Exploring Diradical Chemistry: A Carbon-Centered Radical May Act as either an Anion or Electrophile through an Orbital Isomer

Article abstract of DOI:10.1002/anie.201411334

Diradical intermediates, formed by thermolysis of alkynylcyclobutenones, can display radical, anion, or electrophilic character because of the existence of an orbital isomer with zwitterionic and cyclohexatrienone character. Our realization that water, alcohols, and certain substituents can induce the switch provides new opportunities in synthesis. For example, it can be used to shut down radical pathways and to give access to aryl carbonates and tetrasubstituted quinones.

Full text of DOI:10.1002/anie.201411334

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201411334
German Edition: DOI: 10.1002/ange.201411334
Rearrangements
Exploring Diradical Chemistry: A Carbon-Centered Radical May Act
as either an Anion or Electrophile through an Orbital Isomer**
ThØo P. GonÅalves, Mubina Mohamed, Richard J. Whitby, Helen F. Sneddon, and
David C. Harrowven*
Abstract: Diradical intermediates, formed by thermolysis of
alkynylcyclobutenones, can display radical, anion, or electro-
philic character because of the existence of an orbital isomer
with zwitterionic and cyclohexatrienone character. Our real-
ization that water, alcohols, and certain substituents can induce
the switch provides new opportunities in synthesis. For
example, it can be used to shut down radical pathways and to
give access to aryl carbonates and tetrasubstituted quinones.
I
n the vast majority of pericyclic reactions, the number of
bonds formed is equal to the number of bonds broken such
that the reactivity state of the starting material(s), for
example, anion, radical, closed-shell neutral etc., is mirrored
in the product(s) formed. However, for a small subset of
electrocyclization reactions this generalization does not hold
true, as it is possible for two p-bonds to interact with the
[1]
creation of a single s-bond and two radical centers. This
means of entry into the curious world of diradical chemistry is
[
2]
Scheme 1. A prototypical alkynylcyclobutenone rearrangement showing
the diradical intermediates and their orbital isomers.
typified by the Bergman cyclization, where an enediyne is
transformed into a p-benzyne intermediate through the action
of heat or light.
Many related processes take closed-shell molecules and
transform them into reactive diradical intermediates. These
include the Garratt–Braverman, Hopf, Moore, Myers–
ever, through transfer of an electron from the p-system to the
SOMO in the plane of the s-framework, orbital isomers with
zwitterionic (e.g. 5B) and/or carbenic character (e.g. 6B/C)
[
3]
[4]
[5]
[
6]
[7]
[8]
[9]
Saito, Schreiner–Pascal, Schmittel, and Wang cycliza-
tion reactions. Alabugin et al. have recently summarized the
[
11,12]
can be accessed.
Thus, in principle it is possible for the
[
1]
fascinating chemistry such processes unlock, and pay special
attention to the relationship existing between diradical and
zwitterionic forms of a given intermediate.
carbon-radical center in 5A to display reactivity characteristic
of an anion (5B) or an electrophile (5C), while in 6 it can
additionally exhibit carbene-type character (6C).
[
10]
In Mooreꢀs
thermochemical rearrangement of alkynylcyclobutenones
Herein we demonstrate, for the first time, that all three
modes of reactivity are available to intermediates akin to 5.
Of particular note is a recognition that the nature of the
orbital isomer formed is largely determined by its local
environment and by changing this it is possible to effect
a switch between its diradical (5A) and zwitterionic/cyclo-
hexatrienone (5B/C) forms.
such as 1, two diradical intermediates 5A and 6A can be
[
5]
formed from the transient vinylketene 4 (Scheme 1). How-
[*] Dr. T. P. GonÅalves, Dr. M. Mohamed, Prof. R. J. Whitby,
Prof. D. C. Harrowven
Chemistry, University of Southampton
Highfield, Southampton, SO17 1BJ (UK)
E-mail: dch2@soton.ac.uk
We first became aware of the significance of the zwitter-
ionic orbital isomer 5B during an attempt to use Mooreꢀs
alkynylcyclobutenone rearrangement in target synthesis
Dr. H. F. Sneddon
GlaxoSmithKline
Stevenage, Hertfordshire, SG1 2NY (UK)
[
13]
(Scheme 2). Our plan was to transform the cyclobutenone
into the bicyclic quinone 9 through capture of the aryl
7
[
14]
[
**] Financial support from GlaxoSmithKline, EPSRC (including its
support for the Iridis cluster) and ERDF (IS:CE-Chem and AI-Chem
via InterReg IVa programmes 4061, 4494, and 4196) is gratefully
acknowledged. We also thank Dr. Edmond Lee, Rob Wheeler, and
Dr. Andy Craven and staff at the IRIDIS High Performance
Computing Facility and EPSRC National Service for Computational
Chemistry Software (NSCCS) for their help and support.
radical (11A) by the proximal alkene. Indeed, when a 1,4-
dioxane solution of 7 was heated at 1508C under continuous
flow, the anticipated product 9 was given in modest yield
[15]
(60%) together with the quinone 8 (30%).
Consideration of this outcome led us to wonder if we
could exploit the deuterium-isotope effect to bias the reaction
in favor of cyclization over hydrogen-atom abstraction. We
reasoned that deuterium-atom abstraction from [D]-11A
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201411334.
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modelled the reaction using DFT calculations [at the
[
17,18]
UB3LYP/6-311G(d,p) level].
In line with the work of
[
19]
others, our analysis gave a DE value for the diradical 13A
and it was 4.1 kcalmol lower than that for the zwitterionic
À1
isomer 13B (see Figure 1 and the Supporting Information).
However, when water was included in the calculations the
relative stabilities reversed, with 13B·H O now favored over
2
À1
1
3A + H O by 11.9 kcalmol . Importantly, 13B·H O showed
2
2
no spin contamination, thus confirming its closed-shell
character.
From these and related calculations it was clear that the
availability of two hydrogen bonds between water and 13B
was the trigger for the orbital isomer switch. Calculations also
showed that 13B·H O would collapse to the quinone 14·H O
2
2
through a near spontaneous proton transfer (Figure 1).
Experimentally, we were able to confirm the importance of
hydrogen bonding with the thermolysis of the MOM ether 15
in 1,4-dioxane and 1,4-dioxane containing 1% H O. As
2
Scheme 2. An orbital isomer switch promoted by water (or D O)
diverts the course of the reaction towards the quinone 8 (or [D]-8).
expected, protection of the hydroxy group shut down the
aforementioned proton-transfer relay. As a consequence,
reactions in 1,4-dioxane and aqueous 1,4-dioxane both
proceeded via the diradical intermediate 17A to give
2
[
14d]
would be much slower than hydrogen-atom abstraction from
benzopyran 16 in 70% yield (Scheme 3).
1
1A (kabs), but the rate of cyclization leading to 9 (kcyc) would
Another point of interest revealed by these calculations
relates to the favored geometries of the orbital isomers of 13,
geometries which were markedly different. The diradical
isomer 13A had a near-planar geometry, as expected for an
arene. In contrast, the six-membered ring in 13B and
be unchanged. Thus, it should be possible to increase the yield
of 9 through the simple use of D O as a cosolvent for the
2
[16]
reaction (Scheme 2). The outcome of that experiment was
as unexpected as it was remarkable. Instead of promoting the
radical cyclization pathway, it shut it down! Indeed, the only
product given was [D]-8 in 98% yield upon isolation. A
similar switch to 8 was observed when the thermolysis was
conducted in aqueous 1,4-dioxane.
In the context of radical chemistry these results made no
sense. However, by invoking the zwitterionic orbital isomer
1
13B·H O had a pronounced pucker (Figure 2), thus indicating
2
significant cyclohexatrienone character (13C). From this
observation we concluded that it might be possible for 13 to
act as an electrophile, thus exposing a third mode of reactivity
as yet unrecognized.
To test that hypothesis we examined the reactivity of the
diradical intermediate 19A computationally. Pleasingly, cal-
culations revealed a low-energy cyclization pathway leading
1B, one could envision a rapid O to C proton transfer
catalyzed by water (or D O). To test that hypothesis, we
2
Figure 1. A computational study reveals an orbital isomer switch triggered by water.
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Scheme 4. A computational study predicts the cyclization of the
acetate 19 into zwitterion 20 via a closed-shell transition state.
Scheme 3. Influence of OH protection on the reaction course. MOM=
methoxymethyl.
Scheme 5. Experimental evidence that the closed-shell orbital isomer
of 25 exhibits cyclohexatrieneone character.
Figure 2. Planarity in diradical 13A contrasts with the pronounced
puckering observed for the zwitterion 13B·H O.
2
gave 24 in high yield (Scheme 5). It can also be used to access
catechol carbonates in high yield through the corresponding
Boc ester, for example, 27![29]!30 (Scheme 6). The effi-
ciency of both of these reactions is striking, given that
thermolysis of the free alcohol from which they were derived,
28, yields a 5:4 mixture of the quinone 31 and cyclopentene-
to the zwitterion 20 (Figure 3). Importantly, a puckered,
closed-shell transition state was indicated, consistent with the
reaction proceeding via orbital isomer 19B/C (Scheme 4 and
Figure 3). Experimental evidence for the pathway was
provided by the thermolysis of the alkynylcyclobutenone
[20]
dione 32.
acetate 21 in 1,4-dioxane containing 1% H O, and it led to
In conclusion, our study of the alkynylcyclobutenone
rearrangement has shed new light on the curious world of
diradical chemistry. Our demonstration that the reactive
carbon center in a diradical intermediate may simultaneously
act as a radical, an anion, and an electrophile through its
orbital isomers is especially noteworthy. Similarly, our
realization that water and, by analogy alcohols, can induce
an orbital isomer switch from a diradical intermediate to
a zwitterion is an important finding as it provides new
opportunities in synthesis and helps to explain why many of
these “unimolecular” processes often display a concentration
2
a 1:1 mixture of the acetates 22 and 23 in near quantitative
[
20]
yield (Scheme 5). This unprecedented rearrangement pro-
vided compelling evidence for the intermediacy of the
zwitterion 26 and, by implication, the dual zwitterionic/
cyclohexatrieneone character of the orbital isomer 25B/C.
From a synthetic perspective, the method provides rapid
and efficient access to tetrasubstituted quinones, as saponi-
fication of the crude reaction mixture with NaOH under air
Scheme 6. A new route to catechol carbonates and the influence of alcohol
protection on the course of the reaction. Boc=tert-butoxycarbonyl.
Figure 3. A computational study of the reactivity of the diradical 19A.
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2
Keywords: density functional calculations · flow chemistry ·
radicals · rearrangements · small ring systems
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Received: November 22, 2014
Published online: February 18, 2015
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