Outcomes intermediate

Consequences also can be discussed in terms of intermediate and final outcomes. Intermediate outcomes can serve as a proxy for more relevant final outcomes. For example, achieving a decrease in low-density lipoprotein cholesterol levels with a lipid-lowering agent is an intermediate consequence that may serve as a proxy for a more final outcome such as a decrease in myocardial infarction rate. Intermediate consequences are used commonly in clinical and pharmacoeconomic analyses as proxies predictive of final outcomes because their use reduces the cost and time required to conduct a trial. 

Free-Radical Addition. A different outcome is expected in free-radical addition. The reaction of an a-olefin with a typical free radical affords the most stable intermediate free radical. This species, in turn, reacts further to form the final product, resulting in the anti-Markownikov mode of addition. 

Studies of the stereochemical course of rmcleophilic substitution reactions are a powerful tool for investigation of the mechanisms of these reactions. Bimolecular direct displacement reactions by the limSj.j2 meohanism are expected to result in 100% inversion of configuration. The stereochemical outcome of the lirnSj l ionization mechanism is less predictable because it depends on whether reaction occurs via one of the ion-pair intermediates or through a completely dissociated ion. Borderline mechanisms may also show variable stereochemistry, depending upon the lifetime of the intermediates and the extent of internal return. It is important to dissect the overall stereochemical outcome into the various steps of such reactions. 

Event Tree Analysis (ETA) A method for illustrating the intermediate and final outcomes that may arise after the occurrence of a selected initial event. 

The second C-C bond forming step (step C), while occurring after the first irreversible ee determining step (step B), can affect the observed enantioselective outcome of the reaction. If the radical intermediate collapses without rotation (k3 Ict, k5 ke), then the observed ee would be determined by the first C-C bond forming step (ki vs. k2), that is the facial selectivity (Scheme 1.4.6). However, if rotation is allowed followed by collapse, then the rate of both trans pathways (Ic and k ) will proportionally effect the observed ee of the cis epoxide (ks vs. ks). Should bond rotation be permissible, the diastereomeric nature of the radical intermediates 9a and 9b renders the distinct possibility of different observed ee s for frany-epoxides and dy-epoxides. 

The Nenitzescu process is presumed to involve an internal oxidation-reduction sequence. Since electron transfer processes, characterized by deep burgundy colored reaction mixtures, may be an important mechanistic aspect, the outcome should be sensitive to the reaction medium. Many solvents have been employed in the Nenitzescu reaction including acetone, methanol, ethanol, benzene, methylene chloride, chloroform, and ethylene chloride however, acetic acid and nitromethane are the most effective solvents for the process. The utility of acetic acid is likely the result of its ability to isomerize the olefinic intermediate (9) to the isomeric (10) capable of providing 5-hydroxyindole derivatives. The reaction of benzoquinone 4 with ethyl 3-aminocinnamate 35 illustrates this effect. ... 

Indole has also been demonstrated to undergo a thermally induced condensation with trifluoroacetaldehyde ethyl hemiacetal to give a variety of products depending on the reaction conditions, e.g., the 6,12-dihydroindolo[3,2-f)]carbazole 172, which could be isolated in low yield from the mixture originating from the heating of equimolar amounts of the reactants in the absence of solvent. The formation of an intermediate indolenine species was suggested to account for the outcome (88JFC47). 

Because an S jl reaction occurs through a carbocation intermediate, its stereochemical outcome is different from that of an S 2 reaction. Carbocations, as we ve seen, are planar, sp2-hybndized, and achiral. Thus, if we carry out an S jl reaction on one enantiomer of a chiral reactant and go through an achiral carbocation intermediate, the product must be optically inactive (Section 9.10). The symmetrical intermediate carbocation can react with a nucleophile equally well from either side, leading to a racemic, 50 50 mixture of enantiomers (Figure 11.10). 

Removal of the carbonate ring from 7 (Scheme 1) and further functional group manipulations lead to allylic alcohol 8 which can be dissected, as shown, via a retro-Shapiro reaction to give vinyl-lithium 9 and aldehyde 10 as precursors. Vinyllithium 9 can be derived from sulfonyl hydrazone 11, which in turn can be traced back to unsaturated compounds 13 and 14 via a retro-Diels-Alder reaction. In keeping with the Diels-Alder theme, the cyclohexene aldehyde 10 can be traced to compounds 16 and 17 via sequential retrosynthetic manipulations which defined compounds 12 and 15 as possible key intermediates. In both Diels-Alder reactions, the regiochemical outcome is important, and special considerations had to be taken into account for the desired outcome to. prevail. These and other regio- and stereochemical issues will be discussed in more detail in the following section. 

However, (-)-12 was shown to have (R)- Z) configuration by chemical correlation1033, and thus, in both metal-exchange steps, a/7//-SE2 -processes are involved. This, and the sign of optical rotation of intermediate stannanes, corresponds well with other published results111. Fortunately, this error has no implication for the stereochemical outcome of the overall sequence. 

The reaction of propargylic ethers proceeds through an addition-elimination pathway, which docs not involve the coppcr(III) intermediate. The stereochemical outcome varies with the nature of the halogen component of the Grignard reagent of RMgX6Sc. If the halogen is chloride, overall syn selectivity is obtained however, anti substitution results in the case of iodide. 

The stereochemical outcome could be rationalized by attack on the chelated intermediate from the diastereoface of the enolate that is anti to R1. 

Another example of a [4S+1C] cycloaddition process is found in the reaction of alkenylcarbene complexes and lithium enolates derived from alkynyl methyl ketones. In Sect. 2.6.4.9 it was described how, in general, lithium enolates react with alkenylcarbene complexes to produce [3C+2S] cycloadducts. However, when the reaction is performed using lithium enolates derived from alkynyl methyl ketones and the temperature is raised to 65 °C, a new formal [4s+lcj cy-clopentenone derivative is formed [79] (Scheme 38). The mechanism proposed for this transformation supposes the formation of the [3C+2S] cycloadducts as depicted in Scheme 32 (see Sect. 2.6.4.9). This intermediate evolves through a retro-aldol-type reaction followed by an intramolecular Michael addition of the allyllithium to the ynone moiety to give the final cyclopentenone derivatives after hydrolysis. The role of the pentacarbonyltungsten fragment seems to be crucial for the outcome of this reaction, as experiments carried out with isolated intermediates in the absence of tungsten complexes do not afford the [4S+1C] cycloadducts (Scheme 38). 

This two-step process is an example of a reaction sequence, a series of reactions in which the products of one reaction take part as reactants in another reaction. The equation for the overall reaction, the net outcome of the sequence, is the sum of the equations for the intermediate steps ... 

Rychnovsky demonstrated that the latter explanation is correct in reductive decyanations, the intermediate radical equilibrates to the most stable (axial) radical, and this equilibration determines the stereochemical outcome. Reductive decyanation of a 52 48 mixture of cyanohydrin acetonides 22 provided the 5yn-product 25 with 99 1 selectivity (Scheme 4). Ab initio calculations revealed a ca. 3.5 kcal/mol enthalpy difference between the axial and equatorial radical... 

For example, let s look at the stereochemistry of SnI reactions. We already saw that Sn2 reactions proceed via inversion of configuration. But SnI reactions are very different. Recall that a carbocation is sp hybridized, so its geometry is trigonal planar. When the nucleophile attacks, there is no preference as to which side it can attack, and we get both possible configurations in equal amounts. Half of the molecules would have one configuration and the other half would have the other configuration. We learned before that this is called a racemic mixture. Notice that we can explain the stereochemical outcome of this reaction by understanding the nature of the carbocation intermediate that is formed. 

It must be emphasized that a CBA seeks to put monetary values on one or more of the final or intermediate outcomes. It does not simply compare the amount spent with the amount saved as a result of a treatment the latter would be a cost ojfset analysisy which compares two different levels of expenditure. Many evaluators have carried out cost-offset analyses but erroneously given them the CBA label. Without outcome data an evaluation is certainly not worthless, but its relevance for decision-makers is generally reduced. 

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