Steric effects state

The solubility of a compound is thus affected by many factors the state of the solute, the relative aromatic and aliphatic degree of the molecules, the size and shape of the molecules, the polarity of the molecule, steric effects, and the ability of some groups to participate in hydrogen bonding. In order to predict solubility accurately, all these factors correlated with solubility should be represented numerically by descriptors derived from the structure of the molecule or from experimental observations. 

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). 

Rate IS governed by stability of car bocation that is formed in loniza tion step Tertiary alkyl halides can react only by the SnI mechanism they never react by the Sn2 mecha nism (Section 8 9) Rate IS governed by steric effects (crowding in transition state) Methyl and primary alkyl halides can react only by the Sn2 mecha nism they never react by the SnI mechanism (Section 8 6)... 

The way out of this dilemma is easily stated, although not easily acted upon. It is not adequate to consider any one of these approaches for the explanation of something as complicated as these reactions. Polarity effects and resonance are both operative, and, if these still fall short of explaining all observations, there is another old standby to fall back on steric effects. 

The importance of steric effects in determining the oxidation state of the product can be illustrated by a thioether linkage, eg (57). If a methyl group is forced to be adjacent to the sulfur bond, the planarity required for efficient electron donation by unshared electrons is prevented and oxidation is not observed (48). Similar chemistry is observed in the addition of organic nitrogen and oxygen nucleophiles as well as inorganic anions. 

Lately a third type of transition state has been favored for [2 + 2] cycloadditions forming carbocyclic and heterocyclic four-membered rings. The experimental data on the addition of diarylketenes to arylethylenes are well accommodated by the [ 2s + 2s + 2s] process proposed by Baldwin (70JA4874). The steric effects on the cycloaddition of allenes to ketenes also favor this mechanism (76JA7698). 

Alkyl groups under nonacidic conditions sterically deflect nucleophiles from C, but under acidic conditions this steric effect is to some extent offset by an electronic one the protonated oxirane opens by transition states (Scheme 40) which are even more 5Nl-like than the borderline Sn2 one of the unprotonated oxirane. Thus electronic factors favor cleavage at the more substituted carbon, which can better support a partial positive charge the steric factor is still operative, however, and even under acidic conditions the major product usually results from Cp attack. 

The substituent effects in aromatic electrophilic substitution are dominated by resonance effects. In other systems, stereoelectronic effects or steric effects might be more important. Whatever the nature of the substituent effects, the Hammond postulate insists diat structural discussion of transition states in terms of reactants, intermediates, or products is valid only when their structures and energies are similar. 

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... 

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. 

Nitroalkanes show a related relationship between kinetic acidity and thermodynamic acidity. Additional alkyl substituents on nitromethane retard the rate of proton removal although the equilibrium is more favorable for the more highly substituted derivatives. The alkyl groups have a strong stabilizing effect on the nitronate ion, but unfavorable steric effects are dominant at the transition state for proton removal. As a result, kinetic and thermodynamic acidity show opposite responses to alkyl substitution. 

When this stereoelectronic requirement is combined with a calculation of the steric and angle strain imposed on the transition state, as determined by MM-type calculations, preferences for the exo versus endo modes of cyclization are predicted to be as summarized in Table 12.3. The observed results show the expected qualitative trend. The observed preferences for ring formation are 5 > 6, 6 > 7, and 8 > 7, in agreement with the calculated preferences. The relationship only holds for terminal double bonds. An additional alkyl substituent at either end of the double bond reduces the relative reactivity as a result of a steric effect. 

A which is not observed in individual solutions of the two enones at the same concentrations and may thus be indicative of a complex formation. However, the ratio of isomeric cyclobutane products resulting from such photocycloadditions is generally seen to be a quite sensitive function of steric effects and of the properties of the reaction solvent, of the excited state(s) involved (in some cases two different excited triplet states of the same enone have been found to lead to different adducts) and of the substituents of the excited enone and substrate. No fully satisfactory theory has yet been put forth to draw together all the observations reported thus far. 

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. 

Does this imply that steric effects will be amplified it the transition state, and that the rates of Sn2 reactions wil decrease with increased substitution at carbon ... 

Since equatorial attack is roughly antiperiplanar to two C-C bonds of the cyclic ketone, an extended hypothesis of antiperiplanar attack was proposed39. Since the incipient bond is intrinsically electron deficient, the attack of a nucleophile occurs anti to the best electron-donor bond, with the electron-donor order C—S > C —H > C —C > C—N > C—O. The transition state-stabilizing donor- acceptor interactions are assumed to be more important for the stereochemical outcome of nucleophilic addition reactions than the torsional and steric effects suggested by Felkin. 

With reactive aldehydes an early transition state is probably involved and therefore the steric demands of the aldehyde substituents are not highly influential. On the other hand, with less reactive ketones, the carbon-carbon bond formation is established further along the reaction coordinate, permitting the steric effects to play a greater role in the determination of the transition stale structure. 

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