Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Oct 6;143(39):16041-16054.
doi: 10.1021/jacs.1c06281. Epub 2021 Sep 21.

High Site Selectivity in Electrophilic Aromatic Substitutions: Mechanism of C-H Thianthrenation

Fabio Juliá  1 , Qianzhen Shao  2 , Meng Duan  2 , Matthew B Plutschack  1 , Florian Berger  1 , Javier Mateos  1 , Chenxi Lu  2 , Xiao-Song Xue  2 , K N Houk  2 , Tobias Ritter  1
Affiliations

High Site Selectivity in Electrophilic Aromatic Substitutions: Mechanism of C-H Thianthrenation

Fabio Juliá et al. J Am Chem Soc. .

Abstract

The introduction of thianthrene as a linchpin has proven to be a versatile strategy for the C-H functionalization of aromatic compounds, featuring a broad scope and fast diversification. The synthesis of aryl thianthrenium salts has displayed an unusually high para regioselectivity, notably superior to those observed in halogenation or borylation reactions for various substrates. We report an experimental and computational study on the mechanism of aromatic C-H thianthrenation reactions, with an emphasis on the elucidation of the reactive species and the nature of the exquisite site selectivity. Mechanisms involving a direct attack of arene to the isolated O-trifluoracetylthianthrene S-oxide (TT+-TFA) or to the thianthrene dication (TT2+) via electron transfer under acidic conditions are identified. A reversible interconversion of the different Wheland-type intermediates before a subsequent, irreversible deprotonation is proposed to be responsible for the exceptional para selectivity of the reaction.

PubMed Disclaimer

Conflict of interest statement

The authors declare the following competing financial interest(s): F.B. and T.R. may benefit from royalty payments for sales of thianthrene-related compounds.

Figures

Scheme 1
Scheme 1. (A) Methods for Selective C–H Functionalization of Arenes to Introduce Linchpins and (B) Selectivity-Determining Deprotonation in Aromatic C–H Thianthrenations
Scheme 2
Scheme 2. Elucidation of the Reactive Species in Thianthrenation of Arenes: Possible Reactive Species
Scheme 3
Scheme 3. Assessment of Thianthrene Radical Cation (TT•+) as a Reactive Species
Scheme 4
Scheme 4. Assessment of Protonated (TT+–OH) and Trifluoroacetylated (TT+–TFA) Thianthrenium S-Oxide as Reactive Species
Scheme 5
Scheme 5. C–H Thianthrenations with Trifluoroacetyl Triflate 3
Scheme 6
Scheme 6. Assesment of a Thianthrene Dication (TT2+) as a Reactive Species
Figure 1
Figure 1
1H NMR studies on the characterization of TT+–TFA and its reactivity toward arenes. All spectra were measured at −50 °C in CD2Cl2.
Scheme 7
Scheme 7. Possible Reaction Pathways from TT+–TFA to 2
Figure 2
Figure 2
DFT evaluation of the reaction profile of aromatic C–H thianthrenation of toluene. Gibbs free energies are all relative to TTO. The transition states represented by the dashed lines have not been located computationally.
Figure 3
Figure 3
(A) Hammett parameter vs para/meta selectivity in SEAr presented in Table 2. (B) Hammett parameter vs para/ortho selectivity in SEAr presented in Table 2.
Scheme 8
Scheme 8. Steric Effects in Thianthrenations: Intermolecular Competition Experiment between Toluene and Mesitylene
Figure 4
Figure 4
(A) Structural analysis of isomeric σ-complex intermediates. Distances (d) are given in Å and dihedral angles (θ) in deg. (B) Reaction profile. Free energies are all relative to p-I. (C) Reversible addition and selectivity-determining deprotonation of Wheland intermediates. Transition states indicated by dashed lines have not been located computationally.
Scheme 9
Scheme 9. Reversible Homolytic Cleavage in C–H Functionalization of Arenes with Different Sulfoxides
Figure 5
Figure 5
Analysis of site selectivity on toluene for representative C–H functionalizations. Data from (A)–(C) are extracted from refs ( and 101). sds = selectivity-determining step.
Scheme 10
Scheme 10. Reversible Addition of Electrophile in Highly para Selective C–H Functionalization
See this image and copyright information in PMC

References

    1. Friedel C.; Crafts J. M. Sur une nouvelle méthode générale de synthèse d’hydrocarbures, d’acétones, etc. Compt. Rend. 1877, 84, 1392–1450.
    1. Mortier J.Arene Chemistry: Reaction Mechanisms and Methods for Aromatic Compounds; Wiley-VCH: 2015.
    1. Wencel-Delord J.; Dröge T.; Liu F.; Glorius F. Towards mild metal-catalyzed C–H bond activation. Chem. Soc. Rev. 2011, 40 (9), 4740–4761. 10.1039/c1cs15083a. - DOI - PubMed
    1. Chen X.; Engle K. M.; Wang D.-H.; Yu J.-Q. Palladium(II)-Catalyzed C-H Activation/C-C Cross-Coupling Reactions: Versatility and Practicality. Angew. Chem., Int. Ed. 2009, 48, 5094–5115. 10.1002/anie.200806273. - DOI - PMC - PubMed
    1. Carey F. A.; Sundberg R. J., Aromatic Substitution. In Advanced Organic Chemistry: Part A: Structure and Mechanisms; Springer US: 2000; pp 551–604.

Publication types