Phase-Transfer Chemistry

Introduction

A shortcoming of the KiloMentor blog is that its author retired in 2011. Thus, although a fair account of developments up until that time can be realistically expected anyone wanting a completely up to the present assessment needs to supplement my examination.

Simple reaction conditions and inexpensive reagents become more consequential the larger the scale at which a chemical reaction is practiced. Consequently, phase-transfer methods have become major transformers of process chemistry.

The three initial, principal reviews on Phase-transfer Chemistry were:

 G.W. Gokel and W.P. Weber, J. Chem.. Ed., 35, 350 (19780);

W.E. Keller, Compendium of phase-transfer Reactions and Related Synthetic Methods, Fluka, 1979;

C. M. Starks and C. Liotta, Phase-transfer Catalysis, Academic Press, New York, 1978.

Also, volumes 8, 9,10, 11, 12, 13, 15, and 18 of Fieser & Fieser’s Reagents for Organic Synthesis have entries under the specific heading of Phase-transfer catalysis. In these, select significant examples of applications are listed. KiloMentor has not examined F & F volumes beyond number 18.

The Phase-transfer Concept and its Range

Phase-transfer reactions, as the name conveys, involve the interplay of two phases during the course of a reaction. These two phases can be two partly immiscible liquids or one liquid phase and a solid.

The methodology applies the finding that ion pairs made up of a large organic cation, when present in organic solvents, exhibit reduced solvation of the anion partner. Consequently, the more ‘naked’ anion is more reactive. Particularly practically, when quartenary ammonium cations are paired with hydroxide to extract it from a concentrated aqueous alkaline solution into an organic solvent, the hydroxide is drawn into the organic solvent with many fewer solvating water molecules and so is called a ‘naked' hydroxide ion. This so-called ‘naked’ hydroxide has a much higher apparent base strength and as such deprotonates substances with pKa less than 37. 

According to Halpern et al. [Hydroxide Ion Initiated Reactions Under Phase-transfer Catalysis Conditions: Mechanism and Implications, Angew. Chem. Int. Ed. Engl. 25 (1986) 960-970 pg, 963 ]  “The empirical upper limit found for substrate acidity in anionic reactions occurring via the interfacial mechanism lies at about pKa=23.”


The most frequently used and most promising catalysts are: Methyl trialkyl(C₈-C₁₀)ammonium chloride, whose trivial names are Adogen 464 and Aliquat 336; Tetrabutylammonium hydrogen sulfate; Benzyltriethylammonium chloride; or Cetyltrimethylammonium bromide. Other interesting catalysts are Trident-1, Polysorbate 80, Polyethylene glycol 400, Cyclophosphazenic polypodands (made from Brig 30; JOC 59, 5059 (1994)).  

Anything that increases the effective cation radius and so moves it away from participating in a tight-ion pair to a loose or solvent separated ion pair is likely to increase the nucleophilicity of any associated anion. That is why, even in inorganic chemistry, as the size of the cation increases, as in Li<Na<K<Rb<Cs, the reactivity of any associated anion increases. It is for the same reason that crown ethers and crepitates are sometimes effective.

The earliest phase-transfer applications used an aqueous solution containing dissolved inorganic reactant as one phase; the reaction substrate was in a  second immiscible organic solvent phase. The function of the catalyst was to provide a mechanism for the water-soluble reagent and the organic-soluble substrate to meet with sufficient frequency to provide a practical reaction rate.

Later, the water phase was found to be sometimes unnecessary and sometimes even detrimental. That is, the phase-transfer catalyst could sometimes make possible reaction between a solid phase of essentially insoluble neat reagent and a substrate dissolved in an organic phase. It has been hypothesized that this most often was successful when undetected small amounts of water were adsorbed onto the bulk solid. Where it succeeded this provided an even simpler process. For example, nominally anhydrous potassium or sodium carbonate could be used as the base for the generation of carbanions in a solid-liquid two-phase system using tetraalkylammonium salts or crown ethers as catalysts. Probably the carbanions are generated on the surface of the carbonate and migrate as ion pairs into the organic medium.  [M. Fedorynski, K. Wojciechowski. Z. Matacz, and M. Makosza J. Org. 43, 4682 (1978).] in Fieser & Fieser Vol. 8 pg. 356-361.

Crown Ethers

“Crown ethers have commonly been used as catalysts for reactions between a solid-liquid interface, and quaternary ammonium or phosphonium salts have been used only as catalysts for reactions in two-phase, liquid-liquid reactions.” But crown ethers are expensive, toxic, and very often difficult to recover.  “Several laboratories have reported that less expensive catalysts can satisfactorily replace crown ethers for solid-liquid reactions. Thus, dichlorocarbene can be generated from chloroform and solid sodium hydroxide under catalysis with benzyltriethylammonium chloride in yields comparable to those of the classical Makosza method. { s. Julia and A. Ginebrada, Synthesis, 682 (1977)}. See F & F Vol. 8 pg. 390.

Cheaper than crown ethers is the Trident-1 ligand and even simple polyethylene glycol monoethers. Both act in what can be visualized as wrapping an alkali cation in its tentacles and folds which increase the effective size of the cation and thereby make the associated anion more reactive.

The attraction of phase-transfer catalysis for work at scale is the general simplification of conditions and the use of inexpensive quartenary ammonium (hereafter called quat) catalysts that allow the employment of aqueous sodium hydroxide as a base in organic synthesis instead of the classical, more sensitive, more dangerous, and more expensive alkali metal alkoxides, amides, and hydrides.

The favorable price and availability of the quat ions,  phosphonium ions, the Trident-1 ligand, and cyclophosphazenic polypodands render these catalysts of choice on-scale.

Detailed Mechanisms

There are two competing mechanisms that can be contemplated for the sub-set of phase-transfer catalyzed reactions that require a deprotonation as a step: the interfacial mechanism and the extraction mechanism. The interfacial mechanism does not require deprotonation of the weakly acidic substrate by a quat hydroxide in the bulk organic phase. Rather, the alkali hydroxide deprotonates the substrate at the interface between the two layers. Then the quat exchanges with the alkali cation and carries the reactive deprotonated organic ion pair into the bulk of the organic solvent where it reacts. The presence of the quat cation allows a higher concentration of deprotonated substrate anion in the bulk organic solvent.

 In contrast, in the extraction mechanism, a quat with many large hydrophobic groups forms an ion pair with hydroxide in the bulk aqueous phase and carries it into the bulk organic medium where both deprotonation of substrate and subsequent reaction occurs.

For synthetic organic chemists who are interested in quickly finding good reaction conditions, the importance of the existence of two mechanisms is that each predicts a different preferred structure for the most effective quat catalyst. When one cannot infer the mechanism, each of the two different types of catalyst structure ought to be investigated.

Ion-Pair Extraction (F & F Vol. 11)

Using a full equimolar amount of either a large hydrophobic cation or hydrophobic anion can lead to complete extraction of the complimentary ion into an appropriately selected non-polar organic solvent. Organic substances that have higher carbon-acid acidities such as those with two or more electron-withdrawing functional groups attached to the same carbon can, for example, be extracted as stoichiometric stable anions. Sometimes this is the preferred method for their reaction- even better than phase-transfer catalyzed anion formation and reaction.

Ion pair extraction is more frequently used as a means of separating acids or bases that are very similar in acidity/basicity but markedly different in hydrophobicity. 

Catalyzed Enantioselective Alkylation (F & F Vol. 12 pg.379-380)

Phase-transfer Quat catalysts that are themselves chiral can induce chirality in the alkylation products to promote catalytically. Examples of this are referenced in Fieser & Fieser vol. 12 pg. 379-380 and Vol. 13 pg. 239. I would expect there have been many more examples in the period since 2010.

Catalyst Removal after Reaction Completion

The removal of the catalyst from the organic phase after reaction completion is a frequent problem with strongly hydrophobic phase-transfer quats. If not effectively removed it will often contaminate an organic-soluble product after it is isolated. KiloMentor speculates that the use of a quat that contains two quarternary groups linked together might provide a means to remove that quat from the final product since it is known that dications can be precipitated as insoluble salts with pamoate dianion. Note: this has not been demonstrated.

Quats are also known whose structure contains a degradable link between the hydrophilic head and the hydrophobic tail so the catalyst can be destroyed.

The Role of Water

The higher the salt concentration in any aqueous layer used in a phase-transfer reaction, the less water is available to be extracted as part of the solvation sphere of the anion that is transported by the catalyst into the organic layer. The less the solvation sphere the more reactive the anion whether as a nucleophile or as a base. the reason: high salt concentrations reduce water activity.

Phase-transfer Catalyst Poisoning

A reaction that is being catalyzed by a phase-transfer catalyst often stops before completion. The most common cause is that a more hydrophobic anion has accumulated in the reaction medium and it is pairing with the quat holding it permanently in the organic phase so that it cannot cycle back and forth between aqueous and organic as is required for catalysis. Nucleophilic substitution reactions are particularly prone to this difficulty because the good classical leaving groups are large soft Lewis bases like bromide or iodide that can pair with and immobilize a quat.