Orientation, substituent

The electrostatic interaction of the charge on the orienting substituent and the charge on the ring, or the ring positions in the transition state. 

STO-3G calculations find the corresponding transition state to be more stable than other possible conformations by several kilocalories per raole. The origin of the preference for this transition-state conformation is believed to be a stabilization of the C=0 LUMO by the a orbital of the perpendicularly oriented substituent. 

According to Roberts et al. the direction of addition of ammonia to 3-substituted benzynes might be predicted by considering the amide ion to add so as to provide the most favorable location of the negative charge with respect to the inductive effect of the orienting substituent. Thus, ammonia adds to 3-methoxybenzyne (39) producing chiefly n-aminoanisole (40). 

In general in such transformations, the equatorially oriented substituent is energetically more favourable and it can be represented as follows ... 

The particular array of chemical shifts found for the nuclei of a given polymer depends, of course, on such factors as bond orientation, substituent effects, the nature of nearby functional groups, solvation influences, etc. As a specific example, derivatives of the carbohydrate hydroxyl moieties may give rise to chemical shifts widely different from those of the unmodified compound, a fact that has been utilized, e.g., in studies (l ) on commercially-important ethers of cellulose. Hence, as illustrated in Fig, 2, the introduction of an 0-methyl function causes (lU,15) a large downfield displacement for the substituted carbon. This change allows for a convenient, direct, analysis of the distribution of ether groups in the polymer. Analogously, carboxymethyl, hydroxyethyl and other derivatives may be characterized as well... 

The following examples show how open and closed transition states may be invoked by the choice of the reaction type. For instance, aldol-type addition normally proceeds via a closed transition state because the metal ion is shifted from the enolate oxygen to the carbonyl oxygen in an ene-like mechanism ( Zimmerman-Traxler transition state 9). The crucial interactions in the Zimmerman-Traxler transition state 16 are those between the 1,3-diaxially oriented substituents around the chair-like structure. R2 adopts the location shown, thus R3 avoids the 1,3-interaction and assumes an equatorial position. Therefore, the diastereomeric ratio depends mainly on the ( )/(Z) configuration of the enolate. Whereas (Z)-enolates 13 afford syn-config-urated enantiomers, 17 and 18, the corresponding ( )-enolates 14 lead to anti-configurated adducts 19 and 20 10. 

Osmium tetraoxide-promoted reactions are stevically controlled that is, in all instances, the predominant formation of products having tram-oriented substituents at C-2 and C-3, and C-2 and CA, is ob-served, and, consequently, 277 and 279 preponderate over 278 and 280. However, for 2-0-acetyl-l,6-anhydro-3,4-dideoxy-/3-DL- n/t/iro-hex-3-enopyranose (281), reaction with osmium tetraoxide leads175 to 2-0-acetyl-l,6-anhydro-/3-DL-alloside (282 88%) and -galactoside (283 8%). Obviously, the 1,6-anhydro bridge creates greater steric... 

Woodward hydroxylation of 256 leads mainly to sterically disfavored products having cis-oriented substituents at C-2 and C-3, and C-2 and C-4. In fact, in this case also, the attack of I4 occurs from the less-hindered side. The iodonium ion (284) is then opened by the acetate anion, to afford iodo acetate 285 which, in the following substitution reaction with silver acetate, gives the more-hindered, c/.y-hydroxylation product 286. 

It is possible to reach the desired result by introducing a para-orienting substituent in position 5 of 1-acylaminonaphthalenes. Indeed, heating 1-benzoylamino-5-benzoyloxynaphthalene 159 in polyphosphoric acid leads to 5-benzoyloxy-2-phenyl-benzo[o/]indole 160 which, on alkaline heating, gives rise to 2-phenylbenzo[cd]indole-5-one 161 (80AP977). 

The Oriented Substituent Pharmacophore PRopErtY Space (OSPPREYS) approach, introduced by Martin and Hoeffel [6], is in software terms an extension of CCG s MOE package, written using SVL. The 3D oriented substituent pharmacophores are aimed towards better representation of diversity and similarity in combinatorial libraries in the 3D pharmacophore space. Combinatorial library design often operates only on substituents rather than on the final products as the complications related to the conformational coverage in the 3D space and the scaffold dependency limit the product-based approaches to smaller libraries. The 3D oriented substituent pharmacophores add two more points and the corresponding distances to each substituent pharmacophore which represent the relationship of the substituents in the product with only little additional information. The fingerprints permit the creation of property space by multidimensional scaling (MDS) and, since scaffold independent, can be stored separately and applied to different libraries [6],... 

Martin, E.J., Hoeffel, T. J. Oriented substituent pharmacophore PRopErtY space (OSPPREYS) a substituent-based calculation that describes combinatorial library products better than the corresponding product-based calculation. Journal of Molecular Graphics and Modelling 2000, 18, 383-403. 

What is the reason for this apparent discrepancy It is a solvent effect. In aqueous solution (Figure 9.6), the OH group at the anomeric C atom of the glucose becomes so voluminous due to hydration that it strives for the position in which the steric interactions are as weak as possible. Thus, it moves into the equatorial position—with a AG° value of approximately -1.6 kcal/mol—to avoid a gauche interaction with the six-membered ring skeleton. (Remember that axially oriented substituents on the chair conformer of cyclohexane are subject to two gauche interactions with the two next-to-nearest C. —C bonds. They therefore have a... 

It remains to consider the role of 17a-alkyl substituents in the attachment to the receptor. We can see that the steroid-receptor attachment can accommodate a 17a-methyl or 17a-ethyl group but there is a sharp decrease in activity when a 17a-propyl, or ethynyl group is introduced and the importance of the third-dimensional attachment becomes immediately evident. Inspection of molecular models reveals that a 17ar propyl or 17a-ethynyl substituent protrudes well beyond the molecular dimensions of steroids in the a and in the planar direction. In order to obtain the molecular dimensions of steroids we draw a plane perpendicular to the a- and /S-faces, which connects along the equatorially oriented substituents at carbons 1,2, 11, and 12 on one side, 16 and 17 on the other, and 6 and 7 on the third side. We postulate, therefore, that the steric requirements of the steroid-receptor attachment can accommodate 17a-methyl and 17a-ethyl substituents and the attachment of Ha-alkyl group is two-dimensional at the /3-face and in the third dimension as defined above. 

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