Studies on the Enantioselective Iminium Ion Trapping of Radicals Triggered by an Electron-Relay Mechanism

Article abstract of DOI:10.1021/jacs.7b01446

A combination of electrochemical, spectroscopic, computational, and kinetic studies has been used to elucidate the key mechanistic aspects of the previously reported enantioselective iminium ion trapping of photochemically generated carbon-centered radicals. The process, which provides a direct way to forge quaternary stereocenters with high fidelity, relies on the interplay of two distinct catalytic cycles: the aminocatalytic electron-relay system, which triggers the stereoselective radical trap upon iminium ion formation, and the photoredox cycle, which generates radicals under mild conditions. Critical to reaction development was the use of a chiral amine catalyst, bearing a redox-active carbazole unit, which could rapidly reduce the highly reactive and unstable intermediate generated upon radical interception. The carbazole unit, however, is also involved in another step of the electron-relay mechanism: the transiently generated carbazole radical cation acts as an oxidant to return the photocatalyst into the original state. By means of kinetic and spectroscopic studies, we have identified the last redox event as being the turnover-limiting step of the overall process. This mechanistic framework is corroborated by the linear correlation between the reaction rate and the reduction potential of the carbazole unit tethered to the aminocatalyst. The redox properties of the carbazole unit can thus be rationally tuned to improve catalytic activity. This knowledge may open a path for the mechanistically driven design of the next generation of electron-relay catalysts.

Full text of DOI:10.1021/jacs.7b01446

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Article
Studies on the Enantioselective Iminium Ion Trapping
of Radicals Triggered by an Electron-Relay Mechanism
Ana Bahamonde, John J. Murphy, Marika Savarese, Eric Bremond, Andrea Cavalli, and Paolo Melchiorre
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b01446 • Publication Date (Web): 10 Mar 2017
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Ana Bahamonde, John J. Murphy, Marika Savarese, Eric Bremond, Andrea Cavalli,
,
†,§
and Paolo Melchiorre*
†
ICIQ - Institute of Chemical Research of Catalonia – the Barcelona Institute of Science and Technology, Avinguda Països
Catalans 16, 43007 Tarragona, Spain
‡
D3 CompuNet, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy.
§
ICREA - Catalan Institution for Research and Advanced Studies, Passeig Lluís Companys 23, 08010 Barcelona, Spain.
Supporting Information Available
ABSTRACT: A combination of electrochemical, spectroscopic, computational, and kinetic studies has been used to elucidate the
key mechanistic aspects of the previously reported enantioselective iminium ion trapping of photochemically generated carbon-
centered radicals. The process, which provides a direct way to forge quaternary stereocenters with high fidelity, relies on the inter-
play of two distinct catalytic cycles: the aminocatalytic electron-relay system, which triggers the stereoselective radical trap upon
iminium ion formation, and the photo-redox cycle, which generates radicals under mild conditions. Critical to reaction development
was the use of a chiral amine catalyst, bearing a redox-active carbazole unit, which could rapidly reduce the highly reactive and
unstable intermediate generated upon radical interception. The carbazole unit, however, is also involved in another step of the elec-
tron-relay mechanism: the transiently generated carbazole radical cation acts as an oxidant to return the photocatalyst into the origi-
nal state. By means of kinetic and spectroscopic studies, we have identified the last redox event as being the turnover-limiting step
of the overall process. This mechanistic framework is corroborated by the linear correlation between the reaction rate and the reduc-
tion potential of the carbazole unit tethered to the aminocatalyst. The redox properties of the carbazole unit can thus be rationally
tuned to improve catalytic activity. This knowledge may open a path for the mechanistically driven design of the next generation of
electron-relay catalysts.
the chemistry provided a catalytic method to forge quaternary
6
1
carbon stereocenters with high fidelity by means of an enanti-
Iminium ion activation is an established strategy of mod-
7-9
oselective radical conjugate addition (RCA)
to β-
ern organic chemistry for effectively synthesizing enantio-
enriched chiral molecules. The approach exploits the capacity
of chiral primary or secondary amines to reversibly condense
with unmodified α,β-unsaturated carbonyl compounds to form
iminium ion intermediates A (Figure 1a). The electronic redis-
tribution within A, by lowering the energy of the lowest unoc-
cupied molecular orbital (LUMO), facilitates conjugate addi-
tions of soft nucleophiles to the β-carbon atom. At the same
time, the chiral amine fragment dictates the stereochemistry of
the final β-functionalized products. This catalytic platform has
found many applications in the polar domain over the last 15
years, effectively complementing established metal-based
asymmetric strategies for conjugate additions to unsaturated
carbonyl compounds. However, chiral iminium ions A have
never been used to stereoselectively trap nucleophilic radicals.
This is surprising given the strong tendency of open-shell
disubstituted enones 1 (Figure 1b).
2
3
4
species to react with electron-deficient olefins.
Figure 1. Iminium-ion-mediated catalysis: (a) Established polar
reactivity of chiral iminium ions A in enantioselective conjugate
additions of soft nucleophiles. (b) Radical conjugate addition (RCA)
to chiral iminium ions A catalytically generated from β-disubstituted
enones 1 to forge quaternary stereocenters; filled grey circle repre-
sents a bulky substituent on the chiral amine catalyst.
Recently, our laboratories reported a strategy to fill this gap
in catalytic enantioselective methodology. We showed that the
applicability of iminium ion activation is not limited to two-
electron reaction manifolds. Rather, it can be successfully
5
expanded to include radical reactivity domains. Synthetically,
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In successfully realizing a stereocontrolled iminium ion
trapping of radicals, one factor was crucial: the design of a
chiral amine catalyst, purposely adorned with a carbazole
redox-active moiety. Our design plan was motivated by the
instability of the α-iminyl radical cation B, a short-lived inter-
mediate generated upon radical addition to the cationic imini-
um ion A (Figure 2a). In consonance with the classical behav-
driven intramolecular reduction of B. Meanwhile, the kinetic
stability of the long-lived carbazole radical cation in D allows
for a productive intermolecular SET reduction from the re-
1
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duced photocatalyst (PCred in Figure 2b).
The effectiveness of this electron-relay mechanism was ini-
tially demonstrated in the reaction between the commercially
available β-methyl cyclohexenone 1a and benzodioxole 2a
Figure 3a). We used the inorganic photocatalyst tetrabu-
tylammonium decatungstate (TBADT, 5 mol%). Upon light
excitation, TBADT can easily photogenerate a nucleophilic
carbon-centered radical by homolytically cleaving the meth-
ylene C-H bond in 2a via a hydrogen-transfer mechanism
HAT). The experiments were conducted at 35 ºC in acetoni-
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ior of radical ions, intermediate B has a high tendency to
(
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undergo radical elimination (β-scission), thus reforming the
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more stable conjugated iminium ion A. We recognized that the
main obstacle to reaction development was the high reactivity
and fleeting nature of the distonic radical B.
17
(
trile (CH CN) and under irradiation by a single black-light-
emitting diode (black LED, λmax = 365 nm).
3
Figure 2. (a) Challenges associated with implementing the iminium-
3
ion-catalyzed conjugate additions of radicals (·R ); the grey circle
represents the chiral organic catalyst scaffold. (b) The electron-relay
strategy to bypass the short-lived α-iminyl radical cation B by intra-
molecular reduction, and the role of tautomerization to prevent back-
electron transfer. SET = single-electron transfer. BET = back-electron
transfer. PC = photocatalyst; PCred = reduced form of the photocata-
lyst. The blue ellipse represents the electron-rich reducing carbazole
moiety, while the magenta ellipse represents the persistent carbazole
radical cation.
Figure 3. (a) The model reaction to test the feasibility of the electron-
relay strategy. (b) The unanticipated effect that the redox properties of
the carbazole-based primary amine catalysts 4 have on the reactivity.
1/2 is the reduction potential of the carbazole-based catalysts 4a-d as
3
measured by cyclic voltammetry vs Ag/Ag in CH CN; the carbazole
within 4 undergoes a reversible oxidation to produce the correspond-
ing carbazoliumyl radical cation. (c) Experiments suggesting that, to
make the electron-relay mechanism operative, there needs to be close
spatial proximity between the iminium ion handle and the redox
active carbazole moiety.
E
Our main idea for taming this troublesome intermediate
was to tether an electron-rich carbazole moiety (electron pool
unit in Figure 2b) at a strategic position on the organocatalyst
where it is poised to undergo a very rapid intramolecular sin-
gle-electron transfer (SET) reduction of the unstable species B,
preventing it from breaking down. The nascent enamine in-
termediate C then tautomerizes to form the more stable imine
+
1
2
The chiral cyclohexylamine catalyst 4a, adorned with the
carbazole moiety, provided the desired product 3a with appre-
ciable yield and stereoselectivity (33% yield, 82% ee, Figure
D, thus avoiding a possible competitive back-electron trans-
fer (BET). Finally, the carbazole radical cation (electron hole
unit within D), arising from the intramolecular SET event,
undergoes single-electron reduction from the photoredox
catalyst. This restores the neutral carbazole moiety while
yielding the quaternary product and releasing the original
organocatalyst. Notably, a photocatalyst (PC in Figure 2b)
both creates the nucleophilic radical and promotes the final
SET event (full mechanistic details in Figure 4). Overall, in
this catalytic system, the carbazole unit serves as an electron-
relay center, since it behaves alternately as an acceptor and a
3
b). In consonance with the proposed electron-relay mecha-
nism, the reaction could not be catalyzed by simple cyclohex-
ylamine 5 (20 mol%), which mimics the catalyst’s 4a scaffold
while lacking the redox-active moiety (Figure 3c). Also, an
equimolar combination of cyclohexylamine 5 and exogenous
N-cyclohexyl 3,6-di-tert-butyl-carbazole 6 (20 mol%) proved
unsuitable for catalysis, indicating the importance of a proxim-
ity-driven intramolecular SET process to reduce the unstable
α-iminyl radical cation B.
1
3
donor to shuttle electrons. First, the excellent electron-
donating capabilities of the carbazole trigger a fast proximity-
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However, during the optimization campaign, we came
Herein, we detail how a combination of physical organic
techniques, including electrochemical and kinetic studies,
allowed us to rationalize the effects the electronic properties of
the redox-active carbazole unit have on the reaction rate.
These investigations revealed an unanticipated turnover-
limiting step. They also confirmed the importance of the pro-
posed electron-relay mechanism in triggering the enantioselec-
tive iminium ion trapping of photochemically generated radi-
cals.
across an unanticipated effect of the redox properties of the
carbazole scaffold within the amine catalysts 4 on the reaction
rate (Figure 3b). When modifying the redox-active carbazole
by introducing substituents of different electronic nature at the
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- and 6-positions, we expected the presence of electron-
donating groups to accelerate the overall radical conjugate
addition process. This is because an increase in electron densi-
ty within the carbazole electron pool should facilitate the SET
reduction of intermediate B, a step that we envisioned would
be crucial for reactivity (Figure 2b). In contrast, catalyst 4d,
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bearing a CF electron-withdrawing group at the 3,6-positions
3
Figure 4 presents a detailed description of the proposed
mechanism for the iminium-ion-mediated RCA, which is
characterized by the synergistic activities of two intertwined
manifolds: the iminium ion and the photoredox catalytic cy-
cles. It is important to note that a radical chain mechanism is
not possible in this system. This is because generating a radi-
cal from substrate 2a requires a HAT mechanism, while the
feasibility of a chain propagation sequence could only rely on
the oxidation ability of the carbazole radical cation within
intermediate D-1, which could manifest itself exclusively
through an outer-sphere SET manifold.
of the carbazole which depletes the electron pool, was consid-
erably more active than the more reducing catalyst 4b and 4c
(results in Figure 3b). The redox potentials of catalysts 4a-d,
+
as measured by cyclic voltammetry vs Ag/Ag in CH CN (E
3
1/2
(4b) = +1.16 V; E1/2 (4c) = +1.24 V; and E1/2 (4d) = +1.68 V,
where E1/2 is the reduction potential of the carbazole unit un-
dergoing a reversible oxidation to produce the corresponding
carbazoliumyl radical cation), further indicated that the cata-
lyst 4d, bearing the less reducing carbazole, displayed the
1
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highest catalytic activity. This unexpected result challenged
our understanding of the reaction mechanism and prompted us
to undertake extensive mechanistic investigations.
Figure 4. The electron-relay mechanism underlying the iminium-ion-mediated enantioselective radical conjugate addition to enone 1a. Upon
radical addition to the iminium ion A-1, the electron-relay mechanism bypasses the unstable distonic radical B-1 producing a carbazoliumyl radical
cation C-1, which is prevented from undergoing back-electron transfer by tautomerization of the secondary enamine to the corresponding imine D-
1
. The redox-active carbazole unit plays two critical roles: (i) the carbazole acts as a reducing agent to transform the short-lived α-iminyl radical
cation B-1 into the stable enamine C-1 upon intramolecular SET reduction; (ii) the long-lived carbazoliumyl radical cation in D-1 regenerates the
photocatalyst (TBADT) by intermolecular SET oxidation of the reduced form (TBADT-H), affording the neutral imine E-1, which eventually
hydrolyzes to liberate the aminocatalyst 4. The grey rectangle shows the TBADT-mediated photoredox cycle, which affords the carbon-centered
radical from benzodioxole precursors 2 by means of a HAT mechanism. SET = single-electron transfer, HAT: hydrogen-atom transfer.
The notion that the CF -containing catalyst 4d offered an
However, the intramolecular SET reduction of B-1 to give
the enamine intermediate C-1 is not the only electron-relay
step in which the redox-active carbazole unit is involved.
The carbazole radical cation in the imine D-1, arising from
the tautomerization of the secondary enamine C-1, acts as an
oxidant of the reduced photocatalyst (TBADT-H). This
3
improved reactivity in the model reaction was dissonant with
our mechanistic hypothesis that an easier reduction of the
short-lived α-iminyl radical cation B-1 would facilitate the
reaction (see reactivity trend in Figure 3b). Indeed, this step
should be hampered by an electron-poor carbazole unit.
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bimolecular SET event is essential to restore the neutral
mW/cm . Under this regime, where the reaction is not light-
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carbazole moiety within E-1 while closing the photoredox
cycle, returning the TBADT catalyst in the original state.
This step could be facilitated by an electron-poor substituent
which magnifies the oxidizing power of the carbazole radical
cation in D-1. We performed detailed kinetic studies to as-
sess the relative importance of the two SET steps of the
electron-relay mechanism (intramolecular reduction of B-1
to afford the carbazole radical cation and regeneration of the
neutral carbazole unit in E-1 by intermolecular SET) and
their influence on the overall reactivity.
limited, the overwhelming majority of the TBADT photo-
catalyst could be opportunely excited. Considering the light
intensity/reactivity correlation depicted in Figure 5, all the
following kinetic studies were performed using the set-up
discussed above and an illumination system (HP black LED,
2
λmax = 365 nm) with an irradiance of 60±2 mW/cm . This
ensured the reactions were not light-limited.
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Kinetic Studies. As the model for the kinetic studies, we
chose the reaction between the commercially available β-
methyl cyclohexenone 1a and 2-methyl benzodioxole 2b to
afford the radical conjugate addition product 3b (Scheme 1).
This decision was based on the complete lack of reactivity
0,2
0,1
0
0
20
40
60
80
Irradiance (mW/cm2)
observed in the absence of the chiral aminocatalyst of type
Figure 5. Light intensity/reactivity correlation studies. Model reac-
tions conducted as specified in Scheme 1 and catalyzed by 4b.
20
4
,
which precluded any background process from altering
the kinetic analysis.
We then focused on the unexpected observation that the
catalytic activities of catalysts 4a-d, as detailed in Figure 2b,
inversely correlated with the reducing power of the carbazole
unit. Specifically, we wondered whether the electronic prop-
erties of the chiral catalysts were solely responsible for the
different reactivities, since steric effects could also influence
the reaction rate. For example, the data in Figure 2b clearly
indicated how the steric profile of the carbazole substituents
in catalysts 4a-d was strongly connected with the level of
stereo-induction in the RCA process. To clearly differentiate
the electronic and steric effects, a new family of catalysts,
containing para-substituted aryl moieties at the 3,6-carbazole
positions, was synthetized (catalysts 4e-h, Figure 6a).
Scheme 1. The model reaction for the kinetic investigations. Reac-
tions conducted under irradiation from a high-power (HP) single
black-light-emitting diode (black LED, λmax = 365 nm). [4] = 0.1 M,
[
1a] = 0.5 M, [2a] = 1.5 M, [TBADT] = 0.025 M, [TBABF
4
] = 0.5
4
M and [benzoic acid] = 0.1 M. TBABF : tetrabutylammonium
tetrafluoroborate.
The para-substitution pattern was carefully chosen to
provide the redox-active carbazole unit with a wide range of
electronic properties but a comparable steric shielding abil-
ity. In consonance with this design plan, catalysts 4e-h all
promoted the model reaction to afford the product 3b with
the same level of stereocontrol (in the range of 87-88% of
enantiomeric excess, ee), thus demonstrating that a compara-
ble chiral environment and shielding effect was created at the
The experiments were conducted at ambient temperature
in the presence of the carbazole-based aminocatalyst 4 (20
mol%), TBADT (5 mol%), benzoic acid (20 mol%, to facili-
2
1
tate iminium ion formation), and an excess of radical pre-
cursor 2b (3 equiv). Deuterated acetonitrile (CD CN) was
3
used as the solvent for it secured full substrate solubility and
homogeneity of the system. We applied the method of ini-
tial-rate kinetics, monitoring the progress of the reactions by
22
1
remote β-carbon of the reactive iminium ion intermediate.
H NMR analysis and following the conversion until 15%.
These results suggested that the para-substituted 3,6-aryl
carbazole catalysts 4e-h are characterized by a similar steric
profile, and that possible differences in reaction rate should
arise from electronic factors exclusively.
The initial rates were plotted against concentration to obtain
straight lines (see Section D in the Supporting Information
for details). Our initial-rate kinetic studies required an inde-
pendent reaction to be performed for every data-point at
different times.
On this basis, we explored how varying the electronic
properties of the chiral carbazole catalysts 4e-h affected the
rate of the model reaction depicted in Scheme 1, discounting
any steric contribution. Applying the method of initial-rate
kinetics, we confirmed that catalysts bearing more electron-
withdrawing groups within the carbazole unit imparted a
higher rate, with catalyst 4f providing the faster reaction. In
addition, we observed a positive linear correlation between
the rate constants and the Hammett σpara value of the aryl
moiety in catalysts 4e-h. Figure 6b shows the linear free-
First, we evaluated the influence of the light intensity on
the rate of the model reaction detailed in Scheme 1 and cata-
lyzed by the chiral amine 4b (Figure 5). For the illumination
system, we used a single high-power (HP) black-light-
emitting diode (black LED, λmax = 365 nm) connected to an
external power supply, which allowed us to finely tune and
control the intensity of light emission. The irradiance was
carefully measured with a photodiode light detector at the
start of each reaction. To secure a reliable and consistent
irradiation throughout the kinetic investigation, we used a
set-up that maintained a constant distance of 1.5 cm between
the reaction vessel and the light source (full details in Sup-
plementary Figure 1). The rate of the model reaction cata-
lyzed by 4b was found to linearly correlate with the light
intensity, flattening out for irradiances higher than 40
2
3
energy relationship (LFER) between the electronics of the
carbazole unit within catalysts 4 and the rate constant of the
catalyzed reaction.
Since the electronic properties directly influence the re-
dox power of the carbazole unit, it is unsurprising that the
observed initial rates also correlated linearly with the redox
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potentials of aminocatalysts 4e-h, measured electrochemical-
aryl substituents (Figure 6d). In principle, this correlation
provides a way to predict both the electrochemical potential
and the catalytic activity of new members of the para-
substituted 3,6-aryl carbazole catalyst family.
+
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ly by cyclic voltammetry vs Ag/Ag in CH CN (Figure 6c).
3
A linear relationship also persisted between the catalyst
redox potentials and the σpara value of the para-substituted
b
Hammett Plot
0
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,4
4h
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g
,2
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,0 4f
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y = 0,591x - 0,0326
R² = 0,9858
-
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-
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σpara
c
d
E1/2 vs Hammett
Rates vs E1/2
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,20
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h
0,15
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4h
4
g
4g
4
e
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f
y = 0,2863x + 1,1002
R² = 0,9968
0
,5
y = 0,444x - 0,4054
R² = 0,976
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,05
,00
0
-0,3
0
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1,1
E1/2 (V)
1,2
1,3
σ
para
Figure 6. (a) A new family of chiral catalysts: para-substituted 3,6-aryl carbazole catalysts 4e-h. They promoted the model reaction depicted in
Scheme 1 inferring the same level of stereoselectivity (87-88% ee). E1/2 is the reduction potential of the carbazole-based catalysts 4e-h as measured
+
by cyclic voltammetry vs Ag/Ag in CH
3
CN; the carbazole within 4 undergoes a reversible oxidation to produce the corresponding carbazoliumyl
radical cation. (b) LFER correlating the Hammett σ value of the para-substituted aryl carbazole moiety with the initial rates for the model reaction
depicted in Scheme 1 catalyzed by catalysts 4e-h. (c) Correlations between the initial rates and the redox potentials measured for the different
aminocatalysts 4e-h. (d) Linear relationship between the redox potentials for the different aminocatalysts and the corresponding Hammett σ value
2
of their aryl moiety. Reactions performed in CD
3
CN under illumination by HP black LED, λmax = 365 nm, with an irradiance of 60±2 mW/cm . [4]
= 0.1 M, [1a] = 0.5 M, [2a] = 1.5 M, [TBADT] = 0.025 M, [TBABF
the standard deviation.
4
] = 0.5 M and [benzoic acid] = 0.1 M. The error bars on Figure 6c represent
Collectively, these results indicate that the electronic
properties of the catalyst carbazole unit, which are strictly
correlated with their redox abilities, strongly influence the
rate of the model reaction. Specifically, the larger the reduc-
tion potential of the carbazole tethered to the aminocatalyst,
the faster the reaction proceeds. To fully rationalize this
redox properties/reactivity relationship, we undertook a
reaction-profile analysis and rate-order assessment to estab-
lish the turnover-limiting step. Initial-rate kinetic investiga-
tions of the model reaction depicted in Scheme 1 were per-
formed across a range of concentrations for each reaction
component. In these studies, we used an illumination system
investigated, the rate dependence was found to be curved,
showing a saturation kinetic profile. This behavior indicates
that the amine catalyst 4 is partitioned between the free-state
and the iminium ion intermediate A-1.
(HP black LED, λ = 365 nm) with an irradiance of 60±2
max
2
mW/cm to ensure that the processes were not light-limited.
Figure 7. The model reaction used for initial-rate kinetics and the
1
Two independent series of kinetic investigations were per-
formed using carbazole-based aminocatalysts 4b and 4e,
which provided similar and reproducible kinetic profiles.
This was done to ensure that similar trends could be ob-
served when using catalysts with different architectures and
steric profiles on the redox active carbazole unit.
observed rate orders. Conversions determined by H NMR analysis.
Studies performed across a range of concentrations for each reaction
component in CD CN. The kinetic studies were repeated twice
3
using amines 4b and 4e to catalyze the model transformation; both
studies gave similar kinetic profiles.
1
To corroborate this scenario, we used H NMR spectros-
Figure 7 details the results of our initial-rate kinetic inves-
tigations. The reaction was found to be first order in the
catalyst (both amines 4b and 4e). No order was observed in
copy to investigate the equilibrium of iminium ion formation
under the conditions used in the kinetic experiments (Figure
8
). The protonated free catalyst 4b·PhCO H, the imine F-1,
2
2
-methyl benzodioxole 2b, the radical precursor. Interesting-
and the iminium ion A-1 were detected in a ratio of
:0.3:1.3, respectively. These spectroscopic studies are con-
ly, when the β-methyl cyclohexenone 1a dependence was
1
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Page 6 of 9
sonant with the notion that it is not possible to identify a
.
On the one hand, lowering the amount of photocatalyst is
directly reflected in a lower concentration of reactive
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definitive resting state for catalyst 4b, with the catalyst con-
centration being shared between different closed-shell inter-
mediates.
open-shell intermediates, since they are generated from
substrate 2b through an HAT mechanism triggered by
the photoexcited TBADT. The reduction of the overall
reaction rate could be explained in terms of the turnover-
limiting step being the radical trapping by the iminium
ion A-1 (the radical conjugate addition step which forms
the new carbon-carbon bond while forging the stereogen-
ic center). In this scenario, the strong influence of the
catalyst’s electronic properties on the reaction rate could
be rationalized in terms of the inductive effect of the car-
bazole moiety influencing the electrophilicity of the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 8. The partitioning of the chiral amine catalyst 4b between
different intermediates and the formation of the iminium ion A-1
25
iminium ion intermediate A-1.
1
under the reaction conditions used for the kinetic studies. H NMR
.
On the other hand, less TBADT in solution also
means that a lower amount of the reduced photocatalyst
TBADT-H in Figure 4) would be formed upon radical
experiments performed in anhydrous CD
0.1 M, [1a] = 0.5 M, [2a] = 1.5 M, [TBADT] = 0.025 M,
[NBu BF ] = 0.5 M and [benzoic acid] = 0.1 M. The experiment
3
CN at 298 K with [4b] =
(
4
4
formation (HAT from substrate 2). TBADT-H is directly
involved in the intermolecular SET event that reduces the
long-lived carbazoliumyl radical cation in D-1 to return
both the neutral organic catalyst (intermediate E-1) and
the photoredox catalyst in the original state. This bimo-
lecular SET event, which is essential to close both the
iminium ion and the photoredox cycles, could also be the
turnover-limiting step of the overall process. This could
easily explain the striking correlation (Figures 6c) be-
tween the reaction rate and the reduction potential of the
was conducted in the dark.
In principle, the amount of water in solution might influ-
ence the formation of the iminium ion A-1. We thus explored
the effect of water on the rate of the model reaction. No
alteration of the kinetic profile was observed after the addi-
tion of either 1 or 5 equivalents of H O. These results indi-
2
cate that the turnover is not limited by either the iminium ion
A-1 formation or the hydrolysis of the imine intermediate E-
1, which leads to the alkylation product 3b while liberating
the catalyst 4 (see Figure 4 for the full mechanistic picture).
2
6
carbazole unit tethered to the aminocatalyst 4. Since the
4
-
5-
TBADT /TBADT redox couple is reported at -0.96 V
The zeroth-order dependence on radical precursor 2b is
not surprising, given that the amount of radicals in solution is
dictated by the amount of TBADT photocatalyst, which is
present in low concentration (generally 5 mol%). We thus
focused on the reaction rate’s dependence on TBADT, which
could give useful information for extrapolating the reaction
mechanism. As mentioned before, experiments were per-
formed under saturation of light, so to maximize the amount
of excited photocatalyst in solution. When doubling the
amount of photocatalyst (10 mol%), no change was observed
in the reaction rate (Figure 9). However, lowering the
amount of TBADT to 2.5 or 1.25 mol% decreased the rate of
the model reaction, indicating a saturation kinetic profile in
+ 27
vs Ag/Ag , a larger oxidizing power of the carbazoli-
umyl radical cation should greatly facilitate the oxidation
of TBADT-H by the intermediate D-1. This is because
the exergonicity of SET from TBADT-H to D-1 increas-
es when the electron density on the carbazole unit is re-
duced (4f < 4e < 4g < 4h). This was the exact reactivity
trend observed in the kinetic studies: for example, the re-
action catalyzed by amine 4h (E1/2 = +1.25 V) is faster
than the amine 4f-mediated process (E1/2 = +1.02 V).
Our goal was to unambiguously discriminate between
these two possibilities and to eventually ascertain the overall
rate-limiting event. The second mechanistic scenario re-
quired the bimolecular SET reduction of intermediate D-1
from the reduced photocatalyst TBADT-H to be turnover-
limiting. If this mechanistic hypothesis were to hold true, the
intermediate D-1 would accumulate in solution. In sharp
contrast, if the radical trapping from the iminium ion were
rate-limiting, it would not be possible to detect any carbazo-
liumyl radical cation intermediate during the process. We
therefore performed further experimental studies to detect
the presence of mechanistically relevant transient intermedi-
ates in the reaction medium.
[
TBADT].
0,3
0,2
0,1
0
0
0,02
0,04
0,06
[TBADT] (M)
Figure 9. Reaction profile for different initial concentrations of
TBADT showing saturation kinetic: [TBADT] = 0.006 M, 0.0125
M, 0.025 M, and 0.05 M. The error bars represent the standard
deviation. Model reactions catalyzed by amine 4b performed under
the conditions specified in Figure 7.
Spectroscopic Studies. When treating N-cyclohexyl-3,6-
di-tert-butyl-carbazole 6 with SbCl , we isolated and charac-
5
terized the corresponding shelf-stable carbazoliumyl radical
cation 7 (Figure 10a). The stability of this intermediate is
further evidence of the carbazole radical cation’s persistency.
7 shows a characteristic green coloration. Accordingly, its
visible absorption spectrum displays a maximum value at
800 nm (green spectrum in Figure 10a). The characteristic
absorption of the N-cyclohexyl carbazoliumyl radical cation
7 offered an ideal opportunity to check whether a similar
intermediate accumulated during the reaction. For this pur-
Mechanistically, the kinetic order assessment (particular-
ly the TBADT concentration’s effect on the reaction rate)
can be reconciled with two possible scenarios, characterized
by different turnover-limiting steps (see Figure 4 for a full
mechanistic picture).
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800, and 900 nm (red spectrum in Figure 10b). As a control
pose, we recorded the optical absorption spectrum of the
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reaction mixture. A series of model reactions were per-
experiment, the absorption spectrum of an identically irradi-
ated solution containing a mixture of the TBADT photore-
dox catalyst and the radical precursor 2b was recorded. It is
known that the reduced photocatalyst TBADT-H and its
disproportionated byproduct are blue in solution. Accord-
ingly, characteristic peaks were clearly observable in the
absorption spectrum of the control experiment, with maxima
at 630 nm and 980 nm (black spectrum in Figure 10c).
formed in CH CN under the standard conditions, but in
3
quartz cuvettes. Their absorption spectra were acquired at
different irradiation times (a high-power black LED, λ
=
max
2
28
27
3
65 nm, with an irradiance of 60±2 mW/cm was used as
light source). In all cases, even after an irradiation time as
short as 10 minutes, the absorption spectra of the overall
reaction displayed three maxima in the visible region at 630,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
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9
0
1
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0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 10. Optical absorption spectra recorded in CH
cyclohexyl carbazoliumyl radical cation 7. Green spectrum: [7] = 0.0004 M in CH
0.006 M, [benzoic acid] = 0.006 M, [2b] = 0.09 M, [TBABF ] = 0.03 M and [TBADT] = 0.0015 M dissolved in 1 mL of CH
minutes of illumination by a high-power black LED (λmax = 365 nm) with an irradiance of 60±2 mW/cm . (c) Black spectrum: mixture containing
2b] = 0.09 M, [TBABF ] = 0.03 M and [TBADT] = 0.0015 M dissolved in 1 mL of CH CN after 30 minutes of illumination by a high-power
3
CN in 1 cm path quartz cuvettes. (a) Synthesis and spectroscopic characterization of N-
CN. (b) Red spectrum: mixture containing [1a] = 0.03 M, [4b]
CN after 30
3
=
4
3
2
[
4
3
2
black LED (λmax = 365 nm) with an irradiance of 60±2 mW/cm . (d) Purple spectrum: subtraction of the normalized black spectrum from the red
spectrum.
Figure 10d provides a direct comparison of the absorption
spectra of the reaction mixture and the TBADT absorption
(red and black lines, respectively), showing an obvious dis-
crepancy in the form of a new band which is only present
when all the reaction components are irradiated together. The
purple spectrum in Figure 10d is obtained by subtracting the
normalized spectrum obtained after irradiation of TBADT
and 2b (black line) from the spectrum recorded for the irra-
diated reaction mixture (red line). This new spectrum shows
an absorption maximum at 800 nm, which is very reminis-
cent of the characteristic line shape of the N-cyclohexyl-3,6-
di-tert-butyl-carbazoliumyl radical cation 7 (green spectrum).
Figure 11. Experimental (purple line) and computed (dotted line)
absorption spectra of intermediate D-1. The modeled band spectrum
in CH CN solvent was obtained by a Gaussian convolution (full
3
width at half maximum of 0.2 eV) of vertical transitions computed
at TD-B3LYP/6-31G(d)/PCM level of theory.
We then used theoretical studies (TDDFT method, see
Supporting Information for details) to compute the absorp-
tion spectrum of intermediate D-1, which confirms the in-
tense absorption peak in the red portion of the UV-Vis spec-
trum (Figure 11). The modeled band, centered at 758 nm,
compares well with the experimentally observed band (pur-
Collectively, the spectroscopic studies indicate that the
intermediate D-1 accumulates during the radical conjugate
addition process. This behavior is consistent with the overall
turnover-limiting step being the reduction of the long-lived
carbazoliumyl radical cation in D-1 to return both the neutral
organic catalyst and the TBADT photoredox catalyst in the
original state.
2
9
ple line), providing further support for the carbazoliumyl
radical cation intermediate D-1 being responsible for the
peak experimentally observed at ≈800 nm.
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In summary, we have gained a better understanding of the
factors governing the iminium ion-mediated radical conju-
gate addition to β,β-disubstituted cyclic enones, which set
quaternary carbon stereocentres with high fidelity. We have
achieved this using a combination of electrochemical, spec-
troscopic, computational, and kinetic studies. The chemistry
exploits the ability of the chiral primary amine catalyst 4,
purposely adorned with a redox-active carbazole moiety, to
drive the stereoselective interception of photochemically-
generated carbon-centered radicals by means of an electron-
relay mechanism. An unanticipated turnover-limiting step
has been uncovered, for it is the reduction of the carbazole
radical cation within intermediate D-1 and the regeneration
of the TBADT photocatalyst that dictate the overall rate of
the process. In line with this mechanistic framework, the
carbazoliumyl radical cation was detected by visible absorp-
tion spectrophotometry in the reaction mixture, thus indicat-
ing that this species accumulates before the reaction’s slow
step.
(
1) For pioneering studies on iminium-ion-mediated catalysis, see:
(a) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2000, 122, 4243–4244. (b) Northrup, A. B.; Mac-
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55, 304–308. (d) Bernardi, L.; Fochi, M.; Franchini M. C.;
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Ricci, A. Org. Biomol. Chem. 2012, 10, 2911–2922. (e) Ale-
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(
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(6) For reviews discussing catalytic strategies for forging quater-
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conjugate additions to electron-deficient olefins did not provide
for the formation of sterically demanding quaternary carbons,
see: (a) Sibi, M. P.; Ji, J.; Wu, J. H.; Gürtler, S.; Porter, N. J.
Am. Chem. Soc. 1996, 118, 9200−9201. (b) Sibi, M. P.; Ji, J.;
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The insight that the radical trapping and the enantioselec-
tive carbon-carbon bond forming step is not rate-limiting
may pave the way for the mechanistically driven design of
the next generation of electron-relay catalysts. In this regard,
we have found a strong and predictable correlation between
the reaction rate and the reduction potential of the carbazole
unit tethered to the aminocatalyst 4. The knowledge that the
redox properties can be rationally tuned for improving cata-
lytic activity may enable the development of new iminium
ion-mediated asymmetric RCA of highly reactive open-shell
intermediates. Our ongoing efforts are directed toward the
realization of these aims.
7
517–7526. (c) Gansäuer, A.; Lauterbach, T.; Bluhm, H.;
Noltemeyer, M. Angew. Chem., Int. Ed. 1999, 38, 2909–2910.
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(
T. P. J. Am. Chem. Soc. 2015, 137, 2452−2455. (e) Huo, H.;
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936−6939.
(
8) In general, radical conjugate additions to electron-deficient ole-
fins are rather insensitive to steric hindrance because of the long
incipient carbon-carbon forming bond in the early transition
state, see: (c) Damm, W.; Giese, B.; Hartung, J.; Hasskerl, T.;
Houk, K. N.; Hüter, O.; Zipse, H. J. Am. Chem. Soc. 1992, 114,
4
067–4079. (d) Fischer, H; Radom, L. Angew. Chem., Int. Ed.
Complete experimental procedures, characterization data, and
details on kinetic, computational, and spectroscopic studies.
This material is available free of charge via the Internet at
http://pubs.acs.org.
2001, 40, 1340–1371.
(9) Radical chemistry has found limited application as an enabling
strategy for forging quaternary stereogenic centres in a catalytic
enantioselective fashion. For selected examples, see: (a) Mura-
kata, M.; Jono, T.; Mizuno, Y.; Hoshino, O. J. Am. Chem. Soc.
1997, 119, 11713–11714. (b) Zhu, Y.; Zhang, L.; Luo, S. J. Am.
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(
10) Forbes, M. D. Carbon-Centered Free Radicals and Radical
Cations: Structure, Reactivity, and Dynamics; John Wiley &
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pmelchiorre@iciq.es
(11) Jakobsen, H. J.; Lawesson, S. O.; Marshall, J. T. B.; Schroll, G.;
Williams, D. H. J. Chem. Soc. B 1966, 940–946.
The authors declare no competing financial interests.
(
12) We chose a chiral primary amine as the iminium ion handle
within catalysts 4 because secondary enamines are known to ex-
ist mainly as tautomeric electron-poor imines of type D. This
potentially offered an efficient mechanism to preclude the back-
electron transfer between the enamine and the electron hole
unit. Rappaport, Z.; Ed.; The Chemistry of Enamines, John Wiley
and Sons, Chichester, 1994.
Financial support was provided by the Generalitat de Catalunya
CERCA Program), MINECO (Severo Ochoa Excellence Ac-
(
creditation 2014-2018, SEV-2013-0319), and the European
Research Council (ERC 681840 - CATA-LUX). A.B. is grateful
to the MECD for a FPU fellowship (Ref. FPU13/02402). J.J.M.
thanks the Marie Curie COFUND action (291787-ICIQ-IPMP)
for a postdoctoral fellowship.
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(
14) The idea of proximity-driven redox processes finds support in
the mechanism of electron transfer within biological systems,
where even endergonic SET events can be achieved via electron
tunnelling if the redox centers are in close proximity, see: Page,
C. C.; Moser, C. C.; Chen, X.; Dutton, P. L. Nature 1999, 402,
4
7–52.
(15) The unique redox properties of carbazoles and the correspond-
ing carbazoliumyl radical cations form the basis of the wide ap-
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plication of carbazole derivatives in hole-transport materials for
light-emitting diodes and photovoltaic cells, see: (a) Uoyama,
H.; Goushi, K.; Shizu, K.; Nomura, H.; Adachi, C. Nature
carbazole unit is positioned in such a way as to effectively
shield the Si face of the iminium ion, leaving the Re face ex-
posed for enantioselective bond formation.
1
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(25) Since the transmission of polar effects through σ-bonds dies out
over short distances (the iminium ion nitrogen in A-1 is three σ-
bonds away from the nitrogen carbazole), a more plausible ex-
planation for why the carbazole electronic properties influence
the reaction rate can be as follows: we have already shown that
the electron-rich carbazole unit is engaged in a charge-transfer
interaction with the LUMO of A-1 (see Refs. 5 and 22). The ob-
served reaction behavior may then be explained by a drop in
donation of electron density from the carbazole-bearing elec-
tron-withdrawing substituents into the LUMO of the iminium
ion. This would increase the electrophilicity of A-1 accelerating
the radical trap and the carbon-carbon bond formation.
(26) This scenario could also explain the observed positive linear
correlation between the rate constants and the Hammett σpara
value of the aryl moiety in catalysts 4e-h (Figure 6b) due to the
loss of positive charge associated with the reduction of the car-
bazoliumyl radical cation in D-1 which regenerates the neutral
organic catalyst.
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5
(
18) In addition to modulating the redox properties of the carbazole
scaffold, introducing substituents at the 3- and 6-positions can
further stabilize the carbazole radical cation, see: Prudhomme,
D. R.; Wang, Z.; Rizzo, C. J. J. Org. Chem. 1997, 62, 8257–
10
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46
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52
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55
56
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58
59
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8
260. Concurrently, the increased steric hindrance carries the
additional benefit of inferring a higher stereocontrol, as evinced
when using the highly encumbered primary amine catalyst 4c.
(19) For an overview of the relevance of apparent outliers in mecha-
nistically interrogating asymmetric catalytic processes, see:
Sigman, M. S.; Harper, K. C.; Bess, E. N.; Milo, A. Acc. Chem.
Res. 2016, 49, 1292−1301.
20) The use of benzodioxole 2a as the radical precursor (chemistry
detailed in Figure 3a) resulted in a slow but detectable back-
ground process, with the product 3a being obtained in ≈10%
yield after 15 hours in the absence of any catalyst 4.
21) In the original study (Ref. 5), 40 mol% of benzoic acid were
used to accelerate the formation of iminium ion (the reaction
does not proceed at all without the acid). A careful analysis
conducted before the kinetic investigations revealed that the
amount of acid could be halved without affecting the reaction
rate.
(22) The original study (Ref. 5) provided a model for rationalizing
how the steric hindrance of the carbazole unit affects the stere-
ocontrol. The chiral iminium ion A was generated upon conden-
sation of catalyst 4b and substrate 1a. The X-ray single-crystal
structural analysis of A showed a (Z)-configuration of the C=N
double bond as originating from a stabilizing intramolecular
charge transfer π-π interaction between the electron-rich carba-
zole nucleus and the electron-deficient iminium ion. NMR spec-
troscopic analyses confirmed that this highly organized topolo-
gy is also dominant in solution. It likely governs the stereocon-
trol in the radical conjugate addition. This is because the bulky
(
(
(27) Yamase, T.; Takabayashi, N.; Kaji, M. J. Chem. Soc. Dalton
Trans. 1984, 793–799.
(28) (a) Renneke, R.F.; Pasquali, M.; Hill, C. L. J. Am. Chem. Soc.
1990, 112, 6585–6594. The nature of the active species generat-
ed after the excitation of TBADT is a matter of current debate,
see: (b) Ravelli, D.; Dondi, D.; Fagnoni, M.; Albini, A.; Bagno,
A. Phys. Chem. Chem. Phys. 2013, 15, 2890−2896.
(29) The discrepancy between the computed vertical and the experi-
mental excitations is 0.09 eV. This value fits with the threshold
mean absolute error (MAE) associated to the functional herein
adopted which results to be 0.25 eV, see: Jacquemin, D.;
Wathelet, V.; Perpète, E. a.; Adamo, C. J. Chem. Theory Com-
put. 2009, 5, 2420–2435.
Graphical Abstract
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