For as long as I can remember, I have been fascinated by the periodic table of elements and how it relates chemical properties to an elements position in the table. Its predictive applications and its ability to teach us some of the principles behind chemical transformations are far-reaching and cannot be overestimated.

At the same time, chemical reactivity is much more nuanced than might be gleaned by looking at the rows and periods of Mendeleevs venerable classification. For example, carbon participates in an overwhelmingly diverse set of chemical transformations, yet relatively little can be concluded about carbons context-dependent reactivity by looking at the periodic table alone. So what is the most appropriate means to classify organic transformations?

The prevailing approach, prescribed by most textbooks, centres on functional groups. This method builds on sameness and categorises reactions based on the expected reactivity of atoms in particular environments. But this classification is not optimally conducive to predicting reaction outcomes and establishing the mechanism by which they proceed. While modern theoretical methods based on quantum mechanics are demonstrably appropriate at suggesting detailed ab initio explanations to countless molecular-level phenomena, there might be benefits to a simple structure-driven formalism that builds on reactivitys foundation: the driving force that is needed to run energetically uphill steps. Securing an appropriate match between the driving force and the reactive intermediate that needs to be created or channelled in a particular direction is what chemical reactivity is all about.1

At first, the driving force concept appears straightforward: favoured processes either minimise enthalpy or maximise entropy (or both). But the driving force is anything but an easy concept to understand. Try asking a colleague about how many types of driving forces they know. It is not a simple question. The usual suspects might include strain release, formation of strong bonds and the like, but the answer will be dwarfed by the overwhelming number of documented chemical transformations and their reasons to exist. Even if we had an exhaustive list of all driving forces imaginable, their actual utility would be limited. This is because, in order to benefit from a driving force, one first needs to cross a kinetic barrier. This is why, despite its universal appeal, driving force remains one of the most intangible and abstract concepts in chemistry. While the notion of the driving force is being used and misused all the time, it is not always possible to apply this concept to address chemistry challenges in a logical way.

Try asking a colleague about how many types of driving forces they know

What could help to rationalise chemical reactivity would be to categorise the known driving forces and uphill steps for comparative purposes. One particular embodiment of this way of thinking does exist. In electrochemistry, standard electrode potentials help to find productive combinations of reductants and oxidants based on thermodynamic arguments from electrochemical half-reactions. These numerical values show how easy or difficult it is for a given species to undergo electron transfer. While the experimentally measured and tabulated values for electrode potentials are useful, they are limited to electron transfer processes that involve charged intermediates on electrode surfaces. What if instead of electrode potential, we consider the broader concept of chemical potential and apply it to mechanism-driven organic chemistry? This sounds appealing but, in practice, chemical potential has not been meaningful for practitioners of organic chemistry because it is not apparent how to apply it in rationalising reactivity.

The prevailing approach, prescribed by most textbooks, centres on functional groups. But this classification is not optimally conducive to predicting reaction outcomes and establishing the mechanism by which they proceed. While modern theoretical methods based on quantum mechanics can suggest detailed ab initio explanations to countless molecular-level phenomena, there might be benefits to a simple structure-driven formalism that builds on reactivitys foundation: the driving force that is needed to run energetically uphill steps. Securing an appropriate match between the driving force and the reactive intermediate that needs to be created is what chemical reactivity is all about.1

At first, the driving force concept appears straightforward: favoured processes either minimise enthalpy or maximise entropy (or both). But the driving force is anything but an easy concept to understand. Try asking a colleague about how many types of driving forces they know. The usual suspects might include strain release, formation of strong bonds and the like, but the answer will be dwarfed by the overwhelming number of documented chemical transformations and their reasons to exist. Even if we had an exhaustive list of all driving forces imaginable, their actual utility would be limited. This is because, in order to benefit from a driving force, one first needs to cross a kinetic barrier.

What could help to rationalise chemical reactivity would be to categorise the known driving forces and uphill steps for comparative purposes. One particular embodiment of this way of thinking already exists. In electrochemistry, standard electrode potentials help to find productive combinations of reductants and oxidants based on thermodynamic arguments from electrochemical half-reactions. These numerical values show how easy or difficult it is for a given species to undergo electron transfer. While the experimentally measured and tabulated values for electrode potentials are useful, they are limited to electron transfer processes that involve charged intermediates on electrode surfaces. What if instead of electrode potential, we consider the broader concept of chemical potential and apply it to mechanism-driven organic chemistry? This sounds appealing but, in practice, chemical potential has not been meaningful for practitioners of organic chemistry because it is not apparent how to rationalise reactivity using this concept.

What is lacking is a classification of available driving forces and their matches with appropriate uphill steps. A particularly attractive proposition would be to find new and previously underappreciated correspondence between endergonic and exergonic elementary reactions. I propose that we consider each endergonic or exergonic step as a synthetic half-reaction (SHR), similar to electrochemical half-reactions. SHRs can then be linked if they have matching higher-energy states, corresponding to ionic and radical intermediates or out-of-equilibrium conformations that help drive reactions. This builds on a reasonable assumption that the energetic benefits of the driving force must operate in the area of the molecule where chemical heavy lifting causes a chemical transformation. I refer to such instances as spatioenergetic matches.2

It stands to reason that only some matches between synthetic half-reactions would be productive or interesting. While many of these combinations might correspond to already established processes, I suspect that there will be instances that have not received prior attention and experimental verification. The possibility to find new reactions by understanding how half-reactions can be spatioenergetically matched with one other is an enticing proposition. On a pedagogical level, this way of thinking might encourage new ideas and expand students horizons away from the driving force usual suspects.

There is presently no way to comprehensively evaluate productive combinations of driving forces and their cognate uphill steps. Indeed, search engines such as Reaxys and SciFinder do not offer an opportunity to evaluate higher energy states. I propose creating a continually expanding knowledge base of SHRs. The time is right for the emergence of a system that will allow intuitive understanding of the relationships
between reactive intermediates and other high energy states. This knowledge base should stand as a worthy complement to the periodic table of elements.

While the half-reaction idea should be intuitively clear to any organic chemist, there is presently no way to comprehensively evaluate productive combinations of driving forces and their cognate uphill steps. Indeed, search engines such as Reaxys and SciFinder do not offer an opportunity to evaluate higher energy states. I propose creating a continually expanding knowledge base of SHRs. The time is right for the emergence of a system that will allow understanding of the relationships between reactive intermediates and other high energy states. This knowledge base should stand as a worthy complement to the periodic table of elements.

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Space, energy and synthetic half-reactions | Opinion - Chemistry World