Mechanism of the stereoselective α-alkylation of aldehydes driven by the photochemical activity of enamines

Article abstract of DOI:10.1021/jacs.6b04871

Herein we describe our efforts to elucidate the key mechanistic aspects of the previously reported enantioselective photochemical α-alkylation of aldehydes with electron-poor 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 closed-shell 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.

Full text of DOI:10.1021/jacs.6b04871

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Article
On the Mechanism of the Stereoselective #-Alkylation of
Aldehydes Driven by the Photochemical Activity of Enamines
Ana Bahamonde, and Paolo Melchiorre
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b04871 • Publication Date (Web): 06 Jun 2016
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On the Mechanism of the Stereoselective α-Alkylation of Aldehydes
Driven by the Photochemical Activity of Enamines
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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.
Supporting Information Available
ABSTRACT: Herein we describe our efforts to elucidate the key mechanistic aspects of the previously reported enantioselective
photochemical αꢀalkylation of aldehydes with electronꢀpoor organic halides. The chemistry exploits the potential of chiral
enamines, key organocatalytic intermediates in thermal asymmetric processes, to directly participate in the photoexcitation of subꢀ
strates either by forming a photoactive electron donorꢀacceptor (EDA) complex or by directly reaching an electronically excited
state upon light absorption. These photochemical mechanisms generate radicals from closedꢀshell precursors under mild conditions.
At the same time, the ground state chiral enamines provide effective stereochemical control over the enantioselective radical trapꢀ
ping process. We use a combination of conventional photophysical investigations, nuclear magnetic resonance (NMR) spectroscoꢀ
py, and kinetic studies to gain a better understanding of the factors governing these enantioselective photochemical catalytic proꢀ
cesses. Measurements of the quantum yield reveal that a radical chain mechanism is operative, while reactionꢀprofile analysis and
rateꢀorder assessment indicate the trapping of the carbonꢀcentered radical by the enamine, to form the carbonꢀcarbon bond, as rateꢀ
determining. Our kinetic studies unveil the existence of a delicate interplay between the lightꢀtriggered initiation step and the radiꢀ
cal chain propagation manifold, both mediated by the chiral enamines.
tion merges in a sole chiral organocatalyst, enables lightꢀ
driven enantioselective transformations that cannot be realized
using the thermal reactivity of enamines. Specifically, we used
this approach to develop the αꢀalkylation of aldehydes7 with
electronꢀdeficient 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.
INTRODUCTION
Ground state enamine chemistry has been extensively exꢀ
plored since the 1950s. Following pioneering studies by Gilꢀ
bert Stork, organic chemists have exploited enamines’ nucleoꢀ
philic character to trap electrophiles and develop useful twoꢀ
electron polar processes.1 Successively, chiral enamines I,
generated in situ upon condensation of aldehydes 1 with secꢀ
ondary amine catalysts, have been recognized as key intermeꢀ
diates of organocatalytic enantioselective reactions (Figure
1a).2,3 Singleꢀelectron oxidation of ground state chiral
enamines by a chemical oxidant has also been found to render
3πꢀelectron radical cation intermediates amenable to a range of
unique openꢀshell reaction manifolds (singly occupied molecꢀ
ular orbital (SOMO) activation, Figure 1b).4 Overall, the last
15 years have witnessed the extensive use of the ground state
reactivity of enamines for the stereoselective functionalization
of carbonyl compounds.5
At first glance, both processes depicted in Figure 1c and 1d
seem to be classical substitution reactions of enamines proꢀ
ceeding through a SN2 manifold. However, they do not proꢀ
ceed at all without light illumination. Crucial for reactivity
was the ability of enamines to trigger the photochemical forꢀ
mation of radicals from the alkyl halides 2 under mild condiꢀ
tions. Despite the superficial similarities between the two
chemical transformations, they profoundly diverge in the radiꢀ
cal generation mechanism. The first strategy (Figure 1c) relied
on the formation of photonꢀabsorbing electron donorꢀacceptor
(EDA) complexes,8 generated in the ground state upon associꢀ
ation of the electronꢀrich enamine I with electronꢀdeficient
benzyl and phenacyl bromides. Visible light irradiation of the
colored EDA complex II induced a single electron transfer
(SET), allowing access to the reactive openꢀshell intermediꢀ
ates. In the second approach (Figure 1d), we used the capabilꢀ
ity of the chiral enamine I to directly reach an electronically
excited state (I*) upon light absorption and then to act as efꢀ
fective photoinitiator. SET reduction of the bromomalonate 2c
induced the formation of the carbonꢀcentered radical.
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 exploitꢀ
ing their photochemical activity. We revealed the previously
hidden ability of enamines to actively participate in the photoꢀ
excitation of substrates and trigger the formation of reactive
openꢀshell species from organic halides.6 At the same time,
ground state chiral enamines can provide effective stereoꢀ
chemical control over the enantioselective radical trapping
process. This strategy, where stereoinduction and photoactivaꢀ
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revealed further mechanistic analogies and striking differences
for these enamineꢀmediated photochemical enantioselective
alkylations of aldehydes with electronꢀpoor 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 lightꢀdriven enantioselective cataꢀ
lytic processes.10
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RESULTS and DISCUSSION
Our recent studies6 established that enamines I can interact
with visible light in two different ways, serving either as doꢀ
nors in photoactive EDA complex formation (Figure 1c) or as
photoinitiators upon direct excitation (Figure 1d). As the proꢀ
totypical reactions for mechanistic analysis, we selected the
alkylations of butanal (1a) with 2,4ꢀdinitrobenzyl bromide (2a,
Figure 2a), phenacyl bromide (2b, Figure 2b), and diethyl
bromomalonate (2c, Figure 2c), all promoted by the commerꢀ
cially 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 excluꢀ
sion 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 presꢀ
ence of TEMPO (1 equiv), the latter experiment indicating a
radical mechanism.
Figure 1. Enamines’ reactivity domains. Ground state reactivity:
enamines as (a) nucleophiles in traditional polar processes and (b)
radical precursors upon singleꢀelectron chemical oxidation. Excited
state 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: SOMOꢀphile that can
intercept the enamine radical cation; the grey circle represents the
chiral organic catalyst scaffold.
In this paper, we detail how a combination of photophysiꢀ
cal investigations, nuclear magnetic resonance (NMR) specꢀ
troscopy, kinetic studies, and quantum yield measurements
EDA Complex Activation Strategy
(a)
h
3a yield (%)
ee (%)
h
NO2
O
O
NO2
none
<5
-
(S)-A (20 mol%)
Br
23 W CFL
blue LED ( max450 nm)
band pass @ 450 nm
98*
98*
95
83
82
83
H
H
2,6-lutidine (1 equiv)
MTBE, 25 °C, 6 h
[2a]0 = 0.5 M
Et
Et
NO2
NO2
1a
2a
3a
(b)
h
h
3b yield (%)
ee (%)
O
O
O
(S)-A (20 mol%)
Br
none
<5
-
H
H
23 W CFL
blue LED ( max450 nm)
81*
78*
84
84
2,6-lutidine (1 equiv)
MTBE, 25 °C, 16 h
[2b]0 = 0.5 M
Et
Et
O
1a
2b
3b
Direct Photoexcitation of Enamines
(c)
h
3c yield (%)
ee (%)
CF3
CF3
h
F3C
O
O
CO2Et
CO2Et
none
<5
-
CO2Et
CO2Et
(S)-A (20 mol%)
23 W CFL (6 h)
band pass @ 400 nm
band pass @ 450 nm
94*
95
<5
83
83
-
H
Br
H
2,6-lutidine (1 equiv)
MTBE, 25 °C, 16 h
[2c]0 = 0.5 M
Et
Et
N
CF3
OTMS
H
A
blue LED ( max450 nm) <5
-
1a
2c
3c
Figure 2. The model photochemical alkylations of butanal 1a catalyzed by the chiral secondary amine A: the enamineꢀbased EDA complex activaꢀ
tion in the reaction of (a) 2,4ꢀdinitrobenzyl bromide 2a, and (b) phenacyl bromide 2b; (c) the direct photoexcitation of enamines in the alkylation
of 1a with diethyl bromomalonate 2c; MTBE: methyl tertꢀbutyl ether. NMR yield of 3 determined by 1H NMR spectroscopic analysis of the crude
reaction mixture using 1,1,2ꢀtrichloroethene as the internal standard.*Yield of the isolated products 3.
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Along with these similarities, the lightꢀtriggered reactions
rationalize the different lightꢀwavelength/reactivity correlation
profiles while elucidating the origins of the enamine’s photoꢀ
chemical activity.
in Figure 2 showed striking differences too. When the experiꢀ
ments were conducted under illumination by a 300 W Xenon
lamp equipped with a cutꢀoff filter at 385 nm and a bandꢀpass
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 bandꢀpass filter at 450 nm or
a blue LED (λmax at 450 nm) completely inhibited the reaction
with diethyl bromomalonate 2c. In sharp contrast, the
enamineꢀmediated alkylations with 2a and 2b were not affectꢀ
ed. We decided to conduct spectroscopic investigations to
Spectroscopic Studies. Immediately after mixing an
MTBE solution of the enamine, generated in situ upon conꢀ
densation of butanal 1a (3 equiv) with 20 mol% of catalyst A,
with 2,4ꢀdinitrobenzyl bromide 2a (1 equiv), we observed that
the achromatic solution turned to a marked yellow color (Figꢀ
ure 3a). This observation raised the question of how the color
developed.
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(a)
2
1,5
1
2
(b)
A
1,5
1a
2b
1a
2a
A+2a
1a+A (enamine I)
1a+A+2a (EDA)
1
0,5
0
1a+A (enamine I)
1a+A+2b (EDA)
0,5
0
350
400
450
500
550
600
300
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400
450
500
550
600
Wavelength (nm)
Wavelength (nm)
Figure 3. (a) Optical absorption spectra, recorded in MTBE in 1 mm path quartz cuvettes using a Shimadzu 2401PC UVꢀvisible spectrophotomeꢀ
ter, and visual appearance of the separate reaction components and of the colored EDA complex in the alkylation of 2,4ꢀdinitrobenzyl bromide 2a;
[1a] = 1.5 M; [2a] = 0.5 M; [A] = 0.1 M. (b) Optical absorption spectra in MTBE for the alkylation with phenacyl bromide 2b; [1a] = 1.5 M; [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) The visibleꢀlightꢀtriggered generation of the electrophilic carbonꢀcentered radical IV and the αꢀiminyl radical cation V
using the enamineꢀbased EDA complex strategy; hνCT = chargeꢀtransfer transition energy;16 BET = back electron transfer.
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
chargeꢀtransfer theory.8c According to this theory, the associaꢀ
tion of an electronꢀrich substrate with a low ionization potenꢀ
tial (such as an enamine)14 with an electronꢀaccepting moleꢀ
cule with a high electronic affinity15 (such as electronꢀdeficient
benzyl and phenacyl bromides) can bring about the formation
of a new molecular aggregation in the ground state: the elecꢀ
tron donorꢀacceptor complex. EDA complexes are characterꢀ
ized by physical properties that differ from those of the sepaꢀ
rated substrates. This is because new molecular orbitals form,
emerging from the electronic coupling of the donor and accepꢀ
tor frontier orbitals (HOMO/LUMO). EDA formation is acꢀ
companied by the appearance of a new absorption band, the
chargeꢀtransfer band (hνCT), associated with an intracomplex
transfer of a single electron (SET) from the donor to the acꢀ
ceptor. In many cases, the energy of this transition lies within
the visible range.16 This is what happened when mixing toꢀ
gether the enamine, generated in situ upon condensation of
catalyst A and 1a, with both 2,4ꢀdinitrobenzyl bromide 2a
red
(Epred = ꢀ0.66 V vs Ag/Ag+ in CH3CN) and phenacyl bromide 2b
(Ep = ꢀ1.35 V vs Ag/Ag+ in CH3CN). Indeed, the optical abꢀ
sorption spectra showed a bathochromic displacement in the
visible spectral region, where none of the substrates absorbs
(red lines, Figures 3a and 3b). The new absorption bands,
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the possibility that the direct photoexcitation of the enamine
which in the case of 2a can reach the green region of the visiꢀ
ble range (550 nm), cannot be accounted for by the addition of
the absorption of the separate compounds, which can barely
absorb visible light.
could trigger the radical generation from 2c. This mechanistic
scenario was consonant with the experiment performed using
a bandꢀpass 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 SternꢀVolmer 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 SI for details).
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 2ꢀphenylacetaldehyde17 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 Supporting Information, SI). Concomitantly, an associaꢀ
tion constant (KEDA) of 11.56 ± 0.02 Mꢀ1 for the complex IIa
and 4.9 ± 0.1 Mꢀ1 for IIb in MTBE was determined by specꢀ
trophotometric analysis using the BenesiꢀHildebrand methꢀ
od.19
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The lightꢀwavelength/reactivity correlation for the photoꢀ
chemical alkylations of butanal with 2a and 2b (Figures 2a
and 2b, respectively) can be rationalized on the basis of the
photoactivity of the enamineꢀbased EDA complexes IIa and
IIb (their absorption spectra, which are similar to the EDA
absorption in Figures 3a and 3b, are reported in Figure S6
within the SI). Absorption of lowꢀenergy photons, including
visible light, can induce an electron transfer to occur, leading
to the chiral ion pair III (Figure 3d). Critical to reaction develꢀ
opment 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
carbonꢀcentered radical IV and the αꢀiminyl radical cation V)
which can initiate synthetically useful transformations, i.e. the
alkylation of aldehydes. The enamineꢀbased EDA complex
activation strategy thus provides ready access to openꢀshell
reactive species under very mild conditions and without the
need for any external photoredox catalyst.
Figure 4. Optical absorption spectra acquired in MTBE in 1 cm path
quartz cuvettes; [1a] = 1.5 M; [2c] = 0.5 M; [A] = 0.1 M.
These observations indicate that the photochemical activity
of chiral enamines and their potential for lightꢀinduced radical
generation is not limited to the formation of ground state EDA
complexes. As detailed in Figure 5, the enamine I, upon light
absorption, can reach an electronically excited state (I*) and
act as a photoinitiator, triggering the formation of the electronꢀ
deficient radical IVc through the reductive cleavage of the
bromomalonate C–Br bond via a SET mechanism23 (Epred of 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 SI for details).24 In analꢀ
ogy with the EDA complex activation (Figure 3d), here too the
SET event leads to both an electrophilic radical IV and the αꢀ
iminyl radical cation V.
The enantioselective photochemical alkylation of butanal
1a with diethyl bromomalonate 2c showed profoundly differꢀ
ent behavior. In addition to the distinct effect the light freꢀ
quency 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 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 SI). Closer inspection of the absorpꢀ
tion spectrum indicated that the only photoabsorbing comꢀ
pound at 400 nm (a wavelength suitable for triggering the
reaction) was the enamine22 (green line in Figure 4, absorption
band till 415 nm). This observation prompted us to evaluate
Figure 5. Radical generation strategy based on the direct photoexcitaꢀ
tion of the chiral enamine I; the grey circle represents the chiral orꢀ
ganic catalyst scaffold.
Quantum Yield Measurements and the Proposed Mecha-
nisms. Photophysical investigations established that in situ
generated chiral enamines can use two different photochemiꢀ
cal mechanisms to provide openꢀshell species from organic
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the actinometer, we measured quantum yields of 25, 20, and
halides 2aꢀc while avoiding the need for any external photoreꢀ
dox catalyst. We then focused on the nonꢀphotochemical steps
inherent to the enantioselective alkylation of butanal 1a. As
depicted in Figures 3d and 5, the enamineꢀmediated photoꢀ
chemical pathways bring about the formation of two radical
species: the chiral radical cation V and the electrophilic radiꢀ
cals IV. A stereocontrolled radicalꢀradical coupling of IV and
V can be invoked to account for the formation of the new carꢀ
bonꢀcarbon bond and the αꢀcarbonyl stereogenic center within
the final products 3aꢀc (Figure 6a). This mechanistic frameꢀ
work would require an enamineꢀmediated photochemical
event for every molecule of product generated.
20 for the reactions in CH3CN29 with 2a, 2b, and 2c,30 respecꢀ
tively (λ = 450 nm for 2aꢀb and 400 nm for 2c). These results
are consonant with a selfꢀpropagating radical chain mechaꢀ
nism as the main reaction pathways for the three enamineꢀ
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 nonꢀproductive energyꢀwasting 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 photoꢀinitiation.
To better estimate the actual chain length of the reactions, we
measured the quantum yield of the initiation step,32 determinꢀ
ing a Φinitiation of 0.77, 0.68, and 0.11 for 2a, 2b, and 2c, reꢀ
spectively (λ = 450 nm for 2aꢀb and 400 nm for 2c, details in
Sections G2 and G4 of the SI). Taking these data into account,
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the actual chain lengths of the model reactions (Φestimated
=
Φmeasured / Φinitiation) are considerably 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 alꢀ
kylation of butanal with 2,4ꢀdinitrobenzyl bromide 2a,
phenacyl bromide 2b, and diethyl bromomalonate 2c. They
differ in the nature of the lightꢀtriggered 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 direct excitation, generates radicals IV
from the closedꢀshell intermediates 2aꢀc (Figure 7a).33 This
event, by feeding in radicals from outside the chain, serves as
the initiation of selfꢀpropagating radical chains. The radical
trap from the ground state chiral enamine I forms the new
carbonꢀcarbon bond while forging the stereogenic center (Figꢀ
ure 7b). Considering the consolidated ability of catalyst A to
infer high stereoselectivity in enamineꢀmediated polar reacꢀ
tions,11 it is no surprise that the addition of the radical IV to I
proceeds in a stereocontrolled fashion. Two pathways are feaꢀ
sible for the propagation step (Figure 7c): the αꢀaminoalkyl
radicals VI, resulting from the radical trap, can transfer an
electron to the starting alkyl halides 2. This SET process reꢀ
generates the chainꢀpropagating radical IV while giving the
bromideꢀiminium ion pair VII, which eventually hydrolyzes to
release the product 3 and the aminocatalyst A. The outerꢀ
sphere SET process is facilitated by the formation of the stable
bromide and iminium ions. Alternatively, an atomꢀtransfer
mechanism can be envisaged, where the αꢀaminoalkyl radical
VI would abstract a bromine atom from 2, regenerating the
radical IV while affording an unstable αꢀbromo amine adduct
VIII,34 which would eventually evolve to the iminium ion pair
VII. This pathway would provide a rare example of enantioseꢀ
Figure 6. Possible pathways for the nonꢀphotochemical steps of the
model reactions: (a) inꢀcage radicalꢀradical coupling, and (b) radical
chain propagation manifold. The openꢀshell intermediates V and IV
are generated through the photochemical activity of the enamines, as
detailed in Figures 3d and 5. EWG: electronꢀwithdrawing group. Φ =
overall quantum yield of the alkylation; see Ref. 28 for an explanation
of the quantum yield values.
It must be noted, however, that many radical reactions generalꢀ
ly proceed through selfꢀpropagating radicalꢀchain pathways.25
In chain processes, product formation occurs through propagaꢀ
tion steps that convert the openꢀshell intermediate (originating
from the substrate precursor) into the final product while reꢀ
generating the chainꢀpropagating 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
closedꢀshell substrate). In our case (Figure 6b), a chain propaꢀ
gation sequence can be envisaged such that the nucleophilic
ground state enamine I would trap the photochemicallyꢀ
generated electrophilic radical IV to form the αꢀamino radical
VI. Since αꢀaminoalkyl radicals are known to be strong reducꢀ
ing agents,26 VI would induce the reductive cleavage of the
electronꢀpoor alkyl bromide 2 through an outerꢀsphere SET
process, thereby regenerating the radical IV while releasing
the product 3 and the aminocatalyst A (more mechanistic deꢀ
tails are discussed in Figure 7). In this scenario, the enamineꢀ
based photochemical radical generation strategies, which afꢀ
ford radicals IV and V, would serve only to initiate a radical
selfꢀpropagating chain process.
lective catalytic atom transfer radical addition (ATRA),35
a
historical methodology useful for functionalizing olefins with
organic halides.
To help distinguish between the two mechanisms, we deꢀ
termined the quantum yield (Φ)27 of the model reactions,
which defines the moles of product formed per moles of phoꢀ
tons absorbed by the system.28 Using potassium ferrioxalate as
To discriminate between the possible propagation manifolds,
we prepared and isolated the iminium ion IX (Figure 7d), deꢀ
rived from the condensation of pyrrolidine and isobutyraldeꢀ
hyde, which mimics the actual iminium ion intermediate VII
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involved in the catalytic cycle. VII could not be synthesized
radical of type VI is incapable of reducing either 2b or 2c
because of the steric hindrance of catalyst A hampering a facꢀ
ile condensation with the aldehydic product 3. Evaluating the
redox properties of IX is pertinent since its electrochemical
reduction provides access to αꢀaminoalkyl radical of type VI,
the key intermediate of the chain propagation. We measured
(Epred of 2b = ꢀ1.35 V vs Ag/Ag+ in CH3CN; Epred of 2c = ꢀ1.69
V vs Ag/Ag+ in CH3CN), indicating that a bromineꢀtransfer
mechanism is likely operative with phenacyl bromide and
bromomalonate substrates. In contrast, a SET reduction is the
most likely pathway when using 2a, since its potential (Epred of
2a = ꢀ0.66 V vs Ag/Ag+ in CH3CN) makes a SET reduction
from intermediate VI feasible.
red
by cyclic voltammetry a reduction potential (Ep of IX) of ꢀ
0.95 V vs Ag/Ag+ in CH3CN (irreversible reduction to give the
αꢀaminoalkyl radical X). This value means that the αꢀamino
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(b)
(a)
Radical Chain
Photochemical Initiation
h
Br
N
IVa/b
2
2a 2b
or
SET
N
H
EWG
propagation
step
EDA complex
formation
- Br
Et
VI
H
CF3
CF3
EWG
F3C
EWG
IV
EWG
Et
II
colored EDA complex
N
N
chain process
EWG
IV
N
CF3
Br
OTMS
H
EWG
I
I
*
Et
VII
Et
2c
SET
Et
H2O
CO2Et
h
N
H2O
CF3
F3C
CF3
O
H
- Br
direct
photoexcitation
CO2Et
Et
I*
IVc
H
product 3
N
CF3
Et
OTMS
H
1a
+ HBr
A
Propagation Pathways
(c)
SET manifold
SET
ATRA manifold
bromine-transfer
N
N
N
N
N
Br
Br
H
Br
H
N
EWG
H
EWG
H
EWG
EWG
H
EWG
EWG
IV
EWG
IV
2a
2b/c
VI
VII
VI
VII
Et
Et
Et
Et
Et
VIII
(d)
(e)
NO2
ClO4
Me
EDA Activation
SET manifold
EDA Activation
ATRA manifold
Enamine Excitation
ATRA manifold
O
N
Epred = - 0.95 V
vs Ag/Ag+ in CH3CN
CO2Et
Br
Br
2c
Me
Me
20
0.68
29
2a
25
0.77
32
Br
20
measured
measured
measured
H
H
CO2Et
2b
0.11
initiation
initiation
initiation
NO2
Epred = - 0.66 V
Me
Epred = - 1.69 V
IX
X
182
Epred = - 1.35 V
estimated
estimated
estimated
VII
VI
mimics
mimics
Figure 7. The chain propagation manifold underlying the mechanism of the photochemical enamineꢀmediated enantioselective αꢀalkylation of
butanal. (a) The initiation event, which generates the electrophilic radicals IV, is driven by the photochemical activity of the enamines (EDA comꢀ
plex formation or direct photoexcitation), while (b) the chain process is triggered by the radical trapping by the enamine I. (c) The two possible
propagation pathways as driven either by the SET reduction of 2 or the bromine atom transfer from 2 involving the key αꢀamino radical VI interꢀ
mediate. (d) Evaluating the redox potential of the crucial αꢀaminoalkyl radical of type VI. (e) Summary of the quantum yield measurements for the
three model photochemical reactions. The grey circle represents the chiral scaffold of the organic catalyst A.
Several aspects of the mechanism proposed in Figure 7 deꢀ
serve comment. The underlying radical chain pathway is not
surprising when considering that the transformations closely
resemble ATRA processes35 or a KornblumꢀRussell SRN1ꢀtype
alkylation.36 The SRN1 is a 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 elecꢀ
tron transfer steps with radical ions as intermediates. In some
example of SRN1ꢀtype reactions, electron rich olefins, includꢀ
ing enamines,37 efficiently trap electrophilic radicals. In addiꢀ
tion, electronꢀpoor benzyl37 bromides are suitable substrates
for the SRN1 reaction manifold. On the other side, bromomaloꢀ
nates 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
aminocatalyst 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 aldeꢀ
hyde 1), which is unsuitable for participating in the radical
chain, into the electronꢀrich chiral enamine I, a key intermediꢀ
ate of the propagation cycle. In addition, the enamine is directꢀ
ly involved in both the stereoꢀdefining event and the photoꢀ
chemical initiation. As for the initiation, the fate of the chiral
αꢀiminyl radical cation V, emerging from the photoinduced
SET to 2 (Figures 3d and 5), deserves further comment. Interꢀ
mediate 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 αꢀiminyl radical cation V collapses to
give a variety of degradation products that, despite our efforts,
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have remained unidentified so far.38 Thus, the enamine I
on the dynamic equilibrium system (Figure 8c). We used a
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 deꢀ
stroyed via decomposition of the intermediate V. By using
both gas chromatography (GCꢀFID) 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 followꢀ
ing sections). The irreversible cyclic voltammogram of the
preformed enamine 4 (Figure S16 in the SI) is also congruent
with the proposed enamine degradation pathway.
xenon lamp coupled with a monochromator which, by bringꢀ
ing the light in close contact with the NMR tube through an
optical fiber,42 allowed for the in situ illumination of the samꢀ
ples. 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 obꢀ
served (3.8:1 ratio of I:A after 30 seconds of irradiation). Afꢀ
ter 60 seconds of irradiation, the signals of the free catalyst A
could no longer be detected, meaning that the system dramatiꢀ
cally shifted towards the enamine I. This observation can be
reconciled with the photochemical activity of the enamineꢀ
based EDA complex II, which, upon excitation, induces the
irreversible formation of the electrophilic radical IV (upon
fragmentation of the CꢀBr bond within the ion pair III, see
Figure 3d) and the unstable αꢀiminyl radical cation V.40 These
lightꢀtriggered events decrease the concentration of both the
enamine and 2a, further favoring the forward reactions of the
multiple equilibrium systems depicted in Figure 8c.
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With a clearer mechanistic picture in mind, we decided to
perform kinetic studies to better understand the relative imꢀ
portance of the initiation step and the propagation cycle for the
overall rate, while establishing the turnoverꢀlimiting step of
the model photochemical catalytic alkylations. But 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 soluꢀ
tion has a direct effect on the kinetic profiles of the reactions,
since the enamine is involved in both initiation and chain
propagation (Figures 7a and 7b).
NMR Spectroscopic Studies. The catalytically active
enamine intermediate I is generated via the reversible condenꢀ
sation of the chiral aminocatalyst A with butanal 1a (Figure
8a). This reversible process is characterized by an equilibrium
constant (Kenamine = [I]·[H2O]/[1a]·[A]). As with 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 posiꢀ
tion of equilibrium to the side that opposes the perturbation.
As discussed above (Figure 3c), the formation of the enamineꢀ
based EDA complex is also an equilibrium, where KEDA identiꢀ
fies the association constant. For example, the EDA complex
IIa (formed by the association of the preformed enamine 4
with 2,4ꢀdinitrobenzyl bromide 2a) has a KEDA of 11.6 Mꢀ1 in
MTBE. This scenario suggests that the presence of acceptor 2a
can alter the original state of equilibrium for enamine forꢀ
mation. 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 aminocatalyst A in 0.5 mL
of anhydrous CD3CN, both enamine I and free catalyst A were
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 samꢀ
ples (λ = 470±5 nm, irradiance = 28.8 mW/cm2). (a) The 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) The 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) The
effect of an EDA complex, unable to undergo a photoinduced irreꢀ
versible SET event, on the enamine concentration. BET: back electron
transfer.
detected in a ratio of 1.2:1. An equilibrium constant (Kenamine
)
of 0.155±0.002 was determined (see Section H1 in the SI for
details). The addition of 0.1 mmol of 2a induced a shift in the
position of the equilibrium toward the enamine I, as demonꢀ
strated by the 1.8:1 ratio of I and free catalyst A. This is conꢀ
gruent 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
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The importance of the irreversible events that follow the
photoinduced SET is corroborated by a similar experiment
where 2a was replaced by 2,4ꢀdinitrotoluene 5 (Figure 8d). 5
can act as an acceptor partner in EDA complex formation with
the enamine I (KEDA = 4.6 ± 0.1 Mꢀ1 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 comꢀ
plex 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.
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Figure 9. Model reactions used for initialꢀrate kinetics determined by
1H NMR analysis and the observed rate orders. (a) EDA complexꢀ
triggered photochemical alkylation of butanal 1a with 2,4ꢀ
dinitrobenzyl bromide 2a. (b) Alkylation of 1a with diethyl bromoꢀ
malonate 2c driven by the direct photoexcitation of enamines. Reacꢀ
tion 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
1
using in situ H NMR spectroscopy (λ = 470 and 400 nm for 2a and
These experiments were then repeated with the bromomaꢀ
lonate 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
photoꢀexcitation of the enamine I and does not involve any
preꢀassociation with 2c. Thus, the presence of 2c does not
influence the partitioning of the catalyst A between the free
state and the enamine I.
2c, respectively) to directly monitor the reaction progress. Both apꢀ
proaches gave similar kinetic profiles.
Figure 9 details the results of our initialꢀrate kinetic invesꢀ
tigations, performed across a range of concentrations for each
reaction component. A firstꢀorder dependence on the catalyst
A was inferred for both the EDA complexꢀbased process with
2a (Figure 9a) and the reaction with bromomalonate 2c (Figꢀ
ure 9b). However, striking discrepancies in rate orders were
observed in the dependence on butanal 1a and organic halide
(2a and 2c). The EDA complexꢀmediated alkylation showed a
zerothꢀorder dependence in 1a concentration and an unexꢀ
pected negative fractional order in [2a]. In sharp contrast, the
photochemical alkylation of 2c is characterized by a halfꢀorder
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 apꢀ
proach (details in Figures S31 and S39). No alteration of the
kinetic profiles was observed after the addition of either 1 or 2
equivalents of H2O. These results indicate that the iminium
ion hydrolysis, which leads to the alkylation product 3 while
liberating the catalyst A, is not turnoverꢀlimiting.
Kinetic Studies. We then performed kinetic studies to gain
a better understanding of the factors governing the photoꢀ
chemical enamineꢀbased alkylations of butanal 1a. In particuꢀ
lar, 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 Aꢀcatalyzed alkylation of 1a with 2,4ꢀdinitrobenzyl
bromide 2a was chosen as representative of the EDA complex
activation strategy (Figure 9a),43 while the reaction with diethꢀ
yl bromomalonate 2c exploits the direct photoexcitation of the
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 proꢀ
gress of the two reactions was monitored by 1H NMR analysis
using two different approaches (see Section I in the SI for
details). We used a Xenon lamp with a bandꢀpass filter at 450
nm (irradiance = 4.7 mW/cm2) to illuminate the EDA comꢀ
plexꢀmediated reaction with 2a (Figure 9a), while a cutꢀoff
filter at 385 nm (irradiation at λ ≥ 385 nm; irradiance = 300
mW/cm2) was employed for the process with 2c (Figure 9b).
This setꢀup required an independent reaction to be performed
for every dataꢀpoint at different times. The initialꢀrate kinetic
We then tried to reconcile the strikingly different kinetic
behaviors of the two systems with our previous observations.
The zerothꢀorder dependence on butanal 1a for the EDA comꢀ
plexꢀmediated 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 Figures 8bꢀc 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 forꢀ
mation 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 afꢀ
fect the formation of the reactive enamine catalytic intermediꢀ
ate. 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
1
studies were repeated using in situ H 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
complexꢀbased reaction with 2a was irradiated at 470 nm (irꢀ
radiance = 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.
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free state and the enamine intermediate I. Thus, a definitive
resting state cannot be identified, with the catalyst concentraꢀ
tion 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 halꢀ
ide 2, the negative fractional order in [2a] for the EDA comꢀ
plexꢀdriven process (Figure 10a) deserves inꢀdepth 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 decomposiꢀ
tion of the unstable αꢀiminyl 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
zerothꢀorder dependence in [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 experꢀ
iments by determining the enamine concentration in solution.41
The initialꢀrate measurements in Figure 10b suggest that the
decrease in [A] correlates with 2a concentration. If the rate of
disappearance of [A] is proportional to [2a]n, then the data
should fit Equation 1. As a result, the kinetic data can be plotꢀ
ted as indicated in Equation 2.
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Figure 10. (a) Reaction profiles for different [2a] showing a negaꢀ
tiveꢀorder dependence and observed rate constants. Kobs calculated
from the slope of the plots. (b) Evolution of the catalyst concentration
for the experiments in Figure 10a. We monitored the evolution of A
by determining the enamine concentration in solution. (c) Overlay of
plots for the kinetic data in Figure 10b according to Equation 2. Proꢀ
Disappearance of A = ꢀd[A]/dt ∝ [2a]n (Eq. 1)
1
gress of the reactions followed by H NMR analysis; each point corꢀ
responds to an individual run. Reactions performed in CD3CN under
illumination by a Xenon lamp with a bandꢀpass filter at 450 nm (irraꢀ
diance = 4.7 mW/cm2); [1a]0= 1.5 M, [A]0= 0.1 M; initial concentraꢀ
tions of 2a: 0.25 M (blue plot); 0.5 M (red plot) and 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 SI.
[A] ∝ [2a]n · t
(Eq. 2)
Equation 2 indicates that, for reactions with the same initial
concentrations of aminocatalyst A, plots of [A] versus [2a]n·t
should be superimposable.45 Figure 10c shows such a superꢀ
imposition for three reactions that have comparable initial
concentrations of A but different concentrations of 2a. In Figꢀ
ure 10c, the overlay found for plots of [A] versus [2a]1·t (n =
1 in Equation 2) establishes a firstꢀorder dependence on [2a]
for the catalyst’s disappearance.
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 zerothꢀorder dependence on 1a, the rate equation should
read as Equation 3, with n being the rate order with respect to
2a, overlooking its effect on [A]. In Equation 4, the product
formation is normalized by [A], thus discounting the effect of
the catalyst degradation.
The unitary dependence was also observed using in situ
NMR monitoring of the reaction progress (see Sections F3 and
I1 in the SI for details). Using this approach, we performed
two sets of experiments under the same conditions, but using a
different intensity of irradiation (λ = 470 nm for both sets of
experiments, but irradiance = 28.8 vs 3.0 mW/cm2). In the
latter set of experiments, a lower absolute rate of catalyst deꢀ
composition was determined, in consonance with a less effecꢀ
tive initiation regime. This observation establishes a direct
correlation between the disappearance of catalyst A and the
number of photochemical initiation events, since both the conꢀ
centration of 2a and the intensity of light influence the rate of
degradation for catalyst A.32
Reaction rate = d[3a]/dt ∝ [A]1 · [2a]n (Eq. 3)
[3a]/[A] ∝ [2a]n · t
(Eq. 4)
log ([3a]/[A]·t) = n · log ([2a]) + log (c) (Eq. 5)
The rateꢀorder dependence in [2a] was calculated by plotꢀ
ting the data according to Equation 5, derived from Equation
4. The order (n) is obtained from the slope of the logarithmic
plot displayed in Figure 11a, which indicates a positive fracꢀ
tionalꢀorder dependence on [2a] (n ≈ 0.4), while c is a conꢀ
stant (c = ꢀ2.31) given by the xꢀintercept. Figure 11b displays
the fitting of the kinetic data to Equation 4 for n = 0.4, showꢀ
ing a good overlay.
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Notable, no significant degradation of catalyst A was obꢀ
served during the alkylation with 2c within the timeframe of
interest for the initialꢀrate measurements using the method of
independent experiments.46 When extending the time of irradiꢀ
ation of the photochemical alkylation with 2c, the disappearꢀ
ance 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 alꢀ
kylations of 2a and 2b than 2c (details in Section F of the SI).
This observation, along with the measured quantum yields of
photoꢀinitiation (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 enamineꢀbased 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 condiꢀ
tions make an unproductive relaxation of the excited intermeꢀ
diate, 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 photoꢀinduced SET. In this case, the initiation
mechanism is based on a more efficient unimolecular process.
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Figure 11. (a) Logarithmic plot according to Equation 5 giving a
positive fractionalꢀorder dependence on [2a] (n ≈ 0.4). (b) Plot of the
kinetic data according to Equation 4 for n = 0.4. For this fitting, we
have used the data obtained by in situ NMR monitoring of the reacꢀ
tion progress which gives the same kinetic profiles observed in Figure
10 (Section I1 in the SI). This approach has the advantage to provide
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, [A]0= 0.02 M; initial concentrations of 2a: 0.05 M (blue plot);
0.1 M (red plot) and 0.2 M (green plot).
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 enantiꢀ
oselective photochemical αꢀalkylation of aldehydes with elecꢀ
tronꢀpoor organic halides. Quantum yield measurements estabꢀ
lished that a radical chain propagation mechanism is operative,
while reaction profile analysis and rateꢀorder assessment indiꢀ
cated that the trapping of the carbonꢀcentered radical by the
enamine is the rateꢀdetermining event. Central to these proꢀ
cesses is the unique and diverse reactivity of chiral enamines.
Their photochemical activity, either by EDA complex activaꢀ
tion or direct excitation, generates radicals from the organic
halides 2aꢀc. This event, by feeding in radicals from outside
the chain, serves as the initiation of selfꢀpropagating cycles.
The enamine lies at the heart of the propagation cycle too,
since it traps the radical to generate an intermediate (the αꢀ
amino radical VI) which is key for sustaining the chain seꢀ
quence. We also uncovered how enamine formation and its
concentration in solution are directly influenced by the differꢀ
ent photochemical pathways available to enamines for initiatꢀ
ing the chain process (EDA complex formation vs direct phoꢀ
toexcitation). Overall, the kinetic and spectroscopic investigaꢀ
tions allowed us to understand the delicate interplay between
the lightꢀtriggered initiation step and the radical propagation
manifold, suggesting that this approach can be generally apꢀ
plied 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 phoꢀ
tochemical activity, providing novel reactivity frameworks for
conceiving lightꢀdriven enantioselective catalytic processes.
Overall, Equation 6 gives the empirical rate law for the
EDA complexꢀmediated alkylation of butanal in Figure 9a,
discounting catalyst degradation related to the photochemical
initiation:
rate = d[3a]/dt = k [A]1 · [2a]≈0.4 (Eq. 6)
The rate law indicates a turnoverꢀlimiting step within the
radical chain propagation cycle (see Figure 7 for the general
mechanism). If the initiation step was rateꢀdetermining, a firstꢀ
order dependence with respect to both EDA partners I and 2a
would be expected instead. The firstꢀorder dependence on
catalyst A (whose concentration is equal to the enamine I conꢀ
centration) suggests that the rateꢀdetermining step is the trapꢀ
ping of the electrophilic carbonꢀcentered radical IV from the
ground state chiral enamine I to form the new carbonꢀcarbon
bond. We would expect higherꢀorder dependence in [2a] if the
turnoverꢀlimiting step were the SET process, which regenerꢀ
ates the chainꢀpropagating radical IV from the αꢀaminoalkyl
radicals VI.
The alkylation of 1a with bromomalonate, driven by the diꢀ
rect excitation of enamine, shows halfꢀorder dependence in
[2c]. The overall rate equation is then given by Equation 7:
rate = d[3c]/dt = k [A]1 · [1a]0.5 · [2c]0.5 (Eq. 7)
In analogy with the preceding discussion, the rateꢀorder asꢀ
sessment indicates that the rateꢀdetermining step is the
enamine trapping the electrophilic radical IV, derived from 2c,
to form the carbonꢀcarbon bond (see Figure 7 for the general
mechanism).
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phy, J. J.; Melchiorre, P. J. Am. Chem. Soc. 2015, 137, 5678–
5681.
ASSOCIATED CONTENT
Complete experimental procedures, characterization data, and
details on kinetic and spectroscopic studies. This material is availꢀ
able free of charge via the Internet at http://pubs.acs.org.
(10) Despite their synthetic potential, it is challenging to develop enꢀ
antioselective catalytic variants of visible lightꢀdriven photoꢀ
chemical reactions. For recent reviews discussing the available
strategies, see: (a) Brimioulle, R.; Lenhart, D.; Maturi, M. M.;
Bach, T. Angew. Chem., Int. Ed. 2015, 54, 3872–3890. (b) Megꢀ
gers, E. Chem. Commun. 2015, 51, 3290–3301. For selected exꢀ
amples, see: (c) Bauer, A.; Westkamper, F.; Grimme, S.; Bach, T.
Nature 2005, 436, 1139–1140. (d) Brimioulle, R.; Bach, T.
Science 2013, 342, 840–843. (e) Alonso, R.; Bach, T. Angew.
Chem., Int. Ed. 2014, 53, 4368–4371. (f) Du, J.; Skubi, K. L.;
Schultz, D. M.; Yoon, T. P. Science 2014, 344, 392–396. (g)
Huo, H.; Shen, X.; Wang, C.; Zhang, L.; Röse, P.; Chen, L.ꢀA.;
Harms, K.; Marsch, M.; Hilt, G.; Meggers, E. Nature 2014, 515,
100–103. (h) Kainz, Q. M.; Matier, C. D.; Bartoszewicz, A.;
Zultanski, S. L.; Peters, J. C.; Fu, G. C. Science 2016, 351, 681–
684.
Corresponding Author
pmelchiorre@iciq.es
9
ACKNOWLEDGMENT
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Financial support was provided by the ICIQ Foundation,
MINECO (project CTQ2013ꢀ45938ꢀP and Severo Ochoa Excelꢀ
lence Accreditation 2014ꢀ2018, SEVꢀ2013ꢀ0319), the AGAUR
(2014 SGR 1059), and the European Research Council (ERC
278541 ꢀ ORGAꢀNAUT). A.B. is grateful to the MECD for a FPU
fellowship (Ref. FPU13/02402). The authors are indebted to the
team of the Research Support Area at ICIQ. The authors thank Dr
Elena Arceo and Dr Mattia Silvi for preliminary investigations
and useful discussions.
(11) For a recent review, see: Donslund, B. S.; Johansen, T. K.;
Poulsen, P. H.; Halskov, K. S.; Jørgensen, K. A. Angew. Chem.,
Int. Ed. 2015, 54, 13860–13874.
(12) The reactions required the presence of 1 equiv of a base (2,6ꢀ
lutidine and NaOAc giving similar results) to perform well. Reꢀ
moving the base additive, trace amounts of the alkylation prodꢀ
ucts 3 were formed (<15%), while reagent decomposition along
with acidification of the reaction medium was observed. The likeꢀ
ly role of 2,6ꢀlutidine is to quench the acid generated during the
process, as testified to by the formation of the insoluble lutidiniꢀ
um bromide salt generated during the reaction. The presence of
2,6ꢀlutidine 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% of Ru(bpy)32+ as an exꢀ
ternal photosensitizer significantly increased the reactivity (twoꢀ
fold reaction rate), in consonance with the occurrence of an addiꢀ
tional 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 reꢀ
ported in the Supporting Information of Ref. 6c.
REFERENCES
(1) (a) Stork, G.; Terrell, R.; Szmuszkovicz, J. J. Am. Chem. Soc.
1954, 76, 2029–2030. (b) Stork, G.; Brizzolara, A.; Landesman,
H.; Szmuszkovicz, J.; Terrell, R. J. Am. Chem. Soc. 1963, 85,
207–222.
(2) For seminal papers, see: (a) Eder, U.; Sauer, G.; Wiechert, R. Anꢀ
gew. Chem., Int. Ed. Engl. 1971, 10, 496–497; (b) Hajos, Z. G.;
Parrish, D. R. J. Org. Chem. 1974, 39, 1615–1621. (c) List, B.;
Lerner, R. A.; Barbas III, C. F. J. Am. Chem. Soc. 2000, 122,
2395–2396. (d) Ahrendt, K. A.; Borths, C. J. MacMillan, D. W.
C. J. Am. Chem. Soc., 2000, 122, 4243–4244.
(3) For insightful perspectives on the scientific roots of enamineꢀ
mediated stereoselective catalytic reactions, see: (a) Barbas III, C.
F. Angew. Chem., Int. Ed. 2008, 47, 42–47. (b) List, B. Angew.
Chem., Int. Ed. 2010, 49, 1730–1734.
(4) For the seminal reports of SOMO activation, see: (a) Beeson, T.
D.; Mastracchio, A.; Hong, J.ꢀB.; Ashton, K.; MacMillan, D. W.
C. Science 2007, 316, 582–585; (b) Jang, H.ꢀY.; Hong, J.ꢀB.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2007, 129, 7004–7005.
For mechanistic studies, see: (c) Devery III, J. J.; Conrad, J. C.;
MacMillan, D. W. C.; Flowers II, R. A. Angew. Chem., Int. Ed.
2010, 49, 6106–6110.
(14) Enamines have a low ionization potential; for example 1ꢀ(butꢀ1ꢀ
enyl)pyrrolidine has an IP of 7.2 eV, see: Müller, K.; Previdoli,
F.; Desilvestro, H. Helv. Chim. Acta 1981, 64, 2497–2507.
(15) The electronꢀdonor 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
(5) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev.
2007, 107, 5471–5569.
ox
(Epred in solution). Ep and Epred, which can be estimated by cyꢀ
clic voltammetry measurements, can help in predicting the suitaꢀ
bility of a given substrate to undergo EDA complex formation.
(16) According to the Mulliken theory (Ref. 8c), the chargeꢀtransfer
transition energy (hνCT) is given by the following equation: hνCT
= IP ꢀ EA – ω, where ω is the electrostatic interactions of the
chargeꢀtransfer ion pair (e.g. III in Figure 3d). Qualitatively, the
equation predicts that the chargeꢀtransfer band of the EDA comꢀ
plexes with a given electron donor (in this case, the enamine) unꢀ
dergoes 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) 2ꢀPhenylacetaldehyde is a competent substrate of the photoꢀ
organocatalytic reaction with 2a, 2b, and 2c, providing full conꢀ
version 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 reꢀ
sulting benzylic stereocenter.
(6) (a) Arceo, E.; Jurberg, I. D.; ÁlvarezꢀFernández, A.; Melchiorre,
P. Nature Chem. 2013, 5, 750–756. (b) Arceo, E.; Bahamonde,
A.; Bergonzini, G.; Melchiorre, P. Chem. Sci. 2014, 5, 2438–
2442. (c) Silvi, M.; Arceo, E.; Jurberg, I. D.; Cassani, C.; Melꢀ
chiorre, P. J. Am. Chem. Soc. 2015, 137, 6120–6123.
(7) Prior to our studies, similar enamineꢀmediated enantioselective
alkylations of aldehydes were realized using an external photoreꢀ
dox catalyst, which served to generate the radical species from
alkyl halides, see: (a) Nicewicz, D. A.; MacMillan, D. W. C. Sciꢀ
ence 2008, 322, 77–80. (b) Shih, H.ꢀW.; Vander Wal, M. N.;
Grange, R. L.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010,
132, 13600–13603.
(8) For reviews, see: (a) Foster, R. J. Phys. Chem. 1980, 84, 2135–
2141. (b) Rosokha, S. V.; Kochi, J. K. Acc. Chem. Res. 2008, 41,
641–653. For the seminal studies that inspired the EDA complex
theory, see: (c) Mulliken, R. S. J. Phys. Chem. 1952, 56, 801–
822. (d) H. A. Benesi, J. J. Hildebrand, J. Am. Chem. Soc. 1949,
71, 2703–2707. (e) R. S. Mulliken, J. Am. Chem. Soc. 1950, 72,
600–608. (f) R. M. Keefer, L. J. Andrews, J. Am. Chem. Soc.
1950, 72, 4677–4681.
(18) Job, P. Ann. Chem. 1928, 9, 113−203.
(19) Benesi, H.; Hildebrand, J. J. Am. Chem. Soc. 1949, 71,
2703−2707.
(20) Costentin, C.; Robert, M.; Savéant, J.ꢀM. Chem. Physics 2006,
324, 40–56.
(9) For the use of chiral enolates, generated under phaseꢀtransfer
conditions, to form chiral photoactive EDA complexes while
promoting an enantioselective process, see: Woźniak, Ł.; Murꢀ
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(21) Although the photophysics of EDA complexes have been extenꢀ
catalyst A is destroyed via decomposition of the intermediate V
sively studied (Refs 8aꢀb), their use in chemical synthesis has
found limited applications. This is mainly because the unproducꢀ
tive, back electron transfer (BET), which restores the ground state
EDA complex, is generally faster than other possible processes
leading to products. For a pertinent discussion, see: Rathore, R.;
Kochi, J. K. Advances Phys. Org. Chem. 2000, 35, 193–318.
(22) For an additional example of an enamine, formed upon condensaꢀ
tion of an aliphatic aldehyde and a secondary amine, which
weakly absorbs in the visible region, see: GonzálezꢀBéjar, M.; Peꢀ
ters, K.; HallettꢀTapley, G. L.; Grenier, M.; Scaiano, J. C. Chem.
Commun. 2013, 49, 1732–1734.
(23) For examples of photoinduced reductive cleavage of CꢀX bonds
in electronꢀpoor alkyl halides via a SET from excited substrates,
see: (a) Rico, I.; Cantacuzene D.; Wakselman, C. Tetrahedron
Lett. 1981, 22, 3405–3408. (b) Iwasaki, T.; Sawada, T.; Okuyaꢀ
ma, M.; Kamada, H. J. Phys. Chem. 1978, 82, 371–372. (c) Baꢀ
rataꢀVallejo, S.; Flesia, M. M.; Lantaño, B.; Argüello, J. E.; Peꢀ
ñéñory, A. B.; Postigo, A. Eur. J. Org. Chem. 2013, 998–1008.
(d) Franz, J. F.; Kraus, W. B.; Zeitler, K. Chem. Commun. 2015,
51, 8280–8283.
(24) An electronically excited state possesses a much lower ionization
potential (i.e. it is a better reductant) than the ground state, see:
Turro, N. J.; Ramamurthy, V.; Scaiano, J. C. “Energy transfer
and electron transfer” in Modern molecular photochemistry of
organic molecules, University Science Books, 2010; chapter 7,
pp 383. Since an excited state has an inherent propensity to form
a supramolecular complex, the generation of an exciplex between
the excited enamine I* and bromomalonate 2c cannot be excludꢀ
ed; however, we could not observe any emission diagnostic of
possible excited state aggregations.
(25) (a) Studer, A.; Curran, D. P. Angew. Chem., Int. Ed. 2016, 55,
58–102. (b) Kärkäs, M. D.; Matsuura, B. S.; Stephenson, C. R. J.
Science 2015, 349, 1285–1286.
(26) (a) Ismaili, H.; Pitre, S. P.; Scaiano, J. C. Catal. Sci. Technol.
2013, 3, 935–937. (b) Wayner, D. D. M.; Dannenberg, J. J.;
Griller, D. Chem. Phys. Lett. 1986, 131, 189–191.
(27) Julliard, M.; Chanon, M. Chem. Rev. 1983, 83, 425–506.
(28) For a process in which one photon produces only one molecule of
the product, the quantum yield can be maximum 1, while for a
chain process where one photon forms n molecules of product,
the quantum yield is expected to be > 1. But a value of Φ < 1
does not exclude a possible radical chain mechanism. This is beꢀ
cause of potential nonꢀproductive energy wasting photochemical
processes.
(29) Both the quantum yield measurements and the kinetic experiꢀ
ments 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 would scatter the irradiating light thus precluding a reꢀ
liable measurement.
(30) Yoon recently reported that a related enamineꢀmediated alkylaꢀ
tion of octanal with bromomalonate 2c using a polypyridyl rutheꢀ
nium(II) complex as an external photoredox catalyst possesses a
similar quantum yield (Φ = 18), further indicating a radical chain
mechanism, see: Cismesia, M. A.; Yoon, T. P. Chem. Sci. 2015,
6, 5426–5434.
(31) Nonꢀproductive processes can reduce the efficiency of photoꢀ
initiation (Φinitiation), directly affecting the overall quantum yield
(Φmeasured). For example, the photoꢀexcited enamine could relax to
the ground state via either radiative or vibrational pathways withꢀ
out undergoing electronꢀtransfer processes, while a backꢀelectron
transfer (BET) from the chiral ion pair III (Figure 3d) would unꢀ
productively restore the ground state enamineꢀbased EDA comꢀ
plex 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 manuscript) that the enamine I serves as a sacrificial initiaꢀ
tor of the chain mechanism: for any photoꢀinduced SET event, a
propagating radical IV is generated while a molecule of the chiral
(Figures 3d and 5). If a molecule of the catalyst A decomposes
for any photoꢀinduced initiation, the rate of catalyst degradation
correlates with the efficiency of the initiation. This analysis reꢀ
quires that the catalyst A degradation is triggered by productive
photochemical initiation only, and not by other secondary reacꢀ
tions, a scenario which is consistent with experimental observaꢀ
tions.
(33) The two photochemical initiation manifolds can be both operaꢀ
tive 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, so to avoid any possible conꢀ
tribution from the direct photoexcitation of enamines. Under theꢀ
se conditions, only the EDA complex activation is a viable strateꢀ
gy to generate radicals from 2a and 2b.
(34) Similar atomꢀtransfer mechanisms have been invoked for the alꢀ
kylation 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, page 80.
(35) (a) Kharasch, M. S.; Jensen, E. V.; Urry, W. H. Science 1945,
102, 128. (b) Pintauer, T.; Matyjaszewski, K. in Encyclopedia of
Radicals, volume 4, pp.1851, Wiley, 2012.
(36) (a) Kornblum, N. Angew. Chem., Int. Ed. Engl. 1975, 14, 734–
745. (b) Rossi, R. A., Pierini, A. B., Peñéñory, A. B. Chem. Rev.
2003, 103, 71–168.
(37) Russell, G. A.; Wang, K. J. Org. Chem. 1991, 56, 3475–3479.
(38) As suggested by a reviewer, deprotonation of an acidic αꢀproton
within the αꢀiminyl radical cation V to form an intracyclic iminiꢀ
um ion is a likely degradation pathway.
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(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 photoredoxꢀorganocatalytic
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 inꢀ
termediate 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 (GCꢀFID); deꢀ
tails are reported in Section F within the SI.
(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 to 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. Res. 2013, 232, 39–44. (b) Feldmeier,
C.; Bartling, H.; Magerl, K.; Gschwind, R. M. Angew. Chem.,
Int. Ed. 2015, 54, 1347–1351.
(43) Initialꢀrate kinetic studies on the alkylation of 1a with phenacyl
bromide 2b gave a very similar profile to 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 SI.
(44) We could not use the method of reaction progress kinetic analysis
to provide a rapid and comprehensive kinetic profile of the reacꢀ
tions 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.; Kloek Hanson, S.; 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
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by the presence of oxygen in the system, as in situ monitoring did
not allow for complete deꢀoxygenation of the reaction medium.
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ACS Paragon Plus Environment