Enolate Stabilization by Anion–π Interactions: Deuterium Exchange in Malonate Dilactones on π‐Acidic Surfaces. Issue 8 (11th December 2015)

• Record Type: Journal Article
• Authors: Miros, François N.; Zhao, Yingjie; Sargsyan, Gevorg; Pupier, Marion; Besnard, Céline; Beuchat, César; Mareda, Jiri; Sakai, Naomi; Matile, Stefan
• Is Part Of: Chemistry. Volume 22:Issue 8(2016)
• Page Start: 2648
• Page End: 2657
• Publication Date: 2015-12-11
• Subjects: acidity -- anion–π interactions -- deuterium exchange -- enolates -- macrocycles -- stereoselectivity; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201504008
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: Of central importance in chemistry and biology, enolate chemistry is an attractive topic to elaborate on possible contributions of anion–π interactions to catalysis. To demonstrate the existence of such contributions, experimental evidence for the stabilization of not only anions but also anionic intermediates and transition states on π‐acidic aromatic surfaces is decisive. To tackle this challenge for enolate chemistry with maximal precision and minimal uncertainty, malonate dilactones are covalently positioned on the π‐acidic surface of naphthalenediimides (NDIs). Their presence is directly visible in the upfield shifts of the α‐protons in the 1 H NMR spectra. The reactivity of these protons on π‐acidic surfaces is measured by hydrogen–deuterium (H–D) exchange for 11 different examples, excluding controls. The velocity of H–D exchange increases with π acidity (NDI core substituents: SO2 R>SOR>H>OR>OR/NR2 >SR>NR2 ). The H–D exchange kinetics vary with the structure of the enolate (malonates>methylmalonates, dilactones>dithiolactones). Moreover, they depend on the distance to the π surface (bridge length: 11–13 atoms). Most importantly, H–D exchange depends strongly on the chirality of the π surface (chiral sulfoxides as core substituents; the crystal structure of the enantiopure ( R, R, P )‐macrocycle is reported). For maximal π acidity, transition‐state stabilizations up to −18.8 kJ mol −1 are obtained for H–D exchange. The Brønsted acidity of the enols increases strongly with π acidity of the aromatic surface, the lowest measured p K a =10.9 calculates to a Δp K a =−5.5. Corresponding to the deprotonation of arginine residues in neutral water, considered as "impossible" in biology, the found enolate–π interactions are very important. The strong dependence of enolate stabilization on the unprecedented seven‐component π‐acidity gradient over almost 1 eV demonstrates quantitatively that such important anion–π activities can be expected only from strong enough π acids. Abstract : Beyond uncertainty : Tied up onto chiral π surfaces in solution, stereoselective proton–deuterium exchange was directly followed by 1 H NMR spectroscopy to see malonate acidity increase along a seven‐component π‐acidity gradient up to 5.5 orders of magnitude—commonly considered as impossible in biology. These measurements were used to quantify the stabilization of anionic reactive intermediates and transition states on π‐acidic surfaces, and to secure direct experimental evidence for the long suspected premise that really strong π acids are needed to catch anion–π interactions at work.