Solvent effects bromination

The bromination of 4,5-j -dihydrocortisone acetate in buffered acetic acid does not proceed very cleanly (<70%) and, in an attempt to improve this step in the cortisone synthesis, Holysz ° investigated the use of dimethylformamide (DMF) as a solvent for bromination. Improved yields were obtained (although in retrospect the homogeneity and structural assignments of some products seem questionable.) It was also observed that the combination of certain metal halides, particularly lithium chloride and bromide in hot DMF was specially effective in dehydrobromination of 4-bromodihydrocortisone acetate. Other amide solvents such as dimethylacetamide (DMA) and A-formylpiperidine can be used in place of DMF. It became apparent later that this method of dehydrobromination is also prone to produce isomeric unsaturated ketones. When applied to 2,4-dibromo-3-ketones, a substantial amount of the A -isomer is formed. 

Calo et al. (ref. 5) studied solvent effects on selective bromination of phenol with NBS and found the selectivity of bromination depended on the polarity of the solvents. But thereafter no investigation concerning the solvent effects was reported. We report the effects systematically. 

Most of these results have been obtained in methanol but some of them can be extrapolated to other solvents, if the following solvent effects are considered. Bromine bridging has been shown to be hardly solvent-dependent.2 Therefore, the selectivities related to this feature of bromination intermediates do not significantly depend on the solvent. When the intermediates are carbocations, the stereoselectivity can vary (ref. 23) widely with the solvent (ref. 24), insofar as the conformational equilibrium of these cations is solvent-dependent. Nevertheless, this equilibration can be locked in a nucleophilic solvent when it nucleophilically assists the formation of the intermediate. Therefore, as exemplified in methylstyrene bromination, a carbocation can react 100 % stereoselectivity. 

In these solvents at sufficiently low Br2 concentration (< 10-3 m) the kinetics are first order both in the olefin and in Br2 and the main solvent effect consists of an electrophilic solvation of the departing Br ion. A nucleophilic assistance by hydroxylic solvents has also been recognized recently (ref. 26) (Scheme 10). So far, return during the olefin bromination in methanol had been admitted only for alkylideneadamantanes, and was ascribed to steric inhibition to nucleophilic attack at carbons of the bromonium ion (ref. 26). 

Kinetic data can be discussed in terms of bromine bridging in ionic intermediates if the transition states of the ionization step are late. It appears that this is the case in the bromination of a wide variety of olefins, and in particular of alkenes, stilbenes and styrenes. Large p- and m-values for kinetic substituent and solvent effects (p. 253) consistent with high degrees of charge development at the transition states, are found for the reaction of these compounds. It can therefore be concluded that their transition states closely resemble the ionic intermediates. 

The solvent has no influence on the stereoselectivity of bromine addition to alkenes (Rolston and Yates, 1969b), but it could have some effect on the regioselectivity, since this latter depends not only on polar but also on steric effects. Obviously, it modified the chemoselectivity. For example, in acetic acid Rolston and Yates find that 2-butenes give 98% dibromides and 2% solvent-incorporated products whereas, in methanol with 0.2 m NaBr, dibromide is only about 40% and methoxybromide 60%. There are no extensive data, however, on the solvent effects on the regio- and chemoselectivity which would allow reliable predictions. 

Table 13 Values of p and m for ring-substituent and solvent effects in the bromination of aromatic olefins trans-Ar—C(R)=CHR in methanol at 25°C.

On the other hand, transition-state positions in bromination can be evaluated from solvent effects and their Winstein-Grunwald m-coefficients, since these latter are related mainly to the magnitude of the charge in the activated complexes (p. 274). The p- and m-values for most olefins included either in selectivity relationship A (44) or in B (45) are compared in Table 17. The m-value varies significantly with the reactivity as does p. Since m-variations arise from transition-state shifts, p-variations necessarily come, at least in part, from the same effect. 

Table 17 Selectivity relationships substituent" and solvent effects in bromination of arylolefins as indexes of transition state shifts with reactivity.

In conclusion, bromination is a particularly attractive reaction for studying the origin of reactivity-selectivity effects in detail, since it is now well established that substituent and solvent effects arise not only from changes in the stability of the cationic intermediate but also from transition-state shifts, in agreement with the Bema Hapothle, i.e. RSP, Hammond postulate and Marcus effects. 

Table 19 Substituent and solvent effects in bromination and protonation of styrenes ArCY=CH2. 

Ruasse and Dubois (1984). Rate data for styrenes and a-Me-styrenes (from Durand et al., 1966) and for methoxy- and hydroxystyrenes (from Loudon and Berke, 1974). "Values in parentheses are for bromination in water (Ruasse and Lefebvre, unpublished results). Grunwald-Winstein coefficients for solvent effects. Values in parentheses are for protonation in MeOH (Toullec, 1979 Dubois et al., 1981b). Bronsted exponents. 

Table 20 Solvent effects in alkene bromination dependence of the electrophilic (KSIEs) and nucleophilic assistances (R) on the alkene.

Table 21 Solvent effects in bromination of conjugated olefins transition-state shifts and nucleophilic solvent assistance.

The second series of data on protic solvent effects in bromination that are related to transition states comprises the m-values of solvent-reactivity correlations. First, it is important to underline that 7-parameters, the solvent ionizing powers, established from solvolytic displacements, work fairly well in this electrophilic addition. This is expected since bromination, like SN1 reactions, leads to a cation-anion pair by heterolytic dissociation of the bromine-olefin CTC, a process similar to the ionization of halogenated or ether derivatives (Scheme 14). 

Fig. 15 Reactivity dependence of m, the Winstein-Grunwald coefficients for solvent effects, in the bromination of monosubstituted 1,1-diphenylethylenes (Ruasse and Lefebvre, 1984).

Table 22 Substituent and solvent effects in the bromination of 1,1-diphenylethylenes, DPE, and a-methylstyrenes, a-MS. 1...

According to (57), the main driving force for the reaction in non-protic media is the formation of a tribromide ion from bromine and the developing bromide. Kinetic (Ruasse et al., 1986) and thermodynamic (Bienvenue-Goetz et al., 1980) data on equilibrium (58) are therefore relevant to the effect of non-protic solvents on bromination rates. 

In fact, the analogy between the mechanisms of heterolytic nucleophilic substitutions and electrophilic bromine additions, shown by the similarity of kinetic substituent and solvent effects (Ruasse and Motallebi, 1991), tends to support Brown s conclusion. If cationic intermediates are formed reversibly in solvolysis, analogous bromocations obtained from bromine and an ethylenic compound could also be formed reversibly. Nevertheless, return is a priori less favourable in bromination than in solvolysis because of the charge distribution in the bromocations. Return in bromination implies that the counter-ion, a bromide ion in protic solvents, attacks the bromine atom of the bromonium ion rather than a carbon atom (see [27]). Now, it is known (Galland et al, 1990) that the charge on this bromine atom is very small in bridged intermediates and obviously nil in /f-bromocarbocations [28]. 

Bromination.2 This bromine-crown ether complex, like dioxane-bromine (5, 58), can brominate alkenes, but the stereoselectivity is greater than that with free bromine and is less sensitive to solvent effects. Thus, bromination of trans-ifi-methylstyrene with DBC Br2 occurs exclusively by anti-addition and bromination of dr-/J-methylstyrene occurs by anti-addition to the extent of 95-100%. The bromine complex of polydibenzo-18-crown-63 is a particularly useful reagent because it can be packed as a slurry in a chromatography column. The alkene is then placed on the column and eluted with CC14. 

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