Control unfavorable schemes

We will begin with combinations of level control and feedforward compensation for applications where material-balance control is in the direction opposite to flow. Then we will consider schemes in which material-balance control is in the direction of flow. Unfavorable schemes—those that are hard to design or to make work—will be pointed out their use should be avoided unless no suitable option is available. 

In considering catalyzed olefin-cyclopropane interconversions, an important question arises concerning thermodynamic control and the tendency (or lack thereof) to attain a state of equilibrium for the system. Mango (74) has recently estimated the expected relative amounts of ethylene and cyclopropane for various reaction conditions and concluded that the reported results were contrary to thermodynamic expectation. In particular, the vigorous formation of ethylene from cyclopropane (16) at -78°C was stated to be especially unfavored. On the basis of various reported observations and considerations, Mango concluded that a reaction scheme such as that in Eq. (26) above (assuming no influence of catalyst) was not appropriate, because the proper relative amounts of cyclopropanes and olefins just do not occur. However, it can be argued that the role of the catalyst is in fact an important element in the equilibration scheme, for the proposed metal-carbene and [M ] species in Eq. (26) are neither equivalent nor freely interconverted under normal reaction conditions. Consequently, all the reaction pathways are not simultaneously accessible with ease, as seen in the published literature, and the expected equilibria do not really have an opportunity for attainment. In such a case, absence of thermodynamic control should not a priori deny the validity of Eq. (26). 

The carbon-coupled products 66 were duly characterized. No C-S coupling was observed for these radicals, and this suggested that their electrophilic nature might control their reactivity. This could be rationalized by suggesting a slower combination between these radicals and the S. The retardation could result from an unfavorable transition state (67) where the buildup of positive charge on two adjacent carbons is seen. Calculations by Zaharadnik et al. have shown that the spin density on TTP is distributed as shown in Scheme 12, and so support the involvement of the internal carbons of TTF, rather than the peripheral carbons, in radical coupling. 

The reaction of (41) with electron-deficient imines yields 2-azetidinones resulting from a 1 2 addition (Scheme 45). The total stereoselectivity of the reaction has been explained on the basis of steric approach control and chelation in transition state (43). The intermediate p-lactam enolate (42) is more nucleophilic than the starting ynolate. This unfavorable nucleophilicity ratio is responsible for the formation of a 1 2 adduct. This represents a severe limitation of the reaction as a generd route toward P-lactams. 

When the triple bond is substituted with a trimethylsilyl or a phenyl group (e.g., 159), stereoselectivity is reversed and now kinetically controlled, with H-abstraction providing predominantly the (Z)-olefinic product 160 (Scheme 10-52). This difference in reactivity may be attributed to a linear vinyl radical intermediate which is conjugatively stabilized by the terminal substituent removing A -interactions. Now, unfavorable steric interactions between the H-donor and the allylic substituents are product-determining. 

Protolytic ionization of methylcyclopentane gives an equilibrium mixture of the tertiary 1-methyl-1-cyclopentyl cation (29) (more stable by about 40 kJ/mol) and the secondary cyclohe l cation (32) (Scheme 5). At low temperature, irreversible reaction of 29 with CO leads to ion 30, which, after reaction writh ethanol, gives the 31 ester. Product composition, in this case, reflects the difference in stability of the intermediate carbocations. Since the carbonylation step is reversible at higher temperature, and carbocation 32 has a much higher affinity for CO, the concentration of 33 in solution continuously increases to yield, after quenching with ethanol, the 34 ester. This is an example of a kinetically controlled product formation through a thermodynamically unfavorable intermediate. 

A possible transition state based on the Felkin-Anh model was shown in Scheme 23. Judging from the (2/ ,3R,4S)-configuration of the product 31a, the major product is likely formed via the Felkin TS 33 showing the Si face attack of the Rh-( )-enolate. This step could be the catalyst-controlled reaction with the chiral catalyst. According to the prochiral face discrimination in the phebox-Rh-catalyzed reductive aldol reaction with the linear substrate, the Re face attack of the Rh (fij-enolate in TS 34 is unfavorable. In the case of the (R)-aldehyde, the anri-Felkin-Anh s TS 35, which gives the (2R,3R,4R)-product 31b, takes the unfavorable conformation with the bulky phenyl group at the apical position. 

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