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<\/a><\/p>\nThe previously explored<\/a> pathway invoked an aziridinium cation as an intermediate (Int4<\/strong>). The challenge now is to define a route into this intermediate and another out of it to lead to the eventual product. I previously explored the energy of forming Int4<\/strong> by first using the lone pair of electrons on the nitrogen to form the ring, resulting in a carbanionic ylid which only then gained a proton to form Int4<\/strong>. This time I will try reversing this sequence, by protonation first to form Int5<\/strong> via<\/em> TS4<\/strong>,\u00a0forming a cation resonance stabilized via<\/em> sulfur. Only then does the nitrogen lone pair come into play to form the ring via TS8<\/strong>.\u00a0The free energy barriers for both these species are now within a reasonable range, being within 10 kcal\/mol of the estimated rate barrier (FAIR data for this pathway collected at DOI:\u00a010.14469\/hpc\/7385<\/a>).\u00a0It is also important to note that this is only an exploratory model, which has not yet been “optimized”. Thus to reduce the computer time needed, ammonia is used as a model base. The full model would use morpholine, which as a better base might be expected to eg<\/em> reduce the barrier for TS4<\/strong>. Also, these are bimolecular reactions computed for a standard state of ~0.04M. More concentrated solutions would also reduce the barrier. The anion present along the entire reaction pathway is not included in this model; doing so might also alter slightly the barriers.<\/p>\n Having found a reasonable route to Int4<\/strong>, it now has to be converted in the first instance to \u00a0Int6,\u00a0<\/strong>which is then easily protonated to the initial product, leading eventually to the thioamide outcome of this reaction. After much exploration, a good route was found to unexpectedly involve\u00a0Int7<\/strong>. This is formed by ring opening of Int4<\/strong> via<\/em> TS9<\/strong>, with the sulfur migrating along the carbon chain in preference to forming the rather less resonance stabilized benzylic cation. Int7<\/strong> then reverses this migration, with the base removing a proton and the sulfur migrating back to the carbon atom it had started from in Int4<\/strong>\u00a0via<\/em> TS10. <\/strong>Both these barriers are also <10 kcal\/mol of the barrier inferred from the reaction rate.<\/p>\n<\/a><\/a>