The Lewis acidic nature of organoboranes (BR3) is well understood and makes them reactive towards nucleophilic species, and their ability to participate in free-radical processes widely expands their synthetic use in 1966 [1]. Trialkylboranes (BR3) can easily undergo bimolecular homolytic substitution (SH2) at the boron atom to generate alkyl radicals (R●) and substitution takes place at the boron atom under the oxygen atmosphere conditions, instead of heat or light for radical generation, is highly desirable in chemical synthesis, particularly for the formation of thermally unstable products. As shown in Scheme 1A. Trialkylboranes readily undergo SH2 reactions because the formation of stronger B–X (e.g. B–O) bonds via substitution is highly exothermic [2]. The BDEs (B–C) of BMe3, BEt3, BnPr3, BiPr3, and BnBu3 range from 344 to 354 kJ mol-1 at 298 K, while their typical auto-oxidation products, B(OH)3, B(OMe)3, and B(OEt)3, have BDEs (B–O) ranging from 519 to 522 kJ mol-1 at 298 K [3].
Scheme 1. Classical radical reactions with trialkyl boranes using BBr3[6].
Halolyses
of cyclopropanes to give 1,3-dihaloalkanes by molecular halogens are also
documented although the reactions commonly suffer from the formation of side
products via electrophilic aromatic halogenations [4]. In contrast, obtaining
products with anti-Markovnikov regioselectivity have been considered as one of
the top challenges in the industry [5].
Researchers a group from China and the US both have now applied this concept of radical
generation using BBr3 as a radical Br donor
for the anti-Markovnikov addition of HBr to cyclopropanes. Halogenation reactions are extremely important in chemical
synthesis, since the resulting halogenated products are ideal precursors for
installing a wide range of functional groups through substitution chemistry.
Typically, halogenations of organic molecules using trihaloboranes has been
attributed to their Lewis acidic nature, but the researchers have now shown
that these reagents can also act as halogen radical donors as shown in Scheme
1b [6].
To establish that the
hydrobromination reactivity was occurring via a radical process rather than a
possible acid-mediated pathway, the researchers conducted a series of control
experiments. They initially envisioned that
BBr3/O2 as a suitable system to generate bromine
radicals, and cyclopropylbenzene (1a)
as the model substrate to capture them. The radical reaction might then be
terminated by another halogen radical from reagents such as N-chlorosuccinimide
or N-iodosuccinimide. Unfortunately, messy mixtures were obtained for all entries.
On the other hand, a simple proton source, H2O, was found to be
effective in terminating the radical species. In the control experiment with
only BBr3 and cyclopropylbenzene the anti-Markovnikov
hydrobrominated product 2a was
obtained in 24% yield, together with the formation of Markovnikov product 3a (trace) and dibrominated
cyclopropane 4a (11%). They reasoned
that the proton source was the trace amount of moisture in commercial BBr3 the solution as shown in Scheme 2.
Scheme 2. Reactions of cyclopropane (1a) with hydrobromic acid[6].
Replacing water with
ethanol as the proton source resulted in a significant drop in reaction efficiency.
In contrast, when using bulkier alcohols such as i-PrOH or t-BuOH and less
nucleophilic alcohols such as CF3CH2OH gave a comparable
performance to that of water. Next, they expanded the substrate scope to other
unactivated cyclopropanes using either water or t-BuOH as the proton source.
Electron-neutral, deficient and sterically bulky substrates gave the desired
anti-Markovnikov products in good yields and regioselectivity.
Figure 1. Reaction mechanism: (A) Plausible reaction pathways. (B) Calculated free the energy profile of the anti-Markovnikov hydrobromination. (C) Potential competing pathways[6].
A series of 1H
and 11B NMR experiments were conducted to gain further insight. A
small amount of 2a-d (9%) was also
detected in the reaction with allylbenzene, attributed to the slow 1,2-hydrogen
shift 54 converting H1 to the
more stable benzylic radical B1. These results suggest that the 1,2-hydrogen
shift between the radical
species H and B should be much slower than the radical protonation (Fig. 1A). A
new proton signal at -2.68 ppm also appeared in the 1H NMR study of
the same sample. The two new signals (25.0 ppm in 11B NMR and - 2.68
ppm in 1H NMR) diminished gradually upon the addition of 1a and the amount of anti-Markovnikov
product 2a increased accordingly.
Upon mixing BBr3 with 1a in the absence of O2 and a
proton source, both 1a and BBr3
were mostly consumed, and a new 11B signal at 64 ppm emerged as a
singlet, which is characteristic of an alkyldihaloborane species. When i-PrOH and
BBr3 were mixed in CD2Cl2 under air, the 11B
signal of BBr3 (39 ppm) peak disappeared
and a new signal at 25.0 ppm emerged. Based on the calculated energy profile,
species A is capable of brominating cyclopropane 1a through a radical mechanism to give B (Fig. 1B). In addition, Mechanistic studies and DFT calculations
demonstrate the importance of O2 in the radical initiation process
(Fig 1C).
Our SNB Team
recommended this research article to help the reader to know about that in the
future, they demonstrate that trihaloboranes, like trialkylboranes, can act as
radical donors for halogenation reactions, allowing for previously unreported
anti-Markovnikov selectivity in the hydrobromination of cyclopropanes. This
radical reactivity could be applied in the future for the halogenation of many
different organic molecules, giving way to new methods to affect selectivity
that cannot be achieved using traditional acid-mediated pathways.
References
1) G. Davies,
et al., Chem. Commun., 298 (1966)
2) C.
Ollivier, et al., Chem. Rev., 101, 3415 (2011).
3) J.
B. Holbrook, et al., Polyhedron., 1, 701 (1982).
4) J.
M. Tanko, et al., Angew. Chem., Int. Ed., 38, 159 (1999).
5) Q. Zhu, et al., J. Am. Chem. Soc., 140, 741 (2018).
6) H. G, Matthew, et al., Chem. Sci., 11, 9426 (2020).
Comments
Post a Comment