1336
Langmuir 1991, 7, 1336-1339
Enhanced Cyclization Rates of Large Rings Induced by a Micellar Environment Ling Wei, Adam Lucas, Jenise Yue, and R. Bruce Lennox. Department of Chemistry, McGill University, Montreal, Quebec H3A 2K6, Canada Received October 12,1990.I n Final Form: December 21, 1990 The kinetics of ring formation of a series of o-(w-bromoalkoxy)phenoxides,where the ring size varies from 7 to 20, have been studied in a cationic micellar environment (CTAB). Compared to a homogeneous reaction environment, where the ring closure rate constants decrease by ca. 500-1500-fold on going from the 7-membered ring [7] to the 14-membered ring [14],l only a 6-fold decrease in the micelle-localized reaction is observed. In addition, micellar effective molarities (EM), for these reactions are found to be 7-1900-fold greater than the homogeneous solution EM'S. These results constitute a significant example of true micellar catalysis, where the catalysis is reasoned to originate from an increase in the ground-state free energy of the substrate induced by localization of the phenolate oxygen and alkyl bromide moieties at the polar micelle interface. This localization of the "chain ends" leads to a significant decrease in the ground-stateentropy comparedwith the homogeneous situation and establishee that the conceptof interfacial templating of chemical reactions is valid. Furthermore, these rate enhancements establish that a micellar environment can affect reactivity in a more complex way than via simple medium and/or concentrating effects.
Introduction The formation of medium and large rings is of significant interest from a synthetic point of view2*3*4 given the large number of naturally occurring compounds with 7-20membered rings. Great difficulty arises in forming these rings, however, because the intramolecular rate constants are often small (95%) and were used as received or redistilled before use. The procedure used for synthesizing the o-(a-bromoalkoxy)phenols, where the n-alkyl moieties are composed of C3, C,, c6, Cs, C10, or Cl6 fragments, was as described by Illuminati et al.1 Purification of products was performed by flash chromatography (60-200 mesh silica gel, Aldrich) using 95 % hexane/5 % ethyl acetate as eluant. Spectroscopic data (200 MHz NMR, 70 eV mass spectrometry) were consistent with the expected product and purity was estimated to be >95%. Samples were stored under Nz at -20 OC prior to use. o-(Tetradecy1oxy)phenol was synthesized in an analogous fashion' and also yielded satisfactory spectroscopic data. Kinetic Measurements. (a) Homogeneous Solution. Intra- and intermolecular cyclization kinetics were measured in 99% DMSO (BDH, Poole, UK)/l% HzO (Milli-Q, 18 MQ resistivity) and in 75% EtOH (BDH)/25% HzO (Milli-Q). In a typical intramolecular kinetics experiments, 20 pL of 0.10 M NaOH was added to a 5 X lo-' M solution (1 mL) of a 0-(wbromoalkoxy)phenol to initiate the reaction. Decrease in the phenolate absorbance maximum (310 nm in DMSO) was routinely monitored for 5~112using a Varian DMS 300 UV-vis spectrophotometer. Addition of concentrated HCl to the T = 0 solution revealed that 20-fold excess alkyl bromide. Excellent first-order kinetics were observed for these measurements and the second-order rate constant was calculated by dividing hob by the concentration of alkyl halide. (b) Micellar Solution. Rate measurements in micelle solutions were performed in an analogous manner to those in (b,,,) of the phenolate homogeneoussolution except that the A, anion was shifted to 295 nm in CTAB. Micelle-phenol solutions were prepared in the following manner. A weighed quantity of phenol was dissolved in -100 pL of CHCl3 in a 25-mL beaker (Spectrograde, Aldrich) and the chloroform was blown off with dry N1. A thin film of the phenol resulted. A 1 X 10-8 M stock solution of CTAB (Sigma, twice recrysta1lized)ll was added to the beaker and bath sonicated for 15 min (Branson) at room temperature. This procedure ensured that the phenol was uniformly dispersed in the micelle preparation. The ratio of phenol/CTAB was chosen to ensure that the probability of greater than single occupancy of a micelle was low.1e This precaution greatly reduces the likelihood of dimerization and polymerization reactions. The absence of any significant second-order process was established by varying the initial concentration of phenol (over a 3-fold range); observed rate constants were invariant within experimental error. Under the experimental [phenol] and [CTAB] conditions, virtually all of the phenolate anion is assumed to be bound to the CTAB cationic surface.16
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Results and Discussion We have measured the rates of cyclization of an intramolecular Williamson ether reaction (1)for the formation of [7]-to [20]-membered rings. These rates have (16) Turro, N. J.; Gratzel, M.; Braun, A. M. Angew. Chem., Int. Ed. Engl. 1980, 19, 675.
Table I. Homogeneous Solution and Micellar Rates of Diether Formation at 25 OC k. s-l ring ["I
99% DMSO' 3.7 2.2 x 10-1 8.4 x 10-3 1.0 x 10-2 7.6 x 10-3
171 k3j
75% EtOHa 7.6 X 10-4 3.0 X 1od 3.5 x lP -8.2 x 10-7 6 5.0 x 10-7 -1.5 X lo4
hABC
3.4 x lo-'
8.2 X 1od
9.3 x 1od 5.9 x iod 5.9 X 1od ~ 4 1 -1.0 X 1W2 6.5 X 1od POI a Reference 22. Estimated from a plot of k vs [N], ref lb. This work.
[lo1
[121
*
Table 11. Intermolecular Rate Constnts in Homogeneous Solution and Micellar Solution at 25 OC reaction phenol alkyl halide solvent khntu,M-1 s-1 n-C~HlJ3r 99% DMSO 0.10 ~~
KH,
n-BuBr
OH
n-C~HlJ3r 99% DMSO
aoH
n-C.1HlJ3r
o+cH,~~-~cH,n-C~HlJ3r
a
99% DMSO
~
~
0.295' 0.14
99% DMSO
0.11
1 mM CTAB
0.0216
Reference 22. b Not corrected for micellar volume.
been previously measured in homogeneous solution (99% DMSO, 75% EtOH)g*22 and in this study in 1 mM CTAB (Table I). In order to determine effective molarities as well as t o estimate the polarity of the reaction environment, an analogous intermolecular reaction was also monitored by using the reaction between n-heptyl bromide and an alkoxyphenolate,o-(tetradecy1oxy)phenolate(Table 11,eq 2).
n=3,4,6,8,10,16
The results summarized in Table I reveal that the micellar environment exerts dramatic effects on the absolute and relative rates of the cyclization reaction. On going from [7] to [14] formation, khha decreases by ca. 6-fold in CTAB, by ca. 500-fold in DMSO, and by ca. 1500-fold in 75% EtOH. Because the absolute value of k b t , [7]in CTAB is similar to that measured in pure H20,lB we reckon that the micelle reaction environment is similar to that of bulk water17or aqueous alcohol. Assuming therefore that the locus of the reaction in the micelle is the same for the entire series ([7]to [20]),one can conclude that the large leveling effect for [NJ> [7]originates from catalysis of the cyclization reaction. Insight into the nature of intramolecular rate enhancements can be achieved via interpretation of effective molarities (EM).l8 Effective molarities have been widely used as a quantitative measure of the kinetic advantage of an intramolecular reaction compared with ita intermolecular analogue. Because it is expressed as the ratio khha/kbbr, (17)Cerricelli et al. (ref 15) have very recently reported kbm for [7] formation as 4.02 X lo-' 8-1 in 1 mM CTAB, 5.80 X 1W 8-1 in EtOH, 1.02 X lo-' 8-1 in MeOH, and 2.33 X lo-' 8-l in HzO (all at 25 "C). They conclude that the reaction environment in CTAB has the properties of a hypothetical solvent intermediate between E&% ! MeOH in polarity. Our CTAB (1 mM) [7] rate constant (3.4 X 1W 8-l) is in good agreement with the keh d u e reported by these workers. (18) Kirby, A. J. Adu. Phys. Org. Chem. 1980,17, 183.
Wei et al.
1338 Langmuir, Vol. 7, No. 7, 1991 Table 111. Effective Molarities of Homogeneous Solution and Micellar-Localized Reactions at 25 "C ring size
IM
effective molarity/Ma 99% 75% 1mM DMSOb EtOHb CTABC
[7] [8] [lo] [12] 1141 [20]
12.5 25 170 0.99 41 0.75 47 0.11 0.088 0.034 ~ 0 . 0 2 7 ~ 30 30 0.016 0.026 33 ~ 0 . 0 3 5 ~-0.05od
EM/EM CTAB/ CTAB/ EtOH DMSO 6.8 4.1 X 4.3 x -1.1 X 1.9 x -6.6X
10' 102 103 103 102
1.4 X 5.5 X 5.3 x 8.8X 1.2 x 9.4X
. . . . . . . . . . . . . . .. .. .. .. . . . . . . . . . .
10' 10' 102
lo2 103
lo2
Calculated as ratio of kintra/khbr data from footnotes b and c. C This work, using kmA#" = 2 X 1O-g M-1 s-1. If the reaction volume is considered (unrealistically) to be 100% of the micelle volume, then these values will be reduced by a factor of 3.3; i.e. EM( [7]) = 52 M and EM ([14]) = 9 M. d Estimated from k vs [ N ] plots, ref lb. b Reference 22.
Figure 1. Schematic representation of a CTAB micelle surface (filled circles representing headgroups) and the localization of both phenolate and alkyl bromide at the micelle surface.
EM has the units of molarity (M). Critical to the use of this formalism is the selection of a valid intermolecular analogue reaction. Reaction 2 was measured and the resulting second-order rate constant, kinkr, in DMSO (0.11 M-1 s-l) is in good agreement with the homogeneous o-methoxyphenol derivative rate constant. We have specifically designed the inter model reaction so that we can ensure that both the phenolate (C14 alkyl chain) and the alkyl bromide (C7) are fully micellized under our reaction conditions. Because of concerns that internal chain coiling could provide nonspecific steric blocking of the phenoxide,lgwe have also compared the rate of reaction of the p-dodecylphenolatewith n-heptyl bromide (Table 11). The uniformity of these rates indicate that, in DMSO, chain coiling phenomena do not manifest themselves in the observed kinetics.
The magnitude of this entropic assistance in micelles can be determined directly by temperature-dependentrate studies23 or indirectly by using literature homogeneous solution data and the following assumption. If we reason that because the net reaction (eq 1)occurring in 75 % EtOH is chemically the same as that occurring in CTAB (i.e. the extent of bond making and bond breaking occurring in the rate-determining transition state is the same in these two media and that the solvent effects on the transition state are similar), then we can assume that the AH*value for each substrate in CTAB is the same as that previously measured in 75 % EtOH. Using the relationship R In (k1/ 122) = A(AS*)24 (which equates the difference in two transition state entropies to the difference in their respective rate constants provided A(AH*) is zero), we can estimate the magnitude of change in AS' going from [7] to [20]. For example, A(AS*) for [14] compared with A(ASS) for [7] is -11 eu more positive for the CTABlocalized reaction compared with the reaction in 75 % EtOH. Given that the freezingof a CHzCHz bond rotation contributes a ca. 4.5 eu decrease in the ground-state e n t r ~ p y ,the ~ , CTAB-EtOH ~~ A( AS') value suggests that In order to calculate micellar E M Sone must correct the >2 C-C bonds of [14] are "frozen" by the micelle during observed intermolecular rate constant (k)hbr for simple binding of the phenolate (i.e. prior to reaction) and are micelle concentrating effectsP Assuming that the reaction thus not manifested in the transition state AS*. Catalysis volume in the micelle is roughly equivalent to the Stern of this nature has been described for intramolecular layer, and estimating that this occupies 30% of the total reactions with restricted bond rotations and for enzyme micelle volume, (tZ)inbrfv = (kCTmcom)inkr = 2 X lo* M-' catalysis in a general sense.25 s-l,Z1 where fv is the fraction of the total solution volume The foregoing discussion provides evidence that the cyin which the reaction actually occurs. clization reaction (eq 1) is greatly enhanced in aqueous The micellar EM (EMCTAB) values are large (230M) for all ring sizes measured while the EMDMSO and EME~OH micelles (large EM'S) and that a significant "leveling" process occurs,because there is both a lowering and leveling values are large only for medium rings ([7] 2 12.5 M) and of the activation free energies via a decrease in grounddrop off in a monotonic manner to a nearly uniform value state entropies. Ground-state entropies are decreased of ca. 0.04 M. In an important study, Mandolini further because the binding of the w-functionalized alkoxyphenoted that EM ratios (EMDMso/EME~oH) are almost nolates to the cationic micelle surface involves considerable invariant (1.6 f 1.0) for the series we have examined ([7] conformational restriction (Figure 1). Evidence for the to [20])22 suggestingthat in a homogeneous reaction solvent functional group localization schematically represented EM ratios reflect entropic (Le. chain conformational) in Figure 1 comes from two sources. Suckling et aLZ6have factors and do not reflect enthalpic factors (transition state shown in 1H NMR studies that phenols are highly localized solvation effects, etc.). The EM ratios (Table 111,EM"/ in the Stern layer of ionic micelles and that the electrostatic EME~oH, EMcT~/EMDMso) of up to -1900 observable attraction between a phenolate anion and the tetraalkylwhen comparing micellar and homogeneous solution environments are therefore extraordinary and point to (23) Activation parameters in micellarsolutionsare difficulttointerpret large ASs differences between a micellar and bulk solution because rate changes are accompanied by aggregation, structural, and reaction. partitioning changes as the temperature is changed. (19) Jiang, X.-K. Acc. Chem.Res. 1988,21,362, and referencestherein. (20) Bunton, C. A.; Savelli, G. Adv. Phys. Org. Chem. 1986,22, 213. (21) Using the molar density of CTAB as 3.198 M. Guvelli, D. E.; Kayes, J. B.; Davis, S . S. J. Colloid Interface Sci. 1981,82, 307. (22) DallaCourt, A,; Illuminati, G.; Mandolini, L.; Masci, B. J. Chem. SOC.,Perkin Trans. 1980,1774.
(24) Lowry, T. H.; Richardson,K. S.Mechanism and Theory in Organic Chemistry, 2nd ed.; Harper and Row: New York, 1981. (25) (a) Page, M. I.; Jencks, W. P. Proc. Natl. Acad. Sci. U.S.A. 1971, 68,1678. (b) Fersht, A. Enzyme Structure and Mechanism, 2nd ed.; W . H. Freeman: New York, 1985. (26) Suckling, C. J.; Wilson, A. A. J. Chem. SOC., Perkin Tram. 2 1981, 1616.
Enhanced Cyclization Rates ammonium surfactant headgroup will strongly localizethe phenolate in the Stern layer. While not strongly polar per se, the terminal alkyl bromide is moderately polarizable (dipole moment 2.1 D12)and has been shown to be surface active.14 The overall conclusion derived from these reports and the rate studies reported here is that the o-(w-bromoJ ~ *of ~~ a1koxy)phenolateacta as a bipolar, b o l ~ f o r m ’ ~type surfactant, where the reactive polar moieties occupy the quasi-2D “surface” of the micelle, rather than the 3D volume of a homogeneous solution (Figure 1). An interesting question arises from the schematic representation in Figure 1. One may ask why the micelle does not severely or totally inhibit cyclization. In addition to a “proreactive” looping conformation schematically illustrated in Figure 1,the surface localizationof phenolate and bromide might have been so stable as to inhibit the cyclization process. Menger and Carnahan have recently shown27in an elegant NMR experiment that boloform alkyl chains (Le. -0&(CH2)&02-) dispersed in micelles bind in an all-trans form such that the binding to a curved micellar surface is best described as being secantal in nature. This situation applied to our probe molecules should of course lead to a low probability of phenolate/ alkyl bromide interaction and thus rate retardation. The very large micellar EM’S, and the fact that they level off (27) Menger, F. M.; Carnahan, D. J. Am. Chem. SOC.1986,108,1297.
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Langmuir, Vol. 7, No. 7, 1991 1339
at 30 M establishes that the secant-style conformation of the o-(a-bromoalkoxy)phenolates is disfavored in CTAB and that one or more “hairpin” conformations exists in the chain. Our arguments are consistent with bond rotations being “frozen” by virtue of the alkoxyphenolate being micelle bound. Looping has been shown to be a rather general phenomenon in loosely organized aqueous micelles such as CTAB14v28p29 and, as has been shown using reaction 1 in this work, can lead to dramatic reduction of reaction dimensionally. Investigations into this phenomenon and its relationship to enzymatic catalysis of lipids and rate promotion in bilayer membranes are currently underway in our labs. The results reported in this work clearly show however that interfaces and supermolecular aggregates can affect reactivity in more complex ways than via simple medium (i.e. solvent polarity) and/or concentrating effects.
Acknowledgment. The financial support of NSERC Canada and the McGill Graduate Faculty is gratefully acknowledged. (28) Lennox, R. B.; McClelland, R. A. J. Am. Chem. SOC.1986,108, 3771. (29) (a) Pyter,R. A,; Ramachandran,C.; Mukerjee,P. J. Phye. Chem. 1982,86,3206. (b) Zachariasse, K. A.; Nguyen Van, P.; Kozankiewicz, B. J. Phys. Chem. 1981,85, 2676. (c) Handa, T.; Matsuzaki, K.; Nakagaki, M. J. Colloid Interface Sci. 1987, 116, 50.
