Daniel Whelligan

Dr Daniel Whelligan MSci, PhD

Senior Lecturer in Organic/Medicinal Chemistry

Academic and research departments

Department of Chemistry.


University roles and responsibilities

  • Departmental Assessments Officer


Research interests

My teaching

My publications


Alkaline anion-exchange membranes (AAEMs) containing cationic head-groups (e.g. involving quaternary ammonium and imidazolium groups) are of interest with regard to application in alkaline polymer electrolyte fuel cells (APEFCs). This initial ex situ study evaluated the effect of 1 mmol dm concentrations of model molecules containing (AAEM-relevant) cationic groups on the oxygen reduction reaction on a polycrystalline platinum disk (Pt) electrode in aqueous KOH (1 mol dm(-3)). The cationic molecules studied were tetramethylammonium (TMA), benzyltrimethylammonium (BTMA), 1-benzyl-3-methylimidazolium (BMI), 1-benzyl-4-aza-1-azoniabicyclo[2.2.2]octane (BAABCO) and 6-(benzyloxy)-N,N,N-trimethylhexan-1-aminium (BOTMHA). Both cyclic and hydrodynamic linear sweep rotating disk electrode voltammetry techniques were used. The resulting voltammograms, derived estimates of apparent electrochemically active surface areas, Tafel slopes, apparent exchange-current densities and the number of electrons transferred (per O molecule) were compared. The results strongly suggest that 1 mmol dm(-3) concentrations of BTMA, BAABCO, and (especially) BMI seriously inhibit the catalytic activities of Pt in an aqueous KOH electrolyte at 25 °C. The negative influence of (benzene-ring-free) TMA and Cl anions (KCl control experiment) appeared to be less severe. The separation of the trimethylammonium group from the benzene ring via a hexyloxy spacer chain (in BOTMHA) also produced a milder negative effect.
Sanganee MJ, Steel PG, Whelligan DK (2004) Stereochemistry of the reaction of Si-phenyl silenes with butadienes: elaboration of the silacycloadducts to provide a novel route to substituted lactones., Org Biomol Chem 2 (16) pp. 2393-2402
Silenes generated through a silyl-modified Peterson olefination procedure can be trapped with a range of alkyl butadienes via a [4 + 2] cycloaddition pathway to afford silacycles accompanied by variable amounts of competing ene, [2 + 2] and silene dimer by-products. The silacycles are formed with good chemo- and stereo-selectivity and provide access to diols and lactones via a phenyl-triggered Fleming-Tamao oxidation.
Syntheses of three regioisomers of aromatic-substituted phosphinyl-oxazolinyl-[2.2]paracyclophanes, pseudo-geminal, pseudo-ortho, and ortho, have been carried out or, in the latter two cases, newly developed. It has, therefore, been demonstrated that all aromatic-substituted isomers relevant for use as chelating ligands for asymmetric catalysis are accessible. These P,N-ligands, along with their diastereoisomers, were shown to exhibit widely differing activity and enantioselectivity (up to 89% ee) in the Pd-catalyzed asymmetric allylic alkylation reaction.
Quideau S, Pouysegu L, Avellan AV, Whelligan DK, Looney MA (2001) Hypervalent iodine(III)-mediated oxidative acetoxylation of 2-methoxyphenols for regiocontrolled nitrogen benzannulation, Tetrahedron Lett 42 (42) pp. 7393-7396
Nitrogen-tethered 2-methoxyphenols are conveniently dearomatized into synthetically useful orthoquinol acetates by treatment with phenyliodine(III) diacetate in methylene chloride at low temperature. Subsequent fluoride- or base-induce intramolecular nucleophilic addition reactions furnish indole and quinoline derivatives. The potential of this methodology for the synthesis or a functionalized lycorine-type alkaloid skeleton is introduced here. (C) 2001 Elsevier Science Ltd. All rights reserved.
Whelligan DK (2009) Benzotriazole Linker Units, In: Scott PJH (eds.), Linker Strategies in Solid-Phase Organic Synthesis 11 Wiley
Syntheses of polymer-supported benzotriazoles
Polymer-supported benzotriazole linked reactions
Bolm C, Whelligan DK (2006) The synthesis of pseudo-geminal, pseudo-ortho and ortho hydroxy-oxazolinyl[2.2]paracyclophanes for use as ligands in asymmetric catalysis, Adv Synth Catal 348 (15) pp. 2093-2100
Synthetic routes to pseudo-geminal, pseudo-ortho and ortho hydroxy-oxazolinyl-[2.2]paracyclophanes (and the diastereoisomers of each) for use as N,O ligands in asymmetric catalysis have been devised. The substitution pattern was found to have a strong effect on the rate and enantioselectivity of the formed catalyst in the addition of diethylzinc to benzaldehyde.
Steel PG, Whelligan DK (2002) Silenes: Novel reagents for alkene functionalisation., ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 224 pp. U161-U161 AMER CHEMICAL SOC
Whelligan DK, Thomson DW, Taylor D, Hoelder S (2010) Two-Step Synthesis of Aza- and Diazaindoles from Chloroamino-N-heterocycles Using Ethoxyvinylborolane,J Org Chem 75 (1) pp. 11-15
An efficient two-step route to a broad range of aza- and diazaindoles was established, starting from chloroamino-N-heterocycles, without the need for protecting groups. The method involves an optimized Suzuki-Miyaura coupling with (2-ethoxyvinyl)borolane followed by acetic acid-catalyzed cyclization.
Whelligan DK, Solanki S, Taylor D, Thomson DW, Cheung KMJ, Boxall K, Mas-Droux C, Barillari C, Burns S, Grummitt CG, Collins I, van Montfort RLM, Aherne GW, Bayliss R, Hoelder S (2010) Aminopyrazine Inhibitors Binding to an Unusual Inactive Conformation of the Mitotic Kinase Nek2: SAR and Structural Characterization,J Med Chem 53 (21) pp. 7682-7698
We report herein the first systematic exploration of inhibitors of the mitotic kinase Nek2. Starting from HTS hit aminopyrazine 2, compounds with improved activity were identified using structure-based design. Our structural biology investigations reveal two notable observations. First, 2 and related compounds bind to an unusual, inactive conformation of the kinase which to the best of our knowledge has not been reported for other types of kinase inhibitors. Second, a phenylalanine residue at the center of the ATP pocket strongly affects the ability of the inhibitor to bind to the protein. The implications of these observations are discussed, and the work described here defines key features for potent and selective Nek2 inhibition, which will aid the identification of more advanced inhibitors of Nek2.
Wang L, Magliocca E, Cunningham E, Mustain W, Poynton S, Escudero-Cid R, Nasef M, Ponce-Gonzalez J, Bance-Souahli R, Slade R, Whelligan D, Varcoe J (2016) An optimised synthesis of high performance radiation-grafted anion-exchange membranes,Green Chemistry 19 pp. 831-843 Royal Society of Cemistry
High performance benzyltrimethylammonium-type alkaline anion-exchange membranes (AEM), for application in electrochemical devices such as anion-exchange membrane fuel cells (AEMFC), were prepared by the radiation grafting (RG) of vinylbenzyl chloride (VBC) onto 25 ¼m thick poly(ethylene-co-tetrafluoroethylene) (ETFE) films followed by amination with trimethylamine. Reductions in electron-beam absorbed dose and amount of expensive, potentially hazardous VBC were achieved by using water as a diluent (reduced to 30 ? 40 kGy absorbed dose and 5%vol VBC) instead of the prior-art method that used organic propan-2-ol diluent (required 70 kGy dose and 20%vol VBC monomer). Furthermore, the water from the aqueous grafting mixture was easily separated from residual monomer (after cooling) and was reused for a further grafting reaction: the resulting AEM exhibited an ion-exchange capacity of 2.1 mmol g-1 (cf. 2.1 mmol g-1 for the AEM made using fresh grafting mixture). The lower irradiation doses resulted in mechanically stronger RG-AEMs compared to the reference RG-AEM synthesised using the prior-art method. A further positive off-shoot of the optimisation process was the discovery that using water as a diluent resulted in an enhanced (i.e. more uniform) distribution of VBC grafts as proven by Raman microscopy and corroborated using EDX analysis: this led to enhancement in the Cl- anion-conductivities (up to 68 mS cm-1 at 80°C for the optimised fully hydrated RG-AEMs vs. 48 mS cm-1 for the prior-art RG-AEM reference). A down-selected RG-AEM of ion-exchange capacity = 2.0 mmol g-1, that was synthesised using the new greener protocol with 30 kGy electron-beam absorbed dose, led to an exceptional beginning-of-life H2/O2 AEMFC peak power density of 1.16 W cm?2 at 60°C in a benchmark test using industrial standard Pt-based electrocatalysts and unpressurised gas supplies: this was higher than the 0.91 W cm-1 obtained with the reference RG-AEM (IEC = 1.8 mmol g-1) synthesised using the prior-art protocol.
Berry MB, Griffiths RJ, Sanganee MJ, Steel PG, Whelligan DK (2004) Silenes as novel synthetic reagents: identification of a practical method for silene generation and trapping., Org Biomol Chem 2 (16) pp. 2381-2392
The elucidation of a robust and reliable sequence for the generation of highly reactive transient silenes from simple aldehydes is described. The key step involves a silyl-modified Peterson olefination which critically depends on the presence of a sub-stoichiometric amount of soluble lithium salts (LiBr).
Sanganee MJ, Steel PG, Whelligan DK (2003) Novel one-pot synthesis of aryltris(trimethylsilyl)silanes., J Org Chem 68 (8) pp. 3337-3339
The simple combination of tris(trimethylsilyl)potassium, ArMgBr, and ArBr provides a novel "one-pot" synthesis of aryl(tristrimethylsilyl)silanes. A mechanistic rationale for this conversion is proposed.
Wylie L, Innocenti P, Whelligan DK, Hoelder S (2012) Synthesis of amino-substituted indoles using the Bartoli reaction, Org Biomol Chem 10 (22) pp. 4441-4447
We report herein the concise preparation of a range of functionalised aminoindoles via a new application of the Bartoli reaction. Scope and limitations of the methodology have been extensively studied to reveal the importance of protecting groups and substitution patterns. The use of amino substituted nitroanilines for the Bartoli reaction is to our knowledge unprecedented. Our work thus represents a novel entry into substituted aminoindoles which are relevant building blocks for both the fine chemical and pharmaceutical industry.
Beemelmanns C, Husmann R, Whelligan DK, Özçubukçu S, Bolm C (2012) Planar-Chiral Bis-silanols and Diols as H-Bonding Asymmetric Organocatalysts, Eur J Org Chem pp. 3373-3376
Ponce-González J, Whelligan DK, Wang L, Bance-Soualhi R, Wang Y, Peng Y, Peng H, Apperley DC, Sarode HN, Pandey TP, Divekar AG, Seifert S, Herring AM, Zhuang L, Varcoe J (2016) High performance aliphatic-heterocyclic benzyl-quaternary ammonium radiation-grafted anion-exchange membranes,Energy and Environmental Science 9 (12) pp. 3724-3735
Anion-exchange membranes (AEM) containing saturated-heterocyclic benzyl-quaternary ammonium (QA) groups
synthesised by radiation-grafting onto poly(ethylene-co-tetrafluoroethylene) (ETFE) films are reported. The relative
properties of these AEMs are compared with the benchmark radiation-grafted ETFE-g-poly(vinylbenzyltrimethylammonium)
AEM. Two AEMs containing heterocyclic-QA head groups were down-selected with higher relative stabilities in aqueous KOH
(1 mol dm-3) at 80°C (compared to the benchmark): these 100 ¼m thick (fully hydrated) ETFE-g-poly(vinylbenzyl-Nmethylpiperidinium)-
and ETFE-g-poly(vinylbenzyl-N-methylpyrrolidinium)-based AEMs had as-synthesised ion-exchange
capacities (IEC) of 1.64 and 1.66 mmol g-1, respectively, which reduced to 1.36 mmol dm-3 (ca. 17 ? 18% loss of IEC) after
alkali ageing (the benchmark AEM showed 30% loss of IEC under the same conditions). These down-selected AEMs exhibited
as-synthesised Cl- ion conductivities of 49 and 52 mS cm-1, respectively, at 90°C in a 95% relative humidity atmosphere, while
the OH- forms exhibited conductivities of 138 and 159 mS cm-1, respectively, at 80°C in a 95% relative humidity atmosphere.
The ETFE-g-poly(vinylbenzyl-N-methylpyrrolidinium)-based AEM produced the highest performances when tested as
catalyst coated membranes in H2/O2 alkaline polymer electrolyte fuel cells at 60°C with PtRu/C anodes, Pt/C cathodes, and
a polysulfone ionomer: the 100 ¼m thick variant (synthesised from 50 ¼m thick ETFE) yielded peak power densities of 800
and 630 mW cm-2 (with and without 0.1 MPa back pressurisation, respectively), while a 52 ¼m thick variant (synthesised
from 25 ¼m thick ETFE) yielded 980 and 800 mW cm-2 under the same conditions. From these results, we make the
recommendation that developers of AEMs, especially pendent benzyl-QA types, should consider the benzyl-Nmethylpyrrolidinium
head-group as an improvement to the current de facto benchmark benzyltrimethylammonium headgroup.
Ong AL, Whelligan DK, Fox ML, Varcoe JR (2013) Impact of 1 mmol dm(-3) concentrations of small molecules containing nitrogen-based cationic groups on the oxygen reduction reaction on polycrystalline platinum in aqueous KOH (1 mol dm(-3)), Physical Chemistry Chemical Physics 15 (43) pp. 18827-18834
Alkaline anion-exchange membranes (AAEMs) containing cationic head-groups (e.g. involving quaternary ammonium and imidazolium groups) are of interest with regard to application in alkaline polymer electrolyte fuel cells (APEFCs). This initial ex situ study evaluated the effect of 1 mmol dm concentrations of model molecules containing (AAEM-relevant) cationic groups on the oxygen reduction reaction on a polycrystalline platinum disk (Pt) electrode in aqueous KOH (1 mol dm(-3)). The cationic molecules studied were tetramethylammonium (TMA), benzyltrimethylammonium (BTMA), 1-benzyl-3-methylimidazolium (BMI), 1-benzyl-4-aza-1-azoniabicyclo[2.2.2]octane (BAABCO) and 6-(benzyloxy)-N,N,N-trimethylhexan-1-aminium (BOTMHA). Both cyclic and hydrodynamic linear sweep rotating disk electrode voltammetry techniques were used. The resulting voltammograms, derived estimates of apparent electrochemically active surface areas, Tafel slopes, apparent exchange-current densities and the number of electrons transferred (per O molecule) were compared. The results strongly suggest that 1 mmol dm(-3) concentrations of BTMA, BAABCO, and (especially) BMI seriously inhibit the catalytic activities of Pt in an aqueous KOH electrolyte at 25 °C. The negative influence of (benzene-ring-free) TMA and Cl anions (KCl control experiment) appeared to be less severe. The separation of the trimethylammonium group from the benzene ring via a hexyloxy spacer chain (in BOTMHA) also produced a milder negative effect. © the Owner Societies 2013.
Ong AL, Inglis KK, Whelligan DK, Murphy S, Varcoe JR (2015) Effect of cationic molecules on the oxygen reduction reaction on fuel cell grade Pt/C (20 wt%) catalyst in potassium hydroxide (aq, 1 mol dm(-3)).,Phys Chem Chem Phys 17 (18) pp. 12135-12145
This study investigates the effect of 1 mmol dm(-3) concentrations of a selection of small cationic molecules on the performance of a fuel cell grade oxygen reduction reaction (ORR) catalyst (Johnson Matthey HiSPEC 3000, 20 mass% Pt/C) in aqueous KOH (1 mol dm(-3)). The cationic molecules studied include quaternary ammonium (including those based on bicyclic systems) and imidazolium types as well as a phosphonium example: these serve as fully solubilised models for the commonly encountered head-groups in alkaline anion-exchange membranes (AAEM) and anion-exchange ionomers (AEI) that are being developed for application in alkaline polymer electrolyte fuel cells (APEFCs), batteries and electrolysers. Both cyclic and hydrodynamic linear sweep rotating disk electrode voltammetry techniques were used. The resulting voltammograms and subsequently derived data (e.g. apparent electrochemical active surface areas, Tafel plots, and number of [reduction] electrons transferred per O2) were compared. The results show that the imidazolium examples produced the highest level of interference towards the ORR on the Pt/C catalyst under the experimental conditions used.
Berry MB, Griffiths RJ, Sanganee MJ, Steel PG, Whelligan DK (2003) Silenes as novel synthetic reagents: synthesis of diols and lactones from simple alkyldienes, Tetrahedron Lett 44 (51) pp. 9135-9138
Aryl substituted silenes can be generated by a modified Peterson olefination reaction and trapped in situ to afford silacycles with high diastereoselectivity. These silacycles can be elaborated by 'Fleming-Tamao' type oxidation to provide access to functionalized diols and lactones. (C) 2003 Elsevier Ltd. All rights reserved.
Quideau S, Pouysegu L, Avellan AV, Whelligan DK (2001) Synthetic studies on Amaryllidaceae lycorine-type alkaloids., ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 221 pp. U199-U199 AMER CHEMICAL SOC
In the field of drug discovery, pyrrolopyridine moieties are often incorporated into bioactive molecules. This is due to their ability to form both pi-stacking and hydrogen bonding interactions when binding to target proteins. This project aimed to provide a robust and rapid method of synthesis that will provide access to substituted pyrrolopyridines. The work is based on a previously published method involving the synthesis of ethoxyvinyl(amino)arenes, by Suzuki reaction of halo-aminoarenes, followed by cyclisation. It was hoped this method would be advanced by applying alternative cyclisation reactions to the ethoxyvinyl(amino)arenes to give 3-substituted products in one step. In comparison with previous methods, this route would be inexpensive, robust and applicable to a wide range of substrates. It was also envisaged that alternative starting materials could be used to make it a more generalised method for the synthesis of bicyclic arenes.
Work began with testing the reproducibility of the previously published method of synthesising the ethoxyvinyl(amino)arenes. This was done successfully, although a change in ligand (SPhos to RuPhos) proved beneficial, with seven different analogues being synthesised in yields ranging from 36% to 98%. This same reaction was attempted with halo-hydroxypyridines, with a novel route to furopyridines in mind, but with no success. The synthesis of non-commercially available halo-hydroxypyridines themselves also proved to be challenging with no material being isolated.
Various methods were tested for the bromo-cyclisation of ethoxyvinyl(amino)arenes to 3-bromopyrrolopyridines. A two-step method using acid cyclisation followed by bromination was entirely successful. Two-step, one-pot and one-step methods both appeared to promote polymerisation/oligermisation. Success was achieved with a one-step method employing an acid additive but only on selected ethoxyvinyl(amino)arene isomers and with varying yields.
The work was extended to the attempted synthesis of anti-malarial precursors using the bromo-pyrrolopyridine isomers as building blocks and converting them to alkyl-linked glutarimides. This led to the successful and novel synthesis of the reactants vinyl glutarimide and glutarimylethylborolane. However, successful conditions for their palladium catalysed cross coupling with the bromides were not found.
Wang Lianqin, Brink JJ, Liu Y, Herring AM, Ponce-González J, Whelligan Daniel, Varcoe John (2017) Non-fluorinated pre-irradiation-grafted (peroxidated) LDPE-based
anion-exchange membranes with high performance and stability
Energy & Environmental Science 10 pp. 2154-2167 Royal Society of Chemistry
Radiation-grafted anion-exchange membrane (RG-AEM) research has predominantly focused on the chemical stability of
the polymer-bound positively-charged head-groups that enable anion conduction. The effect of the backbone polymer
chemistry, of the precursor film, on RG-AEM stability has been studied to a lesser extent and not for RG-AEMs made from
pre-irradiation grafting of polymer films in air (peroxidation). The mechanical strength of polymer films is generally
weakened by exposure to high radiation doses (e.g. from a high-energy e?-beam) and this is mediated by chemical
degradation of the main chains: fluorinated films mechanically weaken at lower absorbed doses compared to nonfluorinated
films. This study systematically compares the performance difference between RG-AEMs synthesised from a
non-fluorinated polymer film (low-density polyethylene ? LDPE) and a partially-fluorinated polymer film (poly(ethylene-cotetrafluoroethylene)
? ETFE) using the peroxidation method (pre-irradiation in air using an e?-beam). Both the LDPE and
ETFE precursor films used were 25 ¼m in thickness, which led to RG-AEMs of hydrated thicknesses in the range 52 ? 60 ¼m.
The RG-AEMs (designated LDPE-AEM and ETFE-AEM, respectively) all contained identical covalently-bound
benzyltrimethylammonium (BTMA) cationic head-groups. An LDPE-AEM achieved a OH? anion conductivity of 145 mS cm-1
at 80 °C in a 95% relative humidity environment and a chloride Cl? anion conductivity of 76 mS cm-1 at 80 °C when fully
hydrated. Alkali stability testing showed that the LDPE-AEM mechanically weakened to a much lower extent when treated
in aqueous alkaline solution compared to the ETFE-AEM. This LDPE-AEM outperformed the ETFE-AEM in H2/O2 anionexchange
membrane fuel cell (AEMFC) tests due to high anion conductivity and enhanced in situ water transport (due to the
lower density of the LDPE precursor): a maximum power density of 1.45 W cm-2 at 80 °C was achieved with an LDPE-AEM
alongside a Pt-based anode and cathode (cf. 1.21 mW cm-2 for the benchmark ETFE-AEM). The development of more
mechanically robust RG-AEMs has, for the first time, led to the ability to routinely test them in fuel cells at 80 °C (cf. 60 °C
was the prior maximum temperature that could be routinely used with ETFE-based RG-AEMs). This development facilitates
the application of non-Pt catalysts: 931 mW cm-2 was obtained with the use of a Ag/C cathode at 80 °C and a Ag loading of
0.8 mg cm-2 (only 711 mW cm-2 was obtained at 60 °C). This first report on the synthesis of large batch size LDPE-based RGAEMs,
using the commercially amenable peroxidation-type radiation-grafting process, concludes that the resulting LDPEAEMs
are superior to ETFE-AEMs (for the intended applications).
Ponce-González J, Ouachan I, Varcoe John, Whelligan Daniel (2017) Radiation-induced grafting of a butyl-spacer styrenic monomer
onto ETFE: the synthesis of the most alkali stable radiationgrafted
anion-exchange membrane to date
JOURNAL OF MATERIALS CHEMISTRY A 6 (3) pp. 823-827 The Royal Society of Chemistry
An ETFE-(poly(ethylene-co-tetrafluoroethylene))-based radiationgrafted
anion-exchange membrane (AEM) containing a butylspacer
between the benzene and the methylpyrrolidinium groups
(C4-AEM) had double the ex-situ alkali stability at 80 °C compared
to a methylene benchmark (C1-AEM). H2/O2 fuel cells containing
the C4-AEM still achieved a peak power density of > 1 W cm-2.
A major disadvantage of fossil fuels being the primary source of global energy is the negative effect that the burning of such fuels has on the planet. This is evident in factors including climate change. Reverse electrodialysis (RED) is an emerging membrane-based process for clean energy conversion. The technique works by utilising the transport of cations and anions through ion-exchange membranes (IEMs) to create an electrical current, via differences in chemical potential, when mixing salt solutions of different concentrations. The core components of a RED cell, and the largest factor affecting the performance and economic viability, are the IEMs.
Recently, increased efforts have been made with regard to the preparation of IEMs and understanding the relationships between membrane properties and RED cell power performance. The work in this thesis has focused on the development of RED-focused IEMs by radiation induced grafting polymerisation (RIG). The RIG technique has been used to chemically modify commercially available polymer films to produce a large sample of IEMs targeted for application in RED. The IEM properties were experimentally determined and used as part of a literature recognised mathematical model to estimate the gross power densities that can theoretically be obtained by each IEM in a working RED cell.
The results obtained for RIG IEMs contradicts the earlier notion that IEM permselectivity is of less significance than area resistance and indicate that a minimum permselectivity (H 90%) is required for RED IEMs. A trade-off relationship between the two properties is observed, rationalised by Donnan exclusion factors surrounding IEM water content. Chemical crosslinking was implemented into RIG methods to control excessive gravimetric water uptake (WU%). Linear tertiary diamine head-groups were used to produce crosslinked anion-exchange membranes (AEMs), with tetramethylhexanediamine (TMHDA) head-group yielding theoretical gross power densities of 3.42 W m-2 for single IEM RED model calculations and 1.89 W m-2 for AEM/CEM pair calculations (paired with literature SPEEK 65 CEM). Crosslinked CEMs were produced via chemical crosslinking by divinylbenzene (DVB) and bis(vinylphenyl)ethane (BVPE) was implemented into the RIG method, which resulted in cation-exchange membranes (CEMs) yielding theoretical gross power densities of 5.55 and 5.99 W m-2 respectively, for single IEM RED model calculations and 2.81 and 2.71 W m-2 for AEM/CEM pair calculations (paired with commercial Neospeta® AFN AEM).
Ponce-González J, Varcoe John, Whelligan Daniel (2018) Commercial monomer availability leading to missed opportunities?
Anion-exchange membranes made from meta-vinylbenzyl chloride
exhibit an alkali stability enhancement
ACS Applied Energy Materials 1 (5) pp. 1883-1887 American Chemical Society
Benzyltrimethylammonium-type anion-exchange polymers are
common in alkali membrane fuel cells and water electrolysers but
they suffer from degradation under alkaline conditions. Radiationgrafted
anion-exchange membranes exhibit an alkali stability enhancement
when made using non-commercial meta-only vinylbenzyl
chloride (VBC) monomer, compared to the use of commercially
available para-only or meta/para-mixed VBC isomers. We hypothesize
a mechanism on why the use of meta-VBC eliminates AEM
degradation via chain scission.
The base excision DNA repair (BER) enzyme alkyladenine glycosylase (AAG) can drive DNA damage-induced cell death in specific cell types in mice and can induce frameshift mutagenesis and microsatellite instability in yeast and in human cells. It was hypothesised that humans with overactive AAG, or who encounter higher levels of alkylating agents in the form of pollution, diet or chemotherapy, or suffer an ischaemic reperfusion event such as a stroke, may incur increased tissue damage through this mechanism. An inhibitor of AAG is required to further study this mechanism and form a potential lead for future drug discovery.
In previous work, to discover an inhibitor, a published X-ray co-crystal structure of AAG was used in a virtual screen of two million compounds for potential binding activity. Of the top 49 virtual hits, one real hit triazole-thione-based inhibitor (UNIS00021) with an IC50 of ~60 µM was identified in a biochemical assay. In this thesis, efforts to design and synthesise analogues of UNIS00021 with improved potency against AAG are described.
Successful divergent syntheses were developed which provided access to: 1. analogues varying at the alkyl group of the amide (six different amides); 2. analogues with a free amine in place of the amide and with variation of the length of the alkyl linkage group (five different amines); and 3. analogues bearing a C5-methyl group instead of thiol/thione at the core (one cyclohexylamide triazole). Work was also begun on the synthesis of analogues varying the N4-CH2-aryl group but was not completed due to time constraints.
Two main types of microplate biochemical assay were investigated for assessment of the candidate inhibitors? potencies against AAG using: 1. a surface-bound fluorescein-conjugated substrate DNA-oligomer; and 2. a free substrate oligomer and LCMS. Despite much experimentation, these assays continued to show inconsistent and irreproducible inhibition curves so it was not possible to make conclusions about the candidate inhibitors? potencies.
The action of the DNA repair enzyme alkyladenine DNA glycosylase (AAG), as part of the Base Excision Repair pathway, on alkylation-induced DNA damage has been shown in mice to lead to cell death in the retina, spleen, thymus and cerebellum. The action of AAG has also been linked to damage caused by ischaemia/reperfusion (I/R) events in liver, brain and kidney.
As a result, small molecule inhibitors of AAG are required for ongoing studies into the biological mechanism of this cellular damage, as well as to become potential drug leads for some types of retinal degeneration, I/R-related tissue damage, or as protective agents for patients undergoing alkylative chemotherapy and showing an increased AAG activity. They could also serve the opposite effect, acting as an alkylating agent (TMZ) sensitiser in paediatric glioblastoma (GBM).
Two DNA oligomers, containing etheno-cytidine or an abasic pyrrolidine, are reported in the literature to show potent AAG inhibition in vitro. Unfortunately, their size and the charged nature of DNA chains makes them unsuitable for use as potential drug leads in vivo, as they would show low membrane permeability and face degradation by nucleases. However, the motifs present in these oligomers, together with examination of the enzyme active site, led to the conception of two types of small drug-like pyrrolidine-based inhibitor candidates termed 2-(hydroxymethyl)pyrrolidines and 4-(hydroxymethyl)pyrrolidines.
The synthetic routes to these inhibitor candidates have been studied and optimised. That to the 2-(hydroxymethyl)pyrrolidines failed at the final step of attachment of DNA base-mimicking aryl groups. However, five 4-(hydroxymethyl)pyrrolidines nucleoside mimetics were successfully synthesised, bearing imidazole and pyridine groups to represent a DNA base. These were subsequently tested in vitro against AAG in a surface-bound hairpin loop colorimetric DNA oligomer assay. The most promising candidate, (+)-395, showed an IC50 of 157 µM corresponding to a ligand efficiency of 0.37 kcal·mol-1·heavy atom-1. Due to its low molecular weight (197 g·mol-1), this inhibitor constitutes a viable starting point for a future lead optimisation programme.
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.
This study involved two separate projects, both of which explored the application of RAFT polymerisation for the synthesis of well-defined star polymer-peptide conjugates and developed hydrogels from synthesised star polymer conjugates.
The first project aimed to develop an in situ forming hydrogel from star poly(N-(2hydroxypropyl)methacrylamide) (PHPMA) via covalent cross-linking, catalysed by Sortase A enzyme (SrtA). The use of SrtA as a cross-linking enzyme for hydrogel-based tissue engineering has been only reported previously by Broguiere et al., Arkenberg and Lin. 1,2 Both groups employed mutant enzymes with enhanced kinetics to achieve fast gelation whereas a wild type SrtA was employed in this work. Well defined star PHPMA (Ð The second project focused on developing thermo-responsive hydrogels of the selfassembling peptide CFEFEFKFKK by doping the hydrogels with star (2-, 3-, and 4- arm) poly(N-isopropylacrylamide) (PNIPAM)/CFEFEFKFKK conjugates (C, cysteine; F, phenylalanine; E, glutamic acid; K, lysine). The work was based on a study by Maslovskis et al. who created the novel composite hydrogels containing FEFEFKFK peptide and linear PNIPAM-FEFEFKFK conjugates.3 Well-defined star PNIPAM (Ð
The work in this thesis considers the development and optimisation of methods with regards to the synthesis and formation of polymeric nanomaterials. A particular focus is placed on synthesising polymers based on N-2-hydroxypropyl methacrylamide (HPMA) and µ-caprolactone (PCL) with regards to drug delivery applications. Polyethylene glycol (PEG) and PEG-based materials were intentionally avoided due to the growing body of research surrounding the accelerated blood clearance phenomenon.

Reversible addition-fragmentation chain transfer (RAFT) polymerisation was employed in the synthesis of linear, block and branched forms of poly(N-(2-hydroxypropyl)methacrylamide) (PHPMA). Linear PHPMA was synthesised according to established synthetic methods and found to yield well defined materials (12 ? 17 kg mol-1; Ð 1.02 ? 1.08). Homotelechelic PCL with terminal RAFT functionalities was employed as a macro-CTA in the synthesis of PHPMA-b-PCL-b-PHPMA triblock copolymers. After optimisation of the reaction conditions a reasonably well-defined amphiphilic polymer was obtained (Mn 29 kg mol-1; Ð 1.41) which was observed to undergo spontaneous self-assembly in water (average particle diameter 44 nm). Alternative synthetic routes utilising click methodologies (thiol-ene, hetero-Diels-Alder and copper azide-alkyne cycloaddition) were investigated but ultimately did not yield any improvements when compared to the macro-CTA grafting-from approach. Hyperbranched PHPMA was synthesised by a free-radical crosslinking copolymerisation method which utilised ethylene glycol dimethacrylate (EGDMA) as a divinyl crosslinking agent. Extensive characterisation of branching parameters was performed using a combination of triple detection size-exclusion chromatography (SEC) and 1H NMR. After optimising the reaction conditions, three hyperbranched copolymers of HPMA and acetylated-HPMA (APMA) were synthesised; surface RAFT moieties underwent additional polymerisation with HPMA to ultimately yield novel PHPMA-star-(hb-PHPMA-co¬-PAPMA) core-crosslinked amphiphilic star copolymers (Mn 139 ? 243 kg mol-1, Ð 1.07 ? 1.27).

Additionally, charge controlled nanoprecipitation of homotelechelic carboxyl terminated PCLs in a range of alkaline pH buffered solutions was performed according to a literature procedure. The lowest diameter particles were observed to form when precipitation was performed in a pH 9 aqueous phase (14 ± 1 nm), as determined by dynamic light scattering (DLS).
Overall, synthesis of PHPMA-b-PCL-b-PHPMA block copolymer at higher molecular weight and lower dispersity than previously reported materials from a homotelechelic dithiobenzoate macro-CTA was achieved. Furthermore, three novel PHPMA-star-(hb-(PHPMA-co-PAPMA)) copolymers were synthesised and the branching parameters of the hydrophobic core characterised by 1H NMR spectroscopy. Preliminary work into developing a scalable synthetic procedure for producing PCL nanoparticles was undertaken. Under optimal conditions PCL-oTHPA nanoparticles were produced with a number-average particle diameter of 14 ± 1 nm (error is ± 1 S.D.).

Mas Claret Eduard, Al Yahyaei Balqees, Chu Shuyu, Elliott Ruan M., Imperato Manuel, Lopez Arnaud, Meira Lisiane B., Howlin Brendan J., Whelligan Daniel K. (2020) An aza-nucleoside, fragment-like inhibitor of the DNA repair enzyme alkyladenine glycosylase (AAG),Bioorganic & Medicinal Chemistry 28 (11) 115507 Elsevier
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.
Gérard Samuel F., Hall Belinda S., Zaki Afroditi M., Corfield Katherine A., Mayerhofer Peter U., Costa Catia, Whelligan Daniel K., Biggin Philip C., Simmonds Rachel E., Higgins Matthew K. (2020) Structure of the Inhibited State of the Sec Translocon,Molecular Cell 79 (3) pp. 406-415 Cell Press
Protein secretion in eukaryotes and prokaryotes involves a universally conserved protein translocation chan-nel formed by the Sec61 complex. Unrelated small-molecule natural products and synthetic compoundsinhibit Sec61 with differential effects for different substrates or for Sec61 from different organisms, makingthis a promising target for therapeutic intervention. To understand the mode of inhibition and provide insightinto the molecular mechanism of this dynamic translocon, we determined the structure of mammalian Sec61inhibited by theMycobacterium ulceransexotoxin mycolactone via electron cryo-microscopy. Unexpect-edly, the conformation of inhibited Sec61 is optimal for substrate engagement, with mycolactone wedgingopen the cytosolic side of the lateral gate. The inability of mycolactone-inhibited Sec61 to effectively trans-port substrate proteins implies that signal peptides and transmembrane domains pass through the site occu-pied by mycolactone. This provides a foundation for understanding the molecular mechanism of Sec61 inhib-itors and reveals novel features of translocon function and dynamics.