Isohexides

Isomerization of sorbitol, D-mannitol, L-iditol, and dulcitol occurs in aqueous solution in the presence of hydrogen under pressure and a nickel—kieselguhr catalyst at 130—190°C (160). In the case of the first three, a quasiequiUbrium composition is obtained regardless of starting material. Equilibrium concentrations are 41.4% sorbitol, 31.5% D-mannitol, 26.5% L-iditol, and 0.6% dulcitol. In the presence of the same catalyst, the isohexides estabUsh an equihbrium at 220—240°C and 15.2 MPa (150 atm) of hydrogen pressure, having the composition 57% isoidide, 36% isosorbide, and 7% isomannide (161). 

Chemical Abstracts prefers the sugar terms, especially in the trivial forms however, in some instances, the bicyclo nomenclature is also applied. Surveying the whole original literature, preference is doubtless given to carbohydrate names with frequent use of the trivial isohexide terms, followed by the bridged-systems labeling. The fused systems names are not in vogue. 

Isohexide mono- (10-13), as well as di-, nitrates (14-16) show a weak, positive dichroic band at 265 nm (n— D transition) and a second, stronger one near 228 nm, which is positive for endo-R-nitrato and negative for exo-S-nitrato groups. For isosorbide dinitrate (14), both dichroic bands are positive.12,13... 

The diazides of four isohexides, namely, those of D-isosorbide (17) (2110 cm-1), D-isomannide (18) (2110 cm-1), L-isomannide (19) (2120 cm-1), and L-isoidide (20) (2100 cm-1) differ slightly17 in the position of their azido group vibration (KBr). 

The infrared spectra (benzene solution) of the isohexide nitrates, as well as of their mixed nitric and p-toluenesulfonic esters, are well established. The positions of the v and the bands for the nitrato group are remarkably constant, at 1645 3 cm-1 and 1282 1 -1 (endo), and 1274 1 cm-1... 

Fewer such compounds have thus far been characterized by 13C-n.m.r. spectroscopy. Thus, data were reported for isosorbide,11,21,27 isomannide,11,28 the three isohexide dimesylates,21,29 the 2-deoxy-2-iodo 5-mesylate,21 the dideoxydiiodides of isosorbide and isoidide,21,30 isomannide ditosylate, and bis(2,5-dideoxy-2,5-diphenylphosphino)isoidide,28 of mixed substituted acetates, and of monochloromonodeoxy compounds.21... 

H-Chemical Shifts (S) and Geminal (V) and Vicinal (3J) Coupling Constants for23 the 2.5-Diazido-2,5-dideoxy isohexides 17,18,19, and 20... 

H Chemical Shifts for the Ring System of Isohexide Derivatives Chemical shifts... 

Generally, lower shift values (downfield shifts) are measured for groups in the exo, compared with those in the endo, position.21 29 For mixed 2,5-disub-stituted isohexides, the situation is not so clear in each case.21 The 13C-chemical shifts of the isohexides and selected derivatives are summarized in Table VII. 

C Chemical Shifts of Isohexides and Derivatives in CDCl, versus Me4 Si as Internal Standard... 

The nature of the fragmentation is substantially changed in the case of the monobenzoylated isohexides. The highest mass, observed at m/z 207, corresponds to the fragment 29, following A in Scheme 1. A further way of... 

Four X-ray investigations of isohexide derivatives have been published.39-42 The oldest of them gave very little information about structural details. Two crystallographically independent molecules of 1,4 3,6-dianhydro-2-0-(p-bromophenylsulfonyl)-D-glucitol 5-nitrate (30), having the same conformation, are in the asymmetric unit. 

For isohexide nitrates gas-liquid chromatographic separation methods using OF-1 (Ref. 52), OV-101 (Refs. 53-59), OV-17 (Ref 60), or OV-210 (Ref 61) columns have been reported. Most of the methods described are used to detect traces of nitrates, as well as of their metabolites, in urine and plasma probes.62-69 All known isohexide nitrates can be measured in mixtures by using a DB-5 capillary column.70-71 Electron-capture detection was applied for the g.l.c. determination of isosorbide dinitrate71 and its metabo-lites.7,b... 

Other methods have also been used for quantitative determination of isohexide nitrates, including colorimetry,73-75 infrared spectroscopy,20 n.m.r. spectroscopy,76 and polarography.47-77-80... 

Differential scanning calorimetry can be used to detect isosorbide dinitrate in the presence of various proportions of other isohexide mononitrates in pharmaceutical formulations81 and for testing its hazardous characteristics.82 A complete analytical profile for isosorbide dinitrate, detailing spectroscopic and other physical properties, as well as useful analytical methods, has been reported.83... 

From among the known isohexides (see Section II), isosorbide (3) is that of the highest importance, not least because of the pharmaceutical use of its nitrates and the good solvent properties of its dimethyl ether. 

Among the isohexides, isosorbide (3) has two hydroxyl groups and these are in different steric surroundings that is, the OH-2 group in the exo and the OH-5 group in the endo position of the bicyclic ring-system. Many attempts have been made to control the regioselectivity of reactions at these positions. 

Kinetic studies of the esterification of isohexides were carried out for long-chain fatty acids.109-113-116 Search for optimal reaction conditions for these processes has been described.115-120... 

Some special esters of isohexides (prepared conventionally, however) have been described, including diesters of several long-chain fatty acids121,122 and dicarboxylic acids,123 isomannide-mono-oleate,124 isosorbide dinicotin-ate,125 and perfluorinated long-chain fatty acid diesters of isosorbide and isomannide.126 Bis(chloroformate)s of isosorbide and isomannide, and the... 

As a consequence, in most cases, the preparation of dialkyl isohexides is described in the literature. Some mono ethers have also been prepared, bearing different acyl groups on the second hydroxyl group of the ring system. Only very few examples of monoalkyl derivatives lacking further substituents are known. 

In the mid-sixties, Atlas Chemical Industries investigated the reaction of epoxides with isohexides. Transformation of isosorbide (3) by ethylene oxide affords polyoxyethylene isosorbide (62), which was treated with oleic acid to afford the corresponding diesters (63), and these were further transformed into epoxidized products167 (64) (see Scheme 12). On treating all three iso-... 

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