Aldose reductase is the first enzyme of the polyol pathway in which glucose is converted to fructose via sorbitol. The understanding of this key enzyme is important as it has been linked to some diabetes mellitus complications. The mechanism of the enzyme was investigated using a hybrid quantum mechanics/molecular mechanics (QM/MM) method. It was found that depending on the protonation state of His110 the mechanism can be concerted or stepwise and the proton donor can be either Tyr48 or His110. These findings are different from the previous theoretical studies based on QM/MM calculations using either AM1 or HF/4-31G, in which the reduction is, respectively, a stepwise or one-step process. The QM/MM energy barriers for the reduction of d-glyceraldehyde were evaluated at a B3LYP/6-31G* level for both HIP and HIE protonation states of His110. These were, respectively, 6.5 ± 2.2 and 16.7 ± 1.0 kcal/mol, which makes only the HIE protonation state consistent with the experimental value of 14.8 kcal/mol derived from kinetics experiments and makes Tyr48 the most probable proton donor.Topics: Biochemistry; Molecular association; Molecular dynamics; Molecular recognition; Proteins; Reaction mechanism; Reaction rate theory;

A designed N,N′-dialkyldiketopiperazine (DKP) provides evidence for the role of DKP additives as initiators that act by electron transfer in base-induced homolytic aromatic substitution reactions, involving coupling of haloarenes to arenes.

There is significant interest in the use of unmodified self-assembling peptides as building blocks for functional, supramolecular biomaterials. Recently, dynamic peptide libraries (DPLs) have been proposed to select self-assembling materials from dynamically exchanging mixtures of dipeptide inputs in the presence of a nonspecific protease enzyme, where peptide sequences are selected and amplified based on their self-assembling tendencies. It was shown that the results of the DPL of mixed sequences (e.g. starting from a mixture of dileucine, L2, and diphenylalanine, F2) did not give the same outcome as the separate L2 and F2 libraries (which give rise to the formation of F6 and L6), implying that interactions between these sequences could disrupt the self-assembly. In this study, coarse grained molecular dynamics (CG-MD) simulations are used to understand the DPL results for F2, L2 and mixed libraries. CG-MD simulations demonstrate that interactions between precursors can cause the low formation yield of hexapeptides in the mixtures of dipeptides and show that this ability to disrupt is influenced by the concentration of the different species in the DPL. The disrupting self-assembly effect between the species in the DPL is an important effect to take into account in dynamic combinatorial chemistry as it affects the possible discovery of new materials. This work shows that combined computational and experimental screening can be used complementarily and in combination providing a powerful means to discover new supramolecular peptide nanostructures.

A recent paper identified a series of alternative cyclisation pathways of aryl radicals that resulted from electron transfer to various tethered haloarene–acetylarene substrates, in either benzene or DMSO as solvent. The electron transfer occurred from one of two enolates that were formed in the presence of KOtBu: either the enolate of the acetylarene, within the haloarene–acetylarene substrate, or the enolate 7 of the N,N′-dipropyl diketopiperazine (DKP) additive 6. This paper uses contemporary computational methods to determine the reaction pathways involved; depending on the substrate, the aryl radical underwent (i) SRN1 onto the enolate anion of the acetylarene, (ii) aryl–aryl bond formation, (iii) tandem hydrogen atom abstraction followed by SRN1 cyclisation and even (iv) ArC–N cleavage. The influence of the solvent was investigated. In this paper it is shown that the solvent influences which reactive species are present in the reaction mixture, and whether each species acts as an electron donor or an electron acceptor in the radical initiation or propagation steps. The main initiation step is a single electron transfer from the enolate anion 7 of the DKP additive in benzene, but in DMSO the initiation can occur from the enolate anion of the substrate itself. Using computational techniques a deeper understanding of the radical pathways involved has been obtained, which shows how we can use solvent to preferentially access products arising from either SRN1 or aryl–aryl bond formation pathways.

AbstractRecent studies by Stoltz, Grubbs et al. have shown that triethylsilane and potassium tert-butoxide react to form a highly attractive and versatile system that shows (reversible) silylation of arenes and heteroarenes as well as reductive cleavage of C−O bonds in aryl ethers and C−S bonds in aryl thioethers. Their extensive mechanistic studies indicate a complex network of reactions with a number of possible intermediates and mechanisms, but their reactions likely feature silyl radicals undergoing addition reactions and SH2 reactions. This paper focuses on the same system, but through computational and experimental studies, reports complementary facets of its chemistry based on a) single-electron transfer (SET), and b) hydride delivery reactions to arenes.

Many recent studies have used KOtBu in organic reactions that involve single electron transfer; in the literature, the electron transfer is proposed to occur either directly from the metal alkoxide or indirectly, following reaction of the alkoxide with a solvent or additive. These reaction classes include coupling reactions of halobenzenes and arenes, reductive cleavages of dithianes, and SRN1 reactions. Direct electron transfer would imply that alkali metal alkoxides are willing partners in these electron transfer reactions, but the literature reports provide little or no experimental evidence for this. This paper examines each of these classes of reaction in turn, and contests the roles proposed for KOtBu; instead, it provides new mechanistic information that in each case supports the in situ formation of organic electron donors. We go on to show that direct electron transfer from KOtBu can however occur in appropriate cases, where the electron acceptor has a reduction potential near the oxidation potential of KOtBu, and the example that we use is CBr4. In this case, computational results support electrochemical data in backing a direct electron transfer reaction.

We report on-demand formation of emulsions stabilised by interfacial nanoscale networks. These are formed through biocatalytic dephosphorylation and self-assembly of Fmoc(9-fluorenylmethoxycarbonyl)dipeptide amphiphiles in aqueous/organic mixtures. This is achieved by using alkaline phosphatase which transforms surfactant-like phosphorylated precursors into self-assembling aromatic peptide amphiphiles (Fmoc-tyrosine-leucine, Fmoc-YL) that form nanofibrous networks. In biphasic organic/aqueous systems, these networks form preferentially at the interface thus providing a means of emulsion stabilisation. We demonstrate on-demand emulsification by enzyme addition, even after storage of the biphasic mixture for several weeks. Experimental (Fluorescence, FTIR spectroscopy, fluorescence microscopy, electron microscopy, atomic force microscopy) and computational techniques (atomistic molecular dynamics) are used to characterise the interfacial self-assembly process.

Aromatic peptide amphiphiles are known to self-assemble into nanostructures but the molecular level structure and the mechanism of formation of these nanostructures is not yet understood in detail. Molecular dynamic simulations using the CHARMM force field have been applied to a wide variety of peptide-based systems to obtain molecular level details of processes that are inaccessible with experimental techniques. However, this force field does not include parameters for the aromatic moieties which dictate the self-assembly of these systems. The standard CHARMM force field parameterization protocol uses hydrophilic interactions for the non-bonding parameters evaluation. However, to effectively reproduce the self-assembling behaviour of these molecules, the balance between the hydrophilic and hydrophobic nature of the molecule is essential. In this work, a modified parameterization protocol for the CHARMM force field for these aromatic moieties is presented. This protocol is applied for the specific case of the Fmoc moiety. The resulting set of parameters satisfies the conformational and interactions analysis and is able to reproduce experimental results such as the Fmoc–S–OMe water/octanol partition free energy and the self-assembly of Fmoc–S–OH and Fmoc–Y–OH into spherical micelles and fibres, respectively, while also providing detailed information on the mechanism of these processes. The effectiveness of the parameters for the Fmoc moiety validates the protocol as a robust approach to paramterise this class of compounds.

The utilization of computational methods to predict reactivity is an increasingly useful tool for chemists to save time and materials by screening compounds for desirable reactivity prior to testing in the laboratory. In the field of electron transfer reactions, screening can be performed through the application of Marcus Hush theory to calculate the activation free energy of any potential reaction. This work describes the most accurate and efficient approach for modelling the electron transfer process. In particular, the importance of using an electron transfer complex to model these reactions rather than considering donor and acceptor molecules as separate entities is highlighted. The use of the complex model is found to produce more accurate calculation of the electron transfer energy when the donor and acceptor spin densities are adequately localised.

Low molecular weight gelators are able to form nanostructures, typically fibers, which entangle to form gel-phase materials. These materials have wide-ranging applications in biomedicine and nanotechnology. While it is known that supramolecular gels often represent metastable structures due to the restricted molecular dynamics in the gel state, the thermodynamic nature of the nanofibrous structure is not well understood. Clearly, 3D extended structures will be able to form more interactions than 1D structures. However, self-assembling molecules are typically amphiphilic, thus giving rise to a combination of solvophobic and solvophilic moieties where a level of solvent exposure at the nanostructure surface is favorable. In this study, we introduce a simple packing model, based on prisms with faces of different nature (solvophobic and solvophilic) and variable interaction parameters, to represent amphiphile self-assembly. This model demonstrates that by tuning shape and “self” or “solvent” interaction parameters either the 1D fiber or 3D crystal may represent the thermodynamic minimum. The model depends on parameters that relate to features of experimentally known systems: the number of faces exposed to the solvent or buried in the fiber; the overall shape of the prism; and the free energy penalties associated with the interactions can be adjusted to match their chemical nature. The model is applied to describe the pH-dependent gelation/precipitation of well-known gelator Fmoc-FF. We conclude that, despite the fact that most experimentally produced gels probably represent metastable states, one-dimensional fibers can represent thermodynamic equilibrium. This conclusion has critical implications for the theoretical treatment of gels.Keywords: amphiphiles; gel; low molecular weight gelators; model; packing; self-assembly; soft-matter; thermodynamics;

Under basic conditions aryl halides can undergo SRN1 reactions, BHAS reactions and benzyne formations. Appropriate complex substrates afford an opportunity to study inherent selectivities. SRN1 reactions are usually favoured under photoactivated conditions, but this paper reports their success using ground-state and transition metal-free conditions. In benzene, the enolate salt 12, derived by deprotonation of diketopiperazine 11, behaves as an electron donor, and assists the initiation of the reactions, but in DMSO, it is not required. The outcomes are compared and contrasted with a recent photochemical study on similar substrates. A particular difference is the prevalence of hydride shuttle reactions under relatively mild thermal conditions.Figure optionsDownload full-size imageDownload high-quality image (135 K)Download as PowerPoint slide

Iridium-catalyzed C–H activation and ortho-hydrogen isotope exchange is an important technology for allowing access to labeled organic substrates and aromatic drug molecules and for the development of further C–H activation processes in organic synthesis. The use of [(COD)Ir(NHC)Cl] complexes (NHC = N-heterocyclic carbene) in the ortho-deuteration of primary sulfonamides under ambient conditions is reported. This methodology has been applied to the deuteration of a series of substrates, including the COX-2 inhibitors Celecoxib and Mavacoxib, demonstrating selective complexation of the primary sulfonamide over a competing pyrazole moiety. The observed chemoselectivity can be reversed by employing more encumbered catalyst derivatives of the type [(COD)Ir(NHC)(PPh3)]PF6. Computational studies have revealed that, although C–H activation is rate-determining, substrate complexation or subsequent C–H activation can be product-determining depending on the catalyst employed.Keywords: C−H activation; hydrogen-isotope exchange; iridium; ortho-deuteration; sulfonamide

Protein binding to surfaces is an important phenomenon in biology and in modern technological applications. Extensive experimental and theoretical research has been focused in recent years on revealing the factors that govern binding affinity to surfaces. Theoretical studies mainly focus on examining the contribution of the individual amino acids or, alternatively, the binding potential energies of the full peptide, which are unable to capture entropic contributions and neglect the dynamic nature of the system. We present here a methodology that involves the combination of nonequilibrium dynamics simulations with strategic mutation of polar residues to reveal the different factors governing the binding free energy of a peptide to a surface. Using a gold-binding peptide as an example, we show that relative binding free energies are a consequence of the balance between strong interactions of the peptide with the surface and the ability for the bulk solvent to stabilize the peptide.

Coupling of haloarenes to arenes has been facilitated by a diverse range of organic additives in the presence of KOtBu or NaOtBu since the first report in 2008. Very recently, we showed that the reactivity of some of these additives (e.g., compounds 6 and 7) could be explained by the formation of organic electron donors in situ, but the role of other additives was not addressed. The simplest of these, alcohols, including 1,2-diols, 1,2-diamines, and amino acids are the most intriguing, and we now report experiments that support their roles as precursors of organic electron donors, underlining the importance of this mode of initiation in these coupling reactions.

Recent papers report transition metal-free couplings of haloarenes to arenes to form biaryls, triggered by alkali metal tert-butoxides in the presence of various additives. These reactions proceed through radical intermediates, but understanding the origin of the radicals has been problematic. Electron transfer from a complex formed from potassium tert-butoxide with additives, such as phenanthroline, has been suggested to initiate the radical process. However, our computational results encouraged us to search for alternatives. We report that heterocycle-derived organic electron donors achieve the coupling reactions and these donors can form in situ in the above cases. We show that an electron transfer route can operate either with phenanthrolines as additives or using pyridine as solvent, and we propose new heterocyclic structures for the respective electron donors involved in these cases. In the absence of additives, the coupling reactions are still successful, although more sluggish, and in those cases benzynes are proposed to play crucial roles in the initiation process.

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.

Dispersion corrected density functional theory (DFT-D) has been applied to understand the performance of several palladium metal scavengers. Nine different sulfur-based ligands and three different palladium metal sets have been investigated in detail. Based on a thorough analysis of the thermodynamic binding parameters ΔH, ΔG and ΔS, we have identified the best binding modes for all scavenger ligands. Bis-monodentate coordination is favoured over chelation in ΔH and ΔG values for most of the scavenger ligands. Special attention has been paid to the ligand strain energies, which account for the structural changes of the ligands upon complexation indicating that small (5-membered) chelates are considerably less favourable than expected. Some ligands can use their longest chain (>7-atoms) to yield trans chelates, which ligands with shorter chains (≤6-atoms) are unable to form. A secondary amino nitrogen (RR′NH) is found to be the best donor with highest binding enthalpy for Pd(II) metal systems. In terms of the strength of the initial binding interactions, –SMe > –SH; capping thiols (–SH) as thioethers (–SMe) is therefore suggested to be an effective strategy in scavenger design. These observations mark the beginning of a knowledge base of the full range of possible interactions, leading to the construction of a sulfur ligand database for the design of scavenger systems.

The prevalence of metal-based reducing reagents, including metals, metal complexes, and metal salts, has produced an empirical order of reactivity that governs our approach to chemical synthesis. However, this reactivity may be influenced by stabilization of transition states, intermediates, and products through substrate–metal bonding. This article reports that in the absence of such stabilizing interactions, established chemoselectivities can be overthrown. Thus, photoactivation of the recently developed neutral organic superelectron donor 5 selectively reduces alkyl-substituted benzene rings in the presence of activated esters and nitriles, in direct contrast to metal-based reductions, opening a new perspective on reactivity. The altered outcomes arising from the organic electron donors are attributed to selective interactions between the neutral organic donors and the arene rings of the substrates.

β-Sheets are a commonly found structural motif in self-assembling aromatic peptide amphiphiles, and their characteristic “amide I” infrared (IR) absorption bands are routinely used to support the formation of supramolecular structure. In this paper, we assess the utility of IR spectroscopy as a structural diagnostic tool for this class of self-assembling systems. Using 9-fluorene-methyloxycarbonyl dialanine (Fmoc-AA) and the analogous 9-fluorene-methylcarbonyl dialanine (Fmc-AA) as examples, we show that the origin of the band around 1680–1695 cm–1 in Fourier transform infrared (FTIR) spectra, which was previously assigned to an antiparallel β-sheet conformation, is in fact absorption of the stacked carbamate group in Fmoc-peptides. IR spectra from 13C-labeled samples support our conclusions. In addition, DFT frequency calculations on small stacks of aromatic peptides help to rationalize these results in terms of the individual vibrational modes.

Several short peptide sequences are known to self-assemble into supramolecular nanostructures with interesting properties. In this study, coarse-grained molecular dynamics is employed to rapidly screen all 400 dipeptide combinations and predict their ability to aggregate as a potential precursor to their self-assembly. The simulation protocol and scoring method proposed allows a rapid determination of whether a given peptide sequence is likely to aggregate (an indicator for the ability to self-assemble) under aqueous conditions. Systems that show strong aggregation tendencies in the initial screening are selected for longer simulations, which result in good agreement with the known self-assembly or aggregation of dipeptides reported in the literature. Our extended simulations of the diphenylalanine system show that the coarse-grain model is able to reproduce salient features of nanoscale systems and provide insight into the self-assembly process for this system.Keywords: coarse-grain; computational; dipeptides; molecular dynamics; self-assembly;

Protonated dihydrogen trioxide (HOOOH) has been postulated in various forms for many years. Protonation can occur at either the terminal (HOOO(H)H+) or central (HOOH(OH)+) oxygen atom. However, to date there has been no definitive evidence provided for either of these species. In the current work we have employed ab initio methods, CCSD(T) and MP2, with a large basis set (6-311++G(3df,3pd)) to determine the relative stabilities of these species. It is shown that the terminally protonated species is strongly favored relative to the centrally protonated species (ΔE = 15.8 kcal/mol, CCSD(T)//MP2). The mechanism of formation of HOOO(H)H+ was determined to occur with a low barrier with the H3O+ occurring in a thermoneutral reaction (ΔE = −0.3 kcal/mol, CCSD(T)//MP2). Although HOOO(H)H+ exists as a stable intermediate, it is extremely short-lived and rapidly decomposes (ΔE* = 8.6 kcal/mol, MP2) to H3O+ and O2(1Δg). The decomposition reaction is stabilized by solvent water molecules. The short-lived nature of the intermediate implies that the intermediate species can not be observed in 17O NMR spectra, which has been demonstrated experimentally.

We report our third and final investigation into the use of ruthenium based compounds for catalyzing the hydrosilylation of methylvinyldimethoxysilane with methyldimethoxysilane. The catalytic mechanism of dichloro(p-cymene)ruthenium(II) (B1) is examined and compared to that of previously studied, less active catalysts. Density functional theory (DFT) has been applied to explore the possibility of fine-tuning the catalytic ability of B1. The η6-ligand and the σ-donor ligands were varied to assess the steric and electronic factors that affect the reactivity of the catalyst. The catalytic ability is diminished by increasing the size of the η6-ligand (p-cymene replaced by 1,3,5-cyclooctatriene) or the σ-donor strength of the other ligands (chloride replaced by methyl). The original catalyst (B1) appears to strike an optimum balance with regard to the σ-donor capabilities of the ligands as it is able to interconvert relatively freely between the Ru(II) and Ru(IV) oxidation states. All catalytically active compounds benefit from an initial exchange of one of the σ-donor ligands for a hydride ligand in the induction step.

The variation of the 1H and 13C NMR chemical shifts of heptapeptide ATWLPPR was investigated during a hybrid quantum mechanical (QM)/molecular mechanical (MM = CHARMM) molecular dynamics simulation of the peptide in aqueous solvent. The semiempirical method OM3 was used as the QM method, and the effect of augmenting the OM3 Hamiltonian with an empirical dispersion term (OM3-D) was also explored. The semiempirical MNDO method was used to calculate the chemical shifts of snapshots taken at 50 fs intervals during the 100 ps simulation. The calculated chemical shifts are highly sensitive to fluctuations of the molecular geometry on the time scale of molecular vibrations. However, the time-averaged chemical shift over the full simulation results in reasonable agreement with the experimental NMR chemical shifts and more consistent results compared with the averaged chemical shifts obtained from gas-phase optimized conformations of the peptide. The OM3 and OM3-D methods are stable and reproduce the main features of the experimental geometry during the 100 ps simulation.

The semiempirical methods of the OMx family (orthogonalization models OM1, OM2, and OM3) are known to describe biochemical systems more accurately than standard semiempirical approaches such as AM1. We investigate the benefits of augmenting these methods with an empirical dispersion term (OMx-D) taken from recent density functional work, without modifying the standard OMx parameters. Significant improvements are achieved for non-covalent interactions, with mean unsigned errors of 1.41 kcal/mol (OM2-D) and 1.31 kcal/mol (OM3-D) for the binding energy of the complexes in the JSCH-2005 data base. This supports the use of these augmented methods in quantum mechanical/molecular mechanical (QM/MM) studies of biomolecules, for example during system preparation and equilibration. As an illustrative application, we present QM and QM/MM calculations on the binding between antibody 34E4 and a hapten, where OM3-D performs better than the methods without dispersion terms (AM1, OM3).

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.

Recent papers report transition metal-free couplings of haloarenes to arenes to form biaryls, triggered by alkali metal tert-butoxides in the presence of various additives. These reactions proceed through radical intermediates, but understanding the origin of the radicals has been problematic. Electron transfer from a complex formed from potassium tert-butoxide with additives, such as phenanthroline, has been suggested to initiate the radical process. However, our computational results encouraged us to search for alternatives. We report that heterocycle-derived organic electron donors achieve the coupling reactions and these donors can form in situ in the above cases. We show that an electron transfer route can operate either with phenanthrolines as additives or using pyridine as solvent, and we propose new heterocyclic structures for the respective electron donors involved in these cases. In the absence of additives, the coupling reactions are still successful, although more sluggish, and in those cases benzynes are proposed to play crucial roles in the initiation process.

Dispersion corrected density functional theory (DFT-D) has been applied to understand the performance of several palladium metal scavengers. Nine different sulfur-based ligands and three different palladium metal sets have been investigated in detail. Based on a thorough analysis of the thermodynamic binding parameters ΔH, ΔG and ΔS, we have identified the best binding modes for all scavenger ligands. Bis-monodentate coordination is favoured over chelation in ΔH and ΔG values for most of the scavenger ligands. Special attention has been paid to the ligand strain energies, which account for the structural changes of the ligands upon complexation indicating that small (5-membered) chelates are considerably less favourable than expected. Some ligands can use their longest chain (>7-atoms) to yield trans chelates, which ligands with shorter chains (≤6-atoms) are unable to form. A secondary amino nitrogen (RR′NH) is found to be the best donor with highest binding enthalpy for Pd(II) metal systems. In terms of the strength of the initial binding interactions, –SMe > –SH; capping thiols (–SH) as thioethers (–SMe) is therefore suggested to be an effective strategy in scavenger design. These observations mark the beginning of a knowledge base of the full range of possible interactions, leading to the construction of a sulfur ligand database for the design of scavenger systems.

The semiempirical methods of the OMx family (orthogonalization models OM1, OM2, and OM3) are known to describe biochemical systems more accurately than standard semiempirical approaches such as AM1. We investigate the benefits of augmenting these methods with an empirical dispersion term (OMx-D) taken from recent density functional work, without modifying the standard OMx parameters. Significant improvements are achieved for non-covalent interactions, with mean unsigned errors of 1.41 kcal/mol (OM2-D) and 1.31 kcal/mol (OM3-D) for the binding energy of the complexes in the JSCH-2005 data base. This supports the use of these augmented methods in quantum mechanical/molecular mechanical (QM/MM) studies of biomolecules, for example during system preparation and equilibration. As an illustrative application, we present QM and QM/MM calculations on the binding between antibody 34E4 and a hapten, where OM3-D performs better than the methods without dispersion terms (AM1, OM3).

A recent paper identified a series of alternative cyclisation pathways of aryl radicals that resulted from electron transfer to various tethered haloarene–acetylarene substrates, in either benzene or DMSO as solvent. The electron transfer occurred from one of two enolates that were formed in the presence of KOtBu: either the enolate of the acetylarene, within the haloarene–acetylarene substrate, or the enolate 7 of the N,N′-dipropyl diketopiperazine (DKP) additive 6. This paper uses contemporary computational methods to determine the reaction pathways involved; depending on the substrate, the aryl radical underwent (i) SRN1 onto the enolate anion of the acetylarene, (ii) aryl–aryl bond formation, (iii) tandem hydrogen atom abstraction followed by SRN1 cyclisation and even (iv) ArC–N cleavage. The influence of the solvent was investigated. In this paper it is shown that the solvent influences which reactive species are present in the reaction mixture, and whether each species acts as an electron donor or an electron acceptor in the radical initiation or propagation steps. The main initiation step is a single electron transfer from the enolate anion 7 of the DKP additive in benzene, but in DMSO the initiation can occur from the enolate anion of the substrate itself. Using computational techniques a deeper understanding of the radical pathways involved has been obtained, which shows how we can use solvent to preferentially access products arising from either SRN1 or aryl–aryl bond formation pathways.

We report our third and final investigation into the use of ruthenium based compounds for catalyzing the hydrosilylation of methylvinyldimethoxysilane with methyldimethoxysilane. The catalytic mechanism of dichloro(p-cymene)ruthenium(II) (B1) is examined and compared to that of previously studied, less active catalysts. Density functional theory (DFT) has been applied to explore the possibility of fine-tuning the catalytic ability of B1. The η6-ligand and the σ-donor ligands were varied to assess the steric and electronic factors that affect the reactivity of the catalyst. The catalytic ability is diminished by increasing the size of the η6-ligand (p-cymene replaced by 1,3,5-cyclooctatriene) or the σ-donor strength of the other ligands (chloride replaced by methyl). The original catalyst (B1) appears to strike an optimum balance with regard to the σ-donor capabilities of the ligands as it is able to interconvert relatively freely between the Ru(II) and Ru(IV) oxidation states. All catalytically active compounds benefit from an initial exchange of one of the σ-donor ligands for a hydride ligand in the induction step.

Aromatic peptide amphiphiles are known to self-assemble into nanostructures but the molecular level structure and the mechanism of formation of these nanostructures is not yet understood in detail. Molecular dynamic simulations using the CHARMM force field have been applied to a wide variety of peptide-based systems to obtain molecular level details of processes that are inaccessible with experimental techniques. However, this force field does not include parameters for the aromatic moieties which dictate the self-assembly of these systems. The standard CHARMM force field parameterization protocol uses hydrophilic interactions for the non-bonding parameters evaluation. However, to effectively reproduce the self-assembling behaviour of these molecules, the balance between the hydrophilic and hydrophobic nature of the molecule is essential. In this work, a modified parameterization protocol for the CHARMM force field for these aromatic moieties is presented. This protocol is applied for the specific case of the Fmoc moiety. The resulting set of parameters satisfies the conformational and interactions analysis and is able to reproduce experimental results such as the Fmoc–S–OMe water/octanol partition free energy and the self-assembly of Fmoc–S–OH and Fmoc–Y–OH into spherical micelles and fibres, respectively, while also providing detailed information on the mechanism of these processes. The effectiveness of the parameters for the Fmoc moiety validates the protocol as a robust approach to paramterise this class of compounds.