A Safe and Green Benzylic Radical Bromination Experiment

Abstract

Radical chemistry is an essential part of the organic chemistry curriculum. Free radical halogenation experiments provide an excellent opportunity to introduce important topics related to the outcome and mechanism of organic reactions. In this communication, a green photochemically activated benzylic bromination of p-toluic acid is described. In contrast with previous versions of this reaction, visible light provides the energy necessary to homolytically cleave the BrBr bond and initiate the radical cascade. Thus, photochemical activation allows a safer, faster, and cheaper alternative to chemical free radical initiators. Furthermore, the reaction is conveniently performed in environmentally friendly acetonitrile, as a replacement for toxic and ozone-depleting chlorinated solvents, such as the usual carbon tetrachloride.

Chlorinated Solvents: Their Advantages, Disadvantages, and Alternatives in Organic and Medicinal Chemistry

“…In general, superior selectivity of radical brominations is observed over chlorinations due to the Hammond postulate and also the inverse relationship between selectivity and reactivity . NBS in conjunction with a radical initiator remains the most popular and widespread method for radical bromination of benzylic C–H and allylic C–H groups, i.e., a Wohl–Ziegler type of reaction. − Due to the reactivity of halide radicals, solvents themselves must be unreactive, making solvent choice challenging and promoting CCl 4 to the position of go-to solvent. , CCl 4 was almost exclusively employed by Ziegler in the original studies of this reaction . Benzene is another popular choice, as it generally does not undergo radical attack in the presence of peroxides …”

“…322−324 Due to the reactivity of halide radicals, solvents themselves must be unreactive, making solvent choice challenging and promoting CCl 4 to the position of go-to solvent. 325,326 CCl 4 was almost exclusively employed by Ziegler in the original studies of this reaction. 327 Benzene is another popular choice, as it generally does not undergo radical attack in the presence of peroxides.…”

Photochemical bromination of 2,5-dimethylbenzoic acid as key step of an improved alkyne-functionalized blue box synthesis

“…The photochemical activation of AIBN was previously used to functionalize p-toluic acid, but we are not aware of examples describing the bromination of benzylic positions having a carboxylic acid in the o-position, responsible of the abovementioned problems. [41] Irradiation at 365 nm, where AIBN has an absorption band, afforded a crude reaction mixture where 2 was present as major product, with only traces of other impurities. The bromination was confirmed to be photochemically accessible also in benzene, which however promotes the formation of trisbrominated side product III together with the desired compound 2 with the same 76:24 ratio observed when heating (Table 1).…”

Photochemical Bromination of 2,5‐Dimethylbenzoic Acid as Key Step of an Improved Alkyne‐Functionalized Blue Box Synthesis**

“…The photochemical activation of AIBN was previously used to functionalize p-toluic acid, but we are not aware of examples describing the bromination of benzylic positions having a carboxylic acid in the o-position, responsible of the above-mentioned problems. [32] Irradiation at 365 nm, where AIBN has an absorption band, afforded a crude reaction mixture where 2 was present as major product, with only traces of other impurities. No transformation occurs in the dark (Entry 8, Table 1), confirm- ing that the reactivity is driven by the photochemical activity of AIBN and NBS, which form Br * radicals upon light irradiation.…”