Steric Effects of Substituents

Taft pursued the separation of steric and electronic effects of substituents by introducing a substituent constant that describes the effect of a nearby substituent on the rate of reaction of a compound, specifically the effect of the R substituent on the rate of hydrolysis of an ester, RCH2C02R. By assuming no electronic effect of substituents on the acid-catalyzed hydrolysis of esters, values are calculated directly from this rate [equation (3.6)]. 

Ef values correct values for the possibility of hyperconjugation. In this equation [equation (3.7)], n represents the number of a-hydrogen atoms. 

Although Es and Ef values describe steric hindrance of a substituent to the attack of a reagent on a nearby group, they do not necessarily describe the steric hindrance of a substituent to the binding of a substance to a biomolecule. 

Taft recognized that the substituent effects in some reactions required both electronic and steric factors [equation (3.8)]. 

It is this separation of electronic and steric effects that prompted the Pomona group to propose that a substituent constant for hydrophobicity should be included for biological QSAR.  

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The amino group activates the thiazole ring toward electrophilic centers. This point is illustrated by the rate constants of the reaction between 2-dialkylaminothiazoles (32) and methyl iodide in nitromethane at 25 C (Scheme 23) (158). The steric effects of substituents on nitrogen are... 

The quatemization reaction of the thiazole nitrogen has been used to evaluate the steric effect of substituents in heterocyclic compounds since thiazole and its alkyl derivatives are good models for such study. In fact, substituents in the 2- and 4-positions of the ring only interact through their steric effects (inductive and resonance effects were constant in the studied series). The thiazole ring is planar, and the geometries of the ground and transition states are identical. Finally, the 2- and 4-positions have been shown to be different (259. 260). 

The shade may be varied by choosing amines. For aromatic amines, the steric effect of substituents in the ortho position reduces the conjugation of the anibno group with the anthraquinone moiety, and the result is a hypsochromic shift and brighter shade. Thus Cl Acid Blue 129 (120) has a more reddish and brighter shade than Cl Acid Blue 25 (118). Cycloalkylamines have a similat effect on the shade. Cl Acid Blue 62 [5617-28-7] (125) Cl 62045) is an example. 

Studies of the alkylation of indazoles (67HC(22)1) have been updated by Nunn (73JCS(PD2371) and Palmer (75JCS(P1)1695). The ratio of methylation at positions 1 and 2 is relatively sensitive to the steric effect of substituents at positions 3 and 7 as shown by the results obtained in basic medium for unsubstituted indazole (55 45) and its 3-phenyl (74 26) and7-nitro derivatives (29 71). 

We will discuss shortly the most important structure-reactivity features of the E2, El, and Elcb mechanisms. The variable transition state theoiy allows discussion of reactions proceeding through transition states of intermediate character in terms of the limiting mechanistic types. The most important structural features to be considered in such a discussion are (1) the nature of the leaving group, (2) the nature of the base, (3) electronic and steric effects of substituents in the reactant molecule, and (4) solvent effects. 

Correlations with o in carboxylic acid derivative reactions have been most successful for variations in the acyl portion, R in RCOX. Variation in the alkyl portion of esters, R in RCOOR, has not led to many good correlations, although use of relative rates of alkaline and acidic reactions, as in the defining relation, can generate linear correlations. The failure to achieve satisfactory correlations with cr for such substrates may be a consequence of the different steric effects of substituents in the acyl and alkyl locations. It has been shown that solvolysis rates of some acetates are related to the pA", of the leaving group, that is, of the parent alcohol. The pK of alcohols has been correlated with but this relationship... 

Upon formulating these relationships, phenols with branched alkyl substituents were not included in the data of a-cyclodextrin systems, though they were included in (3-cyclodextrin systems. In all the above equations, the n term was statistically significant at the 99.5 % level of confidence, indicating that the hydrophobic interaction plays a decisive role in the complexation of cyclodextrin with phenols. The Ibrnch term was statistically significant at the 99.5% level of confidence for (3-cyclo-dextrin complexes with m- and p-substituted phenols. The stability of the complexes increases with an increasing number of branches in substituents. This was ascribed to the attractive van der Waals interaction due to the close fitness of the branched substituents to the (3-cyclodextrin cavity. The steric effect of substituents was also observed for a-cyclodextrin complexes with p-substituted phenols (Eq. 22). In this case, the B parameter was used in place of Ibmch, since no phenol with a branched... 

The electronic and steric effects of substituents on cyclopentadienyl ligands that affect the activity of the catalyst have been extensively and intensively... 

The initially obtained product undergoes isomerization and then the addition of phenyl azide to the phosphorus atom takes place. It is proposed that the oxidative imination does not depend on the steric effects of substituents. Actually, the interaction of 5-phenyl-2,4,6-triisopropyI-1,3,5-dioxaphosphorinane, existing as a mixture of three stereoisomers, gives with phenyl azide a mixture of three stereoisomers of 5-phenyl-5-phenylimino-2,4,6-triisopropyl-l,3,5-dioxaphosphorinane (83IZV2550). 

In conclusion, the regiochemistry of radical attack at dienes appears to be rather predictable by considering steric and electronic effects. Attack is almost always preferred at the terminal carbon atoms of the diene. a-Substituents retard the addition significantly in all known cases while the steric effects of -substituents depend on the nature of the attacking radical. 

Activity is strongly influenced by mutagen functionality and structure, its reactivity, hydrophobicity and the steric effects of substituents. 

Realistic prediction of the mutagenic activities of this class of mutagens requires a physicochemical evaluation of steric effects of substituents and the most widely utilised measures of such are Taft steric parameters, Es (Table 17).204,210... 

They are direct-acting mutagens towards S. typhimurium TA100 with demonstrable ability to react with plasmid DNA at G-N7 or A-N3. The versatile synthetic protocol has enabled us to synthesise and test, reliably, many representatives and establish a working QSAR that has enabled us to understand intimate details of their interaction with bacterial DNA. Their biological activity can be sheeted home to binding to DNA followed, most likely, by an SN2 reaction with G-N7. Electronic and steric effects of substituents are in accord with this mechanism. 

Much of the kinetic data have been obtained with the specific components written in Eq. (4), after which determinations were extended to the generalized compounds RC5H4NO and PR3 to characterize the specific electronic and steric effects of substituents. It was easy to demonstrate that the reaction went to completion by applying 1H- and 31P-NMR spectroscopies. Indeed, the reaction took place so rapidly with the concentrations used (44 mM of each reagent and ImM of catalyst 1) that product formation was complete before the first NMR spectrum could be recorded. 

Nichols, D. E., and Kostuba, L. J. (1979) Steric effects of substituents on phenethylamine hallucinogens. 3,4-(Methylenedioxy)amphetamine analogues alkylated on the dioxole ring. J. Med. Chem., 22 1264-1267. 

Similar results were then found for piperidino-debromination of various nitro-activated five-membered ring heterocycles103. The existence of such linear Hammett plots for ortho-substituted substrates was interpreted as a peculiar feature of five-membered ring heterocycles, where steric effects of substituents ortho to the site of the nucleophilic attack are minimized13. 

In conclusion, the chemistry of atropisomers holds a promising future in providing reactivity data for rotamers and information on molecular interactions that are otherwise not detectable. It is especially promising in that a variety of functional groups can be introduced into the 9-arylfluorene and 9-substituted triptycene systems and thus the electronic as well as steric effects of substituents can be examined. In the past, steric effects on reactivity were almost die sole... 

Steric effects of substituents at the ring ortho position are most evident when comparing the formation of 1 and 12. The quantum yield for formation of 1,... 

Diastereoselectivities in complex systems are determined by conformation of the transition states which are affected by chelation and steric effects of substituents and reaction conditions. For example, the stereochemistry of a hydroxyl group derived from a ketone is determined by coordination of hydroxyl and other functional groups, and depends on the presence or absence of HMPA (Equation (42)). 

We examined whether the steric effect of substituents R of type CR1R2R3 can be expressed in terms of the steric effect of component substituents R1, R2 and R3 using E, parameters. With increasing substitution at the a-carbon, the total steric effect of substituents R has been observed to increase telescopically in such series as Me, Et, i-Pr and t-Bu4). Thus, the simple addition of steric parameters for a-substituents is inadequate to represent the situation. We have found that the E° parameter for 24 primary, secondary and tertiary alkyl groups can be formulated as Eq. 21 by a linear combination of E parameters of component a-substituents 20). 

The variation in activity is governed mainly by the steric effect of substituents within the compounds examined in both series. However, the mode of interactions seems to be different, as revealed by the different steric parameters incorporated. The significance of the Arw in Eq. 52 may be that the meso-substituents interact in such a manner that they come into contact with the receptor surface of walls, whereas that of the AVW in Eq. 53 may indicate the importance or fitting into a cavity or pocket on the receptor surface in the region where the (//-substituents direct. The AVW value for C1(0.0) is nearest to the optimum steric condition (AVW 2 —0.24) calculated from Eq. 53. Thus, (//-Cl substituents in lindane are thought to be those which best fit the receptor cavity among the (//-substituents. 

The disubstituted 4 if-1,2,4-triazole 66 reacts with Mel both at N-l and N-2.175 Given the small steric effects of substituents adjacent to the reactive site in azoles,57, 125 the lack of discrimination between the two sites is not surprising. 

The photochemically induced radical addition of alcohols to enones has been described by Fraser-Reid [104-109]. Here again, the sense of addition depends on the steric effects of substituents, attack anti to the C-5 substituent being preferred [108,110]. Other uses of sugar-derived enones to trap radicals have been reported [111]. Enolone 77 gave interesting results in terms of selectivity [112]. In this instance, radical addition occurs with an equatorial selectivity, whereas cuprate addition occurs with an axial selectivity [9,62]. 

Tolman notes that the high sensitivity of the Ni(0) equilibrium constants to structural modifications of the alkene is due to the low ionization potential of Ni(0) and the resulting small energy separation between the HOMO of the metal and the pi orbital of the alkene. Steric effects of substituents... 

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