Halogenation thermodynamic control

An irreversible reaction of the intermediate of a redox reaction will greatly facilitate redox catalysis by thermodynamic control. A good example is the reduction of the carbon halogen bond where the irreversible reaction is the cleavage of the carbon halogen bond associated, or concerted, with the first electron transfer -pEe... 

The halogen-metal exchange of one of a geminal pair of bromine atoms is readily achieved -a carbenoid is formed which may have sufficient stability to react as an organolithium before decomposing to a carbene by a-elimination.. m in cyclic systems, diastereoselectivity in this process has long been known,114116 though the outcome of reactions such as that of 137 is under a mixture of kinetic and thermodynamic control.117... 

Prior to the development of tether-directed functionalization methods, regioisomerically pure higher adducts of C50 usually were obtained by additions of transition metal complexes [31-33] or radical halogenations [34, 35]. These reactions either occur under thermodynamic control or lead to the precipitation of the least soluble derivative. Iso-merically pure higher adducts of C o sometimes are also readily isolated out of more complex product mixtures [36]. Tether-directed remote functionalization of CgQ allows the construction of fullerene derivatives with addition patterns that are difficult to obtain by thermodynamically or kinetically controlled reactions with free untethered reagents. Since the description of the first such reaction in 1994 [7], which is the subject of Section 7.3.1, an increasing variety of such regioselective functionalization protocols have... 

Metal/halogen exchange with 2,5-dibromopyridine leads exclusively and efficiently to 2-bromo-5-lithiopyridine in a thermodynamically controlled process it has been suggested that the 2-pyridyl anion is destabilised by electrostatic repulsion between nitrogen lone pair and the adjacent anion " this same factor is probably important in the greater difficulty found in generating 2,3-pyridyne (see section 5.3.2). The example below illustrates the use of the Weinreb amide of formic acid as a formyl-transfer reagent. ... 

A commonly used alternative to the direct bromination of ketones is the halogenation of enol acetates. This can be carried out under basic conditions if necessary. Sodium acetate, pyridine or an epoxide is usually added to buffer the reaction mixture. The direction of enolization is again dependent upon considerations of thermodynamic and kinetic control therefore, the proportion of enol acetates formed can vary markedly with the reaction conditions. Furthermore, halogenation via enol acetates does not necessarily give the same products as direct halogenation of ketones 3. 23... 

Halogenation of steroid 3-ketones can lead to complicated mixtures by virtue of the fact that the kinetic enol leads to 3 halo products, whereas the thermodynamic product is that halogenated at the 4 position. Carefully controlled reaction of the 5a-androstanolone with chlorine thus leads to the 2a-chloro derivative (29). Reaction of that intermediate with O(p-nitrophenyl)-hydroxylamine affords the androgenic agent ni stremine acetate (30). ... 

Similar observations emerge from addition of halogens to butadiene. Thus, low-temperature bromina-tion gives predominantly the 1,2-adduct. At higher temperatures, the 1,4-adduct is the main product, and the mixture from the lower temperature reaction equilibrates to the same product ratio. The 1,4-product is the thermodynamically more stable it has the more-substituted double bond, and the two large bromine atoms are further apart in this isomer. Mechanisms for formation and equilibration of the products can be written as shown, using bromonium cation intermediates. It is perhaps less easy to see why the 1,2-adduct should be the kinetically controlled product, until... 

The radical chain halogenation of alkanes is a well-known process and is even conmercially practised. The thermodynamics of this process are sufficient to allow the chain to progress for Q2 and Brz, but not for iodine. These halogenations are easy to control and the selectivity of ctdorination has been carefully studied. ... 

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