Kinetic and thermodynamic studies of the ligand substitution reactions of the cobalamins

Student Number : 9006831D - PhD thesis - School of Chemistry - Faculty of ScienceThe ligand substitution reactions of aquacobalamin are fast and hence the usual inertness of the d6 Co(III) ion has been modified. It is well established that the reactions proceed through a dissociative interchange mechanism; however, previous ligand studies were performed in a KCl medium, which led to the formation of the more substitution-inert chloro complex. The kinetics of aquacobalamin were reinvestigated with the ligands N3–, NO2–, SCN–, S2O32–, OCN– and SeCN– in a NaNO3 medium. The reactions proceeded too rapidly for saturation kinetics to be observed and hence only the second-order rate constants could be obtained. These were corrected for pH and determined as a function of temperature, from which the activation parameters were determined. The donor atom of the ambidentate ligands were investigated and correlations were found between the Mulliken population on the donor atom, the energy of the highest occupied molecular orbital (HOMO) with σ symmetry, and Δ, the enthalpy of activation, and Δ, the entropy of activation, respectively. Good correlations occurred when the donor atoms were taken to be N for SCNII‡kHII‡kS– and NO2–; S for S2O32–; O for OCN– and Se for SeCN–. The effect that changing the environment of aquacobalamin has on its kinetics was observed by determining the rate constants for the reaction of pyridine with aquacobalamin in water and 70% ethanol. The rates were faster in water and the activation parameters obtained for the reaction of aquacobalamin with pyridine in 70% ethanol are larger than they are for the reaction in water. The larger ΔH‡ arises due to less bond formation between pyridine and Co in the transition state and ΔS‡ is larger because it is dominated by the freeing of the coordinated water i.e. bond breaking is the dominant process in the transition state. The effects of a bulkier ligand than water on the kinetics of aquacobalamin were investigated. The temperature dependence of the kinetics of the substitution of I– in iodocobalamin by imidazole, N3– and S2O32– was studied. Despite the increase in size of the departing ligand there is still nucleophilic participation of the incoming ligand in the transition state and hence the reaction still proceeds via an Id mechanism. In order to probe the cis-effect of the corrin in vitamin B12 derivatives, comparative studies were undertaken of the reactions of aquacobalamin and aqua-10-Xcobalamin, X = Cl, NO, NH2, where the H at C10 was replaced with an electron-donating (Cl, NH2) or electron-withdrawing (NO) group. Formation constants were obtained for aquacobalamin and aqua-10-chlorocobalamin for the substitution of coordinated H2O with various anions (N3–, NO2–, SCN–, S2O32–, OCN–, SeCN–) and neutral N-donor ligands (CH3NH3, pyridine, imidazole). The anionic ligands bind more strongly to aqua-10-chlorocobalamin than to aquacobalamin with log K values larger by between 0.10 and 0.63 (average 0.26) larger. The converse is true for the neutral N-donor ligands, where log K is smaller by between 0.17 and 0.3 (average 0.25). Semi-empirical molecular orbital (SEMO) calculations using the ZINDO/1 model on the hydroxo complexes show that charge density is delocalised from the axial donor atom to the metal and Cl. Thus the anionic ligands bind more strongly to aqua-10-chlorocobalamin because of the ability of the metal and the Cl at C10 to accept charge density from the ligand. The cobalt ion in aqua-10-chlorocobalamin is more electron rich than it is in aquacobalamin and so it is less likely to accept further electron density from a neutral axial donor ligand. This results in the stability being lower than that of aquacobalamin. The reaction kinetics of the substitution of H2O in aqua-10-chlorocobalamin were determined for the ligands N3– and pyridine. The reaction proceeds via a dissociative interchange mechanism since saturation was seen for pyridine and not for N3–. The activation parameters, ΔH‡ and ΔS‡, are lower for aqua-10-chlorocobalamin than aquacobalamin and hence it can be deduced that bond breaking between the coordinated water and the cobalt atom is more dominant in aquacobalamin. The rates of reaction are faster for aquacobalamin than they are for aqua-10-chlorocobalamin. SEMO calculations show that as the Co–O bond is stretched, the charge density on Co in aquacobalamin is always lower than that on aqua-10-chlorocobalamin, suggesting that aquacobalamin is a better electrophile towards the incoming ligand, thereby explaining the faster kinetics. Aqua-10-nitrosocobalamin was synthesised and characterised by FAB(MS), NMR and UV-vis spectroscopy. The strongly electron-withdrawing NO group has deactivated the metal ion towards ligand substitution, with neither 1.2 M pyridine nor 0.7 M N3– showing any spectroscopic evidence for the displacement of the axial H2O ligand. This provides further evidence that the electronic structure of the corrin ring can directly influence the ligand-binding properties of the metal. Aqua-10-aminocobalamin was synthesised from aqua-10-nitrosocobalamin but is unstable in solution. Hence, only a preliminary UV-vis study could be undertaken with the compound. This study shows that the shifts in the bands occur towards longer wavelengths than that of aqua-10-chlorocobalamin, suggesting that the amino group at the C10 position donates more electron density to the cobalt centre than the chloro group

Application of Advanced Technologies to Small, Short-haul Air Transports

A study was conducted of the application of advanced technologies to small, short-haul transport aircraft. A three abreast, 30 passenger design for flights of approximately 100 nautical miles was evaluated. Higher wing loading, active flight control, and a gust alleviation system results in improved ride quality. Substantial savings in fuel and direct operating cost are forecast. An aircraft of this configuration also has significant benefits in forms of reliability and operability which should enable it to sell a total of 450 units through 1990, of which 80% are for airline use

Emergency department attendances and GP patient satisfaction

Background: Despite invaluable national data, reasons for the relentless rise in England’s emergency department (ED) attendances remain elusive. Setting: All EDs and general practices in England. Question: Are rising ED attendances related to general practice patient satisfaction, i.e. if patients are unable to get a convenient appointment with their general practitioner (GP), then do they attend their local ED for diagnosis, treatment and care instead? Method: GP patient satisfaction and ED attendance data were extracted from national data warehouses and organised into two groups: (i) England clinical commissioning group (CCG) areas and (ii) a London CCG subset. Data from London CCGs were compared with CCGs outside London. Results: ED attendances were strongly correlated with GP patient satisfaction data in non-London CCGs, e.g. if patients said they had difficulty obtaining a convenient appointment at their general practice, then local ED attendances increased. Associations were repeated when other GP perception data were explored, e.g. if patients were satisfied with GPs and practice nurses, then they were less likely to attend their local EDs. However, these associations were not found in the London CCG subset despite lower satisfaction with London GP services. Discussion and Conclusions: Although our study generates valuable insights into ED attendances, the reasons why London general practice patient and ED attendance data don’t show the same associations found outside London warrants further study. Diverting patients from EDs to primary care services may not be straight forward as many would like to believe

Whole system quality: local benchmarking to improve workforce planning

As a team of workforce analysts and academics with an interest in workforce planning, we are aware that the data available to support primary care workforce planning are disorganised and overwhelming. This makes it difficult for General Practice to extract meaningful and relevant information. We deliver workforce planning workshops across England. Participants at our workshops regularly express their frustration with the quantity of information they are required to produce and the quality of information they receive from other parts of the system. We are dismayed at what we sense to be growing cynicism with data generation and information analysis and are interested in stimulating a conversation about what data matter and how primary care teams can extract data that are usefu

Online self-assessment of cardiovascular risk using the Joint British Societies (JBS3)-derived heart age tool: a descriptive study.

OBJECTIVE: A modified version of the Joint British Societies (JBS3) 'heart age' tool was introduced online to broaden access to personalised risk assessment to the general population and encourage participation in the National Health Service (NHS) Health Check programme. This study reports on its early uptake and the profiles of those who used the self-assessment tool to determine their own cardiovascular risk. DESIGN: Observational, retrospective analysis of online tool use. SETTING: Between February and July 2015, user data collected from the NHS Choices website, where the tool was hosted, were analysed anonymously using standard analytic packages. RESULTS: The online tool landing page was viewed 1.4 million times in the first 5 months, with increased activity following limited media coverage. Of the 575 782 users completing the data journey with a valid 'heart age' result, their demographic and risk factor profiles broadly resembled the population of England, although both younger users and males (60%) were over-represented. Almost 50% and 79% did not know or enter their blood pressure or total cholesterol values, respectively. Estimated heart age was higher than chronological age for 79% of all users, and also for 69% of younger users under 40 years who are at low 10-year risk and not invited for NHS Health Checks. CONCLUSIONS: These data suggest a high level of public interest in self-assessment of cardiovascular risk when an easily understood metric is used, although a large number of users lack awareness of their own risk factors. The heart age tool was accessed by a group not easily reached by conventional approaches yet is at high cardiovascular risk and would benefit most from early and sustained risk reduction. These are both important opportunities for interventions to educate and empower the public to manage better their cardiovascular risk and promote population-level prevention

Gravel pits support waterbird diversity in an urban landscape

We assessed the benefit of 11 gravel pits for the settlement of waterbird communities in an urbanized area lacking natural wetlands. Gravel pits captured 57% of the regional species pool of aquatic birds. We identified 39 species, among which five were regionally rare. We used the Self Organizing Map algorithm to calculate the probabilities of presence of species, and to bring out habitat conditions that predict assemblage patterns. The age of the pits did not correlate with assemblage composition and species richness. There was a positive influence of macrophyte cover on waterbird species richness. Larger pits did not support more species, but species richness increased with connectivity. As alternative wetland habitats, gravel pits are attractive to waterbirds, when they act as stepping stones that ensure connectivity between larger natural and/or artificial wetlands separated in space

From Exclusion to Extremism : The Role of Significance Loss and Identity in the Radicalization Process

The present thesis aims to examine the causal role of social exclusion within theradicalization process and further to explore moderating and mediating factors. In recent years there has been a move away from trying to understand who is at risk of becoming an extremist, to exploring what makes someone at risk. Feelings of exclusion, discrimination and marginalization have all been linked to participation in extremist activities. Yet to date there continues to be very little empirical data exploring the pathway of exclusion to extremism. This thesis plans to establish a causal link between exclusion and radicalization and explore the moderating and mediating factors that can impact this mechanism.Paper I found that social exclusion triggers a desire for recognition and thisfunctions as a pathway to radicalization. Four experiments were conducted andfound that exclusion was a driver of radical ideology in individuals sensitive torejection. Further, the findings of these studies revealed that this effect wasconsistent across different social and political issues.Paper II revealed that the pathway of social exclusion on radical activism arisesvia shifts in ingroup identity. Specifically, the source of exclusion impacted ingroup identity shifts and in turn activism intentions. An online experiment revealed that exclusion by an outgroup (not ingroup) led to increased participation and this effect was fully mediated by ingroup identity. This finding was replicated using an online survey that operationalized exclusion via a measure of perceived discrimination. This demonstrated perceived discrimination by an outgroup, led to increased ingroup identity and in turn increased engagement. As such this study highlighted the impact of group-based exclusion and how this impacts identity levels and activism engagement.Paper III investigated the link between identity and exclusion one step further byadding need-threat to the mediation pathway. A quasi-experimental study revealed that exclusion led to threatened fundamental needs. This in turn drove individuals to identify with a radical group and be more willing to endorse and participate in extremist actions.The findings of the thesis highlight the vulnerability of individuals experiencingsocial exclusion and discrimination in relation to radicalization risk. Theexplanatory pathways described in the thesis help explain this mechanism and thus provide empirical data that can help shape informed counter-extremism strategies

The linguistic construction of the self in narratives of obsessive-compulsive disorder (OCD)

Obsessive-compulsive disorder (OCD) is a mental health problem characterised by distressing obsessions and repetitive compulsions. The autogenous-reactive model of OCD outlines two types of obsessions: 1) reactive, which are triggered by stimuli external to the self (e.g. electrical appliances) and 2) autogenous, which are triggered by stimuli internal to the self (e.g. memories) (Lee and Kwon, 2003). This article demonstrates the differences in the linguistic construction of the self within narratives told by people with OCD about reactive and autogenous obsessions. Narratives are analysed by focusing on the entity placed as grammatical subject. It is found that, within autogenous narratives, personified thoughts and the mind are placed as grammatical subject more often than within reactive narratives. autogenous narratives. These patterns potentially construct the self as agentive and responsible in reactive obsessions but in need of protection in autogenous obsessions

The Irony of Ostracism: Can Extreme Political Actions Result From A Process Once Created To Prevent Political Rebellion?

This study investigated how ostracism and social exclusion may lead to individuals being more willing to participate in and recommend extreme action against a political cause and/or against an opposing group that is hindering their aims. In addition, it assessed if rejection sensitivity and right-wing authoritarianism moderated this effect. The participants were asked to read an article describing the proposal to implement tuition fees in Sweden and were then either ‘included’ or ‘excluded’ from a group that opposed the fees. If excluded they were placed in an alternative group. They were then asked to indicate how willing they were to participate and recommend extreme action against the fees and against an opposing group. The results indicated that those who were excluded were more willing to participate in and recommend extreme action against the fees and the opposing group. In addition, on some of the dependent variables this effect was moderated by rejection sensitivity and right-wing authoritarianism