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      Solvent-Mediated Tunable Regiodivergent C6- and N1-Alkylations of 2,3-Disubstituted Indoles with p-Quinone Methides

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          Abstract

          Indium-catalyzed, solvent-enabled regioselective C6- or N1-alkylations of 2,3-disubstituted indoles with para-quinone methides are developed under mild conditions. Notably, highly selective and switchable alkylations were selectively achieved by adjusting the reaction conditions. Moreover, scalability and further transformations of the alkylation products are demonstrated, and this operationally simple methodology is amenable to the late-stage C6-functionalization of the indomethacin drug. The reaction pathways were explained with the support of experimental and density functional theory studies.

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          Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density

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            Density-functional thermochemistry. III. The role of exact exchange

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              Universal solvation model based on solute electron density and on a continuum model of the solvent defined by the bulk dielectric constant and atomic surface tensions.

              We present a new continuum solvation model based on the quantum mechanical charge density of a solute molecule interacting with a continuum description of the solvent. The model is called SMD, where the "D" stands for "density" to denote that the full solute electron density is used without defining partial atomic charges. "Continuum" denotes that the solvent is not represented explicitly but rather as a dielectric medium with surface tension at the solute-solvent boundary. SMD is a universal solvation model, where "universal" denotes its applicability to any charged or uncharged solute in any solvent or liquid medium for which a few key descriptors are known (in particular, dielectric constant, refractive index, bulk surface tension, and acidity and basicity parameters). The model separates the observable solvation free energy into two main components. The first component is the bulk electrostatic contribution arising from a self-consistent reaction field treatment that involves the solution of the nonhomogeneous Poisson equation for electrostatics in terms of the integral-equation-formalism polarizable continuum model (IEF-PCM). The cavities for the bulk electrostatic calculation are defined by superpositions of nuclear-centered spheres. The second component is called the cavity-dispersion-solvent-structure term and is the contribution arising from short-range interactions between the solute and solvent molecules in the first solvation shell. This contribution is a sum of terms that are proportional (with geometry-dependent proportionality constants called atomic surface tensions) to the solvent-accessible surface areas of the individual atoms of the solute. The SMD model has been parametrized with a training set of 2821 solvation data including 112 aqueous ionic solvation free energies, 220 solvation free energies for 166 ions in acetonitrile, methanol, and dimethyl sulfoxide, 2346 solvation free energies for 318 neutral solutes in 91 solvents (90 nonaqueous organic solvents and water), and 143 transfer free energies for 93 neutral solutes between water and 15 organic solvents. The elements present in the solutes are H, C, N, O, F, Si, P, S, Cl, and Br. The SMD model employs a single set of parameters (intrinsic atomic Coulomb radii and atomic surface tension coefficients) optimized over six electronic structure methods: M05-2X/MIDI!6D, M05-2X/6-31G, M05-2X/6-31+G, M05-2X/cc-pVTZ, B3LYP/6-31G, and HF/6-31G. Although the SMD model has been parametrized using the IEF-PCM protocol for bulk electrostatics, it may also be employed with other algorithms for solving the nonhomogeneous Poisson equation for continuum solvation calculations in which the solute is represented by its electron density in real space. This includes, for example, the conductor-like screening algorithm. With the 6-31G basis set, the SMD model achieves mean unsigned errors of 0.6-1.0 kcal/mol in the solvation free energies of tested neutrals and mean unsigned errors of 4 kcal/mol on average for ions with either Gaussian03 or GAMESS.
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                Author and article information

                Journal
                J Org Chem
                J Org Chem
                jo
                joceah
                The Journal of Organic Chemistry
                American Chemical Society
                0022-3263
                1520-6904
                13 February 2023
                03 March 2023
                : 88
                : 5
                : 3132-3147
                Affiliations
                []Department of Chemistry, Faculty of Sciences, Atatürk University , Erzurum 25240, Türkiye
                []Department of Medical Services and Techniques, Vocational School of Health Services, Hakkari University , Hakkari 30000, Türkiye
                Author notes
                Author information
                https://orcid.org/0000-0002-5399-2520
                https://orcid.org/0000-0002-1504-7480
                Article
                10.1021/acs.joc.2c02937
                9990074
                36779866
                50fb2995-d782-445a-9a34-62606bd3f6a7
                © 2023 The Authors. Published by American Chemical Society

                Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained ( https://creativecommons.org/licenses/by/4.0/).

                History
                : 08 December 2022
                Funding
                Funded by: Türkiye Bilimsel ve Teknolojik Arastirma Kurumu, doi 10.13039/501100004410;
                Award ID: 2211/A
                Funded by: Atatürk Üniversitesi, doi 10.13039/501100004951;
                Award ID: FAD-2019-7025
                Funded by: Atatürk Üniversitesi, doi 10.13039/501100004951;
                Award ID: FAD-2018-6642
                Funded by: Türkiye Bilimsel ve Teknolojik Arastirma Kurumu, doi 10.13039/501100004410;
                Award ID: 2211/C
                Categories
                Article
                Custom metadata
                jo2c02937
                jo2c02937

                Organic & Biomolecular chemistry
                Organic & Biomolecular chemistry

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