Control of the Stereochemistry of Kinetic Protonation:  Intramolecular Proton Delivery^1,2

Abstract

Four decades ago, we noted that for delocalized carbanions and enols the protonation transition state is close to sp(2) hybridized and that, as a consequence, under kinetic control protonation takes place from the less hindered approach, most often with formation of the less stable of two possible stereoisomers. The initial report was followed by an extensive series of examples. Nevertheless, a major question remained, namely whether it was possible to deliver the proton to the more hindered face of such a species using intramolecular proton transfer. To this end, silyl ether precursors to the enols of 3-benzoyl-endo-6-phenyl-exo-6-pyridylbicyclo[3.1.0]hexane and its endo-6-pyridyl-exo-6-phenyl stereoisomer were synthesized. The corresponding enols were generated with fluoride anion. The endo-phenyl enol stereoisomers, on kinetic protonation, led stereoselectively to the endo-3-benzoyl product resulting from the less hindered protonation. In stark contrast, the endo-6-pyridyl enol isomer led stereoselectively to the exo-3-benzoyl ketone by intramolecular proton delivery. However, the kinetic orders of the stereochemistries differ; the intramolecular process requires additional proton donor molecules. The log of the ratio of the two stereochemistries is linear with the log of the proton donor concentration with the slope giving the difference in kinetic orders. An aromatic cyclic 14 electron Hückel transition state is proposed. Additionally, the roles of acyl, nitro and cyano delocalizing groups were analyzed with ab initio computations.

Density Functional Theory Study of Carboxylic Acids Adsorption and Enolization on Monoclinic Zirconia Surfaces

“…All studied deprotonation reactions exhibit a late transition state (Table ), having the α carbon near the sp 2 geometry. It is similar to the well-known sp 2 -like geometry of the transition state characteristic for the enol protonation to ketones, which is a reverse reaction to enolization. The geometry of the developing double-bond center in the enolization reaction becomes increasingly flat as the reaction progresses, which is indicated by decreasing the sum of torsion angles, defined in Table , from the starting carboxylate to the transition state and further to the enolized product.…”

“…Therefore, the equilibrium must be significantly shifted toward the starting carboxylate. The enolized product derived from isobutyric acid is slightly more stable because of the well-known effect of the steric hindrance in the kinetic protonation of enolized structures, in this case caused by two methyl groups.…”

Electrochemical Synthesis of [1,2,3]Triazolo[1,5‐a]pyridines through Dehydrogenative Cyclization

“…[1,2,3]Triazolo[1,5‐ a ]pyridines, which exist in equilibrium with the ring‐opening diazo form in solution, have been employed as convenient precursors for carbene species in the synthesis of functionalized pyridine derivatives and several other N‐heterocycles (Scheme a) . Synthesis of [1,2,3]triazolo[1,5‐ a ]pyridines has been achieved through oxidative cyclization of hydrazones of 2‐acylpyridines employing stoichiometric chemical oxidants such as MnO 2 ,– Ag 2 O, NiO 2 , and PhI(OAc) 2 or more recently copper‐catalyzed aerobic oxidation …”

Intramolecular Proton Transfer

“…Recently the question arose whether the stereochemistry could be reversed by intramolecular delivery of the proton to the more hindered face of the enolic system, and one example was uncovered . It now appears that the phenomenon is general, and we report an example in a new molecular system, utilizing the exo and endo 2-pyridyl enols 3 and 4 .…”