Intramolecular reactivity

An intramolecular reaction requires the presence of two suitably positioned functional groups, the substrate function and the reagent function, in the same molecule. The demonstration of an intramolecular process is obvious when the product is cyclic, as in this lactonization  

A favorite strategem is to compare the reactivities of ortho- and para-substituted aromatic substrates, such as 13 and 14 the electronic (inductive and resonance) effects of the substituent should be about the same in the two cases, but only the o/-f/io-substituted compound can undergo intramolecular catalysis. 

Another comparison is between o-hydroxy and o-methoxy compounds, as in 15 and 16 the electronic and steric effects will be, very roughly, similar, but only the hydroxy group is capable of intramolecular catalysis. 

The mechanisms available to intramolecular reactions are the same as those of intermolecular reactions. The same problems of kinetic equivalence of rate terms may arise, and Table 6-3 shows some kinetically equivalent mechanisms for intramolecular reactions of the acyl function. The efficiency of intramolecular reactivity may be difficult to assess. One technique, described above as a method for the detection of an intramolecular reaction, is to make a comparison with an analog incapable of the intramolecular process. Thus p-nitrophenyl 5-nitrosalicylate, 17, hydrolyzes about 2500 times faster than p-nitrophenyl 2-methoxy-5-nitrobenzoate, 18. 

The currently popular approach is to compare the rate of the intramolecular reaction with the rate of an intermolecular reaction in which the reacting groups are closely similar. The intermolecular reaction will usually be overall second-order, in accordance with the rate equation 

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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-... 

To summarize, the properties of triplet and singlet diradicals are closely related to the effectiveness of through-bond and through-space interactions, which are governed by the orbital phase continuity/discontinuity properties. In the next two sections, we will utilize this simple model to predict the spin preference and intramolecular reactivity for a broad range of diradicals. 

The contribution of the frontier orbitals would be maximized in certain special donor-acceptor reactions. The stabilization energy is represented by Eqs. (3.25) and (3.26). Even in a less extreme case, the frontier orbital contribution maybe much more than in the expression of the superdelocalizability. If we adopt the approximation of Eq. (6.3), the intramolecular comparison of reactivity can be made only by the numerator value. In this way, it is understood that the frontier electron density, /r, is qualified to be an intramolecular reactivity index. The finding of the parallelism between fr and the experimental results has thus become the origin of the frontier-electron theory. The definition of fr is hence as follows ... 

Evaluation of the only appropriate Fukui function is required for investigating an intramolecular reaction, as local softness is merely scaling of Fukui function (as shown in Equation 12.7), and does not alter the intramolecular reactivity trend. For this type, one needs to evaluate the proper Fukui functions (/+ or / ) for the different potential sites of the substrate. For example, the Fukui function values for the C and O atoms of H2CO, shown above, predicts that O atom should be the preferred site for an electrophilic attack, whereas C atom will be open to a nucleophilic attack. Atomic Fukui function for electrophilic attack (fc ) for the ring carbon atoms has been used to study the directing ability of substituents in electrophilic substitution reaction of monosubstituted benzene [23]. In some cases, it was shown that relative electrophilicity (f+/f ) or nucleophilicity (/ /f+) indices provide better intramolecular reactivity trend [23]. For example, basicity of substituted anilines could be explained successfully using relative nucleophilicity index ( / /f 1) [23]. Note however that these parameters are not able to differentiate the preferred site of protonation in benzene derivatives, determined from the absolute proton affinities [24],... 

These indices have been used to study the reactivity for a series of chlorobenzenes and a good correlation is observed, for example, between W and toxicity of chlorobenzene [41]. For a detail discussion of this concept and its applications, we refer the readers to a recent review [41,42]. For studying intramolecular reactivity, these philicity indices and local softness contain the same information as obtained from the Fukui functions, because they simply scale the Fukui functions. In some cases the relative electrophilicity and relative nucleophilicity may be used although they provide similar trends as s(r) and co(r) in most cases [43]. In the same vein, the spin-donicity and spin-philicity, which refer to the philicity of open-shell systems [44], could also be utilized to unravel the reactivity of high-spin species, such as the carbenes, nitrenes, and phosphinidenes [45]. 

The acid-catalysed transannular cyclization of 8-10-membered y,5-unsaturated cyclic sulfides (59) or (60) yields c/x-fused bicyclic sulfonium salts (61) independently of the geometry of the double bond. The rate varies linearly with the acidity function -(Ho h with a slope of 1. The rate variations span a range of about 10 , the maximum rate difference being observed for the ( /Z)-thiacyclooct-4-ene pair. The data are consistent with the classical interpretation of the intramolecular reactivity in terms of internal strain of the substrate and/or of the transition state. ... 

There are several instances where reactive intermediates present during the synthesis of septanosides have reacted intramolecularly to give ring-contracted or bicyclic products.91 Similar intramolecular reactions (such as the formation of 1,6-anhydro sugars) have precedents in the pyranose literature. Such cases of intramolecular reactivity described in the literature notably involve novel ethers or thioethers as the nucleophilic species in the ring contractions. 

Note that despite the death of the carbene-alkene complex in the study of benzylchlorocarbene (53) (see above), benzene is able to modulate the intramolecular reactivity of ferf-butylcarbene. ° Some sort of complex must be involved here. Benzene complexes with carbenes have been proposed before. Kahn and Goodman found a transient species on photolysis of diazomethane in benzene, and attributed it to a complex. Moss et al. found that benzene modulated the ratio of intramolecular rearrangement to intermolecular addition for three different carbenes (53), chloropropylcarbene, and chlorocyclopropylcarbene, and proposed that a carbene-benzene complex 70 favored the intramolecular rearrangement (Scheme 7.31). Their proposal was bolstered by ab initio calculations that found such stable complexes for CCI2 and CH3CCI. 

Analysis of the product distributions arising from both sensitized and non-sensitized irradiation of 2-allyloxyphenyldiazo species (8) showed that the C—H insertion product and much of the cyclopropanation arise from the triplet carbene.16 For the singlet carbene, intermolecular 0—H insertion with methanol is about 50 tunes faster than intramolecular addition to the double bond, hi this system, intramolecular reactions and intersystem crossing of the triplet carbene proceed at similar rates, hi the closely related indanyl system (9), the smaller RCR angle stabilizes the singlet state relative to the triplet and the intramolecular reactivity is dominated by the singlet state.17... 

It can be noted that the local softness is obtained by multiplication of the Fukui function with the global softness the local softness can thus be considered as a weighted distribution of the global softness over the molecule. Due to this fact, the local softness should be used as a intermolecular reactivity index, whereas the Fukui function is an intramolecular reactivity index. The definition of local hardness is less trivial and remains a matter of current debate. 

See also Amide ions Anions Carboca-tions and Radical intermediates Intestinal antiseptic, 152 Intramolecular reactivity, see Heterocycliza-tione... 

In their synthetic studies towards lophotoxin and pukalide, Paterson and coworkers explored both intermolecular and intramolecular Stille coupling reactions [108]. The intermolecular approach between vinyl iodide 107 and furylstannane 108 is more successful, giving adduct 109 in 67% yield. The intramolecular version provides the macro-cyclized 14-membered lactone in only 15% yield. Pattenden reported a related investigation towards the synthesis of lophotoxin and observed comparable inter- and intramolecular reactivity in similar Stille reactions [109]. 

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