Direct steric effects

Tandem intra-intermolecular condensation to give 69 has also been reported. Steric effects direct this process to give predominately one stereochemical relationship for the bonds attached to the five-carbon ring [227]. 

Many aspects of intramolecular nitrile oxide cycloadditions are similar to those of the intermolecular ones. Due to the proximity of the reacting groups, however, there are also several items that differ significantly. While HOMO-LUMO interactions and steric effects direct the intermolecular nitrile oxide cycloaddition to 1-alkenes to produce 5-substituted isoxazolines, the intramolecular cases often show a different behavior. With most of them, regioselectivity is determined by geometric constraints and cycloadditions occur in the exo mode to furnish the annulated bicycle (Scheme 6.42). 

The next reaction shows an example where steric effects direct the nucleophile to the 4-position but epimerization is observed to a small extent56. 

The main purpose of this chapter is to discuss the directing effects of functional groups in these reactions. As one would expect, steric effects direct internal nucleophile addition to the less hindered of the electrophilic centers as in the formation of 49. With a C-1 OMe substituent, a addition has been proposed [235]. Internal nucleophile addition to the less hindered of the electrophilic centers has also been reported for 50 [236]. Other examples give mixtures [237]. On the other hand, 1,4-dimethyl substitution on the tj cydoheptadienyl ligand shows regiocon-trol dominated by the C-1 Me group (y selectivity ipso to the C-4Me group) [229]. 

Electronic and steric effects operate m the same direction Both cause the equilib rium constants for hydration of aldehydes to be greater than those of ketones... 

Resonance effects are the primary influence on orientation and reactivity in electrophilic substitution. The common activating groups in electrophilic aromatic substitution, in approximate order of decreasing effectiveness, are —NR2, —NHR, —NH2, —OH, —OR, —NO, —NHCOR, —OCOR, alkyls, —F, —Cl, —Br, —1, aryls, —CH2COOH, and —CH=CH—COOH. Activating groups are ortho- and para-directing. Mixtures of ortho- and para-isomers are frequently produced the exact proportions are usually a function of steric effects and reaction conditions. 

AT-Oxidation is very sensitive to steric effects, since 1-substituted lumazines and pterins give only 5-oxides and the presence of bulky substituents at position 7 also directs oxidation to N-5. The pteridine 5-oxide (52) and 8-oxide (53) and the 5,8-dioxide (55) contain the AT-oxide groups as such, even when the possibility of AT-hydroxy tautomers exists, as in (53) i(54). 

Alkyl substituents supplement the a-directing effect of the heteroatom and direct the incoming substituent into the 2-position. However, steric effects can result in an increased proportion of 5-substitution. 

A mechanism has been proposed to rationalize the results shown in Figure 23. The relative proportion of the A -pyrazolines obtained by the reduction of pyrazolium salts depends on steric and electronic effects. When all the substituents are alkyl groups, the hydride ion attacks the less hindered carbon atom for example when = Bu only C-5 is attacked. The smaller deuterohydride ion is less sensitive to steric effects and consequently the reaction is less selective (73BSF288). Phenyl substituents, both on the nitrogen atom and on the carbon atoms, direct the hydride attack selectively to one carbon atom and the isolated A -pyrazoline has the C—C double bond conjugated with the phenyl (328 R or R = Ph). Open-chain compounds are always formed during the reduction of pyrazolium salts, becoming predominant in the reduction of amino substituted pyrazoliums. 

The more stable the LUMO, the stronger is the interaction with the HOMO of the approaching nucleophile. The observed (Cram s rule) stereoselectivity is then a combination of stereoelectronic effects ftiat establish a preference for a perpendicular substituent and a steric effect that establishes a preference for the nucleophile to approach from the direction occupied by the smallest substituent. 

Substitution reactions by the ionization mechanism proceed very slowly on a-halo derivatives of ketones, aldehydes, acids, esters, nitriles, and related compounds. As discussed on p. 284, such substituents destabilize a carbocation intermediate. Substitution by the direct displacement mechanism, however, proceed especially readily in these systems. Table S.IS indicates some representative relative rate accelerations. Steric effects be responsible for part of the observed acceleration, since an sfp- caibon, such as in a carbonyl group, will provide less steric resistance to tiie incoming nucleophile than an alkyl group. The major effect is believed to be electronic. The adjacent n-LUMO of the carbonyl group can interact with the electnai density that is built up at the pentacoordinate carbon. This can be described in resonance terminology as a contribution flom an enolate-like stmeture to tiie transition state. In MO terminology,.the low-lying LUMO has a... 

The direction of elimination is also affected by steric effects, and if both the base and die reactant are highly branched, steric factors may lead to preferential removal of the less hindered hydrogen. Thus, when 4-methyl-2-pentyl iodide reacts with very hindered bases such as potassium tricyclohexylmethoxide, there is preferential formation of the... 

The direct formation of a dimethyl ketal by reaction of the ketone with methanol is particularly sensitive to steric effects. Only cyclohexanones react under these conditions.In the steroid series only saturated 3-ketones form dimethyl ketals with methanol and acid although partial reaction of a 2-ketone has been observed in the presence of homogenous rhodium catalyst. ... 

The saturated 3-ketone can also be protected as the ethylene ketal, which is prepared directly by reaction with ethylene glycol or by exchange dioxo-lanation. Selective formation of 3-ethylenedioxy compounds is also possible, but the former method is not particularly effective in the presence of 6-, 17- or 20-ketones. However, the exchange dioxolanation technique is more sensitive to steric effects and good selectivity at C-3 can be achieved in the presence of a 17-ketone, provided the reagent does not contain glycol. ... 

The ortho effect may consist of several components. The normal electronic effect may receive contributions from inductive and resonance factors, just as with tneta and para substituents. There may also be a proximity or field electronic effect that operates directly between the substituent and the reaction site. In addition there may exist a true steric effect, as a result of the space-filling nature of the substituent (itself ultimately an electronic effect). Finally it is possible that non-covalent interactions, such as hydrogen bonding or charge transfer, may take place. The role of the solvent in both the initial state and the transition state may be different in the presence of ortho substitution. Many attempts have been made to separate these several effects. For example. Farthing and Nam defined an ortho substituent constant in the usual way by = log (K/K ) for the ionization of benzoic acids, postulating that includes both electronic and steric components. They assumed that the electronic portion of the ortho effect is identical to the para effect, writing CTe = o-p, and that the steric component is equal to the difference between the total effect and the electronic effect, or cts = cr — cte- They then used a multiple LFER to correlate data for orrAo-substituted reactants. 

From the standpoint of geometrical considerations, the major difference is in the far greater steric requirements of the nitro group. This could result in either primary or secondary steric effects. Nevertheless, primary steric effects do not seem to be necessarily distinguishable by direct kinetic comparison. A classic example is the puzzling similarity of the activation parameters of 2-chloropyrimidine and 2,6-dinitrochlorobenzene (reaction with piperidine in ethanol), which has been described by Chapman and Rees as fortuitous. However, that nitro groups do cause (retarding) primary steric effects has been neatly shown at peri positions in the reaction with alkoxides (see Section IV,C, l,c). 

The scope of heteroaryne or elimination-addition type of substitution in aromatic azines seems likely to be limited by its requirement for a relatively unactivated leaving group, for an adjacent ionizable substituent or hydrogen atom, and for a very strong base. However, reaction via the heteroaryne mechanism may occur more frequently than is presently appreciated. For example, it has been recently shown that in the reaction of 4-chloropyridine with lithium piperidide, at least a small amount of aryne substitution accompanies direct displacement. The ratio of 4- to 3-substitution was 996 4 and, therefore, there was 0.8% or more pyridyne participation. Heteroarynes are undoubtedly subject to orientation and steric effects which frequently lead to the overwhelming predominance of... 

The selective reaction of anionic 3,6-dichloro-4-sulfanilamidopy-ridazine with excess methanolic methoxide at the 3-position is another indication of the absence of major steric effects in most nucleophilic substitutions, as a result of the direction of nucleophilic attack (cf. Section II, A, 1). The selectivity at the 3-position is an example of the interaction of substituent effects. The sulfonamide anion deactivates both the 3-chloro (ortho direct deactivation) and... 

Finally, since besides the inductive effect of the sulfoxide and the sulfone functional groups, hydrogen bonding, field effects and steric effects to solvation may or may not work in the same direction, the pKx values can be useful in assigning configurations of suitable pairs of stereoisomeric sulfoxide and sulfone carboxylic acids291. 

When equation (9) is applied to the transition state of the biphenyl system, it gives directly the isotopic difference in the activation enthalpy per interacting pair of atoms, provided we make the reasonable assumption that initial-state steric effects are independent of isotopic substitution in the 6- and 6 -positions. Since there are two pairs of interacting atoms in the coplanar transition state, the final expression is... 

There are also steric effects. In some cases the direction of elimination is determined by the need to minimize steric interactions in the transition state or to relieve steric interactions in the ground state. 

In addition to the geometric, steric effects which flexibility directly modifles, all intramolecular electronic properties of a flexible molecule are also coupled to molecular structure. In a real material, such properties as molecular dipole. 

---