Overriding Intrinsic Reactivity in Aliphatic C−H Oxidation: Preferential C3/C4 Oxidation of Aliphatic Ammonium Substrates

Abstract

The site‐selective C−H oxidation of unactivated positions in aliphatic ammonium chains poses a tremendous synthetic challenge, for which a solution has not yet been found. Here, we report the preferential oxidation of the strongly deactivated C3/C4 positions of aliphatic ammonium substrates by employing a novel supramolecular catalyst. This chimeric catalyst was synthesized by linking the well‐explored catalytic moiety Fe(pdp) to an alkyl ammonium binding molecular tweezer. The results highlight the vast potential of overriding the intrinsic reactivity in chemical reactions by guiding catalysis using supramolecular host structures that enable a precise orientation of the substrates.

New horizons for catalysis disclosed by supramolecular chemistry

“…In this case, the shorter distance between the receptor and the catalytic center reverses the natural reactivity order of the methylenes on the chain enabling a selective oxidation of positions C3 and C4 that are strongly deactivated by the proximal positive charge. 99 Catalysts C3 (M = Fe or Mn) were also shown to oxidize the C-H bonds of different steroids at remote D-ring with a high site-selectivity (>80%), modifying the innate selective of the reaction. 100 This selectivity can be predicted a priori via NMR analysis of the geometry of the catalyst-substrate adduct and is consistent with the one observed for linear amines (i.e., C8 or C9 sites).…”

Site and Enantioselective Aliphatic C−H Oxidation with Bioinspired Chiral Complexes

“…A catalyst bearing a different substrate recognition element has been developed by Tiefenbacher and co‐workers. By appending an alkyl ammonium molecular tweezer to the Fe(pdp) catalyst, a novel catalyst was created (Fe Twz pdp) (scheme 10) that binds alkyl amines and promotes the selective oxidation of the strongly electronically deactivated C3/C4 positions of these substrates [36] …”

“…By appending an alkyl ammonium molecular tweezer to the Fe(pdp) catalyst, a novel catalyst was created (Fe Twz pdp) (scheme 10) that binds alkyl amines and promotes the selective oxidation of the strongly electronically deactivated C3/C4 positions of these substrates. [36] Several pieces of evidence demonstrate that the unusual selectivity towards C3 and C4 sites arises from supramolecular recognition of the protonated amines by the tweezer; in first place, the selectivity was not present when the Fe(pdp) catalyst was used. Methylation of the amine residue in the substrate also erodes selectivity, because the alkylated amine can establish less H-bonds with the receptor, decreasing binding.…”

Tweezer‐Based C−H Oxidation Catalysts Overriding the Intrinsic Reactivity of Aliphatic Ammonium Substrates

“…Our group merged the White‐Chen catalyst Fe(pdp) [3a] with a molecular glycoluril‐based tweezer [15] to deliver Fe(pdp)Twe (Figure 1b). [16] A molecular tweezer is a host molecule with an open cavity defined by two rigid arms [17] . Similar to crown ethers, this tweezer moiety is capable of binding ammonium salts [15] .…”