Hydrogen Bonding of Fluorinated Saccharides in Solution: F Acting as H‐Bond Acceptor in a Bifurcated H‐Bond of 4‐Fluorinated Levoglucosans

Abstract

4‐Fluorinated levoglucosans were synthesised to test if OH⋅⋅⋅F H‐bonds are feasible even when the O⋅⋅⋅F distance is increased. The fluorinated 1,6‐anhydro‐β‐D‐glucopyranoses were synthesised from 1,6 : 3,4‐dianhydro‐β‐D‐galactopyranose (8). Treatment of 8 with KHF2 and KF gave 43% of 4‐deoxy‐4‐fluorolevoglucosan (9), which was transformed into the 3‐O‐protected derivatives 13 by silylation and 15 by silylation, acetylation, and desilylation. 4‐Deoxy‐4‐methyllevoglucosan (19) and 4‐deoxylevoglucosan (21) were prepared as reference compounds that can only form a bivalent H‐bond from HOC(2) to OC(5). They were synthesised from the iPr3Si‐protected derivative of 8. Intramolecular bifurcated H‐bonds from HOC(2) to FC(4) and OC(5) of the 4‐fluorinated levoglucosans in CDCl3 solution are evidenced by the 1H‐NMR scalar couplings h1J(F,OH) and 3J(H,OH). The OH⋅⋅⋅F H‐bond over an O⋅⋅⋅F distance of ca. 3.0 Å is thus formed in apolar solvents, at least when favoured by the simultaneous formation of an OH⋅⋅⋅O H‐bond.

Intramolecular OH⋅⋅⋅FC Hydrogen Bonding in Fluorinated Carbohydrates: CHF is a Better Hydrogen Bond Acceptor than CF2

“…[8] Examination of the Cambridge Structural Database revealed that only 0.6 % of all CF groups are engaged as H-bond acceptors of X À H (X = N or O). [14,15] Scalar coupling between XH and F ( 1h J(XH,F [16] ) in the 1 H NMR spectra is useful for the detection of XÀH···FÀC Hbonds. The two classes of compounds that form XÀH···FÀC H-bonds in the solid state are fluorinated sterically crowded tertiary alcohols and fluorinated polyols.…”

De Novo Synthesis of Racemic 4‐Deoxy‐4,4‐difluoro‐ and 2,4‐Dideoxy‐2,4,4‐trifluorohexosides

“…Herein we present a diversity-oriented approach towards a series of novel racemic 4,4-difluorinated hexopyranosides. [7,8] The installation of a difluoromethylene group at a late stage is synthetically challenging. Electrophilic fluorination allows for the preparation of 2,2-difluoro sugars from 2-fluoroglycals only, [11] and nucleophilic fluorination of carbonyl groups with diethylaminosulfur trifluoride (DAST) [12] can suffer from side reactions resulting from neighboring group participation, migration, or elimination.…”

“…[6] NMR spectroscopy has unveiled the existence of C-F···H-X hydrogen bonds between carbonbound fluorine and intramolecular H-bond donors. [7][8][9] For these investigations, carbohydrate-derived 1,3-diaxial and 1,2-cis-fluoroalcohols are ideal probes by virtue of their rigid ring structure ( Figure 1a). [7,8] No information is available on the effect of gem-difluorination on C-F···H-O bonding, so we initiated a study aimed at accessing representative 4-deoxy-4,4-difluorohexopyranosides (Ϯ)-1 and (Ϯ)-2 for interrogation using NMR spectroscopy (Figure 1b).…”

“…[7][8][9] For these investigations, carbohydrate-derived 1,3-diaxial and 1,2-cis-fluoroalcohols are ideal probes by virtue of their rigid ring structure ( Figure 1a). [7,8] No information is available on the effect of gem-difluorination on C-F···H-O bonding, so we initiated a study aimed at accessing representative 4-deoxy-4,4-difluorohexopyranosides (Ϯ)-1 and (Ϯ)-2 for interrogation using NMR spectroscopy (Figure 1b). A comparative study with the corresponding monofluorinated structural analogs [10] will allow us to gain further insight into the strength and persistence of C-F···H-O bonding in these systems.…”

An Unexpected and Significantly Lower Hydrogen‐Bond‐Donating Capacity of Fluorohydrins Compared to Nonfluorinated Alcohols

“…With the 1,3-coaxial fluorohydrin 5, this energy barrier is raised to 18 kJ mol À1 . [25] This significant variation is attributed to the occurrence of an F···HO interaction, which is particularly favorable in the case of a 1,3-coaxial fluorohydrin, as illustrated by NMR spectroscopy ( h1 J F-HO % 12 Hz), [26] and by the significantly shorter calculated d F···H distance in 5 (2.033 ) than found in the 1,2-fluorohydrins (2.3-2.4 ).…”