3.3.2. Immobilized Catalysts

In the HKR of terminal epoxides catalyzed by Co(III)salen complexes, the main recycling procedure for most homogenous catalysts is to distill off all the volatile fractions and collect the solid residue. However, distillation is not an ideal separation method for industrial purposes due to the large amount of energy needed and may be limited by the stability of the catalysts at elevated temperatures. In light of this, much research has been aimed at improving the separation of the catalyst and products.

One strategy is to use a fluorous biphasic catalytic system, where employing fluorinated catalysts allows the reaction to be worked up through an organic/fluorocarbon phase separation. The products dissolve into the organic phase and the F-containing catalyst dissolves into the fluorocarbon phase. This concept was explored by Pozzi and coworkers [135,136], who synthesized a number of fluorinated Co–salen complexes for the HKR of terminal epoxides. Some of the fluorinated complexes worked well, but some complexes suffered from a compromise between the solubility in organic solvent to induce the reaction and the solubility in fluorocarbon to achieve the biphasic extraction. Other approaches to achieving improved catalyst separation include the use of ionic liquids and solvent-resistant nanofiltration, both of which have been applied successfully [137,138].

Still, the most investigated approach is the immobilization of the catalyst on polymers and inorganic materials. Following this line, Jacobsen and coworkers [139] investigated Co–salen complexes immobilized on polystyrene resin. The hydroxymethylpolystyrene-supported heterogeneous catalyst **108** (Figure 41) was applied in the HKR of epichlorohydrin and 4-hydroxy-1-butene oxide, two substrates that were not suitable for distillation. The HKR of epichlorohydrin was conducted in CH2Cl2, and the HKR of 4-hydroxy-1-butene oxide was run in THF. Both the ring-opened products and the unreacted epoxides were obtained in good yields (36–52% and 38–41%, respectively) and with high enantioselectivities (up to >99% *ee* for the unreacted epoxides and up to 95% *ee* for the ring-opened products). Catalyst **108** was also used for the dynamic HKR of epibromohydrin, affording the ring-opened product in 94% yield and 96% *ee*. The catalyst could be recovered by simple filtration and recycled up to five times with no apparent loss of reactivity or enantioselectivity.

Kirschning and coworkers [140] reported on a related system, where the Co–salen complex was immobilized on a chloromethylpolystyrene resin (catalyst **109** in Figure 41). Catalyst **109** was investigated in the HKR of epichlorohydrin, styrene oxide, and phenyl glycidyl ether in THF, affording ring-opened products and unreacted epoxides in similar or slightly inferior yields and enantioselectivities compared those obtained with homogeneous Co–salen catalyst **64** (Figure 26). Catalyst **109** was also effective in catalyzing the dynamic HKR of epibromohydrin in THF, giving the corresponding diol with 94% yield and 95% *ee*. The same study also included the immobilization of Co–salen complexes on a porous glass/polymer composite material inside a "PASSflow" reactor [141] which was used to study the catalysis of the dynamic HKR of epibromohydrin in THF under continuous-flow conditions. With reactivation after each run, the modified microreactor could be used for four consecutive runs, affording the ring-opened product in 76–87% yield and 91–93% *ee* [140].

**Figure 41.** Resin-supported Co–salen catalysts **108** and **109**.

**109**

Weck and coworkers [142] synthesized polystyrene resin-supported dendronized Co–salen catalyst **110** (Figure 42) which was employed in the HKR of epichlorohydrin, 1,2-epoxyhexane, allyl glycidyl ether, and styrene oxide. Reactions performed with very low catalyst loading (0.04–0.06 mol% Co) and under solvent-free conditions afforded unreacted epoxides in high yields (40–47%) and with excellent enantioselectivities (>99% *ee*). The excellent catalytic properties were attributed to the flexible linkers and the dendronized framework which probably assisted to promote the cooperative interactions among Co–salen sites and facilitate the bimolecular pathway. Catalyst **110** could be used in five successive HKR reactions with maintained reactivity and enantioselectivity.

**110 Figure 42.** Resin-supported dendronized Co–salen catalyst **110**.

Weck and coworkers [143] grafted their macrocyclic oligomeric catalyst **76** (Figure 31) on a polystyrene resin. The resulting catalyst **111** (Figure 43) was used in the solvent-free HKR of epichlorohydrin and 1,2-epoxyhexane, achieving complete resolution (≥50% conversions and 99% *ee* of the unreacted epoxides) in 3 h or less with only 0.01 mol% Co loading. As such, catalyst **111** is the most efficient heterogeneous catalyst for the HKR of terminal epoxides to date. The catalyst could be recovered by filtration and reused up to five times with maintained enantioselectivity, although the reaction time required to reach full conversion increased after each run. A noteworthy observation was that the use of an excess of water (six equivalents instead of 0.6) led to a significant rate enhancement. The enhanced reactivity was attributed to the formation of a biphasic reaction system, in which the formed diol partitions into the aqueous phase, leaving a higher concentration of epoxide and catalyst in the organic phase.

**111 Figure 43.** Resin-supported macrocyclic oligosalen catalyst **111** based on oligomer **76** (Figure 31).

In addition to the immobilization on polystyrene resin, Co–salen catalysts have also been immobilized on different silica-based supports. Compared to polystyrene, silica is a more rigid support and thus potentially better suited for use as a stationary phase in continuous-flow apparatus. Jacobsen and coworkers covalently immobilized a Co–salen complex on silica (Figure 44) [139]. The resulting catalyst **112** was employed as stationary phase in a continuous-flow system for the HKR of 4-hydroxy-1-butene oxide. Employing THF/H2O as mobile phase, the reaction afforded the corresponding triol in a good yield (37%) and with high enantioselectivity (94% *ee*).
