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 TNF. (or high glucose), C242T p22phox inhibited significantly TNF.- induced Nox2 maturation, O2 .- production, MAPK and NF?B activation and inflammation (all p
Howlin BJ, li JM, meijles D BI-AROMATIC AND TRI-AROMATIC COMPOUNDS AS NADPH OXIDASE 2 (Nox2) INHIBITORS, PCT/GB2012/000725
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.
Barakzaia KND, Howlin BJ, Lockley WJS, Sfyrakis K (2009) Analysis of labelled compounds by mass spectroscopy in the presence of heavy isotopes at natural abundance: the NAIC program, JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS 52 (13-14) pp. 559-562 JOHN WILEY & SONS LTD
2,2-Bis(3,4-dihydro-3-phenyl-2H-1,3-benzoxazine)propane (BA-a) is blended with oligomers of polyarylsulfone (PSU) and polyarylethersulfone (PES) of different low/intermediate molecular weights (3000-12 000 g mol-1) and terminal functionality (chloro-, hydroxyl- or benzoxazinyl- (Bz)). Fracture toughness (KIC) is observed to increase from 0.8 MPa m0.5 for cured BA-a to 1 MPa m0.5 with the incorporation of 10 wt % PSU-Bz (12 000 g mol-1). Generally, greater improvements in KIC are observed for the PES oligomers compared with the PSU oligomers of equivalent molecular weight. The terminal functionality of the thermoplastic has a lesser effect on improving toughness than increasing the molecular weight or the nature of the polymer backbone. Surface analysis of the fractured surfaces show greater phase separation and crack pinning in the PES toughened system. Where crack pinning is less obvious, as in the case of hydroxyl-terminated PES (of 6000 g mol-1), this coincides with a drop in fracture toughness. © 2014 American Chemical Society.
Lockley WJS, Sfyrakis K, Howlin BJ, Jones JR, Wilkinson DJ (2007) Some IT and data processing applications for H-2, H-3, C-11, C-13 and C-14-labelling, JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS 50 (5-6) pp. 532-534 JOHN WILEY & SONS LTD
Hamerton I, McNamara LT, Howlin BJ, Smith PA, Cross P, Ward S (2014) Kinetics and cure mechanism in aromatic polybenzoxazines modified using thermoplastic oligomers and telechelics, Macromolecules 47 (6) pp. 1935-1945
A series of blends is prepared comprising 2,2-bis(3,4-dihydro-3-phenyl-2H- 1,3-benzoxazine)propane (BA-a) with variously 5, 10, or 20 wt % of a selected oligomer represented by poly(arylsulfone) (PSU) or poly(arylethersulfone) (PES). The oligomers, comprising either chloro-, hydroxyl- or benzoxazinyl- (Bz) terminal functionality, are of low molecular weight (3000-12000 g mol -1). The introduction of the oligomers is shown to initiate the polymerization of a bisbenzoxazine monomer where the terminal functionality of the oligomer is coreactive (e.g., hydroxyl or benzoxazine) without having a detrimental effect on the polymerization kinetics (similar values for the activation energy and orders of reaction are obtained). The introduction of the nonreactive chloro-terminated oligomer appears to favor the formation of an interpenetrating network (IPN) with a higher energy of activation. The thermal stability of the blends is generally increased compared with the polybenzoxazine homopolymer, regardless of the molecular weight or thermoplastic loading. Aside from the aforementioned PSUCl-containing IPN, the nature of the resulting network is slightly modified by the addition of the thermoplastic with similar or slightly elevated cross-link densities recorded (compared with the polybenzoxazine homopolymer). The heterogeneity of the network increases with a broadening of the tan ´ response, suggesting an improvement in the toughness of the resulting blend. © 2014 American Chemical Society.
Background: A new algorithm has been developed to enable the interpretation of black box models. The developed algorithm is agnostic to learning algorithm and open to all structural based descriptors such as fragments, keys and hashed fingerprints. The algorithm has provided meaningful interpretation of Ames mutagenicity predictions from both random forest and support vector machine models built on a variety of structural fingerprints.A fragmentation algorithm is utilised to investigate the model's behaviour on specific substructures present in the query. An output is formulated summarising causes of activation and deactivation. The algorithm is able to identify multiple causes of activation or deactivation in addition to identifying localised deactivations where the prediction for the query is active overall. No loss in performance is seen as there is no change in the prediction; the interpretation is produced directly on the model's behaviour for the specific query. Results: Models have been built using multiple learning algorithms including support vector machine and random forest. The models were built on public Ames mutagenicity data and a variety of fingerprint descriptors were used. These models produced a good performance in both internal and external validation with accuracies around 82%. The models were used to evaluate the interpretation algorithm. Interpretation was revealed that links closely with understood mechanisms for Ames mutagenicity. Conclusion: This methodology allows for a greater utilisation of the predictions made by black box models and can expedite further study based on the output for a (quantitative) structure activity model. Additionally the algorithm could be utilised for chemical dataset investigation and knowledge extraction/human SAR development. © 2014 Webb et al.; licensee Chemistry Central Ltd.
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.
Hamerton I, McNamara LT, Howlin BJ, Smith PA, Cross P, Ward S (2013) Examining the Initiation of the Polymerization Mechanism and Network Development in Aromatic Polybenzoxazines., Macromolecules 46 (13) pp. 5117-5132
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.
Hamerton I, Howlin BJ, Tilbrook DA (2013) Examining structure property relationships in coatings based on substituted linear aromatic polycyanurates, REACTIVE & FUNCTIONAL POLYMERS 73 (8) pp. 1046-1057 ELSEVIER SCIENCE BV
Hamerton I, Howlin BJ, Mitchell AL (2006) Developing poly(bis-benzoxazines) with improved fracture toughness. 1: Using molecular simulation to determine and predict structure-property relationships, REACTIVE & FUNCTIONAL POLYMERS 66 (1) pp. 21-39 ELSEVIER SCIENCE BV
Meijles DN, Fan LM, Howlin BJ, Li JM (2014) Molecular Insights of p47phox Phosphorylation Dynamics in the Regulation of NADPH Oxidase Activation and Superoxide Production., J Biol Chem 289 (33) pp. 22759-22770
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.
Howlin BJ, Meijles DN, Li JM (2012) Consensus in silico computational modelling of the p22phox subunit of the NADPH
oxidase, Computational Biology and Chemistry 39 pp. 6-13 Elsevier
The p22phox protein is an essential subunit of the cytochrome b558 of the NADPH oxidase (Nox) complex
which by generating reactive oxygen species (ROS) plays important role in regulating cellular function.
p22phox stabilises the Nox enzyme, assists in catalytic core maturation and in the meantime provides an
anchoring site for cytosolic regulatory subunits to bind. However, the protein structure of the p22phox is
still uncertain. In this study we use an in silico computational bioinformatic approach to produce a consensus
3-dimensional model of the p22phox. Based on published protein sequence data of human p22phox
and by using transmembrane specific protein 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 predicted most stable form, p22phox contains three transmembrane helices leading to an extracellular
N-terminus and an extensive (39 a.a.) extracellular loop between helices 2 and 3. Furthermore,
we locate the cytosolic domain phosphorylation site at threonine147 which literature shows is capable of
priming the p22phox, in order to accept its binding partners. Our results are consistent with the biological
characterisation of p22phox derived from experiments using specific antibody or genetic manipulation.
Our 3-D protein model provides insights into the biological function of p22phox and cytochrome b558, and
can be used as tool to investigate the regulatory mechanism of Nox isoforms.
Hamerton I, McNamara LT, Howlin BJ (2013) Examining the effects of selected additives on the polymerisation mechanism and network development in aromatic polybenzoxazines,
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.
Dobreva MA, Green RJ, Mueller-Harvey I, Salminen J-P, Howlin BJ, Frazier RA (2014) Size and Molecular Flexibility Affect the Binding of Ellagitannins to Bovine Serum Albumin, JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 62 (37) pp. 9186-9194 AMER CHEMICAL SOC
Howlin BJ, Hamerton I, Hall S, Mitchell A, McNamara L (2011) Using Molecular Simulation to Predict the Physical and Mechanical Properties of Polybenzoxazines, In: Ishida H, Agag T (eds.), Handbook of Benzoxazine Resins n/a 5 Elsevier
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.
Hamerton I, Howlin BJ, Jewell SL, Patel P (2012) Studying the co-reaction of propenyl-substituted cyanate ester-bismaleimide blends using model compounds, REACTIVE & FUNCTIONAL POLYMERS 72 (4) pp. 279-286 ELSEVIER SCIENCE BV
Hamerton I, McNamara LT, McNamara LT, Howlin BJ, Smith PA, Cross P, Ward S (2014) Examining the kinetics of the thermal polymerization of commercial aromatic bis-benzoxazines, Journal of Polymer Science, Part A: Polymer Chemistry 52 (14) pp. 2068-2081
Three commercial 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 kinetics of the polymerization of BA-a were found to be well described using an autocatalytic model for which values of n = 1.39 and m = 2.49 were obtained for the early and later stages of reaction respectively (activation energy = 81-88 kJ/mol.). Following recrystallization the same monomer yielded values of n = 1.80, m = 0.92, and Ea = 94-97 kJ/mol. BF-a and BT-a were also found to be well described using an autocatalytic model for which values of n = m = 2.11 (BF-a) and n = 2.10, m = 1.47 (BT-a) were obtained for the early and later stages of reaction (activation energy = 80-84 kJ/mol. for BF-a and 88-95 kJ/mol. for BT-a). The kinetic data are compared with parallel studies involving chemically initiated benzoxazine monomers. Molecular simulation is used to examine the rotational freedom of the central bridging units and this is related to the degree of conversion achieved. © 2014 Wiley Periodicals, Inc.
Hassan WAW, Liu J, Howlin BJ, Ishida H, Hamerton I (2016) Examining the influence of bisphenol A on the polymerisation and network properties of an aromatic benzoxazine, Polymer 88 pp. 52-62 ELSEVIER SCI LTD
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.
Malkhasian AY, Howlin BJ (2015) Docking and DFT studies on ligand binding to Quercetin 2,3-dioxygenase., J Biomol Struct Dyn pp. 1-9
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-crystallized 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.
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 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.
Hamerton I, Hay JN, Howlin BJ, Jones J R, Lu S Y, Webb G A, Bader M G (1996) Surface analysis of carbon fibres using a tritium-hydrogen exchange procedure, 7th European Conference on Composite Materials 'Realising their Commercial Potential' 2 (1) pp. 435-439
Hamerton I, Howlin BJ, Yeung S-YC (2014) Studying structure-property relationships in oligomeric engineering thermoplastics by controlled preparation of low molecular weight polymers, Reactive and Functional Polymers 81 (1) pp. 22-32
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
Hamerton I, Howlin BJ, Mooring L, Stone C, Swan M, Thompson S (2014) Studying the effect of the chloral group on the thermal and physical properties of aromatic cyanate esters, Polymer Degradation and Stability 110 pp. 435-446
© 2014 Elsevier Ltd. Two cyanate ester monomers: 2,2-bis(4-cyanatophenyl)propane (1) and l,l-dichloro-2,2-(4-cyanatophenyl)ethylidene (2) are 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). The polymerisation enthalpy for the thermal polymerisation of monomer (2) was recorded as 87.6 ± 0.75 kJ/mol. OCN (75.0 ± 0.80 kJ/mol. OCN following catalysis) and 99.4 ± 1.86 kJ/mol. OCN, 85.8 ± 4.03 kJ/mol. OCN following catalysis for (1). Formulated monomers show little advancement in cure during storage at a several temperatures (ambient, -5 °C and -20 °C) over a period of 2 months. TGA measurements conducted on cured 'puck' sample3s reveal char yields of 38% at 800 °C in the case of (1) and 54% for (2). Pyrolysis-GC shows only minor similarities in the species detected implying that the two polymers undergo significantly different degradation pathways under the analysis conditions, but the low incidence of polynuclear aromatics present (aside from substituted fluorenes, biphenyls and anthracenes) is probably due to the rapidity of heating a short residence times involved.
Hamerton I, Kamyszek G, Howlin B J, Garbarczyk J (1997) Prediction of Tg of polyarylethersulphones, Proceedings of the Europhysics Conference on Macromolecular Physics and 4th International Symposium on Thermoplastic Elastomers 21A
Meijles DN, Howlin BJ, Li J-M (2012) BIOINFORMATIC IMAGING AND MOLECULAR INVESTIGATION FOR A ROLE OF P22(PHOX) C242T POLYMORPHISM IN INHIBITING ENDOTHELIAL ROS PRODUCTION, HEART 98 pp. A68-A69 B M J PUBLISHING GROUP
Crawford AO, Howlin BJ, Cavalli G, Hamerton I (2012) Examining the thermo-mechanical properties of novel cyanate ester blends through empirical measurement and simulation, Reactive and Functional Polymers 72 (9) pp. 596-605
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.
Hamerton I, Howlin BJ (2017) Modern Developments Using Molecular Simulation to Predict the Physical and Mechanical Properties of Polybenzoxazines, In: Ishida H, Froimowicz P (eds.), Advanced and Emerging Polybenzoxazine Science and Technology 8 pp. 111-129 Elsevier
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.
Hamerton I, Howlin BJ, Tilbrook DA (2013) Examining thermal stability and structure property relationships in coatings based on linear aromatic poly(methoxy-thiocyanurate)s, Polymer Degradation and Stability
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 M n = 7000-10,000 g mol-1 were obtained for the polycyanurate and polythiocyanurate homopolymers. DSC reveals polymerisation exotherms with maxima at 197-207 °C (H p = 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. © 2013.
Hamerton I, Heap K, Howlin BJ, McNamara LT (2013) Effects of thermal history on the polymerisation mechanism and network development in aromatic polybenzoxazines, Reactive and Functional Polymers
Baggott A, Bass JR, Hall SA, Hamerton I, Howlin BJ, Mooring L, Sparks D (2014) At the limits of simulation: A new method to predict thermal degradation behavior in cyanate esters and nanocomposites using molecular dynamics simulation, Macromolecular Theory and Simulations 23 (6) pp. 369-372
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.
Three POSS reagents (1,2-propanediolisobutyl POSS, glycidylisooctyl POSS, and triglycidylisobutyl POSS, all 5 wt%) are incorporated into a commercial isotactic polypropylene, PP. Infrared and Raman spectroscopy show that the blending has been successful as evidenced by the presence of Si-O-Si bands at 1098-1110 cm-1, which are not present in the base polymer. The inclusion of 5 wt% of the various POSS reagents leads to a general increase in the loss modulus at the Tg (e.g. the greatest increase being from ca. 125 MPa to ca. 150 MPa) from DMTA data, although the Tg of the PP is slightly diminished by 4-8 K depending on the POSS used. The melting behaviour is also altered as the addition of POSS leads to a more diffuse and multimodal melting endotherm in the blends, although the melting temperature does increase slightly (7 K). TGA data confirm that the thermal and thermo-oxidative stability of PP is not adversely affected by the inclusion of the POSS reagents at this concentration. Tensile data show that the ultimate tensile strength (ca. 24.7 ± 0.1 MPa) remains the same, although the tensile modulus (ca. 1.24 ± 0.06 GPa) is reduced by up to 0.22 GPa and the maximum load does reduce by ca. 80-160 N. Contact angle measurements for the PP (99.72°± 0.73) show that the inclusion of the POSS reagents at this level does reduce its hydrophobic character as the greatest depression in contact angle is effected by the inclusion of 5 wt% triglycidylisobutyl-POSS (85.77°± 1.39). Molecular modelling and QSPR techniques are used to predict selected physical properties of the PP/POSS nanocomposites. © 2013 The Royal Society of Chemistry.
Hamerton I, Howlin BJ (2017) Predictive Methodology and Properties of Polybenzoxazines, In: Ishida H, Froimowic P (eds.), Advanced and Emerging Polybenzoxazine Science and Technology 9 pp. 131-145 Elsevier
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.
Hamerton I, Tilbrook DA, Howlin BJ (2013) Examining the preparation and characterization of coatings based on linear aromatic terpoly(methoxy-cyanurate-thiocyanurate)s, Polymer International
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 M = 8000-13000 g mol were obtained for the polymers based on thiodiphenol and dithiodiphenyl sulfide, and M = 5000-13000 g mol for the polymers based on dihydroxydiphenyl ether and dithiodiphenyl ether. DSC reveals polymerization exotherms with maxima at 184-207 °C (H = 43-59 kJ mol), which are believed to be due to isomerization of the cyanurate to the isocyanurate (activation energies span 159-195 kJ mol). 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.
Hamerton I, Thompson S, Howlin BJ, Stone CA (2013) Examining the thermal stability and degradation mechanisms of polybenzoxazines,
Hamerton I, Howlin BJ, Thompson S, Stone CA (2013) A new method to predict the thermal degradation behaviour of polybenzoxazines from empirical data using structure property relationships, Macromolecules 46 (19) pp. 7605-7615 American Chemical Society
Hamerton I, Deazle A S, Heald C R, Howlin B J, Barton J M (1995) Calculations of the physical and mechanical properties of polymers from computer simulation, Proceedings of the SPSJ 44th Annual Meeting Polymer Preprints Japan (English Edition) 44 (1) pp. E11-E11
Hall SA, Hamerton I, Howlin BJ, Mitchell AL (2008) Validating software and force fields for predicting the mechanical and physical properties of poly(bisbenzoxazine)s, MOLECULAR SIMULATION 34 (10-15) PII 905744462 pp. 1259-1266 TAYLOR & FRANCIS LTD
Hamerton I, Howlin BJ, Yeung S-YC (2013) Designing thermoplastic oligomers with programmed degradation mechanisms using a combined empirical and simulation approach, Polymer Degradation and Stability 98 (4) pp. 829-838
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 =
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.
Palmer RA, Ladd M, Howlin B, Lisgarten DR (2013) X-ray structures of two forms of the antibiotic oligomycin A: An inhibitor of ATP synthase, Future Medicinal Chemistry 5 (8) pp. 881-893
Background: Corrections to the chemical and x-ray structures of two forms of the antibiotic oligomycin A are presented: the original and best known, form (E), from Streptomyces diastatochromogenes, and a new form (C) from Streptomyces diastaticus. Method: The crystal structures are isomorphous, crystallizing in space group P222, with Z = 4[C HO.CHOH] per unit cell. Oligomycin A(E) refined with R1 = 0.0734, using Cu K± x-radiation; and for Oligomycin A(C) R1 = 0.0651 using Mo K± x-radiation. Conclusion: Serious corrections to the previously published structure of oligomycin A(C) are discussed and implemented. As a supplementary study geometry optimization of side group R4 of oligomycin A(E) was undertaken and achieved by energy minimization. These additional results clearly confirm the delocalization in this region observed in both x-ray structures. This result is contrary to the generally accepted formulation. Knowledge of the correct structures is important to those involved in the study and applications of the pharmacological and biological properties of these materials. © 2013 Future Science Ltd.
Hamerton I, Aspin I P, Howlin B J, Jones J R, Parker M J (1997) Kinetic and computer modelling of epoxy resin cure, Proceedings of the Conference on Epoxy Technologies for Ambient Cure Protective Coatings (1)
Lockley WJS, Sfyrakis K, Howlin BJ, Jones JR, Wilkinson DJ (2007) Some IT and data processing applications for 2H, 3H,11C,13C and 14C-labelling, Journal of Labelled Compounds and Radiopharmaceuticals 50 (5-6) pp. 532-534
Hamerton I, Hamerton I, McNamara LT, Howlin BJ, Smith PA, Cross P, Ward S (2014) Developing toughened aromatic polybenzoxazines using thermoplastic oligomers and telechelics, part 1: Preparation and characterization of the functionalized oligomers, Journal of Applied Polymer Science 131 (19)
The preparation and characterization of three families of thermoplastic oligomers (Mn0=02918-13263 g mol-1) based on polyarylsulfone (PSU) differing in both molecular weight and terminal functionality and one series of polyarylethersulfone (PES) of different molecular weights is reported. Infrared and nuclear magnetic resonance spectroscopy data support the formation of both the hydroxyl terminated oligomers and conversion (67-89% depending on molecular weight) to the telechelic PSU oligomer bearing reactive benzoxazine groups. Differential scanning calorimetry reveals that the onset of homopolymerization in the telechelic PSU oligomer occurs at around 100°C (peak maximum 125°C at 10 K/min) and rescans show values of the glass transition (for the homopolymers) ranging from 124 to 167°C depending on molecular weight. The influence on the oligomer backbone and terminal functionality is examined using thermal analysis. © 2014 Wiley Periodicals, Inc.
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 (Hp = 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.
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 (Hp = 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 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.
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.
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.
Lisgarten D, Palmer R, Lobley C, Naylor C, Chowdhry B, Al?Kurdi Z, Badwan A, Howlin BJ, Gibbons N, Saldanha J, Lisgarten J, Basak A (2017) Ultra?high resolution X?ray structures of two forms of human recombinant insulin at 100 K, Chemistry Central Journal 11 (73)
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 (» = 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 S³6?S³11 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.
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.
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.
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.
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 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.
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.
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.
This study uses Molecular Operating Environment (MOE) to generate models to calculate the char yield of polybenzoxazines. A series of benzoxazine 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 a new benzoxazine monomer and a comparison was made of predictions based on the QSPR models with the experimental data. This study shows the quality of predictive models and confirms how useful computational screening is prior to synthesis.
In order to do that, the QSPR models were tested over a series of internal and external validation tests to explore their internal and external predictivity, prior to experimental validations which were performed later and reported in Chapter 7. The internal and external validations found out that the discrepancy in the general model (GM) which was initially thought to be a drawback to the model?s performance was actually not, as it does not compromise the model?s prediction accuracy, both internally and externally. The validation process also found that one of the structure-specific models, Ph-M (aniline-based benzoxazines) is externally predictive whilst another structure-specific model, the Ace-M (acetylenic-based polybenzoxazines) is not internally and externally predictive due to the too small training set that affects its predictivity performance.
An acetylenic-based polybenzoxazine, poly(BA-apa) and a benzylamine-based polybenzoxazine, poly(BO-ba) have been successfully synthesised in this work. Both materials have been characterised using Fourier Transform ? Infra Red Spectroscopy (FT-IR), Nuclear Magnetic Resonance (NMR) spectroscopy (both 1H and 13C) and Liquid Chromatography-Mass Spectrometry (LC-MS) to confirm their structures. These materials were analysed using Differential Scanning Calorimetry (DSC) to study their polymerisation behaviour and were later cured and taken further to Thermogravimetric Analysis (TGA) in order to investigate their thermal properties and the amount of char yield formed upon heating at 800 oC under an inert (nitrogen) atmosphere ? which then will be used for experimental validation of the QSPR models.
The study of DSC thermograms showed that both polymers exhibit a distinct polymerisation behaviour e.g. BA-apa went through two polymerisation reactions simultaneously (the oxazine ring opening polymerisation and the acetylene addition reaction) whilst BO-ba only polymerised via the ring opening reaction from the oxazine rings. It was also found that BA-apa has a lower polymerisation activation energy, consistent to its lower polymerisation temperature in comparison to the BO-ba.
TGA analysis revealed that poly(BO-ba) formed an average of 44.35 % char yield and poly(BA-apa) on the other hand formed approximately 10 % higher char which is 56.28 %. The analysis also discovered that poly(BA-apa) synthesised in this work formed 15 % less char yield than previously reported in the literature (56.28 % vs. 71 %1) due to the shorter curing schedule. The final QSPR validation which is the experimental validation found that the char yield of poly(BO-ba) was predicted very well within 5-7 % error by both GM model and Ph-M. Ace-M which was reported earlier as not internally and externally predictive, has made a nearly accurate prediction towards the char yield of poly(BA-apa), close to the literature value of 71 %. The GM model has also made a close prediction to the Ace-M model, but these predictions deviated 15-17 % from the experimental poly(BA-apa) char yield measured in this work.
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 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).
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 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.
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.