Novel deoxycholic acid alkylamide-phenylurea-derived organogelators

Article abstract of DOI:10.1016/j.tetlet.2009.12.101

Three monomeric and three dimeric deoxycholic acid (DCA) alkylamido-phenylurea derivatives are designed based on known gelators and are synthesized and characterized by ¹H and ¹³C NMR spectroscopy, ESI-TOF mass spectrometry, and elemental analyses. Among them, a monomeric derivative forms supramolecular gels in CHCl₃ and chlorobenzene, whereas a dimeric derivative gels THF and higher 1-alkanols containing 7-10 carbons. The morphologies of their xerogels are studied by scanning electron microscopy (SEM). No signature of macroscopic chirality of the gels is visible.

Full text of DOI:10.1016/j.tetlet.2009.12.101

Tetrahedron Letters 51 (2010) 1199–1201
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Novel deoxycholic acid alkylamide-phenylurea-derived organogelators
*
Juha Koivukorpi , Erkki Kolehmainen
Department of Chemistry, PO Box 35, FI-40014, University of Jyväskylä, Finland
a r t i c l e i n f o
a b s t r a c t
Article history:
Three monomeric and three dimeric deoxycholic acid (DCA) alkylamido-phenylurea derivatives are
designed based on known gelators and are synthesized and characterized by 1H and 13C NMR spectros-
copy, ESI-TOF mass spectrometry, and elemental analyses. Among them, a monomeric derivative forms
supramolecular gels in CHCl3 and chlorobenzene, whereas a dimeric derivative gels THF and higher 1-alk-
anols containing 7–10 carbons. The morphologies of their xerogels are studied by scanning electron
microscopy (SEM). No signature of macroscopic chirality of the gels is visible.
Received 9 November 2009
Revised 11 December 2009
Accepted 16 December 2009
Available online 24 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Bile acids and their derivatives are potential carriers for liver
specific drugs and they can be used as cholesterol-lowering
agents.1 They have also been used for the treatment of bile acid
deficiency and liver diseases such as primary biliary cirrhosis.2
Interest in low molecular weight gelators has grown in recent
years.3 One such group are bile acid derivatives, which are efficient
gelators in aqueous media4 and organic solvents.5 We have earlier
demonstrated that bile acid amidoalcohols are effective organoge-
lators in chlorinated and aromatic organic solvents.6 Also urea
derivatives are known as hydrogelators7 and organogelators.8 Urea
groups are also good binding sites for anions in receptor design.9
Our synthetic design is based on the above-mentioned facts that
both bile acid amidoalcohols and urea derivatives are known
gelators. In continuation of our research with bile acid-based gela-
tors,10 we now present syntheses and the characterization of six
deoxycholic acid alkylamido-phenylurea derivatives, two of them
being effective gelators in organic solvents.
The synthesis of 1–6 proceeds via the reaction of methyl deoxy-
cholate with an -diaminoalkane to give the deoxycholic acid
-aminoalkylamide. This was allowed to react with phenyl isocy-
a,x
x
anate or methylene 4,40-diphenyl diisocyanate to form the desired
product.11 Structural characterization of compounds 1–6 was
based on their one-dimensional 1H, 13C, and 13C DEPT-135 as well
as two-dimensional PFG DQF 1H–1H COSY, PFG 1H–13C HMQC, and
PFG 1H–13C HMBC spectra and by comparison with previous data,6
elemental analyses and ESI-TOF mass spectra.11
Gelation studies were performed in 16 organic solvents (Table
1) at concentrations of 2% and 1% (w/v), and if in the latter case
a gel or a viscose solution was formed, also in 0.5% solution. The
contents of the test-tube was heated at the boiling point until all
Table 1
Gelation properties of compounds 1–6
Solvent
1
2
3
4
5
6
CHCl3
Chlorobenzene
Toluene
p-Xylene
Ethyl acetate
Acetone
S+
P
PS
PS
S
S+
S+
S+
S+
S+
S+
S+
S+
S+
S+
S+
I
I
I
I
I
I
P
S+
S+
S
S
S
S
S
S
S
G (10)
G (5)
P
P
PS
S
S+
S+
S+
S+
S+
S+
S+
S+
S+
S+
I
PS
I
I
I
I
I
I
I
I
I
I
S
S
S
S
S
S
S
PS
PS
I
I
I
I
I
I
I
THF
Ethanol
PS
S+
S+
S+
S+
S+
S+
S
G (10)
S
S
S
S
S
G (20)
G (20)
G (20)
G (20)
1-Propanol
1-Butanol
1-Pentanol
1-Hexanol
1-Heptanol
1-Octanol
1-Nonanol
1-Decanol
S
S
G = gel formed when cooled to room temperature. Minimum gelation concentration
(mg/ml) in parentheses. S+ = soluble at rt without warming, S = dissolved at bp,
PS = partly soluble at the bp, I = insoluble at the boiling point, P = precipitated upon
cooling.
* Corresponding author. Tel.: +358 14 260 2684; fax: +358 14 260 2501.
E-mail address: juha.k.a.koivukorpi@jyu.fi (J. Koivukorpi).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.101

1200
J. Koivukorpi, E. Kolehmainen / Tetrahedron Letters 51 (2010) 1199–1201
Figure 1. SEM images of xerogels: (a and b) 6 in 1-heptanol; (c and d) 6 in 1-octanol; (e and f) 6 in 1-nonanol.
the solid material had dissolved (if soluble), and then cooled in an
ultrasonic bath. The gel formed immediately upon cooling or with-
in half an hour. If no flow was observed when the test-tube was
turned upside down, the contents were considered to be a gel.
The formation of gels is based on self-assembly of organic mol-
ecules driven by intermolecular interactions.12 In our compounds
the hydrogen bonds between the urea, amide, and hydroxy groups
for different applications such as drug delivery, stereospecific syn-
thesis, etc.15
In conclusion, we have designed and synthesized six deoxychol-
ic acid alkylamido-phenylurea derivatives. Two of these deriva-
tives showed gelation ability in organic solvents: monomeric
derivative 3 in chlorinated solvents, and dimeric derivative 6 in
THF and higher 1-alkanols containing 7–10 carbons. No signature
of macroscopic chirality of the gels was visible. It was also found
that the length of the alkyl chain between the amide and urea
groups affects the solubility of the derivative. Our plan is to extend
this research to other common bile acids and study whether some
drug molecules are incorporated in these gels for drug delivery and
other applications.
are the strongest driving forces in gel formation.13 Also, weaker
p–
p
interactions may have some influence.14 A monomeric deriva-
tive, 3 formed supramolecular gels in CHCl3 and chlorobenzene,
whereas dimeric derivative 6 formed a gel in THF and higher 1-alk-
anols containing 7–10 carbons (1-heptanol, 1-octanol, 1-nonanol,
and 1-decanol, respectively) (Table 1). According to these results,
it seems that the long aliphatic chain in alcohols also has an impor-
tant role in gel formation. The other derivatives did not form gels in
any of the 16 solvents studied. Their solubility in alcohols is prob-
ably too good for gel formation in the case of monomeric deriva-
tives 1 and 3, whereas 5, although more sparingly soluble, did
not form a gel regardless. We also expected that dimeric 2 and 4
would form gels in some alcohols as a result of their solubility,
but not even thickening of the solution was observed in the con-
centration range studied. The dimeric derivatives, as well as mono-
meric 5, were sparingly soluble in the other solvents, except
alcohols.
Acknowledgments
We are grateful to Spec. Lab. Tech. Reijo Kauppinen for his help
in running the NMR spectra, Spec. Lab. Tech. Mirja Lahtipera for
running ESI-TOF mass spectra, Lab. Tech. Elina Hautakangas for
elemental analysis, and Lab. Tech. Hannu Salo for SEM images.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.12.101.
The alkyl spacer (varying from ethyl to butyl) between the
amide and urea groups in 1–6 affects their solubilities in the
solvents tested, and it seems to follow the order: propyl > ethyl >
butyl. It is also evident that monomeric derivatives have better sol-
ubility than their dimeric counterparts.
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