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Pd 1,4-Conjugate

Pd 1,4-conjugate addition is another composed-force-field transfer case: the published TSFF combines a base MM3 field with an OPT overlay, and that composition does not carry over faithfully under our engine. The paper reports internal R² > 0.99 under MacroModel MM3*; our reproduction yields R² = −4.94 under the JAX engine.

Scope

  • Type: Transition state (Pd-catalyzed 1,4-conjugate addition)
  • Molecules: 10 TS structures
  • Parameters: 340 (OPT substructure: 20 bonds, 32 angles, 236 torsions)
  • QM reference: B3LYP-D3/6-31G(d)

Publication

Property Value
Paper Wahlers, J. et al. J. Org. Chem. 2021, 86, 5660–5667
DOI 10.1021/acs.joc.1c00136
System Pd-catalyzed 1,4-conjugate addition
Training set 10 transition-state structures
Engine MacroModel MM3*

What the paper fitted and reports

What the original Q2MM workflow fitted

This TSFF belongs to the same Notre Dame Q2MM program: MacroModel MM3* plus the standard multi-target Q2MM fitting logic, not eigenvalue-only projection.1

  • Structural targets
  • Hessian/eigenvalue targets
  • Q2MM optimization under MacroModel MM3*
  • External selectivity validation on literature reactions

What the paper reports

The paper and thesis summary report:1

  • Internal slopes: ~1.01
  • Internal R²: > 0.99
  • External validation: 82 predictions
  • Selectivity R²: 0.88 with y = 0.86x
  • Selectivity MUE: 1.8 kJ/mol

Our reproduction

Metric Value
Overall eigenvalue R² -4.94
Per-molecule R² range all negative
Positive R² values 0 / 10
Aggregate frequency RMSD 764.4 cm⁻¹ (per-molecule avg: 226.5)

What this means: A negative R² means our engine's reproduction of the published eigenspectrum is worse than simply predicting the average — a complete failure of cross-engine transfer, not a small miss.

All molecules fail the reproduction test

Every molecule is negative. The reproduced eigenspectrum is worse than a mean-value model across the whole training set.

Benchmark results

Ratio check failed — optimization skipped

The JaxLoss/ObjectiveFunction ratio (most recent regeneration: 1.20) is just outside the [0.85, 1.15] tolerance. JaxLoss is not yet a reliable surrogate for this system at the Seminario starting point.

Metric Value
Ratio check 1.20 (out_of_band; upper bound is 1.15)
Initial ObjectiveFunction score 8.26 × 10⁶
Optimization Skipped at default ratio_tol=0.15

Why it fails: The Seminario starting FF has negative eigenvalue R² for all 10 molecules (eig_diagonal R² ≈ −4.5). Unconstrained geometry relaxation finds different local minima in JaxLoss vs ObjectiveFunction, producing divergent loss values. Because the ratio (1.20) is only just outside the upper bound (1.15) — vs orders of magnitude for Rh 1,4-conjugate and Heck relay — this system is a candidate for the ratio_tol=None bypass (see Optimizer Comparison for the experimental status).

See Optimizer Comparison for cross-system comparison and methodology details. Raw numbers are in the convergence baseline in ericchansen/q2mm-data, with full provenance (q2mm git SHA, JAX/OpenMM device, ratio_tol, timestamp).

Comparison and gap analysis

Comparison

The literature TSFF is reported as an excellent internal fit and a strong selectivity model. Our reproduction does not retain that internal fit.

Here the leading explanation is again the composed-force-field workflow. The published TSFF is built from a standard MM3 base plus an OPT overlay. If our engine does not interpret that composition exactly the way MacroModel MM3* does, the fitted eigenvalue structure is not preserved.

Frequency-only optimization improves the benchmark metric substantially — the best Adam+cosine run lowers RMSD from 764.4 to 305.3 cm⁻¹ — but the reproduced eigenspectrum is still negative for every molecule. The transfer problem comes before optimizer choice.

Gap analysis

To close the gap for Pd 1,4-conjugate addition, we would need:

  1. MacroModel-faithful composition of the base MM3 field and OPT overlay.
  2. System-specific validation of Pd nonbonded and coupling behavior after composition.
  3. A full Q2MM re-fit under the original objective once the composed starting field behaves correctly.

The negative R² reflects a transfer gap in the composed FF workflow.

Reproduce

python -m q2mm.diagnostics.cli --system pd-conjugate --backend jax --optimizer optax-adam-cosine

Raw data: q2mm-data/benchmarks/pd-1,4-conjugate-addition/.

  1. Wahlers, J. et al. J. Org. Chem. 2021, 86, 5660–5667. DOI: 10.1021/acs.joc.1c00136 ↩↩