Photoinduced, Copper-Catalyzed Enantioconvergent Alkylations of Anilines by Racemic Tertiary Electrophiles: Synthesis and Mechanism

Photoinduced, Copper-Catalyzed Enantioconvergent Alkylations

of Anilines by Racemic Tertiary Electrophiles: Synthesis and

Mechanism

Hyungdo Cho

Hidehiro Suematsu

Paul H. Oyala

Jonas C. Peters

Gregory C. Fu

Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena,

California 91125, United States

Abstract

Transition-metal catalysis of substitution reactions of alkyl electrophiles by nitrogen nucleophiles

is beginning to emerge as a powerful strategy for synthesizing higher-order amines, as well as

controlling their stereochemistry. Herein, we report that a readily accessible chiral copper catalyst

(commercially available components) can achieve the photoinduced, enantioconvergent coupling

of a variety of racemic tertiary alkyl electrophiles with aniline nucleophiles to generate a new C–N

bond with good ee at the fully substituted stereocenter of the product; whereas this photoinduced,

copper-catalyzed coupling proceeds at −78 °C, in the a bsence of light and catalyst, virtually

no C–N bond formation is observed even upon heating to 80 °C. The mechanism of this new

catalytic enantioconvergent substitution process has been interrogated with the aid of a wide array

of tools, including the independent synthesis of proposed intermediates and reactivity studies,

spectroscopic investigations featuring photophysical and EPR data, and DFT calculations. These

studies led to the identification of three copper-based intermediates in the proposed catalytic

cycle, including a chiral three-coordinate formally copper(II)–anilido (DFT analysis points to its

Corresponding Authors

Jonas C. Peters

– Division of Chemistry and Chemical Engineering, California Institute of Technology,

Pasadena, California 91125, United States; jpeters@caltech.edu,

Gregory C. Fu

– Division of Chemistry and Chemical Engineering,

California Institute of Technology, Pasadena, California 91125, United States; gcfu@caltech.edu.

ASSOCIATED CONTENT

Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/

Experimental details, including general information, preparation of electrophiles, enantioconvergent coupling reactions, effect

of reaction parameters, functional-group compatibility data, assignments of absolute configuration, mechanistic studies, DFT

calculations, NMR spectra, and HPLC data (PDF)

Accession codes

CCDC 2098015, 2098016, 2098018, 2098019, 2098022, and 2125108 contains the supplementary crystallographic data for this paper.

These data can be obtained free of charge via

www.ccdc.cam.ac.uk/data_request/cif

, or by emailing data_request@ccdc.cam.ac.uk, or

by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

Complete contact information is available at:

https://pubs.acs.org/

The authors declare no competing financial interest.

HHS Public Access

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. Author manuscript; available in PMC 2023 March 16.

Published in final edited form as:

J Am Chem Soc

. 2022 March 16; 144(10): 4550–4558. doi:10.1021/jacs.1c12749.

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formulation as a copper(I)–anilidyl radical) complex that serves as a persistent radical that couples

with a tertiary organic radical to generate the desired C–N bond with good enantioselectivity.

Graphical Abstract

INTRODUCTION

Amines play an important role in a wide array of disciplines, including biology, materials

science, organic chemistry, and pharmaceutical chemistry.

–

Although the nucleophilic

substitution of an alkyl halide by an amine is an attractive approach to the synthesis of

higher-order amines, traditional S

2 reactions have limited applicability in the case of less

reactive (e.g., hindered and unactivated) electrophiles, which instead engage in undesired

side reactions, such as the elimination of H–X.

Furthermore, conventional substitution

pathways almost never enable the control of stereochemistry at the carbon of the new C–N

bond, starting with a readily available racemic electrophile.

To address these shortcomings with respect to reactivity and enantioselectivity, a number

of laboratories have pursued the use of transition metals to catalyze substitution reactions

of secondary and tertiary alkyl electrophiles by nitrogen nucleophiles.

–

To date,

catalytic enantioconvergent substitutions have only been described for a few families

of (mostly secondary) alkyl electrophiles, e.g., allylic electrophiles,

-halocarbonyl

compounds,

–

-cyano-

-halocarbonyl compounds,

propargylic electrophiles,

benzylic electrophiles,

and unactivated alkyl halides that bear a directing group.

Whereas a variety of bioactive molecules include as a subunit an arylamine (aniline) wherein

the nitrogen is attached to a stereocenter (Figure 1A),

to our knowledge there has

been only one report of the synthesis of this motif via the enantioconvergent alkylation of

an aniline by a racemic alkyl electrophile.

In the present study, we establish that, with

the aid of a chiral copper catalyst and light, anilines can be coupled with a variety of

racemic tertiary alkyl electrophiles to generate N-alkylanilines that bear a fully substituted

stereocenter with good enantiomeric excess (Figure 1B). Mechanistic studies are consistent

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with (

)CuCl acting as a photoreductant and with [(

)Cu(NHAr)]Cl serving as a key

intermediate in the catalytic cycle.

RESULTS AND DISCUSSION

Reaction development.

Seeking to expand the rather limited scope of enantioconvergent substitutions of alkyl

electrophiles by nitrogen nucleophiles, we chose to explore reactions of

-halonitriles

with anilines to generate

-aminonitriles. In particular, we decided to examine the use

of tertiary

-halonitriles as electrophiles so as to produce

-disubstituted

-aminonitriles.

Whereas catalytic enantioselective Strecker reactions of aldimines provide a versatile

approach to the synthesis of enantioenriched

-monosubstituted

-aminonitriles,

corresponding reactions of ketimines to afford

-disubstituted

-aminonitriles are less well-

developed.

–

Upon irradiation (blue LED) in the presence of CuCl and DTBM-SEGPHOS (

), a

racemic tertiary

-chloronitrile undergoes substitution by

-toluidine (1.2 equiv) to furnish

the desired

-disubstituted

-aminonitrile in good yield and ee (Table 1, entry 1: 77% yield,

92% ee; CuCl,

, and BTPP are all commercially available). Control experiments establish

that CuCl,

, and light are critical for coupling under these conditions (entries 2–4; >95%

recovery of the alkyl halide). The yield of the reaction is not particularly sensitive to small

amounts of water or of air, which have no impact on enantioselectivity (entries 5 and 6).

When a lower catalyst loading is employed (2.0 mol% copper), a turnover number greater

than 25 is observed (entry 7). A discrete, isolable copper–

complex, (

)CuCl (

)

may be used in place of CuCl/

(entry 8). Whereas the photoinduced, copper-catalyzed

coupling occurs in good yield at –78 °C, the corresponding S

2 reaction does not proceed to

a significant extent even at 80 °C (entry 9).

An array of racemic tertiary

-halonitriles serve as suitable electrophiles in these

enantioconvergent N-alkylations. For example, consistently good enantioselectivity is

observed as the R

group varies from Me to

-Bu (Figure 2A,

–

; on a gram scale (1.28 g

of product), the coupling to produce

proceeds in 64% yield, 92% ee), although the yield

is sensitive to the size of R

. Functional groups such as an ester, olefin, unactivated alkyl

chloride, aryl fluoride, aryl chloride, aryl bromide, amide, and phosphonate are compatible

with the method (

–

; also, an acetal, alcohol, alkylboronate ester, alkyl bromide, alkyl

iodide, aryl iodide, aryl triflate, benzofuran, epoxide, ketone, sulfide, and tertiary amine:

see the Supporting Information). Not only

-aryl-

-halonitriles (

–

), but also

-acyl-

and

-phosphonyl-substituted (

and

; Br as the leaving group)

-halonitriles, serve as

suitable coupling partners.

The scope of this photoinduced, copper-catalyzed asymmetric N-alkylation is also

reasonably broad with respect to the arylamine nucleophile. In the case of aniline itself,

a substantial amount of addition of the electrophile to the para position is observed (C–

C coupling: 24% yield, 27% ee; C–N coupling: 18% yield, 86% ee). However, if the

para position bears a substituent, moderate-to-good yields and good enantioselectivities are

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obtained with either an electron-poor or an electron-rich aniline as the nucleophile (Figure

2B,

–

). Furthermore, meta substitution of the aniline can sufficiently impede addition

to the para position such that the desired N-alkylation proceeds in fair yield as well as good

enantioselectivity (

–

It is noteworthy that enantioconvergent N-alkylation can be achieved with electrophiles that

bear a leaving group other than chloride or bromide. In the case of a carbonate or a fluoride,

although substitution does not occur in good yield and ee under the standard conditions, the

addition of TBACl/B(OMe)

enables the desired C–N bond formation to proceed smoothly

with good enantioselectivity (eq 1). To our knowledge, this is the first example of an

alkyl fluoride serving as a suitable electrophile in a metal-catalyzed enantioconvergent

substitution by a nitrogen nucleophile.

(1)

The standard reaction conditions can be applied to the enantioconvergent N-alkylation of

anilines by racemic tertiary electrophiles that lack a cyano group. Thus,

-haloamides are

also suitable substrates, leading to coupling with good ee for both N-alkyl and N-aryl

secondary amides (Figure 3,

–

). Furthermore, the chiral catalyst can provide promising

enantioselectivity when it is necessary to distinguish between two alkyl substituents on the

electrophilic carbon, such as secondary vs. methyl (

) or branched primary vs. methyl (

Mechanistic studies.

Our current working hypothesis is that these photoinduced, copper-catalyzed

enantioconvergent C–N couplings may be proceeding through the pathway outlined in

Figure 4. Thus, copper(I) complex

, which is a competent catalyst for the coupling

(Table 1, entry 8; 10 mol%

, rather than 10 mol% CuCl/12 mol%

, was utilized

in all catalyzed reactions for our mechanistic studies) undergoes excitation upon blue-LED

irradiation to generate

, which reacts with electrophile R–Cl to afford organic radical

R• and copper(II) complex

. Complex

then undergoes base-induced substitution by

the aniline to furnish copper complex

, which combines with R• to provide the coupling

product and regenerate copper(I) complex

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A solution of

in toluene at –78 °C shows a characteristic absorption at 376 nm

(

= 3890 M

−1

), as does the reaction mixture (the coupling depicted in Table 1)

prior to irradiation (Figure 5A); because the concentrations of copper for the two UV–vis

spectra are the same, virtually all of the copper in the reaction mixture appears to be

present as

prior to irradiation (see the Supporting Information). As illustrated in Figure

5B, room-temperature

P NMR spectroscopic analysis is consistent with this conclusion

(>95%).

During a catalytic C–N coupling, the concentration of

decreases somewhat

as the reaction progresses, to 54% of total copper at 64% conversion, according to

H NMR

spectroscopy at –78 °C (see the Supporting Information).

Having identified

as a major component of the reaction mixture, we carried out an

investigation of its photophysical properties. The steady-state emission spectrum of

shows a single emission band (

max

= 480 nm) at temperatures ranging from 77 K to room

temperature (see the Supporting Information). The luminescence decay of

observed at

480 nm at room temperature shows two sets of decay curves, with lifetimes of 3.8 ns and

0.36 μs (Figure 5C).

To avoid complications arising from the two competing luminescence-decay pathways, we

measured the lifetime of an excited state of

by transient absorption spectroscopy

(

pump

= 355 nm,

probe

= 580 nm) as a function of electrophile concentration at room

temperature (Figure 5D). Addition of 2-chloro-2-phenylbutane-nitrile results in a decrease

of the excited-state lifetime of

* that allows for the determination of the second-order

rate constant,

= 3.7 × 10

–1

, for the quenching process. The excited-state reduction

potential of

* is estimated to be

1/2

(Cu

II/I*

) ~ –2.6 V (vs Fc/Fc

), based on

(3.0

eV) and

1/2

(Cu

II/I

; ~ 0.4 V vs Fc/Fc

; irreversible), which are derived from emission

spectroscopy and electrochemical characterization by cyclic voltammetry (CV); a CV of the

model electrophile shows an irreversible feature at

~ –2.2 V (Figure 5E).

Steps 1 and 2 of the catalytic cycle (Figure 4).

No reaction between

and 2-chloro-2-phenylbutanenitrile occurs in toluene at –78 °C

after 30 min in the dark, as determined by

H NMR spectroscopy. However, when this

mixture is irradiated at –78 °C for 30 min, the initially colorless solution turns dark

purple, and analysis by

H NMR spectroscopy shows that a C–C coupled dimer derived

from the electrophile is formed (Figure 5F: 43% yield based on

; ~ 1:1 mixture of

diastereomers). Formation of the dimer is readily accommodated by the reaction mechanism

illustrated in Figure 4; specifically, excitation of

(step 1), followed by chlorine atom

transfer, furnishes R• (step 2), which engages in radical–radical coupling in the absence

of aniline (this R–R dimer is observed as a minor side product in the photoinduced,

copper-catalyzed C–N coupling of this electrophile under the standard conditions; see the

Supporting Information).

X-band continuous-wave (CW) EPR spectroscopy of the dark-purple solution obtained

from this photoinduced reduction of 2-chloro-2-phenylbutanenitrile by

shows a signal

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characterized by large

P hyperfine couplings from two phosphorous atoms (Figure

5F, black spectrum). We hypothesized that this paramagnet is (

)CuCl

(

), which

we then independently synthesized from

and CuCl

(toluene, r.t. to –78 °C) and

crystallographically characterized (Figure 5F; see the Supporting Information); the CW-EPR

spectrum of this

at 77 K matches that of the photoinduced reduction of 2-chloro-2-

phenylbutanen-itrile by

(Figure 5F, black and red spectra). Upon monitoring the

standard catalyzed C–N coupling reaction (Table 1), we determined that

is the

predominant, but not the sole, paramagnetic species after 30 min of irradiation (Figure 5F,

blue spectrum; 82% conversion of the electrophile, 66% yield of the coupling product).

and step 3 of the catalytic cycle (Figure 4).

X-band CW-EPR spectroscopic analysis of a catalytic reaction after 10 min of irradiation

shows that a different copper(II) species is dominant at the beginning of the coupling

process (Figure 6A, red spectrum; 32% conversion of the electrophile, 22% yield of the

coupling product; see the Supporting Information). We have determined that a matching

EPR spectrum is observed upon treating

with

-toluidine in the presence of BTPP

at –90 °C (Figure 6A, black spectrum; if either

-toluidine or BTPP is absent, the black

EPR spectrum is not observed). Under the same conditions, use of a different copper halide

complex (Br instead of Cl) or a different base (2-

tert

-butyl-1,1,3,3-tetramethylguanidine

(BTMG) instead of BTPP) leads to no noticeable change in the black EPR spectrum

(including superhyperfine structures resolved in their second derivatives; see the Supporting

Information), consistent with the paramagnet being a copper(II) complex in which

neither the halide nor the Brønsted base is bound (see the Supporting Information). We

therefore postulated that this complex might be three-coordinate [(

)Cu(NHAr)]X (

(

)Cu=NAr, or four-coordinate (

)Cu(NHAr)

This paramagnetic copper complex (

) is unstable at –78 °C, decomposing over 30

min (as observed by CW-EPR spectroscopy) and forming (

)-1,2-di-

-tolyldiazene (this

dimer is observed as a minor side product in photoinduced, copper-catalyzed N-alkylations

-toluidine under the standard coupling conditions). Because the thermal instability of

frustrated our attempts at crystallographic characterization, we investigated its structure

through EPR spectroscopy (Figure 6B). The X-band CW-EPR signal of

is dominated

by hyperfine coupling to

63/65

Cu (

= 3/2) and two inequivalent

P (

= 1/2) nuclei, without

any additional hyperfine splitting being clearly resolved (see the Supporting Information).

We investigated the incorporation of

-toluidine in the spin system using isotopically labeled

-toluidine (

-toluidine-

and

-toluidine-

). The X-band CW-EPR spectra of these

isotopologues show only very subtle differences in the second-derivative plots (Figure 6B,

bottom panel). For quantitative determination of the natural abundance

N and introduced

H and

N couplings, we turned to pulse EPR spectroscopy. Field-dependent Q-band

hyperfine sublevel correlation (HYSCORE) spectra of

N labeled

show a single set

of elongated correlation ridges in the (–,+) quadrant, indicating that the coupling falls into

the strongly coupled regime where

> 2

(Figure 6C, middle panel).

These features

are well simulated by a

single class

of highly anisotropic

N hyperfine tensor with

(

= ±[6, 90, 6] MHz,

iso

(

N) = ±24.3 MHz. The

N signals present in the analogous

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HYSCORE spectra of natural-abundance

also fall into the strong-coupling regime

but are additionally complicated by the influence of

N nuclear quadrupole interaction

(Figure 6C, top panel). These spectra are well simulated by scaling the

N hyperfine

tensor determined from

N HYSCORE by the proportion of

N gyromagnetic ratios

N|/|

N| = 1.403), with further variation of the

N nuclear quadrupole parameters.

The simulated

N quadrupole parameters are identical to those determined for the amide

nitrogen of structurally relevant Ni(III)-amide and -anilido species using similar HYSCORE

spectroscopic methods,

and they are consistent with the presence of a trisubstituted

nitrogen with a lone pair oriented roughly orthogonal to the trigonal plane, as expected

for a Cu–NHAr moiety. Q-band HYSCORE spectroscopy of

H-labeled

shows a

single set of intense cross-peaks in the (+,+) quadrant that thus fall into the weakly

coupled regime where

< 2

(Figure 6C, bottom panel), which are well-simulated by

single class

of relatively anisotropic

H hyperfine tensor with

(

H) = ±[8.9, 4.3, 1.5]

MHz,

iso

(

H) = ±4.9 MHz. The presence of multiple equivalent NHAr ligands could be

ruled out by simulations that showed that the equivalent

/15

N nuclei would generate

combination peaks

that are absent in the observed spectra. Additionally, multiple

equivalent

H couplings of the class detected directly from the

H HYSCORE could not

be accommodated by simulations of the X-band CW-EPR spectra (see the Supporting

Information). Collectively, the spectroscopic data are consistent with the presence of a single

trisubstituted nitrogen with a single N–H, i.e.,

as [(

)Cu(NHAr)]Cl.

Further support for the proposed structure of

has been obtained by comparing the

experimentally derived CW-EPR parameters to values predicted by DFT calculations for the

various possible structures. Only three-coordinate [(

)Cu(NHAr)]Cl is predicted to have

EPR parameters similar to those observed (see the Supporting Information).

DFT calculations of

indicate that there is considerable spin density on the aniline

ligand (0.33 e

−

on NH, 0.32 e

−

on the aromatic ring) and less spin density on copper (0.15

−

) (Figure 6D), indicating that

is more accurately viewed as a copper(I)–(anilidyl

radical) complex, rather than as its formal assignment as a copper(II)–anilido complex.

The substantial spin density at the para carbon of the aniline (0.17 e

−

) is consistent with our

observation of significant C–C bond formation at that position when it is not blocked.

–

CONCLUSION

We have developed a photoinduced, copper-catalyzed method for the enantioconvergent N-

alkylation of anilines by an array of racemic tertiary alkyl electrophiles that generates fully-

substituted stereocenters with good ee. The catalyst, composed of commercially available

components, effects asymmetric C–N bond formation at –78 °C, whereas the corresponding

uncatalyzed coupling does not proceed at a significant rate even at 80 °C. Although the use

of alkyl chlorides as electrophiles is the primary focus of this study, examples have been

presented of the use of uncommon related electrophiles, specifically, an alkyl fluoride and

an alkyl carbonate, under similar conditions. Mechanistic studies have provided support for

key intermediates and elementary steps in the proposed catalytic cycle. Future investigations

will explore the development of other enantioselective bond-forming processes that employ

catalysts based on earth-abundant copper.

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Supplementary Material

Refer to Web version on PubMed Central for supplementary material.

ACKNOWLEDGMENTS

This study is dedicated to Prof. K. Barry Sharpless on the occasion of his 80th birthday. Support has been provided

by the National Institutes of Health (National Institute of General Medical Sciences: R01-GM109194), the Korea

Foundation for Advanced Studies (graduate research fellowship to H.C.), the National Science Foundation (support

of the Caltech EPR Facility; NSF-1531940), the Arnold and Mabel Beckman Foundation (support of the Beckman

Institute Laser Resource Center and the Molecular Materials Resource Center), and the Dow Next-Generation

Educator Fund (grant to Caltech). We thank Dr. Bruce S. Brunschwig (Molecular Materials Resource Center), Dr.

Mona Shahgoli (Mass Spectroscopy Facility), Dr. Michael K. Takase (X-Ray Crystallography Facility), Dr. David

Vander Velde (NMR Facility), Dr. Scott C. Virgil (Center for Catalysis and Chemical Synthesis), Dr. Jay R. Winkler

(Beckman Institute Laser Resource Center), Dr. Caiyou Chen, Dr. Heejun Lee, Dr. Felix Schneck, Dr. Cooper

Citek, Dr. Jaika Dörfler, Dr. Dylan J. Freas, Dr. Pablo Garrido Barros, Dr. Giuseppe Zuccarello, Dr. Suzanne M.

Batiste and Christian M. Johansen for technical assistance and

or helpful discussions.

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We were unable to carry out the 31P NMR spectroscopic studies at −78 °C, due to overlap of the

low-temperature spectrum of

(see also Reference

) with the resonance of BTPP.

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Radical.

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(München, Ger.) 2017, 231, 725–743.

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Aminyl Radical Complexes. J. Am. Chem. Soc 2009, 131, 3878–3880. [PubMed: 19253942]

(40).

We have demonstrated that CuC can couple with an organic radical to afford a new C–N bond. Thus,

generation of

at low temperature, followed by the addition of a persistent trityl-derived

radical, leads to N-alkylation in 41% yield (see the Supporting Information).

(41). Jang ES; McMullin CL; Käß M; Meyer K; Cundari TR; Warren TH Copper (II) Anilides in sp3

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Figure 1.

Anilines wherein the nitrogen is attached to a stereocenter. A) Examples of bioactive

compounds. B) This report: Photoinduced, copper-catalyzed enantioconvergent alkylations

of anilines by racemic tertiary alkyl electrophiles.

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Figure 2.

Tertiary

-halonitriles as electrophiles. A) Scope of electrophiles. B) Scope of nucleophiles.

Reactions were conducted on a 0.8-mmol scale, and yields are for purified compounds. All

data are the average of two runs. X=Cl, unless otherwise noted.

X=Br. Bpin, pinacolboryl.

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Figure 3.

Tertiary

-haloamides as electrophiles. Reactions were conducted on a 0.8-mmol scale,

and yields are for purified compounds. All data are the average of two runs. X=Cl, unless

otherwise noted.

X=Br.

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Figure 4.

Outline of a possible mechanism for the photoinduced, copper-catalyzed enantioconvergent

alkylation of anilines by racemic tertiary electrophiles. P

P =

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Figure 5.

Mechanistic studies:

and

(in toluene at r.t., unless otherwise noted). A) Absorption

and emission spectra of

(0.5 mM), reaction mixture ([

] = 0.5 mM, [2-chloro-2-

phenylbutanenitrile] = 5 mM, [

-toluidine] = 6 mM, and [BTPP] = 6 mM), blue-LED lamp.

P NMR spectroscopy (162 MHz): comparison of a reaction mixture prior to irradiation

versus

. C) Luminescence lifetime of

* (

probe

= 480 nm). D) Stern-Volmer

quenching of

* by 2-chloro-2-phenylbutanenitrile (

pump

= 355 nm,

probe

= 580 nm).

E) Redox potentials (0.1 M TBAPF

in THF; scan rate = 20–50 mV/s). F) Steps 1 and 2

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of the catalytic cycle: X-band CW-EPR spectra of

from a photoinduced reduction of

2-chloro-2-phenylbutanenitrile by

([

] = 5 mM and [2-chloro-2-phenylbutanenitrile]

= 50 mM; black), independent synthesis of

(red; X-ray crystal structure: thermal

ellipsoids at 50% probability (solvents and hydrogen atoms are omitted for clarity)), and a

catalyzed reaction after 30 min at –78 °C (blue); acquisition parameters: MW frequency =

9.37 GHz, MW power = 140 μW, modulation amplitude = 0.4 mT, conversion time = 5.02

ms, and temperature = 77 K.

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Figure 6.

Mechanistic studies:

. A) X-band CW-EPR spectra of a catalyzed reaction after 5 min

at –78 °C (red) and of

prepared independently (black); acquisition parameters: MW

frequency = 9.36 GHz, MW power = 140 μW, modulation amplitude = 0.4 mT, conversion

time = 5.02 ms, and temperature = 77 K. B) X-band CW-EPR spectra (top panel) and 2

derivative (bottom panel) of

in toluene generated from isotopologues of

-toluidine

(black traces); acquisition parameters: MW frequency = 9.372–9.374 GHz, MW power =

140 μW, modulation amplitude = 0.1 mT, conversion time = 5.3 ms, and temperature = 77 K.

C) Q-band HYSCORE of

in toluene generated from isotopologues of

toluidine (left)

measured at 1206 mT (

= 2.015) with overlay of

14/15

N or

H simulation contours (right,

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red) with experimental contours (right, gray); experimental conditions: MW frequency =

34.005 GHz,

= 128 ns, t

= t

= 100 ns, Δt

= Δt

= 12 ns, shot repetition time (srt) = 1.5

ms, and temperature = 30 K. D) Calculated spin-density plot of

viewed perpendicular

to the NHAr plane and at a 45° angle (bp86 def2-TZVP; contour value = 0.005).

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