Makosza mechanism, phase-transfer reaction

Phase-transfer catalysis, also often referred to as ion pair partition" is a novel synthetic technique which has been the subject of much interest in recent years not only in the field of organic synthesis but also in polymer chemistry. The term "phase-transfer catalysis" was first introduced in 1971 by Stark > who studied kinetics in detail and the mechanism of reactions which are catalyzed by small amounts of onium salts such as quaternary ammonium or phosphonium compounds. Brandstrbm and Makosza also made major Initial contributions in the understanding of such reactions and the application thereof in various synthetic reactions. A generally accepted phase-transfer reaction scheme is shown in... 

Reactions performed under two-phase conditions are further complicated by the partitioning of the reactants and catalyst over the two phases. In the case of quaternary ammonium phase-transfer catalysis, the mechanistic aspects have received a great deal of attention (Brandstrom, 1977 Makosza, 1975 Starks and Owens, 1973). In contrast, the mechanism of crown ether-type phase-transfer catalysis has hardly been investigated at all, despite its... 

Compared with the classical procedures, which employ chloroform and dry potassium /ert-butoxide, Makosza s method is several magnitudes superior, in spite of the normally recognized requirements that the dichlorocarbene should be produced under totally anhydrous conditions. Several early reports of the reactions of dichlorocarbene, generated by Makosza s procedure, led to suggestions that the activity of the carbene was considerably greater than that of the classically produced carbenes. This assumption was based on the overall higher yields of dichlorocyclopropanes derived from the reaction with alkenes, and upon the observation that weakly activated alkenes reacted with Makosza carbenes, but not with the classically produced carbenes. A consideration of the mechanism of formation of the carbenes under phase-transfer catalytic conditions exposes the fallacies in the assumptions. 

One of the oldest techniques for overcoming these problems is the use of biphasic water/organic solvent systems using phase-transfer methods. In 1951, Jarrouse found that the reaction of water-soluble sodium cyanide with water-insoluble, but organic solvent-soluble 1-chlorooctane is dramatically enhanced by adding a catalytic amount of tetra-n-butylammonium chloride [878], This technique was further developed by Makosza et al. [879], Starks et al. [880], and others, and has become known as liquid-liquid phase-transfer catalysis (PTC) for reviews, see references [656-658, 879-882], The mechanism of this method is shown in Fig. 5-18 for the nucleophilic displacement reaction of a haloalkane with sodium cyanide in the presence of a quaternary ammonium chloride as FT catalyst. 

Despite wide-scale applications of PTC reactions in the presence of a base, the mechanism of these reactions is not clear. PTC systems operate via different mechanisms in the presence of bases (Makosza, 1977). However, it is an established fact that in most cases it does not involve the transfer of OH by the quat as a OH complex, since Q OH-is highly hydrophilic and has very limited solubility in the organic phase. Alkylation reactions that have been proposed to be mediated through a Q OH intermediate probably involve reaction between2 OH and the organic substrate at the liquid-liquid interface. Rabinovitz et al.(1986) review the effect of anions, base concentration, and water inPTC/OH systems. 

Several quaternary ammonium compounds are used in organic chemistry as phase-transfer catalysts. The mechanism of the catalytic process can be represented by a combination of phase-transfer and ion-exchange equilibria. In the case of substitution reactions in two-phase systems, the negatively charged nucleophile is extracted by the positive ammonium ion from the aqueous phase into the organic phase where substitution takes place (Makosza and rafin, 1965, Makosza, 1969, Dockx, 1973). 

The term phase transfer catalysis was coined by Starks to describe the mechanism of catalysis of reactions between water-soluble inorganic salts and water-insoluble organic substrates by lipophilic quaternary ammonium and phosphonium ions Ql). His investigations of nucleophilic displacement reactions, such as that of aqueous sodium cyanide with 1-chlorooctane, and the investigations of Makosza on reactions of aqueous sodium hydroxide with chloroform to generate dichlorocarbene, and with active ketones and nitriles to generate carbanions, pioneered the field in the mid-1960 s. It was nearly fifteen years before many such processes were adopted in industry. Starks now estimates there are about sixty phase transfer catalytic processes in use worldwide, mostly in pharmaceutical and fine chemical manufacturing (32V... 

Not only does the solvent affect the reaction rate, but it also determines the reaction mechanism. In Starks extraction mechanism of PTC, most reacting compound transfers to the bulk phase. However, reaction may occur at the interface of the two phases. For example hexachlorocyclotriphosphazene has been reported to react very slowly with 2,2,2-trifluoroethanol in an alkaline solution of NaOH/C HjCl two-phase system in the absence of phase-transfer catalyst.Since sodium 2,2,2-trifluoroe anoxide is not soluble in chlorobenzene, the process probably proceeds at the interface region of the system. Similar is the reaction of benzylation of isobutyraldehyde in the presence of tetra-n-butylammonium iodide in an alkaline solution of NaOH/toluene, which is a two-phase system. Makosza interfacial mechanism was employed to rationalize the experimental results. The main reason is that the ammonium salt of the nucleophilic reagent is not soluble in toluene. 

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