Intramolecular rate acceleration

Page, M. L., Jencks, W. P. Entropic contributions to rate accelerations in enzymic and intramolecular interactions and the chelate effect. Proc. Natl. Acad. Sci. USA 68 (1971) 1678-1683... 

FIGURE 16.15 Orientation effects in intramolecular reactions can be dramatic. Steric crowding by methyl groups provides a rate acceleration of 2.5 X 10 for the lower reaction compared to the upper reaction. (Adaptedfrom Milstien,. S., and Cohen, L. A., 1972. Stereopopnlation control I. Rate enhancements in the laetonization of o-hyelroxyhyeJroeinnamie acid. Journal of the American Chemical Society 94 9158-9165.)... 

An additional example of a cycloamylose-induced rate acceleration which may be reasonably attributed to a conformational effect is the facilitation of the transfer of the trimethylacetyl group from the phenolic oxygen of 9 to the aliphatic oxygen of the adjacent hydroxymethyl group to form 10. This intramolecular transesterification is remarkably enhanced relative to a comparable intermolecular reaction,6 and occurs, at pH 7.0 and 25.5°, with a rate constant of 0.0352 sec-1 (Griffiths and Bender, 1972). An even larger rate enhancement is achieved upon inclusion of this material within the cyclohexaamylose cavity—fc2 = 0.16 sec-1. This fivefold acceleration cannot be satisfactorily explained either by a microsolvent effect which would be expected to depress the rate of the reaction or, at this pH, by covalent... 

M. L Page, W. P. Jencks, Entropic Contributions to Rate Accelerations in Enzymic and Intramolecular Reactions and the Chelate Effed , Proc. Nat. Acad Set. USA. 1971, 68,1678-1683. 

Several other intramolecular reactions showed only slight rate accelerations or retardations (VanderJagt et al., 1970). Of potential synthetic use, it has been found that both intramolecular and intermolecular Diels-Alder reactions can be catalysed by /3-CD (Sternbach and Rossana, 1982 Breslow and Guo, 1988). 

The best way to combine all these parameters is to trace back the catalytic action of enzymes to intramolecularity. It is generally accepted that when van der Waals distances (contact distances) are imposed for definite times upon reactive groups, intramolecular reactions occur then at enzyme-like rates (accelerations of 10 to 10 0 are associated to enzyme-catalysed reactions). On the other hand, according to the Page-Jencks theory [17] the fast rates of intramolecular reaction "are merely an entropic consequence of converting a bimolecular reaction into a unimolecular reaction". 

In the intramolecular reactions studied by Bruice and Koshland and their co-workers, proximity effects (reduction in kinetic order and elimination of unfavourable ground state conformations) and orientation effects might give rate accelerations of 10 -10 . Hence, these effects can by themselves account for the enhancements seen in most intramolecular reactions. However, a factor of 10 -10 is less than the rate acceleration calculated for many enzyme reactions and certain intramolecular reactions, for example, hydrolysis of benzalde-hyde disalicyl acetal (3 X 10 ) (Anderson and Fife, 1973) and the lactonization reaction of[l] (10 ) where a trimethyl lock has been built into the system. If hydrolysis of tetramethylsuccinanilic acid (Higuchi et al., 1966) represents a steric compression effect (10 rate acceleration), then proximity, orientation, and steric compression... 

The direct interaction of the reaction center of a molecular entity with a lone pair of electrons of an atom within that same molecular entity that is not associated with the reaction center or, interaction of the reaction center with the reaction center nor conjugated with the reaction center. Rate acceleration by such a process is referred to as anchimeric assistance. See Intramolecular Catalysis Synartetic Acceleration. 

The above dramatic dependence of regio- and stereoselectivity on the nature of the metal can be explained by the reaction mechanism shown in Scheme 11.49 (167). The nitrone cycloadditions of allylic alcohols are again magnesium-specific just like the nitrile oxide reactions described in Section 11.2.2. Magnesium ions accelerate the reaction through a metal ion-bound intramolecular cycloaddition path. On the other hand, zinc ions afford no such rate acceleration, but these ions catalyze the acetalization at the benzoyl carbonyl moiety of the nitrone to provide a hemiacetal intermediate. The subsequent intramolecular regio- and stereoselective cycloaddition reaction gives the observed products. 

Intramolecular attack by coordinated hydroxide (7) appears unlikely in this system in view of the relatively low rate accelerations observed, and the fact that the reaction shows a first order dependence on the hydroxide ion concentration up to pH 8. 

For the reaction of MOH(n 1)+ with propionic anhydride,200 the Bronsted plot of log kMOH versus the pKa of MOH2n+ follows a smooth curve if the values for HzO and OH- are included (Figure 4). However, if the line is drawn to exclude the fcHj0 value, a Bronsted /3 of ca, 0.25 is obtained. Although kMOH for [Co(NH3)5OH]2+ (3 M s 1) is some 103-fold less than k0H, this reaction will compete favourably at neutral pH with base hydrolysis. At pH 7 where the cobalt(III) complex exists almost completely as the MOH2+ species the observed first order rate constant for nucleophilic attack by OH would be ca. 10-4 s 1. AIM solution of [Co(NH3)5OH]2+ would give a value of kobs 2.5 s 1, a rate acceleration of > 104-fold. Since the effective concentration of a nucleophile in the intramolecular reaction could be ca. 102 M, rate accelerations of 10° are possible. The role of the metal ion in such reactions is to provide an effective concentration of an efficient nucleophile at low pH. 

Menger et al. synthesized a Ci4H29-attached copper(II) complex 3 that possessed a remarkable catalytic activity in the hydrolysis of diphenyl 4-nitrophenyl phosphate (DNP) and the nerve gas Soman (see Scheme 2) [21], When 3 was used in great excess (ca. 1.5 mM, which is more than the critical micelle concentration of 0.18 mM), the hydrolysis of DNP (0.04 mM) was more than 200 times faster than with an equivalent concentration of the nonmicellar homo-logue, the Cu2+-tetramethylethylenediamine complex 9, at 25°C and pH 6 (Scheme 4). The DNP half-life is calculated to be 17 sec with excess 1.5 mM 3 at 25°C and pH 6. The possible reasons for the rate acceleration with 3 were the enhanced electrophilicity of the micellized copper(II) ion or the acidity of the Cu2+-bound water and an intramolecular type of reaction due to the micellar formation. On the basis of the pH(6-8.3)-insensitive rates, Cu2+-OH species 3b (generated with pK3 < 6) was postulated to be an active catalytic species. In this study, the stability constants for 3 and 9 and the thermodynamic pvalue of the Cu2+-bound water for 3a —> 3b + H+ were not measured, probably because of complexity and/or instability of the metal compounds. Therefore, the question remains as to whether or not 3b is the only active species in the reaction solution. Despite the lack of a detailed reaction mechanism, 3 seems to be the best detoxifying reagent documented in the literature. 

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