Synthesis and conformation of multi-vicinal fluoroalkane diastereoisomers

Article abstract of DOI:10.1002/anie.200701988

(Chemical Equation Presented) Doing the twist: Differences in behavior between isomers of straight-chain alkanes bearing four vicinal fluorine atoms are revealed by conformational analyses (X-ray diffraction, NMR spectroscopy). For example, computational

Full text of DOI:10.1002/anie.200701988

Angewandte
Chemie
DOI: 10.1002/anie.200701988
ꢀ
C F Compounds
Synthesis and Conformation of Multi-Vicinal Fluoroalkane
Diastereoisomers**
Luke Hunter, Alexandra M. Z. Slawin, Peer Kirsch,* and David OꢀHagan*
The incorporation of fluorine atoms is a powerful method for
modulating the properties of organic compounds.[1] The
selective introduction of one fluorine atom as a replacement
for hydrogen or a hydroxy group can confer important
properties in medicinal chemistry[2] because of the particular
this class of molecules and forms a basis for predicting more
generally how multi-vicinal fluoroalkanes behave.
The first isomer of this series, the all-syn tetrafluoro
compound 5a (Scheme 1), was synthesized in nine steps from
fluoro alkene 1.[5] The synthetic sequence was then adapted
for the preparation of the anti-syn-anti isomer 5b and the
racemic syn-syn-anti isomer 5c.[6]
Tetrafluoroalkanes 5a, 5b, and rac-5c were crystalline,
and their structures were confirmed by single-crystal X-ray
analyses. In the structure of the all-syn isomer 5a[5] (Figure 2),
ꢀ
properties of the C F bond, and perfluorination of alkanes
has led to a wealth of industrially useful compounds.[3]
Intermediate between these compound classes are partially
fluorinated molecules, and they have been studied far less
owing to the lackof good synthesis methods and control in
multiple fluorine introduction. In this area we have been
interested in exploring alkanes bearing multiple vicinal
fluorine substituents (such as shown in Figure 1), a new
Figure 1. Three a,b,g,d-tetrafluoroalkane diastereoisomers.
class of compounds with potential applications as perfor-
mance molecules in organic materials, for example as novel
liquid crystals. Placing single fluorines vicinal to each other
generates stereogenic centers, and careful evaluation of the
properties of such molecules requires control in their syn-
thesis. This stereochemical complexity is a key feature which
sets multi-vicinal fluoroalkanes apart from both their hydro-
carbon and perfluorocarbon analogues.
Our initial investigations developed synthetic routes to
three-[4] and four-[5]vicinal-fluorine systems. Herein we report
the preparation of three different diastereoisomers of a four-
vicinal-fluorine motif (Figure 1, R = OTs, Ts = 4-methylphe-
nylsulfonyl) and the evaluation of their relative conforma-
tions in the solid and solution states. This study is the first for
[*] Dr. L. Hunter, Prof. A. M. Z. Slawin, Prof. D. O’Hagan
Centre for Biomolecular Sciences and School of Chemistry
Universityof St. Andrews
North Haugh, St. Andrews, Fife KY16 9ST (UK)
Fax: (+44)1334-463808
E-mail: do1@st-andrews.ac.uk
Dr. P. Kirsch
Merck Ltd. Japan, Liquid Crystal Technical Center
4084 Nakatsu, Aikawa-machi, Aiko-gun,
243-0303 Kanagawa, (Japan)
Fax: (+81)462-853-838
E-mail: Peer_Kirsch@merck.co.jp
Homepage: http://chemistry.st-and.ac.uk/staff/doh/group
Figure 2. Crystal structures of 5a–c. C white, F green, H blue, O red,
S yellow. Dihedral angles (left to right) between vicinal fluorines:
5a,[5]66.7, 59.7, and 66.78; 5b, 176.8, 66.9, and 176.88; 5c (onlyone
enantiomer shown), 74.7, 77.7, and 32.98. Selected coupling constants
from the 1H NMR spectra of 5a–c are given; values which suggest
differences between the solid- and solution-state conformations are
highlighted in boxes. The solution conformation of 5c is obtained by
[**] We thank the EPSRC for funding this research.
ꢀ
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
rotation of one C C bond (shown in pink) to give a longer zigzag
carbon chain.
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Scheme 1. Synthesis of 5a,[5] 5b and rac-5c. Reagents and conditions:[6] a) Grubbs 2nd-generation catalyst, CH2Cl2, D; b) KMnO4, MgSO4, EtOH, CH2Cl2,
H2O, 08C; c) SOCl2, pyridine, CH2Cl2, room temperature; d) NaIO4, RuCl3, MeCN, H2O, room temperature; e) Bu4NF, MeCN, room temperature; f) H2SO4,
H2O, tetrahydrofuran, RT; g) H2, Pd/C, MeOH, room temperature; h) TsCl, collidine, 508C; i) (MeOCH2CH2)2NSF3 (Deoxo-Fluor), CH2Cl2, D.
the fluoroalkyl portion of the molecule did not adopt an
extended zigzag conformation: instead, the molecule prefer-
red a C2-symmetric “bent” conformation which nevertheless
preserved gauche alignments[7] between each pair of vicinal
fluorines, and also between the outer fluorines and the tosyl
ester oxygen atoms.
conformational flexibility in solution at 298 K. However,
despite this flexibility, the X-ray conformation still seems to
dominate, since the expected gauche alignments all give
smaller 3J values than the expected anti alignments. The
1H NMR spectrum of 5a was also recorded at 215 K, but only
marginal differences in the 3JHH and 3JHF values were found at
this lower temperature.[6]
As seen in the crystal structure[8] of isomer 5b (Figure 2),
the fluoroalkyl moiety also has C2 symmetry, but in contrast
with 5a the chain of 5b adopts an extended zigzag con-
formation in the solid state. This result is perhaps surprising
since this extended conformation precludes two of the
possible three fluorine gauche relationships.[7]
In contrast with the somewhat ambiguous NMR spec-
troscopy results obtained for isomer 5a, a clear picture
emerged of the solution conformation of 5b (Figure 2).[9] In
this case, the conformation displayed in the X-ray structure
was found to dominate in solution at 298 K, as evidenced by
3
The solid-state conformation of syn-syn-anti isomer rac-
5c was also investigated. Although rac-5c is crystalline, X-ray
analysis was not straightforward because of poor crystal
quality, substantial disorder, and the presence of two crystal-
lographically independent, nonsymmetrical enantiomeric
contributors which alternate throughout the solid-state struc-
ture. However, a diffraction data set with acceptably low
disorder was obtained. In the resulting solid-state structure of
rac-5c[8] (Figure 2), all three pairs of vicinal fluorines are
approximately gauche but the dihedral angles deviate con-
siderably from 608. It thus appears that the aromatic tosyl
groups dominate the crystal-packing interactions, with the
fluoroalkyl chain apparently forced to adopt a somewhat
strained conformation. This result highlights an important
issue relating to the crystal structures of all three isomers 5a–c
(Figure 2): Since the tosyl groups are essential for the
crystallinity of the materials, they must by definition domi-
nate the crystal-packing interactions and may therefore
obscure the intrinsic conformational preferences of the
fluoroalkyl chains themselves. Thus, the NMR spectra of
5a–c were examined to gain information about their solution
conformations.
the more ideal JHF values which clearly reflect gauche and
anti alignments consistent with the extended zigzag confor-
mation. Thus, it seems that this conformation is intrinsically
favored by the fluoroalkyl chain itself, and is not a product of
competing crystal-packing forces in the solid state.
The hypothesis that crystal-packing forces are responsible
for distortion of the fluoroalkyl chain of 5c is supported by
evidence of its solution conformation (Figure 2). In this case,
the 3JHH and 3JHF values obtained from the 1H NMR spectrum
of 5c all fell quite clearly into gauche or anti categories,
suggesting that one conformation is strongly preferred in
solution; however, this solution conformation does not match
the X-ray conformation. It seems that in solution, the
fluoroalkyl chain of 5c foregoes one fluorine gauche inter-
action so that a longer section of the carbon chain can adopt
the extended zigzag conformation.
To gain further insight into the behavior of multi-vicinal
fluoroalkanes 5a–c, computational analyses were performed.
Model calculations[10] on fluorohexanes 6a–c (Figure 3)
indicate that of all three isomers in the linear zigzag
conformation, 6b has the lowest-energy. Within the series
6a–c, 6b is the only isomer where the linear conformation
represents the global energy minimum, which is also reflected
in the crystal structure of 5b (Figure 2). For the all-syn isomer
6a, the linear conformation is 6.50 kcalmolꢀ1 higher in energy
For compound 5a, the 3JHH and 3JHF values obtained from
the 1H NMR spectrum were somewhat intermediate in
magnitude[9] (Figure 2), suggesting that 5a exhibits significant
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Angewandte
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hydrogen bridges.[6] The dimerization energies are difficult
to interpret in a quantitative manner because of the large
variation in hydrogen-bond lengths and orientation, but
typical energies seem to be in the range of 1.0–1.6 kcalmolꢀ1
per H···F contact. However, because of steric restrictions,[6]
the maximum dimerization energy is probably limited to
about 6–7 kcalmolꢀ1 for linear all-syn fluoroalkanes.
In summary, we have used our recently described
synthetic methodology[5] to prepare three unique diastereo-
isomeric a,b,g,d-tetrafluoroalkanes, and the conformational
preferences of each isomer in the solid and solution states has
been examined. It emerges that the avoidance of 1,3-repulsive
interactions is the dominant conformational consideration in
these multi-vicinal fluorine compounds, with the fluorine
gauche effect contributing a more subtle conformational
influence, and we have extrapolated our findings to extended
multi-vicinal fluorine systems. This workprovides the first
conformation study on this class of molecules and provides
information on the behavior and properties of future perfor-
mance molecules containing vicinal fluorine motifs.
Figure 3. Left: The simplified model system 6. Middle: Calculated
linear conformations and right: either minimum (6a, 6c) or next-
higher energyconformation ( 6b). C gray, F green, H white; red arrows
indicate g+ gꢀ-F–F interactions.[11] Relative energies are in kcalmolꢀ1
.
Inset: the model system all-syn-CH3(CHF)12CH3 with its helical mini-
mum energyconformation.
Received: May 4, 2007
Published online: September 4, 2007
Keywords: conformation analysis · fluorine · NMR spectroscopy ·
organofluorine chemistry
than the lowest-energy conformer, which corresponds to the
crystal structure of 5a (Figure 2). The lowest-energy confor-
mer calculated for isomer 6c is similar to that for the solution
structure determined by NMR spectroscopy of 5c, providing
further support that the crystal structure of 5c (Figure 2) is
dominated by packing of the tosyl groups.
The major conformational driving force for the structures
in Figure 3 appears to be avoidance of 1,3-F···F and 1,3-
F···CH3 interactions. For the “linear” conformations, 6a has
two g+ gꢀ interactions,[11] whereas 6c has only one, and 6b
none. From the sequence 6a!6c!6b it is estimated that
each g+ gꢀ-F···F interaction costs about 3.4 kcalmolꢀ1 in steric
strain.[12] For the “bent” pair 6b and 6c, the main difference is
a 1,3-F···CH3 interaction, costing 4.04 kcalmolꢀ1. In this
context, the vicinal fluorine gauche effect (ca. 0.8 kcal
molꢀ1)[7] has only a secondary influence.
.
[1] a) P. Kirsch, Modern Fluoroorganic Chemistry, Wiley-VCH,
Weinheim, 2004; b) R. D. Chambers, Fluorine in Organic
Chemistry, Blackwell, Oxford, 2004.
[2] a) F. M. D. Ismail, J. Fluorine Chem. 2002, 118, 27; b) P. Jeschke,
ChemBioChem 2004, 5, 570.
[3] G. G. Hougham, P. E. Cassidy, K. Johns, T. Davidson, Fluoro-
polymers: Synthesis and Properties, Kluwer Academic, New
York, 1999.
[4] M. Nicoletti, D. OꢀHagan, A. M. Z. Slawin, J. Am. Chem. Soc.
2005, 127, 482.
[5] L. Hunter, D. OꢀHagan, A. M. Z. Slawin, J. Am. Chem. Soc.
2006, 128, 16422.
[6] See Supporting Information for further details.
[7] a) N. C. Craig, A. Chen, K. H. Suh, S. Klee, G. C. Mellau, B. P.
Winnewisser, M. Winnewisser, J. Am. Chem. Soc. 1997, 119,
4789; b) L. Goodman, H. Gu, V. Pophristic, J. Phys. Chem. A
2005, 109, 1223.
[8] CCDC-645778 (5b) and CCDC-645779 (5c) contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data request/cif. The data
for 5a can be found through ref. [5].
To gain insight into conformational effects in more
extended sequences, the all-syn-CH3(CHF)nCH3 series was
studied by computational analysis. For each of the homo-
logues from n = 2–12, the energies and structures of the linear
and the lowest-energy conformation were calculated at the
MP2/6-311 + G(2d,p)//B3LYP/6-31G(d) + ZPE
level
of
theory.[10] Only for n = 2 does the linear conformer represent
the energy minimum. There is a clear, first-order relationship
between relative linearization energies and the number of
g+ gꢀ-F···F contacts,[6] with each such interaction incurring an
energetic price of approximately 3.0 kcalmolꢀ1. In the lowest-
energy conformation of the extended all-syn isomers (see
Figure 3 with n = 12), a helical arrangement is adopted which
[9] Three-bond H–H and H–F coupling constants obey Karplus
ꢀ ꢀ ꢀ
ꢀ ꢀ ꢀ
relationships with the corresponding H C C H and H C C F
dihedral angles: “typical” JHH values are 1–3 Hz for gauche
3
alignments and 6–8 Hz for anti alignments (see ref. [13]), while
“typical” 3JHF values are 5–15 Hz for gauche alignments and 25–
35 Hz for anti alignments (see ref. [14]).
[10] Gaussian03 (RevisionD.01): M. J. Frisch et al., see Supporting
Information. The minimum geometries were optimized on the
B3LYP/6-31G(d) level of theory, and were verified to have only
positive eigenfrequencies. The energies of the conformers were
calculated on the MP2/6-311 + G(2d,p) level of theory, using the
B3LYP/6-31G(d) geometries and zero-point energies. The
energies of the dimers were calculated at the same level of
ꢀ
places all the C F bonds gauche with uniform handedness and
thus avoids any g+ gꢀ-F···F repulsions.
An additional stabilization of the linear-chain conforma-
tion of the shorter all-syn- and possibly also of fragments of
the longer oligofluoroalkanes (all-syn-CH3(CHF)nCH3)
might arise from the formation of intermolecular H···F
Angew. Chem. Int. Ed. 2007, 46, 7887 –7890
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theory and basis-set superposition error (BSSE)-corrected using
the counterpoise method.
[11] Review on this type of steric interaction: R. W. Hoffmann,
Angew. Chem. 1992, 104, 1147; Angew. Chem. Int. Ed. Engl.
1992, 31, 1124.
[12] This result is in agreement with a previous computational study
on 1,3-difluoropropane: D. Wu, A. Tian, H. Sun, J. Phys. Chem.
A 1998, 102, 9901.
[13] A. M. Ihrig, S. L. Smith, J. Am. Chem. Soc. 1970, 92, 759.
[14] C. Thibaudeau, J. Plavec, J. Chattopadhyaya, J. Org. Chem. 1998,
63, 4967.
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