Visible-light unmasking of heterocyclic quinone methide radicals from alkoxyamines

Article abstract of DOI:10.1039/c9cc08261a

In nature, the unmasking of heterocyclic quinones to form stabilized quinone methide radicals is achieved using reductases (bioreduction). Herein, an alternative controllable room-temperature, visible-light activated protocol using alkoxyamines and bis-alkoxyamines is provided. Selective synthetic modification of the bis-alkoxyamine, allowed chromophore deactivation to give one labile alkoxyamine moiety.

Full text of DOI:10.1039/c9cc08261a

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Visible-light unmasking of heterocyclic quinone
methide radicals from alkoxyamines†
Cite this: Chem. Commun., 2019,
55, 14665
a
ab
Patrick Kielty,
Fawaz Aldabbagh
Pau Farras,
`
Patrick McArdle,a Dennis A. Smitha and
ac
Received 21st October 2019,
Accepted 14th November 2019
*
DOI: 10.1039/c9cc08261a
rsc.li/chemcomm
In nature, the unmasking of heterocyclic quinones to form stabilized
quinone methide radicals is achieved using reductases (bioreduction).
Herein, an alternative controllable room-temperature, visible-light
activated protocol using alkoxyamines and bis-alkoxyamines is pro-
vided. Selective synthetic modification of the bis-alkoxyamine, allowed
chromophore deactivation to give one labile alkoxyamine moiety.
Nitroxides are bench-stable free radicals and anti-oxidants with a
broad range of applications. The most widely used is commercial
(2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) with applications
in synthesis and catalysis,1a spin labelling,1b magnetic resonance
imaging (MRI),1c fluorescence,1d electrochemistry,1e high-tech
polymers,1f and radical scavenging.1g Nitroxides mask reactive
carbon-centered radicals in the form of alkoxyamines. Homolysis
of alkoxyamines is traditionally achieved via thermal activation,
which for TEMPO usually requires temperatures above 80 1C
(Scheme 1A).2 The high temperature reversible trapping of
initiator-derived alkyl and polymer radicals by nitroxide, is a
process made popular by controlled/living nitroxide-mediated
polymerization (NMP).3 There are examples of NMP using UV-light
driven photodissociation of alkoxyamines.4 From a biomedical
applications perspective, alkoxyamine activation at or near physio-
logical temperature is essential. Low or ambient temperature
activation using UV/visible-light has been reported using alkoxy-
amine derivatives of 4-hydroxy-TEMPO (4-OH-TEMPO),4c,5 including
XEt-TEMPOX.5c Guillaneuf and co-workers coupled benzylic deriva-
tives of naphthalene, benzophenone, coumarin, anthraquinone and
Scheme 1 (A) Literature alkoxyamines (B) DFT-predicted controllable
unmasking of heterocyclic quinone methide radicals using visible-light.
pyrene with 4-OH-TEMPO to give a series of UV/visible-light sensitive alkoxyamines (including the silylated TEMPO derivative).5b For
reported light-sensitive alkoxyamines,4c,5 the formation of thermo-
dynamically stabilized benzylic radicals promotes the loss of TEMPO.
Comparably, the generation of a quinone methide drives enzymatic
a School of Chemistry, National University of Ireland Galway, University Road,
Galway, H91 TK33, Ireland
b Energy Research Centre, Ryan Institute, National University of Ireland Galway,
bioreduction of mitomycin C (MMC) to allow aziridinyl ring-opening
and elimination of the carbamate functionality to give reactive sites
for cross-linking with DNA.6 Benzimidazolequinone anti-tumor alter-
natives to MMC have been designed as prodrugs to form quinone
methide upon bioreduction,7 or with adjustment of pH.8 Herein, we
introduce heterocyclic benzimidazolequinone-based alkoxyamines;
the simplest is TEMPO-Vis, where visible-light activated homolysis is
University Road, Galway, H91 CF50, Ireland
c Department of Pharmacy, School of Life Sciences, Pharmacy and Chemistry,
Kingston University, Penrhyn Road, Kingston upon Thames, KT1 2EE, UK.
E-mail: f.aldabbagh@kingston.ac.uk
† Electronic supplementary information (ESI) available: Supporting figures and
tables, experimental procedures and NMR spectra. CCDC 1948448. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c9cc08261a
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driven by the formation of a quinone methide-type radical (QM-rad),
To investigate the necessity in Bis-TEMPO-Vis of the benzimi-
stabilized by resonance delocalization (Scheme 1B). Bis-alkoxy- dazolequinone chromophore for the release of both attached
amines are described, and visible-light is used for the first time TEMPO residues, a selective epoxidation strategy was devised for
to release up to two equivalents of TEMPO per molecule, using single chromophore deactivation (Scheme 2). Given its asymmetric
Bis-TEMPO-Vis. Bis- or bifunctional alkoxyamine activation has aromatic/non-aromatic nature, 2 was deemed a good substrate for
only been previously achieved by thermal means (at 70–140 1C),3,9 selective quinone functionalization. Subjecting 2 to the Langlois
which for non-TEMPO bis-alkoxyamines leads to nitroxide reaction (using NaSO2CF3),14 gave the electrophilic trifluoro-
decomposition.9c
methylated quinone bis-alkoxyamine 3 in 54% yield. The oxidative
The premise for this room temperature homolysis was demethylation of 3 using NBS and H2SO4 (using Table 1 conditions),
obtained through DFT investigation of the level of delocalization followed by mild epoxidation at the CF3-containing quinone moiety,
of the unpaired electron in QM-rad (Fig. S1, ESI†). DFT supported via air oxidation under basic conditions, furnished epoxide-quinone
the traditional resonance structures with a shortening of the 4 in 78% yield.
2C–CH2 bond relative to TEMPO-Vis, indicating partial double
Visible-light activated alkoxyamine homolysis was carried
bond character (Table S1, ESI†), and significant distribution of out under an O2 atmosphere to trap carbon-centered radicals,4a,5b,15
spin density into the benzimidazolequinone ring system, including while monitoring alkoxyamine decay and TEMPO release by HPLC
onto the quinone 7O-atom. The bond dissociation energy (BDE), (Table 2).9b,16 Under blue LED (420–520 nm), 87% conversion of
and the lowest triplet energy level (ET) of TEMPO-Vis were estimated TEMPO-Vis to TEMPO was observed after 2.25 min. The decay of
using DFT. The model-alkoxyamine (TEMPO-Vis) was found to TEMPO-Vis alkoxyamine was first-order (Fig. 1A), from which the
have a suitably low BDE (85.1 kJ molꢀ1) compared to benzylic dissociation rate constant (kd) was determined, and corresponded to
thermally labile (92.7–108.7 kJ molꢀ1),10 and UV-light activated a half-life (t1/2) of 6 s. By monitoring [TEMPO] growth over time
(80–122 kJ mol )
ꢀ1 4a alkoxyamines, with enough driving force in (Fig. 1B), eqn (1) may be fitted to the plot, to provide an alternative
the ET to support the observed bond dissociation: DGd = BDE ꢀ method to determine kd, which also gave a t1/2 of 6 s.
ET = ꢀ122.3 kJ molꢀ1 (see later discussion).
[TEMPO] = [TEMPO]max(1 ꢀ eꢀk t
)
(1)
d
The preparation of TEMPO-Vis and Bis-TEMPO-Vis from 4,7-
dimethoxybenzimidazole alkoxyamine precursor 1, using one-
Alkoxyamines were indefinitely stable in the absence of light,
step oxidation was investigated (Table 1). Previous work used and the on/off switchable nature of homolysis was demonstrated
NBS in combination with H2SO4 to convert 4,7-dimethoxybenzimid-
azole into benzimidazolequinone.11 In the present work, TEMPO-
Vis was isolated in 52% yield, with some undesirable bromination
of 1 observed. PIFA [(CF3CO2)2IPh] improved the yield of TEMPO-Vis
to 78%. Oxidative dimerization of dimethoxybenzenes to dibenzo-
quinones is reported through the use of CAN [Ce(NH4)2(NO3)6],12
and one report exists of a benzimidazolequinone dimer in low
by alternating periods of light and dark for TEMPO-Vis using blue
LED (Fig. S2, ESI†).
For the bis-alkoxyamine, Bis-TEMPO-Vis, there are two possible
dissociation rate constants, kd1 and kd2 corresponding to TEMPO
release from the starting compound, and from the monoalkoxy-
amine O2-trapped intermediate(s), with hydroperoxide and
aldehyde intermediates detected by HPLC-MS (Fig. S3, ESI†).
yield.13 Treatment of 1 with CAN (2 equiv.) afforded bis- Just over twice as much TEMPO was released from Bis-TEMPO-Vis
alkoxyamine 2 in 86% yield, as the product of oxidative coupling
of dimethoxybenzimidazole TEMPO-Vis with dimethoxybenz-
imidazole 1. Increased amounts of CAN (3.2 equiv.) gave the fully
oxidized Bis-TEMPO-Vis in 82% yield. The selective dimerization at
C5–C50 was confirmed by X-ray crystallography of Bis-TEMPO-Vis,
with alternative couplings at C6–C60, C5–C60 and C6–C50 not
observed (Table 1).
compared to TEMPO-Vis, with 175% released after the same period
of 2.25 min. The kd1 was directly measured from the first-order
decay plot of Bis-TEMPO-Vis, and corresponded to a t1/2 of 15 s in
blue LED. The slower photolysis of Bis-TEMPO-Vis was supported
by the DFT-derived DGd being 11.7 kJ molꢀ1 less favorable
compared to TEMPO-Vis (Table 2). The rate of overall TEMPO release
attained by fitting eqn (1) to the [TEMPO] vs. time plot (Fig. 1B),
Table 1 Oxidation of dimethoxybenzimidazoles to visible-light sensitive benzimidazolequinone-alkoxyaminesa,b
Oxidant
Equiv.
TEMPO-Vis (%)
2 (%)
Bis-TEMPO-Vis (%)
NBSc
PIFAe
CANf
CANf
1.1
1.5
2.0
3.2
52d
78
—
—
—
86
—
—
—
—
82
—
a
b
c
d
Isolated yields. Performed in the absence of light. H2SO4 (1.7 equiv.), THF/H2O, rt, 10 min. Brominated 1 and recovered 1 detected by HPLC-
e
f
MS. rt, 3 h. 0 1C, 20 min.
14666 | Chem. Commun., 2019, 55, 14665--14668
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Scheme 2 Chromophore deactivation.
combines release from the starting bis-alkoxyamine (kd1), as
well as from the O2-trapped intermediate alkoxyamine(s) (kd2).
The rate constant derived in this way was in good agreement
with the rate of Bis-TEMPO-Vis decay (Fig. 1A and Table 2). This
infers that for Bis-TEMPO-Vis, kd1 E kd2, and the homolysis of
the alkoxyamine in the O2-trapped intermediate(s) occurs at an
almost identical rate to that of the starting bis-alkoxyamine.
By removing one of the chromophores of Bis-TEMPO-Vis in
epoxide-quinone 4, the release of o1 equiv. TEMPO occurred
over the same time period (Table 2). The homolysis of one
alkoxyamine of 4 was detected by HPLC-MS, with singly-
homolyzed O2-trapped adducts observed (Fig. S3, ESI†), and
no products of double alkoxyamine homolysis detected. Single
bond homolysis occurred despite the BDE of the alkoxyamine
of the epoxide part mirroring the BDE of Bis-TEMPO-Vis.
TD-DFT calculations (see below) supported the localization of
the frontier molecular orbitals on only the fully-conjugated
quinone moiety of 4 (Fig. 2). The kd of the labile alkoxyamine
Fig. 1 Kinetics (at rt) of alkoxyamine and bis-alkoxyamine homolysis in
blue LED according to (A) (bis-)alkoxyamine decay and (B) TEMPO release.
Eqn (1) was fitted to the plots in (B) using GraphPad Prism software. Key:
TEMPO-Vis (
), Bis-TEMPO-Vis (
) and 4 (
). Conditions according
to Table 2.
of 4 is less than half that of Bis-TEMPO-Vis in blue LED, and (see Table S2, ESI†). Moreover, Bis-TEMPO-Vis underwent
given that the DGd values of the quinone-alkoxyamine in 4 and photolysis at a faster rate than TEMPO-Vis in green LED, in
Bis-TEMPO-Vis are similar (at about ꢀ110 kJ molꢀ1), the accordance with lmax of the former being red-shifted by 12 nm
observed reduction in rate may be attributed to the lower (Fig. S4, ESI†). The result in green LED, is a reversal in the
absorption of the partially deactivated 4 in the visible region magnitude of kd that was observed for blue LED for the two
(Fig. S4, ESI†).
compounds. The same conclusion of kd1 E kd2 for Bis-TEMPO-
The rate of homolysis decreased using green (470–600 nm) Vis was reached for green LED activation.
compared to blue LED by 71-, 19- and 40-fold for TEMPO-Vis,
Bis-alkoxyamine 2 was found to be largely stable under
Bis-TEMPO-Vis, and 4 respectively (Fig. S5, ESI†), due to less visible-light, having a kd three orders of magnitude smaller
absorption. The decrease in absorbance is reflected in reduced than its fully-oxidized derivative, Bis-TEMPO-Vis, in blue and
quantum yields (Fh) with the greater intensity green LED used green LED (Table 2). Although 2 possesses a similar first BDE to
Table 2 Kinetics for room-temperature alkoxyamine homolysis under visible-light,a and DFT-calculated homolysis parameters
kd via alkoxyamine decay
(minꢀ1
kd via TEMPO release
(minꢀ1
mol%d TEMPO released
(time, min)
BDEe
ET
b
c
e
Alkoxyamine
LED color
)
)
(kJ molꢀ1
)
(kJ molꢀ1
)
TEMPO-Vis
Bis-TEMPO-Vis
4
2
TEMPO-Vis
Bis-TEMPO-Vis
4
2
Blue
Blue
Blue
Blue
Green
Green
Green
Green
6.71 ꢁ 0.21
7.29 ꢁ 0.26
87 (2.25)
175 (2.25)
64 (2.25)
78 (480)
80 (25)
162 (15)
43 (65)
85.1
207.4
215.5
209.7
176.8
—
—
—
2.78 ꢁ 0.07
2.66 ꢁ 0.09
104.9
1.27 ꢁ 0.16
1.41 ꢁ 0.24
99.7,f 104.6g
0.00313 ꢁ 0.00055
0.0948 ꢁ 0.0032
0.148 ꢁ 0.002
0.0321 ꢁ 0.0007
o2 ꢂ 10ꢀ4
0.00417 ꢁ 0.00024
0.0993 ꢁ 0.0063
0.146 ꢁ 0.004
0.0346 ꢁ 0.0061
—
104.1,f 111.9g
—
—
—
—
o5 (480)
—
a
Conditions: alkoxyamine (0.25 mM, DCE) illuminated at rt using blue (1 ꢂ 9 W) or green (2 ꢂ 9 W) LED bulbs under O2 balloon with HPLC
b
c
analysis. Experiments performed in triplicate. Dissociation rate (kd) derived from slope of Fig. 1A and Fig. S5A (ESI). Derived from fit of eqn (1)
d
e
to Fig. 1B and Fig. S5B (ESI). HPLC yield based on starting alkoxyamine. M06-2X, or UM06-2X for radicals, 6-311++G (d,p) in the gas phase.
f
g
BDE at benzimidazolequinone part. BDE at epoxide/dimethoxybenzimidazole part.
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to Peter Cannon (Avara Pharmaceutical Services Ltd., Shannon,
Ireland) for acting as the Enterprise Mentor. PF acknowledges
support from Royal Society Newton Alumni programme. We thank
Sylvester Byrne and Benjamin A. Chalmers for laboratory assistance,
and John O’Reilly for consultation on HPLC (all National University
of Ireland Galway). Andrew Benniston (Newcastle University, UK) is
gratefully acknowledged for discussions around the photophysical
and computational studies.
Conflicts of interest
There are no conflicts to declare.
Fig. 2 TD-DFT analysis of ground and excited state orbital delocalization
in epoxide-quinone 4, p-dimethoxybenzene-coupled quinone 2, and
Bis-TEMPO-Vis. Conditions: PCM/M06-2X/6-311++G (d,p), using DCE as
solvent and the natural transition orbital (NTO)17 method for visualization.
Notes and references
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the other alkoxyamines. The lmax of 2 was red-shifted by 96 nm
compared to Bis-TEMPO-Vis, suggesting the presence of a low-
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introduced with room temperature visible-light homolysis providing
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We thank the Irish Research Council for awarding PK an
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14668 | Chem. Commun., 2019, 55, 14665--14668
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