Conformational Analysis of 1,3-Difluorinated Alkanes

Fluorine substitution
can have a profound impact on molecular
conformation.
Here, we present a detailed conformational analysis of how the 1,3-difluoropropylene
motif (–CHF–CH2–CHF–) determines
the conformational profiles of 1,3-difluoropropane, anti- and syn-2,4-difluoropentane, and anti- and syn-3,5-difluoroheptane. It is shown that
the 1,3-difluoropropylene motif strongly influences alkane chain conformation,
with a significant dependence on the polarity of the medium. The conformational
effect of 1,3-fluorination is magnified upon chain extension, which
contrasts with vicinal difluorination. Experimental evidence was obtained
from NMR analysis, where polynomial complexity scaling simulation
algorithms were necessary to enable J-coupling extraction
from the strong second-order spectra, particularly for the large 16-spin
systems of the difluorinated heptanes. These results improve our understanding
of the conformational control toolkit for aliphatic chains, yield
simple rules for conformation population analysis, and demonstrate
quantum mechanical time-domain NMR simulations for liquid state systems
with large numbers of strongly coupled spins.