1994 R.U. Lemieux Award Lecture Hydrolysis of acetals and ketals. Position of transition states along the reaction coordinates, and stereoelectronic effects

Abstract

PIERRE DESLONGCHAMPS, YVES L. DORY, and SHIGUI LI. Can. J. Chem. 72,2021Chem. 72, (1994.Past and recent experimental results on the formation or hydrolysis (or isomerization) of various acetals and ketals including a-and P-glycoside models are presented. Ab initio investigations of simple acetals are also briefly reviewed as well as recent experimental and theoretical support evidence for a synperiplanar effect. A detailed study using the semi-empirical Hamiltonian AM1 defining the reaction pathway in the hydrolysis of various acetals and ketals is reported. This overall study shows that the hydrolysis of acetals and ketals is controlled by powerful stereoelectronic effects.PIERRE DESLONGCHAMPS, YVES L. DORY et SHIGUI LI. Can. J. Chem. 72,2021Chem. 72, (1994.Des rksultats expCrimentaux anciens et nouveaux sur la formation ou l'hydrolyse (ou l'isom6risation) de divers acetals et cttals incluant des modbles d'a-et P-glycosides sont presentis. Des Ctudes ab initio d'acttals simples sont aussi bribvement rapportkes ainsi que de rCcentes evidences experimentales supportCes theoriquement de l'effet synpCriplanaire. Une Ctude dCtaillCe, A l'aide de 1'Hamiltonian semi-empirique AM1, des chemins rCactionnels d'hydrolyse de divers acCtals et cCtals est rapportCe.Cette Ctude globale montre que I'hydrolyse dlacCtals et de cCtals est contr61Ce par de puissants effets stCrCoClectroniques. IntroductionIt has been generally accepted that stereoelectronic effects play a major role in acetal hydrolysis (1, 2). We previously postulated (I), on the basis of the antiperiplanar lone-pair hypothesis, that a-glycosides (axial anomer) are hydrolyzed via their ground state chair conformation whereas P-glycosides (equatorial anomer) must first assume a twist-boat conformation in order to have the ring oxygen with a lone pair properly oriented to eject the leaving group. Since it is well known (3,4) that a -and P-glycosides are hydrolyzed at similar rates, it follows that these compounds must be hydrolyzed via transition states that resemble more closely the geometry of the cyclic oxocarbonium ions rather than that of the protonated glycosides. It was therefore necessary to obtain experimental evidence and theoretical support to establish the position of the transition state along the reaction coordinates in the hydrolysis of acetals and related functions. In this paper, we wish to review our recent published work in this area and to present an AM1 molecular modelling study (5).

Defining the SN1 Side of Glycosylation Reactions: Stereoselectivity of Glycopyranosyl Cations

“…The “opposite” family of structures, located on the southeast side of the sphere, is composed of the range of ( 4 E , 4 H 3 , E 3 , and 2,5 B )-like conformers, which will likely be approached by an incoming nucleophile from the bottom-face (see Figure ,3 and the Supporting Information). , The relative population of all conformational states can be calculated, on the basis of their relative energies as computed above, utilizing the Boltzmann equation (see the Supporting Information for more information). Accordingly, we determined the population of the top- and bottom-face selective families, which should be a measure for the relative stereoselectivity of addition reactions with weak nucleophiles to the glycosyl oxocarbenium ions.…”

Remarkable Reactivity Differences between Glucosides with Identical Leaving Groups

“…This longer bond length for S3 is consistent with inductive effects that favor charge development on the glycosidic oxygen in the early stages of ionization/heterolysis of the glycosidic bond toward the oxocarbenium ion/phenolate pair. Such behavior has been investigated and quantitated in some detail by Kirby et al through determination of X-ray crystal structures of several series of axial and equatorial aryl acetals bearing different aryl substituents within both a tetrahydropyranyl series and a glycosyl series. ,− Within each series Kirby et al observed a linear correlation of the acetal carbon–aryl oxygen bond length with the p K a of the phenol from which it had been derived. The sensitivity (slope) of that correlation varied for each system, being higher for axial than equatorial systems, consistent with expectations of stereoelectronic theory .…”

On the relative rate of hydrolysis of a series of ketals and their proton affinities

“…25 Our previous studies have also provided theoretical evidence that protonation may be involved in the rate-determining step in hydrolysis of ketals. [5][6][7] It still remains to distinguish which phenomenon is dominant during the concomitant protonation-cleavage step. Although protonation and cleavage proceed simultaneously, their relative importance may vary according to the particular substrate.…”

“…Indeed, experiments have shown that the reactivity closely parallels the estimated basicities of the orthoesters. 4 Although no experimental evidence is available for ketal hydrolysis, our recent AM1 calculations [5][6][7] indicated that there is no energy barrier after the protonation. Since it is likely that proton transfer is involved in the rate-limiting step, the basicity of the ketal should be taken into account in studies of the acid-catalyzed hydrolysis of these compounds.…”