Professional Documents
Culture Documents
O
oxidative and reductive redox steps to yield
ver the past decade, transition metal com- reduced catalyst. In the latter case, the reactive arene products functionalized at two distinct
plexes (1–3) and organic dyes (4, 5) have catalyst intermediate may also engage in un- C–H sites from either two or three starting
been investigated extensively as visible wanted chemical reactions, leading to catalyst materials. We designate these reactions as type
light–absorbing catalysts in a wide range decomposition (4, 17). The stability and the B′ and type B″, respectively, to distinguish
of photoredox transformations (4, 6). None- aligned interfacial oxidation and reduction, them from the original process of linear radical
theless, their use is restricted on account of in- without the generation of reactive catalyst re- combinations described by Kisch (Fig. 1)
compatibility with strong acidic or basic reaction dox intermediates, bestow semiconductor pho- (15, 16, 18). When the substrate activation
media (7), strong nucleophiles, electrophiles, or tocatalysts easy control over the primary redox leads to monofunctionalized arene products
reactive radical intermediates (4) exemplified by intermediates, which, depending on semicon- by means of a coupled sacrificial redox pro-
fac-Ir(ppy)3, which reacts with C(sp3) radicals, ductor redox reaction modes, affords the final cess, the processes are classified as oxidative
leading eventually to catalyst deactivation (8, 9). product. Kisch has earlier proposed two differ- or reductive type A, depending on the redox
The photophysical properties of organic photo- ent semiconductor reaction modes in visible- mode (hole or electron) for substrate activation.
catalysts, such as eosin Y, drastically change with light photocatalysis (15, 16, 18): In semiconductor Overall, these transformations include direct
changing pH of the solution (7), and acridinium, type A photoredox reactions, the intermedi- one-pot dual C(sp2)–C(sp3)/C(sp2)–heteroatom
triarylpyryliums, and quinolinium dyes are de- ates generated by oxidation and reduction and C(sp2)–C(sp3)/C(sp2)–C(sp3) C–H function-
activated in the presence of nucleophiles such lead to two separate products, whereas in semi- alizations and innate (that is, at the inherently
as amines, acetates, phosphates, or cyanide ions conductor type B, photocatalysis orchestrated reactive positions) or regiospecific C(sp2)–C(sp3),
(4, 10, 11). oxidative and reductive redox reactions, al- C(sp2)–C(sp2), or C(sp2)–heteroatom bond-forming
Organic semiconductor materials are photo- lowing both intermediates to participate in reactions resulting in the installation of more
and chemically stable toward otherwise reactive yielding the final product. However, a broader than 20 different synthetically important func-
radicals and nucleophiles and have a suitable appreciation of such semiconductor photocata- tionalities onto arenes and heteroarenes under
bandgap between valence band maxima and lytic reaction modes in synthesis was attenuated oxidative, reductive, or dual catalytic reaction
conduction band minima (12, 13) for controlled by the use of toxic metal sulfides as semicon- conditions, as well as in the presence of strong
oxidation and reduction of many practical ductor photocatalysts, which are photocorro- nucleophiles, highly reactive sp3/sp2 C-centered
substrates. Light absorption by heterogeneous sive (15, 19) under synthetic organic reaction radicals, and acids or bases.
semiconductor photocatalysts generates sur- conditions, and only linear sequences of ra-
face redox centers as electron-hole pairs (14–16). dical or radical ion addition reactions were Bifunctionalization of arenes and
As such, a semiconductor photocatalyst, upon realized. heteroarenes by mpg-CN
photoexcitation, accomplishes two aligned re- We report here the application of organic The synthetic examples of semiconductor photo-
dox transformations on the same particle sur- semiconductor mesoporous graphitic carbon catalytic arene C(sp2)–C(sp3)/C(sp2)–heteroatom
face (14–16), whereas a molecular photocatalyst, nitride (mpg-CN) as a heterogeneous photoredox bifunctionalizations at two distinct C–H sites are
after electron transfer to one reaction partner, catalyst for synthetically important functionaliza- shown by using alkyl bromides as the source of
completes the overall redox process through a tions of arenes and heteroarenes. Even though two different functional groups (Fig. 2). Upon
subsequent redox reaction of the oxidized or the first synthesis of mpg-CN dates back to 1834 single-electron reduction, the C(sp3)–bromine
(20), its applications as a photocatalyst have bond in alkyl bromides breaks spontaneously,
only recently received attention, owing to its generating the relevant alkyl radical and a bro-
1
Fakultät für Chemie und Pharmazie, Universität Regensburg, capacity to split water under visible-light illu- mide anion (26) for such bifunctionalizations. In
93040 Regensburg, Germany. 2Department of Colloid mination (12, 21, 22). The metal-free, nontoxic the presence of mpg-CN (27), blue-light irradia-
Chemistry, Max-Planck Institute of Colloids and Interfaces,
Research Campus Golm, 14424 Potsdam, Germany.
(23), straw-yellow powder (24) is easily synthe- tion for 4 hours of a reaction mixture con-
*Corresponding author. Email: markus.antonietti@mpikg.mpg. sized in multigram quantities. Although mpg- taining arene and alkyl bromide [in this case,
de (M.A.); burkhard.koenig@ur.de (B.K.) CN is not commercially available as of yet, the 1-phenylpyrrole and diethyl bromomalonate as
model substrates (Fig. 2)] yielded the C(sp2)–C(sp3) tions (without mpg-CN or no visible-light irradia- tion (supplementary materials). A molecular
product 1a-1 and C(sp2)–Br bond-forming pro- tion) confirmed that photocatalysis by mpg-CN photocatalyst can mediate heteroarene bifunc-
duct 1a-2 (Fig. 2 and fig. S10) (26, 28). Gas chro- is imperative for the formation of 1a. Although tionalization reactions through the generation
matography (GC)–mass spectrometry analysis complex, a likely mechanism for the forma- of oxidized or reduced catalyst species, and we
of the crude reaction mixture revealed the for- tion of bifunctionalized product 1a involves demonstrated this by using Ru(bpy)32+ as a
mation of C(sp2)–C(sp3)/C(sp2)–Br bifunction- the initial redox-neutral C–H arene alkylation photocatalyst yielding product 1a in approxi-
alized product 1a. Irradiation of the reaction and net oxidative bromination of the arene gen- mately 40% GC yield (experimental details in
mixture for longer times led to the formation of erating the monofunctionalized products 1a-1 the synthetic procedures section in the supple-
the bifunctionalized product 1a in 63% isolated and 1a-2 (chemical structures in Fig. 2), respec- mentary materials). However, the photochem-
yield, along with the formation of synthetically tively, which upon further redox-neutral or net ical reaction using eosin Y as a photocatalyst
important dibrominated arene (1a-3, in 27% oxidative redox transformations generate the did not give the desired product 1a. The design
isolated yield) and C(sp2)–C(sp3)/C(sp2)–C(sp3) bifunctionalized products. The net reaction, of photoredox transformations using a molec-
bifunctionalized product 1a-4 as minor product generating the bifunctionalized product 1a, ular photocatalyst leading to bifunctionalized
(Fig. 2). The formation of such bifunctionalized can be viewed as the formal insertion of the heteroarenes and the yields of the reaction
arenes that were obtained in excellent overall heteroarene onto a C(sp3)–Br bond releasing depend on the stability of the oxidized or re-
yield required only mixing of heteroarene, alkyl dihydrogen, which, however, was not detected duced photocatalyst after the initial electron
bromide, and mpg-CN in dimethyl sulfoxide in the head space GC analysis, suggesting the transfer in the presence of different reactive
(DMSO) and irradiation under nitrogen with a role of excess diethyl bromomalonate as redox intermediates and under photoirradiation, their
blue light-emitting diode (LED). Control reac- and proton balance in the overall transforma- respective lifetimes, and associated electron
Fig. 1. Schematic representations of semiconductor photoredox catalytic reaction modes in C–H arene functionalizations. The type B′ mode can
also combine oxidative and reductive photocatalytic steps. Chemical structure, absorption and luminescence spectra, and relative band positions and
redox potentials of mpg-CN with respect to commonly applied photocatalysts are shown.
transfer kinetics to substrates or intermedi- Difficulties arise predominantly from poor synthesis (34),” the primary redox intermediates
ates. The organic semiconductor mpg-CN, upon photocatalyst compatibility under diverse reac- (radicals or radical ions) that are generated by
photoexcitation, naturally generates electron tion conditions. The mpg-CN photocatalytic pro- oxidative and reductive redox steps combine
and hole pairs, and its stability and associated tocol tolerates oxidative and reductive reaction to give coupled end products. Our reaction,
electron-hole transfer kinetics enable easy exe- sequences. described as semiconductor type B″, orches-
cution of such bifunctionalizations, with cat- The C–H bifunctionalization reaction was ex- trated the reaction of two redox intermediates
alyst recoverability and reuse as a practical tended in scope to C(sp2)–C(sp3)/C(sp2)–C(sp3) with one arene, forming two new chemical
advantage. bond-forming reactions when we activated the bonds (Fig. 2). Although the isolated yields of
Biologically relevant pyrrole derivatives con- functional groups of different reaction partners the bifunctionalized products are only moder-
taining different substituents, such as haloarene, by means of complementary redox processes ate to good, the clean conversion, simple op-
alkyl, or –CN functionalities, were compatible (type B″) in a tricomponent system. In this pro- eration, and facile separation and isolation of
with the reaction conditions, yielding the re- cess, we envision arene bifunctionalizations using the products recommend the mpg-CN catalyzed
spective products (1a–1d) in moderate-good yields. two different C(sp3)-centered radicals accessed arene C(sp2)–C(sp3)/C(sp2)–C(sp3) bond-forming
Commodity chemicals, such as bromoform, through oxidative and reductive photoredox trans- bifunctionalization protocol for applications
were also applicable in these bifunctionaliza- formations. Sodium triflinate has an oxidation in organic synthesis. Among other investigated
tion reactions, affording 1e, which contains potential of approximately +1.1 V (versus SCE, substrates, ethyl bromodifluoroacetate, bromo-
both an aldehyde group and a newly formed table S4) and is oxidized by photoexcited mpg- acetonitrile, a-bromo-g-butyrolactone, substituted
C–Br bond. CN, generating the CF3SO2 radical that, upon re- a-bromo-g-butyrolactone, and phenacyl bro-
The formation of such bifunctionalized hetero- leasing SO2, generates a •CF3 (trifluoromethyl) mide were effective precursors of functionally
arenes is an exciting development in photoredox radical. When a reaction mixture containing important alkyl, (substituted) g-butyrolactone,
catalysis. Although photocatalytic multitransfor- arene (in this case, 1-phenylpyrrole as a model and phenacyl radicals. Reactions with these radi-
mations have recently been attempted (29–32), substrate), alkyl bromide ethyl bromodifluoro- cals yielded the corresponding bifunctionalized
challenges remain in developing methods that acetate, sodium triflinate, and mpg-CN was illu- products 2a-g in moderate to good isolated yields
allow for a one-pot orchestrated sequential trans- minated using a blue LED, the twofold C–H considering two new C–C bond-forming reac-
formation, as established in homogeneous me- functionalized product 2a was obtained in 36% tions. Similarly, using this mpg-CN photoredox
tal, organo-, or enzyme catalysis (33). The few isolated yield along with synthetically impor- catalytic protocol, the scope of oxidative part-
reported examples of photocatalytic tandem tant monofunctionalized products (separate ners was easily extended, allowing installation
and cascade reactions often involve combining trifluoromethylated arene and alkylated arene: of medicinally relevant –CH2CF3 (2h) and di-
photo- and enzymatic catalysis or using cas- fig. S12). In typical semiconductor type B photo- fluoromethyl (–CF2H, 2i) groups. The –CH2CF3
cades that combine different activation modes. catalysis (15) or in conventional “paired electro- group is slightly electron withdrawing and an
excellent bioisostere of an ethyl group, and the substrate), mpg-CN, and the commercially avail- to-handle trifluoroiodomethane (a toxic gas)
–CF2H group is a lipophilic hydrogen bond donor able trifluoromethanesulfinic acid sodium salt or trifluoromethanesulfonyl chloride (a corro-
and acts as a bioisostere for alcohol and thiol under air led to the formation of the corre- sive low-boiling liquid). These reactions are
functional groups. sponding trifluoromethylated product 3a in performed under strictly inert conditions by
Although a detailed mechanistic picture of 87% isolated yield. Trifluoromethyl radical cou- using transition metal catalysts. Alternatively,
these transformations remains to be elucidated, plings to boronic acids (36) or unactivated arenes sodium triflinate reactions have required an
the experimental results suggest that sodium tri- (37, 38) are typically performed using difficult- excess of peroxides as radical initiators that
flinate, in addition to being the source of the
•CF3 radical, competed effectively with other
oxidation processes. Irradiation of arene sub-
strates (for example, 1-phenylpyrrole and 1,3,5-
trimethoxybenzene) in the presence of only ethyl
bromodifluoroacetate yielded monofunctional-
ized C–C (examples 6d and 6a in Fig. 3) and
brominated arenes (by means of C–Br bond for-
mation; chemical structures in table S5) as se-
parate products. However, in the presence of
sodium triflinate, the bifunctionalized products
2a and 2b were obtained in 36% and 52% iso-
lated yields, respectively (Fig. 2). Similar obser-
vations were found for other oxidative partners
in their respective reactions.
need careful controlled addition at a larger membered heteroarenes, such as pyrimidines RNA base uracil (3o), 1,3-dimethyluracil (3p),
scale. In contrast, trifluoromethylation reac- (3b), pyrroles (3d to 3g), indoles (3h and 3i), theophylline (3q, respiratory disease medica-
tions using mpg-CN work in the presence of pyridines (3j), thiophenes (3k), 7-deazapurine tion), allopurinol (3r, uric acid medication),
air, and the catalyst is easily recovered for reuse (3n), and medicinally relevant arenes [for ex- caffeine (3s), melatonin (3u, hormone), 4-methyl-
(Fig. 5). Control reactions confirmed that the ample, veratraldehyde (3t), widely used as a 2-(methylthio)pyrimidine (3v, oral antidiabetic
presence of mpg-CN and light irradiation were flavorant or odorant], were cleanly converted to sulfonylureas agent’s precursor), pentoxifyl-
crucial for successful direct C–H transforma- their respective trifluoromethylated products in line (3w, muscle pain medication), uridine
tions of arenes (table S2). Under the optimized good to excellent yields. Pharmaceuticals, hor- (3y), and tryptophan (3z), all showed excel-
reaction condition, a range of five- and six- mones, and bioactive molecules, including the lent reactivity toward trifluoromethylation,
Fig. 4. C–H and C–X (where X = Br, Cl) functionalizations of arenes obtained in 12% isolated yield. †Positional isomers: 16:1. ‡Ipso
at room temperature using alkali metal salts and ligand-free substitution product. §The bifunctionalized product was obtained
mpg-CN/Ni dual photoredox catalytic protocols, respectively. as a major product. ¶The bisubstituted product (7l') was formed
The reactions were carried out using mpg-CN as a heterogeneous in minimal amount. 7l:7l' = 16:1. #The bisubstituted product
photocatalyst and a blue LED. *The bisubstituted product was was obtained in 11%.
yielding the respective products, including the picted in Fig. 4. Simple inorganic or organic or phthalimide (7m and 7n, through the for-
synthesis of trifluridine (3x), in good to excel- alkali metal salts served as precursors for the mation of C–N bonds) or salts such as acetate
lent yields. Similar reactivity and product yields desired functional groups for direct C–H func- (7o, through the formation of C–O bond). The
were obtained when the reactions were per- tionalizations of arenes that encompassed succinimide group serves as a versatile amine
formed on gram scales (examples 3o, 3q, 3s in brominations, relatively less explored thio- equivalent, as the respective products can be
Fig. 3). Similarly, the installation of difluoro- cyanations, and in particular cyanations. These easily transformed into the corresponding amines
methyl (–CF2H) and –CH2CF3 groups onto caf- reactions involve just mixing of substrates, (41). The chlorination reaction using NH4Cl
feine (4a, 4d), theophylline (4b), pentoxifylline the respective alkali metal salts, and mpg-CN, led to the formation of product 7t (Fig. 4).
(4c), and pyrrole derivatives (4e-4f) yielded followed by solvent addition and blue-light These reactions are easily performed on large
the desired products in good to excellent yields illumination of the reaction mixture under scales (gram-scale reaction in examples 7a, 7l,
(Fig. 3). air (or with an oxygen balloon; materials and and 7q in Fig. 4), and the mpg-CN catalyst also
The C–H arene functionalizations using methods). Previously described methods for withstood high-power blue-light illumination
C(sp 2 )-centered radicals under reductive type A arene cyanations required slow-releasing cya- when the reaction was performed in a high–
photocatalytic reaction conditions was demon- nide precursors, such as trimethylsilyl cyanide light-intensity photoreactor with radiant flux
strated through synthetically important direct in photocatalytic reactions using acridinium of 2.0 ± 0.3 W (for comparison, the radiant flux
C–H perfluoroarylations of arenes through the (10) and palladium catalysts (40), as the cyanide of a typical commercial single-spot LED is 0.5 ±
activation of C(sp2)–bromine bonds in perfluoro- ion deactivates both palladium(II) and palla- 0.1 W. Entry 3 in table S3 and fig. S1 present
arylbromides. Upon photoexcitation, mpg-CN dium(0) species in the catalytic cycle (40). These the respective photochemical reaction yield
has a reduction potential of approximately –1.5 V limitations are not observed when mpg-CN is and high–light-intensity reaction setup), un-
(versus SCE) and can therefore assist mesolytic used. Conducting the reactions in the absence der which many conventional photocatalysts
cleavage of the C(sp2)–Br bonds in polyfluoroaryl of light, oxygen, or mpg-CN did not afford the bleach (42).
bromides (reduction potentials in table S4) desired products in reasonable yields (table S3).
Fig. 5. Sequential reactions and evaluation of catalytic recycling. transformation (in this case, the thiocyanation reaction yielding product 7i)
(A and B) Evaluation of catalyst recycling either for the same (in this over four catalytic cycles. The simplicity of the synthetic gram-scale
case a bromination reaction yielding product 7a) or different reactions reactions (in this case trifluoromethylation of caffeine) using mpg-CN
(in this case, consecutive bromination, thiocyanation, cyanation, and as a photcatalyst are depicted in (D, E, and F): (D) required reagents and
C–H amination reactions performed in a sequence yielding products reaction setup; (E) photochemical reaction setup under visible-light
7a, 7c, 7b, and 7n, respectively). (C) Kinetic profile of a photocatalytic illumination; (F) isolated product (product 3s) and the recovered photocatalyst.
into a valuable synthetic tool for cross-coupling bifunctionalized product 9a in 74% yield (Fig. 5). 28. K. Ohkubo, K. Mizushima, R. Iwata, S. Fukuzumi, Chem. Sci.
(45). The use of mpg-CN as a semiconductor This sequential reaction simply required the ad- (Camb.) 2, 715–722 (2011).
29. Z. C. Litman, Y. Wang, H. Zhao, J. F. Hartwig, Nature 560,
photocatalyst allows catalyst recoverability and dition of KBr and continuous irradiation once
355–359 (2018).
reuse as a distinct advantage. The reaction con- the trifluoromethylation reaction was complete. 30. J. B. Metternich, R. Gilmour, J. Am. Chem. Soc. 138,
ditions require no additional ligands for nickel Likewise, when sodium triflinate was added post 1040–1045 (2016).
complexation, the reactions proceed at room cyanation (examples 9b and 9c), the bifunction- 31. M. J. James, J. L. Schwarz, F. Strieth-Kalthoff, B. Wibbeling,
temperature, and the chemical and photosta- alized products containing –CF3 and –CN groups F. Glorius, J. Am. Chem. Soc. 140, 8624–8628 (2018).
32. J. Hou et al., J. Am. Chem. Soc. 140, 5257–5263 (2018).
bilty of mpg-CN allows easy scalability to gram were obtained.
33. Y. Hayashi, Chem. Sci. 7, 866–880 (2016).
quantities (example 8a). Once dissolved in di- Considering all of these results in aggregate, 34. C. Amatore, A. R. Brown, J. Am. Chem. Soc. 118, 1482–1486
methylacetamide (DMA), ethyl 4-bromobenzoate the organic semiconductor mpg-CN stands out (1996).
irradiated with blue light in the presence of as one of the most versatile visible light–activated 35. J. M. R. Narayanam, C. R. J. Stephenson, Chem. Soc. Rev. 40,
morpholine (a heterocycle featuring both amine photocatalysts, providing an inexpensive, non- 102–113 (2011).
36. Y. Ye, M. S. Sanford, J. Am. Chem. Soc. 134, 9034–9037
and ether functional groups), mpg-CN, and a toxic alternative to classical transition metal cat- (2012).
catalytic amount NiBr2•glyme was converted alysts and organic dyes. 37. Y. Ji et al., Proc. Natl. Acad. Sci. U.S.A. 108, 14411–14415 (2011).
into the corresponding C–N functionalized pro- 38. D. A. Nagib, D. W. C. MacMillan, Nature 480, 224–228
duct in 81% isolated yield. The use of o-/m-/p- (2011).
substituted aryl bromides (or even chlorides, RE FERENCES AND NOTES 39. S. Senaweera, J. D. Weaver, J. Am. Chem. Soc. 138, 2520–2523
(2016).
example 8h) yielded the corresponding regio- 1. C. K. Prier, D. A. Rankic, D. W. C. MacMillan, Chem. Rev. 113,
40. M. Sundermeier, S. Mutyala, A. Zapf, A. Spannenberg, M. Beller,
5322–5363 (2013).
specific functionalized products in good to ex- J. Organomet. Chem. 684, 50–55 (2003).
2. M. H. Shaw, J. Twilton, D. W. C. MacMillan, J. Org. Chem. 81,
cellent yields, and different functional groups, 6898–6926 (2016).
41. K. Foo, E. Sella, I. Thomé, M. D. Eastgate, P. S. Baran, J. Am.
such as ester, aldehyde, ketone, amide, trifluo- Chem. Soc. 136, 5279–5282 (2014).
3. D. A. Nicewicz, D. W. C. MacMillan, Science 322, 77–80 (2008).
42. S. Schmidbauer, A. Hohenleutner, B. König, Beilstein J. Org.
romethyl, and cyano, were tolerated under the 4. N. A. Romero, D. A. Nicewicz, Chem. Rev. 116, 10075–10166 (2016).
SUPPLEMENTARY http://science.sciencemag.org/content/suppl/2019/07/24/365.6451.360.DC1
MATERIALS
RELATED http://science.sciencemag.org/content/sci/365/6451/320.full
CONTENT
REFERENCES This article cites 104 articles, 6 of which you can access for free
http://science.sciencemag.org/content/365/6451/360#BIBL
PERMISSIONS http://www.sciencemag.org/help/reprints-and-permissions
Science (print ISSN 0036-8075; online ISSN 1095-9203) is published by the American Association for the Advancement of
Science, 1200 New York Avenue NW, Washington, DC 20005. 2017 © The Authors, some rights reserved; exclusive
licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. The title
Science is a registered trademark of AAAS.