Intrinsic Reaction Coordinates
expanding Rowan’s reaction modeling toolkit; verifying transition states; reaction mechanism insights
Synthesizing new drug-like molecules, OLEDs, and polymers requires extensive work in the lab developing new reactions. To achieve high yields, precise selectivity, and fast reaction rates, chemists must carefully optimize conditions and reaction steps. While brute-forcing different solvents, protecting groups, and catalysts in the lab can eventually reveal a workable synthetic route, the brute-force method often lacks the rationality needed to quickly and efficiently find optimal conditions.
Reaction modeling is a robust field that provides significant insight to those with access to both the tools and compute. Computationally modeling mechanistic pathways can reveal what is happening at an atomistic level, providing insight into how high energy barriers, entropic penalties, and alternative pathways may be slowing the reaction kinetics, limiting the yield, or leading to unwanted side reactions. Sadly, these tools are often unwieldy, slow, and filled with arcane knowledge and “magic incantations” (e.g. the famous B3LYP-D3/6-31G*) that are far from optimal.
At Rowan, we've been working on building a toolkit to support reaction design and optimization that includes scans, transition-state optimizations, and transition-state conformer searches. Today, we're excited to be launching our new intrinsic reaction coordinate (IRC) workflow!
IRC calculations start from an optimized transition-state (TS) structure and take a series of mass-weighted steps along the paths of steepest descent away from TS in both a "forward" and "backward" direction until minima are found (or the maximum number of steps parameter is exceeded). The IRC confirms that a proposed transition state truly bridges the reactants and products, as it is not uncommon for a proposed transition state to lead to a different reaction than the one being targeted, such as an internal rearrangement or even a methyl rotation.
IRC calculations can also provide insight into details of the reaction mechanism. An illustrative example for the linear system H + H₂ is shown in Figure 1 below. (We encourage the interested reader to see our recent blog post, “Reactions from the Bottom Up.”)
For simple systems like linear H + H₂, the transition state and reaction path is obvious, but more complicated systems often have non-obvious transition states and complicated reaction paths. For these more complicated reactions, examination of the IRC can indicate the following:
if the reaction path is elementary or contains intermediates,
whether bond-breaking and bond-forming is a concerted or stepwise process, and
whether unfavorable steric clashes are raising the reaction barrier or favorable electronic interactions are lowering it.
The IRC for the simple ethyl isocyanate + water reaction shows that the nucleophilic attack of the water p-orbital on the carbon in the isocyanate is simultaneous with the transfer of a proton to the hydrogen.
The Diels–Alder reaction of vinyl chloride + butadiene shows an asymmetric cyclization reaction where the β-carbon starts forming a bond with the butadiene before the ɑ-carbon. Though this is still far from a sequential reaction, the IRC reveals the effect of the chlorine's electronegativity in leading to an asymmetric attack of the diene (butadiene) on the dieneophile (vinyl chloride). Alternative substitutions can lead to even more drastic asymmetries.
To run an IRC calculation in Rowan, start by finding a transition state. IRCs must be submitted from a well-converged transition-state geometry at an accurate level of theory. The same level of theory should be used for both transition-state optimization and IRC calculation. For IRC calculations, Rowan uses a default step size of 0.05 amu^(1/2) · Å, but it can be advantageous to decrease the step size for tightly curving reaction paths. While the IRC does not need to descend fully down into the well of reactants and products, it is important to have enough steps to show that the transition state truly does connect them as well as to obtain an understanding of the shape of the IRC.
To calculate accurate barrier heights, we recommend resubmitting reactants and products as optimizations, and, when the preferred conformer is non-obvious, conducting a conformer search of each species. (The multistage optimization workflow can be particularly helpful in this regard, mixing levels of theory to provide significant computational speedups.)
Though we have worked to build as robust of a workflow as possible, it is not uncommon to have an IRC fail for a variety of reasons. If a poor starting geometry is chosen, the forward and backward paths may end up falling into the same local minimum, leading to a “transition state” that fails to bridge the reactants and products. If the step size is too large, the workflow may jump off the intrinsic reaction path and optimize to an incorrect species (or lead to an erratic energy profile). If too many steps are taken, the IRC may take a long time to run; if the reaction is a dissociation, the reaction path may wander aimlessly after the initial dissociation occurs. If you run into any of these failure modes, feel free to reach out for help!
We're constantly innovating to bring you new workflows in the reaction space. If you experience any difficulties, or have any ideas for workflows that would help your work, please don't hesitate to reach out to us at contact@rowansci.com!