LETTER

doi:10.1038/nature17438

Asymmetric catalytic formation of quaternary
carbons by iminium ion trapping of radicals
John J. Murphy1*, David Bastida1*, Suva Paria1, Maurizio Fagnoni2 & Paolo Melchiorre1,3

An important goal of modern organic chemistry is to develop
new catalytic strategies for enantioselective carbon–carbon bond
formation that can be used to generate quaternary stereogenic
centres. Whereas considerable advances have been achieved
by exploiting polar reactivity1, radical transformations have
been far less successful2. This is despite the fact that open-shell
intermediates are intrinsically primed for connecting structurally
congested carbons, as their reactivity is only marginally affected by
steric factors3. Here we show how the combination of photoredox4
and asymmetric organic catalysis5 enables enantioselective radical
conjugate additions to β,β-disubstituted cyclic enones to obtain
quaternary carbon stereocentres with high fidelity. Critical to our
success was the design of a chiral organic catalyst, containing a
redox-active carbazole moiety, that drives the formation of iminium
ions and the stereoselective trapping of photochemically generated
carbon-centred radicals by means of an electron-relay mechanism.
We demonstrate the generality of this organocatalytic radicaltrapping strategy with two sets of open-shell intermediates, formed
through unrelated light-triggered pathways from readily available
substrates and photoredox catalysts—this method represents
the application of iminium ion activation6 (a successful catalytic
strategy for enantioselective polar chemistry) within the realm of
radical reactivity.
Organic chemists generally rely on polar reactivity to address the
challenge of forming quaternary carbon stereocentres in a catalytic
enantioselective fashion1. Of the stereoselective methods available,
metal-catalysed conjugate addition of organometallic nucleophilic
species to trisubstituted unsaturated carbonyl substrates has recently
emerged as a powerful technology7–11 (Fig. 1a). These additions are
reliable processes, but they generally require controlled reaction
conditions and preformed organometallic reagents7–10. In contrast,
there has been limited success in developing analogous transformations with nucleo­ hilic carbon-centred radicals. Although a few
p
examples of metal-catalysed enantioselective radical conjugate additions (RCAs) have been reported12–15, none of these approaches
provide for the formation of sterically demanding quaternary carbons.
The work we report here was prompted by the desire to address this
gap in catalytic enantio­ elective methodology.
s
Our initial motivation stems from the notion that, because of the
long incipient carbon–carbon bond in the early transition state16,
additions of radicals to electron-deficient olefins are rather insensitive to steric hindrance3. This makes radical reactivity particularly
suited to connecting structurally complex carbon fragments while
forging quaternary carbons17. We also recognized that the emerging
field of photoredox catalysis4 had recently provided an effective way
of generating radicals from bench-stable precursors and under mild
conditions. As a result, novel transformations have been invented that
capitalize upon non-traditional open-shell mechanisms18. We sought
to combine this effective radical generation strategy, which does not

require pre-functionalized reagents, with a suitable chiral catalyst that
could drive the stereoselective trapping of photogenerated radicals
while forging quaternary stereocentres. If successful, this combination would provide direct access to chiral molecules that could not be
synthesized using polar conjugate additions.
We used the iminium ion activation strategy6 to attack the problem
of identifying a suitable chiral catalyst. This chemistry exploits the
electrophilic nature of the iminium ion A (Fig. 1b), generated upon
condensation of chiral amine catalysts and α,β-unsaturated ketones, to
facilitate enantioselective conjugate additions of nucleophiles19. This
catalytic platform has found many applications in the polar domain5,6.
However, to date, iminium ions A have not been used to trap nucleophilic
radicals. This is most surprising, given the high tendency of openshell species to react with electron-deficient olefins3. We reasoned that
this dearth of applications could stem from the nature of the radical
intermediate B, generated upon carbon–carbon bond formation
(Fig. 1c). Generally, olefinic radical traps are electrically neutral and
afford long-lived, neutral radical intermediates. In contrast, radical
addition to the cationic iminium ion A generates a short-lived, highly
reactive α-iminyl radical cation B, which, in line with the classical
behaviour of radical ions20, has a high tendency to undergo radical
elimination (β-scission)21 to re-form the more stable iminium ion A.
The instability of B is the main obstacle to productive RCA to iminium ions (Fig. 1d). We considered the possibility of reducing the radical cation B in situ to generate the corresponding enamine C, which
can be hydrolysed in a facile manner to release both the catalyst and
the conjugate addition product. From the outset, we identified three
design elements as key to realizing this goal. First, the high reactivity
of B requires a very rapid single electron transfer (SET) reduction. We
hypothesized that using a chiral amine catalyst with a redox active,
electron-rich moiety (‘e− pool’ unit in Fig. 1d) attached would secure
a fast, proximity-driven intramolecular reduction of B. This idea finds
support in the mechanism of electron transfer within biological systems, where even endergonic redox processes can be achieved via electron tunnelling if the redox centres are in close proximity22. Second, we
needed to identify a rapid process to interrupt a possible equilibrium
between B and the nascent enamine C established by an intramolecular back electron transfer (BET). Since secondary enamines are known
to exist mainly as tautomeric electron poor imines D23, the use of a chiral primary amine catalyst potentially offered an efficient mechanism
to preclude the BET by triggering a tautomeric equilibrium which
converts C into D. Last, the oxidized centre (‘e− hole’ unit in Fig. 1d),
arising from the intramolecular SET, had to be long-lived enough to
undergo SET reduction from the photoredox catalysts, restoring the
redox-active moiety while facilitating productive catalysis. Achieving
a high level of stereocontrol further complicated matters.
To test the feasibility of this electron-relay strategy24, we explored
the reaction between β-methyl cyclohexenone 1a and benzodioxole 2a (Table 1). We used the photocatalyst tetrabutylammonium

1

Institute of Chemical Research of Catalonia (ICIQ), Barcelona Institute of Science and Technology, Avda. Països Catalans 16, 43007 Tarragona, Spain. 2Photogreen Laboratory, Department of
Chemistry, University of Pavia, viale Taramelli 12, 27100 Pavia, Italy. 3Catalan Institution for Research and Advanced Studies (ICREA), Passeig Lluís Companys 23, 08010 Barcelona, Spain.
*These authors contributed equally to this work.
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LETTER RESEARCH
a

Polar reactivity domain
O

O

Metal-based
chiral catalyst

R
R1

R1-M

R

Preformed organometallic
reagents
R1-M
Cryogenic conditions
Metal-based processes

Table 1 | Exploratory studies of the feasibility of the electron-relay
strategy
O
+ H

Quaternary carbon

R2 H

Simple substrates
O
Iminium ion
activation

1a
•R2

O

Chiral amine
catalyst

A

R

β-scission

B

H

N

SET

B

R
R2

BET

e– hole

N

R
R2

R
R2

e– hole

SET

PCred
PC

H2O Amine catalyst

Tautomerization

C

N

R1

Unstable radical cation

D

R
R2

+
quaternarized
product

Figure 1 | Conjugate addition technology for forging quaternary
stereocentres. a, Established metal-catalysed enantioselective conjugate
additions of organometallic reagents (R1-M) via classical polar pathways.
b, Design plan for dual photoredox and iminium ion catalysis of radical
conjugate additions (RCAs); the grey circle represents the chiral organic
catalyst scaffold. c, Challenges associated with implementing iminium
ion-catalysed conjugate addition of radicals (·R2). d, Our electron-relay
strategy to rapidly remove the short-lived α-iminyl radical cation (B) by
intramolecular reduction, and the role of tautomerization to prevent back
electron transfer (BET). SET, single electron transfer. PC, photocatalyst;
PCred, reduced form of the photocatalyst. The blue ellipse represents an
electron rich, reducing moiety, while the red ellipse represents a stable
oxidizing species.

decatungstate25 (TBADT, 5 mol%) because, upon light excitation, it
can easily generate a nucleophilic carbon-centred radical by homolytically cleaving the methylene C–H bond in 2a26 via a hydrogen atom
transfer (HAT) mechanism. The experiments were conducted at 35 °C
in acetonitrile (CH3CN) and under irradiation by a single ultraviolet
(UV)-light emitting diode (UV LED, λmax = 365 nm). We observed
a negligible racemic background process in the absence of any amine
catalyst, which is necessary for realizing a stereoselective process
(entry 1). We then focused on identifying a redox-active moiety that,
when installed within the chiral primary amine catalyst, could instigate a fast intramolecular reduction of the transient radical cation B
and thus trigger the entire RCA. We identified carbazole as a suitable scaffold because of (i) its excellent electron-donating capabilities,
which would provide the e− pool unit, and (ii) the high stability of
the long-lived carbazole radical cation27, which makes it a possible e−
hole moiety. These properties form the basis of the wide application of
carbazoles in hole-transport materials for light-emitting diodes and
photovoltaic cells28. The chiral cyclohexylamine scaffold 4b adorned
with the carbazole provided the product 3a with appreciable yield and
stereoselectivity (33% yield, 82% enantiomeric excess (e.e.), entry 3).
In consonance with the proposed electron-relay mechanism, the reaction could not be catalysed by cyclohexylamine 4a, which mimics the
catalyst 4b’s scaffold while lacking the redox-active moiety (entry 2).
An equimolar combination of 4a and exogenous N-cyclohexyl-3,
6-di-tert-butyl-carbazole (20 mol%) also proved unsuitable for

O
Me

O

3a

N

R1

4

H +
N

•R 2

d
e– pool

4b–d R =

4e R =

Radical addition

R

H +
N

R
NH2

Quaternarized product

R
H +
N

4a R = H

R
R2

A

R

c

2a

O

H +
N

O

Benzoic acid (40 mol%)
TBABF4 (1 equiv.)
CH 3CN, 35 oC

O

Me

b Elusive radical reactivity
Photoredox
activation

Catalyst (20 mol%)
TBADT (5 mol%)
UV LED (365 nm)

O

Entry
1
2†
3
4†
5
6
7
8

4b R 1 = H
4c R 1 = tBu
4d R 1 = CF3

Catalyst

Time
(h)

Epox/Epred (4) versus Ag/AgCl
(V)

3a yield
(%)

e.e.
(%)

None
4a
4b
4a*
4c
4d
4e
4e

48
48
48
48
48
48
48
84

NA
NA
+1.15/−1.32
NA
+1.05/−1.28
+1.51/−1.86
+1.10/−1.38
+1.10/−1.38

Trace
4
33
5
35
52
46
75

ND
0
82
0
84
77
93
93

Redox potential values (Epox and Epred) describe the electrochemical properties of the redox active
carbazole moiety in 4. NA, not applicable; ND, not determined.
*In combination with 20 mol% of exogenous N-cyclohexyl-3,6-di-tert-butyl-carbazole.
†Using 40 mol% of trifluoroacetic acid (TFA) instead of benzoic acid.

catalysis, suggesting the importance of a proximity-driven intramolecular SET process. We then modified the redox properties
of the carbazole scaffold by introducing substituents at the 3- and
6-positions. It is known that this substitution pattern can further
stabilize the carbazole radical cation27. Indeed, we could isolate a
bench-stable carbazoliumyl radical cation salt from N-cyclohexyl-3,
6-di-tert-butyl-carbazole upon treatment with SbCl 5 (see
Supplementary Information). Concurrently, the increased steric
hindrance carried the additional benefit of conferring a higher
stereocontrol. These considerations explain the high yield and enantio­
selectivity achieved when using the encumbered primary amine
catalyst 4e (75% yield and 93% e.e., entry 8). Finally, no product formation was detected in the absence of TBADT, catalyst 4e, or UV light,
demonstrating the need for all these components.
We then undertook studies to better investigate the role of the active
intermediates in the electron-relay mechanism (Fig. 2a). We could
synthesize stable tetrafluoroborate salts of the chiral iminium ion
A-1, generated upon condensation of catalyst 4c and substrate 1a,
which were characterized by X-ray single-crystal analysis (Fig. 2b).
The unusual stability of the iminium ion A-1 and the well-defined
(Z)-configuration of the C=N double bond originate from a stabilizing intramolecular charge transfer π–π interaction between the
electron-rich carbazole and the electron-deficient iminium ion.
As a result, the measured interatomic separation in the solid state
between the carbazole nitrogen and the sp2 α-carbon of the iminium
ion (3.10 Å) is significantly less than the van der Waals distance. This
highly organized topology of A-1, which NMR spectroscopic analy­
ses confirmed to be also dominant in solution, plays a critical dual
role. On the one hand, it governs the stereocontrol of the RCA, since
the bulky carbazole unit is positioned in such a way as to effectively
shield the diastereotopic Si face of the iminium ion, leaving the Re
face exposed for enantioselective bond formation (Re and Si are stereochemical descriptors for heterotopic faces). Importantly, the sense
of asymmetric induction observed in the model reaction is consistent
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RESEARCH LETTER
a

Iminium ion cycle
O

R-H
H
Me

1a

X–

N

N

+

PCred

R

Photoredox cycle

h
PC

PC*

System 1: TBADT - HAT mechanism
h

O

TBADT*

H

oxidant

O

3

Me
A-1

N
R
Me

NH2

H
X–

TBADT 4–

N

N+

4

– H+

N

E-1

SET

D-1

Å

H

O

H
+N N

+

Ar

– H+

reductant

O

O

Me

R1

+

Acid (40 mol%)
TBABF4 (1 equiv.)
CH3CN, 35 °C, 72 h

1b

Ar

Ar

Ir
PCred

Amine (20 mol%)
TBADT (5 mol%)
UV LED (365 nm)

R1-H (2a)

H

N

N

II

E-1

c

–BF
4

7

C-1

Me

SET

R D-1
Me

b
09

IrIII

Tautomerization

PC

Ar

*IrIII

oxidant

R
Me

PC red

3.

h
e– hole

N

Z-configured
C=N bond

System 2: Iridium catalyst - SET mechanism

HN

X–
+
N

R
Me

O

reductant

E-1

X–
+
N

N

TBADT 5– –H
PCred

SET

D-1

Electron relay mechanism

H2O

2a

O

B-1

R
Me

O

HAT

e– pool

R1

A-1

Re face
exposed

R1 =

CCDC 1437991

exo-5

3b

O

Amine 4a
+ TFA

6% yield

3% yield

O

Me

Amine 4e
+ PhCO2H

Traces

40% yield
83% e.e.

Figure 2 | Proposed mechanism and mechanistic investigations.
a, Synergistic activities of the iminium ion and the photoredox catalytic
cycles to realize the enantioselective RCA to enone 1a. Upon radical
addition to the iminium ion A-1, the electron-relay mechanism rapidly
reduces the unstable radical cation B-1 producing a carbazoliumyl radical
cation C-1, which is prevented from undergoing BET by tautomerization
of the secondary enamine to the corresponding imine D-1. Regeneration

of the photocatalyst (PC) is achieved by reduction of the carbazoliumyl
radical cation in D-1, while the aminocatalyst 4 is liberated upon
hydrolysis of imine E-1. b, X-ray crystal structure of the carbazole-based
iminium ion A-1: the distance between the carbazole nitrogen and the
sp2 α-carbon of the cyclohexene moiety is highlighted. c, Cyclization
experiments indicating that the α-iminyl radical intermediate B-1 has
been bypassed when using the carbazole-based catalyst 4e.

with this stereochemical model (Fig. 2b). On the other hand, the
three-dimensional assembly of A-1 suggests that the α-iminyl radical
cation B-1, arising from the radical trapping, is generated in close

proximity to the electron-rich carbazole, allowing for a proximitydriven22 intramolecular reduction. Once the carbazoliumyl radical
cation (e− hole) is generated, the fast tautomerization of the secondary

(S,S)-4e (20 mol%)
TBADT (5 mol%)
Single UV LED (365 nm)

O
+
() n
n = 0–3

O

R2

1

2

Me O

3a
75% yield
93% e.e.

3c
69% yield
97% e.e.

Et

O

Me O

Me O
O

O

Me

3g
70% yield
94% e.e.

3h
63% yield
91% e.e.

Me

O

O

OTBS
3e
57% yield
85% e.e.

3d
56% yield
96% e.e.

O
Me O

() n

O

R1

O
Me
3i
49% yield
91% e.e.

N
NH2
Me
O
Me

O
3f
99% yield
88% e.e.

(S,S)-4e
Organic catalyst

O

Br

Me O

Br

Figure 3 | Substrate scope for the enantioselective trapping of
benzodioxole-derived radicals via the dual photoredox organocatalytic
strategy. Survey of the cyclic enones 1 and substituted benzodioxoles
2 that can participate in the organocatalytic asymmetric radical conjugate
addition (RCA) to forge quaternary stereocentres (as in 3). Yields and
enantiomeric excesses of the isolated products are indicated below each

O

3

Me O

Me O

O
Me

R2

O

O

O

O
Me

O

Benzoic acid (40 mol%)
TBABF4 (1 equiv.)
CH3CN, 35 oC, 72–96 h

O

R1

O
O

O

Photoredox system 1
TBADT - HAT mechanism

O

O
Me

CCDC 1437992

Br

3j
67% yield
1.5:1 d.r., 98% e.e.

O
Me O

Cl

O
Me
3k
61% yield
1:1 d.r., 98% e.e.

entry (3a to 3k). Details of the TBADT-mediated photoredox cycle
to produce carbon-centred radicals from 2 via a HAT mechanism are
reported in Fig. 2a. The carbazole-based organic catalyst 4e is drawn in the
boxed inset. TBS, tert-butyldimethylsilyl; TBABF4, tetrabutylammonium
tetrafluoroborate; d.r., diastereomeric ratio.

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LETTER RESEARCH
a

O

() n

b

R

N

Me

+
n = 0–3

(R,R)-4e (20 mol%)
Ir III catalyst 8 (1 mol%)
White LEDs strip

R2

1

Benzoic acid (40 mol%)
Toluene, 15 °C, 48 h

6

1

Organic catalyst (R,R)-4e

O

CF 3

2
R1 R

N

() n

t-Bu

N
N

7

N
O

O

O

Me Me
N

O

Et Me
N

7a
78% yield
88% e.e.

N
7c
Me
52% yield
64% e.e.

7b
85% yield
84% e.e.

O

O
Me Me

7f
83% yield
82% e.e.

7g
81% yield
80% e.e.

O
Me
N
Ph

Me

7k
85% yield
1.6:1 d.r., 94% e.e.major
72% e.e.minor

c

O
+ Me
1a

Me

Br
O
Me

N

(R,R)-4e (20 mol%)
Benzophenone 9 (10 mol%)
UV LEDs strip

6a

Benzoic acid (40 mol%)
Toluene, 15 °C, 72 h

Me

F

Photoredox system 2
Iridium catalyst 8 - SET mechanism

7e
62% yield
90% e.e.

Me

N

7i
52% yield
80% e.e.

CCDC 1437993

F

Ir[dF(CF 3)ppy ] 2(dtbbpy)PF6 (8)

N

7h
69% yield
87% e.e.

Br

F

CF 3

O

N

Me

7d
92% yield
88% e.e.

O
Me Me

N

Me
Me
N

–

PF 6

Ir

N

t-Bu

O
Me Me
N

Me

F

Br

O

Me
N

7j
71% yield
88% e.e.
O

Me Me

N

7a
76% yield
88% e.e.

Me

N
Me

9

N

Me

Me

Figure 4 | Substrate scope for the enantioselective trapping of
α-amino radicals via the dual photoredox organocatalytic strategy.
a, The photochemical organocatalytic radical conjugate addition (RCA)
developed to forge quaternary stereocentres. b, Survey of the cyclic enones
1 and tertiary amines 6 that can participate in the reaction. Yields and
enantiomeric excesses (e.e.) of the isolated products 7a–k are indicated

below each entry. Details of the iridium-mediated photoredox cycle to
produce carbon-centred radicals via a SET mechanism are reported in
Fig. 2a. The structure of the iridium photoredox catalyst 8 is given in
the boxed inset. c, Fully organocatalytic enantioselective RCA using the
benzophenone photocatalyst 9.

enamine C-1 to afford the imines D-1 precludes the BET. At this point,
the long-lived radical cation in D-1 (Epred > −1.28 V versus Ag/Ag+ in
CH3CN, see Table 1) can be reduced by the photocatalyst (half-wave
potential E1/2 [TBADT4−/TBADT5−−H] = −0.96 V versus Ag/Ag+
in CH3CN)29, closing the photoredox cycle (Fig. 2a, right panel). The
iminium ion cycle terminates with the imine E-1 hydrolysis to regenerate the catalyst 4 while liberating the product 3.
To gain further evidence supporting the electron-relay mechanism,
we used the enone 1b, bearing a β-homoallyl substituent, to trap the
radical photogenerated from 2a (Fig. 2c). The reaction catalysed by
cyclohexylamine 4a provides preferentially the cyclized exo-adduct
5 (5:3b in a 2:1 ratio), demonstrating the propensity of the α-iminyl
radicals, emerging from the radical addition, to undergo cyclization
with unactivated olefins. In sharp contrast, the process catalysed by
the amine 4e almost exclusively affords the conjugate addition product
3b (40% yield, 83% e.e., 3b:5 in a >10:1 ratio). This result is consonant
with a fast redox process, governed by the carbazole-based catalyst,
which rapidly reduces the α-iminyl radical cation B-1 preventing
cyclization.
Adopting the optimized conditions described in Table 1, entry 8, we
then demonstrated the generality of the RCA by evaluating a variety of
cyclic enones 1 and benzodioxoles 2 (Fig. 3). The presence of a methyl
substituent at the methylene position of 2 provides the corresponding
product 3c, bearing two adjacent tetrasubstituted carbons, with nearly
perfect enantioselectivity. Experiments to probe the scope of the enone
component revealed that a wide range of carbocycles and β-olefin substituents are well tolerated. For example, high levels of stereocontrol
are achieved with different β-alkyl groups (products 3d, e) and with a
diverse range of ring sizes, including cyclopentenyl, cycloheptenyl, and
cyclooctenyl architecture (adducts 3f–h). One limitation is that the presence of an aromatic β-substituent completely inhibits the reaction. As
for the benzodioxole substrates 2, different substituents can be installed
at the aromatic ring without compromising the efficiency of the reaction

(adducts 3i–k). Crystals of compound 3i were suitable for X-ray analysis, which secured the absolute configuration of the products.
We then wondered if the synthetic utility of the amine carbazole
catalyst 4e could be expanded to trap other carbon-centred radicals,
formed through an unrelated light-triggered mechanism, while forging quaternary stereocentres. Specifically, we used the commercially
available photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (8) which, upon
absorption of visible light, can generate α-amino radicals directly from
tertiary amines 6 via single electron oxidation18 (SET mechanism in
Fig. 2a). The conjugate addition adducts 7 were provided with high
stereoselectivity by using the combination of catalysts (R,R)-4e and
8 while conducting the reactions with enones 1 at 15 °C in toluene
and under irradiation by a white LED (λemiss > 400 nm) (Fig. 4a).
We next explored the scope of both substrates in this dual photoredox
organocatalytic strategy. As highlighted in Fig. 4b, cyclic enones of
different ring sizes (7c–e) and bearing alkyl β-substituents (products 7a, b) are suitable substrates, while both mixed N-alkyl-N-aryl
(adducts 7a, f, g) and N,N-diaryl tertiary amines (7h–j) efficiently participated in the RCA. Substituents of different electronic nature were
easily accommodated at the aryl para (7f, g, i) or ortho position (7j),
while a cyclic amine afforded compound 7k with high enantiomeric
purity, albeit with a 3:2 diastereomeric ratio. For this enantioselective trap of α-amino radicals, we determined a quantum yield of 0.4
(λ = 400 nm), while Stern–Volmer fluorescence quenching experiments demonstrated that the excited state of the photocatalyst 8 is
quenched by the amine 6. Both experiments are consistent with the
electron-relay mechanism depicted in Fig. 2a. Notably, the RCA can
be performed without any metal when replacing the photocatalyst 8
with the benzophenone 9, which can generate the radical acting as an
organic photosensitizer30 (Fig. 4c).
We have developed the first (to our knowledge) catalytic strategy that allows quaternary carbon stereocentres to be obtained with
high fidelity using an enantioselective RCA manifold. The approach
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RESEARCH LETTER
requires mild conditions and unfunctionalized substrates, effectively
complementing established polar conjugate addition technologies
based on preformed organometallic reagents.
Received 23 November 2015; accepted 17 February 2016.
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Supplementary Information is available in the online version of the paper.
Acknowledgements Financial support was provided by the ICIQ Foundation,
MINECO (project CTQ2013-45938-P and Severo Ochoa Excellence
Accreditation 2014-2018, SEV-2013-0319), AGAUR (2014 SGR 1059), and the
European Research Council (ERC 278541, ORGA-NAUT). J.J.M. and S.P. thank
the Marie Curie COFUND (291787-ICIQ-IPMP) and the CELLEX Foundation,
respectively, for postdoctoral fellowships. We thank M. Minozzi, M. Nappi and E.
Raluy for preliminary investigations, D. Merli and D. Dondi for assistance with
EPR experiments, and D. Ravelli for discussions.
Author Contributions J.J.M., D.B. and S.P. performed the experiments and
analysed the data. J.J.M., D.B., S.P., and P.M. designed the experiments. M.F. and
P.M. conceived the project. P.M. directed the project, and P.M. and J.J.M. wrote
the manuscript with contributions from all the authors.
Author Information Crystallographic data for the iminium ion A-1 and
for compounds 3i and 7h have been deposited with the Cambridge
Crystallographic Data Centre, accession numbers CCDC 1437991, 1437992
and 1437993, respectively. Reprints and permissions information is available
at www.nature.com/reprints. The authors declare no competing financial
interests. Readers are welcome to comment on the online version of the paper.
Correspondence and requests for materials should be addressed to P.M.
(pmelchiorre@iciq.es).

2 2 2 | NAT U R E | VO L 5 3 2 | 1 4 A P R I L 2 0 1 6

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