Steric Effects in Aliphatic Substitution Reactions

When alkyl radicals take part in atom transfer reactions as acceptors 

A conformational effect was detected for the H-transfer reactions from cycloalkanes to a series of attacking radicals. The data of Table 6 show that cyclopentane is generally a better H-donor than cyclohexane. The rate ratio is generally largest for the least reactive radicals because the change in hybridization at transition state 

Bartlett et al.62 on the other hand have found that mainly exo-2-norbornyl halides 28 are obtained from 2-norbornyl radicals 27 and halogen transfer agents. 

The product ratio of exo-halide 28 and endo-isomer 29 was largest for large halogen transfer agents XY. XY apparently approaches 2 7 preferentially from the less shielded exo-side. The torsional effect57 discussed before is probably also of importance. Similar results were obtained more recently for the transfer of hydroxy groups from peracids to 2763.  

Product distribution of chlorinations with N-chloro-diisopropylamine 

A conformational effect was detected for the H-transfer reactions from cyclo- 

X- Cl- CCI4,0 °C f-ButO -CCI4, 0 °C CgHs- -ccia CH3CN, 75 °C BrCCl3-CCl4,75 °C Br CH3CN. 75 °C 

The well known difference in reactivity in transfer reactions of primary, secondary and tertiary hydrogens is most probably neither due to steric acceleration nor to a difference in electronic stability of primary, secondary and tertiary radicals  

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The selectivity for reaction at the less hindered carbon results from steric effects. The selectivity for reaction at a phenyl-substituted carbon of an aziridine has been proposed to result from coordination of the catalyst to the phenyl ring, but computational studies imply that the catalyst coordinates to the aziridine nitrpgen7 In any case, oxidative additions that cleave benzylic C-X bonds are generally favored over oxidative additions that cleave aliphatic C-X bonds, and the preferential insertion of CO into the phenyl-substituted C-N bond of the aziridine is consistent with this general trend. 

In the 1950s Taft devised a method of extending linear free-energy relationships to aliphatic systems.16 He suggested that, since the electronic nature of substituents has little effect on the rate of acid-catalyzed hydrolysis of meta- or para-substituted benzoates (p values are near 0, see Table 2.3), the electronic nature of substituents will also have littie effect on acid-catalyzed hydrolysis of aliphatic esters. All rate changes due to substituents in the latter reactions are, therefore, probably due to steric factors.17 Taft defined Es, a steric substituent constant, by Equation 2.16... 

Reaction with Nitrogen Nucleophiles. The acid-catalyzed reaction of primary, secondary, and tertiary amines with ethyleneimine yields asymmetrically substituted ethylenediamines (71). Steric effects dominate basicity in the relative reactivity of various amines in the ring-opening reaction with ethyleneimine (72). The use of carbon dioxide as catalyst in the aminoethylation of aliphatic amines, for which a patent application has been filed (73), has two advantages. First, the corrosive salts produced when mineral acids are used as catalysts (74,75) are no longer formed, and second, the reaction proceeds with good yields under atmospheric pressure. 

Several catalysts have been found for the ring opening of epoxides. For instance, cyclohexene oxide gave an excellent yield of the trans-fi-amino alcohol when treated with either aromatic or aliphatic amines in the presence of a scandium triflate catalyst.21 Aromatic epoxides react in a regiospeciflc reaction at the benzylic carbon when treated with aromatic amines and scandium triflate but at the least substituted carbon of the epoxide ring when aliphatic amines react. Electronic effects are more important in the reactions of the aromatic epoxides whereas steric factors control the reaction with aliphatic epoxides. 

In general terms, both steric effects and electronic factors are expected to play a role in determinating the reactivity of square-planar platinum complexes. The presence of planar amine ligands in cis- or /ran.y-Pt(anion )2 complexes and their orientation with respect to the coordination plane, as well as their substituents, can reduce the rates of DNA binding or thio binding compared to aliphatic ammine and amine complexes. Especially, substituents close to the coordination site should be expected to slow down axial substitution reactions at Pt. As there is now little doubt that DNA platina-tion is a key event (or THE key event) in the mechanism of action of platinum anticancer drugs, attention to the process of formation of the major adduct (GG) as an intrastrand cross-link between N(7) atoms of two adjacent guanine (G) residues, will remain important. 

The nucleophilic substitution of the reactive chlorine atoms in hexa- and dichloride clathrochelates by a series of aliphatic amines is very sensitive to the effects of the medium (primary, the solvent employed), and the trend of the reaction is determined to a great extent by the donor properties of the amines and the steric accessibility of the nucleophilic centre. The subsequent substitution reaction course and feasible reaction products in the case of hexachloride precursors are presented in Scheme 24. The stepwise-formed clathrochelate complexes are denoted according to the degree of the substitution of chlorine atoms by amine groups ... 

Different chlorine-substituted fragments in partially substituted complexes have similar reactivities, and the direction of the reaction is not determined by the electron density on the carbon atoms (i.e., their electrophilic properties) but by more specific effects an intramolecular activation via hydrogen bonds in the case of sterically unhindered primary amines and sterical hindrances in the case of secondary and sterically hindered primary amines. The reaction with sterically unhindered primary amines occurs via the route An through the substitution of a halogen atom from an already monofunctionalized fragment. In the case of secondary and sterically hindered primary aliphatic amines, the reaction proceeds via the route Bn with sterically controlled substitution. 

This reaction was done with a variety of substituted aromatic and aUphalic carboxylic acids and aldehydes. Unlike the aromatic aldehydes that produced the corresponding products in high purity and good yields, reactions with aliphatic aldehydes produced several unidentified substances together with the desired a-(acyloxy)carboxamide products. In the case of ketones, cyclohexanone was successfully included into this 3-CC process and gave the corresponding products in reasonable yield, but attempts to use acetophenone as the carbonyl substrate failed. The inactivity of the acetophenone in this reaction may be due to the steric effect of the relatively bulky phenyl group. 

The factor 2.48 puts a on the same scale as Hammett s er, and the k0 values are rate constants for acid and base hydrolysis of acetic acid esters (i.e., R is a methyl group in the reference compound). Usually R is an ethyl or methyl group, but in many cases the rate constants do not depend on the nature of R. Equation 8 is based on the fact that acid hydrolysis rates of substituted benzoic acid esters are only slightly affected by the nature of the substituent, but acid hydrolysis rates of aliphatic esters are strongly affected by substituents. These effects were taken to be caused by steric factors thus log(/c//c0)acid defines s. It is reasonable to assume that steric factors affect base-catalyzed rates in the same way. Substituent effects on base hydrolysis of aliphatic compounds are composed of both polar and steric effects, and subtraction of the latter yields a measure of the former. The parameter a is important because it allows one to evaluate substituent effects on aliphatic reaction rates by a formula analogous to the Hammett equation, or by a bivariate relationship, the Taft-Pavelich equation (Pavelich and Taft, 1957) ... 

To put this working hypothesis on a more quantitative basis aromatic nucleophihc substitutions with azide as a nucleophile were tested for catalytic effects with 24 and 25. The corresponding transition states are even more delocalized than their aliphatic counterparts and thus higher rate augmentations should be expected. All or part of this favourable effect, however, can be anihilated due to an unfavourable activation entropy because the formation of the large transition state may suffer from the severe steric restrictions in the cavity of the host. As a corollary it was no surprise to find that the smaller tricyclic host 24 inhibited the substitution of 39 with azide in aqueous methanol The same reaction experienced a big rate acceleration in the... 

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