Strong Hydrogen Bonding to the Amide Nitrogen Atom in an "Amide Proton Sponge": Consequences for Structure and Reactivity

The carbonyl oxygen atom of the amide functional group is universally believed to be the thermodynamically preferred site of protonation in amides;[1] however, N protonation has been proposed to play a key role in biologically important reactions of peptides and proteins such as acid-catalyzed peptide hydrolysis[2] and cis ± trans isomerization about the CÿN bond.[3] Extensive research into the mechanism of acidcatalyzed amide hydrolysis has led to the belief that the O-protonated form is generally the important intermediate on the pathway to hydrolysis.[4] Still, evidence supporting N protonation in certain cases,[2] as well as in the related thiolcatalyzed amide hydrolysis reactions important in cysteine proteases,[5] has also been reported. N-Protonated amides have thus far eluded characterization, probably because they are disfavored thermodynamically relative to the O-protonated form by about 7 pKa units in aqueous solution.[6] Even species showing strong hydrogen bonding between a donor and the amide N atom are unknown.[7] Herein we present the first spectroscopic and crystallographic characterization of a strong hydrogen bond between a charged donor (a protonated amine) and an amide nitrogen atom in a model system, and also disclose unusual reactivity of the amide functionality that stems from this interaction. We designed system 1 in which a protonated amine group can act as a donor suitably positioned to engage in a strong intramolecular hydrogen bond with the amide nitrogen atom rather than with the carbonyl oxygen atom [Eq. (1)].[8] Compound 1 is based on the venerable aproton spongeo 2