Towards novel efficient monomeric surfactants based on serine, tyrosine and 4-hydroxyproline: synthesis and micellization properties

Article abstract of DOI:10.1016/j.tet.2009.03.043

The synthesis of some novel monomeric serine- and tyrosine-based cationic and 4-hydroxyproline-based anionic surfactants, having a long lipophilic alkyl chain directly attached to the nitrogen atom of the amino acid, is described. The most efficient synth

Full text of DOI:10.1016/j.tet.2009.03.043

Tetrahedron 65 (2009) 4156–4164
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Towards novel efficient monomeric surfactants based on serine, tyrosine
and 4-hydroxyproline: synthesis and micellization properties
*
´
´
S. Goreti Silva, J. Enrique Rodrıguez-Borges, Eduardo F. Marques, M. Luısa C. do Vale
Centro de Investigaç˜ao em Qu´ımica (UP), Departamento de Qu´ımica, Faculdade de Cieˆncias, Universidade do Porto, R. Campo Alegre, 687, P-4169-007 Porto, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of some novel monomeric serine- and tyrosine-based cationic and 4-hydroxyproline-based
anionic surfactants, having a long lipophilic alkyl chain directly attached to the nitrogen atom of the
amino acid, is described. The most efficient synthetic methodologies were established: reductive ami-
nation of the corresponding ‘fatty’ aldehydes, followed by methylation and deprotection (serine and
tyrosine) to obtain the cationic surfactants; or reductive amination followed by saponification (4-hy-
droxyproline) to obtain the anionic ones. All the compounds were obtained in good to excellent yields.
An assessment of their micellization properties and surface activity by tensiometry showed fairly good
performance levels.
Received 29 January 2009
Accepted 17 March 2009
Available online 26 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
With regard to amino acids, their potential as raw materials for
the preparation of surfactants has been highlighted in the literature.
The interfacial and self-assembly properties of surfactants in
aqueous environments have been investigated for many decades
owing to their basic interest in physical chemistry, biophysics and
material sciences, and enormous practical relevance.1,2Surfactants
find widespread use in inter alia household products, food and
pharmaceutical formulations, oil recovery products, paints and pa-
per. In view of this importance, the synthesis of a great variety of
these compounds, including alkyl phosphates and sulfates, alkyl-
benzene sulfonates, alkyl glycosides and quaternary ammonium
salts, is already well established. However, the ever growing demand
for environmentally friendly speciality surfactants requires the de-
sign of molecules not only with efficient interfacial properties but
also with high levels of biocompatibility and biodegradability. This is
particularly important for surfactants used for cosmetic or bio-
medical purposes (e.g., drug and gene delivery). Natural surfactants
would fulfil these requirements, but the high cost of work-up is an
insuperable disadvantage: the natural products are usually present
in small quantities and the separation process tends to be time-
consuming and inefficient.3 Thus, surfactants containing natural
structural motifsdlike amino acids, sugars and fatty acidsdmade
from renewable raw materials have emerged as alternatives to re-
duce the impact on the environment and to save fossil resources. The
low toxicity, good biocompatibility and fast degradation of many of
these surfactants are the main reasons for the increasing industrial
interest in these compounds.4–10
Initially used as preservatives for medical and cosmetic applications,
they have been found to possess interesting biological activities
(anti-viral, anti-neoplastic, gene delivery/therapy) and excellent
emulsifying properties.5,11–15 Such monomeric surfactants can be
defined as amphiphilic molecules that contain one amino acid res-
idue as the hydrophilic part and a long chain as the lipophilic moiety.
The long chain can be introduced into the amino acid structure
through the a-amino, the a-COOH or the side chain groups, yielding
different types of surfactants. As can be seen in Scheme 1, reaction of
the amino acid with fatty acids gives the corresponding N-acyl de-
rivatives 1 (fattyacid amides of amino acids), while the reactionwith
alkyl halides (SN2) oraldehydes/ketones (reductive amination) gives
the N-alkyl derivates 3. Furthermore, the reaction of amines or al-
cohols on the carboxylic group of the amino acid yields the corre-
spondingN-alkylamidesoresters (2 or 4), respectively.5 Thecationic
surfactants can then be obtained by methylation of the amine
functionality with an alkylating agent (2, 3 and 4) while the anionic
ones can be accessed by saponification (1 and 3). In addition, com-
pounds of type 3 offer the possibility of preparing zwitterionic sur-
factants. The large variety of amino acid as well as fatty acid
structures allows for a diversity of tailored molecules and, conse-
quently, of physicochemical properties.
Most studies on the synthesis and biological evaluation of amino
acid-based surfactants address arginine and lysine derivatives. Ar-
ginine-based cationic surfactants are found to be less toxic than
conventional quaternary ammonium-based surfactants and to be
readily biodegradable; besides, they show excellent emulsifying
properties and strong antimicrobial activity.16,17 Lysine-based an-
ionic/non-ionic surfactants are interesting for their haemolytic
* Corresponding author. Tel.: þ35 122 040 2557; fax: þ35 122 040 2659.
E-mail address: mcvale@fc.up.pt (M.L.C. do Vale).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.03.043

S.G. Silva et al. / Tetrahedron 65 (2009) 4156–4164
4157
structures.24 In this context, we have performed initial studies on
lysine, envisaging the preparation of the corresponding N,N0-dia-
lkanoyl and N,N0-dialkyl derivatives (type 1 and type 3 surfactants,
respectively, see Scheme 1),25 both structures representing pseudo-
gemini (monomeric double-chained) surfactants. However, with
the novel monomeric surfactants herein described, new possibili-
ties have been opened and are being explored.
2. Results and discussion
The first step in the synthesis of the proposed type 3 surfactants
consists in the introduction of the alkyl chain into the amino acid.
Initially, and according to a previously reported method,26 we
performed a direct alkylation using alkyl halides, but observed the
formation of dialkylated products, the target compounds being
isolated in very poor yields. Attempts to improve the yield modi-
fying the reaction conditions (e.g., order of addition of reagents, use
of different bases, use of various solvents and different reaction
times) did not lead to satisfactory results. Consequently, the in-
troduction of the alkyl chain into the amino acid by reductive
amination of ‘fatty’ aldehydes was attempted (Scheme 2).27,28 The
aldehydes used were octanal (8a), dodecanal (8b), tetradecanal
(8c), hexadecanal (8d) and octadecanal (8e), which, with exception
of octanal and dodecanal (commercially available), were synthe-
sized by oxidation of the corresponding alcohols using TPAP/NMO
(yields 48–63%) according to a method described in the literature.29
The initial studies were performed with serine methyl ester hy-
drochloride (5) and dodecanal (8b).
When sodium triacetoxyborohydride was used as reducing
agent in the presence of NEt3, low yields of 9 were obtained (28%,
Table 1). With sodium borohydride in MeOH (entry 2) only a ves-
tigial amount of the desired product formed (2%), but in the pres-
ence of NEt3 the yield increased significantly (entry 3, 32%). Since
the amino acid ester hydrochloride was being used, the NEt3 was
necessary to liberate the free amine from the salt, thus increasing
the nucleophilicity of the nitrogen atom. In any case the yields were
satisfactory and we attempted the synthesis of the target com-
pounds using the reductive amination under solvent-free condi-
tions, as described by Cho and Kang.30 In this case, the aldehyde
used was octanal (8a) whose choice was due to the fact that it is
liquid at rt and allows for a better mixture of the reagents. Once
again the yield was very low (13%), the work-up of the resulting
mixture being the major problem. In fact, irrespective of the
employed methodology, the compounds obtained in this first step
were very difficult to isolate from the reaction mixture, mainly due
to their strong amphiphilic character.
Scheme 1. Methodologies of synthesis of monomeric surfactants based on amino
acids.
activities and have shown to be environmentally friendly.18,19 In
what concerns the synthesis of these amino acid-based surfactants,
among the different types of linkages between the long aliphatic
chain and the amino acid, the methods described refer essentially
to compounds of type 1, N-alkanoyl derivatives, of type 2, N-alkyl
amides, and of type 4, O-alkyl esters.5
To our knowledge, besides the case of N-dodecyl-N,N-dime-
thylglycine,20 there is only one report on the synthesis of surfac-
tants of type 3 derived from the amino acid cysteine, which has
been obtained by nucleophilic substitution with the corresponding
alkyl halide.21
In the current work, our main aim has been to develop an effi-
cient methodology for the synthesis of novel monomeric surfac-
tants containing serine, tyrosine (cationic) and 4-hydroxyproline
(anionic) as polar head groups, linked to a long lipophilic chain
through an N-alkyl linkage. This work is carried out in the broader
context of the search for new bio-friendly surfactants with poten-
tially interesting physicochemical properties.22,23 Therefore, in
order to make an initial assessment of their interfacial perfor-
mance, in particular with respect to some common homologous
surfactants of commercial origin and widespread use, we also
present here their basic physicochemical properties in aqueous
solution, e.g., the Krafft temperature and critical micelle
concentration.
While these surfactants should be clearly interesting per se, the
presence of the hydroxyl group in the side chain of these amino
acids is intended to allow for the subsequent introduction of
While performing the subsequent reaction (methylation) of the
serine derivative 9b, it was verified that the presence of the hy-
droxyl group in the amino acid side chain was disadvantageous,
a
spacer at the oxygen atoms in order to obtain dimeric
R
H
H3N
R
OCH3
Reductive
Amination
H
O
12b (R=OH)
13b-e (R=O Bu)
14b-e (R=Ph-O Bu)
Cl
OCH3
CF3COOH
CH3I
5-7
HN
t
15b-e (R=OH)
+
t
O
16b-e (R=Ph-OH)
n
n CHO
8a-e
H3C
R
9-11
X- = I-
X- = CF3COO-
H
H3C
H3C
OCH3
5 (R=OH)
N
9a,b (R=OH)
10b-e (R=O Bu)
11b-e (R=Ph-O Bu)
t
a: n = 6
t
6 (R=O Bu)
X
O
t
b: n = 10
c: n = 12
d: n = 14
e: n = 16
t
7 (R=Ph-O Bu)
n
12-16
Scheme 2. Synthesis of cationic monomeric surfactants.

4158
S.G. Silva et al. / Tetrahedron 65 (2009) 4156–4164
Table 1
establishment of the best reaction conditions, the yields were
almost quantitative. Although an additional step, the removal of the
protecting group, is necessary for the obtention of the target
cationic surfactants, now as the corresponding trifluoroacetates,
this methodology is by far advantageous, as the deprotection is
carried out with yields in the order of 60–90% (Table 2).
Reductive amination of aldehydes with serine, tyrosine and 4-hydroxyproline
derivatives
Entry
Methoda
Amino acid
Product
Yield/%
1
2
3
4
5
I
HSerOMe
HSerOMe
HSerOMe
HSerOMe
9b
9b
9b
9a
28
2
32
13
10
IIa
IIb
III
IIb
In what concerns the 4-hydroxyproline derivatives, the syn-
thesis of the corresponding cationic and anionic surfactants was
aimed at. For the obtention of the cationic surfactants, we tried to
establish the reaction sequence using the N-alkylated derivative
18b. After protection of the OH group using tert-butyldiphenyl-
chlorosilane, methylation of the resulting product (19b, 81%) using
the previously established reaction conditions afforded the
O-protected derivative (20b) in good yield (79%) (see Scheme 3).
However, when deprotection was attempted using tetrabuty-
lammonium fluoride, a complex mixture, from which no major
product could be isolated, was obtained. The three different frac-
tions isolated by column chromatography turned out to be tetra-
butylammonium hydroxide, tert-butyldiphenylfluorosilane and
a non-identifiable mixture (NMR, some peaks of the expected
compound were missing). To overcome the difficulties arising from
this protection/deprotection sequence the next synthetic approach
was solid phase organic synthesis (SPOS). We used a 2-chloro-
tritylchloride resin to anchor the amino acid derivative 18b through
its OH group, so there would be no further need for protection/
deprotection of this functionality. Methylation of the resin bound
compound should yield the corresponding quaternary ammonium
(proline) derivative, which upon cleavage with CF3COOH should
render the desired cationic surfactant (Scheme 4).33 After work-up
of the final reaction mixture we verified that the reaction occurred
to a very low extent, yielding only a vestigial quantity of the target
cationic surfactant. Trials to optimize the reaction conditions were
not successful, in part due to the difficulty to account for the ex-
tension of each of the reaction steps. Although there are several
colorimetric tests for the evaluation of the presence of functional
groups on the resin-supported molecules, thus allowing for a quick
and reliable monitoring of most reactions, they were not suited for
the type of compounds used.34 Chromatographic techniques, on the
other hand, require the cleavage of the compound from the solid
support. Furthermore, the need for a large excess of reagents in-
herent to this methodology constitutes a disadvantage, because of
the high cost of the starting material. Despite the fact that the
compounds obtained with this approach showed MS spectra
compatible with the expected structures, the small quantities of
product obtained (1–2 mg) were not sufficient for an NMR analysis
HSer(tBu)OMe
10b
6
7
8
9
I
I
I
HSer(tBu)OMe
HSer(tBu)OMe
HSer(tBu)OMe
HSer(tBu)OMe
10b
10c
10d
10e
79
62
71
84
10
11
12
13
HTyr(tBu)OMe
HTyr(tBu)OMe
HTyr(tBu)OMe
HTyr(tBu)OMe
11b
11c
11d
11e
81
74
61
39
14
15
16
HHypOMe
HHypOMe
HHypOMe
18b
18c
18d
85
54
76
a
I: DCE, NEt3 (1.5 equiv), NaBH(OAc)3 (1.4–1.5 equiv); IIa: MeOH, NaBH4
(1.7 equiv); IIb: MeOH, NEt3 (1.5 equiv), NaBH4 (1.7 equiv); III: NEt3 (1 equiv), TsOH
(1 equiv), NaBH4 (1 equiv).
leading to a complex mixture of products, which could not be
properly separated. Methylation seemed to occur not only at the
nitrogen atom but also at the oxygen of the OH group. Indeed, the
fractions isolated by column chromatography were not homo-
genous by TLC, and the NMR analyses revealed the presence of
various methyl groups, which could be attributed to multiple al-
kylations as well as to a mixture of different alkylated products.
Hence, in order to circumvent this problem, the commercially
available O-tert-butyl protected serine/tyrosine methyl ester hy-
drochlorides, 6 and 7, respectively, were used for the further re-
ductive aminations.
In the case of 4-hydroxyproline, as the desired O-protected de-
rivative was not commercially available, the reductive aminations
were performed using 17 and the OH group of the resulting N-
alkylated derivatives (18b–d) was protected, prior to methylation,
using diphenyl-tert-butylchlorosilane.31
For the reaction of the O-protected serine derivative 6 with
dodecanal (8b), the two best yielding methods, I and IIb, were
tested. While in the case of IIb only 10% of the desired product (10b)
formed, high yields were obtained using method I (entries 5 and 6,
respectively). The reaction proceeded rapidly (6 h) and although it
was not complete as confirmed by TLC, increasing the reaction time
did not increase the yield. The work-up (extraction) of the reaction
mixture was more efficient than when using the unprotected an-
alogue, due to the lower hydrophilic character of the product
imparted by the presence of the tert-butyl group, therefore the
higher yields obtained in comparison to compound 9b (entry 1).
After optimization of the reaction conditions of method I all further
reductive aminations were thus performed. In all cases good to
excellent yields were obtained (Table 1).
The next step in the synthesis of the serine- and tyrosine-based
cationic surfactants consisted in the methylation of the previously
synthesized compounds 9–11.32 As already mentioned, with the
serine N-dodecyl methyl ester (9b) difficulties were encountered
since the excess of methyl iodide/bromide led to alkylation not only
of the amine but also of the hydroxyl group. In order to avoid this
competitive alkylations, only 2 mol equiv of CH3I was used, but
under these conditions the main product obtained was the mono
methylated derivative, while the desired quaternary ammonium
salt (12b) formed in only 16% yield (Table 2, entry 1). Using the
O-tert-butyl protected amino acid derivatives, a large excess of the
alkylating agent could be employed without concerning about
competitive alkylation of the side chain OH group. After the
Table 2
Methylation and removal of the protective group (serine and tyrosine derivatives)
Reaction type
Methylation
Entry
1
Reaction conditions
Product
Yield/%
16
Isopropanol, CH3I
(2 mol equiv), 50–60 ꢀC
12b
2
3
4
5
6
7
8
9
DMF, K2CO3 (2 mol equiv),
18-crown-6 (cat); CH3I
(4 mol equiv)
13b
13c
13d
13e
14b
14c
14d
14e
90
70
96
88
95
52
93
66
Removal of
protective group
10
11
12
13
14
15
16
17
CF3COOH
15b
15c
15d
15e
16b
16c
16d
16e
73
71
62
89
75
37
77
35

S.G. Silva et al. / Tetrahedron 65 (2009) 4156–4164
4159
HO
Ph
Ph
HO
Ph
O
Si
Ph
Si
C(CH3)3
O
C(CH3)3
N
Reductive
Amination
OCH3
OCH3
N
H2
TBDPSCl
Methylation
Cl
O
17
O
OCH3
I
OCH3
19b
N
N
n
+
18b-d
H3C
O
O
20b
O
n
H3C
CHO
n
n
KOH / MeOH
8b-d
Bu4N+F-
HO
HO
a: n = 6
OCH3
b: n = 10
c: n = 12
d: n = 14
O
K
I
N
N
H3C
O
n
n
21b
22b-d
Scheme 3. Synthesis of proline-based monomeric surfactants.
to confirm the results. The SPOS methodology proved not to be
suitable for this type of syntheses and was therefore abandoned.
The anionic hydroxyproline-based surfactants were readily
accessed by saponification of the corresponding N-alkyl-4-
hydroxyproline methyl esters (18) with KOH/MeOH at rt, as de-
scribed by Bodanszky and Bodanszky.35 Although the separation
process was difficult, partly due to the emulsifying properties of the
resulting compounds, they could be isolated in good to excellent
yields (Table 3, Scheme 3).
Concerning the stereochemistry of the compounds obtained,
and taking into account the reaction conditions throughout the
whole syntheses, epimerization of the chiral carbon atom cannot be
excluded. However, the 1H NMR spectra of one of the compounds in
the presence of varying concentrations of Eu(hfc)3 did not show
separation of any of the peaks. Furthermore, when independent
batches of the same compound were used in physicochemical
measurements, no meaningful variation of the determined prop-
ertiesdnamely the critical micelle concentrationdwas observed
(data below). Thus, even if there is any epimerization, surface
tension data strongly suggest that the composition of the final
product is always the same.
The evaluation of the physicochemical properties of the syn-
thesized surfactants has been carried out, in order to probe for their
efficiency and potential as surface-active agents in action. First, it
should be recalled that commercially available cationic surfactants,
such as hexadecyltrimethylammonium bromide (HTAB), are known
to be fairly toxic, with respect to both aquatic and cellular envi-
ronments.4,36 Anionic surfactants, such as sodium dodecyl sulfate,
also suffer from similar shortcomings, albeit in a smaller magnitude
than cationics.19 Efforts to improve the toxicological properties of
functional surfactants using ‘natural’ starting materials, while
keeping a desirable interfacial performance, are therefore a rele-
vant and challenging task, especially when it comes to direct
applications.
The assessment of the basic micellization and surface action
properties for selected synthesized surfactants was carried out by
means of tensiometry. The C16 derivatives were chosendC16Hyp
(22d), C16Tyr (16d) and C16Ser (15d)das well as the complete
series of the Ser-based surfactants (C12 to C18). Figure 1 shows the
surface tension versus log(concentration) curves obtained for the
C16 derivatives and the commercial homologue, HTAB. Similar
curves were obtained for all the other compounds. The critical
micelle concentration (cmc) is the inflection point in the curve, as
graphically illustrated in Figure 1 for C16Hyp. Because no minimum
(or well) in the vicinity of the cmc is seen, a common fingerprint of
surface-active impurities or surfactant mixtures,37 these curves
provide further evidence for the good purity of the surfactants.
In Table 4, the cmc values and other parameters of interest are
listed for the selected surfactants. Values for reference anionic (SDS
and SHS) and cationic (DTAB and HTAB) commercial homologues
are also listed for comparison. Several relevant conclusions can be
withdrawn. (i) The Krafft temperaturedtemperature at which the
surfactant solubilizes to yield micellesdof the new surfactants is
within expected values for the respective alkyl chain length. (ii)
Their cmc values are without exception lower than those of the
commercial homologues. For the cationic amphiphiles, the values
are between two and seven times lower, whereas for the anionic
compounds, 16Hyp and SHS, a 48-fold difference is observed, a re-
markable value, even accounting for the different temperature and
pH of measurement. (iii) The surface tension values at the cmc
plateau of the new surfactants, another measure of interfacial ef-
fectiveness, are comparable to their commercial homologues, and
HO
COOCH3
N
18b
10
O
Cl
COOCH3
Pyridine / THF, 50ºC
N
10
DMF, DBU,
CH3I
HO
I
COOCH3
CH3
O
I
COOCH3
CH3
TFA / DCM
N
N
10
10
21b
Scheme 4. SPOS approach to 4-hydroxyproline-based cationic surfactants.

4160
S.G. Silva et al. / Tetrahedron 65 (2009) 4156–4164
Table 3
activity and potential ocular irritation) performed for C12Ser and
Saponification of N-alkyl-4-hydroxyproline methyl esters (18)
C12Tyr have labelled these molecules as only slightly or moderately
irritant, respectively, showing better results than, for instance,
HTAB.40
All these observations highlight a good potential for application-
related uses of the new molecules. Further studies of their self-
assembly properties in aqueous solution are currently being
undertaken.
Reaction conditions
KOH, methanol
Product
Yield/%
22b
22c
22d
72
53
85
3. Conclusions
In this work, a straightforward and high yielding methodology
for the synthesis of novel serine- and tyrosine-based cationic mo-
nomeric surfactants and 4-hydroxyproline-based anionic mono-
meric surfactants has been developed and optimized. Three
surfactant series with even chain lengths between C12 and C18
have been synthesized. These surfactants differ from most of the
reported amino acid-based ones in that they are N-alkyl derivatives
of amino acids. Because they are prepared from natural sources,
they are expected to be less toxic than conventional ones and thus
of great interest for application purposes. While they structurally
‘mimic’ conventional amphiphiles, surface tension studies dem-
onstrate that they possess enhanced interfacial performance, as
judged from their lower cmc values in comparison to correspond-
ing homologues and, in some cases, decreased surface tension
values at the cmc.
Figure 1. Surface tension versus log(concentration) curves for the hexadecyl amino
acid derivatives, used for the cmc determination, as illustrated graphically for C16Hyp.
The temperature is 40.0 ꢀC, except for C16Hyp, 25.0 ꢀC. For comparison, the curve for
the commercial cationic surfactant HTAB is also shown.
in one case, C12Ser (15b), notably lower (10 mN mꢁ1 difference
with respect to DTAB). Overall, these results indicate good surface
performance levels for the new compounds, and in some parame-
ters even enhanced performance with respect to reference
homologues.
4. Experimental
4.1. General
It should be pointed out that in a recent report we have shown
that both C12Ser and C16Ser, in combination with anionic lysine-
based amphiphiles, are able to spontaneously form vesicles of long-
term stability.38 This type of vesicles, based on cationic/anionic
surfactant mixtures, possess enhanced chemical and colloidal sta-
bility, and good encapsulation properties for drugs, increasingly
arising as a viable alternative to classical lipid-based liposomes for
drug delivery.22,39 It is also known that cationic surfactants per se
can be used for compaction and decompaction of DNA, aiming at
non-viral gene delivery to cells.14 In this context, cationic molecules
based on natural sources and thus of lower toxicity should be
greatly advantageous. Preliminary toxicity tests (haemolytic
Amino acids were purchased from NovaBiochem. Solvents (p.a.
quality) were from Merck. Both, thin layer chromatography (TLC)
aluminium foil plates covered with silica 60 F254 (0.25 mm) and
silica gel 60 (70–230 mesh ASTM) for preparative column chro-
matography were from Merck. TPAP was purchased from TCI, other
chemicals were obtained from Sigma–Aldrich.
When required, solvents were dried and distilled prior to use.
DCM was distilled from P4O10 and Et3N from KOH.
1H NMR and 13C NMR spectra were recorded on a Bruker
DPX250, AMX300 or AMX500 spectrometer. Chemical shifts, d, are
presented in parts per million from tetramethylsilane (TMS, 0 ppm)
as internal standard for CDCl3 and residual solvent peaks for other
deuterated solvents. Coupling constants, J, are in hertz, Hz. Infrared
spectra (IR) were recorded on a Bruker Tensor 27 spectrometer. ESI
mass spectra were recorded on a Finnigan Surveyor instrument,
equipped with mass detector Finnigan LCQ DECA XP MX (Finnigan
Table 4
Micellization properties of amino acid-based surfactants and some reference com-
mercial ionic homologuesa
Surfactant
TKr/ꢀC
Tmeas/ꢀC
cmc/mmol kgꢁ1
gcmc/mN mꢁ1
´
Corp.San Jose, CA, USA) and API (Atmospheric Pressure Ionization)
C16Hyp (22d)
C16Tyr (16d)
C12Ser (15b)
C14Ser (15c)
C16Ser (15d)
C18Ser (15e)
SDS
SHS
DTAB
HTAB
<25
28.7
<25
25.7
31.2
46.7
<25
n.a.
25.0
40.0
25.0
35.0
40.0
48.0
25.0
40.0
25.0
40.0
0.012b
0.14
1.87
1.16
36.5
38.2
29.2
33.0
34.7
34.3
40.0
n.a.
using an ESI interface (Electrospray Ionization). ESI-TOF HRMS
spectra were obtained on a Microtof apparatus. The samples have
been analyzed by direct injection and the spectra were obtained in
positive ESI mode (m/z 50–1000). For the surface tension mea-
surements, a DCAT11 tensiometer from Dataphysics Instruments
GmbH was used (Wilhelmy plate method). Temperature was kept
constant at the desired value (ꢂ0.1 ꢀC) using a thermostated Julabo
water bath. Melting points (MP)/clearing points (CP) of cationic
serine and anionic proline derivatives were determined by com-
bined DSC and polarizing light microscopy using a Setaram DSC141
calorimeter and an Olympus BX51 microscope equipped with
a Linkam TMHS 600 hot-stage, respectively. The temperature
values were extracted from the thermogram using the software
provided by the manufacturer.
0.34
0.049
8.3c
0.58d
13.6
<25
26.0
39.5
36.5
0.84
a
TKr, surfactant Krafft temperature; Tmeas, temperature of cmc measurement; cmc,
critical micelle concentration; gcmc, surface tension value at the cmc. Surfactant ac-
ronyms: SDS, sodium dodecyl sulfate, SHS, sodium hexadecylsulfate; DTAB, dode-
cyltrimethylammonium bromide; HTAB, hexadecyltrimethylammonium bromide.
b
Measured at pH¼12.0, for solubility reasons.
c
From Ref. 2.
d
From Ref. 37.

S.G. Silva et al. / Tetrahedron 65 (2009) 4156–4164
4161
4.2. Representative procedure for reductive amination
(CDCl3, 75 MHz)
d
175.24 (CO), 154.02 (C), 132.12 (C), 129.48 (CH),
124.12 (CH), 78.27 (C), 63.27 (CH), 51.45 (CH3), 48.20 (CH2), 39.12
(CH2), 31.89 (CH2), 29.98 (CH2) [29.63, 29.61, 29.58, 29.53, 29.44,
29.32 (6CH2)], 28.81 (CH3), 27.12 (CH2), 22.66 (CH2), 14.09 (CH3).
FTIR (cmꢁ1, liquid film) 3328 (w), 3028 (s), 2926 (s), 2854 (s), 1739
(s), 1609 (m), 1467 (s), 1389 (s), 1164 (s), 899 (s), 723 (m). MS (ESI,
MeOH) m/z calcd 420.35 [MþH]þ; found 420.54.
4.2.1. N-Dodecyl-O-tert-butyl serine methyl ester (10b)
H-Ser-(tBu)-OMe]$HCl (6) (9.0 mmol, 1.9 g) and triethylamine
(14 mmol, 2.0 mL) were dissolved in DCE (10 mL) and stirred for
15 min to liberate the amine from the salt. Then a solution of
dodecanal (8a) (9.2 mmol, 1.7 mmol) in 20 mL of DCE was added,
followed by sodium triacetoxyborohydride (14 mmol, 3.0 g). The
mixture was stirred at rt under an argon atmosphere for 12 h,
quenched with NaHCO3 (saturated solution) and the product was
extracted with ethyl acetate (3ꢃ20 mL). The ethyl acetate extracts
were washed with brine and dried (Na2SO4). The solvent was
evaporated and the crude product was subjected to column chro-
matography on silica gel using hexane/ethyl acetate (5:1) and DCM/
MeOH (10:1) mixtures as eluents to yield the product as an
4.2.6. N-Tetradecyl-O-tert-butyl tyrosine methyl ester (11c)
1H NMR (CDCl3, 300 MHz)
d
6.98 (d, 2H, J¼8.4 Hz), 6.83 (d, 2H,
J¼8.4 Hz), 3.52 (s, 3H), 3.46 (t, 1H, J¼7.1 Hz), 2.92 (dd, 1H, J¼13.5,
6.5 Hz), 2.81 (dd,1H, J¼13.5, 7.5 Hz), 2.55–2.34 (m, 2H),1.43–1.30 (m,
2H), 1.25 (s, 9H), 1.22–1.14 (m, 22H), 0.87 (t, 3H, J¼6.8 Hz). 13C NMR
(CDCl3, 75 MHz)
d 174.83 (CO), 154.09 (C), 131.83 (C), 129.52 (CH),
124.16 (CH), 78.31 (C), 62.94 (CH), 51.53 (CH3), 47.95 (CH2), 38.78
(CH2), 34.19 (CH2), 31.91 (CH2) [29.64, 29.59, 29.53, 29.46, 29.41,
29.34, 29.27, 29.13 (8CH2)], 28.81 (CH3), 27.09 (CH2), 22.67 (CH2),
14.09 (CH3). FTIR (cmꢁ1, liquid film) 3166 (w), 2954 (s), 2919 (s), 2850
(s),1742 (s),1508 (m),1465 (m),1365 (m),1165 (m),1093 (m), 900 (s).
MS (ESI, MeOH) m/z calcd 448.38 [MþH]þ; found 448.58.
uncoloured oil (yield 79%): 1H NMR (CDCl3, 300 MHz)
d 3.71 (s, 3H),
3.62–3.48 (m, 2H), 3.39 (t, 1H, J¼5.4 Hz), 2.62 (dt, 1H, J¼11.0,
7.2 Hz), 2.47 (dt, 1H, J¼11.2, 7.2 Hz), 1.76 (s, 1H), 1.55–1.40 (m, 2H),
1.35–1.18 (br s, 18H), 1.13 (s, 9H), 0.86 (t, 3H, J¼6.6 Hz). 13C NMR
(CDCl3, 75 MHz)
d 174.03 (CO), 73.12 (C), 63.01 (CH2), 62.10 (CH3),
48.29 (CH2), 31.88 (CH2), 30.12 (CH2) [29.63, 29.60, 29.57, 29.57,
29.55, 29.47, 29.31 (7CH2)], 27.32 (CH3), 27.20 (CH2), 22.65 (CH2),
14.07 (CH3). FTIR (cmꢁ1, liquid film): 3319 (s), 2955 (s), 2854 (s),
1750 (s), 1467 (s), 1364 (m), 1197 (m), 737 (m). MS (ESI, MeOH) m/z
calcd 344.32 [MþH]þ; found 344.37.
4.2.7. N-Hexadecyl-O-tert-butyl tyrosine methyl ester (11d)
1H NMR (CDCl3, 300 MHz)
d
7.05 (d, 2H, J¼8.4 Hz), 6.89 (d, 2H,
J¼8.4 Hz), 3.58 (s, 3H), 3.47 (t, 1H, J¼7.1 Hz), 2.94 (dd, 1H, J¼13.4,
6.8 Hz), 2.86 (dd, 1H, J¼13.4, 7.4 Hz), 2.55 (dt, 1H, J¼11.1, 7.3 Hz),
2.43 (dt, 1H, J¼11.1, 7.1 Hz), 1.65 (br s, 1H), 1.49–1.36 (m, 2H), 1.31 (s,
9H), 1.29–1.20 (m, 26H), 0.87 (t, 3H, J¼6.6 Hz). 13C NMR (CDCl3,
4.2.2. N-Tetradecyl-O-tert-butyl serine methyl ester (10c)
1H NMR (CDCl3, 300 MHz)
d
4.75 (br s, 1H), 3.72 (s, 3H), 3.63–
75 MHz) d 175.25 (CO), 154.02 (C), 132.13 (C), 129.48 (CH), 124.12
3.51 (m, 2H), 3.44 (t, 1H, J¼5.0 Hz), 2.64 (dt, 1H, J¼11.1, 7.4 Hz), 2.51
(CH); 78.26 (C); 63.28 (CH); 51.45 (CH3); 48.21 (CH2); 39.13 (CH2);
31.90 (CH2); 30.00 (CH2); [29.67, 29.64, 29.59; 29.45; 29.34 (10
CH2)]; 28.81 (CH3); 27.13 (CH2); 22.67 (CH2); 14.09 (CH3). FTIR
(cmꢁ1, liquid film) 3329 (w); 3028 (s); 2925 (s); 2854 (s); 1739 (s);
1507 (s); 1467 (s); 1369 (s); 1236 (s); 1164 (s); 1018 (m); 899 (s). MS
(ESI, MeOH) m/z calcd 476.41 [MþH]þ; found 476.62.
(dt,1H, J¼11.1, 7.1 Hz),1.54–1.41 (m, 2H),1.24 (br s, 22H),1.13 (s, 9H),
0.86 (t, 3H, J¼6.8 Hz). 13C NMR (CDCl3, 75 MHz)
d 173.57 (CO), 73.18
(C), 62.60 (CH2), 61.69 (CH), 51.70 (CH3), 47.96 (CH2), 31.89 (CH2),
29.75 (CH2) [29.64, 29.58, 29.54, 29.44, 29.33, (8CH2)], 27.30 (CH3),
27.17 (CH2), 22.66 (CH2), 14.08 (CH3). FTIR (cmꢁ1, liquid film): 3317
(w), 2924 (s), 2853 (s), 1741 (m), 1467 (m), 1364 (m), 1197 (m), 721
(m). MS (ESI, MeOH) m/z calcd 372.35 [MþH]þ; found 372.87.
4.2.8. N-Octadecyl-O-tert-butyl tyrosine methyl ester (11e)
1H NMR (CDCl3, 300 MHz)
d
6.98 (d, 2H, J¼8.4 Hz), 6.83 (d, 2H,
4.2.3. N-Hexadecyl-O-tert-butyl serine methyl ester (10d)
J¼8.7 Hz), 3.52 (s, 3H), 3.41 (t, 1H, J¼7.1 Hz), 2.88 (dd, 1H, J¼13.5,
6.6 Hz), 2.79 (dd,1H, J¼13.5, 7.2 Hz), 2.48 (dt,1H, J¼13.5, 7.2 Hz),1.57
(br s, 1H), 1.41–1.30 (m, 2H), 1.25 (s, 9H), 1.23–1.15 (m, 30H), 0.87 (t,
1H NMR (CDCl3, 300 MHz)
d 3.69 (s, 3H), 3.60–3.45 (m, 2H),
3.37 (t, 1H, J¼5.4 Hz), 2.61 (dt, 1H, J¼11.1, 7.4 Hz), 2.46 (dt, 1H,
J¼11.1, 7.2 Hz), 1.77 (br s, 1H), 1.54–1.35 (m, 2H), 1.22 (br s, 26H),
1.11 (s, 9H), 0.85 (t, 3H, J¼6.6 Hz). 13C NMR (CDCl3, 75 MHz)
3H, J¼6.6 Hz). 13C NMR (CDCl3, 75 MHz)
d 175.24 (CO), 154.01 (C),
132.12 (C),129.47 (CH),124.12 (CH), 78.27 (C), 63.27 (CH), 51.45 (CH3),
48.20(CH2), 39.12 (CH2), 31.90 (CH2), 29.98 (CH2) [29.67, 29.64, 29.59,
29.54, 29.44, 29.33 (12CH2)], 28.80 (CH3), 27.13 (CH2), 22.66 (CH2),
14.08 (CH3). FTIR (cmꢁ1, liquid film) 3329 (w), 2924 (s), 2853 (s),1739
(s),1507 (s),1467 (s),1365 (s),1234 (s),1164 (s),1018 (m), 899 (s). MS
(ESI, MeOH) m/z calcd 504.44 [MþH]þ; found 504.70.
d
173.98 (CO), 73.07 (C), 62.97 (CH2), 62.06 (CH), 51.55 (CH3),
48.25 (CH2), 31.86 (CH2), 30.09 (CH2) [29.63, 29.55, 29.52, 29.45,
29.30, 27.29 (10CH2)], 27.17 (CH3), 22.62 (CH2), 14.04 (CH3). FTIR
(cmꢁ1, Nujol) 3352 (w), 2924 (s), 2853 (s), 1744 (m), 1464 (m),
1377 (m), 1232 (m), 720 (w). MS (ESI, MeOH) m/z calcd 400.38
[MþH]þ; found 400.47.
4.2.9. N-Dodecyl proline methyl ester (18b)
4.2.4. N-Octadecyl-O-tert-butyl serine methyl ester (10e)
1H NMR (CDCl3, 300 MHz)
d 4.50–4.40 (m, 1H), 3.69 (s, 3H), 3.49
1H NMR (CDCl3, 300 MHz)
d
3.72 (s, 3H), 3.65–3.49 (m, 2H), 3.40
(t, 1H, J¼7.8 Hz), 3.40 (dd, 1H, J¼9.9, 5.7 Hz), 2.69–2.58 (m, 1H) 2.50
(br s, 1H), 2.47–2.38 (m, 2H), 2.25–2.15 (m, 1H), 2.07–1.99 (m, 1H),
1.36–1.52 (m, 2H), 1.22 (br s, 18H), 0.85 (t, 3H, J¼6.9 Hz). 13C NMR
(t, 1H, J¼5.3 Hz), 2.63 (dt, 1H, J¼11.1, 7.4 Hz), 2.49 (dt, 1H, J¼11.0,
7.2 Hz), 2.14 (br s,1H),1.55–1.41 (m, 2H),1.24 (br s, 30H),1.13 (s, 9H),
0.87 (t, 3H, J¼6.8 Hz). 13C NMR (CDCl3, 75 MHz)
d
173.98 (CO), 73.14
(CDCl3, 75 MHz) d 174.00 (CO), 70.42 (CH), 64.29 (CH), 61.31 (CH2),
(C), 62.95 (CH2), 62.05 (CH), 51.63 (CH3), 48.25 (CH2), 31.90 (CH2),
30.08 (CH2) [29.67, 29.59, 29.56, 29.48, 29.34 (12CH2)], 27.33 (CH3),
27.21 (CH2), 22.66 (CH2), 14.09 (CH3). FTIR (cmꢁ1, Nujol) 3352 (m),
2917 (s), 2849 (s), 1745 (s), 1463 (s), 1364 (m), 1158 (s), 729 (m). MS
(ESI, MeOH) m/z calcd 428.41 [MþH]þ; found 428.49.
54.39 (CH2), 51.80 (CH3), 39.55 (CH2), 31.91 (CH2) [29.61, 29.47,
29.31, 28.30 (7 CH2)], 27.42 (CH2), 22.68 (CH2), 14.11 (CH3). FTIR
(cmꢁ1, liquid film) 3522 (sharp), 3341 (br), 2853 (s), 1733 (s), 1472
(s), 1377 (m), 1221 (s). MS (ESI, MeOH) m/z calcd 314.27 [MþH]þ;
found 314.44.
4.2.5. N-Dodecyl-O-tert-butyl tyrosine methyl ester (11b)
4.2.10. N-Tetradecyl proline methyl ester (18c)
1H NMR (CDCl3, 300 MHz)
d
7.06 (d, 2H, J¼8.7 Hz), 6.90 (d, 2H,
1H NMR (CDCl3, 300 MHz)
d 4.46–4.36 (m, 1H), 3.65 (s, 3H), 3.46
J¼8.4 Hz), 3.59 (s, 3H), 3.48 (t, 1H, J¼7.1 Hz), 2.95 (dd, 1H, J¼13.5,
6.9 Hz), 2.87 (dd, 1H, J¼13.5, 7.2 Hz), 2.56 (dt, 1H, J¼11.2, 7.2 Hz),
2.44 (dt, 1H, J¼11.2, 7.1 Hz), 1.81–1.69 (m, 1H), 1.53–1.31 (m, 2H),
1.32 (s, 9H), 1.28–1.20 (m, 18H), 0.88 (t, 3H, J¼6.8 Hz). 13C NMR
(t, 1H, J¼7.7 Hz), 3.37 (dd, 1H, J¼10.2, 5.7 Hz, 1H), 2.79 (br s, 1H),
2.66–2.49 (m, 1H), 2.46–2.38 (m, 2H), 2.22–2.10 (m, 1H), 2.08–1.94
(m, 1H), 1.47–1.34 (m, 2H), 1.18 (br s, 22H), 0.87–0.77 (m, 3H). 13C
NMR (CDCl3, 75 MHz)
d 174.05 (CO), 70.25 (CH), 64.34 (CH), 61.32

4162
S.G. Silva et al. / Tetrahedron 65 (2009) 4156–4164
(CH2), 54.48 (CH2), 51.77 (CH3), 39.48 (CH2), 31.88 (CH2) [29.63,
29.54, 29.45, 29.32, 28.29 (9CH2)], 27.40 (CH2), 22.65 (CH2), 14.07
(CH3). FTIR (cmꢁ1, liquid film) 3341 (br), 2918 (s), 2850 (s), 1736 (s),
1469 (s), 1193 (s), 721 (m). MS (ESI, MeOH) m/z calcd 342.30
[MþH]þ; found 342.50.
4.3.4. N-(2-tert-Butyloxy-1-methyloxycarbonyl)ethyl-N,N-
dimethyl-N-octadecylammonium iodide (13e)
1H NMR (CDCl3, 250 MHz)
d 5.32–5.12 (m, 1H), 4.05 (sl, 2H),
3.92–3.62 (m, 2H), 3.73 (s, 3H), 3.47 (s, 3H), 3.44 (s, 3H), 1.92–1.58
(m, 2H), 1.40–1.10 (m, 30), 1.08 (m, 9H), 0.85–0.70 (m, 3H). 13C NMR
(CDCl3, 125 MHz)
d 165.76 (CO), 71.76 (C), 70.44 (CH), 65.52 (CH2),
4.2.11. N-Hexadecyl proline methyl ester (18d)
58.96 (CH2), 53.15 (CH3), 51.15 (CH3), 50.92 (CH3), 31.74 (CH2)
[29.52, 29.47, 29.43, 29.29, 29.24, 29.17, 28.90 (12CH2)], 26.99 (CH3),
26.07 (CH2), 22.86 (CH2), 22.50 (CH2),13.93 (CH3). FTIR (cmꢁ1, liquid
film) 2920 (s), 2851 (s), 1741 (m), 1470 (m), 1368 (m), 1236 (m), 720
(w). MS (ESI, MeOH) positive ESI: m/z calcd 456.44; found 456.71.
1H NMR (CDCl3, 300 MHz)
d 4.54–4.42 (m, 1H), 3.71 (s, 3H), 3.51
(t, 3H, J¼7.7 Hz), 3.43 (dd, 1H, J¼10.1, 5.6 Hz), 2.66 (dt, 1H, J¼12.3,
8.0 Hz), 2.52–2.38 (m, 2H), 2.29–2.14 (m, 1H), 2.12–2.00 (m, 2H),
1.54–1.40 (m), 1.25 (br s, 26H), 0.88 (t, 3H, J¼6.6 Hz). 13C NMR
(CDCl3, 75 MHz)
d 174.19 (CO), 70.36 (CH), 64.36 (CH), 61.39 (CH2),
54.54 (CH2), 51.77 (CH3), 39.55 (CH2), 31.90 (CH2) [29.67, 29.60,
29.56, 29.48, 29.33, 28.40 (11CH2)], 27.41 (CH2), 22.66 (CH2), 14.09
(CH3). FTIR (cmꢁ1, liquid film) 3521 (sharp), 2914 (s), 2850 (s), 1730
(s), 1470 (s), 1376 (m), 1220 (s), 718 (m). MS (ESI, MeOH): m/z calcd
370.33 [MþH]þ; found 370.55.
4.3.5. N-(2-tert-Butyloxyphenyl-1-methyloxycarbonyl)ethyl-N-
dodecyl-N,N-dimethylammonium iodide (14c)
1NMR (CDCl3, 300 MHz)
d
7.21 (d, 2H, J¼8.4 Hz), 6.94 (d, 2H,
J¼8.4 Hz), 4.54 (dd, 1H, J¼11.7, 4.2 Hz), 3.95–3.77 (m, 1H), 3.76–3.61
(m, 2H), 3.67 (s, 3H), 3.55 (s, 3H), 3.50 (s, 3H), 3.16 (t, 1H, J¼12.3 Hz),
1.93–1.72 (m, 2H), 1.32 (s, 9H), 1.25 (br s, 18H), 0.88 (t, 3H, J¼6.8 Hz).
4.3. Representative procedure for methylation
13C NMR (CDCl3, 75 MHz)
d 167.10 (C), 155.20 (C), 130.19 (CH),
126.63 (C), 124.52 (CH), 78.72 (C), 73.63 (CH), 65.23 (CH2), 53.04
(CH3), 50.73 (CH3), 49.99 (CH3), 32.59 (CH2), 31.80 (CH2) [29.51,
29.38, 29.28, 29.23, 29.07 (6ꢃCH2)], 28.73 (CH3), 26.04 (CH2), 22.82
(CH2), 22.58 (CH2), 14.03 (CH3). FTIR (cmꢁ1, Nujol) 2923 (s), 2853
(s), 1743 (s), 1610 (m), 1508 (s), 1460 (s), 1366 (s), 1300 (m), 1239
(m), 1239 (s), 1174 (s), 897 (s), 827 (m), 723 (m). MS (ESI, MeOH)
positive ESI: m/z calcd 448.38; found 448.55.
4.3.1. N-(2-tert-Butyloxy-1-methyloxycarbonyl)ethyl-N-dodecyl-
N,N-dimethylammonium iodide (13b)
To a solution of N-dodecyl-O-tert-butyl serine methyl ester
(10b) (3.0 mmol, 1.0 g) in DMF or dry acetone (5 mL) were added
potassium carbonate (6.0 mmol, 0.80 g), 18-crown-6 (cat) and
iodomethane (12.0 mmol, 0.74 mL). The mixture was stirred at rt
for 6–12 h until the reactants were consumed (TLC). The solvent
was evaporated to give the crude ammonium salt, which was
taken up in ethyl acetate (3ꢃ20 mL) and washed with sodium
thiosulfate (10%) (3ꢃ20 mL). The ethyl acetate layer was dried
(Na2SO4) and after removal of the solvent product 13b was
4.3.6. N-(2-tert-Butyloxyphenyl-1-methyloxycarbonyl)ethyl-N,N-
dimethyl-N-tetradecylammonium iodide (14c)
1H NMR (DMSO-d6, 250 MHz)
2H, J¼8.5 Hz), 4.49 (dd, 1H, J¼12.0, 3.5 Hz), 3.58–3.24 (m, 2H), 3.51
(s, 3H), 3.24 (s, 3H), 3.21 (s, 3H), 3.24–3.02 (m, 2H), 1.85–1.63 (m,
2H), 1.26 (s, 9H), 1.25 (br s, 22H), 0.90–0.80 (m, 3H). 13C NMR
d
7.15 (d, 2H, J¼8.5 Hz), 6.94 (d,
obtained as
300 MHz) 5.32 (m, 1H), 4.11 (s, 2H), 3.92–3.69 (m, 2H), 3.80 (s,
a
white powder (yield 90%): 1H NMR (CDCl3,
d
3H), 3.51 (s, 3H), 3.48 (s, 3H), 1.87–1.68 (m, 2H), 1.32–1.21 (m, 18H),
(DMSO-d6, 75 MHz) d 166.86 (CO), 154.39 (C), 130.03 (CH), 127.88
1.15 (s, 9H), 0.84 (t, 3H, J¼6.2 Hz). 13C NMR (CDCl3, 75 MHz)
(C), 123.79 (CH), 77.93 (C), 73.30 (CH), 63.86 (CH2), 52.84 (CH3),
48.77 (CH3), 48.68 (CH3), 31.19 (CH2) [28.92, 28.81, 28.61 (9 CH2)],
28.41 (CH3), 25.58 (CH2), 21.99 (CH2), 21.65 (CH2), 13.85 (CH3). FTIR
(cmꢁ1, liquid film) 2924 (s), 2852 (s), 1744 (s), 1558 (m), 1507 (s),
1466 (s), 1366 (s), 1238 (s), 1164 (s), 898 (s). MS (ESI, MeOH) positive
ESI: m/z calcd 476.41; found 476.59.
d
165.88 (CO), 75.12 (C), 71.91 (CH), 65.52 (CH2), 58.99 (CH2), 53.20
(CH3), 51.08 (CH3), 50.84 (CH3), 31.77 (CH2) [29.46, 29.32, 29.27,
29.19, 28.95 (6CH2)], 27.04 (CH3), 26.13 (CH2), 22.86 (CH2), 22.55
(CH2), 13.99 (CH3). FTIR (cmꢁ1, liquid film) 2923 (s), 2853 (s), 1759
(w), 1463 (s), 1377 (s). MS (ESI, MeOH) positive ESI: m/z calcd
372.35; found 372.57.
4.3.7. N-(2-tert-Butyloxyphenyl-1-methyloxycarbonyl)ethyl-N-
4.3.2. N-(2-tert-Butyloxy-1-methyloxycarbonyl)ethyl-N,N-
hexadecyl-N,N-dimethylammonium iodide (14d)
dimethyl-N-tetradecylammonium iodide (13c)
1H NMR (DMSO-d6, 250 MHz)
d
7.15 (d, 2H, J¼8.3 Hz), 6.94 (d,
1H NMR (CDCl3, 300 MHz)
d
5.54 (t, 1H, J¼3.0 Hz), 4.14–4.07 (m,
2H, J¼8.5 Hz), 4.49 (dd, 1H, J¼11.8, 3.5 Hz), 3.58–3.39 (m, 3H), 3.51
(s, 3H), 3.24 (s, 3H), 3.21 (s, 3H), 3.14–3.02 (m, 1H), 1.83–1.63 (m,
2H), 1.27 (s, 9H), 1.23 (br s, 26H), 0.90–0.78 (m, 3H). 13C NMR
2H), 4.00–3.65 (m, 2H), 3.77 (s, 3H), 3.47 (s, 3H), 3.43 (s, 3H), 1.84–
1.63 (m, 2H), 1.29–1.13 (m, 22H), 1.12 (s, 9H), 0.86–0.76 (m, 3H). 13C
NMR (CDCl3, 75 MHz)
d
165.62 (CO), 74.94 (C), 71.55 (CH), 65.49
(DMSO-d6, 75 MHz) d 166.83 (CO), 154.37 (C), 130.02 (CH), 127.86
(CH2), 58.81 (CH2), 53.04 (CH3), 51.04 (CH3), 50.84 (CH3), 31.19 (CH2)
[29.34, 29.30, 29.16, 29.12, 29.04, 28.88, 28.77 (8CH2)], 26.87 (CH3),
25.94 (CH2), 22.72 (CH2), 22.37 (CH2),13.82 (CH3). FTIR (cmꢁ1, liquid
film) 2923 (s), 2854 (s), 1744 (w), 1463 (s), 1377 (s). MS (ESI, MeOH)
positive ESI m/z calcd 400.38; found 400.61.
(C), 123.77 (CH), 77.92 (C), 73.29 (CH), 63.85 (CH2), 52.83 (CH3),
48.77 (CH3), 48.69 (CH3), 31.19 (CH2) [28.95, 28.91, 28.81, 28.65,
28.60, 28.36 (11CH2)], 28.41 (CH3), 25.58 (CH2), 21.99 (CH2), 21.66
(CH2), 13.85 (CH3). FTIR (cmꢁ1, Nujol) 2920 (s), 2851 (s), 1754 (s),
1507 (m), 1469 (s), 1365 (m), 1269 (m), 1164 (m), 855 (s), 720 (m).
MS (ESI, MeOH) positive ESI: m/z calcd 504.44; found 504.69.
4.3.3. N-(2-tert-Butyloxy-1-methyloxycarbonyl)ethyl-N-hexadecyl-
N,N-dimethylammonium iodide (13d)
4.3.8. N-(2-tert-Butyloxyphenyl-1-methyloxycarbonyl)ethyl-N,N-
dimethyl-N-octadecylammonium iodide (14e)
1H NMR (CDCl3, 250 MHz)
d
5.31 (t, 1H, J¼3.0 Hz), 4.15–4.00 (m,
2H), 3.95–3.65 (m, 2H), 3.78 (s, 3H), 3.51 (s, 3H), 3.48 (s, 3H), 1.90–
1H NMR (CDCl3, 300 MHz)
d
7.18 (d, 2H, J¼8.4 Hz), 6.91 (d, 2H,
1.60 (m, 2H), 1.19 (br s, 26H), 1.13 (s, 9H), 0.84 (t, 3H, J¼6.5 Hz). 13C
J¼8.4 Hz), 4.52 (dd, 1H, J¼11.7, 4.2 Hz), 3.94–3.78 (m, 1H), 3.77–3.58
(m, 2H), 3.66 (s, 3H), 3.53 (s, 3H), 3.47 (s, 3H), 3.13 (t, 1H, J¼12.3 Hz),
1.92–1.72 (m, 2H),1.29 (s, 9H),1.23 (br s, 30H), 0.85 (t, 3H, J¼6.6 Hz).
NMR (CDCl3, 75 MHz)
d 165.73 (CO), 75.05 (C), 71.70 (CH), 65.52
(CH2), 58.95 (CH2), 53.14 (CH3), 51.14 (CH3), 50.92 (CH3), 31.72 (CH2)
[29.50, 29.46, 29.41, 29.27, 29.23, 29.16, 28.89 (10CH2)], 26.98 (CH3),
26.06 (CH2), 22.85 (CH2), 22.49 (CH2), 13.93 (CH3). FTIR (cmꢁ1, liq-
uid film) 2924 (s), 2853 (s), 1743 (m), 1471 (m), 1367 (m), 1238 (m),
721 (w). MS (ESI, MeOH) positive ESI: m/z calcd 428.41; found
428.66.
13C NMR (DMSO-d6, 75 MHz)
d 166.89 (CO), 154.46 (C), 130.07 (CH),
127.91 (C), 123.84 (CH), 77.98 (C), 73.38 (CH), 63.95 (CH2), 52.86
(CH3), 48.74 (CH3), 48.83 (CH3), 31.26 (CH2) [29.01, 28.88, 28.72,
28.66 (13CH2)], 28.44 (CH3), 25.06 (CH2), 22.06 (CH2), 21.74 (CH2),
13.87 (CH3). FTIR (cmꢁ1, Nujol) 2921 (s), 2851 (s), 1754 (s), 1507 (w),

S.G. Silva et al. / Tetrahedron 65 (2009) 4156–4164
4163
1468 (s), 1377 (m), 1268 (m), 1164 (m), 895 (m). MS (ESI, MeOH):
4.4.5. N-Dodecyl-N-(2-hydroxyphenyl-1-methyloxy-carbonyl)-
positive ESI: m/z calcd 532.47; found 532.70.
ethyl-N,N-dimethylammonium trifluoroacetate (16b)
1H NMR (CDCl3, 300 MHz)
d 6.92–6.74 (m, 4H), 4.32–4.17 (m,1H),
4.4. Representative procedure for removal of the protective
group
3.44 (s, 3H), 3.50–3.16 (m, 3H), 3.22 (s, 6H), 2.94 (t, 1H, J¼11.9 Hz),
1.72 (br s, 2H),1.25 (br s,18H), 0.88 (t, 3H, J¼6.6 Hz).13C NMR (CDCl3,
75 MHz)
d 167.31 (CO), 157.51 (C), 130.32 (CH), 122.04 (C), 116.30
4.4.1. N-Dodecyl-N-(2-hydroxy-1-methyloxycarbonyl)ethyl-N,N-
dimethylammonium trifluoroacetate (15b)
(CH), 74.73 (CH), 64.89 (CH2), 53.00 (CH3), 49.56 (CH3), 48.92 (CH3),
31.99 (CH2), 31.87 (CH2) [29.57, 29.41, 29.30, 28.99 (6CH2)], 26.09
(CH2), 22.64 (CH2), 22.47 (CH2), 14.07 (CH3). FTIR (cmꢁ1, Nujol) 3472
(br), 3043 (w), 2926 (s), 2856 (s),1746 (s),1683 (s),1518 (s),1457 (m),
1379 (m), 1242 (s), 1131 (s), 832 (s), 719 (m). HRMS (ESI-TOF) calcd
for C24H42NO3 requires 392.3159; found 392.3169.
Deprotection was accomplished by stirring N-dodecyl-N,N-di-
methyl-N-(1-methyloxycarbonyl-2-tert-butyloxy)ethylammonium
iodide (13b) with TFA (3–5 mL) for 36 h at rt. The mixture was
treated with ethyl ether until total removal of TFA and then sub-
jected to column chromatography on silica gel, using a DCM/
methanol (5:1) mixture as eluent. The product (15b) was isolated as
an uncoloured oil (73%), which was recrystallized from AcOEt/
Hexane (1:1) to yield white crystals. 1H NMR (CDCl3, 300 MHz)
4.4.6. N-(2-Hydroxyphenyl-1-methyloxycarbonyl)ethyl-N,N-
dimethyl-N-tetradecylammonium trifluoroacetate (16c)
1H NMR (DMSO-d6, 250 MHz)
d 9.54 (s, 1H), 7.02 (d, 2H,
d
4.69 (br s, 1H), 4.41–4.25 (m), 3.84 (s, 3H), 3.83–3.41 (m, 3H), 3.41
(s, 6H), 1.80–1.66 (m, 2H), 1.43–1.14 (m, 18H), 0.88 (t, 3H, J¼6.6 Hz).
13C NMR (CDCl3, 75 MHz)
166.51 (CO), 73.35 (CH), 65.84 (CH2),
J¼8.5 Hz), 6.72 (d, 2H, J¼8.5 Hz), 4.41 (dd, 1H, J¼11.9, 3.4 Hz), 3.55
(s, 3H), 3.65–3.31 (m, 3H masked by the peak of water from DMSO),
3.22 (s, 3H), 3.19 (s, 3H), 3.02(t, 1H, J¼12.5 Hz), 1.73 (br s, 2H), 1.24
d
58.73 (CH2), 53.33 (CH3), 50.94 (CH3), 50.04 (CH3), 31.82
(CH2) [29.50, 29.49, 29.33, 29.23, 28.91 (6CH2)], 26.09 (CH2), 22.60
(CH2), 22.45 (CH2), 14.03 (CH3). FTIR (cmꢁ1, Nujol) 3180 (br), 2923
(s), 2853 (s), 1744 (s), 1672 (s), 1458 (s), 1377 (s), 1172 (m). HRMS
(ESI-TOF) calcd for C18H38NO3 requires 316.2846; found 316.2850.
Clearing point: 91.0–91.7 ꢀC.
(br s, 22H), 0.85 (t, 3H, J¼6.5 Hz). 13C NMR (CDCl3, 75 MHz)
d 167.28
(CO), 157.39 (C), 130.29 (CH), 122.08 (C), 116.30 (CH), 74.72 (CH),
64.91 (CH2), 54.05 (CH3), 49.67(CH3), 48.99 (CH3), 31.90 (CH2),
29.67 (CH2) [29.64, 29.60, 29.44, 29.33, 28.99 (8CH2)], 26.08 (CH2),
22.66 (CH2), 22.44 (CH2), 14.08 (CH3). FTIR (cmꢁ1, Nujol) 3472 (br),
3044 (m), 2920 (s), 2854 (s), 1747 (s), 1684 (s), 1519 (s), 1467 (s),
1388 (m), 1175 (s), 830 (s). HRMS (ESI-TOF) calcd for C26H46NO3
requires 420.3472; found 420.3487.
4.4.2. N-(2-Hydroxy-1-methyloxycarbonyl)ethyl-N,N-dimethyl-N-
tetradecylammonium trifluoroacetate (15c)
1H NMR (CDCl3, 300 MHz)
d
4.78–4.68 (m, 1H), 4.38 (d, 1H,
4.4.7. N-(2-Hydroxyphenyl-1-methyloxycarbonyl)ethyl-N-
J¼13.8 Hz), 4.28 (dd, 1H, J¼13.8, 6.3 Hz), 3.82 (s, 3H), 3.71 (dt, 1H,
J¼12.4, 4.7 Hz), 3.55 (dt, 1H, J¼12.5, 4.5 Hz), 3.40 (s, 6H),1.95–1.55 (m,
2H), 1.40–1.17 (m, 22H), 0.86 (t, 3H, J¼6.5 Hz). 13C NMR (CDCl3,
hexadecyl-N,N-dimethylammonium trifluoroacetate (16d)
1H NMR (DMSO-d6, 250 MHz)
d 9.56 (s, 1H), 7.02 (d, 2H,
J¼8.5 Hz), 6.72 (d, 2H, J¼8.3 Hz), 4.41 (dd, 1H, J¼11.9, 3.4 Hz), 3.55
(s, 3H), 3.66–3.32 (m, 3H masked by the peak of water from DMSO),
3.23 (s, 3H), 3.19 (s, 3H), 3.02 (t, 1H, J¼12.3 Hz), 1.73 (br s, 2H), 1.24
75 MHz)
d 166.56 (CO), 73.40 (CH), 65.88 (CH2), 58.71 (CH2), 53.37
(CH3), 51.02 (CH3), 50.07 (CH3), 31.86 (CH2) [29.61, 29.59, 29.52, 29.36,
29.30,29.26, 28.94(8CH2)], 26.12 (CH2), 22.63 (CH2), 22.49 (CH2),14.06
(CH3). FTIR (cmꢁ1, Nujol) 3401 (br), 2922 (s), 2853(s),1744 (s),1672 (s),
1458 (m), 1377 (w), 1251 (s). HRMS (ESI-TOF) calcd for C20H42NO3
requires 344.3159; found 344.3153. Clearing point: 91.0–94.2 ꢀC.
(br s, 26H), 0.85 (t, 3H, J¼6.5 Hz). 13C NMR (CDCl3, 75 MHz)
d 167.30
(CO), 157.40 (C), 130.35 (CH), 122.11 (C), 116.30 (CH), 74.75 (CH),
64.89 (CH2), 53.04 (CH3), 49.75 (CH3), 49.01 (CH3), 31.90 (CH2),
29.69 (CH2) [29.66, 29.64, 29.61, 29.45, 29.34, 29.01 (10CH2)],
26.11(CH2), 22.66 (CH2), 22.49 (CH2), 14.08 (CH3). FTIR (cmꢁ1, Nujol)
3455 (br), 2923 (s), 2854 (s), 1740 (s), 1682 (s), 1613 (s), 1467 (s),
1388 (m), 1175 (s), 830 (s). HRMS (ESI-TOF) calcd for C28H50NO3
requires 448.3785; found 448.3788.
4.4.3. N-Hexadecyl-N-(2-hydroxyl-1-methyloxycarbonyl)ethyl-
N,N-dimethylammonium trifluoroacetate (15d)
1H NMR (CDCl3, 300 MHz)
d
4.70 (dd,1H, J¼6.6, 2.7 Hz), 4.34 (dd,
1H, J¼13.9, 2.6 Hz), 4.23 (dd, 1H, J¼13.8, 6.6 Hz), 3.77 (s, 3H), 3.66
(dt, 1H, J¼12.5, 4.8 Hz), 3.49 (dt, 1H, J¼12.6, 4.8 Hz), 3.36 (s, 3H),
3.35 (s, 3H), 1.81–1.51 (m, 2H), 1.36–1.07 (m, 26H), 0.81 (t, 3H,
4.4.8.. N-(2-Hydroxyphenyl-1-methyloxycarbonyl)ethyl-N,N-
dimethyl-N-octadecylammonium trifluoroacetate (16e)
J¼6.6 Hz). 13C NMR (CDCl3, 75 MHz)
d
166.61 (CO), 73.46 (CH), 65.92
1H NMR (DMSO-d6, 250 MHz)
d 9.52 (br s, 1H), 7.02 (d, 2H,
(CH2), 58.92 (CH2), 53.39 (CH3), 51.10 (CH3), 50.06 (CH3), 31.89 (CH2)
[29.65, 29.63, 29.60, 29.54, 29.38, 29.33, 29.27, 28.95 (10CH2)],
J¼8.3 Hz), 6.71 (d, 2H, J¼8.5 Hz), 4.41 (dd, 1H, J¼11.8, 3.3 Hz), 3.55
(s, 3H), 3.60–3.30 (m, 3H masked by the peak of water from DMSO),
3.22 (s, 3H), 3.19 (s, 3H), 3.02 (t, 1H, J¼12.3 Hz), 1.73 (br s, 2H), 1.23
(br s, 30H), 0.85 (t, 3H, J¼6.4 Hz). 13C NMR (DMSO-d6, 125 MHz)
26.14 (CH2), 22.65 (CH2), 22.50 (CH2), 14.08 (CH3). FTIR (cmꢁ1
,
Nujol) 3168 (br), 2953 (s), 2922 (s), 2852 (s), 1744 (m), 1671 (s),1458
(s), 1377 (m), 1173 (m). HRMS (ESI-TOF) calcd for C22H46NO3 re-
quires 372.3472; found 372.3475. Melting point: 92.3–94.3 ꢀC.
d
166.85 (CO), 156.70 (C), 130.34 (CH), 123.02 (C), 115.40 (CH), 73.60
(CH), 63.36 (CH2), 52.91 (CH3), 48.69 (CH3), 48.61 (CH3), 31.17 (CH2),
31.00 (CH2) [28.91, 28.79, 28.64, 28.57, 28.34 (12CH2)], 25.57 (CH2),
21.97 (CH2), 21.64 (CH2), 13.82 (CH3). FTIR (cm-1, liquid film) 3455
(br), 2921 (s), 2854 (s), 1740 (s), 1682 (s), 1517 (s), 1454 (s), 1379 (m),
1201 (s), 823 (s). HRMS (ESI-TOF) cal. for C30H54NO3 requires
477.4176; found 477.4194.
4.4.4. N-(2-Hydroxy-1-methyloxycarbonyl)ethyl-N,N-dimethyl-N-
octadecylammonium trifluoroacetate (15e)
1H NMR (CDCl3, 300MHz)
d
4.74 (dd, 1H, J¼6.6, 2.7 Hz), 4.34 (dd,
1H, J¼13.8, 2.7 Hz), 4.23 (dd, 1H, J¼13.9, 6.8 Hz), 3.77 (s, 3H), 3.67
(dt, 1H, J¼12.6, 4.9 Hz), 3.48 (dt, 1H, J¼12.6, 5.1 Hz), 3.36 (s, 6H),
1.82–1.50 (m, 2H), 1.36–1.10 (m, 30H), 0.81 (t, 3H, J¼6.8 Hz). 13C
4.5. Representative procedure for saponification of N-alkyl-4-
hydroxyproline methyl esters
NMR (CDCl3, 75 MHz)
d
166.66 (CO), 73.52 (CH), 65.97 (CH2), 59.02
(CH2), 53.42 (CH3), 51.19 (CH3), 50.08 (CH3), 31.90 (CH2) [29.68,
29.65, 29.61, 29.55, 29.39, 29.34, 29.28, 28.96 (12CH2)], 26.16 (CH2),
22.67 (CH2), 22.51 (CH2), 14.09 (CH3). FTIR (cmꢁ1, Nujol) 3174 (br),
2919 (s), 2852 (s), 1744 (s), 1671 (s), 1469 (s), 1377 (m), 1173 (s), 718
(m). HRMS (ESI-TOF) calcd for C24H50NO3 requires 400.3785; found
400.3788. Melting point: 95.0–97.3 ꢀC.
4.5.1. Sodium N-dodecyl-4-hydroxyprolinate (22b)
Saponification was accomplished by stirring N-dodecyl proline
methyl ester (18b) with NaOH/H2O (1.5 equiv) at rt until total
consumption of reagents (24 h). Upon addition of AcOEt to the
resulting solution, product 22b precipitated and was collected by

4164
S.G. Silva et al. / Tetrahedron 65 (2009) 4156–4164
suction filtration as white crystals (yield 72%): 1H NMR (CD3OD,
300 MHz)
5. Mora´n, M. C.; Pinazo, A.; Pe´rez, L.; Clape´s, P.; Angelet, M.; Garcı´a, M. T.;
Vinardell, M. P.; Infante, M. R. Green Chem. 2004, 6, 233–240.
6. Roy, S.; Das, D.; Dasgupta, A.; Mitra,R. N.;Das, P. K.Langmuir2005, 21,10398–10404.
7. von Rybinski, W.; Hill, K. Angew. Chem., Int. Ed. 1998, 37, 1328–1345.
8. Kirk, O.; Pedersen, F. D.; Fuglsang, C. C. J. Surfactants Deterg. 1998, 1, 37–40.
9. Johansson, I.; Svensson, M. Curr. Opin. Colloid Interface Sci. 2001, 6, 178–188.
10. Hama, I.; Sasamoto, H.; Tamura, T.; Nakamura, T.; Miura, K. J. Surfact. Deterg.
1998, 1, 93–97.
d
4.50–4.30 (m, 1H), 4.04 (dd, 1H, J¼10.5, 7.5 Hz), 3.77
(dd, 1H, J¼12.6, 4.5 Hz), 3.34–3.22 (m, 1H), 3.18–3.00 (m, 2H), 2.38
(dd, 1H, J¼13.5, 7.4 Hz), 2.09 (ddd, J¼13.5, 10.7, 4.5 Hz), 1.85 (s, 1H),
1.72–1.59 (m, 2H), 1.40–1.10 (m, 18H), 0.85 (t, J¼6.6 Hz). 13C NMR
(CD3OD, 75 MHz)
d 173.40 (CO), 70.75 (CH), 70.32 (CH), 62.90
(CH2), 59.14 (CH2), 40.07 (CH2), 33.11 (CH2) [30.80, 30.71, 30.57,
30.52, 30.32, 27.62, 27.00 (8CH2)], 23.78 (CH2), 14.50 (CH3). FTIR
(cmꢁ1, Nujol) 3216 (br), 3036 (s), 2914 (s), 2835 (s), 1617 (s), 1473
(m), 1398 (s). HRMS (ESI-TOF) calcd for C17H34NO3 requires
300.2533; found 300.2537.Clearing point: 185.0–187.3 ꢀC.
11. Claffey, D. J.; Meyer, J. D.; Beauvais, R.; Brandt, T.; Shefter, E.; Kroll, D. J.; Ruth,
J. A.; Manning, M. C. Biochem. Cell Biol. 2000, 78, 59–65.
12. Kondoh, M.; Furutani, T.; Azuma, M.; Ooshima, H.; Kato, J. Biosci. Biotechnol.
Biochem. 1997, 61, 870–874.
13. Rosa, M.; Penacho, N.; Simo˜es, S.; Lima, M. C. P.; Lindman, B.; Miguel, M. G. Mol.
Membr. Biol. 2008, 25, 23–34.
14. (a) Dias, R. S.; Lindman, B.; Miguel, M. G. J. Phys. Chem. B 2002, 106, 12600–
12607; (b) Dias, R. S.; Lindman, B.; Miguel, M. G. J. Phys. Chem. B 2002, 106,
12608–12612.
15. Lewis, J. G.; Lin, K.-Y.; Kothavale, A.; Flanagan, W. M.; Matteucci, M. D.; De-
Prince, R. B.; Mook, R. A., Jr.; Hendren, R. W.; Wagner, R. W. Proc. Natl. Acad. Sci.
U.S.A. 1996, 93, 3176–3181.
4.5.2. Potassium N-tetradecyl-4-hydroxyprolinate (22c)
1H NMR (CD3OD, 300 MHz)
d 4.51–4.44 (m, 1H), 4.13–4.02 (m,
1H), 3.79 (dd, J¼12.5, 4.4 Hz), 3.38–3.24 (m, 2H), 3.33–3.05 (m, 2H),
2.47–2.36 (m, 1H), 2.17–2.04 (m, 1H), 1.76–1.64 (m, 2H), 1.42–1.20
16. Piera, E.; Comelles, F.; Erra, P.; Infante, M. R. J. Chem. Soc., Perkin Trans. 2 1998,
335–342.
17. Pe´rez, L.; Pinazo, A.; Garcia, M. T.; Mora´n, M. C.; Infante, M. R. New J. Chem. 2004,
28, 1326–1334.
(m, 22H), 0.92–0.84 (m, 3H). 13C NMR (CD3OD, 75 MHz)
d 173.32
(CO), 70.79 (CH), 70.34 (CH), 62.91 (CH2), 59.22 (CH2), 40.06 (CH2),
33.12 (CH2) [30.80, 30.79, 30.70, 30.52, 30.29, 30.29, 27.57, 26.96
(10CH2)], 23.78 (CH2), 14.49 (CH3). FTIR (cmꢁ1, Nujol) 3206 (br),
2922 (s), 2852 (s), 1617 (m), 1463 (m), 721 (w). HRMS (ESI-TOF)
calcd for C19H38NO3 requires 328.2846; found 328.2857. Clearing
point: 187.0–188.0 ꢀC.
18. Macia´n, M.; Seguer, J.; Infante, M. R.; Selve, C.; Vinardell, M. P. Toxicology 1996,106,1–9.
´
´
19. Sanchez, L.; Mitjans, M.; Infante, M. R.; Garcıa, M. T.; Manresa, M. A.; Vinardell,
M. P. Amino Acids 2007, 32, 133–136.
20. Diz, M.; Manresa, A.; Pinazo; Erra, P. A.; Infante, M. R. J. Chem. Soc., Perkin Trans.
2 1994, 1871–1876.
21. Yoshimura, T.; Sakato, A.; Tsuchiya, K.; Ohkubo, T.; Sakai, H.; Abe, M.; Esumi, K.
J. Colloid Interface Sci. 2007, 308, 466–473.
22. Brito, R. O.; Marques, E. F.; Gomes, P.; Falca˜o, S.; So¨derman, O. J. Phys. Chem. B
2006, 110, 18158–18165.
23. Rosa, M.; Miguel, M. D.; Lindman, B. J. Colloid Interface Sci. 2007, 312, 87–97.
24. Preliminary results have been presented: (a) Vale, M. L. C.; Arau´ jo, M. J. S. M. P.;
4.5.3. Potassium N-hexadecyl-4-hydroxyprolinate (22d)
1H NMR (CD3OD, 300 MHz)
d
4.52–4.40 (m), 4.07 (dd,1H, J¼10.8,
7.5 Hz), 3.77 (dd, 1H J¼12.5, 4.4 Hz), 3.39–3.22 (m, 1H), 3.21–3.00
(m, 2H), 2.40 (dd, 1H, J¼13.6, 7.4 Hz), 2.08 (ddd, 1H, J¼13.5, 10.8,
4.5 Hz),1.74–1.59 (m, 2H),1.40–1.19 (m, 26H), 0.91–0.80 (m, 3H). 13C
´
Gomes, P. A. C.; Rodrıguez-Borges, J. E.; Marques, E.; Silva, S. G.; Correia, C.
Methodologies of Synthesis of Novel Surfactants Based on Amino Acids, 1st
European Chemistry Congress, Budapest, Hungary, August, 2006; (b) Silva, S. G.;
Oliveira, M.; Borges, J. E.; Marques, E. F.; Vale, M. L. Methodologies of Synthesis of
Monomeric and Dimeric Surfactants Based on Amino Acids, 15th European
Symposium on Organic Chemistry, Dublin, Ireland, July, 2007.
25. Gomes, P.; Arau´ jo, M. J.; Marques, E. F.; Falca˜o, S.; Brito, R. O. Synth. Commun.
2008, 38, 2025–2036.
26. Zana, R.; Benrraou, M.; Rueff, R. Langmuir 1991, 7, 1072–1075.
27. Magid, A. F. A.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J. Org.
Chem. 1996, 61, 3849–3862.
NMR (CD3OD, 75 MHz) d 173.34 (CO), 70.78 (CH), 70.33 (CH), 62.88
(CH2), 59.19 (CH2), 40.08 (CH2), 33.13 (CH2) [30.84, 30.81, 30.72,
30.57, 30.53, 30.31, 27.60, 26.99 (12CH2)], 23.78 (CH2), 14.50 (CH3).
FTIR (cmꢁ1, Nujol) 3208 (br), 3040 (s), 2850 (s), 1618 (s), 1464 (s),
721 (m). HRMS (ESI-TOF) calcd for C21H42NO3 requires 356.3159;
found 356.3169. Clearing point: 174.6–176.5 ꢀC.
28. Ramanjulu, J. M.; Joullie´, M. M. Synth. Commun. 1996, 26, 1379–1384.
29. Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J. Chem. Soc., Chem.
Commun. 1987, 1625–1627.
Acknowledgements
30. Cho, B. T.; Kang, S. K. Tetrahedron 2005, 61, 5725–5734.
We gratefully acknowledge Prof. Paula Gomes for assistance in
SPOS and Rodrigo Brito for surface tension measurements. FCT/
FEDER is acknowledged for financial support through project
POCTI/QUI/44296/2002.
31. Corey, J. E.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190–6191.
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