Hydrolysis, of orthoesters

Reactions are also known which are catalysed not only by H30 , but by other acids in the system as well e.g. in the hydrolysis of orthoesters such as MeC(OEt)3 in the presence of an acid, HA, where it is found that ... 

Kinetics of the Hydrolysis of Orthoesters A General Acid-Catalyzed Reaction 57... 

The acid-catalyzed hydrolysis of orthoesters is very much faster than that of esters. The second-order rate coefficient for the hydrolysis of ethyl acetate is of the order of 10"4 1-mole-1-sec1 at 25°C, whereas that for the hydrolysis of ethyl orthoacetate103 is of the order of 104 l-mole-1-sec 1, and that for the breakdown of a monoalkyl orthoester must be faster still. If the breakdown of the tetrahedral intermediate is partially rate-determining in acid-catalyzed ester hydrolysis, therefore, its concentration must be very small that is, the equilibrium for its formation must be highly unfavourable. This... 

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. 

The formation of esters from the mild acid hydrolysis of orthoesters proceeds through the formation of a hemi-orthoester tetrahedral intermediate as described by the following equation (47-63). 

The first results reported (41) showed that the mild acid hydrolysis of the five cyclic orthoesters 72-76 (Ri H ) gave the corresponding hydroxy-ester as the sole product of the reaction. It was found later by Capon and Grieve (58) that the hydrolysis of orthoester Ti (R=CH3 or C2H5) gave a mixture of hydroxy-ester (=70%) and lactone (30%). The hydrolysis of orthoesters 72-76 was subsequently repeated (59). It was confirmed that orthoester 73 indeed gave a =7 3 mixture of hydroxy-ester and lactone. A similar result was observed with orthoester 72 but the other three orthoesters 74-76 gave exclusively hydroxy-ester as previously reported. 

The same authors have also carried out the hydrolysis of orthoesters 101. When R=CH3, C Hj or CgHg, they found again an almost exclusive formation of... 

In a cyclic orthoester such as 55 (Fig. 5) when the two alkoxy groups are different, there is the possibility of forming three different hemi-orthoesters (56, 57, and 58) which can lead to three different esters, the two hydroxy-esters 59 and 60 and the lactone 6K Thus, there is a possibility that some specific hemi-orthoesters will be generated which will lead to the preferential formation of one of the ester products. The mild acid hydrolysis of orthoesters is therefore a potential method to test the principle of stereoelectronic control in the formation and cleavage of hemi-orthoester tetrahedral intermediates. 

More precise information concerning the course of events in the acid hydrolysis of orthoesters was obtained from the study of the four bicyclic orthoesters 77-80 which have two different alkoxy groups. Each orthoester yielded exclusively the hydroxy-ester resulting from the ejection of the axial alkoxy group. Thus, 77, T, and 79 afforded the same hydroxy methyl ester 81 whereas orthoester 80 furnished the hydroxyl ethyl ester 82. The reverse process which occurs under basic conditions, i,e. the addition of alkoxide ion to the corresponding bicyclic lactonium salt, has already been described (cf. p. 71) and it was shown to take place with the same specificity. 

Ozone oxidation of the trans-decal in di of benzylidene 133 has been carried out (71). Under kinetically controlled conditions, it produces the axial benzoate 134 in preference to the more stable equatorial benzoate 135. Similar results were obtained with an analogous case derived from cholestane-2e,3e-diol. These results are essentially identical to those obtained by King and Allbutt (60, 62) in their study on the hydrolysis of dioxolane orthoesters and dioxolenium salts (cf. p. 82), and can therefore be explained in the same manner. These results further confirm that the oxidation of acetals by ozone produces an intermediate which behaves like the hemiorthoester tetrahedral intermediate which is formed in the hydrolysis of orthoesters. 

In previous studies, i,e. concurrent carbonyl-oxygen exchange in the hydrolysis of esters, acid hydrolysis of orthoesters and oxidation of acetals by ozone, the configuration of the tetrahedral intermediate was determined by the application of the principle of stereoelectronic control. There could be some ambiguity in these experiments as the theory of stereoelectronic control is used to predict both the stereochemistry of the tetrahedral intermediate as well as its breakdown. The oxidation cleavage of vinyl orthoesters can therefore be considered a more powerful experimental technique in that respect because the configuration of the hemi-orthoester... 

The general acid-catalyzed hydrolysis of orthoesters involves proton transfer from the acid to an ester oxygen atom followed by ratedetermining cleavage of a carbon-oxygen bond and formation of... 

The first observation of the instability of carbohydrate orthoesters toward alkali came from Haworth, Hirst and Miller in connection with their experiments on the simultaneous deacetylation and methylation of L-rhamnose methyl 1,2-orthoacetate. These authors noticed that methylation by methyl iodide and silver oxide in the presence of solid sodium hydroxide resulted in the formation of crystalline methyl tri-methyl-/3-L-rhamnopyranoside. A similar result was obtained by Bott, Haworth and Hirst on the simultaneous deacetylation and methylation of triacetyl-D-mannose methyl 1,2-orthoacetate by the use of excessive quantities of dimethyl sulfate and alkali. The reaction produced a mixture of a. and /3 forms of methyl tetramethyl-D-mannopyranoside but the yield was only 40%. When the acetylated orthoester was submitted to methylation with silver oxide and methyl iodide in the presence of sodium hydroxide, the product was mainly trimethyl-rhamnose methyl 1,2-orthoacetate. This result indicates that for the alkaline hydrolysis of orthoesters, hydroxyl ions are necessary. Such ions are present in the dimethyl sulfate-alkali process, but are absent in the methyl iodide treatment except when the reaction mixture contains a little water either by accident or from the decomposition of the sugar molecule. Haworth, Hirst and Samuels examined the behavior of dimethyl-L-rhamnose methyl 1,2-orthoacetate in alkaline solution. When the substance was heated under various conditions with 0.1 A alkali at 70 there was no appreciable hydrolysis at the end of ninety minutes, whereas at 80 for... 

Abstract This chapter emphasises on the important aspects of steric and stereo-electronic effects and their control on the conformational and reactivity profiles. The conformational effects in ethane, butane, cyclohexane, variously substituted cyclohexanes, and cis- and tra/ ,v-decalin systems allow a thorough understanding. Application of these effects to E2 and ElcB reactions followed by anomeric effect and mutarotation is discussed. The conformational effects in acetal-forming processes and their reactivity profile, carbonyl oxygen exchange in esters, and hydrolysis of orthoesters have been discussed. The application of anomeric effect in 1,4-elimination reactions, including the preservation of the geometry of the newly created double bond, is elaborated. Finally, a brief discussion on the conformational profile of thioacetals and azaacetals is presented. 

Potts, R.A. Schaller, R.A. Kinetics of the hydrolysis of orthoesters a general acid-catalyzed reaction. J. Chem. Ed. 1993, 70, 421-424. 

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