Stability Checker

Heuristic stability checker for molecules in retrosynthetic pathways.

When an LLM proposes reactant molecules, some of them may be chemically unstable — strained small rings, anti-aromatic systems, reactive intermediates like carbocations or carbenes, etc. This module catches those problems by inspecting the molecular graph with RDKit descriptors and SMARTS pattern matching. No trained model is required.

from deepretro.algorithms import check_molecule_stability

result = check_molecule_stability("c1ccccc1")
print(result["assessment"])       # "Likely stable"
print(result["stability_score"])  # 100

Checks performed

  1. Strained small rings — 3- or 4-membered rings that contain a heteroatom (N, O, S …) are flagged. Aziridines and azetidines are significantly more strained than plain cyclopropane / cyclobutane.

  2. Anti-aromatic motifs — rings whose π-electron count is a multiple of 4 (Hückel 4n rule) are thermodynamically destabilised. Known patterns (cyclobutadiene, cyclooctatetraene, pentalene) are matched via SMARTS, and π electrons are also counted directly for rings of size 4, 8, 12, or 16.

  3. Fused small rings — two rings of ≤ 4 atoms sharing atoms create extreme angle strain (e.g. bicyclo[1.1.0]butane). These systems can be explosive.

  4. Large heterocycles — rings with ≥ 7 atoms containing heteroatoms tend to be conformationally floppy and often unstable. Very large heterocycles (> 10 atoms, ≥ 3 heteroatoms) get an extra penalty.

  5. Carbocations — positively charged carbon centres are reactive intermediates, not isolable species. The checker distinguishes:

    • sp2 ([C+;X3]) — penalised unless stabilised by an adjacent aromatic ring, allylic double bond, or benzylic position.

    • sp ([C+;X2]) — always penalised heavily.

    • Primary vs secondary — primary is worse because fewer alkyl groups donate electron density.

    • Adjacent to EWG — a carbocation next to F, Cl, Br, I or charged N/S/O is the worst case.

  6. Carbenes — a neutral carbon with two bonds and no hydrogens ([C;X2;H0;+0]) is extremely reactive. Extra penalties if the carbene sits inside a 3- or 4-membered ring or is adjacent to an electron-withdrawing group.

  7. Fused cyclopentane + small hetero ring — a 5-membered all-carbon ring sharing atoms with a 3- or 4-membered hetero ring creates significant ring strain.

  8. Physicochemical outliers — extreme logP values with abs(logP) > 10 or too many rotatable bonds (> 15) each incur a small penalty.

  9. Aromatic bonus — aromatic rings stabilise a molecule, so each one adds a small bonus (capped at +15 total).

Scoring

After all checks, the score is clamped to 0–100:

  • ≥ 80 → "Likely stable"

  • 50–79 → "Moderately stable"

  • < 50 → "Potentially unstable"

Entry points

  • check_molecule_stability — analyse a single SMILES and return a 0–100 stability score with an issue list.

  • is_valid_smiles — quick check that a SMILES string parses.