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Journal articleCiccarelli D, Lancaster BMJ, Braddock DC, et al., 2024,
Structure confirmation, reactivity, bacterial mutagenicity and quantification of 2,2,4-tribromo-5-hydroxycyclopent-4-ene-1,3-dione in drinking water
, Communications Chemistry, Vol: 7, ISSN: 2399-3669The presence of two new disinfectant by-product (DBP) groups in the UK was recently shown using non-target analysis, halogenated-hydroxycyclopentenediones and halogenated-methanesulfonic acids. In this work, we confirmed the structure of 2,2,4-tribromo-5-hydroxycyclopent-4-ene-1,3-dione (TBHCD), and quantified it together with dibromomethanesulfonic acid at 122 ± 34 and 326 ± 157 ng L−1 on average in London’s drinking water, respectively (n = 21). We found TBHCD to be photolabile and unstable in tap water and at alkaline pH. Furthermore, spectral and computational data for TBHCD and three other halogenated-hydroxycyclopentenediones indicated they could act as a source of radicals in water and in the body. Importantly, TBHCD was calculated to have a 14.5 kcal mol−1 lower C-Br bond dissociation enthalpy than the N-Br bond of N-bromosuccinimide, a common radical substitution reagent used in organic synthesis. TBHCD was mutagenic in Salmonella/microsome assays using strains TA98, TA100 and TA102. This work reveals the unique features, activity and toxicity of trihalogenated hydroxycyclopent-4-ene-1,3-diones, prompting a need to more comprehensively assess their risks.
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Journal articleLancaster BMJ, White AJP, Braddock DC, 2024,
Fortuitous enantiomeric self‐rectification of an unreported partial racemisation in the synthesis of a chiral phosphoric acid: a warning to practitioners
, Chemistry – A European Journal, ISSN: 0947-6539Racemisation without Consequence: MOM deprotection of an ether intermediate during a routine synthesis of phosphoric acid 1 promoted partial racemisation of the product BINOL 5. Surprisingly, however, after phosphorylation of the partially racemised BINOL, enantiopure acid 1 was isolated. Further inspection revealed that during phosphorylation, unhydrolysed racemic phosphorochloridate 6 precipitated, thus restoring homochirality in the product phosphoric acid 1. Moreover, MOM deprotection partial racemisation was avoided by conducting reactions at lower temperatures for no longer than the required deprotection time, and/or by application of other deprotection conditions from the literature.
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Journal articleBraddock DC, Lee S, Rzepa HS, 2024,
Modelling kinetic isotope effects for Swern oxidation using DFT-based transition state theory
, Digital Discovery, Vol: 3, Pages: 1496-1508We investigate the model reported by Giagou and Meyer in 2010 for comparing deuterium kinetic isotope effects (KIEs) computed using density functional theory (DFT) for the intramolecular hydrogen transfer step in the mechanism of the Swern oxidation of alcohols to aldehydes, with those measured by experiment. Whereas the replication of the original computed values for the gas-phase reaction proved entirely successful, several issues were discovered when a continuum solvent model was used. These included uncertainty regarding the parameters and methods used for the calculations and also the coordinates for the original reactant and transition structures, via their provision as data in the ESI. The original conclusions, in which a numerical mis-match between the magnitude of the computed and experimentally measured KIE was attributed to significant deviations from transition structure theory, are here instead rationalised as a manifestation of basis-set effects in the computation. Transition state theory appears to be operating successfully. We now recommend the use of basis sets of triple- or quadruple-ζ quality, rather than the split-valence level previously employed, that dispersion energy corrections be included and that a continuum solvent model using smoothed reaction cavities is essential for effective geometry optimisation and hence accurate normal coordinate analysis. An outlying experimental KIE obtained for chloroform as solvent is attributed to a small level of an explicit hydrogen bonded interaction with the substrate. A temperature outlier for the measured KIE at 195 K is suggested for further experimental investigation, although it may also be an indication of an unusually abrupt incursion of hydrogen tunnelling which would need non-Born-Oppenheimer methods in which nuclear quantum effects are included to be more accurately modelled. We predict KIEs for new substituents, of which those for R = NMe2 are significantly larger than those for R = H. Thi
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Journal articleJantan KA, Ekart G, McCarthy S, et al., 2024,
Palladium complexes derived from waste as catalysts for C-H functionalisation and C-N bond formation
, Catalysts, Vol: 14, ISSN: 2073-4344Three-way catalysts (TWCs) are widely used in vehicles to convert the exhaust emissions from internal combustion engines into less toxic pollutants. After around 8–10 years of use, the declining catalytic activity of TWCs causes them to need replacing, leading to the generation of substantial amounts of spent TWC material containing precious metals, including palladium. It has previously been reported that [NnBu4]2[Pd2I6] is obtained in high yield and purity from model TWC material using a simple, inexpensive and mild reaction based on tetrabutylammonium iodide in the presence of iodine. In this contribution, it is shown that, through a simple ligand exchange reaction, this dimeric recovery complex can be converted into PdI2(dppf) (dppf = 1,1′-bis(diphenylphosphino)ferrocene), which is a direct analogue of a commonly used catalyst, PdCl2(dppf). [NnBu4]2[Pd2I6] displayed high catalytic activity in the oxidative functionalisation of benzo[h]quinoline to 10-alkoxybenzo[h]quinoline and 8-methylquinoline to 8-(methoxymethyl)quinoline in the presence of an oxidant, PhI(OAc)2. Near-quantitative conversions to the desired product were obtained using a catalyst recovered from waste under milder conditions (50 °C, 1–2 mol% Pd loading) and shorter reaction times (2 h) than those typically used in the literature. The [NnBu4]2[Pd2I6] catalyst could also be recovered and re-used multiple times after the reaction, providing additional sustainability benefits. Both [NnBu4]2[Pd2I6] and PdI2(dppf) were also found to be active in Buchwald–Hartwig amination reactions, and their performance was optimised through a Design of Experiments (DoE) study. The optimised conditions for this waste-derived palladium catalyst (1–2 mol% Pd loading, 3–6 mol% of dppf) in a bioderived solvent, cyclopentyl methyl ether (CPME), offer a more sustainable approach to C-N bond formation than comparable amination protocols.
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Journal articleBraddock D, Rowley B, Lickiss P, et al., 2023,
On the use of triarylsilanols as catalysts for direct amidation of carboxylic acids
, Journal of Organic Chemistry, Vol: 88, Pages: 9853-9869, ISSN: 0022-3263Triarylsilanols are reported as the first silicon-centred molecular catalysts for direct amidation of carboxylic acids with amines as identified after a screen of silanols, silanediols, disiloxanediols and incompletely condensed silsesquioxanes as potential homogeneous catalysts. Subsequent synthesis and testing of various electronically differentiated triarylsilanols identify tris(p-haloaryl)silanols as more active than the parent triarylsilanol, where the bromide congener was found to be the most active. Catalyst decomposition can be observed by NMR methods, but RPKA methods reveal that product inhibition is operative, where tertiary amides are more inhibitory than secondary amides. Studies using an authentically synthesised triaryl silylester as a putative intermediate in the catalytic system enable a plausible mechanism to be proposed as supported by computations.
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Journal articleBraddock D, Lancaster B, Tighe C, et al., 2023,
Surmounting byproduct inhibition in an intermolecular catalytic asymmetric alkene bromoesterification reaction as revealed by kinetic profiling
, Journal of Organic Chemistry, Vol: 88, Pages: 8904-8914, ISSN: 0022-3263Kinetic profiling has shown that a (DHQD)2PHAL catalysed intermolecular asymmetric alkene bromoesterification reaction is inhibited by primary amides, imides, hydantoins and secondary cyclic amides, which are by-products of common stoichiometric bromenium ion sources. Two approaches to resolving the inhibition are presented enabling the (DHQD)2PHAL loading to be dropped from 10 to 1 mol% while maintaining high bromoester conversions over short reaction times. Iterative post-reaction recrystallisations enabled a homochiral bromonaphthoate ester to be synthesised using only 1 mol% (DHQD)2PHAL.
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Journal articleCiccarelli D, Christopher Braddock D, Surman AJ, et al., 2023,
Enhanced selectivity for acidic contaminants in drinking water: From suspect screening to toxicity prediction
, Journal of Hazardous Materials, Vol: 448, Pages: 1-12, ISSN: 0304-3894A novel analytical workflow for suspect screening of organic acidic contaminants in drinking water is presented, featuring selective extraction by silica-based strong anion-exchange solid-phase extraction, mixed-mode liquid chromatography-high resolution accurate mass spectrometry (LC-HRMS), peak detection, feature reduction and compound identification. The novel use of an ammonium bicarbonate-based elution solvent extended strong anion-exchange solid-phase extraction applicability to LC-HRMS of strong acids. This approach performed with consistently higher recovery and repeatability (88 ± 7 % at 500 ng L-1), improved selectivity and lower matrix interference (mean = 12 %) over a generic mixed-mode weak anion exchange SPE method. In addition, a novel filter for reducing full-scan features from fulvic and humic acids was successfully introduced, reducing workload and potential for false positives. The workflow was then applied to 10 London municipal drinking water samples, revealing the presence of 22 confirmed and 37 tentatively identified substances. Several poorly investigated and potentially harmful compounds were found which included halogenated hydroxy-cyclopentene-diones and dibromomethanesulfonic acid. Some of these compounds have been reported as mutagenic in test systems and thus their presence here requires further investigation. Overall, this approach demonstrated that employing selective extraction improved detection and helped shortlist suspects and potentially toxic chemical contaminants with higher confidence.
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Journal articleMcCarthy S, Desaunay O, Lee Wei Jie A, et al., 2022,
Homogeneous gold catalysis using complexes recovered from waste electronic equipment
, ACS Sustainable Chemistry and Engineering, Vol: 10, Pages: 15726-15734, ISSN: 2168-0485Despite the greater awareness of elemental sustainability and the benefits of the circular economy concept, much waste electrical and electronic equipment (WEEE) is still destined for landfill. Effective methods for valorizing this waste within our society are therefore imperative. In this contribution, two gold(III) complexes obtained as recovery products from WEEE and their anion metathesis products were investigated as homogenous catalysts. These four recovery products were successfully applied as catalysts for the cyclization of propargylic amides and the condensation of acetylacetone with o-iodoaniline. Impressive activity was also observed in the gold-catalyzed reaction between electron-rich arenes (2-methylfuran, 1,3-dimethoxybenzene, and azulene) and α,β-unsaturated carbonyl compounds (methyl vinyl ketone and cyclohexenone). These recovered compounds were also shown to be effective catalysts for the oxidative cross-coupling reaction of aryl silanes and arenes. When employed as Lewis acid catalysts for carbonyl-containing substrates, the WEEE-derived gold complexes could also be recovered at the end of the reaction and reused without loss in catalytic activity, enhancing still further the sustainability of the process. This is the first direct application in homogeneous catalysis of gold recovery products sourced from e-waste.
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Journal articleBraddock D, Duran-Corbera A, Nilforoushan M, et al., 2022,
(±)-Polysiphenol and other Analogues via Symmetrical Intermolecular Dimerizations: a Synthetic, Spectroscopic, Structural and Computational Study
, Journal of Natural Products, Vol: 85, Pages: 2650-2655, ISSN: 0163-3864We report an improved total synthesis of 4,5-dibromo-9,10-dihydrophenanthrene-2,3,6,7-tetraol, (±)-polysiphenol, via intermolecular McMurray dimerization of 5-bromovanillin and subsequent intramolecular oxidative coupling as the key steps. The synthetic route is applicable to 4,5-dichloro- and 4,5-difluoro-halologues (as well as a 4,5-dialkyl-analogue). Distinctive AA′BB′ multiplets in their 1H NMR spectra for the dimethylene bridges of the dibromo and dichloro compounds reveal them to be room-temperature stable atropisomers, while for the difluoro compound they present as a singlet. X-ray crystal structure determinations of their tetramethylated synthetic precursors show atropisomeric twist angles of 48°, 46°, and 32°, respectively, with the former representing the largest yet observed in any 4,5-disubstituted-9,10-dihydrophenanthrene. DFT computational studies reveal an unprecedented two-stage atropisomeric interconversion process involving time-independent asynchronous rotations of the dimethylene bridge and the biaryl axis for halologues containing chlorine or bromine, but a more synchronous rotation for the difluoro analogue.
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Journal articleBraddock D, Limpaitoon N, Oliwa K, et al., 2022,
A stereoselective hydride transfer reaction with contributions from attractive dispersion force control
, Chemical Communications, Vol: 58, Pages: 4981-4984, ISSN: 1359-7345The experimentally determined stereochemical outcome of an unprecedented hydride transfer from a lithium alkoxide to an aldehyde is reported, as deconvoluted by the combined use of a single enantiomer alkoxide in conjunction with a deuterium label. The stereoselective outcome is consistent with a computationally predicted transition state model stabilised by contributions from attractive dispersion forces.
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Journal articleBraddock D, Davies J, Lickiss P, 2022,
Methyltrimethoxysilane (MTM) as a reagent for direct amidation of carboxylic acids
, Organic Letters, Vol: 24, Pages: 1175-1179, ISSN: 1523-7052Methyltrimethoxysilane [MTM, CH3Si(OMe)3] has been demonstrated to be an effective, inexpensive, and safe reagent for the direct amidation of carboxylic acids with amines. Two simple workup procedures that provide the pure amide product without the need for further purification have been developed. The first employs an aqueous base-mediated annihilation of MTM. The second involves simple product crystallization from the reaction mixture providing a low process mass intensity direct amidation protocol.
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Journal articleMcCarthy S, Braddock D, Wilton-Ely J, 2021,
Strategies for sustainable palladium catalysis
, Coordination Chemistry Reviews, Vol: 442, Pages: 1-26, ISSN: 0010-8545Palladium is established both as an indispensable metal in modern synthetic chemistry and as a key component in catalytic converters and electronic equipment. The unrelenting demand for this metal increases both the financial and environmental cost, through mining, of this metal, rendering consumption unsustainable in its current form. This review provides a critical survey of the main approaches being pursued to address this issue, including low-loading catalysis, recyclable catalysts and the use of palladium recovered from secondary sources. The literature discussed herein reveals that catalysts that operate at low loadings are an attractive, sustainable option for many transformations, even when compared to catalyst systems that can be reused multiple times. Both low-loading and reusable catalysts depend on a finite natural supply of palladium, making the development of catalysts based on metal recovered from end-of-life materials (urban mining) a promising field of research. The way in which low-loading is achieved in different catalyst designs influences the choice of reaction temperature and solvent, which has additional environmental implications. Such factors are discussed for a wide range of systems alongside reaction and substrate scope, supported by extensive supplementary information. The survey aims to provide an insight into the relative merits of the approaches being explored and how the field of palladiumbased catalysis might progress towards more sustainable use of this critical metal.
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Journal articleMcCarthy S, Lee Wei Jie A, Braddock D, et al., 2021,
From waste to green applications: the use of recovered gold and palladium in catalysis
, Molecules, Vol: 26, ISSN: 1420-3049The direct use in catalysis of precious metal recovery products from industrial and consumer waste is a very promising recent area of investigation. It represents a more sustainable, environmentally benign, and profitable way of managing the low abundance of precious metals, as well as encouraging new ways of exploiting their catalytic properties. This review demonstrates the feasibility and sustainability of this innovative approach, inspired by circular economy models, and aims to stimulate further research and industrial processes based on the valorisation of secondary resources of these raw materials. The overview of the use of recovered gold and palladium in catalytic processes will be complemented by critical appraisal of the recovery and reuse approaches that have been proposed.
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Journal articleDavies J, Braddock D, Lickiss P, 2021,
Silicon compounds as stoichiometric coupling reagents for direct amidation
, Organic and Biomolecular Chemistry, Vol: 19, Pages: 6746-6760, ISSN: 1477-0520Despite being one of the most frequently carried out chemical reactions in industry, there is currently no amidation protocol that is regarded as safe, high yielding, environmentally friendly and inexpensive. The direct amidation of a carboxylic acid with an amine is viewed as an inherently good solution for developing such a protocol. Since the 1960s, there has been a gradual development in the use of silicon reagents for direct amidation. This review covers the methods published to April 2021 for silicon reagent mediated direct amidation of a carboxylic acid with an amine. This review also covers the use of polymeric SiO2 to promote direct amidation.
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Journal articleBahou K, Braddock D, Meyer A, et al., 2020,
Relay cross metathesis for the iterative construction of terpenoids and synthesis of a diterpene benzoate macrolide of biogenetic relevance to the bromophycolides
, Organic Letters, Vol: 22, Pages: 3176-3179, ISSN: 1523-7052We report a relay cross metathesis (ReXM) reaction for the construction of terpenoids in an iterative protocol. The protocol features the cross metathesis of a relay-actuated Δ6,7-functionalized C10-monoterpenoid alcohol with C10-monoterpenoid citral to form a C15-sesquiterpene. Subsequent functional group manipulation allows for the method to be repeated in an iterative fashion. The method is used for the synthesis of a diterpene-benzoate macrolide of biogenetic relevance to the bromophycolide family of natural products.
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