LETTER RESEARCH
a Diradical geometry
b C–O bonding transition state
METHODS SUMMARY
General procedure for the hydroxylation of arenes. A borosilicate flask was
equipped with a magnetic stir bar, and neat or solid arene (0.2–0.8 mmol) was
added. Addition of hexafluoroisopropanol or trifluoroethanol (2–5 ml) to provide
a 0.2 M solution was followed by the addition of solid phthaloyl peroxide (1,
1.3 equiv.) in portions over 90 s. The reaction flask was placed in a heated oil bath
(23–50 uC). After 3–24 h, the flask was removed from the oil bath and cooled to
ambient temperature (23 uC). The reaction was then concentrated, and under
positive N2 pressure (to avoid potential air oxidation of the phenolic product)
MeOH (3 ml) and saturated aqueous NaHCO3 solution (0.2 ml) were added and
the solution was stirred. After 12 h, the reaction was quenched with phosphate
buffer (5 ml, pH 7.0) and extracted with EtOAc (10ml3 3), and the combined
organic layers were washed with brine (5 ml), dried over Na2SO4 and concen-
trated. The crude material was purified by silica-gel column chromatography to
afford the desired phenolic product. For full experimental details and character-
ization of new compounds, see Supplementary Information.
2.88
3.03
2.01
CASSCF orbitals of two unpaired
electrons in the diradical
Rebound H abstraction step
c
Received 2 November 2012; accepted 7 May 2013.
3.06
1.46
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Figure 6
|
Structures involved in the reverse-rebound mechanism.
a, Diradical geometry and singly occupied orbitals. CASSCF, complete active
space self-consistent field. b, Carbon–oxygen bonding transition state.
c, Rebound hydrogen abstraction step. Distances are given in a¨ngstro¨ms.
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diradical-mediated aromatic C–H oxidation. The direct hydrogen
abstraction to form benzylic radical 2a2H is disfavoured; the corres-
ponding barrier is 5.5 kcal mol21 higher than for the aromatic C–H
functionalization (Fig. 5a). This difference accounts for the aryl select-
ivity under the experimental conditions. By contrast, benzoyloxy radi-
cal D, formed from benzoyl peroxide, reacts with mesitylene (2a) to
give only the benzylic C–H-functionalized product under similar con-
ditions30 (Fig. 5b). The computed activation free energy of the benzylic
hydrogen abstraction by benzoyloxy radical D is 18.9 kcal mol21. In
this case, the two-step aromatic C–H functionalization is disfavoured;
the intermolecular hydrogen abstraction by D from radical intermedi-
ate E becomes rate determining with a much higher overall barrier of
25.8 kcal mol21 (Fig. 5b). This is in agreement with the experimental
fact that benzoyloxy-radical-mediated aromatic C–H oxidation is not
observed.
Although diradical A is predicted to be somewhat more reactive
than radical D, both can be added to the aromatic ring of 2a more
easily than a benzylic hydrogen can be abstracted. With radical D from
benzoyl peroxide, the subsequent bimolecular hydrogen abstraction
from intermediate E has a high barrier, and the reversion to D and 2a
followed by benzylic hydrogen abstraction is favoured. With diradical
A from phthaloyl peroxide, the addition to the aromatic ring is fol-
lowed by an instantaneous intramolecular hydrogen abstraction; the
efficient reverse-rebound mechanism occurs, leading to highly select-
ive aromatic C–H oxidation.
The phthaloyl peroxide (1)-mediated hydroxylation of arenes pro-
vides a new, selective method for the conversions of arenes to phenols.
The hydroxylation procedure is performed under mild conditions
without the use of metallic reagents or strong acids, saving time, cost
and purification steps. Moreover, this methodology possesses broad
functional group compatibility, has excellent selectivity for aromatic
C–H bonds and does not lead to over-oxidation. The tolerance of the
reaction towards a variety of functional groups permits the modifica-
tion of advanced synthetic intermediates. Mechanistic insights into the
reverse-rebound process provide a novel strategy for selective C–H
functionalization and lay the foundation for the discovery of new
chemical transformations using diradicals.
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