Ortho ester, hydrolysis mechanism

Ahmad M et al (1977) Ortho ester hydrolysis. The complete reaction mechanism. J Am Chem Soc 99 4827-4828... 

Ortho Esters, Hydrolysis of. Mechanism and Catalysis for (Coides). 

Ortho ester hydrolysis direct evidence for a three-stag reaction mechanism. Journal of the American Chemical Society, 101, 2669-77. 

Convincing evidence for a surface erosion process is shown in Fig. 8, which shows the concomitant release of the incorporated marker, methylene blue, release of the anhydride excipient hydrolysis product, succinic acid, and total weight loss of the device. According to these data, the release of an incorporated drug from an anhydride-catalyzed erosion of poly (ortho esters) can be unambiguously described by a polymer surface erosion mechanism. 

Cordes, E.H. Mechanism in catalysis for the hydrolysis of acetols, ketols and ortho esters. Prog. Phys. Org. Chem. 1967, 4, 1 4. 

A much more desirable erosion mechanism is surface erosion, where hydrolysis is confined to a narrow zone at the periphery of the device. Then, if the drug is weU-immobihzed in the matrix so that drug release due to diffusion is minimal, the release rate is completely controlled by polymer erosion, and an ability to control erosion rate would translate into an ability to control dmg delivery rate. For a polymer matrix that is very hydrophobic so that water penetration is limited to the surface (thus Hmiting bulk erosion), and at the same time, allowing polymer hydrolysis to proceed rapidly, it should be possible to achieve a drug release rate that is controlled by the rate of surface erosion. Two classes of biodegradable polymers successfully developed based on this rationale are the polyanhydrides [31] and poly (ortho esters) [32], the latter of which is the subject of this chapter. 

The synthesis and characterization of four distinct families of poly (ortho esters) are described and designated as poly (ortho esters) I, II, III and IV. Poly (ortho ester) I is prepared by the transesterification of diethoxytetrahydrofuran with diols. Poly (ortho ester) II is prepared by the condensation of 3,9-bis (ethylidene 2,4,8,10-tetraoxaspiro [5, 5] undecane) with diols to produce a linear polymer or with a triol to produce a crosslinked polymer. Poly (ortho ester) III is prepared by the condensation of a flexible triol with and alkyl orthoacetate to produce ointment-like materials. Poly (ortho ester) IV is prepared by the condensation of a rigid triol with and alkyl orthoacetate to produce solid materials. The detailed mechanism of hydrolysis of these polymers has been determined and drug release data for a number of therapeutic agents are presented. 

Use of basic excipients. As discussed in Sect. 4.2.4, a typical poly(ortho ester) device will be completely permeated by water in a matter of a few weeks so that the use of acidic excipients is limited to delivery systems having a maximum lifetime of about one month. However, ortho ester linkages are stable in devices containing a base, and very long erosion times are possible if the polymer is stabilized with a base which prevents hydrolysis even though the matrix is completely permeated by water. A plausible mechanism for erosion of devices that contain the base Mg(OH)2 is shown in Fig. 18. According to this mech-... 

Ketones or aldehydes can undergo acetal exchange with orthoesters. The mechanism starts off as if the ortho ester 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. 

Eliason R, Kreevoy MM (1978) Kinetic hydrogen isotope effects in the concerted mechanism for the hydrolysis of acetals, ketals, and ortho esters. J Am Chem Soc 100 7037-7041... 

Poly(ortho esters) (POE) eontain ortho ester groups along the chain an ortho ester is a funetional group eontaining three alkoxy groups attached to one earbon atom. Degradation results from a hydrolysis mechanism. These polymers ean be formulated in order to obtain a surfaee erosion degradation. 

The influence of temperature on the ortho effect has been evaluated in the alkaline hydrolysis in aqueous DMSO solutions of ortho-, meta- and para-substituted phenyl benzoates (26). The alcoholysis of phthalic anhydride (27) to monoalkyl phthalates (28) occurs through an A-2 mechanism via rate-determining attack of the alcohol on a carbonyl carbon of the anhydride (Scheme 4). Evidence adduced for this proposal included highly negative A 5 values and a p value of 4-2.1. In the same study, titanium tetra-n-butoxide and tri-n-butyltin ethanoxide were shown to act as effective catalysts of the half-ester formation from (27), the mechanism involving alkoxy ligand exchange at the metal as an initial step. ... 

Hydroxylation of arylamines with persulfate ion, or Boyland-Sims oxidation, gives ortho-substituted aminophenols in good yields [29]. As with the Elbs oxidation, the procedure is also carried out in two steps - first, treatment with the oxidant to obtain an aminophenyl sulfate ester and, second, hydrolysis to obtain the final product. Primary, secondary and tertiary amines can all be used in this reaction. The ortho product is formed, except when no ortho-positions are available, which leads to para-substitution. Electrophilic attack on the ipso-carbon is believed to be the most likely mechanism, although minor radical pathways also seem to be present. 

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... 

The first line shows the normal mechanism for acetal formation and points out the by-product, a molecule of water. This w atcr is consumed in the hydrolysis of the ortho for mate (by an acetal n drolysis mechanism) to give a stable ordinary ester. The favourable second equilibrium pulls the Trst across to the right. 

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