New multifunctional surfactants from natural phenolic acids

Article abstract of DOI:10.1021/jf203133w

Several new multifunctional molecules derived from natural sources such as amino acids and hydroxycinnamic acids were synthesized. They exhibit various activities such as emulsifying, UV-protecting, and radical scavenging, thereby conforming to the latest requirements for cosmetic ingredients. The synthesis comprises only a few steps: (i) the amino acid, the acid groups of which are protected by esterification, is coupled with ferulic or caffeic acid; (ii) the p-hydroxyl group of the cinnamic derivative reacts with dodecyl bromide in the presence of potassium carbonate (the resulting compounds are highly lipophilic and tested as water/oil (W/O) emulsifiers); (iii) these molecules, by deprotonating the acid groups of the amino acids, with successive salification, are more hydrophilic, with stronger O/W emulsifying properties. The new multifunctional surfactants might prove useful for the treatment of multiple skin conditions, including loss of cellular antioxidants, damage from free radicals, damage from UV, and others.

Full text of DOI:10.1021/jf203133w

Article
pubs.acs.org/JAFC
New Multifunctional Surfactants from Natural Phenolic Acids
Marisanna Centini,†,‡ Maria Sole Rossato,† Alessandro Sega,†,‡ Anna Buonocore,†,‡ Sara Stefanoni,‡
and Cecilia Anselmi*,†,‡
†Dipartimento Farmaco Chimico Tecnologico, University of Siena, Via Aldo Moro, 53100 Siena, Italy
‡Centro Interdipartimentale di Scienza e Tecnologia Cosmetiche, University of Siena, Via della Diana 2, 53100 Siena, Italy
ABSTRACT: Several new multifunctional molecules derived from natural sources such as amino acids and hydroxycinnamic
acids were synthesized. They exhibit various activities such as emulsifying, UV-protecting, and radical scavenging, thereby
conforming to the latest requirements for cosmetic ingredients. The synthesis comprises only a few steps: (i) the amino acid, the
acid groups of which are protected by esterification, is coupled with ferulic or caffeic acid; (ii) the p-hydroxyl group of the
cinnamic derivative reacts with dodecyl bromide in the presence of potassium carbonate (the resulting compounds are highly
lipophilic and tested as water/oil (W/O) emulsifiers); (iii) these molecules, by deprotonating the acid groups of the amino acids,
with successive salification, are more hydrophilic, with stronger O/W emulsifying properties. The new multifunctional surfactants
might prove useful for the treatment of multiple skin conditions, including loss of cellular antioxidants, damage from free radicals,
damage from UV, and others.
KEYWORDS: surfactants, hydroxycinnamic acids, amino acids, radical-scavenging activity, UV-filtering activity
rice, wheat, and oats and in fruits and vegetables such as arti-
chokes, pineapples, and tomatoes. Its biological properties and
above all its antioxidant activity have been widely demonstrated.
It is mainly used as a photoprotecting agent in sunscreens on
account of its protective action against skin damage caused by
UV radiation.10,11 Ferulic acid has a wide range of therapeutic
properties: it is anti-inflammatory, antiatherogenic, antidiabetic,
antiaging, neuroprotective, radioprotective, and hepatoprotec-
tive. Many of these activities can be attributed to its antioxidant
capacity because of its phenolic nucleus and extended side-chain
conjugation. It readily forms a resonance-stabilized phenoxyl
radical, which explains its potent antioxidant potential.12
Caffeic acid, 3,4-dihydroxycinnamic acid, and its analogues
are also found widely in the plant kingdom, in coffee seeds,
olives, propoli, fruits, and vegetables; it is the predominant
phenolic acid in sunflower seeds. Caffeic acid and its derivatives
are known for their antibacterial, antiviral, anti-inflammatory,
antiatherosclerotic, antioxidant, antiproliferative, immunostimu-
latory, and neuroprotective actions.13 These properties are asso-
ciated with antioxidant action that displays itself through
various mechanisms: free radical scavenging, chelation of metal
ions, and inhibition of specific enzymes that induce free radicals
and lipoperoxide formation.13 The structural feature respon-
sible for the antioxidant and free radical-scavenging activities is
the o-dihydroxyl function in the catechol ring: this moiety
boosts the antioxidant activity because it further stabilizes
the phenolic radical. This explains why caffeic acid has
greater antioxidant activity than ferulic acid.13 Caffeic acid is
also a potential protective agent against photo-oxidative skin
damage.11
INTRODUCTION
■
In the past few years multifunctionality has attracted the
interest of formulators, with the aim of obtaining products that
offer a range of activities. This can be achieved by introducing
two or more active ingredients, which are even more effective
if they have synergism of action. Research has also pursued an-
other strategy, based on the creation of new single molecules
comprising several functions, reducing the risk of incompati-
bility between ingredients.
Current multifunctional ingredients and/or products includ-
ing a natural extract from Curcuma longa (turmeric) achieve this
goal, with antioxidant, skin-lightening, and UV ray protecting
properties.1 ALGUARD is a purified natural polysaccharide
hydrogel extract from a red microalga (Porphyridium sp.) that
shields the skin against irritants and oxidants and also has anti-
inflammatory and immune-modulating properties.2
Other natural molecules for which new applications have
been found include erythritol, a natural sugar alcohol used as a
sweetening agent with cariostatic action.3 New molecules with
multifunctional activity have also been synthesized, such as potas-
sium azeloyl diglycinate,4 which has skin-lightening and sebum-
normalizing properties, or Diterol AL40, a cosurfactant with
deodorant, emollient, and skin-restructuring properties,5 or per-
fluoropolyether phosphates (PFPE), film-forming agents with
antimicrobial action that foster a good rate of skin renewal after
treatment with high-acid gels and hydroalcoholic solutions.6−8
Phenolic compounds are widespread in the plant kingdom.
These secondary plant metabolites are commonly divided into
five major groups, four flavonoids, namely, the anthocyanidins, the
flavonols/flavones, the flavanones, and the flavan-3-ols, and their
oligomers and polymers, the proanthocyanidins. The fifth group
comprises hydroxycinnamic acids, caffeic and ferulic acids.9
Ferulic acid is the common name for 3-(4-hydroxy-3-meth-
oxyphenyl)-2-propenoic acid, also known as 4-hydroxymethox-
ycinnamic acid. It is found in the seeds of various plants such as
Received: August 4, 2011
Revised: December 5, 2011
Accepted: December 5, 2011
Published: December 5, 2011
© 2011 American Chemical Society
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Journal of Agricultural and Food Chemistry
Article
software, version 3.03. 1H NMR data were acquired at room tempera-
ture on a Bruker AC-200 and a Bruker Avance operating at 200 and
400 MHz, respectively; chemical shifts (δ) are expressed in parts per
million with reference to tetramethylsilane (TMS) used as internal
standard. A Silverson SL mixer, a Kirk 510 stirring paddle, a Brookfield
DV-II rotational viscometer, and an Orma pH-meter were used.
Synthesis. General Procedure for the Synthesis of Compounds
3−5. The acid (10 g) and the amino acid in a 1:1 molar ratio were
suspended in 250 mL of dimethylformamide (DMF) in a 500 mL round
flask; triethylamine and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
(EDC) were added to this solution in a 1:4 molar ratio in relation to
previous reagents, with a catalytic amount of dimethylaminopyridine
(DMAP). The mixture was magnetically stirred under reflux for 4 h.
The solvent was evaporated and the reaction product dissolved in the
smallest volume of dichloromethane and then sequentially washed
with 1 M HCl (100 mL), distilled water (100 mL), a saturated solution
of Na2CO3 (100 mL), and a saturated solution of NaCl (100 mL). The
organic extracts were dried on Na2SO4 and evaporated under vacuum.
The raw products were purified by gradient column chromatography,
starting with petroleum ether and gradually increasing the polarity with
ethyl acetate (from 10 to 100%).
We focused on surfactants based on natural substances,
aiming to create molecules with other functions besides emulsi-
fying and/or detergent activity. We chose surfactants from
among the N-acyl amino acids, specifically N-acyl glycinates
and N-acyl glutamates. In these molecules the hydrophilic and
lipophilic moieties are respectively the amino acid and the alkyl
chain. By playing on the chemical features of the alkyl chain, it
is possible to influence the properties of the various molecules.
The N-acyl amino acids and their salts have been widely
studied and boast a variety of useful properties that make them
key surfactants in numerous applications. Raw materials for
synthesis are easily accessible, and synthesis gives high yields.
Substantivity toward keratin, foam properties at neutral pH
combined with biological compatibility, and degradability open
up a broad field of applications. Acid derivatives can be used as
water/oil (W/O) emulsifiers, wetting agents, and additives in
hydrophobic systems, and the salts are effective detergents and
solubilizers in aqueous systems.14 The hydrophobic chain of
these surfactants often comprises fatty acids such as lauric,
myristic, palmitic, stearic, and oleic. We “functionalized” our
molecules by introducing caffeic or ferulic acid between the
amino acid and the alkyl chain moieties.
Several amides synthesized by coupling hydroxycinnamic
acids with amino acids have been described, such as N-feruloyl-
glycine,15−22 N-caffeoyl-glycine,19,23,24 and N-feruloyl-glutamate,22
but none shows surfactant activity. The aim of the present
study was to synthesize new multifunctional molecules of
natural origin to be used in cosmetics. These were obtained
by combining substances from natural sources, such as amino
acids, and phenolic derivatives such as ferulic and caffeic acids.
The choice of amino acids for obtaining surfactants was based
on the many examples found in the literature and on a patent
by Ajinomoto,25 which reports the synthesis of glycine and
alanine derivatives with long alkyl chains. Thus, we have syn-
thesized several surfactants with W/O and O/W emulsifying pro-
perties as well as UV-filtering and antioxidant/radical-scavenging
activity.
(E)-Ethyl-2-(3-(4-hydroxy-3-methoxyphenyl)acrylamido)acetate
1
(3): yield, 54%; H NMR, δ 1.25 (t, 3H, CH3), 3.90 (s, 3H, OCH3),
4.15 (d, 2H, CH2), 4.22 (q, 2H, OCH2), 5.80 (s, 1H, OH), 6.10 (bt,
1H, NH), 6.35 (d, 1H, CHCO), 6.90 (d, 1H, CH(Ar)), 7.00
(bd, 1H, CH(Ar)), 7.08 (bd, 1H, CH(Ar)), 7.55 (d, 1H, ArCH).
(E)-Dimethyl-2-(3-(4-hydroxy-3-methoxyphenyl)acrylamido)-
pentanedioate (4): yield, 75%; 1H NMR, δ 1.98 (m, 1H, CH
CH2−), 2.20 (m, 1H, CHCH2−), 2.35 (m, 2H, −CH2CO−),
3.57 (s, 3H, COOCH3), 3.67 (s, 3H, COOCH3), 3.83 (s, 3H, OCH3),
4.69 (m, 1H, −CH−), 6.05 (bp, 1H, OH), 6.20 (d, 1H, CH
CO−), 6.38 (bd, 1H, NH), 6.8 (d, 1H, CH(Ar)), 6.9 (s, 1H, CH(Ar)),
6.95 (d, 1H, CH(Ar)), 7.45 (d, 1H, ArCH).
(E)-Ethyl-2(3-(3,4-dihydroxyphenyl)acrylamido)acetate (5): yield,
1
32%; H NMR, δ 1.05 (t, 3H, CH3), 3.6 (s, 2H, CH2CO), 4.2 (q,
2H, OCH2), 6.4 (d, 1H, CHCO), 6.85−7.10 (m, 3H, (Ar)), 7.55
(d, 1H, ArCH).
General Procedure for the Synthesis of Compounds 7−9. The
amide (1 g) and the dodecyl bromide in a 1:1 molar ratio were added
to a suspension of anhydrous K2CO3 (2:1 molar ratio with respect to
the amide) in anhydrous acetone (50 mL) in a 100 mL round flask.
A catalytic amount of KI was added to boost the reaction rate. The
reaction mixture was magnetically stirred, under reflux, in an oil bath at
80 °C for nearly 24 h. The solution was filtered and the solvent eva-
porated under vacuum. The residue was mixed with distilled water
(50 mL) and extracted with chloroform (3 × 50 mL). The organic
solution was dried on Na2SO4 and the solvent eliminated by evaporation
under vacuum. The raw products were purified by gradient column
chromatography following the procedure previously described. The
synthesis of compound 8 gave the formation of byproduct 10.
(E)-Ethyl-2-(3-(4-dodecyloxy-3-methoxyphenyl)acrylamido)-
acetate (7): yield, 53%; 1H NMR, δ 0.85 (t, 6H, 2 × CH3), 1.25 (bp,
18H, 9 × CH2), 1.85 (m, 2H, OCH2CH2), 3.80 (s, 3H, OCH3),
4.05 (t, 2H, OCH2CH2), 4.15 (d, 2H, CH2), 4.25 (q, 2H, O
CH2CH3), 6.10 (bt, 1H, NH), 6.30 (d, 1H, CHCO), 6.80
(d, 1H, CH(Ar)), 7.00 (d, 1H, CH(Ar)), 7,03 (bd, 1H, CH(Ar)), 7.55
(d, 1H, ArCH).
MATERIALS AND METHODS
■
Chemicals. Ferulic acid was purchased from Tsuno Rice Fine
Chemicals Co. Caffeic acid, glycine ethyl ester hydrochloride, glutamic
acid methyl ester hydrochloride, and all other solvents and reagents
were purchased from Sigma-Aldrich. Compounds synthesized were
analyzed and purified with TLC ALUGRAMSIL G/UV254 40 × 80 mm,
thickness = 0.25 mm, silica gel layer with fluorescent indicator
(Macherey-Nagel GmbH, KG), preparative TLC DC-Fertigplatten
Durasil-25 UV254 20 × 20 cm, thickness = 2 mm, silica gel layer with
fluorescent indicator (Macherey-Nagel), silica gel 60 0.063 × 0.2 mm/
70−230 mesh ASTM for column chromatography (Macherey-Nagel).
To prepare emulsions we used Lanette O (cetearyl alcohol) (Henkel);
Dragoxat EH (ethylhexyl ethylhexanoate) (Dragoco Gerberding
GmbH); Syntesqual (polyisoprene) (Vevy Europe Spa Industria
Chimica); sweet almond oil (Prunus amygdalus var. dulcis oil) [B&T];
DC 200 fluid (dimethicone) (Dow Corning); water (aqua); disodium
EDTA (BASF); Kathon CG (methylchloroisothiazolinone, methyl-
isothiazolinone) (Rohm&Haas); glycerin (Carlo Erba); Cutina GMS
(glyceryl stearate) (Cognis); Cutina CP (cetyl palmitate) (Henkel);
stearin (stearic acid) (Farmasystem); triethanolamine (BASF); cera
bellina (polyglyceryl-3 beeswax) (Jan Dekker International); soft
paraffin (petrolatum) (Galeno); mineral oil (paraffinum liquidum)
(Farmasystem); and magnesium sulfate (Sigma-Aldrich). 2,2-Diphen-
yl-1-picrylhydrazyl (DPPH) and ethyl alcohol were purchased from
Sigma-Aldrich to test radical-scavenging activity.
(E)-Dimethyl-2-(3-(4-dodecyloxy-3-methoxyphenyl)acrylamido)-
1
pentanedioate (8): yield, 72%; H NMR, δ 0.81 (t, 3H, CH3), 1.23
(bp, 16H, 8 × CH2), 1.43 (m, 2H, OCH2CH2CH2), 1.85 (m,
2H, OCH2CH2), 2.08 (m, 1H, CHCH2), 2.25 (m, 1H, CH
CH2), 2.45 (m, 2H, −CH2CO), 3.65 (s, 3H, COOCH3), 3.75 (s,
3H, COOCH3), 3.85 (s, 3H, OCH3), 4.03 (t, 2H, OCH2−), 4.75 (m,
1H, −CH−), 6.38 (bt, 1H, NH), 6.5 (d, 1H, CHCO), 6.73 (d,
1H, CH(Ar)), 7.09 (d, 1H, CH(Ar)), 7.55 (d, 1H, CH(Ar)), 7.76 (d,
1H, ArCH).
(E)-Ethyl-2-(3-(4-dodecyloxy-3-hydroxyphenyl)acrylamido)-
acetate (9): yield, 92%; 1H NMR, δ 0.85 (t, 6H, 2 × CH3), 1.25 (bp,
2H, OCH2CH2), 4.05 (t, 2H, OCH2CH2), 4.25 (q, 2H,
OCH2CH3), 6.10 (bt, 1H, NH), 6.30 (d, 1H, CHCO), 6.80
Apparatus. UV−vis spectra were recorded on a Varian Cary 1E
ver. 3.03 spectrophotometer, connected to a PC with Varian Cary 13
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(d, 1H, CH(Ar)), 7.00 (d, 1H, CH(Ar)), 7.03 (bd, 1H, CH(Ar)), 7.55
(d, 1H, ArCH).
Table 2. Composition of O/W Emulsions
fluid
consistent
(E)-Dimethyl-2-(3-(4-((E)-3-(4-(dodecyloxy)-3-methylphenyl)-
acryloyloxy)methoxyphenyl)acrylamido)pentanedioate (10): 1H
NMR, δ 0.85 (t, 3H, CH3CH2), 1.2−1.4 (bp, 16H, −(CH2)8−),
1.45 (bp, 2H, −OCH2CH2CH2−), 1.83 (bp, 2H, −OCH2
CH2−), 2.08 (m, 1H, CHCH2−), 2.3 (m, 1H, −CHCH2), 2.45
(m, 2H, −CH2CO−), 3.65 (s, 3H, −COOCH3), 3.75 (s, 3H,
−COOCH3), 3.84 (s, 3H, −OCH3), 3.89 (s, 3H, −OCH3), 4.03 (t, 2H,
−OCH2), 4.75 (m, 1H, −NHCH−), 6.35 (d, 1H, −NHCH−), 6.4
(bp, 1H, NH), 6.50 (d, 1H, −CH(Ar)), 6.85 (d, 1H, (Ar)), 7.04−7.15
(m, 5H, (Ar)), 7.55 (d, 1H, −CHCO), 7.8 (d, 1H, −CHCO−).
General Procedure for the Synthesis of Compounds 11−13. The
compound (1.4 g) was dissolved in the minimum volume of methanol
and mixed with an aqueous solution of LiOH (1:1.4 molar ratio). The
total volume was brought to 50 mL by adding distilled water. The
reaction mixture was magnetically stirred under reflux in an oil bath at
100 °C for 6 h. The raw product was extracted with ethyl ether (2 ×
50 mL), and then the aqueous solution was acidified with concentrated
HCl and extracted with ethyl ether (3 × 50 mL) and chloroform (2 ×
50 mL). The organic extracts were dried on Na2SO4 and evaporated
under low pressure. The product was purified by column chroma-
tography.
emulsion emulsion
ingredient
INCI name
cetetaryl alcohol
sweet almond oil Prunus amygdalus dulcis oil
% w/w
% w/w
A 1 Lanette O
2.00
2.00
2.00
7.00
1.00
2.00
7.00
1.00
1.00
2
3
4
5
6
7
Cutina GMS
Cutina CP
stearin
glyceryl stearate
cetyl palmitate
stearic acid
DC 200 fluid
surfactant
dimethicone
1.00
0.50
B 8 water
glycerin
aqua
q.s. 100
4.50
q.s. 100
4.50
9
glycerin
10 triethanolamine triethanolamine
q.s.
q.s
C 11 disodium EDTA disodium EDTA
0.15
0.15
0.05
12 Kathon CG
methylchloroisothiazolinone, 0.05
methylisothiazolinone
9 and 10 (phase B). Add B to A while stirring and homogenize. Let the
emulsion cool under stirring, then at 40 °C add 11 and 12 dispersed in
water (10 mL) (phase C).
(E)-2-(3-(4-Dodecyloxy-3-methoxyphenyl)acrylamido)acetic acid
(11): yield, 92%; 1H NMR, δ 0.85 (t, 3H, CH3), 1.25 (bp, 16H,
8 × CH2), 1.40 (m, 2H, OCH2CH2CH2), 1.70 (m, 2H, O
CH2CH2CH2), 3.80 (s, 3H, OCH3), 3.83 (d, 2H, CH2), 3.97 (t,
2H, OCH2), 6.60 (d, 1H, CHCO), 6.97 (d, 1H, CH(Ar)), 7.10
(dd, 1H, CH(Ar)), 7,18 (d, 1H, CH(Ar)), 7.37 (d, 1H, ArCH),
8.18 (bt, 1H, NH).
Emulsion stability was evaluated using the following accelerated
aging processes at some time during 3 months: (a) storage at 5, 25,
and 40 °C; (b) storage at hot/cold cycle (5−40 °C, two cycles per
24 h); (c) centrifugation at 3000 rpm at room temperature.
Radical-Scavenging Activity. Radical-scavenging activity of
some compounds was measured by the DPPH method. In this test
DPPH radical scavenging is followed by recording the decrease in the
absorbance at 517 nm, which is due to antioxidants or radical species.26
We followed the method described by Blois:27 3 mM solutions of the
compounds in ethanol were prepared, and 100 μL of each was added
to 5 mL of DPPH (160 mM in ethanol). The samples were diluted 1:3
in ethanol, and the loss of absorbance at 517 nm was read after 30 min
of incubation at room temperature in the dark. DPPH solution in
ethanol served as the control. Analyses were run in triplicate. Radical-
scavenging activity was expressed as a percentage of the inhibition of
DPPH absorbance and calculated as 100 − (As/Ac × 100), where As
and Ac are the absorbances of the samples with and without the
inhibitors, respectively.
(E)-Ethyl-2-(3-(4-dodecyloxy-3-methoxyphenyl)acrylamido)-5-
methoxy-5-oxopentanoic acid (12): yield, 39%; 1H NMR, δ 0.86 (t,
3H, CH3), 1.34 (m, 18H, 9 × CH2), 1.77 (m, 2H, OCH2CH2), 2.00
(m, 1H, CHCH2), 2.20 (m, 1H, CHCH2), 2.42 (m, 2H, −CH2
CO), 3.22 (s, 3H, OCH3), 3.84 (bt, 2H, OCH2), 4.00 (m, 1H, −CH−),
6.52 (d, 1H, CHCO), 6.94 (m, 1H, CH(Ar)), 7.10 (bd, 1H,
CH(Ar)), 7.16 (bd, 1H, CH(Ar)), 7.47 (d, 1H, ArCH).
(E)-Ethyl-2-(3-(4-dodecyloxy-3-hydroxyphenyl)acrylamido)acetic
1
acid (13): yield, 71%; H NMR, δ 0.86 (t, 3H, CH3), 1.23 (bp, 16H,
8 × CH2), 1.42 (m, 2H, OCH2CH2CH2), 1.81 (m, 2H, OCH2CH2), 4.02
(t, 2H, OCH2), 4.15 (d, 2H, CH2COOH), 6.07 (bt, 1H, NH), 6.31 (d,
1H, CHCO), 6.49 (bp, 1H, OH), 6.83 (d, 1H, CH(Ar)), 7.02
(d, 1H, CH(Ar)), 7.05 (dd, 1H, CH(Ar)), 7.57 (d, 1H, ArCH).
UV Analysis. For UV analysis the products were dissolved in a
mixture of tetrahydrofuran (THF) and distilled water (9:1). Quartz
cells with 1 cm path length were used, and the concentrations of the
samples were around 0.08 mg/mL.
RESULTS
■
Synthesis. These compounds were synthesized through a
three-step procedure. The first step was the formation of the
amides 3, 4, and 5 by reacting ferulic (1a) and caffeic (1b) acids
with the ethyl ester of glycine (2a) or the dimethyl ester of
glutamic acid (2b) using a coupling reaction.15,16,18,20 The reac-
tion was accomplished in the presence of EDC, TEA, and DMAP
as catalysts, according to the scheme reported in Figure 1. Yields
were higher for ferulic acid derivatives 3 and 4 (54 and 75%,
respectively) than for the amide of caffeic acid (32%).
The second step was to introduce the alkyl chain by etheri-
fication to increase the lipophilic behavior of the molecule and
balance the hydrophilic moiety. Thus, the emulsifying capacity
is oriented toward W/O emulsions. The amides 3−5 were alky-
lated by introducing a 12-carbon alkyl chain on the phenolic
hydroxyl group. We selected a chain that, as we have previously
demonstrated in several UV filters, adopts a particular folded
main conformation.28−30 The reaction was accomplished by
treating the amides with dodecyl bromide (6) and potassium
carbonate in anhydrous acetone, according to the scheme
shown in Figure 2.
Emulsifying Activity. Each lipophilic product (7−9) was tested
in W/O emulsions for which compositions are given in Table 1.
Table 1. Composition of the W/O Basic Emulsion
ingredient
surfactant
INCI name
% w/w
A
1
2
3
4
5.0
5.0
cera bellina
soft paraffin
mineral oil
polyglyceryl-3 beeswax
petrolatum
5.0
paraffinum liquidum
25.0
B
5
6
7
water
aqua
q.s. 100
4.5
glycerin
glycerin
magnesium sulfate
magnesium sulfate
0.5
Procedure: heat 1, 2, 3, and 4 to 60−65 °C (A phase); disperse 7 in 5
and heat to 70 °C, then add 6 (B phase). Add B slowly to A while
stirring and homogenize.
Each hydrophilic product (11−13) was tested in two O/W basic
emulsions, lotion (fluid emulsion) and cream (consistent emulsion),
for which compositions are given in Table 2. Procedure: mix 1, 2, 3, 4,
5, 6, and 7 and heat to 70 °C (phase A); heat 8 to 75 °C and then add
The C12 ethers 7 and 8 were obtained in 53 and 71% yields,
respectively, and 9 gave a very high yield (92%). The synthesis
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Journal of Agricultural and Food Chemistry
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Figure 1. Synthesis pathway of amide derivatives of ferulic (3 and 4) and caffeic (5) acids with glycine and glutamic acid by coupling reaction.
Figure 2. Synthesis of C12 ether derivatives 7, 8, and 9 by introducing a 12-carbon alkyl chain on the phenolic hydroxyl group.
Figure 4. Scheme of hydrolysis of the ethero-esters 7, 8, and 9 to
obtain compounds 11, 12, and 13 with the free carboxylic group.
Figure 3. Chemical structure of byproduct 10.
323 nm, respectively, in THF/H2O (9:1) because of their
aromatic moieties conjugated with the double bond of the side
of compound 8 gave two products. After chromatographic sepa-
chain. All of the derivatives had an ipsochromic effect relation
ration and NMR analysis, these molecules were identified as
to the acids 1a and 1b, which was more evident in the free acids
compound 8 and a byproduct 10 containing two ferulic acid
11−13.
moieties. In this last compound the phenolic hydroxyl group
was esterified with a second molecule of ferulic acid (Figure 3).
The last step was hydrolysis of the ester to obtain the free
carboxylic group, which can then be deprotonated to give an-
ionic O/W emulsifiers. The esters were hydrolyzed by reacting
products 7, 8, and 9 with an aqueous solution of LiOH to ob-
tain the corresponding acids 11, 12, and 13 (Figure 4). Yields
were good or very good for compounds 11 (92%) and 13 (71%)
but lower for 12 (39%).
UV Analysis. Spectrophotometric analysis was done on
compounds 7−9 and 11−13 and the intermediates 3−5. Table
3 shows the wavelengths corresponding to absorption maxima
(λmax) and the logarithms of molar extinction coefficients
(log ε). Ferulic (1a) and caffeic (1b) acids gave λmax at 322 and
Caffeic acid derivatives (5, 9, and 13) gave lower log ε values
than the parent compound 1b. Ferulic acid derivatives 3 and 4
had nearly the same log ε values as the parent compound 1a
but lower for the other derivatives, especially compounds
containing the glutamic acid moiety. However, compounds 7
and 11 containing the glycine moiety had good UV-filtering
properties (log ε ≥ 4).
Emulsifying Activity. All synthesized molecules had emul-
sifying properties. The structures of compounds 7−9 had
lipophilic characteristics, so their use will be restricted to W/O
formulations. The synthetic molecules were examined by mixing
them (5% concentration) in a standard cream for which the
composition is given in Table 1.
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Radical-Scavenging Activity. As preliminary screening
for the scavenging activity of ferulic and caffeic acids and some
of their derivatives and intermediates (Figure 5) we tested their
quenching activity against DPPH in homogeneous phase. DPPH
is a stable free radical used to assess the antioxidant activity of
different compounds that act by electron or hydrogen transfer.
Of the compounds containing the caffeic acid moiety, we tested
surfactant 9 and intermediate 5 (with two free hydroxyl groups).
Surfactant 12 and intermediates 4 (one free hydroxyl group) and
3 (glycine ester) were tested among the compounds with the
ferulic acid moiety. The radical-scavenging activities are reported
in Table 6.
Free caffeic acid was more active than free ferulic acid, in
agreement with other results.11,31,32 Caffeic acid derivatives had
lower activity than the free acid, and compound 9 (with only
one free hydroxyl group) was the least active. However, inter-
mediate 5 showed greater activity than free caffeic acid.
The ferulic acid derivatives had lower activity than the free
acid. However, we noted a certain influence of the amino acid
moiety: derivative 3 (glycine ester) had far greater activity than
the corresponding compound 4 (glutamic acid ester). This can
be attributed to the substantial steric hindrance of glutamic acid
that reduces the availability of the aromatic hydroxyl group.
Derivative 12 also gave an interesting result: the aromatic hydroxyl
group was blocked but still showed some activity, probably due
to the amino acid itself.
Table 3. UV Data (in THF/H2O 9:1) of Compounds
Synthesized in Comparison with Ferulic (1a) and Caffeic
(1b) Acids
compd
λmax (nm)
log ε
1a
1b
3
322
323
318
320
322
318
319
320
317
317
316
4.33
4.35
4.34
4.29
3.71
4.02
3.86
3.82
4.14
3.57
3.34
4
5
7
8
9
11
12
13
Table 4. Emulsifying Activity Results of Compounds 7−9
and 11−13
W/O basic
emulsion
O/W fluid
emulsion
O/W consistent
emulsion
surfactant
7
stable emulsion 1
stable emulsion 2
stable emulsion 3
8
9
11
12
13
stable emulsion 4
stable emulsion 6
stable emulsion 8
stable emulsion 5
stable emulsion 7
stable emulsion 9
DISCUSSION
■
The emulsifying power of products 11−13 can be tested in
O/W emulsions because the free salifiable carboxylic function
increases their hydrophilic properties. The emulsifying power of
these compounds, after salification with triethanolamine, was
determined in fluid and consistent emulsions. The compounds
were then mixed (0.5 and 1.0%) in two standard formulations
for which compositions are given in Table 2. Table 4 shows the
emulsifying activity.
The preparations were characterized by measuring the pH
(only in O/W emulsion) at 25 °C (10% in water) and the
viscosity at 0.5 and 1 rpm at 25 °C and by evaluating their
organoleptic properties and stability by accelerated aging tests
(centrifugation and different storage conditions, 5, 25, 40 °C,
and cycle 5/40 °C). Table 5 sets out the results. All formu-
lations remained stable with time (3 months) without showing
signs of separation. The viscosity diagrams, when determinable,
indicated a typical pseudoplastic behavior. The internal phase
droplet size, analyzed by optical microscope, was 5−10 μm.
We obtained several surfactants that combine an emulsifying
property with UV-protecting and radical-scavenging activities.
These molecules can be classified as “natural surfactants” because
their polar head is a natural amino acid: glycine or glutamic acid.
The lipophilic features come from the alkyl chain, and the UV-
protecting and radical-scavenging activities come from natural
molecules with such properties, such as ferulic and caffeic acids.
We synthesized the molecules through a short three-step pro-
cedure. Compounds 7−9, with their strong lipophilic behavior,
present W/O emulsifying properties, producing stable emul-
sions with both polar and medium-polar lipids (data not shown).
Compounds 11−13, which have a free carboxylic function, are
more hydrophilic, so they are O/W emulsifiers. Thus, we ob-
tained fluid, consistent, and stable emulsions with pseudoplastic
rheological behavior. The introduction of a molecule with UV-
filtering properties transferred this capacity to these com-
pounds, although it was slightly weaker than that of the parent
compound.
Table 5. Organoleptic and Physicochemical Characteristics of Emulsions
viscosity (cps)
surfactant
emulsion
pH
0.5 rpm
1 rpm
color
yellow
appearance
7
basic W/O 1
basic W/O 2
basic W/O 3
fluid O/W 4
cream O/W 5
fluid O/W 6
cream O/W 7
fluid O/W 8
cream O/W 9
not determined
too viscous
too viscous
too viscous
8900
homogeneous
homogeneous
homogeneous
homogeneous
homogeneous
homogeneous
homogeneous
homogeneous
homogeneous
8
not determined
white
9
not determined
pale yellow
yellow
11
11
12
12
13
13
7.50
7.02
6.69
5.65
7.65
6.27
5300
too viscous
1800
yellow
1050
4200
5550
white
6300
white
7400
pale yellow
pale yellow
too viscous
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Journal of Agricultural and Food Chemistry
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Figure 5. Structures of ferulic (1a) and caffeic (1b) acids and some of their derivatives tested for scavenging activity against the DPPH radical.
Table 6. DPPH Radical Scavenging Activity
(5) Marchesi, F.; Azrak, G. Bio-compatible multifunctional co-
surfactant derived from natural origin. Household Personal Care Today
2009, 1, 54−57.
inhibition of DPPH
SD (%)
inhibition of DPPH
sample
sample
SD (%)
(6) Pantini, G.; Ingoglia, R.; Brunetta, F. PFPE phosphate: a multi-
functional material. Cosmet. Toiletries 2001, 116, 81−92.
(7) Pantini, G. Using perfluoropolyether phosphate to lower pH
without increasing skin irritation. Cosmet. Toiletries 2005, 120, 79−88.
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Laneri, S. Perfluoropolyether phosphate and skin renewal: the
therapeutic index. Cosmet. Toiletries 2007, 122, 53−60.
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Evans, C. A. Novel biomarkers of the metabolism of caffeic acid
derivates in vivo. Free Radical Biol. Med. 2001, 30, 1213−1222.
(10) Ley, J. P. Phenolic acid amides of phenolic benzylamines against
UVA-induced oxidative stress in skin. Int. J. Cosmet. Sci. 2001, 23, 35−48.
(11) Saija, A.; Tomaino, A.; Lo Cascio, R.; Trombetta, D.;
Proteggente, A.; De Pasquale, A.; Uccella, N.; Bonina, F. Ferulic and
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1a (ferulic acid)
19.52 0.15
51.09 0.18
16.30 0.42
3.14 1.40
5
27.33 0.26
7.79 0.22
5.10 0.15
1b (caffeic acid)
9
3
4
12
The radical-scavenging activity of these molecules also seems
interesting. These experimental data are still only preliminary,
obtained by applying a model in homogeneous solution.
These new cosmetic ingredients hold promise in view of
their potential application because they conform to the re-
quirements of the cosmetic field, such as natural derivatization
and multiple activity. They might prove useful in antiaging
creams and UV sunscreens.
AUTHOR INFORMATION
(12) Srinivasan, M.; Sudheer, A. R.; Menon, V. P. Ferulic acid:
therapeutic potential through its antioxidant property. J. Clin. Biochem.
Nutr. 2007, 40, 92−100.
■
Corresponding Author
*Postal address: Centro Interdipartimentale di Scienza e
Tecnologia Cosmetiche, University of Siena, Via della Diana
2, 53100 Siena, Italy. Phone: +39 577 232039. Fax: +39 577
232070. E-mail: anselmic@unisi.it.
(13) Son, S.; Lewis, B. A. Free radical scavenging and antioxidative
activity of caffeic acid amide and ester analogues: structure-activity
relationship. J. Agric. Food Chem. 2002, 50, 468−472.
(14) Husmann, M.; Weisse, J.; Wragg, P.; Wasko, J. PERLASTAN®
surfactants derived from naturally-occurring amino acids. Cosmet. Sci.
Technol. 2008, 194.
ACKNOWLEDGMENTS
■
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acids and peptides I. The synthesis of N-feruloylamino acids. Bull. Soc.
Chim. Belg. 1973, 82, 243−257.
We thank Tsuno Rice Fine Chemical for supply of ferulic acid.
(16) De Pooter, H.; Haider, A.; Van Sumere, C. F. N-Acylamino
acids and peptides II. The synthesis of N-feruloylglycyl-(L and DL)-
phenylalanine. Bull. Soc. Chim. Belg. 1973, 82, 259−269.
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