Steric hindrance regioselectivity

In the epoxidation of olefins not bearing a complexing group, there is not a great difference in stereoselectivity in comparison with the peracids. The c/s-oxirane is formed from cis-butene-2 and the trans-oxirane from trans-butene-2. Due to steric hindrance, regioselectivity may be observed for nonconjugated dienes. °° ° In terpenes, the attack takes place from the less hindered side. Double bonds in bridged cyclic systems have an effect on the reaction rate. ... 

A regioselective aldol condensation described by Biichi succeeds for sterical reasons (G. Biichi, 1968). If one treats the diaidehyde given below with acid, both possible enols are probably formed in a reversible reaaion. Only compound A, however, is found as a product, since in B the interaction between the enol and ester groups which are in the same plane hinders the cyclization. BOchi used acid catalysis instead of the usual base catalysis. This is often advisable, when sterical hindrance may be important. It works, because the addition of a proton or a Lewis acid to a carbonyl oxygen acidifies the neighbouring CH-bonds. 

There also exists an acidregioselective condensation of the aldol type, namely the Mannich reaction (B. Reichert, 1959 H. Hellmann, 1960 see also p. 291f.). The condensation of secondary amines with aldehydes yields Immonium salts, which react with ketones to give 3-amino ketones (=Mannich bases). Ketones with two enolizable CHj-groupings may form 1,5-diamino-3-pentanones, but monosubstitution products can always be obtained in high yield. Unsymmetrical ketones react preferentially at the most highly substituted carbon atom. Sterical hindrance can reverse this regioselectivity. Thermal elimination of amines leads to the a,)3-unsaturated ketone. Another efficient pathway to vinyl ketones starts with the addition of terminal alkynes to immonium salts. On mercury(ll) catalyzed hydration the product is converted to the Mannich base (H. Smith, 1964). 

The Michael reaction is of central importance here. This reaction is a vinylogous aldol addition, and most facts, which have been discussed in section 1.10, also apply here the reaction is catalyzed by acids and by bases, and it may be made regioselective by the choice of appropriate enol derivatives. Stereoselectivity is also observed in reactions with cyclic educts. An important difference to the aldol addition is, that the Michael addition is usually less prone to sterical hindrance. This is evidenced by the two examples given below, in which cyclic 1,3-diketones add to o, -unsaturated carbonyl compounds (K. Hiroi, 1975 H, Smith, 1964). 

Microwave-assisted Heck reaction of (hetero)aryl bromides with N,N-dimethyl-2-[(2-phenylvinyl)oxy]ethanamine, using Herrmann s palladacycle as a precatalyst, yielded the corresponding /3-(hetero)arylated Heck products in a good EjZ selectivity (Scheme 79) [90]. The a/yd-regioselectivity can be explained by the chelation control in the insertion step. This selectivity is better than 10/90 when no severe steric hindrance is introduced in the (hetero)aryl bromides. The process does not require an inert atmosphere. There is evidence that a Pd(0)/Pd(II)- and not Pd(II)/Pd(IV)-based catalytic cycle is involved. Similarly, other j6-amino-substituted vinyl ethers such as... 

With 3-(l-imidazolyl)-2-alkene-l-ones bearing a substituent at C-3, regioselective 1,2-addition occurs because of steric hindrance.[6]... 

A similar reaction sequence of triisopropylphenylphosphole or mesitylphosphole (17b and 17a, respectively) with phosphorus tribromide afforded the corresponding 2-substituted products. The reaction of dibromophosphine 37 with nucleophiles followed by oxidation or hydrolysis gave phosphonic or //-phosphinic derivatives (39 or 41, respectively) (Scheme 9) [48, 49], The regioselectivity is obviously the consequence of the presence or the lack of the steric hindrance with ortho tert-butyl groups, only position 3 is available, while with the smaller triisopropyl substituent, position 2 may be the appropriate reaction site. 

Scheme 52 explains the [(Cp )Rh(MeCN)3]2+-assisted regioselective hydrogenation of pyridines, benzoquinolines, acridines as well as indoles and benzothiophene.258 The relative hydrogenation rates were attributed to both electronic and steric effects, the rate generally decreasing with increasing basicity and steric hindrance at the nitrogen atom. 

In turn, the propensity of 1 to respond to steric hindrance can be used to control the site of initiation of an RCM reaction in a polyene substrate (Scheme 9) [20]. Thus, dienyne 25 reacts with the catalyst regioselectively at the least substituted site the evolving ruthenium carbene 26 undergoes a subsequent enyne metathesis leading to a new carbene 27, which is finally trapped by the disubsti-tuted olefin to afford the bicyclo[4.4.0]decadiene product 28. By simply reversing the substitution pattern of the double bonds, the complementary bicyclo [5.3.0] compound 32 is formed exclusively, because the cyclization cascade is then triggered at the other end of the substrate. Note that in both examples tri-substituted olefins are obtained by means of a ruthenium based metathesis catalyst [20] ... 

The reaction presumably involves a cis, syn elimination. As Eq. 34 illustrates, regioselectivity can be controlled by choice of base 49). The higher kinetic acidity of the benzylic position of 20 determines the regioselectivity with a- non-hindered base whereas, steric hindrance directs the base to the methyl group. 

Alkoxycarbonylation of 2,3-dichloro-5-(methoxymethyl)pyridine (78) took place regioselectively at C(2) to give ester 79 [79], Aminocarbonylation of 2,5-dibromo-3-methylpyridine also proceeded preferentially at C(2) to give amide 80 despite the steric hindrance of the 3-methyl group [80]. 

The hydrostannation of alkenes and alkynes can be catalyzed by a number of transition metals (Ni, Pd, Pt, Mo, etc.), but most studies have involved palladium.106 The mechanism that is most commonly accepted is shown for an alkyne in Scheme 1 the model for an alkene is similar. This mechanism accounts for the observations that the reactions normally involve cir-addition, that the R3Sn group enters so as to avoid steric hindrance by the largest substituent group on the alkene or alkyne, and that the regioselectivity depends on the polarization of the palladium-hydrogen bond in the sense Pd -H15-. 

Rigby and colleagues also demonstrated that the regioselectivities in the reactions of 1- and 2-substituted dienes with 1-substituted cycloheptatrienes, which do not proceed under metal-free conditions, were generally high. In the case of 1-substituted dienes, this may be completely attributed to steric hindrance. 2- And 3-substituted cycloheptatrienes hardly showed any regioselectivity305. 

Alternative furan ring fusion involves the reactions of phenyliodonium ylides of cyclic seven-membered jS-diketones with alkynes. These processes lead under mild conditions to cyclization products 152. The high regioselectivity can be explained by the formation of dipolar intermediate 151 favored by the predominant enolization of the carbonyl adjacent to phenyl ring. Terminal alkynes react in the similar fashion, although, in this case, mixtures of regioisomers have been reported due to steric hindrance in the intermediate enol (Scheme 30 (1993JOC4885)). 

On the basis of these comparable mechanisms, the observed regioselectivity with various 3-substituents summarized in Table I might be best interpreted in terms of the balance of three effects, namely attractive dispersion force, steric hindrance, and electrostatic repulsion which would all be operative between the 3-substituent and the ferricyanide ion in the rate-determining step. 

It is tempted to speculate the contribution of the remote polar substituent to the regioselective reduction of the endione intermediates employed for the syntheses of tetrodotoxin [270] and reserpine [271]. Without disregarding the steric hindrance of the substituent in each case to the proximal carbonyl, the disjoint relationship of which to... 

Other authors have attempted to rationalize the enzyme selectivity toward sugar derivatives by simulating the interaction of the substrates with the enzyme by molecular modeling [100], although this is not an easy task [101]. The first published example related to the regioselective acylation of sucrose [102]. However, the two observed acylation sites of sucrose were not on the same monosaccharide unit, and therefore a possible explanation of subtilisin selectivity could reside in the different steric hindrances. 

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