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fluoroalkane 2 was also expected to prefer the zigzag
conformation, as this conformation would deliver the max-
imum number of 1,2-fluorine gauche alignments while the
insulating central ethyl linker would preclude any 1,3-fluorine
repulsion. Thus, a comparison of the systems 1a, 1b, and 2
should reveal the importance of such stereoelectronic inter-
actions. The butanecyclohexyl rings at the periphery of the
target molecules were chosen for their ability to impart liquid
crystallinity and to aid structural analysis.
A divergent strategy was envisaged for the synthesis of 1a,
1b, and 2, starting from the common precursor
3
(Scheme 1).[14] A Horner–Wadsworth–Emmons reaction of
aldehyde 3 with triethyl phosphonoacetate gave a,b-unsatu-
rated ester 4, and subsequent reduction with diisobutylalu-
minum hydride generated the allylic alcohol 5. Alcohol 5
underwent
a Sharpless–Katsuki asymmetric epoxidation
reaction[15] and furnished the epoxide 6 with 90% ee. Oxida-
tion gave the corresponding aldehyde 7, which underwent a
Wittig reaction with methyltriphenylphosphonium bromide
to generate allylic epoxide 8. Epoxide 8 underwent ring
opening with triethylamine trihydrofluoride to introduce the
first fluorine substituent. Although this reaction required
somewhat forcing conditions, the ring-opened product 9 was
recovered in satisfactory yield with the desired SN2 product
predominating over potential SN2’ and SN1 products. Fluo-
rohydrin 9 (90% ee) was subjected to a symmetrical cross-
metathesis reaction using the second-generation Grubbs
catalyst,[16] and generated difluorodiol 10 as a single diaste-
reoisomer (> 99% ee) after flash chromatography on silica
gel. The E geometry of alkene 10 was confirmed by X-ray
crystallography.[17,18] Both hydroxy groups of 10 were then
activated as their corresponding triflates to generate 11, and
double displacement with a fluoride ion gave the tetrafluoro-
alkene 12 in modest yield, along with various elimination side-
products. Despite this, the overall reaction sequence to this
point was robust and scalable enough to furnish several grams
of the intermediate 12, which served as a pivotal precursor for
diastereoisomers 1a and 1b as well as the tetrafluoroalkane 2:
a product of the direct hydrogenation of 12.
Figure 2. X-ray crystal structures of 1a, 1b, and 2. Structure 1a (top)
À
has vicinal C F bonds aligned gauche to each other to form a helical
pattern as they progress along the carbon backbone (inset: the
fluoroalkyl portion of 1a viewed along the molecular axis). Structure
1b (middle) shows the carbon backbone in a zigzag conformation
with no 1,3-fluorine repulsion. Structure 2 (bottom) shows the carbon
backbone in a zigzag conformation but with a slight twist, possibly
compensating for a large dipole moment.
achieved. A similar zigzag conformation emerges for the
tetrafluoroalkane 2 (Figure 2), although in this case a slight
twist about the long axis of the molecule is observed,
presumably as a consequence of dipole relaxation or possibly
because of crystal packing forces. The vicinal fluorine atoms
of 2 are gauche and with the insulating ethyl linkage in place
there is no possibility of 1,3-fluorine repulsion.
The 1H and 19F NMR spectra of 1a, 1b, and 2 were
analyzed to obtain information on their conformations in
3
3
solution. The spectra gave JHH and JHF coupling constants
which were related through Karplus-type curves to the
corresponding H-C-C-H and H-C-C-F molecular dihedral
angles.[22] In each case (1a, 1b, and 2) all of the observed
3J values were consistent with the solid-state conforma-
Dihydroxylation of 12 with potassium permanganate
furnished the separable diols 13a and 13b in a 9:1 diastereo-
isomeric ratio (Scheme 1).[19] Diols 13a and 13b were then
progressed through to their respective cyclic sulfates 14a and
14b,[20] which were ring-opened with triethylamine trihydro-
fluoride and gave 15a and 15b, respectively. The final fluorine
atoms were installed using the Deoxo-Fluor reagent[21] to
successfully furnish the hexafluoroalkanes 1a and 1b as air-
stable, white, crystalline solids.
3
3
tions.[17] Moreover the JHH and JHF values of 1a, 1b, and 2
were not noticeably affected by changes in temperature or
solvent.[17] The NMR spectroscopy results indicate that the
solid-state conformations of 1a, 1b, and 2 (Figure 2) are
intrinsically preferred by each fluoroalkyl chain, with no
evidence of any artifacts from competing crystal packing
forces.
Crystals of 1a, 1b, and 2 were subject to X-ray crystallo-
These findings are reinforced with molecular modeling
data obtained from truncated octane models of 1a, 1b, and
2.[17] In the case of the hexafluoroalkanes 1a and 1b, the
molecular modeling data is unequivocal: at the MP2/6-311 +
G(2d,p)//B3LYP/6-31G(d) + ZPE level of theory,[23] the
helical and zigzag structures clearly emerge as the lowest
energy conformers of 1a and 1b, respectively. For compound
2, the linear zigzag conformation is the lowest in energy
although there are several other conformers close in energy to
this minimum.[17] This finding suggests that the zigzag
structure of 2 is somewhat destabilized by a high dipole
graphic analysis (Figure 2).[17,18] The structure of 1a does
À
indeed have a helical arrangement of the C F bonds along the
carbon backbone. This arrangement is most obviously appre-
À
ciated by looking at the arrangement of the C F bonds along
À
the molecular axis (Figure 2, inset). The six C F bonds almost
complete a full pitch of the helix, falling short by a 408 angle
between the first and last bonds. In clear contrast, diastereo-
isomer 1b adopts the expected zigzag conformation
(Figure 2), in which 1,3-fluorine repulsion is avoided and
three out of a possible five fluorine gauche alignments are
5458
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 5457 –5460
Hunter, Luke
