Halonium intermediate

Figure 5. Stylized representation of the reaction of a monoamine halonium intermediate with a l,co-alkenolproceeding to R and S halocyclizedproducts.

The stereocontrolled conversion of (.R)-3-benzyloxymethyl-4-heptadecenoic acid (1) into the halolactone 4 may be interpreted as proceeding via a halonium intermediate 3, which is formed according to the 1,3-allylic strain model 2 and opened via a regio- and stereo-unambiguous SN2 process57. 0 0H... 

The study of gas-phase acid-induced nucleophilic displacement on 2,3-dihalobutanes has provided stereochemical evidence for the occurrence of cyclic chloronium and bromo-nium ions (X = Cl, Br), but not fluoronium ions17. Protonation or methylation of the neutral 2,3-dihalobutane by a suitable acid GA+ produces a halonium intermediate 2, which in the presence of water ultimately leads to the corresponding halohydrin neutral product (Scheme 4). Analysis of these neutral products indicated that the reaction proceeds with retention of configuration when X = Cl, Br and with inversion of configuration when X = F. The results were rationalized by the mechanisms sketched in Scheme 4, namely direct bimolecular nucleophilic displacement by H20 on 2 when X= F and intramolecular nucleophilic displacement to convert 2 into the cyclic halonium ion 3 (with inversion of configuation) followed by bimolecular nucleophilic displacement on 3 (with inversion of configuration) when X = Cl and Br. 

The gas-phase base-induced elimination reaction of halonium ions was thoroughly investigated in radiolytic experiments22. Radiolytically generated acids C/JH5+ (n = 1,2) were allowed to react at 760 Torr with selected 2,3-dihalobutanes to form the halonium intermediates which, in the presence of trimethylamine, undergo base-induced bimolecu-lar elimination as shown in Scheme 6. This elimination reaction occurs in competition with unimolecular nucleophilic displacement to the cyclic halonium ion and subsequent rearrangement. Isolation and identification of the neutral haloalkenes formed and kinetic treatment of the experimental results indicated that 3-halo-1 -butene is formed preferentially with respect to the isomeric 2-halo-2-butenes and that the bimolecular elimination process occurs predominantly via a transition state with an anti configuration22. 

Haloperoxidases have been shown to transform alkenes by a formal addition of hypohalous acid to produce halohydrins. The reaction mechanism of enzymatic halogenatitHi has been debated for some time and it is now accepted that it proceeds via a halonium intermediate [1770, 1771], similar to the chemical formation of halohydrins (Scheme 2.228). The former species is derived from hypohalous acid or molecular halogen, which is in turn produced by the enzyme via oxidation of halide [1772]. In support of this, a HOCl-adduct of Fe -protoporphyrin IX was identified as a direct enzyme-halogen intermediate involved in chloroperoxidase-catalyzed halogenaticHi [1773]. 

Fig. 4.25 The oxidation of 12-halododecanoic acids by atom to the halonium intermediate. This intermediate un-...

Nearly 100% 2inti elimination has been observed for dehydrohalogenation of 2,3-dihalobutanes. In this case, the high specificity is due to the cyclic halonium intermediates, as has been shown by the presence of rapid racemization due to the Br shift (cq. (4)). ... 

Enzymatic reactions " and electrolysis have also been applied in the stereoselective halogenation but are limited to specific substrates. Generally, these approaches are based on the use of an electrophilic halogen source or an anionic halide nucleophile. For the approaches that use electrophilic halogen sources, the formation of a halonium intermediate is the key to stereochemical control. A subsequent nucleophilic attack of the halonium intermediate typically yields a product with an anti-relationship (Scheme 42.1). 

An example of the intermolecular halo-O-functionaliza-tion, which involves the opening of the halonium intermediate with a water molecule, appears in Usami et a/. s synthesis of (+)-pericosine A 26." In Usami et al. s report, the enantioselective formation of bromohydrin intermediate 25 was derived from the enantioenriched cyclohexadiene 24 (Scheme 42.9). (+)-pericosine A 26 has been demonstrated to be an inhibitor of protein kinase epidermal growth factor receptor (EGFR) and human topoisomerase II as well as an antitumor agent against P388 in vivo ... 

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