Enhancer intramolecular reactions

The proximity effect. This is the simple idea that in an intramolecular reaction the substrate function may be exposed to a larger local concentration of the reagent than in an intermolecular reaction, because the two functions are covalently constrained to occupy adjacent space. This effect has been called the approximation or propinquity effect. The proximity effect certainly seems physically reasonable and is likely to make some contribution to intramolecular reactivity, but it cannot be a major contributor when EM is large, because EM is itself a measure of a presumed local concentration, and the observed large EM values are physically impossible concentrations. The magnitude of rate enhancement achievable by prox-... 

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.)... 

Copper(II) triflate is quite inefficient in promoting cyclopropanation of allyl alcohol, and the use of f-butyl diazoacetate [164/(165+166) = 97/3%] brought no improvement over ethyl diazoacetate (67/6 %)162). If, however, copper(I) triflate was the catalyst, cyclopropanation with ethyl diazoacetate increased to 30% at the expense of O/H insertion (55%). As has already been discussed in Sect. 2.2.1, competitive coordination-type and carbenoid mechanisms may be involved in cyclopropanation with copper catalysts, and the ability of Cu(I) to coordinate efficiently with olefins may enhance this reaction in the intramolecular competition with O/H insertion. 

More direct evidence is derived from investigations of solvent effects on cyclisation reactions (for a short review see Galli et al., 1981). Bruice and Turner (1970) found that transfer from water to 1 M water in Me2SO causes little changes in the EM s for the formation of the 5-membered cyclic anhydrides [31] and [32], This was taken as evidence that solvation phenomena contribute very little to rate enhancements of intramolecular reactions. Similar... 

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 most spectacular application of the donor/acceptor-substituted carbenoids has been intermolecular C-H activation by means of carbenoid-induced C-H insertion [17]. Prior to the development of the donor/acceptor carbenoids, the intermolecular C-H insertion was not considered synthetically useful [5]. Since these carbenoid intermediates were not sufficiently selective and they were very prone to carbene dimerization, intramolecular reactions were required in order to control the chemistry effectively [17]. The enhanced chemoselectivity of the donor/acceptor-substituted carbenoids has enabled intermolecular C-H insertion to become a very practical enantioselective method for C-H activation. Since the initial report in 1997 [121], the field of intermolecular enantioselective C-H insertion has undergone explosive growth [14, 15]. Excellent levels of asymmetric induction are obtained when these carbenoids are derived... 

The same models as for intermolccular processes are applied for intramolecular diastereoface differentiating double-bond additions. However, there are some advantages in the intramolecular version. Firstly, the entropy factor lowers the barrier of activation and allows reactions to proceed at lower temperatures, which increases the selectivity. Secondly, the cyclic transition states introduce the elements of ring strain and transannular interactions, which lead to enhanced differences between two diastereomorphous geometries. Both of these factors cooperate to increase the selectivity of the intramolecular reaction. For example, halolactonization, by definition, is an intramolecular process. 

The reaction described above can also be carried out at higher concentration whereby the probability of intramolecular reaction (cyclization) vanishes. So called chain extension processes result from the stoichiometric reaction of a "living" bifunctional precursors with an efficient bifunctional electrophilic deactivator. This polycondensation reaction induces a very large increase of the molecular weight, but is also results in an enhanced polydispersity. - Fractionation is necessary if well defined substances are required. However the average distance between successive hinges along the chain fluctuates only very little. 

The effective concentrations of nucleophiles in intramolecular reactions are often far higher than this. The examples that follow are for unstrained systems. The chemist can synthesize compounds that are strained the relief of strain in the reaction then gives a large rate enhancement. In the succinate and aspirin derivatives that follow, the attacking nucleophile can rotate away from the ester bond to relieve any strain. The observed rate enhancements are due entirely to the high effective concentration of the neighboring group ... 

The combination of a metal-bound hydroxyl group and an intramolecular reaction provides some of the largest rate enhancements that can be found in a strain-free system. The complex of glycylglycine with (ethylenediamine)2Co3+ and a cis-hydroxyl (equation 2.33) hydrolyzes at pH 7 nearly 1010 times faster than the free glycylglycine.40... 

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