Ring Closing Metathesis – Consider ring strain, substituted pattern (acyclic conformation), and entropy. The easier the ring is to form, the more concentrated you can run your reaction. All things being equal, higher dilution will favor intramolecular reactions. But in metathesis as in life, things are never equal. Diluting a reaction will slow the rate, meaning you’ll need to increase your catalyst loading and/or temperature, each of which can lead to more side reactions. Each reaction has a different set of optimal conditions, but as a rule of thumb:
Small rings (5 & 6): >0.5 M
Medium rings (7-9): ~0.5 M
Large rings (10+): higher dilution as ring size increases
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Grela and other collaborators have created a catalyst containing a quaternary ammonium EWG on the benzylidene fragment (Green Chem. 2006, 8, 685). "This is our favorite catalyst now," he says. "It's very easy to prepare, the salts happen to be patent-free, and so we're free to develop and test it." The ammonium group activates the catalyst, allows it to work in solvent-water mixtures, and, because of its affinity to silica gel, allows it to be separated out by filtration. Grela, with chemistry professor at Leibniz University Hannover, developed a similar catalyst that has a protonated amino group and that can be noncovalently attached and immobilized on glass-polymer composite rings ().
Solvent closing metathesis ring - (2017)
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In contrast to the use of the RCM/cross-coupling sequence for the synthesis of medium-sized macrocyclic ethers, the assembly of large-ring lactones such as VII presents additional problems to unite the reacting ends of the now longer acyclic chain. For example, because of the basic nature of fluoride, the TBAF-assisted intramolecular cross-coupling may lead to the cleavage of the lactone. In addition, lactone VII possesses a trans-cis diene system conjugated to a benzene ring that causes the compound to behave as a conjugated triene system that is inherently more rigid and thus more difficult to fuse the reacting termini. Of these problems, the greater ring size and the lability of the ester group in the basic TBAF reaction medium were potentially most challenging and thus led to the investigation of lactones VIII () that are easier to access and modify. These lactones were chosen because they addressed the consequences of placing the carboxyl and hydroxyl groups in different locations with respect to diene moiety. Various ring-sizes of VIII could be accessed from the cyclic siloxanes such as IX. The strategy to use cyclic siloxanes IX was chosen to fix one end of the macrocycle to be formed in a smaller ring to reduce both flexibility and distance between the two reacting termini. The siloxane IX would be derived from ring closing metathesis of silyl ethers X. The silyl ether X could be elaborated with ease from diols XI and the acid XII. The key step in this route is the sequential ring-closing metathesis/intramolecular cross-coupling reaction.
Olefin Metathesis: Theory and Practice
Next, this process was extended to the synthesis of 13- and 14-membered rings. Thus, cross-coupling of siloxane 7d afforded the 13-membered macrocycle 8d in 61% yield. The closure of this macrolactone required longer reaction time (54 h) compared to the 12-membered lactone (40 h). The synthesis of another 13-membered ring 8e that contained a different substitution pattern proceeded in 53% after 48 h. Unfortunately, the alkene region of the 1H NMR spectra of both 13-membered lactones 8d and 8f could not be fully analyzed. Finally, the synthesis of the 14-membered ring 8f was achieved from siloxane 7f in 69% yield after 54 h. Gratifyingly, the alkene resonances for HC(6) and HC(7) were well resolved and showed two doublets of doublets at 6.32 ppm (dd, 3J = 10.5, 10.5 Hz) and 6.23 ppm (dd, 3J = 10.8, 10.8 Hz), respectively.