A key question that's often important to organic chemists is that of reactivity: how reactive will my molecule be with a given reacting partner? While the simplest way to study this question is just to try the reaction experimentally, this can also be costly, slow, and difficult. Purchasing or synthesizing bespoke chemical matter is expensive and time-consuming, and so computational models of reactivity can, in theory, be extraordinarily useful to chemical research.
The most obvious way to model reactivity is simply to model the relevant transition states using quantum chemistry and use the barrier height to predict reaction rate. This approach works, but can be time-consuming: transition states are difficult to find, and locating a transition state with the correct molecularity and conformation often requires extensive study and sometimes additional experimental work.
Furthermore, the transition-state approach necessitates the selection of an appropriate reacting partner. This might not be obvious in certain cases, e.g. covalent inhibitors, where one desires to model reactivity with "the proteome" holistically rather than one specific nucleophile.
Global electrophilicity, computed as electronegativity squared divided by hardness, is a ground-state property of every molecule that has been found to correlate very well with a molecule's reactivity with a "soft" covalent nucleophile. Global electrophilicity thus serves as an efficient estimate of a molecule's electrophilic reactivity, addressing the above issues with transition-state calculations and providing a good solution for rapid virtual screening.
In particular, global electrophilicity has been shown to be very useful in the design of covalent warheads to react with nucleophilic cysteine residues: for many warheads, comparing global electrophilicity values gives the same trend as transition-state calculations for a fraction of the computational cost.
Rowan makes it fast and simple to compute global electrophilicity. Starting from a variety of file formats, including SMILES, users can submit global electrophilicity calculations through the Fukui index workflow. The calculations run in mere seconds, and the results are visible in the top of the output:
The speed and simplicity of this workflow makes it an appealing choice for designing molecules with the desired reactivity and predicting the effect of complex changes (like scaffold hops) on a molecule's electrophilicity.
