Reactivity in functionalized surfactant assemblies

CoUoids and Surfaces, 35 (1989) 121-134 Elsevier Science Publishers B.V., Amsterdam -

121 Printed in The Netherlands

Reactivity in Functionalized Surfactant Assemblies UMBERTO TONELLATO Centro C.N.R. “Meccanismi di Reazioni Organiche”, Dipartimento di Chimica Organica dell’Universitti di Padova, via Marzolo 1, 35131 Padova (Italy) (Received 31 December 1987; accepted 5 April 1988)

ABSTRACT The esterolytic reactivity in mice&r aggregates of functionabzed surfactants in aqueous solutions is examined through examples mostly drawn from our work at Padova. The treatment of rate data, the source of rate enhancement, the enantioselectivity in chiral micellar systems and more recent results obtained in the case of metahomicehes - made up of surfactants capable of chelating metal ions (Cu’+, Zn’ + ) in proximity with a nucleophihc function - are discussed.

INTRODUCTION

Micelles as well as other surfactant aggregates can influence the chemical rates and equilibria in aqueous solutions [ 11. After the early reports of these phenomena [ 2 1, several research groups devoted their attention to the reactivity, particularly of organic processes, in the presence of micellar aggregates and were able to establish the main factors for the rate changes observed [3]. Hydrophobic and electrostatic factors are normally involved. A key feature of micelles is that they can associate solutes and, if made up of ionic surfactants, attract counterions. For example, a cationic micelle can bind a carboxylate ester and attract hydroxide ions: as a consequence, the ester saponification occurs more rapidly in the presence than in the absence of cationic micellar aggregates [ 41. The rate changes in the case of “inert” micelles are usually not very impressive, mostly within one order of magnitude [ 11. Moreover, the rates in micellar solutions are affected by several factors and particularly by the presence of other ions which may compete with the reactive ones surrounding the micellar surface [ 51. There are, however, some interesting, mostly formal, analogies between reactions in micelles and reactions in biological systems which have stimulated research in the field and the search for larger kinetic effects in micelles. A step

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in this direction and also toward a significant refinement of biological models was the synthesis of functionalized surfactants and the study of the reactivity of functionalized micelles [ 1,6,7]. Functionalized surfactants are simply defined as compounds containing reactive functions covalently bound to the molecular structure. Bound substrate molecules can be brought into close proximity with micellar functions, each surfactant molecule being functionalized (at least in the case of homomicelles), with predictable kinetic advantages and without being strongly affected by external factors such as ionic solutes. Since most of these systems were tested in the hydrolysis of esters or amides and since they were claimed to behave as biomimetic agents, the functions [1,7-lo] most frequently used were those present in the active sites of hydrolytic enzymes: hydroxyl, amino (imidazole, in particular) or sulfhydryl groups. This paper reviews the subject of reactivity and selectivity in functional surfactants micellar assemblies in aqueous solutions, and it will be focused on the reactivity of hydrolytic micellar systems, mainly on the basis of the recent and continuing studies in our laboratory. MICELLES CONTAINING

NUCLEOPHILIC

FUNCTIONS

AS ESTEROLYTIC

SYSTEMS

Figure 1 shows the postulated reaction scheme in the case of the hydrolytic cleavage of an ester for micelles containing nucleophilic functions. An association equilibrium, normally fast, is followed by a nucleophilic attack of the function on the substrate resulting in the expulsion of the alcoholic fragment and in the acylation of the surfactant; the acylated surfactant may be deacy/VVVQ-NUH

s uH ts

e

P, + P,

uH

Kb

I” 9

+ P,(H)

Nu(H) kd +

NuH =OH,

SH,

NHR,

=N-OH,

p2

N+,NH,...

Fig. 1. Schematic catalytic cycle for functionalized age of esters.

(nucleophilic)

micelles in the hydrolytic cleav-

123

lated to water and the original reagent restored. The first reaction is therefore referred to as the acylation step and the second one as the deacylation step. The last one is clearly of importance: if it is a rapid process, the whole system is a true catalyst with fast turnover; if it is slow, the system is at best a stoichiometric catalyst. In the past years, we have investigated [8,11] a number of functionalized micellar systems made up of either cationic (mostly quaternary ammonium salts) surfactants or of derivatives of long-chain carboxylic acid (see Table 1). In some cases bifunctional surfactants were also synthesized and investigated. The substrates on which we mainly focused our analysis were the p-nitrophenyl acetate (PNPA) and hexanoate (PNPH) esters. QUANTITATIVE TREATMENT

OF RATES OF REACTIONS IN FUNCTIONALIZED

HOMOMICELLES OR COMICELLES

The kinetic treatment was a problem at the beginning of these studies, but taking advantage of the kinetic models generally accepted and earlier discussed by Martinek et al. [12a] and by Romsted [ 12b] and Bunton [ 131, and following the pseudo-phase separation approach, we derived [ 141 the basic equation (1) which applies to solutions where [substrate, S] -=x [ micellized surfactant, 0’1. Equation (1) relates the observed pseudo-first-order rate constant, k, to k,, the second-order rate constant in the micellar pseudo-phase and to Kb, k

k,+ (k/v)& [ofI Jo+& [of1 w= I+& [of] I+& [of]

(1)

the association (binding) constant of the substrate to the micellized surfactant, Of, and takes into account the pseudo-first-order rate constant observed in the absence of micelles, k,. The product of k,, & and the reciprocal partial molar volume Q of the micellized surfactant is k,, the apparent catalytic rate constant which is a kinetic parameter of practical use and can be easily evaluated from the rate profiles through simple mathematical manipulation together with &. Under conditions: [S] >> [Df], through “burst” kinetics (when observed) and by means of other described methods [ 141 one may evaluate the turnover rate constants which are expressed in terms of molecules of substrate cleaved per molecule of functionalized micellar surfactant per second. We had also to face the problem of the poor solubility of some hydrophobic reagents. In these cases we measured the reactivity of comicelles made of cetyltrimethylammonium bromide (CTABr ) and these reagents [ 151. Through the kinetic treatment worked out for these comicellar systems (with some assumptions and approximations), the catalytic rate constants, k,, could also be evaluated for those poorly soluble functionalized surfactants [ 141. Thus a systematic analysis of the reactivity of the functionalized systems could be carried out for CTABr-functionalized surfactants comicelles.

124

REACTIVITY IN THE CLEAVAGE OF ACTIVATED ESTERS

Table 1 shows the k, and hUrnovervalues for some types of functionalized surfactants for the hydrolytic cleavage of PNPA and PNPH as measured and evaluated under similar conditions at pH 7.95 (Tris buffer; 1% CH&N). As pointed out above, the kc rate constants show the stoichiometric catalytic efficiency and not the overall catalytic efficiency which is indicated instead by the turnover rate constant. Entries l-4 show data for reagents containing the hydroxy function (also in the activated form of oximes of hydroxamic acid derivatives), entry 5 refers to a thiol functionalized reagent, and entries 6-10 to amino (including imidazole) functionalized systems. Finally, entry 11 refers to the enzyme a-chymotrypsin as measured in the standard conditions used. Within each group of functions, TABLE 1 k, ( mole1 9-l) and ktu,nover(s- ’ ) for some functionalizecl reagents” in the cleavage of PNPA and PNPH, pH 7.95 1O4w k turnovsr b

kc PNPA 1, Ic,,I

2. I

- CO-N(Me)-

OH

300

2800

3.

m

-T?(Me)rc(~h)=~-OH

305

2500

4.

[c,,I

-f?(Me),-cO-c(~h)=~-OH

2420

‘u 22000

5.

Ic,,1-

E(hb),-(CH,),-

SH

850

4500

8,

a-

?(Me),-(cH,),-

NH2

7.

8.

18

Ic,JJ - CO-NH-CH(COOH)-CH>-!M

8.5

52

a

8

10. m

$(M&(CHJ-NH-CO-IM

28

- $(M+cH,-IM LH~-cH*-

a

1.8

0.9

9. Ic,,I -

11.

0.15

- :(b&-CHz-,M

a-

7.1

5.5

290

35

1200

50

210

38

OH

chymotrypsin

@+&HI,,,

(PNPH)

PNPH

0 - N(M+(CH,),-OH

2000

;

IM=

N~H.bWhsre

not

140

shown,

k, (3 8’.

c

With

PNPA

E

125

much of the difference in the apparent catalytic rate k, is due to the acidity, the (apparent) pK,, of the functions. For example, on going from the simple choline-type surfactant (entry 1) to the ketooxime derivative (entry 4) the much greater reactivity is to be ascribed to a lower apparent pKa of the latter by approximately 4.7 units: at the pH explored, the fraction of dissociated hydroxyls (much better nucleophiles than the undissociated ones ) is much larger for the ketooxime than for choline derivative. However, the turnover rate is small except in the case of systems containing the imidazole function. When imidazole is the function, particularly when the imidazole is activated, the systems show a remarkable overall catalytic effectiveness. In some cases the activity is not too far from that of the enzyme chymotrypsin measured under identical conditions for these (clearly non-specific ) substrates. BIOMIMETIC SYSTEMS RELATED TO TRYPSIN-LIKE

ENZYMES

Mechanistic studies have shown that the mode of action of these micellar systems is as predicted (see Fig. 1) and the first intramicellar reaction is a nucleophilic attack of the function resulting in its acylation. In many cases the intermediate could be detected if not isolated [ 71. An interesting and somewhat exciting case was that of the bifunctional hydroxy and imidazole containing surfactant (entry 10 of Table 1). This was designed to mimic the action of chymotrypsin which is illustrated in Fig. 2. In the active site of the enzyme three functions are juxtaposed for a proton shuttle which helps the hydroxy function of the serine residue to attack the ester, while the neighbouring imidazole participate in the removal of the proton. Comparison of the kinetic data for the hydroxy- and imidazole-monofunctionalized systems (Table 1, entries 1 and 8) with those for the bifunctionalized system clearly indicate that the dominating role in the case of the bifunctional surfactant is played by the imidazole residue and that the hydroxy function does not participate. However, when we tried to detect the acylated intermediate, we could follow its formation and disappearance from changes in the absorbance at 247 nm, as shown in Fig. 3, in the case of the imidazole-monofunctionalized surfactant but not in the case of the bifunctional one. Observations made by Moss and his coworkers [ 91, and independently by us [lib] , indicated that the hydroxy function had an important role, and we went so far as to think that the mode of action of these bifunctional micelles was analogous to that suggested for the enzyme. The actual mode of action in the bifunctionalized micelles, as first demonstrated by Moss [gal, is indicated in Fig. 4. The imidazole is the nucleophile which is acylated but the acyl group is quite rapidly transferred to the hydroxy function so that there is no detectable build-up of the acylated imidazole intermediate. Interestingly, this would support the hypothesis [ 161 that the catalytic cycle of Fig. 4 applies also to the trypsin-like enzymes in the case of simple activated esters such as PNPA.

126

Asp-102

Ser-195

His-57

Fig. 2. Ester cleavage through the proton shuttle mode of action of trypsin-like enzymes.

1 10 min

[PNPAj:

1.3 x1c4M;

pH 9.1,

0.02

M

[surf]:

borate

2.5xl$M buffer

Fig. 3. Spectral changes due to the formation of an acetylated intermediate.

Ar

RCO,H

HOAr

I

1

m

B

Im-C-R

fast DO-C-R

OH

Fig. 4. Main catalytic cycle of imidaxole- and hydroxy-functionalixed cleavage of activated esters. SOURCE OF MICELLAR RATE ENHANCEMENTS

surfactant micelles in the

IN FVNCTIONALIZED

MICELLES

The overall kinetic effects observed are clearly related to the reaction mechanism and to micellar properties. There were some important questions to be answered concerning the latter point: what are the micellar factors at the origin of the rate enhancements observed? And are the effects somehow predictable? The answers from our own and other published studies [ 131 are the following. Concentration effects: these are obviously important and related to the presence of a very high local concentration of reactive functions and to the pre-

127 TABLE 2 Rate

constants in micellar and aqueous (pseudo-1phases; kre~=k/k, PNPA km

R-CO-NH-CH-CH,-IM

.076

kw .19

PNPH krel

0.4

km

kw

,031

.16

kreI

0.2

609

(+ CTABr)

R% CH3-

CH,-IM’

31.

16.

1.9

19.

24.

0.8

AH, C”3

R%

-KHz),-S’

5.1

2.8

1.8

.5

1.3

0.4

hH,

equilibrium association which favours hydrophobic substrates (compare the overall rates of PNPA and PNPH in Table 1). Electrostatic factors are of importance in the case of ionic micelles since they influence the dissociation of a given function into the much more reactive dissociation form. In the case of micellar cationic surfactants the apparent pK, is 0.5-1.5 units lower than that of non-micellar analogs and the acid dissociation of the functions is also complicated, as in any polyelectrolyte system [ lla,17]. Finally, medium effect is a possible factor related to the problem of acid dissociation in the case of functionalized micelles. To what extent is the micellar microenvironment different from bulk solvent? This is indicated by data in Table 2 which shows both the real micellar rate constants. k, (mol-’ s-l), once corrected for the concentration effects and the apparent pK, of the functions and the secondorder rate constants in water, lz, (mol-’ s-’ ), as measured (and corrected for the pK,) on non-micellar models (R=Me) of the fimctionalized surfactants [ 141. The ratios are close to unity, mostly within (large) experimental errors. Clearly the reactions in functional micelles also occur in a very aqueous environment. This was a rather disappointing finding since there was some expectation that these micellar processes involving the nucleophilic reactivity of dissociated (mostly anionic) functions might enjoy the benefits of a substantial desolvation, as in the case of phase-transfer reactions [ 181. METALLOMICELLES

Employing the micelle-enzyme analogy as a guide, attempts recently to construct analogs of hydrolytic metalloenzymes. attention on systems which may be defined as metallomicelles. of surfactants containing a nucleophilic function and a subunit lating a (transition) metal ion.

have been made We focused our These are made capable of che-

128

The postulated mode of action of these metallomicelles is illustrated in Fig. 5. The surfactants in this case should bring a metal ion in close proximity with the nucleophilic function which should be activated toward a bound ester, thus giving rise to favourable kinetic effects. This was first verified by Tagaki and his coworkers [ 191 using a number of hydrophobic reagents containing the 2hydroxymethylimidazole or analogous subunits in comicelles of CTABr in the presence of Zn (II) and, more recently, Cu (II). After some trying [20], we eventually synthesized the surfactants DN, 1, and DS, 2. The pyridino moiety is the basic chelating subunit, the hydroxy group is the nucleophilic function, and their solubility is ensured by the quaternary ammonium group bound at the end of the hydrophobic tail. In fact, they are reasonably soluble in aqueous solutions (up to 3-5. 10m3M), and form micelles which can effectively chelate metal ions such as Zn (II) or Cu( II). Quite likely both DN and DS, in the presence of metal ions, aggregate like bolaform surfactants [Id]. We also found that they are more effective chelating and catalytic agents than micellar surfactants 3 where the cationic head is closer to the pyridino moiety than in the case of DS. The substrate of choice was the p-nitrophenyl picolinate 4, whose hydrolysis is quite effectively catalyzed by transition metal ions [ 211.

OH

DS , 2

DN ,l

Br

8

CH,-(CHt),,-(CH,),~-(CH,)~-S 3

NO*

OH

4

The micellar systems made of DN or DS are good catalysts of the hydrolysis of the piconilate ester [ 20,221. Figure 6 shows a three-dimensional projection of the rate-concentration profiles in the case of solution of DN and (left) Zn(N03)z in a 2,6-lutidine buffer, pH 7.25, and (right) Cu(N03)z in MES buffer, pH 6.3. Clearly, Cu(I1) ion is much more effective than Zn(I1) ion. Under the conditions of maximum surfactant and metal ion concentrations

129 V”.“‘“‘L&H

s -

P, +

P2

L> tint

&

C-J tibh(H)

_k_

k,

Fig. 5. Schematic catalytic cycle for functionalized metallomicelles in the esterolytic process.

3

2 3 1 =‘

2

!E. 3,

0

z :

0

-

_.

, x 10yM

Fig. 6. Rate-concentration

profiles for the hydrolytic cleavage of p-nitrophenyl picolinate.

used in these profiles, we observed approximately a ZOOO-foldrate enhancement in the case of Zn (II) and a million-fold rate enhancement with Cu (II), relative to pure buffer. The metallomicelles made up of DS are about twice as effective as those of DN under similar conditions.

130

The system is quite effective and we tried to go to the sources of catalytic action of these systems. The mode of action is complicated considerably by a number of equilibria which make a quantitative treatment of the kinetic data exceedingly difficult, at least in our hand: complexation of the metal ion with the ligand, with the substrate, and with products and the formation of binary and ,ternary complexes, both non-productive and productive. The productive one is, by all accounts, the ligand-metal ion-substrate complex. As indicated in Scheme 1, within such a complex, the metal ion acts as a template for a pseudo-intramolecular nucleophilic attack to give a transacylation product. This in turn undergoes rapid, metal ion assisted, hydrolysis, thus ensuring a fast turnover in the system at least insofar as enough metal ion is present.

Scheme 1

Metallomicelles of DN or DS and Cu(I1) ion are also effective catalysts of the hydrolysis of a-amino esters, inluding esters of natural a-amino acids (see below), although not as effective as in the case of the picolinate. ENANTIOSELECTIVITY

Stereoselectivity was also one of the properties of functional micelles which have been investigated since the early seventies using chiral surfactants made of histidine [ 231 or ephedrine derivatives [ 241. With the latter hydroxy-functionalized surfactants we also tried to determine the degree of enantioselectivity using chiral esters [ 251. Table 3 shows some of the chiral reagents and enantiomeric substrates investigated and the enantioselectivity as given by the ratios of the k, constants for the two enantiomers. The largest factor (3.2) was observed in the case of the a-methoxyphenylacetate ester, a system reported in the early literature as virtually non-enantioselective. Factors around three are the largest enantioselectivities reported in the literature for simple micellar systems*. The enantioselectivities appear to be due to transition state rather than initial state interactions; apparently the effects arise solely from the different free energies of diastereomeric transition states. In other words the sit*Impressive enantioselectivities have been recently reported by Ueoka et al. [ 26,271 using small peptides as chiral reagents in aggregates of single- and double-chain surfactants and chiral hydrophobic substrates. Although the nature of the aggregates has not yet been defined, they are certainly not simple spherical micelles.

131 TABLE 3 Enantioselectivity factors kc ( + )/kc ( - ) observed in the presence of the two enantiomers of the surfactant CEB, pH 9.5,25”C Ph-yH-0&+pNP CHa n&-C&+

OM

Hex-YH-OCO,pNP Me

Ph-Y-F-FpNp OHMCMO

yl-p-Ph Cn;Me

OH (+I

a. 31

0.82

1.15

(-1

3.2

1.2

0.84

(CEB)

( PNP

=

uation in simple micelles is not much different to that in non-micellar reactions involving an enantiomeric substrate and a chiral reagent. We thought that in the case of metallomicelles the situation might be more favourable for high enantioselectivities since the metal ion template effect could add a large degree of order to the loose, mobile micellar structure and lead to initial state rather than transition state diastereomeric interactions. Accordingly, we synthesized [ 281 both enantiomers of the chiral surfactants ligand 5.

The structure is somewhat different from that of the chelating surfactants DN or DS discussed above: the hydroxy function is now more removed from the pyridino moiety and bound to a chiral centre and the cationic head is absent. Virtually insoluble in pure water, it is however relatively soluble in mildly acidic solutions and in the presence of Cu (II) ions where it forms micelles (CMC = 35.10b5, pH 5.5, [ Cu (II) ] = 1*1O-4 M). Surfactant 5 is a strong chelating agent for Cu(I1) ions, much stronger than DN or DS, due to the binding ability of tertiary amino nitrogen. The Cu(I1) metallomicelles of 5 are effective catalysts of the hydrolysis of picolinic acid and of other cr-amino acid esters; their mode of action, although not yet fully established, is apparently similar to that of micellar DS (see Scheme 1). Obviously, we then turned our attention to their enantioselectivity in the hydrolysis of natural a-amino acid esters. So far, we have obtained [ 281

132

0

5

[R-:;105M l5 2o

Fig. 7. Rate-concentration profiles for the esterolysis of the enantiomeric esters of PheAla and Leu promoted by the R enantiomer of 5.

the results shown in Fig. 7, which shows the rate profiles for the R-enantiomer of the surfactant and the two enantiomers of the phenylalanine and the leucine p-nitrophenyl esters. The enantioselectivity factor at the largest surfactant concentration used in the experiments (other conditions are shown in the figure) is ca 15 in the first case and 10 in the second one, the faster enantiomer being in both cases the S-ester. Experiments carried out with the S-enantiomer of the surfactant gave (specularly) similar results. These enantioselectivities are by far the largest ever observed in the case of simple chiral micelles. The search of conditions for larger enantioselectivity and, possibly, for the kinetic resolution of amino acids from racemic mixtures of their esters is now under way. CONCLUSIONS

The vast amount of information published in recent years on micellar bioorganic chemistry has served to better define limits and perspectives in the field of reactivity in micellar assemblies. Mechanistic studies have allowed a better definition of the role of micellar aggregates. One cannot expect micelles, per se, to work miracles; the role of

133

micelles is to bring together reactants in a small volume, realizing very high concentrations out of dilute aqueous solutions. The fimctionalized micelles and metallomicelles discussed in this paper are an indication that advances in this area are likely to come from the study of micelles made of well-designed polyfunctional reagents. ACKNOWLEDGMENTS

I would like to thank Professors R. Fornasier and P. Scrimin, Mr E. Castiglione and many collaborators, whose names appear in the reference list.

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2 3 4 5 6 7 8 9 10 11

12

13 14 15 16 17 18

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