BDEs indicate the amount of energy required to homolytically break a bond, creating a pair of radical fragments. It can be a useful indicator of the bonds that are most likely to break in a molecule, whether by UV, redox, or other reactions, thus guiding the rational design of active pharmaceuticals, OLEDS, catalysts, and other molecular species.
Computing BDEs is relatively straightforward. First, the lowest energy conformer of a molecule is selected and optimized. Then the desired bond is broken and the energies of the resulting fragments are subtracted from that of the parent molecule (in the literature, De refers to the electronic energy difference, while D0 includes the zero-point energy contribution). When investigating a new molecule, it can be useful to know a large number of bond-dissociation energies (e.g. all C–H and C–X bonds), and the process of computing all of them and keeping track of the data can become very time consuming. Additionally, it is often useful to add a simple correction to approximate methods to better replicate more accurate methods. This saves a significant amount of computational power, but then requires the selection of an appropriate correction factor.
We have developed a simple workflow that provides a variety of established methods for computing bond-dissociation energies that span the fast–accurate Pareto frontier. The computation of enthalpic and entropic effects can be prohibitively expensive, and often are a constant factor for similar bond dissociations, and thus a simple linear regression is used to correct for these effects (and for the lack of fragment optimization in reckless mode).
| Mode | Optimization Method | Singlepoint Method | Optimize Fragments |
|---|---|---|---|
| RECKLESS | GFN-FF | GFN2-xTB | No |
| RAPID | GFN2-xTB | r²SCAN-3c | Yes |
| CAREFUL | r²SCAN-3c | wB97X-3c | Yes |
| METICULOUS | wB97X-3c | wB97M-D3(BJ)/def2-TZVPPD | Yes |
Table 1: Workflow modes
Here is the output of a BDE calculation for all of the bonds in fluoroethane (CCF) using the RAPID workflow mode:
One can quickly see that the hydrogens bonded to the same carbon as the fluorine have lower bond-dissociation energies than those in the terminal methyl group. These values are similar to the experimental results for the bond-dissociation energy of F–CH3 (114.0 kcal/mol, ref) and H–CH2F (102.0 kcal/mol, ref). Bond-dissociation energies can also be computed for aromatic species, such as fluorobenzene. The much higher bond-dissociation energies observed are consistent with the trends seen in experimentally derived values (F–benzene = 125.6 kcal/mol, ref; H–benzene = 112.9 kcal/mol, ref).
The bonds which are the weakest are the most likely sites for degradation reactions, and a variety of steps may be taken to increase the stability. One common technique is to swap hydrogens for deuteriums, improving the metabolic properties of pharmaceuticals and increasing the working lifetimes of OLEDs due to the kinetic isotope effect. Other substitutions may include the addition of electron-withdrawing/-donating group or substitution of a hydrogen with a methyl group if space allows, as the bulkiness of the methyl can often prohibit degradation by various enzymes and chemical reagents.
