Construction of Two-Component Chemically Reactive Supramolecular Assemblies-Acyl Migration Reactions in Cocrystals of Napthalene-2,3-Diol and Its Diesters.

Reactions in solids are of contemporary interest due to applications in pharmaceutical industries to environmental sustainability. Although several reactive crystals that support chemical reactions have been identified and characterized, the same cannot be said about reactive cocrystals. Earlier we correlated the facile acyl group transfer reactions in crystals with supramolecular parameters obtained from the crystal structures. The structure-reactivity correlation revealed the requirement of proper juxtaposition of electrophile (C=O) and the nucleophile (OH) with distance (∼3.2 Å) and angle (∼90°) along the chain structure. The current article describes the preparation of cocrystals that are capable of supporting intermolecular acyl group transfer reactions in a group of structurally similar molecules. The cocrystals of naphthalene 2,3-diol and its corresponding diesters showed a facile solid state acyl transfer reaction, which has been well correlated with their crystal structures.

Intermolecular Acyl-Transfer Reactions in Molecular Crystals.

It is far more difficult to recognize and predict the chemical reactions that a molecule of an organic compound can undergo in crystalline (solid) state as compared to the solution state (the "organic functional group" approach), since the published data on solid-state structure-reactivity investigations and correlations are scant. The discovery of the first intermolecular acyl-transfer reaction in molecular crystals of racemic 2,4-di- O-benzoyl- myo-inositol-1,3,5-orthoformate (DiBz) during our attempts to develop methods for the synthesis of phosphoinositols, motivated us to find other molecular crystals capable of supporting similar reactions. Small changes to the molecular structure of DiBz yielded analogues with different crystal structures which showed varying degrees of acyl transfer reactivity as compared to the crystals of DiBz. A systematic investigation of the structures, polymorphism, cocrystallization behavior, and the corresponding reactivity of these crystals allowed us to correlate the acyl transfer reactivity with their structures and inherent noncovalent interactions and provided crucial insights into the mechanism of these reactions. Polymorphs or cocrystals of these compounds exhibited dissimilar reactivities due to differences in the molecular conformation and/or arrangements in their crystals. The knowledge of phase transitions between polymorphs enabled us to control and tune the reactivity in the solid state. We could identify three conditions essential for intermolecular acyl transfer: (i) favorable relative geometry of the electrophile (ester C═O) and the nucleophile (OH), (ii) noncovalent interactions (C-H···π) between the reacting molecules which help in maintaining the facility and specificity of the reaction, and (iii) the presence of channels in the lattice which enable propagation of the reaction in the crystal. Based on this supramolecular structure-reactivity correlation, we identified other molecular crystals (composed of molecules of widely different molecular structure from that of DiBz) from a survey of the Cambridge Structural Database (CSD) and predicted their acyl transfer reactivity. The increased availability of user-friendly modern X-ray diffractometers and related software has enabled efficient collection, analysis and interpretation of single crystal X-ray diffraction data, essential for such studies. The rapidly expanding CSD facilitates the identification of crystals with similar structures and reactivity patterns. In a wider perspective, facile reactions in molecular crystals fascinate chemists because these reactions usually exhibit unique product selectivity and have the potential to be developed as sustainable green reactions. We are optimistic that similar approaches for the study of other group transfer reactions in molecular crystals would augment and widen the scope of chemical reactions in molecular crystals in particular and the solid state in general. The ability to predict the reactivity of molecules in their crystals could find applications in organic synthesis, material science and industry. Realization of the involvement of inositol derivatives in cellular processes led to the discovery of cellular signal transduction mechanisms. The ability of inositol derivatives to support facile acyl-transfer reactions in the crystalline state might well have opened a new avenue for research in the area of organic solid-state reactions.

Lithium hydride as an efficient reagent for the preparation of 1,2-anhydro inositols: Does the reaction proceed through 'axial rich' conformation?

scyllo-Inositol derived 1,2-trans-diequatorial halohydrins can be efficiently converted to the corresponding epoxides in the presence of lithium hydride. The structure of one of the epoxides was determined by single crystal X-ray diffraction analysis. This provides a potential route for the preparation of ring modified inositol derivatives. DFT calculations suggest that this epoxide formation could be proceeding through the intermediacy of the cyclohexane ring-inverted axial-rich conformer (1,2-trans-diaxial halohydrin). This is supported by the results of DFT calculations on the formation of inositol orthoformate, where the product is locked in the axial-rich conformation, while the starting inositol has the equatorial-rich conformation.

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

Intermolecular acyl transfer reactivity in several molecular crystals was studied, and the outcome of the reactivity was analyzed in the light of structural information obtained from the crystals of the reactants. Minor changes in the molecular structure resulted in significant variations in the noncovalent interactions and packing of molecules in the crystal lattice, which drastically affected the facility of the intermolecular acyl transfer reactivity in these crystals. Analysis of the reactivity vs crystal structure data revealed dependence of the reactivity on electrophile···nucleophile interactions and C-H···π interactions between the reacting molecules. The presence of these noncovalent interactions augmented the acyl transfer reactivity, while their absence hindered the reactivity of the molecules in the crystal. The validity of these correlations allows the prediction of intermolecular acyl transfer reactivity in crystals and co-crystals of unknown reactivity. This crystal structure-reactivity correlation parallels the molecular structure-reactivity correlation in solution-state reactions, widely accepted as organic functional group transformations, and sets the stage for the development of a similar approach for reactions in the solid state.

Inositol to aromatics -benzene free synthesis of poly oxygenated aromatics.

A method for the preparation of benzene derivatives from myo-inositol, an abundantly available phyto chemical is described. 1,3-Bridged acetals of inososes undergo step-wise elimination leading to the formation of polyoxygenated benzene derivatives. This aromatization reaction proceeds through the intermediacy of a ß-alkoxyenone, which could be isolated. This sequence of reactions starting from myo-inositol, provides a novel route for the preparation of polyoxygenated benzene derivatives including polyoxygenated biphenyl. This scheme of synthesis demonstrates the potential of myo-inositol as a sustainable non-petrochemical resource for aromatic compounds.

Effect of Crystal Packing on the Thermosalient Effect of the Pincer-Type Diester Naphthalene-2,3-diyl-bis(4-fluorobenzoate): A New Class†II Thermosalient Solid.

The pincer-like double ester naphthalene-2,3-diyl-bis(4-fluorobenzoate) (2) is pentamorphic. Upon heating crystals of form I to below their melting point (441-443 K), they undergo a phase transition accompanied by a thermosalient effect, that is, rare and visually striking motility whereby the crystals jump or disintegrate. The phase transition and the thermosalient effect are reversible. Analysis of the crystal structure revealed that form I is a class II thermosalient solid. Crystals of form III also underwent a reversible phase transition in the temperature range of 160 to 170 K; however, they were not thermosalient. Comparison of the structures and the mechanical responses of the two polymorphs revealed that the thermosalient effect of form I was due to reversible closing and opening of the arms of the diester molecules in a tweezer-like action.

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

Minor variations in the molecular structure of constituent molecules of reactive crystals often yield crystals with significantly different properties due to altered modes of molecular association in the solid state. Hence, these studies could provide a better understanding of the complex chemical processes occurring in the crystalline state. However, reactions that proceed efficiently in molecular crystals are only a small fraction of the reactions that are known to proceed (with comparable efficiency) in the solution state. Hence, for consistent progress in this area of research, investigation of newer reactive molecular crystals which support different kinds of reactions and their related systems is essential. The crystal structures and acyl-transfer reactivity of a myo-inositol-1,3,5-orthoformate-derived dibenzoate and its carbonate (4-O-benzoyl-2-O-phenoxycarbonyl-myo-inositol 1,3,5-orthoformate, C21H18O9) and thiocarbonate (4-O-benzoyl-2-O-phenoxythiocarbonyl-myo-inositol 1,3,5-orthoformate, C21H18O8S) analogs are compared with the aim of understanding the relationship between crystal structure and acyl-transfer reactivity. Insertion of an O atom in the acyl (or thioacyl) group of an ester gives the corresponding carbonate (or thiocarbonate). This seemingly minor change in molecular structure results in a considerable change in the packing of the molecules in the crystals of myo-inositol-1,3,5-orthoformate-derived benzoates and the corresponding carbonates. These differences result in a lack of intermolecular acyl-transfer reactivity in crystals of myo-inositol-1,3,5-orthoformate-derived carbonates. Hence, this study illustrates the sensitivity of the relative orientation of molecules, their packing and ensuing changes in the reactivity of resulting crystals to minor changes in molecular structure.

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

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 the solid-state reactivities of racemic 2,4(6)-di-O-benzoyl-myo-inositol 1,3,5-orthoformate and its 4,4'-bipyridine cocrystal with their crystal structures.

Racemic 2,4(6)-di-O-benzoyl-myo-inositol 1,3,5-orthoformate, C21H18O8, (1), shows a very efficient intermolecular benzoyl-group migration reaction in its crystals. However, the presence of 4,4'-bipyridine molecules in its cocrystal, C21H18O8·C10H8N2, (1)·BP, inhibits the intermolecular benzoyl-group transfer reaction. In (1), molecules are assembled around the crystallographic twofold screw axis (b axis) to form a helical self-assembly through conventional O-H···O hydrogen-bonding interactions. This helical association places the reactive C6-O-benzoyl group (electrophile, El) and the C4-hydroxy group (nucleophile, Nu) in proximity, with a preorganized El···Nu geometry favourable for the acyl transfer reaction. In the cocrystal (1)·BP, the dibenzoate and bipyridine molecules are arranged alternately through O-H···N interactions. The presence of the bipyridine molecules perturbs the regular helical assembly of the dibenzoate molecules and thus restricts the solid-state reactivity. Hence, unlike the parent dibenzoate crystals, the cocrystals do not exhibit benzoyl-transfer reactions. This approach is useful for increasing the stability of small molecules in the crystalline state and could find application in the design of functional solids.

myo-Inositol 1,3-acetals as early intermediates during the synthesis of cyclitol derivatives.

Synthetic sequences starting from commercially available myo-inositol necessarily involve protection-deprotection strategies of its six hydroxyl groups. Several strategies have been developed/attempted over the last several decades leading to the synthesis of naturally occurring phosphoinositols, their analogs, and cyclitol derivatives. Of late, myo-inositol 1,3-acetals, which can be obtained by the reductive cleavage of myo-inositol orthoesters have emerged as early intermediates for the synthesis of phosphorylated and other inositol derivatives. This mini-review is an attempt to illustrate the economy and convenience of using myo-inositol 1,3-acetals as early intermediates during syntheses from myo-inositol.

Identification of molecular crystals capable of undergoing an acyl-transfer reaction based on intermolecular interactions in the crystal lattice.

Investigation of the intermolecular acyl-transfer reactivity in molecular crystals of myo-inositol orthoester derivatives and its correlation with crystal structures enabled us to identify the essential parameters to support efficient acyl-transfer reactions in crystals: 1) the favorable geometry of the nucleophile (-OH) and the electrophile (C-O) and 2) the molecular assembly, reinforced by C-H⋅⋅⋅π interactions, which supports a domino-type reaction in crystals. These parameters were used to identify another reactive crystal through a data-mining study of the Cambridge Structural Database. A 2:1 co-crystal of 2,3-naphthalene diol and its di-p-methylbenzoate was selected as a potentially reactive crystal and its reactivity was tested by heating the co-crystals in the presence of solid sodium carbonate. A facile intermolecular p-toluoyl group transfer was observed as predicted. The successful identification of reactive crystals opens up a new method for the detection of molecular crystals capable of exhibiting acyl-transfer reactivity.

Synthesis of the aminocyclitol units of (-)-hygromycin A and methoxyhygromycin from myo-inositol.

Concise and efficient syntheses of the aminocyclitol cores of hygromycin A (HMA) and methoxyhygromycin (MHM) have been achieved starting from readily available myo-inositol. Reductive cleavage of myo-inositol orthoformate to the corresponding 1,3-acetal, stereospecific introduction of the amino group via the azide, and resolution of a racemic cyclitol derivative as its diastereomeric mandelate esters are the key steps in the synthesis. Synthesis of the aminocyclitol core of hygromycin A involved chromatography in half of the total number of steps, and the aminocyclitol core of methoxyhygromycin involved only one chromatography.

Chiral crystals from an achiral molecule: 4,6-di-O-benzyl-1,3-O-benzylidene-2-O-(4-methoxybenzyl)-myo-5-inosose.

The title achiral compound, C(35)H(34)O(7), crystallizes in the chiral monoclinic space group P2(1). The molecules are densely packed to form a helical assembly along the crystallographic twofold screw axis via C-H···O and C-H···π interactions. Interestingly, the unit-translated helical chains are loosely connected via a rather uncommon edge-to-edge Ph-H···H-Ph short contact (H···H = 2.33 Å).

Radical mediated deoxygenation of inositol benzylidene acetals: conformational analysis, DFT calculations, and mechanism.

Xanthates of 1,3-benzylidene acetal derivatives of myo- and neo-inositols undergo dideoxygenation under Barton-McCombie conditions, as a result of intramolecular abstraction of the benzylidene acetal hydrogen and subsequent cleavage of the acetal ring. Scrutiny of structure of these bicyclic inositol derivatives shows that although the conformation of the two rings can vary depending on the configuration of the inositol ring and the phase in which the molecules are present, both the xanthates lead to the formation of the same dideoxyinositol. DFT calculations on these molecular systems suggest that neo-inositol derivatives undergo conformational change prior to radical formation while myo-inositol derivatives undergo conformational change subsequent to radical formation, during the deoxygenation reaction. A low barrier for intramolecular hydrogen transfer supports the extreme facility of this deoxygenation reaction.

Comparison of racemic epi-inosose and (-)-epi-inosose.

The conversion of myo-inositol to epi-inositol can be achieved by the hydride reduction of an intermediate epi-inosose derived from myo-inositol. (-)-epi-Inosose, (I), crystallized in the monoclinic space group P2(1), with two independent molecules in the asymmetric unit [Hosomi et al. (2000). Acta Cryst. C56, e584-e585]. On the other hand, (2RS,3SR,5SR,6SR)-epi-inosose, C(6)H(10)O(6), (II), crystallized in the orthorhombic space group Pca2(1). Interestingly, the conformation of the molecules in the two structures is nearly the same, the only difference being the orientation of the C-3 and C-4 hydroxy H atoms. As a result, the molecular organization achieved mainly through strong O-H···O hydrogen bonding in the racemic and homochiral lattices is similar. The compound also follows Wallach's rule, in that the racemic crystals are denser than the optically active form.

Relative reactivity of hydroxyl groups in inositol derivatives: role of metal ion chelation.

O-Alkylation of myo-inositol derivatives containing more than one hydroxyl group via their alkali metal alkoxides (sodium or lithium) preferentially occurs at a hydroxyl group having a vicinal cis-oxygen atom. In general the observed selectivity is relatively higher for lithium alkoxides than for the corresponding sodium alkoxide. The observed regioselectivity is also dependent on other factors such as the solvent and reaction temperature. A perusal of the results presented in this article as well as those available in the literature suggests that chelation of metal ions by inositol derivatives plays a significant role in the observed regioselectivity. Steric factors associated with the axial or equatorial disposition of the reacting hydroxyl groups do not contribute much to the outcome of these O-alkylation reactions. These results could serve as guidelines in planning synthetic strategies involving other carbohydrates and their derivatives.

Two modes of O--H...O hydrogen bonding utilized in dimorphs of racemic 6-O-acryloyl-2-O-benzoyl-myo-inositol 1,3,5-orthoformate.

The title compound, C(17)H(16)O(8), yields conformational dimorphs [forms (I) and (II)] at room temperature, separately or concomitantly, depending on the solvent of crystallization. The yield of crystals of form (I) is always much more than that of crystals of form (II). The molecule has one donor -OH group that can make intermolecular O-H...O hydrogen bonds with one of the two acceptor C=O groups, as well as with the hydroxyl O atom; interestingly, each of the options is utilized separately in the dimorphs. The crystal structure of form (I) contains one molecule in the asymmetric unit and is organized as a planar sheet of centrosymmetric dimers via O-H...O hydrogen bonds involving the OH group and the carbonyl O atom of the acryloyl group. In the crystal structure of form (II), which contains two independent molecules in the asymmetric unit, two different O-H...O hydrogen bonds, viz. hydroxyl-hydroxyl and hydroxyl-carbonyl (benzoyl), connect the molecules in a layered arrangement. Another notable feature is the transformation of form (II) to form (I) via melt crystallization upon heating to 411 K. The higher yield of form (I) during crystallization and the thermal transition of form (II) to form (I) suggest that the association in form (I) is more highly favoured than that in form (II), which is valuable in understanding the priorities of molecular aggregation during nucleation of various polymorphs.

Enhancing intermolecular benzoyl-transfer reactivity in crystals by growing a "reactive" metastable polymorph by using a chiral additive.

Racemic 2,4-di-O-benzoyl-myo-inositol-1,3,5-orthoacetate, which normally crystallizes in a monoclinic form (form I, space group P2(1)/n) could be persuaded to crystallize out as a metastable polymorph (form II, space group C2/c) by using a small amount of either D- or L- 2,4-di-O-benzoyl-myo-inositol-1,3,5-orthoformate as an additive in the crystallization medium. The structurally similar enantiomeric additive was chosen by the scrutiny of previous experimental results on the crystallization of racemic 2,4-di-O-benzoyl-myo-inositol-1,3,5-orthoacetate. Form II crystals can be thermally transformed to form I crystals at about 145 degrees C. The relative organization of the molecules in these dimorphs vary slightly in terms of the helical assembly of molecules, that is, electrophile (El)...nucleophile (Nu) and C-H...pi interactions, but these minor variations have a profound effect on the facility and specificity of benzoyl-group-transfer reactivity in the two crystal forms. While form II crystals undergo a clean intermolecular benzoyl-group-transfer reaction, form I crystals are less reactive and undergo non-specific benzoyl-group transfer leading to a mixture of products. The role played by the additive in fine-tuning small changes that are required in the molecular packing opens up the possibility of creating new polymorphs that show varied physical and chemical properties. Crystals of D-2,6-di-O-benzoyl-myo-inositol-1,3,5-orthoformate (additive) did not show facile benzoyl-group-transfer reactivity (in contrast to the corresponding racemic compound) due to the lack of proper juxtaposition and assembly of molecules.

Concomitant dimorphs of tri-O-[p-halobenzoyl]-myo-inositol 1,3,5-orthoformates with different halogen bonding contacts: first order crystal-to-crystal thermal phase transition of kinetic form to the thermodynamic form.

Crystallization of tri-O-[p-halobenzoyl]-myo-inositol 1,3,5-orthoformates from ethyl acetate-petroleum ether solution produced concomitant dimorphs that have different halogen bonding contacts; the kinetic form with C-Br...O-C contacts upon heating to 185 degrees C, converts completely to the thermodynamic form with C-Br...O=C contacts via crystal-to-crystal first order phase transition.

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.

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.