To better understand alkyne metathesis reactions of the tritopic precursor, we outlined the kinetically viable pathways the precursor must follow to form the cage product (Figure 4.1). Intermediates are denoted as MXY where X and Y, respectively, represent the number of building
blocks and rings in each intermediate. To form the tetrahedral cage, four monomers must come together to form six proper alkynyl bonds, which generate four rings. There are three different kinetically viable pathways (pathway 1, 2, 3 in Figure 4.1). In the first step, two equivalents of monomer M1 react to form dimeric intermediate M2 via alkyne edge formation. Another M1 can
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intermolecular metathesis to further build tetrameric intermediate M4 (pathway 1) or M3 can
undergo intramolecular metathesis to form the third edge, which completes the first ring in M31
(pathway 2). Both intermediates M4 and M31 can form M41 via intramolecular (pathway 1) or
intermolecular (pathway 2) metathesis, respectively. Another intramolecular metathesis results in the formation of a second ring in M42, which is expected to readily close the last ring to yield the
kinetically trapped tetrahedral cage. Also, M2 can dimerize to build M4 (pathway 3), which then
follows the same pathway as described above to form the cage. All intermediates are susceptible to possible off-target pathway oligomerization via intermolecular metathesis yielding building blocks larger than the tetrameric unit.
Figure 4.1. Reaction pathways the tritopic precursor M1 can undergo during alkyne metathesis. Blue and red arrows represent intermolecular and intramolecular metathesis, respectively. Intermediates are denoted as MXY where X and Y, respectively, represent the number of building blocks and rings in each intermediate.
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Four precursors are required to make six alkynyl bonds and construct the tetrahedral cage. Regardless of the three different pathways, the most critical point is that there must be a balance between intermolecular (blue arrow in Figure 4.1) and intramolecular (red arrow in Figure 4.1) metathesis. The starting precursor must undergo three intermolecular and three intramolecular metatheses to achieve the target. If there is any shift in the balance, for instance, due to retarded intramolecular metathesis or promoted intermolecular metathesis, then the intermediates will be channeled to the off-target pathway oligomerization. Also, it should be noted that only when two reactive alkynes paired in same capping color (blue-blue or red-red in Figure 4.1) undergo metathesis, a productive intramolecular cyclization towards the cage can occur. However, the edges of each intermediate can freely rotate, as indicated by black arrows in M3, and lead to mis-
paired alkyne metathesis (blue-red). This unproductive intramolecular cyclization results in mis- connected intermediates, which may channel intermediates to the off-target pathway.
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Scheme 4.1. a) Head to tail and b) head to head arrangement of alkylidynes resulting in nonproductive and productive cyclization in the cage forming process. Dashed reversible arrow in (b) indicates the ability to switch on/off the backward reaction.
Also, it should be noted that there is an important arrangement requirement for the successful cage formation. As shown in Scheme 4.1, depending on the regioselectivity of the acetylene units added to Mo≡C, there are two possible metathesis outcomes: productive and nonproductive pathways. To form the desired cage product in the final intramolecular cage closing step, the two acetylenes have to access each other in head to head arrangement to undergo a productive metathesis (Scheme 4.1 b). However, such a conformation involves significant angle strains as compared to the conformation in head to tail arrangement. It has been demonstrated that limited flexibility of two reactive acetylene moieties prevent the productive cyclization as two arms are unable to come in close contact. As a result, formation of unpredicted structure as a major product was reported from AM.5 Since the conformation of the tritopic precursor is rather rigid on its vertex, we suspect that the head to tail arrangement is most likely to happen in our cage closing step. However, it is probable that the prefixed orientation of intermediate M42 increases the chance
for productive cage closing metathesis to happen before any interruptive cross-metathesis can occur to form off-target oligomers. We anticipate that change in size of precursor would play both favorable and unfavorable roles. Presumably, larger precursor arm can provide more flexibility to release the angle strain built up during the final cyclization step. However, with increased flexibility and degrees of freedom, the intermediates could have increase access to intermolecular metathesis over intramolecular cage closing reaction.
We suspect that changes in precursor structure shift the balance between intermolecular and intramolecular rates of metathesis. Additionally, structural variables such as flexibility change
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the relative likelihood of unproductive intramolecular metatheses to occur, altering the flux of intermediates. Due to increased complexity in the energy landscape of the multitopic dynamic reactions, off-target pathway intermediates may be removed, at least temporarily, from the relevant pool of dynamic species; they may not convert back to on-target pathways within limited catalyst loading and reaction time. Thus, understanding how structural variables affect the reaction pathways is significant to design-in the kinetically viable pathways. In the rest of the chapter, effects of precursor size on the cage forming pathway are discussed. We report the effects of precursor structure on the reaction pathway and our attempts to model the chemical behavior. Using the insight gained, we further demonstrate how changes in the reaction conditions bias the reaction towards the cage formation.