Molecular mechanism of physical gelation of hydrocarbons by fatty acid amides of natural amino acids

Article abstract of DOI:10.1016/j.tet.2007.05.028

A variety of fatty acid amides of different naturally occurring l-amino acids have been synthesized and they are found to form gels with various hydrocarbons. The gelation properties of these compounds were studied by a number of physical methods including FTIR spectroscopy, X-ray diffraction, scanning electron microscopy, differential scanning calorimetry, rheology, and it was found that gelation depended critically on the fatty acid chain length and the nature of the amino acid. Among them l-alanine based gelators were found to be the most efficient and versatile gelators as they self-assemble into a layered structure to form the gel network. Mechanisms for the assembly and formation of gels from these molecules are discussed.

Full text of DOI:10.1016/j.tet.2007.05.028

Tetrahedron 63 (2007) 7334–7348
Molecular mechanism of physical gelation of hydrocarbons by
fatty acid amides of natural amino acids
*
Asish Pal, Yamuna K. Ghosh and Santanu Bhattacharya
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, Karnataka, India
Received 30 October 2006; revised 19 March 2007; accepted 4 May 2007
Available online 22 May 2007
Abstract—Avariety of fatty acid amides of different naturally occurring L-amino acids have been synthesized and they are found to form gels
with various hydrocarbons. The gelation properties of these compounds were studied by a number of physical methods including FTIR spec-
troscopy, X-ray diffraction, scanning electron microscopy, differential scanning calorimetry, rheology, and it was found that gelation de-
pended critically on the fatty acid chain length and the nature of the amino acid. Among them L-alanine based gelators were found to be
the most efficient and versatile gelators as they self-assemble into a layered structure to form the gel network. Mechanisms for the assembly
and formation of gels from these molecules are discussed.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
the hydrogen bonding sites in the gelator. Oil spills and toxic
solvent-based industrial effluents are major offenders of the
ecological balance and the environment. By transforming
the ‘offending’ oil or toxic organic solvent into a solid-like
gel, containment of the spill, concomitant removal of the
separated ‘solid’ from the affected water body, and subse-
quent retrieval of the spilt oil or solvent may all be accom-
plished. To alleviate these situations involving oil spills, it
is necessary to selectively gelate oil in presence of large
quantities of water. We have previously reported that fatty
acid amides of L-alanine 2c can gelate oil selectively from
oil–water mixtures.13 Since then, several reports have ap-
peared in literature that addresses this important problem
of phase selective gelation.14 However, the fatty acid amides
of amino acid system that were reported by us have one im-
portant advantage in that these molecules are totally biocom-
patible15 and hence biodegradable. Recently, we have shown
that the cavities inside such gel networks can encapsulate
different kinds of nanoparticles to give rise to novel nano-
composites with new properties.16 The LMOG network
can also be used as template to synthesize nanostructured
materials.5c,17 Thus, on one hand, a broad variety of molec-
ular structures are available that form gels under appropriate
conditions. At the same time it is still challenging to design
and synthesize specific gelators especially for a given appli-
cation. Whatever may be the case, gelators based on biocom-
patible molecules are of particular importance in that they do
not contribute any environmental hazard. To design new ge-
lators based on biocompatible frameworks for various appli-
cations, a detailed molecular level understanding of this kind
of LMOGs is necessary. In the present work, we have syn-
thesized a large number of fatty acid amides of different
amino acids (Chart 1) that are related to 2c. We have now
The gelation of organic solvents by a diverse group of small
molecules is a fascinating phenomenon, which involves
molecular self-assembly.1 The supramolecular association
of these low-molecular-mass organogelator (LMOG) leads
to physical gel formation, which represents macroscopic
expression of their self-assembly via various non-covalent
interactions.2 These nanostructured materials are not only
of academic interest but also offer potential application in
industrial fields such as cosmetics, food, medical science,
tissue engineering, etc.3 Such LMOGs include a wide variety
of molecular structures such as long chain hydrocarbons,4
amino acid derivatives,5 carbohydrate derived systems,6
dendrimers,7 steroid derivatives,8 metal complexes,9 and
even two component systems.10 Other types of amphiphilic
molecules have also been used to achieve gelation of water
and/or organic media.11 Some of the above have been devel-
oped by rational molecular design and some have been dis-
covered serendipitously. However, it has been recognized
that an effective gelator should possess functional groups
that interact with each other via temporal associative interac-
tions. This is because an organogelator generally relies on
its ability to self-assemble via non-covalent interactions
including hydrogen bonding.12
Organogelators are generally not capable of gelating organic
solvents in the presence of water because water competes for
Keywords: LMOG; Self-assembly; Organogels; Viscoelastic materials;
Layered structures.
* Corresponding author. Tel.: +91 80 2293 2664; fax +91 80 2360 0529;
e-mail: sb@orgchem.iisc.ernet.in
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.05.028

A. Pal et al. / Tetrahedron 63 (2007) 7334–7348
7335
COOH
O
COOH
O
COOH
O
COOH
O
HN
HN
HN
HN
(CH2)nCH3
(CH2)nCH3
(CH2)nCH3
(CH2)nCH3
1: n = 10
2a-f: n = 6, 8, 10, 12, 14, 16
3a-b: n = 10, 14
4a-b: n = 10, 14
COOH
COOH
HN
HN
O
HN
O
(CH2)nCH3
(CH2)nCH3
5a-d: n = 4, 10, 14, 16
6a-c: n = 10, 14, 16
H2N
COOH
O
COOCH3
O
NH
N
HN
O
(CH2)11CH3
(CH2)10CH3
20
(CH2)10CH3
8c
23
Chart 1. Molecular structures of various fatty acid amides of different amino acids.
carefully investigated the various molecular features that
might be responsible for the onset of gelation. Based on
this study, we have proposed a molecular mechanism that
might be useful for the design of this class of LMOGs for
specific applications.
2.1. Synthesis
The syntheses of all the lipophilic amino acid derivatives
1–6 were easily accomplished in high yields using one or two
step procedures as summarized in Schemes 1–3. The methyl
ester hydrochlorides of individual amino acids were acylated
with the appropriate fatty acid chloride in dry CHCl3 in the
presence of 2 equiv of Et3N. The individual N-acyl amino
acid methyl ester was then carefully hydrolyzed with 1 M
NaOH (2 mL) in MeOH/THF (5:1) as shown in Scheme 1.
Similarly, the N-acyl derivatives of L-amino acids of various
chain lengths were synthesized taking the aliphatic acid of
desired chain length. Another derivative, N-methyl-L-ala-
nine was converted to its N-lauroyl derivative (20) in good
yield and high purity as shown in Scheme 2. For the synthe-
sis of 23, N-benzyloxy-L-alanine was first converted to the
corresponding amide by DCC coupling using n-dodecyl-
amine. Removal of the N-protecting group in 22 by hydroge-
nation in the presence of 10% Pd/C yielded 23 as shown in
Scheme 3. All the compounds isolated were characterized
adequately by analytical and spectroscopic means and the
corresponding data were consistent with their given struc-
tures (cf. Section 4).
2. Results and discussion
We have been interested in designing amphiphilic molecules
that are based on natural components as they are biodegrad-
able and self-assemble in organic solvents to form gels. To-
ward this end, we considered suitable N-acyl-L-amino acid
derivatives. In order to understand the mechanism of gela-
tion as well as to determine the minimal structural motifs
required by these systems to exhibit efficient gelation,
a number of such derivatives were considered. First, five
N-dodecanoyl derivatives of amino acids bearing side chains
of differing hydrophobicities were synthesized (Chart 1).
These are derivatives of naturally occurring amino acids gly-
cine (1), L-alanine (2), L-valine (3), L-leucine (4), L-phenyl-
alanine (5), and L-tryptophan (6). Compound 1 does not
possess chirality while compounds 2–6 are all chiral. Com-
pound 2 has a CH3 side chain, 3 has two CH3 side chains, and
4 has an isopropyl side chain. However, 5 and 6 differ from
the rest in that they have aromatic side chains. In order to
probe the role of the lipophilic segment in determining gela-
tion properties, fatty acid derivatives of the above molecules
with different chain lengths were also synthesized (Chart 1).
2.2. Gelation properties
Gelation of each of the compounds 1–6 was tested by dis-
solution of 10 mg of each new compound individually by
heating in a given solvent (1 mL). Upon cooling to room tem-
perature and inversion of the vial, if the solution did not flow
out of thevial, the compound was judged to be a gelator of the
corresponding solvent. Here the gelation numbers of the ge-
lators represent the maximum number of solvent molecules
that get entrapped per molecule of the gelators.
To investigate the role of the various functional units in such
N-acyl-L-amino acid derivatives toward gelation, 2c was
chosen (Chart 1). Compound 8c was prepared where the
CO2H group in 2c was converted to the corresponding methyl
ester to probe the role of the CO2H moiety in gelation.
Similarly, the secondary –NH–CO– linkage between the
lauroyl chain and the alanine unit in 2c was modified to
the corresponding tertiary amide –N(CH3)–CO– (as in 20)
to examine the importance of this linkage toward self-assem-
bly of 2c, a pre-requisite of gelation. A derivative 23 was
synthesized, where the amine residue in L-alanine was left
free and the lipophilic chain was introduced via an amide
linkage to the –CO2H end.
The abilities of aliphatic amino acid based molecules, 1–4,
to gelate aromatic hydrocarbon solvents like toluene and
aliphatic hydrocarbons like n-heptane and n-hexane were
checked initially (Table 1). Interestingly, 1 did not show ge-
lation in any hydrocarbon and this can be attributed to the
lack of chirality in the molecule. The L-alanine based mole-
cules formed nice transparent and stable gels from various
aromatic hydrocarbons such as toluene, benzene, xylene,

7336
A. Pal et al. / Tetrahedron 63 (2007) 7334–7348
R
COOCH3
O
R
COOCH3
R
COOH
(i)
(ii)
HN
NH2.HCl
NH2
R = H (Gly)
= CH3 (Ala)
= CH(CH3)2 (Val)
= CH2CH(CH3)2 (Leu)
= CH2C6H5 (Phe)
= CH2C8H6N (Trp)
13: R = H
(CH2)nCH3
14: R = CH3
15: R = CH(CH3)2
7: R = H; n =10.
16: R = CH2CH(CH3)2
17: R = CH2C6H5
8a-f: R = CH3; n = 6, 8,10, 12, 14,16.
9a-b: R = CH(CH3)2; n = 10, 14.
10a-b: R = CH2CH(CH3)2; n = 10, 14.
11a-d: R = CH2C6H5; n = 4, 10, 14, 16.
12a-c: R = CH2C8H6N; n = 10, 14, 16.
18: R = CH2C8H6N
(iii)
R
COOH
O
HN
(CH2)nCH3
1: R = H; n =10.
2a-f: R = CH3; n = 6, 8, 10, 12, 14, 16.
3a-b: R = CH(CH3)2; n = 10, 14.
4a-b: R = CH2CH(CH3)2; n = 10, 14.
5a-d: R = CH2C6H5; n = 4, 10, 14, 16.
6a-c: R = CH2C8H6N; n = 10, 14, 16.
Scheme 1. Reagents, conditions, and yields: (i) SOCl2, dry MeOH, 6 h, 99%. (ii) (a) 1 equiv KHCO3/H2O; (b) n-CH3(CH2)nCOCl, dry CHCl3, Et3N (2 equiv),
0 ꢀC, 5 h (7¼94%, 8a¼93%, 8b¼90%, 8c¼97%, 8d¼94%, 8e¼93%, 8f¼95%, 9a¼91%, 9b¼93%, 10a¼81%, 10b¼88%, 11a¼72%, 11b¼83%, 11c¼74%,
11d¼76%, 12a¼83%, 12b¼80%, 12c¼82%). (iii) (a) MeOH/THF, NaOH/H2O, 2 h; (b) 0 ꢀC, HCl/H2O (1¼98%, 2a¼98%, 2b¼93%, 2c¼97%, 2d¼95%,
2e¼94%, 2f¼92%, 3a¼90%, 3b¼93%, 4a¼98%, 4b¼91%, 5a¼78%, 5b¼98%, 5c¼95%, 5d¼93%, 6a¼98%, 6b¼91%, 6c¼88%).
Table 1. Gelation ability of fatty acid amides of amino acids in different
hydrocarbons at 25 ꢀC
COOH
COOH
(i)
Compounda
Toluene
Heptane
Hexane
O
N
NHCH3
19
1
I
I
S
I
2a
2b
2c
2d
2e
2f
3a
3b
4a
4b
5a
5b
5c
5d
6a
6b
6c
S
S
G
G
W
W
S
S
S
S
S
S
S
S
S
S
S
S
G
G
G
P
I
A
A
P
A
I
A
G
W
I
I
I
(CH2)10CH3
G
G
G
W
P
A
A
P
A
I
A
G
W
I
20
Scheme 2. Reagents, conditions, and yields: (i) CH3(CH2)10COCl, dry
DMF, Et3N (1 equiv), 0 ꢀC, 6 h, 64%.
mesitylene, etc. depending on their chain length. Accord-
ingly, modifications of the nature and size of the lipophilic
segment of amino acid based gelators were carried out in
order to probe the role of this part in gelation. While 2c
and 2d showed excellent gelation at 25 ꢀC, 2e and 2f having
C16 and C18 chains, respectively, could only form weak
gels. From Figure 1 it is evident that an optimum lipophilic
long chain is very important for forming good gels and hence
the gelation number of toluene gels of 2c and 2d decreases
with increasing lipophilicity. Again 2b having a C10 chain
could form gels in toluene only at low temperature
I
I
a
Gelator of 1 wt % was used for all tests; G: good gel, S: sol, I: insoluble, P:
immediate precipitation, A: aggregation leading to gradual precipitation,
W: weak gel.
O
COOH
COOH
(CH2)11CH3
(i)
(ii)
N
H
NHCOOCH2Ph
21
NH2
NHCOOCH2Ph
22
O
(iii)
(CH2)11CH3
N
H
NH2
23
Scheme 3. Reagents, conditions, and yields: (i) PhCH2OCOCl, NaOH/H2O, 0 ꢀC, 2 h, 72%. (ii) n-CH3(CH2)11NH2, DCC, dry THF, rt, 24 h, 78%. (iii) 10%
Pd/C, H2, 10 h, 87%.

A. Pal et al. / Tetrahedron 63 (2007) 7334–7348
7337
made the gel weaker. L-Tryptophan based molecules were
mostly insoluble in the aliphatic solvents.
Heptane gel
Hexane gel
Toluene gel
C
12Alanine
600
400
200
The kinetics of gelation were interestingly different depend-
ing on the nature of the amino acid side chain and the length
of the fatty acid chain as well as the solvent molecules in
which the compound is gelated. For aliphatic amino acid
based gelators, the onset of gelation in n-heptane and n-
hexane was very fast and was complete immediately upon
reaching the room temperature (w1–2 min). In contrast, in
aromatic hydrocarbon like toluene the gelation process
was slower and was complete within 10 min at ambient tem-
perature. For the gelators possessing amino acids with aro-
matic side chains, the time required for gelation was much
longer (nearly 1 h). The slower kinetics of gelation for the
gelators with aromatic side chains, or in aromatic hydrocar-
bon solvents, are presumably due to the bulky nature of the
side chain residues relative to that in aliphatic gelators or in
aliphatic hydrocarbons (see below). In addition, in aliphatic
hydrocarbon solvents, it is possible that the fatty acid chain
of the gelators could mix easily to facilitate the process of
self-assembly leading to gelation. It appears that in order
to generate the optimized three-dimensional arrangement
of the aromatic molecules necessary for gelation, the flat aro-
matic side chain residues position themselves for p-stack-
ing interactions, which takes a longer time to attain. Since
there is no possibility of achieving such stabilization for 3
and 4, the isopropyl and isobutyl groups only create steric
congestion leading to inefficient gelation. However, since
the methyl group in 2 is quite small, the self-association is
much faster. Interestingly, 1 was unable to gelate any solvent
due to the lack of chirality although the side chain of glycine
is the smallest. That chirality is essential for these systems to
exhibit gelation is evident from the fact that a racemic form
of 2a failed to gelate any of the solvents.18
C
14Alanine
C16-Phe
C10Alanine
2b
2c
2d
5c
Figure 1. Bar diagram showing gelation numbers of 2b–2d and 5c in
toluene, hexane, and heptane.
(<20 ꢀC) and 2a having a short C8 chain did not show any
observable gelation even at low temperatures (up tow4 ꢀC).
For aliphatic hydrocarbons like n-heptane and n-hexane, gel
formation was restricted to 2b–2d among the L-alanine de-
rivatives having C10, C12, and C14 chain lengths, respec-
tively. Figure 1 shows that the gelation number of the gels
in n-heptane and n-hexane was also dependent on the lipo-
philicity of the gelator molecules and was highest for 2c
with a C10 chain.
Notably, the fatty acid amides of racemic alanine did not
gelate any hydrocarbon solvent irrespective of their chain
lengths. In contrast, individual fatty acid amides of both
D- and L-alanine showed efficient gelation in both aromatic
and aliphatic solvents. This suggests that chirality is an im-
portant determinant for gelation by this class of materials.
2.3. Sites involved in self-association: FTIR studies
Interestingly, replacing L-alanine in these compounds with
L-valine and L-leucine also virtually abolished the gelation
properties. The derivatives of these two amino acids were
completely soluble in toluene, but in n-heptane and n-hexane
they formed aggregates (note that precipitates formed imme-
diately after cooling the solution but aggregates formation
took longer time). These aggregates are not efficient enough
to entrap many solvent molecules as required for good
gelation and hence gelation number could not be accurately
determined. Increasing the lipophilicity and steric bulk near
the chiral carbon center therefore inhibited the resulting fatty
acid amides from forming efficient gel networks.
When the methyl ester 8c, a compound structurally related to
2c, was used, no gelation was observed in any of the above
solvents. Similarly, N-methylation of the amide moiety in 2c
to give 20 again destroyed the gel-forming property of the
former compound. It was therefore evident that the presence
of both the carboxylic acid (–CO2H) residue and the amide
(–NHC]O) residue is essential for the continuous self-asso-
ciation of the monomers of 2c into networks possessing the
ability to entrap solvent.
FTIR studies were carried out to understand the roles of
the –CO2H and –NH–C]O residues of 2c in gelating of
non-polar solvents. First, FTIR spectra of 2c at different
concentrations in a transparent gel-forming solvent like
benzene and a non-gel forming solvent such as CHCl3
were recorded (Fig. 2A and B). The amide N–H asymmet-
ric stretching in CHCl3 appeared at 3430 cmꢁ1 (Fig. 2A),
which remained invariant with the increase in gelator con-
centration. A sample of gel produced in benzene was dried
in vacuum and the resulting solid was examined by FTIR
as a KBr pellet. The N–H stretch in this sample appeared
at 3348 cmꢁ1 (Fig. 2A) suggesting the preservation of
strong intermolecular hydrogen bonding associations in
solid 2c. At pre-gelating concentrations (c¼3 mg/mL) in
benzene, the amide N–H asymmetric stretching was found
For aromatic amino acids, e.g., L-phenylalanine and L-tryp-
tophan based molecules, their high solubilities in toluene
ruled out gelation in aromatic solvents. However, in aliphatic
hydrocarbons, e.g., in n-heptane or n-hexane, gelation was
evident depending on the length of the fatty acid chain
(Table 1). While 5c showed gelation in n-heptane and n-
hexane, the shorter chain versions of L-phenylalanine formed
‘clumped aggregates’ rather than gels. The gelation numbers
of the n-heptane and n-hexane gels of L-phenylalanine deriv-
ative 5c were less than that of the corresponding L-alanine
derivative 2c as evident from Figure 1. Again increasing
the chain length above an optimum lipophilicity, as in 5d,

7338
A. Pal et al. / Tetrahedron 63 (2007) 7334–7348
Figure 2. (A) Fourier transform infrared (FTIR) spectra of 2c in (i) CHCl3 as solution (222 mM), (ii) benzene as solution (222 mM), and (iii) the form of solid.
(B) Effect of concentration on the FTIR spectra of 2c in benzene: (1) 11 mM, (2) 18 mM, (3) 36 mM, (4) 111 mM, (5) 222 mM. The peaks were monitored at (a)
3420–3348 cmꢁ1, (b) 1765–1706 cmꢁ1, (c) 1684–1646 cmꢁ1
.
to appear at 3419 cmꢁ1. However, under strongly gelating
efficiently gelate CCl4 where the solvent molecules cannot
hydrogen bond with 2c. Thus solvents capable of hydrogen
bonding inhibit gelation in these systems by disallowing
the continuation of a hydrogen-bonded superstructure forma-
tion due to self-assembly of 2c. On increasing the concentra-
tion of 2c in benzene, the carbonyl band of the CO2H stretch
between 1770 and 1750 cmꢁ1 disappeared (Fig. 2B(1)) and a
new stretch appeared at 1732 cmꢁ1 (Fig. 2B(4)), which could
be assigned to the formation of CO2H dimer. At c¼60 mg/
mL another stretch appeared at 1706 cmꢁ1 (Fig. 2B(5)) sug-
gesting the presence of a strongly hydrogen-bonded network
as seen in the solid aggregate (1704 cmꢁ1). However, in
CHCl3, 2c exhibited a stretch at 1750 cmꢁ1 at c<5 mg/mL.
Upon increase in c, this stretch shifted to an intermediate
value of 1732 cmꢁ1 (not shown).
concentrations (c¼60 mg/mL) a major peak appeared at
3348 cmꢁ1 at the expense of the signal at 3419 cmꢁ1
,
which was reduced to a minor peak (Fig. 2B). At
5<c<10 mg/mL in benzene, the molecules of 2c are not
as strongly associated as in the solid although the
presence of intermolecular hydrogen bonding is still evi-
dent. This indicates that the solvent molecules do not in-
terfere with the intermolecular association. At identical
concentrations in CHCl3 this association is much weaker,
as CHCl3 can compete for hydrogen bonding with the in-
dividual molecules of 2c. Strong intermolecular hydrogen
bonding in the gel state of benzene is confirmed by the
fact that at gelating concentrations of 2c, this stretch shifts
to 3348 cmꢁ1 from 3430 cmꢁ1, which is identical to that of
the solid non-gelated aggregate.
Taken together these studies show that the gelation by 2c is
caused by the intermolecular hydrogen bonding between the
amide linkages (–N–H/(O)]C–N–H/(O)]C–). Such
intermolecular association in these systems is significantly
affected by the polarity and protic nature of the solvent.
The CO2H sites of 2c in both CHCl3 and benzene
at c>10 mg/mL form dimers of comparable strength
(1732 cmꢁ1). However, there is a notable difference in the
strength of the amide I band under similar conditions. It is
considerably weaker (1669 cmꢁ1) in CHCl3 than in benzene
(1646 cmꢁ1), and it is this difference in strength, which
probably determines whether a solvent promotes or inhibits
gelation. The dimer formation at the CO2H end and hydro-
gen bonding at the amide sites are therefore both required
for effective gelation. This is reflected in the behavior of
The amide I band at c¼3 mg/mL appeared at 1684 cmꢁ1 in
benzene (Fig. 2B(1)). Increase in c showed the appearance
of a hydrogen-bonded species at 1648 cmꢁ1, which became
more intense with increase in c and a concomitant decrease
in the stretch at 1684 cmꢁ1, almost till its disappearance
(Fig. 2B(5)). Notably the amide I band in the gel state of 2c
(Fig. 2B(5)) was found to be almost as strongly hydrogen
bonded as in the solid aggregate, which showed the corre-
sponding stretch at 1646 cmꢁ1. Note also that in CHCl3
only one stretch for 2c occurred at 1669 cmꢁ1, which did
not vary with concentration (not shown). This could be due
to the formation of species where the oxygen of the amide
carbonyl is weakly hydrogen bonded to the acidic H of
CHCl3. This is confirmed by the fact that 2c is able to

A. Pal et al. / Tetrahedron 63 (2007) 7334–7348
7339
23 where, although the amide link still exists, the free amine
cannot associate effectively like the CO2H moiety and hence
gelation does not occur.
The thickness of fibers was less with 5b (1–3 mm) but with
increased lipophilicity in 5c the average thickness of the
fibers increased to 3.0–4.0 mm. Closer scrutiny reveals that
aggregates of L-phenylalanine based gelator show larger
pores in the assembly compared to that of L-alanine based
gelator.
2.4. Scanning electron microscopy (SEM)
In order to discern the nature of the microstructures that may
be present in such gels with such varying gelation capacity
and mechanical strength, we examined the gel samples of al-
anine based derivatives in toluene and n-heptane by scanning
electron microscopy. SEM confirmed the presence of fibrous
networks in all instances. For the toluene gel of 2b, 2d, and
2f, as the chain length of the lipophilic segment was in-
creased, the thickness of the fiber gradually became larger
(Fig. 3A(a–c)). The thickness of fibers was least with 2b
(0.4–0.5 mm), highest with 2f (2.5–3.5 mm), and intermedi-
ate with 2d (0.5–0.6 mm). For the n-heptane gel, a slight var-
iation of fiber dimension was noticed as chain length of the
lipophilic part was increased from C10, C12 to C14
(Fig. 3A(d–f)).
2.5. Differential scanning calorimetry of the gel
To gain further insights into the thermal stability of the gels,
we investigated extensively the thermotropic behavior of the
gel prepared in toluene and heptane. The gel-to-sol melting
transitions of the individual gel were found to be less sharp
than the corresponding freezing transitions from sol to gel.
Also, the melting temperatures (Tm) for gel-to-sol were
higher than the freezing temperature (Tf) for sol-to-gel
transition. This type of hysteresis behavior has also been
observed with other gels.19
For the toluene gels of L-alanine based gelators of different
chain lengths, 2b–2f, both the Tm and Tf were found to in-
crease with increasing chain length (Fig. 4a and Table 2a).
Also the value of DHmelting for the gel-to-sol transition
The aggregates of the phenylalanine based derivatives in
n-heptane were also examined through SEM (Fig. 3B).
Figure 3. [A] SEM pictures of (a) 2b in toluene, (b) 2d in toluene, (c) 2f in toluene, (d) 2b in heptane, (e) 2c in heptane, and (f) 2d in heptane. [B] SEM pictures of
(a) 5b in heptane and (b) 5c in heptane.

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A. Pal et al. / Tetrahedron 63 (2007) 7334–7348
70
60
50
40
30
20
10
0
(a)
(b) 80
Heptane gels of L-Alanine based gelators
Toluene gels of L-Alanine based gelator
75
70
65
60
55
50
45
40
35
30
25
Tm of gel to sol transition
Tf of sol to gel transition
Tm of gel to sol transition
Tf of sol to gel transition
10
12
14
16
number of carbon atoms in fatty acid chain
18
10
11
12
13
14
15
number of carbon atoms in the fatty acid chain
16
(c)
Tm of gel to sol transition
Tf of sol to gel transition
80
70
60
50
40
30
20
10
0
C
16-Alanine
C16-Phenylalanine
C16-Valine
2e
3b
5c
Figure 4. (a) Plot of melting temperature versus number of carbon atoms in the fatty acid chains of L-alanine based gelators for toluene gels. (b) Plot of melting
temperature versus number of carbon atoms in the fatty acid chains of L-alanine based gelators for heptane gels. (c) Bar diagram showing the variation of melting
temperature for different amino acid gelators. Error in measurement is within ꢂ1 ꢀC.
Table 2. The gel melting temperature from DSC measurement
increase in the chain length. For the n-heptane gel of L-
alanine based gelators, 2b–2d, increasing the chain length
makes the gelator assembly more thermally rigid (Fig. 4b
and Table 2b). Since the n-heptane molecules can orient
themselves along the lipophilic chain of the gelators, in-
creased chain length endows the gel assembly with more
thermal stability. This observation is consistent with the fact
that the fiber diameters in these gels increase with the
increase in the fatty acid chain length.
b
Gelatorsa
Upscan Tm (ꢀC)
Downscan Tfb (ꢀC)
(a) Toluene gels
2b
2c
2d
2e
2f
(b) Heptane gels
20.5
34.7
44.7
50.9
55.9
6.1
14.3
22.0
29.9
36.1
2b
2c
2d
2e
3b
5c
54.8
67.7
72.8
75.9
54.0
67.0
28.9
53.2
66.0
68.2
40.8
53.2
To get an insight into the effect of the side chains of the ami-
no acids on the thermal stability of the assembly, palmitoyl
chain derivatized gelators of L-alanine (2e), L-valine (3b),
and L-phenylalanine (5c) in n-heptane were subjected to dif-
ferential calorimetric analysis. Interestingly, both 3b and 5c
were thermally less rigid than 2e (Fig. 4c and Table 2b). This
is presumably due to weaker packing among the gelator mol-
ecules in the self-assembly as the steric bulk of the side chain
hinders the optimal positioning of the individual gelator
molecule while forming a three-dimensional network. This
explains why replacing L-alanine by any other amino acid
makes the gel network significantly weaker. Interestingly,
n-heptane gel of 5c is slightly more rigid than that of 3b,
which could be due to the p-stacking interactions that may
prevail among the phenyl rings of 5c. So for aromatic side
a
Gelator concentration¼10 mg/mL.
b
Error in the measurement was within ꢂ1 ꢀC.
increased with increasing chain length. This indicates that
the van der Waals interactions of the lipophilic portion of
the gelator molecules play a significant role in modulating
gelation properties endowing the system with thermal stabil-
ity. Also, heating scan of toluene gels of 2e and 2f having
C16 and C18 chains gives more than one transition indicat-
ing the polymorphic character of the aggregate due to the

A. Pal et al. / Tetrahedron 63 (2007) 7334–7348
7341
chain based gelator 5c, both steric hindrance and the interac-
tion of the phenyl rings become crucial.
the diffraction angle (2q) decreased (not shown) indicating
a dramatic increase in the aggregate size. The parameters
from XRD data are listed in Table 3. For shorter chains,
we found more than one aggregate but with increasing chain
length not only the sizes of aggregate increased but also only
one aggregate morph predominated. For 2f with a C18 chain
the diffraction angle became even less than 2ꢀ indicating
2.6. Rheological studies of the gel
Under applied stress, viscoelastic samples exhibit resistance
to flow. The stress versus strain plot yields the complex mod-
ulus G* for the sample, which is the ratio of amplitudes of
stress and strain in an oscillatory experiment. G*, in turn,
has two components: (a) G0 or the storage modulus, repre-
senting the ability of the deformed material to restore its
original geometry, and (b) G00 or the loss modulus, represent-
ing the tendency of a material to flow under stress. For vis-
coelastic materials like gels, G0 is an order of magnitude
greater than G00, demonstrating the dominant elastic behav-
ior of the system. The yield stress (sy) refers to the applied
stress above which the gel starts to flow—or in other words,
changes from a dominant elastic-solid-like behavior to
a dominant viscous-liquid like behavior. Usually, this point
is determined by measuring the stress value at which G00 be-
comes larger than G0 (in a so-called stress amplitude sweep
experiment). Each gel has its own particular sy according to
its strength or rigidity to an oscillating stress.20
˚
aggregate sizes were more than 44.7 A.
2.8. Molecular modeling studies
Energy minimization of the structure of a simplified analog,
ethanoyl-L-alanine ‘tetramer’ at restricted Hartree–Fock
(RHF) level using 6-31G* basis sets shows that there is an
existence of hydrogen bonding between the –COOH groups
indicating strong acid dimer formation (dO–H/O¼1.77–
˚
1.91 A) (Fig. 6). The amide linkage also participates in
˚
hydrogen bonding (dN–H/O¼2.20–2.51 A) to connect two
Table 3. Parameters of XRD of xerogels and the long spacing of the aggre-
gates
˚
d001 (A)
Gels in toluene
2q (ꢀ)
2b
2c
2d
2e
2f
2.65, 2.92
2.35, 2.62
2.13, 2.28
2.13
33.3, 30.3
37.6, 33.7
41.5, 38.7
41.5
The viscoelastic properties of toluene gels with different
chain lengths of L-alanine derivative were studied. The yield
stress increased remarkably as the lipophilic chain length
was increased (Fig. 5). It is very clear that increasing the
chain length up to an optimum level makes the gel more vis-
coelastic. Even for n-heptane gels the same trend was ob-
served. As the chain length was changed in the series C10,
C12, and C14 the yield stress also increased from 12 to 20
to 40 Pa. Clearly, the increase in the chain length of the fatty
acid part in L-alanine compounds enhances the resistance of
the gel flow behavior. The n-heptane gel of palmitoyl-L-phe-
nylalanine (5c) showed a yield stress of 20 Pa, which was
even less than that of the C14 derivative of alanine (2d).
Clearly, the chain lengths of the long acyl chains and the
size of the amino acid side chains both determine the visco-
elastic properties of such LMOGs.
<2
44.2
2.7. X-ray diffraction (XRD)
Figure 6. Energy minimized structure of the functional moiety of the gel
formed by L-alanine based gelator molecule as indicated from restricted
Hartree–Fock using 6-31G* level of theory (gray, purple, red, and blue
colors represent carbon, hydrogen, oxygen, and nitrogen atoms, respec-
tively).
To get an idea of the aggregate sizes, XRD of the dried cast
film of toluene gels was estimated. Interestingly, as the lipo-
philic segment of the alanine based gelator was increased,
(a)
160
C14Alanine
(b)
C16Alanine
40
35
30
25
20
15
10
5
140
Toluene gels
120
Heptane gels
100
C14Alanine
C
12Alanine
C16Phe
80
C12Alanine
60
C10Alanine
40
20
0
0
2b
2c
2d
5c
2c
2d
2e
Figure 5. (a) Yield stresses of toluene gels of 2c–2e. (b) Yield stresses of heptane gels of 2b–2d and 5c. Error in measurement is within ꢂ5%.

7342
A. Pal et al. / Tetrahedron 63 (2007) 7334–7348
acid dimers leading to a continuous assembly. Both of these
facts have been experimentally verified from FTIR studies
with the gelator dodecanoyl-L-alanine. So it is clear that
the self-assembly of L-alanine derivatives ensues through
these two types of hydrogen bonding and also that the side
chain plays a role in packing the aggregate. The distance be-
tween the two carbons of the methyl groups remains within
4.2. Materials
All reagents, starting materials, and silica gel for TLC and
column chromatography were obtained from the best known
commercial sources and were used without further purifica-
tion, as appropriate. Glycine, L-alanine, L-valine, L-leucine,
L-phenylalanine, L-tryptophan, N-methyl L-alanine and
N-benzyloxycarbonyl alanine were purchased from Sigma.
Compounds 20, 22, and 23 have been synthesized as reported
previously.19 Solvents were distilled and dried prior to use.
˚
7.01–7.51 A. So an amino acid side chain larger than methyl
poses steric constraints, which may impede efficient packing
of the molecules leading to the formation of self-assembled
organization. Thus in the case of most of the other amino
acid based fatty acid amides, we observed either no gelation
or the formation of a ‘loose’ or weak gel.
4.3. Synthesis
4.3.1. General procedure for the synthesis of N-acyl ami-
no acid methyl ester derivatives. Individual amino acid
methyl ester hydrochloride (13–18) (7.5 mmol) was dis-
solved in water (15 mL) and KHCO3 (0.9 g, 9.0 mmol)
was added to the solution at 0 ꢀC. This solution was extracted
with ether (5ꢃ10 mL) and dried over anhydrous Na2SO4.
Ether was evaporated to give a transparent oil in yields
>99%. Individual amino acid methyl ester (7.5 mmol) was
dissolved in dry CHCl3 (15 mL) to which triethylamine
(0.76 g, 7.52 mmol) was added and cooled in ice. The desired
acyl chloride (7.52 mmol) was added in the form of a solution
in dry CHCl3 (2 mL) dropwise to the ice-cold solution and
stirred for 5 h. The reaction mixture was diluted with
CHCl3 (15 mL) and shaken with 3 M HCl (3ꢃ15 mL), water
(15 mL), and brine (15 mL), and finally dried over anhydrous
Na2SO4. The solvent was removed by rotary evaporation and
the residue purified by column chromatography on silica gel
using a mixture of ethyl acetate/hexanes. The relevant spec-
tral and analytical data for each compound along with the
isolated yields in parentheses are given below.
3. Conclusion
In this work, we have investigated the scope of gelation
properties exhibited by various fatty acid amides of natural
amino acids. It has been found that out of the six non-polar
amino acids examined, L-alanine derivatives are best suited
for the design of this class of gelators. The increase in the
fatty acid chain length improves gel fiber mechanical
strength and also the van der Waals contacts as well as the
thermal stabilities. However, gelation number (capacity to
retain solvent molecules) does not increase linearly with
the fatty acid chain length. The viscoelastic flow behavior
of the physical gels from this class of molecules is dependent
on both the length of the fatty acid chain and the nature of the
side chain of the amino acid.
Taking together the FTIR, XRD results, calculation of func-
tional moiety of gelation at RHF level, and the gelation prop-
erties of various fatty acid amides of L-amino acids, it is
plausible to conclude that the gel assemblies consist of lay-
ered structures. Within the layered framework, the fatty acid
amides of L-amino acids are ‘glued’ together by intra- and
interlayer hydrogen bondings leading to the formation of
a hydrogen-bonded network. These networks develop into
a supramolecular assembly. Gelation is a phenomenon ex-
hibited by molecules that have the capacity to aggregate to
form fibrous networks. Self-assembly of these systems into
fibrous structures is evident from SEM. A particularly in-
triguing aspect of these molecules as gelators is that these
are derived from naturally occurring sources, e.g., fatty acids
and L-amino acid. These can be synthesized very easily and
from inexpensive starting materials. So their use as gelators
does not release any unnatural materials into the environ-
ment, making this class of LMOG excellent materials for
various applications.
4.3.1.1. N-n-Dodecanoyl-methyl glycinate (7). Yield
1.91 g, 94%; mp¼63–64 ꢀC. IR (Neat): n¼3322, 2920,
2850, 1750, 1644, 1540 cmꢁ1
.
1H NMR (400 MHz,
CDCl3) d 0.88 (t, 3H, J¼7.0 Hz), 1.27 (br s, 16H), 1.61–
1.70 (m, 2H), 2.24 (t, 2H, J¼7.8 Hz), 3.77 (s, 3H), 4.05 (d,
2H, J¼5.1 Hz), 5.98 (br s, 1H). 13C NMR (100 MHz,
CDCl3) d 14.09, 22.66, 25.55, 29.22, 29.31 (2C), 29.44,
29.57 (2C), 31.88, 36.41, 41.15, 52.34, 170.60, 173.31.
HRMS (ESI+) calcd for (C15H29NO3Na)+: 294.2045; found:
294.2041. Anal. Calcd for C15H29NO3: C, 66.38; H, 10.77;
N, 5.16. Found: C, 66.44; H, 10.54; N, 5.16.
4.3.1.2. N-n-Octanoyl methyl (L)-alaninate (8a). Yield
1.59 g, 93%. IR (Neat): n¼3295, 2929, 2857, 1749, 1650,
1
1544 cmꢁ1. H NMR (400 MHz, CDCl3) d 0.88 (t, 3H, J¼
6.7 Hz), 1.23 (br s, 8H), 1.40 (d, 3H, J¼7.2 Hz), 1.59–1.67
(m, 2H), 2.21 (t, 2H, J¼7.8 Hz), 3.03 (s, 3H), 4.57–4.64
(m, 1H), 6.06 (d, 1H, J¼4.8 Hz). 13C NMR (100 MHz,
CDCl3) d 14.02, 18.54, 22.55, 25.54, 28.95, 29.13, 31.63,
36.53, 47.82, 52.41, 172.67, 173.72. HRMS (ESI+) calcd
for (C12H23NO3Na)+: 252.1576; found: 252.1591.
4. Experimental section
4.1. General
Melting points were recorded in open capillaries and are un-
corrected. H NMR spectra were recorded in Bruker-400
4.3.1.3. N-n-Decanoyl methyl (L)-alaninate (8b). Yield
1.73 g, 90%. IR (Neat): n¼3294, 2926, 2855, 1750, 1650,
1
1
NMR spectrometer. Chemical shifts are reported in parts
per million downfield from the internal standard, tetrame-
thylsilane. FTIR studies were performed on a JASCO 410
model spectrometer and are reported in wavenumbers
(cmꢁ1).
1545 cmꢁ1. H NMR (300 MHz, CDCl3) d 0.85 (t, 3H,
J¼6.6 Hz), 1.24 (br s, 12H), 1.38 (d, 3H, J¼7.2 Hz), 1.58–
1.63 (m, 2H), 2.19 (t, 2H, J¼7.8 Hz), 3.73 (s, 3H), 4.54–
4.63 (m, 1H), 6.09 (br s, 1H). 13C NMR (75 MHz, CDCl3)
d 14.03, 18.49, 22.60, 25.53, 29.16, 29.20, 29.28, 29.38,

A. Pal et al. / Tetrahedron 63 (2007) 7334–7348
7343
31.80, 36.48, 47.80, 52.37, 172.69, 173.69. HRMS (ESI+)
calcd for (C14H27NO3Na)+: 280.1889; found: 280.1869.
17.80, 18.90, 22.60, 24.75, 25.69, 29.22, 29.31, 29.46,
29.57, 31.31, 31.88, 36.73, 52.13, 56.79, 172.77, 173.20.
HRMS (ESI+) calcd for (C18H35NO3Na)+: 336.2512; found:
336.2515. Anal. Calcd for C18H35NO3: C, 68.97; H, 11.25;
N, 4.47. Found: C, 68.52; H, 11.33; N, 4.31.
4.3.1.4. N-n-Dodecanoyl methyl (L)-alaninate (8c).
Yield 2.07 g, 97%; mp¼65 ꢀC. IR (neat): n¼3300, 2920,
2851, 1732, 1650, 1537 cmꢁ1
.
1H NMR (400 MHz,
CDCl3) d 0.88 (t, 3H, J¼7.2 Hz), 1.28 (br s, 16H), 1.40 (d,
3H, J¼7.1 Hz), 1.59–1.67 (m, 2H), 2.21 (t, 3H, J¼7.8 Hz),
3.75 (s, 3H), 4.57–4.65 (m, 1H), 6.03 (d, 1H, J¼6.8 Hz).
13C NMR (100 MHz, CDCl3) d 14.07, 18.58, 22.65, 25.55,
29.20, 29.30 (2C), 29.44, 29.57 (2C), 31.88, 36.56, 47.84,
52.40, 172.64, 173.72. HRMS (ESI+) calcd for
(C16H31NO3Na)+: 308.2202; found: 308.2204. Anal. Calcd
for C16H31NO3: C, 67.33; H, 10.95; N, 4.91. Found: C,
67.52; H, 11.03; N, 5.05.
4.3.1.9. N-n-Hexadecanoyl methyl (L)-valinate (9b).
Yield 2.57 g, 93%; mp¼68–69 ꢀC. IR (Neat): n¼3292,
1
2915, 2848, 1736, 1647, 1538 cmꢁ1. H NMR (400 MHz,
CDCl3) d 0.81 (t, 3H, J¼7.0 Hz), 0.83 (d, 3H, J¼6.8 Hz),
0.87 (d, 3H, J¼6.8 Hz), 1.23 (br s, 24H), 1.53–1.59 (m,
2H), 2.06–2.10 (m, 1H), 2.17 (t, 2H, J¼7.5 Hz), 3.67 (s,
3H), 4.50–4.53 (m, 1H), 5.89 (d, 1H, J¼8.4 Hz). 13C NMR
(100 MHz, CDCl3) d 14.12, 17.82, 18.93, 22.69, 25.71,
29.25, 29.34, 29.36, 29.49, 29.61 (2C), 29.65, 29.68 (3C),
31.32, 31.92, 36.75, 52.12, 56.78, 172.79, 173.10. HRMS
(ESI+) calcd for (C22H43NO3Na)+: 392.3141; found:
392.3118. Anal. Calcd for C22H43NO3: C, 71.50; H, 11.73;
N, 3.79. Found: C, 71.66; H, 12.02; N, 4.01.
4.3.1.5. N-n-Tetradecanoyl methyl (L)-alaninate (8d).
Yield 2.20 g, 94%; mp¼69–71 ꢀC. IR (neat): n¼3308,
1
2919, 2851, 1730, 1646, 1537 cmꢁ1. H NMR (400 MHz,
CDCl3) d 0.88 (t, 3H, J¼7.0 Hz), 1.25 (br s, 20H), 1.40 (d,
3H, J¼7.2 Hz), 1.61–1.66 (m, 2H), 2.20 (t, 3H, J¼7.8 Hz),
3.75 (s, 3H), 4.57–4.65 (m, 1H), 5.98 (d, 1H, J¼6.1 Hz).
13C NMR (100 MHz, CDCl3) d 14.10, 18.62, 22.67, 25.57,
29.22, 29.33, 29.34, 29.47, 29.57 (2C), 29.63, 29.66,
31.91, 36.59, 47.87, 52.42, 172.63, 173.74. HRMS (ESI+)
calcd for (C18H35NO3Na)+: 336.2515; found: 336.2516.
Anal. Calcd for C18H35NO3: C, 68.97; H, 11.25; N, 4.47.
Found: C, 69.02; H, 11.58; N, 4.60.
4.3.1.10. N-n-Dodecanoyl methyl (L)-leucinate (10a).
Yield 1.99 g, 81%. IR (Neat): n¼3287, 2925, 2855, 1751,
1
1650, 1546 cmꢁ1. H NMR (400 MHz, CDCl3) d 0.88 (t,
3H, J¼7.0 Hz), 0.93 (d, 3H, J¼2.9 Hz), 0.95 (d, 3H,
J¼2.7 Hz), 1.25 (br s, 16H), 1.50–1.54 (m, 1H), 1.60–1.68
(m, 4H), 2.21 (t, 2H, J¼7.8 Hz), 3.73 (s, 3H), 4.65 (dt, 1H,
J1¼8.7 Hz, J2¼4.8 Hz), 5.84 (d, 1H, J¼7.5 Hz). 13C NMR
(100 MHz, CDCl3) d 14.04, 21.95, 22.66, 22.78, 24.86,
25.57, 29.19, 29.30 (2C), 29.46, 29.57 (2C), 31.88, 36.57,
41.76, 50.48, 52.23, 172.91, 173.77. HRMS (ESI+) calcd
for (C19H37NO3Na)+: 350.2671; found: 350.2651. Anal.
Calcd for C19H37NO3: C, 69.68; H, 11.39; N, 4.28. Found:
C, 69.84; H, 11.12; N, 4.46.
4.3.1.6. N-n-Hexadecanoyl methyl (L)-alaninate (8e).
Yield 2.37 g, 93%; mp¼77–78 ꢀC. IR (Neat): n¼3395,
1
2918, 2851, 1732, 1646, 1539 cmꢁ1. H NMR (400 MHz,
CDCl3) d 0.88 (t, 3H, J¼7.0 Hz), 1.25 (br s, 24H), 1.40 (d,
3H, J¼7.2 Hz), 1.60–1.61 (m, 2H), 2.20 (t, 2H, J¼7.9 Hz),
3.75 (s, 3H), 4.57–4.64 (m, 1H), 5.99 (br d, 1H, J¼5.6 Hz).
13C NMR (100 MHz, CDCl3) d 14.11, 18.62, 22.68, 25.56,
29.21, 29.33, 29.35, 29.47, 29.60, 29.64 (2C), 29.68 (3C),
31.91, 36.59, 47.85, 52.45, 172.64, 173.74. HRMS (ESI+)
calcd for (C20H39NO3Na)+: 364.2828; found: 364.2824.
Anal. Calcd for C20H39NO3: C, 70.33; H, 11.51; N, 4.10.
Found: C, 70.36; H, 11.61; N, 4.16.
4.3.1.11. N-n-Hexadecanoyl methyl (L)-leucinate
(10b). Yield 2.52 g, 88%; mp¼52–53 ꢀC. IR (Neat):
1
n¼3327, 2915, 2848, 1754, 1644, 1528 cmꢁ1. H NMR
(400 MHz, CDCl3) d 0.87 (t, 3H, J¼6.6 Hz), 0.93 (d, 3H,
J¼2.9 Hz), 0.94 (d, 3H, J¼2.7 Hz), 1.28 (br s, 24H), 1.49–
1.56 (m, 1H), 1.60–1.67 (m, 4H), 2.20 (t, 2H, J¼7.4 Hz),
3.72 (s, 3H), 4.65 (dt, 1H, J1¼8.7 Hz, J2¼4.8 Hz), 5.84 (d,
1H, J¼7.5 Hz). 13C NMR (100 MHz, CDCl3) d 14.12, 21.97,
22.69, 22.80, 24.88, 25.59, 29.22, 29.34, 29.36, 29.50, 29.61
(4C), 29.65, 29.69, 31.93, 36.60, 41.78, 50.50, 52.26, 172.94,
173.80. HRMS (ESI+) calcd for (C23H45NO3Na)+: 406.3297;
found: 406.3271. Anal. Calcd for C23H45NO3: C, 72.01; H,
11.82; N, 3.65. Found: C, 72.00; H, 11.64; N, 3.73.
4.3.1.7. N-n-Octadecanoyl methyl (L)-alaninate (8f).
Yield 2.69 g, 95%; mp¼82–83 ꢀC. IR (Neat): n¼3314,
1
2917, 2849, 1731, 1645, 1537 cmꢁ1. H NMR (400 MHz,
CDCl3) d 0.81 (t, 3H, J¼7.0 Hz), 1.18 (br s, 28H), 1.39 (d,
3H, J¼7.2 Hz), 1.52–1.58 (m, 2H), 2.13 (t, 2H, J¼7.8 Hz),
3.71 (s, 3H), 4.49–4.59 (m, 1H), 5.97 (br d, 1H, J¼6.6 Hz).
13C NMR (75 MHz, CDCl3) d 14.10, 18.57, 22.67, 25.55,
29.20, 29.33 (2C), 29.44, 29.66 (8C), 31.89, 36.55, 47.82,
52.42, 172.67, 173.72. HRMS (ESI+) calcd for
(C22H43NO3Na)+ 392.3152; found: 392.3141. Anal. Calcd
for C22H43NO3: C, 71.50; H, 11.73; N, 3.79. Found: C,
71.60; H, 11.86; N, 4.05.
4.3.1.12. N-n-Hexanoyl methyl (L)-phenylalaninate
(11a). Yield 1.74 g, 72%. IR (Neat): n¼3292, 2955, 2860,
1747, 1650, 1542 cmꢁ1 1H NMR (400 MHz, CDCl3)
.
d 0.88 (t, 3H, J¼7.0 Hz), 1.22–1.32 (br m, 4H), 1.54–1.61
(m, 2H), 2.16 (t, 2H, J¼7.8 Hz), 3.07 (dd, 1H, J1¼13.7 Hz,
J2¼5.5 Hz), 3.15 (dd, 1H, J1¼13.8 Hz, J2¼5.8 Hz), 3.72
(s, 3H), 4.88–4.92 (m, 1H), 6.04 (br s, 1H), 7.09 (dd, 2H,
J1¼6.7 Hz, J2¼1.2 Hz), 7.21–7.29 (m, 3H). 13C NMR
(100 MHz, CDCl3) d 13.79, 22.24, 25.12, 31.21, 36.33,
37.78, 52.17, 52.82, 127.97, 128.42 (2C), 129.13 (2C),
135.83, 172.14, 172.68. HRMS (ESI+) calcd for
(C16H23NO3Na)+: 300.1576; found: 300.1572.
4.3.1.8. N-n-Dodecanoyl methyl (L)-valinate (9a). Yield
2.13 g, 91%; mp¼41–43 ꢀC. IR (Neat): n¼3306, 2926,
2855, 1746, 1650, 1540 cmꢁ1
.
1H NMR (400 MHz,
CDCl3) d 0.88 (t, 3H, J¼7.0 Hz), 0.92 (d, 3H, J¼6.7 Hz),
0.95 (d, 3H, J¼7.5 Hz), 1.25 (br s, 16H), 1.60–1.65 (m,
2H), 2.13–2.17 (m, 1H), 2.24 (t, 2H, J¼7.4 Hz), 3.74 (s,
3H), 4.59 (dd, 1H, J1¼8.8 Hz, J2¼4.9 Hz), 5.96 (d, 1H,
J¼8.4 Hz). 13C NMR (100 MHz, CDCl3) d 14.09, 17.72,
4.3.1.13. N-n-Dodecanoyl methyl (L)-phenylalaninate
(11b). Yield 2.25 g, 83%; mp¼54–56 ꢀC. IR (Neat):

7344
A. Pal et al. / Tetrahedron 63 (2007) 7334–7348
n¼3300, 2911, 2850, 1740, 1650, 1530 cmꢁ1. H NMR
(300 MHz, CDCl3) d 0.88 (t, 3H, J¼6.6 Hz), 1.25 (br s,
16H), 1.56–1.60 (m, 2H), 2.16 (t, 2H, J¼7.8 Hz), 3.07–
3.19 (m, 2H), 3.73 (s, 3H), 4.87–4.93 (m, 1H), 5.88 (d,
1H, J¼6.6 Hz), 7.08 (dd, 2H, J1¼5.7 Hz, J2¼1.8 Hz),
7.24–7.31 (m, 3H). 13C NMR (100 MHz, CDCl3) d 14.09,
22.66, 25.53, 29.17, 29.24, 29.30, 29.43, 29.58 (2C),
31.88, 36.55, 37.89, 52.29, 52.86, 127.08, 128.53 (2C),
129.23 (2C), 135.85, 172.28, 172.70. HRMS (ESI+) calcd
for (C22H35NO3Na)+: 384.2515; found: 384.2518. Anal.
Calcd for C22H35NO3: C, 73.09; H, 9.76; N, 3.87. Found:
C, 72.83; H, 9.88; N, 3.95.
4.3.1.17. N-n-Hexadecanoyl methyl (L)-tryptophanate
(12b). Yield 2.73 g, 80%; mp¼69–70 ꢀC. IR (Neat):
1
1
n¼3385, 2923, 2852, 1740, 1650, 1536 cmꢁ1. H NMR
(400 MHz, CDCl3) d 0.80 (t, 3H, J¼7.0 Hz), 1.18 (br s,
24H), 1.46–1.50 (m, 2H), 2.08 (t, 2H, J¼8.0 Hz), 3.23 (dd,
2H, J1¼6.0 Hz, J2¼2.5 Hz), 3.60 (s, 3H), 4.89 (dt, 1H, J1¼
7.4 Hz, J2¼5.4 Hz), 5.95 (d, 1H, J¼7.7 Hz), 6.87 (d, 1H,
J¼2.0 Hz), 7.02 (t, 1H, J¼7.2 Hz), 7.10 (t, 1H, J¼7.2 Hz),
7.26 (d, 1H, J¼8.1 Hz), 7.44 (d, 1H, J¼7.9 Hz), 8.38 (br s,
1H). 13C NMR (100 MHz, CDCl3) d 14.07, 22.64, 25.43,
27.60, 29.17, 29.28, 29.31, 29.42, 29.57 (2C), 29.61 (3C),
29.65, 31.87, 36.54, 52.27, 52.87, 109.88, 111.29, 118.46,
119.55, 122.17, 122.71, 127.65, 136.09, 172.51, 172.93.
HRMS (ESI+) calcd for (C28H44N2O3Na)+: 479.3250; found:
479.3248. Anal. Calcd for C28H44N2O3$0.75H2O: C, 71.53;
H, 9.75; N, 5.96. Found: C, 71.41; H, 9.68; N, 5.89.
4.3.1.14. N-n-Hexadecanoyl methyl (L)-phenylalani-
nate (11c). Yield 2.32 g, 74%; mp¼72–73 ꢀC. IR (Neat):
1
n¼3324, 2916, 2849, 1744, 1647, 1532 cmꢁ1. H NMR
(400 MHz, CDCl3) d 0.88 (t, 3H, J¼7.0 Hz), 1.25 (br s,
24H), 1.56–1.59 (m, 2H), 2.16 (t, 2H, J¼7.8 Hz), 3.09 (dd,
1H, J1¼13.8 Hz, J2¼5.7 Hz), 3.16 (dd, 1H, J1¼13.8 Hz,
J2¼5.8 Hz), 3.73 (s, 3H), 4.91 (dt, 1H, J1¼7.8 Hz, J2¼
5.8 Hz), 5.86 (d, 1H, J¼7.6 Hz), 7.08 (dd, 2H, J1¼7.2 Hz,
J2¼1.2 Hz), 7.24–7.31 (m, 3H). 13C NMR (100 MHz,
CDCl3) d 14.10, 22.67, 25.53, 29.19, 29.31, 29.34, 29.45,
29.59, 29.63, 29.66, 29.68 (2C), 31.91 (2C), 36.56, 37.90,
52.29, 52.86, 127.09, 128.53 (2C), 129.24 (2C), 135.86,
172.17, 172.67. HRMS (ESI+) calcd for (C26H43NO3Na)+:
440.3141; found: 440.3141. Anal. Calcd for C28H47NO3:
C, 74.77; H, 10.38; N, 3.35. Found: C, 74.73; H, 10.48;
N, 3.57.
4.3.1.18. N-n-Octadecanoyl methyl (L)-tryptophanate
(12c). Yield 2.97 g, 82% mp¼71–73 ꢀC. IR (Neat):
1
n¼3393, 2917, 2849, 1731, 1645, 1542 cmꢁ1. H NMR
(400 MHz, CDCl3) d 0.81 (t, 3H, J¼7.0 Hz), 1.18 (br s,
28H), 1.45–1.51 (m, 2H), 2.06 (t, 2H, J¼7.8 Hz), 3.25 (dd,
2H, J1¼5.3 Hz, J2¼2.5 Hz), 3.62 (s, 3H), 4.90 (dt, 1H,
J1¼8.0 Hz, J2¼5.3 Hz), 5.90 (d, 1H, J¼7.8 Hz), 6.89 (d,
1H, J¼2.2 Hz), 7.04 (dt, 1H, J1¼7.9 Hz, J2¼0.8 Hz), 7.11
(dt, 1H, J1¼7.1 Hz, J2¼1.0 Hz), 7.28 (d, 1H, J¼8.1 Hz),
7.45 (d, 1H, J¼7.9 Hz), 8.15 (br s, 1H). 13C NMR
(100 MHz, CDCl3) d 14.10, 22.67, 25.45, 27.63, 29.21,
29.30, 29.34, 29.45, 29.60 (6C), 29.64, 29.68, 31.90,
36.60, 52.30, 52.84, 110.12, 111.24, 118.56, 119.65,
122.22, 122.63, 127.70, 136.06, 172.52, 172.83. HRMS
(ESI+) calcd for (C30H48N2O3Na)+: 507.3563; found:
507.3563. Anal. Calcd for C30H48N2O3: C, 74.34; H, 9.98;
N, 5.78. Found: C, 74.07; H, 9.83; N, 5.67.
4.3.1.15. N-n-Octadecanoyl methyl (L)-phenylalani-
nate (11d). Yield 2.53 g, 76%; mp¼75–76 ꢀC. IR (Neat):
1
n¼3327, 2916, 2850, 1746, 1648, 1532 cmꢁ1. H NMR
(400 MHz, CDCl3) d 0.81 (t, 3H, J¼7.0 Hz), 1.18 (br s,
28H), 1.49–1.52 (m, 2H), 2.09 (t, 2H, J¼8.0 Hz), 3.02 (dd,
1H, J1¼13.8 Hz, J2¼5.8 Hz), 3.09 (dd, 1H, J1¼13.8 Hz, J2¼
5.8 Hz), 3.66 (s, 3H), 4.84 (dt, 1H, J1¼5.8 Hz, J2¼2.0 Hz),
5.81 (d, 1H, J¼7.8 Hz), 7.02 (dd, 2H, J1¼6.5 Hz, J2¼
1.5 Hz), 7.17–7.23 (m, 3H). 13C NMR (100 MHz, CDCl3)
d 14.08, 22.66, 25.53, 29.18, 29.31, 29.34, 29.45, 29.60,
29.64, 29.68 (6C), 31.91, 36.56, 37.92, 52.27, 52.88,
127.09, 128.53 (2C), 129.24 (2C), 135.88, 172.18, 172.69.
HRMS (ESI+) calcd for (C28H47NO3Na)+: 468.3454; found:
468.3457. Anal. Calcdfor C28H47NO3: C, 75.46; H, 10.63; N,
3.14. Found: C, 75.69; H, 10.55; N, 3.30.
4.3.2. General procedure for the synthesis of N-alkanoyl
amino acid derivatives. Individual N-alkanoyl amino acid
methyl ester (1.2 mmol) was dissolved in 3 mL of a 1:1 mix-
ture of MeOH and THF. A cold solution of NaOH (0.048 g,
1.2 mmol) in water (1.5 mL) was added to the solution of
ester at 0 ꢀC and stirred for 2 h. The solvent was removed
in vacuo, the aqueous residue was cooled in ice, and 6 M
HCl (5 mL) was added dropwise. The white precipitate so
formed was extracted in ethyl acetate (3ꢃ15 mL). The
residue was precipitated in cold conditions three times
from ethyl acetate/hexane.
4.3.1.16. N-n-Dodecanoyl methyl (L)-tryptophanate
(12a). Yield 2.49 g, 83%; mp¼68–69 ꢀC. IR (Neat):
4.3.2.1. N-n-Dodecanoyl-glycine (1). Yield 0.30 g, 98%;
mp¼119–120 ꢀC. IR (Neat): n¼3315, 2917, 2849, 1702,
1
n¼3300, 2925, 2853, 1740, 1651, 1530 cmꢁ1. H NMR
1
(400 MHz, CDCl3) d 0.88 (t, 3H, J¼7.2 Hz), 1.27 (br s,
16H), 1.54–1.58 (m, 2H), 2.13 (t, 2H, J¼8.1 Hz), 3.32 (dd,
2H, J1¼5.2 Hz, J2¼2.4 Hz), 3.69 (s, 3H), 4.97 (dt, 1H,
J1¼9.3 Hz, J2¼5.3 Hz), 5.96 (d, 1H, J¼7.8 Hz), 6.97 (d,
1H, J¼2.3 Hz), 7.11 (dt, 1H, J1¼8 Hz, J2¼1 Hz), 7.17 (dt,
1H, J1¼8 Hz, J2¼0.4 Hz), 7.36 (dd, 1H, J1¼8 Hz, J2¼
0.4 Hz), 7.53 (dd, 1H, J1¼8 Hz, J2¼0.4 Hz), 8.12 (br s,
1H). 13C NMR (100 MHz, CDCl3) d 14.10, 22.66, 25.45,
27.64, 29.21, 29.30, 29.32, 29.44, 29.58 (2C), 31.89, 36.61,
52.30, 52.83, 110.16, 111.23, 118.58, 119.67, 122.24,
122.61, 127.71, 136.06, 172.51, 172.79. HRMS (ESI+) calcd
for (C24H36N2O3Na)+: 423.2624; found: 423.2610. Anal.
Calcd for C24H36N2O3: C, 71.96; H, 9.06; N, 6.99. Found:
C, 71.90; H, 9.18; N, 6.92.
1643, 1554 cmꢁ1. H NMR (400 MHz, CDCl3) d 0.88 (t,
3H, J¼7.0 Hz), 1.28 (br s, 16H), 1.62–1.66 (m, 2H), 2.26
(t, 2H, J¼7.5 Hz), 4.09 (d, 2H, J¼5.2 Hz), 5.99 (br s, 1H).
13C NMR (100 MHz, CDCl3+1–2 drops of DMSO-d6)
d 13.93, 22.65, 25.41, 29.07, 29.11, 29.15, 29.27, 29.39
(2C), 31.69, 36.18, 41.12, 171.70, 173.32. HRMS (ESI+)
calcd for (C14H27NO3Na)+: 280.1889; found: 280.1891.
Anal. Calcd for C14H27NO3: C, 65.33; H, 10.57; N, 5.44.
Found: C, 65.51; H, 10.66; N, 5.30.
4.3.2.2. N-n-Octacanoyl (L)-alanine (2a). Yield 0.24 g,
98%. IR (Neat): n¼3395, 2918, 2851, 1707, 1646,
1
1539 cmꢁ1. H NMR (400 MHz, CDCl3) d 0.87 (t, 3H,
J¼6.9 Hz), 1.28 (br s, 8H), 1.44 (d, 3H, J¼7.2 Hz),

A. Pal et al. / Tetrahedron 63 (2007) 7334–7348
7345
1.58–1.65 (m, 2H), 2.24 (t, 2H, J¼7.2 Hz), 4.53–4.60 (m,
1H), 6.53 (br s, 1H). 13C NMR (100 MHz, CDCl3)
d 13.99, 18.06, 22.53, 25.56, 28.90, 29.06, 31.59,
36.35, 48.23, 174.19, 175.84. HRMS (ESI+) calcd for
(C11H21NO3Na)+: 238.1419; found: 238.1437.
29.49 (8C), 31.73, 36.37, 47.80, 172.84, 174.84. HRMS
(ESI+) calcd for (C21H41NO3Na)+: 378.2977; found:
378.2984. Anal. Calcd for C21H41NO3: C, 70.94; H, 11.62;
N, 3.94. Found: C, 70.91; H, 11.59; N, 4.08.
4.3.2.8. N-n-Dodecanoyl (L)-valine (3a). Yield 0.32 g,
90%; mp¼97–99 ꢀC. IR (Neat): n¼3332, 2923, 2854,
4.3.2.3. N-n-Decanoyl (L)-alanine (2b). Yield 0.23 g,
93%; mp¼63–64 ꢀC. IR (Neat): n¼3346, 2920, 2851,
1702, 1619, 1551 cmꢁ1 1H NMR (400 MHz, CDCl3)
.
1706, 1646, 1526 cmꢁ1
.
1H NMR (400 MHz, CDCl3)
d 0.88 (t, 3H, J¼7.0 Hz), 0.95 (d, 3H, J¼6.9 Hz), 0.98 (d,
3H, J¼6.8 Hz), 1.25 (br s, 16H), 1.60–1.65 (m, 2H), 2.21–
2.35 (m, 3H), 4.57 (dd, 1H, J1¼8.6 Hz, J2¼4.8 Hz), 6.09
(d, 1H, J¼8.6 Hz). 13C NMR (100 MHz, CDCl3) d 14.09,
17.68, 18.99, 22.66, 25.70, 29.21, 29.29, 29.31, 29.46,
29.58 (2C), 30.91, 31.88, 36.67, 57.04, 174.04, 175.32.
HRMS (ESI+) calcd for (C17H33NO3Na)+: 322.2358; found:
322.2355. Anal. Calcd for C17H33NO3: C, 68.19; H, 11.11;
N, 4.68. Found: C, 67.68; H, 10.91; N, 4.17.
d 0.88 (t, 3H, J¼7.0 Hz), 1.26 (br s, 12H), 1.46 (d, 3H,
J¼7.2 Hz), 1.59–1.67 (m, 2H), 2.24 (t, 2H, J¼7.6 Hz),
4.54–4.61 (m, 1H), 6.09 (br d, 1H, J¼6.5 Hz). 13C NMR
(100 MHz, CDCl3) d 14.09, 17.89, 22.65, 25.51, 29.15,
29.24, 29.28, 29.40, 31.84, 36.42, 48.28, 174.07, 175.46.
HRMS (ESI+) calcd for (C13H25NO3Na)+: 226.1732; found:
226.1728. Anal. Calcd for C13H25NO3: C, 64.16; H, 10.36;
N, 5.76. Found: C, 64.43; H, 10.39; N, 5.96.
4.3.2.4. N-n-Dodecanoyl (L)-alanine (2c). Yield 0.31 g,
97%; mp¼84 ꢀC. IR (Neat): n¼3307, 2921, 2850, 1704,
4.3.2.9. N-n-Hexadecanoyl (L)-valine (3b). Yield
0.39 g, 93%; mp¼81–82 ꢀC. IR (Neat): n¼3324, 2957,
1
1
1646, 1520 cmꢁ1. H NMR (400 MHz, CDCl3) d 0.88 (t,
2918, 2950, 1698, 1650, 1549 cmꢁ1. H NMR (400 MHz,
3H, J¼7.0 Hz), 1.25 (br s, 16H), 1.46 (d, 3H, J¼7.2 Hz),
1.59–1.64 (m, 2H), 2.24 (t, 2H, J¼7.8 Hz), 4.54–4.61 (m,
1H), 6.09 (br s, 1H). 13C NMR (100 MHz, CDCl3) d 14.06,
17.91, 22.67, 25.51, 29.16, 29.28, 29.31, 29.44, 31.89,
36.42, 48.28, 174.06, 175.52. HRMS (ESI+) calcd for
(C15H29NO3Na)+: 294.2045; found: 294.2025. Anal. Calcd
for C15H29NO3: C, 66.38; H, 10.77; N, 5.16. Found: C,
66.37; H, 10.67; N, 5.19.
CDCl3) d 0.87 (t, 3H, J¼7.0 Hz), 0.95 (d, 3H, J¼7.2 Hz),
0.98 (d, 3H, J¼6.8 Hz), 1.25 (br s, 24H), 1.60–1.65 (m,
2H), 2.21–2.27 (m, 3H), 4.56–4.59 (m, 1H), 6.10 (d, 1H,
J¼8.6 Hz). 13C NMR (100 MHz, CDCl3) d 14.07, 17.69,
18.97, 22.66, 25.69, 29.31 (4C), 29.64 (6C), 30.92, 31.90,
36.67, 57.06, 174.05, 175.24. HRMS (ESI+) calcd for
(C21H41NO3Na)+: 378.2984; found: 378.2974. Anal. Calcd
for C21H41NO3: C, 70.94; H, 11.62; N, 3.94. Found: C,
70.91; H, 11.39; N, 3.93.
4.3.2.5. N-n-Tetradecanoyl (L)-alanine (2d). Yield
0.34 g, 95%; mp¼90–92 ꢀC. IR (Neat): n¼3348, 2917, 2849,
1705, 1647, 1526 cmꢁ1. 1H NMR (400 MHz, CDCl3) d 0.88
(t, 3H, J¼7.0 Hz), 1.25 (br s, 20H), 1.46 (d, 3H, J¼7.1 Hz),
1.58–1.64 (m, 2H), 2.24 (t, 2H, J¼7.7 Hz), 4.53–4.58 (m,
1H), 6.20 (br d, 1H, J¼6.5 Hz). 13C NMR (100 MHz,
CDCl3) d 14.11, 17.97, 22.68, 25.54, 29.17, 29.29, 29.34,
29.46, 29.60, 29.63 (2C), 29.67, 31.91, 36.43, 48.30, 174.08,
176.23. HRMS (ESI+) calcd for (C17H33NO3Na)+: 322.2358;
found: 322.2350. Anal. Calcd for C17H33NO3: C, 68.19; H,
11.11; N, 4.68. Found: C, 68.43; H, 11.16; N, 4.45.
4.3.2.10. N-n-Dodecanoyl (L)-leucine (4a). Yield 0.37 g,
98%; mp¼106–107 ꢀC. IR (Neat): n¼3329, 2923, 2853,
1698, 1621, 1553 cmꢁ1 1H NMR (400 MHz, CDCl3)
.
d 0.88 (t, 3H, J¼7.0 Hz), 0.95 (d, 3H, J¼2.9 Hz), 0.96 (d,
3H, J¼3.2 Hz), 1.25 (br s, 16H), 1.53–1.64 (m, 3H), 1.66–
1.76 (m, 2H), 2.24 (t, 2H, J¼8.0 Hz), 4.62 (dt, 1H,
J1¼8.8 Hz, J2¼4.9 Hz), 6.01 (d, 1H, J¼7.5 Hz). 13C NMR
(100 MHz, CDCl3) d 14.09, 21.85, 22.66, 22.81, 24.87,
25.58, 29.18, 29.29, 29.32, 29.47, 29.59 (2C), 31.89,
36.49, 41.12, 50.84, 174.10, 176.31. HRMS (ESI+) calcd
for (C18H35NO3Na)+: 336.2515; found: 336.2500. Anal.
Calcd for C18H35NO3: C, 68.97; H, 11.25; N, 4.47. Found:
C, 69.19; H, 11.25; N, 4.52.
4.3.2.6. N-n-Hexadecanoyl (L)-alanine (2e). Yield
0.31 g, 94%; mp¼91–93 ꢀC. IR (Neat): n¼3315, 2917,
2849, 1704, 1646, 1528 cmꢁ1
.
1H NMR (400 MHz,
CDCl3) d 0.88 (t, 3H, J¼7.0 Hz), 1.25 (br s, 24H), 1.43 (d,
3H, J¼7.1 Hz), 1.59–1.63 (m, 2H), 2.22 (t, 2H, J¼7.6 Hz),
4.49–4.61 (m, 1H), 6.43 (br d, 1H, J¼7.2 Hz). 13C NMR
(100 MHz, CDCl3) d 14.09, 17.98, 22.67, 25.59, 29.18,
29.23, 29.34, 29.45, 29.50, 29.59, 29.63, 29.64, 29.66,
29.69, 31.91, 36.41, 48.44, 174.07, 175.36. HRMS (ESI+)
calcd for (C19H37NO3Na)+: 350.2671; found: 350.2670.
Anal. Calcd for C19H37NO3: C, 69.68; H, 11.39; N, 4.28.
Found: C, 69.66; H, 11.49; N, 4.15.
4.3.2.11. N-n-Hexadecanoyl (L)-leucine (4b). Yield
0.40 g, 91%; mp¼90–92 ꢀC. IR (Neat): n¼3322, 2916,
2849, 1699, 1645, 1535 cmꢁ1
.
1H NMR (400 MHz,
CDCl3) d 0.87 (t, 3H, J¼6.8 Hz), 0.91 (d, 3H, J¼3.4 Hz),
0.94 (d, 3H, J¼4.4 Hz), 1.24 (br s, 24H), 1.55–1.65 (m,
3H), 1.68–1.71 (m, 2H), 2.24 (t, 2H, J¼8.0 Hz), 4.55 (dt,
1H, J1¼8.0 Hz, J2¼4.0 Hz), 6.21 (d, 1H, J¼7.6 Hz). 13C
NMR (100 MHz, CDCl3) d 14.06, 21.82, 22.65, 22.85,
24.91, 25.62, 29.33 (6C), 29.66 (4C), 31.90, 36.48, 41.18,
51.06, 174.18, 176.49. HRMS (ESI+) calcd for
(C22H43NO3Na)+: 392.3141; found: 392.3145. Anal. Calcd
for C22H43NO3: C, 71.50; H, 11.73; N, 3.79. Found: C,
71.35; H, 12.01; N, 3.94.
4.3.2.7. N-n-Octadecanoyl (L)-alanine (2f). Yield
0.39 g, 92%; mp¼102–103 ꢀC. IR (Neat): n¼3307, 2916,
2848, 1703, 1644, 1535 cmꢁ1
.
1H NMR (300 MHz,
CDCl3+1 drop of DMSO-d6) d 0.78 (t, 3H, J¼7.2 Hz), 1.16
(br s, 28H), 1.32 (d, 3H, J¼6.0 Hz), 1.50–1.55 (m, 2H),
2.11 (t, 2H, J¼7.8 Hz), 4.42–4.62 (m, 1H), 6.32 (br d, 1H,
J¼7.2 Hz). 13C NMR (75 MHz, CDCl3+1 drop of DMSO-
d6) d 13.96, 18.32, 22.50, 25.46, 29.07, 29.16 (2C), 29.31,
4.3.2.12. N-n-Hexanoyl (L)-phenylalanine (5a). Yield
0.25 mg, 78%; mp¼137–139 ꢀC. IR (cmꢁ1): 3303, 2928,
2868, 1708, 1611, 1555 cmꢁ1
.
1H NMR (400 MHz,
CDCl3) d 0.87 (t, 3H, J¼7.0 Hz), 1.18–1.26 (br m, 4H),

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A. Pal et al. / Tetrahedron 63 (2007) 7334–7348
1.45–1.53 (m, 2H), 2.12 (t, 2H, J¼7.8 Hz), 3.06 (dd, 1H,
J1¼14.0 Hz, J2¼6.0 Hz), 3.17 (dd, 1H, J1¼14.0 Hz,
J2¼5.6 Hz), 4.79–4.84 (m, 1H), 5.98 (d, 1H, J¼7.6 Hz),
7.09 (dd, 2H, J1¼6.4 Hz, J2¼2.0 Hz), 7.16–7.24 (m, 3H).
13C NMR (100 MHz, CDCl3) d 13.84, 22.28, 25.19, 31.22,
36.38, 37.27, 53.12, 127.20, 125.62 (2C), 129.34 (2C),
135.71, 174.03, 174.51. HRMS (ESI+) calcd for
(C15H21NO3Na)+: 286.1419; found: 286.1418. Anal. Calcd
for C15H21NO3: C, 68.42; H, 8.04; N, 5.32. Found: C,
68.33; H, 8.01; N, 5.64.
J¼8.1 Hz), 7.14 (t, 1H, J¼7.2 Hz), 7.17 (t, 1H, J¼7.2 Hz),
7.35 (d, 1H, J¼8.4 Hz), 7.56 (d, 1H, J¼8.0 Hz), 8.28 (s,
1H). 13C NMR (100 MHz, CDCl3) d 14.11, 22.67, 25.37,
26.98, 29.13, 29.27, 29.33, 29.42, 29.60 (2C), 31.90,
36.44, 53.27, 109.64, 111.37, 118.42, 119.79, 122.29,
123.11, 127.71, 136.08, 174.20, 174.74. HRMS (ESI+) calcd
for (C23H34N2O3Na)+: 409.2467; found: 409.2462. Anal.
Calcd for C23H34N2O3: C, 71.47; H, 8.87; N, 7.25. Found:
C, 71.45; H, 9.12; N, 7.06.
4.3.2.17. N-n-Hexadecanoyl (L)-tryptophan (6b). Yield
0.48 g, 91%; mp¼95–97 ꢀC. IR (Neat): n¼3414, 2923, 2852,
1720, 1632, 1536 cmꢁ1. 1H NMR (400 MHz, CDCl3) d 0.81
(t, 3H, J¼6.4 Hz), 1.19 (br s, 24H), 1.40–1.44 (m, 2H), 2.01
(t, 2H, J¼7.6 Hz), 3.21–3.23 (m, 2H), 4.84–4.88 (m, 1H),
6.06 (d, 1H, J¼7.6 Hz), 6.90 (d, 1H, J¼1.6 Hz), 7.03 (t,
1H, J¼7.2 Hz), 7.11 (t, 1H, J¼7.2 Hz), 7.26 (d, 1H, J¼
8.0 Hz), 7.49 (d, 1H, J¼7.6 Hz), 8.29 (br s, 1H). 13C NMR
(100 MHz, CDCl3) d 14.08, 22.67, 25.38, 27.08, 29.16,
29.33, 29.45 (2C), 29.67 (6C), 31.91, 36.42, 53.34, 109.58,
111.39, 118.39, 119.72, 122.20, 123.19, 127.78, 136.14,
174.28, 175.05. HRMS (ESI+) calcd for (C27H42N2O3Na)+:
465.3093; found: 465.3114. Anal. Calcd for C27H42N2O3:
C, 73.26; H, 9.56; N, 6.33. Found: C, 73.19; H, 9.59; N, 6.14.
4.3.2.13. N-n-Dodecanoyl (L)-phenylalanine (5b).
Yield 0.37 g, 98%; mp¼97–98 ꢀC. IR (Neat): n¼3313,
1
2923, 2852, 1708, 1643, 1538 cmꢁ1. H NMR (300 MHz,
CDCl3) d 0.88 (t, 3H, J¼6.6 Hz), 1.25 (br s, 16H), 1.54–
1.57 (m, 2H), 2.18 (t, 2H, J¼8.1 Hz), 3.12 (dd, 1H, J1¼
14.4 Hz, J2¼5.7 Hz), 3.24 (dd, 2H, J1¼14.1 Hz, J2¼
5.7 Hz), 4.85–4.91 (m, 1H), 6.01 (d, 1H, J¼6.6 Hz), 7.14
(dd, 2H, J1¼6.2 Hz, J2¼2.9 Hz), 7.23–7.32 (m, 3H). 13C
NMR (100 MHz, CDCl3) d 14.09, 22.66, 25.51, 29.12,
29.27, 29.32, 29.43, 29.59 (3C), 31.89, 36.44, 37.21, 53.09,
127.21, 128.62 (2C), 129.32 (2C), 135.65, 173.96, 174.56.
HRMS (ESI+) calcd for (C21H33NO3Na)+: 370.2358; found:
370.2357. Anal. Calcd for C21H33NO3: C, 72.58; H, 9.59;
N, 4.03. Found: C, 72.61; H, 9.96; N, 4.25.
4.3.2.18. N-n-Octadecanoyl (L)-tryptophan (6c). Yield
0.49 g, 88%; mp¼95–97 ꢀC. IR (Neat): n¼3415, 2920,
4.3.2.14. N-n-Hexadecanoyl (L)-phenylalanine (5c).
Yield 0.43 g, 95%; mp¼83–86 ꢀC. IR (Neat): n¼3302,
2851, 1722, 1646, 1525 cmꢁ1
.
1H NMR (400 MHz,
1
2920, 2851, 1709, 1644, 1536 cmꢁ1. H NMR (400 MHz,
CDCl3) d 0.81 (t, 3H, J¼6.4 Hz), 1.18 (br s, 28H), 1.36–
1.43 (m, 2H), 1.99 (t, 2H, J¼7.6 Hz), 3.21–3.30 (m, 2H),
4.82–4.87 (m, 1H), 6.08 (br s, 1H), 6.89 (s, 1H), 7.02 (t,
1H, J¼6.4 Hz), 7.10 (t, 1H, J¼6.4 Hz), 7.24 (dd, 1H,
J1¼8.1 Hz, J2¼2.8 Hz), 7.47 (d, 1H, J¼7.9 Hz), 8.32 (br
d, 1H, J¼8.1 Hz). 13C NMR (100 MHz, CDCl3) d 14.11,
22.68, 25.39, 27.04, 29.15, 29.29, 29.35, 29.47, 29.65
(2C), 29.68, 29.71 (5C), 31.91, 36.40, 53.34, 109.49,
111.40, 118.36, 119.68, 122.16, 123.20, 127.75, 136.07,
174.31, 175.08. HRMS (ESI+) calcd for (C29H46N2O3Na)+:
493.3406; found: 493.3399.
CDCl3) d 0.88 (t, 3H, J¼7.0 Hz), 1.25 (br s, 24H), 1.54–1.57
(m, 2H), 2.18 (t, 2H, J¼7.9 Hz), 3.12 (dd, 1H, J1¼13.8 Hz,
J2¼6.3 Hz), 3.24 (dd, 2H, J1¼14.1 Hz, J2¼5.6 Hz), 4.85–
4.90 (m, 1H), 5.94 (d, 1H, J¼6.1 Hz), 7.16 (dd, 2H,
J1¼6.9 Hz, J2¼1.5 Hz), 7.26–7.32 (m, 3H). 13C NMR
(100 MHz, CDCl3) d 14.11, 22.68, 25.51, 29.13, 29.29,
29.35, 29.45, 29.61, 29.65 (2C), 29.69 (3C), 31.91, 36.45,
37.19, 53.13, 127.24, 128.66 (2C), 129.31 (2C), 135.65,
173.96, 174.35. HRMS (ESI+) calcd for (C25H41NO3Na)+:
426.2984; found: 426.2962. Anal. Calcd for C25H41NO3:
C, 74.40; H, 10.74; N, 3.47. Found: C, 74.29; H, 10.50;
N, 3.57.
4.4. Gelation studies
4.3.2.15. N-n-Octadecanoyl (L)-phenylalanine (5d).
Yield 0.48 g, 93%; mp¼84–86 ꢀC. IR (Neat): n¼3315,
In a typical gelation number determination experiment, to
a weighed amount of a particular compound in a test tube
was added an excess of the chosen solvent. The resulting
mixture was warmed till the compound dissolved. The solu-
tion was then allowed to cool to room temperature. Upon
waiting for some time, a part of the solvent started to develop
into a viscoelastic mass. This was allowed to settle and upon
inversion of the test tube the excess ungelated solvent could
be decanted out leaving the gelated mass inside the tube. On
subtraction of the decanted solvent from the initially added
solvent one could estimate the amount of solvent entrapped
in the assembly. If a gel was formed it was evaluated quan-
titatively by determining the gelation number, which is the
mole ratio of entrapped solvent and gelator dictating the
number of solvent molecule that get immobilized per mole-
cule of gelator. Each experiment was performed in duplicate.
1
2917, 2850, 1714, 1650, 1539 cmꢁ1. H NMR (300 MHz,
CDCl3) d 0.84 (t, 3H, J¼7.0 Hz), 1.21 (br s, 28H), 1.49–
1.55 (m, 2H), 2.15 (t, 2H, J¼7.6 Hz), 3.10 (dd, 1H,
J1¼13.6 Hz, J2¼6.1 Hz), 3.21 (dd, 2H, J1¼14.0 Hz,
J2¼5.8 Hz), 4.81–4.87 (m, 1H), 6.01 (d, 1H, J¼6.3 Hz),
7.13 (d, 2H, J¼6.9 Hz), 7.20–7.28 (m, 3H). 13C NMR
(75 MHz, CDCl3) d 14.11, 22.68, 25.51, 29.13, 29.29,
29.35, 29.46, 29.69 (9C), 31.91, 36.43, 37.21, 53.14,
127.19, 128.62 (2C), 129.31 (2C), 135.71, 173.68, 174.36.
HRMS (ESI+) calcd for (C27H45NO3Na)+: 454.3297; found:
454.3297. Anal. Calcd for C25H41NO3: C, 75.13; H, 10.51;
N, 3.24. Found: C, 75.12; H, 10.84; N, 3.48.
4.3.2.16. N-n-Dodecanoyl (L)-tryptophan (6a). Yield
0.45 g, 98%; mp¼107–109 ꢀC. IR (Neat): n¼3409, 2925,
2854, 1722, 1648, 1525 cmꢁ1
.
1H NMR (300 MHz,
4.5. Scanning electron microscopy
CDCl3) d 0.88 (t, 3H, J¼6.9 Hz), 1.25 (br m, 16H), 1.48–
1.53 (m, 2H), 2.11 (t, 2H, J¼7.2 Hz), 3.31–3.40 (m, 2H),
4.84–4.96 (m, 1H), 6.05 (d, 1H, J¼7.6 Hz), 7.01 (d, 1H,
The gels were carefully scooped onto the brass stubs and
were allowed to dry overnight in air. The samples were

A. Pal et al. / Tetrahedron 63 (2007) 7334–7348
7347
further dried in a vacuum for 1 h, then coated with gold va-
por, and analyzed on a Quanta 200 SEM operated at 5 KV.
Acknowledgements
We are grateful to the Department of Biotechnology, New
Delhi, for financial support. We thank the Institute Nano-
science Initiative and the Department of Science and Tech-
nology, Government of India for SEM and Mr. Saikat Sen
for help with molecular modeling.
4.6. Differential scanning calorimetry
Gel samples in different solvents were prepared as men-
tioned above and their thermotropic behavior was investi-
gated using
a high sensitivity differential scanning
calorimetry using a CSC-4100 model multi-cell differential
scanning calorimeter (Calorimetric Sciences Corporation,
Utah, USA).
References and notes
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