CH...pi interaction in (1), which was previously suspected on geometrical grounds. An analysis of the ellipticity profiles along the bond paths unambiguously shows the pi-delocalization between the imine unit and one N-phenyl group. The weak intermolecular interactions in the crystal of (1) were examined experimentally and theoretically through the pairwise interactions of the seven independent dimeric pairs of (1) responsible for the set of unique intermolecular interactions, and also through examination of the Hirshfeld surface d(norm) property. The theoretical dimeric-pair calculations used the BLYP-D functional which supplements the exchange-correlational functional with an empirical dispersion term to provide a more accurate determination of the energies for the weak intermolecular interactions.

The fluorine-iminium ion gauche effect: proof of principle and application to asymmetric organocatalysis.

The gauche effect that is induced upon reversible formation of an iminium ion (see structure: green F, blue N) provides a powerful method for the preorganization of transient intermediates that are central to secondary amine catalyzed processes. This phenomenon has been exploited in the design of a novel organocatalyst and is showcased in the stereoselective epoxidation of alpha,beta-unsaturated aldehydes.

QM/MM methods for biomolecular systems.

Combined quantum-mechanics/molecular-mechanics (QM/MM) approaches have become the method of choice for modeling reactions in biomolecular systems. Quantum-mechanical (QM) methods are required for describing chemical reactions and other electronic processes, such as charge transfer or electronic excitation. However, QM methods are restricted to systems of up to a few hundred atoms. However, the size and conformational complexity of biopolymers calls for methods capable of treating up to several 100,000 atoms and allowing for simulations over time scales of tens of nanoseconds. This is achieved by highly efficient, force-field-based molecular mechanics (MM) methods. Thus to model large biomolecules the logical approach is to combine the two techniques and to use a QM method for the chemically active region (e.g., substrates and co-factors in an enzymatic reaction) and an MM treatment for the surroundings (e.g., protein and solvent). The resulting schemes are commonly referred to as combined or hybrid QM/MM methods. They enable the modeling of reactive biomolecular systems at a reasonable computational effort while providing the necessary accuracy.

QM/MM studies of enzymes.

Combined quantum-mechanics/molecular-mechanics (QM/MM) methods are making rapid progress both methodologically and with respect to their range of application. Mechanistic studies on enzymes, including contributions towards the understanding of enzyme catalysis, continue to be a major target. They are joined by calculations of pK(a) values, redox properties, ground- and excited-state spectroscopic parameters, and excited-state dynamics. Methodological advances include improved QM/MM schemes, in particular new approaches for an effective treatment of the QM-MM electrostatic interactions, and the incorporation of new efficient and accurate QM methods in QM/MM schemes.

Exploiting QM/MM Capabilities in Geometry Optimization: A Microiterative Approach Using Electrostatic Embedding.

We present a microiterative adiabatic scheme for quantum mechanical/molecular mechanical (QM/MM) energy minimization that fully optimizes the MM part in each QM macroiteration. This scheme is applicable not only to mechanical embedding but also to electrostatic and polarized embedding. The electrostatic QM/MM interactions in the microiterations are calculated from electrostatic potential charges fitted on the fly to the QM density. Corrections to the energy and gradient expressions ensure that macro- and microiterations are performed on the same energy surface. This results in excellent convergence properties and no loss of accuracy compared to standard optimization. We test our implementation on water clusters and on two enzymes using electrostatic embedding, as well as on a surface example using polarized embedding with a shell model. Our scheme is especially well-suited for systems containing large MM regions, since the computational effort for the optimization is almost independent of the MM system size. The microiterations reduce the number of required QM calculations typically by a factor of 2-10, depending on the system.

QM/MM Free-Energy Perturbation Compared to Thermodynamic Integration and Umbrella Sampling: Application to an Enzymatic Reaction.

We used the free-energy perturbation (FEP) method in quantum mechanics/molecular mechanics (QM/MM) calculations to compute the free-energy profile of the hydroxylation reaction in the enzyme p-hydroxybenzoate hydroxylase (PHBH). k statistics were employed to analyze the FEP sampling including estimation of the sampling error. Various approximations of the free-energy perturbation method were tested. We find that it is adequate not only to freeze the density of the QM part during the dynamics at frozen QM geometry but also to approximate this density by electrostatic-potential-fitted point charges. It is advisable to include all atoms of a QM/MM link in the perturbation. The results of QM/MM-FEP for PHBH are in good agreement with those of thermodynamic integration and umbrella sampling.