ARTICLE

https://doi.org/10.1038/s41467-021-21270-9 OPEN

Pd-catalyzed formal Mizoroki–Heck coupling

of unactivated alkyl chlorides
Geun Seok Lee 1, Daeun Kim 1 & Soon Hyeok Hong 1✉

The use of alkyl chlorides in Pd-catalyzed Mizoroki–Heck coupling reactions remains an

unsolved problem despite their significant potential for synthetic utility and applicability. The
1234567890():,;

combination of the high thermodynamic barrier of alkyl chloride activation and kinetic pro-
pensity of alkylpalladium complexes to undergo undesired β-hydride elimination provides
significant challenges. Herein, a variety of alkyl chlorides, even tertiary chlorides, are shown
to efficiently participate in Mizoroki–Heck cross-coupling reactions with excellent functional
group compatibility under mild reaction conditions via photoinduced Pd catalysis. The
reaction is applied to late-stage functionalizations of diverse biologically significant scaffolds
and iterative double Mizoroki–Heck annulations, affording high molecular complexity in a
single step. Notably, studies on the kinetic isotope effects in combination with density
functional theory (DFT)-computations completely exclude the involvement of a previously
proposed β-hydride elimination in the catalytic cycle, revealing that the chlorine atom transfer
process is the key catalytic turnover step. This distinctive single-electron transfer mediated
reaction pathway resolves a longstanding challenge in traditional two-electron based Pd-
catalyzed Mizoroki–Heck cross-coupling with alkyl electrophiles, wherein the β-hydride
elimination is involved in the formation of both the desired product and undesired by-
products.

1 Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. ✉email: soonhyeok.hong@kaist.ac.kr

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T
he Mizoroki–Heck reaction, discovered in the early 1970s, single-electron catalysis, which can prevent undesired β-
represents the first methodology to forge C–C bonds via Pd hydride eliminations through the formation of a Pd(I)/alkyl
catalysis, enabling highly efficient synthesis of multi- radical hybrid11–14. Thermal Pd-catalyzed alkyl Mizoroki–Heck
substituted olefin products1,2. Owing to its high versatility, the reactions of primary and secondary alkyl bromides and iodides
Mizoroki–Heck reaction has been extensively applied in the field were developed by Fu15, Alexanian16–18, and Zhou19 groups.
of organic chemistry from academic research to industrial pro- More recently, photoirradiated Pd catalysis, which harnesses
cesses3–7. Similar to other Pd-catalyzed cross-coupling reactions, visible light energy to generate Pd(I)/alkyl radical hybrid spe-
aryl halides or pseudohalides are mainly utilized as electrophiles cies via the single-electron oxidative addition of Pd(0) to
in the Mizoroki–Heck reactions, owing to their superior reactivity alkyl halides20, has been highlighted as a versatile activation
and robustness in comparison with those of alkyl analogs. The strategy that enables various salient transformations under mild
utilization of alkyl electrophiles for the Mizoroki–Heck reaction is reaction conditions (Fig. 1b)21,22. Such transformations include
significantly more challenging compared with the aryl congeners desaturation23, reduction24, addition to (hetero)arenes25, car-
(Fig. 1a). The rates of Pd oxidative addition to alkyl electrophiles bonylation26, and 1,4-difunctionalization of conjugated
are sluggish and the resulting alkylpalladium species are prone to dienes27–29. By applying this strategy, the Gevorgyan group
undesired β-hydride eliminations8. Unlike other cross-coupling reported the first visible light-induced Pd-catalyzed
reactions, because the β-hydride elimination is the key catalyst Mizoroki–Heck reaction of alkyl bromides and iodides30.
turnover step in the Mizoroki–Heck reactions, simple suppression Subsequently, the Fu group reported the first Pd-catalyzed
of the undesired β-hydride elimination via catalyst or ligand Mizoroki–Heck coupling of tertiary alkyl bromides, which are
design can reduce catalytic efficiency. Therefore, the control of highly susceptible to β-hydride elimination9, expanding the
the productive yet detrimental β-hydride elimination pathways is reactivity to silyl enol ethers and enamides31. Similar reactions
a significant hurdle that must be overcome9,10. have also been reported by using other alkyl electrophiles,
Over the decades, significant progress has been made in the including N-hydroxyphthalimide esters or tertiary alkyl iodides,
field of Pd-catalyzed alkyl Mizoroki–Heck reactions, notably in by Fu32, and Glorius33, and Gevorgyan34 groups.

a
Challenges in Pd-catalyzed Mizoroki-Heck reaction of unactivated alkyl chlorides
kinetically favored
E-hydride elimination [Pd]

[Pd0]

Cl hv or heat [PdII]
R
thermodynamically demanding
Mizoroki-Heck R
oxidative addition
coupling elusive

b
Photoirradiated Pd-catalyzed alkyl-Mizoroki-Heck reaction

[Pd0] R

X hv [PdII] hv [PdI] R

X = Br, I, ONHP Pd(I)/alkyl radical hybrid

Prevention of E-hydride elimination Limited to alkyl bromides and iodides

c
This work: Pd-catalyzed Mizoroki-Heck reaction of unactivated alkyl chlorides

[PdI]

hv
R
Pd Cl
hv
Cl R
R
R
[PdII]
oxidative > 50 examples
catalytic turnover
R

prevent E–H elimination

Simple catalyst/ligand framework Application to bioactive scaffolds

Complete exclusion of E-hydride elimination through radical-polar crossover

Fig. 1 Alkyl Mizoroki–Heck reactions. a Challenges in Pd-catalyzed Mizoroki–Heck reaction of unactivated alkyl chlorides. b Photoirradiated Pd-catalyzed
alkyl Mizoroki–Heck reactions. c Pd-catalyzed Mizoroki–Heck reaction of unactivated alkyl chlorides.

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In particular, alkyl chlorides are the preferred substrates of complex structures. From judiciously designed kinetic experi-
choice over bromides and iodides for a number of reasons35,36. ments and computational studies, the catalytic turnover is shown
Most notably, the diversity and the abundant supply of naturally to occur through an oxidative mass transfer assisted by a chlorine
occurring and commercial chemicals37–39, high economic pre- atom, not the previously conjectured β-hydride elimination. This
ference owing to their low costs8, diminished toxicity compared contradicts with the fundamental principle of excited Pd catalysis
with other alkyl halides40, exceptional stability during multistep as the stabilization of alkylpalladium(II) species prevents β-
synthesis, and late-stage functionalization capability41 make these hydride elimination via Pd(I)/alkyl radical hybrid formation. The
compounds attractive synthetic building blocks. However, the SET-mediated mechanism provides a rationale for the photo-
stronger C–Cl bond strength, both homolytically and hetero- induced Pd catalysis to overcome the mechanistic dichotomy of
lytically, compared with C–Br and C–I bonds has limited the two-electron-based Pd-catalyzed alkyl Mizoroki–Heck coupling,
utilization of alkyl chlorides in transition metal catalysis42,43. This where β-hydride elimination is an essential elementary step for
has resulted in difficulties in both transition metal-mediated product formation and catalytic turnover, but also an undesired
oxidative additions and direct reductions via single-electron side-reaction which must be prevented.
transfer (SET)44.
Regarding the use of alkyl chlorides for Mizoroki–Heck reac-
tions, to overcome the aforementioned challenges, early first-row Results
transition metal catalysts such as a titanocene45 or a Co46,47 Reaction optimization. 4-Methoxystyrene 1a and 1.5 equiv of tert-
catalyst accompanied by over-stoichiometric Grignard reagents as butyl chloride 2a were chosen as the model substrates for reaction
a reductant were developed with limited applicability. Otherwise, condition optimization (Table 1). Thorough examination of the
activated alkyl chlorides such as benzyl chlorides48 or α-acyl reaction variables showed that the desired product could be
chlorides49 were required with Ni or Pd catalytic systems. obtained quantitatively using a readily available Pd(0) precatalyst,
Regarding unactivated alkyl chlorides, thermal Pd-catalyzed Pd(PPh3)4 (entry 1). The commonly used Pd(PPh3)2Cl2 precatalyst,
conditions reported by the Fu group were applicable but lim- with or without a dual phosphine system involving both mono-
ited to intramolecular annulations with only four examples that dentate and bidentate phosphine, delivered only minimal product
proceed under the assistance of the Thorpe-Ingold effect15. The yield, as reported previously (entries 2 and 3)9. A quantitative yield
Zhou group reported a protocol for alkyl iodides amenable to could be also obtained with an additional 10 mol% of PPh3 ligand
primary alkyl chlorides using an in situ Finkelstein reaction with using the Pd(PPh3)2Cl2 precatalyst (entry 4). However, when
LiI to generate alkyl iodides under harsh reaction conditions at Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) or
110 °C19. Despite the recent advances, photoexcited Pd catalysis DPEPhos ((oxydi-2,1-phenylene)bis(diphenylphosphine)) were
has failed to activate of unactivated alkyl chlorides with no added to the Pd(0) precatalyst, the reactivity diminished, indicating
reported example of utilizing alkyl chloride to achieve a C–C that the bidentate phosphine-based system failed to activate 2a
bond formation. Therefore, a general and effective method to (entry 5). Gratifyingly, this reaction condition was suitable for the
activate alkyl chlorides for Mizoroki–Heck coupling is a long- Mizoroki–Heck coupling of tert-butyl bromide (93%) and cyclo-
standing challenge in Pd-catalyzed cross-coupling chemistry. hexyl iodide (87%; entries 6 and 7), indicating that the reaction is
Herein, highly efficient Mizoroki–Heck reactions of various expandable to alkyl bromides and iodides. However, reactions with
unactivated primary, secondary, and even tertiary alkyl chlorides tertiary alkyl iodides undergo rapid decomposition to furnish
are achieved under mild reaction conditions via visible light- intractable mixtures. Simple thermal heating conditions failed to
mediated Pd catalysis (Fig. 1c). The reaction exhibits excellent furnish the product, indicating the importance of the photoexcited
functional group tolerance with wide synthetic applicability, Pd species in the transformation (entry 8). Finally, control experi-
including late-stage transformations of bioactive scaffolds and ments confirmed that Pd catalyst, base, and light are all essential for
annulative double Mizoroki–Heck reactions, directly furnishing the reaction (entry 9).

Table 1 Optimization of the reaction conditionsa.

Pd(PPh3)4 (5 mol %)
t-Bu
K2CO3 (2.0 equiv)
+
MeO Cl DMA [0.1 M], r.t. MeO
24 h, Blue LED
1a 2a 3a

Entry Variation from standard conditions Yieldb (%)

1 No deviation >96 (96c)
2 Pd(PPh3)2Cl2 instead of Pd(PPh3)4 4
3 Pd(PPh3)2Cl2/XantPhos (1:2) instead of Pd(PPh3)4 7
4 Pd(PPh3)2Cl2/PPh3 (1:2) instead of Pd(PPh3)4 >96
5 with the addition of Xantphos or DPEPhos (10 mol %) as ligand 0, 8
6 t-BuBr instead of 2a 93d
7 CyI instead of 2a 87d,e
8 At 100 oC, in the absence of light irradiation 0
9 Without Pd(PPh3)4 or K2CO3 or light irradiation 0
aReaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), Pd(PPh ) (5 mol %), K CO (0.2 mmol), and DMA [0.1 M] under 40 W blue LED irradiation with fan cooling (30 ± 5 °C).
3 4 2 3
bGC yields using dodecane as an internal standard, unless otherwise noted.
cIsolated yield. E:Z > 20:1.
dNMR yields using 1,1,2,2-tetrachloroethane as an internal standard. E:Z > 20:1.
eYield of the cyclohexyl-substituted product.

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Substrate scope evaluation. After determining the optimized Taking advantage of the high efficiency, exceptional functional
reaction condition, the substrate scope of the reaction starting group tolerance, mild reaction conditions, and operative
from alkyl chlorides was explored (Table 2). Simple tert-butyl simplicity of the developed reaction, the synthetic applicability
chloride furnished the desired product in excellent yields (96%, of the alkyl chloride Mizoroki–Heck reaction was investigated
3a), and scaling up the reaction 10 to 1.0 mmol scale did not (Table 4). First, the conditions were applied to complex bioactive
affect the reaction outcome (95%). Adamantyl-containing ter- molecules for bioconjugation and late-stage functionalization. To
tiary alkyl chlorides were also compatible with the reaction offer the highest practicality, the bioactive scaffold-derived
conditions (73–96%, 3b–3d). Other structurally diverse linear compartment was used as the limiting reagent. Complex steroid
and cyclic alkyl chlorides all reacted smoothly to furnish the carbon skeletons residing in either the olefin (vinylated estrone,
desired products (90–96%, 3e–3g). For secondary alkyl chlor- 70%, 24a) or alkyl chloride (cholesteryl chloride, 80%, 3ac)
ides, linear forms, such as isopropyl chloride (92%, 3h) or reacted smoothly to furnish the desired products. It should be
isobutyl chloride (>96%, 3i), produced the product in high noted that a mixture of diastereomers was obtained due to the
yields. In addition, simple carbocyclic chlorides (90–96%, 3j– intermediary radical species, even though a single diastereomer
3l) and 2-indanyl chloride (>96%, 3m) were proficient coupling was used. Terpenoid-derived menthyl chloride also showed good
partners. Secondary alkyl chlorides nested in bridged cyclic reactivity (68%, 3ad). Other bioactive molecules and drug
motifs, such as adamantyl (63%, 3n) and norbornyl (95%, 3o) derivatives, including those of δ-tocopherol (66%, 25a), gemfi-
groups, were also reactive. Heterocyclic structures, including brozil (75%, 3ae), naproxen (70%, 3af), and vanillin (95%, 26a)
tetrahydropyran (>96%, 3p) and piperidine (87%, 3q) rings, showed good to excellent yields. To our delight, even a biotin
were tolerated under standard reaction conditions. A chlor- derivative afforded styrylated biotin in a high yield, providing
ohydrin, which bears a vicinal hydroxyl group to the chloride, opportunities for bioconjugation (81%, 3ag).
delivered the homoallylic alcohol product without any dete- Notably, when 1,5-dichloropentane (2ah) was subjected to the
rioration in reactivity (87%, 3r). Finally, a series of primary reaction conditions with 2 equiv of 1a, an iterative double
alkyl chlorides bearing a wide array of functional groups were Mizoroki–Heck coupling proceeded smoothly to furnish an exo-
tested. Generally, primary alkyl chlorides showed slightly (arylmethylene)cyclohexane framework (60%, 3ah) without the
diminished yields of approximately 70%. Besides, simple ali- aid of the Thorpe-Ingold effect. In addition to simple 1,5-
phatic, aromatic, and silyl groups bearing alkyl chlorides were dichloropentane, oxygen containing 1,5-dichloride smoothly
suitable substrates (74–83%, 3s–3u). When two equiv of 1,4- furnished the tetrahydropyran structure (70%, 3ai). Similarly, a
dichlorobutane was incorporated, only a minimal amount of tert-butoxycarbonyl protected amine (86%, 3aj) or an aniline
difunctionalization product was observed with selective gen- (75%, 3ak) analog could also be incorporated, resulting in 4-
eration of the mono-functionalized product (74%, 3v). The functionalized piperidine derivatives, which are key moieties in a
reaction demonstrated exceptional functional group tolerance variety of drugs including cyproheptadine and its analogs. With
to polar functionalities, including ester (67%, 3w), nitrile (61%, chlorambucil methyl ester 2al, an N-arylpiperidine was prepared
3x), ketone (70%, 3y), and alcohol (69%, 3z) groups. The tet- in a single step (76%, 3al). However, the use of other olefin
rahydrofuran ring remained intact during the reaction (77%, substrates except 1a led to incomplete conversions leading to a
3aa). Surprisingly, the alkyl chloride bearing a terminal alkyne mixture of the mono-Mizoroki–Heck product and the cyclized
group was compatible, demonstrating high chemoselectivity in product. To the best of our knowledge, this type of one-step β,β-
the radical-based Mizoroki–Heck coupling reaction (91%, 3ab). difunctionalization of styrenes has not been previously reported,
Next, the scope of olefins in the developed reaction was which could provide a direct entry to six-membered cyclic
examined (Table 3). A series of electronically neutral alkyl- compounds with an exocyclic double bond.
substituted styrenes underwent smooth functionalization
(92–96%, 4a–7a). A sterically hindered mesityl group was also
tolerated, demonstrating high tolerance to sterics (58%, 8a). Mechanistic investigations. To examine the reaction mechanism,
Halide substituents remained intact, and alkyl chlorides reacted it was first attempted to confirm that the reaction indeed proceeds
preferentially in the presence of aryl chloride (>96% for 9a, 64% through a radical pathway involving a Pd(I)/alkyl radical hybrid,
for 10a). Mizoroki–Heck coupling of a piperonyl substrate also as previously reported20,21,31. First, when a control experiment
proceeded with excellent efficiency (>96%, 11a). Other substi- with a radical scavenger was performed, complete shutdown of
tuents including phenyl (90%, 12a), hydroxymethyl (>96%, 13a), reactivity was observed with the addition of 1 equiv of (2,2,6,6-
methoxy (86%, 14a), and acetoxy (96%, 15a) groups were tetramethylpiperidin-1-yl)oxyl (TEMPO) to the standard reaction
tolerated. The reaction proceeded chemoselectively with a conditions (Fig. 2a). Moreover, the addition of radical clock
pinacolboronate ester (64%, 16a), which can allow for further substrate 2am furnished the ring-opening product 3an exclu-
functionalization. Furthermore, the thiomethyl group did not sively and no direct Mizoroki–Heck product 3am was detected,
degrade the reactivity (>96%, 17a), and vinylnaphthalene was also indicative of cyclopropylmethyl radical generation (Fig. 2b).
compatible (64%, 18a). Apart from simple styrenes, 1,1- Stern–Volmer quenching experiments with 2a also revealed that
diphenylethene (83%, 19a) and vinylcarbazole (75%, 20a) could photoinduced activation of alkyl chlorides through the excited Pd
be applied in the developed protocol. Moreover, an α,β- (0) catalyst was feasible, providing further evidence for a single-
unsaturated amide (54%, 21a) and vinylamide (68%, 22a) were electron reduction event (Supplementary Fig. 3). Thorough
reactive, and the utilization of divinylbenzene produced a doubly kinetic studies using both 1a-d2 and 2n-d1 revealed that the initial
coupled product in good yields (77%, 23a). Although a high reduction of the alkyl chloride is the rate-limiting step, as the
stereoselectivity was generally observed (>20:1), for substrates kinetic isotope effects (KIEs) arising from both the α and β-
bearing extended conjugated systems (12a, 18a, 23a), E/Z position of the styrene were 1.0, whereas that from the alkyl
isomerization occurred after product formation, yielding a chloride was 1.6, indicating a secondary deuterium effect (Sup-
mixture of stereoisomers (Supplementary Fig. 1). Notably, in plementary Figs. 4–6, Fig. 2c).
contrast to previous reports9,32–34, significantly electron-deficient Next, the more controversial step of the reaction mechanism,
styrenes, including those bearing a trifluoromethyl, cyano, or the product forming catalyst turnover step, was examined
ester group, were not compatible with the developed reaction (Fig. 2d). After generation of the alkyl radical, it undergoes facile
condition (Fig. 3a). insertion to the olefin substrate, generating a radical adduct, I-

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Table 2 Alkyl chloride substrate scopea.

Pd(PPh3)4 (5 mol %)
R
K2CO3 (2.0 equiv)
+ Cl R
MeO DMA [0.1 M], r.t. MeO
24 h, Blue LED
1a 2a–2ab 3a–3ab

O
Me
Me
Me
Me
MeO MeO MeO
MeO

3a 96% (95%b) 3b 90% 3c >96% 3d 73%

Me Me Me Me Me Me
Me
Ph Ph Me

MeO MeO MeO MeO

3e 96% 3f 90% 3g 95%c 3h 92%

Me
Me

MeO MeO MeO MeO

3i >96% 3j 90% 3k >96% 3l 96%

MeO MeO MeO

MeO

3m >96% 3n 63% 3o 95% 3p >96%

NBoc
Me TMS

OH MeO MeO
MeO MeO

3q 87% 3r 87%d 3s 80%e 3t 74%e

Cl OEt
Ph CN
O
MeO MeO MeO MeO

3u 83% 3v 74%f,g 3w 67%e 3x 61%e

Me OH O

O
MeO MeO MeO MeO

3y 70% 3z 69%f 3aa 77% 3ab 91%f

aReaction conditions: 1a (0.1 mmol), 2a–2ab (0.15 mmol), Pd(PPh ) (5 mol %), K CO (0.2 mmol), and DMA [0.1 M] under 40 W blue LED irradiation with fan cooling (30 ± 5 °C). All yields are isolated
3 4 2 3
yields. E:Z > 20:1.
bReaction conducted with 1.0 mmol scale of 1a.
cd.r. = 2:1.
dd.r. = 2.7:1.
eE:Z > 10:1.
fE:Z = 7:1.
gWith 0.3 mmol of 1,5-dichlorobutane (2v).

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Table 3 Olefin substrate scopea.

Pd(PPh3)4 (5 mol %)
K2CO3 (2.0 equiv)
+ t-Bu
R R
Cl DMA [0.1 M], r.t.
24 h, Blue LED
1b–1u 2a 4a–23a

Me Me
t-Bu t-Bu t-Bu
t-Bu t-Bu

Me t-Bu
Me Me

4a 92% 5a >96% 6a 85% 7a >96% 8a 58%

t-Bu
t-Bu t-Bu t-Bu t-Bu
O
HO

F Cl O

9a >96% 10a 64% 11a >96% 12a 90%b 13a >96%

t-Bu
t-Bu
t-Bu t-Bu t-Bu
O
B
AcO O MeS
OMe

14a 86% 15a 96% 16a 64% 17a >96% 18a 64%c

t-Bu O O
N t-Bu
t-Bu
N t-Bu N
t-Bu
t-Bu
O

19a 83% 20a 75% 21a 54% 22a 68% 23a 77%c,d

aReaction conditions: 1b–1z (0.1 mmol), 2a (0.15 mmol), Pd(PPh ) (5 mol %), K CO (0.2 mmol), and DMA [0.1 M] under 40 W blue LED irradiation with fan cooling (30 ± 5 °C). All yields are isolated
3 4 2 3
yields. E:Z > 20:1.
bE:Z = 1:1.
cE:Z = 1:2.
dWith 0.3 mmol 2a.

rad. However, the subsequent formation of the olefin product and (as in II) showed clear excitation into the Pd–alkyl antibonding
concomitant regeneration of a Pd(0) species may occur via a few orbitals in the blue light energy region (Supplementary Fig. 11).
possible mechanisms (III). First, the Pd(II) species II formed after Moreover, contrasting observations regarding the substrate
radical ligation may undergo direct β-hydride elimination to electronics were reported, where electron-poor styrenes failed to
furnish the product (Fig. 2d, upper pathway), as previously furnish the Mizoroki–Heck products under the reaction condi-
proposed by the Fu group9. Another reaction mechanism tions herein, whereas they smoothly proceeded with alkyl
involving SET or mass transfer from the Pd(I) species to provide bromides in dual phosphine-based photoinduced Pd catalytic
either I-cat or I-Cl, followed by base-assisted elimination is systems9,32–34. This indicates that an oxidative process may be
equally plausible (Fig. 2d, lower pathway)25,50. involved in the reaction because the reactivity trend is
The Fu group proposed that the β-hydride elimination counterintuitive as radical addition to electron-poor olefins
pathway was operative in the photoirradiated Pd-catalyzed should be more facile. This substrate-dependent reactivity was
Mizoroki–Heck coupling of alkyl bromides9. However, we further studied in a quantitative manner via density functional
questioned its operation in the developed reaction because the theory (DFT) computation of the oxidation potentials of various
photoirradiated Pd catalytic system inherently prevents the I-rad species to I-cat (Fig. 3a). A decreasing trend in
occurrence of β-hydride elimination20. Indeed, time-dependent yields was observed as the oxidation potential of I-rad increased.
density functional theory computations on the Pd–alkyl species Notably, a clear cutoff potential region was identified between

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Table. 4 Synthetic applicationsa.

Late-stage functionalizationa
Pd(PPh3)4 (5 mol %)
K2CO3 (2.0 equiv)
R2
R1 + Cl R2 R1
DMA [0.1 M], r.t.
24 h, Blue LED
1a, 1v–1x 2ac–2ag, 2a 3ac–3ag, 24a–26a

Me
Me
Me
t-Bu H Me
H H Me H Me

H H H
MeO Me Me
O Me
MeO
from estrone from cholesterol from (–)-menthol

24a 70% 3ac 80%b 3ad 68%c

Me
t-Bu O
Me Me Me
Me O O Me
Me O Me Me
Me MeO

from G-tocopherol (vitamin E) from gemfibrozil

25a 66%d 3ae 75%d

O
OMe S
O O
MeO t-Bu H
O H
MeO HN
Me NH
MeO AcO
O
from naproxen from vanillin from biotin

3af 70%d,e 26a 95% 3ag 81%d

Iterative Heck cyclizationf

Pd(PPh3)4 (5 mol %)
K2CO3 (4.0 equiv) 3ah (X = CH2) 60%
X
Cl Cl 3ai (X = O) 70%
+ X 3aj (X = NBoc) 86%
DMA [0.1 M], r.t. MeO
MeO 24 h, Blue LED 3ak (X = NPh) 75%
2ah (X = CH2)
1a 2ai (X = O)
2aj (X = NBoc)
2ak (X = NPh)

Cl
Pd(PPh3)4 (5 mol %)
K2CO3 (4.0 equiv) N
N MeO O
+ Cl O DMA [0.1 M], r.t.
MeO OMe
24 h, Blue LED
OMe

1a from chlorambucil 2al 3al 76%

aReaction conditions: 1a (0.15 mmol), 2ac–2ag (0.1 mmol) or 1aa–1ac (0.1 mmol), 2a (0.15 mmol), Pd(PPh ) (5 mol %), K CO (0.2 mmol), and DMA [0.1 M] under 40 W blue LED irradiation with fan
3 4 2 3
cooling (30 ± 5 °C). All yields are isolated yields.
bd.r. = 3:4.
cd.r. = 2:1.
dPd(PPh ) (10 mol %), 48 h.
3 4
eE:Z = 1.3:1.
fReaction conditions: 1a (0.2 mmol), 2ah–2al (0.1 mmol), Pd(PPh ) (5 mol %), K CO (0.4 mmol), in DMA [0.1 M] under 40 W blue LED irradiation with fan cooling (30 ± 5 °C). All yields are isolated
3 4 2 3
yields.

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a Pd(PPh3)4 (5 mol %)
K2CO3 (2.0 equiv)
t-Bu
TEMPO (1.0 equiv)
+
MeO Cl DMA [0.1 M], r.t. MeO
24 h, Blue LED
1a 2a 3a N.D.

MeO
Pd(PPh3)4 (5 mol %)
3am N.D.
K2CO3 (2.0 equiv)
+ Cl
MeO DMA [0.1 M], r.t.
24 h, Blue LED
1a 2am
MeO

3an 53%

c
Pd(PPh3)4 (5 mol %)
D 2a (1.5 equiv)
t-Bu
K2CO3 (2.0 equiv)
or
D H/D
MeO MeO DMA [0.05 M], r.t. MeO
24 h, Blue LED
1a 1a-E-d2 kH/kD = 1.0 3a/3a-E-d1

Pd(PPh3)4 (5 mol %) H/D

D
2a (1.5 equiv)
t-Bu
K2CO3 (2.0 equiv)
or
MeO DMA [0.05 M], r.t.
MeO MeO
24 h, Blue LED

1a 1a-D-d1 kH/kD = 1.0 3a/3a-D-d1

Pd(PPh3)4 (5 mol %)
Cl Cl 1a (1.0 equiv)
K2CO3 (2.0 equiv)
H or D
H/D
DMA [0.05 M], r.t.
MeO
24 h, Blue LED
2n 2n-d1 kH/kD = 1.6 3n/3n-d1

d
Pd(II)Cl E-H elimination
R
Ar Pd(0)
Pd(I)Cl
II
R
R Ar
Ar Cl Pd(0)
Cl Pd(0) III
I-rad
R or R
oxidation Ar Ar – HCl
I-Cl I-cat

Fig. 2 Mechanistic studies. a TEMPO as radical scavenger. b Radical clock experiment. c Kinetic isotope effect measurements. d Possible product forming
catalyst turnover mechanisms.

R = F and R = CF3, as commonly expected for an oxidative determining step, initial reduction of the alkyl chloride (Fig. 2b),
transformation51,52. The results suggest that an oxidation-based is located prior to the elementary steps of interest, competition-
mechanism is likely operative in the product formation pathway. based kinetic experiments and DFT computations were carefully
Next, in order to independently investigate the catalyst designed to unambiguously determine the KIEs of each step53.
turnover step, a number of kinetic studies using deuterated First, an intramolecular competition experiment, analogous to
substrates were performed to observe and compare the KIE values that reported by the Fu group9, was conducted using 1a-β-d1
in the proposed scenarios (Fig. 3b). As the identified rate- (Supplementary Fig. 7, Fig. 3b, first line). A KIE value of 1.2 was

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a Pd(PPh 3) 4 (5 mol %)
K2CO3 (2.0 equiv) t-Bu

+ Cl
R DMA [0.1 M], r.t.
R
24 h, Blue LED
2a

R= OMe OAc F Cl CF3 CHO CN

Yield a >96% >96% >96% 64% 15% <5% N.D.

E o [I-rad/ I-cat ]b –0.01 V 0.33 V 0.39 V 0.48 V 0.61 V 0.79 V 0.84 V

t-Bu

R
I-rad

t-Bu

R
I-cat

b
Intramolecular competition under standard conditions

D Pd(PPh 3) 4 (5 mol %) t-Bu

K 2CO3 (2.0 equiv)
H + Cl H/D
MeO DMA [0.1 M], r.t. MeO
24 h, Blue LED
1a-E-d1 2a 3a/3a- E-d1
[P D]/[P H] = 1.2

Elimination of benzyl chloride intermediate 27

Cl Cl
Me
Me Me K2 CO3 (20.0 equiv)
+
D D H/D
DMA [0.1 M], r.t. MeO
MeO MeO 1 h, Blue LED
27 27- d2 2ao/2ao- d1
[P D]/[P H] = 1.2

Kinetic isotope effects of E-hydride eliminations

R1 R2 KIE
X
[Pd] [Pd]
E-hydride H H 3.2 c
[Pd] R2 R2
1 elimination
R
KIE H Ph 3.0 c
+
R1 R1
R2 OMe t-Bu 5.0 d

Fig. 3 Mechanistic studies on the product forming step. a Computed oxidation potentials of I-rad and associated reactivity trends. b Kinetic isotope effect
measurements/computations. aYields are isolated yields. bDFT computations were performed at the B3LYP-D3/6-311 + +G**/SDD//B3LYP-D3/6-31
G**/LanL2DZ level of theory in DMA (IEFPCM). The potentials are shown vs N.H.E. cFrom ref. 52. dDFT-computed value.

observed, similar to that obtained by the Fu group (1.4). The Fu hydride elimination pathway for their photoexcited Pd-catalyzed
group interpreted the result by comparison to a general E2 Mizoroki–Heck reaction with alkyl bromides.
reaction, isopropyl bromide elimination with an ethoxide base However, the elimination reaction of benzyl halides would be
(KIE = 6.7)54, and excluded a bromine atom transfer pathway. significantly different from simple aliphatic alkyl halides. To the
They assumed that the involvement of the benzylic brominated best of our knowledge, the KIEs of the elimination reaction of β-
product followed by elimination would have a large KIE, similar alkyl secondary benzyl halides remain largely unstudied. Alter-
to the E2 reaction. Based on the results, they proposed a β- natively, the Balachandran group demonstrated that the

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Cl Pd0L4
L
R K2CO3 R
hv
Cl atom
– KHCO3
transfer
–KCl
Pd0L3*
L

rate-limiting
R single electron R Cl
I
L3Pd Cl reduction

hv, – L R
L
radical L3PdICl R PdII
insertion +L L
Cl

L = PPh3

Fig. 4 Proposed reaction mechanism. Reaction mechanism involving chlorine atom transfer as the key turnover step.

elimination reactions of cumyl chloride55 or 1-chloro-1,2- key turnover process59. Unfortunately, even after numerous
diarylethanes56,57 proceeded via a unimolecular E1 mechanism attempts, capturing the chlorine atom transfer transition state
without rate dependence on the base concentration and with through DFT modeling was unsuccessful.
unimolecular rate dependence on the concentration of the alkyl Combining the above mechanistic investigations, a plausible
chlorides. Hence, we confirmed the KIE value of the elimination catalytic cycle was proposed (Fig. 4). After alkyl chloride
reaction of a secondary benzyl chloride via competition kinetic reduction from the excited Pd(0) species to yield alkyl radicals,
experiments with independently prepared 27 and 27-d2 (Supple- this radical is selectively inserted to the β-position of the styrene,
mentary Fig. 8, Fig. 3b, second line). A secondary KIE value of 1.2 yielding a Pd(I)/benzylic radical hybrid species. As β-hydride
was obtained, likely originating from the carbon hybridization elimination is significantly prevented by irradiation, single-
change during the chloride detachment, supporting an E1 electron oxidation mediated by a chlorine atom occurs to furnish
pathway as in previous reports55–57. The observed KIE values a benzyl chloride species, regenerating the Pd(0) catalyst. A base-
of 1.2 (Fig. 3b, first line) is not consistent with previously reported assisted elimination then produces the Mizoroki–Heck coupling
KIE values observed for the two-electron based Pd-catalyzed product. However, we cannot fully exclude the possibilities of the
Mizoroki–Heck coupling reactions with ethene (KIE = 3.2; engagement of photoexcited Pd species or higher order Pd species
Fig. 3b, third line, R1 = R2 = H), or with styrene (KIE = 3.0; in direct single-electron oxidation events.
R1 = H, R2 = Ph) where β-hydride elimination occurs via In conclusion, a general intermolecular Pd-catalyzed
cleavage of the homobenzylic C–H bond from a benzylic Pd Mizoroki–Heck coupling of alkyl chlorides enabled by photoexcited
species58. DFT computations of the KIE value on the exact Pd catalysis was reported. The developed reaction conditions are
substrate (R1 = OMe, R2 = t-Bu) were performed for the applicable to a wide range of styrenes and other activated olefins as
β-hydride elimination pathway, yielding a primary KIE of 5.0 well as diverse primary, secondary, and even tertiary alkyl chlorides.
(Supplementary Table 2). Overall, these kinetic experiments, The synthetic utility of this reaction was demonstrated via late-stage
along with literature and computational data, strongly oppose the functionalization of bioactive molecules and pharmaceutical scaf-
β-hydride elimination mechanism in the reaction, implying that folds in the context of both olefins and alkyl chlorides. Notably, an
an oxidative mechanism is more plausible. Notably, a benzyl iterative double Mizoroki–Heck coupling of 1,5-dichlorides was
chloride intermediate is smoothly converted to the desired possible under identical reaction conditions, yielding a series of
elimination product under our standard reaction conditions, complex structures in a single step. Concrete mechanistic studies
which is in clear contrast to previous reports of Pd-catalyzed using experimental and computational methods revealed that an
Mizoroki–Heck reactions where the addition of halide transfer oxidative pathway is operative rather than the previously reported
intermediates to the standard reaction conditions led to catalytic β-hydride elimination, rationally overcoming the mechanistic
cycle poisoning9 or only low elimination yields19 (Supplementary challenge of two-electron-based Pd-catalyzed alkyl Mizoroki–Heck
Fig. 9). Moreover, considering that the observed KIE values from coupling. We anticipate that this study will provide mechanistic
the two experiments in Fig. 3b (first and second lines) are almost insights to utilize photoinduced Pd catalysis to achieve traditionally
identical, it is likely that the oxidation occurs via the mass transfer unreachable transformations and expand the synthetic utility of the
of a Cl atom to produce I-Cl as a key reaction intermediate. The widespread Mizoroki–Heck reaction.
computed redox potentials of Pd–Cl species are not sufficient to
directly oxidize I-rad (Fig. 3a, Eocalc[Pd(I)/Pd(0)] = −0.85 V, Methods
Eocalc[Pd(II)/Pd(I)] = −0.83 V vs. N.H.E., Supplementary Fig. 10), General procedure for the alkyl chloride Mizoroki–Heck coupling. To a 4 mL
further indicating that the direct oxidation pathway from I-rad to vial equipped with a stirrer-bar were added Pd(PPh3)4 (5.8 mg, 0.0050 mmol, 0.050
equiv), K2CO3 (27.6 mg, 0.20 mmol, 2.0 equiv), the corresponding olefin (0.10
I-cat is unlikely. Moreover, when tert-butyl N-(acyloxy)phthali- mmol, 1.0 equiv), the corresponding alkyl chloride (0.15 mmol, 1.5 equiv), and N,
mide, a competent electrophile in the previously reported dual N-dimethylacetamide (1.0 mL). The resulting mixture was stirred for 24 h under
phosphine-based photoexcited Pd-catalyzed Heck reaction32, was 40 W blue light-emitting diode irradiation with fan cooling (~30 °C). The reaction
employed, the reactivity was largely diminished (13% yield) under mixture was added brine (10 mL), diluted with EtOAc or Et2O (10 mL), washed
with brine (10 mL), dried (anhydrous Na2SO4), filtered, and concentrated under
the standard conditions as a phthalimide group transfer is
reduced pressure. The resulting residue was purified by flash column chromato-
implausible. The reactivity was moderately recovered (22% yield) graphy (silica gel, hexanes/EtOAc, or hexanes/Et2O gradient elution) to afford the
with the addition of lithium chloride, indirectly suggesting the desired product.
role of chloride in the reaction mechanism (Supplementary
Table 1). An analogous reaction mechanism has been recently Data availability
reported in the identical Pd system to perform alkylation of Detailed experimental procedures, computational details, and all characterization data
unactivated arenes, which involves a bromine atom transfer as the for new compounds are available from the Supplementary Information. Cartesian

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NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-21270-9 ARTICLE

coordinates of DFT-optimized structures are available from the Supplementary Data 1 28. Huang, H.-M. et al. Three-component, interrupted radical Heck/allylic
file. All data are available from the corresponding authors upon reasonable request. substitution cascade involving unactivated alkyl bromides. J. Am. Chem. Soc.
142, 10173–10183 (2020).
Received: 24 September 2020; Accepted: 15 January 2021; 29. Shing Cheung, K. P., Kurandina, D., Yata, T. & Gevorgyan, V. Photoinduced
palladium-catalyzed carbofunctionalization of conjugated dienes proceeding
via radical-polar crossover scenario: 1,2-aminoalkylation and beyond. J. Am.
Chem. Soc. 142, 9932–9937 (2020).
30. Kurandina, D., Parasram, M. & Gevorgyan, V. Visible light-induced room-
temperature Heck reaction of functionalized alkyl halides with vinyl arenes/
heteroarenes. Angew. Chem. Int. Ed. 56, 14212–14216 (2017).
References 31. Zhao, B. et al. Palladium-catalyzed dual ligand-enabled alkylation of silyl enol
1. Heck, R. F. & Nolley, J. P. Palladium-catalyzed vinylic hydrogen substitution ether and enamide under irradiation: scope, mechanism, and theoretical
reactions with aryl, benzyl, and styryl halides. J. Org. Chem. 37, 2320–2322 elucidation of hybrid alkyl Pd(I)-radical species. ACS Catal. 10, 1334–1343
(1972). (2020).
2. Mizoroki, T., Mori, K. & Ozaki, A. Arylation of olefin with aryl iodide 32. Wang, G.-Z., Shang, R. & Fu, Y. Irradiation-induced palladium-catalyzed
catalyzed by palladium. Bull. Chem. Soc. Jpn. 44, 581–581 (1971). decarboxylative Heck reaction of aliphatic N-(acyloxy)phthalimides at room
3. Ruan, J. & Xiao, J. From α-arylation of olefins to acylation with aldehydes: a temperature. Org. Lett. 20, 888–891 (2018).
journey in regiocontrol of the Heck reaction. Acc. Chem. Res. 44, 614–626 33. Koy, M. et al. Palladium‐catalyzed decarboxylative Heck‐type coupling of
(2011). activated aliphatic carboxylic acids enabled by visible light. Chem. Eur. J. 24,
4. Jagtap, S. Heck reaction—state of the art. Catalysts 7, 267–320 (2017). 4552–4555 (2018).
5. Beletskaya, I. P. & Cheprakov, A. V. The Heck reaction as a sharpening stone 34. Kurandina, D., Rivas, M., Radzhabov, M. & Gevorgyan, V. Heck reaction of
of palladium catalysis. Chem. Rev. 100, 3009–3066 (2000). electronically diverse tertiary alkyl halides. Org. Lett. 20, 357–360 (2018).
6. Amatore, C. & Jutand, A. Anionic Pd(0) and Pd(II) intermediates in 35. Sakai, H. A., Liu, W., Le, C. C. & MacMillan, D. W. C. Cross-electrophile
palladium-catalyzed Heck and cross-coupling reactions. Acc. Chem. Res. 33, coupling of unactivated alkyl chlorides. J. Am. Chem. Soc. 142, 11691–11697
314–321 (2000). (2020).
7. Cabri, W. & Candiani, I. Recent developments and new perspectives in the 36. Cybularczyk-Cecotka, M., Szczepanik, J. & Giedyk, M. Photocatalytic
Heck reaction. Acc. Chem. Res. 28, 2–7 (1995). strategies for the activation of organic chlorides. Nat. Catal. 3, 872–886 (2020).
8. Frisch, A. C. & Beller, M. Catalysts for cross-coupling reactions with non- 37. Giedyk, M. et al. Photocatalytic activation of alkyl chlorides by assembly-
activated alkyl halides. Angew. Chem. Int. Ed. 44, 674–688 (2005). promoted single electron transfer in microheterogeneous solutions. Nat. Catal.
9. Wang, G.-Z., Shang, R., Cheng, W.-M. & Fu, Y. Irradiation-induced Heck 3, 40–47 (2020).
reaction of unactivated alkyl halides at room temperature. J. Am. Chem. Soc. 38. Gribble, G. W. Naturally occurring organohalogen compounds. Acc. Chem.
139, 18307–18312 (2017). Res. 31, 141–152 (1998).
10. Oestreich, M. The Mizoroki–Heck Reaction (Wiley, 2008). 39. Ertl, P. & Schuhmann, T. A systematic cheminformatics analysis of functional
11. Kurandina, D., Chuentragool, P. & Gevorgyan, V. Transition-metal-catalyzed groups occurring in natural products. J. Nat. Prod. 82, 1258–1263 (2019).
alkyl Heck-type reactions. Synthesis 51, 985–1005 (2019). 40. Sobol, Z. et al. Genotoxicity profiles of common alkyl halides and esters with
12. Rudolph, A. & Lautens, M. Secondary alkyl halides in transition-metal-catalyzed alkylating activity. Mutat. Res. 633, 80–94 (2007).
cross-coupling reactions. Angew. Chem. Int. Ed. 48, 2656–2670 (2009). 41. Bucher, C., Deans, R. M. & Burns, N. Z. Highly selective synthesis of halomon,
13. Kwiatkowski, M. R. & Alexanian, E. J. Transition-metal (Pd, Ni, Mn)- plocamenone, and isoplocamenone. J. Am. Chem. Soc. 137, 12784–12787
catalyzed C–C bond constructions involving unactivated alkyl halides and (2015).
fundamental synthetic building blocks. Acc. Chem. Res. 52, 1134–1144 (2019). 42. Martin, E. T., McGuire, C. M., Mubarak, M. S. & Peters, D. G.
14. Sumino, S., Fusano, A., Fukuyama, T. & Ryu, I. Carbonylation reactions of Electroreductive remediation of halogenated environmental pollutants. Chem.
alkyl iodides through the interplay of carbon radicals and Pd catalysts. Acc. Rev. 116, 15198–15234 (2016).
Chem. Res. 47, 1563–1574 (2014). 43. Blanksby, S. J. & Ellison, G. B. Bond dissociation energies of organic
15. Firmansjah, L. & Fu, G. C. Intramolecular Heck reactions of unactivated alkyl molecules. Acc. Chem. Res. 36, 255–263 (2003).
halides. J. Am. Chem. Soc. 129, 11340–11341 (2007). 44. Roth, H. G., Romero, N. A. & Nicewicz, D. A. Experimental and calculated
16. Bloome, K. S., McMahen, R. L. & Alexanian, E. J. Palladium-catalyzed Heck- electrochemical potentials of common organic molecules for applications to
type reactions of alkyl iodides. J. Am. Chem. Soc. 133, 20146–20148 (2011). single-electron redox chemistry. Synlett 27, 714–723 (2015).
17. Venning, A. R. O. et al. Palladium-catalyzed carbocyclizations of unactivated 45. Terao, J., Watabe, H., Miyamoto, M. & Kambe, N. Titanocene-catalyzed
alkyl bromides with alkenes involving auto-tandem catalysis. J. Am. Chem. alkylation of aryl-substituted alkenes with alkyl halides. Bull. Chem. Soc. Jpn.
Soc. 139, 11595–11600 (2017). 76, 2209–2214 (2003).
18. McMahon, C. M. & Alexanian, E. J. Palladium-catalyzed Heck-type cross- 46. Ikeda, Y., Nakamura, T., Yorimitsu, H. & Oshima, K. Cobalt-catalyzed
couplings of unactivated alkyl iodides. Angew. Chem. Int. Ed. 53, 5974–5977 Heck-type reaction of alkyl halides with styrenes. J. Am. Chem. Soc. 124,
(2014). 6514–6515 (2002).
19. Zou, Y. & Zhou, J. S. Palladium-catalyzed intermolecular Heck reaction of 47. Affo, W. et al. Cobalt-catalyzed trimethylsilylmethylmagnesium-promoted
alkyl halides. Chem. Commun. 50, 3725–3728 (2014). radical alkenylation of alkyl halides: a complement to the Heck reaction. J.
20. Kancherla, R. et al. Oxidative addition to palladium(0) made easy through Am. Chem. Soc. 128, 8068–8077 (2006).
photoexcited-state metal catalysis: experiment and computation. Angew. 48. Matsubara, R., Gutierrez, A. C. & Jamison, T. F. Nickel-catalyzed Heck-type
Chem. Int. Ed. 58, 3412–3416 (2019). reactions of benzyl chlorides and simple olefins. J. Am. Chem. Soc. 133,
21. Chuentragool, P., Kurandina, D. & Gevorgyan, V. Catalysis with palladium 19020–19023 (2011).
complexes photoexcited by visible light. Angew. Chem. Int. Ed. 58, 49. Glorius, F. Palladium-catalyzed Heck-type reaction of 2-chloro acetamides
11586–11598 (2019). with olefins. Tetrahedron Lett. 44, 5751–5754 (2003).
22. Parasram, M. & Gevorgyan, V. Visible light-induced transition metal- 50. Jiao, Z., Lim, L. H., Hirao, H. & Zhou, J. S. Palladium-catalyzed para-selective
catalyzed transformations: beyond conventional photosensitizers. Chem. Soc. alkylation of electron-deficient arenes. Angew. Chem. Int. Ed. 57, 6294–6298
Rev. 46, 6227–6240 (2017). (2018).
23. Cheng, W.-M., Shang, R. & Fu, Y. Irradiation-induced palladium-catalyzed 51. Meyer, T. E. et al. Correlation between rate constant for reduction and redox
decarboxylative desaturation enabled by a dual ligand system. Nat. Commun. potential as a basis for systematic investigation of reaction mechanisms of
9, 5215 (2018). electron transfer proteins. Proc. Natl Acad. Sci. USA 80, 6740–6744 (1983).
24. Zhou, Z.-Z., Zhao, J.-H., Gou, X.-Y., Chen, X.-M. & Liang, Y.-M. Visible-light- 52. Shibata, H., Moulijn, J. A. & Mul, G. Enabling electrocatalytic
mediated hydrodehalogenation and Br/D exchange of inactivated aryl and Fischer–Tropsch synthesis from carbon dioxide over copper-based electrodes.
alkyl halides with a palladium complex. Org. Chem. Front. 6, 1649–1654 Catal. Lett. 123, 186 (2008).
(2019). 53. Simmons, E. M. & Hartwig, J. F. On the interpretation of deuterium kinetic
25. Zhou, W.-J. et al. Visible-light-driven palladium-catalyzed radical alkylation of isotope effects in C–H bond functionalizations by transition-metal complexes.
C−H bonds with unactivated alkyl bromides. Angew. Chem. Int. Ed. 56, Angew. Chem. Int. Ed. 51, 3066–3072 (2012).
15683–15687 (2017). 54. Shiner, V. J. Substitution and elimination rate studies on some deutero-
26. Torres, G. M., Liu, Y. & Arndtsen, B. A. A dual light-driven palladium catalyst: isopropyl bromides. J. Am. Chem. Soc. 74, 5285–5288 (1952).
Breaking the barriers in carbonylation reactions. Science 368, 318–323 (2020). 55. Balachandran, S. & Kumar, D. S. Kinetics of elimination reactions of cumyl
27. Huang, H.-M. et al. Catalytic radical generation of π-allylpalladium chloride and its substituted derivatives in acetonitrile. Indian J. Chem. Sect. B
complexes. Nat. Catal. 3, 393–400 (2020). 44B, 1731–1734 (2005).

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56. Santhosh Kumar, D. & Balachandran, S. Kinetics of elimination reactions of 1- Additional information
chloro-1-(4-methoxyphenyl)-2-phenylethane in acetonitrile. Indian J. Chem. Supplementary information The online version contains supplementary material
Sect. B 45B, 2751–2753 (2006). available at https://doi.org/10.1038/s41467-021-21270-9.
57. Kumar, D. S. & Balachandran, S. Kinetics of elimination reactions of 1,2-
diphenyl ethyl substrates in acetonitrile: a mechanistic change in the presence Correspondence and requests for materials should be addressed to S.H.H.
of a strong base. Int. J. Chem. Kinet. 40, 481–487 (2008).
58. Shmidt, A. F. & Smirnov, V. V. Kinetic study of the Heck reaction by the Peer review information Nature Communications thanks the anonymous reviewer(s) for
method of competing reactions. Kinet. Catal. 42, 800–804 (2001). their contribution to the peer review of this work.
59. Kim, D., Lee, G. S., Kim, D. & Hong, S. H. Direct C(sp2)–H alkylation of
unactivated arenes enabled by photoinduced Pd catalysis. Nat. Commun. 11, Reprints and permission information is available at http://www.nature.com/reprints
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Acknowledgements
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