Jaguar

The reactivity of cysteine
residues toward compounds under investigation was modeled as reactivity
toward methanethiolate. Reactivity calculations were carried out at
the B3LYP-D3/6-31+G**^{36 (link)−41 (link)} level of theory in Jaguar (Schrodinger LLC, N. Y. (2009) Jaguar,
version 7.6). Implicit solvation was modeled using the Poisson–Boltzmann
finite system; however, in most cases, at least one explicit water
molecule was also included since these have been shown to be implicated
in the most energetically favored transition states (c.f. Ponting
et al. 2019 Figure 6).^{26 (link)} Transition states were deduced initially
using the linear synchronous transit method; however, those that proved
less easy to find were discovered using a variety of techniques including
temporarily constraining the locations of reactive species and variation
of the initial guess. Initial preparation of structures was carried
out using MacroModel (Schrodinger LLC, N. Y. (2009) Jaguar, version
9.7) and Maestro (Schrodinger LLC, N. Y. (2009) Jaguar, version 9.0).
Calculations were performed on a mixture of the C3SE cluster (SNIC
facility located at the Chalmers University of Technology, Gothenburg)
and standalone workstations running CentOS 6.6. For isosorbide bis-epoxides 2 and 3, the structures were truncated by reducing
the isosorbide core to a methyl group for computational efficiency.

Jaguar (Schrödinger Release 2022-1: Jaguar, Schrödinger, LLC, New York, NY, USA, 2022) [45 (link)] was utilized to conduct the DFT calculations [28 (link)] using the B3LYP (Becke’s three-parameter exchange potential and Lee-Yang-Parr correlation function) method [46 (link)] in conjunction with the 6-311++G** (d, p) basis set, which successfully recommended itself for similar tasks and objects [47 (link),48 (link)]. The calculations included the determination of the following properties: HOMO, LUMO, their energy gap (ΔE), ESP, ALIE, NBO, and ED.

After the GC chromatograms were acquired, the area under the peak for the OAS was determined using Chemstation Version B software. A ln(area) vs. time (s) graph was then plotted, and the slope of the line is equal to -k_ob (observed rate constant). The corrected rate constant (k_corr) was calculated by dividing the observed rate constant by the catalyst concertation (M). Under spontaneous conditions, the rate constant (k_spon) is equal to the observed or corrected ones. The polarity (σ*) and the steric effect (E_s) were calculated using Eqs. 7 and 8, respectively^{10 (link)}. The polarity of the attached groups were obtained from ref. ¹⁵ . The molecular volume and pK_a of ethoxy’s oxygen were calculated by QikProp and Jaguar software, respectively, from Schrodinger LLC^{16 (link),17} . The SPARC program from Archem LLC was used to estimate the partition coefficients of OAS between the organic solvents (methanol, acetonitrile, and dioxane) and water, and the hydrogen-bond properties (e.g. alpha and beta)¹⁸ . The thermodynamic quantities of the activated complex were calculated from the activation energies (E_a) and the pre-exponential factors (A), that resulted from the plotting of the Arrhenius graphs, and according to Eqs. 9 to 11. $$\mathrm{\Delta }{H}^{‡}=E_a-RT$$ $$\mathrm{\Delta }{S}^{‡}=Rln(A)-Rln(k_{B}T/h)-R$$ $$\Delta G^{‡}=\Delta H^{‡}$$