permitted for use as a food additive (10). The use offerrocyanide offers notable advantages over bro-mine because it is nonvolatile and noncorrosive,allowing simpler and less expensive materials ofconstruction. In addition, these tri- and tetra-anionic organometallic molecules exhibit low cross-over rates through cation-exchange membranes.The results reported herein highlight the ability

of hydroxy-substituted anthraquinone and ferro-cyanide to function as stable flow battery electro-lytes in alkaline solution. The use of organic andorganometallic coordination complexes in base,rather than aqueous metal ions in acid, resolvesserious cost, corrosion, and safety concerns ofprevious flow battery chemistries. Alkaline flowbatteries can compensate for higher membraneresistance with higher voltage, leading to perfor-mance similar to that of their acidic counter-parts. In addition, quinone-ferrocyanide alkalinechemistry avoids the membrane crossover, cor-rosivity, toxicity, and regulations associated withbromine. This reduced corrosivity can lead to asubstantially lower materials cost because manycomponents can be made of inexpensive poly-olefin or poly(vinyl chloride) plastics.

REFERENCES AND NOTES

1. B. Dunn, H. Kamath, J.-M. Tarascon, Science 334, 928–935(2011).

2. Z. Yang et al., Chem. Rev. 111, 3577–3613 (2011).3. T. Nguyen, R. F. Savinell, Electrochem. Soc. Interface 19, 54–56

(2010).4. D. Biello, Sci. Am. 311, 66–71 (November 2014).5. M. Skyllas-Kazacos, M. H. Chakrabarti, S. A. Hajimolana,

F. S. Mjalli, M. Saleem, J. Electrochem. Soc. 158, R55–R79(2011).

6. B. Huskinson et al., Nature 505, 195–198 (2014).7. R. M. Darling, K. G. Gallagher, J. A. Kowalski, S. Ha,

F. R. Brushett, Energy Env. Sci. 7, 3459–3477(2014).

8. G. G. I. Joseph, A. J. Gotcher, G. Sikha, G. J. Wilson, Highperformance flow battery (2011); www.google.com/patents/US20110244277.

9. J. R. Goldstein, Novel flow battery and usage thereof(2015); www.google.com/patents/US20150048777.

10. “Seventeenth Report of the Joint FAO/WHO ExpertCommittee on Food Additives. Report No. 539,” Wld HlthOrg. Techn. Rep. Ser. (World Health Organization,Geneva, 1974).

11. H. Pal, T. Mukherjee, J. P. Mittal, J. Chem. Soc., Faraday Trans.90, 711–716 (1994).

12. S. Er, C. Suh, M. P. Marshak, A. Aspuru-Guzik, Chem. Sci. 6,885–893 (2015).

13. M. Quan, D. Sanchez, M. F. Wasylkiw, D. K. Smith, J. Am. Chem.Soc. 129, 12847–12856 (2007).

14. Q. Chen, M. R. Gerhardt, L. Hartle, M. J. Aziz, J. Electrochem.Soc. 163, A5010–A5013 (2015).

15. T. S. Balaban, A. Eichhöfer, M. J. Krische, J.-M. Lehn, Helv.Chim. Acta 89, 333–351 (2006).

16. D. Linden, T. B. Reddy, Handbook of Batteries (McGraw-Hill,New York, 2002).

ACKNOWLEDGMENTS

This work was funded by the U.S. Department of EnergyAdvanced Research Projects Agency–Energy awardno. DE-AR0000348 and the Harvard John A. PaulsonSchool of Engineering and Applied Sciences. Methods, alongwith any additional extended data display items andsource data, are available in the supplementary materials;references unique to these sections appear only in the onlineversion of the paper. M.P.M., K.L., R.G.G., and M.J.A.formulated the project. K.L., S.B.K., and D.H. synthesized,analyzed, and purified the compounds. K.L., L.T., and S.B.K.collected and analyzed the NMR and mass spectroscopydata. K.L., A.W.V., and L.E. measured solubility. K.L., Q.C.,L.E., and M.R.G. collected and analyzed the electrochemical

data. K.L., Q.C., M.R.G., M.P.M., R.G.G., and M.J.A. wrote thepaper, and all authors contributed to revising the paper.

SUPPLEMENTARY MATERIALS

www.sciencemag.org/content/349/6255/1529/suppl/DC1Materials and Methods

Supplementary TextFig. S1 to S9References (17–22)

7 April 2015; accepted 24 August 201510.1126/science.aab3033

H-BONDING CATALYSIS

O–H hydrogen bonding promotesH-atom transfer from a C–H bondsfor C-alkylation of alcoholsJenna L. Jeffrey,* Jack A. Terrett,* David W. C. MacMillan†

The efficiency and selectivity of hydrogen atom transfer from organic molecules are oftendifficult to control in the presence of multiple potential hydrogen atom donors and acceptors.Here, we describe the mechanistic evaluation of a mode of catalytic activation thataccomplishes the highly selective photoredox a-alkylation/lactonization of alcohols withmethyl acrylate via a hydrogen atom transfer mechanism. Our studies indicate a particularrole of tetra-n-butylammonium phosphate in enhancing the selectivity for a C–H bonds inalcohols in the presence of allylic, benzylic, a-C=O, and a-ether C–H bonds.

Complexmolecules, such asmedicinal agentsand natural products, often possess multi-ple types of C–Hbonds, eachwith a differentinherent reactivity. This intrinsic reactiv-ity depends on a multifaceted interplay

of steric effects, inductive and conjugative influ-ences, as well as innate strain (1, 2). The inter-molecular catalytic functionalization of C(sp3)–Hbonds in a selective manner represents a long-standing challenge that has inspired decadesof effort within the synthetic community. Nota-ble early studies by Bergman (3), as well as recentadvances in selective intermolecular transitionmetal catalyzed C(sp3)–H activation—including,among others, Hartwig’s rhodium-catalyzedborylation of terminal methyl groups (4) andWhite’s iron-catalyzed oxidation of both sec-ondary (2°) and tertiary (3°) aliphatic C–Hbonds(5)—highlight the importance of catalyst struc-ture on site selectivity.Catalyst structure has also proven critical to the

selectivity of C(sp3)–H functionalization via hydro-gen atom transfer (HAT) catalysis. HAT—the ef-fective movement of a hydrogen atom betweentwo molecular sites—represents a ubiquitous ele-mentary reaction step in organic chemistry (6–8).The rate of hydrogen abstraction fromaC–Hbonddepends not only on the C–H bond dissociationenthalpy (BDE) but also on polar effects in thetransition state. In 1987, Roberts noted that cer-tain electrophilic radicals (such as t-butoxyl) pre-ferentially abstract hydrogen from electron-richC–H bonds, whereas nucleophilic radicals (such

as amine-boryl) selectively cleave electron-deficientC–H bonds (9). The generality of this concept wassubsequently delineated through the broad appli-cation of polarity reversal catalysis (PRC), whichtakes advantage of favorable polar effects to con-trol the regioselectivity ofHAT frommultiple C–Hgroups of similar strength (10).We questioned whether the basic principles of

PRC could be integrated into a catalytic system forthe selective activation of alcohol a-C–H bonds inthe presence of a wide range of other C–H bonds(such as a-C=O, a-ether, or allylic or benzylic C–H)(11, 12). Specifically, we postulated that the se-lective C-alkylation of alcohols could be achievedvia a photoredox-catalyzed,H-bond–assisted bondactivation strategy (Fig. 1) (13–15), in which thehydroxyalkyl C–H bond is selectively polarizedand weakened via O–H hydrogen bonding.It is well known that the strength of a C–H

bonds of alcohols decreases upon deprotonationof the alcohol O–H group. This so-called “oxyanionic substituent effect” (16, 17) leads to theacceleration of a wide range of organic reactions[such as oxyanionic [1,3] and [3,3] sigmatropicrearrangements and HAT from alkoxides (18)].More recently, it has been shown that intermo-lecular hydrogen bonding between alcohols andvarious acceptor molecules gives rise to a similarpolarization and weakening of the adjacent C–Hbond (19), the strength of which is reflected in the13C nuclear magnetic resonance (NMR) chemicalshift and the one-bond 13C–1H coupling constant(1JCH) (20, 21). In particular, it was found that a1 kJ/mol increase in the enthalpy of the H-bondresulted in a 0.2-Hz decrease in 1JCH for hexafluo-roisopropanol complexed to various amines (20).On the basis of these studies, we reasoned that theefficiency and selectivity of alcohol C–Hactivation

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

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SCIENCE sciencemag.org 25 SEPTEMBER 2015 • VOL 349 ISSUE 6255 1533

Fig. 1. Proposedhydrogen bond–assisted C–H activa-tion of alcohols. BDEvalues are availablein (13–15).

Fig. 2. Reaction development. (A) H-bond–assisted C–H activation of alcohols. Shown is a proposed mechanistic pathway for the C-alkylation ofalcohols with Michael acceptors. SET, single-electron transfer. (B) Evaluation of hydrogen-bonding catalysts. Yield determined by means of 1H NMR, usingan internal standard. (C) Selected scope of simple alcohol addition to methyl acrylate. Only products are shown; experimental conditions are as in (B).Isolated yields are reported.

RESEARCH | REPORTS

could be enhanced by catalytic complexation witha suitable hydrogen-bond acceptor. In particular,interaction of the hydroxyl group of an alcoholwith a hydrogen-bond acceptor catalyst shouldincrease n–s* delocalization of the oxygen lonepair, rendering the a C–H bond more hydridic(more polarized) and more susceptible to HAT byan elecrophilic radical species.We demonstrate the selective a-activation of

alcohol C–H bonds in the presence of allylic, ben-zylic, a-oxy, and a-acyl C–H groups via a photo-redox protocol, which relies on the cooperationof three distinct catalysts: an iridium-based pho-toredox catalyst; a HAT catalyst; and tetra-n-butylammonium phosphate (or TBAP), whichis a hydrogen-bonding catalyst. On the basis ofkinetic analyses, NMR structural data, and kineticisotope effects (KIEs), we demonstrate the role ofTBAP in facilitating the highly selective a hydro-gen atom abstraction from alcohols.The past several years have witnessed a dra-

matic increase in the application of photoredoxcatalysis—the use of visible light–activated or-ganic dyes or metal complexes to facilitate single-

electron transfer events—to the development oforganic transformations (22). By combining photo-redox activation with organocatalysis (23, 24) andnickel catalysis (25), we have recently highlightedthe potential of photoredox catalysis to achievebond constructions that are not possiblewithmoretraditional methods.We became interested in the selectivity and

efficiency of C–Hbond activation in the context ofour ongoing campaign to merge visible-light pho-toredox catalysis with HAT catalysis (26–29). Wehave previously demonstrated the utility of thiols(S–H BDE = 87 kcal/mol) as HAT catalysts in thephotoredox coupling of benzylic ethers (C–HBDE = 86 kcal/mol) with arenes (26) and imines(27). We recognized that the ability to catalyticallyactivate stronger C–H bonds, such as those pres-ent in aliphatic alcohols and ethers (a C–H BDE> 90 kcal/mol), would hinge on the identificationof a catalyst that satisfies two critical require-ments: (i) homolytic cleavage of a strong substrateC–Hbondmust be counterbalanced by formationof a stronger H–[catalyst] bond, and (ii) selectiveactivation of hydridic C–H bonds (bonds that are

substantially polarized because of oxygen lonepair donation) must be realized. With these crite-ria in mind, we questioned whether it might bepossible to transiently generate a hydridophilicamine radical cation from quinuclidine (Figs. 2Aand 3)—which would be particularly suited to ab-straction of relatively strong, hydridic C–Hbonds—while resisting a-deprotonation because of poorH–C–N orbital overlap in this rigid bicyclic struc-ture (30, 31). As outlined in Fig. 2A, we envisionedan initial excitation of the well-known 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) to*Ir[dF(CF3)ppy]2(dtbbpy)

+ (2) with visible light.Reductive quenching of 2 [reduction potential(E1/2

red) = +1.21 V versus saturated calomel elec-trode (SCE) in CH3CN] (32) via oxidation of 3(E1/2

ox = +1.1 V versus SCE in CH3CN) (33, 34)would then afford radical cation 4 and Ir(II)(5). At this stage, the electrophilic quinuclidiniumradical 4 should abstract a hydrogen atom froman alcohol (6) to afford a-hydroxy radical 7 andquinuclidinium ion 8 [H–N+ BDE = 100 kcal/mol

1534 25 SEPTEMBER 2015 • VOL 349 ISSUE 6255 sciencemag.org SCIENCE

Fig. 3. Selected alcohol scopefor H-bond–assisted C–Hactivation. Additions to methylacrylate were carried out at 27°Cfor 24 hours, unless otherwisenoted. Isolated yields arereported. Detailed experimentalprocedures and full scope ofalcohols/Michael acceptorsare provided in the supplemen-tary materials. Dagger symbolindicates 40 hours reaction time;double-dagger symbol indicates48 hours reaction time; andasterisk indicates 1:1 mixture ofE/Z isomers. No alkylation ofpositions marked with bluecircles was observed inany case.

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(33)]. Nucleophilic addition of a-oxy radical 7 toan electron-deficient alkene would furnish alkylradical 9. Single-electron reduction of this electron-deficient radical 9 by Ir(II) (5) (E1/2

red = –1.37 Vversus SCE in CH3CN) would then afford thea-alkylated product 10 after protonation andlactonization, while simultaneously regenerat-ing both the photocatalyst (5→1) and the HATcatalyst (8→3) (35, 36).

We initially validated our proposed alkylationprotocol by subjecting 1-hexanol (11) and methylacrylate to blue light in the presence of amine 3[10 mole percent (mol %)] and photocatalyst 1,which afforded after 24 hours g-nonalactone (12)in 67% yield after acidic work-up (Fig. 2B). Wenext evaluated a range of hydrogen-bond acceptorcatalysts, including the tetra-n-butylammoniumsalts of phosphate, trifluoroacetate, and diphenyl

phosphate (Fig. 2B). Superior levels of productformation were achieved with catalytic TBAP(25 mol %), which provided the desired lactonein 84% yield. Initial rate kinetic analysis of thealkylation/lactonization of 11 revealed rate en-hancements in the presence of each hydrogen-bonding catalyst examined, with the largest initialrate acceleration from use of Bu4NCO2CF3 orBu4N(PhO)2PO2 [relative rate (rrel) = 2.6 and 2.5,respectively].We next demonstrated that a wide range of 1°

and2° alcohols undergo selectivea-hydroxy alkyla-tion with methyl acrylate in good to excellentyields usingTBAP catalysis (Fig. 2C). As outlined inFig. 3, these conditions clearly enable the selectiveactivation of alcohol C–H bonds in the presence ofvarious a-oxy C–H groups, including cyclic andacyclic alkyl ethers (21, 24, and 25, 85, 71, and 77%yield, respectively), silyl ethers (23, 73% yield), andesters (22, 81% yield). Moreover, excellent selectiv-ity was achieved in the presence of both allylic andbenzylic hydrogens (for example, 26 to 29, 70 to75% yield). The selectivity of this H-bond–assistedC–Hactivation platformwas further demonstratedvia theC–Halkylation/lactonizationof bifunctionalsteroidderivatives,whichprovided the correspond-ing lactone products in good levels of efficiency(25 and 26, 77 and 70%, respectively). Electron-deficient a-benzoyloxy and a-acyl C–H bonds (22and 26) are expected to be inherently deactivatedtoward HAT with respect to electrophilic radicalHAT systems (10), such as quinuclidinium radicalcation. In the absence of TBAP, higher levels ofsubstrate concentration were required to achieveuseful efficiencies. However, under those condi-tions nonselective C–H abstraction of weaker, lesshydridic C–H bonds was observed. In all casesoutlined in Fig. 3, we only observed alkylationproducts arising fromthe activationof thehydroxy-alkyl C–H bonds present in the various substrates.We next turned our attention to defining the

capacity for selective a-hydroxy C–H functional-ization in the presence of C–H bonds that havesimilar polarity and strength. Specifically, we se-lected tetrahydrofuran (THF) as a prototypicalether substrate, which would normally undergoC–Hactivation viaHATwith rates similar to thoseof alcohol substrates. We found that the dualcatalytic system involving quinuclidine and pho-toredox catalyst 1 enabled the efficient alkylationof THF with rates that were competitive with1-hexanol in competition experiments, affordinga 1.7:1 mixture of lactone and ether products (Fig.4A) (37). However, the addition of 25 mol % ofTBAP catalyst enabled a dramatic increase in over-all reaction selectivity to afford almost exclusivelythe alcohol C–H alkylation product (75% lactone,1% ether).To further understand the role of hydrogen

bonding in thisH-bond–assisted C-alkylation pro-cess, a series of computational calculations andNMR experiments were undertaken. These stud-ies were to evaluate the interaction of 1-hexanolwith various hydrogen-bonding catalysts (high-lighted in Fig. 2B) and to determine their accom-panying effect on thea-hydroxyC–Hbond strength.We performed density functional theory (DFT)

SCIENCE sciencemag.org 25 SEPTEMBER 2015 • VOL 349 ISSUE 6255 1535

Fig. 4. Mechanistic studies. (A) H-bond–dependent selectivity of a-oxy C–H alkylation. (B) Kineticisotope effect determined from two parallel kinetic analyses. (C) Kinetic isotope effect determined fromintramolecular competition experiment. (D) Kinetic isotope effect determined from intermolecular com-petition experiment. (E) Evaluation of the enantiomeric excess of unreacted alcohol under standardC-alkylation conditions. (F) Effect of TBAP on the rate of C–H abstraction from 35.

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calculations using an unrestricted B3LYP func-tional with a 6–31G basis set. In the presence ofeither phosphate, diphenyl phosphate, or trifluo-roacetate tetrabutylammonium salts, a BDE weak-eningof~3kcal/molwas calculated (supplementarymaterials). Although this represents a changein the a-C–HBDE of 1-hexanol from 94.1 kcal/molto 91.0 kcal/mol when bonded to the TBAPcatalyst, it clearly demonstrates that BDE is notthe only factor defining this HAT selectivity, andbond polarization effects are likely important.We also performedNMRexperiments to explore

the influence of both quinuclidine and TBAP ashydrogen-bonding catalysts for 1-hexanol. In theabsence of either additive, the 13C NMR chemicalshift of the a carbon of 1-hexanol (dC1) in CDCl3(38) appeared at 63.1 parts per million (ppm) with1JCH[hexanol] = 141.1 Hz. Addition of an equimolaramount of quinuclidine resulted in a 0.4-ppmupfield shift (dC1hexanol:3 = 62.7 ppm) and a slightdecrease in the one-bond 13C–1H coupling constant(1JCH[hexanol:3] = 140.4 Hz). For comparison, a 1:1mixture of 1-hexanol and TBAP gave rise to asimilarly upfield shift in the 13C signal for C1 of 1-hexanol (dC1hexanol:TBAP = 62.6 ppm; DdC1=0.5ppm), with 1JCH(hexanol:TBAP) = 140.3 Hz. These dataclearly indicate that both quinuclidine and TBAPcan induce bond weakening of the a-C1–H of 1-hexanol via hydrogen bonding. These data are alsoconsistentwith decreased s-character in the hybridcarbon orbitals of the C–H bond (increased hydri-dicity) of hexanol upon H-bond formation (39).To more thoroughly outline the factors govern-

ing both the rate and selectivity of theC-alkylationof alcohols, we performed a suite of mechanisticexperiments. The initial rate of the reaction of 1-hexanol with methyl acrylate showed first-orderdependence on [hexanol]init and [acrylate]init. Theobserved increase in the initial rate of reaction inthe presence of TBAP (Fig. 2B), coupled with first-order dependence on both reactants, implies thatTBAP serves to lower the energy barrier of (i) theC–H abstraction step (owing to a-C–H bondweakening); (ii) the C–C bond forming step, thatis, addition of radical 9 to methyl acrylate (ow-ing to enhanced nucleophilicity of the H-bondeda-hydroxy radical); or (iii) a combination of bothof these steps.In order to distinguish between these three

possibilities, we conducted a series of experimentsto assess potential deuterium kinetic isotope ef-fects on the C–H abstraction step of the proposedcatalytic cycle. First, the rate constants for thecoupling ofmethyl acrylatewith either 3-pentanolor D-3-pentanol (30→16) (Fig. 4B) were found tobe identical—KIE = 1—clearly demonstrating thatC–H/D abstraction from the alcohol 30 does notoccur during the turnover-limiting transition state(TLTS) of our proposed catalytic cycle (Fig. 2A).However, an intramolecular competition experi-ment of monodeuterated alcohol 31 afforded amixture of deuterated and undeuterated lactones(PD and PH) with a 1.6:1 ratio (Fig. 4C). This resultdemonstrates that even though C–H/D abstractionis not rate-limiting, it represents the selectivity-determining step of the C-alkylation of hexanol 31.The recovered starting material from this exper-

iment did not contain any fully protonated 1-hexanol or d2-hexanol, confirming that C–H/Dabstraction is irreversible in this process. The ir-reversibility of theC–Habstraction stepwas furtherconfirmed through two additional experiments:first, in an intermolecular competition between1-hexanol and dideuterated hexanol 32 (Fig. 4D),in which no amount of monodeuterated alcohol31 was detected during the process; and second,in the C-alkylation of enantiopure alcohol 33 (Fig.4E), in which no racemization of startingmaterialwas observed upon recovery of excess startingmaterial (40). Taken together, these results areconsistent with the mechanistic scenario (iii): adual role of TBAP in both accelerating the C–Habstraction from alcohols and enhancing the rateof addition of the resulting radical to Michaelacceptors (41).Last, compelling experimental evidence for our

proposed C–Hactivation pathwaywas attained inthe form of initial rate data for the conversion ofcyclopropyl radical clock alcohol 35 to aldehyde36 in the presence and absence of TBAP catalyst(Fig. 4F). Specifically, we reasoned that C–H ab-straction from35 to generate the2-(alkoxycarbonyl)cyclopropylcarbinyl radical [rate constant for rear-rangement=5× 1010 to 8× 1010 s–1 at 25°C (42–44)]would be rate-limiting. As such, enhancement inthe rate of C–H abstraction via H-bond–assistedC–H activation should be clearly manifested in theobserved rate of conversion of 35 to 36 in thepresence and absence of TBAP catalyst. Indeed,under our photoredox/HAT conditions, a ninefoldrate enhancement in the rate of conversion ofalcohol 35 to aldehyde 36 was observed uponaddition of 25mol%TBAP (45). This result clearlycorroborates ourmechanistic proposal, in whichTBAP facilitates C–H abstraction from alcoholsvia hydrogen bond activation. The activation con-cept presented here is likely pertinent to a widerange of C–H abstraction reactions.

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presence of methyl acrylate (1 equivalent), none of thecorresponding C–alkylation product was observed. Experi-mental details are provided in the supplementary materials onScience Online.

ACKNOWLEDGMENTS

The authors are grateful for financial support provided by the NIHGeneral Medical Sciences (R01 GM078201-05) and gifts fromMerck and Amgen. J.L.J. is grateful for a NIH PostdoctoralFellowship (F32GM109536-01), and J.A.T. thanks Bristol-MyersSquibb for a Graduate Fellowship.

SUPPLEMENTARY MATERIALS

www.sciencemag.org/content/349/6255/1532/suppl/DC1Materials and MethodsSupplementary TextReferences (46–83)DataDFT Calculations

23 June 2015; accepted 12 August 201510.1126/science.aac8555

1536 25 SEPTEMBER 2015 • VOL 349 ISSUE 6255 sciencemag.org SCIENCE

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DOI: 10.1126/science.aac8555, 1532 (2015);349 Science

et al.Jenna L. Jeffreyfor C-alkylation of alcohols

H bonds− CαH hydrogen bonding promotes H-atom transfer from −O

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