3. Natural surfactants: brief introduction to sugar-based amphiphiles

Despite the production of surfactants based on fats, oils, and carbohydrates, being a known area for several decades, on an industrial scale, this is a relatively new issue [35]. These amphiphilic molecules that have one of the main building blocks from a natural source are often called "natural surfactants" [36, 37]. For example, alkyl glycosides which are synthesized from a "natural" sugar unit and a "nonnatural" fatty alcohol are often regarded as natural surfactants. Considering their amphiphilic nature, it has been always a challenge to attach a carbohydrate molecule, such as the hydrophilic group (due to the numerous hydroxyl groups) to a fat and oil derivative, such as a fatty acid or a fatty alcohol. However, nowadays, several successful synthesis routes are well established, and numerous types of natural surfactants are known and available, even on a commercial scale [38]. Nowadays, carbohydrate-based surfactants (CBS) are among the most important classes of amphiphilic compounds [39–41]. Their structure results from the combination of sugar and lipids, naturally biosynthesized within living cells or, alternatively, synthetically prepared by sequential reactions using carbohydrate and fatty materials. The growing interest in such compounds is due to, inter alia, their preparation from renewable raw materials, biodegradability, mildness to the skin, and biocompatibility, among other reasons [42, 43]. In particular, CBS can be relatively easily prepared from the most abundant renewable vegetable raw materials (e.g., cellulose, pectin, hemicellulose, starch, etc.) in a wide range of structures and geometries by modular synthesis thanks to the presence of numerous reactive hydroxyl groups. Such structural diversity makes CBS excellent models to get insight on the surfactant mechanisms in modifying interfacial properties. This knowledge is crucial for the control of the formation and stability of diverse colloidal systems such as micelles, vesicles, foams, and emulsions [44]. An important structural feature of these surfactants is the typical sugar headgroup, a voluminous and relatively rigid moiety that can be functionalized by a myriad of reagents and synthetic schemes. Numerous properties and functionalities can be expected from such almost unlimited number of different compounds that can find specific applications in different industrial areas [45, 46]. CBS also present great advantages on the environmental side; their higher biodegradability and lower toxicity profile are important reasons to consider CBS as valid alternatives to the more common petrochemical-based surfactants.

surface activity and the resulting effects on biological membranes [47]. In the case of CBS (APGs in particular), they present a quite favorable environmental profile: the rate of biodegradation is usually high, and the aquatic toxicity is low. In addition, APGs exhibit favorable dermatological properties, being very mild when exposed to the skin and eye [53]. The inter-

Saenger and Mullerfahrnow [55] and Casu et al. [56] were pioneers in the study of the interactions between APGs and CDs. By surface tension measurements, it was shown that the addition of CDs leads to an increase of surfactant critical micelle concentration. Furthermore, the interaction is most pronounced when the CD cavity and hydrophobic part of the surfactant

the analysis of NMR chemical shifts of octyl- (C8G1) and dodecyl (C12G1) α- and β-Dglucopyranoside and octadecyl β-D-glucopyranoside (C18G1), in the absence and presence of α-CD, two main conclusions were taken: the presence of α-CD only affects the chemical shifts of the surfactant alkyl chain, and the chemical shift of the protons H-3 and H-5, located inside the CD cavity, increases by increasing the length of the alkyl chain [57]. Furthermore, it was observed that no chemical shift is observed for γ-CD/C12G1 mixed systems. These conclusions corroborate previous and subsequent studies, showing that the CD cavity is protruded just by the surfactant tail and the magnitude of the interaction is dependent on the relationship between the volumes of the CD cavity and the surfactant hydrocarbon chain [56, 58]. A better characterization of these complexes was accomplished by the quantification of the binding process. The effect of the length of the alkyl chain and surfactant head group on the association

diffusion, and surface tension (Table 1) [58–60]. Although the comparison between association constants computed on the basis of different physical parameters is a difficult task [5], the analysis of the data allowed concluding that by increasing the alkyl chain length and decreasing the CD cavity volume (from β- to α-CD), the association constant increases. Furthermore, some authors stated that no interactions were observed when γ-CD was used [59, 58]. It is also worth noticing that for all mentioned systems, by subtracting the critical aggregation concentration (cac) of the surfactants from the CD concentration, the critical micelle concentration

α-CD β-CD Obs. <sup>β</sup>-C8G1 3.68 (1.6) <sup>10</sup><sup>3</sup> 0.99 (0.17) <sup>10</sup><sup>3</sup> Self-diffusion NMR [58]

<sup>β</sup>-C9G1 76 (750) <sup>10</sup><sup>3</sup> 275 (5300) <sup>10</sup><sup>3</sup> Self-diffusion NMR [58]

<sup>β</sup>-C10G1 <sup>340</sup> <sup>30</sup> [CD] = 1 mM, <sup>1</sup>

<sup>β</sup>-C12G1 <sup>440</sup> <sup>40</sup> [CD] = 2 mM, <sup>1</sup>

<sup>β</sup>-C12G2 <sup>125</sup> <sup>10</sup> [CD] = 1 mM, <sup>1</sup>

1.85 (0.35) <sup>10</sup><sup>3</sup> Surface tension [60]

, for the inclusion complexes CD/APG.

<sup>410</sup> <sup>40</sup> [CD] = 1 mM, <sup>1</sup>

H and 13C NMR spectroscopy. By

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H NMR spectroscopy, NMR self-

H NMR [59]

H NMR [59]

H NMR [59]

H NMR [59]

ested reader can find excellent overviews on APGs elsewhere [45–47, 51, 54].

3.2. Interaction between alkyl polyglycosides and cyclodextrins

exhibit the tightest fit. Such a view was also supported by <sup>1</sup>

constant of APGs with different CDs was studied by <sup>1</sup>

Table 1. Binding constants, K1,1 in dm<sup>3</sup> mol<sup>1</sup>

#### 3.1. Case study: alkyl polyglycosides

In recent years there has been a growing focus on three classes of surfactants with sugar or a polyol derivative as polar headgroup: alkyl polyglycosides (APGs), alkyl glucamides, and sugar esters. In this chapter, we will focus on APGs, which are regarded as "perfect amphiphilic structures" with excellent surface activity as well as solubility. APGs have been synthesized, for the first time, more than 100 years ago [47]. APGs are completely based on renewable resources and combine very good performance, multifunctionality, and competitive price with mildness. This explains why APGs are the most successful sugar-based surfactants nowadays. It is important to mention that not pure alkyl monoglucosides but rather a complex mixture of alkyl mono-, di-, tri-, and oligoglycosides is produced in the industrial processes. Because of this, the industrial products are called alkyl polyglycosides. The surfactants are thus characterized by the length of the alkyl chain and the average number of glucose units linked to it, the degree of polymerization (DP). Alkyl glycosides are stable at high pH and sensitive to low pH where they hydrolyze to sugar and fatty alcohol. The sugar unit is more water-soluble and less soluble in hydrocarbons than the corresponding polyoxyethylene unit; hence, APGs and other polyol-based surfactants are more lipophobic than their polyoxyethylene-based surfactant counterparts [48]. This makes the physicochemical behavior of APG surfactants in oil/water systems distinct from that of conventional nonionic surfactants. Moreover, APGs do not show the pronounced inverse solubility vs. temperature relationship that normal nonionics do [49]. This makes an important difference in solution behavior between APGs and polyoxyethylenebased surfactants. The critical micelle concentration (cmc) values of the pure alkyl monoglycosides and the technical APG are comparable with those of typical nonionic surfactants and decrease distinctly with increasing alkyl chain length. The alkyl chain length has a far stronger influence on the cmc than the number of glycoside groups of the APG. The influence of the DP of APGs on their phase behavior has been described by Fukuda et al. [50]. The region in which the liquid crystalline phases occur is only slightly dependent on the concentration with a greater expansion in the case of APGs with a higher DP.

Regarding their applications, APGs are mainly used in personal care products such as cosmetics, manual dishwashing, and detergents [51]. APGs have also been used in more advanced applications such as the extraction and purification of membrane proteins, which plays a major role in the determination of protein structures and functions [52]. This is because APGs have reduced protein-denaturing properties in comparison to conventional surfactants. Generally, the environmental fate of surfactants is inextricably linked with their biodegradation behavior. Thus, fast and complete biodegradability is the most important requirement for an environmentally compatible surfactant. The general environmental impact of chemicals lies mainly in their ecotoxicity, which is relatively high in the case of surfactants because of their surface activity and the resulting effects on biological membranes [47]. In the case of CBS (APGs in particular), they present a quite favorable environmental profile: the rate of biodegradation is usually high, and the aquatic toxicity is low. In addition, APGs exhibit favorable dermatological properties, being very mild when exposed to the skin and eye [53]. The interested reader can find excellent overviews on APGs elsewhere [45–47, 51, 54].

#### 3.2. Interaction between alkyl polyglycosides and cyclodextrins

functionalities can be expected from such almost unlimited number of different compounds that can find specific applications in different industrial areas [45, 46]. CBS also present great advantages on the environmental side; their higher biodegradability and lower toxicity profile are important reasons to consider CBS as valid alternatives to the more common

In recent years there has been a growing focus on three classes of surfactants with sugar or a polyol derivative as polar headgroup: alkyl polyglycosides (APGs), alkyl glucamides, and sugar esters. In this chapter, we will focus on APGs, which are regarded as "perfect amphiphilic structures" with excellent surface activity as well as solubility. APGs have been synthesized, for the first time, more than 100 years ago [47]. APGs are completely based on renewable resources and combine very good performance, multifunctionality, and competitive price with mildness. This explains why APGs are the most successful sugar-based surfactants nowadays. It is important to mention that not pure alkyl monoglucosides but rather a complex mixture of alkyl mono-, di-, tri-, and oligoglycosides is produced in the industrial processes. Because of this, the industrial products are called alkyl polyglycosides. The surfactants are thus characterized by the length of the alkyl chain and the average number of glucose units linked to it, the degree of polymerization (DP). Alkyl glycosides are stable at high pH and sensitive to low pH where they hydrolyze to sugar and fatty alcohol. The sugar unit is more water-soluble and less soluble in hydrocarbons than the corresponding polyoxyethylene unit; hence, APGs and other polyol-based surfactants are more lipophobic than their polyoxyethylene-based surfactant counterparts [48]. This makes the physicochemical behavior of APG surfactants in oil/water systems distinct from that of conventional nonionic surfactants. Moreover, APGs do not show the pronounced inverse solubility vs. temperature relationship that normal nonionics do [49]. This makes an important difference in solution behavior between APGs and polyoxyethylenebased surfactants. The critical micelle concentration (cmc) values of the pure alkyl monoglycosides and the technical APG are comparable with those of typical nonionic surfactants and decrease distinctly with increasing alkyl chain length. The alkyl chain length has a far stronger influence on the cmc than the number of glycoside groups of the APG. The influence of the DP of APGs on their phase behavior has been described by Fukuda et al. [50]. The region in which the liquid crystalline phases occur is only slightly dependent on the

concentration with a greater expansion in the case of APGs with a higher DP.

Regarding their applications, APGs are mainly used in personal care products such as cosmetics, manual dishwashing, and detergents [51]. APGs have also been used in more advanced applications such as the extraction and purification of membrane proteins, which plays a major role in the determination of protein structures and functions [52]. This is because APGs have reduced protein-denaturing properties in comparison to conventional surfactants. Generally, the environmental fate of surfactants is inextricably linked with their biodegradation behavior. Thus, fast and complete biodegradability is the most important requirement for an environmentally compatible surfactant. The general environmental impact of chemicals lies mainly in their ecotoxicity, which is relatively high in the case of surfactants because of their

petrochemical-based surfactants.

74 Cyclodextrin - A Versatile Ingredient

3.1. Case study: alkyl polyglycosides

Saenger and Mullerfahrnow [55] and Casu et al. [56] were pioneers in the study of the interactions between APGs and CDs. By surface tension measurements, it was shown that the addition of CDs leads to an increase of surfactant critical micelle concentration. Furthermore, the interaction is most pronounced when the CD cavity and hydrophobic part of the surfactant exhibit the tightest fit. Such a view was also supported by <sup>1</sup> H and 13C NMR spectroscopy. By the analysis of NMR chemical shifts of octyl- (C8G1) and dodecyl (C12G1) α- and β-Dglucopyranoside and octadecyl β-D-glucopyranoside (C18G1), in the absence and presence of α-CD, two main conclusions were taken: the presence of α-CD only affects the chemical shifts of the surfactant alkyl chain, and the chemical shift of the protons H-3 and H-5, located inside the CD cavity, increases by increasing the length of the alkyl chain [57]. Furthermore, it was observed that no chemical shift is observed for γ-CD/C12G1 mixed systems. These conclusions corroborate previous and subsequent studies, showing that the CD cavity is protruded just by the surfactant tail and the magnitude of the interaction is dependent on the relationship between the volumes of the CD cavity and the surfactant hydrocarbon chain [56, 58]. A better characterization of these complexes was accomplished by the quantification of the binding process. The effect of the length of the alkyl chain and surfactant head group on the association constant of APGs with different CDs was studied by <sup>1</sup> H NMR spectroscopy, NMR selfdiffusion, and surface tension (Table 1) [58–60]. Although the comparison between association constants computed on the basis of different physical parameters is a difficult task [5], the analysis of the data allowed concluding that by increasing the alkyl chain length and decreasing the CD cavity volume (from β- to α-CD), the association constant increases. Furthermore, some authors stated that no interactions were observed when γ-CD was used [59, 58]. It is also worth noticing that for all mentioned systems, by subtracting the critical aggregation concentration (cac) of the surfactants from the CD concentration, the critical micelle concentration


Table 1. Binding constants, K1,1 in dm<sup>3</sup> mol<sup>1</sup> , for the inclusion complexes CD/APG. value is obtained. This clearly suggests a 1:1 APG/CD complexation [4], and actually it finds support by the Job's plot [61] reported by Bernat et al. [60]. Another important issue is to understand the reliability of the binding constants reported in Table 1. Rymdén et al. found that an increase of a methylene group for a series of alcohols decreases the standard free energy of the alcohol: β-CD binding for ca. 3.0 kJ/mol [62]. This variation is similar to that observed for K1,1 values obtained by self-diffusion coefficients (Table 1). On the other hand, comparing K1,1 values for C8G1 with those from other monoalkyl surfactants, one can conclude that the APG/CD complex is more stable [63, 64]. This has been justified by the occurrence of hydrogen bonds between the sugar structure and the hydroxyl groups located at the rim of the CD. However, studying the effect of the number of sugar moieties in the surfactant head on the free energy of binding, an algebraic increase in the Gibbs free energy is observed. Indeed, comparing the binding constants for the interactions between β-C12G1 and β-C12G2 with β-CD, it is possible to conclude that the addition of an extra sugar moiety in the surfactant head decreases the K values for the supramolecular association. Thus, it can be hypothesized that no significant sugar-sugar interactions are involved in the interaction with CD, as it was previously discussed. Another hypothesis arises from the effect of carbohydrates on the water structure, for example, Ribeiro et al. have found that the presence of carbohydrates leads to an increase of the entropy in water [65], also called a structure "breaking effect" [66]. Consequently, an increase of the concentration of the sugar molecules in solution may contributes for a decrease in the binding entropy change and, consequently, to an increase in the binding Gibbs free energy.

In this section, the most relevant techniques used to study the interactions between CDs and sugar-based surfactants (e.g., APGs) and phytochemicals (e.g., polyphenols, EOs, and their

NMR spectrometry falls in the group II techniques, and it is used to determine association constants through the chemical shift changes noticed either by the guest or by the CD [73–75]. Focusing on EOs, and as previously discussed, they may present undesired features, such as volatility, poor aqueous solubility, and stability. Therefore, host-guest supramolecular complexes are often obtained by using solid-state-based methods [14] such as freeze-drying [76, 77], coprecipitation [78], and the saturated approach [27], improving the solubility of the EO and thus allowing the use of NMR techniques for the quantitative and qualitative assessment of the complexation process [74]. For example, the complexation of eugenol with β-CD was obtained by using the saturation method, and the obtained complex, in the solid state, was

by the aromatic ring of the eugenol [27]. Other techniques will be mentioned later since they

based substrates [79]. Kfoury et al. report a comprehensive study on the complexation between two phenol isomers (thymol and carvacrol) and CDs by using different NMR techniques, including DOSY [80]. The data allowed concluding that those isomers have a binding constant

The self-diffusion measurements are, in principle, applicable to any systems as long as the free and complexed guests are soluble to an extent that allows for a good signal-to-noise ratio. It is important to note that on account of the rapid exchange on the NMR time scale, average diffusion coefficients for both the guest and for the CD are typically obtained. This method, as well as that involving chemical shift changes analysis, is also limited to systems where no overlapping of welldefined resonances is observed. The method relies on the fact that the self-diffusion coefficients of the uncomplexed guest are higher than the self-diffusion of the host-guest complex, as defined by the Stokes-Einstein equation. The change in the self-diffusion coefficient of the CD upon complexation is often small since the complex is often of the same size as the CD molecule, and thus the

Ultrasonic relaxation technique falls into group II techniques and is based on the application of ultrasound to a given solution, with a frequency ranging from 20 kHz to several GHz, and subsequently measuring the molecular structural relaxation. The relaxation is sensitive to molecular volume changes [81], and thus, it may convey information on the stability constants of the host-guest complexes [82]. Furthermore, the use of a large frequency range allows to follow processes with relaxation times in the range from 20 ps to 20 μs [83], and thus the kinetics of the CD-surfactant association can be investigated. Haller and Kaatze, by using ultrasonic attenuation spectroscopy, were able to quantify the dynamics of unimer-micelle exchange of a sugar-

Also from group II, surface tension has also been used to follow the effect of CDs on the aggregation and interfacial properties of surfactants in CD-surfactant-containing solutions

based surfactant (i.e., octyl-β-D-glucopyranoside (C8G1)) in the presence of α-CD [67].

, respectively.

information from the CD self-diffusion is rather limited [58].

H NMR has been used to study inclusion complexes between CD and different sugar-

H, 13C, or 2D NMR techniques, confirming the thread of CD's cavity

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components) will be highlighted (Table 2).

characterized by either <sup>1</sup>

DOSY <sup>1</sup>

fall on the so-called group II.

of 1344 M<sup>1</sup> and 1336 M<sup>1</sup>

Up to now, we have been discussing the binding process assuming a 1:1 APG/CD (α- and β-) binding stoichiometry. However, it should be stressed that from the study of the interactions between C12G1, and C18G1, and CDs, there are strong evidences for the occurrence of other species consistent with 1:2 complexes [56]. More recently, Haller and Kaatze, studying the interaction between C8G1 and α-CD by ultrasonic attenuation spectroscopy, concluded that besides 1:1 (APG/CD) complexes, the formation of 1:2 and 2:1 complexes (although in very low concentration) should not be ruled out [67].
