Benzoyl Transfer Reactivities of Racemic 2,4‐Di‐O‐acyl‐myo‐inosityl 1,3,5‐Orthoesters in the Solid State: Molecular Packing and Intermolecular Interactions Correlate with the Ease of the Reaction

Abstract

Racemic 2,4-di-O-acyl-myo-inosityl 1,3,5-orthoesters undergo transesterification catalyzed by sodium carbonate with varying ease of reaction in the solid state; reactions in solution and melt do not show such varied differences. An interesting crystal of a 1:1 molecular complex of highly reactive racemic 2,4-di-O-benzoyl-myo-inosityl 1,3,5-orthoformate and its orthoacetate analogue exhibited better reactivity than the latter component alone. Single-crystal X-ray structures of the reactants have been correlated with the observed differences in the acyl-transfer efficiencies in the solid state. Although each of the derivatives helically self-assembles around the crystallographic 2(1) axis linked through O-H...O hydrogen bonding, the pre-organization of the reactive groups (C=O [El] and OH [Nu]), C-H...O and the C-H...pi interactions are significantly more favourable for the reactive derivatives than the less reactive ones. Bond-length distributions also showed differences; the O-C bond of the axial benzoyl group, which gets cleaved during the reaction, is longer (1.345-1.361 A) relative to the chemically equivalent O-C bond of the equatorial benzoyl group (1.316-1.344 A) in the reactive derivatives. These bond-length differences are not significant in the less reactive derivatives. The overall molecular organization is different too; the strikingly discrete helices, which may be viewed as "reaction tunnels" and are held by interhelical interactions, are clearly evident in the reactive derivatives in comparison with the less reactive ones.

Intramolecular Cyclization of Carbonate and Thiocarbonate Derivatives of myo‐Inositol in the Solid State: Implications for Acyl Group Transfer Reactions in Molecular Crystals

“…A comparison of the structure and reactivity of the crystals of racemic 2,4‐di‐ O ‐benzoyl‐ myo ‐inositol‐1,3,5‐orthoformate11a and the corresponding carbonates 4 and 7 as well as the thiocarbonate 8 reveal that, as expected, the discrete molecular packing facilitating a kind of domino reaction leading to the intermolecular acyl transfer in crystals of the former dibenzoate, was not required for the intramolecular reaction in compounds 4 , 7 , and 8 , leading to the formation of cyclic carbonates and thiocarbonates 11 , 13 , and 14 , respectively. However the El⋅⋅⋅Nu interactions do play a prominent role in both these reactions (Figure 1, Scheme ).…”

Identification of Molecular Crystals Capable of Undergoing an Acyl‐Transfer Reaction Based on Intermolecular Interactions in the Crystal Lattice

“…Hence, it is reasonable to expect larger deviation of O···C=O angle (from the tetrahedral angle) as the El···Nu distance increases (beyond 2.5 ), as observed in reactive crystals of myo-inositol orthoester derivatives. Subsequent investigations of structure and benzoyl group-transfer reactions in crystals of other myo-inositol 1,3,5-orthoester derivatives [29][30][31] helped us realize the importance of helical molecular pre-organization in reactive crystals, [35] which functions as a reaction channel and contributes to the facility and almost quantitative conversion of the reactants to products. Hence, we wondered whether 1) El···Nu geometry between potentially reactive centers in molecules; 2) the assembly of these reacting pairs in the crystal, in the form of a channel for the reaction to propagate; and 3) weak intermolecular interactions, [36,37] such as C À H···p, [38,39] which help maintain the topochemical control, could be used as parameters to predict the facility of acyl group-transfer reactivity in molecular crystals.…”

“…Efficient intermolecular oxygen-to-oxygen benzoyl grouptransfer reactions were observed in myo-inositol orthoester derivatives 1, 2, and co-crystals 1·2. Single-crystal X-ray diffraction analysis of these reactive crystals [28,29] revealed that the distance between the reaction centers (HO···C=O), and the angle of approach of the ÀOH (nucleophile = Nu) towards the ester carbonyl group, C=O (electrophile = El) lay in the range of 3.1-3.3 and 84-90 8, respectively. [28] These interatomic distances and angles are close to those arrived for El···Nu interactions through the study of crystal struc-tures and theoretical calculations on a model system, by Bürgi and Dunitz.…”

“…[26] Transacylation was also observed in tablet mixtures of aspirin and drugs with easily acylated functionalities such as phenylephrine hydrochloride, codeine, and acetaminophen. [7][8][9] We had reported (the first instance [27] of) a facile intermolecular benzoyl group transfer in crystals of racemic 2,4-di-O-benzoyl-myoinositol 1,3,5-orthoformate (1), its orthoacetate analogue 2, [28] as well as in co-crystals 1·2 [29] (Scheme 1), which yielded the corresponding tribenzoates 3 and 4 and the diols 5 and 6.…”

Synthesis and characterization of block copolymers from aromatic diols, fumaric acid, sebacic acid and PEG

“…Transacylation was also observed in tablet mixtures of aspirin and drugs with easily acylated functionalities such as phenylephrine hydrochloride, codeine, and acetaminophen 7–9. We had reported (the first instance27 of) a facile intermolecular benzoyl group transfer in crystals of racemic 2,4‐di‐ O ‐benzoyl‐ myo ‐inositol 1,3,5‐orthoformate ( 1 ), its orthoacetate analogue 2 ,28 as well as in co‐crystals 1⋅2 29 (Scheme ), which yielded the corresponding tribenzoates 3 and 4 and the diols 5 and 6 .…”