Radical chlorination regioselectivity

Hammond s postulate can be applied to this series of the selectivity-determining steps of the radical chlorination. They all take place via early transition states, i.e. via transition states that are similar to the starting materials. The more stable the resulting radical, the more similar the transition state is to the starting materials. The stability differences between these radicals are therefore manifested only to a very small extent as stability differences between the transition states that lead to them. All transition states are therefore very similar in energy and thus the different reaction rates are very similar. This means that the regioselectivity of the radical chlorination of saturated hydrocarbons is generally low. 

Fig. 1.23. Thermochemical analysis of that propagation step of radical chlorination (left) and bromination (right) of alkanes that determines the regioselectivity of the overall reaction. The AW values were determined experimentally the values for the activation enthalpies (AW ) are estimates.

Also, according to Equation 1.9, the overall reaction radical chlorination takes place on a given substrate considerably faster than the overall reaction radical bromination. If we consider this and the observation from Section 1.7.3, which states that radical chlorinations on a given substrate proceed with considerably lower regioselectivity than radical brominations, we have a good example of the so-called reactivity/selectivity principle. This states that more reactive reagents and reactants are less selective than less reactive ones. So selectivity becomes a measure of reactivity and vice versa. However, the selectivity-determining step of radical chlorination reactions of hydrocarbons takes place near the diffusion-controlled limit. Bromination is considerably slower. Read on. 

Abstraction of hydrogen by chlorine is exothermic, which, according to Hammond s postulate, means that the transition state for H absfracfion by Cl is reached early in the course of the reaction [Figure 8.3(a)]. Therefore, fhe strucfure of the transition state for this step resembles the reactants, namely the alkane and a chlorine atom, not the product radicals. As a result, there is relatively little radical character on carbon in this transition state, and regioselectively in radical chlorination is only slightly influenced by the relative stabilities of radical intermediates. Products are determined more by whether a chlorine atom happens to collide with a 1°, 2°, or 3° H. 

The radical chain mechanism of the sulfochlorination is very similar to that of the chlorination. Accordingly, in normal cases the regioselectivities of the sulfochlorination and the chlorination are equal. For example, (-1) substituents decrease the reactivities of the adjacent C-H bond. This influence can even be observed at the y position. Thus, the consecutive second sulfochlorination affords no geminal or vicinal disulfochlorides in the product. Where there are differences between the regioselectivities of sulfochlorination and chlorination (as in the case of isoalkanes), it is because under the conditions of sulfochlorination, chlorination also takes place to a considerable extent. Figure 6 shows the main components of a sulfochlorination mixture. Today the kinetics and the regioselectivity of the sulfochlorination of /z-alkanes are so well known that the kinetic modeling of the concentration-conversion curves is possible for all partners of the reaction [12]. 

Methyl tricyclo[4.1.0.0 ]heptane-l-carboxylate gives a cation-radical in which the spin density is almost completely localized on C-1 while the positive charge is on C-7. The revealed structural feature of the intermediate cation-radical fairly explains the regioselectivity of N,N-dichlorobenzenesulfonamide addition to the molecular precursor of this cation-radical. In the reaction mentioned, the nucleophilic nitrogen atom of the reactant adds to electrophilic C-7, and the chlorine radical attacks C-1 whose spin population is maximal (Zverev and Vasin 1998, 2000). 

Breslow s template-directed remote oxidation of steroids utilizes an aryl iodide as a template to direct the oxidation of steroid tertiary carbons by the radical relay mechanism, in which a chlorine radical is transferred from a [9-1-2] [PhICl] radical to the iodine atom of the template and then relayed to a geometrically accessible hydrogen atom. This method allows a highly regioselective functionalization of nonactivated carbon atoms of steroids [Eq. (78)] [137,138]. 

The discrepancy from the experimental values is due to the fact that H atoms bound to different types of C atoms are replaced by chlorine at different rates. The substitution of Cfcrt— H takes place via a tertiary radical. The substitution of Csec—H takes place via the somewhat less stable secondary radical, and the substitution of Cprjm—H takes place via even less stable primary radicals (for the stability of radicals, see Table 1.2). According to Hammond s postulate, the rate of formation of these radicals should decrease as the radical s stability decreases. Hydrogen atoms bound to Ctert should thus be substituted more rapidly than H atoms bound to Csec, and these should in turn be substituted by Cl more rapidly than H atoms bound to Cprjm. As the analysis of the regioselectivity of the monochlorination of isopentane carried out by means of Table 1.4 shows, the relative chlorination rates of C —H, C —H, and C. —H are 4.4 33 1, in agreement with this expectation. 

PhICl2 is the chlorinating agent in the novel template directed radical relay process of remote regioselective chlorination of steroids introduced by Breslow. In this method a... 

The reaction starts with excitation of the quinone, followed by intersystem crossing and electron transfer from the thiophene to the triplet excited quinone. The ion radical pair collapses to a biradical which loses a chlorine and a hydrogen atom. Yields are high (65-78%) when R1 = halogen and R2 = H, fair (57%) when R1 = R2 = H and poor (2-17%) when R1 = H and R2 = halogen. The regioselectivity has been explained on the basis of calculated electron densities in the cation radicals of thiophenes. 

Thus, research efforts in different industrial laboratories have been directed toward the preparation of 1-bro-moalkyl alkyl carbonates assumed to be more stable than the 1-iodo derivatives, and more reactive than the parent chloro compounds. For example, 1-bromoethyl ethyl carbonate was made by the halide exchange of 1-chloroethyl ethyl carbonate with LiBr or NaBr, or by a radical type bro-mination of diethyl carbonate (Ref. 82). However, in the case of halide exchange, the conversion is low and a mixture results. Even with a large excess of bromide salt, this problem remains. Radical bromination was found to give unsatisfactory results for the same reasons than the chlorination, and failed in the case of unsymmetrical dialkyl carbonates because of its non-regioselectivity. 

Nikishin, G. I., Troyanskii, E. L, Lazareva, M. I. Regioselective one-step -chlorination of alkanesulfonamides. Preponderance of 1,5-H migration from sulfonyl versus amide moiety in sulfonylamidyl radicals. Tetrahedron Lett. 1985, 26, 3743-3744. 

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