Amino Acids as Raw Material for Biocompatible Surfactants - Industrial

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Amino Acids as Raw Material for Biocompatible Surfactants Aurora Pinazo,* Ramon Pons, Lourdes Perez, and Maria Rosa Infante Institut de Química Avanc-ada de Catalunya, CSIC Barcelona, Spain ABSTRACT: Surfactants are chemical products consumed in large quantities every day on a worldwide scale. The development of less irritant, less toxic, consumer-friendly surfactants is, therefore, of general interest. Amino-acid-based surfactants constitute a novel class of surfactants produced from renewable raw materials and can be seen as an alternative to conventional surfactants. With the aim of testing their applicability in formulations for pharmaceutical, food, and cosmetic industries we have carried out exhaustive studies to elucidate their properties as surfactants. We considered amino acid-based surfactants with one single chain, cystine or arginine gemini surfactants, lysine derivatives, and surfactants with glycerolipid-like structure.

1. INTRODUCTION Surfactants are chemical products consumed in large quantities every day on a worldwide scale. In recent years, environmental concerns and regulatory pressure have provided the driving force to replace petrochemical-based surfactants partly with those based on naturally occurring renewable sources. The hope that such surfactants would be biodegradable and biocompatible has provided strong incentive for the research of less irritant and less toxic consumer-friendly surfactants. Generally speaking, biobased products are commercial or industrial products composed in whole or in a significant part of biological products or renewable domestic agricultural materials including plants, animal, and forestry materials. In particular, amino-acid-based surfactants are biobased products of which the hydrophilic part is obtained by enzymatic synthesis1 or protein hydrolysates2 and the hydrophobic part is obtained from natural oils.3 Interest in amino-acid-based surfactants traces back to 1909 when for the first time a hydrophobic group was anchored to both glycine and alanine to obtain N-acyl glycine and N-acyl alanine.4 Since then, amino-acid-based surfactants have been the subject of many studies, because of their huge potential applications in pharmaceutical, cosmetic, household, and food products. The amino-acid-based surfactants are derived from acidic, basic, or neutral amino acids. Amino acids such as glutamic acid, glycine, alanine, arginine, aspartic acid, leucine serine, proline, and protein hydrolysates have been used as starting materials to synthesize amino-acid-based surfactants both commercially and experimentally.5 Currently, amino acid surfactants are commercially applied in a number of different areas. Examples are cosmetics (toothpaste, wound cleaners, personal care, shampoo, bubblebath pastes, and aerosols), flooding agents in oil recovery, and reducing agents in corrosion inhibition. More recently, it has been shown that amino acid esters and amides have excellent emulsifying properties and strong antimicrobial properties, which make them an attractive alternative as food additives.6 Our interest is focused on surfactants that are cationic, biodegradable, show low toxicity, and exhibit antimicrobial activity. Biodegradability, low toxicity, and antimicrobial activity are properties common to surfactants derived from amino acids. Among the amino acids with cationic behavior, we chose cystine, arginine, r 2011 American Chemical Society

and lysine. Therefore these amino acids have been the starting point for our developments of new surfactants.7-13 In this paper, we give an overview of our research in the field of cationic amino-acid-based surfactants. Results are presented following the surfactants structure. We consider four different structures: (1) linear or single chain surfactants with one arginine residue as polar head linked to a hydrophobic tail; (2) gemini surfactants consisting in two hydrophilic (cystine or arginine amino acids) and two hydrophobic groups per molecule linked through a spacer chain. (3) double chain surfactants derived from lysine; (4) a glycerolipid like structure with one or two fatty chains and arginine as polar head, linked together through an ester bond in the glycerol backbone. For each structure, we describe the behavior concerning adsorption and aggregation properties. These properties are paramount to elucidate whether our amino acid structures can be applied to fields like spreading aids, cleaning agents, foam, and emulsion stabilizers in cosmetic and pharmaceutical formulations.

2. SINGLE CHAIN AMINO-ACID-BASED SURFACTANTS Single chain amino-acid-based surfactants combine charged or no charged residues (i.e., glutamic acid, lysine, arginine, serine, leucine) as the hydrophilic headgroup with a hydrophobic tail of different structure and length14-19 (i.e., fatty acids, alcohols or amines, Figure 1). Thus, synthetic lipoamino acids could be anionic, cationic, nonionic, or amphoteric compounds depending on the structure of the lipoamino acid. They have in common that are chiral molecules in which the hydrophilic/hydrophobic moieties are linked by ester (1 in Figure 1) and amide (2 and 3 in Figure 1) linkages. This fact explains the diversity of single chain amino acid-based surfactants and the variety of their physicochemical and biological properties.20-24 Among the single chain amino acid-based surfactants that we have developed and studied,25,26 cationic surfactants derived from Special Issue: Puigjaner Issue Received: July 6, 2010 Accepted: December 2, 2010 Revised: November 29, 2010 Published: January 07, 2011 4805

dx.doi.org/10.1021/ie1014348 | Ind. Eng. Chem. Res. 2011, 50, 4805–4817

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Figure 1. Different types of single chain amino acid-based surfactants: (1) O-alkyl esters, (2) N-alkyl amides, and (3) N-acyl amino acids.

arginine have shown the most promising properties. These surfactants were synthesized using aqueous media27 and enzymatic biotechnological methods.28 Compounds properties studied include toxicity, profiles of metabolism, mutagenicity, chronic, subchronic, and acute toxicity, dermal and ocular irritation, and ecotoxicity and biodegradability.29-32 2.1. Single-Chain Cationic Surfactants from Arginine Amino Acid. Long-chain cationic surfactants from arginine amino acid (Figure 2) are surfactants with a satisfactory toxicity profile, high biodegradability, and excellent antimicrobial properties against bacteria, fungi, and yeast.33 We have shown that essential structural factors for their antimicrobial activity include both the fatty residue length and the presence of the protonated based (guanidine or amine) function.34,35 This activity clearly results from a combination of the interfacial activity of the compounds and the ionic structure of their hydrophilic portions. These properties make them good alternatives for a wide range of industrial applications in the personal care, pharmaceutical, and food sectors as well as in the design and synthesis of biomaterials. 2.1.1. Adsorption and Aggregation Properties. Basic physicochemical properties that characterize surfactant solution are critical micellar concentration (cmc), surface tension at the cmc (γcmc), the maximum surface excess concentration at the air/ aqueous solution interface (Γ m), and the area per molecule (Amin) that measures the minimum area per surfactant molecule at air/aqueous solution interface. The cmc is determined from the break point of the surface tension versus concentration curves. From these curves, we can figure out both Γm and Amin using the Gibbs adsorption equation.36 Adsorption and self-aggregation in aqueous media at a range of concentrations and in either presence or absence of other components were evaluated for single chain arginine-based surfactants.37,38 Table 1 summarizes the cmc and the calculated parameters.30,33,39 All compounds show a surfactant character because they lower the surface tension of water and have the

ability of self-aggregate in aqueous media showing a significant cmc value. The values in Table 1 show that cmc values decrease as the number of methylene groups on the alkyl chain length increases. This is a general trend for saturated monoalkyl chain surfactants.36 In contrast, it is not clear whether the number of positive charges on the polar head has an influence on the cmc value because the cmc of LAM (one positive charge) is 5.8 mol m-3 while the cmc of ALA and ALE (surfactants with two positive charges) are 1.8 and 5 mol m-3, respectively. Comparing argininebased surfactants with commercial surfactants with the same fatty chain length, the cmc of the LAM arginine derivative with 12 carbon atoms in the hydrophobic moiety is 1 order of magnitude smaller than that of the conventional dodecyl trimethyl ammonium bromide36 (DTAB) (ca. 15 mol m-3). Similarly, the cmc of the PAM is also smaller than that of the conventional cetyl trimethyl ammonium bromide (CTAB)36 (ca. 0.9 mol m-3). In monoalkyl chain surfactants36 as the charge on the ionic group gets closer to the R-carbon atom of the hydrophobic group, the cmc increases. In the quaternary ammonium surfactants salts the cationic charge is very close to the R-carbon while in the arginine derivative surfactants the group that supports the charge and the R-carbon are linked through five -CH2- groups. Moreover, the effectiveness of these surfactants in reducing surface tension (γCMC around 35 mNm-1) is also higher to those reported for common cationic surfactants (γCMC around 40 mNm-1). 2.1.2. Aggregates Geometry. Once aggregation was established, we applied light scattering and small angle X-diffraction Scattering (SAXS) to study the aggregates geometry. N-acyl amino acids assemble in micelles and liquid crystalline phases in a way similar to that of conventional surfactants. The homologues with shorter carbon atoms tend to form spherical micelles while the homologues with fatty chains of 14-16 carbon atoms tend to form cylindrical aggregates.40 Owing to the amino acid residue 4806

dx.doi.org/10.1021/ie1014348 |Ind. Eng. Chem. Res. 2011, 50, 4805–4817


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Figure 2. Chemical structure of single chain arginine based surfactants: N-decyl arginine methyl ester (CAM), N-dodecyl arginine methyl ester (LAM), N-tetradecyl arginine methyl ester (MAM), N-hexadecyl arginine methyl ester (PAM), N-decyl arginine amide (ACA), N-dodecyl arginine amide (ALA), N-tetradecyl arginine amide (AMA), arginine octyl ester (AOE), arginine decyl ester (ACE), arginine dodecyl ester (ALE).

chirality, N-acyl amino acids present different aggregation shapes when spatial interactions between enantiomers take place.41,42 2.1.3. Phase Behavior. We explored phase behavior of single chain arginine-based surfactants, including structural characterization of CAM, LAM, MAM, and PAM (see Figure 2) as a function of the alkyl chain length and components. Different techniques have been used to obtain the phase diagrams of these compounds: optical microscopy, light scattering, spectrofluorimetry, Fourier transform pulsed gradient spin-echo nuclear magnetic resonance, and dielectric spectroscopy.37,38,35,43 Light microscopy showed that in water/surfactant binary systems, after exceeding the solubility limit of micelles (Krafft temperature) at 25 °C lyotropic liquid crystals of hexagonal (CAM, LAM, MAM, PAM), cubic (LAM, MAM, PAM), and laminar (MAM, PAM) structure appear as a function of the chain length, the hexagonal

liquid crystal being the more favored structure in LAM (Figure 3). As the length of the alkyl chain increases, the concentration at which the liquid crystal phases appear decreases and the temperature increases. CAM form hexagonal phases at 11 °C and 45%, LAM at 24 °C and 27%, MAM at 36 °C and 22%, and PAM at 44 °C and 20%. These results agree with the traditional phase progression predicted for single chain surfactants: as concentration increases in the micellar solution phase, the liquid crystal transitions are first hexagonal, then bicontinuous cubic, and finally become lamellar liquid crystal. In fact, a similar behavior has been reported for the DTAB44 and CTAB.45 The DTAB/water phase diagram showed that at 20 °C and 56% of surfactant a hexagonal phase appears. A cubic phase was observed at 35 °C; at higher temperature and concentration a lamellar phase was formed. The phase diagram obtained for the 4807



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CTAB/water system45 also showed the formation of a hexagonal phase (32 °C and 25%), a cubic phase (40 °C and 76%), and a lamellar phase (50 °C and 87.5%). Ternary systems consisting of water, an alcohol with a chain length in the range (C5-C16), and one of the four N-acyl arginine homologues were studied. In general, in all of them three different monophasic regions were identified: direct micelles, inverse micelles, and laminar liquid crystals. Microemulsion formation in the presence of hydrocarbon components (hexadecane, squalene, and toluene) was also studied.38 Reversed vesicles in a system containing lecithin-LAM/squalene/water were also described by Kunieda.46 2.2. Applications. Currently, the LAM homologue of series a described in Figure 2 is a commercial product. In the food sector, it is known as Mirenat, and Aminat is the commercial brand for cosmetics. They are manufactured by Vedeqsa, Inc. (Les Fonts de Terrassa, Catalonia) which were sold as preservatives with antimicrobial properties.47 Ajinomoto Co., Inc. (Japan) also offers a large number of surfactants derived from amino acids for applications ranging from cosmetics to detergents. We have conducted preliminary studies on different mixtures of cationic arginine-based surfactants (O-lauryl arginine amide, ALA, and NR-lauroyl arginine methyl ester, LAM) with different anionic surfactants in water. They spontaneously form vesicles, cubosomes, and hexosomes dispersed particles with a hexagonal internal structure. The cationic vesicles formed by these argininebased surfactants actually encapsulate DNA.48-51 Given that the Table 1. Adsorption and Aggregation Properties of Single Chain Arginine-Based Surfactants at 25°C γcmc

cmc series

compound

a

CAM

c

a

At 40 °C.

(mol m )

Γmax

Amin -2

14

2

(mN m )

(10 mol m )

(nm )

40

3.6

0.47

5.8

32

2.5

0.67

MAM

2.0

32

ACA

16

-1

LAM PAMa b

-3

0.2 26

35

2.68

0.62

ALA

1.8

37

1.85

0.90

AMA AOE

0.7 38

33 35

1.46 1.73

1.14 0.96

ACE

13

34

2.27

0.72

ALE

5

30

1.37

1.22

reduction of the toxicity effects in sensitive organs becomes imperative in biological applications, the use of these biocompatible surfactants are promising. Lipoamino acids are also particularly attractive as antiviral agents. Certain acyl amino acid derivatives (palmitoyl glycine, palmitoyl valine, palmitoyl alanine, palmitoyl leucine, palmitoyl phenylalanine, palmitoyl histidine and palmitoyl tryptophan) have been found to produce inhibition on influenza neuraminidase.26 A number of N-palmitoylated amino acids have been incorporated into model membranes affecting the transition temperature between the bilayer to hexagonal aggregation, a property associated with antiviral activity against the Cantell strain of the Sendai virus (parainfluenza type).

3. GEMINI SURFACTANTS There are several reasons for the current interest in gemini surfactants in both academia and industry.52 Comparing gemini and their monomeric counterparts, Gemini surfactants have cmc values that are up to 2 orders of magnitude lower than the monomeric ones therefore they are more efficient in decreasing the surface tension of water at very low concentrations. The savings coming from using smaller amounts of surfactant needed for a given effect are larger than the relative higher production cost. Besides, some gemini surfactants with short spacer chain have very high viscosity at low concentration what results in a potential use as hydrogelators.53 Our group has developed and studied gemini surfactants based on two different amino acids: cystine and arginine. Cystine derivatives were synthesized having in mind possible textile application while the goal of arginine derivatives was to promote antibacterial properties. 3.1. Cationic Gemini Surfactants from Cystine Amino Acid. The number of technological processes that demand specific surfactants is growing rapidly.54 In this field, two gemini surfactants have been developed: NRNR0 bis(N-lauryl-NN-dimethyl glycine) cystine dimethyl ester dihydrochloride (DABC) and NRNR0 bis(N-lauryl-NN-dimethyl glycine) cystamine dihydrochloride (DABK)55,56 (see Figure 4). Their targets were applications in keratin finishing as well as in cosmetics and pharmaceuticals as powerful antimicrobial agents.57 The disulfide bond present in these compounds constitutes a potentially reactive group capable of reacting with thiol groups of reduced keratin fibers, providing a good covalently bonded substrate for the attachment of anionic dye molecules. 3.1.1. Adsorption and Aggregation Properties. The equilibrium and dynamic surface tension of aqueous solutions of cationic

Figure 3. Optical microscope images of the hexagonal and cubic liquid crystal phases formed for LAM (A) and the laminar liquid crystal phase formed for PAM (B). 4808



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gemini surfactants from cystine amino acid were studied with the Wilhelmy plate tensiometer or with a bubble surfactometer.58 Dynamic surface tensions were measured under constant area conditions (bubble radius R = 0.40 mm). In the bubble surfactometer, one measures the pressure differences across the bubble interface and calculates the static or dynamic surface tension via the Young-Laplace equation. The surface tensions obtained by the two methods were quite similar; however, cmc values yielded by the plate method were higher than those yielded by the bubble method. There is not a clear reason for these differences. One the one hand, if strong adsorption of the cationic surfactants on the Wilhelmy plate produces hydrophobicity, a smaller cmc for the plate method would be expected. On the other hand, slow adsorption of the molecules at the surface can be responsible for a higher apparent cmc if not enough time is allowed to reach the equilibrium. This can be a problem at very low concentrations where time to reach the equilibrium amount to hours. The

Figure 4. Schematic structure of cationic gemini surfactants DABC and DABK.

Table 2. Critical Micellar Concentration and Adsorption Equilibrium Parameters for DABC, DABK, and DABB surfactant method

cmc (mM)

Γm x 1014 (mol m-2) KL (m3 mol -1)

DABC

plate

0.065 ( 0.010

0.9 ( 0.1

DABC

bubble 0.040 ( 0.010

0.6 ( 0.1

6 ( 4.5 103 8 ( 7.0 104

DABK

plate

0.120 ( 0.020

0.6 ( 0.1

2.6 ( 1.7 104

DABK

bubble 0.070 ( 0.015

0.5 ( 0.1

2.2 ( 2 105

DDAB

bubble 0.180 ( 0.020

1.0 ( 0.1

5.6 ( 2 102

premicellar data were fitted to the Szyskowsky equation.36 The fitting of Szyskowsky equation provides two parameters, the Langmuir adsorption equilibrium constant KL and the maximum adsorption density, Γm (Table 2), which were used subsequently for predictions of dynamic tensions.59 The areas per molecule, obtained from the maximum adsorption density, are higher than what would be expected based on the projected molecular areas. These high values reflect the large size of the polar groups, and probably the strong intermolecular repulsions (in the packed monolayer) due to the dicationic character of the surfactant. Probably, the dicationic nature is also responsible for the relatively low surfactant efficacy (minimum surface tensions above 30 mN m-1). The adsorption equilibrium constants indicate that both compounds were quite surface active (Table 2), and were in fact more active than the monomeric building block, DDAB.60 DABK has a slightly higher adsorption equilibrium constant than DABC, and takes longer to equilibrate. The cmc of monomeric counterparts of cystine derivatives is about 0.180 mM while the cmc of gemini surfactants derived from cystine are in the range 0.04-0.07 mM; that is, the cmc values for Gemini compounds are 3 to 4 times smaller than those of the monomeric counterparts. In section 3.2 we will learn that cmc reduction of gemini arginine derivatives show a cmc reduction of 3 orders of magnitude with respect to the monomeric counterpart. However, since the monomeric counterpart is amphoteric and gemini surfactants are cationic, comparing behaviors has limited value in assessing their relative performance. Comparing cmc of Gemini cystine derivatives to cmc of similarly charged quaternary ammonium derivatives (see the last row in Table 3), we see that the increase in efficiency reaches the expected reduction of about 2 orders of magnitude. For dynamic tensions under constant area, the surface tension decreases much more slowly with time than is predicted by diffusion-limited models,59 indicating that there is a strong barrier to adsorption at the surface. It was postulated that the barrier is primary of electrostatic origin,61 although steric or other effects cannot be ruled out. Similar results were obtained for DABK, except that the equilibration was a bit slower at the higher concentrations. The presence of micelles affects strongly the dynamic adsorption rate but not the equilibrium surface tension, indicating that the rate of micellar dissociation is fast relative to the net rate of adsorption. 3.1.2. Applications. These results obtained with cationic gemini surfactants from cystine were relevant for designing coating, wetting, and foaming formulations with these surfactants, and could provide useful insights into their hair/wool-dyeing applications. Because the

Table 3. Summary of cmc's of Aqueous LAM and Cs(LA)2 Surfactant Solutions with Different Techniques LAM method

cmc, mM

C3(LA)2 cmc1, mM

C6(LA)2 cmc2, mM a

C9(LA)2

cmc1, mM

cmc2, mM

cmc1, mM

cmc2, mM ND

surface tension

6

0.005

ND

0.002

ND

0.003

fluorescence

5

ND

0.4

ND

0.4

ND

0.3

ion activity

6

ND

0.4

ND

0.6

ND

0.3

conductivity

6

ND

0.5

ND

0.4

ND

0.3

conductivity

DTABb

12-3-12b

12-6-12b

12-8-12/12-10-12b

16

0.96

1.03

0.83/0.93

a

ND: not detected. b Dodecyl trimethyl ammonium bromide (DTAB) and dodecyl-bis(dimethyl alkylammonium bromide) [bisquaternary ammonium salts].67 4809



Figure 5. Chemical structure of the bis(Args) surfactants, Cn(LA)2). In the acronym n is the number of the carbon atoms on the spacer chain, n = s þ 2.

efficiency and efficacy of these gemini surfactants are not improved to the degree that can be expected for these structures when compared to the monomeric forms, the question arises whether the identification gemini-high efficacy is general or not. 3.2. Cationic Gemini Surfactants from Arginine Amino Acid. In the last decades, new gemini cationic surfactants, bisquaternary ammonium salts with halides or “bis-quats”, have been synthesized and studied extensively.62 These compounds are double-head surfactants in which two alkyldimethyl quaternary ammonium groups are linked by a hydrocarbon spacer chain. Surfactants with this architecture have been shown to reduce surface tension, adsorb to surfaces, and self-aggregate at considerably lower concentrations than their monomeric building blocks. Owing to their extraordinary surface activity and antimicrobial activity, they are regarded as an outstanding new generation of cationic surfactants with excellent performance with regard to solubilization, soil cleanup, and oil recovery. However, these molecules have a high chemical stability, which is associated to a poor chemical and biological degradability; this results in an elevated risk of toxicity to aquatic organisms; thus, they could be ecologically unacceptable.63 The environmental impact of “bisquats” has been addressed by preparing gemini surfactants from lower impact building blocks such as single chain arginine-based surfactants. In 1996 new classes of gemini cationic surfactants, bis(Args), were synthesized64 from amino acid sources like arginine as a means to reduce the potential ecological risk of “bisquats”. The chemical structure of these compounds is shown in Figure 5. Gemini cationic surfactants consist of two symmetrical long chains NR-acyl-L-arginine residues of 12 carbon atoms linked by amide bonds to an R,ω-alkylenediamine spacer chain of varying length (s = 1, 4, and 7). The first approach used to prepare these compounds involved chemical protecting groups, organic solvents, and chemical catalysts.64 Later, a strategy to reduce the environmental impact was developed. To this end, a novel chemo-enzymatic synthesis of bis(Args) was described.65 The study of the solution behavior of surfactants, particularly concerning self-aggregation and adsorption from solution, is important to determine their possible applications in uses like agrochemical spreading aids, cleaning agents, foam and emulsion

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stabilizers. Surface tension of aqueous solutions of bis(Args) were studied66 and compared to those of corresponding monomeric surfactant, LAM (see Section 2.1). Unconventional aggregation behavior and two cmc's were inferred from tensiometry, fluorescence, conductivity, and ion activity techniques for gemini surfactants (Table 3). Values for the first cmc, denoted cmc1, inferred primarily from tension data and indirectly supported by chloride ion activity and conductivity data, are between 0.002 and 0.005 mM and are about 1000-3000 times smaller than that of LAM. This suggests that the gemini's equilibrium surface activity is 1000 times higher than that of their monomeric counterpart. Fluorescence and ion activity data indicated clearly a conventional cmc, denoted cmc2, at about 0.3-0.6 mM, which is about 2 orders of magnitude higher than that yielded by tension measures. The cmc values obtained from conductivity are comparable to those obtained from conductivity for quaternary ammonium salts (Table 3). The comparison proves conductivity determines a unique critical micellar concentration where globular aggregates are formed. The low-concentration cmc1 may be attributed to two different causes. One is formation of nonglobular aggregates with small aggregation numbers, larger than two or three, that accounts for the nearly constant monomer activity and nearly constant tension above cmc1. The other reason is the small counterion binding parameters. To interpret the conductivity results, micellization and conductivity models for monovalent ionic surfactants68,69 were extended to dicationic surfactants.66 Results yielded by the calculations were consistent with the above inferences and were used to estimate the aggregation number (N) and the counterion binding parameter (β). The nonglobular aggregates have lower β and smaller N values than the globular aggregates (micelles). However, unlike conventional micelles, nonglobular aggregates tend to increase the molar conductivity compared to that of the pre-cmc solution. At concentrations higher than cmc2, strong and diverse evidence shows that surfactants form globular micelles, that their degree of counterion binding is higher, and that their molar conductivity is smaller. This also agrees with the cmc values obtained from fluorescence. However, an alternative explanation based on a strong pKa shift of the guanidinium groups, observed later with diacyl glycero arginine derivatives surfactants,70 would also agree with an increased molar conductivity at low concentrations (conductivity due to increased proton concentrations). Strong pKa shifts have indeed been observed in arginine-based diacyl surfactants. The reduction of charge of the surfactant with the concomitant monomer solubility reduction would give rise to low cmc values and the formation of big lamellar type aggregates at very low concentration, which would reduce their size with increasing concentration. The bis(Args) gemini surfactants form two types of aggregates, which may play a role in the solution behavior, and the practical properties of these surfactants. An important question is how do the dynamic surface properties of gemini surfactants, often reported to show long equilibration times71 compared to those of LAM. The dynamic surface tension behavior of gemini surfactants were studied and compared to that of their monomer, LAM.72 The adsorption of the gemini surfactants above cmc1 is quite slow, but becomes faster between the first and second cmc and even faster above the second cmc. The parameter tγ50, for the tension to drop 50% of its total equilibrium change, decreasing with increasing concentration of each surfactant, correlates best with the reduced concentration, c/cmc2 or c/cmc, for LAM. 4810



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Table 4. Gemini Surfactantsa cmc (mM) RMN

Dmic 1010 (m2 s-1)

Dmon 1010 (m2 s-1)

Rmon(T) (nm)

Rmon (nm)

Rmic (nm)

N

LAM

4.3

0.90

3.6

0.53

0.55

2.2

48

C3(LA)2

0.3

0.59

2.6

0.67

0.77

3.4

88

C6(LA)2

0.1

0.61

2.7

0.68

0.74

3.3

79

C9(LA)2

0.2

0.53

2.2

0.69

0.89

3.8

116

a The cmc, free monomer diffusion coefficient (Dmon), and micelle diffusion coefficient (Dmic), were obtained from the NMR diffusion experiments. The theoretical hydrodynamic radius of the monomer, Rmon(T), hydrodynamic radius of the monomer, Rmon, hydrodynamic radius of the micelle, Rmic, aggregation numbers were also calculated.

The tension equilibration slows down a lot at longer times for the tension to drop 95%, tγ95 being much larger than tγ50 from what would be expected for diffusion-controlled adsorption. The ability of geminis to form stable foams, as measured by the maximum foam heights and the foam stability time, increases as the concentration increases up to about half the cmc2 (or cmc for LAM). The foam lifetime decreases (foam becomes less stable) as the tension equilibration time increases. The gemini surfactants are extraordinarily more efficient than LAM for the equilibrium surface tension (1000 times) and significantly more efficient for the tension equilibration and foam stability (about 20 times). The effect of the spacer length on the shape and size of the micelles formed by bis(Args) has been studied by SAXS and pulsed-gradient spin echo (PGSE-NMR). The results were compared with those obtained for their single chain homologue LAM.73 The PGSE-NMR experiment allowed us to obtain the self-diffusion coefficients of the surfactant at 25 °C using standard procedures.74 From the NMR data we obtained the cmc, the monomer diffusion coefficient (Dmon) and the micelle diffusion coefficient (Dmic) (Table 4). From Dmon and Dmic and using the Stokes-Einstein equation we calculated the hydrodynamic radius for the monomer (Rmon) and for the micelles (Rmic) (Table 4). From the Rmic we determined the aggregation number, and from the molecular weight the theoretical hydrodynamic radius of the monomers was calculated, Rmon(T). Whereas for the LAM, Rmon(T) is similar to that obtained from the diffusion coefficient, for the gemini compounds the Rmon is higher than the Rmon(T). This suggests the presence of small aggregates, dimers, and trimers, before the cmc. These observations agreed with the above-mentioned interpretation of the two cmc's as produced by a first aggregation in small aggregates with low counterion binding and a second cmc corresponding to the formation of globular aggregates.66,71 The high aggregation number obtained for the bis(Args) indicates the formation of large aggregates. It was also observed, by NMR, that, for the C9(LA)2, the intensity of the signals of the simple proton experiment decreases as a function of time. The main peak of the spectrum, corresponding to the -CH2- groups of the alkyl chain, losses half of the intensity after one day and about 80% in six days. This reduction in intensity can be explained by the formation of big aggregates and the subsequent broadening of the NMR peaks due to the slow local anisotropic motions of the alkyl chain, as it is usually observed in vesicular systems.75 Analysis of data with SAXS indicated that LAM compound formed spherical micelles and gemini surfactants C3(LA)2 and C9(LA)2 formed cylinders. For the C9 (LA2) a time evolution of the scattering curves in the region of the structure factor was detected. The intensity at small scattering vector decreased while an increase of the viscosity of the solution was observed. This could

indicate a development of a long-range order with cylindrical aggregates. This agreed with the NMR observation of a reduction of the signal intensity with the time due to the formation of large aggregates. Aggregation behavior of NMR consistently agreed with results obtained by SAXS. Classical spherical micelles were observed for the LAM. Moreover, bigger micelles, which can be considered of cylinder shape, were observed for the three gemini surfactants. This type of aggregation has been also described for bis quaternary ammonium surfactants or bis(Quats) with a short spacer chain.76 The microstructures formed in high concentrated aqueous solutions of bis(Args) have been studied by cryogenic-temperature transmission electron microscopy (cryo-TEM).77 At the lowest concentrations, the single chain LAM forms spheroidal micelles while the gemini surfactants form twisted-ribbons, flatribbons, and threadlike ribbons. The results obtained were in concordance with those obtained by NMR: bis(Args) tended to form aggregates of lower curvature than the corresponding monomeric surfactant LAM. In the short spacer bis(Args) molecule, n = 3, the microstructures observed were spheroidal micelles that changed to threadlike micelles and disklike structures as the concentration was increased. The bis(Args) molecules with longer spacers exhibited lower-curvature microstructures, mainly flat and twisted-ribbons. Studies on gemini surfactants derived from amino acids cystine and arginine showed that in both cases higher efficiency than that of single chain surfactants can be obtained. Quaternary ammonium cystine based surfactants show the expected reduction in cmc for dimerization. cmc values of arginine based gemini surfactants obtained from surface tension are extremely low while cmc values obtained from conductivity and other bulk methods are similar to those of “bis(Quats)”. The second cmc may correspond to the formation of globular structures that can be classified as regular micelles however, the cmc at very low concentration has not been univocally determined. Some results are congruent with highly charged small size aggregates, others agree with big noncharged entities.

4. DOUBLE CHAIN SURFACTANTS FROM LYSINE AMINO ACID Lysine amino-acid-based surfactants have been synthesized in a variety of structural forms.78 Because of the possibility of linking the hydrophobic group through the carboxylic group and the two amino groups, this amino acid offers a wide range of different possible structures for surfactant formation. The fatty chain can be introduced into the lysine amino acid structure through acyl, ester, alkyl or amide linkages. Given the chemical duality of amine and carboxylic acid groups in the amino acid building block, the 4811



Figure 6. Schematic chemical structure of symmetrical NR,Nε-dilauroyl lysine where R can be (a) -NH-(CH2-CH2-O)n Me, (b) -N[ (CH2-CH2-O)n Me]2, (c) -OH, (d) -OMe for nonionic derivatives, and (e) -O Na, -O Lys, -O K, -O Li, -O Tris for anionic derivatives.

ionic nature of the amphiphile lysine derivatives depends on the pH and on the specific structure modification undergone by the surfactant. The synthetic surfactants can yield anionic, cationic, amphoteric, or nonionic derivatives. This wide range of functionalities displayed by lysine amino acid is a great asset where any fine-tuning of the surfactant's performance is concerned; therefore, these features have made them attractive for applications in cosmetics and personal-care products, food, and pharmaceutical formulations. 4. 1. Adsorption and Aggregation Properties. Micellization of NRNε-diacyl lysine compounds with symmetric diacyl chains (Figure 6) have been studied both as nonionic and anionic compounds.79-82 Seguer et al.79,80 studied the micellization properties of the nonionic NRNε-diacyl lysine oxyethylene (OE) derivatives (Figure 6a,b). The ethylene oxide chains increase the water solubility of the products and allow for cmc determination in aqueous unbuffered solutions. Two series of compounds were studied: A single OE chain (Figure 6 a, R = -NH-(CH2-CH2-O)n Me) and two OE chains (Figure 6b, R = -N-[ (CH2-CH2-O)n Me]2) bonded to the same amino group. The cmc and surface tension reduction for the two ethylene oxide derivatives were similar to that of single chain alcohol ethoxylates with the same hydrocarbon chain length and a similar number of ethylene oxide units in the headgroup,36 and much bigger than that of the corresponding lecithins with the same chain length.83 The cmc of the single ethylene oxide chain per headgroup derivatives was smaller than that of derivatives with two chains in the headgroup. Dihexanoyl derivatives with a single ethylene oxide chain in the headgroup presented cmc values of 30-50 mM and 57 mM for the double ethylene oxide derivative. Single ethylene oxide chain dioctanoyl derivative cmc was 1.6 mM, while that of double ethylene oxide chain derivatives was around 6 mM. The cmc of the didecanoyl derivative double ethylene oxide chain was around 1 mM. These findings could indicate that the aggregate formed by these compounds depends essentially on the length of each chain and not on the total number of methylene units. It is possible that the two hydrophobic chains in one molecule of surfactant could interact in such a way that their global hydrophobic effect could be comparable to that of one chain. For lecithins, the contribution of the hydrophobic groups to the cmc value differs from those of double chain surfactants from lysine. An increase in two units of methylene groups per chain in the

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0

Figure 7. Chemical structure of the Nε,Nε -bis(n-acyloxypropyl) lysine methyl ester salts.

lecithins decreased its previous value by 50 units.83 These results presumably indicate that, in the lecithins, the two short chains contribute to the completely molecular hydrophobic character, whereas in the lysine derivatives only one chain was responsible for the whole hydrophobicity in the molecule. Differences could be attributed to the different structure of the central pivot in the trifunctional lysine amino acid and to the higher hydrophilicity of the amide groups when compared with the glycerol and ester groups present on the structure of lecithins. Having in mind possible biocompatible applications, interaction of oxyethylene diacyl lysine with short chain phospholipids like dilauroyl phosphatidylcholine (DLPC) was studied applying surface tension methods that included Langmuir isotherm, equilibrium surface tension, and pulsating surface tension.84 Although the lysine-based surfactants were less surface active than DLPC, synergistic effects produce higher surface pressure values. Aqueous solution and aggregation properties of nonionic (Figure 6c) diacyl lysine surfactants and their salts (Figure 6d) have been reported.82 The cmc values are slightly higher than those of single chain surfactants with the same total carbon number. They present a cmc nearly independent of the counterion. The structures formed above the cmc are spherical or slightly ellipsoidal with a core shell structure according to SAXS data. The cmc of salts of diacyl lysine sodium salt surfactants have also been reported in aqueous media at 25 °C for didecanoyl (3.7 mM)85 and dioctanoyl (11 mM).86 These values roughly agree with those found for the acid derivatives in excess of sodium hydroxide. 4.2. Applications. Because of the biocompatible character of the diacyl lysine surfactants, one of the possible uses of these compounds is for phospholipids bilayer modifications in pharmaceutical preparations.

5. LYSINE BISGLYCIDOL CATIONIC SURFACTANTS Most recently, synthesis of a novel class of lysine-based cationic surfactants have been described.87 These compounds combine several hydroxyl functions and aliphatic chains with 12 or 14 carbon atoms. The chemical structure is shown in Figure 7. These new cationic surfactants show two main new features. First the polar group is a lysine methyl ester residue that confers a cationic character to the molecule linked to a bisglycidol chain, which is a residue of bis (2,3-dihydroxypropil) that carries from one to four aliphatic chains as a part of the hydrophobic moiety. Second, the lysine group is bonded to the polyol skeleton 4812



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Table 5. cmc Values Obtained by Different Techniques on Mono- and Diacyl-glycero Arginine Derivatives with One or Two Charges on the Headgroup compound

Figure 8. Vesicles light microscopic images of didodecanoyl lysine bisglycidol derivative solutions at 25 °C: (a) 2.5 mol m-3 and 5 mol m-3.

ST

conductivity

fluorescence

(mM)

(mM)

(mM)

100R

6a

120R

1.3a

140R

0.2a

88R 1010R

0.07b

5b e

pH

7b c

0.006

LS

(mM) (mM)

0.005e

1.1

0.04e 0.5e 1212R

b

b

0.008

0.25

0.12c

1212RAc 1414 RAc

Figure 9. Structures of glycerolipid-arginine-based surfactants. R0 in the structure can be H or -COCH3. R refers to arginine.

through an N-alkyl amine linkage, which provides increased chemical stability compared to the mono- and diacyl-glycerol arginine derivatives.88 The cmc values of single chain bisglycidol derivatives are similar to those of conventional cationic surfactants with the same chain length while the diacyl derivatives have a further cmc value reduction of an order of magnitude. As a fuction of the number of alkyl chains the compound aggregates as micelles or vesicles at very low concentrations (Figure 8). 5.1. Applications. Potential applications of these compounds are biocompatible cationic surfactants in the area of pharmaceutical and cosmetic formulations.

6. MONO- AND DIACYL-GLYCEROL AMINO-ACIDBASED SURFACTANTS Linkage of an amino acid to a glycerol backbone allows for the preparation of both diacyl glycero amino acids89,90 with a structure related to that of phospholipids, and monoacyl glycero amino acids91 (Figure 9) with a structure related to partial glycerides and lysophospholipids. Structures in the first family differ little from phospholipids. Structures in the second family correspond to a single hydrophobic-chain surfactant with a rather large hydrophilic headgroup. Because of their structure, the monoacylated surfactants will behave closer to classical surfactants while the diacyl surfactants will behave closer to phospholipids,

0.3

0.3b

1414R

a

b

0.002 -0.008 d

b

d

0.09c c

0.002d d

e

From ref 91. From ref 89. From ref 90. From ref 93. From ref 70.

showing a tendency to form lamellar structures when hydrated and rather insoluble monolayers at the water interface. 6.1. Aggregation Properties. Although systematically smaller, monoacyl glycero arginine derivatives (X0R in Figure 7) show cmc values comparable to those of other cationic single chain-single charge surfactants, see Table 5. This has been attributed to the distance from the R-methylene group of the hydrophobic chain to the charge: the closer the charge to the first methylene group the higher the solubility,36 The glycerol group with intermediate solubility sets apart the charge from the Rmethyl group by a significant distance in addition to the bulky arginine headgroup own distance. The dispersion of results obtained from different techniques on the cmc of the diacyl glycero arginine derivatives (XXR, XXRAc) (Table 5 and Figure 9), suggests that each technique must be detecting different phenomena. The differences have been attributed, in part, to the dissociation of proton in the headgroup. At very low concentrations, the proton equilibrium with water is shifted to give a significant amount of neutral surfactant species, which aggregate at very low concentrations. In fact, the light scattering results yielded by 1010R could represent only the limit of detection of the technique. As the concentration is increased, a higher proportion of molecules remain in its charged state and the critical micellar concentration of the charged species could be detected, moreover the change from lamellae to ribbon is achieved by further charging of the aggregates. Therefore, true critical aggregation concentration could even be lower; this was shown by observing similar changes when acidifying the media.70 The pKa shift of the arginine guanidinium group is quite large when compared to other pKa shifts induced by aggregation found in the literature.92 A possible rational for the large shift is that the structures formed are not spherical aggregates but lamellae for which the charge has a stronger influence. Formation of vesicles has also been systematically studied for 1212RAc, 1414RAc, LAM, and 140RAc.93 The size and electrical properties have been studied as a function of the mixing ratio with the anionic phospholipid, dipalmitoyl phosphate monosodium salt (DPPA) (Figure 10), forming pseudotetra and pseudotricatenary catanionic mixtures. Sonicated DPPA and both diacyl 4813



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Figure 11. Images of Brewster angle microscopy of (a) 1,2-glycerolbased amino acid surfactants, (b) 1,3-glycerol-based amino acid surfactants.

Figure 10. Particle size (open symbols) and ζ-potential (solid symbols) of 1212RAc/DPPA mixtures as a function of 1212RAc mole fraction.

products form low lamellarity vesicles and monoacyl products; LAM and 140RAc form micelles above their respective cmc. Mixtures with the diacyl compounds form vesicles positively or negatively charged depending on the major component of the mixture while the monoacyl compounds largely solubilize the phospholipid when they are the major component. In a large region around charge compensation precipitates are found. Mixing produces in all systems an increase in the size of the mixed vesicles with diverging size at equivalence. Surprisingly, the addition of small amounts of the cationic surfactants to the negatively charged vesicles of DPPA results in a small but significant and systematic increase of net negative charge of the vesicles. This has been attributed to strong release of the counterions due to stabilization of the charge by hydrogen bonding with the surfactant. 6.2. Monolayers. Because of their low solubility and their similarities with phospholipids, a significant part of the characterization of the diacyl derivatives has dealt with their monolayer behavior, both in the form of deposited or adsorbed monolayers94-97 as pure compounds or in their mixtures with phospholipids. Arginine and glutamine compounds have been studied. Arginine compounds can be prepared with either two or a single charge per headgroup by methylation of the lateral amino group. Differences in charge did not seem to have a very strong effect on the monolayer behavior, being the main contribution of the headgroup attributable to the size of the polar head.94 Both lauroyl and myristoyl derivatives did show significant interaction at high area per molecule for the singly charged species while the doubly charged species followed the trends of natural amphoteric phospholipids. This could be the result of significant deprotonation of the headgroups, rendering lower charged species than anticipated. The 1,2 substitution tends to form extended phases at higher area per molecule than the natural phospholipid analogues while 1,3 substitution showed the formation of rough and compact domains (Figure 11). This substitution was studied only for one dilauroyl glutamine derivative. This different behavior concerning substitution was attributed to the smaller intra-acyl chain interaction found in this case. The interaction of 1212RAc and 1414RAc with DPPC and DMPC was systematically studied in spread monolayers.95 All synthetic surfactant-phospholipid mixtures showed partial miscibility, except in the case of 1212RAc with DMPC that showed positive values of the excess free energy. Both 1414RAc and

DPPC exhibit gas, expanded liquid, compressed liquid, and solid phases while in 1212RAc and DMPC the gas and expanded liquid showed up just before the monolayer collapse. Mixed isotherms present all possible states; therefore, all components are present in equimolar amount. Both dynamic surface tension and infrared reflection-absorption spectroscopy (IRRAS) of adsorbed mixtures from dispersion indicate miscibility at the surface. Synergism is also observed in the surface tension behavior and in the increased density of the acyl chains packing of both surfactant and phospholipid.97 This synergism has been also evidenced96 by the accelerated adsorption of DPPC dispersions containing small molar fractions of 1414RAc. The reduction of surface tension is faster for these mixtures than for any of the components alone. The final value reached is also lower. The viscoelastic characterization of DPPC1414RAc monolayer is congruent with the rheological parameters, being dominated by the presence of the larger range repulsive force due to the charged surfactant.

6. CONCLUSION In view of the importance of the function played by surfactants in many applications, the development of amino-acid-based surfactants should have an influence in fields such as food, pharmaceuticals, medical science, and cosmetic science. In this review, we have reported on properties of several families of amino-acid-based surfactants with different structures. Because of the nature of the building blocks used in the synthesis, the amino-acid-based surfactants can be prepared from renewable resources. This nature has a strong influence in their environmental impact. This results in high biodegradability, low aquatic toxicity, and moderate cytotoxicity. The functionality of the amino acids allows obtaining a wide range of amino-acidbased surfactants tailored to specific needs. In our research, we have shown that surfactants with high efficiency, antimicrobial activity, and moderate hemolytic activity can be prepared. ’ AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected].

’ ACKNOWLEDGMENT The authors acknowledge financial support from the MICIN Project CTQ 2009-14151-CO2-01and Project CTQ 2010-14897 and from Generalitat de Catalunya Project AGAUR 2009 SGR 1331. 4814



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(63) Boething, R. S. Environmental Aspects of Cationic Surfactants. In Cationirc Surfactants: Analytical and Biological Evaluation; Cross, J., Singer, E. J., Eds.; Marcel Dekker: New York, 1994; pp 95-130. (64) Perez, L.; Torres, J. L.; Manresa, A.; Infante, R. I. Synthesis, aggregation, and biological properties of a new class of gemini cationic amphiphilic compounds from arginine, bis(Args). Langmuir 1996, 12, 5296. (65) Piera, E.; Infante, M. R.; Clapes, P. Chemo-enzymatic synthesis of Arg-based gemini surfactants. Biotechnol. Bioeng. 2000, 70, 323. (66) Pinazo, A.; Wen, X.; Perez, L.; Infante, M. R.; Franses, E. I. Aggregation behavior in water of monomeric and gemini cationic surfactants derived from arginine. Langmuir 1999, 15, 3134. (67) Alami, E.; Beinert, P.; Marie, P.; Zana, R. Alkanediyl-bis(dimethylalkylammonium bromide) surfactants. 3. Behavior at the air-water interface. Langmuir 1993, 9, 1465. (68) Kamrath, R. F.; Franses, E. I. Mass-action model of mixed micellization. J. Phys. Chem. 1984, 88, 1642. (69) Shanks, P. C.; Franses, E. I. Estimation of micellization parameters of aqueous sodium dodecyl sulfate from conductivity data. J. Phys. Chem. 1992, 96, 1794. (70) Pinazo, A.; Perez, L.; Infante, M. R.; Pons, R. Unconventional vesicle-to-ribbon transition behaviour of diacyl glycerol amino-acidbased surfactants in extremely diluted systems induced by pH-concentration effects. Phys. Chem. Chem. Phys. 2004, 6, 1475. (71) Perez, L.; Pinazo, A.; Rosen, M. J.; Infante, M. R. Surface activity properties at equilibrium of novel gemini cationic amphiphilic compounds from arginine, bis(Args). Langmuir 1998, 14, 2307. (72) Pinazo, A.; Perez, L.; Infante, M. R.; Franses, E. I. Relation of foam stability to solution and surface properties of gemini cationic surfactants derived from arginine. Colloids Surf. A 2001, 189, 225. (73) Perez, L.; Pinazo, A.; Infante, M. R.; Pons, R. Investigation of the micellization process of single and gemini surfactants from arginine by SAXS, NMR self-diffusion, and light scattering. J. Phys. Chem. B 2007, 111, 11379. (74) Stilbs, P. Fourier transform pulsed-gradient spin-echo studies of molecular diffusion. Prog. Nucl. Magn. Reson. Spectrosc. 1987, 19, 1. (75) Cocquyt, J.; Olsson, U.; Olofsson, G.; Van der Meeren, P. Temperature quenched DODAB dispersions: Fluid and solid state coexistence and complex formation with oppositely charged surfactant. Langmuir 2004, 20, 3906. (76) Danino, D.; Talmon, Y.; Zana., R. Alkanediyl-R,ω-bis(dimethylalkylammonium bromide) surfactants (dimeric surfactants). 5. Aggregation and microstructure in aqueous-solutions. Langmuir 1995, 11, 1448. (77) Weihs, D.; Danino, D.; Pinazo, A.; Perez, L.; Franses, E. I.; Talmon, Y. Self-aggregation in dimeric arginine-based cationic surfactants solutions. Colloids. Surf. A 2005, 255, 73. (78) Pons, R.; Moran, M. C.; Infante, M. R.; Pinazo, A.; Perez, L. Lysine-Based Surfactants. In Colloids in Biotechnology; Fanun, M., Ed., CRC Press: Boca Raton, FL, 2010; Vol. 152, pp 125-138. (79) Seguer, J.; Infante, M. R.; Allouch, M.; Vinardell, P.; Mansuy, L.; Selve, C. Synthesis and evaluation of nonionic amphiphilic compounds from amino-acids-molecular mimics of lecithins. New J. Chem. 1994, 18, 765. (80) Seguer, J.; Selve, C.; Infante, M. R. New nonionic surfactants from lysine and their performance. J. Disp. Sci. Technol. 1994, 15, 591. (81) Seguer, J.; Selve, C.; Allouch, M.; Infante, M. R. Nonionic amphiphilic compounds from lysine as molecular mimics of lecithins. J. Am. Oil Chem. Soc. 1996, 73, 79. (82) Pinazo, A.; Perez, L.; Lozano, M.; Angelet, M.; Infante, M. R.; Vinardell, M. P.; Pons, R. Aggregation properties of diacyl lysine surfactant compounds: Hydrophobic chain length and counterion effect. J. Phys. Chem. B 2008, 112, 8578. (83) Tausk, R J M. Physical chemical studies of short chain lecithin homologues. I. Influence of the chain length of the fatty acid ester and of electrolytes on the critical micelle concentration. Biophys. Chem. 1974, 1, 175. (84) Pinazo, A.; Seguer, J.; Infante, M. R.; Park, S. Y.; Franses, E. I. Surface properties of aqueous systems of new nonionic double-chain 4816



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Amino Acids as Raw Material for Biocompatible Surfactants - Industrial

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