Methyl formate hydrolysis

Continuing in the line of our studies of chemical reactivity in solution using the MD/ESIE method [4], in the present work we apply our methodology to methyl formate hydrolysis in aqueous solution. We show how the results are improved when the solvent is not described as a continuum but as a discrete system formed by numerous water molecules interacting with the solutes (reactant and transition state). The method differs from that used by other workers [5] in that it uses potentials with interaction parameters obtained from ab initio calculations, and free-energy curves are used to calculate the activation energy. 

Table 23.1 Activation free energies (kcal/mol) for methyl formate hydrolysis...

In sum, the free-energy curves of the species involved in the reaction provide a good description of the thermodynamics of methyl formate hydrolysis in an aqueous medium. These curves, which are constructed on the basis of the solute-solvent interaction energies with the solvent fluctuation being chosen as reaction coordinate, respond acceptably to the activation barrier of this process. Also, to obtain reasonable results for this reaction in solution one must take into account a mechanism that includes the assistance of various water molecules. It was also observed that the activation barrier depends appreciably on other factors, in particular, the basis set used to describe the systems, the components of the interaction energy used in the fits of the potential functions, and the procedure employed to construct and move the curves. 

Formic acid is currently produced iadustriaHy by three main processes (/) acidolysis of formate salts, which are ia turn by-products of other processes (2) as a coproduct with acetic acid ia the Hquid-phase oxidation of hydrocarbons or (3) carbonylation of methanol to methyl formate, followed either by direct hydrolysis of the ester or by the iatermediacy of formamide. 

Coproductioa of ammonium sulfate is a disadvantage of the formamide route, and it has largely been supplanted by processes based on the direct hydrolysis of methyl formate. If the methanol is recycled to the carbonylation step the stoichiometry corresponds to the production of formic acid by hydration of carbon monoxide, a reaction which is too thermodynamicaHy unfavorable to be carried out directly on an iadustrial scale. 

Isomer separation beyond physical fractional crystallization has been accompHshed by derivatization using methyl formate to make /V-formyl derivatives and acetic anhydride to prepare the corresponding acetamides (1). Alkaline hydrolysis regenerates the analytically pure amine configurational isomers. 

Methyl formate and propylene oxide have close boiling poiats, making separation by distillation difficult. Methyl formate is removed from propylene oxide by hydrolysis with an aqueous base and glycerol, followed by phase separation and distillation (152,153). Methyl formate may be hydrolyzed to methanol and formic acid by contacting the propylene oxide stream with a basic ion-exchange resia. Methanol and formic acid are removed by extractive distillation (154). 

Recently, Falk and Seidel-Morgenstern [143] performed a detailed comparison between fixed-bed reactors and fixed-bed chromatographic reactors. The reaction studied was an equilibrium limited hydrolysis of methyl formate into formic acid and methanol using an ion-exchange resin as both the catalyst and the adsorbent. The analysis was based on a mathematical model, which was experimentally verified. The comparison was based on the following four assumptions ... 

Yet a further increase in potency is observed when the para-isobutyl group is replaced by a benzene ring. One published synthesis for that compound is quite analogous to the malonate route to the parent drug. The acetyl biphenyl (50-1) is thus converted to the corresponding arylacetic acid by reaction with sulfur and morpholine, followed by hydrolysis of the first-obtained thiomorpholide. This is then esterified and converted to malonate anion (50-2) with sodium ethoxide and ethyl formate. The anion is quenched with methyl iodide hydrolysis of the esters followed by decarboxylation yields the NSAID flubiprofen (50-3) [51]. 

A vigorous Claisen condensation ensues when a homophthalic ester and methyl formate are treated with sodium ethoxide and the active methylene group is formylated. Cyclization takes place with ease in acidic media to produce a methyl isocoumarin-4-carboxylate (50JCS3375). Hydrolysis under acid conditions is sometimes accompanied by polymerization, but the use of boron trifluoride in acetic acid overcomes this problem. Decarboxylation may be effected in the conventional manner with copper bronze, though it sometimes accompanies the hydrolysis. 

The methyl chloride hydrolysis [Equation (12)] is a type II SN2 reaction. The attacking species is a water molecule, which loses a proton to a solvent water molecule with the hydroxide ion formally substituting the chloride ion in methyl chloride. Thus, during hydrolysis, bond breaking and bond formation involving both solute and solvent molecules take place. It is essential, therefore, to consider the solvent molecules explicitly in modeling the methyl chloride hydrolysis. This is in contrast to type I SN2 reactions, such as the reaction in Equation (11), in which bond breaking and bond formation occur only in the solute molecules and the solvent molecules do not participate actively in the reaction except as a medium. 

Humphreys and Hammett have estimated that in solution the entropy of acetic acid or its derivative is about 4-6 e.u. greater than the entropy of formic acid or its corresponding derivative due to the internal freedom of the methyl group. On this basis the authors concluded that the entropy of the acetate ion must be about the same as that of the formate ion, meaning that the internal motion of the methyl group is frozen out in the ionic species. It would appear from the data, however, that the entropy of the activated complex for acetate hydrolysis is more negative than that for formate hydrolysis by another 5 e.u. A possible explanation is that the charge becomes more concentrated in the acetate complex with a resultant increase in solvent electrostriction. 

Hydrolysis of methyl formate 71 Discontinuous chromatographic reactor... 

For the hydrolysis of methyl formate, HCOOCH3, in acid solutions, the reaction and rate are... 

J. R. Pliego, Jr. and J. M. Riveros, A theoretical analysis of the free-energy profile of the different pathways in the alkaline hydrolysis of methyl formate in aqueous solution, Chem. Eur. J., 8 (2002) 1945-1953. 

Figure 3.11 Application of the cluster-continuum model for basic hydrolysis of the methyl formate.

The chemical resolution process of Scheme 6 was developed into an economically favorable one by the ready recycle of both the FPA resolving agent and the combined (mostly S) amine fractions. FPA, which was prepared by methyl formate reaction with L-phenylalanine, was shown to be stable (no racemization and no hydrolysis) when the resolution and work-up processes were conducted within the pH range of 2-12 at temperatures below 25°C (higher temperatures were not studied). FPA meeting specification was isolated in yields of ca. 95% by simple acidification of its aqueous salt solutions and filtration. 

In the forward direction the ester is formed, and in the reverse direction it is hydrolyzed. For esterification, the alcohol can be used as a solvent as described for methyl acetate synthesis [26]. For ester hydrolysis, water can be used as a solvent, as described for hydrolysis of methyl formate, ethyl formate, methyl acetate and ethyl acetate [28]. Usually, the solvent is taken in large excess and it can be assumed in good approximation that its concentration is constant. For constant alcohol... 

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