Structure-to-process design framework for developing safer pesticides

Abstract

Rational design of pesticides with tunable degradation properties and minimal ecotoxicity is among the grand challenges of green chemistry. While computational approaches have gained traction in predictive toxicology, current methods lack the necessary multifaceted approach and design-vectoring tools needed for system-based chemical development. Here, we report a tiered computational framework, which integrates kinetics and thermodynamics of indirect photodegradation with predictions of ecotoxicity and performance, based on cutoff values in mechanistically derived physicochemical properties and electronic parameters. Extensively validated against experimental data and applied to 700 pesticides on the U.S. Environmental Protection Agency's registry, our simple yet powerful approach can be used to screen existing molecules to identify application-ready candidates with desirable characteristics. By linking structural attributes to process-based outcomes and by quantifying trade-offs in safety, depletion, and performance, our method offers a user-friendly roadmap to rational design of novel pesticides.

Fig. 1.. Design framework.

Structure-to-process framework for the design of safer pesticides based on computed photodegradation (17) and ecotoxicity rules (21).

Fig. 2.. Density scatterplots.

(A) Left: Density scatterplot of octanol-water distribution coefficient (log D_o/w) versus energy difference between the highest occupied and lowest unoccupied molecular orbitals (ΔE). Safer chemical space defined by the current method (mPW1PW91/MIDIX+) is highlighted in the upper left-hand quadrant (log D_o/w < 1.7 and ΔE > 6 eV). The average ecotoxicity point for all 700 compounds was found to be a log D_o/w of 2.87 and a ΔE of 5.29 eV, with SDs of 2.56 and 0.99, respectively. (B) Right: Indirect photodegradation potential is represented by the combined thermodynamic and kinetic performance, where the darker the point, the more likely the molecule is to photodegrade. The average ΔG_et⁰ and log k values for all 700 compounds were found to be 10.68 kcal/mol and 8.65, with SDs of 10.83 and 0.95, respectively. a.u., arbitrary units.

Fig. 3.. Safety assessment by pesticide class.

Percent (%) breakdown of pesticides by safety criteria and by pesticide chemical class. Green, blue, and yellow bars represent % of compounds that met the overall safety cutoffs (log D_o/w < 1.7 and ΔE > 6 eV), predicted the bioavailability safety (log D_o/w < 1.7), and predicted the reactivity safety (ΔE > 6 eV), respectively.

Fig. 4.. Coupling of ecotoxicity and photodegradation.

(A) Top: Scatterplots of ecotoxicity averages (octanol-water distribution coefficient, log D_o/w versus energy difference between the highest occupied and lowest unoccupied molecular orbitals, ΔE) and spread (ellipse radii based on half SD in the x and y directions) for each percentile bracket of photodegradation potential (denoted in the legend on the right). Black arrows represent vectors between adjacent percentile averages. (B) Bottom: Scatterplot of electrophilic-specific ecotoxicity averages (octanol-water distribution coefficient, log D_o/w versus energy of the LUMO, E_LUMO).

Fig. 5.. Substructural-tier results.

(A) Top: Free energy of electron transfer with 3-methoxyacetophenone (ΔG_et⁰) (17), plotted as a function of stabilization energy, E(2). Cutoff values were identified as follows: (i) strongly electron withdrawing (orange), (ii) weakly electron donating or withdrawing (blue), and (iii) strongly electron donating (green). Averages for each group are designated by a red diamond with E(2) value labeled (in kcal/mol). Horizontal bars represent a 99% confidence interval for each group. Vertical dashed lines signify cutoff values that separate groups 1 to 3. Phenols are marked as circular data points, and anilines are denoted by triangles. EWG, electron-withdrawing group; EDG, electron-donating group. (B) Bottom: A univariate correlation between a total Hirshfeld charge on the aromatic ring (∑_rX_C) and ΔG_et⁰. R² = 0.83, ΔG_et⁰ = 146.62 × ∑_rX_C − 38.89, P = 2.68 × 10⁻¹⁷, root mean square error = 4.50, and n = 43. Phenols are marked as circular data points, and anilines are denoted by triangles.

Fig. 6.. Environmental performance of pesticides.

Combined photodegradation and ecotoxicity analysis for a subset of 30 pesticides representing the top, middle, and bottom 10 performers in depletion. Photodegradation: Red indicates higher ΔG_et⁰ values and slower reaction rates, and green indicates lower ΔG_et⁰ values and faster reaction rates. Ecotoxicity: Light green indicates within safer chemical space, and light red indicates outside safer chemical space. E_LUMO (percentile of E_LUMO distribution of no- to low-concern chemicals); purple indicates higher E_LUMO values and increased safety, pink indicates lower E_LUMO values, and black indicates outside E_LUMO safety.

Fig. 7.. Rational design strategy.

Design framework for safer pesticides with controlled degradation.

Fig. 8.. Redesigned pesticides.

Design charts based on protocol outlined in Figure 7 for three exemplary pesticides: DNP (top left), capsaicin (top right), and bromofos (bottom). According to the provided scales, the color of the structures’ outline marks the percentile of E_LUMO distribution of no- to low-concern chemicals; the color of the dot represents percentile of photodegradation (green = highly photodegradable; red = nondegradable), and the position of the dot represents relative safety in terms of log D_o/w and ΔE and the fit in the class- and MOA-defined functional space. Dashed vertical line represents the log D_o/w < 3 limit, i.e., Briggs Rule of 3.