Towards racemizable chiral organogelators

Article abstract of DOI:10.3762/bjoc.6.107

A chiral organogelator has been synthesized that can be racemized and self-assembled in apolar solvents whilst at higher concentrations organogels are formed. Field emission scanning and transmission electron microscopy revealed the formation of bundle fibrils that are able to gelate the solvent. ¹H NMR studies showed hydrogen-bond interactions between the peptide head groups of neighbouring organogelator molecules. The enantiomerically pure organogelator can be racemized by the base DBU (1,8-diazabicyclo[5.4.0]undec-7- ene) as was evident from chiral high-performance liquid chromatography analysis.

Full text of DOI:10.3762/bjoc.6.107

Towards racemizable chiral organogelators
Jian Bin Lin, Debarshi Dasgupta, Seda Cantekin
and Albertus P. H. J. Schenning*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2010, 6, 960–965.
Functional Organic Materials and Devices and Laboratory of
Macromolecular and Organic Chemistry, Eindhoven University of
Technology, PO Box 513, 5600MB Eindhoven, The Netherlands
doi:10.3762/bjoc.6.107
Received: 12 July 2010
Accepted: 20 September 2010
Published: 06 October 2010
Email:
Jian Bin Lin - j.b.lin@tue.nl; Debarshi Dasgupta - d.dasgupta@tue.nl;
Seda Cantekin - s.cantekin@tue.nl; Albertus P. H. J. Schenning* -
a.p.h.j.schenning@tue.nl
Guest Editor: J.-P. Desvergne
©
2010 Lin et al; licensee Beilstein-Institut.
*
Corresponding author
License and terms: see end of document.
Keywords:
chirality; organogels; racemization; self-assembly
Abstract
A chiral organogelator has been synthesized that can be racemized and self-assembled in apolar solvents whilst at higher concentra-
tions organogels are formed. Field emission scanning and transmission electron microscopy revealed the formation of bundle fibrils
that are able to gelate the solvent. 1H NMR studies showed hydrogen-bond interactions between the peptide head groups of neigh-
bouring organogelator molecules. The enantiomerically pure organogelator can be racemized by the base DBU (1,8-diazabi-
cyclo[5.4.0]undec-7-ene) as was evident from chiral high-performance liquid chromatography analysis.
Introduction
Gelation represents a macroscopic manifestation of self-assem- the emergence of specific shapes at a macroscopic level through
bled molecules. Impressive supramolecular architectures have cooperative interactions between molecules. In addition, helical
been reported in which the self-assembled molecules immobi- assemblies possess a potential for applications in advanced ma-
lize solvent to produce a gel phase. Carefully designed self terials and constrained media for chiral synthesis and sep-
complementary building blocks with co-added organizational aration [3-5].
information can make these gels responsive. In recent years,
much effort has been devoted to the design and characterization The development of systems where the chiral supramolecular
of chiral self-assembled fibrillar networks that form organogels assembly responds to specific triggers, should facilitate the
[
1,2]. In such systems the chirality within a molecular building design of smart functional materials in which subtle molecular-
block is transcribed to nano- or mesoscale fibrous assemblies. scale changes have an impact on the macroscopic behavior.
These chiral structures represent excellent models for studying Most of the earliest stimuli-responsive gels undergo a
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Beilstein J. Org. Chem. 2010, 6, 960–965.
UV-induced transformation, which can be reversed by visible is able to form a gel, 3,4-didodecyloxybenzaldehyde [19] was
light. For example, Shinkai and coworkers demonstrated that used in place of 2-methylbenzaldehyde.
trans-cis isomerization of gelator compounds by UV/visible
Results and Discussion
light could induce a gel-sol transition [6]. Feringa and
coworkers have reported a chiral gelator in which the supra- Synthesis
molecular organization of the chiral assemblies can be switched The synthesis of R-3 and S-3 is outlined in Scheme 1. First,
using UV/visible light combined with heating and cooling [7]. concentrated aqueous ammonia was added to ester 1 to yield
Chiral gels that respond to other stimuli such as metal ions [8], pure phenylglycinamide 2 [18]. Reaction of 2 with 3,4-didode-
guest molecules [9] and temperature [10] have also been cyloxybenzaldehyde [19] led to compound 3 in 50% yield
reported.
(Scheme 1). Both R-3 and S-3 were purified by recrystalliza-
tion and fully characterized. Chiral high-performance liquid
In recent years, racemic gel fibers assembled from mixtures of chromatography (HPLC) showed an ee of more than 99% for
enantiomeric building blocks have been described [11-14]. In the enantiomers. Interestingly, 1H NMR spectroscopy in chloro-
most cases, the racemates were less efficient gelators than the form revealed that the two amide protons of 3 behave differ-
pure enantiomers, and sometimes lead to crystallization [7]. ently at different concentration (Figure 1). The signal from one
Interestingly, Higashi and coworkers have observed that the of the amide protons remains the same, even on the addition of
separate enantiomers assemble into fibers with opposite helicity a small amount DMSO-d6, indicating intramolecular hydrogen
while the racemic mixture yield nanoscale, spherical structures bonding. The other amide proton signal was downfield shifted
[
15]. In order to create chiral response materials based on such
systems, it would be interesting to develop organogelators that
can be racemized by a stimulus [16,17]. In the current manu-
script we report our attempt to synthesize a racemizable chiral
organogelator (Scheme 1). The molecular design of our
organogelator (3) is based on a finding that the imine of
2
-methylbenzaldehyde and phenylglycinamide can be race-
mized in the presence of the base DBU (1,8-diazabi-
cyclo[5.4.0]undec-7-ene). Interestingly, a single solid chiral
state from a nearly racemic mixture of this phenylglycinamide
derivative was observed by so-called attrition-enhanced solid-
phase enantioenrichment [18]. In order to obtain a molecule that
Figure 1: Concentration-dependent 1H NMR spectra of R-3 in chloro-
form (CDCl3). The red colours indicate the hydrogen resonances of the
amide unit.
Scheme 1: Synthesis of R-3 and S-3.
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Beilstein J. Org. Chem. 2010, 6, 960–965.
upon increasing the concentration, in accord with intermolec- suggesting effective anisotropic growth. The morphology of the
ular hydrogen bonding.
R-3 organogel in octane at a higher concentration (about 15
mM) also revealed a fibrillar structure, but in this case the
fibrils were much bigger in size (nearly 150 nm in diameter)
Gel formation
The gelation ability of R-3, S-3 and racemic 3 was investigated and in some parts they seemed to form two dimensional sheet
using the “inverse flow” method. At room temperature, R-3 and like lamellar structures (FESEM image, Figure 2d).
S-3 were insoluble in octane. However, on heating at 80 °C,
both R-3 and S-3 became soluble in octane and when cooled to In order to investigate the molecular arrangement of the fibers
room temperature, a stable self-supporting semi-transparent gel in apolar solvent, variable concentration 1H NMR measure-
was formed (Figure 2a). For all the samples, the thermo- ment were carried out in cyclohexane-d12. In contrast to the
reversible gelation process was followed at 0 °C, since the gela- observations in chloroform, in cyclohexane solution upon
tion time becomes much longer at lower concentrations at 20 increasing the concentration the observed chemical shifts of
°
C. For R-3, the critical gelation concentration (CGC) was both the N–H protons were downfield shifted (Figure 3), consis-
detected by the failure of the whole mass to flow when the vial tent with an increased degree of intermolecular hydrogen
was turned upside down. The CGC value was 2.3 mM for R-3, bonding suggesting the formation of intermolecular hydrogen-
which means that R-3 can immobilize approximately 2700 bond interactions between the amide units. Most likely
molecules of octane per gelator molecule. The gel is thermo- hydrogen bonded dimers or tetramers are formed in this apolar
reversible, indicating that the first order phase transition is asso- solvent. Our data suggest that these hydrogen-bonded dimers or
ciated with gel melting and/or gel formation. When the race- tetramers subsequently stack via π-π interaction and via van der
mate (R-3 = S-3 = 2.5 mM) was heated and cooled to room Waals interactions into bundled fibers.
temperature, precipitation was observed (Figure 2b).
Racemization
The morphology of the organogel was further characterized by The racemization of R-3 was investigated by chiral HPLC.
field emission scanning electron microscopy (FESEM) as well After adding 1 equivalent of DBU to a solution of R-3 in octane
as with transmission electron microscopy (TEM). The TEM at room temperature, samples were collected over time and the
image (Figure 2c), of the dried R-3 gel in octane (1 mM) exhib- enantiomeric purity was measured. Racemization was not
ited entangled fibrillar network formation although the concen- observed in the gel state (5 mM) after 18 hours, whilst after
tration stays well below the CGC value (2.3 mM) in this heating and cooling precipitation was observed. At a concentra-
solvent. The critical gelation concentration indicates the tion of 1 mM, where self-assembled fibers are present, the ee of
threshold at which, infinite percolation is achieved within a the solution decreased in time. Figure 4 shows a plot of ln(ee ×
network system, although microgel network structures can still 100) versus time for the racemization of R-3 [18]. The first
be observed below the CGC. The fibers have an average order kinetics expression: ln(ee(t)) = ln(ee(0)) + kt could be
diameter is 60 ± 10 nm and lengths of tens of micrometers used to fit the experimental results and gave a t1/2 of about
Figure 2: a) R-3 gel in octane (5 mM); b) octane solution containing a mixture of R-3 (2.5 mM) and S-3 (2.5 mM) after cooling from 80 °C to room
temperature; c) TEM image of the xerogel of R-3 in octane; d) the surface morphology of the dried gel obtained from R-3 in octane (15 mM) observed
by FESEM.
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Beilstein J. Org. Chem. 2010, 6, 960–965.
Figure 3: a) Concentration-dependent 1H NMR spectra of R-3 in cyclohexane-d12 and b) the shift of N–H signal of amide group versus concentration.
Figure 4: The evolution of ln(ee × 100) for the racemization of R-3 (1 mM) in the presence of 1 equivalent of DBU in octane and THF.
1
77 min. Under the same conditions, the racemization rate in NMR spectra were recorded with a Varian Mercury NMR Spec-
THF is much faster with a t1/2 of about 37 min. This difference trometer. IR spectra were measured on a Perkin Elmer 1600
between the two solvents is most likely due to the difference in FT-IR. MALDI-TOF MS spectra were measured on a Persep-
polarity and the fact that R-3 is self-assembled in octane and tive DE Voyager Mass Spectrometer with α-cyano-4-hydroxy-
molecularly dissolved in the more polar THF.
cinnamic acid as the matrix.
Conclusion
Synthesis
This work demonstrates a route towards racemizable chiral Phenylglycinamide R-2, S-2: The ester salt R-1, S-1 (5.04 g, 25
organogelators. Remarkably, our pure enantiomeric gelator mmol) was stirred with concentrated ammonia solution (20 mL)
could not be racemized in the gel phase, while racemization at room temperature overnight. Subsequently, the product was
takes place in the self-assembled fiber state. We are currently precipitated, filtered, and washed with cold water. The resulting
studying this class of organogelator for the creation of respon- white solid was recrystallized from ethanol to afford 2.65 g of
sive gels and attrition-enhanced solid-phase enantioenrichment colourless crystals (71%) of R-2, S-2. 1H NMR (CDCl3, 400
phenomena [20].
MHz): 7.43 (m, 2H, ArH); 7.31 (m, 3H, ArH); 4.84 (br, 4H,
NH2); 4.44 (s, 1H, COCH). MALDI-TOF MS (calc MW =
Experimental
1
50.08, C8H10N2O): 150.97 [M + H]+. IR ν (cm−1): 3339;
General
3073; 1660; 1454; 1405; 1271; 869; 699.
All chemicals were purchased from Aldrich. Non-deuterated
solvents were purchased from Biosolve. All other solvents and R-3, S-3: To a solution of 3,4-didodecyloxybenzaldehyde (237
chemicals were used as received. Deuterated solvents were mg, 0.5 mmol) in toluene, was added compound R-2, S-2 (75
obtained from Cambridge Isotope Laboratories, United States. mg, 0.5 mmol) and the mixture was refluxed overnight. After
963

Beilstein J. Org. Chem. 2010, 6, 960–965.
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We gratefully acknowledge Anja Palmans, Bert Meijer, Wim
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ments. This research was supported by a Small Scale Collabora-
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