sources or solid-state emitters such as LEDs bythe functionalization of a low-cost infrared diodelaser.

REFERENCES AND NOTES

1. Committee on Optical Science and Engineering, Commissionon Physical Sciences, Mathematics, and Applications, Divisionon Engineering and Physical Sciences, National ResearchCouncil, Harnessing Light: Optical Science and Engineering forthe 21st Century (National Academy Press, Washington, DC,1998).

2. E. F. Schubert, J. K. Kim, Science 308, 1274–1278(2005).

3. S. Pimputkar, J. S. Speck, S. P. DenBaars, S. Nakamura, Nat.Photonics 3, 180–182 (2009).

4. S. Nakamura, T. Mukai, M. Senoh, Appl. Phys. Lett. 64,1687–1689 (1994).

5. S. Nakamura, Rev. Mod. Phys. 87, 1139–1151(2015).

6. C. C. Yang et al., Appl. Phys. Lett. 90, 123503(2007).

7. C. C. Lin, R.-S. Liu, J. Phys. Chem. Lett. 2, 1268–1277 (2011).8. N. C. George, K. A. Denault, R. Seshadri, Annu. Rev. Mater. Res.

43, 481–501 (2013).9. M. Shang, C. Li, J. Lin, Chem. Soc. Rev. 43, 1372–1386

(2014).10. S. Muthu, F. J. Schuurmans, M. D. Pashley, IEEE J. Sel. Top.

Quantum Electron. 8, 333–338 (2002).11. J. H. Burroughes et al., Nature 347, 539–541

(1990).12. M. A. Baldo et al., Nature 395, 151–154 (1998).13. T. Tsujimura, OLED Display Fundamentals and Applications

(Wiley Publishing, Hoboken, NJ, 2012).14. N. Thejokalyani, S. J. Dhoble, Renew. Sustain. Energy Rev. 32,

448–467 (2014).15. J. S. Kim, P. K. Ho, N. C. Greenham, R. H. Friend, J. Appl. Phys.

88, 1073–1081 (2000).16. J. M. Palmer, B. G. Grant, The Art of Radiometry (SPIE Press,

Bellingham, WA, 2009).17. R. R. Alfano, The Supercontinuum Laser Source (Springer-Verlag,

New York, 2016).18. J. M. Dudley, G. Genty, S. Coen, Rev. Mod. Phys. 78, 1135–1184

(2006).19. S. Coen et al., Opt. Lett. 26, 1356–1358 (2001).20. H. Kano, H. O. Hamaguchi, Appl. Phys. Lett. 85, 4298–4300

(2004).21. B. Povazay et al., Opt. Lett. 27, 1800–1802 (2002).22. H. Berwe, A. Haas, Chem. Ber. 120, 1175–1182

(1987).23. Z. Hassanzadeh Fard, M. R. Halvagar, S. Dehnen, J. Am. Chem.

Soc. 132, 2848–2849 (2010).24. J. P. Eußner, S. Dehnen, Chem. Commun. 50, 11385–11388

(2014).25. W. Zhang, J. L. Loebach, S. R. Wilson, E. N. Jacobsen, J. Am.

Chem. Soc. 112, 2801–2803 (1990).26. Materials and methods are available as supplementary

materials on Science Online.27. P. W. Atkins, R. S. Friedman, Molecular Quantum Mechanics

(Oxford Univ. Press, Oxford, ed. 4, 2004).28. K. J. Schafer, B. Yang, L. F. DiMauro, K. C. Kulander, Phys. Rev.

Lett. 70, 1599–1602 (1993).29. P. B. Corkum, Phys. Rev. Lett. 71, 1994–1997

(1993).30. G. G. Paulus, W. Nicklich, H. Xu, P. Lambropoulos, H. Walther,

Phys. Rev. Lett. 72, 2851–2854 (1994).

ACKNOWLEDGMENTS

This work was supported by the Deutsche Forschungsgemeinschaftwithin the framework of the research training group GRK1782.N.W.R., S.W.K., and S.C. thank U. Huttner and M. Kira forstimulating discussions on the model.

SUPPLEMENTARY MATERIALS

www.sciencemag.org/content/352/6291/1301/suppl/DC1Materials and MethodsFigs. S1 to S7Tables S1 to S3References (31–46)

3 March 2016; accepted 12 May 201610.1126/science.aaf6138

ORGANIC CHEMISTRY

Native functionality in triple catalyticcross-coupling: sp3 C–H bonds aslatent nucleophilesMegan H. Shaw,* Valerie W. Shurtleff,* Jack A. Terrett,*James D. Cuthbertson, David W. C. MacMillan†

The use of sp3 C–H bonds—which are ubiquitous in organic molecules—as latentnucleophile equivalents for transition metal–catalyzed cross-coupling reactions has thepotential to substantially streamline synthetic efforts in organic chemistry while bypassingsubstrate activation steps. Through the combination of photoredox-mediated hydrogenatom transfer (HAT) and nickel catalysis, we have developed a highly selective and generalC–H arylation protocol that activates a wide array of C–H bonds as native functionalhandles for cross-coupling. This mild approach takes advantage of a tunable HAT catalystthat exhibits predictable reactivity patterns based on enthalpic and bond polarityconsiderations to selectively functionalize a-amino and a-oxy sp3 C–H bonds in both cyclicand acyclic systems.

Over the past 50 years, transition metal–catalyzed cross-coupling reactions havetransformed the field of synthetic organicchemistry via the evolution of a widevariety of C–C and C–heteroatom bond-

forming reactions (1, 2). During this time, theseminal studies of Negishi, Suzuki, Miyaura, Stille,Kumada, and Hiyama have inspired numerousprotocols to construct carbon–carbonbonds usingpalladium, nickel, or iron catalysis. These strat-egies enable highly efficient and regiospecificfragment couplings with high functional grouptolerance, facilitating the application of modularbuilding blocks in early- or late-stage syntheticefforts. Traditionally, cross-couplingmethods haverelied on the use of organometallic nucleophilessuch as aryl or vinyl boronic acids, zinc halides,stannanes, or Grignard reagents that undergoaddition to a corresponding metal-activated arylor vinyl halide.An emerging strategy for C–C bond formation

has been the application of native organic func-tionality as latent nucleophilic handles for tran-sition metal–mediated cross-couplings. In thiscontext, the use of olefin, methoxy, acetoxy, andcarboxylic acidmoieties as organometallic replace-ments has enabled a variety of carbon–carbonbond formation protocols using feedstock mate-rials (3–8). However, the most common approachfor transition metal–mediated native functional-ization has been the use of C–Hbonds—themostubiquitous chemical bonds found in nature—asnucleophilic coupling partners. Among the well-established challenges with sp3 C–H bond func-tionalization, regioselectivity is perhaps preemi-nent, given that organic molecules incorporate adiverse combination ofmethyl,methylene, and/or

methine groups. Several elegant methodologieshave navigated this question via the use of direct-ing groups to accomplish selective sp3 C–H bondfunctionalization (9–13), or more recently by fo-cusing on the use of inductive effects to de-activate C–H bonds (14). Enzymes accomplishselective sp3 C–Hbond functionalization by takingadvantage of the diverse electronic and enthalpiccharacteristics of carbon–hydrogen bonds foundwithin complex organic molecules (15). Inspiredby this biochemical blueprint, we speculated thata small-molecule catalyst platform could be de-veloped that would differentiate between a di-verse range of C–H groups using a combinationof bond energies and polarization, thereby en-abling a unique pathway toward native arylationor vinylation.A fundamental mechanistic step in organic

synthesis is the simultaneous movement of aproton and an electron—a process termed hydro-gen atom transfer (HAT) (16, 17). HAT has longserved as an effective way to access radical in-termediates in organic chemistry; however, thecapacity to regioselectively abstract hydrogensamong a multitude of diverse C–H locations hasbeen notoriously difficult to control. Recently,driven by developments in small-molecule cata-lyst design, general methods for C–H bond func-tionalization viaHAThave begun to achieve levelsof selectivity that were previously restricted toenzymatic systems (18, 19). In this context, ourlaboratory has demonstrated that photoredox-mediated HAT catalysis can exploit native sp3

C–Hbonds for a range of C–C bond constructions,such as Minisci reactions, conjugate additions,and radical–radical couplings (20–23). Nevertheless,a general strategy for functionalization of C–Hbonds via HAT–transition metal cross-couplinghas yet to be achieved (24, 25).We recently questioned whether it would be

possible to use a tertiary amine radical cation—generated via a photoredox-mediated single-

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Merck Center for Catalysis at Princeton University, Princeton,NJ 08544, USA.*These authors contributed equally to this work. †Correspondingauthor. Email: dmacmill@princeton.edu

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electron transfer (SET) event (23, 26–28)—toaccomplish H-atom abstraction from a diverserange of substrates (Fig. 1). Given the electrophilic

nature of amine radical cations, we proposedthat such a catalytic strategy might allow theselective abstraction of hydridic, electron-rich

C–H bonds in the presence of electron-deficientand neutral C–H bonds, which are abundantthroughout organic molecules. We envisionedthat the exploitation of polarity effects in theabstraction event would impart a high degree ofkinetic selectivity into an otherwise unselectiveHAT process (29). Thereafter, we assumed theresulting radical intermediate might readily in-tersect with a Ni-catalyzed coupling cycle, there-by enabling C–C bond formation with a range ofaryl electrophiles.A detailed description of our proposed mech-

anistic cycle for the sp3 C–H cross-coupling viaphotoredox HAT-nickel catalysis is outlined inFig. 2. Initial excitation of the iridium(III) photo-catalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 [dF(CF3)ppy =2-(2,4-difluorophenyl)-5-(trifluoromethyl)pyridine;dtbbpy = 4,4'-di-tert-butyl-2,2'-bipyridine] (1) wouldproduce the long-lived photoexcited state 2 (t =2.3 ms) (30). The *Ir(III) catalyst 2 is sufficientlyoxidizing to undergo SET with a tertiary amineHAT catalyst (such as 3), to generate Ir(II) 4 andamine radical cation 5 [E1/2

red (*IrIII/IrII) = +1.21 Vversus saturated calomel electrode (SCE) inCH3CN;Ep (3-acetoxyquinuclidine) = +1.22 V versus SCEin CH3CN] (30). As a central design element, wepostulated that amine radical cation 5 would besufficiently electron-deficient to engender a kinet-ically selective HAT event at the most electron-rich site of C–H nucleophile substrate 6, therebyexclusively delivering radical intermediate 7. Atthe same time,wehypothesized that this abstraction

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Fig. 2. Photoredox, HAT, and nickel-catalyzed cross-coupling: proposed mechanistic pathway and catalyst combination. Ac, acetyl; t-Bu, tert-butyl; Boc,tert-butoxycarbonyl; DMSO, dimethyl sulfoxide; LED, light-emitting diode; SET, single-electron transfer; HAT, hydrogen atom transfer.

Fig. 1. Photoredox-mediated hydrogen atom transfer and nickel catalysis enables highly selectivecross-coupling with sp3 C–H bonds as latent nucleophiles.

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Fig. 3. Photoredox, HAT, and nickel-catalyzed cross-coupling: aryl halide and C–H nucleophile scope. All yields are isolated yields. Reaction conditions asin Fig. 2; see supplementary materials for experimental details. Ac, acetyl; t-Bu, tert-butyl; Boc, tert-butoxycarbonyl; Piv, pivalate; Cbz, benzyloxycarbonyl; Bac,tert-butylaminocarbonyl. *Reaction performed with 4-bromobenzotrifluoride to deliver N-Bac 2-(4-trifluoromethylphenyl)-pyrrolidine. †Minor regioisomer isarylated on Me position. ‡Minor regioisomer is arylated on a-amino methylene position. §Yield determined by 1H–nuclear magnetic resonance.

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event should also be thermodynamically favor-able considering the difference in the bond dis-sociation enthalpies (BDEs) of hydridic a- aminoC–H bonds (a-amino C–H = 89 to 94 kcal/mol)and the resultant N–H bond of quinuclidiniumcation [H–N+BDE (quinuclidine) = 100 kcal/mol](31, 32). Concurrent with this photoredox cycle,we assumed that our active Ni(0) species 9—generated in situ via two SET reductions of(4,7-dOMe-phen)Ni(II)Br2 (4,7-dOMe-phen =4,7-dimethoxy-1,10-phenanthroline) by the irid-ium photocatalyst [E1/2

red (IrIII/IrII) = –1.37 Vversus SCE in CH3CN; E1/2

red (NiII/Ni0) = –1.2 Vversus SCE inN,N-dimethylformamide] (30, 33)—would undergo oxidative addition into the arylhalide electrophile 10, forming the electrophilicNi(II)-aryl intermediate 11. This Ni(II) specieswould rapidly intercept radical 7 to generate aNi(III)-aryl-alkyl complex 12, which upon reduc-tive eliminationwould forge the desired C–C bondto formNi(I) complex 13 and benzylic amine 14.Reduction of 13 by 4, the Ir(II) state of thephotocatalyst, would then reconstitute both Ni(0)catalyst 9 and Ir(III) catalyst 1.We began our investigations into the proposed

photoredox-mediated HAT nickel cross-couplingby evaluating a broad range of photoredox cat-alysts, nickel-ligand systems, and quinuclidineanalogs. Upon exposing N-Boc pyrrolidine andmethyl 4-bromobenzoate to visible light [34 Wblue light-emitting diodes (LEDs)] in the presenceof iridium photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6,NiBr2•3H2O, 4,7-dimethoxy-1,10-phenanthroline,and 3-acetoxyquinuclidine, we observed 81% yieldof the desired a-amino C–C coupled product.Moreover, this product was the only detectableregioisomer formed, indicating that quinuclidineHAT catalyst 3was selective for themost hydridicC–H bond available. Notably, using quinuclidinein lieu of 3-acetoxyquinuclidine resulted in di-minished reactivity, indicating the necessity for anelectron-withdrawing substituent. This substan-tial difference in reaction efficiency illustrates thecapacity to tune the reactivity of the HAT catalystvia electronic modification of the substituent atthe 3-position. It is important to note that underthese reaction conditions, amine 3 serves as boththe HAT catalyst and the base (34).

With the optimal conditions in hand, we nextsought to examine the generality of this trans-formation by exploring the scope of the electro-philic aryl halide coupling partner. As outlined inFig. 3, a wide variety of bromoarenes functionefficiently in this HAT cross-coupling protocol.For example, electron-deficient aryl bromidescontaining ketones, trifluoromethyl groups, fluo-rines, sulfones, and esters were all effectivearylating agents (15 to 18, 71 to 84%yield). Notably,4-chlorobromobenzene gave chlorophenyl amineproduct 19 as the only observable arylationproduct in 70% yield, demonstrating that a highdegree of chemoselectivity can be achieved in theoxidative addition step. The HAT arylation strat-egy is further effective for electron-neutral andelectron-rich aryl bromides, as demonstrated bythe installation of phenyl, tolyl, t-Bu-phenyl, andanisole groups (20 to 23, 64 to 79% yield). Thepresence of orthomethyl or fluorine substitutionon the aryl halide was not problematic (24 and25, 70 and 60% yield). With respect to hetero-aromatic systems, pyridine rings were incorpo-rated with good efficiency via the use of thecorresponding heteroaryl bromide (26, 65%yield). Heteroaryl chlorides were also effectiveelectrophiles in the transformation. For example,electron-deficient pyridines and pyrimidines de-liver the benzylic amine products in good effi-ciency (27 to 29, 61 to 83% yield) (35). Thecollective one-step synthesis of the aryl pyrrolidineproducts 14 to 29 from simple N-Boc pyrrolidineclearly demonstrates that synthetic streamliningcan be accomplished with this HAT cross-couplingtechnology (36).We next explored the diversity of amino- and

oxy-bearing C–Hnucleophiles that could be usedas substrates in this photoredox-mediated HATnickel-catalyzed cross-coupling. As demonstratedin Fig. 3, many a-amino methyl- and methylene-containing substrates canbe selectively arylated. Forexample, differentially N-substituted pyrrolidinesubstrates are effective in the transformation, in-cluding those bearing tert-butoxycarbonyl (Boc),benzyloxycarbonyl (Cbz), pivalate (Piv), and tert-butylaminocarbonyl (Bac) groups (14, 30 to 32,51 to 81% yield). Notably, the arylation of N-Bocpyrrolidine can be achieved on gram scale in a sin-

gle batch, delivering 1.34 g of the 2-arylpyrrolidineproduct 14 (78% yield). Cyclic amines of variousring size are readily tolerated, with azetidine,piperidine, and azepane undergoing selective C–Harylation (33 to 35, 42 to 69% yield). Notably,ring systems that incorporate inductively with-drawing alcohols and fluorine substituents at theb-amino position do not unduly retard the C–Habstraction step [36 and 37, 45% yield, >20:1 di-astereomeric ratio (d.r.). and 68% yield, 3:1 d.r.].Moreover, lactams and ureas proved effectivelatent nucleophiles for this coupling, with bothN-Me and N-H substrates providing the corre-sponding arylated products in good yield (38 to42, 62 to 84% yield).The transformation is not restricted to cyclic

substrates, as a range of acyclic amines have beenefficiently functionalizedwith thisHAT arylationprotocol. For example, primarya-aminoC–Hbondsin both N-Boc alkyl amines and ureas can be ar-ylated in good yield (43 to 45, 47 to 74% yield). N-Boc butylamine, possessing a free N–H bond,undergoes selective a-arylation in 58% yield (46),leaving this latent functional handle availablefor further derivatization without the need forprotection or deprotection steps. For acyclicdialkyl amines containing methyl and methyleneC–Hbonds,N-Bac–substituted aminesdelivered thea-arylatedproducts in excellent yield (47 to49, 66to 82% yield), whereas the corresponding Bocsystems provided diminished yet usable effi-ciencies (20 to 30% yield). We attribute thisinteresting reactivity difference to the diminishedelectron-withdrawing nature of the Bac group incomparison to Boc, resulting in an increased rateof hydrogen atom transfer to the electrophilicamine radical cation 5.When unsymmetrical amine substrates were

exposed to this HAT protocol, some interestingregioselectivity patterns were discovered. Forexample, methyl C–H bonds undergo preferen-tial coupling overmethylene C–Hbonds, as shownwithN-Bac butylmethylamine [48, 78% yield, 4:1regioisomeric ratio (r.r.)]. Furthermore, methyland methylene C–H bonds react exclusively overmethine C–H bonds, as demonstrated withN-Bacisopropylmethylamine and N-Boc 2-methylpyrro-lidine, respectively (49 and50, 82 and 62% yield,

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Fig. 4. Regioselective arylation: Using C–H arylation and decarboxylative arylation delivers differentially arylated pyrrolidine products. All yields areisolated yields. See supplementary materials for experimental details.

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1:1 d.r.). This strategy can also be applied to theHAT arylation of a-oxy C–H bonds. Tetrahydro-furan (THF) and oxetane both undergo a-oxy ar-ylation in good efficiency (51 and 52, 76 and 53%yield). Finally, we have demonstrated that thisC–H arylation protocol is effective for benzylic sys-tems as para-xylene is arylated in 54% yield (53).Indeed,we expect that application of this strategyto a broad range of a-oxy, a-amino, and benzylicC–H–bearing substrates will demonstrate the gen-eral utility of this selective C–H arylation protocol.Finally, the capacity to control the regioselec-

tivity of the outlined HAT abstraction along withthe opportunity to utilize C–H bonds as latentnucleophiles brings forward the possibility of en-abling multiple native functionalizations to beconducted in sequence—a strategy that shouldallow the rapid constructionofmolecular complexityfrom a large variety of readily available organicfeedstock chemicals. As one example, we postu-lated thatN-Boc proline methyl ester (54) mightbe differentially arylated via (i) the photoredox-mediated HAT method presented in this work,followed by (ii) a photoredox-mediated Ni(II)decarboxylative arylation. As shown in Fig. 4,N-Bocproline methyl ester underwent selective aryla-tion at the 5-methylene position using the HATcross-coupling strategy described herein (66%yield, 4:1 d.r.). The observed regioselectivity isusefully complementary to that which would beexpected with establishedmethods for transitionmetal–catalyzed cross-coupling. Whereas manycurrent strategies use basic conditions to selec-tively functionalize acidic hydrogens (as in enolatearylations), our developed HAT protocol targetshydridic hydrogen atoms, thereby providing accessto fundamentally distinct product classes. Follow-ing the successful application of the C–Harylationoutlined herein, the corresponding amino acidproduct 55 underwent decarboxylative couplingwith 2-fluoro-4-bromopyridine at the 2-posi-tion, delivering the 2,5-diarylated pyrrolidine ad-duct in excellent yield (56, 73% yield, 4:1 d.r.). Wehave also demonstrated aHAT arylation followedby a nickel-catalyzed C–O coupling (37). N-Boc3-hydroxyazetidine can be selectively arylated atthe 2-position in 45% yield (36, Fig. 3), leaving thealcohol unreacted. The free alcohol can then be sub-sequently arylated with 4-bromo-2-methylpyridineto deliver the aryl ether product in 77% yield (seesupplementary materials).This HAT strategy represents a powerful dem-

onstration of the versatility of using sp3 C–Hbondsas organometallic nucleophile equivalents andwill likely find application in the realmof late-stagefunctionalization. We believe that this protocolwill gainwidespread usewithin the synthetic com-munity as a complement to existing cross-couplingtechnologies.

REFERENCES AND NOTES

1. M. Beller, C. Bolm, Transition Metals for Organic Synthesis,Vol. 1 (Wiley-VCH, Weinheim, 2004).

2. A. De Meijere, F. Diederich, Metal-Catalyzed Cross-CouplingReactions, Vol. 1 (Wiley-VCH, Weinheim, 2004).

3. A. de Meijere, F. E. Meyer, Angew. Chem. Int. Ed. Engl. 33,2379–2411 (1995).

4. L. J. Gooßen, G. Deng, L. M. Levy, Science 313, 662–664 (2006).

5. N. Rodríguez, L. J. Goossen, Chem. Soc. Rev. 40, 5030–5048 (2011).6. L. L. Anka-Lufford, M. R. Prinsell, D. J. Weix, J. Org. Chem. 77,

9989–10000 (2012).7. J. C. Lo, J. Gui, Y. Yabe, C.-M. Pan, P. S. Baran, Nature 516,

343–348 (2014).8. Z. Zuo et al., Science 345, 437–440 (2014).9. V. G. Zaitsev, D. Shabashov, O. Daugulis, J. Am. Chem. Soc.

127, 13154–13155 (2005).10. S. J. Pastine, D. V. Gribkov, D. Sames, J. Am. Chem. Soc. 128,

14220–14221 (2006).11. J. He et al., Science 343, 1216–1220 (2014).12. F.-L. Zhang, K. Hong, T.-J. Li, H. Park, J.-Q. Yu, Science 351,

252–256 (2016).13. J. J. Topczewski, P. J. Cabrera, N. I. Saper, M. S. Sanford,

Nature 531, 220–224 (2016).14. M. Lee, M. S. Sanford, J. Am. Chem. Soc. 137, 12796–12799 (2015).15. J. C. Lewis, P. S. Coelho, F. H. Arnold, Chem. Soc. Rev. 40,

2003–2021 (2011).16. J. J. Warren, T. A. Tronic, J. M. Mayer, Chem. Rev. 110,

6961–7001 (2010).17. J. M. Mayer, Acc. Chem. Res. 44, 36–46 (2011).18. M. S. Chen, M. C. White, Science 327, 566–571 (2010).19. T. Newhouse, P. S. Baran, Angew. Chem. Int. Ed. 50,

3362–3374 (2011).20. K. Qvortrup, D. A. Rankic, D. W. C. MacMillan, J. Am. Chem. Soc.

136, 626–629 (2014).21. J. D. Cuthbertson, D. W. C. MacMillan, Nature 519, 74–77 (2015).22. J. Jin, D. W. C. MacMillan, Nature 525, 87–90 (2015).23. J. L. Jeffrey, J. A. Terrett, D. W. C. MacMillan, Science 349,

1532–1536 (2015).24. D. Liu, C. Liu, H. Li, A. Lei, Angew. Chem. Int. Ed. 52,

4453–4456 (2013).25. D. Liu et al., Org. Lett. 17, 998–1001 (2015).26. J. M. R. Narayanam, C. R. J. Stephenson, Chem. Soc. Rev. 40,

102–113 (2011).27. C. K. Prier, D. A. Rankic, D. W. C. MacMillan, Chem. Rev. 113,

5322–5363 (2013).

28. D. M. Schultz, T. P. Yoon, Science 343, 1239176 (2014).29. B. P. Roberts, Chem. Soc. Rev. 28, 25–35 (1999).30. M. S. Lowry et al., Chem. Mater. 17, 5712–5719 (2005).31. Y.-R. Luo, Handbook of Bond Dissociation Energies in Organic

Compounds (CRC Press, Boca Raton, FL, 2003).32. W.-Z. Liu, F. G. Bordwell, J. Org. Chem. 61, 4778–4783

(1996).33. M. Durandetti, M. Devaud, J. Perichon, New J. Chem. 20, 659

(1996).34. In related studies, we have demonstrated that HAT

processes can be achieved with catalytic quantities of3-acetoxyquinuclidine in the presence of base.

35. For heteroaryl halides, no product was observed in theabsence of nickel catalyst, supporting the cross-couplingmechanism outlined in Fig. 2. See supplementary materialsfor control reactions.

36. K. R. Campos, A. Klapars, J. H. Waldman, P. G. Dormer,C. Y. Chen, J. Am. Chem. Soc. 128, 3538–3539 (2006).

37. J. A. Terrett, J. D. Cuthbertson, V. W. Shurtleff,D. W. C. MacMillan, Nature 524, 330–334 (2015).

ACKNOWLEDGMENTS

We are grateful for financial support provided by the NIHNational Institute of General Medical Sciences (R01 GM078201-05)and gifts from Merck and AbbVie. V.W.S. and J.A.T. thankBristol-Myers Squibb for graduate fellowships. J.D.C. thanksMarie Curie Actions for an International Outgoing Fellowship.

SUPPLEMENTARY MATERIALS

www.sciencemag.org/content/352/6291/1304/suppl/DC1Tables S1 and S2NMR SpectraReferences (38–50)

10 March 2016; accepted 14 April 2016Published online 28 April 201610.1126/science.aaf6635

GLASS TRANSITION

Fifth-order susceptibility unveilsgrowth of thermodynamicamorphous order in glass-formersS. Albert,1 Th. Bauer,2* M. Michl,2 G. Biroli,3,4 J.-P. Bouchaud,5 A. Loidl,2

P. Lunkenheimer,2 R. Tourbot,1 C. Wiertel-Gasquet,1 F. Ladieu1†

Glasses are ubiquitous in daily life and technology. However, the microscopic mechanismsgenerating this state of matter remain subject to debate: Glasses are considered eitheras merely hyperviscous liquids or as resulting from a genuine thermodynamic phase transitiontoward a rigid state.We show that third- and fifth-order susceptibilities provide a definite answerto this long-standing controversy. Performing the corresponding high-precision nonlineardielectric experiments for supercooled glycerol and propylene carbonate, we find strongsupport for theories based on thermodynamic amorphous order. Moreover, when loweringtemperature, we find that the growing transient domains are compact—that is, their fractaldimension df = 3.The glass transitionmay thus represent a class of critical phenomena differentfrom canonical second-order phase transitions for which df < 3.

The glassy state of matter, despite its omni-presence in nature and technology (1),continues to be one of the most puzzlingriddles in condensed-matter physics (1, 2):For all practical purposes, glasses are rigid

like crystals, but they lack any long-range order.Some theories describe glasses as kinetically con-strained liquids (3), becoming so viscous belowthe glass transition that they seem effectivelyrigid. By contrast, other theories (4, 5) are built

on the existence of an underlying thermodynamicphase transition to a state where the moleculesare frozen in well-defined yet disordered posi-tions. This so-called “amorphous order” cannotbe revealed by canonical static correlation func-tions, but rather by new kinds of correlations[i.e., point-to-set correlations or other measuresof local order (6, 7)] that have been detected inrecent numerical simulations (7–9). In these the-ories, thermodynamic correlations lock together

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originally published online April 28, 2016 (6291), 1304-1308. [doi: 10.1126/science.aaf6635]352Science 

Cuthbertson and David W. C. MacMillan (April 28, 2016) Megan H. Shaw, Valerie W. Shurtleff, Jack A. Terrett, James D.bonds as latent nucleophiles

H− C3Native functionality in triple catalytic cross-coupling: sp

 Editor's Summary

   

, this issue p. 1304; see also p. 1277Scienceacross a broad range of substrates.adjacent to nitrogen or oxygen, with no need for prior modification. The reaction is highly selectiveby Fruit). Together, the trio of catalysts can link bromo- or chloroaryl rings directly to C-H sites

now add a third player to the team, a hydrogen atom transfer (HAT) catalyst (see the Perspectiveet al.harvests blue light from a simple light-emitting diode and orchestrates the coupling by the nickel. Shaw

Iridium and nickel are already a proven team for forging carbon-carbon bonds. The iridiumA tip of the HAT to C-C bond formation

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