Gaining Insight Into Reactivity Differences Between Malonic Acid Half Thioesters (MAHT) and Malonic Acid Half Oxyesters (MAHO)

• Published in: Chemistry : a European journal Vol. 23; no. 19; pp. 4557 - 4569
• Main Authors: Bew, Sean P., Stephenson, G. Richard, Rouden, Jacques, Godemert, Jeremy, Seylani, Haseena, Martinez‐Lozano, Luis A.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 03-04-2017
• Subjects: Acids; Aromatic compounds; Benchmarking; Chemistry; density functional calculations; Electron density; Esters; Exchange; hydrogen bonding; isotope exchange; reaction rates; Shelves; Synthesis; Thioesters; density functional calculations; hydrogen bonding; reaction rates; isotope exchange; thioesters
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201605148

An efficient two‐step synthesis of structurally and functionally 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. The synthesis of the MAHTs and MAHOs (the majority of which have not been previously reported) is readily scalable to afford 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 min, k=31) whereas the corresponding 4‐bromothiophenol‐derived MAHT afforded 97 % [2H]‐incorporation (9 min, k=208). In a benchmark procedure and comprehensive DFT study, 54 ester and thioester configurations and conformations were characterized. In the MAHT series, a sulfur‐containing molecular orbital provides a path for increased delocalisation of electron density into the enol that is unavailable in MAHOs. This facilitates keto–enol tautomerisation and consequently enhances the rate and percentage of hydrogen→deuterium exchange.
Easy esters: Three comprehensive studies on the synthesis (from “off the shelf” starting materials and a solvent‐free protocol), reactivity ([2H]‐exchange) and conformational properties of aryl (thio)ester‐derived malonic acid half oxy‐and thioesters (MAHOs and MAHTs) are reported. The synthetically valuable ease of enolisation of the MAHTs is accounted for by the computationally established presence of an additional frontier orbital unique to the MAHT series which provides enhanced π‐delocalisation between the sulfur and the enol.