Strategic Stereoselective Halogen (F, Cl) Insertion: A Tool to Enhance Supramolecular Properties in Polyols

Article abstract of DOI:10.1002/chem.201902983

To improve the supramolecular properties of organic compounds, chemists continuously need to identify new tools. Herein, the influence of the stereoselective insertion of halogen atoms (F or Cl) on different supramolecular properties is analyzed. Insertin

Full text of DOI:10.1002/chem.201902983

A Journal of
Accepted Article
Title: Strategic stereoselective halogen insertion (F, Cl), a tool to
enhance supramolecular properties in polyols
Authors: Céline Sperandio, Guilhem Quintard, Jean Valere Naubron,
Michel Giorgi, Mehdi Yemloul, Jean-Luc Parrain, Jean
Rodriguez, and Adrien Quintard
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Chem. Eur. J. 10.1002/chem.201902983
Link to VoR: http://dx.doi.org/10.1002/chem.201902983
Supported by

10.1002/chem.201902983
Chemistry - A European Journal
FULL PAPER
Strategic stereoselective halogen insertion (F, Cl), a tool to
enhance supramolecular properties in polyols
Céline Sperandio,[a] Guilhem Quintard,[b] Jean-Valere Naubron,[c] Michel Giorgi,[c] Mehdi Yemloul,[a]
Jean-Luc Parrain,[a] Jean Rodriguez,[a] Adrien Quintard,[a]*
Abstract: In order to improve supramolecular properties of organic
structures, chemists continuously need to identify new tools. Herein,
we report a full study analyzing the influence of the stereoselective
insertion of halogen atoms (F or Cl) over different supramolecular
properties. By inserting anti-halohydrins in polyols, we considerably
strengthened the H-Bonding networks as well as other
supramolecular interactions. This behavior resulted in improved
anion binding, H-bonding catalysis or organogel properties of the
designed polyols opening strong perspectives for applications in
other classes of substrates.
as platforms to create promising organic gels for example.7
However, the limited availability and tunability of synthetic
polyols hamper the improvement of the desired properties thus
considerably restricting the potential applications.
In this context, we questioned how halogen insertion (F or Cl)
would impact the supramolecular properties of acyclic polyols
systems.
a) Amphotericin B
OH
OH
O
OH
HO
O
OH OH
OH OH
O
COOH
H
Introduction
b) 1,2-fluorohydrins H-bond acidity:
OH
OR
OH
F
Organic chemistry has evolved over the last decades to become
a pivotal science for understanding and developing physical or
biological tools. As a result, to answer the increasing societal
demand for more elaborated materials or drugs, organic
chemists must continuously invent and understand efficient
molecular interactions. In this regard, the development of new
engineered molecular or supramolecular entities is crucial to
selectively and efficiently create a required chemical, physical or
biological function of interest.
Complex aliphatic polyols are known in nature for their ability to
selectively coordinate with a wide array of molecules. Through
the creation of hydrogen bonding frameworks, polyols bring
crucial bioactivities to the impressive amount of natural products
possessing this particular motif.1 For example, the anti-fungal
activity of natural amphotericin B is in part due to its ion
transportation ability through membrane by supramolecular
assembly (Scheme 1.a).2 To understand and potentially improve
polyols properties, researchers have relied on the development
of synthetic mimics. It has been shown notably by the group of
Kass that in the acyclic series, cooperative effects between the
different hydroxyl functions in 1,3-polyols were responsible for
enhanced H-bonding properties.3 As a result, aside from
medicinal chemistry, recent studies have shown great
expectations by the use of synthetic polyols in anion binding4,5 or
H-bonding catalysis.6 In addition it was also shown that the
hydrogen bonding frameworks created by 1,2-diols could serve
OH
t-Bu
t-Bu
t-Bu
Increased H-bond acidity
F
trans
cis
c) Proposed halogenated polyols:
X = F, Cl
trans-1,2-
halohydrins
-acidity
-conformation
-halogen
H-bonding network
H
H
H
Modular
side chain
O
O
O
X
X
interaction
Halogen insertion =
improved supramolecular
assembly
Scheme 1. Amphotericin B, fluorohydrins acidity and proposed halogenated
1,3,5-triols
In nature, chlorohydrins are central to different natural products
possessing impressive bioactivities.8 However, the exact
implication of these chlorine atoms is not always well
understood.9 On the other part, fluorine is interesting given its
ability to modulate organic molecules lipophilicity, adjacent
functional groups acidity or conformation with poor impact on the
steric environment.10 As a result, it is not surprising that almost
25% of commercial drugs contain at least one fluorine atom.
Often relying on fluorinated aromatics or perfluorinated chains,
the positive effect of fluorine insertion was also used with
success in material sciences.11a The electronic modulation and
conformational restriction through the so-called “gauche effect”
developed in drug design are also useful for the conception of
improved catalysts.11b-c
[a]
C. Sperandio, Prof. J-L. Parrain, Prof. J. Rodriguez, Dr. A. Quintard*
Aix Marseille Univ, CNRS, Centrale Marseille, iSm2, Marseille, France.
E-mail: adrien.quintard@univ-amu.fr
[b]
[c]
G. Quintard
Université de Lyon, INSA LYON, Ingénierie des Matériaux Polymères
IMP-UMR CNRS 5223 F 69621, Villeurbanne, France
Dr. J-V Naubron, Dr. M. Giorgi
Aix Marseille Univ, CNRS, Centrale Marseille, Spectropole, Marseille,
France
Supporting information for this article is given via a link at the end of the
document.
Among fluorinated backbones, 1,2-fluorohydrins have found
limited applications to enhance supramolecular properties of
acyclic alcohols.12 This is surprising given the ubiquity of
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a) Fluorinated triols synthesis:
aliphatic alcohols in biologically active molecules and natural
products and might be due to the lack of general understanding
on the influence of 1,2-fluorohydrins. Indeed, recent studies
aiming at determining the effect of fluorine over the acidity of
cyclohexanols indicated a complex behavior.13 While going from
an alcohol to a trans-1,2-fluorohydrin increased the acidity,
oppositely, going to the cis-1,2-fluorohydrin had a negative effect
on the acidity (Scheme 1.b).13 Given this observation and the
biological role of 1,2-chlorohydrins, we wondered about applying
anti-1,2-halohydrin insertion as a general tool to improve
supramolecular properties in extended 1,3-polyols. We
hypothesized that embedding anti-1,2-halohydrins in such
backbones would considerably strengthen the crucial H-bonding
network (Scheme 1.c). Conformational stabilization and
presence of halogen interactions would additionally positively
impact the structures with great potential in a broad range of
applications.
1)
Ar
Ar
OH OH OH
*
cat1
R
R
R
R
O
N
OTMS
H
Ar = (3,5-CF3)-C6H3
HOOC
R
COOH
F
F
5a-h
(S)-cat1
3, 2, cat1 (20 mol%)
1
+
(Using
)
O
MTBE, rt
or
OH OH OH
1 Cu(acac)
2 (15 mol%),
then
,
NFSI
+
2) NaBH4, THF, MeOH, 0 °C
32-41% over two steps
After recrystallisation:
>95:5 dr; >99:1 er
2
3a-h
F
F
)
ent-5a-h
(Using (R)-cat1
b) Chlorinated triols synthesis and dechlorination:
O
3a, 6,
1)
COOH
HOOC
R
OH OH OH
L-Prolinamide (20 mol%)
CH2Cl2, 0°C to rt
then
2) NaBH4, THF, MeOH, 0 °C
33-34% over two steps
After recrystallisation:
>95:5 dr; >99:1 er
1
+
O
R
R
1 Cu(acac)
2 (15 mol%),
,
NCS
Cl
Cl
+
8a-g
6
TTMSH,
toluene,
3a-g
AIBN
(10 mol%)
110°C, 24 h
85-88%
OH OH OH
This study would bring fundamental knowledge to better
appreciate the impact of 1,2-halohydrins over organic molecules
supramolecular behavior. In our design, modulation of the lateral
chains of such motif would ensure the broad applicability of the
approach in a wide range of domains going from organogel
formation, catalysis to anion binding.
R
R
9a-g
Scheme 2. Multi-catalytic route to halogenated 1,3,5-triols
Finally, to fully assess the halogen insertion influence, radical
dechlorination of 8 provided dehalogenated triols 9 in good
yields.16
Results and Discussion
OH OH OH
OH OH OH
R
R
Polyols synthesis
F
F
X = H: 9a
X
F
X
Development of new chemical tools for physical applications
strongly depends on our ability at rapidly and stereoselectively
constructing the required complex molecular objects of interest
in the most practical, straightforward and economically reliable
manner. Notably, the rapid assembly of acyclic structures
possessing multiple controlled stereocenters as in halogenated
polyols represents a daunting task. To this endeavor, we
5b
:
:
R = n-C8H17
R = n-C10H21
ent 5a
8a
X = F:
X = Cl:
-
5d
OH OH OH
OH OH OH
Ph
Ph
5e
5c
F
F
F
OTBDMS OH OH OH
OTBDMSOH
OH OH OH
OH
recently identified
enantioselective
halogenated 1,3,5-triols 5 and 8 from a bio-sourced ketodiacid 1
(Scheme 2).14
The sequence involves an organocatalyzed enantioselective
halogenation of aldehydes 3 followed by a diastereoselective
a
multi-catalytic sequence enabling the
X
X
X
X
X = H: 9f
X = F:
X = Cl: 8f
X = H: 9g
X = F: ent-
X = Cl: 8g
direct eco-compatible preparation of
ent 5f
-
5g
Scheme 3. 1,3,5-triol structures prepared
copper-catalyzed bi-directional aldolization reaction.
A
Triols structures, aggregation and organogelation
subsequent reduction of the ketodiol intermediates provides a
rapid access to C2-symmetric fluorinated or chlorinated triols 5
and 8. These triols, originally formed as mixtures containing
around 80% of the major diasteromers could be efficiently
obtained in excellent stereoselectivity through single
recrystallization (>95:5 dr and >99:1 er).15
With an easy access to a broad range of different 1,3,5-triols, we
first focused on the structural feature of these synthetic
arrangements in the solid state. Gratifyingly, 1,3,5-triols 5a, 8a
and 9a possessing terminal isopropyl chains were crystalline
and their solid structures could be determined by single crystal
X-ray diffraction (Figure 1).17 The three triols possessing a rigid
bilayer type motif are isostructural with differences in interactions
and packings. Remarkably, concerning 5a, it must be pointed
out that the fluorine atoms are placed trans to the alcohols
without any gauche conformation. The preference of trans-
relation over classical gauche stabilization is of utmost
importance and in contradiction with 1,2-fluorohydrins common
observations.18,11c This effect can be explained through the
stabilization of the linear structure through the triols H-
bonding probably minimizing dipole-dipole interactions. The
same type of conformation is also observed in the parent
chlorinated triol 8a. In 5a and 8a, the halogen atoms are pointing
outside of the strong hydrogen bonding network consisting of
two inter and one intra alcohols hydrogen bond. This
By changing the nature of the starting aldehydes, we have now
applied this multicomponent protocol to the simple and
straightforward preparation of
a family of fluorinated or
chlorinated 1,3,5-triols (Scheme 3). The presence of different
lateral chains on the halo-triols should ensure the required
modulation of the structure to match with the desired
supramolecular properties. The availability of both enantiomers
of cat1 enables access with equal efficiency to both enantiomers
of 5, an interesting features to study the influence of the chirality
over supramolecular properties. The synthesis is scalable (15
mmol of 1) and can be performed easily without the requirement
of column chromatography given the crystallinity of most of the
1,3,5-triols.
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arrangement creates an infinite 1D chain of hydrogen bonds.
The halogen atom insertion (F or Cl) gives a higher packing
index thanks to the presence of additional halogen-hydrogen
intermolecular interactions.19,20 Confirming our hypothesis, the
anti-fluorine crucial trans-relationship electronic repulsion
increases the strength of intermolecular hydrogen bonding with
shorter O-O bond distances of 2.77 and 2.78 Å for 5a vs 2.79
and 2.80 Å for 9a. On the contrary, the larger size of the chlorine
atom probably extends the distance between two molecules by
steric repulsion resulting in longer H-bonding in the self
assembly (2.79 and 2.86 Å for the intermolecular H-bonding).
This effect is counterbalanced by the number of additional
halogen-hydrogen intermolecular interactions resulting in the
higher packing index for this chlorinated triol.
As can be seen from these calculations, 5a with the two trans-
fluorohydrins is highly favored by more than 7.8 Kcal.mol-1
through minimized dipole-dipole interactions as compared to the
other rotamers possessing one or two gauche fluorohydrins
(entry 1 vs entries 2-4).
Table 1 Conformational analysis of 5a and 8a at M06-2X/6.311+G(d,p)
(ZPE corr.) level of theory
Relative
Newman representations
C3-C4 C8-C9
Dihedral angles (°)
X-C-C-O
& O-C-C-X
Entry
energy
(Kcal.mol-1)
1
-178 & -173
-52 & -51
95 & -173
-52 & 56
0
OH OH OH
9a
2
3
4
5
+7.84
+10,95
+11.47
0
O4
O5
O2
O3
O1
°
O1°°°O2 = 2.71 A
Packing index: 62.7
°
O1°°°O4 = 2.79 A
Packing energy: -144.4 kJ.mol-1
°
O3°°°O5 = 2.80 A
OH OH OH
5a
F
O4
F
O2
O5
O3
O1
Packing index: 65.9
Packing energy: -150.2 kJ.mol-1
°
-175 & -175
O1°°°O2 = 2.71 A
°
O1°°°O4 = 2.77 A
°
O3°°°O5 = 2.78 A
OH OH OH
6
7
8
-59 & -171
-58 & 90
+0.77
+3.91
+4.70
8a
Cl
O4
Cl
O5
O2
O3
O1
Packing index: 66.1
°
°
°
O1°°°O2 = 2.74 A
O1°°°O4 = 2.79 A
O1°°°O4 = 2.86 A
Packing energy: -162.3 kJ.mol-1
Figure 1. Single crystal X-ray diffraction and molecular packing of 9a, 5a and
-58 & -59
8a
DFT calculations also confirmed in the gas phase this stabilized
trans-relationship in the halohydrins (Table 1).21 Geometry
optimizations and frequencies calculations were performed at
the DFT level of theory by using the M06-2X functional22 as
implemented in the Gaussian 09.23 For all the atoms, all-electron
standard 6-311+G(d,p) basis set was employed. For each
optimized stationary point vibrational analysis was performed to
establish its nature as a minimum or saddle point, and zero-point
vibrational energy (ZPE) corrections were included in all relative
Interestingly, in the case of chlorohydrin 8a, more conformational
freedom is calculated and the most stable conformation features
two trans-chlorohydrins (entry 5). However, one of the two
chlorohydrin can rotate to obtain a mixed trans/cis conformer of
almost equal energy (0.77 Kcal.mol-1 difference, compare entries
5 and 6). Finally, chlorohydrins with two cis relationships are
disfavored by more than 3.9 Kcal.mol-1 (entries 7 and 8). More
rotational freedom is observed around the central alcohol,
confirming the role of the halogen in conformational rigidification
(see SI). This suggests that the rotational freedom of this central
non-halogenated alcohol allows to adapt the structure to the
energies (E). NBO
6
program,24 which is included in
Gaussian16 suite of programs, was used to obtain natural bond
orbitals (NBOs), atomic net charges and the energetic evaluation
of secondary interactions.
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environment (auto-assembly or anion coordination and catalysis)
(vide infra).
of this particularly small organic molecule (FW = 268) is able to
gel 2.75 mL of petroleum. The gel materials obtained can be
reversibly generated easily through successive heating-cooling
cycles. Using coordinating polar solvents such as CH3CN or
EtOH, no gelation is observed indicating that disruption of the H-
bonding network breaks down the gel.
In order to improve these gel properties, we modulated the
lateral chains of the fluorinated triols notably by increasing their
lipophilicity (see supporting information for all the polyols tested).
Satisfyingly, fluorinated polyol 5b possessing the linear C8H17
chain provided materials with a lowering CGC and efficient for a
broad range of solvents (see Table 2). Notably, even the more
difficult coordinating EtOH and CH3CN could form a gel in the
presence of only 1-2 wt/v% of the fluorinated polyol. The full list
of efficient gelation solvents including diesel, silicon oil, pump oil
(parrafin) can be found in the supporting information. Of interest
for photonic applications,7,25 some of these gels are translucent
as for 5b o-xylene gel shown in Table 1.
The single crystal X-ray diffraction obtained for halogenated
triols clearly demonstrate the ability to create strong H-bonding
networks as well as self-assembly nano-structures, two key
elements for further applications. Thus, we were curious to see
how these changes observed in the solid state would impact
other supramolecular properties.
Gels created by small organic molecules (organogelators)
entrapping solvents in high order 3D networks through fibers
self-assembly have recently gained considerable interests.25 For
example, the potential of these smart materials found
applications in photonics, oil spill recovery, catalysis or as self-
healing materials for example.25 However, the limited structural
variations often based on sensitive acetals and esters functions
can restrict the potential of these organogelators.
solvent
X
X
X
X
X
X
OH OH OH
OH OH OH
OH OH OH
OH OH OH
OH OH OH
OH OH OH
Table 2. Influence of the substitution on gelation in selected solvents (see SI
for other solvents) and 0.33 wt/v% 5b image of an o-xylene translucent gel
OH OH OH
X
X
X
X
monomers
X
X
X
X
3D network:
gel
OH OH OH
OH OH OH
self-assembled
fibers
n-C8H17
n-C8H17
X
X
F
F
X = H: 9a
8a
5b
Scheme 4. Proposed mechanism of gelation with X-triols
X = Cl:
X = F: ent
-5a
The creation of new gels through fibers formation is closely
related to crystallization with subtle differences in the assembly
process conducting to the solvent trapping.26 However, the
rational de novo design of improved organogelators still
represents a daunting challenge. As a result, the discovery of
new tools to enhance gelation of innovative LMOG (Low
Molecular Weight Organogelators) platforms is highly desirable.
Given the solid-state structure of synthetic 1,3,5-triols, we
hypothesized that as in 1,2-diol LMOG's,7 the central polyols
would create the expected H-bonding networks while introducing
two external aliphatic chains would stabilize the gel through van
der Waals interactions with the solvent (Scheme 4). Given the
supposed stronger H-bonding network, halogen preorganization
and hydrophobicity, stronger supramolecular networks and as a
result higher gel efficiency should be obtained through selective
halogen insertion.
Solvent
CGC in wt/v%, Tgel (°C)[a]
9a
8a
NG
NG
5a
5b
Benzene
NG
NG
1%, 50°C
0.66%, 59°C
0.5%, 28°C[c]
Toluene
0.31%,
35°C[c]
o-xylene
NG
2%, 38°C
0.8%, 64°C
0.29%,
60°C[c]
Petroleum[b]
CH3CN
NG
2%, 28°C
NG
0.36%, 78°C 0.25%, 75°C
NG
NG
1%, 53°C
To determine and compare the organogelator efficiency of 1,3,5-
triols we determined several parameters such as Critical
Gelation Concentration (CGC in wt/v%) below which the gel
scrambles and Gel Transition Temperature (Tgel in T°C) at
which the gel starts falling apart by using the classical vial
inversion method (Table 2).27
Comparison of the gelation properties of fluorinated, chlorinated
and non-halogenated triols indicated totally different behaviors.
The non-halogenated polyol 9a did not provide any gelation at 2
wt/v%. On the contrary, a relatively weak gel was observed with
chlorinated polyol 8a in o-xylene or petroleum. The weak
gelation property can be explained based on the crystal
assembly by the size of the chlorine atom repelling the two
polyols layer and decreasing the fibers strength. Gratifyingly,
insertion of fluorine impressively improved the gelation
properties of 5a. In various non-polar organic media such as
benzene, toluene or petroleum, a strong gel is obtained using as
low as 0.36 wt/v% of the organogelator meaning that only 10 mg
CGC = Critical Gel Concentration. Tgel = Gel transition temperature. NG = No
gelation observed at 2 wt/v%. [a]: Tgel measured at 2 wt/v%. [b]: drugstore
bottle of hydroalkanes (C11-C14), iso-alkanes, n-alkanes, cycloalkanes with
35% of toluene as the aromatic constituent. [c]: Translucent gel.
Given the excellent performance of fluorinated triols as LMOG's,
and to understand the effects behind gelation, we decided to
further study in detail the properties and structures of these gels.
First of all, the gel properties obtained by the vial inversion
method were confirmed by rheology (Figure 2 a,b,c and
supporting information). The strength of fluorinated triol gels
such as 5b in petroleum favorably compares to literature data.7
Confirming the gel behavior, the elastic modulus G' is higher
than the viscosity modulus G''. The excellent elastic modulus G'
of 110 000-170 000 Pa indicates an impressively high resistance
for such simple low molecular weight molecule (Figure 2.a).
Monitoring G' and G'' as a function of the stress amplitude
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(Figure 2.b) indicated that 5b gel was resistant until at least 100
rheological properties (G' and G'') as a function of the
Pa of applied stress.
temperature for gel 5a in o-xylene showing a destructuring gel at
a temperature around 62 °C (Figure 2.c). Xerogels were
obtained from the evaporation of the solvent of different gels and
analyzed by Scanning Electron Microscopy (SEM). This
confirmed the gelation process through the formation of large
fibers as in xerogel obtained from 5a or 5b petroleum gel (Figure
2.d and supporting information).
a)
Of interest, doping a 5b gel of petroleum with 0.2 wt/v% of
pyrene resulted in a strongly UV fluorescent gel, opening
perspectives for applications to other doped fluorinated gels
(Figure 2.e, left).
Given the structure of the fluorinated polyols, the great
advantage of the organogels created from 5b are they high
stability in the presence of a broad range of aqueous solutions.
Going from pH = 1 (HCl solution) to pH = 14 (NaOH solution)
solution or in the presence of 3.5% NaCl solution all the gels
kept their resistance (Figure 2.e, right). This behavior is of
importance in a context of water cleaning of industrial leaks and
in contrast to most organogelators based on acid or basic
sensitive functions (esters, amides, acetals...).7,25
b)
NMR and VCD analysis of the fluorinated triols and the related
gels (see SI ford details) seem to indicate that the spatial
arrangement observed in the fibers within the gel is closely
related to the spatial arrangement observed in the solid state by
single crystal X-ray diffraction of 5a. All these observations
suggests that the fibers are exclusively formed by hydrogen
bonds and hydrophobic interactions. Fluorine insertion positively
impact gelation through different manners. First of all, a stronger
H-bond framework is created by the electronegative fluorine,
increasing the strength of the supramolecular assembly. The
presence of the hydrophobic fluorine atoms pointing outside of
the fibers and able to create additional interactions with the
solvent also strengthen the fibers (higher packing). In the case of
c)
d)
chlorinated
triols,
these
increased
interactions
are
counterbalanced by the larger size of the chlorine atom and the
higher conformational freedom arguing for
supramolecular assembly.
a
weaker
As can be seen from this section, halogen insertion notably of
fluorine atoms, affects drastically the organogelation properties
of triols. The small and easy to prepare stereodefined and highly
stable fluorinated triols, allow for a strong gelation of a broad
range of organic solvents and lead us to study other possible
supramolecular interactions.
e)
H-bonding properties and anion binding
Anion binding is a fundamental process in chemistry with
implications in fields ranging from the understanding and
modulation of anion centered biological processes to the
engineering of sensors, materials or catalysts.28 To further probe
the influence of halogen insertion over H-bonding properties and
molecular recognition phenomenon, we subsequently focused
on the anion binding ability of polyols.
Figure 2. Gel properties. a) Frequency sweep of 4 wt/v% of 5b in petroleum.
b) Stress sweep of 4 wt/v% of 5b in petroleum. c) T°C dependence of 2 wt/v%
of 5a in o-xylene. d) SEM image of 5b and 5a xerogels (2 wt/v% in petroleum).
e) Gel images for, left: UV irradiated 5b 0.4 wt/v% in toluene doped with 0.2
wt/v% of pyrene; right: stability of 2 wt/v% 5b gel of petroleum in the presence
of water solutions: 3.5% NaCl; pH = 1 ; pH = 4; pH = 8; pH = 14.
This anion binding behavior was first determined by 1H NMR
titration
experiments
in
CD3CN.
The
addition
of
tetrabutylammonium chloride (TBACl) to polyols resulted in large
downfield shifts of the hydroxyl hydrogens. In addition, the
binding of fluorinated polyols could also be easily monitored by
19F NMR. Association constants from triplicate experiments were
obtained by fitting these spectroscopic data to 1 : 1 binding
It is interesting to point out that the values of Tgel obtained by
the vial inversion method in table 2 can be correlated to the
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isotherm models, using the Thordarson method.29 When a non-
halogenated polyol 9a or 9g is used and in accordance with
Kass results, relatively weak Cl- binding is observed (Scheme 5:
133 or 184 M-1, respectively).3 In contrast, fluorine insertion
considerably improved the anion binding by a factor of 3.1 to 3.6
in 5a and ent-5g. A relatively important Cl- binding constant of
413 M-1 for the simple acyclic polyol 5a was observed.
Interestingly, addition of terminal free alcohol in ent-5g further
increased the anion binding to 670 M-1.
ranging between 169.4° and 177.1° for X-CH-CH-O allows to
efficiently increase the acidity of the alcohols.
Table 3. Calculated properties of polyol•TBACl structures and DFT
modeling of 8a•TBACl structure
The presence of chlorine atoms in 8a was even more
impressive. In this case, an increase by a factor of 4.6 giving 617
M-1 binding constant clearly demonstrated the positive impact of
chlorine insertion.30 Given the presence of chlorohydrins in
numerous highly bioactive molecules, this observation should
find relevant implications in the understanding of their biological
mode of action and in drug design.
N(n-Bu)4
Cl
8a•TBACl
OH OH OH
CD3CN
H
O
H
H
Cl N(n-Bu)4
+
O
O
R
R
ΔH
O(C4-O)-Cl
(Å)[b]
O(C6-O)-Cl
(Å)[b]
O(C8-O)-Cl
(Å)[b]
(Kcal.mol-1)
R
R
[a]
OH OH OH
OH
OH OH OH
OH
9a
5a
8a
-8.36
-11.25
-16.67
3.17
3.15
3.13
3.20
3.22
3.21
3.34
3.28
3.27
9a
9g
K Cl-(25°C) = 133 M-1
OH OH OH
K Cl-(25°C) = 184 M-1
OH OH OH
OH
OH
F
F
ent-5g
F
F
5a
K Cl-(25°C) = 670 M-1
K Cl-(25°C) = 413 M-1
[a]Calculated enthalpy of formation of the polyol•TBACl complexes. [b]Calculated
distance.
OH
OH OH OH
OH
OH OH OH
With this impressive effect of halogen insertion over anion
binding, we also checked the ability of the halogenated polyols
as H-bond donor catalysts. Even though those properties are
closely linked, the binding mode of polyols is different in both
applications. Indeed, it was previously described by Kass that
1,3-polyols bind anions with three hydrogen of alcohols, while
on the contrary, the acidity necessary for H-bonding catalysis
results from a cooperative effect between the alcohol functions
by intramolecular hydrogen bonds.31 This intramolecular network
significantly increases the pKa of the most acidic alcohol
function, subsequently able to activate a suitable electrophile
such as nitroolefins. DFT calculations confirmed this type of
activation using fluorinated polyol 5c in which only one H-bond
was found to be established (Figure 3).
Cl
Cl
Cl
Cl
8a
8g
K Cl-(25°C) = 617 M-1
K Cl-(25°C) = not determined
Scheme 5. Cl- anion binding properties of different 1,3,5-triols in CD3CN
(average of triplicate experiments).
In order to shed light on the mechanism behind the observed
binding improvement by halogen insertion, these values were
correlated with DFT calculations (Table 3).
First of all, calculations of the different enthalpies of
polyol•TBACl complexes formation confirmed the halogen
insertion impact (Table 3). Formation of the TBACl complex was
less favored for 9a (ΔH = -8.36 Kcal.mol-1), while fluorine or
chlorine insertion in 5a and 8a improved the affinity (ΔH = -11.25
or -16.67 Kcal.mol-1, Table 3). This higher affinity of halogenated
polyols clearly arises from the increased acidity resulting from
the presence of F or Cl atoms. This is reflected in the distance
between the different oxygen atoms and the chlorine anion. Most
notably, the distance between Cl- and the two oxygen atoms
adjacent to the halogens (C4-O and C8-O) are much shorter.
This distance varies for C4-O from 3.17 Å for 9a to 3.13 Å for 8a
and for C8-O from 3.34 Å for 9a to 3.27 Å for 8a. On the
contrary, the central oxygen-Cl distance is less modified
depending on the substitution ranging from 3.20 Å for 9a to 3.21
Å for 8a (Table 3). The higher affinity observed for halogenated
polyols is directly arising from the appropriate geometry of the
halohydrin. Indeed, as in the solid state, the dihedral angles
O
O
N
H
H
H
F
O
O
O
Ph
Ph
Ph
F
Figure 3. DFT calculated structure of nitrostyrene  5c in CDCl3
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10.1002/chem.201902983
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To evaluate the catalytic activity of our triols we choose the
Friedel-Crafts addition of N-methyl indole (11) to 2-nitrostyrene
13 (Figure 4).32 Once again, halogen insertion positively
impacted the catalytic ability of polyols. Three times rate
acceleration were observed for fluorinated 5a as compared to
non-halogenated polyol 9a (entries 1-3). It must be pointed out
that both fluorinated and chlorinated polyols provided the same
type of catalytic profiles in this transformation.33
and designing new drugs. Finally, the modularity and the
efficiency of our synthetic approach should allow to considerably
enhance the current observed properties of 1,3,5-triols through
cooperative action of the lateral chains such as with extended
aromatic rings.
Experimental Section
Of interest, preliminary simple modulation of the fluorinated
polyols by incorporating phenyl substituents on the lateral chains
considerably increased the reaction rate. Using 5c, a reaction
rate comparable to binol phosphoric acid derivative 10 was
observed albeit using a molecule with much lower pKa! This
indicates a cooperative effect of the lateral chain possibly
through π-interactions with the substrates opening broad
perspectives for the improvement of these structures for
catalysis through further modulation of the side chain.
See supporting information for details on polyols preparation, X-Ray
single crystal analysis, organogel formation and analysis, anion binding
and catalysis.
Acknowledgements
The Centre National de la Recherche Scientifique (CNRS) and
the Aix-Marseille Université are warmly acknowledged for
financial support. All technical staff from Aix-Marseille
Spectropole are acknowledged for their support.
Ph
NO2
10 mol% catalyst
CDCl3, 25°C
Ph
+
NO2
N
N
Keywords: • supramolecular • fluorine • chlorine •
11
12
OH OH OH
13
halogenohydrins • polyols
O
O
P
OH
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halogen atoms (F or Cl), strongly affected different
supramolecular properties of synthetic 1,3,5-triol structures, a
central motif widely found in nature. By increasing the strength of
the polyol hydrogen bonding networks, halogen insertion
considerably improved their anion binding properties as well as
their H-bonding catalytic abilities. Moreover, the strength of
fibers created by self-assembly is significantly increased,
resulting in robust organogelation properties towards different
solvents. This constitutes a particularly interesting feature for
such unusually small molecules easily available from simple
commercially available materials.
As a result, it should help in the design of future anion binders,
catalysts or innovative organogelators with enhanced properties.
In addition, these observations should also help understanding
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4
acyclic stereogenic centers created
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through disctinct steps. This results in the possible formation of multiply
stereoisomers. From the crude reactions mixture, it is difficult to identify
the exact dr and ee of the reaction but by fluorine NMR, the desired
adducts are formed with around 80% of the major diastereomer, a
stereoselectivity increased through purification.
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not be determined accurately due to a lower stability.
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calculations, see the supporting information for details.
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Entry for the Table of Contents
FULL PAPER
H
H
H
Céline Sperandio, Guilhem Quintard,
Jean-Valere Naubron, Michel Giorgi,
Mehdi Yemloul, Jean-Luc Parrain, Jean
Rodriguez, Adrien Quintard,*
Enhanced
supramolecular
properties
O
O
O
Organogelator
Anion Binding
H-Bonding catalysis
Halohydrins X = F, Cl
Impact
.
: Conformation,
Acidity, Halogen interaction
X
X
Page No. – Page No.
Strategic stereoselective halogen
insertion (F, Cl), a tool to enhance
supramolecular properties in polyols
Anti-1,2-halohydrins provide new tools to enhance supramolecular properties in
natural product looking 1,3,5-triols. Increase in the polyol H-bonding strength as
well as additional Van der Waals interactions improve the resulting 3D association
behavior. This results in enhanced organic gels, anion binding or H-bond donor
catalysis.
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