Abstract

Sustainable and environmentally benign production are key drivers for developments in the chemical industrial sector, as protecting our planet has become a significant element that should be considered for every industrial breakthrough or technological advancement. As a result, the concept of green chemistry has been recently defined to guide chemists towards minimizing any harmful outcome of chemical processes in either industry or research. Towards greener reactions, scientists have developed various approaches in order to decrease environmental risks while attaining chemical sustainability and elegancy. Utilizing catalytic nanoreactors for greener reactions, for facilitating multistep synthetic pathways in one-pot procedures, is imperative with far-reaching implications in the field. This review is focused on the applications of some of the most used nanoreactors in catalysis, namely: (polymer) vesicles, micelles, dendrimers and nanogels. The ability and efficiency of catalytic nanoreactors to carry out organic reactions in water, to perform cascade reaction and their ability to be recycled will be discussed. Introduction It is widely acknowledged that “the best solvent is no solvent”; however, running a reaction under neat conditions is very challenging from the points of view of mass transfer and temperature gradients [1,2]. Therefore, sustainable chemical technologies are often related to the use of a green non-harmful solvent [3], water. In principle, green chemistry refers to (1) the employment of raw material (substrates) in an efficient manner, (2) decreasing the resulting waste or undesired byproducts, and (3) using cheap and environment friendly solvents (i.e., water). Generally, using water as a solvent is an acceptable choice for green chemistry [4-6]. Indeed, water is attractive from both economic and environmental points of view, and is not taken Beilstein J. Org. Chem. 2018, 14, 716–733. 717 Table 1: Representative comparison of E-factors (including the aqueous work-up), of a pharmaceutically relevant synthesis, carried out via a traditional and a micellar process [45]. reaction E-factors in traditional process E-factors in micelles Heck coupling (300 g scale) 136 7.6 Suzuki–Miyaura (302 g scale) 83 8.3 Sonogashira coupling (57 kg scale) 37.9 7.0 into account when the E-factor (defined as mass ratio of waste to desired product) for a chemical process is determined [7,8]. This is to be true for chemical processes where the utility of water is limited to the work-up at the end of the process and not when used as a reaction medium. However, it should be noted that the utility of water as a reaction medium is the safest, but not the greenest choice. Unfortunately, most organic compounds and catalysts are not soluble in water, limiting its utility for most reactions [9,10]. For this reason, scientists across academia and industry have proposed many solutions in order to maximize the outcome of reactions (i.e., yields, enantioselectivities, etc.) in water and, thereby, harness its utility for further applications. The abovementioned issues are particularly relevant in the field of asymmetric catalysis, which besides overcoming catalyst compatibility also has to deal with cost issues [11,12]. Research on asymmetric catalysis has been mainly focused on performing catalytic reactions with high enantioselectivity and efficiency [13,14]. As a result, a wide range of chiral catalysts have been established [15,16]. Chiral catalysts are, however, not only incompatible with aqueous solutions, but also expensive due to the structural complexity of the ligands used and the usage of transition metals. Finding an approach to utilize chiral catalysts in water while minimizing their cost (i.e., recycling) is still a big challenge. In order to accomplish this, various strategies have been proposed and applied [17-19]. One significant, well-established and widely used strategy, is the use of site-isolated techniques, i.e., creating a separate micro environment [20-22] for catalysts to (1) allow their use in incompatible media, (2) to reduce their costs by recycling them, and (3) avoid any unfavorable environmental influences that might affect reaction yield and output [23,24]. Indeed, such a strategy proved to be advantageous for performing reactions in water and minimizing both reaction waste and cost [25,26]. Attempts to support homogeneous metal complexes onto organic or inorganic surfaces to facilitate their removal/extraction from the reaction mixture has proven to be successful [27,28]. In fact, the utility of catalytic supports has been fundamental to the concept of entrapping catalysts in organic nanodomains and bringing the notion of catalytic nanoreactors to light [29,30]. In recent years the use of nanocontainers/reactors wherein catalysts are entrapped and physically separated in an isolated compartment has appeared to be an excellent facile approach to enhance performance of reactions in water [31-34]. Pioneering examples in this field include small molecule host–guest containers such as cavitands [35-37], and calixarenes [38,39]. Besides these supramolecular cage structures compartmentalization can also be achieved in macromolecular nanoreactors. The advantage of employing these polymeric structures is their improved robustness and loading capacity, which makes recycling and efficient usage of catalytic species more achievable. Nanocompartments such as polymersomes [40], micelles [41], dendrimers [42], and nanogels [43,44] represent smart and compact devices to carry out reactions in aqueous media. Besides, their facile recyclability make them very suitable as nanoreactors for a multitude of applications in synthetic chemistry [24,31]. In a recent study the E-factors for different traditional coupling reactions used in the pharmaceutical industry were reported and compared to those achieved in micellar nanoreactors [45], showing for the latter a decrease of at least an order of magnitude, which underlines their considerable potential in green catalysis (Table 1). In this review we will focus on the application of polymeric nanoreactors in green catalysis by highlighting their structure and ability to encapsulate and shield catalysts. Four different types of nanoreactors will be described, namely micelles, polymersomes, dendrimers and nanogels. The choice of discussing these nanoreactors stems from their accredited relevance in the field of catalysis and the significant number of examples published in literature. The advantageous aspects of these four classes of nanoreactors over non-supported homogeneous systems include: 1) the site isolation of reactive components (enabling cascade reactions), 2) the ability to convert hydrophobic substrates in water (under green conditions), and 3) the facile catalyst recovery. All these attractive features are covered in this review. Moreover, in this review we have not attempted to be comprehensive, but we rather want to illustrate the application potential of these nanoreactors with some illustrative examples of the most relevant classes of organic reactions (performed in water), which should interest both academia and industry. Beilstein J. Org. Chem. 2018, 14, 716–733. 718 Review 1. Homogeneous vs heterogeneous catalysis Catalysis, in general, is divided into two major types, homogenous and heterogeneous. In homogeneous catalysis catalyst and substrates are both present and molecularly dissolved in the same phase (typically a liquid phase) [46]. Homogeneous catalysis involves the use of biocatalysts (enzymes), organocatalysts and metal catalysts [47]. Catalysis is defined as heterogeneous when catalysts are in an aggregated state, and are thus in a different phase than the reactants [27,48]. Heterogeneous catalysts typically consist of a solid carrier, the so called “support”, on which catalytic sites are dispersed [49,50]. Homogeneous catalysis is generally performed under milder operative conditions than heterogeneous catalysis [51]. In fact, heterogeneous catalysts generally possess very high decomposition temperatures (above 100 °C) [52]. The presence of a solid phase often results in the formation of temperature gradients when using high temperatures, which leads to an increase in reactant diffusion and a consequent hampering of mass transfer [53]. Furthermore, the catalytic sites in heterogeneous catalysis are often not as welldefined as in homogeneous catalysis. Therefore, homogeneous catalysis usually results in better selectivity and less byproducts [54]. Although homogenous catalysis ensures high selectivity and a better reaction outcome, yet it is expensive (catalyst recycling is not always an option) and it requires the utility of harmful solvents, yielding high E-factors [53]. In order to lower the E-factor, water should be used in the work-up procedure and separation. It has to be pointed out, however, that the presence of water during the process and its purification afterwards, especially when coming from industrial wastes, poses stringent limitations from an economical and environmental point of view. A good method for homogeneous catalysts separation and reuse is offered by the use of biphasic liquid–liquid systems. Recycling can be achieved in the reactor when the organic phase is sampled out, while the aqueous phase containing the catalyst is retained into the vessel, enabling for continuous processing. The main issue that has to be solved in such set-up is the tolerability of the catalyst to water (its solubility, its activity, etc.) [55]. A strategy to overcome this problem is the inclusion and confinement of the homogeneous catalysts into a host nano-architecture [56]. Compartmentalization enables catalyst segregation and shielding, and ensures its facile removal from the reaction mixture after the reaction has taken place [34]; this facilitates reactions to be performed in water followed by liquid–liquid separation of products and catalyst [22]. Moreover, shielding and segregation of catalysts in a nanoreactor facilitates one-pot tandem reactions that, in most cases, require two or more incompatible catalysts [22,57]. Catalyst confinement leads to a high local concentration of the substrate at the active site, which results in higher reaction rates and better conversion [9]. In this review we will highlight some typical nanoreactors that are used to accommodate homogeneous catalysts, holding promise in green organic synthesis. A division will be made between self-assembled nanoreactors, section 2, and covalent systems, section 3. 2. Self-assembled nanoreactors Self-assembled nanoreactors are macromolecular architectures that are non-covalently assembled from their constituent building units [58,59]. Such nanoreactors allow for physical confinement of catalysts, shielding them from their surroundings [60]. Compartmentalization of catalysts in supramolecular nanoreactors is advantageous from kinetic (faster catalytic process) [61] and thermodynamic (lower transition state of reaction) [9] catalysis points of view. Segregation and isolation of catalysts inside nanoreactors guarantee, in most cases, a valuable platform for catalyst recycling [30]. In the following section we will discuss the utility of some of the well-established catalytic nanoreactors towards green(er) chemistry [62]. 2.1. Micelles Micelles are supramolecular architectures that are assembled of amphiphilic molecules [41]. Above the critical micellar concentration (CMC), surfactants with the appropriately designed hydrophilic head (neutral, anionic and cationic) and hydrophobic chain organize themselves in micelles [31]. Micelles have been extensively studied [9,32] and their utility as nanoreactors is well-established [41,58]. Various micellar morphologies can be obtained depending on the ‘packing parameter’ [56-61], which is defined as p = v/ao lc, where v is the volume, lc is the length of the hydrophobic chain and ao is the optimal area of the head groups [62]. As a general rule, if p ≤ 1/3 spherical micelles are obtained, while cylindrical micelles, or the so-called worm-like micelles, form when 1/3 ≤ p ≤ 1/2. A typical micelle acquires a hydrophobic core that is able to accommodate hydrophobic catalysts, providing thermodynamic and kinetic control over chemical reactions [31]. Moreover, carrying out reactions in such a hydrophobic core leads to a concentration effect for hydrophobic substrates, which ensures higher reaction rates than those performed in bulk [63]. Besides, the structure of any micellar catalytic environment is governed by the arrangement of the amphiphilic molecules, creating, in many cases, a regioselective environment (Figure 1) that affects the outcome of some reactions [29]. Non-spherical, high aspect ratio micelles are preferred for catalysis as such structures provide large surface area where reactions could take place [64]. This has been particularly the case Beilstein J. Org. Chem. 2018, 14, 716–733. 719 Figure 1: Assembly of catalyst-functionalized amphiphilic block copolymers into polymer micelles and vesicles. Characteristics of a nanoreactor system are shown using the polymer micelles including (a) the catalysts are protected and isolated from each other by the micellar shell, (b) substrates are effectively sequestered by the core from the surrounding environment, creating a highly concentrated environment for confined catalysis, (c) the nanostructure shell may regulate the access of substrates to the catalyst-containing micelle core. Reprinted with permission from reference [29]. Scheme 1: C–N bond formation under micellar catalyst conditions, no organic solvent involved. Adapted from reference [67]. for dehydration reactions [24]. Due to the combination of the structures’ high aspect ratio and the hydrophobic effect, water could effectively diffuse away from the catalytic site, which enabled the enhanced formation of product. [40]. Catalysis in micelles: Micelles as nanoreactors have been extensively used in organic synthesis [31], allowing reactions in water [65] with better yields and easier catalyst recover [26] than traditional processes. Lipshutz and co-workers have successfully exploited micelles not only as nanoreactors, but as an outstanding platform for achieving greener organic reactions [26,65,66]. They have shown, for example, C–N cross-coupling reactions between heteroaryl bromides, chlorides or iodides and carbamate, sulfonamide or urea derivatives to be successfully realized in water using palladium-loaded TPGS-750-M (dl-α-tocopherol methoxypolyethylene glycol succinate) micelles (Scheme 1). Moreover, this micellar catalytic system allowed for catalyst Beilstein J. Org. Chem. 2018, 14, 716–733. 720 Table 2: Reactions of allylic ethers 1a–e with naphthylmethylaminea. run ether time (h) product yield (%)

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