TUNCHEM2

07.25  Our work on H-shift tautomerization tunneling in thiobenzamide,  a case study on tunneling through high-energy barriers has just be published in J. Org. Chem (link or repository). 

Continuing the investigation described in entry 12.24, wherein we reported the observation of QMT thiol-imine → thione-amino tautomerization of thiobenzamide with a half-life of ∼180 h in argon matrix at 10 and 20 K. Computed CVT/SCT rate constants at the MPWB1K/6–31+G(d,p) level closely reproduce the experimental data.* Remarkably, computations extended to higher temperatures indicate that even at 300 K the H-shift tautomerization is entirely governed by QMT (>99.9%), with a predicted half-life of ∼1 min. At 200 K, the rate constant decreases by over 2 orders of magnitude (half-life of  ∼200 min). These findings reveal an exceptional reaction model for exploring QMT-governed reactivity under solution conditions and for providing new insights into harnessing QMT in molecular design. 

*The lowest tunneling energy was assumed to start at 0.50 kcal mol–1 above E0, which exclude some rearrangement of the C–C torsional angle 

01.25  Our work demonstrating how competitive heavy-atom tunneling reactions can be controlled through electronic effects was published in ChemistryEurope (link-OA)

Here we extended our investigation to explore electronic effects controlling QMT reactivity. Benzazirines were used as model compounds due to their exceptional ability to react via two competing QMT pathways. Three novel benzazirines with increasingly stronger electron-donating substituents at C4 [R = OH, N(CH₃)₂, and N(CH₂)₄] exhibited diferent QMT reactivity. Computed QMT rates showed qualitative agreement with the observed selectivities and were critical to understanding this phenomenon. The QMT ring-opening reaction to arylnitrenes was found to be intrinsically more sensitive to electronic substituent effects than the QMT ring-expansion reaction to cyclic ketenimines. A clear correlation was observed between increased electron-donating strength, increased QMT ring-opening rate to nitrene, and decreased reaction enthalpy or barrier width (along with lower barrier height). Overall, this work shows how subtle electronic effects can tune QMT selectivity. 

12.24  The thiol-imine → thione-amino tautomerizations of thioamide derivatives were selected as a reaction model for investigating QMT from cryogenic to room temperature conditions. Our aim was to uncover a thermally activated QMT regime that could exclusively govern the reactivity under solution conditions. 

QMT H-shift tautomerization in thiourea (R = NH2)  had previously been observed in cryogenic matrices with a half-life of ~36 hours. In addition to thiourea, we computed the tautomerization reaction profiles for several derivatives at M06-2X/6-311+G(2d,p) level of theory and found that thiobenzamide (R = Ph) exhibits a slightly more favorable energy profile compared to thioformamide (R = H) and thioacetamide (R = Me) (Figure 1). The latter two were previously generated in argon matrices (3–15 K), but no evidence of hydrogen QMT was detected over timescales of days.  

The reaction rate constants, computed without (CVT) and with multidimensional quantum tunneling (CVT/SCT) corrections at the M06-2X/6-311+G(2d,p) level, are shown as Arrhenius plots in Figure 2. The computed tautomerization of thiourea (R = NH2) indicate a half-life of ~32.1 h at 10 K (k ≈ 6.0 × 10⁻⁶ s⁻¹), in excellent agreement with the experimental value of ~36 h (k ≈ 5.3 × 10⁻⁶ s⁻¹). For thioformamide (R = H) and thioacetamide (R = Me), QMT reactivity is predicted too slow to be observed, consistent with previous experiments.

In the case of thiobenzamide (R = Ph), the minimum energy path (MEP) involves significant C−C torsional rearrangement, resulting in a long energy tail toward the reactant. If this torsional change is slightly reduced (increasing the energy by a few tenths of kcal/mol), the QMT rate increases significantly at cryogenic temperatures (dot vs. full black lines).

All thiol-imine → thione-amino tautomerizations exhibit non-linear Arrhenius behavior up to room temperature and beyond, indicating that thermally activated tunneling likely dominates the reactivity. The results suggest that thiobenzamide is the most promising system for bridging QMT reactivity between cryogenic and solution conditions, enabling exploration of purely thermally activated QMT (see blue region in Figure 2, representing rates accessible to our spectroscopic observations). Further work is underway.

07.24  Our TUNCHEM2 project start today!