New amino acid-based anionic surfactants and their use as enantiodiscriminating lyotropic liquid crystalline NMR solvents

Article abstract of DOI:10.1016/j.tetasy.2004.01.022

New amino acid-based anionic surfactants have been synthesized and their use as chiral oriented NMR solvents studied. A series of sulfonated amphiphilic L-Phe or L-Ala derivatives with pentyl to tetradecyl tails were prepared by reacting the corresponding

Full text of DOI:10.1016/j.tetasy.2004.01.022

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 971–982
New amino acid-based anionic surfactants and their use as
enantiodiscriminating lyotropic liquid crystalline NMR solvents
a
Krystyna Baczko, Chantal Larpent and Philippe Lesot
a,
b,
*
*
a
Laboratoire de Synth ꢀe se, Interactions et R ꢁe activit ꢁe en Chimie Organique et Bioorganique, SIRCOB, CNRS UMR 8086, Universit ꢁe de
Versailles St-Quentin en Yvelines, 45 Avenue des Etats-Unis, 78035 Versailles Cedex, France
b
Laboratoire de Chimie Structurale Organique, CNRS UMR 8074, ICMMO, B ^a t. 410, Universit ꢁe de Paris-Sud, 91405 Orsay Cedex,
France
Received 12 December 2003; accepted 13 January 2004
Abstract—New amino acid-based anionic surfactants have been synthesized and their use as chiral oriented NMR solvents studied.
A series of sulfonated amphiphilic -Phe or -Ala derivatives with pentyl to tetradecyl tails were prepared by reacting the corre-
sponding amino acid esters with o-sulfobenzoic anhydride. Their critical micelle concentrations (CMCs) range from 1.6 · 10 to
L
L
ꢀ
5
ꢀ2
1
.4 · 10 mol/L and depend on the alkyl chain length as well as on the nature of the amino acid block. These values are com-
paratively lower than those of classical surfactants such as alkylbenzenesulfonates and N-acylamino-acid carboxylates. Their use as
chiral liquid crystals (CLC) for analytical purposes is reported. In particular, it is shown that aqueous solutions of these chiral
sulfonates in the presence of chlorinated solvents (CHCl
able to differentiate between enantiomers of -alanine-2-d
2004 Elsevier Ltd. All rights reserved.
3 2 2 2 2 4 4
, CH Cl , C H Cl , or CCl ) provide homogeneous oriented NMR solvents
D
,L
1
using proton and deuterium NMR spectroscopy.
ꢀ
4
1. Introduction
solvents. Since the pioneering work of Sackmann
5
et al., it is known that two enantiomers can be spec-
Amino acids and peptide-based chiral surfactants have
attracted widespread attention over the last decade and
have been exploited in various ways in chemistry, anal-
ysis, and biology. Molecular aggregates of amphiphilic
amino acids and peptides have been designed as low
molecular weight enzyme mimics and used in catalytic
troscopically differentiated when they are dissolved in
chiral liquid crystals. The choice of the oriented systems
(organic or aqueous) depends obviously on the nature of
enantiomers under study. For chiral organosoluble
compounds, NMR in organic solutions of chiral poly-
peptide made of poly-c-benzyl-
poly-e-carbobenzyloxy- -lysine (PCBLL) appears to be
as one of the most promising and general methods for
L-glutamate (PBLG) or
1
reactions. The use of amino acid-based surfactants as
2
chiral ligands or auxiliaries has been also reported.
L
6;7
Among the various analytical applications proposed in
the literature, we should mention their use as chiral
pseudostationary phases in micellar electrokinetic chro-
the evaluation of enantiomeric excess. In contrast, for
water-soluble chiral molecules, the choice of a suitable
chiral oriented environment is rather limited and only a
few reports of their enantioselective potential can be
3
matography. In these applications, it was shown that
intermolecular hydrogen bonding between the amide
moieties and the chiral solute as well as steric interactions
8–13
found in literature.
Consequently, the investigation
of new chiral lyomesophases as a possible enantio-
differentiating oriented NMR solvents merits a contin-
uous effort.
3
b–e
play a significant role in chiral recognition.
found that even small changes in the polar headgroup
It was also
3f
could have a large impact on the enantioselectivity.
Various N-acylamino acid as carboxylate salts were
designed as chiral surfactants and used to prepare
oriented phases in H O or D O, most often in the
From an NMR point of view, amphiphilic chiral surf-
actants can provide interesting enantioselective oriented
2
2
4;8–10
presence of co-surfactants like fatty alcohols.
8
Thus
L-alaninate, potassium N-dode-
cesium N-dodecanoyl-
canoyl or N-tetradecanoyl-
*
Corresponding authors. Tel.: +33-1-39-25-44-13; fax: +33-1-39-25-
9
D
,
-prolinate, sodium N-dodecanoyl-L-
L
-alaninate, potassium
4
1
4-52 (C.L. for the chemistry); tel.: +33-1-69-15-47-59; fax: +33-1-69-
5-81-05 (P.L. for the NMR); e-mail addresses: larpent@
9a
N-hexadecanoyl-
L
11
10
chimie.uvsq.fr; philesot@icmo.u-psud.fr
prolinate and esters such as O-decanoyl-L-alaninate
0
957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.01.022

972
K. Baczko et al. / Tetrahedron: Asymmetry 15 (2004) 971–982
1
2
or -prolinate hydrochloride were used as chiral hosts.
Most surfactants involved in lyomesophases self-aggre-
gate to form a hydrophobic region, leaving the peptidic
polar headgroups to interact with water. It was shown
that intermolecular amide H-bonding near the head-
group plays a major role in the lyotropic liquid crystal
We choose to introduce an arylsulfonate residue via N-
acylation with o-sulfobenzoic acid anhydride A that
operates under mild conditions, and hence avoids race-
mization. This acylating reagent has been successfully
18
19
used to prepare water-soluble ligands and polymers
-phenylalanine
20
as well as sulfonated proteins. Thus,
derivatives 3a–e with pentyl to tetradecyl chains and
-alanine derivative 4d were readily synthesized in two
L
14
assembly.
L
One of the main disadvantages of carboxylate surfac-
tants is that their solubility, and hence their surfactant
properties are sensitive to protonation. On the other
hand, it is well known that sulfonated surfactants such
as alkali metal alkyl- or alkylaryl-sulfonates are much
less sensitive to pH and consequently retain their
steps from the corresponding natural amino acids
(Scheme 1). Esters 1 and 2, obtained by acid-catalyzed
esterification in toluene, were acylated with almost
quantitative yields. The sulfonated derivatives 3 and 4
were isolated after purification by chromatography with
good overall yields (74–90%).
15
properties over a wide range of pH. Moreover, sulfo-
nate anions can act as hydrogen-bond-accepting bases,
Arylsulfonates 3 and 4 were fully characterized by ele-
mental analyses, optical rotation, IR and NMR spec-
3g
and therefore play a role in chiral recognition.
1
13
troscopies. Complete assignments of the H and
NMR signals were achieved from COSY and HETCOR
C
Herein, we have designed new sulfonated amino acid-
based surfactants and investigated their potential
application as chiral lyomesophases. We first report a
straightforward synthetic pathway to a series of new
anionic chiral surfactants containing a lipophilic chain,
a natural amino acid block and a benzenesulfonate
polar headgroup. Their behavior in aqueous solution as
well as their critical micelle concentrations are reported
and discussed. Additionally, the use of these surfactants
as oriented, chiral NMR solvents is studied. In partic-
ular we show their potential to provide high-resolution
NMR spectra and to discriminate the NMR signals of
1
2D spectra. The most characteristic H NMR signals are
summarized in Table 1. For all of these compounds, a
single resonance was observed with a coupling constant
3
JNH–CH of 6.2 Hz for the amide proton corresponding to
the anti rotamer. The presence of only one isomer in
solution is further evidenced by the absence of any
21
1
13
splitting of other H and C NMR signals. It is note-
worthy that the most deshielded aromatic proton cor-
responds to the proton at the ortho position in regard to
the sulfonate group.
hydrophilic enantiomers such as
1
D,L-alanine-2-d .
2
.2. Solution behavior and surfactant properties
2
. Results and discussion
Compounds 3 and 4 are fairly soluble in water for alkyls
with chain lengths of up to 14 carbon atoms (Table 2).
The solubility in water depends both on the nature of
the amino acid residue and on the length of the aliphatic
tail. Increasing the tail length by nine carbon atoms in
Phe derivatives 3 lowers the solubility 1000-fold. The
Ala derivative 4d is much more soluble in water than its
Phe analogue 3d, thereby indicating a hydrophobic
contribution of the benzyl group.
2
.1. Synthesis and characterization
Most of the previously reported amphiphilic compounds
derived from amino acids are formed by tethering an
alkyl chain either through chemical
N-acylation or esterification. For all of them, the amino
acid residue is the polar headgroup of the surfactant. To
the best of our knowledge, the synthesis of amino acid-
based surfactants containing an additional, more polar
and less pH sensitive, sulfonate polar headgroup has
never been described.
3h;i;16
17
or enzymatic
The critical micelle concentration (CMC) is the main
characteristic of any surfactant. The CMC is the con-
centration above which surfactant molecules self-
O
O
O
(A)
S
O
O
H
N
O
CnH2n+1OH
HOOC
NH2
H2N
O
CnH2n+1
ii
R1
i
O
CnH2n+1
R1
NaO3S
O
R1
3a-e, 4d
1a-e, 2d
Compounds 1a, 3a 1b, 3b 1c, 3c 1d, 3d 1e, 3e 2d, 4d
1
R
CH Ph CH Ph CH Ph CH Ph CH Ph CH3
2
2
2
2
2
n
5
8
10
12
14
12
Scheme 1. Reagents and conditions: (i) APTS, Tol, reflux; (ii) a. Et
3
3
N, THF, 60 ꢁC, b. NaHCO .

K. Baczko et al. / Tetrahedron: Asymmetry 15 (2004) 971–982
Table 1. Main characteristic H NMR resonances of 3d and 4d
973
1
a
Chemical shift in DMSO-d
6
3
d (Phe)
4d (Ala)
1
2
Ph-CH
Ph-CH
2
b
b
2.95 (dd, JHb1–Hb2 14, JHb1–Ha 8.8)
3.17 (dd, JHb2–Hb1 14, JHb2–Ha 5.5)
––
––
––
2
CH
OCH
CH a
3
–CH
1.36 (d, J 7.0)
4.04 (m)
4.42 (m)
2
3.90 (m)
4.62 (ddd, JHb1–Ha 8.8, JHb2–Ha 5.5, JHa–NH 6.2)
b
H
H
o
C@O
7.59 (dd, J
7.84 (dd, J
o
2.0, J
2.0, J
m
7.0)
7.0)
7.59 (dd, J
7.85 (dd, J
o
o
2.0, J
2.0, J
m
m
7.0)
7.0)
ꢀ
c
o
SO
3
o
m
NH
9.70 (d, JHa–NH 6.2)
9.54 (d, JHa–NH 6.2)
a
b
c
The chemical shifts are given in ppm and coupling constants in hertz.
Aromatic proton adjacent to carbonyl group.
Aromatic proton adjacent to sulfonate group.
Table 2. Physico-chemical data for sulfonates 3a–e and 4d
Entry
Compounds
N
C
Micellar parameters derived from CMC
Solubility in H
d
2
O
a
b
ꢂ
2
c
(mmol/L)
CMC (mmol/L)
cmin (mN/m)
s
a per molecule (A )
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
4d
5
8
14
30.5
29.0
29.1
30.4
30.7
33.0
127
95
78
85
70
77
1000
50
1.4
10
12
14
12
12
12
12
0.33
0.063
0.016
0.41
0.94
12.7
12.3
50
10
1
1000
2
2
N–C12
N–C12
H
H
25–Phe
22
25–Ala
–SO
23
C
12
H
25–C
6
H
4
3
Na
27.8
48
a
b
c
2
5 ꢁC.
±
±
0.1.
ꢂ
2
8 A .
d
Approximate values.
assemble into aggregates called micelles. Surface tension
measurements demonstrate that sulfonated amino acid
derivatives 3a–e and 4d are surfactants. The CMC val-
ues and other parameters derived from these measure-
ments are given in Table 2. The CMCs of compounds 3
and 4, that range from 14 to 0.016 mmol/L, are much
lower than those of classical carboxylate amino acid-
based surfactants and alkylbenzenesulfonates. Thus, the
CMCs of 3d and 4d are more than 10-fold lower
0.0
3
a-e
Alkylbenzene sulfonates
-1.0
-2.0
-3.0
22
than those of N-dodecyl-alanine or phenylalanine and
23
2
(
-fold lower than sodium dodecylbenzenesulfonate
entries 7–9 in Table 2). These results indicate that both
-4.0
the aromatic ring and the amino acid block favor the
micellization probably via hydrophobic and/or dipole–
-5.0
24
dipole interactions. The comparison of Phe and Ala
derivatives, 3d and 4d, shows that the benzyl substituent
4.0
8.0
12.0
16.0
20.0
Number of carbon atoms (Nc)
25;26
has a significant hydrophobic contribution
and
strengthens the interfacial packing: 10-fold reduction of
the CMC as well as reduction of the minimum value of
surface tensions cmin above the CMC (about 30 mN/m
for 3d and 33 mN/m for 4d).
Figure 1. Log(CMC) versus number of carbon atoms in the aliphatic
chain.
generates a hydrophobic contribution equivalent to an
increase of the tail by seven to eight carbon atoms. This
observation indicates that the benzyl substituent acts as
a hydrophobic ramification. Furthermore the similar
slopes observed for 3 and alkylbenzenesulfonates show
that the contribution per aliphatic carbon atom to the
free energy of micellization DGmic are close together. The
ease of micellization of our sulfonated surfactants arises
from attractive interactions between the amino acid
The CMCs of Phe derivatives, 3a–e, decrease with the
lengthening of the alkyl chain. The graph log (CMC)
displays a linear dependence on the number of carbon
atoms N , according to Klevenꢀs equation, like classical
C
15
surfactants. The comparison with alkylbenzenesulfo-
nates, given in Figure 1, shows that surfactants 3 have
CMC values similar to benzenesulfonates with longer
aliphatic tails. In other words, the phenylalanine block

974
K. Baczko et al. / Tetrahedron: Asymmetry 15 (2004) 971–982
blocks. The areas per head group at the air–water
interface, a , for surfactants 3 and 4, range from 70 to
30 A and decrease upon lengthening of the alkyl tail as
where the brackets denote an (ensemble or time) average
over molecular tumbling and internal motions (vibra-
tional motions, conformational changes. . .). In this
s
ꢂ
2
1
27;14b
previously described for classical surfactants.
For a
equation, l is the magnetic susceptibility of free space,
0
given tail, Ala and Phe derivatives 3d and 4d present
similar areas, that are much larger than dodecylbenzene
sulfonate, thereby indicating that the amino acid pep-
tidic framework is located in the interfacial region.
cH is the magnetogyric ratio of proton nuclei, rHH is the
internuclear distance between i and j protons, and SHH is
the order parameter for the internuclear vector rHH. The
ꢂ
3
magnitude of kHH is equal to 120.07 kHz A .
For Phe derivatives, the location of the benzyl sub-
stituent on the hydrophobic micellar core is further
evidenced by the H NMR spectra of 3c in D O below
2
Deuterium NMR is also a powerful tool able to provide
various information about the orientational behavior,
the homogeneity and the enantioselectivity of a chiral
1
29;31 2
and above the CMC (respectively at 0.1 and 10 mmol/L).
All the protons of the benzyl substituent (CH Ph) as
well as methylene groups close to the ester function
lyomesophase in a static magnetic field B
0
.
H NMR
spectra in oriented solvents are dominated by the
quadrupolar interaction. Assuming axial symmetry of
the electric field gradient along the C–D bond, this
purely anisotropic interaction can be written as
2
2
(
(
OCH , OCH CH ) are shifted to lower frequencies
2 2 2
Dd ¼ 0.1–0.25 ppm) under aggregationing conditions.
These results support the suggestion that the benzyl
group is embedded within the micellar core. Similar
occurrences were already reported for other surfactants
3
e Q
D C–D
q
h
Dm ¼ 2 K S
with K ¼
and
Q
D
C–D
D
ꢂ
ꢃ
2
B0
0
3
cos h
ꢀ 1
like N-dodecyl-N,N -dimethyl-N-benzyl ammonium
26
CꢀD
S
C–D
¼
;
ð2Þ
25
chloride or cationic phenylalanine-based surfactants.
Above the CMC, two signals were observed for the
2
where KC–D is the deuterium quadrupolar coupling
constant and SC–D is the order parameter along the C–D
aromatic proton ortho to the sulfonate group in the ratio
9
7/3. These signals could be assigned, respectively, to
relative to the magnetic field axis, B
0
. hC–D is the angle
aggregated surfactant molecules and free surfactant
monomeric molecules, the concentration of the latter
being equal to the CMC (0.33 mmol/L). The existence of
the two separated domains in the aggregates may also
account for these two signals as previously reported for
surfactants like N-acylprolinate and N-acylmethyl gly-
between B and the direction of the C–D bond. KC–D
0
strongly depends on the hybridization state of the car-
bon atoms bonded to a given deuteron and varies
6
between 170 and 210 KHz.
11;28
cinate.
2.4. Composition of the NMR samples
From an analytical point of view, an ideal amphiphilic
oriented solvent used for NMR applications should
satisfy several criteria. First, the system should be
homogeneously and uniformly oriented in the static
magnetic field, condition sine qua none to record high-
resolution NMR for solutes. This condition is crucial for
detecting small spectral enantiodiscrimination. Second,
the amphiphilic system should form an oriented medium
over the largest possible range of temperature, centered
if possible on room temperature. This last point is
important for investigating thermosensitive solutes.
Third, the sample should orientate in the magnetic field
as quickly as possible, ideally it should not exceed the
time to reach the thermic equilibrium in order to ensure
an important gain of experimental time. Fourth, it is
necessary to reduce the chemical complexity of the
lyomesophase by adding a minimum of components.
This last occurrence facilitates the preparation of phases
and improves their thermodynamical stability.
2
.3. Some aspects of NMR in lyomesophases
The main advantage of NMR spectroscopy in chiral
liquid crystals compared with classical NMR approaches
dedicated to the enantiomeric analysis, is that no specific
chemical functionalities or molecular topologies in the
investigated compounds are a priori required. Indeed
only the selective orientational ordering of two enantio-
mers inside the phase induces the spectral enantiodis-
crimination. The second advantage is that NMR
spectroscopy in anisotropic media provides basically
numerous analytical tools able to differentiate between
29
30
6
the signal of enantiomers. Thus any magnetically active
nuclei present (proton, carbon-13, deuterium for isoto-
pically enriched compounds) in the molecule is a
potential NMR probe for this aim.
1
1
1
In H NMR, we mainly used H– H residual dipolar
couplings (RDCꢀs) to probe the enantioselectivity of the
phase. In this case, each pair of interacting proton
nuclei (i and j) may produce a direct dipolar coupling
defined in hertz as
6
All of the surfactants synthesized in this work do not
fulfill the various criteria mentioned above. In particu-
lar, it is known that lyomesophases are generally formed
by surfactants having hydrocarbon chains beyond 10–12
8–12
carbon atoms.
As a consequence, we have disre-
ꢀ
ꢁ
l0 hc c
H
H
garded derivatives 3a and b as well as tetradecyl sulfo-
nate 3e, which featured too weak a solubility in water
(Table 2). Although some preliminary tests using 3d as
surfactant showed some encouraging results, we have
focused our study on 3c.
D
HH ¼ ꢀkHH
S
HH with kHH
¼
and
4
p
4p2
ꢂ
ꢃ
2
B0
HH
3
HH
3
cos h ꢀ 1
S
HH
¼
;
ð1Þ
2
r

K. Baczko et al. / Tetrahedron: Asymmetry 15 (2004) 971–982
975
Lyotropic structures can be ternary or quaternary sys-
tems. They are made up of a surfactant; water in which a
co-surfactant (mainly a long chain alcohol) and/or an
inorganic salt is added to destabilize hexagonal, cubic,
32
or lamellar phases to obtain lyotropic nematic phases.
Decanol or other fatty alcohols were widely used with
;8;10
4
classical surfactants,
but preliminary attempts per-
formed with this type of co-surfactant (decanol) and 3c
did not provide a homogeneously oriented phase in the
magnetic field (over a large range of concentrations and
temperatures). This is the reason why we decided to
explore the effect of weakly polar, chlorinated organic
3 2 2 2 2 4 4
solvents such as CHCl , CH Cl , C H Cl , or CCl .
Such additives are rarely used in amphiphilic organized
molecular assemblies, and very few references can be
found in literature. Thus Moulik and co-workers re-
ported that the ternary system cetylpyridinium chloride/
H O/CHCl3 forms an anisotropic liquid crystalline
2
phase in which CHCl
a very weak co-surfactant, as claimed by these authors.
3
moiety plays the role of an oil or
33
In amphiphilic systems, the choice of the composition of
the mixture is essential to obtain oriented phases in the
magnetic field. This choice should in theory be derived
from the phase diagram of the system. This work (spe-
cially for a ternary mixture) is not really necessary for a
preliminary study because we want to establish first the
ability of the system to distinguish between enantiomers
using NMR. Actually two conditions have imperatively
driven our choice. First, the concentration of the sur-
factant should always be above the CMC. Second the
various NMR criteria mentioned above should be ful-
filled. As we will show later, these conditions were
obtained using around 20–25% w/w of 3c, 60–70% w/w
Figure 2. Example of 400.1 MHz 1H spectra of (±)-7d dissolved in 3c/
1
H
2
O/CHCl
monophasic (b). Spectra (a) and (b) were recorded at 305 K, 45 and
20 min after introducing the sample in the magnetic field, respectively.
3
when the system is biphasic (a), and when the system is
1
of H O and 5–20% w/w of chlorinated organic solvent in
2
a range of temperatures around 300–315 K.
concentration in 3c is largely above the CMC, the
presence of isotropic spectral components indicates that
the system has not reached its thermodynamical equi-
librium yet, and hence the micellar self-organization is
not ideal. We found that the proportion of isotropic
signals in the spectra decreases as a function of time, and
purely anisotropic spectra can be recorded after keeping
the sample in the magnetic field for 1–3 h. In fact, it is
more valuable to slightly adjust the sample temperature
(increasing or decreasing) to fully eliminate any isotro-
As a molecular probe, we used a racemic and enantio-
enriched mixture of
1 1
D,L-alanine-2-d (denoted (±)-7d )
selectively deuterated at the stereogenic center. The
main advantage of this chiral molecule is that we benefit
from two abundant nuclei (proton and deuterium), thus
1
2
permitting us to quickly record H and H NMR spectra
with a small amount of chiral material. Furthermore, it
is possible to explore very different internuclear direc-
tions (Hꢁ ꢁ ꢁH or C–D) in the molecule, which should
increase the possibility for us to observe chiral discrim-
pic signals. Figure 2b shows the spectrum of (±)-7d
3c/H O/CHCl when the system is monophasic and
in
1
2
3
6
ination.
macroscopically homogeneous. In this case, the isotro-
pic NMR resonances of the surfactant have totally dis-
appeared, and hence we exclusively observe a broad and
intense peak for water, a sharp and single peak for
chloroform and an anisotropic spectral figure for the
2
.5. Analysis of NMR results
The obtention of a purely anisotropic phase is rarely
complete. Generally isotropic and oriented regions
co-exist in the aligned sample, even if the magnetic field
strength is sufficient enough to orientate the system. To
methyl group of (±)-7d . The elimination of signals of 3c
1
on proton spectra can be used as a pertinent test to
assess if self-organization of the phase in the magnetic
field is correctly achieved or not.
illustrate this point, Figure 2a shows a typical example
1
of H spectra observed with (±)-7d embedded in 3c/
1
Figure 3a shows the proton signals of the methyl group
of (±)-7d . This spectral pattern is featured by the
1
superposition of two triplets of triplets resulting from
RDCꢀs within the three equivalent protons of the methyl
group (jTHꢁꢁꢁHj ¼ j3DHꢁꢁꢁHj) and the total Hꢁ ꢁ ꢁD coupling
H
the anisotropic H signals of (±)-7d
2
O/CHCl
3
when the system is biphasic. In this case,
1
1
(labeled with open
1
circles) is partially masked by the residual isotropic H
spectrum of 3c, thus preventing their analysis. As the

mixture of 7d enriched in an
L
-enantiomer (ee ¼ 73%)
as well as using the pure enantiomer ())-7d . The sample
compositions are the same as that for (±)-7d (see Table
). Both spectra are shown in Figure 4a and b. As ex-
976
K. Baczko et al. / Tetrahedron: Asymmetry 15 (2004) 971–982
1
2
Figure 4. 400 MHz H–{ H} spectrum associated with the methyl
group of 7d using (a) pure -isomer and (b) enantioenriched mixture
in
-isomer (ee ¼ 73%). A Gaussian filtering (GB ¼ 45%, LB ¼ )1 Hz)
was applied in (b) to improve the spectral enantiodiscrimination.
1
L
L
1
1
2
Figure 3. (a) 400 MHz H signal (a) and H-{ H} signal (b) associated
with the methyl group of (±)-7d . In both spectra, a Gaussian filtering
GB ¼ 70%, LB ¼ )5 Hz for (a), and GB ¼ 55%, LB ¼ )3 Hz for (b))
was applied to improve spectral enantiodiscrimination. The assign-
1
(
1
1
2
ment of triplet in (b) is given according to the analysis of H–{ H}
spectrum of ())-7d (shown in Fig. 4).
1
1
1
4
pected a single triplet is now observed for the enantio-
pure compound while two triplets of different intensities
are obtained for the enantioenriched mixture. In this
(
jT
j ¼ jJ þ 2D
HD
j ¼ 11 Hz) between those pro-
HꢁꢁꢁD
HꢁꢁꢁD
6
tons and the deuterium nucleus (spin I ¼ 1). To check
this spectral analysis, we recorded the deuterium-
decoupled proton ( H–{ H}) spectrum of (±)-7d . As
mixture, the smaller THꢁꢁꢁH corresponds to the
D-isomer.
1
2
This allows us to assign the signal for each optical iso-
mer in the racemic mixture (see Fig. 3b). Conclusively,
the analysis of these three spectra clearly demonstrates
1
shown in Figure 3b, we clearly obtained two triplets
with distinct dipolar splittings (jTHꢁꢁꢁHj ¼ 148 and
1
52 Hz) centered on the same chemical shift. Consider-
that the D- and L-amino acids are not ordered the same
way in the phase.
ing the spin system of the molecule, such a spectral
pattern implies that a chiral differentiation occurs on the
basis of a difference of H– H residual dipolar coupling
at the methyl group.
1
1
The existence of two anisotropic spectra for (±)-7d
1
clearly shows that a 9.4 T magnetic field is able to orient
our lyomesophase. A lower magnetic field should also
align the system. Such a study is currently underway.
The range of proton RDCꢀs indicates that the solute is
more oriented than in case of organic solutions of
Note here that the slight difference in peak intensity
between the three (central) or six (outer) components of
the triplet on the H spectrum (Fig. 3a) is due to the
superposition of a second (minority) spectral system
1
6
1
polypeptide for instance. However the H linewidths
measured without any digital filtering (6 and 8 Hz)
indicates a relatively good macroscopic homogeneity.
To support these points and provide better insight on
the orientational behavior of this lyomesophase, we
(
<5%) also made of two triplets of triplets (labeled by
stars). Both coupling patterns (the minority and
majority system) are centered on the same chemical
shift. The minority system possesses similar values of
2
1
jTHꢁꢁꢁHj (149 and 151 Hz) but not the same jTHꢁꢁꢁD
j
analyzed the H–{ H} spectra of (±)-7d
1
dissolved in 3c/
2
1
(
18 Hz), when compared with the majority one. This
H O/CHCl . Figure 5 shows an example of the H–{ H}
spectra when the system is monophasic and homo-
2
3
system also exhibits a spectral enantiodiscrimination,
which could originate from the acid form of the alanine
(
biphasic lyotropic system exhibiting two types of
homogeneous oriented domains cannot be excluded.
geneously aligned. Peaks labeled with open circles cor-
2
pH of the sample ꢂ5). However the hypothesis of a
respond to the H quadrupolar doublets (jDm
Q
j ¼
3200 Hz) of (±)-7d . The two components labeled with
black circles are assigned to the natural abundance
deuterium signal (a quadrupolar doublet) of water
1
34
In order to ensure that the chiral discrimination
1
(HOD isotopomer) in bulk solution. The quadrupolar
splitting of jDm j ¼ 470 Hz indicates that water mole-
cules are also aligned in the bulk solution. The obser-
observed on the H spectra is not an artifact, we
2
recorded the H–{ H} 1D spectrum using a scalemic
Q
1

K. Baczko et al. / Tetrahedron: Asymmetry 15 (2004) 971–982
977
A deeper analysis of the deuterium spectrum also reveals
the presence of a second doublet of very weak intensity
(<1%) that does not clearly emerge from the spectral
baseline (labeled with stars). These signals are more
visible when the sample is biphasic. This doublet
exhibits quadrupolar splitting equal to 1600 Hz, namely
half of the previous splitting. This situation was
31
0
observed when the director was perpendicular to B .
This secondary doublet is probably the residual signa-
ture of the inner wings of the deuterium powder pattern
(
Pake doublet) observed when the director of the phase
As a con-
34;35
is randomly distributed in respect to B0.
sequence it appears that this lyotropic system behaves
like a nematic of positive anisotropy of molecular dia-
magnetic susceptibility (Dv > 0), for which the director
m
31
is homogeneously aligned parallel to B0. At this time,
the low viscosity of the samples and the NMR results
could indicate that this system forms a stable lyotropic
(
chiral) nematic phase in the temperature range of 305–
36
315 K. However, the determination of the mesophase
structure (lamellar, nematic, hexagonal,. . .) is required
and is currently under study.
36
From the enantiomeric analysis, we also observed a
1
2
chiral discrimination on the H–{ H} spectra. The
measured separation between enantiomers is rather
2
1
Figure 5. 61.3 MHz H–{ H} spectra of (±)-7d
1 2
dissolved in 3c/H O/
l
d
small (jDm ꢀ Dm j ¼ 20 Hz, and was only observed after
CHCl when the system is monophasic and highly homogenous. (b)
3
Q
Q
2
1
keeping the sample in the magnetic field for several
hours (Fig. 5b). Considering that the quadrupolar
interaction is the most sensitive NMR interaction to an
H–{ H} spectrum showing
a chiral discrimination. Only the
deshielded component of the doublets is shown here. A Gaussian fil-
tering (GB ¼ 50%, LB ¼ )9 Hz), was applied to improve the spectral
enantiodiscrimination.
6
orientational order difference, this result shows that the
C–D internuclear direction relative to B is very close in
0
2
vation of very high-resolution H NMR spectra for (±)-
7
both enantiomers, and thereby a visible spectral dis-
crimination only occurs when the phase inhomogeneities
(due to temperature or concentration gradients) vanish.
Here again this result confirms that the sample continues
to slowly evolve for several hours to reach the most
thermodynamically stable situation. Although the
spectral separations in proton or deuterium are rather
weak, enantiodifferential ordering forces exist in this
phase, and these results prove the chiral recognition
ability of the system.
d
1
as well as HOD again proves a significant alignment
of the phase in the external, static magnetic field, B . It
can also be pointed out that the linewidths measured in
this example are below 7 Hz while the magnitude of
quadrupolar splitting is over 3000 Hz. This situation is
particularly interesting because it indicates a very weak
angular distribution of the C–D internuclear vector of
0
7
d
1
0
relative to B (see Eq. 1), and subsequently a very
uniform and homogeneous alignment of the solute in
the phase. It is noteworthy that linewidths decrease
generally by keeping the sample in the magnetic field for
several hours or by slightly adjusting the sample tem-
perature. Comparatively, the linewidths measured here
are in the same range of values obtained in polypeptide
weakly ordering systems made of PBLG or PCBLL, but
Encouraged by these first successful results obtained
using chloroform, we investigated other weakly polar
chlorinated organic solvents such as CH
or CCl . The sample compositions are given in Table 4.
Using similar concentrations for the three components
2 2 2 2
Cl , (CHCl ) ,
4
29
1
2
1
the quadrapolar splittings are larger.
of the mixture, high-resolution H and H–{ H} spectra
1
Table 3. NMR results obtained for 7d dissolved in the 3c/water system using various chlorinated entities
2
2
Sample
Organic solvent
ratio chlorinated
solvent/water w/w)
Working sample
temperature
range (K)
H quadrupolar
splitting range
H half-height
linewidth range
Chiral discrimination Chiral discrimination
2
1
(
using H NMR
(DDm /Hz)
using H NMR
b
a
a
a
(Dm
Q
/KHz)
(Dm1=2/Hz)
Q
(DTHH/Hz)
1
2
3
4
CHCl
CH Cl
Cl
(1/1.6)
3
(1/3.7)
305–320
305–315
320–330
330–340
3.2–3.3
3.2–3.3
3.0–3.2
2.8–3.0
5–10
7–10
5–7
Y (15–20)
Y (15–20)
Y (6–8)
Y (6–8)
Y (6–8)
Y (5–7)
2
2
(1/4.4)
C
2
H
2
4
(1/4.3)
N or <linewidth
N or <linewidth
CCl
4
8–10
a
The composition of each sample is given in Table 4.
Coupling between the three equivalent protons of the methyl group.
b

978
K. Baczko et al. / Tetrahedron: Asymmetry 15 (2004) 971–982
were obtained for each of these lyotropic mixtures in a
range of temperatures varying in the 305–340 K.
According to spectral data in Table 3, the range of
deuterium quadrupolar splittings measured for the sol-
ute is very similar from a sample to another one, thus
indicating that the molecular orientational behavior of
the phase (and the solute) is almost unaffected by the
type of chlorinated solvent used. This point suggests an
identical role in the organization of the system for each
of them. In contrast, the small variations in linewidths
could indicate that the macroscopic homogeneity of the
phase can be slightly affected by the nature of this
mixture component. The comparison between the vari-
ous experimental results shows that the system using
tetrachloroethane as oil gives the optimal result since
linewidths of 4–5 Hz were observed while the two com-
ponents of the quadrupolar doublet are split by 3000 Hz.
promising and opens new prospects in the enantiomeric
analysis of small, water soluble, organic compounds.
Several questions arise, but are beyond the scope of this
preliminary work. Among them it will be important to
understand the exact role the chlorinated entities in the
mesophase behavior. The second point will be to
establish if the alanine molecules reside mainly in the
interstitial water or is also able to penetrate into the
micellar region, which is highly oriented. In particular,
in which region of the aggregates the two enantiomers
undergo enantiodifferential ordering forces induced by
the asymmetry of the surfactant. Answering these
questions should help us to improve the chiral selectivity
of this system.
4. Experimental
4
.1. General methods
3. Conclusion
All starting materials were purchased from currently
available commercial sources. Solvents were distilled by
conventional methods. Reactions were monitored by
The design and exploration of new surfactant types as
chiral ordering agents using NMR spectroscopy is a
noteworthy challenge, regarding the continuous efforts
devoted to development of analytical methods for the
determination of the enantiomeric purity. One of
the advantages of using synthetic surfactants is that the
structure can be readily varied.
TLC on plates coated with 0.25 mm silica gel 60 F254
,
which were visualized under UV at 254 nm, 5% sulfuric
acid in ethanol or ninhydrin solution (0.2%) in ethanol
as developing agents. Silica gel Merck Gerduran SI60
(
40–63 lm) was used for column chromatography.
1 13
Routine H and C NMR spectra in isotropic solvents
were recorded on a Bruker AC 300 at 300 and 75 MHz,
respectively. The chemical shifts d were referenced to
residual chloroform (7.27 and 77.0 ppm), water
Herein, we have reported the straightforward synthesis
of the first series of sulfonated amino acid-based chiral
surfactants with modulable properties depending on the
nature of the amino acid residue (Phe or Ala) and the
length of the aliphatic tail. These compounds self-
aggregate in water at low concentration. Their low
CMC as well as their large interfacial area, compared
with classical surfactants, suggest that micellization is
favored by attractive interactions between amino acid
residues at the interface. Phenylalanine derivatives
behave like branched surfactants with the benzyl sub-
stituent embedded within the micellar core.
1
1
(
4.63 ppm), or DMSO (2.50 and 39.50 ppm). H– H
1
13
homonuclear (COSY) and H– C heteronuclear
HETCOR) correlations allowed to elucidate several
(
structures. IR spectra were obtained on a Magna-IR
Spectrometer 550 (KBr pellets) and spectral bands are
ꢀ
1
reported in cm . Mass spectra were obtained using an
electrospray ion-source in negative mode (ES)) on an
MS-Engine HP5989B in methanol/water with 1% tri-
ethylamine and peaks are reported as m=z. Optical
rotations were measured on a Perkin–Elmer Model 241
polarimeter at 25 ꢁC. Melting points are uncorrected.
Elemental analyses were obtained from the Service
Central dꢀAnalyses (CNRS, Vernaison, France).
From an analytical point of view, we have shown that
these anionic surfactants aligned in a magnetic field can
form homogeneous, lyotropic liquid crystalline phases
in the presence of water and weakly polar chlorinated
organic solvents around 320 K. They offer several
practical advantages. The liquid crystal samples them-
selves are rather simple to prepare. They rapidly and
homogenously align in the magnetic field and lead to
sharp NMR resonances. The system behaves like a
chiral nematic phase of positive anisotropy of the
4.1.1. Synthesis of phenylalanine esters 1
4.1.1.1. (2S)-Amino-3-phenyl-propionic acid pentyl ester
1a.
A mixture of L-phenylalanine (1.00 g, 6.1 mmol),
molecular diamagnetic susceptibility (Dv > 0), with the
pentanol (0.64 g, 7.3 mmol), and PTSA (1.15 g,
7.3 mmol) in toluene (50 mL) was heated at reflux
overnight, using Dean–Stark apparatus. After removal
of the solvent, the reaction mixture was diluted with
Et O, washed successively with NaOH (1 M) and brine
2
2 4
and dried over Na SO . The crude product isolated after
m
director uniformly and homogeneously aligned parallel
to the static magnetic field. In addition we have dem-
onstrated that enantioselective interactions between a
chiral solute and the chiral polar head of the surfactant
was sufficient to spectroscopically differentiate the NMR
signal of enantiomers like
D
- and
L
-alanine-2-d
1
.
removal of the solvent was purified by column chro-
matography on silica gel with EtOAc/cyclohexane 1/2,
then EtOAc to provide the ester 1a as oil (1.23 g, 86%):
The first NMR results using these new lyotropic systems
as potential high-resolution oriented solvent are very
1
R
f
0.38 (EtOAc/cyclohexane 1/2); H NMR (DMSO-d
6
),

K. Baczko et al. / Tetrahedron: Asymmetry 15 (2004) 971–982
979
1
3
d (ppm): 0.84 (t, 3H, J 7.0 Hz, CH
3
), 1.19 (m, 4H, CH
.46 (m, 2H, CH CH O), 1.89 (br s, 2H, NH ), 2.79 (dd,
2
),
4.10 (t, 2H, J 7.0 Hz, CH
NMR (CDCl ), d (ppm): 14.11 (CH
28.53, 28.61, 29.22, 29.34, 29.49, 29.56, 29.64, 29.66,
29.67, 31.90 (CH ), 41.19 (CH Ph), 55.88 (CH), 65.14
(CH O), 126.78 (C ), 128.51 (C ), 129.27 (C ), 137.29
Cipso), 175.15 (C@O).
2
O), 7.23 (m, 5H, Harom);
C
1
2
2
2
3
3
), 22.68, 25.86,
H, J 13.5Hz, J 7.0Hz, CHHPh), 2.85 (dd, H, J 13.5 Hz,
J 6.6 Hz, CHHPh), 3.54 (dd, H, J 7.0 Hz, J 6.6 Hz, CH),
2
2
3
.93 (m, 2H, CH
2
O), 7.20 (m, 5H, Harom).
2
p
o
m
(
4.1.1.2. (2S)-Amino-3-phenyl-propionic acid octyl ester
1b. Prepared as described above for 1a, starting from
L-phenylalanine (1.00 g, 6.1 mmol), octanol (0.94 g,
7.3 mmol), and PTSA (1.15 g, 6.1 mmol) in toluene
4.1.2. Synthesis of alanine ester 2. 4.1.2.1. (2S)-Amino-
propionic acid dodecyl ester 2d. Prepared as described
(
(
0
2
50 mL) to provide ester 1b as oil (1.40 g, 83%); R
f
0.30
above for 1a, starting from
11.2 mmol), dodecanol (2.50 g, 13.4 mmol), and PTSA
(2.13 g, 11.2 mmol) in toluene (25 mL) to provide ester
L-alanine (1.00 g,
1
EtOAc/cyclohexane 1/2); H NMR (CDCl ), d (ppm):
3
.89 (t, 3H, J 7.0 Hz, CH ), 1.24 (m, 10H, CH ), 1.47 (m,
3
2
H, CH
2
CH
2
O), 3.32 (dd, H, J 14 Hz, J 7.4 Hz,
2d as oil (2.71 g, 94%); R
f
0.27 (EtOAc/cyclohexane1/2);
1
CHHPh), 3.47 (dd, H, J 14 Hz, J 5.4 Hz, CHHPh), 4.03
t, 2H, J 6.6 Hz, CH O), 4.44 (dd, H, J 7.4 Hz, J 5.4 Hz,
H NMR (DMSO-d ), d (ppm): 0.85 (t, 3H, J 6.5 Hz,
6
(
CH CH ), 1.15 (d, 3H, J 7.0 Hz, CH CH), 1.24 (m, 20H,
2
3
2
3
CH), 7.30 (m, 5H, Harom).
CH
7
2
and NH
.0 Hz, CH), 4.03 (m, 2H, CH
2
), 1.56 (m, 2H, CH
2
CH O), 3.38 (q, H, J
2
13
2
O); C NMR (DMSO-
4.1.1.3. (2S)-Amino-3-phenyl-propionic acid decyl ester
1c. Prepared as described above for 1a, starting from
L-phenylalanine (2.00 g, 12.1 mmol), decanol (2.30 g,
14.5 mmol), and PTSA (2.30 g, 12.1 mmol) in toluene
d ), d (ppm): 13.94 (CH CH ), 15.72 (CH CH), 22.08,
6
3
2
3
25.14, 27.93, 28.59, 28.69, 28.90, 28.95, 29.02, 31.28
(CH ), 47.80 (CH), 65.52 (CH O), 174.03 (C@O).
2
2
(
100 mL) to provide the ester 1c as oil (3.50 g, 95%): R
f
0
+
.35 (EtOAc/cyclohexane 1/2); ½aꢃ ¼ +14.8, ½aꢃ
¼
4.1.3. Synthesis of arylsulfonated Phe esters 3
D
436
1
28.8, ½aꢃ ¼ +48.8 (c 1, DMF); H NMR (DMSO-d
6
),
365
d (ppm): 0.85 (t, 3H, J 7.0 Hz, CH ), 1.23 (m, 14H,
4.1.3.1. Sodium, 2-(1-pentyloxycarbonyl-2S-phenyl-ethyl
carbamoyl)-benzene sulfonate 3a. To a solution of ester
1a (1.13 g, 4.8 mmol), triethylamine (6.60 mL,
48.0 mmol) in dry THF (60 mL) under nitrogen was
added o-sulfobenzoic acid cyclic anhydride (1.30 g,
7.1 mmol). After stirring for 6 h at 60 ꢁC, THF was
evaporated and the resulting mixture solubilized in
3
CH
.77 (dd, H, J 13.5 Hz, J 7.0 Hz, CHHPh), 2.84 (dd, H,
J 13.5 Hz, J 6.6 Hz, CHHPh), 3.54 (dd, H, J 7.0 Hz,
J 6.6 Hz, CH), 3.95 (m, 2H, CH O), 7.20 (m, 5H, Harom);
), d (ppm): 13.93 (CH ), 22.09,
5.27, 28.03, 28.61, 28.89, 28.91, 31.28 (CH ), 40.95
2 2 2 2
), 1.46 (m, 2H, CH CH O), 1.73 (br s, 2H, NH ),
2
2
13
C NMR (DMSO-d
6
3
2
2
(
(
CH
C
2
Ph), 55.78 (CH), 63.87 (CH
), 129.14 (C
2
O), 126.19 (C
), 137.90 (Cipso), 174.99 (C@O).
p
), 128.04
EtOAc, washed with HCl (1M), NaHCO
brine, dried over Na SO . The crude product was iso-
3
saturated,
o
m
2
4
lated after removal of the solvent and purified by col-
umn chromatography on silica gel with EtOAc, then
EtOAc/MeOH (9/1) to give sulfonate 3a (1.82 g, 86%) as
4
1
L
2
.1.1.4. (2S)-Amino-3-phenyl-propionic acid dodecyl ester
d. Prepared as described above for 1a, starting from
-phenylalanine (3 g, 18.2 mmol), dodecanol (4.05 g,
1.8 mmol), and PTSA (3.45 g, 18.2 mmol) in toluene
white solid: mp 73 ꢁC; R 0.28 (EtOAc/MeOH 9/1);
f
½aꢃ ¼ +27.6, ½aꢃ ¼ +62.9, ½aꢃ ¼ +115.9 (c 1.5, EtOH
D
436
365
ꢀ
1
(
150 mL) to provide the ester 1d as oil (4.82 g, 80%):
0.29 (EtOAc/cyclohexane 1/2); ½aꢃ ¼ +13.1,
96%); IR (KBr), mmax (cm ): 3421, 3266 (NH), 1736
R
f
(OC@O), 1652 (NHC@O), 1541 (NH), 1240–1081
D
1
1
½
aꢃ ¼ +26.4, ½aꢃ ¼ +47.2 (c 1, DMF); H NMR
(S@O); H NMR (DMSO-d ), d (ppm): 0.81 (t, 3H, J
436
365
6
(
(
CDCl
3
), d (ppm): 0.84 (t, 3H, J 6.5 Hz, CH
3
), 1.23–1.60
7.0 Hz, CH
CH CH
3.18 (dd, H, J 13.6 Hz, J 5.5 Hz, CHHPh), 3.89 (m, 2H,
CH O), 4.63 (ddd, H, J 5.5 Hz, J 8.4 Hz, J 6.3 Hz, CH),
7.26 (m, 5H, Harom-Phe), 7.44 (dt, 2H, J 7.3 Hz, J 1.8 Hz,
Harom), 7.59 (dd, 1H, J 6.9 Hz, J 1.8 Hz, Harom), 7.84
3 2
), 1.14 (m, 4H, CH ), 1.37 (m, 2H,
m, 22H, CH
.9 Hz, CHHPh), 2.84 (dd, H, J 13.4 Hz, J 5.5 Hz,
CHHPh), 3.72 (dd, H, J 7.9 Hz, J 5.5 Hz, CH), 4.10 (t,
2
and NH
2
), 2.86 (dd, H, J 13.4 Hz, J
2
2
O), 2.97 (dd, H, J 13.6 Hz, J 8.4 Hz, CHHPh),
7
2
13
2
(
2
4
1
H, J 6.9 Hz, CH
CDCl ), d (ppm): 14.23 (CH
8.67, 29.34, 29.46, 29.61, 29.68, 29.76, 32.03 (CH ),
2
O), 7.25 (m, 5H, Harom); C NMR
o
m
3
3
), 22.80, 25.98, 28.03,
o
m
2
(dd, 1H, J 6.9 Hz, J 1.8 Hz, Harom), 9.70 (d, H, J
o m
13
1.31 (CH
28.64 (C
2
Ph), 56.00 (CH), 65.25 (CH
2
O), 126.89 (C
p
),
6.3 Hz, NH); C NMR (DMSO-d
(CH ), 21.82, 27.47, 27.68 (CH ), 37.36 (CH
CH), 64.34 (CH O), 126.71, 126.82, 128.39, 129.26,
6
), d (ppm): 13.92
o
), 129.39 (C ), 137.40 (Cipso), 175.25 (C@O).
m
3
2
2
Ph), 55.11
(
2
1
29.36, 129.86, 130.37 (Carom), 133.18 (Cipso–CO), 137.00
), 167.72 (CONH), 171.13
(COO); Anal. Calcd for C H NNaO SÆ1/2H O: C,
4
.1.1.5. (2S)-Amino-3-phenyl-propionic acid tetradecyl
(Cipso-Phe), 144.36 (Cipso–SO
3
ester 1e. Prepared as described above for 1a, starting
from -phenylalanine (2.00 g, 12.1 mmol), tetradecanol
3.11 g, 14.5 mmol), and PTSA (2.30 g, 12.1 mmol) in
toluene (100 mL) to provide the ester 1e as oil (3.60 g,
21
24
6
2
L
55.99; H, 5.77; N, 3.11. Found: C, 55.74; H, 5.64; N,
3.15.
(
1
8
(
2
5%): Rf 0.22 (EtOAc/cyclohexane 1/2); H NMR
CDCl ), d (ppm): 0.89 (t, 3H, J 7.0 Hz, CH ), 1.27 (m,
4H, CH ), 1.58 (m, 4H, CH CH O and NH ), 2.88 (dd,
4.1.3.2. Sodium, 2-(1-octyloxycarbonyl-2S-phenyl-ethyl
carbamoyl)-benzene sulfonate 3b. Prepared as described
above for 3a, starting from ester 1b (0.62 g, 2.0 mmol),
triethylamine (2.20 mL, 15.8 mmol), and o-sulfobenzoic
anhydride (0.54 g, 3.0 mmol) in dry THF (35 mL) to
3
3
2
2
2
2
H, J 13.6 Hz, J 7.7 Hz, CHHPh), 3.09 (dd, H, J 13.6 Hz,
J 5.5 Hz, CHHPh), 3.73 (dd, H, J 7.7 Hz, J 5.5 Hz, CH),

980
K. Baczko et al. / Tetrahedron: Asymmetry 15 (2004) 971–982
provide the sulfonate 3b (0.88 g, 93%) as a white solid:
0.30 (EtOAc/MeOH 9/1); ½aꢃ ¼ +29.6,
CH
7.25 (m, 5H, Harom-Phe), 7.44 (dt, 2H, J
2
O), 4.62 (ddd, H, J 5.5 Hz, J 8.8 Hz, J 6.2 Hz, CH),
7.3 Hz, J 1.8 Hz,
mp 104 ꢁC; R
f
o
m
D
½
aꢃ ¼ +64.9, ½aꢃ ¼ +118.7 (c 1.5, EtOH 96%); IR
Harom), 7.59 (dd, 1H, J 6.9 Hz, J 1.8 Hz, Harom), 7.84
436
365
1
o
m
ꢀ
(
1
KBr), mmax (cm ): 3421, 3266 (NH), 1741 (OC@O),
(dd, 1H, J
6.2 Hz, NH); C NMR (DMSO-d
o
6.9 Hz, J
m
1.8 Hz, Harom), 9.70 (d, H, J
1
13
650 (NHC@O), 1544 (NH), 1240–1082 (S@O);
NMR (DMSO-d ), d (ppm): 0.85 (t, 3H, J 7.0 Hz, CH ),
H
6
), d (ppm): 13.99
(CH ), 22.14, 25.23, 27.93, 28.65, 28.75, 28.92, 28.99,
6
3
3
1
.20 (m, 10H, CH
2
), 1.37 (m, 2H, CH
2
CH
2
O), 2.95 (dd,
29.04, 29.08, 31.34 (CH
64.25 (CH O), 126.56, 126.77, 128.26, 129.16, 129.70,
130.22 (Carom), 133.16 (Cipso–CO), 137.00 (Cipso-Phe),
144.40 (Cipso–SO ), 167.69 (CONH), 171.01 (COO); SM
2 2
), 37.28 (CH Ph), 54.98 (CH),
H, J 14.0 Hz, J 8.5 Hz, CHHPh), 3.15 (dd, H, J 14.0 Hz,
J 5.5 Hz, CHHPh), 3.90 (m, 2H, CH O), 4.62 (ddd, H, J
2
2
5
.5 Hz, J 8.5 Hz, J 6.2 Hz, CH), 7.25 (m, 5H, Harom-Phe),
3
7
.45 (dt, 2H, J
o
7.3 Hz, J
m
1.8 Hz, Harom), 7.59 (dd, 1H,
(-ES, m/z): 516 (M)Na, 100%); Anal. Calcd for
C H NNaO SÆH O: C, 60.30; H, 7.23; N, 2.51. Found:
C, 60.61; H, 7.31; N, 2.63.
J 6.6 Hz, J 2.0 Hz, H
), 7.86 (dd, 1H, J 7.4 Hz, J
o
m
arom
o
m
28 38
6
2
13
1
(
.8 Hz, Harom), 9.70 (d, H, J 6.2Hz, NH); C NMR
DMSO-d ), d (ppm): 13.94 (CH ), 22.07, 25.18, 27.87,
8.53, 28.55, 31.17 (CH ), 37.24 (CH Ph), 54.94 (CH),
6
3
2
6
1
2
2
4.1.3.5. Sodium, 2-(1-tetradecyloxycarbonyl-2S-phenyl-
ethyl carbamoyl)-benzene sulfonate 3e. Prepared as de-
scribed above for 3a, starting from ester 1e (1.60 g,
6.2 mmol), triethylamine (6.70 mL, 48.3 mmol), o-sulfo-
benzoic anhydride (1.68 g, 9.1 mmol) in dry THF
(100 mL) to provide the sulfonate 3e (2.64 g, 92%) as
4.17 (CH O), 126.51, 126.70, 128.22, 129.08, 129.12,
2
29.65, 130.22 (Carom), 133.09 (Cipso–CO), 136.95
(
C
ipso-Phe), 144.43 (Cipso–SO
3
), 167.56 (CONH), 170.95
(
COO); Anal. Calcd for C H NNaO SÆ3/4H O: C,
24
30
6
2
5
2
7.99; H, 6.31; N, 2.82. Found: C, 58.06; H, 6.40; N,
.89.
white solid: mp 71 ꢁC; R
f
0.37 (EtOAc/MeOH 9/1);
½
aꢃ ¼ +25.8, ½aꢃ ¼ +57.5, ½aꢃ ¼ +104.2 (c 1.5, EtOH
D
436
365
ꢀ
1
4
.1.3.3. Sodium, 2-(1-decyloxycarbonyl-2S-phenyl-ethyl
96%); IR (KBr), mmax (cm ): 3421, 3266 (NH), 1740
carbamoyl)-benzene sulfonate 3c. Prepared as described
above for 3a, starting from ester 1c (1.50 g, 4.9 mmol),
triethylamine (5.40 mL, 39.3 mmol), and o-sulfobenzoic
anhydride (1.60 g, 8.8 mmol) in dry THF (75 mL) to
provide the sulfonate 3c (2.38 g, 95%) as white solid: mp
(OC@O), 1647 (NHC@O), 1541 (NH), 1240–1085
1
(S@O); H NMR (DMSO-d
6
), d (ppm): 0.85 (t, 3H, J 6.6
Hz, CH ), 1.24 (m, 22H, CH ), 1.37 (m, 2H,
3
2
2 2
CH CH O), 2.98 (dd, H, J 13.6 Hz, J 8.5 Hz, CHHPh),
3.15 (dd, H, J 13.6 Hz, J 5.5 Hz, CHHPh), 3.89 (m, 2H,
1
02 ꢁC; Rf 0.21 (EtOAc/MeOH 9/1); ½aꢃ ¼ +26.4,
CH O), 4.63 (ddd, H, J 5.5 Hz, J 8.5 Hz, J 6.2 Hz, CH),
D
2
½
aꢃ ¼ +59.4, ½aꢃ ¼ +108.0 (c 1.5, EtOH 96%); IR
7.25 (m, 5H, Harom-Phe), 7.44 (dt, 2H, J
arom), 7.58 (dd, 1H, J 7.0 Hz, J 1.8 Hz, Harom), 7.86
(dd, 1H, J 7.0 Hz, J 1.8 Hz, Harom), 9.69 (d, H, J
o m
7.3 Hz, J 1.8 Hz,
436
365
ꢀ
1
(
KBr), mmax (cm ): 3421, 3290 (NH), 1745 (OC@O),
H
o
m
1
1
643 (NHC@O), 1544 (NH), 1245–1086 (S@O);
NMR (DMSO-d ), d (ppm): 0.86 (t, 3H, J 6.6 Hz, CH
.23 (m, 14H, CH ), 1.37 (m, 2H, CH CH O), 2.97 (dd,
H
o
m
13
6
3
),
6.2 Hz, NH); C NMR (DMSO-d
(CH ), 22.10, 25.19, 27.89, 28.61, 28.71, 28.88, 28.95,
29.03, 29.05, 31.29 (CH ), 37.24 (CH Ph), 54.93 (CH),
6
), d (ppm): 13.95
1
2
2
2
3
H, J 13.6 Hz, J 8.6 Hz, CHHPh), 3.17 (dd, H, J 13.6 Hz,
2
2
J 5.3 Hz, CHHPh), 3.89 (m, 2H, CH O), 4.61 (ddd, H, J
64.18 (CH O), 126.50, 126.71, 128.21, 129.08, 129.65,
2
130.19 (Carom), 133.11 (Cipso–CO), 136.96 (Cipso-Phe),
2
5
.3 Hz, J 8.6 Hz, J 6.2 Hz, CH), 7.25 (m, 5H, Harom-Phe),
7
.44 (dt, 2H, J
o
7.3 Hz, J
m
1.8 Hz, Harom), 7.59 (dd, 1H,
3
144.40 (Cipso–SO ), 167.62 (CONH), 170.96 (COO);
J 6.9 Hz, J 1.8 Hz, H
), 7.84 (dd, 1H, J 6.9 Hz, J
Anal. Calcd for C H NNaO S: C, 63.47; H, 7.46; N,
6
2.47. Found: C, 63.02; H, 7.52; N, 2.41.
o
m
arom
o
m
30 42
13
1
.8 Hz, Harom), 9.71 (d, H, J 6.2 Hz, NH); C NMR
DMSO-d ), d (ppm): 13.97 (CH ), 22.10, 25.18, 27.87,
8.60, 28.69, 28.89, 31.27 (CH ), 37.25 (CH Ph), 54.97
(
6
3
2
2
2
(
CH), 64.16 (CH
2
O), 126.55, 126.76, 128.25, 129.16,
4.1.4. Synthesis of arylsulfonated Ala ester 4d
1
29.70, 130.21 (Carom), 133.16 (Cipso–CO), 136.99
Cipso-Phe), 144.40 (Cipso–SO ), 167.69 (CONH), 171.01
(
(
4.1.4.1. Sodium, 2-(1-dodecyloxycarbonyl-2S-ethyl car-
bamoyl)-benzene sulfonate 4d. Prepared as described
above for 3a, starting from ester 2d (1.60 g, 6.2 mmol),
triethylamine (6.70 mL, 48.3 mmol), and o-sulfobenzoic
anhydride (1.68 g, 9.1 mmol) in dry THF (100 mL) to
provide the sulfonate 4d (2.59 g, 90%) as white solid: mp
3
COO); Anal. Calcd for C26
H
34NNaO
0.56; H, 6.84; N, 2.72. Found: C, 60.39; H, 6.54; N,
6
SÆ1/4H
2
O: C,
6
2
.55.
4
.1.3.4. Sodium, 2-(1-dodecyloxycarbonyl-2S-phenyl-
ethyl carbamoyl)-benzene sulfonate 3d. Prepared as de-
scribed above for 3a, starting from ester 1d (2.50 g,
71 ꢁC; Rf 0.33 (EtOAc/MeOH 9/1); ½aꢃ ¼ +10.4,
D
½aꢃ ¼ +36.0, ½aꢃ ¼ +49.3 (c 1.5, EtOH 96%); IR
436
365
ꢀ
1
7
.5 mmol), triethylamine (8.30 mL, 60.0 mmol) and o-
sulfobenzoic anhydride (2.10 g, 11.4 mmol) in dry THF
125 mL) to provide the sulfonate 3d (3.72 g, 92%) as
0.41 (EtOAc/MeOH 9/1);
(KBr), mmax (cm ): 3412, 3279 (NH), 1740 (OC@O),
1
1647 (NHC@O), 1554 (NH), 1085 (S@O); H NMR
(DMSO-d ), d (ppm): 0.85 (t, 3H, J 6.6 Hz, CH CH ),
(
6
3
2
white solid: mp 85 ꢁC; R
f
1.24 (m, 18H, CH
2
), 1.36 (d, 3H, J 7.0 Hz, CH
3
CH),
½
aꢃ ¼ +24.7, ½aꢃ ¼ +55.6, ½aꢃ ¼ +101.5 (c 1.5, EtOH
1.56 (m, 2H, CH
H, J 7.0 Hz, J 6.2 Hz, CH), 7.44 (dt, 2H, J 7.4 Hz, J
m
2 2 2
CH O), 4.04 (m, 2H, CH O), 4.42 (dq,
D
436
365
ꢀ
(cm ): 3418, 3255 (NH), 1738
max
1
9
6%); IR (KBr), m
o
(
(
6
OC@O), 1650 (NHC@O), 1544 (NH), 1245–1081
o m
1.8 Hz, Harom), 7.59 (dd, 1H, J 6.6 Hz, J 2.2 Hz, Harom),
1
S@O); H NMR (DMSO-d
.6 Hz, CH ), 1.22 (m, 18H, CH
CH CH O), 2.95 (dd, H, J 14 Hz, J 8.8 Hz, CHHPh),
6
), d (ppm): 0.85 (t, 3H, J
7.85 (dd, 1H, J
6.2 Hz, NH); C NMR (DMSO-d ), d (ppm): 13.95
o
6.6 Hz, J
m
2.2 Hz, Harom), 9.54 (d, H, J
1
3
3
2
), 1.36 (m, 2H,
6
2
2
(CH CH ), 16.71 (CH CH), 22.09, 25.26, 28.07, 28.62,
3
2
3
3
.17 (dd, H, J 14 Hz, J 5.5 Hz, CHHPh), 3.90 (m, 2H,
2
28.71, 28.94, 28.99, 29.03, 31.29 (CH ), 48.62 (CH),

K. Baczko et al. / Tetrahedron: Asymmetry 15 (2004) 971–982
981
Table 4. Compositions of liquid-crystalline NMR samples made of (±)-7d
1
in surfactant 3c–d
Organic solvent
Sample
Surfactants
H
2
O
Solute
/% w/w
a
a
a
a
/mg
/% w/w
/ mg
/% w/w
/mg
/% w/w
/mg
1
2
3
4
5
6
7
3c
3c
3c
3c
3c
3c
3d
110
111
110
111
110
113
110
24
25
25
21
24
25
27
260
262
260
262
270
261
261
58
59
59
48
60
58
63
CHCl
CH Cl
Cl
3
70
60
16
14
14
29
14
15
8
10
10
12
11
10
10
7
2
2
2
2
2
2
2
2
2
C
2
H
2
4
60
CCl
Toluene
Decanol
4
160
60
70
CHCl
3
33
a
The accuracy on the weighting is ±1 mg.
6
1
1
4.29 (CH
33.19 (Cipso–CO), 144.46 (Cipso–SO
72.49 (COO); SM (-ES, m/z): 440.5 (M)Na, 100%);
2
O), 126.74, 129.04, 129.58, 130.12 (Carom),
sample was obtained. In a second step, chlorinated
solvent (CHCl , CH Cl , C Cl , CCl ) was added to
3
), 167.40 (CONH),
3
2
2
2
H
2
4
4
the mixture by portion of 10–20 mg and the sample
mixed (by centrifugation) until a rather clear optically
homogeneous birefringent phase was obtained. Note
that a very viscous, rather white, mixture was observed
if the w/w concentration in chlorinated entity was too
low. When this concentration was optimal (8–29% w/w),
a rather fluid, transparent phase was obtained. The
changes in the macroscopic characteristics of the sample
allowed us to easily control the optimal amount of or-
ganic solvent to be added. Note that the reproducibility
of NMR results strongly depend on sample preparation,
and in particular the homogeneity of the mixture.
Anal. Calcd for C H NNaO SÆ1/2H O: C, 55.92; H,
22
34
6
2
7
.47; N, 2.96. Found: C, 55.58; H, 7.36; N, 3.06.
4
.2. Surface tension measurements
Surface tension measurements were obtained by the Du
No u€ y method with a platinum ring using a Kr u€ ss K 10T
tensiometer, thermostated at 25 ꢁC. The aqueous solu-
tions of compounds 3 and 4 were prepared using ultra-
pure water (MilliQ) and the surface tension c was
measured at the equilibrium (15 smin) for various con-
centrations.
1
1
2
2
4
{
a
.3.2. NMR spectroscopy. The H, H–{ H} and H–
1
Below CMC, the superficial tension, c decreases when
the surfactant concentration C increases, according to
Gibbsꢀ equation (Eq. 3):
H} 1D NMR experiments were performed at 9.4 T on
Bruker DRX 400 high-resolution spectrometer
equipped with a BBO probe and a standard variable
temperature unit (BVT 3200). The samples were not
spun in the magnetic field. Note however that the
spinning of the mixture does not affect the micellar
organization of the system. In order to remove the
proton–deuterium scalar and dipolar couplings, the
protons were broadband decoupled using a WALTZ-16
composite pulse sequence. Other experimental NMR
parameters or details are given in the figure captions.
dc ¼ ꢀ2 ꢄ 2:3CRTdðlogðCÞÞ
assuming a complete dissociation of the counter ion.
ð3Þ
Above the CMC c reaches a minimum value, cmin, and
remains constant. The CMC value is determined from
the inflection point in the c versus log (C) curve. The
2
superficial excess C in mol/m is deduced from the slope
of c versus log(C) below the CMC. The area per head
ꢂ
2
group at the air–water interface a (A /molecule) is given
s
by Eq. 4:
1
as ¼
ð4Þ
NC
with N being Avogadroꢀs number.
Acknowledgements
The authors thanks Dr. Jean-Pierre Bayle and Profs.
J. C. Courtieu and J. W. Emsley for helpful discussions.
4.3. NMR spectroscopy in amphiphilic chiral oriented
solvents
4
.3.1. Sample preparation. The composition of oriented
NMR samples is listed in Table 4. The amount of the
components was optimized in order for the total volume
of the sample to be optimal when compared to the
length of the coil of a 5 mm diameter NMR probe-head.
In the first step, around 110 mg of surfactant (21–27%
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