Oxalyl retro-peptide gelators. Synthesis, gelation properties and stereochemical effects

Article abstract of DOI:10.3762/bjoc.6.106

In this work we report on gelation properties, self-assembly motifs, chirality effects and morphological characteristics of gels formed by chiral retro-dipeptidic gelators in the form of terminal diacids (1a-5a) and their dimethyl ester (1b-5b) and dicarb

Full text of DOI:10.3762/bjoc.6.106

Oxalyl retro-peptide gelators. Synthesis, gelation
properties and stereochemical effects
Janja Makarević, Milan Jokić, Leo Frkanec, Vesna Čaplar,
Nataša Šijaković Vujičić and Mladen Žinić*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2010, 6, 945–959.
Laboratory for Supramolecular and Nucleoside Chemistry, Ruđer
Bošković Institute, P.O.B. 180, HR-10002 Zagreb, Croatia
doi:10.3762/bjoc.6.106
Received: 30 June 2010
Accepted: 23 August 2010
Published: 04 October 2010
Email:
Mladen Žinić* - zinic@irb.hr
* Corresponding author
Guest Editor: J.-P. Desvergne
Keywords:
© 2010 Makarević et al; licensee Beilstein-Institut.
chiral; organogel; oxalamide; retro-peptide; self-assembly
License and terms: see end of document.
Abstract
In this work we report on gelation properties, self-assembly motifs, chirality effects and morphological characteristics of gels
formed by chiral retro-dipeptidic gelators in the form of terminal diacids (1a–5a) and their dimethyl ester (1b–5b) and dicarbox-
amide (1c–5c) derivatives. Terminal free acid retro-dipeptides (S,S)-bis(LeuLeu) 1a, (S,S)-bis(PhgPhg) 3a and (S,S)-bis(PhePhe) 5a
showed moderate to excellent gelation of highly polar water/DMSO and water/DMF solvent mixtures. Retro-peptides incorpor-
ating different amino acids (S,S)-(LeuPhg) 2a and (S,S)-(PhgLeu) 4a showed no or very weak gelation. Different gelation effective-
ness was found for racemic and single enantiomer gelators. The heterochiral (S,R)-1c diastereoisomer is capable of immobilizing up
to 10 and 4 times larger volumes of dichloromethane/DMSO and toluene/DMSO solvent mixtures compared to homochiral (S,S)-
1c. Based on the results of 1H NMR, FTIR, CD investigations, molecular modeling and XRPD studies of diasteroisomeric diesters
(S,S)-1b/(S,R)-1b and diacids (S,S)-1b/(S,R)-1a, a basic packing model in their gel aggregates is proposed. The intermolecular
hydrogen bonding between extended gelator molecules utilizing both, the oxalamide and peptidic units and layered organization
were identified as the most likely motifs appearing in the gel aggregates. Molecular modeling studies of (S,S)-1a/(S,R)-1a and (S,S)-
1b/(S,R)-1b diasteroisomeric pairs revealed a decisive stereochemical influence yielding distinctly different low energy conforma-
tions: those of (S,R)-diastereoisomers with lipophilic i-Bu groups and polar carboxylic acid or ester groups located on the opposite
sides of the oxalamide plane resembling bola amphiphilic structures and those of (S,S)-diasteroisomers possessing the same groups
located at both sides of the oxalamide plane. Such conformational characteristics were found to strongly influence both, gelator
effectiveness and morphological characteristics of gel aggregates.
Introduction
Reversible processes of peptide, protein and nucleic acids self- pathological changes leading to diseases such as Alzheimer’s,
assembly are of paramount importance in biotic systems and are Parkinson’s and prion diseases, type II diabetes, etc. are asso-
central to vital biological functions. On the other hand, some ciated with anomalous self-assembly of smaller peptides into
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Beilstein J. Org. Chem. 2010, 6, 945–959.
amyloid fibrils which finally result in the formation of amyloid been intensively studied as peptidomimetics due to their higher
plaques [1-4]. During the last two decades there has been a proteolytic stability and bioavailability compared to natural
growing interest in self-organization of small peptide models counterparts [44-47]. Despite very promising biomedicinal
capable of self-assembling into highly organized supra- properties, very little is known about the self-assembly poten-
molecular structures with potential use as novel bio- or nano- tial of this class of compounds in solution. Computer simula-
materials possessing advanced properties and functions [5-10]. tions of some malonamide retro-peptides have shown that the
It has been shown that even short peptides, such as dipeptides, extended conformations are less stable than the helical ones
tripeptides or tetrapeptides, themselves or incorporated into [48,49]. Nevertheless, the crystal structure of the retro–inverso
more complex structures, are capable of self-assembling into peptide Bz–S–gAla–R–mAla–NHPh revealed it’s unidirec-
fibers or fibrils [11-15]. In a number of cases such organization tional self-assembly by intermolecular β-sheet type of hydrogen
results in formation of gels consisting of self-assembled fibrous bonding so that malonamide retro-peptides could be considered
aggregates usually containing a large volume of solvent [16]. In as potential candidates for development of new gelator mole-
gels, the fibers are heavily entangled into 3-dimensional cules [50]. The oxalamide based retro-peptides are relatively
networks which immobilize the solvent and prevent fluidity in rare and much less studied than the more flexible malonamide
the system [17-23]. In the last 15 years many low molecular retro-peptides [51-54]. In contrast to the malonamide group, the
weight gelling molecules of wide structural diversity, including planar and much more rigid oxalamide fragment is self-comple-
a variety of amino acid and small peptide derivatives, have been mentary and exhibit a strong tendency for intermolecular
prepared and studied [24-41]. These investigations revealed that hydrogen bonding both in the solid state and in the solution [55-
gelator assemblies of various morphologies, including fibers 60]. Hence, the oxalyl retro-peptides are expected to preferably
and fiber bundles of diverse diameters, helical fibers or ribbons, form extended conformations capable of intermolecular
tapes and nano-tubules, sometimes simultaneously present with oxalamide–oxalamide hydrogen bonding and the formation of
micelles or vesicles, could be found [17-23]. For many gel unidirectional assemblies the latter being a necessary condition
systems evidence for hierarchical organisation was provided for gelation [24-31,58-60]. Herein, we provide experimental
which determined the final morphological appearance of the and molecular modeling evidence that the oxalamide retro-
aggregates [26]. It appears that gelation induced by aggregation peptides indeed tend to form unidirectional hydrogen bonded
of small abiotic or bio-inspired organic molecules represents an assemblies of gelator molecules that adopt fully extended
advantageous experimental system allowing in depth studies of conformations. We also present the evidence that for the (S,R)-
the self-assembly as a general phenomenon. Such studies bis(LeuLeu) 1a and (S,S)-bis(LeuLeu) 1a retro-peptidic gela-
should ultimately result in revealing the relationship between tors, the stereochemistry has a decisive impact on their gelation
gelator structures, self-assembly motifs and apparent morpholo- effectiveness and final gel morphology in their water/DMSO
gies of final assemblies as well as assisting in the elucidation of gels.
the role of solvent, which has been largely neglected in the
Results and Discussion
majority of studies carried out to date. However, such an under-
standing of gelation is still out of reach; it is still hardly possible Synthesis of oxalyl retro-dipeptidic gelators
to predict gelation capability on the basis of the structure of a A series of chiral bis(dipeptide)oxalamides was prepared as
candidate molecule and it is even more difficult to predict outlined in Scheme 1. The synthesis and analytical characteriza-
which solvents and how effectively they would be gelled tion of the prepared compounds are collected in the Supporting
[42,43]. Hence, systematic studies of gels formed by struc- Information. Two sets of bis(dipeptide)oxalamides were
turally diverse small gelator molecules comprising elucidation prepared: the first incorporating a single amino acid and vari-
of their self-assembly motifs, gelation effectiveness toward able terminal groups such as carboxylic acid, methyl ester and
solvents of different structure and physical characteristics, esti- carboxamide, namely (S,S)-bis(LeuLeu) 1a, b, c; (S,S)-
mation of solvation and stereochemical effects and their influ- bis(PhgPhg) 3a, b, c and (S,S)-bis(PhePhe) 5a, b, c and, the
ence on the morphological characteristics of final gel assem- second containing two different amino acids, (S,S)-bis(LeuPhg)
blies may be rewarding, and should provide a much better 2a, b, c and (S,S)-bis(PhgLeu) 4a, b, c (configurations of only
understanding of the self-assembly processes involved in gela- two of the four stereogenic centers are denoted corresponding to
tion.
that of oxalamide α- and β-amino acid, respectively, as depicted
in Scheme 1).
In this work we report on gelation properties, self-assembly
motifs, chirality effects and morphological characteristics of Compared to the previously studied bis(amino acid)-oxalamide
gels formed by chiral bis(dipeptide)oxalamides. Structurally, gelators (Figure 1), the retro-dipeptidic gelators, in addition to
such gelators belong to the group of retro-peptides, which have the oxalamide hydrogen bonding unit, also contain two peptidic
946

Beilstein J. Org. Chem. 2010, 6, 945–959.
Scheme 1: Oxalyl retro-dipetide gelators; each b to a, (a) LiOH/MeOH, H2O; (b) H+; each b to c: (c) NH3/MeOH.
units with specifically oriented hydrogen bond donor and Gelation properties
acceptor sites and amino acid lipophilic substituents. Such Terminal diacid retro-dipeptides
structural characteristics enable multiple structural and stereo- Gelation observed for selected gelator–solvent pairs is
chemical variations of the basic gelator structure and subse- expressed by gelator effectiveness (Geff, mL) corresponding to
quent studies of structural and stereochemical influences on the maximal volume of solvent that could be immobilized by 10
gelation properties, self-assembly motifs and gel morphology. mg of the gelator (Table 1). The oxalamides 1a, 3a and 5a were
insoluble in water but showed moderate to excellent gelation of
water/DMSO and water/DMF solvent mixtures. The Leu
containing gelator 1a appeared more than 2 times more effec-
tive in gelation of water/DMSO or DMF mixtures than the
aromatic acid containing gelators 3a and 5a. However, 3a and
5a also gelled small to moderate volumes of EtOH and rac-2-
octanol, whilst Leu incorporating 1a formed gels with the more
lipophilic solvents, decalin and tetralin. The retro-dipeptides
Figure 1: Chiral bis(amino acid)-(I) and bis(amino alcohol)-(II)-
oxalamide gelators.
containing two different amino acids showed no or only weak
gelation; (S,S)-(LeuPhg) 2a lacked any gelation ability toward
the tested solvents, while (S,S)-(PhgLeu) 4a showed only weak
The influence of stereochemistry on self-aggregation and gelation of water/DMSO, dichloromethane and toluene. Appar-
morphology was studied with 1a–c combining different config- ently, the retro-peptides incorporating aliphatic and aromatic
urations of Leu: (S,R)-1a, b, c and (R,S)-1a, b, c. Gelation prop- amino acids are less versatile gelators compared to retro-
erties of pure enantiomers (S,S)-1b and (S,R)-1b are compared peptides containing identical amino acid fragments. The latter
with those of (S,S)-1b/(R,R)-1b and (S,R)-1b/(R,S)-1b racemic points to the importance of intermolecular lipophilic interac-
mixtures (Scheme 1).
tions for the stabilization of gel assemblies being stronger in the
947

Beilstein J. Org. Chem. 2010, 6, 945–959.
Table 1: Gelator effectivenesses (Geff, mL) of retro-dipeptides 1a–5a and bis(Leu)oxalamide I in gelation of various solvents and solvent mixtures
(sol.: soluble; ins.: insoluble; cr.: crystallization; [A] gel/sol mixture).
Solvent
I
(S,S)-1a
(S,R)-1a
(S,R)-1a/
(R,S)-1a
(S,S)-1a/ 2a
(R,R)-1a
3a
4a
5a
H2O
0.4
ins.
ins.
ins.
ins.
cr.
ins. ins.
ins.
1.0+1.0
cr.
ins.
H2O/DMSO
H2O/DMF
EtOH
0.8+0.4
cr.
5.09+2.98 15.0+4.5
5.84+3.25 7.5+2.0
5.3+5.3
2.8+1.7
cr.
cr.
cr.
2.3+1.6
2.5+1.1
1.1+0.5
2.8+0.7
1.1
cr.
1.5
sol.
ins.
sol.
ins.
cr.
cr.
cr.
sol. cr.
sol. 1.25
sol. sol.
ins. ins.
sol. cr.
ins. ins.
ins. ins.
ins. ins.
sol. ins.
sol.
cr.
±2-octanol
THF
10.95
0.4
sol.
sol.
cr.
cr.
5.75
sol.
sol.
ins.
cr.
sol.
ins.
cr.
sol.
0.25
ins.
0.5
CH2Cl2
CH3CN
toluene
p-xylene
decalin
tetralin
1.5+0.05a
0.95
1.95
2.45
0.2
ins.
cr.
7.0
cr.
cr.
0.25
cr.
sol.
ins.
0.2
1.8
ins.
0.8
jelly
0.25
jelly
0.2
[A]
cr.
1.7
0.5
ins.
jelly
ins.
3.0
4.0
aDMSO.
case of identical amino acids either lipophilic or aromatic, and more hydrogen bonding sites and lipophilic groups in the retro-
weaker for mixed aromatic-lipophilic amino acid fragments dipeptides appears less favorable for gelation of water and
present in the gelator molecule.
solvents of medium and low polarity presumably due to
decreased solubility and increased crystallization tendency
Interestingly, the (S,R)-bis(LeuLeu) retro-peptide 1a, the compared to bis(amino acid)oxalamides. However, their effi-
diastereomer of (S,S)-1a, exhibited an increased Geff for the cient gelation of water/DMSO and water/DMF solvent mixtures
water/DMSO mixture and decalin which however is absent for presents a striking difference where DMSO and DMF
water/DMF solvent mixture (Table 1). The latter exemplifies co-solvents could sufficiently increase their solubility up to the
the strong stereochemical influence on gelator effectiveness in point necessary for aggregation into sufficiently long fibers
certain solvents.
capable of networking.
In many cases of chiral gelators, pure enantiomers were found Terminal dimethyl ester retro-dipeptides
more effective gelators than the racemates, although several In the previously studied series of bis(amino acid)oxalamide
exceptions were observed showing that the racemic form could gelators transformation of terminal carboxylic acid groups into
be a more effective gelator of certain solvents than the corres- methyl esters resulted in the complete loss of gelation ability
ponding pure enantiomer [60-68]. Therefore, we also compared [59]. In the retro-dipeptide series the gelation properties of
gelation properties of selected enantiomers and racemates and methyl ester derivatives 1b–5b, were not significantly different
found that the (S,R)-1a/(R,S)-1a racemate was considerably less from those of the respective diacid derivatives 1a–5a except
effective in gelation of both, water/DMSO and water/DMF that the diester derivatives appear slightly more versatile ex-
solvent mixtures compared to the pure enantiomer (S,R)-1a, hibiting gelation also with some lipophilic solvents (Table 1 and
while the racemate (S,S)-1a/(R,R)-1a lacked any gelation ability Table 2). This could be explained by the increased lipophilicity
and tended to crystallize from both solvent mixtures.
of the diester derivatives and, consequently increased solubility
in more lipophilic solvents compared to the diacid gelators. It
Generally, it can be concluded that the retro-dipeptides are less should be noted that the diester racemates (S,R)-1b/(R,S)-1b and
effective and less versatile gelators compared to the previously (S,S)-1b/(R,R)-1b showed significantly increased effectiveness
studied bis(amino acid)oxalamides. Table 1 shows that in gelation of water/DMSO and water/DMF solvent mixtures
bis(Leu)oxalamide I is much more versatile and a more effi- compared to the respective free acid racemates (S,R)-1a/(R,S)-
cient gelator compared to (S,S)-1a and (S,R)-1a, and is capable 1a and (S,S)-1a/(R,R)-1a (Table 1), respectively. Also, in
of gelling water and various solvents of medium and low contrast to the free acid gelators, the diester racemates were up
polarity. However, I is considerably less efficient in gelation of to two times more efficient in the gelation of water/DMF and
highly polar water/DMSO and water/DMF solvent mixtures water/DMSO mixtures than their pure enantiomer counterparts
compared to both 1a diasteroisomers. Hence, the presence of (S,R)-1b and (S,S)-1b (Table 2). The latter provides additional
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Beilstein J. Org. Chem. 2010, 6, 945–959.
Table 2: Gelator effectiveness (Geff, mL) of bis(dipeptide)oxalamide dimethyl esters 1b–5b in gelation of various solvents and solvent mixtures (sol.:
soluble; ins.: insoluble; cr.: crystallization; [A] gel/sol mixture; (F): cotton-like fiber aggregates; ** the mixture of crystals and gel.).
Solvent
(S,S)-1b
(S,R)-1b
(S,R)-1b/
(R,S)-1b
(S,S)-1b/
(R,R)-1b
2b
3b
4b
5b
H2O
ins.
ins.
ins.
ins.
ins.
0.15+0.5
cr.
ins.
1.1+2.7
cr.
ins.
ins.
cr.
H2O/DMSO
H2O/DMF
EtOH
3.95+6.75
5.1+4.8
cr.
9.7+10.0
11.5+11.7
cr.
13.2+9.65
13.8+9.1
5.4+3.4
cr.
0.2+0.5
cr.
13.1+7.8
cr.
cr.
cr.
2.00
cr.
(F1.3)
(F0.5)
sol.
0.9
2.05
cr.
±2-octanol
THF
cr.
cr.
cr.
cr.
1.85
sol.
sol.
cr.
sol.
cr.
sol.
sol.
cr.
sol.
sol.
ins.
cr.
CH2Cl2
CH3CN
toluene
p-xylene
decalin
tetralin
sol.
sol.
sol.
sol.
cr.
cr.
cr.
cr.
cr
cr.
[A]
0.15
0.5
**
0.55
1.3
1.1
ins.
ins.
ins.
0.4
1.25
1.1
2.0
2.5
1.7
0.5
[A]
**
1.1
2.3
0.8
1.75
sol.
5.6
2.0
4.8
cr.
0.2
sol.
0.6
0.9
examples that in some cases racemates could be more effective to 10 and 4 times larger volumes of dichloromethane and
gelators than the pure enantiomers. Hence, in the search for toluene solvent mixtures containing a little DMSO, respective-
highly effective gelators for targeted solvents, the racemic form ly (Table 3). Also the bis(LeuPhgNH2) 2c and bis(PhgLeuNH2)
of a chiral gelator must be tested.
4c incorporating different amino acids appeared more versatile
than the corresponding diacids (2a, 4a) and diesters (3b, 4b). It
appears that the increased hydrogen bonding potential of
Terminal dicarboxamide retro-dipeptides
The diamide derivatives bis(LeuLeuNH2) 1c, bis(PhgPhgNH2) terminal diamide derivatives provides somewhat more versatile
3c and bis(PhePheNH2) 5c appeared more versatile being gelators capable of gelating solvents of medium and low
capable of gelling a larger set of tested solvents compared to the polarity where intermolecular hydrogen bonding is favored.
respective dicarboxylic acid (1a, 3a, and 5a) and dimethyl ester
derivatives (1b, 3b and 5b) (Tables 1–3). The influence of TEM and DSC investigations
stereochemistry on gelator versatility and effectiveness can be As reported previously, TEM investigations of bis(amino
illustrated by the considerably improved gelation properties of acid)oxalamide gels revealed in most cases formation of very
the heterochiral (S,R)-1c diastereoisomer compared to dense networks consisting of heavily entangled tiny fibers with
homochiral (S,S)-1c; the former is capable of immobilizing up diameters in the range of 10–20 nm [58-60]. A similar
Table 3: Gelation effectiveness (Geff, mL) of bis(amino acid and dipeptide-CONH2)oxalamides 1c–5c in gelation of various solvents and solvent
mixtures (sol.: soluble, ins.: insoluble; cr.: crystalline; [A] gel/sol mixture).
Solvent
(S,S)-1c
(S,R)-1c
2c
3c
4c
5c
H2O
ins.
ins.
ins.
ins.
cr.
ins.
ins.
H2O/DMSO
H2O/DMF
EtOH
0.55+1.4
0.45+0.75
cr.
0.8+1.2
0.8+0.6
[A]
1.8+2.9a
1.05+11a
ins.
4.7+5.0
1.7+1.8
3.4
1.3+1.6
2.7+3.0
ins.
cr.
ins.
ins.
ins.
ins.
ins.
ins.
ins.
ins.
ins.
±2-octanol
THF
ins.
3.0
5.0+0.1a
1.1+0.05a
2.0+0.1a
ins.
cr.
ins.
ins.
ins.
ins.
ins.
CH2Cl2
CH3CN
toluene
p-xylene
decalin
tetralin
1.05+0.2a
ins.
11.0+0.84a
0.5+0.04a
4.0+0.4a
7.5+0.4a
ins.
1.5+0.4
ins.
ins.
ins.
1.05+0.2a
ins.
2.2+0.2a
6.9+0.2a
0.8
0.75+0.1a
0.95+0.08a
ins.
ins.
ins.
ins.
0.5(ins.)
2.0
7.3
sol.
2.0
1.0
aDMSO.
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Beilstein J. Org. Chem. 2010, 6, 945–959.
Figure 4: TEM images (PWK staining) of: (S,R)-1b toluene gel
Figure 2: TEM images (PWK staining) of: (S,S)-1a H2O/DMSO gel.
showing the presence of short tape like aggregates.
morphology was observed for the bis(PhePhe)-5a-EtOH gel The TEM observed thicknesses of gel aggregates existing in
(fiber d’s 6–20 nm) and bis(PhgLeu) 4a water/DMSO gel (fiber water/DMSO and toluene gels could be also correlated with
d’s 5–15 nm) (see Supporting Information File 1, Figure S1a,b). gelator effectiveness (Geff, mL, see Table 1 and Table 2). It
TEM images of diastereomeric (S,S)-1a and (S,R)-1a water/ appears that (S,R)-1b (Geff 19.5 mL, water/DMSO gel) orga-
DMSO gels (Figure 2 and Figure 3) show highly distinct nized in thinner fibers is more than twice effective a gelator
morphology of gel networks. In the first gel rather straight than its diasteroisomer (S,S)-1a (Geff 8.0 mL, water/DMSO gel)
fibers and fiber bundles with diameters in the range of 40–100 which forms thicker fiber bundles. In the toluene gel, (S,R)-1b
nm could be observed. However, the (S,R)-1a network showed organizes into wide and short tapes with low networking
a lower bundling tendency (Figure 3) and contained mostly capacity which is reflected in a very low (Geff 0.15 mL) gelator
fibers with diameters between 20–40 nm. In contrast to water/ effectiveness.
DMSO gels, the TEM image of the methyl ester derivative
(S,R)-1b gel with toluene had a totally different morphology DSC investigation of the highly efficient (S,R)-1a gelator of
characterized by the presence of short and very wide tapes water/DMSO solvent mixture showed only one transition in the
(Figure 4). As observed earlier for other gel systems, gelator heating (Tm) and cooling (Tc) cycle with gelation enthalpy
effectiveness Geff depends not only solubility but also depends changes of 37.70 and −38.20 kJ/mol, respectively (Table 4).
on the thickness of fibers constituting the network [43,59,60]. The (S,R)-1a/(R,S)-1a racemic mixture being almost two times
Since solvent is entrapped by capillary forces, the formation of less effective in gelation of the same solvent mixture compared
a dense network composed of thin fibers should possess smaller to (S,R)-1a, showed two transitions in the DCS heating and
compartments and hence a higher solvent immobilization cooling cycle neither of which corresponded to those observed
capacity compared to those less dense formed by thick fibers. with (S,R)-1a. Moreover, the racemate showed considerably
lower enthalpy changes compared to pure enantiomer gel (Ta-
ble 4). The latter observations for the racemate gel indicate
higher complexity of such systems and suggest possible interac-
tions of enantiomers that lead to diasteromeric assemblies with
a certain level of organization.
Table 4: ΔH and transition temperatures for selected retropeptide
DMSO/water obtained from DSC heating and cooling cycles.
Gelator/solvent
Tm
ΔHm
Tc
ΔHc
°C
kJ/mol °C
kJ/mol
(S,R)-1a/water/DMSO 93.2
37.70
82.6
−38.20
(S,R)-1a/(R,S)-1a/
water/DMSO
97.6
137.0
20.36
2.32
78.2
123.2
−23.95
−2.80
Figure 3: TEM images (PWK staining) of: (S,R)-1a H2O/DMSO gel.
950

Beilstein J. Org. Chem. 2010, 6, 945–959.
Figure 5: The concentration dependence of NH and C*H chemical shifts in (S,R)-1b toluene-d8 gel samples (concentration range 0.001–0.1 M): a)
oxalamide-NH protons (▲); Leu-NH’s (Δ) and b) oxalamide-α-Leu-C*H (■) and oxalamide-β-Leu-C*H (□) protons.
FTIR, 1H NMR and CD investigations
appear in the region of 3260–3320 cm−1 corresponding to a
To identify supramolecular interactions that stabilize gel assem- hydrogen bonded NH. In addition, the ester carbonyl and amide
blies, the selected gels were studied by 1H NMR, FTIR and CD I bands are located at 1750 and 1653 cm−1, respectively, the
spectroscopy. Valuable information on the self-assembly of position of the latter being in accord with its participation in
gelator molecules in the pre-gelation state and in the gel could hydrogen bonding.
be obtained by analysis of the concentration and temperature
dependent 1H NMR and FTIR spectra. It was previously 1H NMR investigation showed significant concentration
reported that the planar and self-complementary oxalamide unit dependence of N–H and C*H proton shifts in the (S,R)-1b
persistently forms intermolecular hydrogen bonds and repre- (Figure 5), (S,S)-1b and its racemate (S,S)-1b/(R,R)-1b
sents the major organizational element in the gel assemblies of (Figure 6) toluene-d8 gel samples. In the first case the
both, bis(amino acid)- and bis(amino alcohol)oxalamides, and oxalamide NH and Leu-NH protons were downfield shifted by
also has the major influence on their organization in the solid 1.6 and 1.8 ppm, respectively, for a gelator concentration
state [55-60]. In addition, the latter gelators tend to exhibit increase from 0.001–0.1 mol dm−3. The oxalamide-α-Leu
layered organization in their gel assemblies due to their struc- methine protons (C*H) were also significantly downfield
tural resemblance to bola-amphiphiles.
shifted (ΔδC*H = 0.566 ppm) while the β-Leu-C*H proton shifts
were less significant. Strong downfield shifts of the oxalamide-
In the FTIR spectra of (S,S)-1b and (S,R)-1b toluene gels one and Leu-NH protons as well as the α-Leu-C*H proton closest to
wide band or two poorly resolved NH bands, respectively, the oxalamide unit suggest simultaneous participation of both
Figure 6: The concentration dependence of NH and C*H chemical shifts in (S,S)-1b and its racemate (S,S)-1b/(R,R)-1b toluene-d8 gels (concentra-
tion range 0.001–0.1 mol dm−3): a) (S,S)-1b oxalamide-NH protons (▲) and Leu-NH protons (Δ); the racemate oxalamide-NH protons (●) and Leu-
NH protons (O); b) (S,S)-1b oxalamide-α-Leu-C*H (■);(S,S)-1b oxalamide-β-Leu-C*H (□); the racemate oxalamide-α-Leu-C*H ( ); racemate
oxalamide-β-Leu-C*H ( ).
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Beilstein J. Org. Chem. 2010, 6, 945–959.
the oxalamide and Leu-NH protons in intermolecular hydrogen bonding. The determined higher saturation point and MGC of
bonding. A comparison of the magnitudes of concentration 0.12 mol dm−3 for (S,R)-1b compared to the saturation point of
induced shifts for diastereomeric gelators (S,R)-1b (Figure 5; the (S,S)-1b diastereoisomer (0.03 mol dm−3) could be
oxalamide-NH protons Δδ 0.25 ppm; Leu-NH protons Δδ 0.17 explained by the increased solubility of the (S,R)-1b assemblies
ppm; α-Leu-C*H Δδ 0.13 ppm) and (S,S)-1b (Figure 6, in toluene compared to those formed by the second diastereo-
oxalamide-NH protons Δδ 1.50 ppm; Leu-NH protons Δδ 1.55 isomer [69]. However, despite of the lower saturation point and
ppm; α-Leu-C*H Δδ 0.53 ppm) shows large differences. The lower solubility, the (S,S)-1b assemblies cannot form the gel
monitored protons of (S,S)-1b are more strongly downfield which points toward possible solvation effects taking a decisive
shifted than the corresponding protons of (S,R)-1b for the same role in the self-assembly of the diastereoisomers. Recently,
concentration range. Similar trends of NH and C*H concentra- Meijer et al. [70] presented convincing evidence that co-organi-
tion induced shifts are observed for (S,S)-1b and its racemate zation of solvent at the periphery of the gel aggregates plays a
(S,S)-1b/(R,R)-1b toluene-d8 gels (Figure 6). Again the magni- direct role in the assembly processes evident, even during the
tudes of the NH and C*H concentration induced shifts are formation of the pre-aggregates. The influence of solvent struc-
higher for the (S,S)-1b than for the racemate gel. It should be ture on the length of the aggregates was clearly demonstrated.
noted that the higher concentration induced shifts are observed Hence, different solvation effects of toluene operating in the
for (S,S)-1b which forms sol–gel mixture in toluene compared self-assembly of (S,S)-1b and (S,R)-1b may be responsible for
to both (S,R)-1b and the racemate (S,S)-1b/(R,R)-1b forming the formation of insufficiently long aggregates of the first dia-
stable toluene gels (Table 2).
stereoisomer resulting in the formation of the sol–gel mixture,
and sufficiently long assemblies of the second one being
The concentration induced shift curves show that for the exam- capable of networking and the formation of a self-supported gel.
ined gelators, the self-assembly equilibrium is reached at
different gelator concentrations; for (S,S)-1b and its racemate The variations of oxalamide NH, Leu-NH, α- and β-Leu-C*H
(S,S)-1b/(R,R)-1b, the saturation point is reached at the same proton chemical shifts with increasing temperature in the
concentration of 0.03 mol dm−3 (Figure 6a,b) which corre- toluene-d8 gel samples of the diastereomeric (S,R)-1b and (S,S)-
sponds to the experimentally determined minimal gelation 1b (concentrations of 0.5 mol dm−3) are shown in Figure 7. For
concentration (MGC) for the racemate of 0.034 mol dm−3. If the the (S,R)-1b gel, a temperature increase from 20–50 °C induced
racemate were organized in the conglomerate as separate enan- only slight downfield shifts of both the oxalamide- and Leu-NH
tiomeric (S,S)-1b and (R,R)-1b assemblies, the magnitudes of protons as well as the α- and β-Leu-C*H protons; in the higher
the concentration induced shifts should be similar to those temperature interval (50–90 °C) all protons were downfield
measured the for (S,S)-1b assemblies. Since this was not shifted in accord with the breaking of intermolecular hydrogen
observed (Figure 6a, b) the results suggest formation of racemic bonds involving both the oxalamide and Leu NH protons. In
gel assemblies composed of both enantiomers. The latter also contrast, the respective protons of the (S,S)-1b are continuously
points to the lack of any resolution at the supramolecular level shifted downfield with increasing temperature (Figure 7c).
which was found to occur for some racemic gelators and Hence, a clear difference in the thermal behavior of (S,S)-1b
specific solvents [60]. The observation that (S,S)-1b with weak gel and (S,R)-1b gels was observed. Similar discontin-
toluene gives a sol/gel mixture while the racemate gives a stable uous temperature variation curves to those observed for (S,R)-
gel implies that the enantiomer forms insufficiently long assem- 1b were also found for bis(amino acid)oxalamide gelators
blies incapable of efficient networking and of forming of self- which were shown to exhibit the layered type of organization in
supported gel, while the opposite holds for the racemic assem- their gel assemblies [59,60]. Small downfield shifts of the
blies which are capable of forming the gel network
oxalamide- and LeuNH protons observable in the low tempera-
ture regime (Figure 7a) were explained by the less energy
The discontinuous concentration induced shift curves obtained demanding disassembly that occurred at lipophilic sites of the
for (S,R)-1b diasteroisomer may indicate the presence of interacting bilayers resulting in small deshielding of these
different assemblies at lower and higher gelator concentrations. protons. In the higher temperature regime the downfield shifts
It appears that the first saturation point is reached at a concen- of the same protons indicate the breaking of intermolecular
tration around 0.03 mol dm-3 and the second at 0.12 mol dm−3, hydrogen bonds. This conclusion is supported by molecular
the latter corresponding nicely to the experimentally deter- modeling (see the respective paragraph) which showed that the
mined MGC of 0.116 mol dm−3. It should be noted that in the low energy conformation of (S,R)-1b is similar to those found
low and high concentration ranges downfield shifts of for bis(amino acid)oxalamides and that both show a strong
oxalamide- and Leu-NH protons are observed indicating that resemblance to bola-amphiphiles which are known to organize
both assemblies are formed by intermolecular hydrogen into bilayers [71].
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Beilstein J. Org. Chem. 2010, 6, 945–959.
Figure 7: Temperature dependence of: a) oxalamide NH protons (▲), Leu-NH protons (Δ) and b) oxalamide-α-Leu-C*H (■) and oxalamide-β-Leu-C*H
(□) chemical shifts in 0.5 mol dm−3 (S,R)-1b toluene-d8 gel sample; c) and d) induced shifts of the respective protons in (S,S)-1b toluene-d8 gel.
The temperature dependence of CD spectra of decalin gels electronic absorption band (Figure 8f), but similarly to (S,R)-1b
formed by diastereoisomeric methyl esters (S,R)-1b and (S,S)- the intensity of CD band increased with increasing temperature.
1b (Figure 8a, b, respectively) was also investigated. At room
temperature (S,R)-1b shows negative Cotton effect at λ = 245 It should be noted that the temperature induced changes in the
nm of moderate intensity which decreases on increasing CD spectra of both, (S,R)-1b and (S,S)-1b decalin gels are
temperature from 20 to 50 °C. Further temperature increase of different to those obtained for 5a ethanol and
the gel sample resulted in the appearance of a new negative CD bis(Leu)oxalamide 1-butanol gels (Figure 8c, d). With these
peak at λ = 234 nm corresponding to the shoulder band in the latter gels a decrease of CD peak intensities with increasing
gelator UV spectrum (Figure 8e); the intensity of the band temperature was observed in accord with the disassembly of the
increased with increasing temperature (Figure 8a). As reported chiral gel aggregates which has also been observed for some
for the self-assembled alanine based gelators, the CD signal at other chiral gels [76]. Consequently, the CD results described
around 232 nm can be ascribed to the n,π*-transition of the for the (S,R)-1b and (S,S)-1b gels, characterized by the increase
amide carbonyl [72-74]. Hence, the λ = 234 nm band that of CD signals with increasing gel temperature, indicate that in
appeared at 60 °C could be ascribed to the intrinsic chirality of these systems there is no aggregation increased chirality as
disassembled gelator molecules. Although the origin of the λ = observed for some other gels of the chiral gelators.
245 nm CD band is not clear, it could be the consequence of
circular differential scattering which was shown to contribute to XRPD, molecular modeling and packing model
the CD spectra of large aggregated biomolecules [75].
The X-ray powder diffraction (XRPD) pattern of (S,S)-1b
xerogel showed strong peaks corresponding to periodic dis-
By contrast, the CD spectra of the (S,S)-1b gel showed a nega- tance d of 16.1 and 13.4 Å and a weaker peaks corresponding to
tive CD band at λmin 238.6 nm (Figure 8b) corresponding to its d’s of 15.1 and 8.6 Å (Figure 9b).
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Beilstein J. Org. Chem. 2010, 6, 945–959.
Figure 8: Temperature dependent CD spectra of: a) (S,R)-1b decalin gel (c = 3.4·10−2 M); b) (S,S)-1b decalin gel (c =7.6·10−3 M); c) 5a ethanol gel
(c =1·10-2 M) and d) (S,S)-bis(Leu)oxalamide I 1-butanol gel (c = 2.8·10−2 M); e), f) UV spectra of (S,R)-1b (red curve), (R,S)-1b and (S,S)-1b taken
in decalin at specified concentrations.
Figure 9: X-ray powder diffractograms of (a) (S,R)-1b and (b) (S,S)-1b xerogels prepared from their toluene gels.
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Beilstein J. Org. Chem. 2010, 6, 945–959.
For the (S,R)-1b xerogel, strong peaks corresponding to d’s of
14.9 and 13.4 Å and smaller peaks to d’s of 13.98, 8.6 and 7.5
Å could be observed (Figure 9a). Molecular modeling of (S,R)-
1b and (S,S)-1b yields low energy extended conformations with
lengths of 15.1 and 15.9 Å, respectively (Figure 10a) [77].
The measured extended conformation lengths correspond nicely
to the largest periodic distances of 14.9 and 16.1 Å obtained by
XRP diffraction of (S,R)-1b and (S,S)-1b xerogels indicative of
the formation of assemblies of the extended gelator molecules.
However, the low energy conformations of (S,R)-1b and (S,S)-
1b are distinctly different with all i-Bu groups cis-oriented in
(S,R)-1b, while the i-Bu groups in α- and β-Leu of (S,S)-1b
have the trans-arrangement with respect to the plane containing
the amide and oxalamide groups (Figure 10a). Conformational
analysis reveals why such arrangements of i-Bu groups occur
(Figure 10b, Newman projections of two stereogenic centers
only). Our earlier results based on single crystal X-ray analysis
of bis(amino acid)oxalamides showed that their most stable
conformations are characterized by vicinal positioning of the
methine proton at the stereogenic centre and oxalamide carbon-
yl oxygen atom which produces the lowest steric repulsion.
Similarly, in the conformation A of (S,R)-1b with cis-arrange-
ment of the i-Bu groups, the smallest group (H) of the β-Leu
chiral centre is located close to amide carbonyl; the conforma-
tions with trans-arrangement of i-Bu groups should be less
stable due to increased steric repulsion between the amide car-
bonyl oxygen and either the i-Bu or carboxymethyl group.
Among the conformations of (S,S)-1b denoted B, C and D with
trans-, cis- and trans-arrangement of i-Bu groups, respectively,
the conformation D appears the most stable due to the vicinal
position of the smallest group (H) and amide carbonyl oxygen
atom. These conclusions are supported by molecular modeling
(Figure 10a); the lowest energy conformations of (S,R)-1b and
(S,S)-1b generated by systematic search of their conformational
space correspond to A and D of Figure 10b, respectively. In
support, the values of the vicinal NH-Cα-H coupling constants
JNH-CH for the (S,R)-1b oxalamide NH-Leu Cα-H and Leu
NH-Leu Cα-H (8.63 and 8.48 Hz) and (S,S)-1b (8.63 and 8.33
Hz) obtained from their 1H NMR spectra taken in CDCl3
correspond to dihedral angles close to trans-coplanar posi-
tioning of NH and Cα-H protons in both groups
Figure 10: (a) Fully minimized the lowest energy conformations of
(S,S)-1b (top) and (S,R)-1b generated by systematic conformational
search (SYBYL package; second graphic); (b) Partial Newman projec-
tions of two stereogenic centers of (S,R)-1b and (S,S)-1b showing
conformations with cis-arrangement of i-Bu groups in the former (A)
and trans- (B, D) and cis- (C)-arrangements of i-Bu groups in the latter.
by lipophilic interactions is 13.4 Å corresponding exactly to d
The low energy conformations of (S,R)-1b and (S,S)-1b were of 13.4 Å found in its XRPD. The (S,S)-1b model of the dimer
used for docking calculations to generate the hydrogen bonded formed by lipophilic packing gives a thickness of 13.9 Å. Based
dimers of extended gelator molecules involving both, the on these results and those of the FTIR and 1H NMR studies,
oxalamide and Leu-NH protons (Supporting Information File 1, which suggested intermolecular hydrogen bonding between
Figure S3). The thicknesses of such dimers estimated from gelator molecules involving both the oxalamide and Leu amide
models are between 7.5 and 8.6 Å (Figure 11) which corres- units, a basic packing model for (S,S)-1b and (S,R)-1b can be
pond well to periodic distance d of 8.6 Å found in their XRP proposed which consists of layers of hydrogen bonded gelator
diffractograms. The thickness of the (S,R)-1b dimer generated molecules (Figure 11).
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Beilstein J. Org. Chem. 2010, 6, 945–959.
Figure 11: Schematic presentation of the proposed (S,S)-1b and
(S,R)-1b basic packing model based on XRPD, 1H NMR, FTIR and
molecular modeling results.
Figure 12: X-ray powder diffraction (XRPD) diagram of (S,R)-1a water/
DMSO xerogel.
In contrast to the diester gelators (S,R)-1b and (S,S)-1b a (S,S)-1b and (S,R)-1b shown in Figure 10a, b. In both cases, the
detailed spectroscopic investigation of (S,S)-1a and (S,R)-1a major organizational driving force is provided by extensive
organization in their water/DMSO gel assemblies was not intermolecular hydrogen bonding. In lipophilic solvents, where
possible due to solvent unsuitability.
such types of intermolecular interactions are highly favored,
formation of wide and relatively short tapes could be observed
Nevertheless, the FTIR spectrum of the (S,R)-1b xerogel (TEM, (S,R)-1b toluene gel, Figure 4) possibly due to the
prepared from its water/DMSO gel was found to differ from enhanced self-assembling in the direction of intermolecular
that of the crystalline sample; the positions of NH stretching, hydrogen bonds. In contrast, gelling of the highly polar and
carboxylic acid and amide I carbonyl stretching, and NH hydrogen bond competitive water/DMSO solvent mixture
bending amide II bands in the spectra of crystalline and xerogel (TEM, (S,S)-1a and (S,R)-1a water/DMSO gels, Figure 2 and
samples appear at 3281.2 1724.4 1655.6 1543.6 1510.4 cm−1 Figure 3) results in the formation of tiny fibers or fiber bundles
and 3303.4 3273.5 1728.5 1651.6 1534.2 1510.5 cm−1, respect- due to less favored self-assembly in the direction of intermolec-
ively. The positions of the xerogel bands are similar to those ular hydrogen bonding and more pronounced intermolecular
found in the spectrum of previously studied bis(Leu)oxalamide lipophilic interactions.
water/DMSO gel assemblies (3300 1729 1658 1515 cm−1) and
which was shown to organize by intermolecular hydrogen Conclusion
bonding between oxalamide units and lateral carboxylic acid A series of chiral bis(dipeptide)oxalamides was prepared repre-
hydrogen bonding [59]. The appearance of two NH stretching senting a novel family of retro-peptidic gelators. Their gelation
and amide II bands in the (S,R)-1b xerogel spectrum (3303.4 properties towards a defined set of solvents was assessed and,
3273.5 1534.2 1510 cm−1) can be attributed to the intermolec- their conformational characteristics, organization in gel assem-
ular hydrogen bonds formed by Leu amide units. The XRPD of blies and thermal and morphological characteristics of selected
(S,R)-1a water/DMSO gel (Figure 12) showed two diffraction gels were studied by molecular modeling, 1H NMR, FTIR, CD,
peaks at 2θ = 5.509 and 10.501 corresponding to periodic DCS, TEM and XRPD. Gelation experiments have shown that
distances d of 16.04 and 8.42 Å which also suggests formation the group of terminal free acid retro-dipeptides (S,S)-
of hydrogen bonded assemblies between extended forms of bis(LeuLeu) 1a, (S,S)-bis(PhgPhg) 3a and (S,S)-bis(PhePhe) 5a
gelator molecules as in the cases of the diester derivatives (S,S)- showed moderate to excellent gelation of polar water/DMSO
1b and (S,R)-1b (Figure 11).
and water/DMF solvent mixtures and were much less efficient
in gelating solvents of medium and low polarity. Interestingly,
These results indicate that the dicarboxylic retro-dipeptides the free acid gelators incorporating different amino acids (S,S)-
(S,S)-1a and (S,R)-1a also show similar basic organization as (LeuPhg) 2a and (S,S)-(PhgLeu) 4a had no or very weak
their dimethyl ester counterparts (S,S)-1b and (S,R)-1b gelating ability. The observed difference in gelation between
(Figure 11). Also molecular modeling of (S,S)-1a and (S,R)-1a retro-peptides incorporating identical or two different amino
generated very similar low energy conformations to those of acids is intriguing. It seems that the intermolecular lipophilic
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Beilstein J. Org. Chem. 2010, 6, 945–959.
interactions that stabilize gel assemblies in polar solvents are conformational differences were found to strongly influence
more favorable for identical amino acid fragments (lipophilic or both, gelation effectiveness and the morphology characteristics
aromatic) and less favorable when aromatic–lipophilic amino of gel network.
acid fragments are present in the gelator molecule. Gelation
properties of methyl ester derivatives 1b–5b, were not signifi-
Supporting Information
cantly different to those of the respective diacid derivatives
1a–5a except that the former appear slightly more versatile and
Supporting Information File 1
were capable of gelating some lipophilic solvents presumably
due to increased solubility (Table 1 and Table 2). The diamide
derivatives bis(LeuLeuNH2) 1c, bis(PhgPhgNH2) 3c and
bis(PhePheNH2) 5c were even more versatile and were capable
of gelating a larger set of tested solvents compared to the
respective dicarboxylic acid (1a, 3a, and 5a) and dimethyl ester
derivatives (1b, 3b and 5b) (Tables 1–3). It appears that the
increased hydrogen bonding potential of terminal diamide
derivatives gives somewhat more versatile gelators which could
also gel solvents of medium and low polarity where intermolec-
ular hydrogen bonding is favored. Stereochemical influences on
gelation properties are exemplified by the following observa-
tions: (i) the racemate (S,R)-1a/(R,S)-1a exhibited considerably
lower gelation effectiveness than the pure enantiomer (S,R)-1a
while the (S,S)-1a/(R,R)-1a racemate had no gelation ability and
tended to crystallize, (ii) terminal diester racemates (S,R)-
1b/(R,S)-1b and (S,S)-1b/(R,R)-1b were two times more effi-
cient in the gelation of water/DMF and water/DMSO mixtures,
respectively, than the pure enantiomers (S,R)-1b and (S,S)-1b;
the latter provides additional examples that some racemates
could be more effective gelators of specific solvents than the
pure enantiomers; (iii) among the terminal carboxamide gela-
tors the heterochiral (S,R)-1c diastereoisomer is capable of
immobilizing up to 10 and 4 times larger volumes of
dichloromethane and toluene solvent mixtures containing a little
DMSO, respectively, compared to homochiral (S,S)-1c. The
combined results of 1H NMR, FTIR, XRPD and molecular
modeling studies of terminal diester (S,S)-1b and (S,R)-1b and
terminal free acid (S,S)-1a and (S,R)-1a derivatives gave a
consistent picture of their basic organization in gel assemblies.
In lipophilic solvents and also in the highly polar water/DMSO
mixture, the intermolecular hydrogen bonding between
extended gelator molecules utilizing both, the oxalamide and
Leu amide hydrogen bonding functionalities represents the
major organizational driving force for aggregation. The TEM
investigations have shown that in the highly lipophilic solvents
the extensive intermolecular hydrogen bonding may lead to the
formation of wide and relatively short tapes giving a gel
network of low solvent immobilization capacity. Molecular
modeling studies revealed that the homochiral (S,S)-1a and
(S,S)-1b form the low energy conformations with cis-trans-
arrangement of i-Bu groups in contrast to the heterochiral (S,R)-
1a and (S,R)-1b conformations possessing the all-cis-arrange-
ment of i-Bu groups with respect to the oxalamide plane. Such
Full experimental procedures and characterization details
for all new compounds, molecular modeling and TEM
images.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-6-106-S1.pdf]
Acknowledgements
The authors thank L. Horvat, B.sc and Dr. N. Ljubešić for TEM
investigations. The financial support from the Croatian Ministry
of Science, Education and Sports (Projects No. 098-0982904-
2912) and EU COST Action D31 is gratefully acknowledged.
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