Initial Studies Directed toward the Rational Design of Aqueous Graphene Dispersants.

This study presents preliminary experimental data suggesting that sodium 4-(pyrene-1-yl)butane-1-sulfonate (PBSA), 5, an analogue of sodium pyrene-1-sulfonate (PSA), 1, enhances the stability of aqueous reduced graphene oxide (RGO) graphene dispersions. We find that RGO and exfoliated graphene dispersions prepared in the presence of 5 are approximately double the concentration of those made with commercially available PSA, 1. Quantum mechanical and molecular dynamics simulations provide key insights into the behavior of these molecules on the graphene surface. The seemingly obvious introduction of a polar sulfonate head group linked via an appropriate alkyl spacer to the aromatic core results in both more efficient binding of 5 to the graphene surface and more efficient solvation of the polar head group by bulk solvent (water). Overall, this improves the stabilization of the graphene flakes by disfavoring dissociation of the stabilizer from the graphene surface and inhibiting reaggregation by electrostatic and steric repulsion. These insights are currently the subject of further investigations in an attempt to develop a rational approach to the design of more effective dispersing agents for rGO and graphene in aqueous solution.

Accurate prediction of adsorption energies on graphene, using a dispersion-corrected semiempirical method including solvation.

The accurate prediction of the adsorption energies of unsaturated molecules on graphene in the presence of water is essential for the design of molecules that can modify its properties and that can aid its processability. We here show that a semiempirical MO method corrected for dispersive interactions (PM6-DH2) can predict the adsorption energies of unsaturated hydrocarbons and the effect of substitution on these values to an accuracy comparable to DFT values and in good agreement with the experiment. The adsorption energies of TCNE, TCNQ, and a number of sulfonated pyrenes are also predicted, along with the effect of hydration using the COSMO model.

Forming a ruthenium isomerisation catalyst from Grubbs II: a DFT study.

A DFT investigation into the mechanism for the decomposition of Grubbs 2nd generation pre-catalyst (2) in the presence of methanol, is presented. Gibbs free energy profiles for decomposition of the pre-catalyst (2) via two possible mechanisms were computed. We predict that decomposition following tricyclohexylphosphane dissociation is most favoured compared to direct decomposition of the pre-catalyst (2). However, depending on the reaction conditions, an on-pathway mechanism may be competitive with ruthenium hydride formation.

Quantum chemical approaches: semiempirical molecular orbital and hybrid quantum mechanical/molecular mechanical techniques.

The use of computational quantum chemical methods to aid drug discovery is surveyed. An overview of the various computational models spanning ab initio, density function theory, semiempirical molecular orbital (MO), and hybrid quantum mechanical (QM)/molecular mechanical (MM) methods is given and their strengths and weaknesses are highlighted, focussing on the challenge of obtaining the accuracy essential for them to make a meaningful contribution to drug discovery. Particular attention is given to hybrid QM/MM and semiempirical MO methods which have the potential to yield the necessary accurate predictions of macromolecular structure and reactivity. These methods are shown to have advanced the study of many aspects of substrate-ligand interactions relevant to drug discovery. Thus, the successful parametrization of semiempirical MO methods and QM/MM methods can be used to model noncovalent substrate-protein interactions, and to lead to improved scoring functions. QM/MM methods can be used in crystal structure refinement and are particularly valuable for modelling covalent protein-ligand interactions and can thus aid the design of transition state analogues. An extensive collection of examples from the areas of metalloenzyme structure, enzyme inhibition, and ligand binding affinities and scoring functions are used to illustrate the power of these techniques.

Reactions of Cp2M (M = Ni, V) with dilithium diamido-aryl reagents; retention and oxidation of the transition metal ions.

The reactions of dilithium 1,2-diamidobenzene, [1,2-(HN)2C6H4]Li2 (L(1)H2)Li2, and dilithium 1,8-diamidonaphthalene, [1,8-(NH)2C10H6]Li2 (L(2)H2)Li2, with Cp2Ni and Cp2V have been used to obtain the new complexes (L(2)H2)2Ni{Li(THF)2}2 (3), (L(2)H2)3V{Li(THF)2}3 (4) and (L(1)H2)6Ni6·{[(L(1)H2)3(L(1)H)3Ni6Li(THF)](2-)·2[Li(THF)4](+)} (5), in which retention or oxidation of the initial metal(ii) centre is observed. Whereas 3 and 4 contain one transition metal ion within ion-paired structures, 5 has a complicated co-crystalline composition which contains octahedral Ni6-cages constructed from six square-planar (16e) Ni(II) centres.

Insights into the activity and specificity of Trypanosoma cruzi trans-sialidase from molecular dynamics simulations.

Trypanosoma cruzitrans-sialidase (TcTS), which catalyzes the transfer or hydrolysis of terminal sialic acid residues, is crucial to the development and proliferation of the T. cruzi parasite and thus has emerged as a potential drug target for the treatment of Chagas disease. We here probe the origin of the observed preference for the transfer reaction over hydrolysis where the substrate for TcTS is the natural sialyl donor (represented in this work by sialyllactose). Thus, acceptor lactose preferentially attacks the sialyl-enyzme intermediate rather than water. We compare this with the weaker preference for such transfer shown by a synthetic donor substrate, 4-methylumbelliferyl α-d-acetylneuraminide. For this reason, we conducted molecular dynamics simulations of TcTS following its sialylation by the substrate to examine the behavior of the asialyl leaving group by the protein. These simulations indicate that, where lactose is released, this leaving group samples well-defined interactions in the acceptor site, some of which are mediated by localized water molecules; also, the extent of the opening of the acceptor site to solvent is reduced as compared with those of unliganded forms of TcTS. However, where there is release of 4-methylumbelliferone, this leaving group explores a range of transient poses; surrounding active site water is also more disordered. The acceptor site explores more open conformations, similar to the case in which the 4-methylumbelliferone is absent. Thus, the predicted solvent accessibility of sialylated TcTS is increased when 4-methylumbelliferyl α-d-acetylneuraminide is the substrate compared to sialyllactose; this in turn is likely to contribute to a greater propensity for hydrolysis of the covalent intermediate. These computational simulations, which suggest that protein flexibility has a role in the transferase/sialidase activity of TcTS, have the potential to aid in the design of anti-Chagas inhibitors effective against this neglected tropical disease.

Reversible aryl migrations in metallated ureas: controlled inversion of configuration at a quaternary carbon atom.

Deprotonation with strong bases of N-vinyl ureas carrying an N'-aryl substituent leads to migration of the N'-aryl group from N to C via an allyllithium; with weaker bases and electron-deficient aryl rings the direction of the migration reverses, and aryl substituents α to the urea N atom may migrate from C to N.

Lithium choreography: intramolecular arylations of carbamate-stabilised carbanions and their mechanisms probed by in situ IR spectroscopy and DFT calculations.

Deprotonation of O-allyl, O-propargyl or O-benzyl carbamates in the presence of a lithium counterion leads to carbamate-stabilised organolithium compounds that may be quenched with electrophiles. We now report that when the allylic, propargylic or benzylic carbamate bears an N-aryl substituent, an aryl migration takes place, leading to stereochemical inversion and C-arylation of the carbamate α to oxygen. The aryl migration is an intramolecular S(N) Ar reaction, despite the lack of anion-stabilising aryl substituents. Our in situ IR studies reveal a number of intermediates along the rearrangement pathway, including a "pre-lithiation complex," the deprotonated carbamate, the rearranged anion, and the final arylated carbamate. No evidence was obtained for a dearomatised intermediate during the aryl migration. DFT calculations predict that during the reaction the solvated Li cation moves from the carbanion centre, thus freeing its lone pair for nucleophilic attack on the remote phenyl ring. This charge separation leads to several alternative conformations. The one having Li(+) bound to the carbamate oxygen gives rise to the lowest-energy transition structure, and also leads to inversion of the configuration. In agreement with the IR studies, the DFT calculations fail to locate a dearomatised intermediate.

Lithiated tertiary carbanions display variable coordination modes: evidence from DFT and NMR studies.

Density functional calculations reveal that, whereas the reaction of 2-propyl-N,N-diisopropylbenzamide (6) with tBuLi in the presence of potentially tridentate donor ligands may result in lateral deprotonation of 6, the behavior of the Lewis base is non-trivial. The ability of N and O donor centers in the co-solvent to resist Li(+) coordination is found to be synonymous with interaction of lithium with the formally deprotonated carbanion center. Low-energy structures have been identified whose predicted (1)H and (13)C NMR spectroscopic shifts are in excellent agreement with experiment. Reaction of 2-isopropyl-N,N-diisopropylbenzamide (5) with tBuLi in the presence of bidentate Lewis base N,N,N',N'-tetramethylethylenediamine (TMEDA) yields material that is suggested by NMR spectroscopy to be laterally deprotonated and to have the formulation 5-Li(l)·TMEDA. In spite of the tertiary aliphatic group at the 2-position in 5, X-ray crystallography reveals that the crystalline material isolated from the treatment of 5/(-)-sparteine with tBuLi is a lateral lithiate in which amide coordination and solvation by bidentate Lewis base results in the Li(+) ion interacting with the deprotonated α-C of the 2-iPr group (2.483(8) Å). The tertiary carbanion center remains essentially flat and the adjacent aromatic system is highly distorted. The use of a chiral co-solvent results in two diastereomeric conformers, and their direct observation in solution suggests that interconversion is slow on the NMR timescale.

On the control of secondary carbanion structure utilising ligand effects during directed metallation.

N,N-Diisopropyl-2-propylbenzamide 6-H undergoes lateral deprotonation by t-BuLi in the presence of the Lewis base PMDTA (N,N,N',N″,N″-pentamethyldiethylenetriamine) to give a benzyllithium 6-Li(l)·PMDTA that incorporates a trigonal planar secondary carbanion. In the solid state, the amide directing group and the PMDTA additive work together to abstract the metal ion from the deprotonated α-C of the propyl group (4.107(4) Å). A short distance of 1.376(3) Å is observed between the deprotonated carbon centre and a planar aromatic system that shows a pattern of bond lengths which contrasts with that reported for related tertiary carbanion systems. Analogous benzylic deprotonation is seen if 6-H is treated with t-BuLi in the presence of diglyme to give 6-Li(l)·DGME. X-ray crystallography now shows that the metal ion more closely approaches the tertiary carbanion (2.418(6) Å) but that the planarity of the deprotonated carbon centre and the bonding pattern in the organic anion seen in the PMDTA complex are retained. DFT analysis corroborates both the short distance between aromatic ring and carbanion centre and the unperturbed nature of aromaticity in 6-Li(l)·L (L = Lewis base). The observation of two structure-types for the carbanion in solution is explained theoretically and by NMR spectroscopy in terms of cis and trans isomerism imparted by partial double bond character in the arene-(α-C) bond.

Is nevirapine atropisomeric? Experimental and computational evidence for rapid conformational inversion.

The non-nucleoside reverse transcriptase inhibitor nevirapine displays in its room temperature (1)H-NMR spectrum signals characteristic of a chiral compound. Following suggestions in the recent literature that nevirapine may display atropisomerism-and therefore be a chiral compound, due to slow interconversion between two enantiomeric conformers-we report the results of an NMR and computational study which reveal that while nevirapine does indeed possess two stable enantiomeric conformations, they interconvert with a barrier of about 76 kJ mol(-1) at room temperature. Nevirapine has a half life for enantiomerisation at room temperature of the order of seconds, is not atropisomeric, and cannot exist as separable enantiomers.

Why is RCM favoured over dimerisation? Predicting and estimating thermodynamic effective molarities by solution experiments and electronic structure calculations.

The thermodynamic effective molarities of a series of simple cycloalkenes, synthesised from α,ω-dienes by reaction with Grubbs' second generation precatalyst, have been evaluated. Effective molarities were measured from a series of small scale metathesis reactions and agreed well with empirical predictions derived from the number of rotors and the product ring strain. The use of electronic structure calculations (at the M06-L/6-311G** level of theory) was explored for predicting thermodynamic effective molarities in ring-closing metathesis. However, it was found that it was necessary to apply a correction to DFT-derived free energies to account for the entropic effects of solvation.

The mechanism of the reduction of [AnO2]2+ (An = U, Np, Pu) in aqueous solution, and by Fe(II) containing proteins and mineral surfaces, probed by DFT calculations.

The fate of actinyl species in the environment is closely linked to oxidation state, since the reduction of An(VI) to An(IV) greatly decreases their mobility due to the precipitation of the relatively insoluble An(IV) species. Here we study the mechanism of the reduction of [AnO(2)](2+) (An = U, Np, Pu) both in aqueous solution and by Fe(II) containing proteins and mineral surfaces, using density functional theory calculations. We find a disproportionation mechanism involving a An(V)-An(V) cation-cation complex, and we have investigated how these complexes are formed in the different environments. We find that the behaviour of U and Pu complexes are similar, but the reduction of Np(V) to Np(IV) would seems to be more difficult, in line with the experimental finding that Np(V) is generally more stable than U(V) or Pu(V). Although the models we have used are somewhat idealised, our calculations suggest that there are strong similarities between the biotic and abiotic reduction pathways.

Ligand effects in the formation of tertiary carbanions from substituted tertiary aromatic amides.

Reaction of 2-isopropyl-(N,N-diisopropyl)-benzamide 5 with tBuLi in ether results in ortho deprotonation and the formation of a hemisolvate based on a tetranuclear dimer of (5-Li(o))(2)⋅Et(2)O. The solid-state structure exhibits a dimer core in which the amide oxygen atoms fail to stabilize the metal ions but are instead available for interaction with two metalated monomers that reside peripheral to the core. Reaction of 5 with tBuLi in the presence of the tridentate Lewis base PMDTA (N,N,N',N'',N''-pentamethyldiethylenetriamine) takes a different course. In spite of the tertiary aliphatic group at the 2-position in 5, X-ray crystallography revealed that a remarkable benzylic (lateral) deprotonation had occurred, giving the tertiary benzyllithium 5-Li(l)⋅PMDTA. The solid-state structure reveals that amide coordination and solvation by PMDTA combine to distance the Li(+) ion from the deprotonated α-C of the 2-iPr group (3.859(4) Å), thus giving an essentially flat tertiary carbanion and a highly distorted aromatic system. DFT analysis suggests that the metal ion resides closer to the carbanion center in solution. In line with this, the same (benzylic) deprotonation is noted if the reaction is attempted in the presence of tridentate diglyme, with X-ray crystallography revealing that the metal is now closer to the tertiary carbanion (2.497(4) Å). Electrophilic quenches of lithiated 5 have allowed, for the first time, the formation of quaternary benzylic substituents by lateral lithiation.

What is the initiation step of the Grubbs-Hoveyda olefin metathesis catalyst?

Density function theory calculations reveal that the Grubbs-Hoveyda olefin metathesis pre-catalyst is activated by the formation of a complex in which the incoming alkene substrate and outgoing alkoxy ligand are both clearly associated with the ruthenium centre. The computed energies for reaction are in good agreement with the experimental values, reported here.

How do enzymes reduce metals? The mechanism of the reduction of Cr(VI) in chromate by cytochrome c7 proteins proposed from DFT calculations.

Various bacteria are effective in metal reduction, and there is an increasing use of such micro-organisms for decontaminating polluted environments. Iron-containing electron transfer proteins, particularly those of the cytochrome c7 family, can bind a number of toxic metals in their high oxidation states, and can reduce them via electron transfer mechanisms. We report a computational investigation of the binding of CrO4(2-) to the cytochrome c7 of Desulfuromonas acetoxidans and explore possible mechanisms for the subsequent reduction of Cr(VI) to Cr(III). Our modelling strategy is to identify the binding site of D. acetoxidans for the chromate di-anion, and to use this structure as a starting point to generate realistic models for DFT calculations of the structures and energetics of species along the pathway for reduction. We address the following aspects of the mechanism: (i) How do the neighbouring residues, particularly the nearby lysines, modulate the reduction process? (ii) What is the speciation of chromium as the oxidation state is reduced from VI? (iii) How is the electron transfer made energetically feasible, considering the initial species (chromate) has a high negative charge? We suggest that both electron transfer from the heme and proton transfer from the lysines occur, followed by a disproportionation mechanism involving Cr(V). This mechanism is compared with our proposed mechanism for the reduction of actinyl species.

Cadmium sulfide and cadmium phosphide thin films from a single cadmium compound.

Aerosol-assisted chemical vapor deposition of Cd[(SP(i)Pr(2))(2)N](2) leads to the growth of cadmium sulfide and/or phosphide thin films on glass. Decomposition of the precursor has been studied by pyrolysis-gas chromatography/mass spectrometry and modeled by density functional theory.

The structure and interaction energies of the weak complexes of CHClF2 and CHF3 with HCCH: a test of density functional theory methods.

The structure and interaction energies of the weak non-covalent complexes of CHClF(2) and CHF(3) with HCCH have been predicted using a number of density functional based approaches, and compared with both high resolution spectroscopic data recently reported by Sexton et al. [Phys. Chem. Chem. Phys., 2010, 12, 14263-14270], and with high level benchmark calculations reported herein. We find that this is another case where the M05 and M06 families of functionals, as well as the DFT-D approach, are competitive with the more costly wavefunction based methods. We highlight the problem of deriving unique intermolecular structural parameters from the experimental microwave data.

Low temperature CVD growth of PbS films on plastic substrates.

The low temperature growth of crystalline PbS films has been achieved on plastic substrates by CVD using a xanthate. The possible mechanism involved in this low temperature deposition has been probed by density functional theory calculations.

Mapping the potential energy surfaces for ring-closing metathesis reactions of prototypical dienes by electronic structure calculations.

The potential energy surfaces for ring-closing metathesis reactions of a series of simple α,ω-dienes which lead to 5-10 membered ring products, have been explored using density functional theory methods. We have investigated both the conformational aspects of the hydrocarbon chain during the course of the reactions, as well as the stationary structures on the corresponding potential energy surfaces. Extensive conformational searches reveal that the reaction proceeds via the conformation that would be expected for the cycloalkene product, though most unexpectedly, cyclohexene forms via complexes in boat-like conformations. The M06-L density functional has been used to map out the potential energy surfaces, and has identified metallocyclobutane fragmentation as being generally the highest barrier along the pathway. The structural variations along the pathway have been discussed for the reactant hydrocarbons of differing chain length to identify points at which cyclisation events may begin to affect reaction rates. Our study provides an excellent starting point from which to begin to learn about the way RCM reaction outcomes are controlled by diene structure.