Selectivity bromine addition

Halogen-substituted succinimides are a class of products with important appHcations. /V-Bromosuccinimide [128-08-5] mp 176—177°C, is the most important product ia this group, and is prepared by addition of bromine to a cold aqueous solution of succinimide (110,111) or by reaction of succinimide with NaBr02 iu the presence of HBr (112). It is used as a bromination and oxidation agent ia the synthesis of cortisone and other hormones. By its use it is possible to obtain selective bromine substitution at methylene groups adjacent to double bonds without addition reactions to the double bond (113). 

Systematic studies of the selectivity of electrophilic bromine addition to ethylenic bonds are almost inexistent whereas the selectivity of electrophilic bromination of aromatic compounds has been extensively investigated (ref. 1). This surprising difference arises probably from particular features of their reaction mechanisms. Aromatic substitution exhibits only regioselectivity, which is determined by the bromine attack itself, i.e. the selectivity- and rate-determining steps are identical. 

Whereas the three possible selectivities, stereo-, regio- and chemo-selectivity, of bromine addition are determined in steps posterior to the formation of the ionic intermediate. Bromine addition is, therefore, more complex than bromine substitution, as regards the variety of the selectivities and as regards the mechanistic aspects which determine the product formation. 

Finally we mention in this section the non-catalytic selective bromination of aniline by the application of a zeolite pre-loaded with Bt2 as a slow release reagent (ref. 27). Aniline, dissolved in CCI4 was treated with Br2 adsorbed onto various zeolites and zeolite CaA was found to be most selective for monosubstitution (92%). The addition of organic bases improved the performance, probably due to scavenging of HBr. Also the toluidines could be monobrominated with this system with >95% selectivity. 

Since bromine addition to olefins leads to brominated compounds of synthetic interest, there are many studies of bromination products in the literature. Typical examples have been reviewed by Schmid and Garratt (1977). However, there are few systematic product analysis studies related to the role of the structure and the solvent in determining bromination selectivities. 

Analogously, bromine bridging is not the only factor affecting the elimination-nucleophilic trapping ratio. Pre-association with a nucleophilic solvent can explain the increased selectivity towards addition products with respect to elimination products, as observed in bromination of 1,1-diphenylethylene in methanol. 

Another approach in the study of the mechanism and synthetic applications of bromination of alkenes and alkynes involves the use of crystalline bromine-amine complexes such as pyridine hydrobromide perbromide (PyHBts), pyridine dibromide (PyBn), and tetrabutylammonium tribromide (BiMNBn) which show stereochemical differences and improved selectivities for addition to alkenes and alkynes compared to Bn itself.81 The improved selectivity of bromination by PyHBn forms the basis for a synthetically useful procedure for selective monoprotection of the higher alkylated double bond in dienes by bromination (Scheme 42).80 The less-alkylated double bonds in dienes can be selectively monoprotected by tetrabromination followed by monodeprotection at the higher alkylated double bond by controlled-potential electrolysis (the reduction potential of vicinal dibromides is shifted to more anodic values with increasing alkylation Scheme 42).80 The question of which diastereotopic face in chiral allylic alcohols reacts with bromine has been probed by Midland and Halterman as part of a stereoselective synthesis of bromo epoxides (Scheme 43).82... 

The chemoselectivity of olefin bromination is reported84 to occur after the attack of the bromine on the double bond, but the formation of the bromonium ion is the slow step of the reaction. As a consequence, the distribution of products and the selectivity of addition of nucleophiles can hardly be explained by substituent effects (both steric and electronic) bonded to the C=C double bond in a fast step of the reaction. 

Since Condon s original application, this procedure has been extended to many additional reactions. Highly successful treatments of the rates of reaction of the polymethylbenzenes were observed for mercuration (Brown and McGary, 1955c), bromination (Brown and Stock, 1957a), chlorination (Brown and Stock, 1957b Baciocchi and Illuminati, 1958) and protodesilylation (Eaborn and Moore, 1959). A comparison of two sets of calculated and experimental relative rates is presented for selective bromination and non-selective mercuration in Table 28. 

The additivity treatment also allows one to evaluate the influence of substituents which are otherwise obtainable only with difficulty. The study of the non-catalytic bromination of the halo-substituted poly-methylbenzenes by Illuminati and Marino (1956) allowed the evaluation of the partial rate factors for the highly deactivating m- and p-halogens. These data for the slow, highly selective bromination are inaccessible by other techniques. Analysis of the relative rates is made by application of the additivity equations (5) and (6) as described in Section I. An important aspect of the chemistry of the substituted polymethyl-benzenes, in contrast to the monosubstituted benzenes, is the large difference in p for bromination. The partial rate factors derived for each reaction are correlated with good precision by the tr4 -constants (Figs. 11 and 19). Yet the susceptibility of the reactions to the influence of substituents is altered by more than 25%. As already noted, this aspect of the problem is not well defined and is worthy of additional attention. 

The nitration of isoquinoline also occurs predominantly at the 5- and 8-positions and may be achieved in tandem with bromination to give access to bromonitroisoquinolines in a one-pot procedure <20050S98>. Isoquinoline is selectively brominated at the 5-position using A-bromosuccinimide (NBS) in sulfuric acid and nitration, without isolation of 5-bromoisoquinoline, occurs on addition of potassium nitrate to afford moderate yields of 5-bromo-8-nitroisoquinoline 6 (Equation 3). 

Selective bromine-mediated addition of BOC-protected-guanidine 81 to dihydropyridine 56 occurs across the electron-rich 5,6-alkene to give, after acid deprotection, r-2-amino-l,3a,5,7a-dihydroimidazo[4,5-b]pyridine 82 (Scheme 23). Aminal bond cleavage under basic conditions affords substituted 2-aminoimidazole 83 <2004OL3933>. Replacement of guanidine 81 with urea or thiourea leads, similarly, to 2-aminooxazoles or 2-ami-nothiazoles, respectively however, the yields are considerably lower than that of 82 due to the sensitivity of the ureas to bromine oxidation <2005JOC8208>. 

In addition reactions of bromine to alkenes, Risbood and Ruthven154 have shown that 5A zeolite preadsorbed with bromine can selectively brominate styrene in presence of cyclohexene. By simple alteration of the order of adsorption of reactants to Pentasil zeolites, Smith and Fry155 have been able to add selectively bromine to the double bond of linear alkenes in presence of cyclic and branched alkenes, or to brominate cyclic or branched alkenes in presence of linear ones. An example is shown in equation 9. 

In spite of these uncertainties, however, the utility of the reactivity-selectivity principle has been illustrated for a number of diverse areas of mechanistic interest. Such applications are being extended to other areas as well. For example, Olah has recently studied the mechanism of electrophilic addition to multiple bonds using selectivity data and concluded that the transition states of the bromine addition to alkenes are of a 7r-complex nature (Olah and Hockswender, 1974). Finally the large number of reactivity-selectivity relationships which have been discovered offer considerable experimental support for the various expressions and formulations of the Hammond postulate whose profound effect on modem mechanistic chemistry is now beyond question. 

A thoughtful reader would have noticed that, while plenty of methods are available for the reductive transformation of functionalized moieties into the parent saturated fragments, we have not referred to the reverse synthetic transformations, namely oxidative transformations of the C-H bond in hydrocarbons. This is not a fortuitous omission. The point is that the introduction of functional substituents in an alkane fragment (in a real sequence, not in the course of retrosynthetic analysis) is a problem of formidable complexity. The nature of the difficulty is not the lack of appropriate reactions - they do exist, like the classical homolytic processes, chlorination, nitration, or oxidation. However, as is typical for organic molecules, there are many C-H bonds capable of participating in these reactions in an indiscriminate fashion and the result is a problem of selective functionalization at a chosen site of the saturated hydrocarbon. At the same time, it is comparatively easy to introduce, selectively, an additional functionality at the saturated center, provided some function is already present in the molecule. Examples of this type of non-isohypsic (oxidative) transformation are given by the allylic oxidation of alkenes by Se02 into respective a,/3-unsaturated aldehydes, or a-bromination of ketones or carboxylic acids, as well as allylic bromination of alkenes with NBS (Scheme 2.64). 

The diene-Br2 complex is again in equilibrium with the reagents, and nucleophilic attack at carbon can be carried out either by the bromide of the ammonium bromide ion pair, formed at the moment of the electrophilic attack, or by the less nucleophilic pyridine added in excess in the reaction medium. It is noteworthy that this mechanism is characterized by a rate- and product-limiting nucleophilic step which should be quite insensitive to steric hindrance around the double bond. In agreement with a weak influence of the steric effects, pyridinium perbromide reacts in chloroform and tetrahydrofuran with substituted conjugated and non-conjugated dienes to give selectively (>95%) bromine addition to the more alkylated double bond (equation 44). 

In case of iodine or bromine additions, the deposition of tungsten does not occur at the place where it was evaporated, so hot spots will form by thinning in time, finally resulting in failure of the lamp. Computer calculations have demonstrated that fluorine additions would result in a selective deposition of tungsten directly on the hot spot. However, such additions are not practicable, because they would destroy the glass bulb [7.1]. 

A problem arises at this point how do we brominate the Cs-Cs double bond without brominating the C22-C23 double bond at the same time If we compare the two double bonds, we will see that the Cs-Ce double bond is trisubstituted, while the C22-C23 double bond is disubstituted. To see how this will help us selectively brominate the Cs-Ce double bond, we must look at the mechanism for addition of halogens to alkenes. When a halogen molecule is near a double bond, it becomes polarized ... 

The cavity of crown ethers is not involved in the interaction with Bt2 rather, a bromine-oxygen interaction is at issue. A mixture of dibenzo-18-crown-6 and bromine, when used as a bromine-addition reagent, is completely selective (giving tra 5-addition) for (E)-PhCH=CHMe in a variety of solvents, regardless of solvent polarity, in contrast to the use of bromine alone or of bromine plus pyridine. The implication of this observation is that the bromonium ion (59) is stabilized by the crown ether relative to the open carbo-cation in all solvents, and moreover this stabilization is greater than that found in the ion from the (Z)-isomer, which nevertheless exhibits enhanced stereoselective addition. The... 

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