Daniel Whelligan

Dr Daniel Whelligan MSci, PhD


Senior Lecturer in Organic/Medicinal Chemistry

Academic and research departments

Department of Chemistry.

Biography

University roles and responsibilities

  • Departmental Assessments Officer (2019 - present)
  • MSc Drug Discovery Programme Director (2011 - 2015)
  • MRes Chemistry Programme Director (2015 - 2019)

    Research

    Research interests

    Research projects

       

        Research Group and Facilities

        Current PhD Students

        Thomas Warren (3rd year)

        Jacob Hiles (2nd year)

        Isobel Beard (1st year)

        Nermin Ener (1st year)

        Applications for PhD Studentships

        Any funded PhD studentships that become available will be advertised on the University of Surrey Chemistry PhD website. Applications from self-funded or overseas government-funded students are welcome. Please email Daniel Whelligan in the first instance.

        Facilities

        All organic synthesis is carried out in the recently refurbished Joseph Kenyon laboratory containing 24 state-of-the-art double fume cupboards, spectroscopy suite and cold room. The lab was shortlisted for the 'Safe, Successful and Sustainable Laboratory Award 2014' and is equipped with all necessary equipment for normal and air-sensitive organic chemistry.

        The Department possesses 500 and 400 MHz NMR spectrometers, an Agilent 6550 QToF LCMS and several LCMS, GCMS, IR and UV-Vis instruments.

        My teaching

        My publications

        Publications

        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.

        S Quideau, L Pouysegu, AV Avellan, DK Whelligan, MA Looney (2001)Hypervalent iodine(III)-mediated oxidative acetoxylation of 2-methoxyphenols for regiocontrolled nitrogen benzannulation, In: Tetrahedron Lett42(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.

        S Quideau, L Pouysegu, AV Avellan, DK Whelligan (2001)Synthetic studies on Amaryllidaceae lycorine-type alkaloids., In: ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY221pp. U199-U199 AMER CHEMICAL SOC
        Lianqin Wang, E Magliocca, E Cunningham, W Mustain, S Poynton, R Escudero-Cid, M Nasef, J Ponce-Gonzalez, R Bance-Souahli, Robert Slade, Daniel Whelligan, John Varcoe (2016)An optimised synthesis of high performance radiation-grafted anion-exchange membranes, In: Green Chemistry19pp. 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 μm 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.

        PG Steel, DK Whelligan (2002)Silenes: Novel reagents for alkene functionalisation., In: ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY224pp. U161-U161 AMER CHEMICAL SOC

        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.

        Samuel F. Gérard, Belinda S. Hall, Afroditi M. Zaki, Katherine A. Corfield, Peter U. Mayerhofer, Catia Costa, Daniel K. Whelligan, Philip C. Biggin, Rachel E. Simmonds, Matthew K. Higgins (2020)Structure of the Inhibited State of the Sec Translocon, In: Molecular Cell79(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.

        MJ Sanganee, PG Steel, DK Whelligan (2003)Novel one-pot synthesis of aryltris(trimethylsilyl)silanes., In: J Org Chem68(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.

        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.

        DK Whelligan (2009)Benzotriazole Linker Units, In: Linker Strategies in Solid-Phase Organic Synthesis(11) Wiley

        Syntheses of polymer-supported benzotriazoles Polymer-supported benzotriazole linked reactions

        MB Berry, RJ Griffiths, MJ Sanganee, PG Steel, DK Whelligan (2004)Silenes as novel synthetic reagents: identification of a practical method for silene generation and trapping., In: Org Biomol Chem2(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).

        J Ponce-González, DK Whelligan, Lianqin Wang, Rachida Bance-Soualhi, Ying Wang, Y Peng, H Peng, DC Apperley, HN Sarode, TP Pandey, AG Divekar, S Seifert, AM Herring, L Zhuang, John Varcoe (2016)High performance aliphatic-heterocyclic benzyl-quaternary ammonium radiation-grafted anion-exchange membranes, In: Energy and Environmental Science9(12)pp. 3724-3735 Royal Society of Chemistry

        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 μm 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 μm thick variant (synthesised from 50 μm 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 μm thick variant (synthesised from 25 μm 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.

        C Beemelmanns, R Husmann, DK Whelligan, S Özçubukçu, C Bolm (2012)Planar-Chiral Bis-silanols and Diols as H-Bonding Asymmetric Organocatalysts, In: Eur J Org Chempp. 3373-3376
        AL Ong, KK Inglis, DK Whelligan, S Murphy, JR Varcoe (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)), In: PHYSICAL CHEMISTRY CHEMICAL PHYSICS17(18)pp. 12135-12145 ROYAL SOC CHEMISTRY
        AL Ong, Daniel Whelligan, ML Fox, John Varcoe (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)), In: PHYSICAL CHEMISTRY CHEMICAL PHYSICS15(43)pp. 18992-19000 ROYAL SOC CHEMISTRY

        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.

        J Ponce-González, John Varcoe, Daniel Whelligan (2018)Commercial monomer availability leading to missed opportunities? Anion-exchange membranes made from meta-vinylbenzyl chloride exhibit an alkali stability enhancement, In: ACS Applied Energy Materials1(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.

        DK Whelligan, S Solanki, D Taylor, DW Thomson, KMJ Cheung, K Boxall, C Mas-Droux, C Barillari, S Burns, CG Grummitt, I Collins, RLM van Montfort, GW Aherne, R Bayliss, S Hoelder (2010)Aminopyrazine Inhibitors Binding to an Unusual Inactive Conformation of the Mitotic Kinase Nek2: SAR and Structural Characterization, In: J Med Chem53(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.

        DK Whelligan, DW Thomson, D Taylor, S Hoelder (2010)Two-Step Synthesis of Aza- and Diazaindoles from Chloroamino-N-heterocycles Using Ethoxyvinylborolane, In: J Org Chem75(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.

        Lianqin Wang, JJ Brink, Y Liu, AM Herring, J Ponce-González, Daniel Whelligan, John Varcoe (2017)Non-fluorinated pre-irradiation-grafted (peroxidated) LDPE-based anion-exchange membranes with high performance and stability, In: Energy & Environmental Science10pp. 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 μm in thickness, which led to RG-AEMs of hydrated thicknesses in the range 52 – 60 μm. 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).

        Ana Laura Gonçalves Biancolli, Daniel Herranz, Lianqin Wang, Gabriela Stehlíkov, Rachida Bance-Soualhi, Julia Ponce-González, Pilar Ocón, Edson A. Ticianelli, Daniel K. Whelligan, John R. Varcoe, Elisabete I. Santiago (2018)ETFE-based anion-exchange membrane ionomer powders for alkaline membrane fuel cells: a first performance comparison of head-group chemistry, In: Journal of Materials Chemistry A Royal Society of Chemistry

        In the last few years, the development of radiation-grafted powder-form anion-exchange ionomers (AEI), used in combination with anion-exchange membranes (AEM), have led to the assembly of AEM-based fuel cells (AEMFC) that routinely yield power densities ranging between 1 – 2 W cm-2 (with a variety of catalysts). However, to date, only benzyltrimethyammonium-type powder AEIs have been evaluated in AEMFCs. This study presents an initial evaluation of the relative AEMFC power outputs when using a combination of ETFE-based radiation-grafted AEMs and AEIs containing three different head-group chemistries: benzyltrimethylammonium (TMA), benzyl-N-methylpyrrolidinium (MPY), and benzyl-N-methylpiperidinum (MPRD). The results from this study strongly suggest that future research should focus on the development and operando long-term durability testing of AEMs and AEIs containing the MPRD head-group chemistry.

        L Wylie, P Innocenti, DK Whelligan, S Hoelder (2012)Synthesis of amino-substituted indoles using the Bartoli reaction, In: Org Biomol Chem10(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.

        Eduard Mas Claret, Balqees Al Yahyaei, Shuyu Chu, Ruan M. Elliott, Manuel Imperato, Arnaud Lopez, LISIANE BORGES MEIRA, Brendan J. Howlin, Daniel K. Whelligan (2020)An aza-nucleoside, fragment-like inhibitor of the DNA repair enzyme alkyladenine glycosylase (AAG), In: Bioorganic & Medicinal Chemistry28(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.

        MB Berry, RJ Griffiths, MJ Sanganee, PG Steel, DK Whelligan (2003)Silenes as novel synthetic reagents: synthesis of diols and lactones from simple alkyldienes, In: Tetrahedron Lett44(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.

        J Ponce-González, I Ouachan, John Varcoe, Daniel Whelligan (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, In: JOURNAL OF MATERIALS CHEMISTRY A6(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.