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Structural Chemistry

, Volume 30, Issue 5, pp 1941–1956 | Cite as

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

  • Swarada Peerannawar
  • Abha Sood
  • Alicia Brown
  • Christian Schäfer
  • Judith Alonzo
  • Steven Sutton
  • Matthew Christianson
  • Raven Stocking
  • Nicole Naclerio
  • Béla TörökEmail author
  • Shainaz M. LandgeEmail author
Original Research
  • 29 Downloads

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.

Keywords

Indoles Organofluorine Solvent effect 1H NMR spectroscopy DFT calculations Regioselective Chemoselective Solvent-substrate interaction Modeling 

Notes

Funding information

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.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

11224_2019_1386_MOESM1_ESM.pdf (465 kb)
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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Swarada Peerannawar
    • 1
  • Abha Sood
    • 2
  • Alicia Brown
    • 2
  • Christian Schäfer
    • 1
  • Judith Alonzo
    • 1
  • Steven Sutton
    • 2
  • Matthew Christianson
    • 2
  • Raven Stocking
    • 2
  • Nicole Naclerio
    • 2
  • Béla Török
    • 1
    Email author
  • Shainaz M. Landge
    • 2
    Email author
  1. 1.Department of ChemistryUniversity of Massachusetts BostonBostonUSA
  2. 2.Department of Chemistry and BiochemistryGeorgia Southern UniversityStatesboroUSA

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