Molecular tailored histidine-based complexing surfactants: from micelles to hydrogels

Article abstract of DOI:10.1002/ejoc.200900137

Novel histidine-based complexing surfactants, designed as AA-His-EO _m-C_n, containing trifimctional moduli (peptidic/ hydrophllic/hydrophobic) were synthesized, by a modular step-by-step procedure, which allowed easy structural change

Full text of DOI:10.1002/ejoc.200900137

FULL PAPER
DOI: 10.1002/ejoc.200900137
Molecular Tailored Histidine-Based Complexing Surfactants:
From Micelles to Hydrogels
Patrick Gizzi,[a] Andreea Pasc,[a] Nicolas Dupuy,[a] Stéphane Parant,[b] Bernard Henry,[b]
and Christine Gérardin*[a]
Keywords: Peptides / Surfactants / Self-assembly / Gels / Chelates / Amphiphiles
Novel histidine-based complexing surfactants, designed as
AA-His-EOm-Cn, containing trifunctional moduli (peptidic/
hydrophilic/hydrophobic) were synthesized by a modular
step-by-step procedure, which allowed easy structural
range 8–10, micellization took place for decyl compounds (n
= 10), whereas hydrogelation occurred for longer chain
lengths (n = 12, 14), and this, at very-low concentrations of
surfactant (Ͻ0.3 wt.-%), could thus act as low molecular
changes, and consequently correlations between their mo- weight gelator (LMWG). The driving forces for gel formation
lecular structures and their self-assembling properties could
be established. Thus, micelles or hydrogels could be ob-
tained by simply modifying the hydrophobic tail lengths or
the junction between the different moduli of the designed
compounds. At low pH values, all compounds were surface
active in aqueous solutions. At higher pH values, in the
were noncovalent intermolecular interactions such as π-
stacking and hydrophobic and hydrogen-bonding interac-
tions.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
peptides and peptidoamines exhibit a large variety of coor-
Introduction
dination modes toward transition-metal ions such as Cu2+
,
Inspired by biologically active carnosine or carcinine
(Figure 1), respectively, histidine-peptide and histidine-pep-
tidoamine, which are known for their intrinsic antioxidant
properties and their potential therapeutic effects in many
diseases, for example, Wilson, Parkinson, Alzheimer, or in-
flammatory diseases,[1] histidine (His) di- or tripeptides ap-
pear as promising building blocks for new therapeutics and
might constitute a straightforward approach for the design
of bioactive formulations with direct applications in the
medical field, and more particularly for oxidation stress
problems.
Ni2+, Zn2+, and Co2+ [5–10]
and some of them, such as
,
Cu2+or Ni2+ complexes, are of significant biological impor-
tance. Some glycine (Gly)-peptides show similar proper-
ties.[11]
On the other side, new formulations such as soft materi-
als known as hydrogels have gathered much attention
recently, owing to their unique properties and versatile
applications in many areas, from applied chemistry to bio-
medicine.[12,13] In this respect, a major challenge is the de-
velopment of biocompatible and/or biodegradable low mo-
lecular weight (LMW) hydrogelators with well-defined
chemical structures and predictable properties with respect
to their polymeric counterparts. To this end, amphiphilic
molecules, namely surfactants, appear as suitable candi-
dates, as they can form well-characterized supramolecular
structures. When appropriately grafted with amino
acid[14,15] moieties they may conduct to stimuli-sensitive hy-
drogels through weak noncovalent interactions between gel-
ator molecules and entrapped solvent molecules.
On the basis of anterior results on peptidoamines and
surfactants with complexing properties,[16–18] this study
concerns the synthesis and the physicochemical characteri-
zation of trimodulus compounds, designed as AA-EOm-
Alkn, bearing (i) a hydrophobic alkyl group, (ii) a polar pep-
tide group with complexing properties, and (iii) a variable
hydrophilic junction modulus, allowing HLB (Hydrophilic
Lipophilic Balance) control. Depending on the junction
type between these moduli, ester or amide, three types of
Figure 1. Structure of carnosine and carcinine.
Their antioxidant properties are directly related to the
presence of the imidazole moiety and might be enhanced in
the corresponding metallocomplexes.[2–4] Indeed, His-oligo-
[a] Groupe “Valorisation chimique de la Biomasse, LERMAB,
IFR110, EFABA, Université Henri Poincaré,
B. P. 70239, 54506 Vandoeuvre-lès-Nancy, France
Fax: +33-3-83684322
E-mail: Christine.Gerardin@lermab.uhp-nancy.fr
[b] Groupe SUCRES, UMR 7565, Université Henri Poincaré,
B. P. 70239, 54506 Vandoeuvre-lès-Nancy, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900137.
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compounds were synthesized: amide–ester AA-His-a-EOm-
All compounds were prepared by a modular strategy of
e-Cn, ester–amide AA-His-e-EOm-a-Cn, and amide–amide synthesis, as described below. The first stage of synthesis
AA-His-a-EOm-a-Cn. Thus, by small structural modula- corresponds to the grafting of a fatty acid onto an eth-
tions, intermolecular interactions might be easily tailored.
oxylated amino alcohol or a diamine by an amide or ester
In this work our interests focus on the synthesis of new link. The second step consists of the grafting of the histi-
histidine-based surfactants and their self-assembling prop- dine carboxylic acid function onto the free moiety of the
erties for the rational design of hydrogels. Moreover, as a bimoduli compound, and the third step corresponds to the
result of their complexing properties, such systems, micelles coupling with other amino acids.
or hydrogels, might be used for selective extraction of met-
allic cations, for example, Ni2+ or Cu2+. In order to easily Synthesis of Bimoduli Compounds
tailor the molecular structure, the strategy of the synthesis
The first step involved association of a hydrophilic part
was based on a step-by-step coupling, mimicking peptide
(ethoxylated amino alcohol or ethoxylated diamine) with
synthesis.
the hydrophobic part. Three types of compounds were syn-
thesized by variation of the links between the two parts.
H2N-EOm-e-Cn esters and HO-EOm-a-Cn amides were pre-
pared from the corresponding ethoxylated amino alcohols,
whereas H2N-EOm-a-Cn amides were prepared from eth-
oxylated diamines.
Results and Discussions
Molecular Design and Synthesis
A mixture of the fatty acid and an excess amount of the
ethoxylated amino alcohol, under acidic and azeotropic
conditions, led mainly to esterification, whereas by micro-
wave activation, the regioselectivity was reversed and the
amidation products were predominant. Preventive protec-
tion of the ethoxylated diamine by trityl groups was neces-
sary to obtain monoacylation (Scheme 2). Deprotection
with the use of HCl was quantitative.
The general structure of the target compounds is pre-
sented in Scheme 1.
Grafting of Histidine
The activation of carboxylic acid by peptide coupling
agents like BOP led rapidly and efficiently to the desired
products; the removal of the tert-butyloxycarbonyl moiety
was realized with gaseous HCl. The two parts were grafted
Scheme 1. General structure of the three moduli target compounds. by either of two methods: (i) by an ester link between histi-
Scheme 2. Synthesis of bimoduli amphiphilic compounds.
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Molecular Tailored Histidine-Based Complexing Surfactants
Scheme 3. Histidine grafting by an ester link.
Scheme 4. Histidine grafting by an amide link.
dine and the ethoxylated amino alcohol (Scheme 3), or (ii)
Similar compounds exempt of diethylene oxide moieties
by an amide link between histidine and the ethoxylated were investigated in this work; their synthesis will be re-
amino alcohol or ethoxylated diamine (Scheme 4).
ported elsewhere (Scheme 6).
Grafting of the Peptidic Moiety
Grafting by various coupling and protection–deprotec-
tion steps led to “ester–amide” compounds designed as
AA-His-e-EOm-a-Cn (3a and 4a) or “amide–esters” de-
signed as AA-His-a-EOm-e-Cn (3b and 4b) or “amide–
amide” compounds designed as AA-His-a-EOm-a-Cn (3c
and 4c) (Scheme 5). All compounds were obtained with
good overall yields; Boc deprotection reactions were quanti-
tative.
Scheme 6. Structure of amphiphilic bimodular pseudopeptides 5
and 6 (n = 9, 11).
Scheme 5. Grafting of complexing peptide modulus/preparation of pseudopeptides AA-His-EOm-Cn.
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Complexing Properties
lower than those of corresponding non-ethoxylated pep-
tides or pseudopeptides. The decrease in the pKa values
could be related to the inductive attractor effect of the oxye-
thylene moiety, which thus alters the acidity constant of
imidazole. In the case of the β-Ala derivative, deprotonation
is easier than for Gly-Gly derivatives, because the electron-
withdrawing effect of the carbonyl group in the β-ala resi-
due is weaker.
To prove that the presence of two moduli, hydrophilic
ethylene oxide and hydrophobic alkyl chains, do not alter
the complexing properties of the His-peptide moiety, pro-
tonation and metal coordination studies (with Cu2+ and
Ni2+) were performed.
Protonation
The deprotonation constants of some amphiphilic com-
pounds were determined through titration curves of the li-
gands generated by pH-metry. The macroscopic proton-
ation constants K1 and K2 of the free ligands are listed in
Table 1. They can be approximately assigned to the proton-
ation of the amino group and imidazole ring, respectively.
The pKa values obtained for the terminal amino group were
similar to those of similar peptides (Gly-Gly-His, βAla-His)
or pseudopeptides (Gly-Gly-Ha, βAla-Ha). In contrast, the
pKa of the imidazole ring of the amphiphilic peptides were
Table 1. pKa values of “amide–ester” trimoduli amphiphiles and
peptidoamine analogs (T = 25 °C, I = 0.1 ).
Products
pK1 (amino)
pK2 (imidazole)
Gly-Gly-His-aEO2e-C10 (4d)
Gly-Gly-His[19]
7.79
7.94
7.85
9.13
9.24
9.35
9.21
6.14
6.82
6.81
5.95
6.20
6.74
6.84
Gly-Gly-Ha[20]
β-Ala-His-aEO2e-C10 (3d)
β-Ala-His-aEOe-C10 (3b)
β-Ala-His[22]
β-Ala-Ha[21]
Figure 2. Chemical structures of an amphiphilic trimoduli compound (a), predominant complexes MLH–2 of the Gly-Gly-His derivative
(b) and the β-Ala-His derivative (c); species repartition diagram as a function of pH for Cu2+ (d), Ni2+ (e); and X-ray structure Cu2+
Gly-Gly-Ha[20] (f).
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Molecular Tailored Histidine-Based Complexing Surfactants
Table 2. Cu2+and Ni2+ formation constants of complexes of hydrophilic Gly-Gly-His-aEO2e-C4 compared to Ala-Gly-Ha and Gly-Gly-
Ha (T = 25 °C, I = 0.1 ).
Gly-Gly-His-aEO2e-C4
Ala-Gly-Ha[10]
Gly-Gly-Ha[22]
Cu2+
Ni2+
Cu2+
Ni2+
Cu2+
Ni2+
MLH
ML
MLH–1
MLH–2
–
–
–
–
11.59 (06)
–
2.36 (02)
–2.86 (01)
–15.12 (02)
5.22
10.21 (08)
–
–1.68 (02)
–7.89 (01)
–19.87 (02)
6.21
12.02 (03)
6.61 (04)
1.65 (09)
–2.48 (04)
–14.34 (02)
4.13
10.48 (02)
4.15 (04)
–2.87 (12)
–7.99 (01)
–19.56 (02)
5.12
3.68 (03)
–0.85 (02)
–12.68 (04)
4.53
–0.88 (03)
–6.67 (01)
–17.59 (03)
5.79
MLH–3
MLH–1
pK
pK
MLH–2
MLH–2
11.83
10.92
12.26
11.98
11.86
11.57
MLH–3
Metal(II) Coordination
hydrophobic than Gly-Gly-Ha or Ala-Gly-Ha. The pres-
ence of the hydrophobic chain seems to have only a slight
influence on the stability of the complexes; however, the
capacity of complexation of the amphiphile (ligand) is con-
served.
Gly-Gly-His-aEO2e-C4 was used as a complexing model,
as the resulting complexes are easier to assign with respect
to their βAla-His counterparts. In fact, in the presence of
Cu or Ni, the repartition diagram of the species shows only
one major complex, namely, MLH–2, existing over a large
range of pH values. This is probably related to the coopera-
tive effect of deprotonation, which provides four donor
atoms that are able to fully occupy the coordination sphere
of the metallic center, whereas carnosine derivatives exhibit
only three donor centers and, therefore, several complexes
might be formed (Figure 2).
Amphiphilic Properties
First of all, the stability of the synthesized compounds
has been assessed. The “ amide–ester” compounds designed
as AA-His-a-EOm-e-Cn (3b-h and 4b–h) appear to be stable
under acidic conditions for at least several days, whereas
hydrolysis occurs under basic conditions in less than 1 h, as
estimated by 1H NMR spectroscopy by following the disap-
pearance of the CH2 signal in the position α to the ester
bond (see Scheme 7 and Supporting Information). Interest-
ingly, the position of the ester bond influences dramatically
the stability of the amphiphile in water. Thus, “ester–
amide” compounds, designed as AA-His-e-EOm-a-Cn (3a
and 4a) are rapidly hydrolyzed under both acidic and basic
conditions. The cleavage between the ethoxylated moiety
and the His residue might be related to the catalytic effect
of the imidazole ring, which is in proximity to the ester link.
Consequently, as a result of this low stability of the “ester–
amide” compounds, their amphiphilic properties could not
be determined.
The pH titration curve of an equimolar solution of Cu2+
and Gly-Gly-His-aEO2e-C4 shows a sharp break (pH 5.5
to 10) after the consumption of four equivalents of base per
metal ion, suggesting the deprotonation and coordination
of the two nitrogen atoms of the peptidic bond besides the
terminal amino and imidazole groups (in the MLH–2 spe-
cies), analogous to the Cu2+-Gly-Gly-Ha system (Table 2).
The titration curve shows that only 1:1 complexes are
formed for any metal-to-ligand ratio. Consequently, the for-
mation of bis complexes can be neglected. The visible ab-
sorption spectra taken at variable pH values show the grad-
ual formation of a dominant species at pH 5–10, with λ
d–d
= 530 nm. At this pH, CuLH–2 is the largely predomi-
max
nant species and the metal is coordinated by four nitrogen
donor atoms: one amino nitrogen atom, two nitrogen atoms
of the peptidic bond, and the N3 atom of the imidazole
ring. In the case of Ni2+, complex formation starts at higher
pH values than for Cu2+, but the titration curves are iden-
tical above pH 7, suggesting the formation of the same
complexes in both systems. The color of Ni2+-containing
solutions changes from light green to yellow between pH 6
and 7, indicating the formation of diamagnetic, square-
d–d
planar complexes (λ
= 425 nm). For both systems, fur-
max
ther deprotonation occurs above pH 10, where the MLH–3
complex appears, as shown by the changes in the visible
spectra, indicating the deprotonation of the N1 nitrogen
atom of the imidazole ring.
Scheme 7. Hypothetical mechanism of the self-catalyzed hydrolysis
of AA-His-e-EOm-a-Cn (3a and 4a).
The Cu2+ complexes are more stable than Ni2+ com-
plexes, which is in agreement with the Irving–Williams
series. The complexes CuLH and CuL are not detected,
To increase the stability of the surfactants under both
probably as a result of the strong acidity of imidazole, but acidic and basic conditions “amide–amide” compounds
the stability of the CuLH–1 species is higher than with Gly- were synthesized. Moreover, this provided increased hydro-
Gly-Ha or Ala-Gly-Ha. These differences may be due to philicity and additional hydrogen-bonding centers (Fig-
a phenomenon of solvation because the complex is more ure 3).
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(1)
where Γ is the surface excess concentration (molm–2), k the
Boltzmann constant, T the absolute temperature, γ the sur-
face tension, and C the surfactant concentration. For all
investigated compounds, the mean area per molecule A in
the monolayer was estimated to be in the range 73–83 Å2.
These close values of area per molecule of surfactant, with
variations within the limits of the experimental error, are
relatively high, more than four times the minimum area per
Figure 3. Possible sites of interaction between amphiphiles.
The amphiphilic properties of the synthesized com- molecule for a hydrocarbon chain (18 Å2). Therefore, it
pounds were evaluated by two techniques, generally used seems that the major contribution in the formation of the
for this purpose, namely, surface tension measurements and film is related to the peptidic moiety rather than to the flexi-
spectrofluorimetry with the use of pyrene as a probe. For ble EO spacer or the hydrophobic tail. This can be due to
solubility reasons, the measurements were made at pH 2.
interactions with the aqueous subphase and to the forma-
As indicated in Table 3, all compounds have critical mi- tion of intermolecular hydrogen bonds between the peptidic
cellar concentration (CMC) values in the same order of polar heads, stabilizing the Gibbs film (Figure 4).
magnitude varying from 10–3 to 10–2 ; the small variations
At pH 8, surfactants behave differently, depending on the
observed are consistent with the thermodynamic theory of EO spacer and the alkyl chain length. Non-ethoxylated
self-assembling behavior: (i) When the number of ethylene compounds precipitate independently from the alkyl chain
oxide moieties increase, the hydrophilicity increases and length (Cn), whereas ethoxylated products form either mi-
consequently, the CMC value too. (ii) When the hydro- cellar solutions, when n = 10, or hydrogels, when n = 12 or
phobic alkyl chain length increases, the CMC values de- 14.
crease. Moreover, decyl pseudopeptides, with or without an
To evaluate their gelator properties, gel-to-solution tran-
EO spacer, decrease the surface tension to 35 mNm–1. Sur- sition temperatures were estimated by using the inversion
face tension measurements allowed us also to estimate the method (Table 4). Compounds 3g,h or 4g,h were thus
main area per molecule A [Equation (1)] of the adsorbed placed in small vials, and an aqueous solution of appropri-
cationic surfactant, from the inverse of Γ calculated accord- ate pH was added. Mixtures (6%w/v) were heated to 60 °C
ing to the Gibbs equation.
for 10 min and then allowed to stand for 30 min (unless
Table 3. CMC values of the various trimodulus amphiphiles in aqueous solutions.
Compound
CMC [mM]
Compound
CMC [mM]
β-Ala-His-C10 (6a)
β-Ala-His-aEO2e-C10 (3d)
β-Ala-His-C12 (6b)
Gly-Gly-His-C10 (5a)
Gly-Gly-His-aEO2e-C10 (4d)
2.4[a]
5.7[a]
1.1[b]
5.7[a]
8.9[a]
β-Ala-His-aEOe-C10 (3b)
β-Ala-His-aEO3a-C10 (3f)
β-Ala-His-aEO3a-C12 (3g)
Gly-Gly-His-C12 (5b)
3.3[a]
9.8[b]
2.8[b]
3.0[b]
4.6[b]
Gly-Gly-His-aEO3a-C12 (4g)
[a] CMC values were determined by spectrofluorimetry at 25 °C, pH 2. [b] CMC values were determined by surface tension measurements
at 25 °C, pH 2.
Figure 4. Surface tension curves γ = f(logC) at pH 2.
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Molecular Tailored Histidine-Based Complexing Surfactants
otherwise specified) at 20 °C. The vials were then turned highly anisotropic fibrous networks. Deeper insight into the
upside down, and samples were considered successfully characteristics of these gels will be reported elsewhere and
gelled if the solvent was completely immobilized. Indeed, their use as “soft space organizers” and aligner molecules
as reported in the literature,[22] when the hot solution is co- as well as the formation of supramolecular architectures
oled, the molecules start to condense and three situations through molecularly controlled self-assembling is currently
are possible: (i) a highly ordered aggregation giving rise to under investigation.
crystals, (ii) a random aggregation resulting in an amorph-
ous precipitate, or (iii) an aggregation process intermediate
Conclusions
between these two, yielding a gel. In our case, the appropri-
ate balance between hydrophilic and hydrophobic modulus,
as well as the appropriate number of H-donor and H-
acceptor centers seems to be responsible for the gelation
phenomenon.
In summary, we reported herein the modular synthesis of
new His-based surfactants containing trifunctional building
blocks. Slight modifications of each part as well as the na-
ture of the spacer in between (ester or amide) induced con-
siderable changes on their self-assembling properties, the re-
sults reaching from micelles to hydrogels. Moreover, we as-
sessed the gelation properties of new LMWGs based on
His-containing peptides and could show that they are due
to weak noncovalent interactions, which thereby create
highly anisotropic supramolecular hydrogels. As a result of
their complexing properties, these compounds are suitable
candidates for selective binding of biologically relevant cat-
ions such as Cu2+ or Ni2+, and therefore, they can be used
in a straightforward approach for the design of bioactive
formulations and, more particularly, for oxidation stress
problems.
Table 4. Gel-to-solution transition temperatures of the trimoduli
“amide–amide” amphiphiles in aqueous solutions (pH 8).
Compound
Gly-Gly-His-aEO3a-Cn
β-Ala-His-aEO3a-Cn
n
12 (4g)
26
14(4h)
35
12(3g)
31
14(3h)
42
Tgel [°C]
Polarized optical microscopy (POM) of the hydrogel re-
vealed the presence of entangled fibers (Figure 5). Deeper
insight into the morphology of these fibers was obtained
from scanning electron microscopy (SEM; Figure 6). The
micrographs show bundles containing thin (less than
100 nm) aligned fibers that form the gel. The fibers are hun-
dreds of micrometers long but less than 1 µm wide, and
water molecules are trapped in the interstitial spaces. Upon
gelation, it seems that 1D fiber-like self-assembly of these
low-molecular weight molecules results in the formation of
Experimental Section
Materials: All solvents were reagent grade and used without further
purification. All reagents were obtained from Aldrich and used
without further purification. BOP [benzotriazole-1-yloxytris(dime-
thylamino)phosphonium hexafluorophosphate] was supplied from
Neosystem. Stock solutions of metal perchlorates (Alpha Ventron
products) were standardized by complexometry.
Methods: The purity of products was checked by NMR spectro-
scopic measurements, elemental analysis, and acid–base titrations.
1H and 13C NMR spectroscopic data were recorded with a Bruker
AM-400 spectrometer. SEM micrographs of dried samples were
registered with a Hitachi FEG S4800 microscope.
Fluorescence emission spectra were recorded by employing an exci-
tation wavelength of 334 nm by using pyrene as a probe, and the
intensities I1 and I3 were measured at wavelengths corresponding
to the first and third vibronic bands located at ca. 373 and 384 nm.
The ratios I1/I3 were plotted as a function of the total surfactant
concentration. The CMC was taken from the best fit of the par-
tition between the micelle and water, corresponding approximately
to the abrupt decrease scale I1/I3 ratio as represented in Figure 1
(see Supporting Information). The fluorescence measurements were
recorded with a Fluorolog-3 Horiba-Jobin Yvon spectrofluorime-
ter.
Figure 5. POM of 1% (w/v) supramolecular hydrogel of 3g (left)
and 3h (right) indicating fiber bundles.
The coordination equilibria were investigated by potentiometric ti-
trations under an argon atmosphere. For the equilibrium measure-
ments, a PC-controlled full automatic titration set was used, includ-
ing a potentiometric titrator Metrohm (721Net titrino) and an
Orion 710 pH meter (precision 0.1 mV). The ionic strength was
adjusted to 0.1 moldm–3 with NaClO4 and the cell was thermostat-
ted to 298.0Ϯ0.1 K. Changes in pH were followed by using a
Thermo (ref Orion 9103SC) combined glass electrode. For the
quantitative evaluation of the data, a correlation [Equation (2)] was
Figure 6. SEM micrographs of 3h hydrogels after drying.
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used between the experimental electromotive force values (E) and
the equilibrium hydrogen ion concentrations [H+], where jH and
jOH are fitting parameters in acidic and alkaline media for the cor-
rection of experimental errors, mainly due to the liquid junction
potential and to the possible alkaline and acidic errors of the glass
electrode, and Kw is the autoprotolysis constant of water[23]
(10–13.75).
C12H26ClNO3 (267.78): calcd. C 53.82, H 9.78; found C 54.01, H
10.20.
1
1c: Yield: 1.34 g, 80%. M.p. 90 °C. IR, H NMR, and 13C NMR
spectral data are identical to those of 1b. C6H14ClNO2 (168.58):
calcd. C 42.99, H 8.37; found C 43.01, H 8.50.
1d: Yield: 2.21 g, 75%. IR (KBr): Data are identical to those of 1b.
1H NMR (400 MHz, CD3OD): δ = 0.90 (t, 3J = 6.5 Hz, 3 H, CH3)
1.2–1.4 (m, 12 H, CH2 fatty chain) 1.62 (m, 2 H, CH2 in β of CO)
2.34 (t, 3J = 7.5 Hz, 2 H, CH2CO) 3.12 (t, 3J = 5 Hz, 2 H,
CH2NH3+), 3.72 (m, 4 H, CH2O) 4.26 (t,3J = 5 Hz, 2 H, CH2OCO)
ppm. 13C NMR (100.58 Hz, CD3OD): δ = 15.3 (CH3) 24–35 (CH2
fatty chain) 35.7 (CH2 in α of CO) 41.4 (CH2NH3+) 65.1
(2)
The formation constants (βpqr) for the generalized reaction given
in Equation (3) were evaluated from the pH-metric titration data
with the PSEQUAD computer program.[24] In this notation, L is
the neutral ligand, consequently the fully protonated ligands are
referred to as LH2. The metal-promoted deprotonation of the neu-
tral ligand or, equivalently, the formation of mixed hydroxido com-
plexes are denoted as MLH–1 and MLH–2. The constants were cal-
culated from an average of six independent titrations. The metal-
to-ligand ratio was varied from 1:1 to 1:4 with metal-ion concentra-
tions between 5ϫ10–3 and 2ϫ10–3 moldm–3.
(CH2OCO) 68.6 and 71.1 (CH2O) 176.2 (C
= 0) ppm.
C14H30ClNO3 (295.83): calcd. C 56.84, H 10.22; found C 57.02, H
9.99.
1
1e: Yield: 1.49 g, 70%. IR, H NMR, and 13C NMR spectral data
are identical to those of 1d. C8H18ClNO3 (211.69): calcd. C 45.39,
H 8.57; found C 45.10, H 8.35.
Alkylamido[2-Aminoethoxyethoxy]ethyl Hydrochlorides (1f–h)
Step 1: Amino-ethoxy-ethoxy-ethyl-triphenyl-methylamine: In a 500-
mL flask placed in an ice bath, chlorotriphenylmethane (7.5 g,
27 mmol, 1 equiv.) was added in small portions, over 1 h, to a solu-
tion of (ethylendioxy)bisethylamine (47.4 g, 320 mmol, 12 equiv.) in
chloroform (200 mL). During addition, the reaction mixture was
stirred at 5–10 °C. Then, room temperature was reached, and the
pM + qL + rH = MpLqHr
(3)
N-[2-(2-hydroxyethoxy)ethyl]decanamide (1a): A mixture of dec-
anoic acid (10 mmol) and 2-(2-aminoethoxy)ethanol (1 equiv.) was
homogenized by heating and then exposed to microwave irradiation
for 3 min. After cooling to room temperature, the syrup was dis-
persed in ethyl acetate (50 mL) and successively washed with a satu-
rated aqueous solution of NaHCO3 (30 mL) and a saturated solu-
tion of NaCl (2ϫ30 mL). The organic phase was dried with
MgSO4, and the solvent was removed under reduced pressure. The
white powder was recrystallized from Et2O. Yield: 2.35 g, 90%.
solution was washed with
a saturated solution of NaCl
(2ϫ100 mL) and dried with MgSO4. The solvent was then re-
moved under vacuum, and the crude product was purified by silica
gel chromatography (AcOEt/MeOH) to give a colorless solid (9.4 g,
24 mmol, 90%). IR (KBr): ν = 3382, 1120, 1094, 743, 703 cm–1. 1H
˜
NMR (400 MHz, CD3OD): δ = 1.35 (br. s, 3 H, NH and NH2),
3
3
M.p. 70 °C. R (EtOH/AcOEt, 1:5) = 0.65. IR (KBr): ν = 2910,
2.02 (t, J = 5.2 Hz, 2 H, CH2 in α of NH2), 2.53 (t, J = 5.2 Hz,
2 H, CH2 in α of NH), 3.20–3.50 (m, 8 H, CH2), 7.00–7.50 (m, 15
˜
f
1633, 1560, 1130 cm–1. 1H NMR (400 MHz, CD3OD): δ = 0.94
(t,3J = 6.5 Hz, 3 H, CH3) 1.2–1.4 (m, 12 H, CH2 fatty chain) 1.64 H, Ar-H) ppm. 13C NMR (100.58 MHz, CDCl3): δ = 42.0 (CH2 in
3
(m, 2 H, CH2 in β of CO) 2.29 (t, J = 7.5 Hz, 2 H, CH2CO) 3.40
α of NH2), 43.3 (CH2 in α of NH), 70.4, 70.6, 71.5, 73.6 (CH2),
(t, 3J = 5 Hz, 2 H, CH2NH) 3.57 (m, 4 H,CH2O) 3.71 (t, 3J = 5 Hz, 126.5, 128.1, 129.0 (Ar), 146.4 (Cq) ppm. C25H30N2O2 (392.61):
2 H, CH2OH) ppm. 13C NMR (100.58 MHz, CD3OD): δ = 15.2 calcd. C 76.48, H 7.70; found C 76.95, H 7.50.
(CH3) 24–37.5 (CH2 fatty chain) 37.9 (CH2 in α of CO) 41.1
Step 2: Condensation of Fatty Acid: To a 250-mL flask was added
(CH2NH) 63 (CH2OH) 71.4 and 74.2 (CH2O) 177.2 (C=O) ppm.
a solution of the fatty acid (10 mmol, 1 equiv.) in CH3CN (50 mL),
C14H29NO3 (261.41): calcd. C 64.32, H 11.18; found C 64.10, H
BOP (4.42 g, 10 mmol, 1 equiv.), triethylamine (2.02 g, 20 mmol,
11.50.
2 equiv.), and amino-ethoxy-ethoxy-ethyl-triphenyl-methylamine
Salts 1b–e: To a 250-mL flask equipped with a Dean Stark and
containing a solution of alcanoic acid (10 mmol) in toluene was
added 2-(2-aminoethoxy)ethanol (10 mmol) and para-toluenesul-
fonic acid (11 mmol). The mixture was stirred and with azeotropic
reflux for 18 h. Then, room temperature was reached, and the solu-
tion was concentrated to 50% of its volume. Compounds 1b–e pre-
cipitated as white powders. The precipitate was separated by fil-
tration, washed by ethyl acetate and recrystallized from ethyl ace-
tate. The powder was dispersed in anhydrous Et2O (100 mL) and
then treated with anhydrous HCl (g) obtained from the reaction of
NaCl (40 g) with a mixture of concentrated H2SO4 (36 mL) and
H2O (16 mL). After removal of the solvent, a white powder was
obtained.
(3.9 g, 10 mmol, 1 equiv.). The pH of the solution was brought to
ca. 8 by the addition of triethylamine, if necessary. The reaction
mixture was stirred at room temperature for 15 h. Evaporation of
the solvent under reduced pressure afforded an orange viscous li-
quid, which was solubilized in ethyl acetate (30 mL) and washed
successively with HCl (0.1 , 20 mL), saturated NaHCO3 (20 mL),
and saturated NaCl (2ϫ20 mL). Then, the organic phase was dried
with MgSO4, and the solvent was removed under reduced pressure.
The triphenylmethyl moiety was removed after treatment with a
mixture of CH2Cl2 (15 mL), THF (40 mL), and HCl (37%, 40 mL).
The solvent mixture was then removed, and the crude material was
purified by recrystallization from CH3CN. The white powder was
dried under vacuum to give 1f–h.
1b: Yield: 2.12 g, 81%. M.p. 80 °C. IR (KBr): ν = 3080, 2921, 1f: Yield: 2.35 g, 69%. IR (KBr): ν = 3256, 2921, 1633 cm–1. 1H
˜
˜
1739 cm–1. 1H NMR (400 MHz, CD3OD): δ = 0.90 (t, 3J = 6.5 Hz,
NMR (400 MHz, CD3OD): δ = 0.94 (t, 3J = 6.5 Hz, 3 H, CH3),
3 H, CH3) 1.2–1.4 (m, 12 H, CH2 fatty chain) 1.6 (m, 2 H, CH2 in 1.20–1.40 (m, CH2 fatty chain), 1.64 (m, 2 H, CH2 in β of CO),
3
3
3
3
β of CO) 2.28 (t, J = 7.5 Hz, 2 H, CH2CO) 3.01 (t, J = 5 Hz, 2
2.23 (t, J = 6.5 Hz, 2 H, CH2 in α of CO), 2.96 (t, J = 5 Hz, 2
H, CH2NH3+) 4.32 (t, 3J = 5 Hz, 2 H, CH2O) ppm. 13C NMR H, CH2 in α of NH3+), 3.4 (t, J = 5 Hz, 2 H, CH2 in α of NH),
(100.58 MHz, CD3OD): δ = 15.3 (CH3) 24–35 (CH2 fatty chain)
35.2 (CH2CO) 40.2 (CH2 NH3+) 67.1 (CH2O) 176.4 (C = 0) ppm. H, CH2 in β of NH), 3.68 (s, 4 H, CH2-O) ppm. 13C NMR
3
3
3
3.58 (t, J = 5 Hz, 2 H, CH2 in β of NH3+), 3.63 (t, J = 5 Hz, 2
3960
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3953–3963

Molecular Tailored Histidine-Based Complexing Surfactants
(100.58 MHz, CDCl3): δ = 15.3 (CH3), 22–38 (8 CH2), 40.9 and (CH=C), 134 (C=NH), 137.18 (C=CH) 175 and 176 (C=O) ppm.
+
41.5 (CH2 in α of NH3 and CH2 in α of NH), 68–72 (4 CH2-O),
177.2 (C=O) ppm. C16H35ClN2O3 (338.9): calcd. C 56.70, H 10.41;
found C 56.23, H 9.95. M.p. 156 °C.
C18H34Cl2N4O3 (425.40): calcd. C 50.82, H 8.06; found C 49.98, H
7.62.
1
2c: Yield: 1.70 g, 75%. IR, H NMR, and 13C NMR spectral data
1g: Yield: 2.80 g, 76%. M.p. 120 °C. IR, H NMR, and 13C NMR
1
are identical to those of 2b. C12H22Cl2N4O3 (341.24): calcd. C
spectral data are identical to those of 1f. C18H39ClN2O3 (366.97):
42.24, H 6.50; found C 41.98, H 6.85.
calcd. C 58.91, H 10.71; found C 59.23, H 10.84.
2d: Yield: 2.92 g, 80%. M.p. 125 °C, 1H NMR (400 MHz,
CD3OD): δ = 0.90 (t, 3J = 6.5 Hz, 3 H, CH3), 1.2–1.4 (m, CH2
1
1h: Yield: 3.38 g, 85%. M.p. 80 °C. IR, H NMR, and 13C NMR
3
spectral data are identical to those of 1f. C20H43ClN2O3 (398.06).
fatty chain), 1.62 (m, 2 H, CH2 in β of CO), 2.34 (t, J = 7.5 Hz,
3
2 H, CH2 in α of CO), 3.12 (t, J = 5 Hz, 2 H, CH2NH), 3.37 (m,
Decylamido-ethoxy-ethyl Histidinoate Hydrochloride (2a): To a 250-
mL flask was added a solution of Boc-His (2 g, 7.8 mmol, 1 equiv.)
in CH3CN (50 mL), BOP (3.45 g, 7.8 mmol, 1 equiv.), triethylamine
(2.36 g, 23.4 mmol, 3 equiv.), and 1a (7.8 mmol, 1 equiv.). The reac-
tion mixture was stirred at room temperature for 15 h. Evaporation
of the solvent under reduced pressure afforded a syrupy liquid that
was solubilized in ethyl acetate (30 mL) and washed successively
with HCl (0.1 , 20 mL), saturated solution of NaCl (20 mL), satu-
rated solution of NaHCO3 (20 mL), and saturated solution of
NaCl (2ϫ20 mL). Then, the organic phase was dried with MgSO4,
and the solvent was removed under reduced pressure. The white
powder was washed with diethyl ether. Powder was dispersed in
anhydrous ether and then treated with anhydrous HCl (g) obtained
from the reaction of concentrate H2SO4 (30 mL) and NaCl (40 g) in
water (10 mL). The final product was a hygroscopic powder. Yield:
3.03 g, 83%. C20H38Cl2N4O4 (469.37): calcd. C 51.17, H 8.15;
2 H, CH2 Im), 4.26 (t, 3J = 5 Hz, 2 H, CH2OCO) 4.34 (t, 3J =
7 Hz, 1 H, CH-NH3+), 6.97 (s, 1 H, CH=C), 7.51 (s, 1 H, CH=N)
ppm. 13C NMR (100.58 MHz, CDCl3): δ = 15.3 (CH3), 23–36 (CH2
fatty chain), 34.7 (CH2CO), 42.7 (CHNH3+), 55.6 (CH2NHCO),
63.8 (CH2OCO), 70–71 (CH2O) 118.2 (CH=C), 133.4 (C=NH),
137.2 (C=CH) 175 and 176 (C=O) ppm. C20H37Cl2N4O4 (468.44):
calcd. C 51.25, H 7.95; found C 50.98, H 7.62.
1
2e: Yield: 2.02 g, 70%. IR, H NMR, and 13C NMR spectral data
are identical to those of 2d. C14H26Cl2N4O3 (369.14): calcd. C
45.53, H 7.10; found C 45.35, H 7.42.
2f: Yield: 3.16 g, 81%. M.p. 170 °C. IR (KBr): ν = 3291, 2921,
˜
1
3
1648, 1633 cm–1. H NMR (400 MHz, CD3OD): δ = 0.94 (t, J =
6.5 Hz, 3 H, CH3), 1.2–1.4 (m, CH2 fatty chain), 1.63 (m, 2 H, CH2
3
in β of CO), 2.25 (t, J = 7 Hz, 2 H, CH2 in α of CO), 3.4–3.7 (m,
12 H, CH2), 4.28 (t, 3J = 6.7 Hz, 1 H, CH-NH3+), 7.58 (s, 1 H,
CH=C), 8.97 (s, 1 H, CH=N) ppm. 13C NMR (100.58 MHz,
CDCl3): δ = 15.3 (CH3), 22–38 (CH2 long chain and CH2 of His),
40.9 and 41.5 (2 CH2 in α of NH), 55.7 (CH-NH3+), 68–72 (4 CH2-
O), 118.2 (CH=C), 133.4 (CH=N), 137.2 (Cq), 175–176 (2 C=O)
ppm. C21H43Cl2N5O4 (500.46): calcd. C 50.39, H 8.66; found C
49.98, H 8.22.
found C 50.67, H 7.95. M.p. 130 °C. IR (KBr): ν = 3310, 2921,
˜
1
1739, 1642, 1121 cm–1. H NMR (400 MHz, CD3OD): δ = 0.94 (t,
3J = 6.5 Hz, CH3) 1.2–1.4 (m, 12 H, CH2 fatty chain) 1.63 (m, 2
3
H, CH2 in β of CO) 2.24 (t, J = 7.5 Hz, 2 H, CH2CO) 3.40 (m, 2
H, CH2 Im) 3.47 (t, 3J = 5 Hz, CH2NH) 3.73 (t, 3J = 5 Hz, CH2O)
4.3–4.6 (m, 3 H, CH2OCO, CH His) 7.59 (s, 1 H, CH Im) 7.74 (s,
1 H, CH Im) ppm.
1
2g: Yield: 3.73 g, 88%. M.p. 134 °C. IR, H NMR, and 13C NMR
Alkyl-amido-ethoxy-ethoxy-ethylamidohistidine
Dihydrochloride
spectral data are identical to those of 2f. C24H47Cl2N5O4 (540.53):
(2b–h): To a 250-mL flask was added a solution of Boc-His (2 g,
7.8 mmol, 1 equiv.) in CH3CN (50 mL), BOP (3.45 g, 7.8 mmol,
1 equiv.), triethylamine (2.36 g, 23.4 mmol, 3 equiv.), and 2b–h
(7.8 mmol, 1 equiv.). The reaction mixture was stirred at room tem-
perature for 15 h. Compounds 2g–h precipitated as white powders.
The precipitate was separated by filtration, washed with CH3CN
(50 mL) and Et2O (50 mL) and then recrystallized from acetoni-
trile. Compounds 2b–f did not precipitate. Evaporation of the sol-
vent under reduced pressure afforded a syrupy liquid that was solu-
bilized in ethyl acetate (30 mL) and washed successively with HCl
(0.1 , 20 mL), saturated solution of NaCl (20 mL), saturated solu-
tion of NaHCO3 (20 mL), and saturated solution of NaCl
(2ϫ20 mL). Then, the organic phase was dried with MgSO4, and
the solvent was removed under reduced pressure. The mixture was
dried with MgSO4, the solvent was removed under reduced pres-
sure, and the white powder was washed with Et2O and filtered. For
all compounds, the powders were dispersed in anhydrous ether and
then treated with anhydrous HCl (g) obtained from the reaction of
concentrated H2SO4 (30 mL) and NaCl (40 g) in water (10 mL).
The final products were hygroscopic white solids.
calcd. C 53.33, H 8.76; found C 53.25, H 8.45.
1
2h: Yield: 3.99 g, 90%. M.p. 112 °C. IR, H NMR, and 13C NMR
spectral data are identical to those of 2f. C26H51Cl2N5O4 (568.58):
calcd. C 54.92, H 9.04; found C 54.55, H 8.65.
Alkyl-amido-ethoxy-ethoxy-ethylamido-β-alanyl-histidine Dihydro-
chloride (3a–h): The procedure was similar to that used for the
preparation of 2b–f. Boc-β-alanine was used to replace Boc-His.
3a: Yield: 3.29 g, 82%. M.p. 150 °C. IR (KBr): ν = 3250, 2921,
˜
1737, 1646, 1620, 1122 cm–1. 1H NMR (400 MHz, CD3OD): δ =
3
0.92 (t, J = 6.5 Hz, 3 H, CH3) 1.2–1.4 (m, 12 H, 6CH2) 1.62 (m,
3
2 H, CH2 in β of CO) 2.24 (t, J = 7.5 Hz, 2 H, CH2CO) 2.72 (t,
3J
= 7.5 Hz, 2 H, CH2CO β-alanine) 3.15–3.30 (m, 4 H,
3
CH2NHCO and CH2 Im) 3.44 and 3.57 (t, J = 5 Hz, CH2O) 3.70
(t, 3J = 7.5 Hz, 2 H, CH2NH3+) 4.30 (t, 3J = 6.5 Hz, CH2OCO)
3
4.76 (t, J = 7.5 Hz, CH His), 7.41 and 7.88 (s, 1 H, CH Im) ppm.
C23H43Cl2N5O5 (543.34): calcd. C 50.82, H 7.97; found C 50.35, H
7.60.
3b: Yield: 3.11 g, 82%. M.p. 146 °C, IR (KBr): ν = 3240, 2926,
˜
2b: Yield: 2.73 g, 82%. M.p. 120 °C. IR (KBr): ν = 3304, 2921, 1739, 1648, 1621 cm–1. H NMR (400 MHz, CD3OD): δ = 0.90 (t,
1
˜
1
3
1739, 1648 cm–1. H NMR (400 MHz, CD3OD): δ = 0.90 (t, J = 3J = 6.5 Hz, 3 H, CH3), 1.2–1.4 (m, CH2 fatty chain), 1.62 (m, 2
3
6.5 Hz, 3 H, CH3), 1.2–1.4 (m, CH2 fatty chain), 1.62 (m, 2 H, CH2
H, CH2 in β of CO), 2.48 (t, J = 7.5 Hz, 2 H, CH2 in α of CO),
3
3
in β of CO), 2.34 (t, J = 7 Hz, 2 H, CH2 in α of CO), 3.01 (t, J 2.72 (t, 3J = 7.5 Hz, 2 H, CH2CO β-alanine) 3.29 (m, 2 H, CH2
3
= 5 Hz, 2 H, CH2NH), 3.37 (m, 2 H, CH2 Im), 4.24 (t, J = 7 Hz, Im), 3.41 (t, 3J = 5 Hz, 2 H, CH2NH), 3.70 (t, 3J = 7 Hz, 1 H, CH-
1 H, CH-NH3+), 4.32 (t, J = 5 Hz, 2 H, CH2OCO) 7.02 (s, 1 H, NH3+), 4.33 (m, 2 H, CH2OCO) 4.74 (t, 3J = 7.5 Hz, 1 H, CH
3
CH=C), 7.45 (s, 1 H, CH=N) ppm. 13C NMR (100.58 MHz,
His) 7.02 (s, 1 H, CH=C), 7.45 (s, 1 H, CH=N) ppm. 13C NMR
CDCl3): δ = 15.3 (CH3), 23–36 (CH2 fatty chain), 35.2 (CH2CO), (100.58 MHz, CDCl3): δ = 15.3 (CH3), 23–36 (CH2 fatty chain),
54.3 (CHNH3+), 55.2 (CH2NHCO), 63.8 (CH2OCO), 118.82 37.7 (CHNH3+), 52.3 (CH His), 55.3 (CH2NHCO), 63.6
Eur. J. Org. Chem. 2009, 3953–3963
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3961

P. Gizzi, A. Pasc, N. Dupuy, S. Parant, B. Henry, C. Gérardin
FULL PAPER
3
(CH2OCO), 120.3 (CH=C), 130.2 (C=NH), 147 (C=CH), 170 and 0.90 (t, J = 6.5 Hz, 3 H, CH3), 1.2–1.4 (m, CH2 fatty chain), 1.62
3
176 (C=O) ppm. C21H40Cl2N5O4 (500.28): calcd. C 50.41, H 8.06,
N 14.11; found C 50.61, H 7.87, N 13.92.
(m, 2 H, CH2 in β of CO), 2.21 (t, J = 7.5 Hz, 2 H, CH2 in α of
CO), 3.29 (m, 2 H, CH2 Im), 3.41 (t, 3J = 5 Hz, 2 H, CH2NH),
3.78 (s, 2 H, CH2 Gly), 4.12 (s, 2 H, CH2NH3+) 4.34 (m, 2 H,
CH2OCO) 4.45 (m, 1 H, CH His) 7.42 (s, 1 H, CH=C), 7.83 (s, 1
H, CH=N) ppm. 13C NMR (100.58 MHz, CDCl3): δ = 15.3 (CH3),
23–36 (CH2 fatty chain and CH2 Gly), 44.1 (CHNH3+), 52.3 (CH
His), 55.3 (CH2NHCO), 63.6 (CH2OCO), 120.3 (CH=C), 130.2
(C=NH), 147.1 (C=CH) 170 and 176 (C=O) ppm. C22H40Cl2N6O5
(542.29): calcd. C 48.72, H 7.43, N 15.58; found C 48.62, H 7.38,
N 15.32.
3c: Yield: 2.51 g, 78%. IR, H NMR, and 13C NMR spectral data
are identical to those of 3b. C15H27Cl2N5O4 (412.32): calcd. C
43.70, H 6.60; found C 44.01, H 6.45.
1
3d: Yield: 3.56 g, 84%. M.p. 150 °C. 1H NMR (400 MHz,
CD3OD): δ = 0.90 (t, 3J = 6.5 Hz, 3 H, CH3), 1.2–1.4 (m, CH2
fatty chain), 1.62 (m, 2 H, CH2 in β of CO), 2.48 (t, J = 7.5 Hz,
3
3
2 H, CH2 in α of CO), 2.72 (t, J = 7.5 Hz, 2 H, CH2NH), 3.15–
3.30 (m, 4 H, CH2 Im and CH2NHCO), 3.42 and 3.57 (t, 3J =
1
4c: Yield: 2.85 g, 80%. IR, H NMR, and 13C NMR spectral data
5 Hz, 2 H, CH2O) 3.70 (t, J = 7.5 Hz, 2 H, CH2NH3+) 4.25 (t, J
3
3
are identical to those of 4b.C16H28Cl2N6O5 (455.34): calcd. C 42.20,
H 6.20; found C 42.25, H 6.45.
= 6.5 Hz, 2 H, CH2OCO) 4.75 (t, 3J = 7 Hz, 1 H, CH-NH3+), 7.41
(s,
1 H, CH=C), 7.88 (s, 1
H, CH=N) ppm. 13C NMR
4d: Yield: 3.73 g, 82%. M.p. 152 °C. 1H NMR (400 MHz,
CD3OD): δ = 0.90 (t, 3J = 6.5 Hz, 3 H, CH3), 1.2–1.4 (m, CH2
(100.58 MHz, CDCl3): δ = 15.3 (CH3), 23–36 (CH2 fatty chain),
37.7 (CH2NH3+), 39.2 (CH2OCO) 52.3 (CHNH3+), 63.5
(CH2NHCO), 70 and 71 (CH2O) 120.1 (CH=C), 130.2 (C=NH),
147.1 (C=CH) 170 and 176 (C=O) ppm. C23H43Cl2N5O5 (543.54):
calcd. C 50.82, H 7.97, N 12.96; found C 50.91, H 7.88, N 12.89.
3
fatty chain), 1.62 (m, 2 H, CH2 in β of CO), 2.21 (t, J = 7.5 Hz,
3
2 H, CH2 in α of CO), 3.30 (m, 2 H, CH2 Im), 3.45 (t, J = 5 Hz,
3
CH2NHCO) 3.58 and 3.71 (t, J = 5 Hz, 4 H, CH2O) 3.77 (s, 2 H,
+
CH2 Gly) 3.99 (s, 2 H, CH2NH3 Gly) 4.32 (m, 2 H, CH2OCO)
3e: Yield: 2.57 g, 72%. IR, H NMR, and 13C NMR spectral data
are identical to those of 3d.C17H31Cl2N5O5 (456.37): calcd. C
44.74, H 6.85; found C 45.10, H 6.45.
1
4.82 (m, 1 H, CH His), 7.44 (s, 1 H, CH=C), 7.84 (s, 1 H, CH=N)
ppm. 13C NMR (100.58 MHz, CDCl3): δ = 15.3 (CH3), 23–36 (CH2
fatty chain and CH2 Gly) 39.2 (CH2OCO) 43.7 (CHNH3+) 53.3
(CH His) 63.5 (CH2NHCO) 70 and 71 (CH2O) 120.1 (CH=C)
130.0 (C=NH), 147.0 (C=CH) 170–176 (C=O) ppm.
C24H44Cl2N6O6 (583.50): calcd. C 49.40, H 7.60, N 14.40; found C
48.92, H 7.48, N 14.12.
3f: Yield: 3.98 g, 87%. M.p. 220 °C. IR (KBr): ν = 3245, 2916,
˜
1
1681, 1643, 1623 cm–1. H NMR (400 MHz, CD3OD): δ = 0.94 (t,
3J = 6.5 Hz, 3 H, CH3), 1.33 (m, CH2 fatty chain), 1.63 (m, 2 H,
3
CH2 in β of CO), 2.23 (t, J = 7 Hz, 2 H, CH2 in α of CO), 2.74
(m, 2 H, CH2 in β of NH3+), 3.20–3.40 (m, 8 H, 2 CH2NH, CH2
Im and CH2NH3+), 3.58 (t, 3J = 5 Hz, 2 H, CH2), 3.66 (s, 4 H,
CH2), 4.75 (t, 3J = 6.6 Hz, 1 H, CH), 7.44 (s, 1 H, CH=C), 8.89 (s,
1 H, CH=N) ppm. 13C NMR (100.58 MHz, CDCl3): δ = 15.5
(CH3), 24–38 (CH2), 41.4 (CH2-NH3+), 54.5 (CH), 71–72 (4 CH2-
O), 119.2 (CH=C), 131.7 (CH=N), 135.7 (Cq), 172–177 (3 C=O)
ppm. C25H48Cl2N6O5 (583.60): calcd. C 51.45, H 8.29, N 14.40;
found C 50.97, H 8.18, N 14.12. C25H48Cl2N5O5 (586.96): calcd. C
51.15, H 8.29, N 14.40; found C 50.97, H 8.18, N 14.12.
1
4e: Yield: 2.81 g, 72%. IR, H NMR, and 13C NMR spectral data
are identical to those of 4d. C18H32Cl2N6O6 (499.39): calcd. C
43.29, H 6.46; found C 43.76, H 6.82.
4f: Yield: 4.22 g, 86%. M.p. 219 °C. IR (KBr): ν = 3286, 2916,
˜
1685–1620 cm–1 (4 νCO). H NMR (400 MHz, CD3OD): δ = 0.89
1
(t, 3J = 6.5 Hz, 3 H, CH3), 1.20–1.40 (m, CH2 fatty chain), 1.60
(m, 2 H, CH2 in β of CO), 2.23 (t, 3J = 7 Hz, 2 H, CH2 in α of
CO), 3.10–3.45 (m, 6 H, 2 CH2NH and CH2 Im), 3.50–3.60 (m, 4
H, CH2 in β of NH), 3.63 (s, 4 H, CH2O), 3.81 (s, 2 H, CH2 Gly),
1
3g: Yield: 4.17 g. 87%. M.p. 198 °C. IR, H NMR, and 13C NMR
3.94 (s, 2 H, CH2NH3+), 4.28 (t, J = 6.7 Hz, 1 H, CH), 7.42 (s, 1
3
spectral data are identical to those of 3f. C27H52Cl2N6O5 (611.65):
calcd. C 53.02, H 8.57, N 13.74; found C 52.92, H 8.49, N 13.68.
H, CH=C), 8.83 (s, 1 H, CH=N) ppm. 13C NMR (100.58 MHz,
CDCl3): δ = 15.2 (CH3), 24–38 (CH2), 44.5 (CH2-NH3+), 54.5
(CH), 71–72 (4 CH2-O), 119.4 (CH=C), 131.8 (CH=N), 137.2 (Cq),
169–178 (4 C=O) ppm. C26H49Cl2N7O6 (626.62): calcd. C 49.84, H
7.88, 15.65; found C 50.07, H 7.99, N 15.76. C26H49Cl2N7O6
(630.05): calcd. C 49.56, H 7.84, N 15.65; found C 50.07, H 7.99,
N 15.76.
1
3h: Yield: 4.61 g, 92%. M.p. 224 °C. IR, H NMR, and 13C NMR
spectral data are identical to those of 3f. C29H56Cl2N6O5 (639.70):
calcd. C 54.45, H 8.82, N 13.14; found C 54.62, H 8.92, N 13.29.
Alkyl-amido-ethoxy-ethoxy-ethylamidoglycyl-glycyl-histidine Dihy-
drochloride (4a–h): The procedure was similar to that used for the
preparation of 3. Boc-glycyl-glycine was used to replace Boc-β-Ala-
nine.
4g: Yield: 4.36 g, 85%. M.p. 210 °C. IR, H NMR, and 13C NMR
spectral data are identical to those of 4f. C28H53Cl2N7O6 (654.68):
1
calcd. C 51.37, H 8.16, N 14.98; found C 51.02, H 8.36, N 14.88.
4a: Yield: 3.70 g, 81%. M.p. 140 °C. IR (KBr): ν = 3225, 2921,
˜
1739, 1683, 1653, 1618 cm–1. 1H NMR (400 MHz, CD3OD): δ =
1
4h: Yield: 4.82 g, 90%. M.p. 169 °C. IR, H NMR, and 13C NMR
3
0.92 (t, J = 6.5 Hz, 3 H, CH3) 1.2–1.4 (m, 12 H, 6CH2) 1.61 (m,
spectral data are identical to those of 4f. C30H57Cl2N7O6 (682.73):
calcd. C 52.78, H 8.42, N 14.36; found C 52.67, H 8.48, N 14.26.
3
2 H, CH2 in β of CO) 2.22 (t, J = 7.5 Hz, 2 H, CH2CO) 3.35 (m,
3
3
2 H, CH2 Im) 3.45 (t, J = 5 Hz, 2 H, CH2O) 3.58 and 3.71 (t, J
Supporting Information (see footnote on the first page of this arti-
cle): Dependence of relative fluorescence intensity I/I0 of pyrene on
different “amide–ester” surfactant concentrations; hydrolysis of the
“amide–ester” trimoduli amphiphiles as followed by 1H NMR
+
= 5 Hz, 4 H, CH2O) 3.77 (s, 2 H, CH2 Gly) 3.99 (s, 2 H, CH2NH3
Gly) 4.32 (m, 2 H, CH2OCO) 4.79 (m, 1 H, CH His) 7.54 and 7.74
(s, 1 H, CH Im) ppm. 13C NMR (100.58 MHz, CDCl3): δ = 15.2
(CH3), 24–36 (CH2 fatty chain), 42.6 (CH2NHCO) 44.2 (CH2-
1
spectroscopy; temperature-dependent H NMR spectra of 3h.
+
NH3 Gly), 53.8 (CH His), 66.8 (CH2OCO) 71 and 72 (CH2-O),
119.8 (CH=C), 131.4 (CH=N), 135.9 (Cq), 169 and 172 (4 C=O)
ppm. C24H44Cl2N6O6 (586.62): calcd. C 49.14, H 7.56; found C
49.40, H 7.60.
Acknowledgments
4b: Yield: 3.42 g, 81%. M.p. 149 °C. IR (KBr): ν = 3380, 2921, This work is supported by the Institute Jean Barriol, France (pro-
˜
1738, 1686, 1649, 1626 cm–1. 1H NMR (400 MHz, CD3OD): δ = ject PRIME 2008). We would like to thank the “Ministère de l’En-
3962
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3953–3963

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Received: February 11, 2009
Published Online: July 6, 2009
Eur. J. Org. Chem. 2009, 3953–3963
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3963