Gaining insight into reactivity differences between malonic acid half thioester (MAHT) and malonic acid half oxyesters (MAHO)

Sean P. Bew, G. Richard Stephenson, Jacques Rouden, Jeremy Godemert, Haseena Seylani, Luis A. Martinez-Lozano

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An efficient two-step synthesis of structure- and function-diverse thiophenol- and (cyclo)alkyl-derived malonic acid half thioesters (MAHTs) and phenol-derived malonic acid half oxyesters (MAHOs) has been achieved using cheap, readily available and easily handled starting materials. Our syntheses of MAHTs and MAHOs, the majority of which have not been previously reported, is readily scalable affording gram quantities of product. In a hydrogen deuterium exchange, an interesting stereoelectronic effect was observed when different aryl groups were incorporated. Significant changes in the rates of hydrogen deuterium exchange and levels of isotope incorporation were observed. By way of example, using [2H]methanol and 4-bromophenol-derived MAHO afforded only 14% [2H]-incorporation (9 minutes, k = 31) whereas the corresponding 4-bromothiophenol-derived MAHT afforded 97% [2H]-incorporation (9 minutes, k = 208). In a benchmarked procedure and comprehensive DFT study 54 ester and thioester configurations and conformations where characterised. This established in the MAHT series a sulfur-containing molecular orbital provides a path for increased delocalisation of electron-density into the enol which is unavailable in MAHOs, which facilitates keto-enol tautomerisation and consequently enhances the rate and percentage of hydrogen deuterium exchange.
Original languageEnglish
Pages (from-to)4557–4569
Number of pages13
JournalChemistry - A European Journal
Issue number19
Early online date31 Jan 2017
Publication statusPublished - 3 Apr 2017


  • thioester
  • isotope exchange
  • DFT
  • reaction rate
  • delocalisation

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