Reaction phase transfer

Some organic reactions can be accomplished by using two-layer systems in which phase-transfer catalysts play an important role (34). The phase-transfer reaction proceeds via ion pairs, and asymmetric induction is expected to emerge when chiral quaternary ammonium salts are used. The ion-pair interaction, however, is usually not strong enough to control the absolute stereochemistry of the reaction (35). Numerous trials have resulted in low or only moderate stereoselectivity, probably because of the loose orientation of the ion-paired intermediates or transition states. These reactions include, but are not limited to, carbene addition to alkenes, reaction of sulfur ylides and aldehydes, nucleophilic substitution of secondary alkyl halides, Darzens reaction, chlorination 

ASYMMETRIC catalysis with purely organic compounds 

ASYMMETRIC CATALYSIS WITH PURELY ORGANIC COMPOUNDS 

Very successful results have been obtained with functionalized quaternary ammonium salts derived from cinchona alkaloids. An example 

ASYMMLTRIC CATALYSIS WITII PURELY organic compounds 

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Class (2) reactions are performed in the presence of dilute to concentrated aqueous sodium hydroxide, powdered potassium hydroxide, or, at elevated temperatures, soHd potassium carbonate, depending on the acidity of the substrate. Alkylations are possible in the presence of concentrated NaOH and a PT catalyst for substrates with conventional pX values up to - 23. This includes many C—H acidic compounds such as fiuorene, phenylacetylene, simple ketones, phenylacetonittile. Furthermore, alkylations of N—H, O—H, S—H, and P—H bonds, and ambident anions are weU known. Other basic phase-transfer reactions are hydrolyses, saponifications, isomerizations, H/D exchange, Michael-type additions, aldol, Darzens, and similar... 

On the other hand, elimination of the hydrazino group in 3-hydrazinopyridazines is possible with p-toluenesulfonamide under phase transfer reaction conditions (78TL3059). 

Catalytic asymmetric synthesis with participation and formation of heterocycles (including asymmetric phase transfer reactions and asymmetric reactions with chiral Lewis catalysts) 93MI1. 

Complexation with crown ethers increases the notoriously low solubilities of diazonium salts in most solvents (with the obvious exception of water). Therefore, it is possible to carry out phase-transfer reactions with complexed diazonium ions (review Gokel et al., 1985). Useful examples can be found in a paper from Gokel s group (Beadle et al., 1984a) on the Gomberg-Bachmann and Pschorr reactions (see Sec. 10.10). 

Nitrobenzoyl chloride and 3,5-dinitrobenzoyl chloride were each reacted with dl-1-phenylethylamine and 4-amino-l-benzylpiperidine using a phase-transfer reaction [23]. The amines were in the aqueous phase and the acid chlorides in the organic phase. By this means, a 2 x 2 library was created in one experimental run. 

OS 10] [R 10] [P 9] The specific interfadal area was varied for a phase-transfer reaction for four amide formations from two amines and two acid chlorides [23[. This was done by filling the solutions in normal test-tubes of varying diameter (1-5 X cm ) and using a micro reactor which had the largest specific interface (45 X cm ). The yields of all foiu reactions are highly and similarly dependent on... 

In phase transfer catalysis of the solid/liquid type, the organic phase (containing dissolved organic reactant and a small amount of the crown) is mixed directly with the solid inorganic salt. Such a procedure enables the reaction to proceed under anhydrous conditions this is a distinct advantage, for example, when hydrolysis is a possible competing reaction. Because of their open structure, crown ethers are readily able to abstract cations from a crystalline solid and are often the catalysts of choice for many solid/liquid phase transfer reactions. 

M J. O Donnell, Asymmetric Phase Transfer Reactions , In Catalytic Asymmetric Synthesis (Ed. L Ojima), VCH, New York, 1993, Chapter 8 (pp. 390-411). 

AmwG° Standard free-energy change for the phase-transfer reaction between membrane ... 

A more recent method starts from2,2 -diacetylamino-l,l -dianthraquinonyl, which is cyclized in a phase-transfer reaction in chlorobenzene using tetrabuty-lammonium bromide and a 30% aqueous sodium hydroxide solution [20],... 

The unique ability of crown ethers to form stable complexes with various cations has been used to advantage in such diverse processes as isotope separations (Jepson and De Witt, 1976), the transport of ions through artificial and natural membranes (Tosteson, 1968) and the construction of ion-selective electrodes (Ryba and Petranek, 1973). On account of their lipophilic exterior, crown ether complexes are often soluble even in apolar solvents. This property has been successfully exploited in liquid-liquid and solid-liquid phase-transfer reactions. Extensive reviews deal with the synthetic aspects of the use of crown ethers as phase-transfer catalysts (Gokel and Dupont Durst, 1976 Liotta, 1978 Weber and Gokel, 1977 Starks and Liotta, 1978). Several studies have been devoted to the identification of the factors affecting the formation and stability of crown-ether complexes, and many aspects of this subject have been discussed in reviews (Christensen et al., 1971, 1974 Pedersen and Frensdorf, 1972 Izatt et al., 1973 Kappenstein, 1974). 

Q, Q+ quaternary ammonium or phosphonii in phase transfer reactions)... 

Figure 5.11 A simplified representation of the steps in a phase transfer reaction cycle...

Probably the most important group of phase transfer reactions, and certainly the commonest, are those in which an anion is transferred from the aqueous phase into the organic solvent, where nucleophilic substitution occurs. These would once have been performed in a dipolar aprotic solvent such as DMF. A good example is the reaction between an alkyl halide (such as 1-chlorooctane), and aqueous sodium cyanide, shown in Scheme 5.5. Without PTC, the biphasic mixture can be stirred and heated together for 2 weeks and the only observable reaction will be hydrolysis of the cyanide group. Addition of a catalytic amount of a quaternary onium salt, or a crown ether, however, will lead to the quantitative conversion to the nitrile within 2 h. 

There are two generally accepted mechanisms for simple phase transfer reactions under neutral conditions. The first of these is a mechanism in which the whole cation-anion complex moves between the two phases as shown in Scheme 5.6 [42],... 

Scheme 5.6 Mechanism for biphasic anion displacement, in which the cation performing the phase transfer reaction, Q+, shuttles between the two phases...

The Influence of Catalyst Structure on Phase Transfer Reactions... 

The optimum concentration of the inorganic substrate, and the role of water itself in phase transfer reactions is a complex issue. Even a simple anion displacement... 

As is the case in all other quinine-catalyzed reactions, the quininium-salt-catalyzed phase-transfer reactions are subject to strong solvent effects (Table 8) (81). The fact that, in the presence of water, polar solvents lower the e.e., whereas apolar solvents raise the e.e., indicates that these are true phase-transfer reactions in which the ion pairs within the organic layer are responsible for the asymmetric induction. 

The synthesis of polyhalide salts, R4NX , used in electrophilic substitution reactions, are described in Chapter 2 and H-bonded complexed salts with the free acid, R4NHX2, which are used for example in acid-catalysed cleavage reactions and in electrophilic addition reactions with alkenes, are often produced in situ [33], although the fluorides are obtained by modification of method I.I.I.B. [19, 34], The in situ formation of such salts can inhibit normal nucleophilic reactions [35, 36]. Quaternary ammonium chlorometallates have been synthesized from quaternary ammonium chlorides and transition metal chlorides, such as IrClj and PtCl4, and are highly efficient catalysts for phase-transfer reactions and for metal complex promoted reactions [37]. 

The ability of quaternary ammonium halides to form weakly H-bonded complex ion-pairs with acids is well established, as illustrated by the stability of quaternary ammonium hydrogen difluoride and dihydrogen trifluorides [e.g. 60] and the extractability of halogen acids [61]. It has also been shown that weaker acids, such as hypochlorous acid, carboxylic acids, phenols, alcohols and hydrogen peroxide [61-64] also form complex ion-pairs. Such ion-pairs can often be beneficial in phase-transfer reactions, but the lipophilic nature of H-bonded complex ion-pairs with oxy acids, e.g. [Q+X HOAr] or [Q+X HO.CO.R], inhibits O-alkylation reactions necessitating the maintenance of the aqueous phase at pH > 7.0 with sodium or potassium carbonate to ensure effective formation of ethers or esterification [49,64]. 

Phase-Transfer Reactions Catalyzed by Metal Complexes... 

Butenolides are formed in the alkyne-CH3l--Co2(CO)3 phase transfer reaction. When the latter process is effected in the presence of ruthenium carbonyl, a second metal catalyst, y-keto acids are isolated in good yields(17). 

This is an authentic bimetallic phase transfer reaction in which the second metal species intercepts an organocobalt intermediate. 

The latter may prove to be a valuable catalyst for a variety of phase transfer reactions. 

A perusal of the data in Table I reveals that for the series of cations surveyed, two rules can be formulated, (i) All of the crowns in this series bind K+ more strongly than any of the three other cations, (ii) 18-Crown-6 is the best cation binder in this group of five ligands regardless of which cation is considered. From these data, it is clear that the less expensive 18-crown-6 would not only be acceptable for phase transfer reactions involving Na" " salts, it would be preferable. 

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