Phase Transfer Catalysis: Fundamentals, Techniques, and Recent Advances (PDF)
Phase Transfer Catalysis: A Powerful Technique for Organic Synthesis
Phase transfer catalysis (PTC) is a widely used method for enhancing the reactivity of organic compounds by facilitating their interaction with inorganic or aqueous reagents. In this article, we will explore the basic principles, mechanisms, applications, and recent developments of PTC, as well as some frequently asked questions about this fascinating technique.
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Many organic reactions involve the use of reagents that have different solubility preferences. For example, a common synthetic strategy is to react an organic electrophile with an inorganic or aqueous nucleophile. However, these reagents are often immiscible with each other, resulting in slow or incomplete reactions. To overcome this problem, a phase transfer catalyst (PTC) can be employed to facilitate the transport of one reagent into the other phase, thereby increasing the contact and reactivity between them.
A phase transfer catalyst (PTC) is a substance that can act as a soluble carrier or mediator for a reactant from one phase to another. Typically, a PTC is a quaternary ammonium or phosphonium salt that can form a complex with an anionic reagent (such as hydroxide, cyanide, or halide) in the aqueous or solid phase, and transfer it into the organic phase where it can react with an electrophile. Alternatively, a PTC can be a crown ether or a cryptand that can bind to a cationic reagent (such as sodium, potassium, or cesium) in the aqueous or solid phase, and transfer it into the organic phase where it can react with a nucleophile.
The use of PTC has many advantages over conventional methods of organic synthesis. Some of these advantages are:
PTC can enable reactions that are otherwise impossible or difficult to perform due to solubility issues.
PTC can increase the reaction rate and yield by enhancing the concentration and availability of the reactants.
PTC can reduce the amount and toxicity of solvents and reagents by allowing the use of mild and inexpensive conditions.
PTC can simplify the reaction procedure and purification by avoiding the need for multiple extractions and separations.
However, PTC also has some disadvantages that need to be considered. Some of these disadvantages are:
PTC can introduce unwanted side reactions or byproducts due to the presence of additional species or intermediates.
PTC can decrease the selectivity or stereoselectivity of the reaction due to the loss of control over the orientation or configuration of the reactants.
PTC can degrade or deactivate over time due to hydrolysis, oxidation, or decomposition.
PTC can pose environmental or health hazards due to the persistence or toxicity of some PTAs or their complexes.
Basic Mechanisms of PTC
The exact mechanism of PTC depends on the nature of the reactants, the PTA, and the reaction conditions. However, two general mechanisms have been proposed to explain the role of PTC in facilitating the reactions between organic and inorganic or aqueous reagents: the Starks extraction mechanism and the Makosza interfacial mechanism.
Starks extraction mechanism
The Starks extraction mechanism, proposed by Starks in 1971, involves the extraction of an anionic reagent from the aqueous or solid phase into the organic phase by the PTA. The PTA moves back and forth across the interface between the two phases, forming a complex with the anion in the aqueous or solid phase, and transferring it into the organic phase where it reacts with the electrophile. The PTA then returns to the aqueous or solid phase to repeat the cycle. This mechanism is illustrated in Scheme 1 for the reaction of 1-chlorooctane with sodium cyanide catalyzed by hexadecyltributylphosphonium bromide.
Makosza interfacial mechanism
The Makosza interfacial mechanism, proposed by Makosza in 1974, involves the formation and reaction of an onium carbanion intermediate at the interface between the two phases. The PTA forms a complex with the anion in the aqueous or solid phase, and brings it to the interface where it deprotonates the organic substrate to form an onium carbanion. The onium carbanion then reacts with the electrophile in the organic phase to form the product. The PTA remains at the interface to repeat the cycle. This mechanism is illustrated in Scheme 2 for the reaction of benzyl chloride with sodium cyanide catalyzed by benzyltriethylammonium chloride.
Factors affecting the efficiency of PTC
The efficiency of PTC depends on several factors that influence the generation, transport, and reactivity of the onium carbanion species. Some of these factors are:
The structure and solubility of the PTA. The PTA should have a large hydrophobic group to increase its solubility in the organic phase, and a small hydrophilic group to increase its affinity for the anion. The PTA should also have a low pKa to facilitate its deprotonation by the base.
The nature and concentration of the base. The base should be strong enough to deprotonate the organic substrate, but not too strong to deprotonate or decompose the PTA. The base should also be present in excess to ensure a high concentration of the anion.
The nature and concentration of the electrophile. The electrophile should be sufficiently reactive to react with the onium carbanion, but not too reactive to react with other species or undergo side reactions. The electrophile should also be present in stoichiometric or slight excess to ensure a high conversion of the substrate.
The nature and polarity of the solvent. The solvent should be immiscible with water or solid base, but soluble with both phases. The solvent should also have a low polarity to increase the solubility and nucleophilicity of the onium carbanion.
The temperature and agitation of the reaction mixture. The temperature should be high enough to increase the solubility and mobility of the reactants and catalysts, but not too high to cause decomposition or evaporation. The agitation should be vigorous enough to increase the contact area and mass transfer between the phases, but not too vigorous to cause emulsification or foaming.
Applications of PTC in Organic Synthesis
PTC has been widely applied in various types of organic reactions, such as alkylation, nucleophilic substitution, oxidation, reduction, and cycloaddition. In this section, we will briefly review some examples of these reactions using PTC.
Alkylation reactions involve an electrophile to a nucleophile. PTC can enable alkylation reactions that are otherwise difficult or impossible to perform due to solubility or reactivity issues. For example, PTC can allow the use of aqueous or solid bases such as sodium hydroxide, sodium carbonate, or potassium fluoride to deprotonate and alkylate acidic organic compounds such as ketones, esters, nitriles, sulfones, or malonates. PTC can also allow the use of a variety of electrophiles such as alkyl halides, allyl halides, propargyl halides, benzyl halides, acrylates, or dibromoalkanes. PTC can also increase the rate and yield of alkylation reactions by enhancing the concentration and availability of the nucleophilic and electrophilic reagents. Some examples of alkylation reactions using PTC are shown in Scheme 3.
Nucleophilic substitutions involve the replacement of a leaving group by a nucleophile. PTC can facilitate nucleophilic substitutions by increasing the solubility and nucleophilicity of aqueous or solid nucleophiles such as hydroxide, cyanide, azide, thiocyanate, or sulfide. PTC can also enable nucleophilic substitutions that are otherwise hindered by steric or electronic factors. For example, PTC can allow the substitution of tertiary alkyl halides or hindered aryl halides by aqueous or solid nucleophiles. PTC can also allow the substitution of activated aryl halides by weak nucleophiles such as water or alcohols. Some examples of nucleophilic substitutions using PTC are shown in Scheme 4.
Oxidation reactions involve the increase of the oxidation state of an organic compound by removing electrons or adding oxygen atoms. PTC can enhance oxidation reactions by increasing the solubility and reactivity of aqueous or solid oxidizing agents such as hydrogen peroxide, hypochlorite, permanganate, or dichromate. PTC can also enable oxidation reactions that are otherwise slow or incomplete due to low solubility or reactivity of the oxidizing agent or the organic substrate. For example, PTC can allow the oxidation of alcohols to aldehydes, ketones, or carboxylic acids by aqueous or solid oxidizing agents. PTC can also allow the oxidation of sulfides to sulfoxides or sulfones by aqueous or solid oxidizing agents. Some examples of oxidation reactions using PTC are shown in Scheme 5.
Reduction reactions involve the decrease of the oxidation state of an organic compound by adding electrons or removing oxygen atoms. PTC can improve reduction reactions by increasing the solubility and reactivity of aqueous or solid reducing agents such as sodium borohydride, sodium dithionite, sodium sulfite, or sodium sulfide. PTC can also enable reduction reactions that are otherwise slow or incomplete due to low solubility or reactivity of the reducing agent or the organic substrate. For example, PTC can allow the reduction of ketones, aldehydes, esters, nitriles, nitro compounds, or epoxides by aqueous or solid reducing agents. PTC can also allow the reduction of aromatic compounds by aqueous or solid reducing agents. Some examples of reduction reactions using PTC are shown in Scheme 6.
Cycloaddition reactions involve the formation of a cyclic compound by the addition of two or more unsaturated molecules. PTC can facilitate cycloaddition reactions by increasing the solubility and reactivity of aqueous or solid reagents such as azides, diazo compounds, nitrile oxides, or nitrile imines. PTC can also enable cycloaddition reactions that are otherwise difficult or impossible to perform due to solubility or reactivity issues. For example, PTC can allow the 1,3-dipolar cycloaddition of azides, diazo compounds, nitrile oxides, or nitrile imines with alkynes, alkenes, or carbonyl compounds. PTC can also allow the DielsAlder reaction of dienes with dienophiles in aqueous media. Some examples of cycloaddition reactions using PTC are shown in Scheme 7.
Recent Developments and Future Perspectives of PTC
PTC is a well-established and versatile technique for organic synthesis, but it is still evolving and improving with new discoveries and innovations. In this section, we will briefly highlight some of the recent developments and future perspectives of PTC in terms of combining PTC with other techniques, developing asymmetric PTC and chiral PTAs, and promoting green PTC and environmentally benign PTAs.
Combination of PTC with other techniques
One of the recent trends in PTC is to combine PTC with other techniques such as sonochemistry, microwaves, electrochemistry, or photochemistry to achieve synergistic effects and enhance the performance of PTC. For example, sonochemistry can increase the mass transfer and interfacial area between the phases, as well as generate reactive radicals by acoustic cavitation. Microwaves can increase the temperature and dielectric constant of the reaction medium, as well as activate the reactants and catalysts by selective heating. Electrochemistry can provide an external potential to drive the redox reactions, as well as generate reactive intermediates by electrolysis. Photochemistry can provide light energy to initiate or accelerate the reactions, as well as generate reactive species by photolysis. Some examples of the combination of PTC with other techniques are shown in Scheme 8.
Asymmetric PTC and chiral PTAs
Another recent trend in PTC is to develop asymmetric PTC and chiral PTAs to achieve enantioselective synthesis of chiral compounds. Asymmetric PTC can be achieved by using chiral PTAs that can induce stereocontrol over the reactions by forming diastereomeric complexes with the reactants or intermediates. Chiral PTAs can be classified into two types: chiral quaternary ammonium or phosphonium salts that can transfer anionic reagents, and chiral crown ethers or cryptands that can transfer cationic reagents. Chiral PTAs can be derived from natural or synthetic sources, such as amino acids, sugars, terpenes, alkaloids, or binaphthyls. Some examples of asymmetric PTC and chiral PTAs are shown in Scheme 9.
Green PTC and environmentally benign PTAs
A third recent trend in PTC is to promote green PTC and environmentally benign PTAs to achieve sustainable and eco-friendly synthesis of organic compounds. Green PTC can be achieved by using environmentally benign PTAs that can reduce the toxicity, waste, and energy consumption of the reactions. Environmentally benign PTAs can be classified into two types: biodegradable or recyclable quaternary ammonium or phosphonium salts that can transfer anionic reagents, and biocompatible or biomimetic crown ethers or cryptands that can transfer cationic reagents. Biodegradable or recyclable PTAs can be derived from renewable or natural sources, such as fatty acids, glycerol, starch, cellulose, or lignin. Biocompatible or biomimetic PTAs can be derived from biological or natural sources, such as peptides, proteins, nucleic acids, or cyclodextrins. Some examples of green PTC and environmentally benign PTAs are shown in Scheme 10.
In this article, we have reviewed the basic principles, mechanisms, applications, and recent developments of PTC, a powerful technique for organic synthesis. We have shown that PTC can enable, improve, and simplify various types of organic reactions by facilitating the transport and interaction of organic and inorganic or aqueous reagents. We have also highlighted some of the recent trends and future perspectives of PTC in terms of combining PTC with other techniques, developing asymmetric PTC and chiral PTAs, and promoting green PTC and environmentally benign PTAs. We hope that this article can provide a comprehensive and useful overview of PTC for both beginners and experts in the field of organic chemistry.
What are some examples of commercial products synthesized by PTC?
Some examples of commercial products synthesized by PTC are: ibuprofen (an anti-inflammatory drug), naproxen (an analgesic drug), phenylacetic acid (a fragrance ingredient), methyl methacrylate (a monomer for polymers), and ethyl acetate (a solvent).
How can I choose the best PTA for a given reaction?
There is no general rule for choosing the best PTA for a given reaction, but some factors that can be considered are: the solubility and stability of the PTA in both phases, the affinity and selectivity of the PTA for the reagent to be transferred, the reactivity and stereoselectivity of the PTA-complexed reagent, and the cost and availability of the PTA.
How can I optimize the reaction conditions for PTC?
Some parameters that can be optimized for PTC are: the type and ratio of the solvents, the type and amount of the base, the type and amount of the electrophile, the type and amount of the PTA, the temperature and agitation of the reaction mixture, and the duration and monitoring of the reaction.
What are some safety precautions when using PTC?
Some safety precautions when using PTC are: to wear appropriate personal protective equipment (gloves, goggles, lab coat), to work in a well-ventilated area or a fume hood, to avoid contact with or inhalation of toxic or corrosive reagents or catalysts, to dispose of waste materials properly according to local regulations.
Where can I find more information and resources on PTC?
Some sources of information and resources on PTC are: books (e.g., Phase-Transfer Catalysis: Fundamentals, Applications, and Industrial Perspectives by Starks et al., Phase-Transfer Catalysis: Principles and Techniques by Dehmlow et al.), journals (e.g., Journal of Phase-Transfer Catalysis), websites (e.g., www.phasetransfer.com), conferences (e.g., International Symposium on Phase-Transfer Catalysis).