Dr Brendan J. Howlin joined the University of Surrey in September 1987 to teach on the new computer aided chemistry degree course. He currently teaches IT skills, advanced mathematics, molecular modelling and DNA profiling.
He graduated with BSc and PhD from the University of Essex, having studied the inorganic chemistry of microbial iron transport compounds, using Mossbauer spectroscopy and X-ray crystallography. He also carried out postdoctoral pharmaceutical and protein modelling studies at Birkbeck College in the University of London and Pfizer Ltd.
Areas of specialism
University roles and responsibilities
- Chemistry Athena Swan Lead
- Member of IT Governance Committee
- Member of FEPS Equality and Diversity Committee
26 FEB 2018
Alternative to traditional batteries moves a step closer to reality after exciting progress in supercapacitor technology
In the media
My research interests currently centre on molecular modelling and developing supercapacitors. Molecular modelling covers molecular mechanics, molecular dynamics, QSPR and molecular orbital calculations on synthetic polymers, proteins and drug design. The supercapacitor research involves developing the next generation of high energy density supercapacitor materials
- Major scientific breakthrough research has discovered new materials offering an alternative to battery power proven to be between 1,000-10,000 times more powerful than the existing battery alternative - a supercapacitor.
- The new technology is believed to have the potential for electric cars to travel to similar distances as petrol cars without the need to stop for lengthy re-charging breaks of between 6-8 hours, and instead re-charge fully in the time it takes to fill a regular car with petrol.
- The scientific findings made by Augmented Optics Ltd and its wholly owned subsidiary Supercapacitor Materials Ltd with the University of Surrey and University of Bristol have produced a safer, faster charging, more efficient and greener alternative to battery power and supercapacitor abilities as we currently know them.
We collaborate with supercapacitormaterials on supercapacitors (http://www.supercapacitormaterials.com/)
Dr Ian Hamerton (University of Bristol) on polymeric materials (http://www.bristol.ac.uk/engineering/people/ian-hamerton/index.html)
Dr Daniel Meijles (St. George's, University of London) on anti-ageing drugs (https://www.sgul.ac.uk/research-profiles-a-z/daniel-n-meijles)
Postgraduate research supervision
Currently supervising a PhD student (Maryam Sairi, sponsored by the Malaysian Government) on predicting the char yield of Benzoxazines by QSPR. These materials are widely used as fire retardant coatings, so maximising the char yield is paramount.
Completed postgraduate research projects I have supervised
Lisa Mc Namara
Meqna Wan Hassan
Courses I teach on
The thermal decomposition of polyphenolic resins was studied by reactive molecular dynamics (RMD) simulation at elevated temperatures. Atomistic models of the polyphenolic resins to be used in the RMD were constructed using an automatic method which calls routines from the software package Materials Studio. In order to validate the models, simulated densities and heat capacities were compared with experimental values. The most suitable combination of force field and thermostat for this system was the Forcite force field with the Nosé–Hoover thermostat, which gave values of heat capacity closest to those of the experimental values. Simulated densities approached a final density of 1.05–1.08 g/cm3 which compared favorably with the experimental values of 1.16–1.21 g/cm3 for phenol-formaldehyde resins. The RMD calculations were run using LAMMPS software at temperatures of 1250 K and 3000 K using the ReaxFF force field and employing an in-house routine for removal of products of condensation. The species produced during RMD correlated with those found experimentally for polyphenolic systems and rearrangements to form cyclopropane moieties were observed. At the end of the RMD simulations a glassy carbon char resulted.
The DNA repair enzyme AAG has been shown in mice to promote tissue necrosis in response to ischaemic reperfusion or treatment with alkylating agents. A chemical probe inhibitor is required for investigations of the biological mechanism causing this phenomenon and as a lead for drugs that are potentially protective against tissue damage from organ failure and transplantation, and alkylative chemotherapy. Herein, we describe the rationale behind the choice of arylmethylpyrrolidines as appropriate aza-nucleoside mimics for an inhibitor followed by their synthesis and the first use of a microplate-based assay for quantification of their inhibition of AAG. We finally report the discovery of an imidazol-4-ylmethylpyrrolidine as a fragment-sized, weak inhibitor of AAG.
Three cyanate ester monomer or oligomer species: 2,2-bis(4-cyanatophenyl)propane 1, 1-1-bis(4-cyanatophenyl)ethane (2), and the oligomeric phenolic cyanate (PrimasetTM PT30) (3), are blended in various ratios with bis(4-maleimidophenyl)methane, (4), to form binary and ternary mixtures (11 in total) and cured, in the absence of catalysts (3 K/min to 150 °C + 1 hour; 3 K/min to 200 °C + 3 hours), followed by a post cure (3 K/min to 260 °C + 1 hour). The use of liquid monomer, (2), offers the possibility of liquid processing in blends containing minority compositions of bismaleimide. Glycidylmethacrylate is explored as a reactive diluent (2.5-10 wt %) to linked interpenetrating network polymer structures comprising cyanate ester and bismaleimide components with glass transition temperatures of 267-275 ºC, depending on composition; the onset of thermo-oxidative degradation ranges from 386-397 ºC. When a binary blend of (2) and (3) (with the former in the minority) is co-cured with (4), an excellent balance of properties is achieved with liquid processing, a Tg greater than 400 C and onset of degradation of 425 ºC in static air. Kinetic analysis of DSC data using Ozawa and Kissinger methods yield activation energies of between 107- 112 kJ/mole for a binary blend of (1)90-(4)10, which is in good agreement with literature. Molecular dynamics simulation of the same blend in cured form gave a simulated glass transition temperature of 250 C that is in very close agreement with empirical DMTA data.
Four structurally related ionic liquids (1-ethyl-3-methylimidazolium acetate, 1-ethyl-3-methylimidazolium diethyl phosphate, 1-ethyl-3-methylimidazolium dicyanamide, and 1-ethyl-3-methylimidazolium thiocyanate) are examined for their storage characteristics and its effect on their ability to initiate the cure of epoxy resins. At ambient temperature, epoxy formulations containing 1-ethyl-3-methylimidazolium acetate and 1-ethyl-3-methylimidazolium thiocyanate display marked colour changes to yield dark red samples with greatly increased viscosity after one day; after six days both samples have undergone vitrification. The epoxy formulation containing 1-ethyl-3-methylimidazolium acetate continued to polymerise even at sub-zero temperatures. Storage in dark bottles retarded the reaction during the 30-minute period that the sample is removed from the freezer prior to an aliquot being taken, but once the autocatalytic low temperature reaction has started, the dark glass no longer provides effective protection. Samples of 1-ethyl-3-methylimidazolium dicyanamide/epoxy were also stored and sampled in the same manner, but no differences were exhibited between the samples in clear and dark brown glass bottles. Infrared and nuclear magnetic resonance studies confirmed that the hygroscopic ionic liquids pick up water readily (coordinating to the H atom at the 2-position on the imidazolium ring), but once dried the initiating ability is lost.
A series of copoly(methoxy-thiocyanurate)s is prepared in good yield and purity, and fully characterised. Many of the resulting polymers, formed at room temperature using phase transfer catalysis, can be cast into films with good resilience and thermal stability (some examples suffer practically no mass loss when held isothermally at 190 °C and only display appreciable losses when held continuously at 225 °C). Char yields of 61-64% are achieved in nitrogen depending on backbone structure. Some problems were encountered with solubility, particularly with copolymers, which limited molecular weights analysis, but values of Mn = 7000-10,000 g mol-1 were obtained for the polycyanurate and polythiocyanurate homopolymers. DSC reveals polymerisation exotherms with maxima at 197-207 °C (ΔHp = 39-48 kJ/mol), which are believed to be due to isomerisation of the (activation energies span 172-205 kJ/mol), since X-ray powder diffraction measurements reveal no evidence of crystalline structure in the resulting product.
Modification of polymer properties by blending is a common practice in the polymer industry. We report here a study of blends of cyanurate polymers by molecular modelling that shows that the final experimentally determined properties can be predicted from first principles modelling to a good degree of accuracy. There is always a compromise between simulation length, accuracy and speed of prediction. A comparison of simulation times shows that 125ps of molecular dynamics simulation at each temperature provides the optimum compromise for models of this size with current technology. This study opens up the possibility of computer aided design of polymer blends with desired physical and mechanical properties.
The use of molecular simulation techniques in connection with structural polymers is now becoming more widely accepted and is employed as a legitimate way to not only visualize complex structures, but also to replicate empirically determined parameters. In this chapter, the authors present the state-of-the-art uses of molecular simulation (molecular mechanics and molecular dynamics) based on some 24 years of practical experience in the field.
In order to understand the structural basis of the observed properties of benzoxazine materials, the technique of quantitative structure-property relationships can be applied to sets of monomers or polymers and the understanding gained can then be used to design new monomers or polymers with the desired properties. In the chapter, this technique is applied to some datasets to predict char yield and glass transition temperature, and to illustrate that, despite the limited nature of the datasets currently available, useful predictions can be made.
Bisbenzoxazines form highly crosslinked, network structures with relatively high Tg (180oC+) and thermal oxidative stability but inherent brittleness (G1C = 168 J/m2) - limiting their applications. We have used synthetic polymer chemistry and molecular simulation to probe the structure/property relationships in model and commercial systems with the aim of understanding the factors governing toughness in these materials. Our previous experience, gained over 20 years, leads us to ensure that the molecular model represents as accurately as possible the real network, e.g. incorporating molecular defects derived from empirical data. We report the preparation and characterisation of selected bisbenzoxazine monomers chosen to exemplify both brittle and tough behaviour to provide a wide spectrum of mechanical characteristics and produce a wider understanding of the factors affecting brittleness. This enables us to design and execute the synthesis of new monomers with the potential for enhanced fracture toughness based on rational molecular design.
Three cyanate ester monomer or oligomer species: 2,2-bis(4-cyanatophenyl) propane 1, 1-1-bis(4-dicyanatophenyl)ethane 2, and the oligomeric phenolic cyanate (Primaset™ PT30) 3, are blended in various ratios to form binary mixtures, formulated with copper(II) acetylacetonate (200 ppm) in dodecylphenol (1% w/v active copper suspension) and cured (2 K/min to 150 °C + 1 h; 2 K/min to 200 °C + 3 h) followed by a post cure (2 K/min to 260 °C + 1 h). Thermal analysis using DSC reveals good agreement with literature data for the homopolymers: typical polymerisation enthalpies of ca. 97-98 kJ/mol. cyanate are obtained for 1 and 2, with slightly lower values (ca. 80-90 kJ/mol.) obtained for Primaset™ PT30. DMTA data show the possibility of using binary blends of the polymers to yield novel materials with similar thermal and mechanical properties to Primaset™ PT30, while improving the processability of the more highly aromatic oligomer. Two of the homopolymers (1 and 2) and a binary (1:1) blend of the same were simulated. Molecular dynamics experiments reveal good agreement with empirical data generated using DSC, DMTA and TGA. © 2012 Elsevier Ltd. All rights reserved.
Molecular simulation is becoming an important tool for both understanding polymeric structures and predicting their physical and mechanical properties. In this study, temperature ramped molecular dynamics simulations are used to predict two physical properties (i.e., glass transition temperature and thermal degradation temperature) of a previously synthesised and published telechelic benzoxazine. Plots of simulated density versus temperature show decreases in density within the same temperature range as experimental values for the thermal degradation. The predicted value for the thermal degradation temperature for the cured polybenzoxazine based on the telechelic polyetherketone (PEK) monomer was ca. 400°C, in line with the experimental thermal degradation temperature range of 450°C to 500°C. Mechanical Properties of both the unmodified PEK and the telechelic benzoxazines are simulated and compared to experimental values (where available). The introduction of the benoxazine moieties are predicted to increase the elastic moduli in line with the increase of crosslinking in the system.
A series of adducts were prepared based on the reaction of 1-ethyl-3-methylimidazolium acetate and benzal- dehyde in various stoichiometries (from equimolar reaction to benzaldehyde in 10-fold excess) and the resulting adducts were characterized using nuclear magnetic resonance spectroscopy (¹H, ¹³C, DEPT, and HQSC experi- ments). Differential scanning calorimetry was used to examine the initiating behaviour of the adducts towards mono- and di-functional epoxy resins and the data were used to determine kinetic parameters for the poly- merization. The lower temperature peak, due to carbene formation, is sensitive to adduct concentration; the residual ionic liquid in the adduct mixture contributes towards the initiation of the curing reaction. When a monofunctional epoxy and the 1:1 adduct was subjected to a 2-week period of storage at room temperature and sub-zero temperatures in the freezer, the profiles of the thermograms for the frozen samples do not change considerably over the storage period and the formulation retains a light yellow colour (rather than the viscous, dark red appearance of the formulation stored at room temperature).
This study uses the Molecular Operating Environment software (MOE) to generate models to calculate the char yield of polybenzoxazines (PBz). A series of benzoxazine (Bz) monomers were constructed to which a variety of parameters relating to the structure (e.g., water accessible surface, negative van der Waals surface area and hydrophobic volume, etc.) were obtained and a quantitative structure property relationships (QSPR) model was generated. The model was used to generate data for new Bz monomers with desired properties and a comparison was made of predictions based on the QSPR model with the experimental data. This study shows the quality of predictive models and confirms how useful computational screening is prior to synthesis.
The Molecular Operating Environment software (MOE) is used to construct a series of benzoxazine monomers for which a variety of parameters relating to the structures (e.g. water accessible surface area, negative van der Waals surface area, hydrophobic volume and the sum of atomic polarizabilities, etc.) are obtained and quantitative structure property relationships (QSPR) models are formulated. Three QSPR models (formulated using up to 5 descriptors) are first used to make predictions for the initiator data set (n = 9) and compared to published thermal data; in all of the QSPR models there is a high level of agreement between the actual data and the predicted data (within 0.63-1.86 K of the entire dataset). The water accessible surface area is found to be the most important descriptor in the prediction of T(g). Molecular modelling simulations of the benzoxazine polymer (minus initiator) carried out at the same time using the Materials Studio software suite provide an independent prediction of T(g). Predicted T(g) values from molecular modelling fall in the middle of the range of the experimentally determined T(g) values, indicating that the structure of the network is influenced by the nature of the initiator used. Hence both techniques can provide predictions of glass transition temperatures and provide complementary data for polymer design.
A series of bis-benzoxazines, prepared in high yield and purity using two synthetic procedures, is reported. Differential scanning calorimetry reveals similar temperatures for the onset of polymerisation (162-180 °C); the higher values representing monomers containing polar bridges or rigid backbones. Dynamic viscoelasticity data reveal glass transition temperatures for the polybenzoxazines ranging from 187 °C to 235 °C; a fluorinated polybenzoxazine consistently yields the highest T of the polymers studied. The latter is interesting since it is superior to many commercial benzoxazines with a relatively high T (235 °C), flexural modulus (5.0 GPa) and flexural strength (146.7 MPa), but coupled with a breaking strain (3.06%) that is uncharacteristically high for polybenzoxazines. The incorporation of fluorine results in a low dielectric loss properties (D = 3.71-4.12 at 10 MHz, D = 0.0109 - 0.0980 at 10 MHz), which are comparable with commercial polybenzoxazines, FR4 and aerospace epoxy resins and superior to commercial bismaleimides.
Updated models of the Rat Cytochrome P450 2D enzymes are produced based on the recent x-ray structures of the Human P450 2D6 enzyme both with and without a ligand bound. The differences in species selectivity between the epimers quinine and quinidine are rationalised using these models and the results are discussed with regard to previous studies. A close approach to the heme is not observed in this study. The x-ray structure of the enzyme with a ligand bound is shown to be a better model for explaining the observed experimental binding of quinine and quinidine. Hence models with larger closed binding sites are recommended for comparative docking studies. This is consistent with molecular recognition in Cytochrome P450 enzymes being the result of a number of non-specific interactions in a large binding site.
The aim of this chapter is to introduce the reader to the practical applications of modern molecular simulation techniques with literature examples drawn specifically from the field of polybenzoxazine research. The increases in computational power ensure that it is possible to apply molecular mechanics and molecular dynamics techniques to the visualisation and simulation of comparatively large model structures comprising in some cases more than six thousand atoms (constructed from a repeat unit containing ca. 250 atoms). This, in turn, offers the potential to replicate a variety of physical and mechanical characteristics with a high degree of accuracy and precision. However, the apparent ease with which modelling may be carried out using modern software is beguiling; the need to validate simulations with real, empirical data is essential to ensure that the researcher obtains meaningful results.
Phagocyte superoxide production by a multicomponent NADPH oxidase is important in host defense against microbial invasion. However inappropriate NADPH oxidase activation causes inflammation. Endothelial cells express NADPH oxidase and endothelial oxidative stress due to prolonged NADPH oxidase activation predisposes many diseases. Discovering the mechanism of NADPH oxidase activation is essential for developing novel treatment of these diseases. The p47(phox) is a key regulatory subunit of NADPH oxidase; however, due to the lack of full protein structural information, the mechanistic insight of p47(phox) phosphorylation in NADPH oxidase activation remains incomplete. Based on crystal structures of three functional domains, we generated a computational structural model of the full p47(phox) protein. Using a combination of in silico phosphorylation, molecular dynamics simulation and protein/protein docking, we discovered that the C-terminal tail of p47(phox) is critical for stabilizing its autoinhibited structure. Ser-379 phosphorylation disrupts H-bonds that link the C-terminal tail to the autoinhibitory region (AIR) and the tandem Src homology 3 (SH3) domains, allowing the AIR to undergo phosphorylation to expose the SH3 pocket for p22(phox) binding. These findings were confirmed by site-directed mutagenesis and gene transfection of p47(phox-/-) coronary microvascular cells. Compared with wild-type p47(phox) cDNA transfected cells, the single mutation of S379A completely blocked p47(phox) membrane translocation, binding to p22(phox) and endothelial O2 (⨪) production in response to acute stimulation of PKC. p47(phox) C-terminal tail plays a key role in stabilizing intramolecular interactions at rest. Ser-379 phosphorylation is a molecular switch which initiates p47(phox) conformational changes and NADPH oxidase-dependent superoxide production by cells.
The miscibility of the dicyanate of bisphenol A, with three dicyanate monomers, with aryl/alkylene ether backbones is studied at different compositions of a binary blend. Solubility parameters are calculated for dicyanate monomers and selected oligomers using the methods of Small and Fedors to predict compatibility. The results are evaluated in terms of the accuracy of the model in reproducing observed data. Gibbs free energy of mixing (ΔGmix) values for selected blends are calculated using the BLENDS module of Cerius2. Empirical data (HPLC and MS) are used to inform the construction of selected models to represent different stages of polymer conversion. DMTA analysis is performed to examine the thermo-mechanical properties of the resulting blends and compared with the simulated blend data.
For the first time we present nanoindentation analysis of charred, cured aromatic cyanate esters, which exhibit outstanding mechanical properties when analysed under applied loads of 0.1–300 mN. Following charring (900 C for 10 minutes to achieve graphitised structures), the samples display a remarkable combination of a modulus of elasticity of around 25 GPa and nanohardness of 300 kgf mm2, making them some 30–40% stiffer than bone and practically as hard as tooth enamel. At the same time we find that under the same conditions the chars are highly resilient, displaying complete elastic recovery with very little plastic deformation. When cured in the presence of copper(II) acetylacetonate (200 ppm) in dodecylphenol (1% w/v active copper suspension) to form a polycyanurate, compound (2) forms a dense, consolidated structure compared with compound (1) under the same conditions. At high magnification, the presence of a nanoscale, fibrillar structure is observed, accounting for the high resilience.
A commercial diglycidyl ether of bisphenol A monomer (Baxxores™ ER 2200, eew 182 g/mole, DGEBA) is thermally polymerized in the presence of an ionic liquid, 1-ethyl-3-methylimidazolium acetate at a variety of loadings (5–45 wt %). The loss modulus data for cured samples, containing 5 wt % initiator, display at least two thermal transitions and the highest storage modulus occurs in the sample that has been cured for the shortest time at the lowest temperature. Samples that are exposed to higher temperatures (140, 150 °C) yield more heterogenous networks, whereas following exposure to a much shorter/lower temperature cure schedule (80 °C) exhibits a considerably higher damping ability than the other samples, coupled with a lower glass transition temperature. Differential scanning calorimetry reveals that the latter sample achieves a conversion of 95%, while crosslink densities for the DGEBA samples containing 5 wt % and 15 wt % are respectively 9.5 × 10-3 mol. dm-3 and 1.2 × 10-3 mol. dm-3 (when cured to 80 °C) and 2.0 × 10-2 mol. dm-3 and 2.4 × 10-3 mol. dm-3 (when cured to 140 °C).
The reaction of phenyl glycidyl ether (PGE) with 1-ethyl-3-methylimidazolium acetate and 1-ethyl-3-methylimidazolium thiocyanate to initiate the polyetherification reaction was examined using thermal and spectral analysis techniques. The influence of the nucleophilicity of the anions on the deprotonation of the 1-ethyl-3-methylimidazolium cation determined the reaction pathway. The thermal degradation of the ionic liquid liberated the acetate ion and led, subsequently, to the deprotonation of the acidic proton in the imidazole ring. Thus, polymerisation of PGE occurred via a carbene intermediate. The more nucleophilic thiocyanate anion was not sufficiently basic to deprotonate the 1-ethyl-3-methylimidazolium cation, and thus proceeded through direct reaction with the PGE, unless the temperature was elevated and a competing carbene mechanism ensued.
A series of reactive blends, comprising a commercial benzoxazine monomer, 2,2-bis(3,4-dihydro-3-phenyl-2H-1,3-benzoxazine)propane, and bisphenol A is prepared and characterized. Thermal analysis and dynamic rheology reveal how the introduction of up to 15 wt % bisphenol A lead to a significant increase in reactivity (the exothermic peak maximum of thermal polymerization is reduced from 245 °C to 215 °C), with a small penalty in glass transition temperature (reduction of 15 K), but similar thermal stability (onset of degradation = 283 °C, char yield = 26%). With higher concentrations of bisphenol A (e.g. 25 wt %), a significantly more reactive blend is produced (exothermic peak maximum = 192 °C), but with a significantly lower thermal stability (onset of degradation = 265 °C, char yield = 22%) and glass transition temperature (128 °C). Attempts to produce a cured plaque containing 35 wt % bisphenol A were unsuccessful, due to brittleness. Molecular modelling is used to replicate successfully the glass transition temperatures (measured using thermal analysis) of a range of copolymers.
A series of commercial difunctional benzoxazine monomers are characterised carefully using thermal and thermo-mechanical techniques before constructing representative polymer networks using molecular simulation techniques. Good agreement is obtained between replicate analyses and for the kinetic parameters obtained from differential scanning calorimetry data (and determined using the methods of Kissinger and Ozawa). Activation energies range from 85-108 kJ/mol (Kissinger) and 89-110 kJ/mol (Ozawa) for the uncatalysed thermal polymerisation reactions, which achieve conversions of 85-97 %. Glass transition temperatures determined from differential scanning calorimetry and dynamic mechanical thermal analysis are coomparable, ranging from BA-a (151 °C, crosslink density 3.6 x 10-3 mol cm-3) containing the bisphenol A moiety to BP-a, based on a phenolphthalein bridge (239-256 °C, crosslink density 5.5-18.4 x 10-3 mol cm-3, depending on formulation). Molecular dynamics simulations of the polybenzoxazines generally agree well with empirical data, indicating that representative networks have been modelled.
A recyclable mercury (II) selective dimer based on a calixpyrrole derivative has been synthesised and characterised by Mass and FT- IR Spectrometry, Scanning Electron Microscopy (SEM) and Energy Dispersive X-ray (EDX). Information regarding the ability of the dimer to interact with metal cations was obtained from FTIR and SEM-EDX analyses. A striking feature of micrographs of the loaded dimer is the change of morphology with the cation. Based on these results, optimal conditions for removing cations from water were assessed under different experimental conditions. Results obtained demonstrate that the removal process is fast. Capacity values and selectivity factors show that the dimer is selective for Hg(II) in one and in multiple component metal solutions relative to other cations. Single-ion transfer Gibbs energies from water to a solvent containing common functionalities to those of the dimer were used to assess the counter-ion effect on the removal process. Agreement is found between these data and energy calculations derived from Molecular Simulation studies. Studies on polluted water in the presence of normal water components in addition to toxic metal cations are reported. Further experimental work on wastewater from the mining industry is in progress.
The effect of heating rate (2, 8 and 15 K min-1) during the initial stages of cure of 2,2-bis(3,4-dihydro-3- phenyl-2H-1,3-benzoxazine)propane is examined. The rate of heating has a marked effect on the observed modulus, measured by DMTA, with the higher heating rate giving rise to an increase in storage modulus of ca. 1000 MPa, although this is not accompanied by an increase in glass transition temperature. The thermal stability of the resulting polybenzoxazines also differs with the slower heating rate giving rise to less thermally stable structures. Data obtained from Raman spectroscopy (when combined with principal components analysis) suggest subtle changes in the mechanism during the early stages of reaction associated C–N–C and C–O moieties, some of which persist following a higher temperature postcure step leading to a crosslinked network with higher aliphatic character.
Medicinal chemistry has in the past been dominated by learned insights from experienced organic chemists. However, with the advent of computer based methods, computer aided drug design has become prominent. We have compared here the ability of locally sourced expert medicinal chemists to purely automated methods and found that the automated method produces a better potential candidate drug than the expert input. The example chosen is based on inhibitors to Abl-kinase and the successful anti-leukaemic drug imatinib. The proposed molecule is a simple modification of nilotinib and has a docking energy of 4.2 kJ/mol better than the best intuitive molecule.
A new partially substituted calix pyrrole derivative obtained by the introduction of three thioamide functionalities in the N-rim has been synthesised and fully characterised by 1H,13C, HSQC, ROESY NMR and mass spectroscopy. Computer modelling suggested an alternate conformation which was confirmed through ROESY 1H NMR. The receptor interacts only with the silver cation as shown by 1H NMR. The strength of interaction is quantitatively assessed by titration calorimetry. N-rim modification eliminates the possibility of interaction with anions. Unlike calix pyrrole derivatives obtained by the introduction of functionalities through the meso-position, addition of Hg(NO3)2 leads to the degeneration of the receptor as demonstrated by 1H NMR, FTIR and XPS analyses. This is for the first time reported. Molecular simulation studies show significant strain in the mercury bound ligand in bonds, angles, torsions leading to the destruction of the receptor. Given the negative environmental impact produced by the availability of silver ions in aquatic organisms, the fundamental studies indicate that this receptor offers potential applications for monitoring silver (ion selective electrode) or indeed as a decontaminating material for removing silver ions from water.
Molecular Operating Environment (MOE) software has great potential when combined with the Quantitative Structure-Property Relationship (QSPR) approach, and was proven to be useful to make good prediction models for series of polybenzoxazines [1–3]. However, the effect of heterogeneities in the crosslinked network to the prediction accuracy is yet to be tested. It was found that polybenzoxazines with polymerisable functional group (e.g. acetylene-based benzoxazines) form up to 40% higher char yield compared to their analogue polybenzoxazines due to the contribution of the polymerisable functional group (e.g. ethynyl triple bond) in the cross-linked network. In order to investigate the effect of the inconsistent cross-linking network, a data set consisting of thirty-three benzoxazines containing various structures of benzoxazines was subdivided into two smaller data sets based on their functional group, either benzoxazines with polymerisable functional group (acetylene-based benzoxazines set (Ace-M)) or non-polymerisable functional group (aniline-based benzoxazines (Ani-M)). Char yield predictions for the polybenzoxazines for these data sets (Ace-M and Ani-M) were compared with the larger thirty-three polybenzoxazines data set (GM) to investigate the effect of the inconsistency in crosslink network on the quality of prediction afforded by the model. Prediction performed by Ace-M and Ani-M were found to be more accurate when compared with the GM with total prediction error of 3.15% from both models compared to the GM (4.81%). Ace-M and Ani-M are each better at predicting the char yields of similar polybenzoxazines (i.e. one model is specific for a polymerisable functional group; the other for non-polymerisable functional group), but GM is more practical as it has greater ‘general’ utility and is applicable to numerous structures. The error shown by GM is considerably small and therefore it is still a good option for prediction and should not be underestimated.
Molecular simulation is used to probe the structure property relationships displayed by polysulphone (PS) and polyethersulphone (PES) and reproduces closely the temperatures at which thermal degradation occurs (and the glass transition temperatures). Both data sets agree well with those obtained empirically using TGA. The examination of the thermal and thermo-oxidative stability of thermoplastic oligomers (M = 5454-33,866 g mol , PDI 1.33-1.82) based on PS, PES, polyetherimide (PEI) and poly(amide-imide) (PAI), is reported. TGA reveals the least thermally stable polymer is PES (T = ∼250 °C), while PAI (T = ∼350 °C) is the highest: the materials usually display two-step decomposition patterns: scission of bridging group and degradation of backbone structure. A possible mechanism for the degradation of a PAI is proposed on the basis of the empirical and simulation data. This work provides a general method for the prediction of the thermal stability of oligomeric modifiers (and high molecular weight polymers). © 2013 Elsevier Ltd. All rights reserved.
The synthesis and characterisation of a partially substituted calixarene, namely, 5,11,17,23- tetra-tert-butyl,25,27-bis[aminoethoxy] 26,28-dihydroxycalixarene are reported. Its interaction with commonly used pharmaceuticals (clofibric acid, diclofenac and aspirin) was investigated by spectroscopic (1 H NMR and UV), electrochemical (conductance measurements) and thermal (titration calorimetry) techniques. It is concluded on the basis of the experimental work and molecular simulation studies that the receptor interacts selectively with these drugs. Preliminary studies on the selective extraction of these pharmaceuticals from water by the calix receptor are reported and the potential for a carrier mediated sensor based on this ligand for ‘on site’ monitoring of pharmaceuticals is discussed.
Two series of terpoly(methoxy-cyanurate-thiocyanurate)s based on thiodiphenol and dithiodiphenyl sulphide, and dihydroxydiphenylether and dithiodiphenyl ether, are prepared in good yield and purity, and fully characterised. Most of the resulting polymers, formed at room temperature using phase transfer catalysis, can be cast into films with good resilience and thermal stability. Two series of terpoly(methoxy-cyanurate-thiocyanurate)s based on thiodiphenol and dithiodiphenyl sulfide and on dihydroxydiphenyl ether and dithiodiphenyl ether, were prepared in good yield and purity and fully characterized. Most of the resulting polymers, formed at room temperature using phase transfer catalysis, can be cast into films with good resilience and thermal stability (some examples suffer practically no mass loss when held isothermally at 190 °C and only display appreciable losses when held continuously at 225 °C). Char yields of 53%-61% are achieved in nitrogen depending on backbone structure. Some problems were encountered with solubility, particularly with copolymers, which limited molecular weight analysis, but values of Mn = 8000-13000 g mol-1 were obtained for the polymers based on thiodiphenol and dithiodiphenyl sulfide, and Mn = 5000-13000 g mol-1 for the polymers based on dihydroxydiphenyl ether and dithiodiphenyl ether. DSC reveals polymerization exotherms with maxima at 184-207 °C (ΔHp = 43-59 kJ mol-1), which are believed to be due to isomerization of the cyanurate to the isocyanurate (activation energies span 159-195 kJ mol-1). Molecular simulation shows that diphenylether and diphenylsulfide display very similar conformational energy surfaces and would therefore be expected to adopt similar conformations, but the diphenylsulfide offers less resistance to deformations that increase the proximity of the two phenyl rings and results in more resilient films. © 2013 Society of Chemical Industry.
Three bis-benzoxazine monomers based on the aniline derivatives of bisphenol A (BA-a), bisphenol F (BF-a), and 3,3'-thiodiphenol (BT-a) are examined using a variety of spectroscopic, chromatographic, and thermomechanical techniques. The effect on the polymerization of the monomers is compared using two common compounds, 3,3'-thiodiphenol (TDP) and 3,3'-thiodipropionic acid (TDA), at a variety of loadings. It is found that the diacid has a greater effect on reducing the onset of polymerization and increasing cross-link density and T g for a given benzoxazine. However, the addition of >5 wt % of the diacid had a detrimental effect on the cross-link density, T g, and thermal stability of the polymer. The kinetics of the polymerization of BA-a were found to be well described using an autocatalytic model for which values of n = 1.64 and m = 2.31 were obtained for the early and later stages of reaction (activation energy = 81 kJ/mol). Following recrystallization the same monomer yielded values n = 1.89, m = 0.89, and E a = 94 kJ/mol (confirming the influence of higher oligomers on reactivity). The choice of additive (in particular the magnitude of its pK a) appears to influence the nature of the network formation from a linear toward a more clusterlike growth mechanism.
Despite their inability to model bond breaking molecular dynamics simulations are shown to predict thermal degradation temperatures of polycyanurate (cyanate ester) homopolymers and nanocomposites in very close agreement with experimental data. Simulated polymer density, used to predict T also shows a reduction within the same temperature range as experimental values for the thermal degradation. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
The preparation of a series of oligomeric engineering thermoplastics (PS, PES, PEI and PAI) is reported. H and C NMR and FT-IR/ATR spectroscopic techniques are combined to determine the chemical structure of the synthetic polymers, which are produced in good yield and purity. GPC measurements show the weight average molecular weight (M ) of the synthesised thermoplastics fall in the range 5454-33,866 g mol and display polydispersity indices in the range 1.33-1.82. Glass transition temperatures (T) values measured by DSC, occur between 107 and 257 °C and fall in the pattern PS < PES < PEI < PAI. Molecular simulation is used to probe the structure property relationships displayed by PS and PES and reproduces the elastic properties of PS well within the range of the literature; while the values of PES are less well reproduced. The simulated T values of both oligomers agree well with those obtained empirically using DSC. © 2014 Elsevier Ltd. All rights reserved.
The mechanism of reaction between 1-ethyl-3-methylimidazolium acetate and the difunctional diglycidyl ether of bisphenol A (DGEBA) is explored using thermal and spectroscopic methods. Investigation of the 1,3-dialkylimidazolium based ionic liquids comprising the common cation (1-ethyl-3-methylimidazolium) and different anions (acetate, diethyl phosphate, dicyanamide or thiocyanate) via thermogravimetric analysis revealed 1-ethyl-3-methylimidazolium acetate to be the least thermally stable, both in air and nitrogen, and 1-ethyl-3-methylimidazolium dicyanamide to be the most thermally stable. Dynamic differential scanning calorimetry reveals the formulations comprising DGEBA and ionic liquid where it was revealed that the lowest and highest temperature for the onset of reaction were observed for formulations with 1-ethyl-3-methylimidazolium acetate and 1-ethyl-3-methylimidazolium dicyanamide respectively. 1-Ethyl-3-methylimidazolium acetate was shown, via nuclear magnetic resonance (NMR) spectroscopy and residual gas analysis, to degrade at 150 °C to yield dealkylated products including methyl acetate and ethyl acetate as well as 1-methylimidazole and 1- ethylimidazole. The dealkylated imidazole ring is proposed as a route for initiation of the epoxy ring. Adduct formation between 1-ethyl-3-methylimidazoloium acetate and benzaldehyde at room temperature was observed leading to the proposal of the generation of a carbene species as a route for initiation of the epoxy ring in formulations with the acetate anion. NMR analysis of formulations comprising 1-ethyl-3-methylimidazolium thiocyanate and epoxy are believed, at room temperature, to initiate via reaction of the thiocyanate anion with the epoxy ring.At elevated temperatures, it is proposed that a second, competing reaction, involving deprotonation of the imidazolium ring, also becomes active. The three proposed reaction pathways, namely the carbene route, the imidazole route and the counter-ion route, are all proposed to occur when an ionic liquid is used to initiate an epoxy resin.
The p22phox is a key component of the cytochrome b558 of the NADPH oxidase (Nox), which by generating reactive oxygen species (ROS) is involved in the pathogenesis of cardiovascular disease. A p22phox polymorphism (C242T) has been found to reduce oxidative stress in the cardiovascular system and is negatively associated with the incidence of coronary heart disease (CHD). However, the mechanism involved remains unknown. In this study we used computer molecular modelling and bioinformatics to investigate the potential effect of C242T polymorphism on the 3-D protein structure of the p22phox. Based on the published sequence data of p22phox and the principle of regulated prediction algorithms, we found that p22phox consists of two domains: an N-terminal transmembrane domain (124 a.a.) and a C-terminal cytoplasmic domain (71 a.a.). In its most stable form, it has three e26 Heart September 2010 Vol 96 No 17 BSCR Spring 2010 Meeting Abstracts Downloaded from heart.bmj.com on January 31, 2012 - Published by group.bmj.com transmembrane helices leading to an extracellular N-terminus and an extracellular loop between helices two and three. The C242T polymorphism causes a change of His72 to Tyr72. This change results in significant morphological changes of the extracellular loop of the p22phox, which is in the putative interactive region of the p22phox with the catalytic subunit (Nox2). This may interfere with their association, and subsequently result in a reduced cytochrome b function and a reduced ROS production by NADPH oxidase. These results give us insight into the molecular mechanism of this polymorphism in reducing vascular oxidative stress and may explain how this polymorphism is linked with reduced incidence of CHD.
The p22phox is a key component of the cytochrome b558 of the NADPH oxidase (Nox), which by generating reactive oxygen species (ROS) is involved in the pathogenesis of cardiovascular disease. A p22phox polymorphism (C242T) has been found to reduce oxidative stress in the cardiovascular system and is negatively associated with the incidence of coronary heart disease (CHD). However, the mechanism involved remains unknown. In this study we used computer molecular modelling and bioinformatics to investigate the potential effect of C242T polymorphism on the 3-D protein structure of the p22phox. Based on the published sequence data of p22phox and the principle of regulated prediction algorithms, we found that p22phox consists of two domains: an N-terminal transmembrane domain (124 a.a.) and a C-terminal cytoplasmic domain (71 a.a.). In its most stable form, it has three transmembrane helices leading to an extracellular N-terminus and an extracellular loop between helices two and three. The C242T polymorphism causes a change of His72 to Tyr72. This change results in signifi cant morphological changes of the extracellular loop of the p22phox which is in the putative interactive region of the p22phox with the catalytic subunit (Nox2). This may interfere with their association, and subsequently result in a reduced cytochrome b function and a reduced ROS production by NADPH oxidase. These results give us insight into the molecular mechanism of this polymorphism in reducing vascular oxidative stress and may explain how this polymorphism is linked with reduced incidence of CHD.
Wet processes of phosphoric acids produce untreated wastewater containing large amounts of fluoride leading to serious environmental problems. This paper reports fundamental studies on two lower rim functionalised calixarene based receptors namely 5, 11, 17, 23 tetra-tert-butyl, 25, 27 bis [diethylphenylurea]ethoxy, 26, 28 dihydroxycalixarene, 1 and 25, 27 bis[diethylphenylurea]ethoxy, 26, 28 dihydroxycalixarene, 2 and their ionic interactions. It is shown that these receptors only interact with fluoride and phosphate in acetonitrile. Their receptive properties are higher for phosphate (2:1 anion:receptor complex) relative to fluoride (1:1 complex).However thermodynamics shows that these receptors are more selective for fluoride relative to phosphate in the formation of the 1:1 complex. The pathway from fundamental studies to the use of these receptors for removing these anions from water has been tested. The receptive properties of 1 for phosphate are held when the extraction involves aqueous solutions containing individual ions. However in mixtures containing both anions, the kinetics of the process and the selectivity of 1 for fluoride predominate and as a result, fluoride is better extracted than phosphate. The counter-ion effect on the removal process is assessed from Molecular Simulation studies. The removal of fluoride from phosphate is discussed taking into account existing technologies.
The technique of Quantitative Structure Property Relationships has been applied to the glass transition temperatures of polyarylethersulphones. A general equation is reported that calculates the glass transition temperatures with acceptable accuracy (correlation coefficients of between 90–67%, indicating an error of 10–30% with regard to experimentally determined values) for a series of 42 reported polyarylethersulphones. This method is quite simple in assumption and relies on a relatively small number of parameters associated with the structural unit of the polymer: the number of rotatable bonds, the dipole moment, the heat of formation, the HOMO eigenvalue, the molar mass and molar volume. For smaller subsets of the main group (based on families of derivatives containing different substituents) the model can be simplified further to an equation that uses the volume of the substituents as the principal variable.
Background—T NADPH oxidase, by generating reactive oxygen species, is involved in the pathophysiology of many cardiovascular diseases and represents a therapeutic target for the development of novel drugs. A single-nucleotide polymorphism (SNP) C242T of the p22phox subunit of NADPH oxidase has been reported to be negatively associated with coronary heart disease (CHD) and may predict disease prevalence. However, the underlying mechanisms remain unknown. Methods and Results—Using computer molecular modelling we discovered that C242T SNP causes significant structural changes in the extracellular loop of p22phox and reduces its interaction stability with Nox2 subunit. Gene transfection of human pulmonary microvascular endothelial cells showed that C242T p22phox reduced significantly Nox2 expression but had no significant effect on basal endothelial O2 .- production or the expression of Nox1 and Nox4. When cells were stimulated with TNFĮ (or high glucose), C242T p22phox inhibited significantly TNFĮ- induced Nox2 maturation, O2 .- production, MAPK and NFțB activation and inflammation (all p
Materials science is beginning to adopt computational simulation to eliminate laboratory trial and error campaigns—much like the pharmaceutical industry of 40 years ago. To further computational materials discovery, new methodology must be developed that enables rapid and accurate testing on accessible computational hardware. To this end, the authors utilise a novel methodology concept of intermediate molecules as a starting point, for which they propose the term ‘symthon’a rather than conventional monomers. The use of symthons eliminates the initial monomer bonding phase, reducing the number of iterations required in the simulation, thereby reducing the runtime. A novel approach to molecular dynamics, with an NVT (Canonical) ensemble and variable unit cell geometry, was used to generate structures with differing physical and thermal properties. Additional script methods were designed and tested, which enabled a high degree of cure in all sampled structures. This simulation has been trialled on large-scale atomistic models of phenolic resins, based on a range of stoichiometric ratios of formaldehyde and phenol. Density and glass transition temperature values were produced, and found to be in good agreement with empirical data and other simulated values in the literature. The runtime of the simulation was a key consideration in script design; cured models can be produced in under 24 h on modest hardware. The use of symthons has been shown as a viable methodology to reduce simulation runtime whilst generating accurate models.
The construction of molecular models of crosslinked polymers is an area of some difficulty and considerable interest. We report here a new method of constructing these models and validate the method by modelling three epoxy systems based on the epoxy monomers bisphenol F diglycidyl ether (BFDGE) and triglycidyl-p-amino phenol (TGAP) with the curing agent diamino diphenyl sulphone (DDS). The main emphasis of the work concerns the improvement of the techniques for the molecular simulation of these epoxies and specific attention is paid towards model construction techniques, including automated model building and prediction of glass transition temperatures (T(g)). Typical models comprise some 4200-4600 atoms (ca. 120-130 monomers). In a parallel empirical study, these systems have been cast, cured and analysed by dynamic mechanical thermal analysis (DMTA) to measure T(g). Results for the three epoxy systems yield good agreement with experimental T(g) ranges of 200-220°C, 270-285°C and 285-290°C with corresponding simulated ranges of 210-230°C, 250-300°C, and 250-300°C respectively.
The crystal structure of a commercially available form of human recombinant (HR) insulin, Insugen (I), used in the treatment of diabetes has been determined to 0.92 Å resolution using low temperature, 100 K, synchrotron X-ray data collected at 16,000 keV (λ = 0.77 Å). Refinement carried out with anisotropic displacement parameters, removal of main-chain stereochemical restraints, inclusion of H atoms in calculated positions, and 220 water molecules, converged to a final value of R = 0.1112 and Rfree = 0.1466. The structure includes what is thought to be an ordered propanol molecule (POL) only in chain D(4) and a solvated acetate molecule (ACT) coordinated to the Zn atom only in chain B(2). Possible origins and consequences of the propanol and acetate molecules are discussed. Three types of amino acid representation in the electron density are examined in detail: (i) sharp with very clearly resolved features; (ii) well resolved but clearly divided into two conformations which are well behaved in the refinement, both having high quality geometry; (iii) poor density and difficult or impossible to model. An example of type (ii) is observed for the intra-chain disulphide bridge in chain C(3) between Sγ6–Sγ11 which has two clear conformations with relative refined occupancies of 0.8 and 0.2, respectively. In contrast the corresponding S–S bridge in chain A(1) shows one clearly defined conformation. A molecular dynamics study has provided a rational explanation of this difference between chains A and C. More generally, differences in the electron density features between corresponding residues in chains A and C and chains B and D is a common observation in the Insugen (I) structure and these effects are discussed in detail. The crystal structure, also at 0.92 Å and 100 K, of a second commercially available form of human recombinant insulin, Intergen (II), deposited in the Protein Data Bank as 3W7Y which remains otherwise unpublished is compared here with the Insugen (I) structure. In the Intergen (II) structure there is no solvated propanol or acetate molecule. The electron density of Intergen (II), however, does also exhibit the three types of amino acid representations as in Insugen (I). These effects do not necessarily correspond between chains A and C or chains B and D in Intergen (II), or between corresponding residues in Insugen (I). The results of this comparison are reported.
The degradation behaviour of five polybenzoxazines (PBZs) is studied using pyrolysis-GC/MS. Upon heating to 800 °C in helium the PBZs generate a variety of similar pyrolysis products including aniline (the major product in all cases), substituted phenols, acridine, and 9-vinylcarbazole. During the initial stages of heating (200–300 °C) aniline is the dominant pyrolysis product; from 350 °C onwards substituted phenols are released, particularly 2-methylphenol and 2,6-dimethyl phenol. The same major species are produced on heating in air, but in addition isocyanatobenzene is observed which results from the oxidation of Mannich bridges, along with a number of sulphurous species from the monomer containing a thioether bridge. This suggests that sulphur is more likely to be retained in the char in a helium atmosphere, but takes part in oxidative reactions to form pyrolysis fragments in air. During the ramped temperature cycles in both air and helium atmospheres the release of aniline was observed to rise, fall and then to rise again. This may be due a combination of the very high heating rate, poor thermal conduction of the polymer and the availability of the Mannich bridges to undergo breakdown.
Simple molecular docking calculations on quercetin, kojic acid and diethylcarbamatodithoic acid using the software package MOE are shown to be close to the geometries reported in the X-ray crystal structures of the protein co-crystallised with the respective ligands. Furthermore DFT optimization of the docked conformations is shown to reproduce the essential features of previous studies on quercetin, showing that docking can be used to provide good starting structures for mechanistic study. The flavone ligand, lacking the hydroxyl group of the quercetin is shown by docking to be unable to approach closely the copper atom, indicating the necessity of the presence of the hydroxyl group and providing a prediction of the likely binding environment of this ligand.
Three cyanate ester monomer or oligomer species: 2,2-bis(4-cyanatophenyl)propane 1, 1-1-bis(4-dicyanatophenyl)ethane 2, and the oligomeric phenolic cyanate 3, are blended in various ratios to form binary mixtures (18 in total), formulated with copper(II) acetylacetonate (200 ppm) in dodecylphenol (1 % w/v active copper suspension) and cured (3 Kmin-1 to 150 °C + 1 hour; 3 Kmin-1 to 200 °C + 3 hours) followed by a post cure (3 Kmin-1 to 260 °C + 1 hour). Cured copolymers were exposed to environments of elevated relative humidity (75 % RH) and parallel immersion testing in H2O, H2SO4 (10 %) and NaOH (10 %) at 25 °C for a period of up to 2 years and accelerated ageing in boiling water (14 days). Periodic measurements are made of moisture gain along with infrared spectra and compared with cured homopolymers. Changes in mass are recorded periodically throughout exposure, prior to destructive thermo-mechanical analyses. Dynamic mechanical thermal analysis data comparing neat and exposed blends demonstrate the detrimental effect of moisture ingress whilst data from thermogravimetric analysis demonstrate no change in degradation onset between neat and exposed materials. An optimised blend of 1:1 of monomer units 1 and 2 was found to absorb less moisture than blends of different stoichiometry or between other respective monomeric units, consequently limiting the deleterious effect of moisture ingress.
Bi- and tri-aromatic compounds of the formula (I) wherein R1 to RIO and X are as defined, are Nox2 inhibitors that are useful as medicaments for the treatment of a disease or condition selected from: cardiovascular diseases, respiratory diseases, inflammatory diseases, cancers, ageing and age related disorders, kidney diseases, neurodegenerative diseases, diabetes and conditions associated with diabetes. The compounds, their preparation and pharmaceutical compositions comprising them are disclosed.