A general strategy for C(sp3)–H functionalization with nucleophiles using 1 methyl radical as a hydrogen atom abstractor 2

3 Isabelle Nathalie-Marie Leibler,‡ Makeda A. Tekle-Smith,‡ and Abigail G. Doyle 4

5 Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States 6

7

The development of general strategies for C(sp3)–H functionalization is critical to the 8

advancement of modern methods for molecular diversification. In recent years, photoredox 9

catalysis has provided many approaches to C(sp3)–H functionalization that enable selective 10

oxidation and C(sp3)–C bond formation via the intermediacy of a carbon-centered radical. 11

While highly enabling, functionalization of the carbon-centered radical is largely mediated 12

by electrophilic reagents, many of which require multi-step preparation and feature low 13

functional group tolerance. By contrast, nucleophilic reagents represent an abundant and 14

practical reagent class. However, few strategies for nucleophilic C(sp3)–H functionalization 15

from carbon-centered radicals have been identified and existing methodologies either 16

require strong stoichiometric oxidants or are not general for diverse nucleophile 17

incorporation. Here we describe a strategy that transforms C(sp3)–H bonds into 18

carbocations via sequential hydrogen atom transfer (HAT) and oxidative radical-polar 19

crossover, effecting formal hydride abstraction in the absence of a strong Lewis acid or 20

strong oxidant. The resulting carbocation can be functionalized by a variety of 21

nucleophiles—including halides, water, alcohols, thiols, an electron-rich arene, and an 22

azide—to affect diverse bond formations. Reaction development is demonstrated in the 23

context of nucleophilic fluorination of secondary and tertiary benzylic and allylic C(sp3)–H 24

bonds and is applicable to late-stage diversification of bioactive molecules. Mechanistic 25

studies indicate that HAT is mediated by methyl radical, a previously unexplored HAT agent 26

with complementary polarity to those used in photoredox catalysis. Accordingly, this 27

method can deliver unique site-selectivity for late-stage C(sp3)–H functionalization, as 28

illustrated for the fluorination of ibuprofen ethyl ester. 29

Catalytic methods for C(sp3)–H functionalization are of broad value for the construction of 30

synthetic building blocks from feedstock chemicals and for the late-stage derivatization of complex 31

molecules.1,2 While significant progress has been made in this area, interfacing the cleavage of 32

strong bonds with diverse and useful functionalization remains an outstanding challenge. Chemists 33

have identified multiple strategies for C(sp3)–H bond cleavage: oxidative addition with a transition 34

metal, concerted C(sp3)–H insertion, heterolytic cleavage via deprotonation or hydride abstraction, 35

and homolytic cleavage via hydrogen atom transfer (HAT) (Figure 1A).3–9 Among these tactics, 36

hydride abstraction has seen limited development as a result of the requirement for exceptionally 37

strong Lewis acids, which are often incompatible with desirable substrates and functionalization 38

reagents.6 Nevertheless, access to a carbocation from a C(sp3)–H bond represents a valuable 39

disconnection due to the versatility of the functionalization step, which can be general for a variety 40

of heteroatom and carbon-centered nucleophiles in their native state. 41

In contrast to hydride abstraction, HAT can offer a mild and versatile approach to C(sp3)–H 42

cleavage through the conversion of C(sp3)–H bonds to radical intermediates.8,10 While strategies 43

for the homolytic cleavage of C(sp3)–H bonds have been highly enabling, radical functionalization 44

in these methodologies is primarily restricted to electrophilic reagents (e.g., Selectfluor for 45

fluorination, peroxides for alkoxylation, azodicarboxylates for amination, and electron-deficient 46

arenes for C–C bond formation) (Figure 1B).11–15 Electrophilic reagents are often strong oxidants, 47

expensive to purchase, or require multi-step synthesis, posing significant limitations to their 48

use.16,17 Whereas nucleophilic reagents represent an abundant and practical reagent class, few 49

strategies have been reported for radical-based C(sp3)–H functionalization with nucleophiles.4,7,18–50

20 This deficit likely reflects the challenge of productively engaging a nucleophilic carbon-centered 51

radical with a nucleophilic functionalizing reagent.21 52

53 Figure 1. (A) Current mechanisms employed for C(sp3)–H activation and subsequent 54 functionalization. (B) Array of common electrophilic and nucleophilic functionalizing reagents. 55 (C) Recent examples of nucleophilic C(sp3)–H functionalization.22–28 (D) This work. HAT = 56 hydrogen atom transfer. 57

Recent contributions have centered on the use of a transition-metal catalyst to mediate radical 58

capture and bond formation, rendering the nucleophile an electrophilic ligand in the presence of a 59

stoichiometric oxidant. For example, Stahl and coworkers have demonstrated the utility of copper-60

catalysis for several nucleophilic C(sp3)–H functionalization methods, including C(sp3)–H 61

etherification, cyanation, and azidation (Figure 1C).22–24 Additionally, seminal work from Groves 62

and coworkers has provided strategies for nucleophilic C(sp3)–H halogenation and azidation using 63

a bioinspired Mn porphyrin catalyst (Figure 1C).25–28 Zhang and coworkers have also developed 64

a fluorination of C(sp3)–H bonds using a CuIII fluoride complex generated in situ from fluoride.29 65

While highly enabling, the requirement for strong or super-stoichiometric oxidants in these 66

methods limits their application in synthesis and generality across diverse nucleophile coupling 67

D. This work: Radical-polar crossover for nucleophilic C(sp3)–H functionalization

mild conditions modular strategy complementary site-selectivity

C. Prior art: Radical relay for nucleophilic C(sp3)–H functionalization

GrovesH Nu

LMn, PhIO

nucleophile

Stahl

H NuLCu, NFSI

nucleophileLCu

N N

NN

Ar

Ar

Ar

Ar

MnIII

Cl

Nu: F, Cl, N3

MeAr MeAr

Nu: ROH, CN, N3

N

O X

N

O

R RCu

LMn

B. C(sp3)–H diversification reagents

Electrophile Pool Nucleophile Pool

multi-step preparationoften strong oxidants

inexpensive, native functionalityfunctional group tolerant

H2O

Bu4N X

R2NH

NaN3

EDG

RSH

MX

[18F]KFOR

OSiR3

X2

NN

Cl

F2X N

X

O O

Me

ON

NRO2CCO2R

A. C(sp3)–H bond-breaking strategies

SSR

R

H

R R

R R

FG

R RHAT

hydride abstraction

R R+

electrophiles

Radical-Polar Crossover

R3R2

R1

Nu: F, Cl, ROH, RSH, ArH, N3

NuR1

R3

R2R1

R3

R2

HAT Nu

nucleophiles

R1 R2R3

HMe

partners.19 Thus, the identification of mechanistically distinct strategies for the application of 68

nucleophilic coupling partners could advance the scope and practicality of C(sp3)–H 69

functionalization methods in chemical synthesis. 70

Recently, we disclosed a photocatalytic strategy for the decarboxylative nucleophilic 71

fluorination of redox-active esters.30 This methodology leveraged N-acyloxyphthalimides as alkyl 72

radical precursors and an oxidative radical-polar crossover (ORPC) mechanism for the generation 73

of a carbocation poised for nucleophilic addition.31 Seeking to develop a modular nucleophilic 74

C(sp3)–H functionalization without the requirement for strong oxidants, we questioned whether 75

photocatalytic ORPC could be combined with principles of HAT to achieve formal hydride 76

abstraction from C(sp3)–H bonds. Given the versatility of carbocation intermediates, such a 77

reaction platform could provide a general route to numerous desirable transformations such as 78

C(sp3)–H halogenation, hydroxylation, and C–C bond formation by combining two abundant and 79

structurally diverse feedstocks. While access to carbocation intermediates may be accomplished 80

electrochemically, contemporary methodologies are largely limited by the high overpotential 81

required for reactivity, thereby restricting the scope of amenable C(sp3)–H and nucleophile 82

coupling partners.32,33 Whereas C(sp3)–H functionalization via HAT-ORPC has been proposed in 83

a recent study from Liu and Chen, the method uses a strong, stoichiometric oxidant and solvent 84

quantities of nucleophile.7 Here we report a HAT-ORPC platform for C(sp3)–H functionalization 85

using a mild, commercially available N-acyloxyphthalimide as HAT precursor. The platform 86

enables C(sp3)–H fluorination of secondary and tertiary benzylic and allylic substrates using 87

Et3N•3HF. Additionally, we demonstrate the versatility of the reaction platform to achieve C(sp3)–88

H chlorination, hydroxylation, etherification, thioetherification, azidation, and carbon–carbon 89

bond formation. 90

Our initial investigations focused on C(sp3)–H fluorination, a valuable transformation in 91

organic synthesis due to the unique chemical properties conferred by fluorine substitution.34,35 Few 92

reports detailing C(sp3)–H fluorination with fluoride have been disclosed, due not only to the broad 93

challenges posed by C(sp3)–H activation, but also the attenuated nucleophilicity of 94

fluoride.18,25,29,36–38 Despite these challenges, the development of nucleophilic C(sp3)–H 95

fluorination methods is desirable given the low cost of fluoride sources and their application to 96

radiofluorination for positron emission tomography (PET) imaging.35 97

To evaluate the feasibility of the HAT-ORPC strategy for C(sp3)–H fluorination, we 98

investigated the conversion of diphenylmethane to fluorodiphenylmethane 2 using a variety of 99

phthalimide-derived HAT precursors (Table 1). We focused on N-acyloxyphthalimides and N-100

alkoxyphthalimides, as these redox-active species deliver a radical HAT agent via reductive 101

fragmentation, leaving an oxidized photocatalyst available to execute ORPC; furthermore, these 102

reagents are easy to prepare and tune, and are less oxidizing than the stoichiometric oxidants used 103

in radical relay strategies.39 Optimization of the HAT precursor focused on three design elements: 104

1) redox compatibility, 2) bond dissociation energy (BDE) of the radical generated upon 105

fragmentation (favorable thermodynamics), and 3) nucleophilicity of the HAT byproduct 106

(competitive carbocation functionalization). We were pleased to find that using Ir(p-F-ppy)3 as a 107

photocatalyst, Et3N•3HF as a fluoride source, and HAT abstractor 3 (MeO–H BDE = 105 108

kcal/mol) in pivalonitrile afforded alkyl fluoride 2 in 45% yield (Table 1, entry 1).40,41 In addition 109

to desired fluoride 2, we observed generation of the corresponding benzhydryl methyl ether in 7% 110

yield, resulting from competitive trapping of 111

the carbocation with methanol. Moreover, 112

analysis of the reaction mixture indicated 113

poor conversion of 3, possibly arising from 114

inefficient single-electron reduction and 115

fragmentation of the N-alkoxyphthalimide 116

(E1/2red ∼ −1.42 V vs. SCE).42 117

These observations prompted us to 118

evaluate N-acyloxyphthalimide 4 (E1/2red ∼ 119

−1.2-1.3 V vs. SCE), a benzoyloxy radical 120

precursor.42 Upon HAT, this radical generates 121

benzoic acid, a less nucleophilic byproduct 122

than methanol. However, 4 did not improve 123

the reaction yield (Table 1, entry 2), likely 124

due to competitive generation of the 125

insufficiently reactive phthalimide radical 126

upon SET and fragmentation (phthalimide 127

N–H BDE = 89.1 kcal/mol vs. benzoic acid 128

O–H BDE = 111 kcal/mol).43 Instead, we 129

found that N-acyloxyphthalimide 1 —a methyl radical precursor— was the most effective HAT 130

reagent, delivering the desired fluoride 2 in 88% yield (Table 1, entry 3). Abstractor 1 is likely 131

effective because there is a strong thermodynamic and entropic driving force associated with 132

formation of methane (BDE = 105 kcal/mol), an inert, non-nucleophilic byproduct.40 Notably, 1 is 133

Table 1. Reactions performed on 0.15 mmol scale with 1-fluoronaphthalene added as an external standard (19F NMR yield). t-BuCN = pivalonitrile. All potentials given are versus a saturated calomel electrode (SCE) and taken from ref. 46. aParentheses indicate yield of the benzhydryl methyl ether product (1H NMR yield). bEach control reaction was completed independently in the absence of key reaction components.

N

O

O

O

O

4-F-C6H4

4

Deviation % Yield 2

none

CH2Cl2 instead of t-BuCN

1 equiv. diphenylmethane

abstractor 4

abstractor 3

20

abstractor 5 3

Entry

3

5

6

8

2

1a

4

2

45 (7)

88

Ir(p-F-ppy)3 (1 mol%)Et3N•3HF (6 equiv.)

t-BuCN (0.6 M)

34W blue LEDs, 6 h

Ph Ph Ph Ph

F

ON

O

OH

[Ir(dF-CF3-ppy)2(dtbpy)]PF6 instead of Ir(p-F-ppy)3

Ir(ppy)3 instead of Ir(p-F-ppy)3

without abstractor, without photocatalyst, without light

3 equiv. diphenylmethane9

10

11b

7 MeCN instead of t-BuCN

N

O

O

O

ON

O

O

MeOCl

Cl

ClCl

5

Me

3

Ir(p-F-ppy)3

21

43

25

44

53

17

0

N

FN

F

N

F

Ir

Ir(ppy)3

N

N NIr

[Ir(dF-CF3-ppy)2(dtbpy)]PF6

N

F

N

N

N

F3C

Ir

t-Bu

t-Bu

F3CF

F

F

PF6

6 equiv.Me

O

1

IrIV/*IrIII = -1.9 VIrIV/IrIII = 0.96 V

IrIV/*IrIII = -1.73 VIrIV/IrIII = 0.78 V

IrIV/*IrIII = -0.89 VIrIV/IrIII = 1.7 V

commercially available and can also be prepared on multi-decagram scale in one step from low-134

cost, readily available materials.44 Tetrachlorophthalimide analogue 5 was also investigated, but 135

the poor solubility of 5 led to trace conversion (Table 1, entry 4).45 With 1, Ir(p-F-ppy)3 was the 136

optimal photocatalyst for this transformation, presumably because Ir(p-F-ppy)3 allows for both the 137

reductive generation of methyl radical (*IrIII/IrIV E1/2 = -1.9 V vs. SCE for Ir(p-F-ppy)3 and E1/2red 138

= -1.24 V vs. SCE for 1) and the oxidation of diphenylmethyl radical (IrIV/IrIII E1/2 = 0.96 V vs. 139

SCE and E1/2ox = 0.35 V vs. SCE for 2° benzylic).42,46,47 Use of either less reducing or less oxidizing 140

photocatalysts resulted in diminished yields (Table 1, entries 5-6). While highest yields were 141

observed with 6 equivalents of the C(sp3)–H partner, 3 equivalents and 1 equivalent of the substrate 142

could also be used, albeit with diminished reactivity (53% and 17% yield respectively) (Table 1, 143

entry 9 and 10). Finally, control reactions indicate that HAT reagent 1, photocatalyst, and light 144

are all necessary for reactivity (Table 1, entry 11). 145

With optimized conditions established, we set out to examine the scope of C(sp3)–H 146

fluorination (Figure 2). Notably, benzhydryl C(sp3)–H partners supplied fluorinated products in 147

good to excellent yield (2, 6-10). ortho-Substitution was also tolerated (9). For substrates 148

possessing both primary and secondary benzylic C(sp3)–H bonds (8-10), excellent regioselectivity 149

was observed for secondary benzylic fluorination (e.g., 10:1 2°:1° for 8, >20:1 2°:1° for 9 and 10). 150

Next, a series of electronically diverse ethylbenzene derivatives were examined. A broad range of 151

functional group handles, including halogen (16-18), ether (11 and 12), carbonyl (19 and 20), 152

nitrile (22), and trifluoromethyl (21) substituents, afforded the corresponding fluorinated products. 153

Electron-rich functionality, traditionally vulnerable to electrophilic reagents or stoichiometric 154

oxidants, was well tolerated (11 and 12).48,49 In general, electron-rich ethylbenzenes displayed 155

higher reactivity (11-13 and 15) than more electron-deficient analogues (19-22). This trend is 156

consistent with electron donating substituents conferring higher carbocation stability than electron 157

withdrawing analogues. For substrates possessing multiple secondary benzylic C(sp3)–H bonds, 158

selective monofluorination was observed (23-25). The geometric constraints inherent to the 159

frameworks of acenaphthene and 9H-fluorene resulted in diminished yields, suggesting that 160

carbocation planarity and stabilizing hyperconjugation effects are advantageous structural 161

characteristics (25 and 26).50 162

163 Figure 2. Scope of C(sp3)–H fluorination (0.25 mmol scale, 6.0 equiv. C(sp3)–H coupling partner, 164 6.0 equiv. Et3N•3HF, 19F NMR yields). a 3.0 equiv. C(sp3)–H coupling partner. b Reaction 165 performed with 20 mol % n-Bu4NPF6. c Reaction performed using Ir(p-CF3-ppy)3 as photocatalyst, 166 1,2-difluorobenzene as solvent, and abstractor 3. 167

Tertiary benzylic C(sp3)–H partners underwent functionalization to generate fluorinated 168

products often inaccessible via nucleophilic fluorination due to slow substitution and competitive 169

elimination (28, 29, and 35).51 Fluorination of benzal chloride yielded a tetra-substituted center 170

with mixed multi-halogenation (27). Moreover, fluorination of triphenylmethane proceeded in 171

Ir(p-F-ppy)3 (1 mol%) 1 (1 equiv.)

t-BuCN (0.6 M)

34W blue LEDs, 6 h

R

H

RR

F

R

benzylic fluorination

26 29% yielda

FF

23 68% yield 24 41% yield

FF

25 29% yielda

allylic fluorination

31 63% yield

N

F

PhPh Me

S

F

32 47% yield

Br

Me

S

33 20% yield

F

Me

F

R11-22

111213

52% yield36% yield44% yieldMe

OPhOMe

65% yield1516 38% yieldF

Cl

Ph

17 35% yield14 38% yieldH Br18 31% yield

21% yield1920 14% yieldCOMe

CF3

CO2Me

21 11% yieldCN22 11% yield

28 58% yield

Me

F

Me

30 95% yielda

Ph

F

PhF

MeMei-Pr

i-Pr

F

39 55% yield

F

42 15% yielda,b

HO

OMe

Me F

40 14% yield

celestolide

t-Bu

OMe

Me Me

F

36 68% yieldbisacodyl

MeCO2 O2CMe

N

F

37 49% yielda

F

43 15% yieldc, 14:1 rr

34 71% yield

29 55% yield

Me

FO

MeMe

Me

HO

O

N

SF

35 43% yielda

febuxostat derivative

aliphatic fluorination

rotenone

OO

MeO

H

H

O

OMe

OMe

ibuprofen ethyl ester38 34% yield, 2.4:1 rr

Me

Me

Me

O

OEtF

41 33% yielda, 4.5:1 dr

F

Et3N•3HF

9 ortho 43% yield10 para 61% yield

F

MeF

R R

80% yield26 77% yieldF

Cl

H

7 50% yield

Me8 58% yield1,6-8

27 27% yield

Cl

F

Cl

95% yield from only 3 equiv. of the C(sp3)–H coupling partner (30). Notably, 4-pyridyl 172

diphenylmethane underwent fluorination in 63% yield, demonstrating tolerance to a valuable N-173

heterocycle scaffold (31).52 Other heterocycles such as thiophenes, furans, and thiazoles were also 174

tolerated under the reaction conditions (32-35). Since many bioactive compounds contain 175

heterocyclic fragments, this observation prompted us to evaluate the method for the late-stage 176

derivatization of various pharmaceuticals and complex molecules. Gratifyingly, commercially 177

available bioactive molecules such as a febuxostat derivative, celestolide, bisacodyl, and ibuprofen 178

ethyl ester gave the corresponding fluorinated products in 43%, 68%, 49%, and 34% yield, 179

respectively (35-38). 180

Nucleophilic fluorination could also be extended to allylic C(sp3)–H coupling partners. Allylic 181

fluorides are valuable motifs in medicinal chemistry and are useful building blocks in synthesis.53 182

The development of allylic C(sp3)–H fluorination methods has proven challenging, as most 183

electrophilic reagents and stoichiometric oxidants utilized in fluorination methodologies favor 184

olefin oxidation over C(sp3)–H functionalization; alternatively most sources of fluoride facilitate 185

competitive elimination.29,37,54,55 As an illustration of the mildness of a HAT-ORPC strategy, the 186

fluorination of cyclohexene proceeded in 55% yield (39), a significant improvement to our prior 187

efforts in the allylic C(sp3)–H fluorination of this substrate using a Pd/Cr cocatalyst system.37 188

Furthermore, the fluorination of 4-methyl-2-pentenoic acid and the pesticide rotenone occurred in 189

14% and 33% yield, respectively (40 and 41). Finally, as a proof of concept, the unactivated 190

C(sp3)–H scaffolds of cyclooctane and adamantane underwent fluorination to deliver 42 and 43 in 191

low yield. 192

Difluoromethylene units have emerged as 193

important lipophilic bioisosteres of hydroxyl 194

and thiol functional groups in drug design.56 195

Deoxyfluorination with (diethylamino)sulfur 196

trifluoride (DAST) and pre-oxidized ketones is 197

typically used to install this group.57 198

However, given the handling difficulties 199

associated with DAST and its tendency to promote elimination, novel strategies for 200

difluoromethylation are in high demand. We envisioned that benzylic fluorides generated in situ 201

from their monochlorinated precursors could deliver difluorinated products under optimized 202

C(sp3)–H fluorination conditions. To our delight, difluorinated products 44 and 45 were obtained 203

in 63% and 29% yield from the corresponding benzyl chloride (Figure 3). To our knowledge, this 204

represents the first nucleophilic C(sp3)–H fluorination to achieve difluorinated motifs. Notably, 205

difunctionalization is not observed to an appreciable extent in the fluorination of ArCH2R 206

precursors, even though HAT with the mono-fluorinated product is favorable on account of weaker 207

BDFEs and polarity matching (methyl radical is mildly nucleophilic).58 We hypothesize that 208

monofluorination selectivity results from the relative stoichiometry of starting material and 209

abstractor, which likely serves to mitigate unproductive side-reactivity involving methyl radical.59 210

Next, we evaluated whether this strategy could serve as a platform for C(sp3)–H 211

functionalization with other nucleophiles (Figure 4). Indeed, we were pleased to find that only 212

minor adjustments to the standard fluorination conditions were needed to accommodate 213

nucleophiles other than Et3N•3HF. Irradiation of 4,4′-difluorodiphenylmethane with 1 mol % Ir(p-214

F-ppy)3, 15 mol % Et3N•3HF, HAT precursor 1, and 6 equiv. of water in pivalonitrile afforded 215

Figure 3. Scope of C(sp3)–H difluorination (0.25 mmol scale, 19F NMR yield). See SI for reaction details.

Ir(p-F-ppy)31, Et3N•3HF

t-BuCN

34W blue LEDs, 6 h

H

R

Cl F

R

FH

R

FEt3N•3HF

44 63% yield

F F

45 29% yield

F

Me

F

t-Bu

benzhydryl alcohol 46 in 36% yield (vide infra). Hydroxylation took place with no evidence of 216

overoxidation to the ketone in the synthesis of both 46 and 47, a common limitation of many 217

C(sp3)–H oxidation methods.60 These conditions were also amenable to the hydroxylation of a 218

tertiary C(sp3)–H substrate (57). Furthermore, nucleophiles such as methanol and methanol-d4 219

afforded methyl ether products 48 and 49 in 40% and 42% yield, respectively. More complex 220

oxygen-centered nucleophiles, including a 1,3-diol and dec-9-en-1-ol, were also compatible (52 221

and 53). Furthermore, we were pleased to accomplish the installation of a C(sp3)–Cl bond using 222

HCl•Et2O as a nucleophile61 (50), and to discover that C(sp3)–N bond formation could be achieved 223

through cross coupling with azidotrimethylsilane (51). The construction of medicinally valuable 224

thioethers was also possible, using cyclohexanethiol (54) and methylthioglycolate (55) as sulfur-225

based nucleophiles. In particular, the implementation of sulfur nucleophiles highlights the 226

mildness of reaction conditions, as thiol oxidation could otherwise interfere with C(sp3)–S bond 227

formation under alternative C(sp3)–H functionalization approaches. Finally, carbon–carbon bond 228

formation via a mild, direct Friedel-Crafts alkylation was accomplished in 41% yield from the 229

coupling of 1,3,5-trimethoxybenzene and 4,4′-difluorodiphenylmethane (56). Friedel-Crafts 230

reactions typically require pre-oxidized substrates—such as alkyl halides—and Lewis or Brønsted 231

acid conditions that are often incompatible with the desired nucleophiles.62,63 232

233 Figure 4. Scope of general nucleophilic C(sp3)–H functionalization (0.25 mmol, 6.0 equiv. C(sp3)–234 H coupling partner, 6.0 equiv. nucleophile, isolated yields). a 3.0 equiv. nucleophile. b 19F NMR 235 yield. c 6 hour reaction. d Reaction was performed without Et3N•3HF. e Reaction was performed 236 without Et3N•3HF and with 0.15 equiv. H2O. 237

Having evaluated the scope of this transformation, we set out to interrogate its mechanism 238

(Figure 5). According to our prior studies30 and literature precedent64, we propose that visible light 239

irradiation of the photocatalyst Ir(p-F-ppy)3 generates a long-lived excited state that serves as a 240

single-electron reductant of 1. Fragmentation of the resulting radical anion followed by extrusion 241

of CO2 forms phthalimide anion and methyl radical. Since methyl radical is thermodynamically 242

disfavored to undergo oxidation by IrIV, it is instead available to facilitate HAT with the C(sp3)−H 243

coupling partner to deliver a carbon-centered radical and methane as a byproduct (E1/2ox ~2.5 V 244

vs. SCE for methyl radical). Oxidative radical-polar crossover between IrIV and the substrate 245

radical generates a carbocation and turns over the photocatalyst. Subsequent nucleophilic trapping 246

of the carbocation intermediate furnishes the desired product (Figure 5A). 247

Ir(p-F-ppy)3 (1 mol%) Et3N•3HF (0.15 equiv.)

1 (1 equiv.)

t-BuCN (0.6 M)34W blue LEDs, 24 h

H Nu

46 36% yieldb

56 41% yielda

48 40% yieldb,c

OH

49 42% yieldb,c 50 25% yieldd

57 41% yield

Me

OH

Me

54 31% yieldc 53 33% yielda 55 30% yieldc 52 42% yielda

47 40% yieldb 51 17% yieldb,e

18OH OMe OCD3 Cl N3

O Ph

HO

O 7 S S OMeO

OMe

MeOOMe

F F F F

tertiary hydroxylation

nucleophile

248 Figure 5. (A) Proposed catalytic cycle. (B) Radical trapping experiments. (C) Investigation of 249 regioselectivity via competition experiments among 3°, 2° and 1° C(sp3)–H coupling partners. (D) 250 Investigation of kinetic isotope effect via parallel initial rates experiment with ethylbenzene and 251 ethylbenzene-d10. (E) Hammett analysis and correlation of selectivity with computed BDFE for a 252 series of ethylbenzene derivatives (See SI). a For reaction conditions see Figure 2 (19F NMR 253 yields). b Reaction performed with 1.5 equiv. TEMPO (1H NMR yield). 254

Consistent with the proposed first step of this mechanism, emission quenching experiments 255

demonstrated that 1 is the only reaction component that quenches the excited state of the 256

photocatalyst (See SI). Our analysis also indicates that the rate of quenching is moderately 257

enhanced in the presence of Et3N•3HF. This observation is consistent with the higher yields 258

observed when Et3N•3HF is employed as a catalytic additive for the construction of C(sp3)–O, 259

C(sp3)–S, and C(sp3)–C bonds. The presence of an acidic additive could aid reduction of 1 via 260

proton-coupled electron transfer, as reported for related systems in the literature.65 In addition, the 261

additive could prevent back-electron transfer and aid fragmentation of the reduced N-262

acyloxyphthalimide 1. 263

A. Catalytic Cycle

B. Radical Trapping

Ph

Phreaction conditionsa

ONPhth

O

Me MePh

F Ph

59 98% yield

Ph

H TEMPOb

reactionconditionsa

58 32% yield

PhNO

Me

MeMe

MeMe

Ph

F

Ph

2 4% yield

ONPhth

O

Me

C. Selectivity Competition Experiments

E. Linear Free-Energy Relationships

D. Intermolecular KIE Experiment

photocatalytic cycle

*IrIII

reductant

IrIV

oxidant

IrIII

RR'

R''

RR'

R'' Nu

ON

O

O

O

Me

SET

N

O

O

CO2

HAT

HR'R''

R

Me MeH

RR'R''

Nu

SET

hυvisible light nucleophile

trapping

H

MePh MePh

F

MePh MePhMe

F

5 equiv. 5 equiv.

65% 35%

MeH

:

H

Ph Ph

F

Ph Ph

F

5 equiv. 5 equiv.

95% 5%

H

:

reaction conditionsa

reaction conditionsa

Me Me

1

1

1

1428

6014

-0.5 0.0 0.5 1.0-0.6

-0.4

-0.2

0.0

0.2

0.4

σp

log

Rat

io R

/H

OPh

MeOMe

H

FCl

CN

CF3y = -0.64x + 0.03R2 = 0.92

77.0 77.5 78.0 78.5 79.0-0.6

-0.4

-0.2

0.0

0.2

0.4

BDFE (kcal/mol)

log

Rat

io R

/H

CN

CF3

Cl

OMe Me

HF

OPh

y = 0.21x – 16.45R2 = 0.19

reaction conditionsa

kH/kD = 12.1

D5C6 CD3

D D

6 equiv.

D5C6 CD3

F D

Ph Me

H

6 equiv.

Ph Me

Freaction conditionsa

14

61

Next, radical trapping experiments were conducted to evaluate the identity of key radical 264

intermediates in the proposed mechanism. When the fluorination of diphenylmethane was 265

conducted under standard conditions in the presence of 1.5 equiv. of TEMPO, we observed the 266

methyl radical–TEMPO adduct (58) in 32% yield, accompanied by nearly complete suppression 267

of fluorination (Figure 5B). Additionally, when 1,1-diphenylethylene was employed as a substrate 268

under standard conditions, nearly quantitative carbofluorination was observed, wherein methyl 269

radical addition into the olefin followed by radical oxidation and nucleophilic fluorination 270

delivered product 59. (Figure 5B). This example of carbofluorination not only provides clear 271

evidence for methyl radical formation, but also serves as a useful framework for sequential C(sp3)–272

C(sp3) and C(sp3)–F alkene difunctionalization. As further evidence, in situ NMR studies revealed 273

evolution of methane gas as the reaction proceeded, supporting the involvement of methyl radical 274

in HAT (Figure S25). 275

To our knowledge, methyl radical guided HAT has not been previously explored for 276

photocatalytic C(sp3)–H functionalization. As such, we set out to understand the reactivity and 277

selectivity effects inherent to the system. We conducted a series of competition experiments with 278

cumene, ethylbenzene, and toluene under standard C(sp3)–H fluorination conditions (Figure 5C). 279

We found that HAT mediated by methyl radical and subsequent ORPC is preferential for 3°>2°>1° 280

benzylic C(sp3)–H bonds. The data suggest that steric or polarity effects associated with HAT from 281

a mildly nucleophilic methyl radical are minimal in these systems. Instead, the observed site-282

selectivity is consistent with the relative BDFEs and radical oxidation potential of the tertiary, 283

secondary, and primary substrates. 284

To probe the independent roles of HAT and radical oxidation, we first conducted a kinetic 285

isotope effect (KIE) study with ethylbenzene. A KIE of 12.1 was measured via parallel initial rate 286

experiments using ethylbenzene and ethylbenzene-d10 (Figure 5D). The magnitude of the KIE is 287

consistent with prior studies of HAT involving methyl radical and suggests that HAT is the 288

turnover-limiting step.66,67 To probe the effect of electronics on a HAT-ORPC mechanism, a 289

Hammett analysis of the relative rate of benzylic fluorination across a series of para-substituted 290

ethylbenzenes (determined by competition experiments, see SI) was performed (Figure 5E). 291

Given the mild nucleophilicity of methyl radical, we might expect electron-deficient ethylbenzenes 292

to undergo fluorination at a faster rate than electron-rich ethylbenzenes. However, the measured r 293

value of -0.64 ± 0.07 (R2 = 0.92) indicates that electron-rich ethylbenzenes undergo C(sp3)–H 294

fluorination more favorably than electron-deficient derivatives. We interpret this result to suggest 295

that radical oxidation—wherein electronic effects should contribute significantly to carbocation 296

stabilization—is irreversible and governs product distribution. Additionally, analysis of selectivity 297

outcomes with respect to computed C(sp3)–H BDFEs across the ethylbenzene series indicates no 298

significant correlation between product selectivity and BDFE (Figure 5E).68 These findings are 299

most consistent with turnover-limiting HAT followed by an irreversible, product-determining 300

radical oxidation. Further studies are ongoing to probe additional mechanistic details. 301

Altogether, this work suggests that a HAT-ORPC strategy can provide a site-selective platform 302

for C(sp3)–H functionalization. An advantage to this method is the utilization of phthalimide-303

derived species as redox-active HAT reagents; these reagents are not only readily available, but 304

also are highly tunable. In this context, we questioned whether site-selectivity in the fluorination 305

of ibuprofen ethyl ester—a complex substrate possessing various C(sp3)–H bonds—could be tuned 306

on the basis of the radical species used in HAT (Figure 6A). Under standard conditions with the 307

methyl radical precursor 1, the fluorination of ibuprofen ethyl ester favored C(sp3)–H 308

functionalization at the tertiary benzylic site over the secondary benzylic site (38, 2.4:1 rr) (Figure 309

6A). This site-selectivity is orthogonal to previously reported HAT-guided strategies (Figure 310

6B)7,22,38 but consistent with our mechanistic studies that indicate a preference for tertiary C(sp3)–311

H functionalization according to BDFE and radical oxidation potential considerations (Figure 312

5C). Furthermore, methyl radical is polarity matched to abstract a hydrogen atom proximal to an 313

electron withdrawing group. By contrast, the prior art relies on electrophilic HAT mediators that 314

are polarity mismatched to abstract a hydrogen atom proximal to an electron withdrawing group. 315

As such, we hypothesized that employment of 3, a precursor to the electrophilic methoxy radical, 316

would afford distinct site-selectivity, favoring more electron-rich C(sp3)–H sites. Indeed, we 317

observed a reversal of site-selectivity in this case, wherein ibuprofen ethyl ester was fluorinated in 318

31% yield with a 5.3:1.5:1 rr favoring the secondary benzylic site (62). This example demonstrates 319

the potential for this platform to engage readily available small molecule HAT reagents for tunable 320

and predictable site-selective C(sp3)–H functionalization. 321

322 Figure 6. (A) Tunable selectivity for the C(sp3)–H functionalization of ibuprofen demonstrating 323 favorable secondary benzylic fluorination with methoxy radical (left) and favorable tertiary 324 benzylic fluorination with methyl radical (right). (B) Previous examples of site-selectivity in the 325 C(sp3)–H functionalization of ibuprofen. a Reaction performed using abstractor 3 and standard 326 reaction conditions described in Figure 2. b Reaction performed using abstractor 1 and standard 327 reaction conditions described in Figure 2. 328

In conclusion, we have developed a photocatalytic method that employs widely available, low-329

cost nucleophiles and a readily accessible HAT precursor for C(sp3)–H fluorination, chlorination, 330

etherification, thioetherification, azidation, and carbon–carbon bond formation. Mechanistic 331

B. Prior ibuprofen site selectivityA. Tunable regioselectivity guided by HAT reagent identity

Me

Me

Me

O

O MeH

H

38 34% yieldb

Me

Me

Me

O

OEtF

47 31% yielda

Me

Me

Me

O

OEt

F

MeMeOibuprofen ethyl ester

N N

NN

Ar

Ar

Ar

Ar

MnIII

Cl

N

O

N

O

R RCu

Groves StahlChen

Me

Me

Me

O

OMe

FMe

Me

Me

O

OMe

NHAcMe

Me

Me

O

OMe

OMe

O I OH

O

precedent affords C(sp3)–H functionalization exclusively at secondary benzylic siteregioselectivity: 5.3 : 1.5 : 1 regioselectivity: 2.4:1

studies are consistent with methyl radical-mediated HAT and linear free-energy relationships 332

suggest that radical oxidation influences site-selectivity. Furthermore, this approach was highly 333

effective for the construction of multi-halogenated scaffolds and the late-stage functionalization 334

of several bioactive molecules and pharmaceuticals with tunable regioselectivity. 335

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63. We considered the possibility that nucleophilic addition in this context could proceed via 486 nucleophilic substitution from the in situ generated benzylic fluoride, as per: Vasilopoulos, A., 487 Golden, D. L., Buss, J. A. & Stahl, S. S. Copper-Catalyzed C–H Fluorination/Functionalization 488 Sequence Enabling Benzylic C–H Cross Coupling with Diverse Nucleophiles. Org. Lett. 22, 5753–489 5757 (2020). However, further experiments exploring this possibility indicated that triethylamine 490 HF does not contribute to a sequential functionalization-substitution mechanism in the context of 491 these nucleophiles. See SI for an extended discussion. 492

64. Huihui, K. M. M., Caputo, J. A., Melchor, Z., Olivares, A. M., Spiewak, A. M., Johnson, K. 493 A., DiBenedetto, T. A., Kim, S., Ackerman, L. K. G. & Weix, D. J. Decarboxylative Cross-494 Electrophile Coupling of N-Hydroxyphthalimide Esters with Aryl Iodides. J. Am. Chem. Soc. 138, 495 5016–5019 (2016). 496

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66. Salomon, M. Isotope Effects in Methyl Radical Abstraction Reactions. Can. J. Chem. 42, 610–501 613 (1964). Large KIEs observed in this study are in accordance with KIEs observed in previous 502 experimental and theoretical studies for methyl radical HAT. 503

67. Baik, M.-H., Newcomb, M., Friesner, R. A. & Lippard, S. J. Mechanistic Studies on the 504 Hydroxylation of Methane by Methane Monooxygenase. Chem. Rev. 103, 2385–2420 (2003). 505

68. BDFEs were computed according to: John, P. C. St., Guan, Y., Kim, Y., Kim, S. & Paton, R. 506 S. Prediction of organic homolytic bond dissociation enthalpies at near chemical accuracy with 507 sub-second computational cost. Nat. Commun. 11, 2328 (2020). In our experience, different levels 508 of theory give slightly different ordering of the compounds by BDFE. This is due to energetic 509 differences that are small relative to the error associated with DFT. However, all levels of theory 510 evaluated gave similarly poor correlations and do not affect the conclusions drawn. 511

512

513

Data Availability 514

Materials and methods, experimental procedures, mechanistic studies, characterization data, 515 spectral data, and xyz files (in accompanying zip drive) associated with computational data are 516 available in the Supplementary Information. 517

Acknowledgements. Financial support was generously provided by NSF (CHE-1565983). M. A. 518 T.-S. wishes to thank Princeton’s Presidential Postdoctoral Fellowship for funding. István Pelzer, 519 Kenneth Conover, and John Eng are acknowledged for analytical aid. We thank Dr. Eric W. 520 Webb for early intellectual and experimental contributions to the project. 521 522 Author Contributions. Authors I. N.-M. L. and M. A. T.-S. contributed equally. 523 524 Competing Interests. The authors declare no competing interests. 525 526 Additional information 527 Supplementary information is available in the online version of the paper. 528 Correspondence and requests for materials should be addressed to A. G. D. 529

530 531