“…There is substantial evidence that the specific-acid catalyzed hydrolysis of acetals, ketals, and orthoesters occurs by an A-1 mechanism (Scheme ) . General acid catalysis is observed only for substrates with good leaving groups and potentially stable oxocarbenium ions (1-(aryloxy)tetrahydrofurans [THF-OAr] and -tetrahydropyrans [THP-OAr]) or exceedingly stable carbenium ions (tropone diethyl ketal, and dioxolane hemi and ortho esters). Acetals and ketals formed from “ordinary” carbonyl compounds and weakly basic aliphatic alcohols do not undergo general-acid catalysis .…”
Factors affecting the cleavage of the carbon-oxygen bond in linear and cyclic aldehyde hydrates, heimacetals, acetals, and methyl ribosides and glucosides have been investigated using semiempirical calculations (AM1 and PM3). (For some systems, low- and high-level ab initio energies are available for comparison with the semiempirical results. With one exception, the results obtained by the two methods show excellent agreement in relative energies and trends in reactivity.) The effects on reactivity and stability caused by substituting a sulfur for the alpha oxygen in the oxocarbenium ion were also studied. In general, systems that can have an antiperiplanar alignment of lone pairs on the leaving group and potential oxocarbenium ion oxygens undergo spontanteous cleavage. An examination of various conformers of the leaving group relative to the potential oxocarbenium oxygen shows, however, that lone pair repulsion and steric factors for MeOH as the leaving group are more important than the antiperiplanar effect for bond cleavage. All compounds in which the alpha-oxygen in the potential carbenium ion is replaced by sulfur undergo spontaneous cleavage regardless of the leaving group or structure of the compound. Energy profiles, DeltaH(), and DeltaH(R) values show that linear and cyclic thiocarbenium ions are much more stable than the corresponding oxocarbenium ions. Comparison of results for methyl ribosides and glucosides with results for corresponding pyridinium substrates suggests that both should hydrolyze through an A-1 mechanism. General-acid catalysis with hydronium as the acid was studied. With solution results, the computations suggest that substrates with either a good leaving group or stable oxocarbenium ion react with rate-limiting proton transfer from the acid to the leaving group but that substrates with both a good leaving group and stable carbenium ion react with concerted proton transfer and bond cleavage.
“…There is substantial evidence that the specific-acid catalyzed hydrolysis of acetals, ketals, and orthoesters occurs by an A-1 mechanism (Scheme ) . General acid catalysis is observed only for substrates with good leaving groups and potentially stable oxocarbenium ions (1-(aryloxy)tetrahydrofurans [THF-OAr] and -tetrahydropyrans [THP-OAr]) or exceedingly stable carbenium ions (tropone diethyl ketal, and dioxolane hemi and ortho esters). Acetals and ketals formed from “ordinary” carbonyl compounds and weakly basic aliphatic alcohols do not undergo general-acid catalysis .…”
Factors affecting the cleavage of the carbon-oxygen bond in linear and cyclic aldehyde hydrates, heimacetals, acetals, and methyl ribosides and glucosides have been investigated using semiempirical calculations (AM1 and PM3). (For some systems, low- and high-level ab initio energies are available for comparison with the semiempirical results. With one exception, the results obtained by the two methods show excellent agreement in relative energies and trends in reactivity.) The effects on reactivity and stability caused by substituting a sulfur for the alpha oxygen in the oxocarbenium ion were also studied. In general, systems that can have an antiperiplanar alignment of lone pairs on the leaving group and potential oxocarbenium ion oxygens undergo spontanteous cleavage. An examination of various conformers of the leaving group relative to the potential oxocarbenium oxygen shows, however, that lone pair repulsion and steric factors for MeOH as the leaving group are more important than the antiperiplanar effect for bond cleavage. All compounds in which the alpha-oxygen in the potential carbenium ion is replaced by sulfur undergo spontaneous cleavage regardless of the leaving group or structure of the compound. Energy profiles, DeltaH(), and DeltaH(R) values show that linear and cyclic thiocarbenium ions are much more stable than the corresponding oxocarbenium ions. Comparison of results for methyl ribosides and glucosides with results for corresponding pyridinium substrates suggests that both should hydrolyze through an A-1 mechanism. General-acid catalysis with hydronium as the acid was studied. With solution results, the computations suggest that substrates with either a good leaving group or stable oxocarbenium ion react with rate-limiting proton transfer from the acid to the leaving group but that substrates with both a good leaving group and stable carbenium ion react with concerted proton transfer and bond cleavage.
“…This case ordinarily obtains for the hydrolysis of ortho esters and orthocarbonates [6,7]. It has also been observed for hydrolysis of acetals and ketals which possess either particularly facile leaving groups or form particularly stable carbonium ion intermediates [8,9]. For our subsequent considerations, the important point is that the transition state involves cleavage of a carbon-oxygen bond, which may be preceded by or accompanied by proton transfer, leading to carbonium ion formation.…”
Section: / 'mentioning
confidence: 71%
“…A method developed by Richards and collaborators involving elution of the substrate from columns of molecular seives as a function of the concentration of surfactant provides a means for attacking the first question [10]. For a specific case of interest here, the equilibrium constant for interaction of methyl orthobenzoate with micelles of sodium dodecyl sulfate at 25° has a value of 73 M-1 , based on the total concentration of surfactant in the ;ystem (not on the concentration of micelles) [11]: (8) Thus, at a concentration of sodium dodecyl sulfate (SDS) near 0.014 ~, we calculate that about half of the methyl orthobenzoate ought to be associated with the micelles formed from this surfactant and the other half ought to be present in the bulk solution. The relationship of this value to the kinetics of hydrolysis of this ortho ester in the presence of SDS will become apparent shortly.…”
Section: Interaction Of Acetals and Related Substrates With Micellesmentioning
“…In addition, the t 1/2 values of these heterodimers were larger than the values of PTX-7-K-EG 3 , probably because of the greater steric bulk of the promoieties in the former. The difference between the t 1/2 values of the same prodrug at the two pHs was not only related to the difference between the two pH values (ΔpH), probably because ketal hydrolysis proceeds by general acid catalysis, the rate of which can be affected by multiple factors (e.g., the composition of the buffer) 57 , 61 , 62 . Fig.…”
Isopropenyl ethers are critical intermediates for accessing medicinally valuable ketal-based prodrugs and biomaterials, but traditional approaches for the synthesis of isopropenyl ethers suffer from poor functional group compatibility and harsh reaction conditions. Here, we develop an organocatalytic transisopropenylation approach to solve these challenges, enabling the synthesis of isopropenyl ethers from various hydroxyl-group-containing small-molecule drugs, polymers, and functional building blocks. The method provides a straightforward and versatile synthesis of isopropenyl ethers, features excellent tolerance of diverse functional groups, applies to a wide range of substrates, and allows scalable synthesis. The development of this organocatalytic transisopropenylation approach enables access to modular preparation of various acid-sensitive ketal-linked prodrugs and functionalized ketalated biomaterials. We expect our syntheses and transformations of isopropenyl ethers will find utility in several diverse fields, including medicinal chemistry, drug delivery, and biomaterials.
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