Contenido de la Acción de Nulidad

4.4.1 Monitoring Cage Formation via GPC

The successful syntheses of the tetrahedral cages in different sizes were demonstrated. Further, the experimental results supported our hypothesis that the precursor size affects cage fidelity such that the larger precursors, PM and PL, diverge away from the ideal behavior observed

from the small precursor, PS. To further explore the effects of precursor size on cage forming

pathways, reaction progress was monitored via GPC. Precursors were subjected to AM under the same reaction conditions previously described (Figure 4.4), and aliquots were taken and quenched at various time points for analysis. As discussed in the section 4.2, successful cage formation

98

requires construction of tetrameric building blocks via intermolecular metathesis, and productive intramolecular metathesis to close four rings (Figure 4.1). Monitoring the reaction progress of each precursor revealed that all three precursors follow similar pathways in the beginning of the reaction. According to the normalized GPC traces (Figure 4.11), consumption of precursors to form dimeric, trimeric, tetrameric, and longer oligomeric intermediates was observed. During the metathesis of PS, those oligomeric intermediates undergo efficient dynamic bond exchange to

rapidly assembly into TS. However, in the extended systems, not all oligomers converged to the

cages as the reaction proceeded. Notably, in the case of metathesis of PL, oligomerization

continued over time as evidenced by the broadening of the GPC trace (Figure 4.11c). While the GPC traces are relatively clean for the metathesis of PM, longer oligomers formed from PMsuffered

from low solubility. Indeed, intermediates began to form precipitates after 1 h and those precipitates were filtered off during GPC sample preparation and thus not observed in the obtained trace.

99

Figure 4.11. Reaction monitored by GPC at different time points for a) PS, b)PM,and c)PL. All reactions were performed in 10mM CHCl3 with 5 mol % [Mo] catalyst at room temperature. Additional 5 mol % catalyst was added at 16 h time point to obtain the final GPC data after 24 h for reactions of PM and PL as no changes were observed after 8 h. Each GPC trace is normalized by area.

The GPC data indicate that extending the precursor size opens competing pathways in addition to the cage forming pathways, promoting the formation of longer oligomers. As mentioned earlier, this phenomenon is closely related to the reduced effective molarity due to increased flexibility and degrees of freedom. Extending the precursor size causes the connecting points to deviate from optimal orientation for efficient intramolecular metathesis to occur. Hence, intermolecular metathesis competes with intramolecular metathesis, which promotes off-target pathway oligomerization. Further, increased flexibility and degrees of freedom lowers the probability of “encounter frequency” for productive cyclization metathesis. Unproductive intramolecular metathesis results in mis-connected intermediates, which may channel intermediates off-target pathway. While the static nature of cage facilitated quantitative yield of

100

TS from PS, the inefficient bond exchange observed in the extended precursor reaction mixtures is

presumed to impede oligomeric intermediates from converging to the desired cage products. Those oligomers could eventually enter a region, as described by Levinthal ‘golf-course potential’ landscape,14 where the reaction equilibrium is limited by the given reaction time, catalyst loading, and solubility.

4.4.2 Design-in Kinetically Viable Pathways to Alleviate the Effects from Extended Precursor Size

A simple experiment was designed to further confirm our hypothesis that increasing precursor size results in decreased effective molarity and promotes competing intermolecular side reactions. We suspected that the reduced effective molarity caused by the extension of precursor size is offset by diluting the reaction. By changing concentration, we expected to confine reaction pathways toward the cage formation, favoring intramolecular reactions relative to intermolecular reactions and providing opportunities for unproductive cyclization products to self-correct to return to on-target pathway. The precursors were subjected to AM under more dilute conditions, 1 mM in chloroform. However, in the diluted condition, the reaction was significantly slower as AM is diffusion controlled. As a result, even after 24 hours, a substantial amount of precursor remained when reacted with 5 mol % catalyst (Figure 4.12). To maintain a reasonable reaction timescale, the catalyst loading was increased to 30 mol %. Then each reaction was monitored by GPC over time.

The normalized GPC traces revealed the suppressed formation of oligomers and better confined cage formation (Figure 4.13). Comparing the final product distribution of each precursor in two different reaction concentrations shows an enlarged cage peak area from both PM and PL

101

approximately 40 % larger when PL was subjected to 1 mM reaction conditions as opposed to the

original 10 mM reaction conditions. Also, no precipitation of oligomers was observed from the metathesis of PM in the diluted condition. By simply changing the reaction concentration, we

successfully alleviated the effects of precursor size on cage forming process by guiding the extended precursors toward better confined reaction pathways. This highlights the importance of understanding the effects of structural variables on reaction pathways. Further, this demonstrates how such insights can be used to design kinetically viable pathways towards desired products.

Figure 4.12. GPC traces demonstrating a slower reaction of AM of PS in diluted (1 mM CHCl3)

reaction condition with 5 mol% [Mo] catalyst loading.

102

Figure 4.13. Reaction monitored by GPC at different time points for a) PS, b) PM, and c) PL with 30 mol % [Mo] catalyst in 1mM CHCl3. Additional 5 mol % catalyst was added at 16 h time point

to obtain the final GPC data after 24 h for reactions of PM and PL as no changes were observed after 4 h. Each GPC trace is normalized by area.

Figure 4.14. GPC trace presenting product distribution of PS, PM, and PL after 24 h of metatheses in different reaction conditions; a) 10mM CHCl3 with 5 mol % [Mo] catalyst and b) 1mM CHCl3

with 30 mol % [Mo] catalyst. GPC trace is normalized by area.