The Mechanistic Hypothesis

If the reactions involving C,H activation were conducted in an intermolecular manner, a ring expansion was possible, as only one new five-membered ring was formed [45]. 

Alkenes also could be intermolecular reaction partners of the diynes 29, and thus benzocyclobutenes were formed [46]. Two important observations were made in this context  

2) Bergman-like cyclization pathways of the ene-diynes substructures in the substrates, which would involve radical intermediates, can be excluded as the typical interceptor for such radicals, the hydrogen atom donor 1,4-cyclohexadiene (44), also provided benzocyclobutene 45 and not products 

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Allenamide ( )-13 was prepared by trapping the corresponding lithioallene with carbon dioxide, followed by conversion of the carboxylate to the amide. Chromatographic resolution of the enantiomers of 13 was easily accomplished on a 10x250mm Chiralcel OD HPLC column. Addition of vinyllithium 14 to (+)-13, followed by quenching the reaction with aqueous NaH2P04, led to cyclopentenone (—)-15 in 64% yield with >95% chirality transfer (Eq. 13.4). The absolute stereochemistry of (-)-5 is consistent with the mechanistic hypothesis put forth in Eq. 13.3 [8]. 

It is of interest that the mechanism shown in Fig. 8.5 should be applicable to all catechol monoesters, but this is only seen when hydrolysis is comparatively slow. More studies are needed to examine the mechanistic hypothesis presented in Fig. 8.5 and the pharmacokinetic consequences of intramolecular acyl migration in monoesters of catechols. 

The mechanistic hypothesis was tested with experiments involving a pair of substrates differing only in olefin geometry abont the a,[3-unsatnrated ester. If the assumption that proton transfer occnrs faster than the bond rotation of converting C to D is valid then the ( )- and (Z)-isomers are expected to prodnce opposite diastereomers. In the event, ( )-99 provides 42 1 dr while (Z)-99 provides 1 6 dr favoring the opposite diastereomer (Scheme 14). 

Our design of bimetallic catalysts based on crown-complexed alkaline-earth metal ions, for use in reactions of ester and activated amides endowed with a distal carboxylate anchoring group, is based on the mechanistic hypothesis outlined in Scheme 5.3. Such hypothesis critically rests on the finding that in EtOH solution... 

From a mechanistic point of view two possible hypotheses were discussed (Scheme 2). Since radical cations are intrinsically very acidic [29-32] one would expect enol radical cation 27 to deprotonate efficiently and rapidly thus providing an a-carbonyl radical (mechanism 1). In a further one-electron oxidation step the a-carbonyl cation is formed, that cyclizes to an intermediate cyclohexadienyl cation 28. After a 1,2-methyl shift and deprotonation the benzofuran 29 is obtained. The mechanistic proposal is in line with benzofuran formation from a-carbonyl cations as demonstrated by Okamoto [120]. Interestingly, the above mechanism was first proposed by Bailey to explain the formation of 3% of benzofuran 24 in the ozonization of enol 8 [121], Years later, however, the mechanistic hypothesis was proven to be untenable [122] under ozonization conditions. A priori, it cannot be excluded that intramolecular cyclization of the enol radical cation 27 " is faster than deprotonation (mechanism 2). The distonic radical cation formed is expected to lose a proton readily and after a second one-electron oxidation the same cyclohexadienyl cation intermediate as in mechanism 1 is formed. 

The reaction coordinate calculations [100] confirmed the mechanistic hypothesis depicted in Scheme 1, i.e., the entire chemical reaction process consists of four individual steps (ES TSl INTI TS2 INT2 TS3 INT3 TS4 EB). The calculated energy barriers (A a) and Gibbs free energy barriers (AGa) are summarized in Table 3. 

A separation of the racemic mixture of chiral zirconocene compounds into the optically active pure enantiomers is performed using 0-acetyl-(/ )-mandelic acid as chiral auxiliary (Structure 28). Using this enantiomerically pure metallocene in oligomerization experiments confirms the mechanistic hypothesis of stereospecificity predicting the topicity of insertion [69]. 

The excited state lifetime of the GFP chromophore is very long in the protein (cfl. 3 ns) but much shorter (less than 0.3 ps) in solution. The mechanistic hypothesis is that the decay is due to a Z/E isomerization. Thus, while in solution the fluorophore may undergo an ultrafast internal conversion, the protein should act by restraining the isomerization. In contrast in Rh the excited state lifetime is ca. 150 fs. However, if we look at the solution lifetime this is increased of one order of magnitude. Furthermore, one has 24% quanmm yield in solution and 65% quantum yield in the protein. Thus, in this case the protein is catalyzing the reaction. The absorption maxima (A]iiax) of... 

Some discrete observations relevant to the mechanistic hypothesis have been reported. It has been shown that an equilibrium is attained between a starting acetylene and the alkenyl Grignard reagent produced by the hydromagnesialion, provided that the acetylene is a silylated one (cq. 3.38) [ 102]. rims, the addition of a different acetylene to the silylulkenyl Grignard reagent, preformed front the... 

Mechanism-based enzyme inactivators are also powerful tools in the determination of enzyme mechanisms. Because some understanding of the enzyme mechanism is required for the design of an inactivator, the success of the compound provides support for the mechanistic hypothesis. Analysis of the intermediates and products of an inactivation reaction can be extremely useful in illuminating the normal mechanism of enzymic catalysis. For example, the covalent modification of an enzyme by a mechanism-based inactivator facilitates isolation of active site peptides and identification of cataiytically relevant amino acids. 

Let us return to the flow sheet of Scheme 13-2. In step VI we made a preliminary choice of catalyst by using theoretical considerations. However, since experiments are the only sure method for testing the mechanistic hypothesis, the next step is catalyst testing. 

We wanted to prove this mechanistic hypothesis and synthesized a catalyst with the same basic ligand framework, but with a non-rotatable substituent at the Cp ring. This catalyst is shown in Fig 22 below the box. Its stereospecific polymerization behavior lies between hemiisotactic and atactic and, indeed, scarcely changed with rising temperature. Hence, the mechanistic hypothesis of the rotating group seems to be tme. Quod erat demonstranduml... 

To clarify the mechanistic hypothesis, the authors carried out a series of experiments by treating the zirconacycle 310 with aUyl electrophiles in the absence of an alkynyl bromide (Scheme 10.104). 

According to the proposed mechanism, the electrophilic arylpaUadium iodide 326, formed by an oxidative addition of Ar-1 to a Pd(0) species, was proposed to activate the central carbon-carbon double bond in the cyclic cumulene intermediate 317b to form the complex 327. A subsequent attack by the Zr-C(sp ) nucleophilic center produces the aUcenylpalladium intermediate 325, which upon reductive elimination furnishes the corresponding alkenylzirconium species 324. Hydrolysis of the latter finally produces the 3-methylenecyclopentene 319. To support the mechanistic hypothesis, deuterolysis was carried out to provide the deuterated compound 319-D in 60% yield with a high level of deuterium incorporation [87]. 

Based on studies with model compoimds and the known dependence of polydiene microstructure on diene monomer (D) and chain-end concentrations as shown in Table 6, the mechanistic hypothesis shown below was advanced. 

The mechanistic hypothesis is supported by several lines of evidence. First, the reaction rate for a simple three component system was found to be first order in each of the three components. Since reactions that proceed by a rate-limiting step in which three components simultaneously collide are rare, an intervening pre-equilibrium step is proposed. 

Mechanistic understanding of the Kumada coupling was expanded by the isolation of a nickel(I) intermediate by Matsubara and coworkers (Figiu-e 13.11) [17], and further investigated by Louie [18]. A niunber of experiments support the mechanistic hypothesis uivolvuig the generation of a nickel(I) species in the reaction between nickel(0)-NHC complexes with aryl halides. Fiuther studies... 

In this case, things turn out well for the mechanistic hypothesis shown in Figure 9.36, and the Markovnikov rule is followed in hydration reactions. 

Let s set about finding an experiment to test the requirement of the theory for suprafacial [1,5] motion. What will we know at the end of the experiment If we find that the [1,5] shift is indeed strictly suprafacial, the theory will be supported (not proved ), and we will certainly feel better about the mechanistic hypothesis. If we find antarafacial motion, or both suprafacial and antarafacial motions, the theory will be proved (yes, proved) wrong. There is no way our hypothesis can accommodate antarafacial motion there is an absolute demand for suprafaciality, which nicely illustrates the precarious life of a theory. It can always be disproved by the next experiment, and it can never become free of this state of affairs. 

In 2007, the groups of MacMillan and Sibi almost simultaneously introduced a new mode of organocatalytic activation, termed SOMO (singly occupied molecular orbital) catalysis, which was founded upon the transient production of a 37r-electron radical cation species that could function as a generic platform of induction and reactivity. This new mode of organocatalytic activation, was founded upon the mechanistic hypothesis that one-electron oxidation of a transient enamine intermediate, derived from the aldehyde and the chiral amine catalyst, rendered a 37i -electron SOMO-activated species, which could readily participate in asymmetric bond construction. 

The first reported controlled polymerization based on the OMRP-RT principle appears to have been presented by Minoura in a series of articles starting in 1978, where the redox initiating system BPO/Cr was used for the polymerization of vinyl monomers.Not only were the kinetics different than in free-radical polymerization (very low reaction orders in Cif and BPO), but also the polymerization was observed to continue after all Cr had been converted by the peroxide to Cr and the degree of polymerization was found to increase with monomer conversion at low temperatures (<30 0). These studies included the report of a block copolymer (PMMA-b-PAN). Polydispersity indexes were not reported for these studies. Minoura formulated the mechanistic hypothesis of the formation of a metal complex with the free radical and stated that "the recombination of free radicals formed by the dissociation of the complexed radicals competes with a disproportionation of free radicals". However, these studies did not have a great impact in the polymer community, being cited only a handful of times before 1994. A few subsequent contributions reported the application of similar conditions to other metals but well-controlled polymerizations were not found."- " ... 

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