Thermomorphic system

To eliminate the need to recover the product by distillation, researchers are now looking at thermomorphic solvent mixtures. A thermomorphic system is characterized by solvent pairs that reversibly change from being biphasic to monophasic as a function of temperature. Many solvent pairs exhibit varying miscibility as a function of temperature. For example, methanol/cyclohexane and n-butanol/water are immiscible at ambient temperature, but have consolute temperatures (temperatures at which they become miscible) of 125°C and 49°C, respectively (3). 

The use of thermomorphic systems has recently been studied as a way of achieving catalyst separation in homogeneous catalysis. For example, a biphasic hydroformylation catalyst system was developed to take advantage of the unusual solvent characteristics of perfluorocarbons combined with typical organic solvents (4). Fluorous/organic mixtures such as perfiuoromethylcyclohexane... 

Thermomorphic solvent mixtures have been tested for hydroformylation of 1-octene and 1-dodecene to determine the ease of product recovery and catalyst recycling. Using both batch and continuous reactors, we demonstrated the efficacy of a biphasic, thermomorphic, system that had the following advantages ... 

Batch Experiments with Thermomorphic Systems. As a reference, we tested the hydroformylation of 1-octene in a completely homogeneous system using the same rhodium triphenylphosphine catalyst that is used for hydroformylation of lower aldehydes. This is sample R39 in Table 28.1, and gives us a baseline to compare the performance of our systems in terms of conversion and selectivity. To maintain consistency, we performed all the reactions at 100°C using the same amounts of reactants, catalysts and solvents. Under these conditions we only detected aldehyde products no alcohol or alkene isomers were formed. 

In summary, what we have found is that the combination of a thermomorphic system and a surfactant is very effective for the hydroformylation of 1-octene and 1-dodecene. We believe that although a 90 10 ethanol/water and heptane system becomes miscible at 70°C, the additional water in a 50 50 ethanol/water and heptane system raises the miscibility temperature to >100°C. When a surfactant is added, the miscibility temperature is lowered and the biphasic solution becomes monophasic below the reaction temperature, resulting in good reaction rates. In addition, the presence of the surfactant also enhances the selectivity compared to the completely homogeneous system from 1.8 to 5.3 L/B... 

Continuous Experiments with Thermomorphic Systems. For the continuous experiments, we used the best solvent system we identified in the batch reactions, which was 50 50 1,4-dioxane/water. Heptane was the nonpolar solvent and CTAB the surfactant. We chose this system over the 50 50 ethanol/water system because it gave us better selectivity and there is no chance that unwanted acetal side products will be formed by the reaction of ethanol with the aldehyde. We initially used 1-octene as the olefin and after we worked out the process conditions for 1-octene, we tested the higher olefin 1-dodecene. 

The idea to use solvent systems enabling homogeneous reaction conditions at elevated temperatures and liquid/liquid phase separation at lower— preferably room—temperature seems to be obvious. Nevertheless, it is only recently that thermomorphic solvent systems gain attention [30-33] for product separation or multiphase catalysis [34,35]. The main reasons for the delayed engagement is that an efficient choice of a useful solvent system is not easy to achieve. There is also a lack of experience with thermomorphic systems in general. Reactions are optimized to be carried out in solvents having certain distinct solubility and polarity characteristics. A thermomorphic solvent system of choice will have to fulfill these requirements and to show the thermomorphic effect in addition. 

An extension of these dendritic phosphine ligands for Pd-catalyzed allylic ami-nation was recently described using a thermomorphic system for separation [72]. 

Figure 6.7 (a) NIPAM-POM hybrid catalyst [124, 125] and (b) simplified representation of a thermomorphic system with a NIPAM-POM hybrid catalyst [128]. 

There are several different methods to separate PNIPAM-supported catalysts from the reaction mixtures. Both liquid-solid separations and liquid-liquid separations can be used. The most frequently used liquid-solid separation method takes advantage of the varying solubility of polymers in different solvents. For example, PNIP AM can be precipitated from THF into hexanes. PNI-PAM copolymers also exhibit lower critical solution temperature (LCST) behavior. Specifically, PNIPAM and its copolymers can be prepared such that these polymers are soluble in water at low temperature but precipitate when heated up. This property may be used as either a purification method or a separation tech-nique.[l 1] A thermomorphic system is a liquid-liquid biphasic system developed in our group. It uses various solvent mixtures with temperature-dependent miscibility to effect separation of catalysts from substrates and products, as shown in Figure 2. 

While recovery of a polymer-bound catalyst like 115 in a thermomorphic system is quantitative based on the absence of detectable Pd in the nonpolar phase, product yields can often be lowered in the first few cycles. This is illustrated by the data in Table 1 for Heck and Suzuki reactions like Eqs. 51 and 52... 

A problem with using thermomorphic systems whose catalysts reside in the polar phase in room-temperature biphasic mixtures of nonpolar and polar solvents is that a nonpolar solvent like heptane is not a good solvent for most polar organic products. Thus, the low yields seen in early cycles in the above chemistry can be even more problematic with compounds more polar than those listed in Table 1 when polar polymers are used in polar thermomorphic systems. Moreover, many of these reactions produce salt by-products and salts that ac-cmnulate in the polar phase. Such salt accumulation will eventually frustrate the miscibUization of solvents that facilitates a thermomorphic process. To avoid these problems, other nonpolar polymer supports have been developed. 

Dendrimers too can be used in thermomorphic systems. In a report describing dendrimer-bound Pd(0) catalysis [163], Kaneda compared the liq-uid/liquid thermomorphic separation scheme with more established membrane and solvent precipitation procedures. Starting with commercially available third-, fourth-, and fifth-generation poly(propylene imine) dendrimers, the primary amine groups at the periphery were converted into chelating phosphines. The resulting phosphines were in turn allowed to react with Cl2Pd(PhCN)2 to form Pd(II) complexes that were reduced by hydrazine in the presence of triphenylphosphine to form the Pd(0) catalyst 126 (Eq. 63). This catalyst was successfully used in the allylic amination shown in Eq. 64. In this example, solvent precipitation, membrane filtration, and thermomorphic liq-uid/liquid separation were all used to recycle 126. The latter procedure proved to be simplest with the best recovery of active catalyst. 

A second nucleophilic catalyst supported by PtBS is the polymer-bound di-methylaminopyridine analog that was also used in latent biphasic catalysis with the poly(JV-alkylacrylamide) support 129 [131]. This example of a nucleophilic catalyst (133) was used to catalyze formation of a t-Boc derivative of 2,6-di-methylphenol (Eq. 70). In this case, the extent of recovery of the catalyst and the yields of product were directly comparable to those seen with thermomorphic systems. The isolated yield for the first five cycles of this reaction were 34.3, 60.9,82.2,94.6, and 99%. In this case we reused catalyst 133 through 20 cycles. Yields after the first few cycles were essentially quantitative (ca. 93% average for each of 20 cycles). Separation of the polymer from the aqueous ethanol phase was quantitative as judged by either visual observation or UV-visible spectroscopic analysis. 

Polymers are a general alternative to low molecular weight ligands in always biphasic liquid/liquid systems. Just as the nonpolar or polar polymers above imparted phase-selective solubility to catalysts in thermomorphic systems, the appropriate polymer can impart aqueous or fluorous phase-selective solubility to a catalyst. Several recent examples illustrate this for aqueous, fluorous, and other biphasic catalysts. 

The Plenio group recently described the advantages of using simple PEG supports with sterically demanding phosphines in biphasic and thermomorphic systems. In their work, the best ligand was the diadamantylbenzylphos-phine 138 (Eq. 79). They chose to use a 2,000-Da polymer because H NMR... 

The first application of dendrimers in a thermomorphic system was described by Kaneda and co-workers. Poly(propylene imine) dendrimer-bound Pd(0) complexes were synthesized by reduction of dendritic Pd(II) systems with hydrazine and used for the allylic substitution of trans-cinnamyl acetate with dibutylamine [Eq. (5)] [14]. 

Figure 6. Thermomorphic system where the catalysis is carried out homogeneously at 70 °C in a monophasic system but where the separation is carried out at room temperature in a biphasic system with the soluble polymer-supported catalyst (e,g, 5 or 6) exclusively dissolved in the aqueous ethanol phase at 20...

Kim S, Tsuruyama A, Ohmori A, Chiba K (2008) Solution-phase oligosaccharide synthesis in a cycloalkane-based thermomorphic system. Chem Commun 15 1816-1818... 

Chiba K, Kono Y, Kim S, Nishimoto K, Kitano Y, Tada M (2002) A liquid-phase peptide synthesis in cyclohexane-based biphasic thermomorphic systems. Chem Commun 16 1766-1767... 

---