Steric crowding, effects alkylation

However, although the accuracy of these predictions is impressive one must remember that they apply to a very closely defined series. We are still unable to predict the specific effects of substituents and have no answer to the intriguing question of why does the introduction of the OCH2 unit into the phenylethanolamines give such good (3-blockers, or why the addition of a polar group (amide or ether) to a para-alkyl substituent to some extent relieves the steric crowding (cf ICI 66082 (15) and metoprolol (id)) table 2. 

Diels-Alder reactions of oxazoles afford useful syntheses of pyridines (Scheme 53) (74AHC( 17)99). A study of the effect of substituents on the Diels-Alder reactivity of oxazoles has indicated that rates decrease with the following substituents alkoxy > alkyl > acyl >> phenyl. The failure of 2- and 5-phenyl-substituted oxazoles to react with heterodienophiles is probably due to steric crowding. In certain cases, bicyclic adducts of type (359) have been isolated and even studied by an X-ray method (87BCJ432) they can also decompose to yield furans (Scheme 54). With benzyne, generated at 0°C from 1-aminobenzotriazole and lead tetraacetate under dilute conditions, oxazoles form cycloadducts (e.g. 360) in essentially quantitative yield (90JOC929). They can be handled at room temperature and are decomposed at elevated temperatures to isobenzofuran. 

Rhodium(II) acetate appears to be the most generally effective catalyst, and most of this discussion will center around the use of this catalyst with occasional reference to other catalysts when significant synthetic advantages can be gained. Cyclopropanation of a wide range of alkenes is possible with alkyl diazoacetate, as is indicated with the examples shown in Table l.l6e>37 The main limitations are that the alkene must be electron rich and not too sterically crowded. Poor results were obtained with trans-alkenes. Comparison studies have been carried out with copper and palladium catalysts and commonly the yields were lower than with rhodium catalysts. Cyclopropanation of styrenes and strained alkenes, however, proceeded extremely well with palladium(ll) acetate, while copper catalysts are still often used for cyclopropanation of vinyl ethers.38-40... 

The two different ways of inserting an alkene into a metal-hydrogen bond, as shown by 5.4 and 5.5, are called anti-Markovnikov and Markovnikov addition, respectively. Insofar as hydroformylation with high selectivity to n-butyralde-hyde is concerned, it is considered to be primarily an effect of steric crowding around the metal center. The normal alkyl requires less space and therefore formed more easily than the branched one in the presence of bulky ligands. 

Early experiments using simple alkyl cobalt compounds as models for AdoCbl fostered the notion that steric crowding around the CooC bond might be an important factor that enzymes could exploit to effect the remarkable rate enhancements for homolysis of AdoCbl (Ng et al, 1983). These studies demonstrated that the more bulky the alkyl group attached to cobalt, the faster the rate of homolysis, leading to the idea that the enzymes might distort the coenzyme and thereby weaken the CooC bond. 

Clearly, the steric crowding that influences reaction rates in Sn2 processes plays no role in SnI reactions. The order of alkyl hahde reactivity in SnI reactions is the same as the order of carbocation stability the more stable the carbocation, the more reactive the alkyl halide. We have seen this situation before in the reaction of alcohols with hydrogen halides (Section 4.12), in the acid-catalyzed dehydration of alcohols (Section 5.9), and in the conversion of alkyl hahdes to alkenes by the El mechanism (Section 5.17). As in these other reactions, an electronic effect, specifically, the stabilization of the carbocation intermediate by alkyl substiments, is the decisive factor. 

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