Supramolecular packing of alkyl substituted Janus face all-cis2,3,4,5,6-pentafluorocyclohexyl motifs

Article abstract of DOI:10.1039/d1sc02130c

This study uses X-ray crystallography, theory and Langmuir isotherm analysis to explore the conformations and molecular packing of alkyl all-cis2,3,4,5,6-pentafluorocyclohexyl motifs, which are prepared by direct aryl hydrogenations from alkyl- or vinyl-pentafluoroaryl benzenes. Favoured conformations retain the more polar triaxial C-F bond arrangement of the all-cis2,3,4,5,6-pentafluorocyclohexyl ring systems with the alkyl substituent adopting an equatorial orientation, and accommodating strong supramolecular interactions between rings. Langmuir isotherm analysis on a water subphase of a long chain fatty acid and alcohol carrying terminal all-cis2,3,4,5,6-pentafluorocyclohexyl rings do not show any indication of monolayer assembly relative to their cyclohexane analogues, instead the molecules appear to aggregate and form higher molecular assemblies prior to compression. The study indicates the power and potential of this ring system as a motif for ordering supramolecular assembly.

Full text of DOI:10.1039/d1sc02130c

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Supramolecular packing of alkyl substituted Janus
face all-cis 2,3,4,5,6-pentafluorocyclohexyl motifs†
Cite this: Chem. Sci., 2021, 12, 9712
b
Joshua L. Clark,a Alaric Taylor,
Ailsa Geddis,a Rifahath M. Neyyappadath,a
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
Bruno A. Piscelli,c Cihang Yu,a David B. Cordes,
Alexandra M. Z. Slawin,
a
a
c
b
a
*
Rodrigo A. Cormanich,
Stefan Guldin
and David O'Hagan
This study uses X-ray crystallography, theory and Langmuir isotherm analysis to explore the conformations
and molecular packing of alkyl all-cis 2,3,4,5,6-pentafluorocyclohexyl motifs, which are prepared by direct
aryl hydrogenations from alkyl- or vinyl-pentafluoroaryl benzenes. Favoured conformations retain the more
polar triaxial C–F bond arrangement of the all-cis 2,3,4,5,6-pentafluorocyclohexyl ring systems with the
alkyl substituent adopting an equatorial orientation, and accommodating strong supramolecular
interactions between rings. Langmuir isotherm analysis on a water subphase of a long chain fatty acid
and alcohol carrying terminal all-cis 2,3,4,5,6-pentafluorocyclohexyl rings do not show any indication of
monolayer assembly relative to their cyclohexane analogues, instead the molecules appear to aggregate
and form higher molecular assemblies prior to compression. The study indicates the power and potential
of this ring system as a motif for ordering supramolecular assembly.
Received 15th April 2021
Accepted 4th June 2021
DOI: 10.1039/d1sc02130c
rsc.li/chemical-science
their performance due to an orientated polarity introduced by
selective uorination of an organic material (Fig. 1b).6
Introduction
We have developed an interest in the synthesis and proper-
ties of selectively uorinated cyclohexanes and nd that partial
uorination of aliphatic rings can lead to highly polar aliphatic
motifs, particularly if isomers are selected that place uorines
on the same side of the cyclohexane ring.7 All-syn-1,2,3,4,5,6-
hexauorocyclohexane 1 shown in Fig. 2a is the prototype
compound of this class.8 Cyclohexane 1 has all of its six uo-
rines on one face of the ring and is considered to be among the
most polar aliphatic compounds known.9 The molecule
Organouorine compounds have long made important contri-
butions to organic materials chemistry and society more
generally.1 Peruorocarbons where all of the hydrogens in an
aliphatic material are replaced by uorines display very high
heat stabilities and are known for their chemical stability as well
as their immiscibility with both hydrocarbons and water and
ability to dissolve gases.2 The ‘uorous phase’3 has been coined
to recognise the unique properties of this class of materials
which is exemplied most prominently by the ‘non-stick’ poly-
mer and coating poly(tetrauoroethylene) (PTFE).4 Partially
uorinated materials have very different properties and are
characterised by an increasing polarity relative to uorocarbons
or hydrocarbons. Selective uorination will induce polarity, and
a polymer such as poly-(vinylidine uoride)-PVDF displays
piezoelectric properties due to dipoles created by the alter-
nating –CF2– and –CH2– groups, a property maximised by
poling (Fig. 1a).5 Similarly there are a range of liquid crystalline
materials which are used in modern displays and which derive
ꢀ
decomposes/sublimes at 208 C, extraordinarily high for a low
molecular weight aliphatic, and it has a molecular dipole
moment of 6.2 D [calculated at M11/6-311G(2d,p) level], again
extraordinarily high for an aliphatic. The polarity arises because
there are three axial C–F bonds in the cyclohexane ring which
are co-aligned and which generate a strong orientated dipole
due to the maximal electronegativity of uorine. The hydrogens
aSchool of Chemistry, University of St Andrews, North Haugh, St Andrews, Fife, KY16
9ST, UK. E-mail: do1@st-andrews.ac.uk
bDepartment of Chemical Engineering, University College London, Torrington Place,
London, WC1E 7JE, UK
cChemistry Institute, University of Campinas, Monteiro Lobato Street, Campinas, Sao
Paulo, 13083-862, Brazil
Fig. 1 (a) Minimal structures of (PTFE) and polar (PVDF) organofluorine
polymers; (b) selectively fluorinated ꢁve dieletric anisotropic liquid
crystal;6a (c) representation of benzene–hexafluorobenzene stacking
in the solid state.11,12
† Electronic supplementary information (ESI) available. CCDC 2068702–2068707.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/d1sc02130c
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been made by the Glorius laboratory,14 who have demonstrated
that multiply-uorinated aromatics can be directly hydroge-
nated to generate the corresponding all-cis uorocyclohexane
products in one step, without any signicant loss of uorine.
The method used the cyclic(alkyl)(amino)carbene (CAAC)/Rh
catalyst 2 developed by Zeng15 for aryl hydrogenations. Glorius
demonstrated that cyclohexane 1 could be efficiently prepared
from hexauorobenzene by this approach as illustrated in
Fig. 3a reducing the original twelve step protocol to one step. It
follows that a range of monosubstituted alkyl derivatives of
cyclohexane 1 could now be prepared by direct hydrogenation of
alkyl substituted pentauorobenzenes, an approach that forms
the focus of this paper. Indeed, we nd that both the R ¼ Me 3
and R ¼ Et 4 (Fig. 4) substituents are accessible directly by
hydrogenation of their pentauoroaryl precursors, as the rst
examples of alkyl all-cis 1,2,3,4,5-pentauorocyclohexyl deriva-
tives. Developing this further, we also report the synthesis and
some properties the bis-cyclohexyl tethered rings 5 and 6 with
short and long alkyl spacers between the rings and then systems
7–9, with longer alkyl chains terminating in either alkyl, alcohol
or carboxylic acid residues. These compounds are illustrated in
Fig. 3b. In order to gain insight into supramolecular assembly
we have determined the solid state structures of the 3 and 4, bis-
ring systems 5 and 6, as well as 8 and 9 and we have investigated
the deposition of the long chain alkyls 7–9 on a water subphase.
The outcomes are reported below.
Fig. 2 Hexafluorocyclohexane 1 (a) structure and non-equivalent
facial polarity profile; (b) X-ray structure of the prototype Janus face
all-cis hexafluorocyclohexane 1; (c) theoretically predicted optimal
molecular packing of 1 differs from the observed X-ray derived
structure.11
around the ring, three of them co-axial, become polarized by the
geminal uorine atoms rendering them electropositive.7b
Accordingly the molecule has an electrostatically biased nega-
tive (uorine) face and an electrostatically biased positive
(hydrogen) face. More generally aromatic rings are electrostat-
ically negative on both faces and cycloalkanes are neutral and
hydrophobic, however there is no obvious counterpart ring in
organic chemistry that has a ꢁve and a +ve face. This polarised
aspect has led to 1 being described as a ‘Janus face’ ring
system,10 and it can be envisaged that electrostatic attraction
between the uorine and hydrogen faces of such ring systems
could play a role as a motif for ordering and stabilising supra-
molecular assembly. Perhaps the closest related phenomenon
to that described for these Janus face cyclohexanes is the widely
celebrated outcome, described in the early 1960's by Patrick and
Prosser, when benzene and hexauorobenzene are mixed
equally (Fig. 1c).1ꢀ1 The two liquid components generate a solid
material (mp 24 C) which has stacked and alternating (offset)
aryl- and hexauoroaryl-rings, an arrangement accommodated
by the complementary electrostatic proles of these ring
systems. For benzene the ring core is electronegative and the
peripheral hydrogens electropositive, whereas for the hexa-
uorobenzene the ring core is electropositive and the peripheral
uorines are electronegative. This ordering opened up a wide
area of supramolecular exploration which remains active until
the present.12 Janus rings of 1 can be considered to approximate
a fusion of benzene and hexauorobenzene, with the ability to
display a similar ordering phenomenon within a single ring
system. When rings of 1 associate, they order electrostatically
with the uorine face of one ring contacting the hydrogen face
Results and discussion
Hydrogenation (50 bar H2) of pentauoroaryl-toluene and
pentauoroaryl-ethylbenzene using catalyst 2 generated the
corresponding methyl- and ethyl-functionalised all-cis penta-
uorocyclohexanes 3 (55% yield) and 4 (76% yield) respectively
(Fig. 4). Cyclohexanes 3 (mp ¼ 182 ꢀC) and 4 (mp ¼ 148 ꢀC) have
high melting points consistent with strong electrostatic attrac-
tion between the rings, and this contrasts with their hydro-
carbon or peruorocarbon analogues which are liquids at
ambient temperature. It was of immediate interest in the
context of supramolecular assembly to establish if the alkyl
substituents preferred an axial over an equatorial orientation as
it was not obvious if the steric effect of an axial Me/Et group and
two axial C–F bonds would be more or less stabilising than the
of another (Fig. 2b). Theoretical studies indicate that the
interaction energy of two isolated rings of 1 is ꢂ8.2 kcal molꢁ1
,
13
about the strength or stronger than a hydrogen bond, an energy
that will be substantial in supramolecular ordering. The crystal
structure of 1 (Fig. 2b) has the rings arranged such that stacking
is offset from the perpendicular, however theoretical studies
indicate that perpendicular packing shown in Fig. 2c should be
optimal and that there is a relatively low energy between these
polymorphic arrangements. In this paper we explore supramo-
lecular ordering of mono-alkyl substituted derivatives of cyclo-
hexane 1.
A clear challenge in order to explore the properties of these
Janus face systems is access to an appropriate syntheses to
prepare such compounds. Recent and important progress has
Fig. 3 (a) Aryl hydrogenation developed by Glorius14b was adapted to
the synthesis of alkyl substituted all-cis 1,2,3,4,5-penta-
fluorocyclohexane rings systems; (b) structures of alkyl substituted all-
cis pentafluorocyclohexanes 3–9 prepared in this study.
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Electrostatic (NCE) analysis,16b and hyperconjugation DE(NL),
with
electrostatics
favouring
the
axial
conformer
(ꢁ0.95 kcal molꢁ1) and global hyperconjugation interactions
favouring the equatorial conformer in 3 (1.17 kcal molꢁ1) (Table
S1 in ESI†). On the other hand, the Et derivative 4 has a higher
preference for the equatorial conformer, because now the
electrostatic term [DE(L)] (0.68 kcal molꢁ1) also favours the
equatorial conformer. This arises from replacing a positively
charged H atom in 3 by a CH3 group with a negatively charged C
atom in 4 (Fig. 5), the interactions with the axial F atoms
become destabilising (see Tables S2 and S3 in the ESI† for
individual atom–atom interactions) and disfavour the axial
geometry to a greater extent (DG ¼ 1.63 kcal molꢁ1).
Fig.
4 (a) Calculated (M06L-D3/aug-cc-pVTZ level) equilibrium
energies between axial/equatorial conformers of alkyl substituted all-
cis 1,2,3,4,5,-pentafluorocyclohexanes 3 and 4; (b) solid state X-ray
structures of 3 (upper) and 4 (lower). In each case the equatorial
conformer is favoured.
Another interesting feature of the NBO analysis is the
possibility to decompose the total molecular dipole moment
quantitatively into the individual bonds and lone pairs that sum
to give the overall value.16 Since the total dipole moment of
compounds 1, 3 and 4 is mainly directed from the hydrogen to
the uorine face of the cyclohexane ring, we analysed the bonds
and lone pairs that contribute to this axis (Table S5 in the ESI†).
Accordingly, each C–Fax bond contributes ꢂ1.8 D, and the Fax
lone pairs ꢂ1.4 D, to the total dipole, whereas the C–Feq bonds
and Feq lone pairs contribute only ꢂ0.5 D and 0.4 D, respec-
tively. Thus, by replacing an equatorial C–Feq bond from 1 by an
alkyl group as in 3 and 4, only a small decrease in the total
dipole moment occurs, and therefore the mono substituted ring
retains high polarity.
The bis-cyclohexane systems 5 and 6 were next prepared,
with two all-cis 1,2,3,4,5-pentauorocyclohexyl rings anchored
between a shorter and a longer aliphatic spacer. The synthesis
routes to 5 and 6 are summarised in Fig. 6 and 7. Compound 5
was prepared by direct hydrogenation of decauorostilbene 11,
a known substrate readily accessible by a McMurry coupling of
pentauorobenzaldehyde 10.19 The hydrogenation reaction
(catalyst 2, 50 bar H2) proved sluggish and product 5 was
notably highly insoluble in standard chromatography solvents.
As a consequence, a suitable sample for crystal structure anal-
ysis was isolated by recrystallisation rather than column chro-
matography. It was notable that bis-cyclohexane 5 did not have
electrostatic repulsion associated with three axial C–F bonds
when the Me/Et group is equatorial (Fig. 4a).
Since both 3 and 4 are crystalline solids their crystal struc-
tures were determined by X-ray analyses and are illustrated in
Fig. 4b. In each case the solid-state structures have the alkyl
groups equatorial with triaxial C–F bonds. To gain a deeper
insight into the favoured conformations of these mono alky-
lated cyclohexyl systems a theory study (M06L-D3/aug-cc-pVTZ
level) was carried out to establish the relative energies
between the axial and equatorial conformers of 3 and 4 in the
gas phase.16 This theory level showed the best results in
benchmarking calculations using the DLPNO-CCSD(T)/def2-
TZVP level as the benchmark (see ESI†). The results are sum-
marised in Fig. 4a. For cyclohexane 3 it emerged that the
equatorial Me conformer is of lower energy despite it having
a signicantly higher molecular dipole (3ax ¼ 3.87 D versus 3eq
¼
5.49 D), although the energy difference between conformers is
not large (DG ¼ 0.76 kcal molꢁ1), tending towards an iso-
energetic situation, and being signicantly less than for
example methylcyclohexane (ꢂ1.74 kcal molꢁ1).17 However the
equatorial preference increases signicantly (DG
¼
1.63 kcal molꢁ1) for ethylcyclohexane 4 although the situation is
a little more complex due to ethyl group rotation. The equilib-
rium energy difference was calculated aer rotational energy
proles (see ESI†) established the minimum energies for the
axial and equatorial conformers of 4. The conformations in the
solid-state structures of 3 and 4 are clearly equatorial, rein-
forced by the strong intermolecular association between the
more polar conformers in the solid state, and this augers well
for the reliability of supramolecular packing for this series (alkyl
all-cis 1,2,3,4,5-pentauorocyclohexane motifs) more generally.
Natural bond orbital (NBO) analysis16,18 was carried out to
rationalise the signicantly larger equatorial preference for 4
over 3 (Table S1 in the ESI†). NBO analysis separates the relative
global electronic energy [DE(T)] into its Natural Lewis energy
[DE(L)], which accounts for a chemical structure without any
delocalisation and therefore representing steric and electro-
static contributions only, from Natural Non-Lewis energies
[DE(NL)] which account for hyperconjugation. NBO analysis
indicates that the increase in energy difference between the ax/
eq conformers of 4 relative to 3 is due to a balance between
electrostatics DE(NCE) as calculated from the Natural Coulomb
Fig. 5 Calculated NPA charges for the axial and equatorial conformers
of 3 and 4 at the M06-2X/aug-cc-pVTZ level. Blue and red represent
positive and negative charges, respectively (in au).
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solid state. A suitable crystal of 5 was selected for crystal
structure analysis and views of the resultant structure are shown
in Fig. 6.
In the solid state, the linking alkyl chain lies equatorial and
molecules of 5 pack in an interdigitated manner rather than one
on top of each other. The rings of adjacent molecules associate,
with the complementary uorine and hydrogen faces contacting
each other. When two molecules are viewed one above the other
(Fig. 6a) an axial uorine of one ring is pointing directly towards
the axial hydrogens of the next ring. The three CF/HC contact
Fig. 6 (a) Synthesis of 5. (i) Zn, TiCl4, THF, 70 ꢀC, 4 h, 19% yield; (ii) 50
bar H2 gas, 1 mol% cat (2), 4 A MS, hexane, 24 h, 28% yield. (b) X-ray
crystal structure showing two molecules of 1,2-bis-(all-cis-2,3,4,5,6-
pentafluorocyclohexyl)ethane 5 with one molecule lying above the
other and (c) with an orientation highlighting an interdigitated packing.
ꢀ
ꢀ
ꢀ
distances are almost equidistant, (2.46 A, 2.46 A & 2.54 A) and
ꢀ
below the van der Waals contact distance (2.67 A)20 for hydrogen
ꢀ
and uorine. The orientation of the peripheral cyclohexyl rings
in any molecule of 5 is antiparallel, consistent with an
arrangement which reduces the molecular dipole of an isolated
molecule and reduces the net polarity of the crystal.
The bis-cyclohexyl system 6 with a longer linker was
prepared as illustrated in Fig. 7 aer a metathesis reaction21
between styrene 12 and methyl undec-1-enoate, to generate
ester 13. Selective reduction gave aldehyde 14 which was
amenable to a Horner–Wadsworth–Emmons olenation22 with
phosphonate 15 to generate bis-olen 16. Exhaustive hydroge-
nation of both the double bonds and the aryl rings with catalyst
2 generated the desired product 6, again as a solid material. The
melting point of 6 (188 ꢀC) was lower than that of 5 presumably
on account of the longer aliphatic spacer.
In the solid state, the structure shows simpler packing than
5, with the peripheral rings in 6 stacked directly one above
another along the b-axis, and where the linking chains align,
ꢀ
spaced by a repeat distance of 5.19 A for both the cyclohexane
rings and the aliphatic chains, slightly longer than the typical
ꢀ
(4.5–5.0 A) distances for optimal packing in hydrocarbon chain
assemblies.23 There are three CF/HC contacts within stacks of
ꢀ
ꢀ
molecules, two at 2.39 A and 2.46 A, and one notably short at
ꢀ
a CF/HC distance of 2.27 A. Such distances are among the
shortest CF/HC contacts found in the Cambridge Structural
Database24 and well below the sum of the van der Waal's F/H
20
ꢀ
contact distance (2.67 A) suggesting that the electrostatic
attraction between the uorine and hydrogen faces of the rings
is leading to a compression and accommodating these non-
classical hydrogen bonds. As well as these contacts within
stacks, adjacent stacks are also linked by CF/HC contacts, at
Fig. 7 (a) Synthesis route to 6 involving the exhaustive hydrogenation
of 16. (i) Methyl 10-undecenoate 2nd generation Hoveyda–Grubbs
catalyst, CH2Cl2, 40 ꢀC, 14 h, 54%; (ii) DIBAlH, CH2Cl2, ꢁ78 ꢀC, 1 h,
quantitative; (iii) NaH, THF, 0 ꢀC then 14, 0 ꢀC to 66 ꢀC, 53%; (iv) H2 (50
ꢀ
2.32 A.
The study was then extended to the synthesis of the long
chain fatty acid 7 with a terminal pentauorocyclohexane ring
system. The classical amphiphilic nature of fatty acids is such
that they adopt organised supramolecular assemblies in the
solid state or on the surface of water supported by hydrogen
ꢀ
bar), 2 (5 mol%), 4 A MS, hexane, r.t., 33%. (b) X-ray crystal structure
showing the alignment of adjacent molecules of 6. Short CF/HC
ꢀ
contacts (2.27 A) are illustrated which suggest a strong electrostatic
interaction between the cyclohexane rings. (c) View incorporating
a third molecule of an adjacent stack illustrating the condensed bonding of the carboxylate head groups and van der Waals
packing of the alkyl chains.
interactions of the aliphatic chains, typical of lipid
membranes.25 In the solid state such arrangements can be
interdigitated to form a repeat monolayer or the molecules can
a classical melting prole; showing discolouration at 210 ꢀC and
remaining unmelted at 300 ꢀC! This unusual behaviour for
arrange head to head and form bilayers. On water, the carbox-
ylate head groups associate with the aqueous subphase and
a relatively low molecular weight aliphatic is similar to that
observed for cyclohexane 1 (mp ¼ 208 ꢀC),8 and it is indicative of
the strong electrostatic interactions between the rings in the
chains aggregate into monolayer or bilayer assemblies,
a process that can be monitored in a Langmuir trough through
pressure area isotherm analysis.26 Therefore long chain fatty
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Table 1 Melting point comparisons between cyclohexyl and all-cis
2,3,4,5,6-pentafluorocyclohexyl systems
Pentauoro
Hydrocarbon
Fatty acids
Long chain alcohols
Tridecylcyclohexane
7 ¼ 178 ꢀ
8 ¼ 140 ꢀ
9 ¼ 121 ꢀ
C
C
C
21 ¼ 65 ꢀ
22 ¼ 34 ꢀ
14 ꢀCa
C
C
a
Ref. 25.
Scheme 1 Synthetic routes to non-fluorinated cyclohexyl fatty acid 12
and long chain alcohol 13. (i) 4-phenylbutene 18, Grubbs first gener-
ation catalyst ®, CH2Cl2, 40 ꢀC, 14 h, 39%; (ii) H2 (50 bar), 2 (8 mol%), 4
by reduction to generate alcohol 22 or it was hydrolysed to the
desired fatty acid 21. The synthesis of carboxylic acid 7 and
alcohol 8 was accomplished as illustrated in Scheme 2. This
involved a Horner–Wadsworth–Emmons (HWE) olenation23
between pentauoroaryl phosphonate 26 and long chain ester-
aldehyde 24 to generate ester 27 as a mixture of E and Z
stereoisomers. Direct aryl hydrogenation under pressure resul-
ted in the formation of the saturated ester 28. Ester 28 was then
hydrolysed to generate fatty acid 7 and was separately reduced
to long chain alcohol 8. In a separate sequence, a cross
metathesis reaction between terminal alkene 29 and 1-dode-
cene to generate olen 30 generated the resultant olen 30
which was also submitted to an exhaustive hydrogenation
reaction with catalyst 2 (ref. 15) to generate alkylcyclohexane 9.
Melting point comparisons where made between the analogous
partially uorinated and non-uorinated products as an
immediate comparator of the anticipated difference in physical
properties between the two series. These are summarised in
Table 1.
A MS, hexane, r.t., 74%; (iii) NaOH, H2O, MeOH, 65 ꢀC; (iv) DIBALH,
ꢀ
CH2Cl2, ꢁ78 ꢀC to r.t., 1 h, 81%.
acid 7 was targeted as a molecular tool in which to further
explore the mode of supramolecular assembly of the all-syn
pentauorocyclohexyl motif. The study extended to preparing
the corresponding alcohol 8 and methyl terminated alkane 9.
The analogous long chain fatty acid 21 and alcohol 22, without
any uorines, were also prepared as reference compounds for
Langmuir isotherm analyses.
The synthesis routes to fatty acid 21 and long chain alcohol
22 are illustrated in Scheme 1. The length of the chain was
assembled by fusing together methyl 10-undecenoate 17 and
phenylbutene 18 in a cross-metathesis protocol.21 This proved
to be relatively straightforward and the resultant ester 19 was
subject to an exhaustive aryl/olen hydrogenation reaction with
catalyst 2. The product aliphatic ester 20 was either progressed
It is clear that the melting points are very much higher for
the uorinated analogues consistent with electrostatic
Fig. 8 Views of the X-ray determined crystal structures of tridecyl
alkane 9 (upper) and long chain alcohol 8 (lower). (a) Cross sectional
Scheme 2 (a) Synthetic routes to all-cis pentafluorocyclohexyl fatty view down the b-axis of the packing arrangement of tridecyl alkane 9
acid 7 and alcohol 8. (i) (COCl)2, DMSO, Et3N, CH2Cl2, ꢁ78 ꢀC, 74%; (ii) and (b) the stacking arrangement of three molecules of 9 showing an
P(OEt)3, microwave, 140 ꢀC, 5 min, 99%; (iii) NaH, THF, 0 ꢀC to 50 ꢀC, angled (130ꢀ) arrangement between the alkyl chains and the cyclo-
14 h, 58%; (iv) 2 (3 mol%), H2 (50 bar), silica gel, hexane, r.t., 22%; (v) HCl hexyl rings. (c) Cross sectional view down the (1 ꢁ1 0) axis of the
(6 N), H2O, 100 ꢀC, 14 h, 95%; (vi) DIBAlH, CH2Cl2, ꢁ78 ꢀC to r.t., 64%. packing arrangement of long chain alcohol 8 and (d) the stacking
(b) Synthetic route to all-cis pentafluorocyclohexyl long chain aliphatic arrangement of three molecules of 8 also showing an angled (120ꢀ)
9. (i) Grubbs first generation catalyst, 1-dodecene, CH2Cl2, 40 ꢀC, 14 h; arrangement optimised for intermolecular contacts between the alkyl
ꢀ
(ii) H2 (50 bar), 2 (3 mol%), 4 A MS, hexane, r.t., 32% over two steps.
chains and cyclohexyl rings.
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attraction between the faces of the all-cis-2,3,4,5,6-penta-
uorocyclohexyl rings in the solid state.
Long chain alkane 9 and alcohol 8 generated suitable crys-
tals for X-ray crystal structure analysis. The resultant packing
structures are shown in Fig. 8.
Compound 9 (Fig. 8a and b) adopts a packing structure
similar to that found for hexauorocyclohexane 1 where there is
an offset between adjacent cyclohexane rings. The equivalent
ꢀ
ring atoms (uorines or hydrogens) are 5.62 A apart, which is an
ꢀ
increase on the equivalent spacing found in 6 (5.19 A). The long
chain alkane moiety extends linearly in a classical extended anti
zig-zag conformation and the terminal methyl groups interface
to form a double lamellar (bilayer) hydrophobic domain. The
aliphatic chains are compact running parallel to each other at
ꢀ
a regular distance of 4.0–4.2 A along the chains. To accommo-
date this narrowing relative to the cyclohexane ring spacing
ꢀ
(5.62 A) and to presumably maximise van der Waals interac-
tions, the chains are orientated at an angle 130ꢀ with respect to
the plane of the cyclohexane rings.
Fig. 9 (a) Pressure–area isotherms26 on a water subphase of long
chain cyclohexyl fatty acids 21 (left) and 7 (right). Fatty acid 21 presents
a classical isotherm indicating an initial monolayer collapsing to
a bilayer on compression. Fatty acid 7 only displays a low surface area
isotherm indicative of a bi- or multi-layer formation. (b) Pressure–area
isotherms of long chain cyclohexyl alcohols 22 and 8. The aliphatic
alcohol 22 displays classical monolayer behaviour whereas the fluo-
rinated alcohol 8 displays bilayer behaviour.
In the case of long chain alcohol 8 (Fig. 8c and d), the
molecules arrange in a similar manner but there is an addi-
tional extended hydrogen bonding network, forming chains
running along the a-axis between the terminal alcohol moieties
of two molecular domains. The pentauorocyclohexane rings
are again offset, one above another, and the rings associate edge
to edge at the molecular interface with the rings of another
domain of extended molecules forming an innite bilayer array.
Again, the extended aliphatic chains run parallel and are set at
an angle of 120ꢀ to the plane of the cyclohexane ring in a similar
arrangement to that found in 9. This angle allows the aliphatic
evidence at all for an initial monolayer transition for 7. This is
consistent with pre-aggregation of 7 in the 2D-gas phase.
The long chain alcohols 8 and 22 gave more consistent data
due to the increased solubility of 8 as illustrated in isotherms in
Fig. 9b. The reference isotherm for the nonuorinated alcohol
22 indicated well behaved monolayer formation on the aqueous
ꢀ
chains to approach closely (4.0–4.1 A), because the equivalent
ꢀ
atoms of the cyclohexane rings are spaced more widely (5.57 A
ꢀ2
apart), an arrangement that accommodates close van der Waals
contacts between the long chains.
subphase with a condensed phase apparent at around 22–23 A
per molecule.
By comparison, isotherms for the pentauorinated cyclo-
hexyl alcohol 8 did not show monolayer formation. Aer
deposition from a solution in chloroform, a rst phase transi-
Langmuir isotherm analysis
Surface pressure–area isotherms26 were recorded aer deposi-
tion of fatty acids 21 and 7 and long chain alcohols 22 and 8 on
a water subphase in a Langmuir trough, in order to compare the
inuence of cyclohexyl uorination on the surface behaviour
(see ESI†). In the rst instance the non-uorinated fatty acid 21
was deposited onto the water subphase from a solution in
chloroform, as a reference. The resultant isotherm for 21 is
illustrated in Fig. 9a. There is a very clear monolayer transition
ꢀ2
tion is apparent at an area per molecule of 13–14 A , below half
that for the transition observed for reference alcohol 22, indic-
ative of a spontaneous bilayer formation. Interestingly, when
the long chain alcohol 8 is deposited from a solution which
contains acetone (10% by volume in chloroform), then this
perturbs the surface isotherm. A rst compression is apparent
ꢀ2
indicating a more classical monolayer, at an area of 24 A per
molecule. However with further compression a phase transition
ꢀ2
ꢀ2
at about 28–31 A per molecule, a little expanded relative to
to the bilayer (at 13 A ) becomes favoured as illustrated in the
a fatty acid such as stearic acid. With additional compression
this monolayer collapses until a second transition is apparent at
right hand isotherm in Fig. 9b. It would appear that the more
polar solvent (acetone), helps disperse pre-formed aggregations
such that a monolayer becomes observable, before reorganisa-
tion to a bilayer on compression. Repeated compressions and
expansion cycles could not recover any evidence of the mono-
layer. This is illustrated in Fig. 10.
These experiments suggest that the all-syn penta-
uorocyclohexyl ring systems 7 and 8 pre-aggregate and
generate bilayers directly, whereas the non-uorinated cyclo-
hexane systems 21 and 22 display classical behaviour. It is clear
ꢀ2
ꢂ12 A per molecule, suggesting a thermodynamically stable bi-
or multi-layer, before innite compression. Deposition of the
uorocyclohexyl fatty acid 7 required preparation of a pre-
solution with 50% acetone in chloroform to overcome its rela-
tively poor solubility. The resultant isotherm in Fig. 9a shows
ꢀ2
a clear single transition at about 7–9 A per molecule for 7,
similar in area to the second compression for the reference fatty
acid 21. The outcome is indicative of the immediate formation
of at least a bilayer assembly on the surface. There was no
© 2021 The Author(s). Published by the Royal Society of Chemistry
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molecular dipole (polarity) with this arrangement. This augurs
well for strong intermolecular associations which are not
impeded sterically as there will be stronger electrostatic inter-
actions between the more polar equatorial conformers. This
conformation is consistently observed in the solid-state struc-
tures presented here. The study illustrates that these function-
alised rings constitute a novel motif for the design of
supramolecular organic frameworks, a prospect that becomes
practical due to improved methods for the synthesis of building
blocks by the recent developments in peruoroaryl
hydrogenations.27
Author contributions
University of St Andrews, UK: Joshua L. Clark (PhD student)
synthesised compounds 4, 7, 8 and 9, 21 and 22. Cihang Yu
(PhD student) made and crystallised compound 3. Rifahath M.
Neyyappadath (post doc) and Ailsa Geddis (Master's student)
worked together and made and crystallised compound 5. David
Cordes (SEO) and Alexandra Slawin (Professor) are crystallog-
raphers, who between them solved the structures of compounds
Fig. 10 Schematic illustration of the Langmuir isotherms behaviour of
the u-cyclohexyl and u-pentafluorocyclohexanol fatty acids and
alcohols on the water subphase. Arrows indicate the movement of the
barriers to reduce surface area. (A) u-Cyclohexyl fatty acid 21 and
alcohol 22 behave classically to generate a coherent condensed 3, 4, 5, 6, 8 & 9. They also deposited cifs and data at the CCDC.
monolayer, which further compresses to a multilayer. (B) u-Penta-
fluoroyclohexyl fatty acid 7 and alcohol 8 pre-aggregate due to
associations between the terminal rings and compression progresses
directly to a multilayer.
David O'Hagan (Professor) guided the work, arranged the
collaborations and wrote the manuscript. University College
London, UK: Alaric Taylor (post doc) and Stefan Guldin
(Professor) are surface scientists at UCL London, where the
Langmuir isotherm studies were carried out for compounds 7
and 8 and 21 and 22. University of Campinas, Brazil: Rodrigo
that the all-cis petauorocyclohexyl ring systems are self-
Cormanich (Professor) and Bruno Piscelli (PhD student) are
associating. The interaction energy of these rings has been
theorists based at the University of Campinas in Brazil. They
calculated13 to be ꢂ6–8 kcal molꢁ1 and competitive with the
carried out the theory analysis of compounds 3 and 4.
strength of hydrogen bonding interactions between the polar
head groups and water, and this is consistent with the observed
Conflicts of interest
deviation from classical behaviour.
In conclusion, in this study we have prepared the rst
examples of alkyl substituted 2,3,4,5,6-pentauorocyclohexanes
There are no conicts to declare.
where all of the substituents are cis. The bis ring systems 5 and 6
Acknowledgements
were prepared and structure 6 with the longer alkyl spaces
shows a simpler packing arrangement, in that both rings for
each molecule associate with both on adjacent molecules,
rather than the more interdigitated arrangement observed in 5.
The very high melting points (>210 ꢀC for 5 and 188 ꢀC for 6) for
We thank EPSRC for a grant (EP/R013799/1) and for Student-
ships (AT & JC) through a Centre for Doctoral Training (EP/
L016419/1) and a Doctoral Training Partnership (EP/M507970/
1). FAPESP is also gratefully acknowledged for a studentship
these bis-ring systems are striking and is also indicative of the
(BAP, #2019/03855-3), and a Young Research Award (RAC,
strong intermolecular interactions between these cyclohexane
#2018/03910-1). CENAPAD-SP, CESUP and SDumont are
rings. Long chain alkane 9, alcohol 8 and carboxylic acid 7 were
prepared and all had very signicantly higher melting points
relative to their hydrocarbon analogues. These long chain alkyl
acknowledged for computational clusters used in theory
calculations.
derivatives were variously subject to crystal structure and pres-
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Chem. Sci., 2021, 12, 9712–9719 | 9719