Orthoester formation, mechanism

The results obtained are shown in Table III (see p. 26). The mutarotation of the product indicated, in each case, that the /3-D-modification predominated for the acetyl sugars formed from reaction with water. The data show that the reaction was only slightly affected by change of solvent or of temperature, and was free of orthoester formation. These facts, and the almost exclusive formation of 1,2-trans products from the 1,2-cis-bromide, was interpreted as evidence that the reaction proceeds by way of the Sw2 mechanism. It was suggested that the increase of O-acetyl-a-D-glucoside formed at 50° (over that at 20°) may be due to racemization through carbonium-ion formation. 

Ketones or aldehydes can undergo acetal exchange with orthoesters. The mechanism starts off as if the orthoester is going to hydrolyse but the alcohol released adds to the ketone and acetal formation begins. The water produced is taken out of the equilibrium by hydrolysis of the orthoester. 

The formation of orthoester may be explained tiy the preferential addition of tlie ketene acetal to the most reactive alcohol function (primary hydroxyl g,roup) giving thc f non - i so 1 a t ed) acyclic orthoester whicti is attacked by the neighbouring OH-4 with subsequent elimination of methanol. The partial hydrolysis of the diacetate is assumed to proceed through protonation of the methoxyl group (7), via the dioxocarbenium ion 8 and the orthoacid 9. collapse of 9 by either [lath b or path a accor-ding to the mechanism generally proposed (see, for instance, ref. 29 and refs. cited therein) affords the compounds 5 or respectively. 

Triazines 347 were obtained from amidoximes 346 and ethyl orthoacetate (equation 151). The mechanism of formation of products 347 includes Beckmann rearrangement of amidoximes to carbodiimides, followed by reaction with amidoxime and orthoester. ... 

Jencks and his coworkers (Funderburk et al., 1978) proposed a mechanism for the breakdown of hemiacetals catalysed by hydroxide-ion which consists of the reversible formation of the anion followed by its unimolecular breakdown. A similar mechanism can be written for the breakdown of hemi-orthoesters (7), (8). For at least one hemiorthoester viz. 2-hydroxy-2-... 

On the other hand, formation of methyl benzoate was also found to occur in methanol, indicating that, together with a general base-catalysis to produce benzamide and with the intramolecular, orthoester mechanism (see p. 110) to give the nitrogenated sugars, a transesterification reaction takes place in which the alkoxide ions play an important role. This can be exemplified by the following sequence. 

In the discussion of the general base catalyzed addition step above (p. 120) the objection was raised that it was difficult to believe that general base catalysis would be necessary for the addition of water to so reactive a species as a protonated ester. An answer to this objection is implicit in the discussion above of the mechanism of hydrolysis of orthoesters. It appears that the protonated orthoester, which would be the initial product of the simple addition of a molecule of water to a protonated ester, is too reactive a species to exist in aqueous solution, and that carbon-oxygen bond-cleavage is concerted with the transfer of the proton to the orthoester. The formation of a protortated orthoester by the addition of a molecule of water to the conjugate acid of an ester will be even less likely, and it seems entirely reasonable, therefore, that the formation of the neutral orthoester, by a general base catalyzed process, should be the favoured mechanism. 

Indeed, as shown by Verin and Kuznetsov (89UP1), the oxidation of 159 with hydrogen peroxide in ethanol gives rise to cyclic orthoester 217, and the formation of this compound corroborates the mechanism suggested earlier for this reaction. 

One can also acetalize carbonyl compounds completely without using the alcohol in excess. This is the case when one prepares dimethyl or diethyl acetals from carbonyl compounds with the help of the ortho formic acid esters trimethyl ortho formate HC(OCH3)3 or triethyl ortho formate HC(OC2H5)3, respectively. In order to understand these reactions, one must first clearly understand the mechanism for the hydrolysis of an orthoester to a normal ester (Figure 9.13). ft corresponds nearly step by step to the mechanism of hydrolysis of 0,0-acetals, which was detailed in Figure 9.12. The fact that the individual steps are analogous becomes very clear (see Figure 9.13) when one takes successive looks at... 

We won t go through the mechanism again—you ve already seen it as the reverse of acetal formation (and you have a hint of it in the orthoester hydrolysis just discussed), but the fact that acetals are stable to base is really a very important point, which we will use on the next page and capitalize on further in Chapter 24. 

In the NMR experiments carried out by Wenthe and Cordes [187] with methyl orthobenzoate and methyl orthocarbonate in CD3OD—D20 solutions, the rate coefficients for the disappearance of orthoester and those for the formation of CH3OD and of carboxylic ester have been found identical within experimental error (Table 15). This indicates that there is no exchange of methoxy groups prior to hydrolysis. The same result has been obtained from product analysis studies of the carboxylic esters formed. Consequently, the rate-determining step must be carbonium ion formation or a previous step. The findings do not support an A2 mechanism, for the following reason. As the nucleophilic reactivities of water and methanol are similar, the A2 reaction with attack of water... 

The A2 mechanism can be excluded with certainty for the hydrolyses of all orthoesters discussed. This is done on the basis of the determined volume of activation, AF = +2.4 cm3 (Table 1) for ethyl orthoformate [32], on the basis of the strongly increased rate in comparison to orthoformate (no steric hindrance) for orthoacetate and orthopropionate, and on the basis of the results of experiments with added nucleophiles for orthobenzoate [183] and orthocarbonate [192]. The observed AS values (Table 12) are in agreement with these conclusions. Consequently, the mechanism of orthoester hydrolysis must be either A1 or A-SE2, or possibly a concerted process with proton transfer and carbonium ion formation in the same step. 

The third example is essentially the same except that the reagent is one orthoester and th product is another. The volatile by-product is methanol and distillation of this pushes tr.. equilibrium across. The mechanism is very similar to the first example with the formation methanol and an oxonium ion starting the process off. This time, an oxonium ion must be invoh in the capture of each alcohol. 

Reductions at anomeric positions, both by ionic and radical mechanisms, deliver hydrogen from the axial direction. Kahne prepared the hemithio orthoester 75 from thiolactone and subjected it to tin hydride reduction, which resulted in predonunant formation of the -glycoside [116] (O Scheme 40). 

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