Probing Intramolecular Electron Transfer in Redox Tag Processes

Article abstract of DOI:10.1021/acs.orglett.9b02808

Herein, we show that redox tag-guided intermolecular formal [2 + 2] cycloaddition can be used as a probe to investigate intramolecular single-electron transfer (SET) mechanisms. The efficacy of intramolecular SET can be evaluated in association with concomitant carbon-carbon bond formation and/or cleavage, leading to cycloaddition or cross-metathesis. Experimental and theoretical results suggest that the intramolecular SET is under both thermodynamic and kinetic control and can also occur through bonds, not only through space.

Full text of DOI:10.1021/acs.orglett.9b02808

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Probing Intramolecular Electron Transfer in Redox Tag Processes
Naoya Maeta, Hidehiro Kamiya, and Yohei Okada*
Department of Chemical Engineering, Tokyo University of Agriculture and Technology, 2-24-16 Naka-cho, Koganei, Tokyo
184-8588, Japan
S
* Supporting Information
ABSTRACT: Herein, we show that redox tag-guided
intermolecular formal [2 + 2] cycloaddition can be used as
a probe to investigate intramolecular single-electron transfer
(SET) mechanisms. The efficacy of intramolecular SET can be
evaluated in association with concomitant carbon−carbon
bond formation and/or cleavage, leading to cycloaddition or
cross-metathesis. Experimental and theoretical results suggest
that the intramolecular SET is under both thermodynamic and
kinetic control and can also occur through bonds, not only
through space.
he electron has recently been recognized as an environ-
form the first carbon−carbon bond (Figure 1). The resulting
Tmentally sustainable catalyst and redox reagent in the transient cyclobutyl radical cation (C•+) is immediately
field of synthetic organic chemistry.1 The addition or removal
of an electron serves as an exceptionally simple mode for small
molecule activation. Reductive or oxidative single electron
transfer (SET) can produce radical ions from neutral closed-
shell molecules to provide distinctive open-shell reactivity
together with the charge, enabling transformations that are
otherwise difficult to achieve. Subsequent protonation or
deprotonation of radical ions can generate neutral radicals as
well, offering further unique reactivity that is complementary to
polarity-driven two-electron pathways.2 Electrochemical3 and
photochemical4 approaches have proven to be highly beneficial
in this field to induce SET under mild conditions. Under-
standing SET mechanisms is a prerequisite to the design of
novel radical (ion) reactions.
Intermolecular SET can be regarded simply as a reductive or
oxidative process where either the highest occupied molecular
orbital (HOMO) or the lowest unoccupied molecular orbital
(LUMO) is engaged. Although the importance of intra-
molecular SET in the field of synthetic organic chemistry has
been noted by Moeller,5 MacMillan,6 and Melchiorre,7
Figure 1. Oxidative SET-triggered cycloaddition and cross-meta-
understanding the mechanism has been rather elusive since it
is a net redox-neutral process that occurs in a closed system.
Having an experimental or theoretical basis for intramolecular
SET would expand the application of radical (ion) reactions in
this field.
We have been developing oxidative SET-triggered radical
cation reactions by electrocatalysis8 and photocatalysis9 in
lithium perchlorate (LiClO4)/nitromethane (CH3NO2) sol-
ution.10 Carbon−carbon bond formation involving an alkenyl
radical cation is facilitated by the LiClO4/CH3NO2 solution,
where the trapping thereof by unactivated alkenes is made
possible. For example, the enol ether radical cation (1•+)
produced by an oxidative SET is trapped by 1-hexene (2) to
thesis.
transformed into an aryl radical cation (A•+) by an intra-
molecular SET with a concomitant second carbon−carbon
bond formation (i.e., ring closure), affording the cycloadduct
(3) by reductive SET. This mechanistic understanding is
supported both experimentally and theoretically. When the
enol ether (4), which has a nonsubstituted phenyl ring, is used
instead, the synthetic outcome is switched from cycloaddition
Received: August 8, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02808
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
to cross-metathesis (5).11 This observation suggests that the
first carbon−carbon bond formation takes place, but it is not
followed by an intramolecular SET and instead leads to
carbon−carbon bond cleavage. DFT calculations have also
shown significant shifts of spin density and positive charge in
relation to the second carbon−carbon bond formation, which
agrees with the formal intramolecular SET mechanism.12 We
questioned whether these synthetic outcomes can be used as
probes to further investigate the efficacy of intramolecular SET
(Figure 2). Described herein is our finding that intramolecular
Scheme 1. Synthetic Outcomes of the Reactions of the Enol
Ethers (6−9) with 1-Hexene (2)
a
Figure 2. Current working model.
SET in the redox tag process is under both thermodynamic
and kinetic control and can also occur through bonds, not only
through space.
The present work began with the synthesis of additional enol
ethers (6−9) with alkyl linkers of varied lengths (Figure 3).
a
Reactions were carried out on a 0.20 mmol scale of the enol ethers
(6−9) with 20 equiv of 1-hexene (2) and 100 mg of TiO2 in 4 mL of
1.0 M LiClO4/CH3NO2 using a 15 W UV lamp (365 nm) at rt for 30
min under air.
Figure 3. Structures of the enol ethers (1,4, and 6−9).
The synthetic outcomes of the reactions with 1-hexene (2)
under TiO2 photocatalysis conditions are summarized in
Scheme 1. As expected, the enol ether with the shortest linker
(6) selectively gave the cycloadduct (10) in high yield. When
the enol ether without a methoxy group (7) was used instead,
only the metathesis product (13) was obtained. Previously,
DFT calculations demonstrated that spin densities and positive
charges in the optimized structure of the radical cations (3•+,
15•+) were localized in the aryl ring or cyclobutyl moiety,
respectively (Figure S1).9b,12 This trend was further confirmed
by calculating the radical cations (10•+, 12•+), which suggested
that the aryl radical cation was more stable than the cyclobutyl
radical cation for the radical cattion (10•+) (Figure 4). The
opposite was true for the radical cation (12•+); the cyclobutyl
radical cation was more stable than the aryl radical cation.
These observations indicated that intramolecular SET from the
methoxyphenyl ring to the cyclobutyl radical cation was
thermodynamically favored, while this was not the case for that
from the nonsubstituted phenyl ring. The enol ether with an
Figure 4. Spin density distributions in the radical cations (10•+ and
12•+).
elongated linker (8) was found to be the boundary between
cycloaddition and cross-metathesis. Indeed, the enol ether (9)
selectively gave the metathesis product (19). DFT calculations
for the radical cations (16•+, 18•+) showed that spin densities
in the optimized structures were localized in the methox-
yphenyl rings, suggesting that intramolecular SET is
thermodynamically favored, which disagrees with the synthetic
outcomes (Figure 5). Therefore, it can be rationalized that
intramolecular SET is kinetically disfavored.
To gain further insight into the intramolecular SET
mechanisms, the enol ethers (20−23) were synthesized
(Figure 6 and Scheme S1). The enol ethers (20, 22) have a
B
DOI: 10.1021/acs.orglett.9b02808
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
synthetic outcomes of the reactions of enol ethers (20−23)
with 1-hexene (2) are summarized in Scheme 2 and Figure S8.
Scheme 2. Synthetic Outcomes of the Reactions of the Enol
Ethers (20−23) with 1-Hexene (2)
Figure 5. Spin density distributions in the radical cations (16•+, 18•+).
Figure 6. Structures of the enol ethers (20−23).
rigid linker, where the aryl ring and enol ether moiety cannot
come close to each other. As controls, the enol ethers (21, 23)
were designed to have flexible linkers with aryl rings of the
same electron densities as those of the enol ethers (20, 22).
Indeed, cyclic voltammetry measurements confirmed that the
oxidation curves for the enol ethers (20, 21) were similar
(Figure 7), and this is also true for the enol ethers (22, 23)
The enol ethers with methoxyphenyl rings (20, 21) selectively
gave the cycloadducts (24, 28), while the metathesis products
(25, 29) were hardly obtained. On the other hand, when the
enol ethers without methoxy groups (22, 23) were used
instead, cross-metathesis took place selectively and cyclo-
addition scarcely occurred. These observations confirm that
intramolecular SET from the methoxyphenyl ring to the
cyclobutyl radical cation is indeed crucial for ring closure and
suggest that the flexibility of the linker that tethers the electron
donor (i.e., methoxyphenyl ring) and the electron acceptor
(i.e., cyclobutyl radical cation) has a negligible impact on the
efficacy of intramolecular SET. Taken together, it is fair to say
that intramolecular SET can also take place through bonds, not
only through space.
In conclusion, we have demonstrated that redox tag-guided
intermolecular formal [2 + 2] cycloaddition can be used as a
probe to investigate intramolecular SET mechanisms. The
synthetic outcomes, cycloaddition, and cross-metathesis are
directly reflected by the efficacy of intramolecular SET, which
is under both thermodynamic and kinetic control. The use of
enol ethers with rigid linkers indicates that intramolecular SET
in the redox tag processes can also occur through bonds, not
only through space. We believe that understanding SET
mechanisms will inform the design of novel radical (ion)
reactions. Further experimental and theoretical studies of
reactions involving intramolecular SET are under investigation
in our laboratory.
Figure 7. Cyclic voltammograms of the enol ethers (20, 21) (2 mM)
recorded in 1.0 M LiClO4/CH3NO2 at 50 mV/s.
(Figure 8). Furthermore, DFT calculations showed that the
distributions of the HOMO and spin densities resembled the
respective optimized structures (Figures S2−S7). The
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02808.
Additional schemes and figures, Cartesian coordinates of
all optimized structures, general remarks, and synthesis
1
and characterization data, including copies of H and
13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Figure 8. Cyclic Voltammograms of the Enol Ethers (22, 23) (2 mM)
recorded in 1.0 M LiClO4/CH3NO2 at 50 mV/s.
*E-mail: yokada@cc.tuat.ac.jp.
C
DOI: 10.1021/acs.orglett.9b02808
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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Yohei Okada: 0000-0002-4353-1595
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported in part by JSPS KAKENHI Grant
Nos. 16H06193, 17K19221 (to Y.O.) and 16H02413 (to
H.K.).
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DOI: 10.1021/acs.orglett.9b02808
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