## 2 Direct \(\alpha\)-Halogenation of Aryl Ketones
### Metal Halides (MX)
Based on the experimental data, both TBHP and H\({}_{2}\)O\({}_{2}\) had similar bromination efficiency. Ring bromination instead of \(\alpha\)-bromination exclusively occurred for OH-substituted ketones, highlighting this routes' selectivity issues. DMSO was also shown to be an effective oxidant in the HBr-mediated bromination of ketones (Scheme 37) [100]. However, the substrate scope was again limited, making it difficult to evaluate the system's efficacy and overall applicability. An alternative HBr-based bromination was reported by [PERSON] and co-workers [101], which made use of Cu(NO\({}_{3}\))\({}_{2}\) (0.5 equiv.) and molecular oxygen to mediate the halogenation. Although the scope is not very broad, the bromination yields were quite good (83-94%). In most cases, dibromination of the substrate was observed, which again complicates purification. The electrochemical \(\alpha\)-bromination of aryl ketones was also reported by [PERSON] and co-workers [102]. HBr was added to the ketone in acetonitrile in an undivided electrolytic cell containing two Pt electrodes (Scheme 38). A variety of aryl ketones were brominated in good to excellent yields. This method's fine control over the experimental conditions through its set-up is quite intriguing. Despite the acidic conditions, the presence of acid-sensitive functional groups (i.e., OH) was well tolerated. In addition, this route showed excellent selectivity, as only monochrominated products were observed. In 2008, a photocatalytic flavin-based method was developed for the chlorination of arenes and aromatic ketones [103]. Halogenases, enzymes catalysing the chlorination of aromatic compounds, provided the inspiration for this catalytic system. Stirring a solution of riboflavin tetraacetate (RFT), methoxy benzyl alcohol (MBA) and HCl in acetonitrile under visible light irradiation, afforded a range of chlorinated arenes. \(\alpha\)-chwhen phenylethanolamine was used, generating the desired \(\alpha\)-bromoketone (Scheme 39). The authors claimed that, under these conditions, the peroxide concentration was kept consistently low, preventing undesired polychlorination of the substrates. Despite the moderate chlorination yields, this route stands out as it is the only catalytic direct halogenation route to date, that mimics an enzymatic process. ILs are generally considered better alternatives to typical organic solvents as reaction media [104], mainly due to their recyclability and the subsequent ease in product isolation, as biphasic systems can be readily designed. In 2013, [PERSON] and [PERSON] developed an ethylammonium nitrate ([EtNH3+][NO3-])- and HX-mediated bromination and chlorination, yielding a variety of ring halogenated arenes. Under these conditions, the \(\alpha\)-bromoketone was exclusively obtained in 90% yield upon addition of HBr and [EtNH3+][NO3-] to 1-phenylethanolamine (Scheme 40). However, the recurring problem of ring bromination was observed for the \(p\)-OMe substituted phenylethanolamine. Another ring halogenation carried out in an IL was reported by [PERSON] and co-workers [105]. Herein, the role of 3-methylimidazolium nitrate ([Hmim][NO3]) was shown to be twofold; it acts as a co-solvent and promotor of the halogenation (Figure 6). At this point, it is widely believed that the use of ILs in these reactions will always involve some sort of IL-based activation role. Under these conditions, aryl ketones showed exclusive \(\alpha\)-chlorination. 2-Bromo-1-phenylethanolamine was isolated in 90% yield when the IL (2 equiv.) and an aqueous HCl solution (1 equiv.) were added to the corresponding ketone. Recycling experiments demonstrated that the IL could be reused in four successive runs without a significant loss in activity. The scope was limited to one aryl ketone, which again makes it difficult to assess this route's applicability.