Revisiting the Case of an Intramolecular Hydrogen Bond Network Forming Four- and Five-Membered Rings in d-Glucose

Abstract

The conformational behavior of cyclic monosaccharides has been widely studied over the past years, but there is no general agreement about which effects are in fact responsible for the observed conformational preferences. A recent microwave spectroscopy study determined the conformational equilibrium of d -glucose in the gas phase with a preference for a counterclockwise arrangement of the hydroxyl groups. Nevertheless, the effects that control this orientation are still uncertain because the role of intramolecular hydrogen bonds (IHBs), electrostatic and steric repulsions is not clear. This work reports a density functional theory approach based on the conformational energies of d -glucose and of some derivatives in which the anomeric hydroxyl is replaced with hydrogen (H, small and not prone to participate in proton transfer), fluorine (F, small, electronegative, and as capable as OH of forming hydrogen bonds as a proton acceptor), and chlorine (Cl, big and not anticipated to be involved in effective hydrogen bond formation) to obtain insights into the effects of the substituent at the anomeric carbon on the arrangement of the hydroxyl groups in d -glucose. The nature of the substituents at this position is crucial to determine the orientation of the remaining hydroxyl groups. Natural bond orbital (NBO) and quantum theory of atoms in molecules (QTAIM) analyses, in addition to NMR chemical shift calculations, have been provided to support the conformational energy outcomes. Overall, the results agree with the lack of IHBs forming four- and five-membered rings in d -glucose and emphasize that steric and electrostatic repulsions involving the hydroxyl groups in the clockwise orientation are driving forces of the conformational behavior.

Vacuum Ultraviolet Electronic Circular Dichroism Study of d-Glucose in Aqueous Solution

“…It has been reported that the interaction between the hydroxyl groups at C-4 and C-6 in the TG conformation involves unfavorable stereochemistry, 4,44 and steric repulsion has been clearly confirmed using quantum theory. 57 Although further experimental and theoretical studies are necessary, it can be suggested that steric repulsions in addition to the hydration around the hydroxyl group at C-6 affect the structural stabilization of rotamers or rotamerization.…”

Cooperativity in alkane‐1,2‐ and 1,3‐polyols: NMR, QTAIM, and IQA study of O─H…OH and C─H…OH bonding interactions

“…However, cooperativity between O─H … OH hydrogen bonds in the 1,2‐diol and 1,3‐diol motifs of pyranoses is irregular and not necessarily reciprocal 45, 46 . Klein claims that there is negative cooperativity in glucopyranose, 47 and other authors consider that the driving forces for conformational preferences are steric effects, electrostatic repulsion, and hyperconjugation 48, 49 . The idea of cooperativity involving 1,2‐diol motifs raises the question of hydrogen bonding in such systems: From a topological viewpoint, because there is no bond critical point (BCP), there is no bond 50–58 (and even the idea that a BCP indicates a bond has been discredited—see below).…”

A True Reverse Anomeric Effect Does Exist After All: A Hydrogen Bonding Stereocontrolling Effect in 2-Iminoaldoses

“…Among the stereoconformational aspects controlling the molecular arrangements observed in carbohydrates, the anomeric, exoanomeric, and gauche effects are the most prominent . Not by chance, the interpretation of the anomeric effects and other associated stereoelectronic effects in six-membered saturated heterocycles has been extensively documented. ,− …”