Off the Throne: Century Old Mechanism is Wrong
It is a great as well as a trembling moment when something that has been established for over a century is proven wrong. One such instance occurred in 1919, when Eddington's team verified General Theory of Relativity against Newton's Gravitation, literally disproving him over Einstein.
This time, it may not be as legendary as overthrowing Gravity, but we are shocked to discover what we have been doing as a valid reaction mechanism is completely wrong.
Jakob Meisenheimer published his famous paper "About Aromatic Nitro body Reactions" in 1902. And since then, over the past century, research has culminated in what is now known as Aromatic Nucleophilic Substitution, where nucleophilic substitution takes place at electron-poor aromatic rings.
This is already of great interest because nucleophilic substitutions do not occur at vinylic and phenylic positions as the corresponding transition states or the carbocation intermediates are very high in energy. This limits our approach towards constructing a natural molecule because most of them contain multiple stable aromatic rings. But with recent speculations, this may not be the case anymore.
Maybe this should not come as a surprise; as recent developments in chemistry have shown that almost anything is possible, we just have to look for it. This is evident from the rise of many modern fields like C-H bond Activation, Asymmetric Synthesis etc.
The reaction was thought to proceed via an addition-elimination two-step mechanism, with a carbanionic intermediate known as the Meisenheimer Complex. The rate of the reaction was known to be directly dependent on the stability of this complex, making the first step of the reaction the slow rate-determining step. This is the main reason why electron-withdrawing groups on the aromatic ring promote such reactions.
In 2016, a nature paper, first challenged the two-step mechanism of this reaction, showing a one-step concerted reaction in electron-rich deoxyfluorination reaction. But this was only one reaction, so people might not help to put it in one of their well-this-is-an-exception categories. But this recent paper nailed it. They have done "Kinetic Isotope Effect (KIE) studies and computational analyses to provide evidence that prototypical SnAr reactions, in fact, proceed through concerted mechanisms."
The concerted aromatic nucleophilic reaction proceeds via a transition state which resembles the would-have-been Meisenheimer complex. They called it the 'Meisenheimer Transition state". The reaction involved a nucleophilic attack of fluoride on aromatic heterocyclic pyridine compound, with bromine being the leaving group.
They have shown that both two-step reactions via Meisenheimer complex and concerted mechanism via transition state are possible depending on the structural features and reaction conditions.
In the authors' words, "For nucleophilic substitutions on aryl rings, stepwise mechanisms are only predicted to occur when both a strongly electron-withdrawing substituent (for example, nitro) is present and fluoride is the nucleophile or leaving group. For substitutions on pyridine, pyrazine, pyrimidine, no step-wise mechanism is predicted."
This time, it may not be as legendary as overthrowing Gravity, but we are shocked to discover what we have been doing as a valid reaction mechanism is completely wrong.
Jakob Meisenheimer published his famous paper "About Aromatic Nitro body Reactions" in 1902. And since then, over the past century, research has culminated in what is now known as Aromatic Nucleophilic Substitution, where nucleophilic substitution takes place at electron-poor aromatic rings.
This is already of great interest because nucleophilic substitutions do not occur at vinylic and phenylic positions as the corresponding transition states or the carbocation intermediates are very high in energy. This limits our approach towards constructing a natural molecule because most of them contain multiple stable aromatic rings. But with recent speculations, this may not be the case anymore.
Maybe this should not come as a surprise; as recent developments in chemistry have shown that almost anything is possible, we just have to look for it. This is evident from the rise of many modern fields like C-H bond Activation, Asymmetric Synthesis etc.
The reaction was thought to proceed via an addition-elimination two-step mechanism, with a carbanionic intermediate known as the Meisenheimer Complex. The rate of the reaction was known to be directly dependent on the stability of this complex, making the first step of the reaction the slow rate-determining step. This is the main reason why electron-withdrawing groups on the aromatic ring promote such reactions.
In 2016, a nature paper, first challenged the two-step mechanism of this reaction, showing a one-step concerted reaction in electron-rich deoxyfluorination reaction. But this was only one reaction, so people might not help to put it in one of their well-this-is-an-exception categories. But this recent paper nailed it. They have done "Kinetic Isotope Effect (KIE) studies and computational analyses to provide evidence that prototypical SnAr reactions, in fact, proceed through concerted mechanisms."
The concerted aromatic nucleophilic reaction proceeds via a transition state which resembles the would-have-been Meisenheimer complex. They called it the 'Meisenheimer Transition state". The reaction involved a nucleophilic attack of fluoride on aromatic heterocyclic pyridine compound, with bromine being the leaving group.
"The result can be viewed as 'Meisenheimer Transition state'."Their analysis shows that as traditional SN2 type attack where the HOMO of the nucleophile donates to the σ-LUMO orbital of the C-Br bond is not possible it rather donates to the π-LUMO orbital of C=N bond of the aromatic ring, and then the lone pair of N donates to the σ-LUMO orbital of the Br atom to make it leave.
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| Orbital Interactions in Concerted Mechanism. (the diagram is reproduced from the nature paper) |
They have shown that both two-step reactions via Meisenheimer complex and concerted mechanism via transition state are possible depending on the structural features and reaction conditions.
In the authors' words, "For nucleophilic substitutions on aryl rings, stepwise mechanisms are only predicted to occur when both a strongly electron-withdrawing substituent (for example, nitro) is present and fluoride is the nucleophile or leaving group. For substitutions on pyridine, pyrazine, pyrimidine, no step-wise mechanism is predicted."
"Given that many SnAr reactions of interest are performed on heterocycles with good leaving groups (for example Cl, Br), it is likely that concerted mechanisms are actually very common."So, we can expect quite a change in the views and application of aromatic nucleophilic substitution reactions down the road. I am really excited to see how this new discovery of the concerted mechanism is exploited in total synthesis.
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