Cleavable surfactants

Current Opinion in Colloid & Interface Science 12 (2007) 81 – 91 www.elsevier.com/locate/cocis

Cleavable surfactants Alireza Tehrani-Bagha a,b , Krister Holmberg a,⁎ a

Chalmers University of Technology, Department of Chemical and Biological Engineering, SE-412 96 Göteborg, Sweden b Institute for Colorants, Paints and Coatings, Tehran—Iran Available online 29 May 2007

Abstract The review covers the development within the field of cleavable surfactants since 2003. Cleavable surfactants are amphiphiles in which a weak linkage has been deliberately inserted, normally, but not always, between the hydrophobic tail and the polar headgroup. Alkali labile linkages that have been used for the purpose include normal ester bonds, betaine esters, and carbonates. Ketals and ortho esters are example of bonds that are susceptible to acid hydrolysis. Several investigations deal with cationic ester-containing surfactants, both monomeric and dimeric species, the latter being gemini surfactants. Ester, amide and carbonate containing surfactants have been investigated with respect to enzyme catalyzed hydrolysis. The main incentive for the development of novel cleavable surfactants is to improve the biodegradation characteristics and the rate of biodegradation has consequently been studied for several of the surfactants. One interesting observation is that there is often very little correlation between rate of chemical and enzymatic hydrolysis on the one hand and rate of biodegradation on the other hand. A completely new type of cleavable surfactant is based on a Diels–Alder reaction between a maleimide derivative and a substituted furan. The product formed undergoes a retro-Diels–Alder reaction at a temperature of around 60 °C. This is an example of a thermally cleavable surfactant. © 2007 Elsevier Ltd. All rights reserved. Keywords: Surfactant; Cleavable; Hydrolyzable; Destructible; Temporary; Triggerable; Chemodegradable; Acid-sensitive; Alkali-sensitive

1. Introduction There is an increasing interest in surfactants that contain a linkage that breaks down in a controlled way. The mechanism by which the cleavage occurs may vary and examples include acid hydrolysis, alkaline hydrolysis, UV irradiation, and heat decomposition. The common denominator of all examples is that the surfactant is stable under a given set of conditions, usually as an aqueous solution under neutral pH, but is cleaved as the conditions are changed. The weak bond is usually positioned between the polar headgroup and the hydrophobic tail but there are also examples of surfactants with the sensitive linkage situated somewhere in the tail. Surfactants with a weak bond deliberately inserted into the structure are commonly called cleavable surfactants but the terms chemodegradable surfactants, destructible surfactants, triggerable surfactants, temporary surfactants, hydrolyzable surfactants, and acid (alkali) sensitive surfactants can also be found in the recent literature.

⁎ Corresponding author. E-mail address: [email protected] (K. Holmberg). 1359-0294/$ - see front matter © 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.cocis.2007.05.006

The main objective behind the development of cleavable surfactants is to improve the rate of biodegradation. Environmental concern is today a major driving force for the development of new surfactants and the concept of “helping” the microorganisms to degrade the compound by deliberately inserting weak bonds is therefore logical. As will be shown in this review, a rapid chemical degradation does not always lead to a fast biodegradation, however. 2. Early work The concept of cleavable surfactants is by no means new. The most well-known, and probably the most commercially viable example of cleavable surfactants is the family of ester quats. The ester quats have now taken over most of the market for textile softeners in Europe and in the United States. The stable quats that used to dominate the market, and which are still used in many countries, consist of a quaternary nitrogen with two long and two very short alkyl (often methyl) substituents and with a halide, acetate, or methyl sulfate as counterion. The ester quats have the same general structure but the two long alkyl chains are fatty acid esters. Thus, a typical ester quat may be a fatty acid diester of a small diol that contains a quaternary ammonium

82

A. Tehrani-Bagha, K. Holmberg / Current Opinion in Colloid & Interface Science 12 (2007) 81–91

group, such as di(2-hydroxyethyl)dimethylammonium acetate. Chemical or lipase-catalyzed hydrolysis in the sewage plant leads to degradation into long-chain fatty acid soap and a small very water soluble cationic entity [1,2]. There are many other early examples of cleavable surfactants and a variety of weak linkages have been explored. Examples of such bonds include different types of esters, amides, acetals, ketals, monoalkyl carbonates, surfactants containing a siloxane group or a sulfone group, as well as surfactants containing azo groups or other UV sensitive linkages. The work up to around 2002 is summarized in several book chapters and journal reviews [3–6]. This overview mainly covers the development from 2003. 3. Stability vs. degradability Weak bonds in a surfactant may cause problems in terms of insufficient stability. This has been known for a long time for one of the most widely used surfactants, sodium dodecylsulfate or SDS. SDS, which is a monoester of sulfuric acid, is readily cleaved when exposed to acid and the cleavage generates sulfuric acid. The acid formed gradually brings down the pH further, thereby accelerating the breakdown. This autocatalytic degradation of SDS is well-known by those who formulate surfactant-containing products and has been regarded as a substantial disadvantage. Today it is seen both as a potential problem and as an asset. The relatively fast biodegradation of SDS, under both aerobic and anaerobic conditions, is probably related to the weak bond in the molecule. There are several other traditional surfactants that contain a bond that is sensitive to specific conditions, usually high or low pH. Ester-containing surfactants are common, with fatty acid ethoxylates being the most well-known example, and experience has taught that these should be handled and used at neutral or slightly alkaline pH. Sugar based surfactants containing glucosidic bonds behave in the opposite way; they may be used under very alkaline conditions but they break down at low pH. Such surfactants have been used since many decades and their stability characteristics have been successfully mastered. Since the early 1990's a weak bond in surfactants has more and more been seen as an asset and the concept of cleavable surfactant has been established. The term “cleavable surfactants” was probably coined by Jaeger in 1990 [7].

4. Recent developments 4.1. Degradation of ester surfactants There is a wide variety of surfactants that contain an ester bond. Fatty acid ethoxylates, glycerol and polyglycerol esters of fatty acids, sorbitol esters and ethoxylated sorbitol esters sulfosuccinate esters, isethionates, and the above-mentioned ester quats are pertinent examples of normal carboxylic acid esters. There are also surfactants that contain a phosphoric acid ester bond and those, like SDS, that contain a sulfuric acid ester bond. All these surfactants are established on the market since long back and their solution properties have been extensively investigated. In a recent series of papers the degradation characteristics of surface active alcohol ethoxylates with different substitution pattern near the hydrolyzable bond were studied. Four homologue pure surfactants were synthesized by reacting the appropriate acid chloride with a large excess of tetra(ethylene glycol) in the presence of pyridine [8••]. The structures of the four surfactants are shown in Fig. 1. In order to elucidate how the hydrolytic stability of the ester bond is influenced by substitution at the α-carbon of the acyl chain, the base-catalyzed hydrolysis of the ester surfactants was investigated (at concentrations well below the CMC). The halflife of the methyl-substituted surfactant 2 was almost the same as that of the unsubstituted surfactant 1, indicating that one methyl substituent in α-position does not influence the hydrolysis to any large extent. However, the surfactant with two methyl substituents, 4, underwent a much more sluggish hydrolysis, with the half-life being about two orders of magnitudes longer than that of the unsubstituted surfactant. Somewhat surprisingly the ethyl-substituted surfactant 3 had almost the same half-life as the surfactant with two methyl groups in α-position. Evidently, an ethyl substituent gives rise to much more severe steric hindrance than a methyl substituent. Whereas the half-life of the surfactant was constant at concentrations below the CMC it was found to increase linearly with increasing surfactant concentration above the CMC [9••]. Fitting the data from the hydrolysis to rate equations showed that while below the CMC the values were in accordance with the pseudo first-order rate equation, above the CMC they fitted a zero-order rate equation. For zero-order reactions the rate is

Fig. 1. Four fatty acid ethoxylates with different substituents on the acyl carbon next to the ester bond, i.e., the α-carbon.

A. Tehrani-Bagha, K. Holmberg / Current Opinion in Colloid & Interface Science 12 (2007) 81–91

independent of the concentration of the reacting species. This implies that only surfactant molecules present as unimers are cleaved. Those residing in micelles are protected from hydrolysis. There are at least two possible reasons for this. Firstly, it is known that hydroxide ions are depleted from polymers containing polyoxyethylene groups [10]; hence, the stabilizing effect exerted by micellization of the ester surfactant can be due to the hydroxide ions being depleted from the oxyethylene chains surrounding the micelle. Secondly, the micelles will carry a negative charge because the hydrolysis of the unimers in bulk solution will generate a surface active alkanoate, i.e., an anionic surfactant, and this amphiphile will form mixed micelles with the starting nonionic surfactant. This negative charge of the micelles, although small, is likely to repel anions such as hydroxyl ions. The possibility to control the hydrolysis rate of ester surfactants by addition of an ionic surfactant was investigated by studying the alkaline hydrolysis of the linear ester surfactant 1 in mixtures with a stable cationic surfactant or a stable anionic surfactant using hydrolysis of the ester surfactant alone as reference [11•]. It was found that addition of the stable ionic surfactant affected the hydrolysis rate of the ester significantly. Whereas the hydrolysis rate was increased when the cationic surfactant was added, the hydrolysis was retarded when the nonionic ester surfactant was mixed with the anionic surfactant. The former effect is attributed to the formation of positively charged micelles that attract hydroxyl ions. The latter is probably a consequence of the micelles becoming negatively charged, as was discussed above. The rate acceleration when a cationic surfactant is added is an example of the well-known phenomenon called micellar catalysis and the decrease in hydrolysis of the nonionic ester obtained by addition of an anionic surfactant may analogously be referred to as micellar retardation. Degradation of ester-containing surfactants in the sewage plant is likely to involve enzyme catalyzed hydrolysis. It was therefore logical to investigate the stability of the abovementioned series of ester surfactants against lipase catalyzed hydrolysis. Two different microbial lipases, Mucor miehei lipase (MML) and Candida antarctica lipase B (CALB), were used for the purpose, see Fig. 2 [9••]. It is obvious that with both CALB and MML hydrolysis of the unsubstituted surfactant is

83

much faster than that of the substituted surfactants, i.e., increased steric hindrance near the ester bond leads to decreased hydrolysis rate. Since the specificity of the enzyme against its substrate is determined by the structure of the active site, it can be concluded, as expected, that the straight chain surfactant most easily fits into the active site of both enzymes. Lipases generally show low hydrolytic activity when their ester substrates are dissolved in aqueous media and present in unimeric form. A pronounced increase in activity is observed when the substrate concentration reaches the solubility limit and a separate phase is formed. In the case of surfactants this implies that a possible increase in activity can be expected above the CMC. Attempts to investigate how the hydrolysis is affected by micellization were made for the linear surfactant 1 of Fig. 1. The CMC of this surfactant is 10 mM, and a marked change in the activity of the MML is indeed observed when this concentration is exceeded, see Fig. 3. The initial reaction is faster (steeper slope) above the CMC. When CALB was used to catalyze the reaction no increase of the reaction rate was observed above the CMC. It was also found that the rate, expressed in moles of surfactant consumed per minute, was independent of the starting concentration (same slope). A tentative explanation to the fact that the MML-catalyzed hydrolysis, but not the CALB-catalyzed, is accelerated by the presence of micelles may be that MML but not CALB is able to interact with the hydrophobic core of the micelle and thereby become activated. It is known that MML, but not CALB, has a “lid” covering its active site and that this lid needs to open to allow the substrate to enter. The bottom of the lid has a hydrophobic character and the lid-opening process is driven by hydrophobic interactions, which in this case may be interactions with the hydrophobic core of the surfactant micelles. Fig. 4 shows biodegradation tests of the four ester surfactants. It can be seen that the linear, the methyl and the ethyl substituted ester surfactants (1, 2 and 3, respectively, of Fig. 1) biodegrade by almost the same path in a plot of biodegradation versus time. All three had reached 60% biodegradation at day 28; hence, these substances meet the main criterion for ready biodegradability. The disubstituted ester surfactant (4 of Fig. 1) had reached only 31% biodegradation after 28 days. The sluggish rate of biodegradation of the disubstituted surfactant was due to slow hydrolysis of the ester bond, as proved by the

Fig. 2. Hydrolysis of the esters surfactants in the presence of lipase at 20 °C. Left: (♦) Linear ester + MML, (⋄) linear ester + CALB, and (▵) methyl substituted ester + CALB. Right: (▴) Methyl substituted ester + MML, (■) ethyl substituted ester + MML, (●) dimethyl substituted ester + MML, (□) ethyl substituted ester + CALB, and (○) dimethyl substituted ester + CALB. MML and CALB stand for Mucor miehei and Candida antarctica B, respectively.

84

A. Tehrani-Bagha, K. Holmberg / Current Opinion in Colloid & Interface Science 12 (2007) 81–91

Fig. 3. Hydrolysis of the linear ester surfactant in the presence of lipase at 20 °C Left: 0.5 g/L MML. (⋄) 5 mM, (•) 10 mM, (□) 15 mM, and (▵) 20 mM. Right: 0.5 g/ L CALB. (⋄) 5 mM, (□) 15 mM, and (▵) 30 mM. MML and CALB stand for Mucor miehei and Candida antarctica B, respectively.

fact that the biodegradation of a 1:1 mixture of the two hydrolysis products, 2,2-dimethylhexanoic acid and tetra (ethylene glycol), was much faster than the biodegradation of the intact surfactant. Hence, it could be concluded that central scission was the rate determining step of the biodegradation of the disubstituted ester surfactant. By comparing the results from the biodegradation tests with those obtained from the study of chemical hydrolysis on the one hand and lipase-catalyzed hydrolysis on the other hand it is obvious that it is difficult to predict the rate of biodegradation from such simple chemical experiments. The physical chemical properties of the surfactants that contain an ester bond between the hydrophobic tail and the polar head group are very similar to those of alcohol ethoxylates of the same alkyl chain length and the same number of oxyethylene units. The CMC and the cloud point values of the linear ester surfactant 1 of Fig. 1 are approximately the same as those of the straight chained alcohol ethoxylate tetra(ethylene glycol)monooctyl ether (C8E4), i.e., around 10 mM and 40 °C, respectively [8••]. Thus, it appears that the carbonyl group of the ester bond gives approximately the same driving force for aggregation as does a methylene group, when situated inbetween the hydrophobe and the hydrophile.

Fig. 4. Biodegradation of the PEG monoesters in a Closed Bottle test. For numbering of the surfactants, see Fig. 1.

4.2. Novel monomeric and dimeric betaine surfactants Betaine ester surfactants are esters between a long-chain fatty alcohol and the natural amino acid betaine (trimethylglycine). This ester bond shows a very strong pH dependence. Whereas in an alkaline environment the rate of hydrolysis is much higher for these substances than for esters in general, they are more stable in an acidic environment [12]. In fact, betaine esters are hydrolyzed at a significant rate by the base-catalyzed mechanism even at neutral pH. The special hydrolysis characteristics of betaine esters can be explained by two effects caused by the presence of the strongly electron-withdrawing, positively charged quaternary ammonium group in close proximity to the ester bond. Firstly, this will, in the same way as described for the ester quats above, give rise to a decreased electron density at the carbonyl carbon and thereby make it more prone to nucleophilic attack by hydroxyl ions. The other effect is an inherent destabilization of the ground state, caused by repulsion between the partial positive charge at the carbonyl carbon and the positive charge on the nitrogen atom. This repulsion is relieved by attack of a hydroxide ion, but augmented by protonation. For a surface active betaine ester the rate of alkaline hydrolysis shows significant concentration dependence. Due to

Fig. 5. Concentration dependence of the pseudo first-order rate constants in a 100 mM phosphate buffer at pD 7.5 and 37 °C for a number of surface active betaine esters with hydrophobic tails of different sizes. For comparison, the rate constant for a non-surface active compound (ethyl betainate) is included. (○) Oleyl betainate, (•) tetradecyl betainate, (□) dodecyl betainate, (■) decyl betainate, (⋄) ethyl betainate. All compounds have chloride counterions.

A. Tehrani-Bagha, K. Holmberg / Current Opinion in Colloid & Interface Science 12 (2007) 81–91

a locally elevated concentration of hydroxyl ions at the cationic micellar surface, i.e., a locally increased pH in the micellar pseudophase, the reaction rate has been shown to be substantially higher when the substance is present at a concentration above the critical micelle concentration compared to the rate observed for a unimeric surfactant or a non-surface active betaine ester under the same conditions [13•]. This behavior, which is illustrated in Fig. 5, is an example of micellar catalysis. The decrease in reaction rate observed for the surface active betaine esters at higher concentrations is a consequence of competition between the reactive hydroxyl ions and the inert surfactant counterions at the micellar surface. This effect is in line with the essential features of the pseudophase ion-exchange model of micellar catalysis [14].

85

The physical chemical behavior of betaine esters of longchain alcohols shows strong similarities to the common, closely related alkyltrimethylammonium surfactants both in dilute and concentrated aqueous systems. In consistence with the findings about CMC:s of surfactants containing normal ester bonds (see above) it was shown that the CMC for a betaine ester with a hydrocarbon chain of n carbons is very close to the value for an alkyltrimethylammonium chloride surfactant with a hydrocarbon chain of n + 2 carbons [15]. The binary phase diagram of dodecyl betainate–water has an appearance very similar to that of an alkyltrimethylammonium surfactant with a hydrophobic tail of a similar size [16]. The effects of “dilution” of the micellar surface charge on the rate of alkaline hydrolysis of a betaine ester surfactant have

Fig. 6. Synthesis of (left) a betaine ester gemini surfactant, and (right) an ester quat gemini surfactant.

86

A. Tehrani-Bagha, K. Holmberg / Current Opinion in Colloid & Interface Science 12 (2007) 81–91

Fig. 7. Biodegradation of the cationic surfactants and of the small diquats in a Closed Bottle test. (▴) Dodecyl betainate monomer, (Δ) dodecyl betainate gemini, (■) dodecyl ester quat monomer, (□) dodecyl ester quat gemini, (●, dashed line) small dihydroxy diquat, and (⋄, dashed line) small dicarboxy diquat.

been investigated for a mixture of decyl betainate and a nonionic surfactant with a similar CMC. It was shown that the relation between micellar composition and the hydrolysis rate essentially parallels the relation between micellar composition and counterion binding to mixed micelles made up of ionic and nonionic surfactants [11••]. Karlberg et al. have studied a system comprising dodecyl betainate and hydrophobically modified hydroxyethylcellulose (HM-HEC) [17•]. It is well-known that the viscosity of mixtures of polymers and surfactants is often strongly dependent on the concentration of the amphiphile. By preparing a mixture of the surface active betaine ester and HM-HEC in a solution buffered at a pH at which the surfactant was gradually hydrolyzed it was possible to make a gel with a time-dependent viscosity. Since surface active betaine esters can be degraded under mild conditions and the hydrolysis products, i.e., the amino acid betaine and a long-chain alcohol, can be expected to be less toxic than the intact surfactant, these amphiphiles are interesting candidates for use in applications where surfactant toxicity is an issue. Surface active betaine esters have been evaluated as temporary bactericides [18] and have been studied as potential candidates for use as pharmaceutical excipients (pharmaceutical helper molecules) [16]. In a recent study two cationic gemini surfactants having ester bonds between the hydrophobic tail and the cationic moiety were synthesized according to the methods shown in Fig. 6 [19••]. As can be seen from the figure, the ester bonds are either

with the ester carbonyl group away from the positive charge (ester quat type arrangement) or facing the positive charge (betaine ester type arrangement). The chemical hydrolysis of the surfactants was investigated and compared with the hydrolysis of the corresponding monomeric surfactants. The betaine ester type of surfactants was found to hydrolyze much faster than the ester quat surfactants. It was also seen that above the CMC the gemini surfactants were much more susceptible to alkaline hydrolysis than the corresponding monomeric surfactants. This may be due to an unexpectedly high degree of micelle ionization of the geminis, probably caused by these surfactants forming very small aggregates in solution. The biodegradation of the geminis and the monomeric surfactants were also studied and compared, see Fig. 7 [19••]. It was found that whereas the monomeric surfactants were rapidly degraded, the two gemini surfactants were more resistant to biodegradation and could not be classified as readily biodegradable. Thus, there was no correlation between rate of chemical hydrolysis and rate of biodegradation. The poor biodegradability of the cationic ester gemini surfactants is most likely due to slow degradation of the dicationic species that are generated after the initial cleavage of the two ester bonds in the molecules. As can be seen from Fig. 7, these species, which were synthesized and tested for biodegradation in a separate experiment, degraded very slowly in the Closed Bottle test that was used in the study.

Fig. 8. Principle for cytosolic delivery of a macromolecule utilizing a liposome based on an acid-labile gemini surfactant. (From Ref. [20] with permission).

A. Tehrani-Bagha, K. Holmberg / Current Opinion in Colloid & Interface Science 12 (2007) 81–91

87

4.3. Other cleavable gemini surfactants In an elegant strategy for cytosolic delivery of macromolecules using liposomes an acid-labile gemini surfactant was used [20•]. The surfactant was a cationic gemini with an acid labile ketal bond in the spacer unit. The delivery principle is shown in Fig. 8. In Step 1 the liposome, loaded with the macromolecule, is exposed to acid. The gemini is hydrolyzed, generating normal cationic surfactants. Initially these are likely to go into the liposome bilayer but eventually, as a certain fraction of the gemini surfactant has been transformed into regular single tailsingle headgroup species, the liposome collapses releasing the macromolecules together with surfactant micelles. The cationic surfactant formed will damage the endosomal membrane, creating holes through which the macromolecules can pass. The principle was successfully applied to cytosolic delivery of antisense oligonucleotides. 4.4. Amide surfactants Amide bonds, like ester bonds, can be cleaved either by chemical hydrolysis or by enzyme catalyzed hydrolysis. The amide bond is more stable than the ester bond to alkaline hydrolysis but is usually more susceptible to acid catalyzed cleavage. Amidases and peptidases are examples of amidesplitting enzymes. Lipases, which are normally associated with ester bond cleavage, sometime work also on amide bonds. A nonionic surfactant containing an amide bond between the hydrophobic tail and a short polyoxyethylene chain was synthesized and characterized [21]. Values of CMC, surface tension at the CMC, area per molecule at the air–water interface, and cloud point were compared with the corresponding values for an ester surfactant and for an ether surfactant with the same length of the hydrophobic tail and the same number of oxyethylene units. The values are compiled in Table 1. As can be seen from the table, the amide surfactant packs less densely than the corresponding ester and ether surfactants. The amide-containing surfactant also has markedly higher CMC and cloud point values. The more hydrophilic character of amide surfactants than of the corresponding ester and ether surfactants is due to the fact that the amide bond is highly polar, giving rise to higher water solubility of the amide surfactant. The chemical stability of the amide bond was found to be high. When the surfactant was subjected to 1 M sodium hydroxide during five days at room temperature, only 5% was Table 1 Physical chemical data for three nonionic surfactants, all having eight carbons in the hydrophobic tail and four oxyethylene units but differing in the linkage between the hydrophobic and hydrophilic moieties

Amide Ester Ether a

CMC

γCMC

ACMC

CP

(mM)

(mN/m)

(nm2)

(°C)

65 10 9

36 31 30

0.61 0.4 a 0.49

N100 42 40

Uncertain due to the non-distinct slope of the surface tension isotherm.

Fig. 9. Biodegradation of the amide surfactant. During the first period, approximately until day 12, the microorganisms degrade the alkyl chain. During the second period, beyond day 12, the ethoxylate chain is being degraded.

cleaved. The corresponding experiment performed in 1 M HCl resulted in no hydrolysis. The amide bond was, however, found to be slowly hydrolyzed when lipase from Candida antarctica or peptidase was used as catalyst. Amidase and lipase from Mucor miehei was found to be ineffective. Despite the very high chemical stability, the amide surfactant biodegraded by a similar path in the plot of biodegradation versus time as the corresponding ester surfactant, reaching 60% biodegradation within 28 days (Fig. 9). Hence, it can be classified as readily biodegradable. Menger and coworkers have recently synthesized and characterized a group of amphiphiles with multiple amide bonds, so-called peptoads [22••]. Fig. 10 shows an example of a peptoad. These polyamide surfactants exhibit some interesting properties. In the solid state they assemble in layers with both intra- and interlayer hydrogen bonding between the amide bonds. Peptoads with short hydrocarbon chains were water soluble. Light microscopy showed that at high concentration the solutions consisted of long fibers dispersed in the liquid. The intermolecular forces are evidently very strong. Nevertheless, these short chain peptoads were very surface active, lowering the surface tension of water as efficiently as a normal surfactant with much longer hydrocarbon tail. A comparison was made between a peptoad with two internal amide linkages and a terminal CONMe2 group and an ethoxylated alkanoic acid amide with four oxyethylene units [23•]. Both surfactants were based on octanoic acid and the physical chemical behavior was compared with that of the corresponding fatty alcohol ethoxylate, i.e., tetra(ethylene glycol)monooctyl ether. The solubilization behavior of the amide-containing surfactants was very different from that of the

Fig. 10. Structures of peptoad surfactants.

88

A. Tehrani-Bagha, K. Holmberg / Current Opinion in Colloid & Interface Science 12 (2007) 81–91

Fig. 11. X-ray structure of a peptoad with a central block containing three amide bonds surrounded by heptyl chains. Hydrogen bonds between amide groups are indicated. (From Ref. [22] with permission).

normal ethoxylate. A hydrophobic solubilizate, hexamethyldisilane (HMDS), was found to be completely stuck in the individual micelles of the amide surfactants. In micellar solution of the alcohol ethoxylate, on the other hand, HMDS moved rapidly between the self-assemblies. The lack of exchange of solubilized molecules between the micelles is probably due to the strong intermolecular forces exerted by the amide groups present in the headgroup region of the micelles. The peptoad surfactants were found to be efficient solubilizers of a hydrophobic drug, paclitaxel (Taxol). A molecular dynamics simulation of the system peptoad–water–paclitaxel indicated that the drug molecule was positioned in the interior of the aggregate where it interacted with the surfactant by multiple hydrogen bonds [24]. The structure was also reinforced by intermolecular hydrogen bonds in the polar headgroup region of the aggregates. Such intermolecular associations were also confirmed by X-ray analysis of crystallized peptoad [22••] (Fig. 11). 4.5. Carbonate surfactants Surfactants containing the carbonate bond are rare but such amphiphiles are relatively easy to prepare and the carbonate linkage has a reasonable chemical stability. Homologue pure nonionic surfactants containing a carbonate bond were recently synthesized by the route shown in Fig. 12 [25•]. The CMC of the linear carbonate surfactant was found to be a factor of three smaller than the CMC of the linear ether surfactant with the

same number of carbon atoms in the hydrophobic tail. Thus, the carbonate linkage gives a hydrophobic contribution to the surfactant molecule, just like the ester bond does, and can be treated as an integral part of the hydrophobic tail, giving the same apparent hydrophobic contribution as a methylene group. By comparing the rate of base-catalyzed hydrolysis of a linear carbonate surfactant and a linear ester surfactant it was found that the carbonate bond was more stable against alkaline hydrolysis than the ester bond [25•]. The time needed to hydrolyze 50% of the carbonate surfactant was twice as long as the time needed to hydrolyze 50% of the ester surfactant. This result was somewhat unexpected since the carbonyl carbon of the carbonate, having electronegative atoms on both sides, would at first sight be expected to be strongly electrophilic and thus readily attacked by the nucleophilic hydroxyl ion. A possible contributing factor for the relative stability of the carbonate bond is that it is stabilized by resonance. Delocalization of the electrons over the three oxygen atoms of the carbonate bond is likely to reduce the electrophilicity of the carbonyl carbon. The activity of three ester splitting enzymes, Candida antarctica lipase B (CALB), Mucor miehei lipase (MML), and esterase, towards the carbonate surfactant was studied. While CALB and esterase were found to catalyze the hydrolysis of the carbonate bond, MML showed no activity. Biodegradation test showed that the carbonate surfactants were readily biodegradable. In comparative tests the rate of biodegradation of the carbonate surfactants was found to be somewhat higher than

Fig. 12. Synthesis of a nonionic carbonate surfactant.

A. Tehrani-Bagha, K. Holmberg / Current Opinion in Colloid & Interface Science 12 (2007) 81–91

89

Fig. 13. Hydrolysis of a nonionic ortho ester surfactant.

that of the corresponding surfactants containing an ester bond [25•]. 4.6. Cleavable surfactants for emulsions Alkyl ketene dimer (AKD) is a common hydrophobizing agent (usually referred to as sizing agent) in paper-making. It is usually added as a solid dispersion to the aqueous fiber suspension and the dispersion is made by emulsification of AKD above its melting temperature. The surfactant used in the emulsification will accompany the AKD into the paper where it will eventually make its way to the surface. It may then influence physical chemical properties such as wetting. This may cause problems in terms of print quality, etc. Thus, AKD dispersions are a possible practical case for cleavable surfactants. The pH of the pulp slurry is usually slightly basic and the pH will increase as water evaporates. In the final stage of the process the remaining water will have high pH and the temperature will, for a short period of time, be that of boiling water. Under these conditions alkali-labile surfactants are likely to degrade rapidly. Combinations of ester-containing nonionic and cationic surfactants were chosen as emulsifying system [26•]. The reason for choosing a cationic surfactant was that the surfactant aggregates formed – micelles in the bulk phase and monolayers or hemimicelles at most surfaces – would be positively charged.

Positively charged surfactant assemblies are known to attract negatively charged ions as counterions, which is the basis for micellar catalysis. Micellar catalysis is a well-known phenomenon for surfactant aggregates in bulk, i.e., micelles, but there is no reason why the concept should not be equally valid for surfactant aggregates on surfaces, for instance, a mixed surfactant layer stabilizing the oil–water interface of a dispersion. Two cleavable cationic surfactants were used, an ester quat and a betaine ester, both in combination with a nonionic ester surfactant. As expected, the cationic surfactant was more alkali labile than the nonionic surfactant and the betaine surfactant degraded faster than the ester quat. As discussed above, the alkali sensitivity of the betaine surfactant can be explained by the positively charged nitrogen in close proximity to the ester bond pulling electrons away from the carbonyl carbon, thus increasing its electrophilicity. The hydrolysis rate for the betaine surfactant was considerably faster above than below the CMC, which is a sign of micellar catalysis. This is in accordance with expectations. For the ester quat no difference was found in rate of degradation between concentrations above and below the CMC, which indicates that there is no micellar catalysis. This is somewhat surprising. Ortho ester surfactants are of interest as cleavable surfactants if one wants alkali-stable amphiphiles that break down easily

Fig. 14. Synthesis of a thermally labile surfactant by a Diels–Alder reaction.

90

A. Tehrani-Bagha, K. Holmberg / Current Opinion in Colloid & Interface Science 12 (2007) 81–91

Fig. 15. Hydrolysis of a silicone-based surfactant.

under acidic conditions. Ortho ester surfactants are more acidlabile than the better known acetal and ketal based surfactants [6,27,28]. Nonionic ortho ester surfactants are usually made from a fatty alcohol, an end-capped poly(ethylene glycol) (PEG) and ethylorthoformate. Acid hydrolysis gives ethanol and formic acid together with regenerated fatty alcohol and PEG derivative, as illustrated in Fig. 13. A series of nonionic ortho ester surfactants of the general formula shown in Fig. 13 was used as emulsifiers for a hydrophobic oil, squalene [29]. A surface active polymer was used as emulsion stabilizer. The intention was to first use an efficient emulsifying system to prepare a good emulsion and then decompose the surfactant by addition of acid, a procedure that would result in an emulsion stabilized by the polymer only. There is an interest, again in the paper-making process, for emulsions that do not contain low molecular weight amphiphiles. Exposure to acid (pH 4) lead to rapid cleavage of the surfactant, which, in turn, resulted in a slow growth of the emulsion droplets. Evidently, the polymer-only stabilized emulsion is not as stable as the emulsion stabilized by a combination of polymer and nonionic surfactant. 4.7. Cleavable surfactants for microemulsions Ketal-based surfactants for use in microemulsions have been synthesized by first reacting glycerol with a hydrophobic ketone, 3-hexadecanone, and subsequently reacting the remaining hydroxyl group of the glycerol, after activation with NaH, with the mesylate of a monomethyl-PEG. The resulting surfactant is a PEG chain attached to a branched C-16 hydrophobic tail via a five-membered cyclic ketal [30]. Ketals are known to hydrolyze under acidic conditions, although somewhat less readily than ortho esters [6]. The nonionic ketal surfactant was used for making pHsensitive microemulsions [30,31]. Such microemulsions may be of interest for extractive isolation and purification of proteins and in drug delivery. The surfactants turned out to be much less efficient in making microemulsions than regular nonionic surfactants of the fatty alcohol ethoxylate type, however. It seems that insertion of the bulky five-membered ring between the hydrocarbon tail and the headgroup of the surfactant significantly reduces its surface activity.

Diels–Alder addition reaction, as shown in Fig. 14 [32•]. The aryl-substituted maleimide derivative is an excellent dienophile and the hydrophobic furan derivative is a good diene in a Diels– Alder reaction and the syntheses proceeded at low temperature giving exclusively the exo isomer in high yield. Treatment of the Diels–Alder adduct with base gave the surface active species. The surfactants proved to form spherical micelles with a CMC of around 1 mM. The surface tension at the CMC was high, around 50 mN/m. When exposed to elevated temperatures (N 60 °C), the retro Diels–Alder reaction occurs and the surfactant is decomposed into its hydrophilic and hydrophobic constituents with loss of surface activity. Such surfactants may be of interest for processes that require surfactant destruction by a completely non-invasive triggering mechanism. The authors suggest that the surfactants may be used as removable templates in the synthesis of microporous zeolitic materials. 4.9. Siloxane-based surfactants Surfactants that contain a cleavable bond between a polydimethylsiloxane segment and surrounding PEG chains have been synthesized and tested with regard to physical chemical solution behavior and cleavage mechanism. The products were stable under neutral and alkaline conditions but were rapidly hydrolyzed at low pH, see Fig. 15 [33]. The hydrolysis can be speeded up by simultaneous UV irradiation. Such surfactants are intended for use as textile finishing agents. The fabric is treated with the amphiphilic silicone and in a subsequent step exposed to a solution of pH around 4. After washing, a hydrophobized fabric is obtained that shows excellent water repellency. References and recommended reading [1] Overkempe C, Annerling A, van Ginkel CG, Thomas PC, Boltersdorf D, Speelman J. Esterquats. In: Holmberg K, editor. Novel surfactants. New York: Marcel Dekker; 2003. p. 347–84. [2] Garcia MT, Campos E, Sanchez-Leal J, Ribosa I. Anaerobic degradation and toxicity of commercial cationic surfactants in anaerobic screening tests. Chemosphere 2000;41:705–10. [3] Jaeger DA. Cleavable surfactants. Supramol Chem 1995;5:27–30. [4] Hellberg P-E, Bergström K, Holmberg K. Cleavable surfactants. J Surfactants Deterg 2000;3:81–91. [5] Holmberg K. Cleavable surfactants. In: Texter J, editor. Reactions and synthesis in surfactant systems. New York: Marcel Dekker; 2003 . p. 317–45.

4.8. Thermally cleavable surfactants Surfactants that contain a thermally labile bond between the hydrophobic tail and the headgroup have been prepared by a

• ••

Of special interest. Of outstanding interest.

A. Tehrani-Bagha, K. Holmberg / Current Opinion in Colloid & Interface Science 12 (2007) 81–91 [6] Stjerndahl M, Lundberg D, Holmberg K. Cleavable surfactants. In: Holmberg K, editor. Novel surfactants. 2nd ed. New York: Marcel Dekker; 2003. p. 317–45. [7] Jaeger DA, Mohebalian J, Rose PL. Acid-catalyzed hydrolysis and monolayer properties of ketal-based cleavable surfactants. Langmuir 1990;6:547–54. [8] Stjerndahl M, Holmberg K. Synthesis and chemical hydrolysis of surface •• active esters. J Surfactants Deterg 2003;6:311–8. The paper shows that whereas cationic ester surfactants in micellar form undergo rapid hydrolysis due to micellar catalysis, nonionic esters of the fatty acid ethoxylate type are protected from hydrolysis in micelles, “micellar protection”. [9] Stjerndahl M, van Ginkel CG, Holmberg K. Hydrolysis and biodegradation •• studies of surface active esters. J Surfactants Deterg 2003;6:319–24.The paper shows that for ester surfactants with different degree of substitution in α-position to the ester carbonyl carbon there is no relationship between rate of chemical and enzymatic hydrolysis on the one hand and rate of biodegradation on the other hand. [10] Holmberg K, Jönsson B, Kronberg B, Lindman B. Surfactants and polymers in aqueous solution. 2nd ed. Chichester: Wiley; 2003. p. 111. [11] Lundberg D, Stjerndahl M, Holmberg K. Mixed micellar systems of • cleavable surfactants. Langmuir 2005;21:8658–63. The paper shows that hydrolysis of a nonionic ester surfactant present in micelles is faster in combination with a cationic surfactant and slower in combination with an anionic surfactant compared to the hydrolysis rate of the nonionic surfactant only. [12] Thompson RA, Allenmark S. Factors influencing the micellar catalyzed hydrolysis of long-chain alkyl betainates. J Colloid Interface Sci 1992;148:241–6. [13] Lundberg D, Holmberg K. NMR Studies on hydrolysis kinetics and • micellar growth in solutions of surface-active betaine esters. J Surfactants Deterg 2004;7:239–46. The paper illustrates the effect of surfactant tail length and the effect of surfactant concentration on the rate of hydrolysis of ester-containing cationic surfactants. The effects seen are in compliance with the pseudophase micellar catalysis concept. [14] Romsted LS. A general kinetic theory of rate enhancements for reactions between organic substrates and hydrophilic ions in micellar systems. In: Mittal KL, editor. Micellization, solubilization, microemulsions. New York: Plenum Press; 1977. p. 509–30. [15] Rozycka-Roszak B, Przestalski S, Witek S. Calorimetric studies of the micellization of some amphiphilic betaine ester derivatives. J Colloid Interface Sci 1988;125:80–5. [16] Lundberg D, Ljusberg-Wahren H, Norlin A, Holmberg K. Studies on dodecyl betainate in combination with its degradation products or with phosphatidyl choline — phase behavior and haemolytic activity. J Colloid Interface Sci 2004;278:478–87. [17] Karlberg M, Stjerndahl M, Lundberg D, Piculell L. Mixed solutions of an • associating polymer with a cleavable surfactant. Langmuir 2005;21:9756–63.The paper describes the system betaine ester surfactant–hydrophobically modified hydroxyethylcellulose. This combination forms a gel with a rheology that changes with time as the betaine ester is decomposed into non-surface active products. Thus, a temporary gel is obtained. [18] Lindstedt M, Allenmark S, Thompson RA, Edebo L. Antimicrobial activity of betaine esters, quaternary ammonium amphiphiles which spontaneously hydrolyze into nontoxic components. Antimicrob Agents Chemother 1990;34:1949–54. [19] Tehrani-Bagha AR, Oskarsson H, van Ginkel CG, Holmberg K. Cationic •• ester-containing gemini surfactants. J Colloid Interface Sci in press. The paper shows that ester-containing cationic gemini (dimeric) surfactants in micellar state hydrolyse much faster than the corresponding monomeric surfactants. The paper also shows that there is no correlation between the rate of chemical hydrolysis of different dimeric and monomeric cationic ester surfactants and their biodegradation rates. [20] Asokan A, Cho MJ. Cytosolic delivery of macromolecules. 3. Synthesis • and characterization of acid-sensitive bis-detergents. Bioconjug Chem

[21] [22] ••

[23] •

[24] [25] •

[26] •

[27] [28]

[29] [30]

[31]

[32] •

[33]

91

2004;15:1166–73. The paper illustrates an elegant principle for drug delivery using liposomes based on a cationic gemini surfactant having an acid-labile linkage in the spacer unit. As the surfactant is hydrolyzed normal, single headgroup–single tail surfactants are formed that destroy the cell membrane, allowing delivery of macromolecules that were initially embedded in the liposome. Stjerndahl M, Holmberg K. Synthesis and stability studies of a surfaceactive amide. J Surfactants Deterg 2005;8:1–6. Menger FM, Zhang H. Peptoads, a group of amphiphilic long-chain triamides. Langmuir 2005;21:10428–38. The surfactants with multiple amide bonds exhibit most interesting properties caused by the strong interaction (hydrogen bonding) between the oligopeptide headgroups. The concept of an oligoamide headgroup in a surfactant is novel and could be practically useful. Stjerndahl M, Lundberg D, Zhang H, Menger FM. NMR studies of aggregation and hydration of surfactants containing amide bonds. J Phys Chem 2007;111:2008–14. The peptoad surfactants are effective solubilizers of hydrophobic molecules. The unique feature of these self-assembled surfactant structures is that the solubilized molecules seem to be stuck inside the micelle. There is virtually no exchange of material between the different micelles. The effect is most likely due to the strong intermolecular associations between the surfactants that make up the micelle. Menger FM, Zhang H, de Jannis J, Kindt JT. Solubilization of paclitaxel (Taxol) by peptoad self-assemblies. Langmuir 2007;23:2308–10. Stjerndahl M, Holmberg K. Hydrolyzable nonionic surfactants. Stability and physicochemical properties of surfactants containing carbonate, ester and amide bonds. J Colloid Interface Sci 2005;291:570–6. The paper demonstrates that surfactants containing a carbonate bond between the hydrophobic tail and the polar headgroup are interesting candidate cleavable surfactants. The carbonate bond is surprisingly stable toward alkaline hydrolysis (slightly more stable than ester bonds) and the surfactants studied were found to be rapidly biodegradable. Mohlin K, Karlsson P, Holmberg K. Use of cleavable surfactants for alkyl ketene dimer (AKD) dispersions. Colloids Surf A Physicochem Eng Asp 2006;274:200–10. The paper demonstrates a practically interesting application of cleavable surfactants: as emulsifiers for AKD emulsions. Such emulsions are used in paper-making. The rationale for using cleavable surfactants for the purpose is to avoid surfactants in the final paper, which is sometimes a problem. Hellberg P-E, Bergström K, Juberg M. Nonionic cleavable ortho ester surfactants. J Surfactants Deterg 2000;3:369–79. Bergström K, and Hellberg P-E. Ortho ester-based surfactants, its preparation and use. US Patent 7,002,045 B2 (2006). (To Akzo Nobel N.V.). Mohlin K, Holmberg K. Nonionic ortho ester surfactants as cleavable emulsifiers. J Colloid Interface Sci 2006;299:435–42. Iyer M, Hayes DG, Harris JM. Synthesis of pH-degradable nonionic surfactants and their applications in microemulsions. Langmuir 2001;17:6816–21. Rairkar ME, Diaz ME, Torriggiani M, Cerro RL, Harris JM, Rogers SE, Eastoe J, Gomes del Rio JA, Hayes DG. Three-component microemulsions formed using pH-degradable 1,3-dioxolane alkyl ethoxylate surfactants. Colloids Surf A Physicochem Eng Asp 2007;301:394–403. McElhanon JR, Zifer T, Kline SR, Wheeler DR, Loy DA, Jamison GM, et al. Thermally cleavable surfactants based on furan-maleimide Diels–Alder adducts. Langmuir 2005;21:3259–66. The paper shows how the Diels– Alder reaction can be used to prepare surfactants that spontaneously decompose at moderate temperature (N60 °C) as a result of a retro Diels– Alder reaction taking place. The degradation products have no surface activity. Lin L-H, Chen K-M. Surface activity and water repellency properties of cleavable-modified silicone surfactants. Colloids Surf A Physicochem Eng Asp 2006;275:99–106.