Conformational Analysis of 1,3-Difluorinated Alkanes

Abstract

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.

Figure 1

Summary of prior art on the 1,3-difluoropropylene motif. In conformation indices, l refers to like (both dihedrals have the same sign) and u refers to unlike (different signs).

Figure 2

Full conformational profile of 3,5-difluoroheptanes 14 (A) and 15 (B) in chloroform. See Charts S5–S12 for complete data. The 9 × 9 grids represent conformations involving all internal C–C bonds; the inner CC–CC bond 3 × 3 grids (C,E) represent the conformations involving the central C–C bonds, summed over all 9 possible respective conformations of the respective outer internal C–C bonds and vice versa for the outer CC–CC bonds (D,F). See Figure S5 for details.

Scheme 1. Synthesis of the 3,5-Difluoroheptanes

Figure 3

Experimental (red dots) and theoretical (blue lines) 471 MHz ¹⁹F NMR spectrum of meso-3,5-difluoroheptane 15 in CDCl₃ clearly showing the lack of symmetry in the signal. See Figures S19–S22 for all ¹H and ¹⁹F NMR fitting spectra.

Figure 4

Workflow of the process to extract the experimental coupling constants from the spectra of the 3,5-difluoroheptanes. The ensemble average J-couplings and the experimental fitted J-couplings are given in Tables S4, S6, S8, S10, and S12.

Figure 5

Contributions from different orders of spin correlation to the system trajectory in the pulse-acquire ¹H NMR simulation of anti-3,5-difluoroheptane 14 (16 spins). Different curves correspond to the norms of the projection of the density matrix into the subspace of one-, two-, three-, etc. spin correlations. The two traces in the lower part of the figure correspond to nine- and ten-spin correlations—there are no detectable changes in the simulated spectrum when they are dropped: only correlations of up to eight spins need to be accounted for in this system.

Figure 6

Energy minimum structures of high-population conformers of syn- and anti-2,4-difluoropentane, illustrating imperfect staggering.

Figure 7

Boltzmann probability densities at 298 K obtained from a relaxed potential energy scan for anti-2,4-difluoropentane 12 (top right), syn-2,4-difluoropentane 13 (top left), anti-3,5-difluoroheptane 14 (bottom right), and syn-3,5-difluoroheptane 15 (bottom left). The calculations were performed using the DFT M06/cc-pVTZ method in SMD chloroform.

Figure 8

Correlation between the calculated percentage antiperiplanar conformation of a H–C–C–H (A) or H–C–C–C–F (B) unit and its corresponding experimental J-coupling constant, for all internal CC–CC bonds of 12–15.

Figure 9

1,3-Difluoro motif conformational population changes according to the medium, for 1, 12–15 (M05-2X/6-311+G**). The populations shown represent the sum of any degenerate structures. ^a Each population value of a given heptane conformation represents the sum of the populations of the nine possible conformations involving the outer C–C bonds. ^b Major conformation having this motif. ^c Identical conformers. ^d Enantiomeric conformers.

Figure 10

Hydrocarbon chain population changes according to the medium, for pentane, heptane, and the syn-substrates 13 and 15. The data points represent the population of a single conformation, even for degenerate conformers. The data for the heptanes again refer to the central C–C bonds, with each such population representing the sum of the populations of all possible conformations involving the outer C–C bonds. Color coding is the same as in Table 2. ^aThe population shown refers to only one of the degenerate conformers.

Figure 11

Comparison between the two possible conformers of 13,15 with one C–C–C–C gauche-interaction.