Professor William Lockley

Simulated ageing of 2,4-dinitro-1-ethylbenzene (DNEB) in DMSO in the presence of O2 in a closed system at 85–105°C gave benzylic oxidised products 1-(2,4-dinitrophenyl)ethanol (DNPE) and 2,4-dinitroacetophenone (DNAP), with the latter as the major product. Evidence for the formation of 3-methyl-6-nitro-2,1-benzoisoxazole (an ‘anthranil’), suggested in the literature as a likely decomposition product, is scant. A mechanism with initial H-abstraction to yield an electron-rich benzylic radical as the rate-limiting step is suggested, supported by a small kinetic isotope effect kH/kD ~2 and a reactivity in the order 2,4,6-trinitro-1-ethylbenzene TNEB > DNEB > 4-nitro-1-ethylbenzene (NEB). The activation energy for DNEB oxidation is 40 kJ mol−1, a value that translates to 1% oxidative decomposition of DNEB after ~ 14 d under an O2 atmosphere, or 70 d in air at ambient temperature.

Isotopic chemistry offers the opportunity for organic chemists to explore a surprisingly large variety of scientific avenues. It lends itself naturally to multidisciplinary research projects and provides the sophisticated tools with which the most complex of processes can be investigated. This Melvin Calvin Award lecture will keep to a broadly chronological theme and will give examples of how the remarkable versatility of the two heavy hydrogen isotopes has been utilised during collaborative studies in areas as varied as: plant and insect biochemistry, drug metabolism and pharmacokinetics, structure determination, NMR spectroscopy, reaction mechanisms, molecular energetics, and novel catalyst development. Few other careers can provide the opportunity to study such varied and fundamental subjects and still provide challenges that are as compelling and exciting some four decades later.

This paper describes the deuterium-labelling of alkylnitroaromatics by base-catalysed exchange with deuterium oxide. As the alkyl protons alpha to the aromatic ring are the most acidic sites in the molecule, regioselective hydrogen isotope exchange at this benzylic location leads to a regiospecifically deuterated product. The exchange labelling takes place in good yields and with high atom% abundance in the presence of an appropriate nitrogen base. Alkylated 2,4-dinitrobenzenes deuterate at room temperature under catalysis by triethylamine, whilst alkylated 2-nitro- or 4-nitrobenzenes and related mono-nitroaromatics require higher temperatures and catalysis by 1,5-diazobicyclo[4.3.0]non-5-ene (DBN). The labelling reactions require an inert gas atmosphere, but otherwise are simple and high yielding with no obvious byproducts. Those compounds in which the benzylic protons are in an ortho-orientation with respect to the nitro group label somewhat more slowly than the analogues where there is a para relationship. In addition, higher alkyl homologues undergo benzylic deuteration at slower rates than methyl.

A review of catalytic isotope exchange methodology

Metal catalysed hydrogen isotope exchange has been widely used in the preparation of deuterium and tritium labelled compounds. This review will detail the development and utility of homogeneous and heterogeneous rhodium and ruthenium catalysts for the preparation of deuterium and tritium labelled compounds by hydrogen isotope exchange methodology.

The 23rd annual symposium of the International Isotope Society (UK Group) took place at the Møller Centre, Churchill College, Cambridge, UK, on Friday, 14 November 2014. The meeting was attended by 68 delegates from academia and industry, the life sciences, chemical, radiochemical and scientific instrument suppliers. Delegates were welcomed by Dr Ken Lawrie [GlaxoSmithKline, UK, chair of the International Isotope Society (UK group)]. The subsequent scientific programme consisted of oral and poster presentations on isotopic chemistry and applications of labelled compounds, or of chemistry with potential implications for isotopic synthesis. Both short-lived and long-lived isotopes were represented, as were stable isotopes. An innovation at this year's symposium was the inclusion of short ‘flash’ presentations in association with particular posters. These proved very successful. The symposium was divided into a morning session chaired by Prof Chris Willis (University of Bristol, UK) and afternoon sessions chaired by Dr Alan Dowling (Syngenta, UK) and by Dr Nick Bushby (AstraZeneca, UK). The UK meeting concluded with remarks from Dr Ken Lawrie (GlaxoSmithKline, UK).

Improvements to thin layer chromatography (TLC) analysis can be made easily and cheaply by the application of digital colour photography and image analysis. The combined technique, digitally enhanced TLC (DE-TLC), is applicable to the accurate quantification of analytes in mixtures, to reaction monitoring and to other typical uses of TLC. Examples are given of the application of digitally enhanced TLC to: the deuteromethylations of theophylline to [methyl−2H3]caffeine and of umbelliferone to [2H3]7-methoxycoumarin; the selection of tertiary amine bases in deuterodechlorination reactions; stoichiometry optimisation in the borodeuteride reduction of quinizarin (1,4-dihydroxyanthraquinone) and to the assessment of xanthophyll yields in Lepidium sativum seedlings grown in deuterated media.

Nitrated alkylaromatics are an important class of compounds and are utilised as intermediates in many high-volume industrial processes. This poster describes an approach to the regiospecific labelling of these systems by exploiting the differences in acidity between their aromatic and benzylic protons. In alkylnitroaromatics the benzylic protons are rendered particularly acidic by the presence of electron withdrawing nitro-substituents in the aromatic nucleus. Hence the compounds should be amenable to labelling if the appropriate anion can be generated in the presence of a suitable deuterium donor. We have investigated the labelling using deuterium oxide as the isotope donor in the presence of a various bases and aprotic cosolvents. In the case of dinitro-alkylaromatics, a carefully selected tertiary amine base proved ideal, yielding, in the absence of oxygen, an effective labelling reaction at room temperature. E.g. 2,4-dinitrotoluene (pKa 15.3) exchanges easily, regiospecifically and with high atom% abundance under catalysis by triethylamine (pKa 10.8) without any of the expected complications due to the formation of the Meisenheimer complex.  Although the reaction of dinitro-systems is particularly facile, mono-nitro compounds with the alkyl substituent ortho or para to the nitro group can also be smoothly labelled using this approach provided that a stronger base, a longer reaction time and a higher temperature are applied. In this case a typical procedure utilises DBN base at 95oC degrees for 18h.Overall we have examined the relative labelling propensities of a range of alkyl mono-nitroaromatics and two alkyl dinitro-aromatics under various conditions. Our results show clear effects of the substitution pattern and of the stereochemical orientation of the nitro and alkyl substituents upon the extent and ease of labelling. The poster will discuss these effects in addition to providing efficient protocols for the labelling of both mono- and dinitro-systems.

The cyclooctadienyliridium(I) dionates provide an alternative ortho-labelling approach to the more conventional iridium catalysts reviewed elsewhere in this special issue. The catalysts are utilized in DMF or DMA, removing potential problems of substrate insolubility in the solvents conventionally used for exchange labelling. Moreover, while readily prepared in a single step, the catalysts are also commercially available. In most cases recoveries are high, while the labelling achieved is both efficient and regiospecific. In addition, the reaction conditions are simple, requiring only conventional laboratory facilities and equipment.

The 20th annual symposium of the International Isotope Society's United Kingdom Group took place at the Wellcome Genome Campus, Hinxton, Cambridge, UK on Tuesday 18 October 2011. The meeting was attended by around 70 delegates from academia and industry, the life sciences, chemical, radiochemical and scientific instrument suppliers. Delegates were welcomed by Dr Ken Lawrie (GlaxoSmithKline, UK, chair of the IIS UK group). The subsequent scientific programme consisted of oral and poster presentations on isotopic chemistry and applications of labelled compounds or of chemistry with potential implications for isotopic synthesis. Both short-lived and long-lived isotopes were represented, as were stable isotopes. The symposium programme was divided into a morning session chaired by Prof. Chris Willis (University of Bristol, UK) and afternoon sessions chaired by Mr Mike Chappelle (Quotient Biosciences, UK) and by Dr Nick Bushby (AstraZeneca, UK). The UK meeting concluded with remarks from Dr Ken Lawrie (GlaxoSmithKline, Stevenage, UK).

The 21st annual symposium of the International Isotope Society's United Kingdom Group took place at the Møller Centre, Churchill College, Cambridge, UK, on Friday 12th October 2012. The meeting was attended by around 60 delegates from academia and industry, the life sciences, chemical, radiochemical and scientific instrument suppliers. Delegates were welcomed by Dr Ken Lawrie (GlaxoSmithKline, UK, chair of the IIS UK group). The subsequent scientific programme consisted of oral and poster presentations on isotopic chemistry and applications of labelled compounds or of chemistry with potential implications for isotopic synthesis. Both short‐lived and long‐lived isotopes were represented, as were stable isotopes. The symposium programme was divided into a morning session chaired by Professor Chris Willis (University of Bristol, UK) and afternoon sessions chaired by Mr Mike Chappelle (Quotient Biosciences, UK) and by Dr Sofia Pascu (University of Bath, UK). The UK meeting concluded with remarks from Dr Ken Lawrie (GlaxoSmithKline, Stevenage, UK).

Base catalysed exchange with sodium hydroxide, calcium oxide or N,N,N,N-tetramethylguanidine in deuterium oxide is a viable procedure for the preparation of terminally deuterated alkynes for those alkynes stable to strong base. The use of silver perchlorate as a catalyst is an alternative practical option when labelling alkynes which are sensitive to base or contain functionalities which would lead to labelling elsewhere in the molecule. Labelling with this catalyst takes place smoothly at ambient temperature in a mixture of N,N-dimethylformamide and deuterium oxide.

Catalytic dehalogenation of aromatic halides using isotopic hydrogen gas is an important strategy for labelling pharmaceuticals, biochemicals, environmental agents and so forth. To extend, improve and further understand this process, studies have been carried out on the scrambling of deuterium isotope with protium during the catalytic deuterodehalogenation of model aryl chlorides using deuterium gas and a palladium on carbon catalyst in tetrahydrofuran solution. The degree of scrambling was greatest with electron-rich chloroarene rings. The tetrahydrofuran solvent and the triethylamine base were not the source of the undesired protium; instead, it arose, substantially, from the water content of the catalyst, though other sources of protium may also be present on the catalyst. Replacement of the Pd/C catalyst with one prepared in situ by reduction of palladium trifluoroacetate with deuterium gas and dispersed upon micronised polytetrafluoroethylene led to much reduced scrambling (typically 0–6% compared with up to 40% for palladium on carbon) and to high atom% abundance, regiospecific labelling. The improved catalytic system now enables efficient polydeuteration via the dehalogenation of polyhalogenated precursors, making the procedure viable for the preparation of MS internal standards and, potentially, for high specific activity tritium labelling.

Owing to recent developments in tritium chemistry and analysis, high‐quality tritium‐labelled drugs can now be prepared simply, cheaply and in timescales commensurate with those needed for rapid drug discovery in adsorption, distribution, metabolism and excretion (ADME) projects. Such 3H‐labelled drugs are enabling high‐quality decision‐making at key points in the drug discovery process, thus ensuring more effective research projects, a key issue in commercial success. In addition, tritium‐labelled compounds continue to play a significant role in ADME studies later in the pharmaceutical development process. This is especially so for highly potent and hence low‐dose agents, for drugs with complex structures and for those compounds that undergo molecular fragmentation as a result of metabolism. Recent developments in tritium chemistry and analysis mean that high‐quality tritium‐labelled drugs can now be prepared simply, cheaply and in timescales commensurate with those needed for rapid drug discovery projects. This rapid‐labelling approach is ensuring more effective pharmaceutical research projects, a key issue in commercial success. At later stages in the pharmaceutical development process, the same tritium labelling and analysis methodologies can also be utilised to support high quality adsorption, distribution, metabolism and excretion studies.

Meeting Summary The 22nd annual symposium of the International Isotope Society's United Kingdom Group took place at the Møller Centre, Churchill College, Cambridge, UK, on Friday, 18 October 2013. The meeting was attended by 65 delegates from academia and industry; the life sciences; and chemical, radiochemical and scientific instrument suppliers. Delegates were welcomed by Dr Ken Lawrie (GlaxoSmithKline, UK, chair of the IIS UK group). The subsequent scientific programme consisted of oral and poster presentations on isotopic chemistry and applications of labelled compounds, or of chemistry with potential implications for isotopic synthesis. Both short‐lived and long‐lived isotopes were represented, as were stable isotopes. The symposium programme was divided into a morning session chaired by Dr Karl Cable (GlaxoSmithKline, UK) and afternoon sessions chaired by Mr Mike Chappelle (Quotient Biosciences, UK) and by Dr Nick Bushby (AstraZeneca, UK). The UK meeting concluded with remarks from Dr Ken Lawrie (GlaxoSmithKline, UK).

The 24th annual symposium of the International Isotope Society's United Kingdom Group took place at the Møller Centre, Churchill College, Cambridge, UK on Friday 6th November 2015. The meeting was attended by 77 delegates from academia and industry, the life sciences, chemical, radiochemical and scientific instrument suppliers. Delegates were welcomed by Dr Ken Lawrie (GlaxoSmithKline, UK, chair of the IIS UK group). The subsequent scientific programme consisted of oral presentations, short 'flash' presentations in association with particular posters and poster presentations. The scientific areas covered included isotopic synthesis, regulatory issues, applications of labelled compounds in imaging, isotopic separation and novel chemistry with potential implications for isotopic synthesis. Both short-lived and long-lived isotopes were represented, as were stable isotopes. The symposium was divided into a morning session chaired by Dr Rebekka Hueting (University of Oxford, UK) and afternoon sessions chaired by Dr Sofia Pascu (University of Bath, UK) and by Dr Alan Dowling (Syngenta, UK). The UK meeting concluded with remarks from Dr Ken Lawrie (GlaxoSmithKline, UK).

The 25th annual symposium of the International Isotope Society's United Kingdom Group took place at the Møller Centre, Churchill College, Cambridge, UK on Friday 11th November 2016. The meeting was attended by around 90 delegates from academia and industry, the life sciences, chemical, radiochemical and scientific instrument suppliers. Delegates were welcomed by Dr Ken Lawrie (GlaxoSmithKline, UK, chair of the IIS UK group). The subsequent scientific programme consisted of oral presentations, short “flash” presentations in association with particular posters, and poster presentations. The scientific areas covered included isotopic synthesis, regulatory issues, applications of labelled compounds in imaging, and novel chemistry with potential implications for isotopic synthesis. Both short-lived and long-lived isotopes were represented, as were stable isotopes. The symposium was divided into a morning session chaired by Prof. Franklin Aigbirhio (Cambridge Neuroscience, UK) and afternoon sessions chaired by Dr. Rebekka Hueting (University of Oxford, UK) and by Dr. Andrew Kohler (Arcinova, UK). The meeting concluded with remarks from Dr Ken Lawrie (GlaxoSmithKline, UK).

The 26th annual symposium of the International Isotope Society's United Kingdom Group took place at the Møller Centre, Churchill College, Cambridge, UK on Friday, November 17, 2017. The meeting was attended by around 90 delegates from academia, industry and the life sciences, and from chemical, radiochemical, and scientific instrument suppliers. Delegates were welcomed by Dr Chris Winfield (Selcia, UK, chair of the IIS UK group). The subsequent scientific programme consisted of oral presentations, short “flash” presentations in association with particular posters, and poster presentations. The scientific areas covered included isotopic synthesis, regulatory issues, applications of labelled compounds in imaging, and novel chemistry with potential implications for isotopic synthesis. Both short-lived and long-lived isotopes were represented, as were stable isotopes. The symposium was divided into a morning session chaired by Dr Andrew Kohler (Arcinova, UK) and afternoon sessions chaired by Prof Franklin Aigbirhio (Cambridge Neuroscience, and by Mr. Mike Chappelle (Pharmaron, UK). The meeting concluded with remarks from Dr Chris Winfield (Selcia, UK).

Abstract The long-term collaboration with Prof. John R Jones has enabled the development or discovery of a range of one-step 3H- and 2H-labelling approaches. These include; (a) RhCl3.3H2O and COD.Ir.Acac catalysed ortho-exchange of aromatic acids, amides, benzylamines, anilides, sulphonamides, etc, using isotopic water as the donor in DMF or DMA solution, (b) the COD.Ir.F6Acac catalysed ortho-labelling of anilines, benzylamines and other N-heterocyclics using isotopic hydrogen gas in DMA at RT, (c) the α- and β-labelling of piperidines, piperazines and other secondary amines using catalytic Ru(CO)6Cl2 or (C6H5)2RuCl2 with deuterium oxide in DMSO, (d) the α-labelling of pyridines and other N-heteroaromatics using rhodium and ruthenium heterogeneous catalysts with isotopic hydrogen gas in THF at RT and (e) the preparation of an efficient and clean polystyrene-based Ir(I) phosphine catalyst for the labelling of aromatic esters, aromatic ketones, sulphones, amides, anilides, etc, using isotopic hydrogen gas in dichloromethane at RT.  Latterly, screening for the terminal-methylene labelling of 1-monosubstituted and 1,1-disubstituted alkenes has provided new catalytic systems for this transformation. In addition, it has provided evidence for the significance of secondary metal alkyl intermediates in the general mechanism of catalytic alkene exchange and reduction. These studies were facilitated by the application of a 3H-NMR cryoprobe.Keywords: isotope-exchange, ortho-labelling, catalysis, alkene-exchange, hydrogenation-mechanism, deuteration, tritiation.

2-Deuterated anilides demonstrate a significant upfield shift of the remaining 6- proton in their 1H-NMR spectra. This is occasioned by a preference for the conformation in which the deuteron is adjacent to the anilide carbonyl group. The electronic effects in this system have been investigated by the preparation of a range of structural variants. The results are consistent with a hydrogen-bonding hypothesis but further work is required to investigate alternative explanations.

Raman spectroscopy is used less commonly than other spectroscopic techniques by isotopic chemists. The University of Surrey has recently become a regional centre for the technique following our acquisition of a powerful high-resolution multi-laser Raman spectromicroscope (Renishaw inVia, model RE04, via EPSRC grant EP/M022749/1). This poster reports some early experience with the technique as applied to the analysis of deuterated compounds. The spectrometer is based around Raman scattering from any of five lasers ranging from the ultraviolet to blue, green, red and near infrared (244–785 nm). The sampling beam has an area of just 2-10µm and hence the spectrometer has the ability to automatically scan tiny sample areas, offering the possibility of obtaining Raman imaging for 2-D and (via confocality) even 3-D samples. Investigations into isotopic applications of these multidimensional abilities are in progress.  The high resolution of the system also enables excellent spectra to be recorded from very tiny samples, e.g. from a small part of this 200µm crystal of [2H8]naphthalene.  The poster provides examples of the following advantages when deuterated compounds are analysed by Raman:Improved sensitivity is available via powerful lasers and digital spectral accumulationRapid generation of high quality one-dimensional Raman spectra from various sample typesLow matrix effects for glass enables direct analysis within ordinary sealed glass lab vialsHigh spectral and spacial resolution provides the ability to work with tiny samples/areasHighly specific results, as vibrational modes can be very sensitive to isotopic substitutionDirect quantitative analysis of isotopic mixtures is possible by selecting the appropriate peaksLow background from silicagel means TLC & HPTLC applications are possibleSurface enhanced Raman spectra (SERS) can be simply obtained via stable silver colloids