Intermolecular reactions mechanisms

Many ring systems have been prepared by cycloaddition of acetylenic compounds, following concerted or multi-step intra- or intermolecular reaction mechanisms. In-particular, the placing in close proximity of triple bonds or a triple bond and another unsaturated system, such that intramolecular cycloaddition might lead to four-seven-membered rings, would seem of interest. This section deals with transannular carbon-carbon bond formation of triple bonds in acyclic and cyclic systems. 

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. 

For this example EM = 1260 M. In ealculating EM it is necessary that the intermolecular reaction selected for the comparison possess the same mechanism as the intramolecular reaction. 

The reaction mechanism " is not rigorously known. Evidence for an intramolecular pathway as well as an intermolecular pathway has been found ... 

What Do We Need to Know Already This chapter draws on the introduction to organic formulas and nomenclature in Sections C and D, the structure of molecules (Chapters 2 and 3), intermolecular forces (Sections 5.3-5.5), reaction enthalpy (Section 6.13), reaction mechanisms (Sections 13.7-13.9), and isomers (Section 16.7). 

Examples of the intermolecular C-P bond formation by means of radical phosphonation and phosphination have been achieved by reaction of aryl halides with trialkyl phosphites and chlorodiphenylphosphine, respectively, in the presence of (TMSlsSiH under standard radical conditions. The phosphonation reaction (Reaction 71) worked well either under UV irradiation at room temperature or in refluxing toluene. The radical phosphina-tion (Reaction 72) required pyridine in boiling benzene for 20 h. Phosphinated products were handled as phosphine sulfides. Scheme 15 shows the reaction mechanism for the phosphination procedure that involves in situ formation of tetraphenylbiphosphine. This approach has also been extended to the phosphination of alkyl halides and sequential radical cyclization/phosphination reaction. ... 

Aryl halides can be dehalogenated by Friedel-Crafts catalysts. Iodine is the most easily cleaved. Dechlorination is seldom performed and defluorination apparently never. The reaction is most successful when a reducing agent, say, Br or 1 is present to combine with the I" or Br coming off." Except for deiodination, the reaction is seldom used for preparative purposes. Migration of halogen is also found," both intramolecular and intermolecular." The mechanism is probably the reverse of that of 11-11." ... 

This behaviour was rationalised by a stepwise reduction mechanism, in which a high catalyst or KOH concentration gives a high hydride concentration and leads to the aniline formation and suppression of intermolecular reactions to the dimeric azo-compound. 

The proposed reaction mechanism involves intermolecular nucleophilic addition of the amido ligand to the olefin to produce a zwitterionic intermediate, followed by proton transfer to form a new copper amido complex. Reaction with additional amine (presnmably via coordination to Cn) yields the hydroamination prodnct and regenerates the original copper catalyst (Scheme 2.15). In addition to the NHC complexes 94 and 95, copper amido complexes with the chelating diphosphine l,2-bis-(di-tert-bntylphosphino)-ethane also catalyse the reaction [81, 82]. 

Hydrogen Abstraction Photoexcited ketone intermolecular hydrogen atom abstraction reactions are an interesting area of research becanse of their importance in organic chemistry and dne to the complex reaction mechanisms that may be possible for these kinds of reactions. Time resolved absorption spectroscopy has typically been nsed to follow the kinetics of these reactions but these experiments do not reveal mnch abont the strnctnre of the reactive intermediates. " Time resolved resonance Raman spectroscopy can be used to examine the structure and properties of the reactive intermediates associated with these reactions. Here, we will briefly describe TR experiments reported by Balakrishnan and Umapathy to study hydrogen atom abstraction reactions in the fluoranil/isopropanol system as an example. 

Reaction step 5 in Scheme 3.1 can be rnled ont becanse the flnoranil ketyl radical (FAH ) reaches a maximum concentration within 100 ns as the triplet state ( FA) decays by reaction step 2 while the fluoranil radical anion (FA ) takes more than 500 ns to reach a maximum concentration. This difference snggests that the flnoranil radical anion (FA ) is being produced from the fluoranil ketyl radical (FAH ). Reaction steps 1 and 2 are the most likely pathway for prodncing the flnoranil ketyl radical (FAH ) from the triplet state ( FA) and is consistent with the TR resnlts above and other experiments in the literatnre. The kinetic analysis of the TR experiments indicates the fluoranil radical anion (FA ) is being prodnced with a hrst order rate constant and not a second order rate constant. This can be nsed to rnle ont reaction step 4 and indicates that the flnoranil radical anion (FA ) is being prodnced by reaction step 3. Therefore, the reaction mechanism for the intermolecular hydrogen abstraction reaction of fluoranil with 2-propanol is likely to predominantly occur through reaction steps 1 to 3. 

Triple bonds can also participate in the metathesis reaction. Intramolecular reactions give vinylcycloalkenes, whereas intermolecular reactions provide conjugated dienes.301 The mechanism is similar to that for a, to-diene metathesis, but in contrast Reactions involving to diene cyclization, no carbon atoms are lost.302... 

Although the high reactivity of metal-chalcogen double bonds of isolated heavy ketones is somewhat suppressed by the steric protecting groups, Tbt-substituted heavy ketones allow the examination of their intermolecular reactions with relatively small substrates. The most important feature in the reactivity of a carbonyl functionality is reversibility in reactions across its carbon-oxygen double bond (addition-elimination mechanism via a tetracoordinate intermediate) as is observed, for example, in reactions with water and alcohols. The energetic basis... 

Thermally induced intra-intermolecular criss-cross cycloaddition of nonsymmetrical azines 363 in the presence of phenyl isocyanate provides the corresponding products of the mixed criss-cross cycloaddition 364 (Scheme 55) <2002TL6431>. Two different reaction mechanisms, intra-intermolecular and inter-intramolecular, of the mixed criss-cross cycloaddition with opposite sequence of reaction steps are possible. Quantum chemistry calculations suggest the intra-intermolecular mechanism as the most probable mechanism of this reaction <2004CCC231>. 

Intramolecular oxonium ylide formation is assumed to initialize the copper-catalyzed transformation of a, (3-epoxy diazomethyl ketones 341 to olefins 342 in the presence of an alcohol 333 . The reaction may be described as an intramolecular oxygen transfer from the epoxide ring to the carbenoid carbon atom, yielding a p,y-unsaturated a-ketoaldehyde which is then acetalized. A detailed reaction mechanism has been proposed. In some cases, the oxonium-ylide pathway gives rise to additional products when the reaction is catalyzed by copper powder. If, on the other hand, diazoketones of type 341 are heated in the presence of olefins (e.g. styrene, cyclohexene, cyclopen-tene, but not isopropenyl acetate or 2,3-dimethyl-2-butene) and palladium(II) acetate, intermolecular cyclopropanation rather than oxonium ylide derived chemistry takes place 334 ). 

The ring cleavage of 3-aryl-2-substituted-2//-azirines by molybdenum hexacarbonyl has been described earlier in regard to the synthesis of pyrroles, pyrazoles and isoxazoles. In contrast to this behavior, analogous reactions of 2-unsubstituted derivatives lead to the formation of mixtures of 2,5-diarylpyrazines (139) and isomeric 3,6- and 1,6-dihydropyrazine derivatives (140,141) (Scheme 163).47,53 It is possible that the pyrazine products are formed by an intermolecular nitrene mechanism akin to the intramolecular processes described earlier (see Scheme 22 in Section IV,A,1). 

The use of mesitoate esters in the elucidation of reaction mechanisms has been pioneered by Burrows and Topping (1969,1970). This system has been used to suppress the competitive intermolecular reaction by steric bulk effects and to detect participation by the identification of the products formed. Under identical conditions (pH 11.28 at 30°C in 9.5% ethanol-water), 2-acetylphenyl mesitoate [41]is hydrolysed 130 times more readily than 4-acetylphenyl mesitoate, clearly indicating intramolecular catalysis. However, the products of hydrolysis provided no clue to the mechanism of... 

Determination of reaction mechanisms by combining the observed intermediates in a catalytic cycle. To do this, it is often necessary to measure under different conditions - that is, variable temperature NMR. The use of high-pressure NMR cells is crucial in order to measure under the real catalytic conditions. The EXSY experiment helps to unravel exchange pathways, both intra-and intermolecular. 

The mechanism of the Meerwein-Pondorf-Verley reaction is by coordination of a Lewis acid to isopropanol and the substrate ketone, followed by intermolecular hydride transfer, by beta elimination [41]. Initially, the mechanism of catalytic asymmetric transfer hydrogenation was thought to follow a similar course. Indeed, Backvall et al. have proposed this with the Shvo catalyst [42], though Casey et al. found evidence for a non-metal-activation of the carbonyl (i.e., concerted proton and hydride transfer [43]). This follows a similar mechanism to that proposed by Noyori [44] and Andersson [45], for the ruthenium arene-based catalysts. By the use of deuterium-labeling studies, Backvall has shown that different catalysts seem to be involved in different reaction mechanisms [46]. 

The first propynoate molecule undergoes a carbon—carbon bond-forming reaction with the zirconacyclopentadiene. The second molecule of the propynoate then donates a proton to the zirconacycle to open the ring. Further intermolecular Michael addition to the resulting carbon—carbon double bond produces the cyclopentadiene compounds. Investigations using deuterated propynoate were clearly indicative of the reaction mechanism shown in Eq. 2.47. 

The measurement of accurate EM s, as defined above, clearly has very stringent requirements. First, the mechanisms of both intermolecular and intramolecular reactions must be known and have been shown to be the same. Then acceptable rate measurements must be carried out under the same conditions for both reactions. Generally it is not possible to measure the rates of both the intermolecular reaction and the intramolecular process (thus catalysed by the same group) under the same conditions measurements on the intermolecular reaction catalysed by a series of catalytic groups are necessary to define the EM accurately. 

Section III (Table H), intramolecular general acid catalysis, is the smallest because this mechanism is less common and because where it is observed (mostly in acetal chemistry) the corresponding intermolecular reactions often cannot be detected. 

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