Selected Abstracts

Transition state stabilization by micelles: thiolysis of p-nitrophenyl alkanoates in cetyltrimethylammonium bromide micelles

Abstract: Thiolysis of p-nitrophenyl esters (acetate to decanoate) by the anion of 2-mercaptoethanol (ME) is catalyzed by micelles of cetyltrimethyl- ammonium bromide (CTAB) in aqueous solution.  At fixed [ME], the observed rate constants (k_obs) show saturation with respect to added [CTAB], consistent with ester binding in the micelles.  Plots of k_obs vs. [ME] are linear in the absence and in the presence of the CTAB, and analysis of the slopes of the plots afford rates constants for thiolate ion attack on the esters in the aqueous phase (k_N) and in the micellar phase (k_cN).  The strengths of substrate binding and transition state binding to the micelles are strongly correlated to one another, with a slope of one, meaning they have exactly the same sensitivity to the ester chain. Consequently, the catalytic ratios (k_cN/k_N) are independent of the length of the ester acyl chain.  Similar behaviour is found for the thiolysis by the dianions of mercaptoacetic acid, 3-mercaptopropionic acid, and cysteine, and also for ester cleavage by the anions of glycine and 2,2,2-trifluoro-ethanol, as it was earlier for cleavage by hydroxide ion.  The results are consistent with Kirby’s dissection of transition state binding into “passive” and “dynamic” components.  The passive component involves hydrophobic binding of the acyl chain which is more or less the same as in the substrate binding; the dynamic component is associated with nucleophilic attack in the Stern layer of the micelle, and its magnitude varies with the nucleophiles because of differences in their ease of exchange between the aqueous medium and the Stern layer. 

Oswald S. Tee*, Samer M. I. Hussein, Isabelle E. Turner and Ogaritte J. Yazbeck, Can. J. Chem., 2000, 78, 436-443.

Abstract: The acid-catalyzed hydrolysis reactions of acetophenone dimethyl acetal (ADMA) and trimethyl orthobenzoate (TMOB) are retarded by cyclodextrins (CDs): α-CD, β-CD, hp-β-CD = "hydroxypropyl-β-cyclodextrin" and γ-CD, and the observed first order rate constants (k_obs) vary with [CD] in the manner expected for simple 1:1 binding between the substrates and the CDs. Similar behaviour was found recently for the hydrolysis of benzaldehyde dimethyl acetal (BDMA) [J. Chem. Soc. Perkin Trans. 2, 123 (1998)]. With β-CD and hp-β-CD, the binding of all three substrates is strong and the CD-bound forms are relatively unreactive. By contrast, substrate binding by α-CD is much weaker, and the CD-bound forms have appreciable, though reduced, reactivities. Substrate binding by γ-CD is also relatively weak, but its bound forms have very low reactivities. 
     The hydrolysis reactions of ADMA, TMOB, and BDMA have been evaluated as kinetic probes of the binding of guests to CDs. For α-CD, β-CD, and hp-β-CD, the addition of guests reduces the free CD, and so alleviates retardation of the hydrolysis rates by the CD. The resultant rate increases can be analyzed to provide estimates of CD host-guest dissociation constants, K_G. For aliphatic alcohols and ketones binding to β-CD and hp-β-CD, all three probe reactions provide values of K_G that agree very well with each other and with literature values determined by other methods. The approach does not work well with α-CD because of its weak substrate binding and the less pronounced dependence of k_obs on [α-CD]. In the case of γ-CD, the approach cannot be used because added guests cause a further lowering in the rate of hydrolysis, suggesting the formation of an unreactive ternary (substrate/CD/guest) complex. 

Timothy A. Gadosy, Michael J. Boyd and Oswald S. Tee*, J. Org. Chem., 2000, 65, 6879-6889.

Abstract: The effects of four cyclodextrins (α-CD, β-CD, γ-CD, and "hydroxypropyl-β-CD" ) on the aminolysis of p-nitrophenyl alkanoate esters (acetate to heptanoate) by primary alkylamines (n-propyl to n-octyl, iso-butyl, iso-pentyl, cyclopentyl, cyclohexyl, benzyl) in aqueous solution have been investigated. In the first instance, the results are analysed to give second order rate constants for amine attack on the free (unbound) and CD-bound esters (k_N and k_cN, respectively), taking into account binding of the substrates to the CD. Viewed in these terms, the CD-mediated reactions have reactivity ratios (k_cN/k_N) which vary between 0.08 and 180, spanning the range from retardation to strong catalysis by the CDs. Alternatively, the CD-mediated reaction may be viewed in terms of reaction of free ester with CD-bound amine (k_Nc), in which case the ratios k_Nc/k_N vary between 0.2 and 28. Either way, there is clear evidence of catalysis in several cases and retardation in others.
     As the amine, ester, and CD are varied there are systematic changes in the reactivity ratios and other parameters which indicate that more than one mode of transition state binding is operative. The reaction of short p-nitrophenyl alkanoates with short alkylamines (<C₆) occurs by the attack of free amine on aryl-bound ester whereas for longer amines, the free ester reacts with alkylamine that is bound to the CD. The reaction of long alkanoate esters with long amines, which is catalyzed by β-CD and γ-CD , also involves inclusion of the alkylamine but there may also be partial inclusion of the acyl group of the ester since kinetic parameters are sensitive to the binding ability of the amine and to that of the ester, to a lesser extent. In the case of γ-CD , the larger cavity may allow the inclusion of the aryl group of the ester and the alkyl group of the amine in the transition state. For none of the amine/ester/CD combinations that were studied did reaction between acyl-bound ester and free amine appear to be important.

Oswald S. Tee* and Michael J. Boyd, Can. J. Chem. 1999, 77, 950-959.

Abstract: The effect of cyclodextrins (CDs) on the rate of nucleophilic attack on 1- and 2-naphthyl acetates (1-NA and 2-NA) in aqueous solution have been investigated. Analysis of the variation of the pseudo-first order rate constants with [nucleophile] and [CD] affords rate constants for reaction of the nucleophiles with free ester (k_N) and with ester bound to the CD (k_cN). The reaction of 1-NA and 2-NA with the trifluoroethoxide anion is slowed down by β-CD as the ratios k_cN/k_N are 0.11 and 0.30, respectively. For reaction of the two esters with the anion of 2-mercaptoethanol in the presence of α-CD, β-CD, "hydroxypropyl- β-CD" (hp- β-CD) and γ-CD, the reactivity ratios k_cN/k_N vary between 0.04 and 2.4, ranging from strong retardation to modest catalysis; the retardations arise with β-CD and hp- β-CD which bind the esters most strongly. By contrast, the attack of primary alkylamines is generally accelerated, and in many cases substantially so. For the aminolysis of 1-NA in the presence of β-CD, values of k_cN/k_N range from 7 to 460, assuming that free amine reacts with CD-bound ester. Alternatively, if the CD-catalyzed reaction is viewed in terms of free ester reacting with CD-bound amine, with rate constant k_Nc, the ratios k_Nc/k_N fall in the range from 43 to 140. Either way, there is appreciable catalysis of the aminolysis of 1-NA by β-CD. For the corresponding aminolysis of 2-NA, the effects are less dramatic: the ratios k_cN/k_N range from 0.19 to 17 and values of k_Nc/k_N vary from 17 to 110. The aminolysis of 1-NA by n-hexylamine is also catalyzed by γ-CD. 
      The variations of kinetic parameters with alkylamine chain length suggest that the CD-catalyzed aminolysis basically takes place by the attack of CD-bound amine on the free ester. However, there must be some stabilizing interactions between the aryl group of the ester and the CD during the reaction since the transition state stabilization is different for 1-NA and 2-NA, as well for other esters.

Oswald S. Tee,* Alexei A. Fedortchenko and Patrick Lim Soo, J. Chem. Soc. Perkin Trans. 2, 1998, 123-128.

Hydrolysis of benzaldehyde dimethyl acetal (1) in aqueous acid is slowed down greatly by cyclodextrins (CDs): α-CD, β-CD, hp-β-CD = "hydroxypropyl-β-cyclodextrin", and γ-CD. The variations of the observed first order rate constants (k_obs) with [CD] exhibit saturation behaviour, consistent with 1:1 binding between 1 and the CDs. In the case of β-CD and hp- β-CD, the binding is relatively strong and the CD-bound acetal is unreactive. In contrast, binding of the acetal by α-CD and γ-CD is much weaker, but only with α-CD does the CD-bound form show significant reactivity. The four CD-mediated reactions have been evaluated as probe reactions for determining dissociation constants of {CD."guest"} complexes. In this approach, added guests attenuate the retarding effect of CD.substrate binding, and cause an increase in the rate of acetal hydrolysis. The method works well for aliphatic alcohols and ketones binding to β-CD and hp- β-CD, but it is less successful with α-CD because of the shallow dependence of k_obs on [α-CD] in the probe reaction. With γ-CD, the approach is not applicable at all, because added guests cause a further reduction in the rate of acetal hydrolysis, not an increase. Various implications of these findings are discussed. 

Elizabeth C. Carmichael, Valerie D. Geldart, Robert S. McDonald,* David B. Moore, and Sheila Rose ( Department of Chemistry, Mount St. Vincent University, Halifax, Nova Scotia, Canada B3M 2J6) Lawrence D. Colebrook, Georgia D. Spiropoulos, and Oswald S. Tee* ( Department of Chemistry and Biochemistry, Concordia University, Montréal, Québec, Canada H3G 1M8 ), J. Chem. Soc. Perkin Trans. 2, 1997, 2609-2619.

Kinetic studies of the ring-opening and reclosure reactions of thiamine and three other thiazolium ions (Q⁺) in aqueous solution, in the pH range 0 - 13, have been carried out by stopped-flow and conventional UV-visible spectrophotometry. At high pH, ring-opening of thiamine exhibits a temporary diversion to the well-known "yellow form". Otherwise, the ring-opening reactions are simply first-order in [OH-], consistent with rate-limiting attack of hydroxide ion at C(2) of the Q⁺ ring, producing a pseudobase, T^o, which rapidly consumes a second equivalent of hydroxide ion to form the ring-opened enethiolate, ETh. In contrast, ring closure of the enethiol in acidic solution exhibits rather complex kinetic behaviour: two processes are observed for most enethiols, including that derived from thiamine. Both the fast process (a) and the slower process (b) produce the thiazolium ion Q⁺ and they exhibit pH- and buffer-independent rate plateaus at low pH. Rapid, repetitive uv spectral scans and nmr spectral studies show that the two processes arise from the independent formation of Q⁺ from the two amide rotamers of the enethiol which do not equilibrate under the reaction conditions. The major amide rotamer (75%) gives rise to the fast process (a) and the minor rotamer to the slow reaction (b). The pH-rate profile and buffer catalysis studies reveal that the reclosure reaction undergoes a change in rate-limiting step from uncatalysed formation of T^o at low pH to its general acid-catalysed breakdown at higher pH. The latter process is characterized by a Brønsted a of 0.70. Additionally, for process (b), a general base-catalysed pathway for formation of T^o can be observed, for which the Brønsted β is 0.74. The mechanistic details of the ring-opening and reclosure pathways are discussed. 

Oswald S. Tee* and Alexei A. Fedortchenko, Can. J. Chem., 1997, 75, 1434-1438.

The cleavage of p-nitrophenyl alkanoates (acetate to octanoate) at high pH is modestly catalyzed by micelles formed from cetyltrimethylammonium bromide (CTAB) in aqueous solution. Rate constants exhibit saturation behaviour with respect to [CTAB], consistent with substrate binding in the micelles. The strength of substrate binding and transition state binding to the micelles increase monotonically with the acyl chain length, and with exactly the same sensitivity. As a result, the extent of acceleration (or catalytic) ratio is independent of the ester chain. These and earlier results are consistent with the reaction centre being located in the Stern layer of the micelle, with the acyl chain of the ester being directed into their hydrophobic micellar interior. The chain length dependence of kinetic parameters found in this work is comparable to that found previously for ester cleavage by cyclodextrins and by various enzymes with hydrophobic binding sites, as well as to that observed for other phenomena involving hydrophobic effects. 

The Effect of Alcohols on the Basic Cleavage of m-Nitrophenyl Hexanoate by β-Cyclodextrin: Allosteric Reaction Mode Switching

Oswald S. Tee* and Javier B. Giorgi, J. Chem. Soc. Perkin Trans. 2, 1997, 1013-1018.

Evidence is presented of a reacting guest/host system where binding of an "allostere" to the host inhibits its reaction with the guest by one particular mode and promotes its reaction by another. Simple aliphatic alcohols do not slow down the basic cleavage of m-nitrophenyl hexanoate by β-cyclodextrin (β-CD) to the extent required for competitive inhibition and so an additional, alcohol-mediated reaction must be taking place. Rate constants for this process correlate well with the ability of the alcohol to bind to β-CD, as do those for the analogous reaction of p-nitrophenyl hexanoate, suggesting that the alcohol is in the cavity of β-CD during the reaction. Transition state binding parameters for the alcohol-mediated reaction of the two nitrophenyl esters are very similar, and they show the same dependence on the binding ability of the alcohols. Overall, the results are consistent with a switch in the mode of reaction from cleavage of m-nitrophenyl hexanoate by aryl group inclusion (1) to its cleavage by acyl group inclusion (2), brought about by binding of a simple alcohol, acting as an "allostere".

Effect of β-cyclodextrin on the reaction of α-amino acid anions with p-nitrophenyl acetate and p-nitrophenyl hexanoate

Oswald S. Tee*, Timothy A. Gadosy, and Javier B. Giorgi, Can. J. Chem., 1997, 75, 83-91.

The effects of β-cyclodextrin (β-CD) on the kinetics of the reaction of α-amino acid anions with p-nitrophenyl acetate (pNPA) and p-nitrophenyl hexanoate (pNPH) have been investigated. Pseudo-first order rate constants obtained with various [nucleophile] and [β-CD], in aqueous solution at pH 9.88, were analyzed to yield rate constants for reaction of the nucleophiles with free ester (k_N) and with ester bound to β-CD (k_cN). For pNPA reacting with amino acids that bind weakly to β-CD, if at all, the ratio k_cN/k_N is very close to one, but for amino acids that bind appreciably to β-CD this ratio is greater than one (up to 3.5). Generally similar behaviour is observed for reactions with pNPH, but the rate ratios are smaller and all less than one. 
     These findings are quite comparable to those obtained in this laboratory for the CD-mediated reactions of p-nitrophenyl alkanoate esters with other nucleophiles, including simple alkylamines which bind quite strongly to CDs, but they differ from those reported in an earlier study of the reaction of pNPA with amino acid anions (Can. J. Chem., 69, 1124 (1991)) where the data analysis suggested more substantial catalysis by cyclodextrins. 

Oswald S. Tee* and Robert A. Donga, J. Chem. Soc. Perkin Trans. 2, 1996, 2763-2769.

In basic aqueous solution, enolate formation from 2-indanone (2, pK_a = 12.2) exhibits saturation kinetics when cyclodextrins (CDs) are added, consistent with the formation of 1:1 complexes between 2 and the CDs. With alpha;-CD, β-CD, gamma;-CD, "hydroxyethyl-β-CD" and "hydroxypropyl-β-CD", the reaction is accelerated up to 22-fold, but "dimethyl- β-CD" slows it down by about 46%. All of the CDs (pK_a 12.2) are more reactive towards 2 than is trifluoroethanol (pK_a = 12.4). Kinetic parameters for the CD-catalyzed deprotonation are discussed in terms of the differences between transition-state binding and initial-state binding, and of the structures of the various CDs. It is concluded that anions of the CDs act as general bases towards 2, facilitated by partial inclusion of the transition state in the CD cavity, the extent of which depends on the CD. Enolate formation catalyzed by β-CD is slowed by simple alcohols (n-propanol to n-heptanol) but it is not totally inhibited by them, even though they bind to β-CD. Apparently, de-protonation of 2 by an anion of β-CD can still take place with an alcohol in the CD cavity, albeit more slowly. 

OSWALD S. TEE*, TIMOTHY A. GADOSY, AND JAVIER B. GIORGI, Can. J. Chem., 1996, 74, 736-744.

Dissociation constants (K_d) of host-guest complexes formed from β-cyclodextrin or "hydroxypropyl-β-cyclodextrin" (β-CD and Hp-β-CD) and several types of aliphatic guests (alcohols, alkanesulfonate ions, alkylamines and -amino acids), with up to 8 carbons in a chain, are reported. These constants were determined by inhibition kinetics and by a spectrofluorometric displacement method based on competition with 1-anilino-8-naphthalenesulfonate ion as a fluorescent probe. The value of K_d for a particular amine is close to that for the corresponding alcohol. For linear alkyl derivatives, there are strong correlations between pK_d (= -log K_d) and the chain length of the guest, with slopes around 0.5, complementing trends that were noted earlier. Furthermore, the strengths of binding of various aliphatic derivatives to β-CD and to Hp-β-CD are close, with K_d values for the two CDs usually being within a factor of 2 of each other. Overall, for the binding of over 50 alkyl-bearing derivatives, there is a good correlation of pK_d for Hp- β-CD with that for β-CD, with unit slope. These observations imply that the binding of simple aliphatic guests to Hp- β-CD is not greatly influenced by the modification of the hydroxyl groups on the primary side of the β-CD cavity but this may not be true for longer aliphatic derivatives (>C₈) or for aromatics that penetrate farther into the CD cavity. 

Oswald S. Tee*, Alexei A. Fedortchenko, Paul G. Loncke and Timothy A. Gadosy, J. Chem. Soc. Perkin Trans. 2, 1996, 1243-1249. 

Dissociation constants (K_d) for the complexation of 22 simple ketones with α-, β-, and hydroxypropyl-β-cyclodextrin (α-CD, β-CD, and hp-β-CD) in aqueous solution have been determined. For these constants, there are various correlations involving pK_d ( = -log K_d) which have the form of linear free energy relationships. In particular, there are strong correlations between the pK_d values of ketones (RCOR') and related secondary alcohols (RCH(OH)R'), including cases where R and R' form a ring. As with other n-alkyl derivatives, pK_d values for 2-alkanones and 3-alkanones increase monotonically with chain length, with slopes about 0.4, corresponding to Gibbs energy increments of ca. 2.3 kJ/mol for each CH₂ group that is sequestered by the CD. The strengths of binding of linear derivatives to α-CD and β-CD correlate well, but bulky and cyclic ketones bind more weakly to α-CD, due to its smaller cavity. The pK_d values for complexation of 18 of the 22 ketones by hp-β-CD and β-CD are fairly close and linearly related with a slope of 0.96 ± 0.03. These data are a subset of a larger set for 68 aliphatic compounds for which the slope is 0.99 ± 0.02. Thus, the strength of binding of such aliphatics to hp-β-CD and β-CD is generally close, although the penetration of the CD cavity by the guests is not necessarily the same for these two CDs. 

Oswald S. Tee*, Massimo Bozzi, Nicolas Clement, and Timothy A. Gadosy,  J. Org. Chem., 1995, 60, 3509-3517.

Abstract. The cleavage of p-nitrophenyl alkanoates (acetate to hexanoate) by β-cyclodextrin (β-CD) in basic aqueous solution is catalyzed by additives (ROH, RCO₂^-, RSO₃^-) that are expected to be inhibitors. The magnitude of the catalysis by n-butanol increases with the acyl chain length of the ester.  For RCO₂^- and RSO₃^- as the potential inhibitors (PIs), the kinetics of cleavage of p-nitrophenyl hexanoate (pNPH) are analyzable in terms of reaction between the CD.ester complex and one molecule of PI. Rate constants for this process (k_a) increase systematically with the ability of PI to bind to β-CD, implying that the catalytic reaction is better viewed as being between the PI.CD complex and the ester; rate constants for the latter process (k_b) show little variation and are not very different from the second order rate constant for the ester reacting with β-CD alone. With alcohols as the PIs, saturation kinetics implicate ternary complexes, {PI.CD.ester}, and for pNPH the dissociation constants of these complexes (K_t) strongly parallel those of the binary {PI.CD} complexes (K_I). The reactivity of the ternary complexes (k_t) varies little with the structure of the alcohol or the ester. Catalysis of the cleavage of pNPH by α-CD is more restricted: simple alcohols catalyze the reaction modestly but show no evidence of ternary complex formation. Alkanoate ions inhibit the reaction but the limited results for RSO₃^- were equivocal. 
     The results are discussed in terms of the Kurz approach to transition state stabilization. For the PI-catalysis there are LFERs with strong correlations between the parameters for initial state and transition state binding of the PIs, suggesting that binding is very similar in the two states. In contrast, transition state binding of n-BuOH is insensitive to the chain length of the ester being cleaved, implying that the ester chain is not in direct contact with the alcohol bound in the CD cavity. 

Oswald S. Tee* and Michael J. Boyd, J. Chem. Soc. Perkin Trans. 2, 1995, 1237-1243. 

The reactions of 1- and 2-naphthyl acetate (1-NA and 2-NA) with four cyclodextrins (CDs): α-CD, β-CD, γ-CD, and "hydroxypropyl-β-CD" (Hp-β-CD), in basic aqueous solution, all show saturation kinetics. Even though the strength of substrate binding varies appreciably, the limiting accelerations at high [CD] are all relatively modest (3 to 30-fold). The effects on the two isomeric esters are generally similar but there are significant differences between the CDs. These differences are discussed in terms of the relative importance of transition state and initial state binding, and in relation to structural variations in the four cyclodextrins. Except for one case, the second order rate constants (k₂) for the reactions of 1-NA and 2-NA with the CDs are appreciably greater than those for reaction with trifluoroethanol (TFE), as expected for stabilization of the transition state by inclusion of part of the ester in the CD cavity. For 2-NA reacting with α-CD, k₂ is virtually the same as that for reaction with TFE, suggesting that inclusion is not a significant factor in this particular case. Consistent with this suggestion, the cleavage of 2-NA by α-CD is not competitively inhibited by alcohols, it is mediated by them. The cleavage of 1-NA by β-CD can also be mediated by alcohols and by alkanesulphonate ions, but the analogous reaction of 2-NA is not as susceptible. 

Cooperative Behavior by Two Different Cyclodextrins in a Reaction: Evidence of Bimodal Transition State Binding

Javier B. Giorgi and Oswald S. Tee*, J. Am. Chem. Soc., 1995, 117, 3633-3634.

Evidence is presented of a reaction that is mediated by two different cyclodextrins, acting cooperatively. In basic solution containing both "dimethyl-β-cyclodextrin" (dime-β-CD) and γ-cyclodextrin (γ-CD), p-nitrophenyl octanoate reacts up to 2.4 times more rapidly than is attributable to the separate reactions of the individual CDs. The additional reactivity is quantitatively explained by a third order process involving the ester + dime-β-CD + γ-CD. Transition state binding parameters for this process are consistent with inclusion of the acyl group of the ester in dime-β-CD and of its aryloxy group in γ-CD. 

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