Thermodynamics hemiacetal

A novd example of a catalytic enantioselective domino process1201 is the inter-intramolecular nitro-aldol reaction described by Shibasaki et al which generates substituted indanones. As catalyst a praseodym-heterobimetallic complex with binaph-thol as chiral ligand is employed. Treatment of keto-aldehyde 41 with nitromethane in the presence of the catalyst 46 at -40 °C and successive warming to room temperature affords diredly the produd 42 in an overall yield of 41 % and 96 % ee after several recrystallizations (scheme 9). As intermediates the nitromethane adduct 43 and the hemiacetal 44 can be proposed. In a second aldol reaction 44 leads to 45 which isomerizes to the thermodynamically more stable epimer 42. 

Conventionally, the use of NaH or Cs2C03 as a base for the reaction of glycosyl hemiacetals with C13CCN often yields the thermodynamically favored a-glycosyl trichloroacetimidates, whereas the use of K2C03 often yields kinetically controlled P-glycosyl trichloroacetimidates (Scheme 3.26). The use of l,8-diazabicyclo[5.4.0] undec-7-ene (DBU) often provides a/p mixtures, mostly favoring a-products. 

Although addition of activated phosphoramidite to hemiacetals of manno-pyranoses under thermodynamic control has been reported to deliver exclusively a-phosphates in some cases,43 anomeric mixtures with preponderance of a-anomer have been reported in other examples.10,44 Since formation of phosphorotetrazolidite is a rate-limiting step of the process, initial activation of phosphoramidite followed by addition of nucleophilic hemiacetal should accelerate condensation and favour the formation of the thermodynamic a-product. Indeed, reaction of hemiacetal 101 with dibenzyl phosphorotetrazolidite assured exclusive a-selectivity of the resulting glycosyl phosphate 102.43 The accumulation in the reaction mixture of mildly acidic 1H-tetrazole, which is liberated upon reaction of tetrazolidite with hydroxylic component, could also favour predominant formation of the a-phosphate (Scheme 18, A). Conventional hydrogenolysis afforded the a-mannosyl phosphate 103. 

Although the mechanism of eqns (7) and (8) may be a reasonable one for the breakdown of [109], for some of the more reactive species, especially those derived from chloroacetic or dichloracetic acid, it may not be, as shown by the following considerations. For this mechanism to be valid the value of fc2 calculated from the relationship /cHO- = A fc2must be (i) less than the time constant for a molecular vibration (1012-1014s-1) fii) less than the value of based on the estimated Ka and the assumption that the ionization equilibrium (7) is diffusion controlled in the thermodynamically favourable direction, i.e. k1 = 10nM-1s-1. These two conditions are easily fulfilled with the hemiacetals and the less reactive hemiorthoesters derived from pinacol monoesters (see Table 15), but with the more reactive hemiorthoesters the calculated values of k2 lie close to or are greater than the cal-... 

The much lower thermodynamic stability of hemiorthoesters compared to hemiacetals is illustrated by comparing the equilibrium constant for the formation of [121] from the corresponding hydroxyester, 5 x 10-7 to 1 x 10" 6 (Table 17) with that for the formation of hemiacetal [123] from the corresponding hydroxyaldehyde [122] which is 8.1 in 75 25 dioxan-water... 

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... 

Kinetic data on acetal formation and cleavage in alcohols are scarce although kinetic and thermodynamic data in the same experimental conditions are of great interest (Davis et al., 1975). It should be noted that under these conditions inequality (53) is inverted and that, therefore, the rate-limiting step corresponds to water addition to an alkoxycarbenium ion (Step 3) or hemiacetal cleavage (Step 4). Recent data by El-Alaoui (1979) on forward and reverse rates are in agreement with those expected the acetal formation rate is independent of water concentration for a series of substituted acetophenones. 

Well, you saw a diagram like this in the last chapter when we were discussing kinetic and thermodynamic products (p. 329) and you can probably also apply something of what you now know about the reactivity of carbonyl compounds towards nucleophiles to work out what is happening in this reaction between a carbonyl compound and an amine. The hydroxylamine first adds to the ketone to form an unstable intermediate similar to a hemiacetal. 

A particularly elegant application of DERA is the sequential synthesis of thermodynamically stable cyclic hemiacetal. Two DERA-catalyzed aldol reactions convert one equivalent of acceptor and two equivalents of acetaldehyde into this stable compound. A mild subsequent oxidation yielded the corresponding lactone in ex-... 

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... 

Reaction of tetrahydro-4/7-thiopyranone 795 with meso-794 gave the bridged oxathiocins 775 in 68% yield and 92% ee, respectively. Oxazocine 775 existed exclusively in the hemiacetal form, suggesting that the stereocenter originating from C-6 in 794 could be set under thermodynamic control. Reaction of 795 with the readly available 3.5 1 mixture of ( )-794 and meso-794, respectively, produced 775 in the same yield and ee. 

Acetals and hemiacetals imbedded in 5- and 6-membered rings are remarkably stable and their deliberate conversion to the acyclic carbonyl derivatives can be a problem. The high thermodynamic and acid stability of the corresponding 5,5-acetals can be used to liberate a carbonyl by using a 2-stage transprotection protocol. During a synthesis of the macrolide antibiotic Erythronolide B, Martin... 

Higher aldehydes, for example acetaldehyde or n-butyraldehyde, have much less tendency to polymerize compared to formaldehyde [5, 6]. Reasons have been given in thermodynamic terms by referring to the lower enthalpy of polymerization (about —7 kcal mole" ) as compared to formaldehydes (—12 kcal mole" ), which results in ceiling temperatures of —40°C. In terms of reactivity, aliphatic aldehydes undergo hydration and hemiacetal formation to an extent of about 50%. 

Fructose-1,6-diphosphate (FDP) aldolase catalyzes the reversible aldol addition of DHAP and D-glyceraldehyde-3-phosphate (G3P) to form D-fructose-1,6-diphosphate (FDP), for which eq 10 M in favor of FDP formation (Scheme 13.9). RAMA accepts a wide range of aldehyde acceptor substrates with DHAP as the donor to stereospecifically generate 3S,4S vicinal diols (Scheme 13.8). The diastereoselectivity exhibited by FDP aldolase depends on the reaction conditions. Racemic mixtures of non-natural aldehyde acceptors can be partially resolved only under conditions of kinetic control. When six-membered hemiacetals can be formed, racemic mixtures of aldehydes can be resolved under conditions of thermodynamic control (Scheme 13.10). 

We have not previously considered stereochemistry. Hemiacetal (and acetal) formation is thermodynamic control as aU the reactions are reversible. The dimer and trimer crystallize frc-liquid so the stereochemistry may be governed by the formation of the most stable p . compound or by the fact that the crystallization of the least soluble diastereoisomer removes the equilibrium and so more is formed. We can see some reasons why the diastereoisomer i might be the most stable. The as ring junction between the two five-membered rings is much m stable than the trans, the two acetyl groups may prefer to be trans to each other, and there ma. > H bond in the crystal. We cannot be sure of these reasons but they are explored more in Chap . ... 

The hemiacetal gives a locally planar oxonium ion that can add the phenol from the top or bottom face. The bottom face is preferred in this instance as axial C-O bonds are more stable in acetals because of the anomeric effect (p. 1130) and acetal formation is under thermodynamic control. 

This Lewis acid accomplishes several functions. (1) Noncovalent protection of the 4-N-OH group which is accepted as fourth ligand to boron and thus possibility to take over electron density released from the 7-methoxy group in the critical case of DIMBOA (2) enhancement of the nucleophilic properties of the hemiacetal which was also shown to interact with the Lewis acid (3) promoter function for activation of the trichloroacetimidate glucosyl donor (4) equilibration conditions of any non-favoured diastereomers to the thermodynamically more stable... 

The term stable is ambiguous in organic chemistry parlance. When a compound is said to be stable, it sometimes means that it has low energy (AG°), i.e., it is thermodynamically stable, and it sometimes means that the barrier for its conversion to other species is high (AG ), i.e., it is kinetically stable. For example, both benzene and tetra-t-butyltetrahedrane are surprisingly stable. The former is both kinetically and thermodynamically stable, whereas the latter is kinetically stable and thermodynamically unstable. Certain kinds of compounds, like hemiacetals, are kinetically unstable and thermodynamically stable. In general, stable usually means kinetically stable, but you should always assure yourself that that is what is meant. When in doubt, ask. 

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