Synthesis of organic liquid crystals containing selectively fluorinated cyclopropanes

Article abstract of DOI:10.3762/bjoc.16.65

This paper describes the synthesis of a series of organic liquid crystals (LCs) containing selectively fluorinated cyclopropanes at their termini. The syntheses used difluorocarbene additions to olefin precursors, an approach which proved straightforward such that these liquid crystal candidates could be efficiently prepared. Their physical and thermodynamic properties were evaluated and depending on individual structures, they either displayed positive or negative dielectric anisotropy. The study gives some guidance into effective structure–property relationships for the design of LCs containing selectively fluorinated cyclopropane motifs.

Full text of DOI:10.3762/bjoc.16.65

Synthesis of organic liquid crystals containing selectively
fluorinated cyclopropanes
Zeguo Fang*1, Nawaf Al-Maharik1,2, Peer Kirsch3, Matthias Bremer3,
Alexandra M. Z. Slawin*1 and David O’Hagan*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2020, 16, 674–680.
1School of Chemistry, Biomedical Sciences Research Complex,
University of St Andrews, North Haugh, St Andrews, Fife KY16 9ST,
United Kingdom, 2Department of Chemistry, Faculty of Science, An
Najah National University, Nablus, Palestine and 3Merck KGaA,
Liquid Crystal R&D Chemistry, Frankfurter Str. 250, 64293 Darmstadt,
Germany
doi:10.3762/bjoc.16.65
Received: 08 February 2020
Accepted: 03 April 2020
Published: 14 April 2020
This article is part of the thematic issue "Organo-fluorine chemistry V".
Associate Editor: P. J. Skabara
Email:
Zeguo Fang* - zf20@st-andrews.ac.uk; Alexandra M. Z. Slawin* -
amzs@st-andrews.ac.uk; David O’Hagan* - do1@st-andrews.ac.uk
© 2020 Fang et al.; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
dielectric anisotropy; difluorocarbene; organic liquid crystals;
selectively fluorinated cyclopropanes
Abstract
This paper describes the synthesis of a series of organic liquid crystals (LCs) containing selectively fluorinated cyclopropanes at
their termini. The syntheses used difluorocarbene additions to olefin precursors, an approach which proved straightforward such
that these liquid crystal candidates could be efficiently prepared. Their physical and thermodynamic properties were evaluated and
depending on individual structures, they either displayed positive or negative dielectric anisotropy. The study gives some guidance
into effective structure–property relationships for the design of LCs containing selectively fluorinated cyclopropane motifs.
Introduction
Display materials associated with modern electronic devices molecular dipole moment is oriented parallel to the long axis of
such as personal mobile phones and TV sets, have changed the molecule, while for the current vertical alignment (VA)
dramatically in the past decades as liquid crystal display (LCD) LCD technology, liquid crystals with negative dielectric
technology has evolved [1,2]. A key challenge is to make suit- anisotropy are required [3]. Fluorine, as the most electronega-
able liquid crystalline (LC) materials that satisfy the require- tive atom, forms stable bonds to carbon and can thus induce
ments for different LCD technologies. For the traditional polarity. It is also attractive as a design feature due to the low
twisted nematic (TN) LCD technology, devices require liquid polarizability of the C–F bond relative to other polar substitu-
crystals with display positive dielectric anisotropy by which the ents such as nitrile and ester groups, and this reduces intermo-
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lecular interactions leading to lower viscosities and thus in- carboxylates as potential chiral dopants to induce a cholesteric
creased life time reliability [4,5]. A significant effort has been phase, but this was not extended to the exploration of positive
devoted to the development of liquid crystals with either posi- or negative dielectrics. Recently, we reported the efficient syn-
tive or negative dielectric anisotropy by introducing the C–F thesis of α,β,β-trifluorocyclopropanes 7 (Figure 2) through
bond or the dipole of a CF2 group either parallel or perpendicu- difluorocarbene addition to alpha-fluorostyrenes [13]. This used
lar to the long molecular axis. For example, in the area of nega- the extraordinary useful method for the generation of difluoro-
tive liquid crystalline materials, Kirsch et al. have reported the carbene from the Ruppert–Prakash (TMSCF3) reagent [14].
synthesis of bicyclohexane and bis(cyclohexyl)ethane liquid DFT analysis suggests the lowest energy conformer of aryl
crystals which contain axial fluorine substituents (Figure 1, 1 α,β,β-trifluorocyclopropane 7 orients the C–F bond perpendicu-
and 2), however, due to the propensity for HF elimination from lar to the aryl ring. So, if the α,β,β-trifluorocyclopropane motif
these molecules over time, these liquid crystals have not been were introduced into an appropriate LC scaffold, it could
adopted as commercial products [6,7]. 2,3-Difluoroaryl motifs reasonably induce negative dielectric anisotropy if the dipole
such as 3 have proven to be a successful class of negative associated with the cyclopropane remains oriented perpendicu-
dielectric anisotropic liquid crystals and the more rigid 1,1,6,7- lar to the molecular axis. Based on this idea, we report the
tetrafluoroindane 4 led to an enhanced polarity and improved design and synthesis of cyclopropanes 8 and 9 with an objec-
negative dielectric anisotropy character [8]. Other liquid crys- tive to assess their LC properties. Cyclopropane 8 with a single
tals of this class are the recently reported fluorinated cyclo- CF2 group offered a control to assess the influence of the alpha-
hexane 5 and 1,1,2,2-tetrafluorocyclohexane 6 [9,10], but the fluorine atom in cyclopropane 9 containing three fluorines. In
complexity of their synthesis has limited their development as order to extend the study to explore other selectively fluori-
practical materials.
nated cyclopropane motifs we set out to prepare liquid crystal
candidates 10 and isomers 11a and 11b. Ether 10 should have
As a consequence, it continues to be a research objective to significant rotational freedom due to rotation around the ether
introduce polar substituents in a manner that can influence the bonds and will be compared with isomers 11a and 11b which
nature of the dielectric anisotropy of the resultant material. In are much more conformationally constrained (Figure 2).
this context we explore the cyclopropane motif containing fluo-
rine atoms. Selectively fluorinated cyclopropanes have been Therefore, the aim of the study was to prepare these target
widely used in pharmaceutical research [11], however, the liquid crystals and evaluate their properties relative to each
introduction of fluorinated cyclopropanes into liquid crystal other, to establish if there were any obvious structure–activity
scaffolds has not received much attention. Haufe et al. [12], re- relationships to emerge for the design of positive or negative
ported enantiomerically pure fluorinated diphenylcyclopropane dielectric materials. Also the fixed spiro CF2-containing cyclo-
Figure 1: Examples of liquid crystal candidates with negative values for dielectric anisotropy (Δε) [6-10].
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Figure 2: Synthetic candidate LC targets 8–11.
propanes 11a and 11b became targets to assess the impact of a of 4:1. There was no requirement to separate these isomers at
configurationally rigid bicyclic motif. It is relatively obvious this stage. Subsequent addition of potassium tert-butoxide into a
that for each of these isomers the CF2 dipole in each cyclo- mixture of 13a and 13b in dichloromethane (DCM) resulted in
propane is orientated either along the molecular axis (for 11a) an efficient elimination to generate vinyl fluoride 14 as a major
or perpendicular to the molecular axis (for 11b), and these were product. Vinyl fluoride 14 was purified by column chromatog-
anticipated at the outset to give positive and negative dielectric raphy in a 42% yield over the two steps. Finally, difluorocar-
anisotropy values, respectively.
benene (:CF2) addition using the TMSCF3/NaI protocol was
used to generate the target product 9 in 46% yield.
Results and Discussion
Synthesis of liquid crystal candidates 8–11
The preparation of cyclopropyl ether 10 was accomplished as
The synthesis of cyclopropane 8 started from olefin 12 illustrated in Scheme 3. Reduction of cyclohexanone 15 with
(supplied by Merck KGaA, Darmstadt), as illustrated in NaBH4 gave cyclohexanol 16 in a ratio of 2:1. The major trans
Scheme 1. Difluorocyclopropane 8 can be directly prepared product 16a was purified as a single entity by column chroma-
through a [2 + 1] carbene cycloaddition reaction. Thus, treat- tography and was isolated in 45% yield. Vinyl ether 17 could be
ment of 12 with trimethyl(trifluoromethyl)silane (TMSCF3) and efficiently prepared using the methodology developed by Bosch
sodium iodide under refluxing conditions [13,14] gave the cor- [16]. Accordingly, treatment of 16a with butyl vinyl ether,
responding product 8 in one step and a 55% yield.
bathophenanthroline (BPhen) and Et3N, using palladium(II) tri-
fluoroacetate as a catalyst, gave vinyl ether 17 in 62% yield in a
The synthesis of trifluorocyclopropane 9 is shown in Scheme 2. single step. Finally, difluorocarbene-mediated difluorocyclo-
Compound 9 was prepared through bromofluorination of 12, propanation generated 10 in 50% yield.
followed by base-induced HBr elimination [15], and then diflu-
orocarbene addition to generate 9. The starting olefin 12 was The synthesis of the diastereoisomers of spiro LC candidates
exposed to an excess of N-bromosuccinimide (NBS) and HF·Py 11a and 11b also started from ketone 15 as illustrated in
to generate 13a and 13b as a mixture of regioisomers in a ratio Scheme 4. Treatment of ketone 15 with methylenetriphenyl-
Scheme 1: Synthesis of 8. Reagents and conditions: a) TMSCF3, NaI, THF, reflux, 55% [13,14].
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Beilstein J. Org. Chem. 2020, 16, 674–680.
Scheme 2: Synthesis of 9. Reagents and conditions: a) NBS, HF·Py, DCM; b) t-BuOK, DCM, 42% in two steps [15]; c) TMSCF3, NaI, THF, reflux,
46%.
Scheme 3: Synthesis of compound 10. Reagents and conditions: a) NaBH4, MeOH, rt, 45%; b) C4H9OCH=CH2, Pd(TFA)2, BPhen, Et3N, 75 °C, 62%
[16]; c) TMSCF3, NaI, THF, reflux, 50%.
phosphine which was generated in situ from methyltriphenyl- 11b for subsequent analysis. Stereoisomer 11a was a crys-
phosphonium bromide (PPh3CH3Br), generated exo-methylene talline solid and a suitable crystal was subject to X-ray struc-
cyclohexane 18 in a very straightforward manner, and the prod- ture analysis and the structure is shown in Scheme 4. In this
uct could be isolated by chromatography in 72% yield [17]. way the stereochemistry of 11a and 11b could be confirmed un-
This olefin was then subject to a difluorocarbene cyclopropan- ambiguously.
ation using TMSCF3 and NaI, and this generated both isomers,
11a and 11b, in a ratio of 5:1, respectively. After three recrys- Evaluation of liquid crystal candidates 8–11a
tallizations, the major isomer 11a could be isolated as a single With the four difluorocyclopropanes 8–11a in hand, our atten-
stereoisomer. It proved impossible to isolate a sample of isomer tion focused on an experimental evaluation of their thermo-
11b without a significant and dominant contamination with 11a. dynamic and physical properties, such as birefringence (Δn) and
Thus, it was with some frustration that we were unable to dielectric anisotropy (Δε). DSC and POM analysis (Table 1) in-
prepare a suitable sample, both in quantity and purity, of isomer dicated that only compounds 8 and 9 exhibited smectic phases.
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Scheme 4: Synthesis of compounds 11. Reagents and conditions: a) PPh3CH3Br, t-BuOK, diethyl ether, 0 °C to rt, 72% [17]; b) TMSCF3, NaI, THF,
reflux; c) recrystallization, 27%.
The smectic phase of LC 8 was maintained over a broad tem- low, which is entirely consistent with their core aliphatic struc-
perature range (54–84 °C), whereas that for 10 and 11a only tures, unlike materials with aromatic rings. The differences for
showed a melting point and these compounds did not display Δn for 8, 9 and 10, were found to be small, whereas the spiro-
any obvious liquid crystallinity (Table 1). Therefore, any devel- cyclopropane 11a had a significantly, decreased Δn.
opment of these latter materials would require extended core
structures to enhance their LC potential.
Table 2: Physical properties of compounds 8–11.
Compound
Δn
Δε
Table 1: Phase transition temperatures of compounds 8–11.
Phase transfer
temperature [°C]
8a
0.056
0.055
0.063
−0.5
−0.2
1.3
9b
10b
11aa
11ac
11bc
0.036
0.054
0.051
4.8
4.3
−1.1
C 54 SmB 84 I
aΔn were extrapolated from a 10 wt % solution in liquid crystal mixture
Merck ZLI-4792. Δε were extrapolated from a 10 wt % solution in liquid
crystal mixture Merck Merck ZLI-2857. bΔn were extrapolated from a
5 wt % solution in liquid crystal mixture Merck ZLI-4792. Δε were
extrapolated from a 10 wt % solution in liquid crystal mixture Merck
Merck ZLI-2857. cCalculated data only at AM1//B3LYP/6-31G(d) level
[18].
8
Tg −70 SmB 82 Ia
9
C35 Ia
C 42 I
As discussed, either positive or negative dielectric anisotropy is
an important parameter related to the driving voltage of LC
displays and in order to reduce energy consumption, good mate-
rials should induce a large value for dielectric anisotropy. Com-
pounds 8 and 9 were found to exhibit the expected negative Δε
values, however, the overall polarity is low (8 = −0.5, 9 = −0.2).
This is presumably due to the ability of the C–C bond attached
to cyclopropane to rotate, and thus the compound will adopt
conformations with low overall molecular polarities. A compar-
10
11a
aDecomposition (C = crystalline, SmB = smectic B, I = isotropic,
Tg = glass transition temperature).
The birefringence Δn (Table 2) for compounds 8–11a was ison of the Δε for 8 and 9 illustrates that incorporation of the
measured (Abbe refractometer). In all cases the Δn values were third alpha-fluorine lowers the overall Δε value. This is presum-
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ably due to a resulting decrease in the overall molecular dipole interested in assessing the energy required for the bispirocyclo-
moment ( ) along the minor axis. When an ether was used as hexane ring to adopt an axial rather than the lower energy equa-
the linkage in compound 10, the compound becomes more flex- torial arrangement. For 11a, the lowest energy conformer found
ible and, perhaps surprisingly, the overall Δε parameter became was a rotamer around the central C–C bond linking the cyclo-
more positive. Clearly the effect of introducing a C–O bond hexane rings, but an essentially isoenergetic conformer is
renders this molecule dissimilar from the others in this series. that found in the X-ray crystal structure. The first conformers
However, changing the core aliphatic structure to the more rigid where the terminal bispirocyclohexane ring lies axial are
spiro structure 11a, brought about a dramatic enhancement of significantly higher in energy (ΔG = +1.25 kcal/mol−1 and
the molecular dipole moment (μ||), resulting in a much more ΔG = +1.19 kcal/mol−1) than the equatorial conformers as illus-
positive and increased parameter value (Δε = 4.8). This experi- trated in Figure 3. Notably for both the axial and equatorial
mental value was close to the predicted calculated value conformers, the orientation of the CF2 group, and therefore its
(Δε = 4.3) as shown in Table 2. It is clear that there is an advan- dipole, remains perpendicular to the long molecular axis
tage in a rigid structure for imparting a maximum polarity. As (requirement for +ve dielectric). A similar result was obtained
stated above, we were unable to obtain a stereochemically pure for stereoisomer 11b (see Supporting Information File 1) again
sample of diastereoisomer 11b, free from 11a, however, theory with the first axial conformer at ΔG = +1.14 kcal/mol−1 above
indicates that 11b should display negative dielectric anisotropy, the ground state equatorial conformer. In this case the orienta-
although the magnitude of the parameter was relatively low tion of the CF2 group, and therefore the dipole, remains perpen-
(Δε = −1.1). Thus the two isomers constitute two different dicular to the long molecular axis (requirement for −ve dielec-
classes of LC materials, entirely as a consequence of stereo- tric) for both the axial and equatorial conformers. This analysis,
chemistry.
and that of the X-ray structure, suggests that the equatorial
conformers will dominate in condensed phases, and that the
The best compound of this series is 11a and it was of interest to overall molecular dipoles will not be compromised by minor
get some insight into its conformational flexibility. Thus, a con- contributions of axial conformers.
formational analysis of 11a (and 11b) was conducted computa-
tionally (ωB97X-D/6-311+G(2d,p)//ωB97X-D/6-31G(d) + ZPE Conclusion
level (see Supporting Information File 1)). There are many In conclusion, a series of candidate liquid crystals 8–11a with
potential low energy conformations arising from alkyl side difluorocyclopropane motifs at their termini were prepared in a
chain C–C bond rotations which would not be anticipated to straightforward manner. In all cases the cyclopropane was intro-
change the overall properties significantly, however, we were duced by difluorocarbene addition to an olefin, the difluorocar-
Figure 3: Theory study exploring the relative energies for different conformers of 11a.
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be compromised by conformational flexibility. Although none
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Supporting Information
Supporting Information File 1
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Experimental protocols and NMR spectra.
[https://www.beilstein-journals.org/bjoc/content/
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Supporting Information File 2
Crystallographic information file of compound 11a.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-16-65-S2.cif]
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Acknowledgements
The EPSRC Mass Spectroscopy Service at Swansea is acknowl-
edged for analysis.
License and Terms
Funding
We thank the Chinese Scholarship Council for a studentship
This is an Open Access article under the terms of the
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(ZF).
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ORCID® iDs
Nawaf Al-Maharik - https://orcid.org/0000-0002-7014-6190
Peer Kirsch - https://orcid.org/0000-0002-9024-7933
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
Alexandra M. Z. Slawin - https://orcid.org/0000-0002-9527-6418
David O’Hagan - https://orcid.org/0000-0002-0510-5552
(https://www.beilstein-journals.org/bjoc)
References
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The definitive version of this article is the electronic one
which can be found at:
Weinheim, Germany, 2013. doi:10.1002/9783527651351
doi:10.3762/bjoc.16.65
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