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. 2018 Sep;10(9):917-923.
doi: 10.1038/s41557-018-0079-7. Epub 2018 Jul 16.

Concerted Nucleophilic Aromatic Substitutions

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Free PMC article

Concerted Nucleophilic Aromatic Substitutions

Eugene E Kwan et al. Nat Chem. .
Free PMC article

Abstract

Nucleophilic aromatic substitution (SNAr) is one of the most widely applied reaction classes in pharmaceutical and chemical research, providing a broadly useful platform for the modification of aromatic ring scaffolds. The generally accepted mechanism for SNAr reactions involves a two-step addition-elimination sequence via a discrete, non-aromatic Meisenheimer complex. Here we use 12C/13C kinetic isotope effect (KIE) studies and computational analyses to provide evidence that prototypical SNAr reactions in fact proceed through concerted mechanisms. The KIE measurements were made possible by a new technique that leverages the high sensitivity of 19F as an NMR nucleus to quantitate the degree of isotopic fractionation. This sensitive technique permits the measurement of KIEs on 10 mg of natural abundance material in one overnight acquisition. As a result, it provides a practical tool for performing detailed mechanistic analyses of reactions that form or break C-F bonds.

Conflict of interest statement

Competing Interests

The authors declare no competing financial and non-financial interest.

Figures

Figure 1
Figure 1
Scope of study. (a) Previously observed Meisenheimer complexes have always been highly stabilized by poor leaving groups and electron-deficient rings. (b) The SNAr reactions studied here. Bold letters denote Meisenheimer complexes, which span a range of stabilities. (The term ‘complex’ does not necessarily indicate that the structure is a true intermediate.)
Figure 2
Figure 2
Assessing 13C isotopic fractionation by suppressing NMR signals from fluorine atoms bound to 12C. (a) Standard 19F{1H} spectrum showing the parent 12C–19F peak flanked by two 13C–19F satellites. (b) The standard spectrum in (a), enlarged 125×. Accurate satellite integrals cannot be obtained directly due to overlap with the parent peak. (c) MQF 19F{1H} spectrum. Suppression of the parent peak allows accurate integration of the satellites.
Figure 3
Figure 3
Computational analysis of the transition from stepwise to concerted behavior (B3LYP-D3BJ/jun-cc-pVTZ). (a) Potential energy surface for reaction A. An intermediate is apparent (lower left). (b) Predicted KIE as a function of geometry for reaction A. The lowest-energy stepwise mechanism follows the white path, avoiding the region of large KIEs. (c) Potential energy surface for reaction B. The “Meisenheimer region” is very high in energy (white). (d) Predicted KIE as a function of geometry for reaction B. The lowest-energy concerted mechanism follows the black path, resulting in a KIE that approaches the maximum possible value. (e) Potential energy (top) and charge distribution (bottom) along the intrinsic reaction coordinate for reaction B. Negative charge is distributed between the nucleophile, the leaving group, and the ring in the non-aromatic TS. Breaks in the curves indicate the position of transition state B. (f) Potential energy surface for reaction C. A typical trajectory (dotted path) reflects a fleeting intermediate or long-lived TS in the Meisenheimer region (lower left).
Figure 4
Figure 4
Simplified Marcus analysis of stepwise vs. concerted SNAr reactions. (a) In stepwise reactions, the Meisenheimer structure is highly stabilized, leading to a minimum along the reaction coordinate (reaction A). (b) Concerted reactions result if the Meisenheimer structure is less stable. This is the typical situation (reaction B). (c) When the Meisenheimer structure is highly stabilized, but leaving group elimination is facile, a borderline situation (reaction C) results. (d) Meisenheimer transition states are stabilized by concurrent donor-acceptor interactions (transition state B is shown).

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References

    1. Williams A. Concerted Organic and Bio-Organic Mechanisms. CRC; Boca Raton: 1999.
    1. Terrier F. Modern Nucleophilic Aromatic Substitution. Wiley-VCH; Weinheim: 2013.
    1. Terrier F. Rate and equilibrium studies in Jackson–Meisenheimer complexes. Chem Rev. 1982;82:77–152.
    1. Brown DG, Boström J. Analysis of past and present synthetic methodologies on medicinal chemistry: where have all the new reactions gone? J Med Chem. 2016;59:4443–4458. - PubMed
    1. Neumann CN, Hooker JM, Ritter T. Concerted nucleophilic aromatic substitution with 19F− and 18F−. Nature. 2016;534:369–373. - PMC - PubMed

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