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

Abstract

Racemic 4-O-phenoxycarbonyl and 4-O-phenoxythiocarbonyl derivatives of myo-inositol orthoformate undergo thermal intramolecular cyclization in the solid state to yield the corresponding 4,6-bridged carbonates and thiocarbonates, respectively. The thermal cyclization also occurs in the solution and molten states, but less efficiently, suggesting that these cyclization reactions are aided by molecular pre-organization, although not strictly topochemically controlled. Crystal structures of two carbonates and a thiocarbonate clearly revealed that the relative orientation of the electrophile and the nucleophile in the crystal lattice facilitates the intramolecular cyclization reaction and forbids the intermolecular reaction. The correlation observed between the chemical reactivity and the non-covalent interactions in the crystal of the reactants provides a way to estimate the chemical stability of analogous molecules in the solid state.

Correlation of Intermolecular Acyl Transfer Reactivity with Noncovalent Lattice Interactions in Molecular Crystals: Toward Prediction of Reactivity of Organic Molecules in the Solid State

“…Examples of the same reaction are however rare in the crystalline state . We had earlier reported the synthesis and structures of several molecular crystals and co-crystals that exhibit efficient intermolecular acyl transfer reactions (Scheme ).…”

Engineering crystals that facilitate the acyl-transfer reaction: insight from a comparison of the crystal structures ofmyo-inositol-1,3,5-orthoformate-derived benzoates and carbonates

“…Cyclization between the axial hydroxy group and the C2-equatorial carbonate group in (2) and (3) is sterically forbidden since they are trans-disposed (marked by an arc in Scheme 3). Cyclization occurs only when the two groups are 1,3-cis diaxially disposed in a cyclohexane system (Tamboli et al, 2015). Carbonates (2) and (3) did not undergo intramolecular cyclization irrespective of the medium (solid/solution) due to the reasons mentioned above.…”

“…In contrast, facile cyclization occurs in crystals of (4) and (5), due to cis-oriented hydroxy and carbonate groups that can form stable cyclic carbonate structures (10) and (11), respectively (Scheme 3). Similarly, compounds (6) and (7) (Scheme 1), having both hydroxy and carbonate groups in axial positions (cis-orientated), also displayed a facile intramolecular cyclization reaction (Tamboli et al, 2015). Cyclization between the axial hydroxy group and the C2-equatorial carbonate group in (2) and (3) is sterically forbidden since they are trans-disposed (marked by an arc in Scheme 3).…”

“…Structural modifications of dibenzoate (1) resulted in variations in crystal structure and reactivity which could be correlated. In Scheme 1, arrows A-E indicate structural modifications to (1) that have been investigated: 'A' denotes the substitution of the orthoformate hydrogen (Sarmah et al, 2005;Murali et al, 2007Murali et al, , 2009, 'B' indicates substitution of benzoyl groups with other acyl groups (Krishnaswamy et al, 2009), 'C' specifies the substitution of a ring H atom (Krishnaswamy et al, 2010), 'D' shows the insertion of an O atom (to form carbonates) (Tamboli et al, 2015) and 'E' represents the substitution of oxygen with sulfur (to form thiocarbonates) (Tamboli et al, 2015).…”

“…Some of these carbonates and thiocarbonates, i.e. (4)-(7) (Scheme 1), underwent facile intramolecular cyclization in their crystals (Tamboli et al, 2015) to yield the corresponding cyclic product instead of undergoing intermolecular acylgroup transfer, as observed in the parent racemic dibenzoate (1).…”