Acetyl iodide, hydrolysis

Water is essential, since acetic acid is formed by the reaction between water and acetyl iodide or the Ni-acetyl complex. Acetic acid is also formed via the hydrolysis of any methyl acetate that is formed by methanol attack on acetyl iodide or the Ni-acetyl complex. 

Acetyl iodide is very reactive and it reacts efficiently with water or methanol leading to acetate compounds. Hydrolysis of acetyl iodide along with the subsequent conversion of methanol to methyl iodide are very rapid under the reaction conditions leading to a complete mechanistic cycle. 

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]. 

Carbonylation of alkyl halides is rare. As an exception, AcOH is produced commercially by the Monsanto process from MeOH and CO using Rh as a catalyst in the presence of HI. In this process (Scheme 3.10), Mel is generated in situ from MeOH and HI and undergoes oxidative addition. Insertion of CO generates an acetylrhodium intermediate, and nucleophilic attack of water produces AcOH, regenerating the Rh catalyst and HI (or reductive elimination to give acetyl iodide and hydrolysis). 

Acetyl iodide is the real product of the primary catalytic cycle. Water, though required for the hydrolysis of acetyl iodide, is generated in the reaction of methanol with HI. It is therefore not involved in the overall stoichiometry. To make the cycle operational, small amounts of CH3I and water are added in the beginning. 

Mankind has produced acetic acid for many thousand years but the traditional and green fermentation methods cannot provide the large amounts of acetic acid that are required by today s society. As early as 1960 a 100% atom efficient cobalt-catalyzed industrial synthesis of acetic acid was introduced by BASF, shortly afterwards followed by the Monsanto rhodium-catalyzed low-pressure acetic acid process (Scheme 5.36) the name explains one of the advantages of the rhodium-catalyzed process over the cobalt-catalyzed one [61, 67]. These processes are rather similar and consist of two catalytic cycles. An activation of methanol as methyl iodide, which is catalytic, since the HI is recaptured by hydrolysis of acetyl iodide to the final product after its release from the transition metal catalyst, starts the process. The transition metal catalyst reacts with methyl iodide in an oxidative addition, then catalyzes the carbonylation via a migration of the methyl group, the "insertion reaction". Subsequent reductive elimination releases the acetyl iodide. While both processes are, on paper, 100%... 

Commercial methanol carbonylation processes have employed each of the group 9 metals, cobalt, rhodium and iridium as catalysts. In each case acid and an iodide co-catalyst are required to activate the methanol by converting it into iodomethane (CH3OH + HI CH3I + H2O) catalytic carbonylation of iodomethane into acetyl iodide is followed by hydrolysis to acetic acid. A problem common to all these processes arises because the mixture of HI and acetic acid is highly corrosive this necessitates special techniques for plant construction involving the use of expensive steels. We discuss each catalyst system in turn below. 

The methyl iodide undergoes carbonylation by the transition metal catalyst to give (formally) acetyl iodide (Equation (6)), which is rapidly hydrolyzed to the product acetic acid (Equation (7)). The intermediacy of acetyl iodide is difficult to establish under aqueous conditions, and acetic acid may arise directly from hydrolysis of a metal-acetyl species. 

The acetyl complex, [Rh(CO)l3(COMe)], exists as an iodide-bridged dimer [ Rh(CO)l2(g-I)(COMe) 2]2 in the solid state [23] and in non-coordinating solvents, but it is readily cleaved to monomeric species ([Rh(CO)(sol) I3(COMe)r or [Rh(CO)(sol)2l2(COMe)]) in coordinating solvents [24-26]. Coordination of CO to [Rh(CO)l3(COMe)] rapidly gives the frans-dicarbo-nyl acetyl species, [Rh(CO)2l3(COMe)], for which low-temperature 13C NMR spectra reveal restricted rotation of the acetyl ligand [24]. Stoichiometric addition of acetyl iodide to [Rh(CO)2l2] initially generates czs,/flc-[Rh(CO)2l3(COMe)], which subsequently isomerizes to the thermodynamically preferred frans-dicarbonyl isomer [27]. The observation that acetyl iodide readily adds to [Rh(CO)2l2] shows that, for the overall catalytic reaction to be driven forward, the acetyl iodide must be scavenged by hydrolysis. 

An alternative to sequential reductive elimination and hydrolysis of acetyl iodide is direct reaction of water with a rhodium acetyl complex to give acetic acid. The relative importance of these two alternative pathways has not yet been fully determined, although the catalytic mechanism is normally depicted as proceeding via reductive elimination of acetyl iodide from the rhodium center. 

The proposed reductive elimination of acetyl iodide from the Rh(III) coordination sphere is an important step in the Monsanto methanol carbonylation process (2) [73]. In the proposed catalytic cycle (Scheme 30), the oxidative addition of iodo-methane, formed from HI and methanol, is followed by the carbonyl insertion into the Rh-Me bond. The reductive elimination of acetyl iodide followed by its rapid hydrolysis furnishes the acetic acid and regenerates free HI. 

The reactive methylrhodium(III) complex thus formed then undergoes CO insertion to give an acetylrhodium species as shown in Scheme 1.8. Reductive elimination of the acetyl and iodide ligands liberates acetyl iodide, which is hydrolyzed to produce acetic acid. The hydrolysis generates HI, which is recycled on reaction with methanol regenerating methyl iodide. The important elementary processes of CO insertion will be discussed in Chapter 7. 

Rhodium-catalyzed carbonylation of methanol is known as the Monsanto process, which has been studied extensively. From the reaction mechanism aspect, the study of kinetics has proved that the oxidative addition of methyl iodide to the [Rh(CO)2l2] is the rate-determining step of the catalytic cycle. It was also observed that acetyl iodide readily adds to [Rh(CO)2l2], indicating that the acetyl iodide must be scavenged by hydrolysis in order to drive the overall catalytic reaction forward. An alternative to sequential reductive elimination and the hydrolysis of acetyl iodide is the nucleophilic attack of water on the Rh acetyl complex and the production of acetic acid. The relative importance of these two alternative pathways has not yet been fully determined, although the catalytic mechanism is normally depicted as proceeding via the reductive elimination of acetyl iodide from the rhodium center. The addition of iodide salts, especially lithium iodide, can realize the reaction run at lower water concentrations thus, byproduct formation via the water gas shift reaction is reduced, subsequently improving raw materials consumption and reducing downstream separation. In addition to the experimental studies of the catalytic mechanism, theoretical studies have also been carried out to understand the reaction mechanism [17-20]. 

HI is necessary to the prior transformation of methanol to methyl iodide, because methanol does not undergo oxidative addition onto rhodium. Methyl iodide does undergo oxidative addition onto rhodium (I) leading to the formation of the Rh-CH3 bond in which CO can insert. Finally, reductive elimination of acetyl iodide is followed by its hydrolysis to acetie acid, which regenerates the cocatalyst HI. The meehanism thus consists in a coupling between organometallic catalysis and acid catalysis. 

The sequence involves the formation of methyl iodide from HI and methanol, oxidative addition to an anionic Rh species, CO-insertion, then reductive elimination of acetyl iodide, followed by its hydrolysis to acetic acid and HI. 

The conditions employed for iridium-catalyzed carbonylation (ca. 180-190 °C, 20-40 bar) are comparable to those of the rhodium-based process. A variety of iridium compounds (e.g., I1CI3, IrU, H2I1CI6, Ir4(CO)i2) can be used as catalyst precursors, as conversion into the active iodocarbonyl species occurs rapidly under process conditions. In a working catalytic system, the principal solvent component is acetic acid, so the methanol feedstock is substantially converted into its acetate ester (Equation (2)). Methyl acetate is then activated by reaction with the iodide co-catalyst (Equation (3)). Catalytic carbonylation of methyl iodide formally gives acetyl iodide (Equation (4)) prior to rapid hydrolysis to the product acetic acid (Equation (5)). However, it is difficult to establish the true intermediacy of acetyl... 

The precise mechanism of the reductive elimination step of the catalytic cycle is not known with certainty. It is often depicted as a concerted elimination of acetyl iodide from the Ir center, which has been modeled theoretically for both [Ir(CO)2l3(COMe)] and [Ir(CO)3l2(COMe)]. In practice, however, this is difficult to distinguish from hydrolysis of an Ir-acetyl complex to give acetic acid without the intermediacy of acetyl iodide. Indeed, solvolysis was suggested to be the rate-determining step in an early study. Scheme 9 represents the elimination step as a hydrolysis of the anion. 

The organic part of the catalytic cycle is exactly the same as that of Figure 4.1. Acetic acid is formed by the hydrolysis of acetyl iodide, and... 

Reaction of 4.14 with iodide gives 4.15, which reductively eliminates acetyl iodide to regenerate 4.10. Hydrolysis of 4.14 and 4.15 to... 

Veratramine, C27H3g02N, occurs naturally in V. viride and V. grandi-florum and is also formed by the hydrolysis of veratrosine. It has m.p. 209-210-5°, fa] — 68° (MeOH), and yields a dihydro-derivative, m.p. 198-200°, and a triacetyl-derivative, m.p. 204-6°, which on controlled hydrolysis leaves a. V-acetyl derivative, m.p. 177-180°. Aceording to Saito, veratramine on treatment with methyl iodide in methyl alcohol in presence of sodium carbonate, yields A-methylveratramine methiodide, m.p. 268° (dec.), from whieh the methoehloride, m.p. 277°, ean be prepared. 

Acetylisothiazoles have been prepared by ketonic hydrolysis of the jS-ketoesters derived from the Claisen condensation on 5-ethoxycar-bonylisothiazoles. 5-Acetyl-3-methylisothiazole is also obtained from the reaction of 5-cyano-3-methylisothiazole with methylmagnesium iodide. ... 

Glycosyl-linkages were determined by GC-EIMS of the partially methylated alditol acetates. RG-II samples (2 mg) were methylated using sodium methyl sulfmyl carbanion and methyl iodide in dimethyl sulfoxide [24] followed by reduction of the uronosyl groups with lithium triethylborodeuteride (Superdeuteride , Aldrich) [23,25]. Methylated and carboxyl-reduced samples were then submitted to acid hydrolysis, NaBIlt reduction and acetylation, partially methylated alditol acetates being analysed by EIMS on two fused-silica capillary columns (DB-1 and DB-225) [20]. 

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