Hemi-orthoester

Similar experiments were also carried out with dichloroketene diethyl and dimethyl acetals but no intermediate could be detected. This is readily explained since the cyclic ketene acetals undergo acid-catalysed hydration about 30 times more rapidly than the corresponding acyclic ones (Straub, 1970 Chiang et al., 1974 Kresge and Straub, 1983) whereas cyclic hemi-orthoesters undergo acid-catalysed breakdown 50-60 times more slowly than the corresponding acyclic ones do (see p. 70). Therefore the ratio of rate constants favourable for the detection of the cyclic hemiorthoesters becomes unfavourable with the acyclic hemiorthoesters. 

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-... 

Calculated equilibrium constants and free energies for the formation of cyclic hemi-orthoesters from the corresponding esters at 25° °... 

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 next operation consists in the analysis of the hydration of lactonium ion 63 and the subsequent breakdown of the resulting hemi-orthoester. A stereoelectronically controlled attack of water on the lactonium ion 63 must take place on the b face yielding the tetrahedral conformer 66 (Fig. 7). As previously discussed for the case of lactones (cf. p. 70), a reaction with water on the a face of 63 would result in a tetrahedral intermediate having a boat conformation, and this process is therefore eliminated. 

The cis bicyclic orthoester 87 can exist in the two different conformations 91 and 92. The conformation 92 corresponds to that of the unreactive tricyclic orthoester 62, i. e. conformer it can therefore be eliminated. Con-former 91 can undergo the cleavage of the axial C —0 bond with stereoelectronic control to produce the lactonium ion 93 which after hydration will give the hemi-orthoester 94. Since the chair inversion in 94 is not favored because the hydroxyalkyl side chain would have to take the axial orientation, it is expected that 94 would give the dihydroxy methyl ester 89 preferentially. 

According to the present theory, these reactions can be explained in the following manner. Since dioxolenium ions are essentially planar (8, 9), the chair form of ring B of salt 98 must be distorted towards a half-chair. Hydration of 98 with stereoelectronic control must take place from the a face to give the half-chair hemi-orthoester 102 (Fig. 8), because the steric hindrance between the incoming water molecule and ring B must inhibit... 

Halogenation of ketones, 275 Hemi-orthoester, 63 Hemi-orthoamide, 103-105 Hemi-orthothioamide, 144 Hemi-orthothiol esters, 93-97 Hinesol, 250... 

Hemi-orthoester intermediates have a weakly acidic hydrogen (from the 0-H group), and they have electron pairs on the oxygen atoms which can be pro-tonated in acidic medium. They can exist in three different ionic forms T+, T°, and T" depending on the acidity or the basicity of the medium. Since the pKa of a hemi-orthoester is about 10, it will exist in the T+ and the T° forms in acidic medium and essentially in the T° form in neutral. In slightly basic medium (pH =8-10), it will exist in the T° and the T" forms whereas in stronger basic medium (pH >11), only T" should be present. 

In acidic medium, the 1° form should be present in equilibrium with the T+ form because hemi-orthoesters are weak bases. Consequently, hemiortho-esters must be allowed to undergo molecular rotation prior to their breakdown in this medium. Also, there is no evidence so far that molecular rotation can compete with the breakdown of an intermediate in the T+ ionic form. What we know is that the barrier for cleavage should be definitely lower in the T+ than in the T° form (24). At pH higher than 11, hemiortho-esters will exist exclusively in the T ionic form, and it will be seen that in some cases, the energy barrier for the cleavage of T is lower than that of molecular rotation. 

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. 

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... 

An additional difficulty occurring with hemisuccinates was discovered by Sandman et al These authors, in studying the stability of chloramphenicol succinate, found an unusual partial acyl transfer reaction of the succinyl group to give a cyclic hemi-orthoester (Figure 38.6). 

FIGURE 38.6 Formation of cyclic hemi-orthoesters from a hemisuccinated ... 

We shall now consider the cleavage of each of the above hemi-orthoester con-formers under stereoelectronic control just as we dealt previously with the cleavage of the important orthoester conformers first, 96a will cleave to the hydroxy Z-ester 98, as shown in Eq. 25 second, 96b will not cleave and constitute the neutral conformer third, 96c will cleave to the hydroxy E-ester 99, as shown in Eq. 26. Interestingly, neither of 96a and 96c can cleave to a lactone because no ring oxygen electron pair orbital is in stereoelectronic effect with the equatorial aC-OMe bond. Thus, in instances where the tetrahydropyran ring cannot easily undergo chair inversion, lactone will not be formed. Additionally, since the Z-ester is more stable than the E-ester, hydrolysis will take place preferentially via the conformer 96a and the hydroxy Z-ester 98 will be formed. 

The reaction of ozone with tetrahydropyranyl ether is similar to the reaction of ozone with an acetal. Since the hydrotrioxide cleaves to an oxy anion, the control elements that influence the chemistry of hemi-orthoesters will also control the chemistry of such hydro trioxides. The relative orientation of the hydrotrioxide functional group is therefore not important. However, the steric interactions need to be considered in arriving at the predominant conformers 120a, 120b, and 120c. 

Orthoesters and pentaalkoxyphosphoranes are the alkylated analogues of tetrahedral and TBP intermediates respectively. Numerous examples of stable orthoesters exist in the literature, and some examples of stable (but reactive) pentaalkoxyphosphoranes are known (Hamilton et ai, 1965 Ramirez, 1968). The true analogues of tetrahedral and TBP intermediates are hemi-orthoesters and hydroxy phosphoranes. Again, a number of examples of stable hemi-orthoesters have been isolated (e.g. [3]) or observed... 

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