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Effect of solvent polarity on the regioselective hydroxyalkylation of indole with trifluoroacetaldehyde hemiacetals

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Abstract

The effect of solvents has been found as a crucial factor in determining the regioselectivity of the hydroxyalkylation of indole with trifluoroacetaldehyde hemiacetals. The appropriate selection of the solvent ensured to achieve absolute N1 or C3 regio/chemoselectivity of the reaction depending on the polarity and dielectric constant of the medium. Reaction conditions were optimized considering the effect of solvent, including temperature, time, and molar ratio of reactants to base. In order to rationalize this effect, density functional theory has been employed in which implicit as well as explicit role of solvent was studied, which were further validated with in situ 1H NMR spectroscopy experiments. The comparison of transition states derived from the implicit calculations revealed that the lowest energy path of the reaction in dimethyl sulfoxide (DMSO) leads to product formation with N-selectivity. Further DFT calculations on explicit interactions of indole with DMSO indicated enhanced nucleophilicity on the N atom compared to that of C3 atom, which is evident from the calculated electrostatic potential (ESP) fit charges of these complexes. These findings appear to support the experimental data and explain the N-selectivity in DMSO.

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Funding

Financial support from the Department of Chemistry and BioChemistry, Georgia Southern University (GSU); Department of Chemistry, University of Massachusetts (UMASS), Boston; and the College Office of Undergraduate Research (COUR-GSU) is gratefully recognized.

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Authors and Affiliations

  1. Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Blvd., Boston, MA, USA

    Swarada Peerannawar, Christian Schäfer, Judith Alonzo & Béla Török

  2. Department of Chemistry and Biochemistry, Georgia Southern University, 521 College of Education Drive, Statesboro, GA, 30460-8064, USA

    Abha Sood, Alicia Brown, Steven Sutton, Matthew Christianson, Raven Stocking, Nicole Naclerio & Shainaz M. Landge

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  1. Swarada Peerannawar
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  2. Abha Sood
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Correspondence to Béla Török or Shainaz M. Landge.

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Peerannawar, S., Sood, A., Brown, A. et al. Effect of solvent polarity on the regioselective hydroxyalkylation of indole with trifluoroacetaldehyde hemiacetals. Struct Chem 30, 1941–1956 (2019). https://doi.org/10.1007/s11224-019-01386-x

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  • DOI: https://doi.org/10.1007/s11224-019-01386-x

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