This is the peer reviewed version of the following article: “Enhancing the potential of enantioselective
organocatalysis with light”which has been published in final form at DOI:10.1038/nature25175. This article may be
used for non-commercial purposes in accordance with Springer Nature Terms and Conditions for Self-Archiving."

Enhancing the potential of enantioselective organocatalysis with light
Mattia Silvi1, & Paolo Melchiorre2,3*
1 – School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, United Kingdom
2 – ICIQ, Institute of Chemical Research of Catalonia - the Barcelona Institute of Science and Technology, Avenida Països Catalans 16 – 43007,
Tarragona, Spain.
2 – ICREA, Catalan Institution for Research and Advanced Studies, Passeig Lluís Companys 23 – 08010, Barcelona, Spain.
*email: pmelchiorre@iciq.es

Organocatalysis, catalysis mediated by small chiral organic molecules, is a powerful technology for enantioselective
synthesis, and has found extensive applications within traditional ionic, two-electron-pair reactivity domains. Recently,
organocatalysis has been successfully combined with photochemical reactivity to unlock previously inaccessible reaction
pathways, thereby creating new synthetic opportunities. Here, we critically describe the historical context, scientific
reasons, and landmark discoveries that were essential to expanding the functions of organocatalysis to include oneelectron-mediated chemistry and excited-state reactivity.
The preparation of chiral molecules with a well-defined, three-dimensional spatial arrangement is central to synthetic
chemistry. Enantioselective organocatalysis offers powerful solutions to this challenging task 1. This strategy, which uses purely
small organic molecules as chiral catalysts, has greatly enriched the synthetic toolbox, complementing traditional metal-based and
enzymatic approaches to asymmetric catalysis2. Although sporadic examples of organic catalyst-mediated processes were
documented in the twentieth century3-6, enantioselective organocatalysis gained prominence from 2000 onwards7,8. A review9
published in 2008 argued that the field of organocatalysis had blossomed so dramatically in a relatively short period of time
thanks to the identification of a few generic mechanisms of substrate activation and stereochemical induction (detailed in Box 1),
which provided powerful tools for reaction invention. At that time 9, organocatalysis was almost exclusively applied within
traditional two-electron-pair reactivity domains, and reached high levels of efficiency, as evidenced by applications in the total
synthesis of natural products10,11. Because of this progress, the general perception within the chemistry community was that it
would be difficult to further expand the synthetic potential of organocatalysis. But this perception has been challenged by the
merging of organocatalysis and photochemical reactivity12, two powerful strategies of molecule activations that had remained
largely unrelated.
Here we outline the historical context and the scientific reasons that motivated the combination of photocatalysis13 and
organocatalysis. Instead of providing an exhaustive list of reactions, this review critically describes developments since 2008,
charting the essential ideas, serendipitous observations, and landmark discoveries that were crucial to moving organocatalysis
beyond the established patterns of polar reactivity. A selection of pioneering studies will demonstrate how the merging of
organocatalysis and light-mediated chemistry has profoundly influenced other fields of chemical research, such as radical
chemistry14 and enantioselective photochemistry15 (see Box 2). In terms of stereoselectivity, impressive results have been achieved
in many one-electron-mediated transformations, dispelling the long-held notion that the high reactivity of radicals limits their use
in enantioselective catalysis16. Similarly, some of the organocatalytic tools have been used to enforce high stereocontrol in
photochemical processes, challenging the idea that photochemistry is too unselective to enable efficient preparation of chiral
molecules. This review will also highlight the strong connections and ancestral lineage between organocatalysis and the rapidly
growing field of visible-light-mediated photoredox catalysis17.
BOX 1
Generic mechanisms of organocatalytic reactivity.
Organic catalysts can exert their functions by following two different substrate activation patterns:
Covalent-based modes of activation exploit the ability of an organic catalyst to covalently bind a substrate in a reversible
fashion and form a reactive intermediate that can participate in many reaction types with consistently high enantioselectivity.
Chiral primary and secondary amines belong to this class, activating carbonyl substrates via the formation of nucleophilic
enamines I7,18 (from enolisable aldehydes and ketones), electrophilic iminium ions II8,19 (from unsaturated carbonyl compounds),
and α-iminyl radical cation intermediates III20 (upon single-electron oxidation of enamines by a chemical oxidant). N-heterocyclic
carbene (NHC) catalysts21 offer an alternative activation mechanism for aldehydes, conferring an inverted (umpolung) reactivity
to the normally electrophilic carbonyl carbon atom upon formation of Breslow intermediate IV22, which acts as an acyl anion
equivalent23,24. These activation modes, which rely on strong, directional interactions, allow the stereoselective functionalisation
of unmodified carbonyl compounds at the ipso, α, and β positions.
Non-covalent approaches are based on the cooperation of multiple weak attractive interactions between the catalyst and a
basic functional group on the substrates25. Although the catalyst/substrate interactions are generally weaker and less directional
than their covalent counterparts, they operate in concert to ensure a high level of transition state organisation, resulting in a high

degree of enantioselectivity. Hydrogen-bonding activation26,27, phase-transfer catalysis6,28, anion-binding activation29, and
Brønsted acid catalysis30-32 are all useful organocatalytic strategies for making chiral molecules33.

BOX 2
Light in organocatalysis. Two main strategies, the dual- and the single-catalyst approach, have been used to successfully combine
organocatalysis and photochemical reactivity.
In the dual-catalyst approach, the activity of a photoredox catalyst17 synergistically combines with the generic mechanisms of
activation, which define the ground-state reactivity of chiral organocatalytic intermediates. This approach exploits the ability of
visible light-absorbing metal or organic photocatalysts, upon excitation, to either remove an electron from or donate an electron to
simple organic substrates. This single-electron transfer (SET) mechanism facilitates access to radical species under mild
conditions34. The unique reactivity of such photocatalytically generated open-shell intermediates allows the expansion of the
organocatalytic functions from a polar to a radical reactivity domain. The field of photoredox catalysis, which is a fast-moving
area of modern synthetic chemistry17, has led to the development of many novel synthetic methodologies.
The single-catalyst approach exploits the ability of organocatalytic intermediates to directly reach an excited state upon light
absorption, and to participate in the activation of substrates, without external photocatalysts. At the same time, the chiral
organocatalyst ensures effective stereochemical control. This approach demonstrates that the synthetic potential of organocatalytic
intermediates is not limited to the ground-state domain, but can be expanded by exploiting their photochemical activity. By
bringing an organocatalytic intermediate to an electronically excited-state, light excitation unlocks reaction manifolds that are
unavailable to conventional ground-state organocatalysis.

Merging Organo- & Photoredox Catalysis
Why was organocatalysis combined with photochemical reactivity? What were the scientific motivations for exploring
beyond the established boundaries of two-electron-pair reactivity? As it is often the case in science, progress was spurred by a
specific goal that could not be achieved with the available technologies. Here, that goal was the intermolecular enantioselective αalkylation of carbonyl substrates with alkyl halides (Fig. 1a) using an enamine-mediated catalytic process. It is important to
understand why this simple transformation greatly attracted the interest of the enantioselective catalysis community 35. The αalkylation of carbonyl compounds is among the most important classical synthetic reactions 36. Generally, the process requires the
preformation of stoichiometric metal enolate nucleophiles that undergo an S N2-type reaction with alkyl halides37. Developing an
enantioselective catalytic version, however, has proven difficult, with the few reported methodologies being limited in scope 38,39.
Clearly, it was ambitious to seek to develop catalytic asymmetric methods that could directly functionalise unmodified carbonyl
substrates. Enamine-based chemistry was considered the most promising approach here. This goes back to Gilbert Stork’s
fundamental studies40 in the 1960s, which taught organic chemists that stoichiometric enamines could react with alkyl halides via
SN2 pathways. With the advent of enamine-mediated catalysis7, it was thought that implementing a direct stereoselective
intermolecular α-alkylation of aldehydes would be not only feasible, but also straightforward. However, this synthetic target
turned out to be much more difficult than expected 41. The main reason was the modest reactivity of alkyl halides, which
complicates the ionic alkylation step while favouring side reactions, e.g. N-alkylation of the Lewis basic amine catalysts and selfaldol condensation.
In 2008, the group of David MacMillan42 realised that the main hurdle to overcome was intrinsic to the ionic SN2 pathway.
Therefore, they used alkyl bromides not as electrophiles but as precursors for generating radicals. The underlying idea was to
exploit the innate tendency of electron-deficient radicals to rapidly react with π-rich olefins, thus allowing the formation of
difficult-to-make carbon-carbon bonds43. A ruthenium-based polypyridyl photocatalyst 5 ([Ru(bpy)3]2+ where bpy is 2,2′bipyridine) was used to easily generate open-shell species from α-bromo carbonyl compounds 2 (Fig. 1b). Photocatalyst 5 had a
rich history as a SET catalyst for facilitating inorganic applications 44, but had found limited use in synthetic chemistry up to that
point45.
The reaction mechanism (Fig. 1c) is based on the integration of two independent catalytic cycles. On one side, the
photoredox cycle proceeds through the reductive cleavage of 2, instigated by SET reduction from the Ru(I) intermediate 7, to
afford electrophilic radical 8. Concurrently, the organocatalytic pathway provides for the generation of the enamine Ia upon
condensation of organocatalyst 4 with aldehyde 1. Then, the ground-state chiral enamine stereoselectively traps radical 8 to form
the stereogenic centre within α-amino radical 9 with high fidelity. In the original study, it was proposed that this electron-rich
intermediate 9 was finally oxidised by the excited state of the Ru(II) photocatalyst 6, a SET event which closes the photoredox
cycle while affording iminium ion 10. Hydrolysis of the latter species furnishes the α-alkylation product 3 while regenerating the
catalyst 4. Luminescence quenching studies revealed that the reducing [Ru(bpy) 3]+ species 7 was initially generated by oxidation
of a sacrificial amount of enamine Ia by the excited *Ru(II) catalyst 6. Later, mechanistic investigations established a radical
chain manifold as the main reaction path (Fig. 1d)46. Thus, the photoredox catalyst initiates a self-propagating radical process
which is sustained by the ability of the α-amino radical 9 to regenerate radical 8 by directly reducing the organic bromide 2. The
same reaction can be conducted replacing the ruthenium photocatalyst with organic dyes 47 or different metal-based polypyridyl
complexes48.
This study has had many far-reaching implications. Synthetically, by combining enamine-mediated catalysis with the action
of a photoredox catalyst, it was possible to develop mechanistically related enantioselective α-alkylation reactions (Fig. 1e),

including trifluoromethylation49, benzylation50, and cyanoalkylation51 processes. It also allowed the enantioselective α-alkylation
of 1,3-dicarbonyl substrates, forging synthetically useful yet difficult-to-form quaternary carbon stereocentres52. However, the
main synthetic impact was the demonstration that radical intermediates could be generated at ambient temperature, simply by
using a photocatalyst activated by visible light. This meant that the tools and the mechanisms of stereocontrol of enantioselective
organocatalysis, which require mild conditions for optimal efficiency, could be successfully applied within radical reactivity
patterns. These studies, along with other investigations dealing with non-stereocontrolled transformations53,54, also laid the
foundations for the development of the field of photoredox catalysis 17. Today, synthetic chemists are exploring the benefits of
integrating the activity of photoredox catalysts with other catalytic systems, including metal-based catalysis55 and chiral Lewis
acid catalysis56, though these aspects fall out of the scope of this review.

Dual-Catalyst Systems - Covalent Organocatalysis
The use of redox-active photocatalysts in synergy with well-established chiral organocatalytic intermediates other than
enamines was successively explored.
Merging SOMO activation & photoredox catalysis
The example of singly-occupied molecular orbital (SOMO) activation illustrates how the combination with photoredox
catalysis could lead to unconventional transformations. This mode of organocatalytic reactivity was introduced in 2007 20. It
exploits the SET oxidation of enamines I by a chemical oxidant, which renders an electrophilic α-iminyl radical cation III
amenable to a range of open-shell reactions. Since III can be stereoselectively intercepted by electron-rich functionalised olefins
(e.g. allyl silanes), the resulting α-alkylation products result from umpolung reactivity. The main drawback of this strategy is that
it requires an excess of stoichiometric oxidant. This issue was solved using a light-activated catalyst that could trigger the key
SET oxidation of enamines to access the intermediate III (Fig. 2a)57. The milder radical-generation conditions offered the
possibility of intercepting III with unactivated olefins, such as simple styrenes, in a stereocontrolled fashion (path (i) in Fig. 2a)58.
By avoiding the use of organic halides, this approach further expanded the potential of the organocatalytic intermolecular αalkylation technology. The chemistry required the combination of organocatalysis with both an iridium photoredox catalyst59,
which generated intermediate III, and a hydrogen atom transfer (HAT)60 thiol catalyst, which reduced the intermediate V
emerging from the radical addition to the styrene.
The chemistry of α-iminyl radical cation III, generated under photoredox conditions, is not limited to radical addition
manifolds. It can be expanded to realise unconventional and difficult-to-achieve transformations, such as the direct β-arylation of
unsaturated carbonyl substrates61 (path (ii) in Fig. 2a). The allylic C–H bonds in intermediate III are sufficiently weakened to
allow for proton abstraction by a suitable base, such as DABCO (1,4-diazabicyclo[2.2.2]octane), giving the β-enaminyl radical
intermediate VI. This species can undergo radical coupling with the long-lived radical anion 13, generated upon SET reduction of
1,4-dicyanobenzene 12 from an iridium (III) photocatalyst. This bond-forming event, which is governed by the persistent radical
effect62, forms a new carbon-carbon bond at the original carbonyl β-position. The strategy is synthetically appealing, given the
lack of alternative methods for the direct β-functionalization of carbonyl substrates bearing saturated alkyl chains. However, only
a single enantioselective example has been reported. Still, this study provided an initial demonstration that classical
organocatalytic tools, such as the chiral amine catalyst 14, could serve to control the stereochemical outcome of a radical coupling
event, which is greatly complicated by its intrinsic high rate 63.
Overall, the studies detailed in Fig. 2a indicate that the native reactivity of an established organocatalytic intermediate (i.e.
enamines) can be switched from a closed-shell to an open-shell manifold with a light-activated photoredox catalyst. They also
highlight the ability of traditional organic catalysts, generally used in enantioselective ionic processes, to control the geometry of
the ensuing radical intermediates (such as V and VI) while creating a suitable chiral environment for stereocontrolled bond
formation.
Merging iminium ion & photoredox catalysis
Iminium ion activation has found many applications in ionic domains, facilitating the conjugate additions of soft nucleophiles
to the β-carbon atom of unsaturated carbonyl compounds. However, it has not been trivial to develop a stereoselective trap of
nucleophilic radicals. This is because the addition of radicals to a cationic iminium ion II creates a reactive α-iminyl radical cation
VII (Fig. 2b), an unstable intermediate with a high tendency to undergo β-scission64 and reform the more stable iminium ion II.
Recently, a strategy was reported that enabled enantioselective radical conjugate additions to β,β-disubstituted cyclic enones 15 in
order to set quaternary carbon stereocentres with high fidelity65. To bypass the species VII, an electron-rich carbazole moiety was
tethered at a strategic position of the chiral primary amine catalyst 17, where it is poised to undergo a rapid intramolecular SET
reduction of the unstable VII, preventing it from breaking down. A fast tautomerisation of the transient enamine intermediate (not
shown) leads to the more stable imine VIII, thus avoiding a possible competitive back-electron transfer (BET). Finally, the longlived carbazole radical cation in VIII, emerging from the intramolecular SET, undergoes single-electron reduction from the
reduced photoredox catalyst (PCred in Fig. 2b). This restores the neutral carbazole moiety while yielding the quaternary product
16. Notably, a photocatalyst (PC) both creates the nucleophilic radical and promotes the final redox process, which was identified
as being the turnover-limiting step of the overall reaction66.
The process provides a way to construct quaternary carbon stereocentres in an enantioselective manner and exploits the
tendency of radicals to connect structurally congested carbons because their reactivity is only marginally affected by steric
factors67. However, radical-based catalytic enantioselective strategies had previously found limited application to construct

quaternary carbon sterecenters52, and were not mentioned in a recent comprehensive survey of available methods 68. It appears that
organocatalysis, in combination with photoredox catalysis, may offer effective tools to better exploit the intrinsic merits of radical
reactivity.
Also N-heterocyclic carbene (NHC) catalysis could be used in conjunction with photoredox catalysts69. Although this
approach has not yet been used to stereoselectively trap photochemically generated radicals, this target appears feasible.

Dual-Catalyst Systems - Noncovalent Organocatalysis
Noncovalent modes of organocatalytic reactivity have also been used with photoredox catalysis. To date, there have been few
reports, but these have offered solutions to synthetically meaningful problems. Initial approaches used photochemical strategies to
in situ generate reactive closed-shell species (e.g. iminium ions70, singlet oxygen71), which were successively intercepted by chiral
organocatalytic intermediates. The first application of noncovalent organocatalysis in light-mediated radical chemistry provided a
strategy to perform an asymmetric aza-pinacol cyclisation (Fig. 3a)72. The combination of the chiral phosphoric acid catalyst 20
and an iridium photoredox catalyst promoted the intramolecular reductive coupling between the ketone and hydrazone moieties
within substrate 18 to furnish the syn 1,2-amino alcohol derivatives 19 with high enantioselectivity. The process is triggered by
the formation of the ketyl radical 21, which is generated by a concerted proton-coupled electron transfer (PCET) process73 driven
by the cooperation of the photoredox and organic catalyst. PCET uses the simultaneous transfer of a proton and an electron in a
single elementary step to allow processes that would be precluded via sequential, discrete proton and electron transfer steps. In
this specific case, the direct SET reduction of the aryl ketone in 18 by the iridium photocatalyst alone would not be feasible. The
ketyl radical 21, generated by PCET, is primed to cyclise into the hydrazone. Subsequent HAT from a terminal reductant
(Hantzsch dihydropyridine) to the emerging hydrazyl radical leads to the final product 19. The high level of enantiocontrol
indicates that the neutral ketyl radical 21 could maintain a meaningful association, via tight hydrogen-bonding interactions, with
the coordinating phosphate anion of the chiral Brønsted acid 20 during the course of the stereo-defining cyclisation. This study
established the possibility of using concerted PCET to realise enantioselective radical processes by streamlining the preparation of
radicals that are otherwise difficult to achieve. It also suggested the somewhat unexpected finding that the weak interactions
inherent to noncovalent organocatalysis are suited to selectively binding radical intermediates while channelling the resulting
processes toward stereoselective manifolds.
Recently, Takashi Ooi expanded on this by using chiral P-spiro tetraaminophosphonium ion 25, which could selectively bind
the anion-radical 26 via ion-pairing interactions (Fig. 3b)74. The system required the concomitant action of an iridium photoredox
catalyst to reduce N-sulfonyl aldimines 22 and oxidise N,N-arylaminomethanes 23. The radical coupling of 26 and 27, governed
by the chiral ion pair, gave the amine product 24 in high enantioselectivity. This study further demonstrated that organocatalysis
can provide effective approaches to address issues in enantioselective radical chemistry that were previously considered
unattainable, such as the precise stereocontrol of radical coupling processes 63.

Organocatalysis in the Excited State
The great potential of combining photoredox catalysis and organocatalysis lies mainly in the possibility of accessing openshell species whose unique reactivity allows transformations not accessible through polar pathways. A different strategy has
recently emerged, which offers possibilities to expand the field of organocatalysis. Researchers are exploring the potential of some
chiral organocatalytic intermediates to directly reach an excited state upon visible-light absorption to turn on new catalytic
functions. The chemical reactivity of electronically excited molecules differs fundamentally from that in the ground state75. For
example, an excited-state molecule is both a better electron-donor (i.e. a better reductant) and electron-acceptor (i.e. a better
oxidant) than in the ground state76. This explains why, on excitation, some organocatalytic intermediates can activate substrates
via SET manifolds without the need for an external photocatalyst. At the same time, the chiral intermediate can provide effective
stereochemical control over the ensuing bond-forming process. In this strategy, stereoinduction and photoactivation combine in a
single chiral organocatalyst.
Photochemistry of enamines
The reaction in Fig. 1b was also instrumental in the discovery that the synthetic potential of chiral enamines is not limited to
the ground-state domain, and can be expanded by exploiting their photochemical activity. During investigations on the direct αalkylation of aldehydes with electron-deficient alkyl bromides 28 using the organocatalyst 11 (Fig. 4a), a control experiment
revealed that the reaction could be efficiently conducted in a stereoselective fashion under light illumination but without the need
for any external photoredox catalyst77. Mechanistic studies revealed the ability of enamines Ib to trigger the photochemical
formation of radicals from alkyl bromides using two different photochemical mechanisms, depending on the substrate. The first
mechanism77 relies on the formation of visible-light-absorbing electron donor-acceptor (EDA) complexes78,79, generated in the
ground state upon association of the electron-rich enamine Ib with the electron-deficient dinitro-benzyl bromide 28a (Fig. 4a, path
i). Irradiation of the coloured EDA complex IX induces a SET event, allowing access to the radical intermediate 30a. A second
radical generation mechanism80 (Fig. 4a, path ii) exploits the ability of the enamine Ib to directly reach an electronically excited
state (Ib*) upon light absorption and then act as a potent single-electron reductant. SET reduction of bromomalonate 28b induces
the formation of radical 30b. Mechanistic studies81 established that both enamine-mediated photochemical alkylations proceeded
through a self-propagating radical chain mechanism (Fig. 4a, right panel) 82, in analogy to the processes performed in the presence
of a photoredox catalyst (Fig. 1d).

These studies demonstrated that light excitation can turn enamines (which behave as nucleophiles in the ground state) into
reductants and trigger the formation of radicals. At the same time, ground-state chiral enamines control the stereochemical course
of the radical trapping event. This strategy was expanded to develop mechanistically related enantioselective α-functionalization
reactions, including phenacyl alkylation77, amination83, and arylsulfonyl alkylation84 of aldehydes and the alkylation of cyclic
ketones85.
Photochemistry of other organocatalytic intermediates
The discovery that the catalytic functions of enamines can be expanded by using their excited-state reactivity77 motivated the
quest for other chiral organocatalytic intermediates that could use similar photochemical mechanisms. The electronic similarities
with enamines suggested the use of enolates of type XI, generated in situ under phase-transfer catalysis (PTC) conditions28 (see
Box 1) by deprotonation of cyclic β-ketoesters 31, as suitable donors to facilitate the formation of photoactive ground-state EDA
complexes (Fig. 4b)86. Perfluoroalkyl iodides (RFI 32) served as electron-accepting substrates, leading to the formation of the
coloured EDA complex XII. A visible-light-promoted SET triggered the formation of the perfluoralkyl radical 34 (RF•) through
the reductive cleavage of the C–I bond. The electrophilic nature of RF• allowed the stereoselective trap by the chiral enolate XI,
generated using cinchonine-derived PTC catalyst. The chemistry provided access to enantio-enriched ketoester products 33
bearing either a perfluoroalkyl-containing quaternary stereocentre.
Recently, it was also established that iminium ions participate in photochemistry (Fig. 4c)87. Condensation of the chiral amine
catalyst 38 with aromatic enals 35 converts an achromatic substrate into a coloured iminium ion II. Selective excitation with a
violet-light-emitting diode (LED) forms an electronically excited state (II*). This turns an electrophilic species into a strong
oxidant88, which can trigger the formation of radicals through SET oxidation of organic silanes 36. The latter event furnishes the
β-enaminyl radical intermediate XIII along with the radical 39, which is generated upon irreversible fragmentation of the carbon–
silicon bond. A stereocontrolled intermolecular coupling of the chiral β-enaminyl radical XIII and 39 then forms the stereogenic
centre in the β-functionalised aldehyde product 37. The silane reagents 36 are non-nucleophilic substrates, which are recalcitrant
to classical conjugate addition manifolds. Thus, in contrast to other examples of excited-state organocatalytic intermediates, the
excitation of chiral iminium ions enables transformations that could not be realised by conventional catalytic asymmetric
methodologies. A further difference is that stereoselectivity is dictated by the chiral radical intermediate XIII, which governs the
radical coupling event, and not by the ground-state iminium ion.
Noncovalent activation in asymmetric photochemistry
The photochemical organocatalytic strategies discussed so far all relied on the stereoselective interception of photogenerated
radicals or radical ions in their ground states. But organocatalysis can also provide effective tools for catalytic stereocontrol in
reactions of electronically excited intermediates. This is a difficult target because it requires the control of a photochemical
process in a high-energy hypersurface, where the action of a catalyst is greatly complicated by the absence of significant
activation barriers. Hydrogen-bonding catalysis27, which relies on multiple weak interactions to activate the substrates, has
provided effective solutions. Chiral ketones, properly adorned with hydrogen-bonding motifs89, were used to catalyse lighttriggered stereocontrolled cyclisations90. The ketone-based organic catalysts effectively bind the substrate through a directional
double H-bond interaction, thus enabling the selective photoexcitation of a chiral catalyst-substrate complex. This ensured that the
substrate resided in a suitable chiral environment when reaching an excited-state. This strategy was successfully used in both
photo-induced redox processes and energy-transfer-induced photochemical reactions. In an example of the latter (Fig. 5a) 91, a
visible-light-absorbing thioxanthone moiety was incorporated within the catalyst 42. The lactam functionality of 42 was essential
for binding the substrate 40 via a double hydrogen-bond interaction. Meanwhile, the thioxanthone, upon light-excitation, activated
the substrate via a proximity-driven Dexter energy transfer mechanism75 and directed the [2+2] cyclization in the triplet energy
hypersurface. The final product 41 was obtained with excellent enantioselectivity.
Other strategies for the enantioselective catalysis of photochemical processes 15,92 have been successively developed. For
example, it was demonstrated that a mechanistically similar intramolecular [2+2] photocycloaddition is promoted with high
stereoselectivity by chiral thiourea catalysts93, traditional ground-state hydrogen-bonding organocatalysts94.
Photoexcitation of enzyme cofactors
Recently, a strategy has been reported that uses the excited-state reactivity of common biological cofactors to allow enzymes to
catalyse completely different processes than those for which they evolved. The natural reactivity of nicotinamide-dependent
ketoreductases (KREDs) can be altered upon light excitation of the NADH/NADPH cofactor, which is bound into the enzyme
active site95. KREDs have found extensive use in the preparation of chiral alcohols upon reduction of ketones 96. This native polar
reactivity is enabled by the ability of such enzymes to simultaneously bind, through noncovalent weak interactions, a carbonyl
compound and the cofactor, and the tendency of NADH (or NADPH) to serve as a hydride (H -) source. Visible-light excitation,
however, switches on a completely distinct reactivity, for the NAD(P)H becomes a strong reducing agent 97, allowing access to
radical manifolds (Fig. 5b). This photochemical behaviour was used to perform an enantioselective dehalogenation of racemic αbromo lactones 43. Once the NAD(P)H and the substrate 43 are brought into close proximity in the enzyme active site, they can
form a visible-light-absorbing EDA complex XIV, which triggers the formation of the prochiral radical intermediate 45 upon
reductive cleavage of the substrate C-Br bond. The cofactor radical cation 46 drives the formation of the reduced chiral product
44.

This brief detour in enzymatic catalysis98 highlights how the power of photochemistry to unlock unconventional reactivity is
influencing other established fields of catalytic enantioselective synthesis, including metal catalysis 99.

Conclusions and outlook
Over the last decade, the combination with light has created exciting opportunities for expanding the scope of organocatalysis
beyond conventional two-electron reactivity. Groundbreaking developments have taught synthetic chemists how to translate the
generic mechanisms of activation, which govern the success of enantioselective polar organocatalysis, into the realm of excitedstate reactivity and radical chemistry. The resulting light-driven methodologies are greatly expanding the way chemists think
about making chiral molecules sustainably.
Major developments are probably still to come. This prediction is motivated by the fast-growing stream of innovation in
photoredox catalysis, which is continuously offering new ways to generate radicals, and by the fact that the potential of excitedstate organocatalytic reactivity is far from being fully revealed. Novel synthetic developments are expected to arise from the
combination of photoredox catalysis and the activation mechanisms of ground-state organocatalysis. Considering the powerful
photoredox methods available for generating radicals upon selective C−H activation of unactivated substrates (i.e. PCET and HAT
mechanisms), the development of challenging enantioselective C(sp 3)-C(sp3) coupling strategies will likely set an ambitious
target. Efforts will also be devoted to the use of continuous flow photoreactors, which may enable the scale-up of photochemical
organocatalytic asymmetric methods100. Another central goal for the continued expansion of organocatalysis will be to fully
explore the unique modes of reactivity enabled by excitation of organocatalytic intermediates. Along these lines, traditional
photosensitisers could provide a reliable support for facilitating, by means of energy transfer mechanisms, the generation of
excited-state chiral intermediates that cannot be accessed by direct light absorption. This approach will require a deep
understanding of the photophysical properties of the organocatalytic intermediates. It is expected that the combination of
conventional physical organic chemistry tools with photophysical investigations will play an increasingly relevant role. Another
force for innovation may arise by integrating the photochemical activity of chiral organocatalytic intermediates within metalmediated catalytic cycles, which could enable unconventional mechanisms for stereocontrolled bond-formation. Finally, we
expect great strides in the development of photochemical radical cascade processes, where the unique excited-state
organocatalytic reactivities can be combined to provide powerful transformations for the one-step synthesis of complex chiral
molecules10.
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Acknowledgements P.M. thanks the Generalitat de Catalunya (CERCA Program), MINECO (CTQ2016-75520-P), and the European
Research Council (ERC 681840 - CATA-LUX) for financial support. M.S. thanks the EU for a Marie Skłodowska-Curie Fellowship (grant no.
744242).
Author contributions P.M. outlined the content of the review and defined its scope. M.S. and P.M. worked together to prepare and edit
the manuscript, figures, and references.
Additional information Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing
financial interests. Correspondence should be addressed to P.M. (pmelchiorre@iciq.es).
Competing financial interests The authors declare no competing financial interests.

Figure Legends

Box 1 | Organocatalytic mechanisms. Timelines: enamine-mediated catalysis – first applications (1970s)3,4, conceptualisation
(2000)7, review18; iminium-mediated catalysis – first application (2000)8, review19; SOMO activation – first application (2007)20;
N-heterocyclic carbene catalysis – first application (1973)23, conceptualisation (2002)24, review21; hydrogen-bonding catalysis –
first application (1998)26, review27; phase-transfer catalysis – first application (1984)6, review28; anion-binding catalysis – first
application (2007)29, review33; Brønsted acid catalysis – first application (2004)30,31, review32.

Figure 1 | Merging photoredox and enamine catalysis. a, The synthetic challenge of developing an intermolecular catalytic
enantioselective α-alkylation of unmodified carbonyl substrates with alkyl halides via an ionic SN2 path. b, The solution provided
by the combination of enamine-mediated catalytic reactions and photoredox catalysis. c, The originally proposed closed catalytic
cycle. d, The key propagation step of the radical chain mechanism. e, Further synthetic applications of this dual catalytic strategy
for the direct stereocontrolled α-alkylation of aldehydes. CFL: compact fluorescence lamp; SET: single-electron transfer. These
reactions are described in refs 49, 50, 51 and 52, respectively.

Figure 2 | Merging photoredox and covalent organocatalysis. a, Irradiation of an iridium (III) photocatalyst generates an
excited state that can take an electron from the enamine I to afford the radical cation III. The chiral intermediate III can follow
two different reaction manifolds: i) it can be intercepted by styrenes to eventually afford α-homobenzylated aldehydes; ii) it can be
deprotonated to furnish the β-enaminyl radical intermediate VI, which can then engage in a radical coupling with the radical anion
13. In both cases, the stereo-defining event is controlled by a chiral open-shell organocatalytic intermediate; Ar’: 3,5-(CF3)2C6H3.
b, To implement an iminium-ion-catalysed conjugate addition of radicals, the short-lived radical intermediate VII must be
bypassed. This is achieved by intramolecular reduction from the electron-rich carbazole moiety within catalyst 17. HAT:
hydrogen atom transfer; TMS: trimethylsilyl; LED: light-emitting diode; DABCO:1,4-diazabicyclo[2.2.2]octane; TIPB:
triisopropylbenzene; TBADT: tetrabutylammonium decatungstate; TBABF4: tetraethylammonium tetrafluoroborate; PC:
photoredox catalyst; PCred: reduced photocatalyst.

Figure 3 | Merging photoredox and noncovalent organocatalysis. a, The synergistic action of a chiral Brønsted acid and an
iridium (III) photoredox catalyst facilitates both the formation of the ketyl radical 21, by concerted proton-coupled electron
transfer (PCET), and the ensuing stereocontrolled aza-pinacol cyclisation. b, The chiral ion pair, formed between the cationic
catalyst 25 and the photochemically generated radical anion 26, governs an enantioselective radical coupling to afford products
24. Ms: methanesulfonyl; BArF: tetrakis[3,5-bis(trifluoromethyl)phenyl]borate.

Figure 4 | Excited-state reactivity of chiral organocatalytic intermediates. a, Light-driven enantioselective α-alkylation of
aldehydes: the photochemical activity of the enamines, either by EDA complex formation (path i) or direct photoexcitation (path

ii), generates the electrophilic radicals 30 from electron-poor organic bromide 28. The stereoselective radical trap, which is
governed by the ground-state chiral enamine Ia, triggers a chain propagation mechanism. b, Phase-transfer-catalysed
enantioselective perfluoroalkylation of β-ketoesters, driven by the photoactivity of the enolate-based EDA complex XII. c,
Exploiting the direct photoexcitation of chiral iminium ions II to enable stereocontrolled β-alkylation of enals with nonnucleophilic alkyl silanes 36; the chiral β-enaminyl radical XIII, emerging from the SET reduction of the excited iminium ion II*,
governs the stereocontrolled radical coupling to afford products 37. The filled grey circle represents the bulky chiral amine
catalyst (see86 for catalyst structure); PG: protecting group; TFA: trifluoroacetic acid; TDS: thexyl-dimethylsilyl; RF:
perfluoroalkyl fragment.

Figure 5 | Noncovalent interactions in enantioselective photochemistry. a, Hydrogen-bonding catalysis of enantioselective
photochemical [2+2] cycloaddition via triplet energy-transfer mechanism. b, Photoexcitation of a NAD(P)H-dependent enzyme
enables a non-natural reactivity, allowing an enantioselective debromination of 43. KRED: nicotinamide-dependent ketoreductase.