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Mechanism of the Stereoselective α‑Alkylation of Aldehydes Driven
by the Photochemical Activity of Enamines
Ana Bahamonde† and Paolo Melchiorre*,†,‡
†

ICIQInstitute of Chemical Research of Catalonia, The Barcelona Institute of Science and Technology, Avinguda Països Catalans
16, 43007 Tarragona, Spain
‡
ICREACatalan Institution for Research and Advanced Studies, Passeig Lluís Companys 23, 08010 Barcelona, Spain
S
* Supporting Information

ABSTRACT: Herein we describe our efforts to elucidate the
key mechanistic aspects of the previously reported enantioselective photochemical α-alkylation of aldehydes with electronpoor organic halides. The chemistry exploits the potential of
chiral enamines, key organocatalytic intermediates in thermal
asymmetric processes, to directly participate in the photoexcitation of substrates either by forming a photoactive
electron donor−acceptor complex or by directly reaching an
electronically excited state upon light absorption. These
photochemical mechanisms generate radicals from closedshell precursors under mild conditions. At the same time, the
ground-state chiral enamines provide effective stereochemical
control over the enantioselective radical-trapping process. We use a combination of conventional photophysical investigations,
nuclear magnetic resonance spectroscopy, and kinetic studies to gain a better understanding of the factors governing these
enantioselective photochemical catalytic processes. Measurements of the quantum yield reveal that a radical chain mechanism is
operative, while reaction-profile analysis and rate-order assessment indicate the trapping of the carbon-centered radical by the
enamine, to form the carbon−carbon bond, as rate-determining. Our kinetic studies unveil the existence of a delicate interplay
between the light-triggered initiation step and the radical chain propagation manifold, both mediated by the chiral enamines.

■

INTRODUCTION
Ground-state enamine chemistry has been extensively explored
since the 1950s. Following pioneering studies by Gilbert Stork,
organic chemists have exploited enamines’ nucleophilic
character to trap electrophiles and develop useful two-electron
polar processes.1 Successively, chiral enamines I, generated in
situ upon condensation of aldehydes 1 with secondary amine
catalysts, have been recognized as key intermediates of
organocatalytic enantioselective reactions (Figure 1a).2,3
Single-electron oxidation of ground-state chiral enamines by a
chemical oxidant has also been found to render 3π-electron
radical cation intermediates amenable to a range of unique
open-shell reaction manifolds (singly occupied molecular
orbital (SOMO) activation, Figure 1b).4 Overall, the past 15
years have witnessed the extensive use of the ground-state
reactivity of enamines for the stereoselective functionalization
of carbonyl compounds.5
Recently, our research laboratories demonstrated that the
synthetic potential of chiral enamines is not limited to the
ground-state domain, but can be further expanded by exploiting
their photochemical activity. We revealed the previously hidden
ability of enamines to actively participate in the photoexcitation
of substrates and trigger the formation of reactive open-shell
species from organic halides.6 At the same time, ground-state
chiral enamines can provide effective stereochemical control
© 2016 American Chemical Society

over the enantioselective radical-trapping process. This strategy,
where stereoinduction and photoactivation merge in a sole
chiral organocatalyst, enables light-driven enantioselective
transformations that cannot be realized using the thermal
reactivity of enamines. Specifically, we used this approach to
develop the α-alkylation of aldehydes7 with electron-deficient
benzyl and phenacyl bromides (Figure 1c)6a and bromomalonates 2c (Figure 1d).6c The reactions were conducted at
ambient temperature using household compact fluorescence
light (CFL) bulbs as the light source.
At first glance, both processes depicted in Figure 1c,d seem
to be classical substitution reactions of enamines proceeding
through an SN2 manifold. However, they do not proceed at all
without light illumination. Crucial for reactivity was the ability
of enamines to trigger the photochemical formation of radicals
from the alkyl halides 2 under mild conditions. Despite the
superficial similarities between the two chemical transformations, they profoundly diverge in the radical generation
mechanism. The first strategy (Figure 1c) relied on the
formation of photon-absorbing electron donor−acceptor
(EDA) complexes,8 generated in the ground state upon
association of the electron-rich enamine I with electronReceived: May 11, 2016
Published: June 6, 2016
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bromomalonate 2c induced the formation of the carboncentered radical.
In this paper, we detail how a combination of photophysical
investigations, nuclear magnetic resonance (NMR) spectroscopy, kinetic studies, and quantum yield measurements revealed
further mechanistic analogies and striking differences for these
enamine-mediated photochemical enantioselective alkylations
of aldehydes with electron-poor alkyl halides. From a broader
perspective, these studies explain how it is possible to translate
the effective tools governing the success of ground-state
asymmetric enamine catalysis into the realm of photochemical
reactivity,9 thus providing novel reactivity frameworks for
conceiving light-driven enantioselective catalytic processes.10

■

RESULTS AND DISCUSSION
Our recent studies6 established that enamines I can interact
with visible light in two different ways, serving either as donors
in photoactive EDA complex formation (Figure 1c) or as
photoinitiators upon direct excitation (Figure 1d). As the
prototypical reactions for mechanistic analysis, we selected the
alkylations of butanal (1a) with 2,4-dinitrobenzyl bromide (2a;
Figure 2a), phenacyl bromide (2b; Figure 2b), and diethyl
bromomalonate (2c; Figure 2c), all promoted by the
commercially available diarylprolinol silyl ether catalyst A11
(20 mol %).12 The reactions with 2a and 2b are representative
of the EDA complex activation strategy,6a,b while the chemistry
in Figure 2c is triggered by the direct photoexcitation of the
enamine.6c For all the processes, and in accordance with the
original reports, we confirmed that irradiation by a household
23 W CFL bulb was needed to achieve the alkylation products
3a−3c in high yield and enantioselectivity.13 The careful
exclusion of light completely suppressed the reactions,
confirming their photochemical nature. The inhibition of the
reactivity was also observed under an aerobic atmosphere or in
the presence of TEMPO (1 equiv), the latter experiment
indicating a radical mechanism.
Along with these similarities, the light-triggered reactions in
Figure 2 showed striking differences too. When the experiments
were conducted under illumination by a 300 W xenon lamp

Figure 1. Enamine reactivity domains. Ground-state reactivity:
enamines as (a) nucleophiles in traditional polar processes and (b)
radical precursors upon single-electron chemical oxidation. Excitedstate domain: enamines can drive the photochemical generation of
radicals by (c) inducing the formation of ground-state, photoactive
EDA complexes and (d) acting as a photoinitiator upon direct light
excitation. SET = single-electron transfer. So = SOMO-phile that can
intercept the enamine radical cation. The gray circle represents the
chiral organic catalyst scaffold.

deficient benzyl and phenacyl bromides. Visible light irradiation
of the colored EDA complex II induced a single-electron
transfer (SET), allowing access to the reactive open-shell
intermediates. In the second approach (Figure 1d), we used the
capability of the chiral enamine I to directly reach an
electronically excited state (I*) upon light absorption and
then to act as an effective photoinitiator. SET reduction of the

Figure 2. Model photochemical alkylations of butanal (1a) catalyzed by the chiral secondary amine A: enamine-based EDA complex activation in the
reaction of (a) 2,4-dinitrobenzyl bromide (2a) and (b) phenacyl bromide (2b); (c) direct photoexcitation of enamines in the alkylation of 1a with
diethyl bromomalonate (2c). MTBE = methyl tert-butyl ether. NMR yield of 3 determined by 1H NMR spectroscopic analysis of the crude reaction
mixture using 1,1,2-trichloroethene as the internal standard. The asterisk indicates the yield of the isolated products 3.
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Figure 3. (a) Optical absorption spectra, recorded in MTBE in 1 mm path quartz cuvettes using a Shimadzu 2401PC UV−vis spectrophotometer,
and visual appearance of the separate reaction components and of the colored EDA complex in the alkylation of 2,4-dinitrobenzyl bromide (2a).
[1a] = 1.5 M, [2a] = 0.5 M, and [A] = 0.1 M. (b) Optical absorption spectra in MTBE for the alkylation with phenacyl bromide (2b). [1a] = 1.5 M
and [2b] = [A] = 0.2 M. (c) Investigating the formation of the EDA complexes in MTBE using the preformed enamine 4. KEDA is the association
constant for the EDA complex formation. Epred for 2a and 2b (irreversible reduction) and Epox for 4 (irreversible oxidation) measured by cyclic
voltammetry vs Ag/Ag+ in CH3CN. (d) Visible-light-triggered generation of the electrophilic carbon-centered radical IV and the α-iminyl radical
cation V using the enamine-based EDA complex strategy. hνCT = charge-transfer transition energy.16 BET = back electron transfer.

equipped with a cutoff filter at 385 nm and a band-pass filter at
400 nm (irradiation at λ ≥ 385 nm and λ = 400 nm,
respectively), the reactivity of the three processes remained
unaltered. However, the use of a band-pass filter at 450 nm or a
blue light-emitting diode (LED) (λmax at 450 nm) completely
inhibited the reaction with diethyl bromomalonate (2c). In
sharp contrast, the enamine-mediated alkylations with 2a and
2b were not affected. We decided to conduct spectroscopic
investigations to rationalize the different light-wavelength/
reactivity correlation profiles while elucidating the origins of the
enamine’s photochemical activity.
Spectroscopic Studies. Immediately after mixing a methyl
tert-butyl ether (MTBE) solution of the enamine, generated in
situ upon condensation of butanal (1a) (3 equiv) with 20 mol
% catalyst A, with 2,4-dinitrobenzyl bromide (2a) (1 equiv), we
observed that the achromatic solution turned to a marked
yellow color (Figure 3a). This observation raised the question
of how the color developed.
The appearance of strong color on bringing together two
colorless organic compounds is not uncommon. In 1952, this
phenomenon inspired Robert Mulliken to formulate the
charge-transfer theory. 8c According to this theory, the
association of an electron-rich substrate with a low ionization
potential (such as an enamine)14 with an electron-accepting
molecule with a high electronic affinity15 (such as electrondeficient benzyl and phenacyl bromides) can bring about the
formation of a new molecular aggregation in the ground state:
the electron donor−acceptor complex. EDA complexes are
characterized by physical properties that differ from those of the

separated substrates. This is because new molecular orbitals
form, emerging from the electronic coupling of the donor and
acceptor frontier orbitals (highest occupied molecular orbital
(HOMO)/lowest unoccupied molecular orbital (LUMO)).
EDA formation is accompanied by the appearance of a new
absorption band, the charge-transfer band (hνCT), associated
with an intracomplex transfer of a single electron (SET) from
the donor to the acceptor. In many cases, the energy of this
transition lies within the visible range.16 This is what happened
when the enamine, generated in situ upon condensation of
catalyst A and 1a, was mixed with both 2,4-dinitrobenzyl
bromide (2a) (Epred = −0.66 V vs Ag/Ag+ in CH3CN) and
phenacyl bromide (2b) (Epred = −1.35 V vs Ag/Ag+ in
CH3CN). Indeed, the optical absorption spectra showed a
bathochromic displacement in the visible spectral region, where
none of the substrates absorb (red lines, Figures 3a,b). The new
absorption bands, which in the case of 2a can reach the green
region of the visible range (550 nm), cannot be accounted for
by the addition of the absorption of the separate compounds,
which can barely absorb visible light.
To further examine the implication of the enamine in the
formation of photoactive EDA complexes, we synthesized the
enamine 4 (Epox = +0.60 V vs Ag/Ag+ in CH3CN), prepared by
condensation of catalyst A and 2-phenylacetaldehyde17 in the
presence of molecular sieves. Upon isolation, 4 was mixed with
electron acceptors 2a and 2b (Figure 3c). Using Job’s method18
of continuous variations, we readily established a molar
donor:acceptor ratio of 1:1 in solution for both colored EDA
complexes IIa and IIb, respectively (details in section D of the
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prompted us to evaluate the possibility that the direct
photoexcitation of the enamine could trigger the radical
generation from 2c. This mechanistic scenario was consonant
with the experiment performed using a band-pass filter at 450
nm (a wavelength that could not be absorbed by the enamine),
since a complete inhibition of the reaction was observed
(Figure 2c). The implication of the enamine within the
photochemical regime was unambiguously established by
Stern−Volmer quenching studies. As detailed in our original
study,6c we recorded the emission spectra of enamine 4 upon
excitation at 365 nm. The excited state of 4 and its emission
were effectively quenched by bromomalonate 2c (see section
E2 in the Supporting Information for details).
These observations indicate that the photochemical activity
of chiral enamines and their potential for light-induced radical
generation are not limited to the formation of ground-state
EDA complexes. As detailed in Figure 5, the enamine I, upon

Supporting Information). Concomitantly, an association
constant (KEDA) of 11.56 ± 0.02 M−1 for the complex IIa
and 4.9 ± 0.1 M−1 for IIb in MTBE was determined by
spectrophotometric analysis using the Benesi−Hildebrand
method.19
The light-wavelength/reactivity correlation for the photochemical alkylations of butanal with 2a and 2b (parts a and b,
respectively, of Figure 2) can be rationalized on the basis of the
photoactivity of the enamine-based EDA complexes IIa and IIb
(their absorption spectra, which are similar to the EDA
absorption in Figure 3a,b, are reported in Figure S6 in the
Supporting Information). Absorption of low-energy photons,
including visible light, can induce an electron transfer to occur,
leading to the chiral ion pair III (Figure 3d). Critical to reaction
development is the presence of the bromide anion within the
radical anion partner in III. The bromide, acting as a suitable
leaving group, triggers an irreversible fragmentation event20
rapid enough to compete with a possible back electron transfer
(BET), which would unproductively restore the ground-state
EDA complex II instead.21 This fragmentation productively
renders two reactive radical intermediates (the electrophilic
carbon-centered radical IV and the α-iminyl radical cation V)
which can initiate synthetically useful transformations, i.e., the
alkylation of aldehydes. The enamine-based EDA complex
activation strategy thus provides ready access to open-shell
reactive species under very mild conditions and without the
need for any external photoredox catalyst.
The enantioselective photochemical alkylation of butanal
(1a) with diethyl bromomalonate (2c) showed profoundly
different behavior. In addition to the distinct effect the light
frequency had on the reactivity (as discussed in Figure 2), we
did not observe any color change in the solution, which
remained achromatic during the reaction progression. The
absence of any photoabsorbing ground-state EDA complex was
further confirmed by the optical absorption spectrum of the
reaction mixture (red line in Figure 4), which perfectly overlaid

Figure 5. Radical generation strategy based on the direct photoexcitation of the chiral enamine I. The gray circle represents the chiral
organic catalyst scaffold.

light absorption, can reach an electronically excited state (I*)
and act as a photoinitiator, triggering the formation of the
electron-deficient radical IVc through the reductive cleavage of
the bromomalonate C−Br bond via an SET mechanism23
(Epred(2c) = −1.69 V vs Ag/Ag+ in CH3CN). The reduction
potential of the excited enamine was estimated as <−2.0 V (vs
Ag/Ag+ in CH3CN) on the basis of electrochemical and
spectroscopic measurements (see section E3 in the Supporting
Information for details).24 In analogy with the EDA complex
activation (Figure 3d), here too the SET event leads to both an
electrophilic radical, IV, and the α-iminyl radical cation V.
Quantum Yield Measurements and the Proposed
Mechanisms. Photophysical investigations established that in
situ generated chiral enamines can use two different photochemical mechanisms to provide open-shell species from
organic halides 2a−2c while avoiding the need for any external
photoredox catalyst. We then focused on the nonphotochemical steps inherent to the enantioselective alkylation of butanal
(1a). As depicted in Figures 3d and 5, the enamine-mediated
photochemical pathways bring about the formation of two
radical species: the chiral radical cation V and the electrophilic
radicals IV. A stereocontrolled radical−radical coupling of IV
and V can be invoked to account for the formation of the new
carbon−carbon bond and the α-carbonyl stereogenic center
within the final products 3a−3c (Figure 6a). This mechanistic
framework would require an enamine-mediated photochemical
event for every molecule of product generated.
It must be noted, however, that many radical reactions
generally proceed through self-propagating radical chain
pathways.25 In chain processes, product formation occurs
through propagation steps that convert the open-shell
intermediate (originating from the substrate precursor) into

Figure 4. Optical absorption spectra acquired in MTBE in 1 cm path
quartz cuvettes. [1a] = 1.5 M, [2c] = 0.5 M, and [A] = 0.1 M.

the absorption of the enamine, generated upon condensation of
the catalyst A with 1a (green line in Figure 4). In a separate
experiment, we observed that the addition of a large excess of
2c to a solution of enamines did not change the absorption
spectra, further excluding any EDA association in the ground
state (Figure S13 in the Supporting Information). Closer
inspection of the absorption spectrum indicated that the only
photoabsorbing compound at 400 nm (a wavelength suitable
for triggering the reaction) was the enamine22 (green line in
Figure 4, absorption band until 415 nm). This observation
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reductive cleavage of the electron-poor alkyl bromide 2 through
an outer-sphere SET process, thereby regenerating the radical
IV while releasing the product 3 and the amino catalyst A
(more mechanistic details are discussed in Figure 7). In this
scenario, the enamine-based photochemical radical generation
strategies, which afford radicals IV and V, would serve only to
initiate a radical self-propagating chain process.
To help distinguish between the two mechanisms, we
determined the quantum yield (Φ)27 of the model reactions,
which defines the moles of product formed per moles of
photons absorbed by the system.28 Using potassium ferrioxalate
as the actinometer, we measured quantum yields of 25, 20, and
20 for the reactions in CH3CN29 with 2a, 2b, and 2c,30
respectively (λ = 450 nm for 2a and 2b and 400 nm for 2c).
These results are consonant with a self-propagating radical
chain mechanism as the main reaction pathways for the three
enamine-mediated photochemical alkylations of butanal under
study. The measured quantum yields (Φmeasured) refer to the
overall reactions. As such, these values do not take into account
any possible nonproductive energy-wasting processes,31 including parasitic quenching by energy or electron transfer as well as
unimolecular decay processes, which do not lead to product
formation but which affect the efficiency of photoinitiation. To
better estimate the actual chain length of the reactions, we
measured the quantum yield of the initiation step, 32
determining a Φinitiation of 0.77, 0.68, and 0.11 for 2a, 2b, and
2c, respectively (λ = 450 nm for 2a and 2b and 400 nm for 2c,
details in sections G2 and G4 of the Supporting Information).
Taking these data into account, the actual chain lengths of the
model reactions (Φestimated = Φmeasured/Φinitiation) are consid-

Figure 6. Possible pathways for the nonphotochemical steps of the
model reactions: (a) in-cage radical−radical coupling and (b) radical
chain propagation manifold. The open-shell intermediates V and IV
are generated through the photochemical activity of the enamines, as
detailed in Figures 3d and 5. EWG = electron-withdrawing group. Φ =
overall quantum yield of the alkylation. See ref 28 for an explanation of
the quantum yield values.

the final product while regenerating the chain-propagating
radical. Reactions will occur if the propagation sequence is
rapid enough in comparison with possible termination
pathways, and if there is a suitable mode of initiation (that is,
effective radical formation from a closed-shell substrate). In our
case (Figure 6b), a chain propagation sequence can be
envisaged such that the nucleophilic ground-state enamine I
would trap the photochemically generated electrophilic radical
IV to form the α-amino radical VI. Since α-aminoalkyl radicals
are known to be strong reducing agents,26 VI would induce the

Figure 7. Chain propagation manifold underlying the mechanism of the photochemical enamine-mediated enantioselective α-alkylation of butanal.
(a) The initiation event, which generates the electrophilic radicals IV, is driven by the photochemical activity of the enamines (EDA complex
formation or direct photoexcitation), while (b) the chain process is triggered by the radical trapping by the enamine I. (c) Two possible propagation
pathways as driven either by the SET reduction of 2 or by the bromine atom transfer from 2 involving the key α-amino radical VI intermediate. (d)
Evaluating the redox potential of the crucial α-aminoalkyl radical of type VI. (e) Summary of the quantum yield measurements for the three model
photochemical reactions. The gray circle represents the chiral scaffold of the organic catalyst A.
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process through which nucleophilic substitution is achieved on
aromatic and aliphatic compounds that bear a suitable leaving
group and that do not react through polar nucleophilic
mechanisms. This class of transformations is characterized by
an innate chain mechanism involving electron-transfer steps
with radical ions as intermediates. In some examples of SRN1type reactions, electron-rich olefins, including enamines,37
efficiently trap electrophilic radicals. In addition, electronpoor benzyl37 bromides are suitable substrates for the SRN1
reaction manifold. On the other side, bromomalonates and
phenacyl bromides34 are suitable substrates for ATRA
processes, which classically proceed via radical chain mechanisms.35
Another aspect to consider is the central role of the chiral
amino catalyst A. Although the process is characterized by an
innate radical chain, the organic catalyst plays a direct role in
product formation. Indeed, A is essential for the propagation
mechanism since it transforms an inactive substrate (the
aldehyde 1), which is unsuitable for participating in the radical
chain, into the electron-rich chiral enamine I, a key
intermediate of the propagation cycle. In addition, the enamine
is directly involved in both the stereodefining event and the
photochemical initiation. As for the initiation, the fate of the
chiral α-iminyl radical cation V, emerging from the photoinduced SET to 2 (Figures 3d and 5), deserves further
comment. Intermediate V is an unproductive species, since it
lies outside of the chain propagation manifold which converts
substrates into products. We have obtained evidence that V is
an unstable intermediate which cannot be reduced back to the
progenitor enamine I. Instead, the α-iminyl radical cation V
collapses to give a variety of degradation products that, despite
our efforts, have remained unidentified so far.38 Thus, the
enamine I serves as a sacrificial initiator of the chain
mechanism39 since, for any photoinduced SET event, a
propagating radical IV is generated while a molecule of the
chiral catalyst A is destroyed via decomposition of the
intermediate V. By using both gas chromatography (GC-FID;
FID = flame ionization detection) and NMR analyses,40 we
established that the amount of catalyst A decreases constantly
during the photochemical alkylation in correlation with the
number of initiation events (further discussions in the following
sections). The irreversible cyclic voltammogram of the
preformed enamine 4 (Figure S16 in the Supporting
Information) is also congruent with the proposed enamine
degradation pathway.
With a clearer mechanistic picture in mind, we decided to
perform kinetic studies to better understand the relative
importance of the initiation step and the propagation cycle
for the overall rate, while establishing the turnover-limiting step
of the model photochemical catalytic alkylations. However,
before this, we investigated whether the different photochemical pathways available to enamines for initiating the chain
process (EDA complex formation vs direct photoexcitation)
might have an influence on the enamine formation and its
concentration in solution. This matters because the amount of
enamine in solution has a direct effect on the kinetic profiles of
the reactions, since the enamine is involved in both initiation
and chain propagation (Figure 7a,b).
NMR Spectroscopic Studies. The catalytically active
enamine intermediate I is generated via the reversible
condensation of the chiral amino catalyst A with butanal (1a)
(Figure 8a). This reversible process is characterized by an
equilibrium constant (Kenamine = [I][H2O]/[1a][A]). As with

erably longer, with a lower limit of 32, 29, and 182 for 2a, 2b,
and 2c, respectively.
Figure 7 details the general mechanism proposed for the
alkylation of butanal with 2,4-dinitrobenzyl bromide (2a),
phenacyl bromide (2b), and diethyl bromomalonate (2c). They
differ in the nature of the light-triggered initiation step, but are
characterized by a similar propagation cycle in which the
ground-state enamine I traps the photogenerated electrophilic
radical IV. Overall, the mechanism exploits the dichotomous
reactivity profile of enamines in the ground and excited states.
The photochemical activity of the enamines, either by EDA
complex activation or by direct excitation, generates radicals IV
from the closed-shell intermediates 2a−2c (Figure 7a).33 This
event, by feeding in radicals from outside the chain, serves as
the initiation of self-propagating radical chains. The radical trap
from the ground-state chiral enamine I forms the new carbon−
carbon bond while forging the stereogenic center (Figure 7b).
Considering the consolidated ability of catalyst A to infer high
stereoselectivity in enamine-mediated polar reactions,11 it is no
surprise that the addition of the radical IV to I proceeds in a
stereocontrolled fashion. Two pathways are feasible for the
propagation step (Figure 7c): the α-aminoalkyl radicals VI,
resulting from the radical trap, can transfer an electron to the
starting alkyl halides 2. This SET process regenerates the chainpropagating radical IV while giving the bromide−iminium ion
pair VII, which eventually hydrolyzes to release the product 3
and the amino catalyst A. The outer-sphere SET process is
facilitated by the formation of the stable bromide and iminium
ions. Alternatively, an atom-transfer mechanism can be
envisaged, where the α-aminoalkyl radical VI would abstract a
bromine atom from 2, regenerating the radical IV while
affording an unstable α-bromo amine adduct, VIII,34 which
would eventually evolve to the iminium ion pair VII. This
pathway would provide a rare example of enantioselective
catalytic atom-transfer radical addition (ATRA),35 a historical
methodology useful for functionalizing olefins with organic
halides.
To discriminate between the possible propagation manifolds,
we prepared and isolated the iminium ion IX (Figure 7d),
derived from the condensation of pyrrolidine and isobutyraldehyde, which mimics the actual iminium ion intermediate
VII involved in the catalytic cycle. VII could not be synthesized
because of the steric hindrance of catalyst A hampering a facile
condensation with the aldehydic product 3. Evaluating the
redox properties of IX is pertinent since its electrochemical
reduction provides access to an α-aminoalkyl radical of type VI,
the key intermediate of the chain propagation. We measured by
cyclic voltammetry a reduction potential (Epred of IX) of −0.95
V vs Ag/Ag+ in CH3CN (irreversible reduction to give the αaminoalkyl radical X). This value means that the α-amino
radical of type VI is incapable of reducing either 2b or 2c
(Epred(2b) = −1.35 V vs Ag/Ag+ in CH3CN; Epred(2c) = −1.69
V vs Ag/Ag+ in CH3CN), indicating that a bromine-transfer
mechanism is likely operative with phenacyl bromide and
bromomalonate substrates. In contrast, an SET reduction is the
most likely pathway when using 2a, since its potential
(Epred(2a) = −0.66 V vs Ag/Ag+ in CH3CN) makes an SET
reduction from intermediate VI feasible.
Several aspects of the mechanism proposed in Figure 7
deserve comment. The underlying radical chain pathway is not
surprising when considering that the transformations closely
resemble atom-transfer radical addition (ATRA) processes35 or
a Kornblum−Russell SRN1-type alkylation.36 The SRN1 is a
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catalyst A. This is congruent with the fact that the formation of
the EDA complex, by sequestering I, shifts the dynamic
equilibrium of enamine formation to the side that reduces the
perturbation (in this case, the forward reaction).41 Since these
studies were made in the absence of light, we then studied the
effect of illumination on the dynamic equilibrium system
(Figure 8c). We used a xenon lamp coupled with a
monochromator, which, by bringing the light in close contact
with the NMR tube through an optical fiber,42 allowed for the
in situ illumination of the samples. When the EDA complex
mixture, originally kept in the dark, was irradiated in situ in the
NMR spectrometer (λ = 470 ± 5 nm, irradiance 28.8 mW/
cm2), a large shift in the position of the enamine equilibrium
was immediately observed (3.8:1 ratio of I to A after 30 s of
irradiation). After 60 s of irradiation, the signals of the free
catalyst A could no longer be detected, meaning that the system
dramatically shifted toward the enamine I. This observation can
be reconciled with the photochemical activity of the enaminebased EDA complex II, which, upon excitation, induces the
irreversible formation of the electrophilic radical IV (upon
fragmentation of the C−Br bond within the ion pair III; see
Figure 3d) and the unstable α-iminyl radical cation V.40 These
light-triggered events decrease the concentration of both the
enamine and 2a, further favoring the forward reactions of the
multiple equilibrium systems depicted in Figure 8c.
The importance of the irreversible events that follow the
photoinduced SET is corroborated by a similar experiment
where 2a was replaced by 2,4-dinitrotoluene (5) (Figure 8d). 5
can act as an acceptor partner in EDA complex formation with
the enamine I (KEDA = 4.6 ± 0.1 M−1 in MTBE with enamine
4), but it cannot undergo an irreversible fragmentation, since it
lacks a suitable leaving group (e.g., the bromine within 2a). In
the dark, the addition of 1 equiv of 5 to a solution of catalyst A
and butanal (1a) induced a displacement in the equilibrium of
the enamine formation, changing the I:A ratio from 1.2:1 to
1.6:1. This is because an EDA complex, II, can be generated,
which perturbs the equilibrium of enamine formation. In sharp
contrast, illumination did not change the concentration of the
enamine I to any extent. This observation is consonant with an
unproductive photoinduced SET and a fast back electron
transfer (BET) that, by restoring the ground-state EDA
complex II, do not influence either the overall equilibrium of
the system or the distribution of catalyst A, which is partitioned
between the free state and the enamine I.
These experiments were then repeated with the bromomalonate 2c (results not shown in Figure 8). In this case, the
equilibrium of the enamine formation (Kenamine = 0.155 as in
Figure 8a) was not perturbed by the addition of 2c. This is
because the mechanism of initiation is based on the direct
photoexcitation of the enamine I and does not involve any
preassociation with 2c. Thus, the presence of 2c does not
influence the partitioning of the catalyst A between the free
state and the enamine I.
Kinetic Studies. We then performed kinetic studies to gain
a better understanding of the factors governing the photochemical enamine-based alkylations of butanal (1a). In
particular, we sought to assess whether the existence of two
different initiation methods, but seemingly similar propagation
cycles, would bring about distinct or analogous kinetic profiles.
The amine-A-catalyzed alkylation of 1a with 2,4-dinitrobenzyl
bromide (2a) was chosen as representative of the EDA complex
activation strategy (Figure 9a),43 while the reaction with diethyl
bromomalonate (2c) exploits the direct photoexcitation of the

Figure 8. Influence of the EDA complex formation on the amount of
enamine in solution. 1H NMR experiments were performed in
CD3CN at 298 K using a xenon lamp coupled with a monochromator
and equipped with an optical fiber for the in situ illumination of the
samples (λ = 470 ± 5 nm, irradiance 28.8 mW/cm2). (a) Equilibrium
constant for the enamine I formation (Kenamine, measured in CD3CN
dried over 4 Å molecular sieves) and the following equilibrium to form
an EDA complex, II, with 2a (KEDA). (b) Effect on the position of
equilibrium for enamine formation in the absence and the presence of
the EDA acceptor 2a. (c) Effect of light illumination and the
irreversible step (triggered by the photoactivity of the EDA complex
II) on the concentration of enamine in solution (see Figure 3d for
more details and the structures of intermediates III and V). (d) Effect
of an EDA complex, unable to undergo a photoinduced irreversible
SET event, on the enamine concentration. BET = back electron
transfer.

all chemical equilibria, the system follows Le Châtelier’s
principle. As a consequence, any perturbation of the
equilibrium (as induced by a change in concentration, for
example) will shift the position of equilibrium to the side that
opposes the perturbation. As discussed above (Figure 3c), the
formation of the enamine-based EDA complex is also an
equilibrium, where KEDA identifies the association constant. For
example, the EDA complex IIa (formed by the association of
the preformed enamine 4 with 2,4-dinitrobenzyl bromide (2a))
has a KEDA of 11.6 M−1 in MTBE. This scenario suggests that
the presence of acceptor 2a can alter the original state of
equilibrium for enamine formation. In other words, it can
directly influence the relative concentration of free catalyst A
and enamine I in solution (Figure 8a).
To verify this possibility, we used 1H NMR spectroscopic
analysis to investigate the equilibrium of enamine formation
under the reaction conditions (Figure 8b). Upon mixing 0.3
mmol of 1a and 0.02 mmol of the amino catalyst A in 0.5 mL of
anhydrous CD3CN, both enamine I and free catalyst A were
detected in a ratio of 1.2:1. An equilibrium constant (Kenamine)
of 0.155 ± 0.002 was determined (see section H1 in the
Supporting Information for details). The addition of 0.1 mmol
of 2a induced a shift in the position of the equilibrium toward
the enamine I, as demonstrated by the 1.8:1 ratio of I and free
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product 3 while liberating the catalyst A, is not turnoverlimiting.
We then tried to reconcile the strikingly different kinetic
behaviors of the two systems with our previous observations.
The zeroth-order dependence on butanal (1a) for the EDAcomplex-mediated alkylation with 2a implies that the enamine
I, generated in situ upon condensation of A and 1a, is the
resting state of catalyst A. This conclusion is consonant with
the NMR spectroscopic studies reported in Figure 8b,c
indicating that, under the reaction conditionsthat is, when
the EDA complex between the enamine I and 2a is formed and
under illuminationthe equilibrium position of the enamine
formation is completely shifted toward the enamine I. This
means that a negligible amount of catalyst A is available in its
free state and, consequently, the concentration of 1a does not
affect the formation of the reactive enamine catalytic
intermediate. In sharp contrast, our NMR studies established
that the equilibrium of the enamine formation is not perturbed
by the addition of bromomalonate 2c. In the direct photoexcitation of the enamine I, the amine catalyst A is partitioned
between the free state and the enamine intermediate I. Thus, a
definitive resting state cannot be identified, with the catalyst
concentration shared between different intermediates. This
situation is congruent with the observed positive fractional
order in [1a] (Figure 9b).
Concerning the reaction rate’s dependence on the alkyl
halide 2, the negative fractional order in [2a] for the EDAcomplex-driven process (Figure 10a) deserves in-depth
discussion. As previously mentioned, for any SET event taking
place within the photoactive EDA complex (Figure 3d and
initiation step in Figure 7), a propagating radical, IV, is
generated while a molecule of the chiral catalyst A is destroyed
via decomposition of the unstable α-iminyl radical cation V.40
To verify whether the disappearance of the catalyst was related
to the number of initiation events, we followed the evolution of
[A] over time across a range of concentrations of 2a, which is
the acceptor partner in EDA complex formation. Since there is
zeroth-order dependence on [1a] and due to the fact that we
could not detect any trace of catalyst A in its free state by NMR
analysis, we monitored the evolution of A in our experiments
by determining the enamine concentration in solution.41 The
initial-rate measurements in Figure 10b suggest that the
decrease in [A] correlates with the 2a concentration. If the
rate of disappearance of A is proportional to [2a]n, then the
data should fit eq 1. As a result, the kinetic data can be plotted
as indicated in eq 2.

Figure 9. Model reactions used for initial-rate kinetics determined by
1
H NMR analysis and the observed rate orders. (a) EDA-complextriggered photochemical alkylation of butanal (1a) with 2,4dinitrobenzyl bromide (2a). (b) Alkylation of 1a with diethyl
bromomalonate (2c) driven by the direct photoexcitation of enamines.
Reaction conditions: studies performed across a range of concentrations for each reaction component in CD3CN, irradiation at 450
and >385 nm for 2a and 2c, respectively. The kinetic studies were
repeated using in situ 1H NMR spectroscopy (λ = 470 and 400 nm for
2a and 2c, respectively) to directly monitor the reaction progress. Both
approaches gave similar kinetic profiles.

enamine (Figure 9b). Initial rate experiments were performed
in acetonitrile as the solvent to avoid the precipitation of the
lutidinium bromide, generated during the reaction.29 The
progress of the two reactions was monitored by 1H NMR
analysis using two different approaches (see section I in the
Supporting Information for details). We used a xenon lamp
with a band-pass filter at 450 nm (irradiance 4.7 mW/cm2) to
illuminate the EDA-complex-mediated reaction with 2a (Figure
9a), while a cutoff filter at 385 nm (irradiation at λ ≥ 385 nm,
irradiance 300 mW/cm2) was employed for the process with 2c
(Figure 9b). This setup required an independent reaction to be
performed for every data point at different times. The initialrate kinetic studies were repeated using in situ 1H NMR
spectroscopy to directly monitor the reaction progress.44 In this
second case, we used a xenon lamp coupled with a
monochromator, which allowed for the in situ illumination of
the samples. The EDA complex-based reaction with 2a was
irradiated at 470 nm (irradiance 28.8 mW/cm2), while 400 nm
(irradiance 20.4 mW/cm2) was used for the alkylation
chemistry with 2c. Both approaches gave similar and
reproducible kinetic profiles.
Figure 9 details the results of our initial-rate kinetic
investigations, performed across a range of concentrations for
each reaction component. A first-order dependence on the
catalyst A was inferred for both the EDA-complex-based
process with 2a (Figure 9a) and the reaction with
bromomalonate 2c (Figure 9b). However, striking discrepancies in rate orders were observed in the dependence on
butanal (1a) and organic halides 2a and 2c. The EDA-complexmediated alkylation showed a zeroth-order dependence on the
1a concentration and an unexpected negative fractional order in
[2a]. In sharp contrast, the photochemical alkylation of 2c is
characterized by a half-order dependence on both [1a] and
[2c]. We also explored the effect of water on the kinetic profile
of the two processes using both the independent measurement
method and in situ NMR approach (details in Figures S31 and
S39). No alteration of the kinetic profiles was observed after the
addition of either 1 or 2 equiv of H2O. These results indicate
that the iminium ion hydrolysis, which leads to the alkylation

disappearance of A = − d[A]/dt ∝ [2a]n

(1)

[A] ∝ [2a]n t

(2)

Equation 2 indicates that, for reactions with the same initial
concentrations of amino catalyst A, plots of [A] versus [2a]nt
should be superimposable.45 Figure 10c shows such a
superimposition for three reactions that have comparable initial
concentrations of A but different concentrations of 2a. In
Figure 10c, the overlay found for plots of [A] versus [2a]t (n =
1 in eq 2) establishes a first-order dependence on [2a] for the
catalyst’s disappearance.
The unitary dependence was also observed using in situ
NMR monitoring of the reaction progress (see sections F3 and
I1 in the Supporting Information for details). Using this
approach, we performed two sets of experiments under the
same conditions, but using a different intensity of irradiation (λ
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Figure 11. (a) Logarithmic plot according to eq 5 giving a positive
fractional-order dependence on [2a] (n ≈ 0.4). (b) Kinetic data
according to eq 4 for n = 0.4. For this fitting, we have used the data
obtained by in situ NMR monitoring of the reaction progress, which
gives the same kinetic profiles observed in Figure 10 (section I1 in the
Supporting Information). This approach has the advantage of
providing a larger number of data, thus allowing for a more reliable
fitting. Experiments performed in NMR tubes at 298 K in CD3CN
using a monochromatic light (λ = 470 nm, irradiance 28.8 mW/cm2).
[1a]0 = 0.3 M and [A]0 = 0.02 M. Initial concentrations of 2a: 0.05 M
(blue plot); 0.1 M (red plot); 0.2 M (green plot).

Figure 10. (a) Reaction profiles for different [2a] values showing a
negative-order dependence and observed rate constants. Kobsd
calculated from the slope of the plots. (b) Evolution of the catalyst
concentration for the experiments in (a). We monitored the evolution
of A by determining the enamine concentration in solution. (c)
Overlay of plots for the kinetic data in (b) according to eq 2. Progress
of the reactions followed by 1H NMR analysis. Each point corresponds
to an individual run. Reactions performed in CD3CN under
illumination by a xenon lamp with a band-pass filter at 450 nm
(irradiance 4.7 mW/cm2). [1a]0 = 1.5 M and [A]0 = 0.1 M. Initial
concentrations of 2a: 0.25 M (blue plot); 0.5 M (red plot); 1 M
(green plot). The same kinetic profiles have been observed using in
situ NMR monitoring of the reaction progress. See section I1 in the
Supporting Information.

−2.31) given by the x-intercept. Figure 11b displays the fitting
of the kinetic data to eq 4 for n = 0.4, showing a good overlay.
Overall, eq 6 gives the empirical rate law for the EDAcomplex-mediated alkylation of butanal in Figure 9a,
discounting catalyst degradation related to the photochemical
initiation.
rate = d[3a]/dt = k[A][2a]∼ 0.4

= 470 nm for both sets of experiments, but an irradiance of 28.8
mW/cm2 vs 3.0 mW/cm2). In the latter set of experiments, a
lower absolute rate of catalyst decomposition was determined,
in consonance with a less effective initiation regime. This
observation establishes a direct correlation between the
disappearance of catalyst A and the number of photochemical
initiation events, since both the concentration of 2a and the
intensity of light influence the rate of degradation for catalyst
A.32
We then wanted to measure the real effect of [2a] on the rate
of alkylation leading to product 3a, discounting the effects of
catalyst A degradation in the initiation regime. Considering the
zeroth-order dependence on 1a, the rate equation should read
as eq 3, with n being the rate order with respect to 2a,
overlooking its effect on [A]. In eq 4, the product formation is
normalized by [A], thus discounting the effect of the catalyst
degradation.
reaction rate = d[3a]/dt ∝ [A][2a]n

rate = d[3c]/dt = k[A][1a]0.5 [2c]0.5

(4)

log([3a]/[A]t ) = n log([2a]) + log(c)

The rate law indicates a turnover-limiting step within the
radical chain propagation cycle (see Figure 7 for the general
mechanism). If the initiation step was rate-determining, a firstorder dependence with respect to both EDA partners I and 2a
would be expected instead. The first-order dependence on
catalyst A (whose concentration is equal to the enamine I
concentration) suggests that the rate-determining step is the
trapping of the electrophilic carbon-centered radical IV from
the ground-state chiral enamine I to form the new carbon−
carbon bond. We would expect higher order dependence on
[2a] if the turnover-limiting step were the SET process, which
regenerates the chain-propagating radical IV from the αaminoalkyl radicals VI.
The alkylation of 1a with bromomalonate, driven by the
direct excitation of enamine, shows half-order dependence on
[2c]. The overall rate equation is then given by eq 7.

(3)

[3a]/[A] ∝ [2a]n t

(6)

(5)

(7)

In analogy with the preceding discussion, the rate-order
assessment indicates that the rate-determining step is the
enamine trapping the electrophilic radical IV, derived from 2c,
to form the carbon−carbon bond (see Figure 7 for the general
mechanism).
Notable, no significant degradation of catalyst A was
observed during the alkylation with 2c within the time frame
of interest for the initial-rate measurements using the method
of independent experiments.46 When the time of irradiation of

The rate-order dependence on [2a] was calculated by
plotting the data according to eq 5, derived from eq 4. The
order (n) is obtained from the slope of the logarithmic plot
displayed in Figure 11a, which indicates a positive fractionalorder dependence on [2a] (n ≈ 0.4), while c is a constant (c =
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the photochemical alkylation with 2c was extended, the
disappearance of catalyst A became significant. However,
using the same 23 W CFL light source and considering the
same time interval, the catalyst degradation was much higher in
the alkylations of 2a and 2b than the alkylation of 2c (details in
section F of the Supporting Information). This observation,
along with the measured quantum yields of photoinitiation
(Φinitiation = 0.77, 0.68, and 0.11 for 2a, 2b, and 2c, respectively),
suggests that the direct excitation of the enamine I is a less
effective radical generation strategy than the enamine-based
EDA complex approach. This scenario can be rationalized on
the basis of the bimolecular nature of the initiation mechanism
with 2c, which requires the excited enamine to encounter 2c for
an effective SET. These conditions make an unproductive
relaxation of the excited intermediate, which restores the
ground-state enamine, more likely. In contrast, the photochemistry underlying the processes with 2a and 2b is
dominated by EDA complexes. These form in the ground
state, holding together the two partners involved in the
following photoinduced SET. In this case, the initiation
mechanism is based on a more efficient unimolecular process.

■

AUTHOR INFORMATION

Corresponding Author

*pmelchiorre@iciq.es
Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS
Financial support was provided by the ICIQ Foundation,
MINECO (Project CTQ2013-45938-P and Severo Ochoa
Excellence Accreditation 2014-2018, SEV-2013-0319), the
AGAUR (Grant 2014 SGR 1059), and the European Research
Council (Grant ERC 278541ORGA-NAUT). A.B. is grateful
to the MECD for an FPU fellowship (ref FPU13/02402). We
are indebted to the team of the Research Support Area at ICIQ.
We thank Dr. Elena Arceo and Dr. Mattia Silvi for preliminary
investigations and useful discussions.

■

■

CONCLUSIONS
In summary, we have used a combination of conventional
photophysical investigations, NMR spectroscopy, and kinetic
studies to elucidate the key mechanistic aspects of the
enantioselective photochemical α-alkylation of aldehydes with
electron-poor organic halides. Quantum yield measurements
established that a radical chain propagation mechanism is
operative, while reaction profile analysis and rate-order
assessment indicated that the trapping of the carbon-centered
radical by the enamine is the rate-determining event. Central to
these processes is the unique and diverse reactivity of chiral
enamines. Their photochemical activity, either by EDA
complex activation or by direct excitation, generates radicals
from the organic halides 2a−2c. This event, by feeding in
radicals from outside the chain, serves as the initiation of selfpropagating cycles. The enamine lies at the heart of the
propagation cycle too, since it traps the radical to generate an
intermediate (the α-amino radical VI) which is key for
sustaining the chain sequence. We also uncovered how enamine
formation and its concentration in solution are directly
influenced by the different photochemical pathways available
to enamines for initiating the chain process (EDA complex
formation vs direct photoexcitation). Overall, the kinetic and
spectroscopic investigations allowed us to understand the
delicate interplay between the light-triggered initiation step and
the radical propagation manifold, suggesting that this approach
can be generally applied to the mechanistic elucidation of chain
processes. From a broader perspective, this study demonstrates
that the synthetic potential of chiral enamines is not limited to
the ground-state domain, but can be further expanded by
exploiting their photochemical activity, providing novel
reactivity frameworks for conceiving light-driven enantioselective catalytic processes.

■

Complete experimental procedures, characterization
data, and details on kinetic and spectroscopic studies
(PDF)

REFERENCES

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ASSOCIATED CONTENT

* Supporting Information
S

The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.6b04871.
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(28) For a process in which one photon produces only one molecule
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chain process where one photon forms n molecules of product, the
quantum yield is expected to be >1. However, a value of Φ < 1 does
not exclude a possible radical chain mechanism. This is because of
potential nonproductive energy-wasting photochemical processes.
(29) Both the quantum yield measurements and the kinetic
experiments were performed in acetonitrile to avoid the precipitation
of the lutidinium bromide salt generated during the reaction (see ref
12), which is insoluble in MTBE instead. The presence of a precipitate
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the ground state via either radiative or vibrational pathways without
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(BET) from the chiral ion pair III (Figure 3d) would unproductively
restore the ground-state enamine-based EDA complex II.
(32) The quantum yield of the initiation step (Φinitiation) was
measured by monitoring the decomposition of catalyst A. The analysis
is based on the observation (extensively discussed in a later section of
the paper) that the enamine I serves as a sacrificial initiator of the
chain mechanism: for any photoinduced SET event, a propagating
radical, IV, is generated while a molecule of the chiral catalyst A is
destroyed via decomposition of the intermediate V (Figures 3d and 5).
If a molecule of the catalyst A decomposes for any photoinduced
initiation, the rate of catalyst degradation correlates with the efficiency
of the initiation. This analysis requires that the catalyst A degradation
is triggered by productive photochemical initiation only, and not by

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(12) The reactions required the presence of 1 equiv of a base (2,6lutidine and NaOAc giving similar results) to perform well. Removing
the base additive, trace amounts of the alkylation products 3 were
formed (<15%), while reagent decomposition along with acidification
of the reaction medium was observed. The likely role of 2,6-lutidine is
to quench the acid generated during the process, as testified to by the
formation of the insoluble lutidinium bromide salt generated during
the reaction. The presence of 2,6-lutidine does not contribute to the
absorption in the visible region to any extent.
(13) Performing the alkylation with 2c under the conditions set out
in Figure 2c but in the presence of 0.5 mol % Ru(bpy)32+ as an
external photosensitizer significantly increased the reactivity (2-fold
reaction rate), in consonance with the occurrence of an additional
photoinduced electron-transfer pathway; see ref 7a. The increase in
reactivity becomes larger in polar solvents (DMF, CH3CN), where
Ru(bpy)32+ is completely soluble. Details are reported in the
Supporting Information of ref 6c.
(14) Enamines have a low ionization potential. For example, 1-but-1enylpyrrolidine has an IP of 7.2 eV; see: Müller, K.; Previdoli, F.;
Desilvestro, H. Helv. Chim. Acta 1981, 64, 2497−2507.
(15) The electron-donor property of a donor molecule is indicated
by the magnitude of its ionization potential (IP in the gas phase) or its
oxidation potential (Epox in solution). Conversely, the viability of a
compound as an acceptor is indicated by the magnitude of its electron
affinity (EA in the gas phase) or its reduction potential (Epred in
solution). Epox and Epred, which can be estimated by cyclic voltammetry
measurements, can help in predicting the suitability of a given
substrate to undergo EDA complex formation.
(16) According to the Mulliken theory (ref 8c), the charge-transfer
transition energy (hνCT) is given by the following equation: hνCT = IP
− EA − ω, where ω is the electrostatic interaction of the chargetransfer ion pair (e.g., III in Figure 3d). Qualitatively, the equation
predicts that the charge-transfer band of the EDA complexes with a
given electron donor (in this case, the enamine) undergoes a
bathochromic shift (absorption at longer wavelengths) with increasing
EA of the acceptor component. The same effect can be obtained by
increasing the electron donicity (decreasing the IP) of the donor.
(17) 2-Phenylacetaldehyde is a competent substrate of the photoorganocatalytic reaction with 2a, 2b, and 2c, providing full conversion
into the corresponding products under the conditions set out in Figure
2. However, a low level of enantioselectivity was observed (below 30%
ee), a consequence of the lability of the resulting benzylic stereocenter.
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(21) Although the photophysics of EDA complexes have been
extensively studied (refs 8a and 8b), their use in chemical synthesis has
found limited applications. This is mainly because the unproductive,
back electron transfer (BET), which restores the ground-state EDA
complex, is generally faster than other possible processes leading to
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Journal of the American Chemical Society
other secondary reactions, a scenario which is consistent with
experimental observations.
(33) The two photochemical initiation manifolds can both be
operative in the alkylations of butanal with 2a and 2b, but only when
using a light that can be absorbed by the transiently generated enamine
I (λ < 415 nm). Both kinetic experiments and quantum yield
measurements with 2a and 2b have been conducted using higher
wavelengths of irradiation, to avoid any possible contribution from the
direct photoexcitation of enamines. Under these conditions, only the
EDA complex activation is a viable strategy to generate radicals from
2a and 2b.
(34) Similar atom-transfer mechanisms have been invoked for the
alkylation of enol ethers and enamides with electrophilic radicals; see:
(a) Curran, D. P.; Ko, S.-B. Tetrahedron Lett. 1998, 39, 6629−6632.
(b) Friestad, G. K.; Wu, Y. Org. Lett. 2009, 11, 819−822. This
pathway was also proposed in ref 25a, p 80.
(35) (a) Kharasch, M. S.; Jensen, E. V.; Urry, W. H. Science 1945,
102, 128. (b) Pintauer, T.; Matyjaszewski, K. Encyclopedia of Radicals;
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745. (b) Rossi, R. A.; Pierini, A. B.; Peñeñory, A. B. Chem. Rev. 2003,
́
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(37) Russell, G. A.; Wang, K. J. Org. Chem. 1991, 56, 3475−3479.
(38) As suggested by a reviewer, deprotonation of an acidic α-proton
within the α-iminyl radical cation V to form an intracyclic iminium ion
is a likely degradation pathway.
(39) Interestingly, an analogous sacrificial role of the enamine was
proposed to support the mechanism of the alkylation of aldehydes
with bromomalonate 2c, using a dual photoredox−organocatalytic
system; see ref 7a.
(40) By using an internal standard and in situ NMR spectroscopic
analysis, we confirmed that the overall amount of the catalyst A
decreased over time, further supporting the instability of the
intermediate V generated upon photoinduced SET. Studies on the
disappearance of the catalyst are reported in Figure 10. The same
studies were repeated using gas chromatography (GC-FID); details are
reported in section F in the Supporting Information.
(41) 1H NMR spectroscopic analysis did not allow us to discriminate
between the free enamine I and the enamine which engages in EDA
complex formation with 2a. The reported I:A ratio refers to the total
amount of enamine I present in solution.
(42) For the description and use of a similar illuminating device,
based on LED, see: (a) Feldmeier, C.; Bartling, H.; Riedle, E.;
Gschwind, R. M. J. Magn. Reson. 2013, 232, 39−44. (b) Feldmeier, C.;
Bartling, H.; Magerl, K.; Gschwind, R. M. Angew. Chem., Int. Ed. 2015,
54, 1347−1351.
(43) Initial-rate kinetic studies on the alkylation of 1a with phenacyl
bromide 2b gave a profile very similar to that of the alkylation with 2a
(Figure 9a).This is consistent with the EDA complex activation being
the underlying photochemical initiation for both systems. Kinetic
studies for the reaction with 2b are detailed in section I2 of the
Supporting Information.
(44) We could not use the method of reaction progress kinetic
analysis to provide a rapid and comprehensive kinetic profile of the
reactions because of the significant catalyst degradation pathway. For
an overview highlighting the potential of this approach, see:
Blackmond, D. G. Angew. Chem., Int. Ed. 2005, 44, 4302−4320.
(45) For a similar treatment of kinetic data for a reaction proceeding
through a radical chain mechanism, see: Boisvert, L.; Denney, M. C.;
Hanson, S. K.; Goldberg, K. I. J. Am. Chem. Soc. 2009, 131, 15802−
15814.
(46) When monitoring the progress of the alkylation with 2c using in
situ NMR methodology, we did observe catalyst degradation. This is
presumably because of decomposition pathways triggered by the
presence of oxygen in the system, as in situ monitoring did not allow
for complete deoxygenation of the reaction medium.

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