A Theoretical Study of Favorskii Reaction Stereochemistry. Lessons in Torquoselectivity
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Bibliographic record
Abstract
The mechanisms of the chloroenolate-->cyclopropanone step of the "normal" Favorskii rearrangement have been investigated in detail using high-level ab initio calculations. A series of simple alpha-chloroenolates, based on chloroacetone (6), all monomethyl derivatives (7-9), a dimethyl analogue (10), and 1-acetyl-1-chlorocyclohexane (11) was first used to explore and define the basic features of the mechanism, which include the finding of both an "inversion" and a "retention" transition state and that in most cases these arise from separate ground-state conformations of the chloroenolate. These theoretical studies were then extended to an isomeric pair of chloroenolates 1 and 2, the cis- and trans-2-methyl derivatives of 11, which are the reactive intermediates involved in a well-known experimental study carried out by Stork and Borowitz (S-B). Finally, three alpha-chlorocyclohexanone enolate systems 12-14 were studied, since these intermediates have a more restricted enolate geometry. The "inversion" mechanism has been described as an SN2 process but the present results, while supporting a concerted process, is better described as an oxyallyl structure undergoing concerted ring closure. The "retention" mechanism has been described as SN1-like, but the calculations show that this process is also concerted, although much less so, and again involves oxyallyl-like transition-states. The model systems 6-8, 10, and 11 with a potential plane of symmetry have two enantiomeric transition states for inversion and another two for retention of configuration (at the C-Cl center). With 9 and the S-B models 1 and 2, with no symmetry plane, there are a calculated total of four diastereomeric transition states for cyclopropanone ring closure in each case, two for inversion and two for retention. While the transition-state energies calculated for simple chloroenolates favor the inversion process, the S-B models 1 and 2 have almost equal inversion-retention transition-state energies. Solvation simulation calculations of ground states and transition states suggest that the retention mechanism becomes relatively more favored in polar solvents, in agreement with some experimental results. In the chloroenolates 12-14, both inversion and retention mechanisms were also located, these arising from two different ground-state ring conformations of the enolate. In these models, one also finds similar inversion and retention transition-state energies, but again with a small preference for the inversion process.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it