REVIEW ARTICLE PUBLISHED ONLINE: 21 AUGUST 2014 | DOI: 10.1038/NCHEM.2031

The electron is a catalyst Armido Studer1* and Dennis P. Curran2* The electron is an efficient catalyst for conducting various types of radical cascade reaction that proceed by way of radical and radical ion intermediates. But because electrons are omnipresent, catalysis by electrons often passes unnoticed. In this Review, a simple analogy between acid/base catalysis and redox catalysis is presented. Conceptually, the electron is a catalyst in much the same way that a proton is a catalyst. The ‘electron is a catalyst’ paradigm unifies mechanistically an assortment of synthetic transformations that otherwise have little or no apparent relationship. Diverse radical cascades, including unimolecular radical substitution reactions (SRN1-type chemistry), base-promoted homolytic aromatic substitutions (BHAS), radical Heck-type reactions, radical cross-dehydrogenative couplings (CDC), direct arene trifluoromethyl­ ations and radical alkoxycarbonylations, can all be viewed as electron-catalysed reactions.

C

atalysis is ubiquitous in organic synthesis, and catalysts come in many flavours. Common classes of catalyst include enzymes, transition metals, Lewis acids and bases, organocatalysts and hydrogen-bonding catalysts. Among the smallest catalysts are the two principal charged atomic particles — the proton (H+) and the electron (e−). The proton is small (1.0 g mol−1) and the electron is tiny (0.55 mg mol−1), although each particle is accompanied in solution by a counterion. Addition or removal of a proton — that is, acid/base catalysis — is an exceptionally common and powerful mode of catalysis. Much less well recognized in modern organic synthesis is catalysis by addition or removal of an electron. This type of catalysis is naturally important in synthetic radical chemistry. Today it is most commonly called redox catalysis, but 30 years ago Eberson1, Chanon2 and Bauld3 use terms such as ‘electron-induced catalysis’ (EIC), ‘electron transfer catalysis’ (ETC) and ‘double activation induced by single electron transfer’ (DAISET). Redox catalysis occurs in multistep reactions that have reaction intermediates either one oxidation-state level above or one level below that of the substrates and products. In other words, during a redox-catalysed reaction, an electron is temporarily added or removed. The process of electron addition/removal is variously called electron transfer (ET), single-electron transfer (SET) or charge transfer (CT). The terms are equivalent — electrons transfer singly and the charge has to transfer with the electron. Here we use the term electron transfer. The aims of this Review are to modernize and simplify concepts of redox catalysis of radical and radical ion chain reactions in the setting of organic synthesis. To show the fundamental nature of catalysis by adding or removing an electron, we first compare it to the familiar concepts of acid/base catalysis. We then focus on redox reactions that result when a catalytic cycle is initiated by electron transfer to a substrate: in other words, reactions in which the electron is a catalyst 4. We suggest that several apparently unrelated subsets of recently reported synthetic reactions can be unified under this paradigm.

Catalysis in radical reactions

Most reactions between radicals and closed-shell molecules (hereafter called radical–molecule reactions) are fast, so at first glance

a catalyst might seem unnecessary in synthetic radical chemistry. Indeed, many radical chain reactions proceed very well with only initiation. But because so many kinds of radical–molecule reaction are fast, selectivity is often a problem. When side reactions intervene in non-radical reactions, the natural result is formation of a side product. So in ionic or pericyclic reactions, for example, side reactions are often easy to diagnose. In radical chain reactions, however, the result of a side reaction is often not formation of an observable side product but instead formation of no product. This is because side reactions break chains. So side reactions in radical chemistry can be difficult to diagnose by product analysis. Radical– solvent side reactions, for example, can completely spoil otherwise useful transformations. Because radicals are so reactive, a different thought process is needed in catalysis. Traditionally, catalysts are often used to solve a ‘no reaction’ problem. A stubborn Diels–Alder diene/dienophile pairing, for example, needs a catalyst to get the reaction to work in the first place. In contrast, most radicals and (to a lesser extent) radical ions are transient, so once a radical or radical ion is generated, there is no such thing as ‘no reaction’. The problem is not to make a given elementary reaction (addition to a π-bond or aromatic ring, for example) work in the first place. Instead, the interlocking problems are to create a setting where radicals and radical ions are smoothly generated, reacted and removed5,6, and to impose a selectivity in favour of one among several elementary competing reactions. Accordingly, catalysis has a central role in radical chemistry. In chain reactions, one slow hydrogen transfer step can be superseded by two fast ones in a concept called polarity reversal catalysis7. Here a viable chain replaces a non-viable one. In non-chain reactions, various critical enzymes can form radicals and control their reactions8. In polymer chemistry, nitroxides and redox active metals can control chain growth by the persistent radical effect 9–12. Redox and especially so-called photoredox catalysis methods have boosted preparative radical reactions recently 13,14, although it is not always clear whether the so-called catalysts serve as both initiators and catalysts (an underlying chain is not viable) or just initiators (an underlying chain is viable). There has also been rapid growth recently in a diverse set of preparative radical reactions that the catalysis community often classifies as ‘transition-metal-free reactions’. This ‘metal-centric’ view

Organisch-Chemisches Institut, Westfälische Wilhelms-Universität, Corrensstrasse 40, 48149 Münster, Germany. 2Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA. *email: [email protected]; [email protected] 1

NATURE CHEMISTRY | VOL 6 | SEPTEMBER 2014 | www.nature.com/naturechemistry

© 2014 Macmillan Publishers Limited. All rights reserved

765

REVIEW ARTICLE

NATURE CHEMISTRY DOI: 10.1038/NCHEM.2031

a Base-catalysed reactions

Generic reaction P–H

cat

Generic reaction

3

2

rxn(s)

S

Ox

cat

P

3 S

O

R1

H

O

HO R2

cat

rxn(s)

P

d Hole-catalysed Diels–Alder reaction

Base-catalysed cross aldol reaction O

2

Catalytic cycle

Catalytic cycle

c

initiation S

P

P

S–H

Ox

1

Initiation S

P–H

B

S

B

1

S–H

b Hole-catalysed reactions

S–H

R1

OH

Ar3N R2

cat O R1

Catalytic cycle

O

OH

1

O R1

initiation O

R2

R

Catalytic cycle

HO

1

1

Ar3N

initiation

R2CHO

1

R

3

3

2 O R1

2

O R2

Figure 1 | A simple mechanistic analogy between base catalysis and hole catalysis. a, A generic base-catalysed reaction. b, A generic hole-catalysed reaction. c, A base-catalysed cross aldol reaction. d, A hole-catalysed Diels–Alder reaction. The specific examples given in c and d reinforce the parallel between base catalysis and hole catalysis.

brands these radical reactions by what is absent (a metal) rather than what is present 15. It substitutes mystery for mechanistic insight. We recently suggested that a subset of these reactions could best be classified as ‘base-promoted homolytic aromatic substitution (BHAS) reactions’16. A number of other reactions have emerged recently with names like transition-metal-free Heck reactions, dehydrogenative cross-couplings, and so on. Such processes typically have an established radical–molecule reaction as one elementary step, but otherwise seem unrelated. The notion that the electron is a catalyst reveals the commonality of these processes.

Catalysis of reactions by elementary charged particles

New students of chemistry are exposed early on to the simple yet powerful concepts of Brønsted acid/base catalysis. In these reactions, a principal charged atomic particle — the proton — is either added or removed. Figures 1 and 2 compare this pair of reactions with the analogous pair of reactions involving addition or removal of the other principal charged atomic particle — the electron. These reactions of electrons are of course redox reactions. Base catalysis and hole catalysis. The pair of reactions shown in Fig.  1 involve removal of a charged atomic particle. The generic examples illustrate one common formal charge variant among several. (For example, a negatively charged base is illustrated, but bases can also be neutral.) In the familiar base-catalysed reaction (Fig. 1a), a base (B:−) initiates a cycle by removing a proton from a starting material (S–H) to give an anion reactive intermediate (S:−) (step 1), which in turn undergoes one (or more) reactions (rxn) to provide a product anion (P:−) (step 2). The cycle is turned over by proton transfer to give the product (P–H) and starting anion (step 3). The analogous reaction involving an electron rather than a proton is a process that is usually called ‘hole catalysis’ (Fig. 1b) 1–3. An electron is removed from a starting material by an oxidant (Ox+•, 766

the analogue of a base) to give a substrate radical cation intermediate (S+•) (step 1). This undergoes one (or more) reactions to form a product radical cation (P+•) (step 2). Now turnover in the barebones cycle occurs by electron transfer from the starting material to the product radical cation (step 3). Both of the catalytic cycles are chain reactions that have initiation (with the base or oxidant), propagation (the cycle proper) and termination (any reaction that departs irreparably from the cycle). Figure 1c and 1d show examples of base catalysis and hole catalysis, respectively. The familiar base catalysis is illustrated by a cross aldol reaction with its associated catalytic cycle of enolate formation by deprotonation (step 1), aldol addition (step 2) and reprotonation (step 3). Hole catalysis of pericylic reactions was extensively studied by Bauld and others over two decades starting in the mid-1980s3, and a typical example is the dimerization of cyclohexadiene. This stubborn Diels–Alder reaction (>200 °C needed thermally) can be induced by adding a small amount of a stable triarylammonium radical cation oxidant (Ar3N+•). Initiation of the dimerization occurs by electron transfer from cyclohexadiene to the triarylammonium radical cation (step 1). This gives a triarylamine (Ar3N:) and the radical cation of cyclohexadiene. This radical cation reacts with a second molecule of cyclohexadiene to give the radical cation of the product (the endo stereoisomer is favoured, step 2). This cycloaddition reaction is exothermic because π-bonds are converted to σ-bonds. At the same time, the stability of the radical cation decreases (the starting radical cation is conjugated; the product radical cation is not). This change provides the driving force for electron transfer to close the cycle, giving the final dimer product and the starting cyclohexa­ dienyl radical cation (step 3). Acid catalysis and electron catalysis. The flip side to catalysis by removal of charged atomic particles is catalysis by addition, as NATURE CHEMISTRY | VOL 6 | SEPTEMBER 2014 | www.nature.com/naturechemistry

© 2014 Macmillan Publishers Limited. All rights reserved

REVIEW ARTICLE

NATURE CHEMISTRY DOI: 10.1038/NCHEM.2031 a Acid-catalysed reactions

Generic reaction P

cat

3

Generic reaction

S

2

S

rxn(s)

P

cat

3

PH

S

R1

O

O

H

cat

R2

H

O

OH

1

2

Ph

N

2

R

R

N N

e

Ph

cat

P

R2

OH

R1

H R2

R2

3 O 2

R

H

N

Catalytic cycle

initiation

1

R

O N e

1

O

1

H

R

N

O

N 2

N

O

R1

OH

O

initiation

OH

N O

O

1

N

O

H

2 H

Ph + N2

Ph

H

1

N

N

O

O

Catalytic cycle

O N

N

O

O

rxn(s)

Catalytic cycle

O

+

2

d Electron-catalysed Diels–Alder reaction

Acid-catalysed cross aldol reaction

O

initiation

S

P

Red

Catalytic cycle

c

Red

1

initiation SH

P

H

S

H

1

S

b Electron-catalysed reactions

S

N

N

N

2

4

Ph

O O Ph

N O

N

O N N

Ph

O

Ph

O

Ph

N

N

N O

O N

N N

Ph

3

O

O

N O

N Ph

N2

Figure 2 | A simple mechanistic analogy between acid catalysis and electron catalysis. a, A generic acid-catalysed reaction. b, A generic electroncatalysed reaction. c, An acid-catalysed cross aldol reaction. d, An electron-catalysed Diels–Alder reaction. The specific examples given in c and d reinforce the parallel between acid catalysis and electron catalysis.

summarized in Fig. 2. In the familiar acid reaction (Fig. 2a), protonation of a neutral substrate (S) gives a cationic reactive intermediate (SH+) (step 1) that further transforms to a product cation (PH+) (step 2). Proton transfer from this cation to the substrate provides the free product (P) and closes the cycle (step 3). In electron catalysis (Fig. 2b), an electron is transferred from a reductant into the catalytic cycle in conceptually the same way that an acid transfers a proton. Reduction of a neutral starting material gives a radical anion intermediate (S•−) (step 1). One or more reactions convert this to a radical anion product (P•−) (step 2), which then releases its electron back to the starting material to give the product and close the catalytic cycle (step 3). Just as a free proton does not appear in the cycle of acid catalysis, a free electron does not appear in the cycle of electron catalysis. Like protons, electrons in solution are typically carried in some way. Still, the electron is a catalyst in the same way that the proton is a catalyst. Examples of acid catalysis and electron catalysis are also shown in Fig. 2. The cross aldol reaction of a ketone with an aldehyde is again used to show acid catalysis (Fig. 2c). Here the familiar steps are protonation of the aldehyde (step 1), addition of the enol tautomer of the ketone to form the protonated product (step 2) and proton transfer to close the cycle (step 3).

Cycloaddition reactions can also be promoted by electron catalysis. For example, injection of one electron into double-stranded DNA can repair more than one thymine dimer lesion by reverse [2+2]-cyloaddition17. Preparatively, Borhani and Greene reported18 in 1986 that the treatment of N-phenyl-1,2,4-triazoline dione with 1% sodium naphthalenide provided a high yield of 1 with expulsion of dinitrogen (Fig. 2d). The same reaction could be conducted with small amounts of sodium, sodium iodide, potassium tert-butoxide and several other initiators. This reaction occurs by reduction of the triazoline dione to radical anion (step 1), followed by a Diels–Alder reaction with a molecule of starting material (step 2). Loss of dinitrogen gives the product radical anion (step 3), which then transfers an electron to a molecule of starting material to close the cycle (step 4). In this example, two reaction steps (2 and 3) occur between injection and return of the electron. Still, all the intermediates are radical anions of some form. In the initial cycloaddition step, the radical and the anion are separated (that is, not conjugated) but remain in the same molecule. This type of species is called a distonic radical anion. In one of the most common variants of electron-catalysed reactions, the radical and the anion separate into two different molecules by a fragmentation reaction during the reaction stage of the

NATURE CHEMISTRY | VOL 6 | SEPTEMBER 2014 | www.nature.com/naturechemistry

© 2014 Macmillan Publishers Limited. All rights reserved

767

REVIEW ARTICLE

NATURE CHEMISTRY DOI: 10.1038/NCHEM.2031

a

b Classical view of the SRN1-mechanism Br

H N

H N

hν 99%

1 ET

H N

R–X

4

5

2

4

R–X

e

2

X (R–X)

(R–Nu) Tos

NHMe

(10 mol%) Br

R–Nu

R–Nu

NHMe

Electron injection

1

(R–X)

3

ET

N

‘Precatalyst’ (initiator)

R–X

NH3, KOtBu

2

c SRN1-process considering the electron as a catalyst

N

K2CO3, toluene

99%

(R–Nu)

N Tos

R

Nu

5

3

4

3 Nu

R

X

Figure 3 | C–C and C–N bond formations by SRN1 type reactions. a, Example SRN1 reactions: the photochemical formation of carbazole from a diarylamine; cyclization of tosylhydrazone to form a N-protected indazole. b, The classical mechanistic view. c, New mechanistic picture viewing the electron as a catalyst.

cycle, only to recombine later in new forms to give a product radical anion. The temporary disappearance of radical anion intermediates and the varied transformations that occur during the reaction stage can mask the underlying electron catalysis. The goal of the upcoming section is to lift that mask. These analogies of base- and hole-catalysed reactions and in turn acid- and electron-catalysed reactions are founded on a core mechanistic principle — the proton or the electron either goes into the catalytic cycle, or it comes out. Bauld3, Alder 19 and others drew the reverse analogies1,2 — that is, between acid catalysis and hole catalysis and in turn between base catalysis and electron catalysis. Such analogies are based on the reactivity of the intermediates that are produced in the catalytic cycles. Acid- and hole-catalysed reactions both generate electrophilic (often cationic) intermediates, whereas base- and electron-catalysed reactions generate nucleophilic (often anionic) intermediates. Furthermore, radical cations are potential acids and radical anions are potential bases. Both analogies are valid in their own right. In the cascade reactions considered below, however, the intermediate radical cations do not act as acids nor do the radical anions act as bases. Moreover, it is more the open-shell situation of the radical ion intermediates than polar effects that lower activation energies. Therefore, we apply here the analogy based on addition/removal of a charged atomic particle rather than the analogy based on the philicity of the resulting intermediates. To summarize, we have drawn a plain mechanistic analogy between acid/base-catalysed reaction and redox-catalysed reactions. Both large classes of reactions involve addition/removal of a charged atomic particle to/from a substrate to form a reactive intermediate. Evolution to a product reactive intermediate by one or several reactions is then followed by the reverse of the original particle transfer reaction to close a catalytic cycle. Mechanistically, the redox analogue of base catalysis is hole catalysis, and the redox analogue of acid catalysis is electron catalysis. The simple view that the charged particle itself is a catalyst is a shared theme of acid catalysis and electron catalysis.

Examples of electron-catalysed reactions

In this core section of the Review, we present a series of classical and new reactions that can be viewed through the paradigm of electron catalysis. To highlight the role of the electron as a catalyst, we use a formalism in which we write the electron in the catalytic cycle proper. Unimolecular radical substitution reactions (SRN1-chemistry). Figure  3a shows two examples of unimolecular radical nucleophilic substitutions, commonly called SRN1 reactions20,21. In the 768

first example, diarylamine 2 reacts under typical SRN1 conditions (NH3, irradiation) to give carbazole 3 in quantitative yield22. The second example shows an intramolecular C–N bond formation. Aryl bromide 4 cyclizes efficiently under basic conditions to give indazole 5  in 99% yield23. The inorganic product of these reactions is KBr. Like SN1 and SN2 substitutions, these net reactions are redox neutral. SRN1 chemistry is well established for the formation of C–C and C–heteroatom bonds. Common electrophiles are aryl halides and sometimes alkenyl halides. Other leaving groups than halides can also be employed, and many kinds of nucleophile (C, P, Sn, As, Sb, Se and Te-type anionic nucleophiles) have been used21. The generally accepted chain mechanism for the SRN1 reaction is presented in Fig. 3b. The chain is initiated by an electron transfer (ET) to the halide R–X from a suitable electron source (step 1) generating a radical anion (R-X)•− which upon fragmentation provides the corresponding radical R• along with the halide X− (step 2). Reaction of the radical R• with a nucleophile then generates a product radical anion (R–Nu)•−, which reacts as an electron transfer reagent to eventually give the R–Nu coupling product after ET to the radical precursor (steps 3 and 4). The initial radical anion (R–X)•− may or may not be a fleeting intermediate. The existence of aryl radical anions is well established, but electron transfer to aryl halides may occur with simultaneous bond dissociation to a radical and the ion. This is called dissociative electron transfer, and when it occurs (R–X)•− is a transition state. A theme of the eventual reaction of the radical with the nucleophile is that a stabilized (often conjugated) radical anion is formed. Notice that step 1 in Fig.  3b corresponds to the initiation step in the simple electron catalysis reaction of Fig. 2b and step 4 corresponds to the turnover step. Steps 2 and 3 are the reaction steps. Notice also how the common radical ion fragmentation reaction (step 2) crosses the cycle over from a radical anion manifold to a radical manifold, whereas the addition of the nucleophile to the radical (step 3) crosses it back. The potential of the separate radical manifold is not realized in this example, but is evident nonetheless. To unmask electron catalysis in transformations like the SRN1 reaction, we find it helpful to write a formal mechanism. The formalism is to write the electron itself into the catalytic cycle. If the electron later returns to the cycle, then electron catalysis is occurring. The formal mechanism for the SRN1 reaction is shown in Fig. 3c. The catalytic cycle is started by injection of an electron from a suitable donor (step 1). This is a chain initiation step. In the language of catalysis, the initiator is a precatalyst (it provides the actual catalyst, the electron). Hereafter we use the term ‘initiator’ instead of ‘precatalyst’ because we are dealing with chain reactions. NATURE CHEMISTRY | VOL 6 | SEPTEMBER 2014 | www.nature.com/naturechemistry

© 2014 Macmillan Publishers Limited. All rights reserved

REVIEW ARTICLE

NATURE CHEMISTRY DOI: 10.1038/NCHEM.2031 The electron catalyst in the second step then reduces the substrate R–X to generate the corresponding radical anion (R–X)•−, which upon fragmentation provides the radical R• along with the halide X− (step  3), as discussed above. Trapping of the radical R• with a nucleophile then generates a radical anion (R–Nu)•− (step  4) that acts as an electron transfer reagent in step 5 to give the product R– Nu, thereby sustaining the chain by formally liberating the electron back to the catalytic cycle. Clearly the SRN1 reaction is catalysed by an electron. A formal mechanism is not a real mechanism any more than a formal charge is a real charge. The formalism of taking the electron out of bound states and writing it into the catalytic cycle serves to illustrate the point that the electron is a catalyst. The SRN1 reaction is redox neutral. Reduction reactions can also occur through catalytic cycles, of course. However, if you attempt to formalize a reduction cycle by placing an electron into it, you find that the electron departs the cycle with a product. It is consumed, so cannot be a catalyst. Base-promoted homolytic aromatic substitutions (BHAS). Transition-metal-free radical direct C–H arylation of arenes with aryl halides has emerged as a valuable alternative to the intensively investigated Pd- and Rh-catalysed CH activation reactions24–26. This young research field, which has been ignited by the groups of Itami27, Shi28, Shirakawa and Hayashi29, and Lei30, is now an intensively investigated branch of radical chemistry. In these transformations, an aryl halide (mostly iodide or bromide) is reacted with KOtBu (3 equiv.) in the presence of a catalytic amount of a ligand (for example 1,10-phenanthroline, DMEDA (N,Nʹ-dimethylethane1,2-diamine)) with an arene (large excess) at high temperature. For example, various aryl iodides 6 reacted in good to excellent yields in benzene to the corresponding biphenyls 7 (Fig. 4a)30. BHAS can also be conducted intramolecularly as shown in the scheme for the transformation of bromide 8  to 9 (see ref.  28). A theme that cuts across all this work is positive results in tests (cyclizations, isotope effects) for free radical intermediates. In 2011 we suggested that such reactions follow an established mechanistic pathway called ‘base-promoted homolytic aromatic substitution’16. This is shown in Fig.  4b. In the initiation step (1), an electron is transferred either directly or perhaps more likely indirectly (see below) from a complexed KOtBu to the aryl halide generating the corresponding aryl radical anion (Ar–X)•−. This subsequently fragments to an aryl radical Ar• and the halide X− (step 2). a

The aryl radical adds, in step 3, to the arene31 to give the cyclohexadienyl radical, which is deprotonated with KOtBu to generate a biaryl radical anion (step  4). This radical anion then transfers an electron to the starting aryl halide to eventually give the homolytic aromatic substitution product along with the arene radical anion (Ar–X)•−, thereby sustaining the chain (step 5). In contrast to the SRN1 chemistry, the aryl radical in BHAS reacts with a neutral arene and radical anion generation occurs via subsequent deprotonation. In the SRN1 process the reaction of an anionic nucleophile with an aryl radical directly generates the chain-carrying radical anion. If aryl anions are used as nucleophiles, the BHAS with the neutral arene provides the same product as the corresponding SRN1 process with the aryl anion32–34. Analogously to the SRN1 chemistry, we formalize the overall transformation as a process catalysed by an electron (Fig. 4c). The initiator first injects an electron (step  1) into the cycle, which is transferred to the substrate halide (step 2). The generated aryl radical anion (Ar–X)•− fragments to the corresponding aryl radical Ar• and the halide X− (step 3). Addition of the aryl radical to the arene (step 4) and subsequent deprotonation (step 5) generates the biaryl radical anion which can formally liberate an electron providing the product in step  6. The electron then enters as a catalyst the next catalytic cycle. The phenanthroline-complexed KOtBu is not an ideal electron donor (initiator), and indeed may not be the actual electron donor that initiates a given reaction35. A macrocyclic aromatic pyridine pentamer complexed with the K-alcoholate is a good initiator for such BHAS36. We have recently shown that PhNKNH2 as initiator, readily generated from PhNHNH2 with KOtBu, gives good yields in such transition-metal-free direct C–H arylations.37 Moreover, Rossi and co-workers showed that under irradiation using typical SRN1-conditions, formation of biaryls can even be achieved at room temperature, showing that the deprotonation of the cyclohexadienyl radical in the catalytic cycle works efficiently at low temperature38. A typical feature of electron-catalysed chain reactions is that they can be initiated in different ways, with both organic and metal donors. This is well illustrated by both SRN1 and BHAS reactions. The counterion that the initiating system provides surely cannot be neglected because it pairs with various reactive intermediates. Still, because the electron is the catalyst, the tolerance for different counterions is potentially broad. Again this compares well with acid reactions, where many different acids (protons and their associated

b

R

+ 6

DMEDA (20 mol%) 80 °C

H

1 7

Ar

68–92% Benzene

ET Ar–X t

O

KO Bu (3 equiv.) O H

Br

8

Phenanthroline (40 mol%) Mesitylene 100 °C 73%

BHAS considering the electron as a catalyst

Ar–X

KOtBu (3 equiv.) R

I

c

BHAS

Initiator

ET Ar

(Ar–X)

Ar–X

e

5

6

X

2

2 (Ar–X)

Ar Ar

Ar

HOtBu

Electron injection

1

3

4 H

9 KOtBu

HOtBu

KOtBu

3

5

X H Ar

4

Ar

Ar

Figure 4 | Base-promoted homolytic aromatic substitution (BHAS) reactions. a, Example BHAS reactions: formation of a biaryl from an aryl iodide and benzene; a similar reaction, this time intramolecular to form a benzochromene. b, The classical mechanistic view. c, New mechanistic picture viewing the electron as a catalyst. NATURE CHEMISTRY | VOL 6 | SEPTEMBER 2014 | www.nature.com/naturechemistry

© 2014 Macmillan Publishers Limited. All rights reserved

769

REVIEW ARTICLE a I +

NATURE CHEMISTRY DOI: 10.1038/NCHEM.2031 c Heck-type arylation considering the electron as a catalyst

KOtBu (3 equiv.) EtOH (20 mol%)

H

Initiator

Styrene

10

Electron injection

1

DMF, 80 °C 73%

Ar

11

Ar–X

Ar'

e

6

b

Ar O Ph

I Ph

12

KOtBu (3 equiv.) Phenanthroline (40 mol%) Mesitylene, 160 °C

O

O

2 (Ar–X)

Ar'

HOtBu

3

5 Ph

Ph

63% Heck intermediate

Ph

Ph

X

KOtBu

Ar

4

Ar'

13

Ar

H Ar'

Figure 5 | Transition-metal-free Heck-type arylations. a, Intermolecular Heck-type reaction to form a styrene. b, Intramolecular Heck-type reaction to form a benzofuran. c, Mechanism of the intermolecular reaction considering the electron as a catalyst.

counterions) can be used to catalyse a given reaction. Compare this feature of electron- and acid-catalysed reactions with transitionmetal-catalysed reactions, where only a limited number of metals with proper ligand arrangements serve as catalysts. Transition-metal-free Heck-type reactions. Recent examples of transition-metal-free Heck-type coupling reactions39–41 share features with BHAS reactions16,24. In Fig. 5a the successful β-arylation of styrene with aryl iodide 10  to give stilbene derivative 11 using KOtBu as base and radical initiator in DMF is depicted39. In addition, an example of the intramolecular variant is shown. The orthoiodophenyl ether 12 first undergoes cyclization to give the Heck product as an intermediate, which in turn will isomerize under the basic conditions applied to eventually provide the corresponding benzofurane 13 in good yield (Fig. 5b)41. Like BHAS reactions, strong bases are used and tests for free radicals are positive. We suggest that these kinds of transformations are chain reactions that are again initiated by electron injection (step 1) from an initiator such as complexed KOtBu or an organic SET donor that is formed in  situ from phenanthroline under the reaction conditions (very high temperature)35. In Fig. 5c and the following figures, we show only the formal ‘electron in cycle’ mechanism. To get the standard stepwise mechanism, simply inject the electron into the first reactant (rather than the cycle) and bridge together the two half-reactions on either side of the now-absent electron. Reduction of the starting aryl halide generates an aryl radical anion (step  2), which fragments the halide to give an aryl radial (step 3, Fig. 5c). Aryl radical addition to the styrene derivative in step  4 delivers a benzylic radical, which will be deprotonated by KOtBu (step 5) providing the corresponding radical anion that can formally liberate an electron affording the Heck coupling product (step 6). The electron as the catalyst then enters the next catalytic cycle, documenting its catalytic role. Radical cross-dehydrogenative coupling reactions via BHAS. In direct C–H-arylation, the arene coupling partner is often an activated aryl or alkyl halide. The C–C bond is constructed from a C–X and a C–H bond by formally liberating HX. Even more atom-economical is the so called cross-dehydrogenative coupling (CDC) process where prefunctionalization of the reaction partners is not necessary 42–45. Reaction occurs via coupling of two C–H bonds under formal generation of H2. Recently, we were able to prepare various fluorenones 15 from the corresponding ortho-formyl-biphenyls 14 via radical CDC reactions in moderate to good yields (Fig. 6a)46,47. These transformations are best initiated by using FeCp2; however, other initiators such as Bu4NI can be used48 to start the radical chain reaction. 770

In the case of FeCp2-initiation, the catalytic cycle is started by the reaction of TBHP (tBuOOH) with the Fe(ii)-complex via formal electron transfer to provide Fe(iii)OH and the tert-butoxyl radical which enters the catalytic cycle (Fig. 6b, step 1). If initiation is performed with Bu4NI, then the iodide anion is the initiator formally delivering an electron and an iodine radical. SET-reduction of TBHP by the electron generates the tert-butoxyl radical along with OH− (step  2). This O-centred radical then abstracts the H-atom from the aldehyde to give an acyl radical in step  3 which attacks the arene to generate the corresponding cyclohexadienyl radical (step  4). Deprotonation with the basic hydroxide anion leads to a biaryl radical anion (step 5). Deprotonation is facilitated by a

O H H

O

FeCp2 (0.1 mol %)

R1 R2

14

b

TBHP (2.2 equiv.) MeCN, 90 °C

R2

R1

15

56–84%

Initiator

O

Electron injection

1

t

BuOOH O

e

H H

2

6

tBuO

OH

O

3 tBuOH

O H

5 H2O

O

H

4

Figure 6 | Cross-dehydrogenative coupling reactions. a, Ferrocene-initiated radical cross-dehydrogenative coupling in the preparation of fluorenones from ortho-formylbiphenyls. b, Mechanism of the fluorenone synthesis considering the electron as a catalyst. NATURE CHEMISTRY | VOL 6 | SEPTEMBER 2014 | www.nature.com/naturechemistry

© 2014 Macmillan Publishers Limited. All rights reserved

REVIEW ARTICLE

NATURE CHEMISTRY DOI: 10.1038/NCHEM.2031 a

R2 F3C

R1

I

R2

O O Bu4NI (5 mol%)

+ N

C

Togni reagent (1.5 equiv.)

16

b

R1

1,4-dioxane 80 °C

N

52–85%

C

CF3

17

Initiator Electron injection

N

C

I

F3C

1

O O

e

CF3

2

6

CF3 N

3

C

ArylCO2 N

C

CF3

N

5

C

CF3

4

ArylCO2H

N

C

H

This in turn suggests that many other homolytic aromatic substitution reactions may proceed via the BHAS mechanism even in the absence of any strong base58. Alkoxycarbonylation of aryl halides. Lei and co-workers recently disclosed a transition-metal-free radical alkoxycarbonylation of various aryl iodides 18 with CO in the presence of KOtBu using 1,10-phenanthroline as ligand59. The reaction was shown to proceed via radical intermediates, and tert-butyl esters 19 were isolated in moderate to good yields (Fig. 8a). These reaction conditions are similar to those used for metalfree biaryl formation or Heck reactions. Therefore the initiation (step 1) probably also occurs via electron transfer from the phenanthroline complexed KOtBu to the aryl iodide generating, via the aryl radical anion (step  2), the corresponding aryl radical along with the iodide (step 3, Fig. 8b). Carbonylation of the aryl radical under high pressure with CO provides an acyl radical (step  4)60. The acyl radical then reacts in step  (5) with KOtBu to give the corresponding ester radical anion (ester analogue of a ketyl radical anion), which is a strong reducing reagent. This reaction is in essence a nucleophilic substitution where the acyl radical acts as π-electrophile and the alkoxide is the nucleophile61. Renewed ET from the ester radical anion to the starting aryl iodide generates the product ester and the corresponding iodoaryl radical anion, closing the catalytic cycle. In the product-forming step, the ester radical anion returns an electron to the catalytic cycle, thereby documenting electron catalysis (step 6).

Conclusions and next steps

CF3

Figure 7 | Trifluoromethylarene synthesis by base-promoted homolytic aromatic substitution. a, Synthesis of 6-trifluoromethylated phenanthridines. b, Mechanism considering the electron as catalyst.

the neighbouring carbonyl group. This radical anion then further reacts to the product fluorenone, thereby formally liberating the catalytic electron, closing the catalytic cycle (step 6). Hence, even though the substrate is oxidized, the overall process belongs to the class of base-promoted homolytic aromatic substitutions catalysed by the electron.49

In summary, redox catalysis in organic synthesis has two branches, hole catalysis and electron catalysis. In hole catalysis, the electron is removed first, then later replaced. This is analogous to base catalysis, where a proton is removed and replaced. In electron catalysis, an electron is added first, then later removed. This is analogous to acid catalysis, where a proton is added and removed. The electron catalysis branch has grown rapidly of late, but most of the growth has been placed in other contexts. a I

Arene trifluoromethylation via BHAS. Another example of a cascade reaction that involves site-specific radical arene functionalization catalysed by the electron is the recent synthesis of 6-trifluoromethylated phenanthridines 17 starting from readily available 2-isocyanobiphenyls 1650,51. The Togni reagent 52–54 was used as a CF3-radical precursor, and the trifluoromethylated heterocycles were isolated in good yields (Fig. 7a)55,56. Bu4NI turned out to be the best initiator for this transformation but other initiators able to inject an electron can also be applied55. The catalytic cycle is started by electron injection (step 1, Fig. 7b) from the iodide anion to the Togni reagent generating a CF3radical57 and the ortho-iodobenzoic acid anion with Bu4N+ as the countercation (step 2). CF3-radical addition to the isonitrile50,51 generates an imidoyl radical (step 3), which undergoes base-promoted homolytic aromatic substitution via steps 4 to 6 to eventually give the product phenanthridine along with the electron, which enters the second catalytic cycle. The ortho-iodobenzoic acid anion acts as base in step 5 for the BHAS reaction. This is supported by high-level calculations using density functional theory, which showed that the indicated proton in the depicted cyclohexadienyl radical has an extremely high acidity. Its relative acidity is 18 pKa units lower than ortho-iodobenzoic acid, which has a pKa of around 3 in water. Hence, the estimated pKa of that cyclohexadienyl radical in water is about −15! The calculations clearly showed that appropriately substituted cyclohexadienyl radicals have very high Brønsted acidity.

+ CO

R

18

+

(60 atm)

KOtBu

Benzene, 90 °C

O

R

19

36–81%

(4 equiv.)

b

O

Phenanthroline (40 mol%)

Initiator Electron injection

1 ArCO2tBu

Ar–X e

6

2

t

(Ar–X)

(ArCO2 Bu)

3

5

X

O

KOtBu Ar

Ar

4 CO

Figure 8 | Alkoxycarbonylation of aryl halides. a, Production of tert-butyl esters by coupling of aryl iodide with carbon monoxide in the presence of excess potassium tert-butoxide and phenanthroline ligand. b, Mechanism considering the electron as a catalyst.

NATURE CHEMISTRY | VOL 6 | SEPTEMBER 2014 | www.nature.com/naturechemistry

© 2014 Macmillan Publishers Limited. All rights reserved

771

REVIEW ARTICLE

NATURE CHEMISTRY DOI: 10.1038/NCHEM.2031

We have collected an assortment of classical and new reactions under the paradigm of the electron as a catalyst. Many of these transformations give positive tests for free radicals, but are otherwise apparently unrelated. Through the electron catalysis lens, the electron and the charge are injected together, then are temporarily separated by an ensuing fragmentation reaction. Later, the separate radical and anion intermediates reunite in an addition reaction, then the new radical anion undergoes chain transfer. These types of cross over-and-back mechanism (radical anion, to radical, back to radical anion) offer diverse opportunities for conducting both radical anion and radical reactions. Electron catalysis chain mechanisms require initiation steps. In principle, any initiator with the appropriate reduction potential (thermodynamics) and the ability to transfer an electron at a reasonable rate (kinetics) can start a chain. Reducing metals, for example, offer a large source of potential initiators for electron catalysis. A corollary to this is that some reactions that are said to be catalysed by an added chemical entity may instead be catalysed by electrons. In such cases, the so-called catalyst instead serves as an initiator and does not appear in the propagation steps. Indeed, the observation that many different ‘catalysts’ work for the same reaction may be a clue to electron-catalysed reactions. It follows that an essential reaction component used in ‘catalytic amounts’ in such reactions may not be a catalyst at all. Initiators and catalysts are both used in small amounts but fill different roles. Initiators start chains; catalysts aid their propagation. Importantly, catalysts appear in the catalytic cycle whereas initiators do not. These are major differences, and no mechanism can be said to be understood until it is clear whether the necessary reaction components present in ‘catalytic amounts’ are catalysts, initiators or both. A corollary here is that it is important not to mistake the counterion in electron catalysis for the catalyst. Radical anion intermediates in electron-catalysed chains must have counterions. Typically these are metal ions that come either from the initiator or the base. The nature of a counterion can naturally affect the structure, stability and reactivity of its associated radical anion. Likewise, because radical ions are involved, solvents will also play an important role. This situation is analogous to cationic metals that routinely associate with anionic intermediates in a metal-alkoxide-catalysed aldol reaction. In the simple view of the aldol reaction, the alkoxide (the base) is productively viewed as the catalyst rather than the metal counterion. Likewise, in the reactions described here, the electron is the catalyst. Electron-catalysed reactions can in principle be initiated both electrochemically and photochemically. In electrochemical reactions, it is relatively simple to experimentally probe whether the electron acts as a catalyst or not. If the number of faradays necessary to complete a reaction is finite but small compared with the amounts of reactants (the initiation energy), then the process must be catalysed by the electron. Indeed, electron catalysis has been verified in this manner for SRN1-type reactions62,63. Likewise, light energy can be used to release an electron to initiate a catalytic cycle, and the role of the light can be probed by measuring the quantum yield. For example, the photoinitiated SRN1 reaction of sodium azide with p-nitrocumylchloride to give p-nitrocumylazide has a quantum yield of about 6,000 (ref. 64). This means that one photon initiates a chain that propagates through 6,000 cycles (on average) before termination. The chemical, electrochemical or light energy in electron-catalysed reactions is spent on initiation and not on driving the precursors to the products. Generally this driving force is already built in because the products are more stable. To solve problems with preparative electron-catalysed reactions in a non-Edisonian fashion, one needs to think about redox potentials and chain dynamics. Redox potentials are to redox catalysis what pKa is to acid/base catalysis. Like pKa values, redox potentials 772

are highly solvent dependent. Beyond that, however, the simple analogy fades. Most exothermic and even many endothermic acid/base reactions are fast. In contrast, even exothermic electron transfer reactions can have large kinetic barriers in practice. Thus, when problems occur in electron-catalysed reactions, the electron transfer steps, whether initiation or propagation or termination, are prime suspects. The principles of electron catalysis as introduced almost 50 years ago1–3 and augmented here are general, extending well beyond the example reactions that we have provided. Consider, for example, the recent Grignard cross-coupling reactions of Shirakawa25,65 or the metal-catalysed carbonylative cross-couplings of Ryu66, both of which are readily formulated as electron-catalysed reactions. The unifying concept of ‘the electron as a catalyst’ provides a framework to identify relationships between existing reactions, to solve problems with inefficient reactions, and to design new reactions and sequences of reactions. Received 29 January 2014; accepted 3 July 2014; published online 21 August 2014

References

1. Eberson, L. in Electron Transfer Reactions in Organic Chemistry 172–189 (Springer, 1987). 2. Chanon, M. & Tobe, M. L. A mechanistic concept for inorganic and organic chemistry. Angew. Chem. Int. Ed. Engl. 21, 1–23 (1982). 3. Bauld, N. L. in Advances in Electron Transfer Chemistry Vol. 2 (ed. Mariano, P. S.) 1–66 (Jai, 1992). 4. Shirakawa, E. Single electron catalyzed coupling of aryl halides. Yukigouseikagaku-Kyokaishi [J. Synth. Org. Chem.] 71, 526–533 (2014). 5. Curran, D. P. The design and application of free radical chain reactions in organic synthesis. Part 1. Synthesis 417–439 (1988). 6. Curran, D. P. The design and application of free radical chain reactions in organic synthesis. Part 2. Synthesis 489–513 (1988). 7. Roberts, B. P. Polarity-reversal catalysis of hydrogen-atom abstraction reactions: concepts and applications in organic chemistry. Chem. Soc. Rev. 28, 25–35 (1999). 8. Buckel, W. & Golding, B. T. in Encyclopedia of Radicals in Chemistry, Biology and Materials Vol. 3 (eds Chatgilialoglu & C. Studer, A.) 1501–1546 (Wiley, 2012). 9. Hawker, C. J., Bosman, A. W. & Harth, E. New polymer synthesis by nitroxide mediated living radical polymerizations. Chem. Rev. 101, 3661–3688 (2001). 10. Fischer, H. The persistent radical effect: A principle for selective radical reactions and living radical polymerization. Chem. Rev. 101, 3581–3610 (2001). 11. Studer, A. The persistent radical effect in organic synthesis. Chem. Eur. J. 7, 1159–1164 (2001). 12. Studer, A. Tin-free radical chemistry using the persistent radical effect: alkoxyamine isomerization, addition reactions and polymerizations. Chem. Soc. Rev. 33, 267–273 (2004). 13. Narayanam, J. M. R. & Stephenson, C. R. J. Visible light photoredox catalysis: applications in organic synthesis. Chem. Soc. Rev. 40, 102–113 (2011). 14. Prier, C. K., Rankic, D. A. & MacMillan, D. W. C. Visible light photoredox catalysis with transition metal complexes: applications in organic synthesis. Chem. Rev. 113, 5322–5363 (2013). 15. Curran, D. P. Free at last! Nature Chem. 4, 958 (2012). 16. Studer, A. & Curran, D. P. Organocatalysis and C–H activation meet radicaland electron-transfer reactions. Angew. Chem. Int. Ed. 50, 5018–5022 (2011). 17. Giese, B. et al. Excess electron transport through DNA: A single electron repairs more than one UV-induced lesion. Angew. Chem. Int. Ed. 43, 1848–1851, (2004). 18. Borhani, D. W. & Greene, F. D. Triazolinediones. Conversion to deaza dimers by electron-transfer catalysis. A possible radical anion Diels–Alder reaction. J. Org. Chem. 51, 1563–1570 (1986). 19. Alder, R. W. Electron-transfer chain catalysis of substitution reactions. Chem. Commun. 1184–1186 (1980). 20. Bunnett, J. F. & Kim, J. K. Evidence for radical mechanism of aromatic ‘nucleophilic’ substitution. J. Am. Chem. Soc. 92, 7463–7464 (1970). 21. Bardagí, J. I., Vaillard, V. A. & Rossi, R. A. in Encyclopedia of Radicals in Chemistry, Biology and Materials Vol. 1 (eds Chatgilialoglu, C. & Studer, A.) 333–364 (Wiley, 2012). 22. Budén, M. E., Vaillard, V. A., Martin, S. E. & Rossi, R. A. Synthesis of carbazoles by intramolecular arylation of diarylamide anions. J. Org. Chem. 74, 4490–4498 (2009). NATURE CHEMISTRY | VOL 6 | SEPTEMBER 2014 | www.nature.com/naturechemistry

© 2014 Macmillan Publishers Limited. All rights reserved

REVIEW ARTICLE

NATURE CHEMISTRY DOI: 10.1038/NCHEM.2031 23. Thomé, I., Besson, C., Kleine, T. & Bolm, C. Base-catalyzed synthesis of substituted indazoles under mild, transition-metal-free conditions. Angew. Chem. Int. Ed. 52, 7509–7513 (2013). 24. Yanagisawa, S. & Itami, K. tert-Butoxide-mediated C–H bond arylation of aromatic compounds with haloarenes. ChemCatChem 3, 827–829 (2011). 25. Shirakawa, E. & Hayashi, T. Transition-metal-free coupling reactions of aryl halides. Chem. Lett. 41, 130–134 (2012). 26. Chan, T. L., Wu, Y., Choy, P. Y. & Kwong, F. Y. A radical process towards the development of transition-metal-free aromatic carbon–carbon bond-forming reactions. Chem. Eur. J. 19, 15802–15814 (2013). 27. Yanagisawa, S., Ueda, K., Taniguchi, T. & Itami, K. Potassium t-butoxide alone can promote the biaryl coupling of electron-deficient nitrogen heterocycles and haloarenes. Org. Lett. 10, 4673–4676 (2008). 28. Sun, C-L. et al. An efficient organocatalytic method for constructing biaryls through aromatic C–H activation. Nature Chem. 2, 1044–1049 (2010). 29. Shirakawa, E., Itoh, K-I., Higashino, T. & Hayashi, T. tert-Butoxidemediated arylation of benzene with aryl halides in the presence of a catalytic 1,10-phenanthroline derivative. J. Am. Chem. Soc. 132, 15537–15539 (2010). 30. Liu, W. et al. Organocatalysis in cross-coupling: DMEDA-catalyzed direct C–H arylation of unactivated benzene. J. Am. Chem. Soc. 132, 16737–16740 (2010). 31. Bonin, H., Sauthier, M. & Felpin, F-X. Transition metal-mediated direct C–H arylation of heteroarenes involving aryl radicals. Adv. Synth. Catal. 356, 645–671 (2014). 32. Shirakawa, E. et al. Cross-coupling of aryl Grignard reagents with aryl iodides and bromides through SRN1 pathway. Angew. Chem. Int. Ed. 51, 2198–221 (2012). 33. Uchiyama, N., Shirakawa, E. & Hayashi, T. Single electron transfer-induced Grignard cross-coupling involving ion radicals as exclusive intermediates. Chem. Commun. 49, 364–366 (2013). 34. Shirakawa, E., Watanabe, R., Murakami, T. & Hayashi, T. Single electron transfer-induced cross-coupling reaction of alkenyl halides with aryl Grignard reagents. Chem. Commun. 49, 5219–5221 (2013). 35. Zhou, S. et al. Organic super-electron donors: initiators in transition metal-free haloarene–arene coupling. Chem. Sci. 5, 476–482 (2014). 36. Zhao, H., Shen, J., Guo, J., Ye, R. & Zeng, H. A marcocyclic aromatic pyridone pentamer as a highly efficient organocatalyst for the direct arylations of unactivated arenes. Chem. Commun. 49, 2323–2325 (2013). 37. Dewanji, A., Murarka, S., Curran, D. P. & Studer, A. Phenyl hydrazine as initiator for direct arene C–H arylation via base promoted homolytic aromatic substitution. Org. Lett. 15, 6102–6105 (2013). 38. Budén, M. E., Guastavino, J. F. & Rossi, R. A. Room-temperature photoinduced direct C–H-arylation via base-promoted homolytic aromatic substitution. Org. Lett. 15, 1174–1177 (2013). 39. Shirakawa, E., Zhang, X. & Hayashi, T. Mizoroki–Heck-type reaction mediated by potassium tert-butoxide. Angew. Chem. Int. Ed. 50, 4671–4674 (2011). 40. Sun, C-L., Gu, Y-F., Wang, B. & Shi, Z-J. Direct arylation of alkenes with aryl iodides/bromides through an organocatalytic radical process. Chem. Eur. J. 17, 10844–10847 (2011). 41. Rueping, M., Leiendecker, M., Das, A., Poisson, T. & Bui, L. Potassium tert-butoxide mediated Heck-type cyclization/isomerization-benzofurans from organocatalytic radical cross-coupling reactions. Chem. Commun. 47, 10629–10631 (2011). 42. Li, C-J. Cross-dehydrogenative coupling (CDC): exploring C–C bond formations beyond functional group transformations. Acc. Chem. Res. 42, 335–344 (2009). 43. Yeung, C. S. & Dong, V. M., Catalytic dehydrogenative cross-coupling: forming carbon–carbon bonds by oxidizing two carbon–hydrogen bonds. Chem. Rev. 111, 1215–1292 (2011). 44. Wu, Y., Wang, J., Mao, F. & Kwong, F. Y. Palladium-catalyzed crossdehydrogenative functionalization of C(sp2)–H bonds. Chem. Asian. J. 9, 26–47 (2014). 45. Girard, S. A., Knauber, T. & Li, C-J. The cross-dehydrogenative coupling of Csp3–H bonds: a versatile strategy for C–C bond formations. Angew. Chem. Int. Ed. 53, 74–100 (2014). 46. Wertz, S., Leifert, D. & Studer, A. Cross dehydrogenative coupling via basepromoted homolytic aromatic substitution (BHAS): synthesis of fluorenones and xanthones. Org. Lett. 15, 928–931 (2013).

47. Shi, Z. & Glorius, F. Synthesis of fluorenones via quaternary ammonium saltpromoted intramolecular dehydrogenative arylation of aldehydes. Chem. Sci. 4, 829–833 (2013). 48. Finkbeiner, P. & Nachtsheim, B. J. Iodine in modern oxidation catalysis. Synthesis 45, 979–999 (2013). 49. Leifert, D., Daniliuc, C. G. & Studer, A. 6-Aroylated phenanthridines via base promoted homolytic aromatic substitution (BHAS). Org. Lett. 15, 6286–6289 (2013). 50. Ryu, I., Sonoda, N. & Curran, D. P. Tandem radical reactions of carbon monoxide, isonitriles, and other reagent equivalents of the geminal radical acceptors/radical precursor synthon. Chem. Rev. 96, 177–194 (1996). 51. Spagnolo, P. & Nanni, D. in Encyclopedia of Radicals in Chemistry, Biology and Materials Vol. 2 (eds Chatgilialoglu, C. & Studer, A.) 1019–1057 (Wiley, 2012). 52. Eisenberger, P., Gischig, S. & Togni, A. Novel 10-I-3 hypervalent iodinebased compounds for electrophilic trifluoromethylation. Chem. Eur. J. 12, 2579–2586 (2006). 53. Wiehn, M. S., Vinogradova, E. V. & Togni, A. Electrophilic trifluoromethylation of arenes and N-heteroarenes using hypervalent iodine reagents. J. Fluorine Chem. 131, 951–957 (2010). 54. Matousek, V., Togni, A., Bizet, V. & Cahard, D. Synthesis of α-CF3-substituted carbonyl compounds with relative and absolute stereocontrol using electrophilic CF3-transfer reagents. Org. Lett. 13, 5762–5765 (2011). 55. Zhang, B., Mück-Lichtenfeld, C., Daniliuc, C. G. & Studer, A. 6-Trifluoromethyl-phenanthridines through radical trifluoromethylation of isonitriles. Angew. Chem. Int. Ed. 52, 10792–10795 (2013). 56. Wang, Q., Dong, X., Xiao, T. & Zhou, L. PhI(OAc)2-Mediated synthesis of 6-(trifluoromethyl)phenanthridines by oxidative cyclization of 2-isocyanobiphenyls with CF3SiMe3 under metal-free conditions. Org. Lett. 15, 4846–4849 (2013). 57. Studer, A. A ‘renaissance’ in radical trifluoromethylation. Angew. Chem. Int. Ed. 51, 8950–8958 (2012). 58. Ji, Y. et al. Innate C–H trifluoromethylation of heterocycles. Proc. Natl Acad. Sci. USA 108, 14411–14415 (2011). 59. Zhang, H. et al. Transition-metal-free alkoxycarbonylation of aryl halides. Angew. Chem. Int. Ed. 51, 12542–12545 (2012). 60. Chatgilialoglu, C., Crich, D., Komatsu, M. & Ryu, I. Chemistry of acyl radicals. Chem. Rev. 99, 1991–2069 (1999). 61. Matsubara, H., Falzon, C. T., Ryu, I. & Schiesser, C. H. Radical masquerading as electrophiles: a computational study of the intramolecular addition reactions of aryl radicals to imines. Org. Biomol. Chem. 4, 1920–1926 (2006). 62. Saveant, J. M. Catalysis of chemical reactions by electrodes. Acc. Chem. Res. 13, 323–329 (1980). 63. Francke, R. & Little, R. D. Redox catalysis in organic electrosynthesis: Basic principles and recent developments. Chem. Soc. Rev. 43, 2492–2521 (2014). 64. Wade, P. A., Morrison, H. A. & Kornblum, N. The effect of light on electron-transfer substitution at a saturated carbon atom. J. Org. Chem. 52, 3102–3107 (1987). 65. Haines, B. E. & Wiest, O. SET-induced biaryl cross-coupling: an SRN1 reaction. J. Org. Chem. 79, 2771–2774 (2014). 66. Sumino, S., Ui, T. & Ryu I. Synthesis of alkyl aryl ketones by Pd/light induced carbonylative cross-coupling of alkyl iodides and arylboronic acids. Org. Lett. 15, 3142–3145 (2013).

Acknowledgements

D.P.C. thanks the NIH and NSF for funding. A.S. thanks the Deutsche Forschungsgemeinschaft and the programme ‘Sustainable Chemical Synthesis (SusChemSysc)’ which is co-financed by the European Regional Development Fund (ERDF) and the state of North Rhine-Westphalia, Germany, under the Operational Programme ‘Regional Competitiveness and Employment’ 2007–2013.

Additional information

Reprints and permissions information is available online at www.nature.com/reprints. Correspondence and requests for materials should be addressed to A.S. or D.P.C.

Competing financial interests

The authors declare no competing financial interests.

NATURE CHEMISTRY | VOL 6 | SEPTEMBER 2014 | www.nature.com/naturechemistry

© 2014 Macmillan Publishers Limited. All rights reserved

773