Hemiacetal formation, study

Relaxation kinetics. In the course of a study of hemiacetal formation with a phenol nucleophile, an equation was given for the relaxation time in the system ... 

Hemiacetal formation was first observed in optical studies on D-glucose. The optical rotation ([ ) of a freshly dissolved sample of D-glucose changes with time because it possesses two stereoisomeric hemiacetals (anomers) that are interconvertible in solution (fig. 12.5). One of these anomers, a-D-glucose, has [a]D=113 the other, a-L-glucose, has [a]D= 19. The optical rotation of a freshly prepared solution of either of these compounds eventually approaches an intermediate value that depends on the equilibrium between the two anomers. 

Detailed studies of the periodate oxidation of dextran and inulin (4-6) have shown evidence for the occurrence of hemiacetal structures formed by reaction of aldehydes with hydroxyl groups of either the same unit (intra-residual) or a neighbouring unit (inter-residual). Inter-residual hemiacetal formation reduces the number of diol struc-... 

In contrast to the relative scarcity of thermodynamic data for acetal and hemiacetal formation in alcohols, a lot of work has been devoted to the study of acetal hydrolysis, essentially in water or dioxan-water mixtures. Under these conditions, it is generally agreed that the mechanism described in (52) is valid... 

The most studied compound in this group is the oxidation product from methyl a-D-glucopyranoside, which, of course, can be prepared from other glycosides. At least six structures are theoretically possible for this dial-dehyde the free dialdehyde (48) or its hydrated form, a dioxane derivative formed by hemiacetal formation (49) or its hydrate, a fused tricyclic form (50) by further hemiacetal formation in (49), and a hemialdal form (51). Equilibria between the various forms should be possible, and, in different reactions detailed below, derivatives of the different forms are produced. Some workers have sought one structure for the dialdehyde, ... 

Non-specific solute-solvent interactions are reviewed elsewhere in this Volume (p. 83). However certain interactions that are chemical in nature and can be studied by n.m.r. will be mentioned. These include the hydration of pyruvic acid and hydration and hemiacetal formation from carbonyl compounds. 

The mechanism for the acid-catalyzed conversion of a hemiacetal to an acetal is divided into four steps. As you study this mechanism, note that acid is a true catalyst in this reaction. The protonated alcohol is used to add a proton in Step 1, but another proton-ated alcohol is generated in Step 4. The latter steps of this mechanism are very similar to those for hemiacetal formation. 

Leino and Vogt [70] studied the hydroformylation-hemiacetal formation of polyols in an aqueous medium (Scheme 5.79). For example, the reaction with a rhodium catalyst based on Sulfoxantphos gave in water almost full conversion and excellent yield of the hemiacetal. The intermediary aldehyde could not be detected. Extraordinary results were likewise noted with a Xantphos catalyst under these conditions. 

Hemiacetal formation from formaldehyde and methanol has been studied by intrinsic reactivity analysis at the B3LYP/6-311-l-l-G(d,p) level and the beneficial combined assistance of watermolecules and Brpnsted acids has been quantified. Theoretical study of hemiacetal formation from methanol with derivatives of CH3CHO (X = H, F, Cl, Br, and I) has shown that the energy barrier can be reduced by a catalytic molecule (MeOH or hemiacetal product)." ... 

Patulin (Fig. 1) was discovered by Birkinshaw etal. (1943), and its chemical structure elegantly proved and synthesized by Woodward and Singh (1949, 1950). The oxime was independently prepared by another route (Serratosa, 1961). A recent crystallographic study by Hubbard et al (1977) confirmed the structure of patulin and gave the bond distances and angles of the patulin molecule. Patulin isolated from natural sources has one asymmetric center on carbon 1. Patulin is, however, racemic. One explanation could be that the center at C(l) may racemize easily during work-up. Another possibility could be that the hemiacetal formation is not enzyme controlled. 

In a study of the acid-catalyzed formation of the hemiacetal, Grunwald has shown that the data best fit a mechanism in which the three steps shown here are actually all concerted that is, the reaction is simultaneously catalyzed by acid and base, with water acting as the base ... 

The metabolism of NPYR is summarized in Figure 1. a-Hy-droxylation (2 or 5.position) leads to the unstable intermediates and decomposition of gives 4-hydroxybutyraldehyde [ ]. The latter, which exists predominantly as the cyclic hemiacetal 1, has been detected as a hepatic microsomal metabolite in rats, hamsters, and humans and from lung microsomes in rats (9-13). The role of 1 and as intermediates in the formation of 6 and 7 is supported by studies of the hydrolysis of 2-acetoxyNPYR and 4-(N-carbethoxy-N-nitrosamino)butanal, which both gave high yields of 7 (9,14). In microsomal incubations, can be readily quantified as its 2,4-dinitrophenylhydrazone derivative (15). The latter has also been detected in the urine of rats treated with NPYR ( ). 

Pacsu4 5 has suggested a structure for starch involving a small number of non-cyclic hemiacetal linkages, the number being presumably sufficient to account for the number of endgroups determined by the methylation method. Halsall, Hirst and Jones6 have commented on this structure, however, and have shown it to be incompatible with the results of periodate-oxidation studies. In addition, these authors pointed out that it would be difficult to explain enzymic hydrolysis and dextrin formation on the basis of such a structure. 

Grunwald also studied the mechanism of the base-catalyzed formation of the hemiacetal, and found it to be the same as that of base-catalyzed hydration (6-1, mechanism a) Grunwald J. Am. Chem. Soc. 1985,107, 4710. Sec also S0rensen Pedersen Pedersen Kanagasabapathy McClelland J. Am. Chem. Soc. 1988,110, 5118 Leussing J. Org. Chem. 1990, 55. 666. 

Periodate oxidation is generally performed in aqueous solution, but Yu and Bishop studied oxidation with periodic acid in dimethyl sulfoxide.81 They observed limited oxidation, probably attributable to rapid formation of hemiacetals. Concentrated solutions of periodic acid in dimethyl sulfoxide may explode 82 therefore, only dilute solute) T. Painter and B. Larsen, A eta Chem. Scand., 24, 2366-2378 (1970). 

The formation and the hydrolysis of acyclic and cyclic acetals have been studied in rather great detail [91]. Several reviews on this topic are available [92] and some comments have been made [13] concerning the carbohydrate series. We have shown in Schemes 1,2, and 3 that a common feature of this reaction seems to be the intermediacy of an oxocarbenium ion. However, the cyclization of such an intermediate has been questioned more recently [93] in the light of the Baldwin s rules for ring closure [94]. At least for the five-membered ring, an SN2-type displacement mechanism far the protonated form (B) of die hemiacetal (A) (favorable 5-exo-tet cyclization) has been proposed rather than the unfavorable 5-endo-trig cyclization of the oxocarbenium ion (C) (Scheme 5). Except when the formation of the enol ether (D) is structurally impossible, the intermediacy of such a compound remains feasible. 

An alternative mechanism (shown in Scheme 10) for the formation of (109) from demethylcorynantheine (102) postulates the prior formation of a hemiacetal (110) followed by an irreversible attack on the mercurinium ion by the hydroxy-group to give an intermediate of structure (111). The inherent plausibility of such a mechanism led Goutarel et al.75 to study the mercuration-demercuration of cory-nantheine which, in an aqueous medium, can in principle give rise to the same hemiacetal (110), and thence the acetal (111). In fact this reaction gave a mixture of the acetals (104), (109), and their C-16 epimers which, on treatment with polyphosphoric acid, gave a mixture of ajmalicine (85a) and 19-epiajmalicine (85b) in a ratio of ca. 45 55. 

In DERA reactions, where acetaldehyde is the donor, products are also themselves aldehydes. In certain cases a second aldol reaction will proceed until a product has been formed that can cyclize to a stable hemiacetal.71 For example, when a-substituted aldehydes were used, containing functionality that could not cyclize to a hemiacetal after the first aldol reaction, these products reacted with a second molecule of acetaldehyde to form 2,4-dideoxyhexoses, which then cyclized to a hemiacetal, preventing further reaction. Oxidation of these materials to the corresponding lactone, provided a rapid entry to the mevinic acids and compactins (Scheme 5.43). Similar sequential aldol reactions have been studied, where two enzyme systems have been employed72 (Scheme 5.44). The synthesis of 5-deoxy ketoses with three substitutents in the axial position was accomplished by the application of DERA and RAMA in one-pot (Scheme 5.44). The long reaction time required for the formation of these thermodynamically less stable products, results in some breakdown of the normally observed stereoselectivity of the DERA and FDP aldolases. In a two-pot procedure, DERA and NeuAc aldolase have... 

---