Exploring potential pathways

The 3Fe(CO)3(H2) species is the one that can be formed most readily from the separated reactants, but there are several other minima on the [Fe,C3,03,H2] singlet and triplet potential energy surfaces that could conceivably also be formed in the reaction. Most notably, we located isomers 1Fe(CO)3(H2), 3Fe(CO)3(H)2, and 1Fe(CO)3(H)2, located, respectively, at 4.8, 14.9, and —1.4 kcalmol-1 with respect to 3Fe(CO)3(H2) (see Table III and Scheme 5, and Ref. (24)). The triplet dihydride species lies higher in energy than separated H2 and Fe(CO)3, and hence is unlikely to be formed in this system. However, the two singlet species are lower in energy and might be formed hence, we have also explored the pathways for interconversion. 

P-gp outlined above are potential pathways that can be exploited to improve or prevent the transplacental passage of drugs. It should be noted that most of these pathways involve a complex interplay of several factors that may vary in a cell- or tissue-specific manner and hence their contribution to placental P-gp should be explored. 

A comparative ab initio study [22] on these two alternative reaction pathways concludes that a zwitterionic structure of the type suggested by Westheimer is not a stationary point on the explored potential energy surfaces for the systems H2O + (H0)2P(0)H and H2O + (H0)3P(0). Two types of critical points were found for these model systems. The first type corresponds to transition structures for the concerted addition of water to these phosphoryl compounds (Figure 3.1). 

Of course, many more potential pathways for the chemical degradation of phosphonates need to be explored. The C-P bond in alkylphosphonates, for example, is weakened by electron-withdrawing substituents. Alpha-carbonyl phosphonates such as the antiviral pharmaceutical phosphonoformate are especially susceptible towards hydrolysis (60). Metal ion-catalyzed conversion of phosphonates into phosphonamides has been observed nucleophilic attack of amine groups at the electrophilic phosphorus atom is believed responsible (61). 

Newson, M., Baker, A., and Mounsey, S. (2001). The potential role of freshwater luminescence measurements in exploring runoff pathways in upland catchments. Hydrol. Process., 15(6), 989-1002. 

In highly exothermic reactions such as this, that proceed over deep wells on the potential energy surface, sorting pathways by product state distributions is unlikely to be successful because there are too many opportunities for intramolecular vibrational redistribution to reshuffle energy among the fragments. A similar conclusion is likely as the total number of atoms increases. Therefore, isotopic substitution is a well-suited method for exploration of different pathways in such systems. 

Figure 12 (from the chapter Exploring Multiple Reaction Paths to a Single Product Channel ). Two-dimensional cut through the potential surface for fragmentation of the transition state [OH CH3 ] complex as a function of the CF bond length and the FCO angle. All other coordinates are optimized at each point of this PES. Pathway 1 is the direct dissociation, while pathway 2 leads to the hydrogen-bonded [CH3OH F ] structure. The letter symbols correspond to configurations shown in Fig. 11. Reprinted from [63] with permission from the American Association for the Advancement of Science.

Finally, it may be difficult to sample all the relevant conformations of the system with fixed. This problem is more subtle, but potentially more serious, as illustrated by Fig. 4.2. Several distinct pathways may exist between A and B. It is usually relatively easy for the molecule to enter one pathway or the other while the system is close to A or B. However, in the middle of the pathway, it may be very difficult to switch to another pathway. This means that, if we start a simulation with fixed inside one of the pathway, it is very unlikely that the system will ever cross to explore conformations associated with another pathway. Even if it does, this procedure will likely lead to large statistical errors as the rate-limiting process becomes the transition rate between pathways inside the set = constant. 

The opportunity for tandem cyclization was explored. Here, the results can be accommodated by postulating the intermediacy of a vinyl radical [66]. For example, the controlled potential reduction of enol phosphate 246 affords 247 as a mixture of stereoisomers, in addition to a 15% yield of the linearly fused tricyclopentanoid 248. Assuming that the initial reduction cleaves the phosphate unit, then there exists the opportunity for the resulting radical 249 to be further reduced to afford a carbanion, or undergo a 5-exo-trig radical cyclization onto the pendant alkene. Given the nature of the products and the fact that they are inconsistent with the expectations of carbanion chemistry, it seems clear that the latter pathway dominates. 

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