Reactions and Polymerizations at the LiquidâLiquid Interface

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Reactions and Polymerizations at the Liquid−Liquid Interface Keti Piradashvili,† Evandro M. Alexandrino,† Frederik R. Wurm,*,† and Katharina Landfester*,† †

Max Planck Institute for Polymer Research, Ackermannweg 10, 55128 Mainz, Germany ABSTRACT: Reactions and polymerizations at the interface of two immiscible liquids are reviewed. The confinement of two reactants at the interface to form a new product can be advantageous in terms of improved reaction kinetics, higher yields, and selectivity. The presence of the liquid−liquid interface can accelerate the reaction, or a phase-transfer catalyst is employed to draw the reaction in one phase of choice. Furthermore, the use of immiscible systems, e.g., in emulsions, offers an easy means of efficient product separation and heat dissipation. A general overview on low molecular weight organic chemistry is given, and the applications of heterophase polymerization, occurring at or in proximity of the interface, (mostly) in emulsions are presented. This strategy can be used for the efficient production of nano- and microcarriers for various applications.

CONTENTS 1. Introduction 2. Emulsification Techniques Microfluidics Microchannel Emulsification Membrane Emulsification High Energy Emulsion Preparation: Mini- or Nanoemulsions by Ultrasonication and HighPressure Homogenization 3. Reactions at the (Droplet) Interface Reactions at Macroscopic Interfaces Reactions at the Droplet’s Interface Polymerizations at the Droplet Interface Ionic Polymerizations Cationic Polymerization Anionic Polymerization Radical Polymerization Free Radical Polymerization Polycondensation and Polyaddition 4. Conclusion and Outlook Author Information Corresponding Authors Author Contributions Notes Biographies Acknowledgments References

the preparation of (nano)materials, which are not accessible by any other technique. The interface between hydrophilic and hydrophobic liquids can be used to combine immiscible reaction partners or to protect sensitive partners, from hydrolysis for example. There are many types of reactions that can be conducted at the interface of two immiscible liquids, either in a static environment or mechanically stirred. The surface can be adjusted by the choice of an emulsification technique. The use of different environments for selectively solubilizing the partners of a reaction is a convenient and efficient pathway, which is widely used, e.g., for the formation of esters and amides by the reaction of electrophilic acid chlorides (carboxylic acid, phosphoric acid, etc.) dissolved in an organic phase with nucleophiles, dissolved in an aqueous environment. Catalysis at the interface is also an interesting approach with the catalyst in one phase, the product in the other. The adjustment of the reactivity of each compound in the mixture is important to guarantee high yield reactions, i.e., the competition between the hydrolysis of the acid chloride vs the amidation, in the case of an amide formation. This was taken to the industrial level already in the 1930s with the first interfacial polycondensation of Nylon, which was presented to the public at the New York World’s Fair in 1939.1−3 Besides the vast applications of interfacial reactions (from macro to nano) for the formation of low molecular weight compounds, one should also note their potential as a tool for modern polymer chemistry.4−11 This article will present a comprehensive summary of strategies and techniques for both chain-growth and step-growth polymerizations conducted at the interface of droplets. We will focus on the developments in the past decade, however, with a short historical context.

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1. INTRODUCTION 130 years after Schotten and Baumann, reactions at the liquid−liquid interface still hold a great potential for synthetic chemistry. Reactions “on water”, “at the interface”, or by “phase-transfer” are important platforms for modern chemistry, especially as in most cases water can be used as the second phase. Immiscible reaction partners react at the interface of two liquids, which is especially a convenient and versatile route for © 2015 American Chemical Society

Special Issue: Frontiers in Macromolecular and Supramolecular Science Received: September 24, 2015 Published: December 28, 2015 2141

DOI: 10.1021/acs.chemrev.5b00567 Chem. Rev. 2016, 116, 2141−2169

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Figure 1. Schematic representation of reactions at the liquid−liquid interface.

stirring is used in order to increase the interfacial area and thus to optimize the reaction. Various emulsification techniques have been developed to produce droplets from micrometer to nanometer scale which can be used to conduct the interfacial reaction. Control over the size, shape, and dispersity of the formed droplet additionally to the rate of droplet formation are the major criteria for preferring one technique over the other. A short overview of the procedures most commonly used for emulsion formation will be given in the following pages before we focus on reactions at the droplet interface. Figure 2 presents the techniques for the formation of droplets with average diameter in the micrometer or nanometer range, and the relevant techniques for reactions at droplet interfaces will be presented in more detail. For the formation of droplets at the micrometer scale, membrane, microchannel, and microfluidic devices are widely used.18 In all these techniques microengineered devices control the droplet size by their geometry.19 For the formation of nanodroplets, mechanical (ultrasonication;20 high pressure homogenization5,21) and spontaneous (Ouzo effect22 and phase inversion phenomenon21,23) formation can be applied. For all methods, the composition of the emulsion, hydrodynamic conditions, and wetting effects and the nature of the surfactants also have an influence on the system.24−26

At the droplet interface, monomers provided from either phase meet and react to generate a polymer, which can be soluble or insoluble in one or both phases. If an insoluble polymer is generated it can−on the macroscale−be removed from the interface. If the droplet size is reduced to micro and nanometers, a shell surrounding a liquid core, i.e., a hollow capsule is generated. This platform allows the generation of smart nanocarriers for various applications. The reaction at the interface can be regarded as a molecular “screw clamp” forcing two or more molecules to undergo a reaction. This allows performing reactions that cannot be performed in homogeneous solutions. For example, alkyne− azide click reactions normally need copper catalysts, which are not necessary in heterogeneous conditions, as the interface, i.e., the close proximity of the two components, promotes the reaction.12 This technique allows the encapsulation of various compounds (bioactive or sensitive molecules, as enzymes, vitamins, DNA, or proteins, monomers). If watersoluble compounds are encapsulated, they will be protected by the polymeric shell from the organic solvent at the outside. After the reaction, the carriers can be transferred in an aqueous dispersion and are used in materials science applications or biomedical applications. This review is structured as follows: In the first part, a brief overview is given about emulsification strategies, which are used to generate high interfacial areas. In the second part, organic reactions both at the macro- and nanoscopic liquid−liquid interfaces are summarized. The last part deals with polyreactions at the interface either to control polymer microstructure and reaction kinetics or to prepare nanocarriers.

Microfluidics

For the production of emulsions with narrow droplet size distributions and droplet diameters as small as 5 μm,27 dropletbased microfluidics can be used. The precise control over single droplets,28 a high throughput at kHz rates25,29 with lab-on-chip devices,30,31 and the generation of almost monodisperse droplets32,33 (with coefficients of variation as low as 1.3%34) represent the main advantages of droplet-based microfluidics. Furthermore, the versatility of structures that can be obtained, the generation of double28,35 or multiple emulsions,36−38 the synthesis of irregular particles,39−42 core−shell structures,43−46 Janus particles,47,48 and liposomes49,50 or polymersomes51,52 have contributed to the popularization of microfluidic devices.

2. EMULSIFICATION TECHNIQUES A reaction at the interface of two liquids can be performed with macroscopic phase separation, i.e., typically under static conditions, without stirring and only relying on the diffusion of the reactants to the interface, where the reaction takes place. In most examples of interfacial reactions, however, heavy 2142


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Figure 2. Schematic representation of the emulsification techniques used in the production of droplets in the micrometer region, as microchannel, microfluidics, or membrane emulsification, or in the nanometer range. The production of nanodroplets is divided in high-energy methods, as ultrasonication or high pressure homogenization, or low-energy methods as phase inversion methods (pH, temperature, composition) and spontaneous emulsification (“Ouzo” effect). Images reprinted with permission from refs 13−17. Copyright 2014 Elsevier B.V. Copyright 2013 Elsevier B.V. Copyright 2011 Royal Society of Chemistry. Copyright 2008 Microfluidics International Corp. Copyright 2003 AIP Publishing LCC. Copyright 2010 Elsevier Ltd.

Microchannel Emulsification

The simplest microfluidic device for droplet generation consists of a T-junction (see top image in Figure 2).53 The continuous phase and the disperse phase are introduced in two perpendicular channels and form an interface at the junction. Due to the shear force exerted by the continuous phase, the disperse phase is dragged into the channel of the continuous phase and breaks into discrete droplets.54 Another commonly used geometry is the flow-focusing device developed by Anna et al. where the disperse phase flows in the middle channel and the continuous phase in two outer channels (see top image in Figure 2).13 A small orifice is located downstream of the channels and the two phases are forced to pass through it. Through pressure and shear stress applied from the continuous phase the inner fluid forms a narrow thread and breaks eventually into droplets. For a stable droplet generation, it is crucial that the disperse phase does not wet the channel walls, whereas the wettability by the continuous phase and the chemical stability of the channel material toward the fluids should be guaranteed.

Microchannel emulsification allows the production of droplets from approximately 4 to 100 μm55−57 with a coefficient of variation below 5%.58 The microchannel device consists of a comb-like channel array on a silicon chip fabricated via photolithography. The microchannel modules can be designed either as dead-end or cross-flow devices. In the dead-end module microchannels are arranged on a terrace at all four sides of a silicon chip.59 The disperse phase is placed in the center of the terrace and pushed through the channels. At the end of the terrace the droplet detaches and flows into the continuous phase.60 No external shear stress is required for the droplet production as the formation is governed by the interfacial tension force.61 The droplet is pushed through the microchannels and inflates on the terrace in a disc-like shape.62 This shape has a higher interfacial area per volume than a spherical shape and is thus hydrodynamically unstable. This instability is the driving force for the droplet detachment as the preferred spherical shape is regained.63 To summarize, via this method uniform droplets are formed spontaneously at mild conditions as a high energy input and 2143


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turbulent mixing with high shear forces are not required.64,65 Thus, it is especially attractive for sensitive compounds in the food and pharmaceutical industry.66−68 Furthermore, a direct microscopic observation of the emulsion formation process is possible.69 However, this method still suffers from a low emulsion formation rate compared to standard emulsification methods59 making large scale productions challenging.

volume fraction, temperature, salinity, etc., so that the resulting nanodroplets are at the critical borderline between stability and instability. Additionally the size and size distribution also depend on the shear rate and emulsion rheology, which will vary depending on the ultrasonication conditions, process parameters, and the system physicochemical properties.79 After the formation of the droplets, Ostwald ripening can still affect the stability of the miniemulsion. Ostwald ripening describes the growth of larger objects at the cost of the consumption of smaller ones, when monomodal distribution is not given.81 Ostwald ripening is a consequence of the higher surface energy, and hence high Gibbs free energy, of smaller droplets in comparison to larger ones. Ostwald ripening can be counterbalanced by the use of highly hydrophobic or lipophobic molecules (for direct or indirect emulsion respectively) inside of the dispersed droplets. Typically a low content of hydro-/lipophobe is mixed in the droplets, which can hardly diffuse through the continuous phase, i.e., exchange between the droplets, generates an increase in the osmotic pressure, counterbalancing partially and generating a final state of equal pressure inside of the droplets. Thus, a final steadystate miniemulsion is obtained.5

Membrane Emulsification

In membrane emulsification, the fluid representing the disperse phase is injected through a microporous membrane with uniform pore size into the continuous phase. Alternatively, a premix is passed through the membrane resulting in the homogenization of the mixture.70,71 Through membrane emulsification minimal droplet sizes of 0.1 μm17 can be obtained. With this method much higher throughputs compared to microfluidic and microchannel devices can be achieved making membrane emulsification suitable for a scaleup to large-scale productions. However, due to the relatively broad size distribution (with a coefficient of variation of around 10%34), fouling of the membrane material,17 and the sensitivity to the viscosity of the disperse phase, this method is of limited use for particle preparation but can be used to generate reactors for the interfacial reaction.72 In comparison to conventional turbulence-based methods, less energy is needed to achieve emulsification, avoiding a raise in temperature, and less stress is applied.73 Thereby, this method is applicable for temperature and shear-sensitive substances, such as proteins or enzymes.74,75

3. REACTIONS AT THE (DROPLET) INTERFACE Processes taking place at the interface of two immiscible liquids have been investigated intensively as they differ from those in bulk and often occur only due to the unique features of this region. One of the most famous examples of a chemical reaction at the interface is, as previously mentioned, the synthesis of Nylon discovered by Wallace Hume Carothers at DuPont in 1935.2,82 Nevertheless, the historical background of the use of the interface as a shortcut to enable or improve chemical reactions starts much earlier, with the early works of Schotten83 and Baumann84 at the end of the 19th century. Since then, systematical improvement of the setups has been investigated, e.g., stabilization of the interface between two immiscible liquids and increase thereof through droplet formation. Starting from an introduction of reactions at a macroscopic liquid/liquid interface, examples of reactions in emulsified systems/at droplet interfaces are given in the following.

High Energy Emulsion Preparation: Mini- or Nanoemulsions by Ultrasonication and High-Pressure Homogenization

According to the IUPAC recommendation, miniemulsions (or nanoemulsions) are defined as emulsions, i.e., systems, formed by one disperse and one continuous phase, with the disperse phase having diameters between 50 nm and 1 μm.76 Other emulsions characterized by nanoscale dimension are the so-called microemulsions. Both systems are classified according to the composition as direct (oil-in-water) or inverse (water-inoil) emulsions.5 While miniemulsions are kinetically stable systems, stabilized against coalescence and against diffusion degradation (Ostwald ripening),5,76,77 microemulsions are defined as thermodynamically stable systems, containing a high amount of surfactant and possibly a cosurfactant in their formulation. Microemulsions are formed spontaneously, while miniemulsions need external force to be generated (e.g., ultrasound).78 The mechanical emulsification process for the formation of a miniemulsion starts with a pre-emulsification step, with the initial two phases and additives being mixed, generating droplets with a large size distribution which are stabilized by surfactants,5 typically in the range of 1 to 20 μm.79 Diverse methods can be used subsequently for the formation of the miniemulsion. The provision of an energy higher than the surface tension multiplied by the amount of surface is necessary to break the droplets from the micrometer scale into nanometer droplets.5 Today, for bench scale experiments the main source of energy for the formation of stable and well-defined miniemulsions are ultrasonication and high-pressure homogenization (HPH).5,80 The final size and size distribution of the obtained miniemulsion are controlled by a Fokker−Planck type dynamic rate equilibrium of droplet fusion and fission processes and can be controlled by the applied conditions like surfactant load,

Reactions at Macroscopic Interfaces

As previously mentioned, the works from Schotten and Baumann were the starting point of the exploration of the liquid−liquid interface for organic chemistry. The so-called “Schotten-Baumann reaction conditions” involve the synthesis of amides from amines and acid chlorides in a biphasic reaction mixture. Even though this is one of the most classic examples of organic synthesis in a biphasic system, in this case both product and reactants are present in the organic phase. The use of the interface is crucial to force the equilibrium toward the formation of the products. An alkaline aqueous solution is added to the reaction mixture and reacts at the interface with the protons of the amine-acid chloride reaction, preventing the amine from being protonated. This classic example is for sure not the only case where the presence of water is primordial to perform organic synthesis. Even though water is not a classic solvent applied in organic reactions, a series of examples can be found in the literature, where the use of biphasic aqueous/ organic systems provides unique conditions. One of the most popular examples nowadays is the use of the so-called “on water” organic synthesis protocol. “On water” synthesis is 2144


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Figure 3. “On water” approach developed by Sharpless et al.: (a) the initial macroscopic biphasic system containing the substrates and the aqueous phase is submitted to (b) vigorous stirring, transforming the system in a suspension and thus increasing the surface area between the water phase and the substrates. (c) After the end of the stirring process, the product can be easily separated either by precipitation or by forming a film between both phases. Reprinted with permission from ref 87. Copyright 2005 Nature Publishing Group.

related to a series of different chemical reactions that happen or are catalyzed by the interface in biphasic systems (where one of the phases is always water). One of the first to demonstrate the catalytic effect of such systems, Breslow has studied how Diels− Alder reactions could be accelerated in the presence of water.85 He attributed this effect to be a “hydrophobic effect”, which forces organic molecules in water to aggregate resulting in increased reaction kinetics. The term “on water” reactions was coined almost 15 years later in the work of Sharpless and collaborators.86 The authors presented a series of examples where insoluble reactants were stirred in an aqueous suspension (Figure 3). Many of the studied systems presented a certain level of acceleration when performed in “on water” conditions, but even where negligible acceleration was observed, the authors claimed many other advantages of these systems, such as ease of product isolation and safety. Since the work of Sharpless, a high level of interest in the investigation of the mechanism of action and on the possibilities of such “on water” systems has been seen in the scientific community. Manna and Kumar more recently performed an exhaustive analysis in order to understand how the interface influences the mechanism of “on water” organic reactions.88 The authors studied the reaction between cyclopentadiene and alkyl acrylates, demonstrating that the increase of the interfacial area between organic and aqueous phase leads to an increase of the kinetics for this system (Figure 4). The authors considered the nature of the interface and the ease of hydrogen bonding between water and the reactants in the disperse phase (or the transition state) as vital factors together with the hydrophobicity and cohesive energy density at the interfacial region. Butler and Coyne have recently investigated the effects of protons and Li+ ions in the aqueous phase and the presence of nonreacting competing hydrogen bond acceptor molecules in the organic phase on Huisgen cycloadditions.89 Such hydrogen acceptor molecules in the organic phase caused an initial reduction of the reaction yield, but the further increase of the concentration did not produce a continuous effect. The authors conclude that for compounds with basic pKa values (pKa 3−5 of the conjugate acid) proton transfer across the water/organic interface is involved in the catalysis, while for weaker bases trans-phase H-bonding occurs. Another interesting approach to prove the vital importance of hydrogen bonds was the investigation of the “on water” reactions in D2O instead of H2O. The reaction between quadricyclane and dimethyl azodicarboxylate was completed in 10 min in a biphasic system

Figure 4. (A) Reaction performed by Manna and Kumar in the investigation of “on water” reactions; (B) the decrease of the interfacial are with the increase of the stirring rate resulted in the (C) increase of the kinetics. Adapted with permission from ref 88. Copyright 2013 American Chemical Society.

with H2O, while the same reaction was completed in 45 min in D2O. Therefore, it seems to be clear that the presence of hydrogen bonds at the interfacial region is essential in the catalytic performance of such systems. Sharpless and co-workers observed that reaction times in oil/water systems can decrease by a factor of 300 compared to solvent-free conditions. As already described, they termed these reactions “on water” reactions since only the existence of an interface seems to be the cause of this acceleration.86 Although the mechanism of these reactions is still unclear, the difference in kinetics between neat and “on water” reactions could be due to the unique nature of the oil−water boundary. As shown before, it has been proposed by several authors that a structural change of the water at the interface compared to bulk could have the major influence.90−92 Taking the results of Sharpless et al. as the basis for their theoretical models, Jung and Marcus calculated rate constants of a model reaction in bulk (neat), in homogeneous aqueous solution and in an oil/water emulsion.93 The reaction is catalyzed by the OH-groups via the formation of hydrogen bonds. For the “on water” reaction, rate enhancement of 5 orders of magnitude compared to the 2145


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Figure 5. Scheme of the “on water” catalysis and the catalysis in homogeneous solution. ksurface is the rate constant of the interfacial reaction, khomogeneous of the reaction in water and kneat is the rate constant of the reaction in bulk. Reproduced with permission from ref 93. Copyright 2007 American Chemical Society.

reaction in bulk, and of 600-fold compared to the aqueous solution, were obtained. It was calculated that in every four interfacial water molecule there is a free OH group catalyzing reactions by forming in the organic phase hydrogen bonds with reagents in the transition state. In bulk water on the contrary, the reactants are surrounded by an H-bond network which has to be broken first to obtain a necessary number of OH groups to catalyze a reaction as efficiently as in the “on water” system (see Figure 5). This acceleration mechanism is of course not valid for every reaction. However, where this is the case, formation of an emulsion can be beneficial as shown in the next section. Another important characteristic of the interfacial region in “on water” protocols is the transport of ions between the aqueous and organic phase. Mirkin et al. investigated the transport of ions between aqueous and organic solvents in nanosized interfaces, prepared with nanopipettes, claiming the nonvalidity of the generally accepted one-step mechanism for the transfer of ions between phases and providing a new mechanism involving the presence of a transient interfacial ion paring and shuttling of the ions in a mixed solvent layer (Figure 6).94

Figure 7. (A) Diels−Alder reaction system applied for the investigation of the influence of alcoholic cosolvents in “on water” systems; (B) Apparent rate constants for the Diels−Alder reaction presented in (A) as a function of the mole fraction of methanol, xMeOH at 298 K; (C) relative rates for the formation of the endo (■) and the exo (●) isomers against percent volume fraction of methanol in water at 298 K. Adapted with permission from ref 95. Copyright 2009 American Chemical Society.

excellent overview about the diverse types of organic synthetic approaches that can be achieved using the “on water” protocol, including Diels−Alder reactions, 1,3-dipolar cycloadditions, cycloadditions of azodicarboxylates, Claisen rearrangement, nucleophilic substitution reactions, oxidation and reductions, etc.6 One topic not covered in this review is enzymatic catalysis at liquid−liquid interfaces. The principles of increased enzymatic activity in liquid interfaces have been described by Straathof.96 The reasons of the interface influencing enzymatic system include, as pointed out by the author, higher concentration of the enzymes or the substrate at the interfacial region, and the activation of enzymes through specific interactions in the interfacial region. In the end of the following section this will be covered in more detail. The catalytic effect of interfaces is, as can be seen, a very important topic in nowadays organic synthesis. And in order to achieve better results, the maximization of the surface interfacial area is required. In microchannel reactors, as an example, contact area and time between immiscible liquids can be increased, yielding better results than conventional stirring. Mikami and co-workers reported a dramatic increase in

Figure 6. Shuttling mechanism of ionic transfer at the aqueous organic phase interface proposed by Mirkin et al.:94 the transfer of the cation into the organic phase involves the formation of a short-lived ion pair with an hydrophobic anion. Adapted with permission from ref 94. Copyright 2006 American Chemical Society.

Tiwari and Kumar investigated the influence of alcoholic cosolvents in the interfacial reactivity and selectivity of “on water” systems.95 While homogeneous aqueous reactions are generally negatively influenced by the addition of alcoholic cosolvents, the addition thereof to “on water” systems resulted in an initial increase of the reaction rates, together with an increase in selectivity of Diels−Alder reactions (Figure 7). Organic syntheses “on water” have also been the topic of some reviews. The review of Chanda and Fokin provides an 2146


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reactivity of Mukaiyama aldol reaction in a “fluorous nanoflow” system (nanoflow microreactor with fluorous lanthanide catalysts) (Figure 8) even at very low Lewis acid catalyst

Figure 8. Mukaiyama aldol reaction in a “fluorous nanoflow” system. Reprinted with permission from ref 97. Copyright 2003 Elsevier Ltd. Figure 9. Photocycloaddition of 9-substituted anthracene. 97

concentrations (less than 0.1 mM). The reaction was complete within seconds of a biphasic contact time, whereas under vigorous stirring, it required more than 2 h and showed poor yields. A narrower width and a longer channel, thus a larger contact area, led to further improvement. In the next section diverse examples are covered, describing systems in which stable droplets are applied in order to increase the interfacial area.

Figure 10. Structures of amphiphilic organocatalysts used in ref 101 for the asymmetric aldol reactions in emulsion.

Reactions at the Droplet’s Interface

In general, synthesis of small molecules in disperse systems instead of bulk can lead in some cases to higher efficiency, such as high yields, reduced temperature, and less catalyst, due to the existence of a large interfacial area. Major advantages also comprise the direction of regio- and stereoselectivity, overcoming reagent incompatibility, and rate enhancements.7 Using heterogeneous solvent systems forces molecules with polar and apolar groups to accumulate at the interface in analogy to surfactants. This can be used to induce formation of products with specific regioselectivity. In an early work, Jaeger and co-workers observed this phenomenon in a Diels−Alder reaction of two hydrophobic molecules.98 In pure organic solvents both regioisomers were produced in the same amounts whereas in water a 3-fold excess of one isomer over the other was found. The excess was attributed to the micellar orientation of the two starting compounds in aqueous environment yielding predominantly one regioisomer. Similar observations were made by Wu et al. for the photocycloaddition of 9-substituted anthracenes (with polar or ionic substituents) in w/o microemulsions.99 While in methylene chloride predominantly head-to-tail photocyclomers were obtained, in microemulsion exclusively head-to-head regioisomers were formed due to a preorientation of the substrate molecules at the interface (see Figure 9). Hayashi and co-workers reported successful cross-aldol reactions catalyzed by a proline-surfactant also acting as an organocatalyst with high diastereo- and enanioselectivites upon emulsification.100 However, the role of water and emulsion formation was not clear from these results. For deeper insight, Zhong et al. used a similar amphiphilic organocatalyst in a w/o emulsion for the direct asymmetric aldol reactions with cyclohexanone and different aldehydes (Figure 10).101 Both a rate enhancement and higher stereoselectivity than in homogeneous media were observed. The authors attributed these findings to the large surface area created with the emulsion and the uniform distribution of the catalyst molecules creating a well-ordered two-dimensional chiral surface.

Enantioselective enzymatic catalysis at the interface in miniemulsion has been reported for the preparation of optically active α- and β-amino acids at very high substrate concentrations (up to 800 g/L) and enantiomeric excess of >99% ee.102 Phase transfer catalysts facilitate reactions between reactants located in different phases. Typically, in liquid−liquid phase transfer catalysis (PTC) an anionic reactant is transferred from the aqueous phase to the organic phase by the catalyst, usually quaternary ammonium (e.g., tetrabutylammonium bromide, benzyltrimethylammonium chloride), phosphonium salts (based on tributylphosphines), or crown ethers and cryptands (see Figure 11). In the organic phase it can react with a

Figure 11. Schematic representation of phase transfer catalysis with Q+ as the quaternary ammonium cation, forming an ion pair with the anionic reactant X−. In the organic phase, it reacts with the substrate R-Y, yielding the product R-X and the anionic leaving group Y− which pairs with the catalyst. In the aqueous phase the leaving group is exchanged against another anionic reactant, completing the catalytic cycle.

lipophilic molecule. Due to a weaker solvation in the organic phase, the anions exhibit an enhanced nucleophilicity and are thus more reactive. Increasing the interfacial area between the two phases by emulsification can increase the reaction speed further. Rate enhancement was reported by Ooi and co-workers for several alkylations of carbonyl substrates and epoxidations of ketones when ultrasonication was applied.103 Similar observations were made for the saponification of vegetable oil, an industrially important reaction for the production of fatty acid salts.104 By 2147


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applying ultrasound (20 kHz) instead of the conventional agitation, the yield increased from 8% to 93%. The comparison of the cationic surfactants and phase transfer catalysts cetyltrimethylammonium bromide (CTAB), tetrabutyl ammonium bromide, and benzyl triethylammonium bromide showed that CTAB was the most efficient. Due to the longer alkyl chains it preferentially accumulates at the interface, lowers the surface tension, and facilitates the formation of smaller droplets, resulting in higher contact area between water and the organic phase and thus more transfer possibilities. The synthesis of acid- and base-labile epoxides has also been reported by phase transfer reaction of epichloro- or epibromohydrine and alcohols to the respective glycidyl ethers catalyzed by quarternary ammonium salts (Figure 12).105−107

Figure 12. Synthesis of ferrocenyl glycidyl ether via phase transfer catalysis with epichlorohydrine and tetrabutylammonium bromide (TBAB) as the phase transfer catalyst.

Figure 13. Principles of an inverse phase transfer catalysis (IPTC) and interfacial catalysis (IC) with a surfactant as catalyst (S, substrate; R, reactant; P, product). Reproduced with permission from ref 112. Copyright 2002 Royal Society of Chemistry.

Similarly to PTC, inverse phase transfer catalysis (IPTC) has also been developed by Mathias and Vaidya.108 Though not as commonly exploited as PTC, it further expands the potential use of phase transfer reactions. In IPTC, similar to PTC, a lipophilic substrate is transferred into the aqueous phase by the catalyst and the reaction takes place in the aqueous phase. Pyridine derivatives such as DMAP are popular catalysts due to their low cost but also cyclodextrins,109,110 calixarenes,111 and, as shown in the following example, surfactants are applicable. Boyer and co-workers used the surfactant dodecyltrimethylammonium bromide as catalysts for IPTC. They evaluated the influence of the stirring speed on the epoxidation of chalcone by hydrogen peroxide and observed two different mechanisms of reaction: at low stirring the reaction occurs via the inverse phase transfer catalysis (IPTC) while upon emulsion formation via ultrasonic stirring interfacial catalysis (IC) takes place.112 In IPTC the reaction takes place in micelles. In IC the substrates react at the interface (Figure 13). Under ultrasonic mixing the reaction proceeded faster than under mechanical stirring, due to the production of a larger surface area. Furthermore, it was proven that under these conditions surfactants can be used in catalytic amounts since micelle formation is not necessary. Besides emulsification methods, an increase of the interface for a successful PTC reaction can be achieved by droplet-based microfluidics generating discrete droplets from femtoliter to nanoliter volumes in a continuous carrier phase. The exceptionally high surface-to-volume ratio and internal flow circulation enable an effective mass transfer and a rapid conversion. This has been shown for the synthesis of benzyl phenyl ether catalyzed by tetrabutylammonium bromide (see Figure 14).113 The examples above have shown that emulsion formation is beneficial for reactions with reagent incompatibility. PTC is often susceptible to a decrease in reactivity over time and respectively the yield as the phase transfer agent can partition completely into the organic phase forming an ion pair with the lipophilic anion. As a consequence, the phase transfer agent is hindered to carry more anions from the aqueous phase to the

organic phase for reaction. In this case the use of microemulsions can be of advantage. In microemulsion reactions, the substrates are not transferred from one medium to another, but rather, the reaction is confined at the oil−water interface. The interfacial area in microemulsions is very large and can reach values as high as 105 m2/L.114 Microemulsions can be applied both in combination with PTC, yielding even higher reaction rates, but even without it they can be superior to conventional biphasic reaction media.115−117 Microemulsions have been applied in several types of reactions such as nucleophilic substitution reactions,118 esterifications,119 alkylations,120 and oxidations of hydrophobic substrates.121,122 Reagent incompatibility is a major issue for many organic reactions. When PTC is not possible, often polar aprotic solvents, such as DMSO or DMF, are used. However, these solvents are difficult to remove and mostly toxic. Microemulsions and emulsions in general might be another approach for this problem. For this reason, Jiang and Cai exploited the microemulsion for the copper- and ligand-free Sonogashira reaction and the ligand-free Heck reaction of iodobenzene and styrene.123,124 The microemulsion was beneficial for several reasons: surfactants stabilized the Pd nanoparticles acting as the catalyst but also enlarged the interfacial area, lowering mass transfer resistance. Water in the five-component microemulsion accelerated the Heck reaction promoting the migratory insertion step and overall a mild reaction environment with high conversion and selectivity was provided. Zayas et al. performed the Heck reaction in miniemulsion resulting in high yields compared to neat toluene or DMF (99% in miniemulsion compared to 0% in toluene and 51% in DMF), and high control in stereoselectivity (>90% E-isomer).125 Dark-singlet oxidation of the poorly reactive species 1,4,5trimethylnaphthalene in a three-liquid-phase microemulsion was performed with “balanced catalytic surfactants” based on double-tailed quaternary ammonium salts and molybdate counterions (see Figure 15).122 The upper oil phase and the 2148


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Figure 14. Schematic representation of PTC reaction in a droplet-based microfluidic device. From left to right: Overview of the microfluidic chip device, product formation by PTC while the organic droplets travel through water in the hydrophilic microchannels. Adapted with permission from ref 113. Copyright 2012 Royal Society of Chemistry.

interfacial zone accelerates or impedes the reaction speed. ́ ó et al. showed that for SN1 type solvolysis reactions Garcia-Ri the intrinsic rate constant decreases with lowering the water ratio since the polarity of the interface also decreases.129 SN2 reactions, on the contrary, are accelerated due to a stronger nucleophilicity of the interfacial water. The differences in kinetic behavior in the nucleophilic substitution of 4-tertbutylbenzyl bromide and potassium iodide in oil/water microemulsion was also attributed to the role of water activity in the interfacial zone.130 The reaction is assumed to occur only inside the surfactant layer and rates were dependent on the surfactant type. A possible explanation is that the sugar-based octyl glycoside as surfactant gets more hydrated than dodecyl ethoxylate and thus the dielectrical constant changes in the interfacial zone. As already mentioned, the more polar reaction environment retards this type of SN2 reaction. In a following study using 127I NMR spectroscopy measurements, it was shown that there is a temperature-dependent accumulation of iodide at the oil/water interface.131 In bulk, a rise in temperature accelerated the reaction. In microemulsion, however, a decrease at elevated temperatures was observed due to a decrease of iodide at the interface. The unexpectedly high reactivity in microemulsion could be therefore attributed to the accumulation of the iodide at the interface. With dodecyl ethoxylate as the surfactant the iodide is less solvated at the interfacial layer, rendering it more nucleophilic. Besides rate acceleration, the mechanism of a reaction can ́ ó and also be influenced by the microenvironment. Garcia-Ri co-workers studied the kinetic behavior of butylaminolysis of 4-nitrophenyl caparate in bis(2-ethylhexyl) sulfosuccinate (AOT)/chlorobenzene/water microemulsions.132 They observed a first and second order dependence on the butylamine concentration caused by the reaction pathways at the interface and in the continuous medium. This kinetic behavior was attributed to the rate-determining step of the reaction which is different at the interface and in bulk. At the interface the ratedetermining step is the formation of the addition intermediate whereas in the continuous phase, it is the base-catalyzed decomposition of this intermediate. For solvolysis of benzoyl halides, the same group observed that a change of water ratio in the microemulsion alters the mechanism of solvation by means of either an associative or dissociative pathway.133,134 Mechanistic changes depending on the water ratio have also been reported for other solvolytic reactions, ester hydrolysis, and nucleophilic aromatic substitutions.135,136 Reactions confined at the interface are susceptible to changes of this interface. Increase or decrease of the droplet size as well as changes in the surface polarity by altering the solvent ratio or surfactant and cosurfactant concentrations influence the solubility of the reactants and the reaction kinetics. Shrikhande

Figure 15. Schematic representation of dark singlet oxygenation of substrate S in a three-liquid-phase microemulsion. Reprinted with permission from ref 121. Copyright 2008 American Chemical Society.

aqueous excess phase act as reservoirs for the reactants while the reaction itself takes place solely in the interface. This system benefits from the existence of these two interfaces as only there the reactants can meet. Engberts and co-workers observed an acceleration of a Diels−Alder reaction between cyclopentadiene and N-ethylmaleimide in microemulsion with increasing water content compared to pure isooctane.126 The rate enhancement was explained by hydrogen bond stabilization of the activated complex and enforced hydrophobic interactions.127 An accelerating effect in microemulsion was also reported for 1,3-dipolar cycloaddition of benzonitrile oxide to N-ethylmaleimide by the same group.128 An increase of the local concentration of the reactants due to confinement at the interface is one reason for the rate enhancement. Furthermore, electrostatic interactions with the negatively charged headgroups of the surfactant cause a destabilization of the negative charge of the benzonitrile oxide and favors the 1,3 dipolar cycloaddition (Figure 16).

Figure 16. (a) Orientation of benzonitrile oxide in microemulsion; (b) destabilization of the negative charge of benzonitrile oxide due to the negatively charged environment causing reaction rate acceleration. Reproduced with permission from ref 128. Copyright 2006 American Chemical Society.

Depending on the type of reaction, increasing the water ratio in a microemulsion and thereby changing the polarity of the 2149


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and co-workers showed that for the condensation of benzaldehyde and acetone in cationic o/w microemulsion an increase of oil and cosurfactants ratio lowered the reaction rate.137 This was correlated to an increase of droplet size and thereby less interfacial area. An increase of surfactant concentration also had a negative influence on the reaction rate since less space for the reactant at the interface is left. Additionally, the water content on the interface may increase with growing polarity and also occupy the space. By this the authors showed that the reaction takes place at the interface as otherwise these effects would not have been observed. Similar findings were made for the furfural/cysteine reaction as a model for the Maillard reaction.138 To understand and control the Maillard reaction is especially important for the food industry as it is involved in the process of flavor generation. Rate enhancement in o/w microemulsion compared to bulk water was found. It was suggested that the reaction is mainly compartmentalized at the interface rather than in the continuous medium since a change of the overall concentration of the reactants did not affect the rate. Furthermore, lower activation energies were determined for the o/w microemulsions compared to water and water/propylene glycol mixtures. The authors proposed that the interface could force the molecules to obtain already the specific configuration or orientation needed for reaction. Interestingly, for silica microcapsule formation in water/oil/ water (w/o/w) emulsion systems (aqueous solution of sodium silicate/ n-hexane with surfactants/aqueous solution with precipitant), the choice of precipitant (NH4HCO3 and NH4Cl) influences whether the reaction takes place at the outer or inner interface.139 However, the authors did not provide any explanation for this phenomenon. Already in the 1970s, it was found that during this preparation method for inorganic particles several factors can influence the mechanism. For example, calcite is the common modification for CaCO3 under ambient conditions, but vaterite formation was observed in a w/o/w emulsion system. The authors showed that vaterite formation was dependent on the surfactant concentration, and their HLB values.140 Since vaterite transforms to calcite upon contact with water, vaterite fraction increases with increasing surfactant concentration shielding vaterite from water. However, above the critical micelle concentration (cmc) the vaterite fraction decreases again, since a thick surface layer hinders the internal water from the w/o/w emulsion to escape, increasing thereby the contact time of water with vaterite. Why vaterite is formed initially was not explained by the authors and this topic could already reach in the field of solid liquid interactions, which is beyond the scope of this review. In general, various types of inorganic nanoparticles can be synthesized in emulsions in an “oil−water interface-controlled reaction”. Metal cations (e.g., Ba2+) added to an o/w (oil/water) microemulsion accumulate due to Coulombic attraction to negatively charged surfactants at the interface and due to a stronger solvation in the polar media.11 Upon addition of a precipitating agent (e.g., CrO42−), this balance is destroyed by reaction of the ions leading to precipitation of small particles at the interface. The authors propose two possible pathways for reaction. Either the anions react with the cations close to the interface or the reaction occurs at the interface of two colliding droplets. In the latter case, the anions react with cations from both interfaces. Recent reviews by Rao et al.10 and Munoz-Espi ́ et al.91 summarize the features of crystallization processes at liquid− liquid interfaces.10,141

For biomolecular engineering, liquid−liquid interfaces constitute an interesting platform for various fields ranging from biomedical applications to food industry. Proteins adsorb spontaneously at the interface, and the more rigid the ternary structure, the stronger the interfacial networks that are formed.142 Upon adsorption, proteins partially unfold exposing residues which are inaccessible under normal conditions, for example, free thiol residues or hydrophobic patches. Proteins are thus used as surfactants in the food and cosmetics industry; native proteins typically do not possess surfactant properties, only the contact with an interface (water−air or water−oil) leads to partial denaturation and rearrangement, allowing their use as surfactants. In nature, several enzymatic reactions, such as the digestion of fat, proceeding at the liquid−liquid interface, can be found. As already discussed, enlarging the surface can increase the reaction speed and efficiency. Furthermore, structural differences induced by the interface also play a role. Upon confinement at the interface, it has been shown that lipase experiences an enhanced activity which could be the result of a rearrangement and displacement of the lid covering the active site.143 Maximal activity for lipases is observed in emulsions rather than in bulk media.144,145 Nature has already recognized this, since most dietary fats are consumed in an emulsified form (milk) or emulsified in the mouth, stomach or intestine.146 However, the structure of the lipid−water interface is also crucial for lipase activity.147 With obesity levels increasing worldwide, prolonging lipid digestion to reduce hunger and hence energy uptake could constitute an effective method for long-term weight reduction. For regulating lipase activity at the interface, a study of the efficiency and rate of lipolysis of olive oil was performed.148 Therefore, the physicochemical nature of the interface at which this reaction occurs was altered by different kinds of lipids stabilizing the emulsion. While monogalactosyldiacylglycerol (MGDG) did not show any inhibitory effect, digalactosyldiacylglycerol (DGDG) slowed down the lipolysis. It was argued that the large digalactosyl headgroup of DGDG sterically hinders the adsorption of lipase and colipase at the interface. Incorporation of lecithin, however, altered the organization of the closely packed structure of DGDG at the interface and interfered with the headgroup interactions, favoring lipolysis again (Figure 17). Additionally to these steric reasons, lecithin is assumed to facilitate the opening of the pancreatic lipase lid domain and to stabilize the active conformation.

Figure 17. Schematic representation of lipolysis at the oil/water interface. Reprinted with permission from ref 148. Copyright 2009 American Chemical Society. 2150


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Cationic Polymerization. For cationic polymerizations, the ideal reactions conditions are normally at the lowest possible temperature (especially for vinyl monomers) to reduce transfer reactions.152 This has been the greatest challenge in cationic heterophase polymerization during the last 15 years. The Lewis acid Yb(OTf)3 was the first water-tolerant catalyst to polymerize p-methoxystyrene (pMOS) in aqueous suspension or emulsion at 30 °C.153−156 For the cationic polymerization at the droplet/particle interphase, a combination of initiator and surfactant (INISURF) was used.157 The reaction is initiated by the surfactant: typically a hydroxyl group of the surfactant and the resulting active species associates with the anionic counterion of the surfactant. The chain growth proceeds at the interface until it is terminated by water. Bulkiness of the ion pair as well as hydrophobicity of the surfactant influences the polymerization rate. Cauvin and co-workers used dodecylbenzenesulfonic acid as the INISURF for the cationic polymerization of pMOS in miniemulsion.158 However, only oligomers with Mn’s < 1000 g/mol were achieved due to the decreasing surface activity of the dormant species with increasing chain length. The same group obtained higher molecular weights (up to 3000 g/mol) in an inverse miniemulsion by combining dodecyl benzenesulfonic acid with the Lewis acid Yb(OTf)3 as the initiator. The authors propose that the triflate anions generate a bulky strong Brønsted superacid H+Yb(OTf)−4 that acts as the initiator. Chain growth appears rapidly and the termination reaction is reduced due to the increasing hydrophobicity of the interface caused by the oligomers.159 Still, these systems suffer from a high termination rate producing only oligomers. The hydrophobicity of the growing polymer chains results in a loss of their surface activity (commonly referred to as the “critical DP effect”160). For this reason, research has been focused on transferring the chain growth from the interface to the droplet core by designing Lewis acid-surfactant combined catalysts (LASC).156 The solubility of LASC in the monomer phase is enhanced through an electrosteric surfactant bearing poly(ethylene glycol) chains which repel the ligated water from the ytterbium atom161 (see Figure 18). A weak organic base is used as the initiator generating bulky superacids through association with the LASC. The authors obtained for the polymerization of pMOS Mn’s up to 40 000 g/mol after 100 h reaction time but no control over polymerization was achieved. Recently, Vasilenko and co-workers presented an optimized LASC with a hyperbranched sodium dodecyl benzenesulfonate as the complexating surfactant.162 Compared to the latter, this system is not only suitable for the cationic emulsion polymerization of pMOS but also of styrene and isoprene. For all three monomers, the polymerization was completed in less than a day and exceptionally high molecular weights were achieved (up to 30 000 g/mol for pMOS, up to 190 000 g/mol for styrene, and 100 000 g/mol for isoprene). Extension of this method to additional monomers, fast reaction times, and high molecular weights constitute undoubtedly an advantage of this catalyst system. However, also with this new LASC the cationic polymerization does not proceed in a controlled manner resulting in broad molecular weight distributions (all above 1.7, in most cases above 3). Sawamoto et al. used BF3OEt2, coupled to the adduct of water and pMOS, as the initiating system for the cationic polymerization of styrene derivatives, such as p-hydroxystyrene without the need of protecting groups.163 Interestingly, the polymerization proceeds in a controlled fashion when a large

Thus, by modifying the DGDG/lecithin ratio at the emulsion interface a regulation of lipolysis is possible, and these findings could contribute to the regulation of dietary fat uptake and the treatment of obesity. Polymerizations at the Droplet Interface

Besides the synthesis of low molecular weight compounds, polymerizations can also be performed in a liquid−liquid biphasic reaction medium. In contrast to the examples mentioned above, polymerizations, especially chain-growth polymerization, are limited in two phases, due to transfer and termination reactions. This is especially obvious if water is one phase and cationic or anionic polymerizations are considered. Alternating radical copolymerization or metathesis polymerization tolerate water and are examples for beneficial properties of the interface to the product formation. With confinement to the interface not only more complex structures with stimuli responsiveness can be produced (as shown in the examples below) but also higher reaction rates and yields in aqueous emulsions have been reported in certain cases.149 Polycondensation and polyaddition, e.g. Nylon (see above), or the crosslinking of multifunctional nucleophiles, such as starch, with diisocyanates are interesting examples of interfacial polyreactions that lead mainly to nanocarriers (see below). This section will summarize the basic principles of different reaction types that can be conducted at the interface of two immiscible liquids that are ionic and radical polymerizations, and polyadditions/polycondensations. The current trends and challenges of each platform will also be discussed using selected examples. Ionic Polymerizations

Classical anionic and cationic polymerization are very sensitive to traces of water and other impurities in the reaction media and are therefore carried out under strictly anhydrous conditions.150 The use of two solvents and possibly surfactants (carrying functional groups) is an obvious challenge for ionic polymerization. Especially aqueous emulsions seem to be challenging. Ionic polymerization in emulsion has been achieved due to faster reaction kinetics inside of an organic droplet than the hydrolysis of the active chain end to produce rather low molecular weight polymers. For a reaction at the droplet interface with two immiscible monomers the reaction conditions are yet to be established. However, there are several reports in the literature relying on rather conventional polymerization conditions inside of emulsion droplets; also an increasing number of catalytic systems that are stable in aqueous environment have been developed, enabling the use of less strict and simpler experimental conditions.151 However, as many more examples for other polymerization techniques (discussed in the following sections) are currently available, even the development of novel catalysts for ionic polymerization makes the benefits for heterophase polymerizations (and especially for reactions at the droplet interface) questionable. In bulk or homogeneous solution ionic polymerization is still the best controlled platform for polymers with an almost monomodal molecular weight distribution, the avoiding of heavy metal catalysts, and allows direct access to block copolymers. This is definitively a great benefit for ionic polymerization compared to all controlled radical polymerization techniques. However, in heterophase polymerization this will probably not be enough to compete with the other techniques. 2151


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Figure 18. Structure of Lewis acid-surfactant combined catalyst (LASC). Reprinted with permission from ref 161. Copyright 2005 Royal Society of Chemistry.

Figure 19. Proposed polymerization mechanism for the polymerization of n-butyl cyanoacrylate in miniemulsion. Reprinted with permission from ref 176. Copyright 2003 American Chemical Society.

polymerization system in perfluoroalkane-in-oil emulsion has been developed by Schuster et al. to polymerize isobutylene.169 Mn’s of over 20 000 g/mol were achieved and it was suggested that the system could be applied also for the polymerization of 2-oxazolines or epoxides. Anionic Polymerization. The number of reported anionic polymerizations in emulsion or heterophase, similar to cationic polymerization, in general is limited. This is due to the high sensitivity of the propagating species toward water. Nevertheless, living/controlled polymerization is highly desired, since well-defined polymers with narrow molecular weight distributions can be obtained. Anionic emulsion polymerization has mostly been reported for the ring-opening polymerization (ROP) of cyclic siloxanes,170,171 glycidyl ethers,172,173 and the polymerization of cyanoacrylates.174,175 The polymerization of n-butyl cyanoacrylate (BCA) in miniemulsion was conducted in the presence of dodecylbenzenesulfonic acid (DBSA). The surfactant releases protons at the interface and thus slows down the interfacial anionic polymerization of n-BCA through (reversible) termination reactions (see Figure 19). Fair control of oligomer generation is exerted, but in all experiments the final oligomer distribution is composed of three to five units

excess of water over BF3OEt2 (6 to 100) is used. The polymerization operates via the reversible dissociation of the aliphatic C−OH bond by BF3OEt2, and it is assumed that water plays the role of a chain transfer agent.164 High molecular weights (Mn up to 15 000 g/mol) were achieved but the polymers exhibited a broad distribution (Đ ≈ 2).165 Instead of BF3OEt2, which slowly hydrolyzes in water,151 B(C6F5)3 has been used as the co-initiator for the controlled polymerization of styrene,152,166 cyclopentadiene,167 or isobutylene168 as B(C6F5)3 is a known water-tolerant Lewis acid and forms aqueous adducts.166 The research toward cationic polymerizations insensitive to moisture as described herein represents major progress for implementation of this technique in industrial processes. An advantage of cationic polymerization is the polymerizability of industrially important monomers such as styrene, cyclopentadiene or isobutylene, and fast reaction rates. To date, however, compared to anhydrous conditions, the polymers are often broadly distributed or high molecular weights are not always accessible. To circumvent the use of water but still benefit from a disperse system, reactions in organic emulsion could be envisioned. For example, a nonaqueous emulsion 2152


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Figure 20. Proposed mechanism for AROP of PGE in miniemulsion. Adapted with permission from ref 172. Copyright 2000 American Chemical Society.

due to the interfacial polymerization/depolymerization. The prepared particles are destabilized by Ostwald ripening of the partly water-soluble hydroxylated oligomers. When sodium hydroxide was added after the sonication the formation of longer polymers (up to 1200 g/mol) and higher particle stability was achieved.176 For biomedical applications, the anionic polymerization of alkyl cyanoacrylates at the interface of emulsion droplets is the employed method to produce partly biodegradable nanocapsules due to the hydrolysis of the pendant side chain.20,177 Musyanovych et al. obtained poly(n-BCA) nanocarriers with encapsulated DNA via the anionic polymerization of n-BCA initiated by water at the interface of water-in-oil droplets of an inverse miniemulsion.174 Cyclosiloxanes are reactive monomers and start to polymerize at the interface until the growing chains collapse into the particle core. For this reason, high molecular weights are limited, similar to cationic polymerization, through the critical DP effect. Condensation and transfer reactions lead to an increase in molar mass but also to a broadening of the MWD.176 Barrère et al. compared the anionic ring-opening polymerization (AROP) of octamethylcyclotetrasiloxane in aqueous miniemulsion and in bulk.178 At up to 70% conversion they obtained a narrow MWD in miniemulsion and molar masses up to 30 000 g/mol. Initiation, propagation, and reversible termination occur at the interface. Backbiting reactions also occur similar to the bulk polymerization, but in contrast to the latter, predominantly small cycles (four to five membered rings) are produced which can be removed. As backbiting takes place at the interface, steric constraints through ion-pairing limit the size of the rings and macrocycles as found in bulk polymerization were not observed. For 1,3,5-tris(trifluoropropylmethyl)cyclotrisiloxane, Barrère and co-workers even obtained higher yields than in bulk or solution

polymerization as backbiting reactions were suppressed through the steric hindrance of the surfactant.170 Maitre et al. investigated the minimemulsion polymerization of phenyl glycidyl ether (PGE) initiated by didodecyldimethylammonium hydroxide acting as an inisurf, i.e., exhibiting both surface-active behavior and a hydroxyl group for the initiation of the AROP. Stable miniemulsions were obtained by ultrasonication and α, ω-dihydroxylated polyethers were produced.172 The authors compared the miniemulsion with the bulk polymerization: besides the expected initiation, propagation, and termination steps that were found in both systems, additional transfer reactions did not occur in miniemulsion. After termination, the resulting oligomers with hydroxyl end groups possess high affinity to the surface when the chains are short enough (see Figure 20). It is assumed that they act as a costabilizer increasing the solubility of PGE in the interfacial layer. Thus, when a certain oligomer concentration is reached, propagation over termination is favored leading to a sudden increase in polymerization rate after 30% conversion. Nevertheless, low molecular weights are obtained as only a few chains are left propagating at this degree of conversion and having reached a degree of polymerization of ca. eight, they lose their surface activity. From these results it is proposed that surfactants stabilizing the oligomers at the interface could therefore help to achieve higher molecular weights. Another example for an AROP in direct emulsion with the monomers as the disperse phase was reported by Rehor and coworkers.179 They showed that episulfides can be polymerized through a living mechanism, possibly caused by the high nucleophilicity of the sulfide chain ends. The monomer and initiator were dispersed with pluronics as the surfactant in water and initiated by the addition of DBU to the aqueous phase which initiated the polymerization at the interface. Only low monomer conversion was obtained, which was mainly 2153


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Figure 21. Anionic polymerization of episulfides in emulsion and postfunctionalization approaches. Reprinted with permission from ref 179. Copyright 2002 American Chemical Society.

attributed to viscosity effects by the authors. Alternatively, the reason may lie in a preliminary consumption of the initiator. In this case the addition of a higher amount of initiator could have led to full conversion. However, as in the living polymerization the end-groups remain active, chain extension by the bifunctional end-capper divinylsulfone or an end-functionalization of the polymer chains was envisioned (see Figure 21). In a later study the same group showed that the low molecular weights are due to disulfide impurities, acting as a chain transfer agent, thereby lowering the degree of polymerization.180 Nevertheless, the possibility of attaching bioactive groups to the surface of polysulfide particles or loading of sensitive compounds and subsequent release by oxidation of the polysulfide could make these materials appealing for biomedical purposes. Under similar conditions, Endo and co-workers grafted polysulfides to human hair under aqueous conditions, relying on the high reactivity of the sulfide anions.181 Alternatively, to avoid disulfide formation, and to gain higher control over the molecular weight distribution, 2,2′(ethylenedioxy)diethanethiol can be used as the initiator, with which intramolecular disulfide formation is less likely.182 In this case AROP in emulsion has a controlled character leading to polymers with narrow molecular weight distribution (Đ = 1.1 instead of 1.4−1.6 in the presence of disulfides). With this method stimuli-responsive polysulfide nanoparticles with a homogeneous cross-linking density were obtained. Due to the high susceptibility of the anionic propagating species, emulsions with water as the disperse or as the continuous phase will remain challenging for any anionic polymerization.

A growing environmental concern and increasing application of polymers in pharmaceutical and medical fields are creating a demand for environmentally and chemically benign solvents.186 As radical polymerizations are in general robust and also proceed under “wet” conditions, they represent an attractive platform to be performed in aqueous emulsion. Radical polymerizations in aqueous dispersions have therefore experienced rising interest for industrial production. Free Radical Polymerization. In free radical polymerization, the alternating copolymerization in particular is an interesting example where the benefits of an interfacial reaction can be shown. Wu and co-workers synthesized aqueous-core capsules in an inverse emulsion by alternating copolymerization of hydrophobic maleate esters with hydrophilic poly(hydroxy vinyl ethers) analogous to classical interfacial polycondensation (see Figure 22).187,188 The polymerization is constrained to proceed at the oil−water interface due to the low solubilities of the hydrophilic/hydrophobic monomers in the respective phase and the reluctance of each monomer to homopolymerize. Therefore, the conversion and the polymerization kinetics are limited by the monomer diffusion to the interface. As a consequence, full conversion is only possible at low monomer concentrations having in turn an impact on the capsule shell thickness and permeability. The main drawback of free radical polymerization in a disperse system remains the poor control over particle size and morphology. During the synthesis of capsules, for example, full particles are also obtained to a certain degree as especially at high monomer concentrations homogeneous nucleation occurs. As showed by the example above, it is important to confine the reaction at the oil/water interface. Cao et al. observed that for polystyrene nanocapsules, the proportion of capsules over particles can be increased by using N-isopropyl acrylamide (NIPAM) as a comonomer and with reaction temperatures above the lower critical solution temperature (LCST) of polyNIPAM.189 At the reaction temperature of 70 °C pNIPAM is neither soluble in water nor in oil and the pNIPAM oligomers phase separate at the oil droplet/water interface and promote the interfacial free radical polymerization. The thermoresponsiveness of pNIPAM was also employed by Sun

Radical Polymerization

While examples of ionic polymerization in dispersion and at the interface of immiscible liquids are quite scarce, a plethora of radical polymerizations in disperse phase can be found. For detailed discussions about radical emulsion polymerization, the reader should refer to the excellent and detailed review articles and literature therein covering the developments in the field of (controlled) radical polymerization in heterophase until 2008.183−185 2154


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NIPAM monomer was first dissolved in the aqueous phase and a w/o emulsion with toluene was generated. A redox initiating system with benzoyl peroxide in the oil phase and tetraethylenepentamine in the water phase was used to generate free radicals at the oil/water interface. The polymerization of NIPAM thus started spontaneously at the interface. At reaction temperatures above the LSCT pNIPAM is insoluble in both phases and consequently a pNIPAM layer at the interface is formed. Divinylbenzene was then used to cross-link the pNIPAM layer. Thereby, thermoresponsive hollow microspheric structures were formed with diameters from 1 to 3 μm and wall thicknesses of 100 nm. Sarkar and co-workers obtained polymer capsules with a hydrophobic poly(tert-butyl acrylate) shell and a hydrophilic poly(allylamine) interior by interfacial free radical polymerization in inverse miniemulsion.191 In the water phase hydrogen peroxide initiates the formation of a radical from the watersoluble amine polymer. The macroradicals act as emulsifier molecules and assemble at the water/oil interface. The propagation reaction with the hydrophobic acrylate monomers occurs for this reason exclusively at the water/oil interface. With a difunctional cross-linker in the oil phase narrowly dispersed polymer nanocapsules were obtained. Subsequent hydrolysis of the tert-butyl group under mild conditions allows the formation of an amphiphilic shell surface for further functionalization. Polycondensation and Polyaddition

Interfacial step-growth polymerization is one of the most applied approaches in the preparation of micro- and nanocapsules, going back to the early works of Chang for encapsulation of aqueous solutions of proteins within polymer shells.192 Ideally for capsule formation, the reaction of two monomers, each soluble in one phase of a biphasic system, begins at the interface of the two liquids and the resulting polymer is insoluble in either phase, precipitating at the interface, forming the capsule wall. Whereas, when the reaction locus is shifted to the droplet core, particles are obtained. It was proposed to divide the process of capsule formation by interfacial polycondensation in three steps: the initial polycondensation period, primary membrane formation and subsequent wall thickening.193 The author proposes that shell properties can be influenced by variation of the solubility parameters in the

Figure 22. Top: Alternating interfacial free-radical polymerization of miniemulsion oil droplets (I) to form liquid-core polymer capsules (II) via (b) alternating copolymerization of dibutyl maleate (1) and hydrophilic PEG-divinyl ether 2, initiated with surface active initiator 3 at the oil/water. Bottom: (A) Fluorescence image of dehydrated aqueous-core capsules. (B) Confocal image of the horizontal cross section of the particle shown by the arrow. Adapted with permission from refs 187 and 188. Copyright 2005,2006 American Chemical Society.

and Deng to synthesize hollow microspheres (see Figure 23).190 An interfacial polymerization process was developed based on the property of pNIPAM that it turns hydrophobic above the LCST and hydrophilic below this temperature. Therefore, the

Figure 23. Left: Synthesis scheme of temperature sensitive hollow microspheres via free radical polymerization in inverse emulsion. Right: scanning electron microscopy images of pNIPAM microspheres; A: overview picture (scale bar 2 μm); B: cross section (scale bar 1 μm). Adapted with permission from ref 190. Copyright 2005 American Chemical Society. 2155


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Figure 24. (A) Synthetic scheme applied in the production of polyurea, polythiourea, and polyurethane nanocapsules in an inverse miniemulsion system, which could be further applied for reduction of silver nitrate; (B) polyurea nanocapsules and (C) polyurea nanocapsules produced with double amount of monomers in comparison to panel B. The increase of the shell thickness is evidenced. Adapted with permission from ref 194. Copyright American Chemical Society.

system and swelling ability of the solvents for the forming polymer. Furthermore, the rate of precipitation of polymer chains, i.e., rate of polycondensation can control the shell morphology. A low rate of polymer precipitation leads to a more uniform and denser capsule wall. Further growth of the shell membrane is dependent on the diffusion of at least one of the monomers to the other. For the development of capsules on a nanometer scale via interfacial polyreactions, miniemulsion has been used in diverse works, with both inverse and direct miniemulsions, and stepgrowth reaction approaches have been applied in the preparation of linear as well as cross-linked polymeric films at the interfacial region. Based on this strategy, the chemistry of polyurethanes and polyureas stands out. Crespy et al.194 studied systematically the synthesis of polyurea, polythiourea and polyurethane nanocapsules by interfacial polycondensation and cross-linking reactions. They used an inverse miniemulsion to produce hollow nanocapsules (Figure 24A). The authors investigated the influence of the nature of the monomers and the continuous phase on the formation and morphology of the

capsules. Control over size could be gained by the rate of addition of the second monomer. It was proposed that a slower addition could allow rearrangements in the conformation of the polymer forming the shell leading to larger hydrodynamic diameters. Besides, with control of the amount of the monomer in the disperse phase (in the case diethylenetriamine) the wall thickness was also controlled (Figure 24B,C) and these capsules were further applied as nanoreactors in the reduction of silver nitrate. Gaudin and Sintes-Zydowicz195 studied the effect of the droplet size in the molecular and thermal properties in polymer shells of poly(urethane-urea) nanocapsules. The authors used a direct miniemulsion and compared the properties of the formed membranes at droplets of 70 or 200 nm, concluding that no influence in the final chemical properties of the shell was observed, obtaining polymers in both cases with molar masses of around 2000 g mol−1 due to the inevitable hydrolysis of the diisocyanate monomer. The fact that miniemulsion systems can show large size distribution, a point not discussed in detail in the presented work, together with the use of a small difference 2156


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Similarly to Polenz and co-workers, Wagh et al. performed an experimental study of polycondensation reactions at the oil/water interface for polyurea microcapsule production.198 They observed a solvent dependency of the reaction kinetics, concluding that the reactions takes place on the organic solvent-side (i.e., from the disperse phase) of the interface and thus the polarity of the organic solvent is responsible for rate acceleration. Condensation reactions at the interface are suitable for a broad range of applications and capsule materials. For example, they have also been applied in the preparation of inorganic shells at the surface of droplets in miniemulsion. Fickert et al.199 produced silica nanocapsules containing thiol or amine groups at the surface using a direct miniemulsion. Hydrolysis occurred at the interface between the continuous phase (water) and the droplets composed of the monomers for the shell formation, originating the condensation reaction for the formation of the silica membrane (Figure 27). The droplets also contained a hydrophobe, a self-healing monomer and catalyst. A second approach was applied were one monomer was first dispersed in the organic droplets and a second monomer was added dropwise after emulsification. In both systems similar size and size distribution were obtained and thickness of the shell could be controlled upon control of the formulation. Another important option for the production of polyurethane capsules, but with less side reactions and no polyurea formation, was achieved by the use of nonaqueous emulsions. Crespy and Landfester reviewed the use and preparation of nonaqueous (mini)emulsions and their possible applications.200 The reaction between diisocyanates and diols was performed in inverse miniemulsions with a solution of the diol dissolved in formamide as the disperse phase and cyclohexane as the continuous phase. After the polyaddition at the interface, hollow morphologies were obtained (Figure 28A);194 when the diols were purely used as the disperse phase, solid nanoparticles (Figure 28B) were prepared.201 Besides the reduction of side reactions in hydrolysis-sensitive mixtures, nonaqueous emulsions can also be applied in polymerizations which require high temperatures. For such application, ionic liquids, with their characteristic low vapor pressure and thermal stability, are perfect candidates to be one the components of the emulsion. Frank et al.202 synthesized polyimide nanoparticles (Figure 28C) by the heterophase polycondensation of aromatic tetracarboxylic acids and diamines in an imidazolium-based ionic liquid as the continuous phase, being able to produce the miniemulsion without the need of a surfactant, due to the amphiphilic character of the ionic liquid. The authors prepared polyimide nanoparticles with average diameter of 100 nm and the synthesis was completed in 10 h at 190 °C. The importance of the isocyanate chemistry at the interface in the preparation of nanocapsules is obvious by the number of different works found in the literature.203−207 The highly reactive isocyanates enable a fast nucleophilic addition that occurs at the interface rather selectively to form hollow structures (compare above). Especially the polyaddition of toluene diisocyanate (TDI) and different biopolymers in miniemulsion has been studied to generate nanocapsules for biomedical applications. Taheri et al.208 produced hybrid nanocapsules based on starch and TDI as the cross-linker loaded with silver nanoparticles (Figure 29), producing nanocapsules with mean diameter between 290 and 370 nm and different shell thicknesses, depending on the concentration of TDI.

in the average droplet size and the use of a direct miniemulsion, with water in a high concentration and therefore with an increased rate of hydrolysis, make this conclusion still a matter of discussion. The kinetics of the polymeric shell formation by interfacial polycondensation has also been discussed in the literature. Zhang et al.196 evaluated the kinetics and modeled the formation of waterborne polyurethane shells in direct miniemulsions, relating diffusion processes through the formed polymer membrane and reactivity of the monomers. A schematic representation of the model is shown in Figure 25.

Figure 25. Schematic representation of the kinetic model applied by Zhang et al.196 in the study of the kinetics of waterborne polyurethanes. The zone I is the capsule core, zone II is denominated as the capsule shell, zone III the aqueous solution, and zone δ as the reaction zone. Reprinted with permission from ref 196. Copyright 2012 Elsevier B.V.

While highly reactive aromatic isocyanates proved to exhibit a diffusion-controlled fast reaction, the moderate reactivity of aliphatic isocyanates resulted in a reaction-controlled process. More recently, Polenz et al.197 used microfluidic polydimethylsiloxane devices to monitor the kinetics of reactions at the interface of emulsion droplets. The polyurea shell formation was followed using the droplet deformation as the analysis parameter. A microfluidic chip with a series of expansionconstriction chambers was used and provided the capacity to follow the shell formation with a time resolution of the order of milliseconds. Figure 26A shows the isocyanates, amines and surfactants used in this work and Figure 26B presents a general scheme of the procedure applied for the kinetics measurements. This is a very interesting approach, first due to the time resolution obtained. The kinetics of polycondensations at the droplet interface is in general very fast and thus analysis techniques are limited. Furthermore, the authors conclude that different reactions laws are followed in direct and inverse systems and influence their behavior in relation to the concentration of both monomers and the reaction kinetics. While not providing an explanation, this work concludes that the component dissolved in the continuous phase has major influence in the reaction kinetics. The authors assume that the type of surfactant can also interfere by blocking the interface and interacting with the reactants. A reduction by a factor of 10 was observed with the use of sodium dodecyl sulfate (HLB-value ∼40) in comparison to a nonionic surfactant (Abil EM 90 with a HLB value of approximately 5). Influences on the reaction kinetics of interfacial polycondensation reactions seem to be a matter of discussion. 2157


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Figure 26. (A) Chemical structures of the monomers and surfactants applied in the study of microencapsulation dynamics of polyurea microcapsules; (B) Schematic representation of the microfluidic chip design for monitoring of the reactive encapsulation in direct and inverse emulsions and the measurement of the droplet deformation as a function of time. The scale bar is 50 μm. Reprinted with permission from ref 197.

The nanocapsules showed effective antibacterial properties against Staphylococcus epidermidis and Escherichia coli. Another example for a biopolymer used for the formation of nanocapsules by cross-linking with TDI is lignin (Figure 30). Hollow nanocapsules have been prepared, which were degraded in the presence of the enzyme laccase produced by certain fungi, generating a strategy for the development of delivery systems for agricultural applications.209 A similar approach was applied by Piradashvili et al.210 in the preparation of protein nanocontainers based on albumin and TDI, thus resulting in biocompatible and biodegradable nanocarriers that are uptaken and opened by dendritic cells. Even though the use of the polyurethanes and TDI chemistry is one of the most widespread approaches for the preparation of

nano- and microcontainers, some drawbacks are connected with this approach. In particular, there are limitations regarding the types of molecules which can be efficiently encapsulated through this strategy since the highly reactive electrophilic isocyanates can undergo unwanted reactions with the cargo if it is carrying additional nucleophilic groups as it is the case, for example, for biomolecules such as proteins and siRNA. In order to provide more efficient approaches for the formation of nanocapsules, different step-growth polymerization approaches have been used in miniemulsion. Various click reactions, which are designed as bioorthogonal reactions for protein/peptide or drug conjugation, can be used in aqueous systems and for the encapsulation of functional molecules.211 Therefore, the introduction of click chemistry for 2158


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preparation of glyco-nanocapsules using a copper catalyzed azide−alkyne (CuAAC) interfacial click approach in miniemulsion (Figure 31). In this work 6,6′-diazido-6,6′-dideoxysucrose was reacted with bis(propargyloxy)butane in a direct miniemulsion by copper-catalyzed Huisgen-cycloaddition. The reaction was conducted with or without the use of microwave heating to increase the kinetics of the reaction and nanocapsules with an average mean diameter of 200 nm with mygliol as a core were prepared.212 In this way hydrophilic cargo can be encapsulated in the carrier systems. Besides the fact that the monomers and the core of the formulation were biocompatible the use of the copper catalyst can be regarded as a potential drawback of this strategy as it is hard to remove completely after the reaction.213 Siebert et al.12 used a copper-free alkyne−azide click reaction at the interface of inverse miniemulsion droplets for the preparation of nanocapsules relying on electron deficient alkynes (Figure 32). The approach produced polymers with molecular weights up to Mw 33 600 g mol−1 in miniemulsion (lower than

Figure 27. Silica shell nanocontainers for self-healing applications prepared by Fickert et al. Reprinted with permission from ref 199.

the preparation of nanocapsules in miniemulsion is an attractive strategy for the encapsulation of biomolecules and therapeutic substances. Roux et al.212 presented an approach for the

Figure 28. Examples of step-growth polymerizations performed in nonaqueous emulsions: (A) polyurethane nanocapsules (Reprinted with permission from ref 194. Copyright 2007 American Chemical Society); (B) nanoparticles (Reprinted with permission from ref 201. Copyright 2011 Springer-Verlag); and (C) polyimide nanoparticles (Reprinted with permission from ref 202. Copyright 2009 American Chemical Society).

Figure 29. Schematic representation of the approach used by Taheri et al. for the preparation of starch nanocapsules loaded with silver nanoparticles. Reprinted with permission from ref 208. 2159


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Figure 30. (A) Schematic representation of the synthetic protocol applied in the synthesis of lignin-based nanocapsules by Yiamsawas et al.; (B) SEM (top) and TEM (bottom) images of the lignin-based nanocapsules cross-linked with different amount of 2,4-toluene diisocyanate (TDI). Reproduced with permission from ref 209.

Figure 31. (A) CuAAC polyaddition of 6,6′-diazido-6,6′-dideoxysucrose (1) with bis(propargyloxy)butane (2) for the formation of glyconanocapsules in miniemulsion; (B) SEM (top) and TEM (bottom) images of the nanocapsules produced in the cited “click” approach. Adapted with permission from ref 212. Copyright 2012 American Chemical Society.

the ones obtained in the solution approach (Mw 45 500 g mol−1) and nanocapsules with mean diameters of ca. 280 nm were obtained. Copper-free alkyne−azide click reactions are

generally dependent on temperature and relatively high temperatures are necessary for satisfactory kinetics (in this work 50 °C). This can be problematic when sensitive compounds 2160


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mechanism. In such a situation, only the increase of the local concentration is capable to explain the increase of the overall consumption of the monomer in the continuous phase. Besides the Huisgen cycloaddition, other click reactions at the interface can be used for the preparation of nanocapsules in miniemulsion, e.g., the thiol−ene polyaddition. Paiphansiri and co-workers215 produced glutathione-responsive DNA-based nanocapsules by the thiol−disulfide exchange and the thiol− ene click reaction for the preparation of biodegradable and fluorescent labeled systems, with potential for theranostic applications (Figure 34). Chen and co-workers216 used the thiol−ene approach in the preparation of chitosan nanocapsules through the cross-linking of N-maleoyl-functionalized chitosan, used both as a surfactant and precursor in the system, and bis(3-mercapto-propionate) as the cross-linker. As many other thiol−ene polymerizations, this reaction is initiated by UV-light and this is one of the main drawbacks for this reaction in miniemulsion. The scattering caused in the emulsion lowers the efficiency of the reaction, which probably explains the fact that the conversion was increased with the decrease of the droplet size. In addition, encapsulation of UV-sensitive materials is limited. The development of metathesis reactions in the presence of water could open up the way to the synthesis of polar polymers and biomolecules besides advantages in terms of security, economy and environmental friendliness. Reported reactions in the presence of water still proceed mostly inside the organic phase (see the minireview in ref 149), and the catalysts are designed to tolerate water. Nevertheless, since this reaction can be considered as bioorthogonal, it makes olefin metathesis a tool of high interest for the development of new nanocapsules for biomedical applications. Malzahn and co-workers217 presented a bioorthogonal interfacial olefin cross metathesis for the preparation of hollow dextran-alkylphosphate nanocapsules (Figure 35). The olefin metathesis is a reaction which can be performed at mild conditions and the use of phosphate-cross-linkers also offers the possibility of further addition of functionalities to the polymeric shell, as for example the addition of fluorescent units. EDX and ICP-OES analysis revealed efficient removal of the ruthenium

Figure 32. (A) Schematic representation of the alkyne−azide polyaddition approach studied by Siebert et al.12 between the diazide 2,2-bis(azidomethylene)-1,3-propanediol (BAP) and the alkynes 1,7octadiyne (OD), 1,4-diethynyl-benzene (DEB), and the activated alkyne 1,6-hexanediol dipropriolate (HDDP). Reproduced with permission from ref 12.

such as proteins or siRNA are encapsulated. However, studies of the cycloaddition reaction kinetics at the interface in miniemulsion performed by 1H NMR demonstrated the acceleration of the kinetics (Figure 33).214 This effect was attributed to the increase of the local concentrations at the droplet’s interface, allowing the use of lower temperatures (25 °C). This catalyst-free 1,3-dipolar cycloaddition can be additionally employed to generate a surfactant in situ which can be used for the stabilization of nanodroplets after ultrasonication (Figure 33A, bottom). The increase of the local concentration has been used to explain the effect on the kinetics of other cycloaddition reactions previously, based in the concepts described in the so-called pseudophase model. Engberts et al.128 studied the 1,3-dipolar cycloaddition between benzonitrile oxide and N-ethylmaleimide in microemulsions, observing an 150-fold and 35-fold increase of the reaction kinetics in comparison to the same reaction in pure isooctane or water, respectively, which were used for the preparation of the microemulsion. The authors attributed the increase to two factors: local concentration increase and electrostatic interactions due to the head groups of the ionic surfactant. In the case of the click chemistry presented in Figure 32, the use of a nonionic surfactant avoids the influence of charges in the reaction

Figure 33. (A, top) Schematic representation of the polymerizable system investigated in the analysis of the kinetics of Cu-free alkyne−azide cycloadditions in inverse miniemulsion; (A, bottom) in situ surfactant formation via the click reaction to stabilize a direct miniemulsion of styrene in water during radical polymerization to produce polystyrene nanoparticles; (B) Curves obtained for the consumption of the monomer 1,6-hexanediol dipropiolate against time, monitored through 1H NMR measurements at 298 and 323 K in an inverse miniemulsion system (red and black curves) and in solution (DMSO-d6, orange and blue curves). Reproduced with permission from ref 214. 2161


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Figure 34. (A) Schematic representation of the synthetic approach used for the preparation of the different functional monomers and the DNAbased nanocapsules using a thiol−ene “click” reaction approach at the interface; (B) TEM images from dichloromethane phase: B-1 with BPB monomer only; B-2 with BPB and BODIPY monomer; B-3with only BODIPY monomer. Reproduced with permission from ref 215. Copyright 2014 John Wiley & Sons Inc.

Figure 35. (A) Schematic representation of the interfacial olefin cross metathesis strategy applied by Malzahn et al. (B) TEM micrographs of the dextran-based nanocapsules obtained through interfacial olefin cross metathesis. Adapted with permission from ref 217. Copyright 2014 American Chemical Society. 2162


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Figure 36. left: principle of the ring opening cross-metathesis presented by Breitenkamp and Emrick; right: confocal laser scanning micrograph cross-section of microcapsules. Reprinted with permission from ref 219. Copyright 2003 American Chemical Society.

can be conducted at the interface of two immiscible liquids. This reaction platform will definitively earn more interest in the near future, especially for the design of drug carriers and this makes the development of new chemistries, compatible or even reliable on the interface, necessary. As more and more proteins can be used as efficient therapeutics, their encapsulation in polymeric carriers will be more important. However, in general, if a reaction can be conducted in two phases/at the interface to water, the amount of organic solvent can be reduced, making these reactions interesting for industry as well, not only to reduce organic waste, but also for efficient heat transfer or the synthesis of water-soluble materials.

catalyst (which is only soluble in the continuous phase). Up to date, few studies involving metathesis in miniemulsion are available in the literature. Cardoso et al.218 studied the efficiency of the acyclic diene metathesis reaction of natural oil in direct miniemulsion systems, evaluating the influence of the different types of surfactant, showing that Ru-indenylidene catalysts and nonionic surfactants were more effective in comparison to Ru-benzylidene and ionic surfactants, respectively. Ring opening cross-metathesis at toluene/water interface was used by Breitenkamp and Emrick to synthesize microcapsules from amphiphilic graft copolymers (Figure 36).219 Due to the amphiphilic nature of the shell material the capsules are able to swell both in water and organic solvent. Similarly to the example above incorporation of a fluorescent monomer enabled the visualization of the capsules by fluorescence confocal microscopy and showed a strong preference of the graft copolymer for the interface (see Figure 36, right). “Tagged” ruthenium catalysts that are developed to achieve certain affinity to the reaction media and even be soluble in the aqueous phase, and surface active catalysts could expand the possibilities for metathesis reactions at the oil/water interface further.220−222

AUTHOR INFORMATION Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest.

4. CONCLUSION AND OUTLOOK In conclusion, the interface between two immiscible liquids can be used as the location for many reactions. Organic reactions with two reactants dissolved in the other phase are either accelerated, their regiochemistry is influenced, or just the presence of water as the second phase with the two reactants in the organic phase influences the product geometry. By the addition of surfactants or phase transfer catalysts the stability of the two phases are changed and reactions can be taken selectively into one phase, for example, to protect the product from hydrolysis in the other phase. Polymerizations, especially polycondensation, can also be conducted in heterophase. This can be achieved on a large scale, e.g., Nylon trick, or on the nanoscale in miniemulsion to generate nanocarriers for various applications. Chemistry evolved from the first nucleophilic addition conducted in heterophase 130 years ago to reactions “on water”, phase transfer catalysts, or bioorthogonal reactions that

Biographies

Keti Piradashvili studied chemistry at RWTH Aachen with focus on macromolecular chemistry and catalysis. After a stay in the group of 2163


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Prof. Joanna Aizenberg at the School of Engineering and Applied Sciences at Harvard University, she completed her studies with a master’s thesis at DWI − Leibniz-Institute for Interactive Materials in Aachen. She received her M.Sc. degree in 2013. Currently, she is pursuing her Ph.D. research in the group of Prof. Katharina Landfester at the MPI for Polymer Research within the Max Planck Graduate Center. Her research interests include the development of biodegradable nanocarriers for drug delivery.

Prof. Dr. Katharina Landfester joined the Max Planck Society in 2008 as one of the directors of the Max Planck Institute for Polymer Research in Mainz. She studied Chemistry at the Technical University of Darmstadt and in Strasbourg. In 1995, she received her doctoral degree in Physical Chemistry in Mainz. After a postdoctoral stay at Lehigh University, she returned to Germany, working at the Max Planck Institute of Colloids and Interfaces in Golm. In 2003, she accepted a chair (C4) of Macromolecular Chemistry at the University of Ulm. Evandro M. Alexandrino received his bachelor’s degree in chemistry at the State University of Campinas (UNICAMP-Brazil) in 2009, where he followed his studies to obtain a master’s degree in physical chemistry in 2012, working under the guidance of Prof. Maria I. Felisberti. For his Ph.D. research, he joined the group of Prof. Katharina Landfester at the Max Planck Institute for Polymer Research in Mainz, Germany. His Ph.D. thesis mainly focused on the development of polyphosphate colloids for biomedical and optical applications and on the study of the influence of nanointerfaces on the kinetics of polyaddition and polycondensation reactions. He completed his Ph.D. studies successfully in 2015.

ACKNOWLEDGMENTS K.P. and F.R.W. thank the Max Planck Graduate Center for financial support. REFERENCES (1) Hume, C. W., Diamine-dicarboxylic acid salts and process of preparing same. U.S. Patent 2,130,947, 1938. (2) Carothers, W. H., Linear polyamides and their production. U.S. Patent 2,130,523, 1938. (3) Hume, C. W., Synthetic fiber. U.S. Patent 2,130,948, 1938. (4) Landfester, K.; Musyanovych, A.; Mailander, V. From Polymeric Particles to Multifunctional Nanocapsules for Biomedical Applications Using the Miniemulsion Process. J. Polym. Sci., Part A: Polym. Chem. 2010, 48, 493−515. (5) Antonietti, M.; Landfester, K. Polyreactions in miniemulsions. Prog. Polym. Sci. 2002, 27, 689−757. (6) Chanda, A.; Fokin, V. V. Organic synthesis “on water. Chem. Rev. 2009, 109, 725−748. (7) Holmberg, K. Organic reactions in microemulsions. Curr. Opin. Colloid Interface Sci. 2003, 8, 187−196. (8) Volkov, A. G. Liquid Interfaces In Chemical, Biological And Pharmaceutical Applications; CRC Press: Boca Raton, FL, 2001. (9) Shui, L.; Eijkel, J. C.; van den Berg, A. Multiphase flow in microfluidic systems−Control and applications of droplets and interfaces. Adv. Colloid Interface Sci. 2007, 133, 35−49. (10) Rao, C.; Kalyanikutty, K. The liquid−liquid interface as a medium to generate nanocrystalline films of inorganic materials. Acc. Chem. Res. 2008, 41, 489−499. (11) Ge, J. P.; Chen, W.; Liu, L. P.; Li, Y. D. Formation of disperse nanoparticles at the oil/water interface in normal microemulsions. Chem. - Eur. J. 2006, 12, 6552−6558. (12) Siebert, J. M.; Baier, G.; Musyanovych, A.; Landfester, K. Towards copper-free nanocapsules obtained by orthogonal interfacial ″click″ polymerization in miniemulsion. Chem. Commun. 2012, 48, 5470−5472. (13) Anna, S. L.; Bontoux, N.; Stone, H. A. Formation of dispersions using “flow focusing” in microchannels. Appl. Phys. Lett. 2003, 82, 364−366. (14) Fu, T.; Ma, Y.; Funfschilling, D.; Zhu, C.; Li, H. Z. Squeezingto-dripping transition for bubble formation in a microfluidic Tjunction. Chem. Eng. Sci. 2010, 65, 3739−3748.

Dr. Frederik R. Wurm is currently research group leader at the Max Planck Institute for Polymer Research, Mainz (D). He studied Chemistry at the JGU Mainz (D) and received his Ph.D. in 2009 under guidance of Prof. Holger Frey. After a two year stay at EPFL (CH) as a Humboldt fellow, he joined the department of Prof. Katharina Landfester at MPIP and was selected as Junior Faculty Member of the Max Planck Graduate Center. In his interdisciplinary research synthetic poly(ether)s, poly(phosphoester)s, and biopolymers are the key materials with interfacial reactions as a major synthetic platform to prepare novel materials for adhesives, tissue engineering, sensing, nanocarriers, and polymer therapeutics. 2164


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