Steric, factor hindrance

In the absence of steric factors e.g. 5 ), the attack is antiparallel (A) (to the adjacent axial bond) and gives the axially substituted chair form (12). In the presence of steric hindrance to attack in the preferred fashion, approach is parallel (P), from the opposite side, and the true kinetic product is the axially substituted boat form (13). This normally undergoes an immediate conformational flip to the equatorial chair form (14) which is isolated as the kinetic product. The effect of such factors is exemplified in the behavior of 3-ketones. Thus, kinetically controlled bromination of 5a-cholestan-3-one (enol acetate) yields the 2a-epimer, (15), which is also the stable form. The presence of a 5a-substituent counteracts the steric effect of the 10-methyl group and results in the formation of the unstable 2l5-(axial)halo ketone... 

In addition to the intramolecular effects, steric factors are of considerable influence. The most usual one consists of steric hindrance to attack on the lactam nitrogen atom. Certain examples of this will be given. By comparison with uracil, it would be expected that uric acid (10) would be iV-methylated in the pyrimidine ring, but that in the imidazole ring 0-methylation should also be possible. However, the experiments of Biltz and Max show that all uric acid derivatives which carry a hydrogen atom in the 9-position are converted by ethereal diazomethane into l,3,7-trimethyl-8-methoxyxanthine (11). The following are examples uric acid and its 1-methyl, 3-methyl, 7-methyl, 1,3-dimethyl, 1,7-dimethyI, 3,7-dimethyl, and 1,3,7-trimethyl derivatives. Uric acid derivatives which arc substituted by alkyl groups in the 3- and 9-positions (e.g., 3,9-dimethyl-, 1,3,9-trimethyl-, and 3,7,9-trimethyl-uric acid)do not react at all with diazomethane, possibly because of insufficient acidity. Uric acids which are alkylated... 

Steric factors are also important in hydrodimerizations carried out in acidic media. Excessive steric hindrance about the 0-carbon in an a, 0-unsaturated carbonyl compound can retard tail-to-tail coupling, e.g., 2 130 - 131, and lead to products of head-to-head (and occasionally head-to-tail) coupling. Thus in the reduction of mesityl oxide at pH lg.4 there is also formed a small amount of ketone 140, apparently formed via head-to-head coupling of 130 and subsequent pinacol rearrangement of 139 134) ... 

These facts suggest that, for the fluorinated Ti-FI catalysts that we discovered, the steric hindrance provided by the substutuent ortho to the phenoxy-O exercises no significant influence on the living nature, implying that steric factors do not play a pivotal role in achievement of the living polymerization [68, 74]. 

It is observed that insertion into a zirconacyclopentene 163, which is not a-substituted on either the alkyl and alkenyl side of the zirconium, shows only a 2.2 1 selectivity in favor of the alkyl side. Further steric hindrance of approach to the alkyl side by the use of a terminally substituted trans-alkene in the co-cyclization to form 164 leads to complete selectivity in favor of insertion into the alkenyl side. However, insertion into the zirconacycle 165 derived from a cyclic alkene surprisingly gives complete selectivity in favor of insertion into the alkyl side. In the proposed mechanism of insertion, attack of a carbenoid on the zirconium atom to form an ate complex must occur in the same plane as the C—Zr—C atoms (lateral attack 171 Fig. 3.3) [87,88]. It is not surprising that an a-alkenyl substituent, which lies precisely in that plane, has such a pronounced effect. The difference between 164 and 165 may also have a steric basis (Fig. 3.3). The alkyl substituent in 164 lies in the lateral attack plane (as illustrated by 172), whereas in 165 it lies well out of the plane (as illustrated by 173). However, the difference between 165 and 163 cannot be attributed to steric factors 165 is more hindered on the alkyl side. A similar pattern is observed for insertion into zirconacyclopentanes 167 and 168, where insertion into the more hindered side is observed for the former. In the zirconacycles 169 and 170, where the extra substituent is (3 to the zirconium, insertion is remarkably selective in favor of the somewhat more hindered side. 

The results of the alkylbenzene series may also be readily explained in terms of ir complex adsorption. In this series, the molecular orbital symmetry of individual members remains constant while the ionization potential, electron affinity, and steric factors vary. Increased methyl substitution lowers the ionization potential and consequently favors IT complex adsorption. However, this is opposed by the accompanying increase in steric hindrance as a result of multiple methyl substitution, and decrease in electron affinity (36). From previous data (Tables II and III) it appears that steric hindrance and the decreased electron affinity supersede the advantageous effects of a decreased ionization potential. The results of Rader and Smith, when interpreted in terms of tt complex adsorption, show clearly the effects of steric hindrance, in that relative adsorption strength decreases with increasing size, number, and symmetry of substituents. 

Concerning steric factors, 43 is attacked in the most hindered position ( inverse effect of substitution ) likewise, 39 is attacked at the most hindered carbon. Obviously, the transition states for the formation of 44 or 50 show limited sensitivity to the degree of substitution, and the relief of ring strain is a more significant factor than the steric hindrance in the transition state. On the other hand, steric factors are important in systems such as P-phellandrene radical cation 40 which is attacked at the xo-methylene carbon (most easily accessible), or the tricyclane radical cation 56 which is attacked at the less hindered 3° carbon further removed from the dimethyl-substituted bridge (approach a). Both reactions also benefit Irom the formation of the most highly substituted, hyperconjugatively stabilized free radicals. 

Note The steric factor reflects the effect of hindrance to free rotation. 

We suggest that in a secondary alcohol, there will be steric hindrance, which will limit the number of molecules that can get near the ion. This is shown, cartoon fashion, in Fig. 6. As one can see, the steric factors might well limit the ability of the alcohols to pack around an anion. 

At present, the precise reason for low reactivity of alkylbenzothiophenes and alkyldibenzothiophenes is not definitely known. It is clear that steric factors are indeed important, and it has been proposed that steric hindrance lowers the adsorption constant for these species (5, 17, 25, 26). Molecular... 

There are many examples of the reaction of carbohydrates with Rydon reagents [16] the reaction is controlled by steric factors. Thus, no reaction occurred between 1,2-0-isopropylidene-5,6-di-0-methyl-a-D-glucofuranose and either 6 or bromotriphenoxyphos-phonium bromide, presumably because of the steric hindrance caused by the trioxabicyclo [3.3.0]octane ring-system, whereas methyl 2,5,6-tri-O-methyl-p-D-glucofuranoside reacted with 6 to give a 3-deoxy-3-iodo derivative in 31% yield. 

Steric factors play a major role in the acylation of /V-alkyl amino acids during peptide synthesis. It is expected that the increased nucleophilicity of secondary amines, as compared to primary amines, will increase the rate of acylation. However, the opposite is observed acylation of /V-alkyl amino acids (except for Pro) is usually slower than the acylation of primary amines. This is explained by steric hindrance exerted by the /V-alkyl group, which shields the nucleophilic center. The steric effect increases with the size of the /V-alkyl group and is enhanced by bulky side chains and, to a lesser extent, by other remote groups. The relative rate of acylation of various types of /V-alkyl amino acids, as compared to amino acids, is shown in Scheme 35. 

Enone 113 can adopt two different conformations 116 and 117. Attack on the top face of the most stable conformation 116 gives the chair-like enolate ion 1 8 while an attack from below the plane of the molecule yields the boat-like enolate ion 119. On the other hand, an attack on the bottom face of the less stable conformation 117 gives the chair-like intermediate 120 while that on the top face gives the boat-like intermediate 22K The formation of the boat-like 121 where the two groups (R and Y) are cis can be readily eliminated. The chair-like 118 which leads to the cis isomer has to compete with the boat-like 119 and the chair-like 120 which lead to the trans isomer. The possibility of steric hindrance between the incoming nucleophile and the alkyl group at C-4 exists only in the formation of 118. Therefore, this extra steric factor would disfavor the formation of the cis isomer. 

---