Photochemical generation of acyl and carbamoyl radicals using a nucleophilic organic catalyst: Applications and mechanism thereof

Article abstract of DOI:10.1039/d0sc02313b

We detail a strategy that uses a commercially available nucleophilic organic catalyst to generate acyl and carbamoyl radicals upon activation of the corresponding chlorides and anhydrides via a nucleophilic acyl substitution path. The resulting nucleophilic radicals are then intercepted by a variety of electron-poor olefins in a Giese-type addition process. The chemistry requires low-energy photons (blue LEDs) to activate acyl and carbamoyl radical precursors, which, due to their high reduction potential, are not readily prone to redox-based activation mechanisms. To elucidate the key mechanistic aspects of this catalytic photochemical radical generation strategy, we used a combination of transient absorption spectroscopy investigations, electrochemical studies, quantum yield measurements, and the characterization of key intermediates. We identified a variety of off-the-cycle intermediates that engage in a light-regulated equilibrium with reactive radicals. These regulated equilibriums cooperate to control the overall concentrations of the radicals, contributing to the efficiency of the overall catalytic process and facilitating the turnover of the catalyst. This journal is

Full text of DOI:10.1039/d0sc02313b

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Photochemical generation of acyl and carbamoyl radicals using a
nucleophilic organic catalyst: applications and mechanism thereof
Eduardo de Pedro Beato,a Daniele Mazzarella,a Matteo Balletti,a and Paolo Melchiorre*a,b,†
Received 00th January 20xx,
Accepted 00th January 20xx
We detail a strategy that uses a commercially available nucleophilic organic catalyst to generate acyl and carbamoyl radicals
upon activation of the corresponding chlorides and anhydrides via a nucleophilic acyl substitution path. The resulting
nucleophilic radicals are then intercepted by a variety of electron-poor olefins in a Giese-type addition process. The
chemistry requires low-energy photons (blue LEDs) to activate acyl and carbamoyl radical precursors, which, due to their
high reduction potential, are not readily prone to redox-based activation mechanisms. To elucidate the key mechanistic
aspects of this catalytic photochemical radical generation strategy, we used a combination of transient absorption
spectroscopy investigations, electrochemical studies, quantum yield measurements, and the characterization of key
intermediates. We identified a variety of off-the-cycle intermediates that engage in a light-regulated equilibrium with
reactive radicals. These regulated equilibriums cooperate to control the overall concentrations of the radicals, contributing
to the efficiency of the overall catalytic process and facilitating the turnover of the catalyst.
DOI: 10.1039/x0xx00000x
Introduction
Free radical chemistry is extensively used for the synthesis of
agrochemicals, pharmaceuticals, and materials.1 This is because
radicals offer ways of making molecules that are often
complementary to strategies proceeding via ionic pathways.2
Traditional methods for generating radicals require unstable
initiators, or stoichiometric oxidants or reductants.3 These
relatively harsh conditions (high temperatures, UV light, toxic
reagents, or strong redox-active reagents) significantly affect
the applicability and generality of radical processes. Recently,
photoredox catalysis4,5 have provided milder and more effective
platforms for generating open-shell intermediates. Overall,
these radical generation strategies mainly rely on either atom
abstraction or electron transfer mechanisms. Therefore, they
require precursors with suitable bond-dissociation energies
(BDE) or redox properties6 (Fig. 1a). These intrinsic features
pose a limit to the generality of the radical precursors that can
be used.
Our laboratory recently reported a photochemical catalytic
strategy that harnesses different physical properties of the
substrates to generate radicals. Specifically, our method
capitalizes solely on the electrophilic properties of a given
precursor (Fig. 1b).7
Fig. 1. (a) Traditional strategies for generating radicals require precursors with
suitable bond-dissociation energies (BDE) or redox properties. (b) Our recently
developed SN2-based method uses a nucleophilic dithiocarbamate anion catalyst
A to photochemically generate radicals based on the electrophilicity of
substrates. (c) Presented photochemical generation of acyl and carbamoyl
radicals based on a nucleophilic acyl substitution mechanism.
a.ICIQ - Institute of Chemical Research of Catalonia - the Barcelona Institute of
Science and Technology, Avenida Països Catalans 16 – 43007, Tarragona, Spain
E-mail: pmelchiorre@iciq.es
Homepage: http://www.iciq.org/research/research_group/prof-paolo-
melchiorre/.
ICREA – Passeig Lluís Companys 23 – 08010, Barcelona, Spain.
Inspired by pioneering contributions on xanthate transfer
chemistry by Barton8 and Zard,9 we designed the air- and
b.
moisture-stable dithiocarbamate anion catalyst A 7
, which is
† In memory of Kilian Muñiz (1970-2020).
Electronic Supplementary Information (ESI) available: complete experimental
procedures and full compound characterization. CCDC 1894404 (4a) contains the
supplementary crystallographic data for this paper. See DOI: 10.1039/x0xx00000x
adorned with an indole chromophoric unit. This nucleophilic10
organic catalyst can activate alkyl electrophiles by displacing a
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variety of leaving groups via an SN2 pathway. The ensuing photolysis of the catalytic intermediate
I, whichVsieywnAtrhticeletiOcnalilnlye
photon-absorbing intermediates
I
afford radicals upon was not limited within the constraintsDoOfI: 1a0.1g0r3o9u/Dp0StCra02n3s1f3eBr
excitation by visible light and homolytic cleavage of the weak C- mechanism. Along these lines, we surmised that the
S bond. This catalytic SN2-based strategy grants access to photogenerated acyl/carbamoyl radical II would be intercepted
stabilized radicals (including benzyl, allyl, and radicals bearing by an electron-poor olefin
2 to forge a new C-C bond. The
either a heteroatom or an electron-withdrawing moiety at the emerging electrophilic radical IV would then abstract a
α-position) from substrates that would be inert to other radical- hydrogen atom from γ-terpinene (a H donor), thus forming the
forming methodologies. These open-shell intermediates have final product
been used to forge new C-C7,11 and C-B bonds.12
catalyst turnover would be an SET reduction of the
To date, our strategy has been limited by the need for dithiocarbonyl radical III from the cyclohexadienyl radical
substrates amenable to an SN2 displacement. Herein, we which would eventually close the catalytic cycle by returning
3 and the cyclohexadienyl radical V. Crucial for
V,
expand the potential of this photochemical catalytic approach catalyst
to include nucleophilic acyl substitution as a suitable manifold
for radical generation. Specifically, we generated acyl and
carbamoyl radicals upon activation of the corresponding
chlorides and anhydrides. We then intercepted the resulting
nucleophilic radicals with electron-poor olefins in a Giese-type
addition process. The chemistry uses commercially available
nucleophilic organic catalysts and low-energy photons (blue
LEDs) to activate acyl and carbamoyl chlorides that, due to their
high reduction potential, are not readily prone to a SET-based
activation mechanism. In addition, we detail how a combination
of photophysical investigations, electrochemical studies, and
quantum yield measurements along with the characterization
A.
of key intermediates provided
a more comprehensive
mechanistic picture of this photochemical catalytic radical
generation strategy.
Design plan
Fig. 2. Initial design plan; the mechanism strictly resembles the machinery
proposed in our previous studies (Ref. 7).
Fig. 2 details the proposed mechanism for the photochemical
catalytic generation of acyl and carbamoyl radicals from the
corresponding chlorides. This initial mechanistic picture was
based on our previous works dealing with the SN2 activation of
alkyl electrophiles.7,11-12 By analogy, we envisioned a catalytic
Here, we detail the successful realization of this proposal. We
also report extensive mechanistic studies, which highlight how
the underlying mechanism of this catalytic radical generation
strategy is more complex than originally thought.
cycle where the dithiocarbamate anion catalyst
activate acyl/carbamoyl chlorides by means of a nucleophilic
acyl substitution path. The resulting intermediate possesses a
A would
1
I
weak C-S bond, which could be cleaved by low-energy photons
to generate the target nucleophilic radical II and the
dithiocarbonyl radical III. The feasibility of this crucial step
found support in pioneering studies by Barton and Zard,13 who
demonstrated the tendency of stoichiometric acyl xanthates to
undergo photolysis affording acyl radicals. A few studies have
also established the tendency of thiocarbonyl compounds of
Results and discussion
Acyl Radical Formation and Applications. Acyl radicals are
nucleophilic intermediates that are useful for many organic
transformations.16 Traditional strategies for their generation
relied on the activation of stoichiometric acyl chalcogenes by
means of radical initiators or photolytic bond cleavage.13,16c-e
Catalytic methods for acyl radical formation mainly rely on
hydrogen atom transfer (HAT) processes17 or electron transfer
mechanisms.18,19 While the HAT process from aldehydes
provides an elegant and atom-economical entry to acyl radicals,
this approach is biased by regioselectivity issues when it is
applied to complex molecules.17c Photoredox catalytic
methods20 require purposely designed substrates adorned with
redox active auxiliaries. For example, acyl radicals could be
achieved either by SET oxidation of α-keto acids,18a-d acyl
silanes,18e or 4-acyl dihydropyridine derivatives,18f-h or upon SET
reduction of hypervalent iodine reagent.19a-b Acyl chlorides21
and anhydrides22 are rarely used in acyl radical chemistry,23
type
I to generate radicals upon photolytic cleavage and
promote polymerizations acting as photoiniferters.14 In
addition, a report from Grainger highlighted how carbamoyl
dithiocarbamates could generate carbamoyl radicals upon UV
irradiation.15 Overall, these strategies required the use of
stoichiometric pre-formed intermediates of type I and were all
characterized by a group transfer mechanism.9,13-15 In addition,
these approaches found limited application in processes
involving acyl radicals, mainly because of their tendency to
generate alkyl radicals upon decarbonylation.13b,c Our goal was
to implement a general and effective catalytic process to
generate acyl/carbamoyl radicals using blue light to trigger the
2 | Chem. Sci., 2020, 10, xx-xx
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Table 1. Optimization studies and control experiments.a
since the radical formation can be further complicated by polar
side reactions.24 In addition, these substrates are not easily
prone to SET activation. For example, while the redox potentials
of aromatic acid chlorides (e.g. benzoyl chloride, Ered = -1.6 V vs
SCE)25 fall within the range of commonly used photoredox
catalysts, their alkyl counterparts cannot be easily reduced (e.g.
cyclohexyl carbonylchloride, Ered = -2.1 V vs SCE).26
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DOI: 10.1039/D0SC02313B
We therefore envisaged that the photochemical strategy
depicted in Fig. 2 could be a suitable platform for generating
acyl radicals from the chloride precursors. We anticipated that,
when successfully developed, this approach would provide
significant synthetic benefits. For example, the use of mild
reaction conditions would preclude undesired decarbonylation
processes, which are often a problem when acyl radical
formation is achieved at high temperatures.27 In addition, since
our strategy relies on the electrophilicity of the acyl radical
precursors, this approach should be viable for a variety of
readily available acyl electrophiles, including chlorides and
anhydrides, independent of the nature of the substituent (aryl
or alkyl).
To test the feasibility of our strategy, we selected
commercially available benzoyl chloride 1a as the acyl radical
precursor and acrylonitrile 2a as the radical trap (Table 1). The
experiments were conducted at 60 °C in dichloromethane
(DCM) using a blue LED strip emitting at 465 nm, γ-terpinene as
the H donor (3 equiv.), and 10 mol% of the nucleophilic catalyst.
Na3PO4 (2 equiv.) was used to neutralize the hydrochloric acid
generated during the process. Surprisingly, the indole-
entry
catalyst
deviation
yield 3a (%)a
1
2
3
4
5
6
7
8
A
none
none
7
B
83 (82)b
C·3H2O
none
34
86
40
60
0
C
B
none
40 ºC
B
under air
no light
none
B
none
0
a Reactions performed on a 0.5 mmol scale at 60 °C for 16 h using 2.0 mL of
DCM under illumination by blue LED strip (λmax = 465 nm, 14 W) and using
catalyst (10 mol%), 1.5 equiv. of 1a, and 2 equiv. of Na3PO4. Yield
determined by 1H NMR analysis of the crude mixture using trichloroethylene
as the internal standard. Yield of the isolated product 3a. LED: Light-
emitting diode.
b
c
Using the optimized conditions detailed in entry 2 of Table 1,
we then tested the possibility of using acyl electrophiles other
than chlorides as the radical precursors. Benzoic anhydride 1b
provided the acylation product 3a in moderate yield (Scheme
1a). The unsymmetrical anhydride 1c, generated by reaction of
benzoic acid and ethyl chloroformate and directly used upon
simple filtration, afforded 3a in a yield comparable to when
using acyl chloride (Scheme 1b). Interestingly, this simple
procedure avoids the need for an external base, since its role is
played by the ethoxide anion generated during the process.
Overall, this sequence allows the use of easily available
carboxylic acids as acyl radical precursors.28
containing dithiocarbonyl anion catalyst
A, which was
successful in our previous studies,7,11-12 provided poor results
and was not suitable for the generation of acyl radicals (entry
1). We then used the commercially available potassium ethyl
xanthate catalyst
acyl xanthates of type
nucleophilic acyl substitution of
photolytic cleavage.13-14 We confirmed by UV/Vis spectroscopy
B
. This choice was informed by the notion that
(see Fig. 2), resulting from the
, are known to undergo
I
1
that an authentic sample of the intermediate of type
I,
generated upon nucleophilic acyl substitution of with 1a
B
,
could absorb light in the visible region, despite the lack of the
indole chromophoric unit (see Figure S10 in the ESI).
Importantly, the xanthate catalyst
product 3a with high chemical yield (entry 2). The commercially
available sodium diethyldithiocarbamate was not a suitable
B provided the target
C
catalyst for this transformation (entry 3). However, this
commercial salt is sold in its hydrate form (C·3H2O). Since the
presence of water was deleterious for the stability of substrate
1a, we synthesized catalyst
C as an anhydrous salt, which
showed a fully recovered catalytic activity (entry 4). Based on
these results, we selected the commercially available xanthate
catalyst
B for further investigations (see section C1.2, Tables 1-
Scheme 1. Use of other acyl radical precursors: (a) benzoic anhydride; (b)
sequential procedure for the formation of anhydride 1c from benzoic acid and the
ensuing acyl radical chemistry.
6 in the ESI for full details of the optimization phase). The
reaction efficiency was affected by a lower temperature and by
the presence of air, but synthetically useful yields were still
achieved (entries 5 and 6, respectively). Control experiments
showed the need for light and for the nucleophilic catalyst
(entries 7 and 8).
The optimized conditions were then used to evaluate the
scope of this catalytic acyl radical generation strategy (Fig. 3). In
general, the reaction proceeded smoothly leading to the
exclusive formation of the desired acylation products. Alkylated
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adducts, arising from a possible decarbonylation of the acyl acyl radicals and, sometimes, from the formation of the
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DOI: 10.1039/D0SC02313B
radicals, were not observed. The main by-products formed corresponding aldehydes via an HAT process, presumably from
during the process, which account for the moderate yields γ-terpinene.
observed in some examples, arose from the dimerization of the
Fig. 3. Photochemical catalytic generation of acyl radicals from the chloride precursors and their use in Giese addition processes. Reactions performed on 0.5 mmol scale
using 1.5 equiv. of acyl chloride 1 and 2.0 mL of dichloromethane (DCM); yields of products refer to isolated materials after purification; the bold orange bond denotes
the newly formed C-C bond. Unless otherwise indicated, reactions with aromatic acyl radical precursors were performed at 60 °C, and with alkyl acyl radical precursors
at 40 °C. a Yield measured by 1H NMR analysis using trichloroethylene as the internal standard. b Reaction time: 60 h. c Reaction temperature: 60 °C. d Product isolated as
a 6:1 mixture with the olefin substrate; the corrected yield is reported. PMP: p-Methoxyphenyl; Pr: propyl; EWG: electron-withdrawing group.
We first focused on the Giese addition using a variety of shown by the reaction of dimethyl fumarate (3l), propyl
electron-poor olefins as the radical trap. Commercially available maleimide (3m), and diethyl ethylidene malonate (3n).
para-methoxy benzoyl chloride was used as the radical
We then evaluated the acyl radical precursors suitable for this
precursor, since it facilitated the purification of products while transformation. Aroyl chlorides bearing electron-poor,
3
providing comparable results to 1a (e.g. reaction with electron-rich, or hindered moieties on the aryl ring all provided
acrylonitrile 2a provided the corresponding products 3b and 3a the Giese addition products to phenyl vinyl sulfone in
in 84% and 82% yield, respectively). Terminal olefins with synthetically useful yields (4a-f). Aromatic acyl chlorides bearing
different electron withdrawing groups, including a cyano, an heterocyclic moieties, which are common scaffolds in medicinal
ester, an aldehyde, a ketone, a phosphonate, a sulfone, and a chemistry programs,29 including benzofuran (4g) and isoxazole
sulfonamide moiety, all delivered the acylation products 3b
-
k
in
(4h), were successfully used as radical precursors.
synthetically useful yields. Internal olefins could also be used, as
Because of the unique mechanism of activation of this radical
generation strategy, which exploits the electrophilicity of the
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substrates, alkyl acyl chlorides could also be readily activated by chloride substituent selectively reacted at the acyl moiety under
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the xanthate catalyst
acyl chlorides would be recalcitrant to SET activation strategies precursors containing 5-, 4- and 6-membered rings, adorned
due to their high redox potential. Primary (5a ), secondary (5d with nitrogen (6c g), fluorine (6d ), or oxygen (6f) atoms or a
), and bridged tertiary (5k ) acyl electrophiles reacted with tertiary bridged structure (6h), successfully delivered the
Michael acceptors to afford products in moderate to excellent corresponding products upon Giese reaction with electron-poor
yields. As a limitation of the system, benzylic and non-bridged olefins.
B to give the corresponding radicals. Alkyl the optimized conditions (
6b). MorDeOoIv: 1e0r.,103a9c/Dy0l SCr0a2d3i1c3aBl
-
c
-
,
,e
j
-l
5
tertiary acyl electrophiles were not suitable substrates, since
In a different procedure, already highlighted in Scheme 1b,
the resulting radicals underwent decarbonylation. A complete we showed that unsymmetrical anhydrides could be generated
list of moderately successful and unsuccessful substrates is by reaction of carboxylic acids and ethyl chloroformate. Upon
reported in section C7 of the ESI. Notably, our strategy tolerates simple filtration, and without further purification, they are then
functionalities that would be incompatible with other activated by catalyst
B to form an acyl radical. This approach
approaches relying on HAT or SET mechanisms. For example, may offer a powerful alternative when using substrates bearing
aldehydes (3e), iodides (4d), and dioxolanes (4f) smoothly functionalities that are incompatible with the generation of acyl
reacted under the optimized conditions.
We then implemented a two-step telescoped sequence to which did not react under the conditions reported in Fig. 4a,
form the acyl chlorides in situ and use it without further could be effectively functionalized to afford product upon
chlorides. For example, the natural product dehydrocholic acid,
1
7
purification (Fig. 4a). This one-pot procedure allowed access to treatment with ethyl chloroformate and formation of its mixed
functionalized acyl radical precursors from readily available anhydride (Fig. 4b). This procedure was also suitable for a gram
carboxylic acids upon simple treatment with oxalyl chloride. For scale synthesis of adduct 5e starting from the carboxylic acid
example, highly functionalized heteroaromatic derivatives (6a
)
substrate: using common laboratory glassware and a simple set-
could be used as radical precursors. Alkyl derivatives bearing a up, 1.13 grams of product 5e (55% yield) could be obtained.
Fig. 4. Photochemical catalytic generation of acyl radicals from carboxylic acids upon (a) in situ preparation of acyl chlorides and (b) sequential formation of anhydrides.
Reactions performed on 0.5 mmol scale using 1.5 equiv. of 1 and 2.0 mL of dichloromethane; yields of products refer to isolated material after purification; the bold
orange bond denotes the newly formed C-C bond. Unless otherwise indicated, all entries with aromatic acyl radical precursors were performed at 60 °C, and with alkyl
acyl radical at 40 °C. a Yield calculated by 1H NMR using trichloroethylene as internal standard. b Reaction temperature: 60 °C. c 30 mol% of catalyst B. Ts: Tosyl, EWG:
electron-withdrawing group.
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Carbamoyl Radical Formation and Applications. The general
applicability of a chemical strategy is a crucial parameter for
evaluating its usefulness. To further explore the potential of our
photochemical radical generation approach, we investigated
the activation of carbamoyl chlorides. The formation of
carbamoyl radicals upon SET reduction of the progenitor
chlorides is hampered by their exceedingly high reduction
potential. Indeed, such an SET-based approach has never been
reported to the best of our knowledge. The available strategies
to generate carbamoyl radicals rely on a HAT process from the
corresponding formamide17c,30 or on SET activation of
substrates purposely adorned with suitable electron-auxiliary
groups.18a,31 We reasoned that, because of the unique
mechanism of substrate activation that relies on the
electrophilicity of the substrates, our strategy could be
successful for activating carbamoyl chlorides towards the
formation of radicals. Our reasoning was supported by a
previous report15 demonstrating that stoichiometric carbamoyl
dithiocarbamates (which, in our approach, would be generated
upon acyl substitution of the chloride substrates from the
nucleophilic catalyst) can generate carbamoyl radicals32 upon
light irradiation. Translating the catalytic system to the
photochemical activation of carbamoyl chlorides required
slightly different conditions. Because of the lower
electrophilicity of carbamoyl chlorides, the more nucleophilic10
commercially available dithiocarbamate catalyst C·3H2O was
used. Acetonitrile (CH3CN) emerged as the most appropriate
solvent, while potassium phosphate was used as the base.
Finally, irradiation at 405 nm secured an efficient photolysis of
Fig. 5. Photochemical catalytic generation of carbamoyl radicals from the chloride
precursors and their use in intermolecular Giese addition processes. Reactions
performed on 0.2 mmol scale using 2 equiv. of 8 and 0.8 mL of acetonitrile; yields
of products refer to isolated material after purification; the bold orange bond
denotes the newly formed C-C bond.
Since substrates containing substituted piperidines proved
suitable for this transformation, we tested the reactivity of
piperidine-containing pharmaceutically active compounds.
Indeed, the paroxetine-derived carbamoyl chloride delivered
the corresponding Giese addition product (9k), although with a
lower chemical yield than simpler substrates. In general, for
low-yielding substrates we observed partial degradation of the
catalyst and the formation of byproducts arising from
dimerization or H-abstraction (HAT process) of the carbamoyl
radicals, the latter path leading to the corresponding
formamide derivatives.
We then tested the possibility of applying this carbamoyl
radical generation strategy to drive an intramolecular process
leading to cyclic products. We synthesized carbamoyl chlorides
10 with nitrogen atoms decorated with an alkyl chain bearing a
double bond, primed to a radical cyclization (Fig. 6). By using the
optimized conditions and simply lowering the amount of γ-
terpinene (1.5 equivalents), substrates 10 could be efficiently
converted to the corresponding β-lactams fused with a 6-
membered ring (11a). Since this strategy of radical formation is
not reliant on the redox potential of the substrate, both
the carbamoyl dithiocarbamate intermediate of type I, whose
absorption is blue-shifted with respect to the analogous acyl
intermediate (see Figure S14 for UV-VIS absorption studies).
The progress toward the optimized conditions for the
carbamoylation catalytic system is detailed in Tables S8 in the
ESI.
The results summarized in Fig. 5 illustrate the potential of this
catalytic approach to generate carbamoyl radicals from the
chloride precursors and their synthetic application in Giese
addition processes. Different electron-poor olefins smoothly
reacted with dimethylcarbamoyl chloride to furnish the
corresponding amides (Fig. 5a, 9a-9c). A variety of carbamoyl
chloride substrates could be successfully reacted with vinyl
sulfone. Interestingly, this process offers a synthetic entry into
electron-withdrawing
(11b) and electron-donating (11c)
Weinreb amide
compared to the classical one. Oxygen-, sulfur-, nitrogen-,
chlorine- and fluorine-containing chlorides (9e 9i) reacted with
(9d) through an unusual disconnection
substituents at the nitrogen atom were tolerated well.
Additionally, a nitrogen benzyl moiety on the substrate was not
needed for the positive outcome of the reaction: a simple alkyl
chain delivered the product, albeit with lower yields (11d). The
method allows the straightforward synthesis of β-lactams33
fused with a 6-membered, a 5-membered (11e), or without any
-
good levels of efficiency. The carbamoyl chloride obtained from
proline methyl ester was also successfully functionalized (9j).
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fused ring (11f). Here the efficiency of the cyclization was depicted in Fig. 2 to focus on the most relevant individual steps,
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DOI: 10.1039/D0SC02313B
particularly plagued by the competitive HAT of the carbamoyl while characterizing the key intermediates responsible for the
radical, leading to the formamide byproduct instead of the reactivity.
desired lactam. In addition, both 5-membered and 6-membered
ring lactams could be obtained in good yields (11g ).
Nucleophilic Acyl Substitution and Photochemical Behavior
of Intermediate I. Potassium ethyl xanthate is nucleophilic
,h
B
enough10 to readily react with 1a and afford the quantitative
formation of the acylxanthate intermediate Ia (Fig. 7a). We
wanted to verify if intermediate Ia, which absorbs light in the
visible region (see Figure S10 in the ESI), could generate the
benzoyl radical IIa upon illumination by a blue LED, the light
source used in the synthetic applications. A stoichiometric
amount of acylxanthate Ia, prepared in situ by reacting
B and
1a, was irradiated in the presence of the radical trap 2,2,6,6-
tetramethylpiperidine 1-oxyl (TEMPO). This experiment
afforded product 12, arising from the TEMPO trapping of the
photochemically generated benzoyl radical IIa (Fig. 7b). When
adding TEMPO to the catalytic model reaction (Fig. 7c), the
reactivity was almost completely inhibited, leading to only
traces of hydroacylation product 3a
. Collectively, these
experiments indicate the radical nature of the process and that
the transiently generated acylxanthate Ia plays an active role in
the chemistry.
Fig. 6. Carbamoyl radical formation and intramolecular processes. Reactions
performed on 0.2 mmol scale using 0.8 mL of acetonitrile; yields of products refer
to isolated material after purification; the bold orange bond denotes the newly
formed C-C bond.
Mechanistic studies
Our mechanistic understanding of the photochemical
catalytic generation of acyl and carbamoyl radicals depicted in
Fig. 2 was originally based on our related works7-11,12 dealing
with the use of nucleophilic dithiocarbamate anion catalysts.
The crucial steps of this mechanistic machinery are: (i) the
ability of the nucleophilic organic catalyst to activate substrates
upon nucleophilic attack; (ii) the photoactivity of the ensuing
0,06
0,05
0,04
0,03
0,02
intermediate of type I, which can undergo photolytic cleavage
upon visible light absorption; and (iii) the ability of the emerging
dithiocarbonyl radical III to undergo SET reduction from the
cyclohexadienyl radical V, which represents the turnover event
of the proposed catalytic cycle. While evidence in support of
points (i) and (ii) were collected in our previous studies, other
important mechanistic questions remained unanswered. For
example, the proposed catalyst turnover step (point iii) requires
an SET event between two fleeting radical intermediates, which
is a rather unlikely scenario. In addition, xanthates and
0,01
No irrad
12.5 min
0,00
-0,01
-0,02
3450
3500
3550
3600
Field strength (G)
Fig. 7. (a) The possible role of the acylxanthate Ia. Mechanistic experiments to
probe that Ia is an active reaction intermediate: (b) the benzoyl radical IIa is
generated during the process, and (c) the model reaction is inhibited by a radical
scavenger. (d) Transient absorption spectroscopic studies: absorption at 620 nm of
the transient xanthyl radical IIIa generated upon 355 nm laser excitation of
acylxanthate Ia ([Ia]0 = 3x10-3 M in CH3CN); absorption decay (black line) processed
through Savinsky Golay filter to facilitate lifetime measurement. Note logarithmic
scale for time; ΔOD: optical density variation. (e) EPR spectrum generated from Ia
([Ia]0 = 0.1 M in toluene) at 298 K after 12.5 minutes (black line) of light irradiation
by a 100 W mercury lamp.
thiocarbamates of type I have a great tendency to participate in
group transfer manifolds,9 and it is not clear whether this
mechanistic path could play an important role in our catalytic
system too. We therefore performed extensive mechanistic
investigations on the catalytic activation of acyl chlorides by the
xanthate catalyst
B and the ensuing Giese addition. Our
reasoning was that this process might serve as a suitable probe
for testing the mechanism and elucidating unclear aspects, thus
providing general information on this radical generation
strategy.
To better corroborate that the light-induced homolytic
cleavage of Ia was the key acyl radical generation step (Fig. 7a),
we used laser flash photolysis to detect the transient formation
of the sulfur-centered radical IIIa. The xanthyl radical IIIa has
been reported to display a characteristic absorption peak with
We selected the reaction between benzoyl chloride 1a and
acrylonitrile 2a catalyzed by catalyst
B for mechanistic studies.
Specifically, we deconstructed the general catalytic cycle
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a maximum at 620 nm.34 Accordingly, when a freshly prepared
authentic sample of intermediate Ia was excited with a laser
beam centered at 355 nm, we observed the formation of a
transient species absorbing at 620 nm (half lifetime = 0.1 ± 0.01
ms), consistent with the characteristic line shape of xanthyl
radical IIIa (Fig. 7d).
View Article Online
DOI: 10.1039/D0SC02313B
We also tried to detect that benzoyl radical IIa by electron
paramagnetic resonance (EPR) spectroscopy. We conducted
EPR analysis of a solution of Ia in toluene, performed at 298 K
under light illumination by a mercury lamp. However, this
provided a signal that was not consistent with that of benzoyl
radical (singlet).35a The EPR spectrum (Fig. 7e) showed a pattern
(sharp triplet centered at 3505 G, g-value = 2.00272, hyperfine
splitting value = 2.6 G) that is consistent35b with a more
stabilized carbon radical of type VI, which lies in proximity of
two sulfur atoms and an ethoxy moiety. The formation of radical
VI is consistent with the high tendency of xanthates of type I,
and related thiocarbonylthio congeners, to trap radicals. This
feature is the underlying reason for the xanthates’ success as
RAFT agents in polymerization.36 Indeed, xanthates of type
I can
readily react with acyl radicals of type II in a reversible addition-
fragmentation equilibrium, leading to intermediate VI (Fig. 8).
Fig. 9. Absorption of dimer VIIa at different concentration in CH3CN.
To verify that this intermediate was catalytically competent,
we used an authentic sample of dimer VIIa (5 mol%) to catalyze
the model reaction (Scheme 2). Irradiation with a blue LED
afforded product 3a in high yield.38 Importantly, no reaction was
observed when the same experiment was performed in the
dark. These results are very informative of the reaction
mechanism, since they imply that dimer VIIa is a photoactive
species in equilibrium with the progenitor xanthyl radical IIIa
.
This dimerization manifold confers a longer lifetime to IIIa 39
,
preventing other reaction pathways. Thanks to the
dimerization, the sulfur-centered radical IIIa gains a persistent
radical character. On this basis, the proposed turnover of
catalyst
B, based on the SET reduction of radical IIIa from radical
V
(see Fig. 2) becomes feasible. Indeed, according to the
persistent radical effect,39 processes between two fleeting
radicals are feasible when one of them has a relatively longer
lifetime.
Fig. 8. The reaction of the acyl radical IIa with its precursor Ia is reversible and
imparts an increased lifetime to IIa.
This equilibrium controls the overall concentration of highly
reactive active radicals (such as II) by forming the more
stabilized radical VI, which acts as a dynamic reservoir, while
increasing their effective lifetime in the medium. This
mechanism37 is at the basis of the success of the degenerative
radical addition transfer of xanthates, and may also be
operative in the present catalytic system. This possibility is
further discussed below.
Scheme 2. Experiment indicating that dimer VIIa is a catalytically (photo)active
species and the light-driven equilibrium between the xanthyl radical IIIa and the
dimer VIIa.
Fate and Behavior of the Xanthyl Radical IIIa. One of the
main mechanistic aspects to elucidate concerned the reactivity
of the sulfur-centered radical of type III, generated upon
To gain further insights into the light-driven equilibrium
between the dimer and its radical progenitor IIIa shown in
Scheme 2, we evaluated the behavior of dimer VIIa under the
reaction conditions using 1 equivalent of γ-terpinene and under
blue light illumination (Scheme 3). Dimer VIIa was completely
photolytic cleavage of intermediate
on the use of the indole-based dithiocarbamate anion catalyst
, we detected the formation in small amounts of the dimer VII
I
. During a recent study[11b]
A
,
which arises from the self-reaction of the sulfur-centered
radical III. We wondered if the catalyst dimer could play an
important role in the present process too. Dimer VIIa, readily
consumed to produce 1.65 equivalents of catalyst
provides compelling evidence to rationalize the mechanism of
turnover of catalyst Importantly, considering the
B. This result
synthesized in one step from the xanthate catalyst
in the visible region (Fig. 9).
B, can absorb
B
.
stoichiometry of the reaction in Scheme 3, it appears that γ-
terpinene can provide two different pathways to reduce the
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xanthyl radical IIIa, namely an HAT process followed by an SET catalyst
reduction from the ensuing cyclohexadienyl-type radical catalyst
B and dimer VIIa (Fig. 11). We first VfieowcAursticeledOnloinne
B
, which was electrochemicallyDaOnI:a1l0y.z10e3d9/dDu0rSiCn0g23t1h3eB
V
.
initial forward scan applying an increasingly reducing potential
(0 to -2.0 V, Fig. 11a). No reduction peaks were observed. During
the reverse scan towards oxidation (from -2.0 V to +1.5 V), an
A
irreversible peak appeared (Ep = Eox = 0.73 V in CH3CN vs
Ag/AgCl), which is ascribable to the oxidation of catalyst
form the xanthyl radical IIIa (orange dot). We then
electrochemically analyzed catalyst in the opposite order (Fig.
B to
B
11b), first applying an increasingly oxidizing potential (0 to +1.5
V). As expected, during oxidation, we observed the same signal
as in the previous experiment, which is congruent with the
formation of radical IIIa upon SET oxidation of
B (orange dot).
Interestingly, during the reverse scan towards reduction (from
+1.5 V to -2.0 V), an additional peak was observed (EpC = Ered = -
1.40 V in CH3CN vs Ag/AgCl), which was not detected in the
previous experiment (blue dot).
Scheme 3. Experiment that probes the ability of γ-terpinene to reduce the xanthyl
radical IIIa via both an HAT and an SET manifold.
We also performed laser flash photolysis studies on dimer
VIIa (Fig. 10a). When exposed to irradiation at 355 nm, the same
transient species observed in the experiment with intermediate
I
was detected (Fig. 7d), which is consistent with the formation
of the xanthyl radical IIIa. This transient was also detected when
a laser beam centered at 420 and 460 nm was used (see Figures
S27 and S28 in the ESI). This observation further confirms the
light-driven equilibrium that links dimer VIIa with its radical
progenitor IIIa (shown in Scheme 2). Moreover, the lifetime of
the transient IIIa decreased upon addition of γ-terpinene
(orange, green, and blue lines in Fig. 10b), which corroborates
the notion, discussed in Scheme 3, that these two species can
readily react.
Fig. 11. Cyclovoltammetric studies of catalyst B [0.02 M] in [0.1 M] TBAPF6 in
CH3CN: (a) reduction-oxidation scan sequence; (b) oxidation-reduction scan
sequence. (c) The xanthyl radical IIIa, which can be formed by SET reduction of
VIIa and oxidation of B, is the link between catalyst B and dimer VIIa. (d-e)
Cyclovoltammetric studies of dimer VIIa [0.02 M] in [0.1 M] TBAPF6 in CH3CN: (d)
oxidation-reduction scan sequence; (e) reduction-oxidation scan sequence.
Sweep rate: 500 mV/s. Pt electrode working electrode, Ag/AgCl (KCl 3.5 M)
reference electrode, Pt wire auxiliary electrode.
Fig. 10. (a) Absorption at 620 nm of the transient xanthyl radical IIIa generated
upon 355 nm laser excitation of dimer VIIa ([VIIa]0 = 3x10-3 M in acetonitrile). (b)
Decrease of the lifetime of IIIa upon addition of γ-terpinene. Note logarithmic scale
for time; ΔOD: optical density variation. Absorption decays (orange, green, and
blue lines) observed in the presence of increasing amounts of γ-terpinene. Green
line: ratio VIIa/γ-terpinene mimics the reaction conditions. ΔOD: optical density
variation.
These results can be rationalized based on a fast dimerization
of radical IIIa, generated during the forward oxidation scan, that
forms dimer VIIa, which is prone to SET reduction (Fig. 11c). This
proposal is consonant with the following observation: i) the
Collectively, the experiments detailed in Schemes 2 and 3
along with the laser flash photolysis studies reported in Fig. 10
provide compelling evidence that dimer VIIa can form xanthyl
radical IIIa upon photolytic cleavage. To collect direct evidence
of the dimerization tendency of the sulphur-centered radical
IIIa, we performed cyclic voltammetry analysis of both
formation of the stable dimer makes the oxidation of catalyst
B
irreversible, since IIIa is rapidly sequestered in the form of its
dimer; ii) it is only in the cyclic voltammetric analysis that starts
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with oxidation (Fig. 11b) that a reduction peak appears, which efficiency of the Giese addition path under stoichiometric
View Article Online
is ascribable to the reduction of dimer VIIa: this is because the conditions could be a consequence of thDeOeI:q1u0i.l1i0b3r9iu/Dm0SsCh0o2w31e3dB
dimer first requires the oxidation of catalyst
(Fig. 11c).
B
to be generated in Fig. 8, i.e. a higher amount of intermediate
I inhibits the
radical addition to the olefin since the acyl radicals are
To corroborate this proposal, we repeated the same analysis sequestered by
using dimer VIIa. Applying an initial forward scan towards an
increasingly oxidizing potential (0 to +1.5, Fig. 11d), no oxidation
was observed. As expected, during the reverse scan (from +1.5
V to -2.0 V), the reduction peak of dimer VIIa (blue dot) was
recorded (EpC = Ered = -1.61 V in CH3CN vs Ag/AgCl). But when we
started the electrochemical analysis towards reduction (0 to -
2.0 V and then to +1.5 V, Fig. 11e), an additional oxidation peak
could be observed (EpA = Eox = 0.53 V in CH3CN vs Ag/AgCl). This
is because the reduction of dimer VIIa furnishes the xanthyl
I.
radical IIIa along with the anionic catalyst B; the latter species is
then oxidized during the reverse scan phase (orange dot), in
agreement with the experiments depicted in Figures 11a-b.
The comparison of the cyclic voltammograms indicates a clear
correlation between the new reduction peak observed in the
analysis of catalyst
B in Fig. 11b with the peak observed upon
reduction of dimer VIIa (Fig. 11e). A correlation exists also
between the new oxidation peak in the analysis of dimer VIIa in
Fig. 11e and the oxidation of catalyst
Collectively, these studies indicate that the link between
catalyst and dimer VIIa is the xanthyl radical IIIa (Fig. 11c).
They also show the strong tendency of the xanthyl radical IIIa to
dimerize and form VIIa
B
(Figures 11a-b).40
B
.
Trap of the Acyl Radical and Ensuing Processes. The
mechanistic investigations conducted so far allowed us to
elucidate the photochemical acyl radical generation mechanism
while providing a rationale for the turnover of catalyst B. We
then focused on the C-C bond formation, which is triggered by
the trap of photogenerated acyl radical IIa by acrylonitrile 2a
(Fig. 12a). The emerging electrophilic radical IVa would then
abstract a hydrogen atom from γ-terpinene, affording the final
Fig. 12. (a) Focusing on the acyl radical addition step. The model reaction in the
presence of a stoichiometric amount of B and (b) in the absence or (c) in the
presence of γ–terpinene (group transfer conditions). (d) The behavior of group
transfer product IXa under the reaction conditions and upon blue light irradiation.
product 3a and the cyclohexadienyl radical
V. Since xanthates
and thiocarbamates of type have a strong tendency to
I
We then prepared an authentic sample of the group transfer
product IXa and subjected it to the optimized reaction
participate in group transfer manifolds,9 we wondered whether
this mechanistic path played an important role in the present
catalytic system. We therefore conducted investigations to
probe the possible intermediacy of the group transfer product
of type IXa. Intermediate IXa might be generated via a xanthate
transfer manifold between IVa and Ia, which would also
generate a benzoyl radical IIa (Fig. 12a). IXa could also arise
conditions, but in the absence of catalyst
B: the Giese-type
adduct 3a was obtained in moderate yield (35% yield, Fig.
12d).41 This experiment is relevant to the reaction mechanism,
since it implies the ability of the group transfer product, upon
irradiation by blue LEDs and in the presence of γ–terpinene, to
afford product 3a. This suggests that the group transfer product
IXa, upon irradiation, may regenerate the progenitor radicals
IIIa and IVa (inset in Fig. 12d). We also performed laser flash
photolysis studies of intermediate IXa, observing a transient
that is consonant with the xanthyl radical IIIa, generated upon
photolysis (see Figure S30 in the ESI).
Although we never detected the group transfer adduct of
type IX under catalytic conditions, we cannot exclude that this
pathway is operative in our catalytic system. It is possible that
intermediate IX may serve as another stabilizing, off-the-cycle
intermediate, which can control the concentration of radical IIIa
in solution through an additional equilibrium.
from a cross-coupling process between radicals IIIa and IVa
When excluding γ-terpinene from the reaction, performed
using an excess of xanthate (1.4 equiv.), the group transfer
.
B
product IXa was isolated in 35% yield (Fig. 12b). The Giese-type
adduct 3a was not detected, which indicates the importance of
γ-terpinene in enabling the radical conjugate addition manifold.
By contrast, under identical conditions but in the presence of γ–
terpinene, no traces of the group transfer product IXa could be
detected, while the product 3a was exclusively formed (23%
yield, Fig. 12c). Interestingly, the yield of 3a was much lower
with respect to the experiment conducted using catalytic
amounts of
B (10 mol%, 82% yield). We suppose that the lower
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radical IIIa, e.g. a direct HAT process and an SET reVdieuwcAtirtoicnlefOrnolimne
Overall Catalytic Cycle and Full Mechanistic Picture. The the ensuing cyclohexadienyl-type radical DOI: 10.1039/D0SC02313B
mechanistic studies provided important clues to better The main feature of the proposed mechanism in Fig. 13 is that
delineate the mechanism of the photochemical Giese addition it proceeds through a photocatalytic process, where the
process. The full mechanistic picture is detailed in Fig. 13. We photoactivity of intermediate dictates the formation of any
V
.
I
have identified that the overall catalytic cycle is regulated by molecule of the product. This scenario stands in contrast to a
different equilibriums that are essential to stabilizing the radical possible alternative radical chain propagation manifold, which
intermediates and controlling their overall concentration. For would require the photoactivity of intermediate
example, the highly reactive acyl radical II could be intercepted as an initiation event. A tool to discriminate between these two
by xanthates of type in a reversible addition-fragmentation mechanistic possibilities is to measure the quantum yield (Φ) of
I to serve only
I
equilibrium, leading to intermediate VI. At the same time, the the overall reaction.42 We performed this measurement on the
xanthyl radical IIIa can both dimerize to form dimer VIIa and model reaction, and the quantum yield was found to be as low
engage in a cross-coupling process with radical IVa to afford the as 0.034 (λ = 460 nm, using potassium ferrioxalate as the
xanthate transfer product IXa. These equilibriums, which are actinometer). This result suggests that a radical chain process,
regulated by light, confer a persistent radical character to the based on either a xanthate group transfer manifold (Fig. 12a) or
xanthyl radical IIIa, facilitating its reduction and the turnover of an SET from intermediate IV to intermediate
the catalyst . Importantly, we have demonstrated that γ- Instead, the low quantum yield is congruent with the proposed
terpinene can use two different pathways to reduce the xanthyl photocatalytic mechanism depicted in Fig. 13.
I
, is unlikely.43
B
Fig. 13. Detailed mechanistic picture, comprehensive of the off-the-cycle equilibriums, based on the mechanistic investigations conducted on the model reaction of acyl
chloride 1a and acceptor 2a catalyzed by B.
transient
absorption
spectroscopy
investigations,
electrochemical studies, quantum yield measurements, and the
characterization of key intermediates. Collectively, these
studies identified a variety of off-the-cycle intermediates that
are in a light-regulated equilibrium with the reactive radicals.
These regulated equilibriums cooperate to control the overall
concentrations of the radicals, contributing to the efficiency of
the process. The knowledge of the mechanistic details
underlying this radical generation strategy may enable the
rational development of new reactions. Our ongoing efforts are
directed toward these aims.
Conclusions
In summary, we have developed a catalytic methodology that
requires visible light and commercially available organic
catalysts to access a wide range of acyl and carbamoyl radicals.
These reactive intermediates are then trapped with a variety of
electron-poor olefins in a Giese addition manifold. This
methodology relies on the electrophilicity of the substrates
rather than their reduction potential, allowing the use of readily
available carboxylic acids/chlorides and carbamoyl chlorides
(which would be recalcitrant to other radical generation
strategies) as acyl and carbamoyl radical precursors. Extensive
mechanistic investigations have been performed, including
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15 R. S. Grainger and P. Innocenti, Angew. Chem., Int. Ed., 2004,
Conflicts of interest
There are no conflicts to declare.
View Article Online
43, 3445–3448.
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Acknowledgements
D. Crich and A. Papadatos, J. Am. Chem. Soc., 1992, 114
,
8313−8314; (e) D. Crich, C. Chen, J.-T. Hwang, H. Yuan, A.
We thank MINECO (CTQ2016-75520-P), and the European
Research Council (ERC 681840 - CATA-LUX) for financial
support. D.M. thanks H2020-MSCA-ITN-2016 (722591–
PHOTOTRAIN) for a predoctoral fellowship. We thank Dr.
Bertrand Schweitzer-Chaput (ICIQ), Dr. Frank A. Arroyave (ICIQ),
Mr. Davide Spinnato (ICIQ), and Dr. Robert Davidson (Dr.
Reddy’s Laboratories) for useful discussions and precious
mechanistic insights. We thank Dr. Javier Pérez Hernández
(ICIQ) for assistance with laser flash photolysis experiments.
Papadatos and R. I. Walter, J. Am. Chem. Soc., 1994, 116
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13 (a) D. H. R. Barton, M. V. George and M. Tomoeda, J. Chem.
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28 For a recent photoredox catalytic method of acyl radical
formation from carboxylic acids, see: (a) E. E. Stache, A. B.
and S. Z. Zard, Org. Lett., 2004, 6, 4969−4972; (d) J. H. Penn
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14 J. Lalevée, N. Blanchard, M. El-Roz, X. Allonas and J. P.
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12 | Chem. Sci., 2020, 10, xx-xx
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Chemical Science
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Chemical Science
EDGE ARTICLE
9
, 3517; (c) J. I. Martinez Alvarado, A. B. Ertel, A. Stegner, E. E. 42 L. Buzzetti, G. E. M. Crisenza and P. Melchiorre, AVniegweAwrt.icClehOenmlin.e,
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Yoon, Chem. Sci., 2015, , 5426–5434.
43 In general, a low quantum yield (Φ < 1) does not completely
exclude a possible radical chain process, since it can be a
consequence of a highly inefficient initiation step. In our case,
the non-productive photoprocesses depicted in Figure 13
29 D. C. Blakemore, L. Castro, I. Churcher, D. C. Rees, A. W.
6
Thomas, D. M. Wilson and A. Wood, Nat. Chem., 2018, 10
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,
30 (a) M. C. Quattrini, S. Fujii, K. Yamada, T. Fukuyama, D. Ravelli,
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(e.g., VIIa to IIIa, IXa to IVa), while inferring long lifetime to
radical IIIa, can affect the quantum yield of the overall
process.
31 For examples on carbamoyl radicals generated through single
electron oxidation: (a) M. Jouffroy and J. Kong, Chem. Eur. J.,
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Table of Contents
32 For the generation of carbamoyl radicals from
carbamoylxanthates through the use of a thermal initiator,
see: (a) G. López-Valdez, S. Olguín-Uribe and L. D. Miranda,
Tetrahedron Lett., 2007, 48, 8285–8289; (b) A. Millán-Ortiz, G.
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33 S. Hosseyni and A. Jarrahpour, Org. Biomol. Chem., 2018, 16
6840–6852.
,
A commercially available nucleophilic organic catalyst uses low-
energy photons to generate acyl and carbamoyl radicals upon
activation of the corresponding chlorides and anhydrides via a
nucleophilic acyl substitution path. The synthetic potential and the
mechanism of this catalytic radical generation strategy are discussed
herein.
34 A. Kaga, X. Wu, J. Y. J. Lim, H. Hayashi, Y. Lu, E. K. L. Yeow and
S. Chiba, Beilstein J. Org. Chem., 2018, 14, 3047–3058.
35 (a) B. Bieszczad, L. A. Perego and P. Melchiorre, Angew.
Chem., Int. Ed., 2019, 58, 16878–16883; (b) D. G. Hawthorne,
G. Moad, E. Rizzardo and S. H. Thang, Macromolecules, 1999,
32, 5457–5459.
36 S. Perrier, Macromolecules, 2017, 50, 7433−7447.
37 S. Z. Zard, Helv. Chim. Acta, 2019, 102, e1900134.
38 In analogy with the experiment depicted in Scheme 2, we also
found that the dimer of catalyst
C, which is commercially
available, is a competent catalyst to promote the formation of
carbamoyl radicals. Specifically, under the conditions
reported in Figure 5, 10 mol% of the dimer of
C promotes the
reaction of dimethylcarbamoyl chloride and vinyl sulfone to
afford the Giese adduct 9a in 53% yield, see Section D1.5 in
the ESI for details.
39 (a) D. Griller and U. K. Ingold, Acc. Chem. Res., 1976, 9, 13–19;
(b) K. S. Focsaneanu and J. C. Scaiano, Helv. Chim. Acta., 2006,
89, 2473–2482; (c) D. Leifert and A. Studer, Angew. Chem., Int.
Ed., 2020, 59, 74–108.
40 The small discrepancy in the values of the redox potentials are
due to the difference in concentrations of the redox-active
species. For example, in the case of the reduction peaks (Ered),
which refer to the SET reduction of dimer VIIa, the
concentration of VIIa is much higher in the analysis depicted
in Figures 11d-e than in Figure 11b. This is because, in the
latter case, dimer VIIa is in situ generated upon oxidation of
catalyst
B and dimerization of the ensuing xanthyl radical IIIa.
41 We collected evidence that the group transfer intermediate
of type IX may play a mechanistic relevant role also in the
intramolecular process involving carbamoyl radicals detailed
in Fig. 6. Specifically, when an authentic sample of a group
transfer adduct, prepared according to Ref. 15, was subjected
to the optimized conditions for the intramolecular process,
but in the absence of the dithiocarbamate catalyst
C, the
cyclization product 11a was obtained in moderate yield (48%
yield). This experiment implies that, in analogy to the
intermolecular process, the group transfer adduct may be a
relevant intermediate also in the intramolecular variant. See
section D1.6, page S48 of the ESI for details.
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